Pyrimidine and Pyridine Derivatives and Their Pharmaceutical Use and Compositions

Field of the Invention

This invention relates to pyrimidine and pyridine derivatives Such compounds have been shown to inhibit matrix metalloproteinase enzymes These compounds are useful for treating diseases resulting from MMP-mediated tissue breakdown such as heart disease, cardiac insufficiency, inflammatory bowel disease, multiple sclerosis, osteoarthritis, rheumatoid arthritis, arthritis other than osteo- or rheumatoid arthritis, heart failure, age-related macular degeneration, chronic obstructive pulmonary disease, asthma, periodontal diseases, psoriasis, atherosclerosis, fibrotic disorders in the kidney, lung, and/or osteoporosis

Background of the Invention

Matrix metalloproteinases (sometimes referred to as MMPs) are naturally occurring enzymes found in most mammals Over-expression and activation of MMPs, or an imbalance between MMPs and inhibitors of MMPs, have been suggested as factors in the pathogenesis of diseases characterized by the breakdown of extracellular matrix or connective tissues To date, 24 different members of the MMP family have been identified in vertebrates, 23 of which are found in human, including collagenases (MMP-1 , MMP-8, MMP-13), gelatinases (MMP-2 and MMP-9), stromelysins (MMP-3, MMP-10, MMP-1 1 ), matπlysins (MMP-7 and MMP-26), membrane-type (MMT-14, MMP-15, MMP-16, MMT-17, MMP-24, MMT-25), as well as metalloelastases (MMP-12, MMP-19, MMP-20, MMP-22, MMP-23) (See Visse and Nagase (2003) Circ Res 92 827-839) These enzymes have been implicated with a number of diseases which result from breakdown of connective tissue, including such diseases as rheumatoid arthritis, osteoarthritis, osteoporosis, periodontitis, multiple sclerosis, gingivitis, corneal epidermal and gastric ulceration, atherosclerosis, neointima! proliferation which leads to restenosis and ischemic heart failure, and tumor metastasis Inhibiting matrix metalloproteinase enzymes, thereby curtailing and/or eliminating the breakdown of connective tissues that results in the disease states, is a recognized method for preventing and treating these and other diseases

There is a catalytic zinc domain in matrix metalloproteinases that is typically the focal point for inhibitor design The modification of substrates by introducing zinc-chelating groups has generated potent inhibitors such as peptide hydroxamates and thiol-containing peptides Peptide hydroxamates and the natural endogenous inhibitors of MMPs (TIMPs) have been used successfully to treat animal models of cancer and inflammation MMP inhibitors have also been used to prevent and treat congestive heart failure and other cardiovascular diseases, see, e.g , U S Patent No 5,948,780

A major limitation on the use of currently known MMP inhibitors is their lack of specificity for any particular enzyme Recent data has established that specific MMP enzymes are associated with some diseases, with no effect on others The MMPs are generally categorized based on their substrate specificity, and indeed the collagenase subfamily of MMP-1 , MMP-8, and MMP-13 selectively cleave native interstitial collagens, and thus are associated only with diseases linked to such interstitial collagen tissue This is evidenced by the recent discovery that MMP-13 alone is over-

expressed in breast carcinoma, while MMP-1 alone is over expressed in papillary carcinoma (see Chen et al , J Amer Chem Soc , 2000,122 9648-54)

Selective inhibitors of MMP-13 include a compound named WAY 170523, which has been reported by Chen et al , supra, 2000 Other selective inhibitors of MMP-13 are reported in International Patent Application Publication No WO 05/105760 Other selective inhibitors of MMP-13 are reported in U S Patent Application Publication No US20030229103 Other selective inhibitors of MMP-13 are reported in U S Patent Application Publication No US20040167120 Other selective inhibitors of M M P- 13 are reported in U S Patent Application Publication No US20050004111 Other selective inhibitors of MMP-13 are reported in U S Patent Application Publication No US20060173183 Other selective inhibitors of MMP-13 are reported in International Patent Application Publication No WO 06/128184 Other selective inhibitors of MMP-13 are reported in Co-assigned International Patent Application Publication No WO 02/64572 Other selective inhibitors of MMP-13 are reported in Co- assigned International Patent Application Publication No WO 02/64599 U S Patent No 6,008,243 discloses inhibitors of MMP-13 However, no selective or nonselective inhibitor of MMP-13 has been approved and marketed for the treatment of any disease in any mammal Accordingly, the need continues to find new low molecular weight compounds that are potent and selective MMP inhibitors, and that have an acceptable therapeutic index of toxicity/potency to make them amenable for use clinically in the prevention and treatment of the associated disease states

Summary of the Invention The present invention provides compounds of Formula I

wherein

G is (Ci ₃ alkylenyl)-R ^a or R ^a , wherein said C,. ₃ alkylenyl may be substituted by one or more substituents selected from OH and F, R ^a is Ci-s alkyl, 3- to 7-membered heterocycloalkyl, or 3- to 8-membered cycloalkyl, wherein said C ₁ ^ alkyl may be substituted by one or more substituents selected from F, -OR ³⁴ , -SR ³⁴ , -C(=O)NR ³⁴ R ³⁵ , -NR ³⁴ R ³⁵ , -NR ³⁴ C(=O)R ³⁵ , or -NR ³⁴ SO ₂ R ³⁶ , and wherein said heterocycloalkyl and cycloalkyl may be substituted by one or more substituents selected from R ² , R ³ , R ⁴ , R ⁵ , R ¹⁰ , R ¹¹ , and R ²¹ , M is N or C-R ^b ,

Q is N or C-R ^c , provided that if Q is C-R ^c , M is N,

W is phenyl-(Ci- ₆ alkylenyl), pyrιdyl-(C,- ₆ alkylenyl), or 9-membered heteroaryl-(C,- ₆ alkylenyl), wherein said phenyl, pyridyl, or 9-membered heteroaryl is substituted by one or more groups selected from R ³⁰ and R ³¹ , Y is Ci- ₆ alkyl, d- ₆ haloalkyl, or C ₁ ^ hydroxyalkyl,

L is 5-membered heteroaryl,

R ² is H, F, CN, -OR ⁵ , R ¹² , -C(=O)R ⁷ , -NR ⁶ R ³³ , -NR ^β C(=O)R ⁹ , -NR ⁸ SO ₂ R ³⁶ , or -SO ₂ R ¹² , R ³ Is H, F ₁ CN, or -OR ²² , R ⁴ is H, -(C _{1 6} alkylene)R ⁶ , -C(=O)R ⁹ , or -SO ₂ R ¹² , R ⁵ is H or -(C _1-6 alkyl), wherein said C ₁₄ alkyl may be substituted by one or more R substituents,

S _/ O _R 23

¹ \\ //

R ⁶ rs H, CN, -OR ²³ , -SO ₂ R ³⁷ , -NR ²⁴ C(=O)R ²³ , -NR ²⁴ SO ₂ R ³⁷ , or ^N ~ ^N R ⁷ is -(C ₁ .,, alkyl), -(Ci-β haloalkyl), -(C ₁₄ atkylene)OH, -NR ³⁸ R ³⁹ , -NHSO ₂ CH ₃ , or -OR ²⁵ , R ⁹ is -(Ce alkylene)R ²⁸ , -NHR ²⁴ , or -OR ²⁵ , R ¹⁰ Is H, F, CN, R ¹² , or -C(=O)R ⁷ ,

_R ^{i i} _{|S Hi} F, CN, -OR ⁶ , R ¹² , -C(=O)R ⁷ , -NR ⁸ R ³³ , -NR ^e C(=O)R ⁹ , -NR ⁸ SO ₂ R ³⁶ , or -SO ₂ R ¹² , R ¹² is -(C ₁₄ alkyl), wherein said C _{1 6} alkyl may be substituted by one or more substituents selected from CN, -OR ²³ , -SR ²³ , -SO ₂ R ³⁷ , -NR ⁸ R ³³ , -NR ²⁴ C(=O)R ²³ , and -NR ²⁴ SO ₂ R ²³ , provided that any one carbon atom of said C ₁₄ alkyl is not substituted by more than one CN or more than one -OR ²³ ,

R ^b , R°, R ⁸ , R ²⁰ , R ²² , R ²⁴ , R ²⁵ , R ³³ , R ³⁴ . and R ³⁵ are independently H or -(C ₆ alkyl), R ²¹ Is H, F, or R ¹² ,

R ²³ is H, -(C _1-6 alkyl), or -(C ₆ alkylene)OH, R ²⁶ is H, OH, halo, NH ₂ , or SH, R ²⁸ is H, NH ₂ , or -OR ²⁹ ,

R ²⁹ is H ₁ (C ₁₄ alkyl), or -C(O)(C ₁₄ alkyl), R ³⁰ is H or F,

R ³¹ is F, Cl, Br, -CN, -C(=O)NH ₂ , -OH, -OR ³² , -OCH ₂ CH ₂ OR ²⁵ , R ³² , ,or (C ₁₄ alkyl) optionally substituted by -OR ²⁵ or -OCH ₂ CH ₂ OR ²⁵ where R ³⁰ and R ³¹ when adjacent may be taken together to constitute a group of the formula -

O-(CH ₂ ) _n - or -0-(CHz) _n -O-, n is 1 or 2,

R ³² is -(C _t4 alkyl) optionally substituted with one, two, or three F, R ³⁶ is -(C _1-6 alkyl) or -(C ₃₄ cycloalkyl), and R ³⁷ is -(C ₁₄ alkyl), -(C ₃₄ cycloalkyl), or -(C ₁₄ alkylene)OH,

R ³⁸ and R ³⁹ are independently H, -(C ₁₄ alkyl), or R ³⁸ and R ³⁹ taken together form a 5- or 6- membered heterocycloalkyl, or a pharmaceutically-acceptable salt thereof

This invention also includes pharmaceutically acceptable salts, solvates and hydrates of compounds of Formula I This invention also includes all tautomers and stereochemical isomers of these compounds

This invention also is directed, in part, to a method for treating an MMP-13 mediated disorder in a mammal Such disorders include rheumatoid arthritis and osteoarthritis The method comprises

administering a compound of Formula I or a pharmaceutically acceptable salt thereof, to the mammal in an amount that is therapeuticalty-effective to treat the condition

Detailed Description of the Invention

One embodiment of the invention is a compound of Formula I as shown above Another embodiment of the invention is a compound of Formula I wherein R ^a is C _L6 alkyl, 1 ,4- dioxanyl, piperidinyl, cyclohexyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, tetrahydropyranonyl, pyrrolidinyl, cyclopentyl, 7-oxa-bιcyclo[2 2 1]heptanyl, piperazinyl, 1 ,1 '-dιoxothιomorpholιnyl, tetrahydro-1 ,1 '-dιoxothιopyranyl, tetrahydrothiopyranyl, ptperidinonyl, tetrahydrofuryl, pyrrolidinonyl, or oxazolidinonyl, wherein said alkyl may be substituted by one or more substituents selected from -OR ³⁴ , -SR ³⁴ , -Ci=O)NR ³⁴ R ³⁵ , -NR ³⁴ R ³⁵ , -NR ³⁴ Cl=O)R ³⁵ , or -NR ³⁴ SO ₂ R ³⁵ , and wherein said 1 ,4- dioxyl, piperidinyl, cyclohexyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, tetrahydropyranonyl, pyrrolidinyl, cyclopentyl, 7-oxa-bιcyclo[2 2 1]heptanyl, piperazinyl, 1 ,1 '-dιoxothιomorpholιnyl, tetrahydro-1 ,1 '-dιoxothιopyranyl, tetrahydrothiopyranyl, piperidinonyl, tetrahydrofuryl, pyrrolidinonyl, or oxazolidinonyl may be substituted by one or more substituents selected from R ² , R ³ , R ⁴ , R ⁵ , R ¹⁰ , R ¹¹ , and R ²¹

Another embodiment of the invention is a compound of Formula I wherein R ³ is C,. ₆ alkyl, 1 ,4- dioxanyl substituted by R ¹⁰ and R ²¹ , piperidinyl substituted by R ² and R ³ or by R ⁴ , cyclohexyl substituted by R ² and R ³ or by R ⁴ , morpholinyl substituted by R ⁴ , thiomorpholinyl substituted by R ¹⁰ and R ²¹ , tetrahydropyranyl substituted by R ³ and R ¹¹ or by R ¹⁰ and R ²¹ , tetrahydropyranonyl, pyrrolidinyl substituted by R ² and R ³ or by R ⁴ , cyclopentyl substituted by R ² and R ³ , 7-oxa- bιcyclo[2 2 1]heptanyl, piperazinyl substituted by R ⁴ and R ⁵ , 1 ,1'-dιoxothιomorpho!ιnyl, tetrahydro-1 ,1 '- dioxotbiopyranyl, tetranydroth/opyranyl, piperidinonyl substituted by R ⁵ , tetrahydrofuryl substituted by R ³ and R ¹¹ , pyrrolidinonyl substituted by R ⁵ , oxazolidinonyl substituted by R ⁵ , wherein said alkyl may be substituted by one or more substituents selected from -OR ³⁴ , -SR ³⁴ , -C(=O)NR ³⁴ R ³⁵ , -NR ³⁴ R ³⁵ , -NR ³⁴ C(=O)R ³⁵ , or -NR ³⁴ SO ₂ R ³⁵

Another embodiment of the invention is a compound of Formula I wherein R ^a is C,. ₆ alkyl,

, or , wherein said alkyl may be substituted by one or more substituents selected from -OR ³⁴ , -SR ³⁴ , -C(=O)NR ³⁴ R ³⁵ , -NR ³⁴ R ³⁵ , -NR ³⁴ C(=O)R ³⁵ , or -NR ³⁴ SO ₂ R ³⁵ , and

X is N or CH, provided that when X is N, G is (C ₂ - ₃ a!kylenyl)-R ^a , wherein said C ₁ ^ alkylenyl may be substituted by one or more substituents selected from OH and F.

Another embodiment of the invention is a compound of Formula I wherein R ^a is C ₁ ^ alkyl,

R , wherein said alkyl may be substituted by one or more substituents selected from -OR ³⁴ , -SR ³⁴ , -Ci=O)NR ³⁴ R ³⁵ , -NR ³⁴ R ³⁵ , -NR ³⁴ Ci=O)R ³⁵ , or -NR ³⁴ SO ₂ R ³⁵ Another embodiment of the invention is a compound of Formula I wherein R ^a is C ₁ ^ alkyl, wherein said alkyl may be substituted by one or more substituents selected from -OR ³⁴ , -SR ³⁴ , -C(=O)NR ³⁴ R ³⁵ , -NR ³⁴ R ³⁵ , -NR ³⁴ C(=O)R ³⁵ , or -NR ³⁴ SO ₂ R ³⁵

Another embodiment of the invention is a compound of Formula I wherein R ^a is C ₁ ^ alkyl, wherein said alkyl may be substituted by one or more -OR ³⁴ Another embodiment of the invention is a compound of Formula I wherein R ^a is

Another embodiment of the invention is a compound of Formula I wherein R ^a is

Another embodiment of the invention is a compound of Formula Il

wherein G is (C _{1 3} alkylenyl)-R ^a or R ^a , wherein said C ₁ . ₃ alkylenyl may be substituted by one or more substituents selected from OH and F ₁

R ^a is C ₁ ^ alkyl, 3- to 7-membered heterocycloalkyl, or 3- to 8-membered cycloalkyl, wherein said C _{1 6} alkyl may be substituted by one or more substituents selected from F, -OR ³⁴ , -SR ³⁴ , -C(=O)NR ³⁴ R ³⁵ , -NR ³⁴ R ³⁵ , -NR ³⁴ C(O)R ³⁵ , or -NR ³⁴ SO ₂ R ³⁶ , and wherein said heterocycloalkyl and cycloalkyl may be substituted by one or more substituents selected from R ² , R ³ , R ⁴ , R ⁵ , R ¹⁰ , R ¹¹ , and R ²¹ ,

W is phenyl-(C _r6 alkylenyl), pyridyl-(Cr ₆ alkylenyl), or 9-membered heteroaryl-(C _r6 alkylenyl), wherein said phenyl, pyridyl, or 9-membered heteroaryl is substituted by one or more groups selected from R ³⁰ and R ³¹ ,

Y is C _r6 alkyl, Cr ₆ haloalkyl, or C _r6 hydroxyalkyl, L is 5-membered heteroaryl,

R ² is H, F, CN, -OR ⁵ , R ¹² , -C(=O)R ⁷ , -NR ⁸ R ³³ , -NR ⁸ C(=O)R ⁹ , -NR ⁸ SO ₂ R ³⁶ , or -SO ₂ R ¹² , R ³ Is H, F, CN, or -OR ²² , R ⁴ is H, -(C ₁ - _S alkylene)R ⁶ , -C(=0)R ⁹ , or -SO ₂ R ¹² ,

RR ⁵⁵ .iss H or -(C ₁ ^ alkyl), wherein said C ₁ ^ alkyl may be substituted by one or more R ²⁶ substituents,

W //

R ⁶ is H, CN, -OR ²³ , -SO ₂ R ³⁷ , -NR ²⁴ C(=O)R ²³ , -NR ²⁴ SO ₂ R ³⁷ , or ^N ~ ^N

R ⁷ is -(C ₆ alkyl), -(C ₆ haloalkyl), -(C ₆ alkylene)OH, -NR ³⁸ R ³⁹ , -NHSO ₂ CH ₃ , or -OR ²⁵ , R ⁹ is -(Cn ₃ alkylene)R ²⁸ , -NHR ²⁴ , or -OR ²⁵ ,

R ¹⁰ Is H ₁ F ₁ CN, R ¹² , or -C(=O)R ⁷ , R ¹¹ is H, F, CN, -OR ⁵ , R ¹² , -C(=O)R ⁷ , -NR ⁸ R ³³ , -NR ⁸ C(O)R ⁹ , -NR ⁸ SO ₂ R ³⁶ , or -SO ₂ R ¹² ,

R ¹² is -(C, .a alkyl), wherein said C, ₆ alkyl may be substituted by one or more substituents selected from CN, -OR ²³ , -SR ²³ , -SO ₂ R ³⁷ , -NR ⁸ R ³³ , -NR ²⁴ C(=O)R ²³ , and -NR ²⁴ SO ₂ R ²³ , provided that any one carbon atom of said C ₁ ^ alkyl is not substituted by more than one CN or more than one -OR ²³ , R ^b , R ^c , R ⁸ , R ²⁰ , R ²² , R ²⁴ , R ²⁵ , R ³³ , R ³⁴ , and R ³⁵ are independently H or -(C _1-6 alkyl),

R ²¹ is H, F, or R ¹² ,

R ²³ is H, -(C _1-6 alkyl), or -(C _1-6 alkylene)OH,

R ²⁶ is H, OH, halo, NH ₂ , or SH,

R ²⁸ is H, NH ₂ , or -OR ²⁹ , R ²⁹ is H, (C ₆ alkyl), or -C(=O)(C,.β alkyl),

R ³⁰ is H or F,

R ³¹ is F, Cl, Br, -CN, -C(=O)NH ₂ , -OH, -OR ³² , -OCH ₂ CH ₂ OR ²⁵ , R ³² , ,or (C ₆ alkyl) optionally substituted by -OR ²⁵ or -OCH ₂ CH ₂ OR ²⁵ where R ³⁰ and R ³ ' when adjacent may be taken together to constitute a group of the formula O-(CH ₂ ) _n - or -O-(CH ₂ ) _n -O-, n is 1 or 2,

R ³² is -(Ci-e alkyl) optionally substituted with one, two, or three F,

R ³⁶ is -(C ₁ ^ alkyl) or -(C ₃ ^ cycloalkyl), and

R ³⁷ is -(C _1-6 alkyl), -(C _3-6 cycloalkyl), or -(C ₁ ^ alkylene)OH, R ³⁸ and R ³⁹ are independently H, -(C _1-6 alkyl), or R ³⁸ and R ³⁹ taken together form a 5- or 6- membered heterocycloalkyl, or a pharmaceutically-acceptable salt thereof

Another embodiment of the invention is a compound of Formula HA

wherein R ^a , W, Y, and L are as defined heremabove for Formula Il Another embodiment of the invention is a compound of Formula UA wherein L is triazolyl, tetrazolyl, or oxadiazolyl Another embodiment of the invention is a compound of Formula HA wherein L is

Another embodiment of the invention is a compound of Formula HA wherein L is

Another embodiment of the invention is a compound of Formula IIA-1

wherein R ^a , W, and Y are as defined heremabove for Formula Il

Another embodiment of the invention is a compound of Formula IIA-2

wherein R ^a , W, and Y are as defined heremabove for Formula Il Another embodiment of the invention is a compound of Formula IIA-3

IIA-3 wherein R ^a , W, and Y are as defined heremabove for Formula Il Another embodiment of the invention is a compound of Formula IIA-4

wherein R ^a , W, and Y are as defined heremabove for Formula Il Another embodiment of the invention is a compound of Formula HA, IIA-1 , IIA-2, IIA-3, or IIA-4

wherein R ^a is C ₁ - _S alkyl,

be substituted by one or more substituents selected from -OR ³⁴ , -SR ³⁴ , -C(=O)NR ³⁴ R ³⁵ , -NR ³⁴ R ³⁵ , -NR ³⁴ C(=O)R ³⁵ , or -NR ³⁴ SO ₂ R ³⁵

Another embodiment of the invention is a compound of Formula HA, IIA-1 , IIA-2, IIA-3, or IIA-4

wherein R ^a is C _1-6 alkyl, R ⁴

, or , wherein said alkyl may be substituted by one or more substituents

35 selected from -OR ³⁴ , -SR ³⁴ , -C(=O)NR ³⁴ R ³⁵ , -NR ³⁴ R ³⁵ , -NR ³⁴ Ci=O)R ³⁵ , or -NR ³⁴ SO ₂ R

Another embodiment of the invention is a compound of Formula HA, IIA-1 , IIA-2, IIA-3, or IIA-4 wherein R ^a is C ₁ ^ alkyl, wherein said alkyl may be substituted by one or more substttuents selected from -OR ³⁴ , -SR ³⁴ , -C(=O)NR ³⁴ R ³⁵ , -NR ³⁴ R ³⁵ , -NR ³⁴ C(=O)R ³⁵ , or -NR ³⁴ SO ₂ R ³⁵

Another embodiment of the invention is a compound of Formula HA, IIA-1 , IIA-2, IIA-3, or IIA-4 wherein R ^a is C _1-6 alkyl, wherein said alkyl may be substituted by one or more -OR ³⁴

Another embodiment of the invention is a compound of Formula HA, IIA-1 , IIA-2, IIA-3, or IIA-4

Another embodiment of the invention is a compound of Formula HA, IIA-1 , IIA-2, IIA-3, or IIA-4 wherein Y is methyl

Another embodiment of the invention is a compound of Formula HA, IIA-1 , IIA-2, IIA-3, or IIA-4 wherein W is phenyl-(C _r6 alkylenyl), wherein said phenyl is substituted by one or more groups selected from R ³⁰ and R ³ '

Another embodiment of the invention is a compound of Formula HA, IIA-1 , IIA-2, IIA-3, or IIA-4 wherein W is phenylmethyl, wherein said phenyl is substituted by one or more groups selected from R ³⁰ and R ³¹ Another embodiment of the invention is a compound shown in Table 1

Another embodiment of the invention is a compound of Formula

wherein G is (C ₁ ^ alkylenyl)-R ^a or R ^a , wherein said C,. ₃ alkylenyl may be substituted by one or more substituents selected from OH and F,

R ^a is C ₁ ^ alkyl, 3- to 7-membered heterocycloalkyl, or 3- to 8-membered cycloalkyl, wherein said Ci ₆ alkyl may be substituted by one or more substituents selected from F, -OR ³⁴ , -SR ³⁴ , -C(=O)NR ³⁴ R ³⁵ , -NR ³⁴ R ³⁵ , -NR ³⁴ C(=O)R ³⁵ , or -NR ³⁴ SO ₂ R ³⁶ , and wherein said heterocycloalkyl and cycloalkyl may be substituted by one or more substituents selected from R ² , R ³ , R ⁴ , R ⁵ , R ¹⁰ , R ¹¹ , and R ²¹ ,

W is phenyl-(Cr ₆ alkylenyl), pyrιdyl-(Cr ₆ alkylenyl), or 9-membered heteroaryl-(Cr ₆ alkylenyl), wherein said phenyl, pyÏ€dyl, or 9-membered heteroaryl is substituted by one or more groups selected from R ³⁰ and R ³ ',

Y is C re alkyl, C,-β haloalkyl, or C,- ₆ hydroxyalkyl, L is 5-membered heteroaryl,

R ² is H, F, CN, -OR ⁵ , R ¹² , -C(=O)R ⁷ , -NR ⁸ R ³³ , -NR ⁸ C(=O)R ⁹ , -NR ⁸ SO ₂ R ³⁶ , or -SO ₂ R ¹² , R ³ is H, F, CN, or -OR ²² , R ⁴ is H, -(C ₆ alkylene)R ⁶ , -C(=O)R ⁹ , or -SO ₂ R ¹² ,

R ⁵ is H or -(Ci-β alkyl), wherein said C _1-6 alkyl may be substituted by one or more R ²⁶ substituents,

S .0 _R 23

¹ \\ // R ⁶ is H, CN, -OR ²³ , -SO ₂ R ³⁷ , -NR ²⁴ C(=O)R ²³ , -NR ²⁴ SO ₂ R ³⁷ , or ^N ~ ^N

R ⁷ is -(C _1-6 alkyl), -(C,* haloalkyl), -(C,* alkylene)OH, -NR ³⁸ R ³⁹ , -NHSO ₂ CH ₃ , or -OR ²⁵ , R ⁹ is -(C _1-6 alkylene)R ²⁸ , -NHR ²⁴ , or -OR ²⁵ , R ¹⁰ is H, F, CN, R ¹² , or -C(=O)R ⁷ , R ¹¹ is H, F, CN, -OR ⁵ , R ¹² , -C(=O)R ⁷ , -NR ⁸ R ³³ , -NR ⁸ C(=O)R ⁹ , -NR ⁸ SO ₂ R ³⁶ , or -SO ₂ R ¹² ,

R ¹² is -(C ₁ * alkyl), wherein said C, ₆ alkyl may be substituted by one or more substituents selected from CN, -OR ²³ , -SR ²³ , -SO ₂ R ³⁷ , -NR ⁸ R ³³ , -NR ²⁴ C(=O)R ²³ , and -NR ²⁴ SO ₂ R ²³ , provided that any one carbon atom of said C _1-6 alkyl is not substituted by more than one CN or more than one -OR ²³ , R ^b , R ^c , R ⁸ , R ²⁰ , R ²² , R ²⁴ , R ²⁵ , R ³³ , R ³⁴ , and R ³⁵ are independently H or -(C ₁ * alkyl),

R ²¹ is H, F, or R ¹² ,

R ²³ is H, -(C ₁ * alkyl), or -(C ₁ * alkylene)OH, R ²⁶ is H, OH, halo, NH ₂ , or SH, R ²⁸ is H, NH ₂ , or -OR ²⁹ , R ²⁹ is H, (C ₁ * alkyl), or -C(=0)(C,* alkyl),

R ³⁰ is H or F,

R ³¹ is F, Cl, Br, -CN, -C(=O)NH ₂ , -OH, -OR ³² , -OCH ₂ CH ₂ OR ²⁵ , R ³² , ,or (C ₁ * alkyl) optionally substituted by -OR ²⁵ or -OCH ₂ CH ₂ OR ²⁵ where R ³⁰ and R ³¹ when adjacent may be taken together to constitute a group of the formula O-(CH ₂ ) _n - or -0-(CH ₂ VO-, n is 1 or 2,

R ³² is -(C ₁ * alkyl) optionally substituted with one, two, or three F, R ³⁶ is -(C ₁ * alkyl) or -(C ₃ * cycloalkyl), and R ³⁷ is -(C,* alkyl), -(C ₃ * cycloalkyl), or -(C ₁ * alkylene)OH, R ³⁸ and R ³⁹ are independently H, -(C ₁ * alkyl), or R ³⁸ and R ³⁹ taken together form a 5- or 6- membered heterocycloalkyl, or a pharmaceutically-acceptable salt thereof

Another embodiment of the invention is a compound of Formula IDA

wherein R ^a , R ^b , W, and Y are as defined hereinabove for Formula III

Another embodiment of the invention is a compound of Formula IHA wherein L is triazolyl, tetrazolyl, or oxadiazolyl

Another embodiment of the invention is a compound of Formula IHA wherein L is

Another embodiment of the invention is a compound of Formula HIA wherein L is

Another embodiment of the invention is a compound of Formula IIIA-1

wherein R ^a , R ^D , W, and Y are as defined hereinabove for Formula III Another embodiment of the invention is a compound of Formula IIIA-2

wherein R ->a , R Dd , W, and Y are as defined hereinabove for Formula III Another embodiment of the invention is a compound of Formula IIIA-3

wherein R ₁ R ₁ W, and Y are as defined hereinabove for Formula III Another embodiment of the invention is a compound of Formula IIIA-4

wherein W ₁ and Y are as defined hereinabove for Formula III Another embodiment of the invention is a compound of Formula IHA, IIIA-1 , IIIA-2, IIIA-3, or

IIIA-4 wherein R ³ is Cue alkyl,

be substituted by one or more substituents selected from -OR ³⁴ , -SR ³⁴ , -C^=O)NR ³⁴ R ³⁵ , -NR ³⁴ R ³⁵ , -NR ³⁴ C(=O)R ³⁵ , or -NR ³⁴ SO ₂ R ³⁵

Another embodiment of the invention is a compound of Formula IHA, IIIA-1 , IIIA-2, IIIA-3, or

one or more substituents selected from -OR ³⁴ , -SR ³⁴ , -C^=O)NR ³⁴ R ³⁵ , -NR ³⁴ R ³⁵ , -NR ³⁴ C(=O)R ³⁵ , or -NR ³⁴ SO ₂ R ³⁵

Another embodiment of the invention is a compound of Formula IHA, IIIA-1 , IIIA-2, IIIA-3, or IIIA-4 wherein R ^a is d. ₆ alkyl, wherein said alkyl may be substituted by one or more substituents selected from -OR ³⁴ , -SR ³⁴ , -C(=O)NR ³⁴ R ³⁵ , -NR ³⁴ R ³⁵ , -NR ³⁴ C(=O)R ³⁵ , or -NR ³⁴ SO ₂ R ³⁵

Another embodiment of the invention is a compound of Formula IDA, IIIA-1 , IIIA-2, IIIA-3, or IIIA-4 wherein R ^a is C ₁ ^ alkyl, wherein said alkyl may be substituted by one or more -OR ³⁴

Another embodiment of the invention is a compound of Formula IHA, IIIA-1 , IIIA-2, IIIA-3, or

IIIA-4 wherein R ^a is R ^{1 1}

Another embodiment of the invention is a compound of Formula IHA wherein R ^a is methyl, ethyl, 1 -propyl, 2-propyl, 1-butyl, 2-butyl, 2,2-dιmethylethyl, 1-pentyl, 2-pentyl, 2,2-dιmethylpropyl, 1 -hexyl, aziridinyl, azetidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, pipeπdinyl, piperazinyl, oxiranyl, oxetanyl, tetrahydrofuryl, dioxolyl, tetrahydropyranyl, dioxanyl, oxazetidinyl,

isoxazolidinyl, oxazolidmyl, morpholinyl, oxazinanyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, wherein said methyl, ethyl, 1 -propyl, 2-propyl, 1 -butyl, 2-butyl, 2,2-dιmethylethyl, 1-pentyl, 2-pentyl, 2,2-dιmethylpropyl, or 1-hexyl may be substituted by one or more substituents selected from -OR ³⁴ , -SR ³⁴ , -C(=O)NR ³⁴ R ³⁵ , -NR ³⁴ R ³⁵ , -NR ³⁴ C(=O)R ³⁵ , or -NR ³⁴ SO ₂ R ³⁶ , and wherein said aziridinyl, azetidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, pipeÏ€dinyl, piperazinyl, oxiranyl, oxetanyl, tetrahydrofuryl, dioxolyl, tetrahydropyranyl, dioxanyl, oxazetidinyl, isoxazolidinyl, oxazolidmyl, morpholinyl, oxazinanyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl may be substituted by one or more substituents selected from R ² , R ³ , R ⁴ , R ⁵ , R ¹⁰ , R ¹¹ , and R ²¹ , W is phenyl-(Cr ₆ alkylenyl), pyridy>-(C-i- ₆ alkylenyl), or ιndolyl-(C,- ₆ alkylenyl), wherein said C _{1 6} alkylene is methylene, ethylene, 1 -propylene, 2-propylene, 1-butylene, 2-butylene, 2,2- dimethylethylene, 1 -pentylene, 2-pentylene, 2,2-dιmethylpropylene, or 1-hexylene, and wherein said phenyl, pyridyl, or indolyl is substituted by one or more groups selected from R ³⁰ and R ³¹ ,

Y is methyl, ethyl, 1 -propyl, 2-propyl, 1 -butyl, 2-butyl, 2,2-dιmethylethyl, 1 -pentyl, 2-pentyl, 2,2- dimethylpropyl, or 1 -hexyl, wherein Y may be substituted by OH or by one or more substituents selected from F, Cl, and Br,

L is triazolyl, tetrazolyl, or oxadiazolyl,

R ⁴ is H, -(C ₁ ^ alkylene)R ^δ , -C(=O)R ⁹ , or -SO ₂ R ¹² , wherein said C ₆ alkylene is methylene, ethylene, 1 -propylene, 2-propylene, 1-butylene, 2-butylene, 2,2-dιmethylethylene, 1 -pentylene, 2- pentylene, 2,2-dιmethylpropylene, or 1-hexylene, and wherein said phenyl, pyridyl, or indolyl is substituted by one or more groups selected from R ³⁰ and R ³¹ ,

R ⁵ is H, methyl, ethyl, 1 -propyl, 2-propyl, 1 -butyl, 2-butyl, 2,2-dιmethylethyl, 1 -pentyl, 2-pentyl, 2,2-dιmethylpropyl, or 1-hexyl, wherein said methyl, ethyl, 1 -propyl, 2-propyl, 1 -butyl, 2-butyl, 2,2- dimethylethyl, 1 -pentyl, 2-pentyl, 2,2-dιmethylpropyl, or 1 -hexyl, may be substituted by one or more R ²⁶ substituents,

R ⁷ is methyl, ethyl, 1 -propyl, 2-propyl, 1 -butyl, 2-butyl, 2,2-dιmethylethyl, 1 -pentyl, 2-pentyl, 2,2-dιmethylpropyl, 1 -hexyl, -NHR ²⁴ , or -OR ²⁵ , wherein said methyl, ethyl, 1 -propyl, 2-propyl, 1 -butyl, 2-butyl, 2,2-dιmethylethyl, 1 -pentyl, 2-pentyl, 2,2-dιmethylpropyl, or 1-hexyl may be substituted by OH or by one or more substituents selected from F, Cl, and Br, R ⁹ is -(C ₁ ^ alkylene)R ²⁸ , -NHR ²⁴ , or -OR ²⁵ ,

R ¹² is methyl, ethyl, 1 -propyl, 2-propyl, 1 -butyl, 2-butyl, 2,2-dιmethylethyl, 1-pentyl, 2-pentyl, 2,2-dιmethylpropyl, or 1-hexyl, wherein R ¹² may be substituted by one or more substituents selected from CN, -OR ²³ , -SO ₂ R ³⁷ , -NR ⁸ R ³³ , -NR ²⁴ C(=O)R ²³ , and -NR ²⁴ SO ₂ R ²³ , provided that any one carbon atom of R ¹² is not substituted by more than one CN or more than one -OR ²³ , R ^b , R ^c , R ⁸ , R ²⁰ , R ²² , R ²⁴ , R ²⁵ , R ³³ , R ³⁴ , and R ³⁵ are independently H, methyl, ethyl, 1 -propyl, 2- propyl, 1 -butyl, 2-butyl, 2,2-dιmethylethyl, 1-pentyl, 2-pentyl, 2,2-dιmethylpropyl, or 1-hexyl,,

R ²³ ts H ₁ methyl, ethyl, 1-propyl, 2-propyl, 1 -butyl, 2-butyl, 2,2-dιmethylethyl, 1 -pentyl, 2-pentyl, 2,2-dιmethylpropyl, or 1 -hexyl, wherein said methyl, ethyl, 1 -propyl, 2-propyl, 1 -butyl, 2-butyl, 2,2- dimethylethyl, 1 -pentyl, 2-pentyl, 2,2-dιmethylpropyl, 1-hexyl, may be substituted by OH, R ²⁶ is H, OH, F, Cl, Br, NH ₂ , or SH,

R ²⁹ is H, -C(=O)CH ₃ , -Ci=O)CH ₂ CH ₃ , -C(=O)(CH ₂ ) ₂ CH ₃₎ -C(=O)CH(CH ₃ ) ₂ , -C(=O)(CH ₂ ) ₃ CH3, -C(=O)CH(CH ₃ )CH ₂ CH ₃ , -C(=O)CH ₂ CH(CH ₃ ) ₂ , -C(=O)(CH ₂ ) ₄ CH _3l -Ct=O)CH ₂ CH(CH ₃ )CH ₂ CH ₃ , -C(=O)CH ₂ C(CH ₃ ) ₃ , or -C(=O)(CH ₂ ) ₅ CH ₃ ,

R ³¹ is Cl, Br, -OR ³² , methyl, ethyl, 1 -propyl, 2-propyl, 1 -butyl, 2-butyl, 2,2-dιmethylethyl, 1- pentyl, 2-pentyl, 2,2-dιmethylpropyl, 1-hexyl, or -OCH ₂ CH ₂ OR ²⁵ ,

R ³² is methyl, ethyl, 1 -propyl, 2-propyl, 1 -butyl, 2-butyl, 2,2-dιmethylethyl, 1 -pentyl, 2-pentyl, 2,2-dιmethylpropyl, or 1-hexyl, wherein R ³² may be substituted with one, two, or three F,

R ³⁶ is methyl, ethyl, 1 -propyl, 2-propyl, 1 -butyl, 2-butyl, 2,2-dιmethylethyl, 1 -pentyl, 2-pentyl, 2,2-dιmethylpropyl, or 1 -hexyl, and R ³⁷ is methyl, ethyl, 1 -propyl, 2-propyl, 1 -butyl, 2-butyl, 2,2-dιmethylethyl, 1 -pentyl, 2-pentyl,

2,2-dιmethylpropyl, or 1 -hexyl, wherein said methyl, ethyl, 1 -propyl, 2-propyl, 1-butyl, 2-butyl, 2,2- dimethylethyl, 1 -pentyl, 2-pentyl, 2,2-dιmethylpropyl, 1-hexyl, may be substituted by OH, or a pharmaceutically-acceptable salt thereof

Another embodiment of the invention is a compound of Formula IHA, IIIA-1 , IIIA-2, IIIA-3, or IIIA-4 wherein Y is methyl

Another embodiment of the invention is a compound of Formula IV

wherein G is (C ₁ ^ alkylenyl)-R ^a or R ^a , wherein said C _{1 3} alkylenyl may be substituted by one or more substituents selected from OH and F, R ^a is C _1-6 alkyl, 3- to 7-membered heterocycloalkyl, or 3- to 8-membered cycloalkyl, wherein said Ci- ₆ alkyl may be substituted by one or more substituents selected from F, -OR ³⁴ , -SR ³⁴ , -C(=O)NR ³⁴ R ³⁵ , -NR ³⁴ R ³⁵ , -NR ³⁴ Ci=O)R ³⁵ , or -NR ³⁴ SO ₂ R ³⁶ , and wherein said heterocycloalkyl and cycloalkyl may be substituted by one or more substituents selected from R ² , R ³ , R ⁴ , R ⁵ , R ¹⁰ , R ¹¹ , and R ²¹ , W is phenyl-(C ₁ - ₆ alkylenyl), pyrιdyl-(C ₁ - ₆ alkylenyl), or 9-membered heteroaryl-(C _r6 alkylenyl), wherein said phenyl, pyridyl, or 9-membered heteroaryl is substituted by one or more groups selected from R ³⁰ and R ³ ',

Y is Cr ₆ alkyl, C _t - ₆ haloalkyl, or C _r6 hydroxyalkyl,

L is 5-membered heteroaryl, R ² is H, F, CN, -OR ⁵ , R ¹² , -C(=O)R ⁷ , -NR ⁶ R ³³ , -NR ⁸ C(=O)R ⁹ , -NR ⁸ SO ₂ R ³⁶ , or -SO ₂ R ¹² ,

R ³ Is H, F, CN, or -OR ²² ,

R ⁴ is H, -(C^ alkylene)R ⁶ , -C(=O)R ^S , or -SO ₂ R ¹² ,

R ⁵ is H or -(C ₁ ^ alkyl), wherein said Ci _-6 alkyl may be substituted by one or more R ²⁶ substituents,

R ⁶ is H, CN, -OR ²³ , -SO ₂ R ³⁷ , -NR ²⁴ C(=O)R ²³ , -NR ²⁴ SO ₂ R ³⁷ , or ^N ~ ^N

R ⁷ is -(C ₁ ^ alkyl), -(C _1-6 haloalkyl), -(C _1-6 alkylene)OH, -NR ³⁸ R ³⁹ , -NHSO ₂ CH ₃ , or -OR ²⁵ , R ⁹ is -(C ₁ * alKylene)R ²⁸ , -NHR ²⁴ , or -OR ²⁵ , R ¹⁰ Is H, F, CN, R ¹² , or -C(=O)R ⁷ ,

R ¹¹ is H, F, CN, -OR ⁵ , R ¹² , -C(=O)R ⁷ , -NR ⁸ R ³³ , -NR ⁸ C(=O)R ⁹ , -NR ⁸ SO ₂ R ³⁶ , or -SO ₂ R ¹² , R ¹² is -(Ci- ₆ alkyl), wherein said C ₆ alkyl may be substituted by one or more substituents selected from CN, -OR ²³ , -SR ²³ , -SO ₂ R ³⁷ , -NR ⁸ R ³³ , -NR ²⁴ C(=O)R ²³ , and -NR ²⁴ SO ₂ R ²³ , provided that any one carbon atom of said C _1-6 alkyl is not substituted by more than one CN or more than one -OR ²³ ,

R ^B , R ^c , R ⁸ , R ²⁰ , R ²² , R ²⁴ , R ²⁵ , R ³³ , R ³⁴ , and R ³⁵ are independently H or -(C _1-6 alkyl), R ²¹ ιs H, F, or R ¹² ,

R ²³ is H, -(C ₁ .* alkyl), or -(C _1-6 alkylene)OH, R ²⁶ is H, OH, halo, NH ₂ , or SH, R ²⁸ is H, NH ₂ , or -OR ²⁹ , R ²⁹ is H, (C _1-6 alkyl), or -C(=O)(C, ₄ alkyl), R ³⁰ is H or F,

R ³¹ is F, Cl, Br, -CN, -C(=O)NH ₂ , -OH, -OR ³² , -OCH ₂ CH ₂ OR ²⁵ , R ³² , ,or (C _1-6 alkyl) optionally substituted by -OR ²⁵ or -OCH ₂ CH ₂ OR ²⁵ where R ³⁰ and R ³¹ when adjacent may be taken together to constitute a group of the formula O-(CH ₂ ) _n - or -O-(CH ₂ ) _n -O-, n is 1 or 2,

R ³² is -(Ct- ₆ alkyl) optionally substituted with one, two, or three F, R ³⁶ is -(C _1-6 alkyl) or -(C _3-6 cycloalkyl), and R ³⁷ is -(C _1-6 alkyl), -(C _3-6 cycloalkyl), or -(C ₁ ^ alkylene)OH,

R ³⁸ and R ³⁹ are independently H, -(C _1-6 alkyl), or R ³⁸ and R ³⁹ taken together form a 5- or 6- membered heterocycloalkyl, or a pharmaceutically-acceptable salt thereof

Another embodiment of the invention is a compound of Formula IVA

wherein R ^a , R ^c , W ₁ Y, and L are as defined heremabove for Formula IV Another embodiment of the invention is a compound of Formula IVA wherein L is triazolyl, tetrazolyl, or oxadiazolyl

Another embodiment of the invention is a compound of Formula IVA wherein L is

Another embodiment of the invention is a compound of Formula IVA wherein L is

Another embodiment of the invention is a compound of Formula IVA- 1

IVA- 1 wherein R ^a , R ^c , W, Y, and L are as defined hereinabove for Formula IV Another embodiment of the invention is a compound of Formula IVA-2

wherein R ³ , R ^c , W, Y, and L are as defined hereinabove for Formula IV Another embodiment of the invention is a compound of Formula IVA-3

wherein R ^a , R ^c , W, Y, and L are as defined hereinabove for Formula IV Another embodiment of the invention is a compound of Formula IVA-4

wherein R ^a , R ^c , W, Y, and L are as defined hereinabove for Formula IV Another embodiment of the invention is a compound of Formula IVA, IVA-1 , IVA-2, IVA-3, or

IVA-4 wherein R ^a is C ₆ alkyl, R ⁴

be substituted by one or more substituents selected from -OR ³⁴ , -SR ³⁴ , -Cf=O)NR ³⁴ R ³⁵ , -NR ³⁴ R ³⁵ , -NR ³⁴ C(=O)R ³⁵ , or -NR ³⁴ SO ₂ R ³⁵

Another embodiment of the invention is a compound of Formula IVA, IVA-1 , IVA-2, IVA-3, or

, wherein said alkyl may be substituted by one or more substituents selected from -OR ³⁴ , -SR ³⁴ , -Ci=O)NR ³⁴ R ³⁵ , -NR ³⁴ R ³⁵ , -NR ³⁴ C(=O)R ³⁵ , or -NR ³⁴ SO ₂ R ³⁵

Another embodiment of the invention is a compound of Formula IVA, IVA-1 , IVA-2, IVA-3, or IVA-4 wherein R ^a is C _1-6 alkyl, wherein said alkyl may be substituted by one or more substituents selected from -OR ³⁴ , -SR ³⁴ , -Ci=O)NR ³⁴ R ³⁵ , -NR ³⁴ R ³⁵ , -NR ³⁴ Ci=O)R ³⁵ , or -NR ³⁴ SO ₂ R ³⁵

Another embodiment of the invention is a compound of Formula IVA, IVA-1 , IVA-2, IVA-3, or IVA-4 wherein R ^a is C _1-6 alkyl, wherein said alkyl may be substituted by one or more -OR ³⁴

Another embodiment of the invention is a compound of Formula IVA, IVA-1 , IVA-2, IVA-3, or

IVA-4 wherein R ^a

Another embodiment of the invention is a compound of Formula IVA, IVA- 1 , IVA-2, IVA-3, or

IVA-4 wherein R ^a is R ² >11

, or

R ² is CH(CH ₃ )OH, C(CH ₃ ) ₂ OH, -NR ⁸ C(O)(C, .<; alkylene)R ²⁸ , or -NR ⁸ SO ₂ R ³⁶ , R ¹⁰ Is CH(CH ₃ )OH, or C(CH ₃ ) ₂ OH, and

R ¹¹ is CH(CH ₃ )OH, C(CH ₃ ) ₂ OH, -NR ⁸ C(=O)(C _1-6 alkylene)R ²⁸ , or -NR ⁸ SO ₂ R ³⁶ Another embodiment of the invention is a compound of Formula IVA, IVA-1 , IVA-2, IVA-3, or IVA-4 wherein Y is methyl

Another embodiment of the invention is a compound of Formula IVA, IVA-1 , IVA-2, IVA-3, or IVA-4 wherein W is phenyl-(Cr ₆ alkylenyl), wherein said phenyl is substituted by one or more groups selected from R ³⁰ and R ³¹

Another embodiment of the invention is a compound of Formula IVA, IVA-1 , IVA-2, IVA-3, or IVA-4 wherein W is phenylmethyl, wherein said phenyl is substituted by one or more groups selected from R ³⁰ and R ³¹ Another embodiment of the invention is a compound shown in Table 2

Another embodiment of the invention is a compound of Formula I ₁ II, III, or IV wherein G is -CH ₂ R ³ , -CH ₂ CH ₂ R ³ , -CH(R ^a )CH _3> -CH ₂ CH ₂ CH ₂ R ³ , -CH ₂ CH(CH ₃ )R ³ ,

-CH(R ^a )CH ₂ CH ₃ , or R ^a , wherein said CH, CH ₂ , and CH ₃ groups may be substituted by one or more substituents selected from OH and F,

R ^a is methyl, ethyl, 1-propyl, 2-propyl, 1 -butyl, 2-butyl, 2,2-dιmethylethyl, 1 -pentyl, 2-pentyl, 2,2-dιmethylpropyl, 1 -hexyl, aziridinyl, azetidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, oxiranyl, oxetanyl, tetrahydrofuryl, dioxolyl, tetrahydropyranyl, dioxanyl, oxazetidinyl, isoxazolidinyl, oxazolidinyl, morpholinyl, oxazinanyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, wherein said methyl, ethyl, 1-propyl, 2-propyl, 1 -butyl, 2-butyl, 2,2-dιmethylethyl, 1-pentyl, 2-pentyl, 2,2-dιmethylpropyl, or 1-hexyl may be substituted by one or more substituents selected from -OR ³⁴ , -SR ³⁴ , -C(=O)NR ³⁴ R ³⁵ ,

-NR ³⁴ R ³⁵ , -NR ³⁴ C(=O)R ³⁵ , or -NR ³⁴ SO ₂ R ³⁶ , and wherein said aziridinyl, azetidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, oxiranyl, oxetanyl, tetrahydrofuryl, dioxolyl, tetrahydropyranyl, dioxanyl, oxazetidinyl, isoxazolidinyl, oxazolidinyl, morpholinyl, oxazinanyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl may be substituted by one or more substituents selected from R ² , R ³ , R ⁴ , R ⁵ , R ¹⁰ , R ¹¹ , and R ²¹ ,

W is phenyl-(d- ₆ alkylenyl), pyrιdyl-(C ₁ - ₆ alkylenyl), or IHdOIyI-(Cr ₆ alkylenyl), wherein said C _t . ₆ alkylene is methylene, ethylene, 1 -propylene, 2-propylene, 1-butylene, 2-butylene, 2,2- dimethylethylene, 1-pentylene, 2-pentylene, 2,2-dιmethylpropylene, or 1-hexylene, and wherein said phenyl, pyridyl, or indolyl is substituted by one or more groups selected from R ³⁰ and R ³ \

Y is methyl, ethyl, 1 -propyl, 2-propyl, 1 -butyl, 2-butyl, 2,2-dιmethylethyl, 1-pentyl, 2-pentyl, 2,2- dimethylpropyl, or 1-hexyl, wherein Y may be substituted by OH or by one or more substituents selected from F, Cl, and Br, L is triazolyl, tetrazolyl, or oxadiazolyl,

R ⁴ is H, -(C ₁ ^ alkylene)R ⁶ , -C(=O)R ⁹ , or -SO ₂ R ¹² , wherein said C ₁ ^ alkylene is methylene, ethylene, 1 -propylene, 2-propylene, 1 -butylene, 2-butylene, 2,2-dιmethylethylene, 1 -pentylene, 2- pentylene, 2,2-dιmethylpropylene, or 1-hexylene, and wherein said phenyl, pyridyl, or indolyl is substituted by one or more groups selected from R ³⁰ and R ³¹ , R ⁵ is H, methyl, ethyl, 1-propyl, 2-propyl, 1 -butyl, 2-butyl, 2,2-dιmethylethyl, 1-pentyl, 2-pentyl,

2,2-dιmethylpropyl, or 1 -hexyl, wherein said methyl, ethyl, 1 -propyl, 2-propyl, 1-butyl, 2-butyl, 2,2- dimethylethyl, 1-pentyl, 2-pentyl, 2,2-dιmethylpropyl, or 1 -hexyl, may be substituted by one or more R ²⁶ substituents,

R ⁷ is methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2,2-dιmethylethyl, 1-pentyl, 2-pentyl, 2,2-dιmethylpropyl, 1-hexyl, -NHR ²⁴ , or -OR ²⁵ , wherein said methyl, ethyl, 1-propyl, 2-propyl, 1 -butyl, 2-butyl, 2,2-dιmethylethyl, 1 -pentyl, 2-pentyl, 2,2-dιmethylpropyl, or 1 -hexyl may be substituted by OH or by one or more substituents selected from F, Cl, and Br, R ⁹ is -(C ₆ alkylene)R ²⁸ , -NHR ²⁴ , or -OR ²⁵ ,

R ¹² is methyl, ethyl, 1 -propyl, 2-propyl, 1-butyl, 2-butyl, 2,2-dιmethylethyl, 1 -pentyl, 2-pentyl, 2,2-dιmethylpropyl, or 1 -hexyl, wherein R ¹² may be substituted by one or more substituents selected

from CN, -OR ²³ , -SO ₂ R ³⁷ , -NR ⁸ R ³³ , -NR ²⁴ C(=O)R ²³ , and -NR ²⁴ SO ₂ R ²³ , provided that any one carbon atom of R ¹² is not substituted by more than one CN or more than one -OR ²³ ,

R ^b , R ^c , R ⁸ , R ²⁰ , R ²² , R ²⁴ , R ²⁵ , R ³³ , R ³⁴ , and R ³⁵ are independently H, methyl, ethyl, 1 -propyl, 2- propyl, 1-bÏ…tyl, 2-butyl, 2,2-dιmethylethyl, 1 -pentyl, 2-pentyl, 2,2-dιmethylpropyl, or 1 -hexyl,, R ²³ is H, methyl, ethyl, 1 -propyl, 2-propyl, 1 -butyl, 2-butyl, 2,2-dιmethyletbyl, 1-pentyl, 2-pentyl,

2,2-dιmethylpropyl, or 1-hexyl, wherein said methyl, ethyl, 1 -propyl, 2-propyl, 1 -butyl, 2-butyl, 2,2- dimethylethyl, 1-pentyl, 2-pentyl, 2,2-dιmethylpropyl, 1-hexyl, may be substituted by OH,

R ²⁶ is H, OH ₁ F, Cl, Br ₁ NH ₂ , or SH,

R ²⁹ is H, -C(=O)CH ₃ , -C(=O)CH ₂ CH ₃ , -C(=O)(CH ₂ ) ₂ CH ₃ , -C(=O)CH(CH ₃ ) ₂ , -C(=O)(CH ₂ ) ₃ CH ₃ , -C(=O)CH(CH ₃ )CH ₂ CH ₃ , -C(=O)CH ₂ CH(CH ₃ ) ₂ , -C(=O)(CH ₂ ) ₄ CH ₃ , -C(=O)CH ₂ CH(CH ₃ )CH ₂ CH ₃ , -C(=O)CH ₂ C(CH ₃ ) ₃ , or -C(=O)(CH ₂ ) ₅ CH _3l

R ³¹ is Cl, Br, -OR ³² , methyl, ethyl, 1 -propyl, 2-propyl, 1-butyl, 2-butyl, 2,2-dιmethylethyl, 1 - pentyl, 2-pentyl, 2,2-dιmethylpropyl, 1-hexyl, or -OCH ₂ CH ₂ OR ²⁵ ,

R ³² is methyl, ethyl, 1 -propyl, 2-propyl, 1 -butyl, 2-butyl, 2,2-dιmethylethyl, 1-pentyl, 2-pentyl, 2,2-dιmethylpropyl, or 1-hexyl, wherein R ³² may be substituted with one, two, or three F,

R ³⁶ is methyl, ethyl, 1 -propyl, 2-propyl, 1-butyl, 2-butyl, 2,2-dιmethylethyl, 1-pentyl, 2-pentyl, 2,2-dιmethylpropyl, or 1-hexyl, and

R ³⁷ is methyl, ethyl, 1 -propyl, 2-propyl, 1 -butyl, 2-butyl, 2,2-dιmethylethyl, 1 -pentyl, 2-pentyl, 2,2-dιmethylpropyl, or 1-hexyl, wherein said methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2,2- dimethylethyl, 1-pentyl, 2-pentyl, 2,2-dιmethylpropyl, 1 -hexyl, may be substituted by OH, or a pharmaceutically-acceptable salt thereof

Another embodiment of the invention is a compound shown in Table 3

Table 3

Example Compound Name N o.

1 λy-(4-Fluoro-3-methoxybenzyl)-6-(2-((^rans-4-amιnocyclohex yl)methyl)-

2/-/-tetrazol-5-yl)pyrιmιdιne-4-carboxamιde

λ/-(4-Fluoro-3-methoxybenzyl)-6-(2-((<rans-4-

((methylsulfonyl)arnιno)cyc!ohexyl)methyl)-2/-/-tetrazol -5- yl)pyπmιdιne-4-carboxamιde λ/-(3-Chloro-4-fluorobenzyl)-6-(2-((<rans-4-amιnocycloh exyl)methyl)-2H- tetrazol-5-yl)pyrιmιdιne-4-carboxamιde

W-(3-Cnloro-4-fluorobenzyl)-6-(2-((/ra/?s-4-

((methylsulfonyl)amιno)cyclohexyl)methyl)-2H-tetrazol-5- yl)pyrιmιdιneO1 -4-carboxamιde /V-(3-Methoxybenzyl)-6-(2-(((frans)-4-amιnocyclohexyl)methy l)-2/-/- tetrazol-5-yl)-2-methylpyrιmιdιne-4-carboxamιde

Table 3

Example Compound Name N o.

6 λ/-(3-Methoxybenzyl)-2-methyl-6-(2-«(trans-4-

(methylsulfonamιdo)cyclohexyl)methyl)-2H-tetrazol-5- yl)pyrιmιdιne-4-carboxamιde

7 λ/-(3-Methoxybenzyl)-6-(2-((frans-4-acetamιdocyclohexyl)me thyl)-2H- tetrazol-5-yl)-2-methylpyrιmιdιne-4-carboxamιde

8 λ/-(3-Methoxybenzyl)-6-(2-(((fraπs)-4-(2- hydroxyacetamιdo)cyclohexyl)methyl)-2/-/-tetrazol-5-yl)-2- methylpyrιmιdιne-4-carboxamιde N-(4-F!uoro-3-methoxybenzyl)-6-(2-(<rans-4-amιnocyclohex yl)methyl)-

2H-tetrazol-5-yl)-2-methylpyπmιdιne-4-carboxamιde

10 W-(4-F!uoro-3-methoxybenzyl)-2-methyl-6-(2-((/rans-4-

(methylsulfonamιdo)cyclohexyl)methyl)-2H-tetrazol-5- yl)pyrιmιdιne-4-carboxamιde

1 1 λl-(4-Fluoro-3-methoxybenzyl)-6-(2-((<rans-4- acetamιdocyclohexyl)methyl)-2H-tetrazol-5-yl)-2- methylpyrιπnιdιne-4-carboxamιde 2 λ/-(4-Fluoro-3-methoxybenzyl)-6-(2-(((frans)-4-(2- hydroxyacetamιdo)cyclohexyl)methyl)-2H-tetrazol-5-yl)-2- methylpyrιmιdιne-4-carboxamιde 3 λ/-(3-(2-Hydroxyethoxy)benzyl)-6-(2-(((frans)-4- aminocyclohexyl)methyl)-2H-tetrazol-5-yl)-2-methylpyrimidine -4- carboxamide 4 W-(3-(2-Hydroxyethoxy)benzyl)-6-(2-(((/rans)-4- acetamιdocyclohexyl)methy!)-2H-tetrazo!-5-yl)-2- me(hylpyrιmιdιne-4-carboxamιde 5 λ/-(3-(2-Hydroxyethoxy)benzyl)-2-methyl-6-(2-(((frans)-4-

(methylsulfonamιdo)cyclohexyl)methyl)-2H-tetrazol-5- yl)pyπmιdιne-4-carboxamιde 6 λ/-(3-(2-Hydroxyethoxy)benzyl)-6-(2-(((fraπs)-4-(2- hydroxyacetamιdo)cyclohexyl)methyl)-2/-/-tetrazol-5-yl)-2- methylpyrιmιdιne-4-carboxamιde 7 λ/-(4-Fluoro-3-(2-hydroxyethoxy)benzyl)-6-(2-((((rans)-4- acetamιdocyclohexyl)methyl)-2H-tetrazol-5-yl)-2- methylpyrιmιdιne-4-carboxamιde 8 λ/-(4-Fluoro-3-(2-hydroxyethoxy)benzyl)-2-methy!-6-(2-(((fr ans)-4-

(methy!sulfonamιdo)cyclohexyl)methyl)-2/-/-tetrazol-5- yl)pyrιmιdιne-4-carboxamιde 9 λ/-(4-Fluoro-3-(2-hydroxyethoxy)benzyl)-6-(2-(((frans)-4-(2 - hydroxyacetamιdo)cyclohexyl)methyl)-2H-tetrazo!-5-y!)-2- methylpyπmιdιne-4-carboxamιde 0 /rans-Methyl 4-((5-(6-((4-fluoro-3-methoxybenzyl)carbamoyl)-2- methylpyrιmιdιn-4-yl)-2/-/-tetrazol-2- yl)methyl)cyclohexanecarboxylate

Table 3

Example Compound Name N o.

21 trans-4-((5-(6-((4-Flυoro-3-melhoxybenzyl}carbamoyl)-2- methylpyrιmιdιn-4-yl)-2H-tetrazol-2- yl)methyl)cyclohexanecarboxylιc acid

22 (frans)-Methyl 4-((5-(6-((3-methoxybenzyl)carbamoyl)-2- methylpyrιmιdιn-4-yl)-2/-/-tetrazo!-2- yl)methyl)cyc!ohexanecarboxy!ate 3 (/raπs)-4-((5-(6-((3-Methoxybenzyl)carbamoy!)-2-methy!pyrι mιdιn-4-yl)-

2AV-tetrazol-2-yl)methyl)cyclohexanecarboxylιc acιd 4 λ/-(3-Methoxybenzyl)-6-(2-(((/rans-4-cyanocyclohexyl)methyl )-2H- tetrazol-5-yl)-2-methylpyrιmιdιne-4-carboxamιde 5 W-(4-Fluoro-3-methoxybenzyl)-6-(2-(((/rans-4-cyanocyclohexy! )me{hyl)-

2H-tetrazol-5-yl)-2-methylpyrιmιdιne-4-carboxamιde 6 λ/-(3-(2-Hydroxyethoxy)benzyl)-6-(2-(((fraπs)-4- cyanocyclohexyl)methyl)-2/-/-tetrazol-5-yl)-2-methylpyrιmι dιne-4- carboxamide 7 λ/-(4-Fluoro-3-(2-hydroxyethoxy)benzyl)-6-(2-(((/rans-4- cyanocyclohexy^methyl^H-tetrazol-S-yO^-methylpyrimidme^- carboxamide 8 N-(3-Methoxybenzyl)-6-(2-((((rans)-4-hydroxy-4-

(hydroxymethy!)cyc!ohexyl)methyl)-2H-tetrazol-5-yl)-2- methylpyrιmιdιne-4-carboxamιde 9 λ/-(3-Methoxybenzyl)-6-(2-(((c/s)-4-hydroxy-4-

(hydroxymethyl)cyclohexyl)methyl)-2H-tetrazol-5-yl)-2- methylpyrιmιdιne-4-carboxamιde 0 W-(3-chloro-4-fluorobenzyl)-6-(2-((fraπs-4-hydroxy-4-

(hydroxymethyl)cyclohexy!)mBthy!)-2H-tetrazol-5-yl)-2- methylpyrιmιdιne-4-carboxamιde 1 rac-λ/-(4-Fluoro-3-methoxybenzyl)-6-(2-(((1 S ^* ,3R ^* )-3- aminocyclopentyl^ethyO^H-tetrazol-S-yO^-methylpyrimidine- 4-carboxamιde 2 λac-λ/-(4-Fluoro-3-methoxybenzyl)-6-(2-(((1 S ^* ,3fT)-3- acetamιdocyclopentyl)methyl)-2H-tetrazol-5-yl)-2- methylpyrιnnιdιne-4-carboxamιde 3 (+)-λ/-(4-Fluoro-3-methoxybenzyl)-6-(2-(((1 S ^* ,3f? ^* )-3- acetamιdocyclopentyl)methyl)-2/-/-tetrazol-5-yl)-2- methylpyrιmιdιne-4-carboxamιde 4 (-)-N-(4-Fluoro-3-methoxybenzyl)-6-(2-(((1 R ^* ,3S ^* )-3- acetamidocyclopentyOmethyO-^H-tetrazol-S-yl)^- methylpyrιmιdιne-4-carboxamιde 5 rac-λ/-(4-F!uoro-3-methoxybenzy!)-2-methyl-6-(2-(((1 S ^* ,3R ^* )-3-

(methylsulfonamιdo)cyclopentyl)methyl)-2H-tetrazol-5- yl)pyrιmιdιne-4-carboxamιde 6 (+)-λ/-(4-Fluoro-3-methoxybenzyl)-2-methyl-6-(2-(((1 fr,3S ^* )-3-

(methy!sυlfonamιdo)cyc!opentyl)methyl)-2H-tetrazol-5- yl)pyrιmιdιne-4-carboxamιde

Table 3

Example Compound Name N o.

37 (-)-λ/-(4-Fluoro-3-methoxybenzyl)-2-methyl-6-(2-(((1 S*,3/? ^* )-3-

(methylsulfonamιdo)cyclopentyl)methyl)-2H-tetrazol-5- yl)pyπmιdιne-4-carboxamιde

38 /V-(3-Methoxybenzyl)-2-methyl-6-(2-((S)-morpholιn-2-ylmethy l)-2H- tetrazol-5-yl)pyrιmιdιne-4-carboxamιde 9 λ/-(3-Methoxybenzyl)-6-(2-(((S)-4-acetylmorpholιn-2-yl)met hyl)-2/-/- tetrazol-5-yl)-2-methylpyrιmιdιne-4-carboxamιde 0 W-(3-Methoxybenzyl)-2-methyl-6-(2-(((f?)-4-(methylsulfonyl)m orpholin-2- yl)methyl)-2H-tetrazol-5-yl)pyrιmιdιne-4-carboxamιde 1 N-(4-Fluoro-3-methoxybenzyl)-2-methyl-6-(2-((S)-morpho!in-2- ylmethyl)-

2H-tetrazol-5-yl)pyrιmιdιne-4-carboxamιde 2 N-(4-fluoro-3-methoxybenzyl)-6-(2-(((S)-4-acetylmorpholιn-2 -yl)methyl)-

2H-tetrazol-5-yl)-2-methylpyrιmιdιne-4-carboxamιde 3 λ/-(4-Fluoro-3-methoxybenzyl)-2-methyl-6'(2-(((R)-4-

(methylsulfonyl)morpholιn-2-yl)methyl)-2H-tetrazol-5- yl)pyπmιdιne-4-carboxamιde 4 λ/-(3-Methoxybenzyl)-2-methyl-6-(2-((R)-morpholιn-2-ylmeth yl)-2/-/- tetrazo!-5-y!)pyrιmιdιne-4-carboxamιde 5 N-(3-Methoxybenzyl)-6-(2-(((f?)-4-acetylmorpholιn-2-yl)meth yl)-2H- tetrazol-5-yl)-2-methylpyπmιdιne-4-carboxamιde

46 N-(3-Methoxybenzyl)-2-methyl-6-(2-(((S)-4-(methy!su!fonyl)mo rpho!ιn-2- yl)methyl)-2H-tetrazol-5-yl)pyrιmιdιne-4-carboxamιde 7 /V-(3-Chloro-4-fluorobenzyl)-2-methyl-6-(2-((S)-morpholιn-2 -ylmethyl)-

2H-tetrazol-5-yl)pyrιmιdιne-4-carboxamιde 8 λ/-(3-Chloro-4-fluorobenzyl)-2-methyl-6-(2-(((f?)-4-

(methylsulfonyl)morpholιn-2-yl)methyl)-2H-tetrazol-5- yl)pyπmtdιne-4-carboxamιde 9 λ/-(3-Ethyl-4-fluorobenzyl)-2-methyl-6-(2-((S)-morpholιn-2 -ylmethyl)-2H- tetrazol-5-yl)pyrιmιdιne-4-carboxamιde 0 N-(3-Ethyl-4-fluorobenzyl)-2-methyl-6-(2-(((R)-4-

(methylsulfonyl)morpholιn-2-yl)methyl)-2H-tetrazol-5- y!)pyrιmιdιne-4-carboxamιde 1 rac-6-(2-((1 ,4-Dιoxan-2-yl)methyl)-2H-tetrazol-5-yl)-λ/-(3- methoxybenzyl)-2-methylpyrιmιdιne-4-carboxamιde 2 rac-6-(2-((1 ,4-Dιoxan-2-yl)methyl)-2H-tetrazol-5-yl)-λ/-(4-fluoro-3- methoxybenzyl)-2-methyipyrιmιdιne-4-carboxamιde 3 6-(2-(((R)-1 ,4-dιoxan-2-yl)methyl)-2/-Metrazol-5-yl)-λ/-(3- methoxybenzyl)-2-methylpyrιmιdιne-4-carboxamιde 4 6-(2-(((/?)-1 ,4-dιoxan-2-yl)methyl)-2H-tetrazol-5-yl)-λ/-(4-fluoro-3- methoxybenzyl)-2-methylpyrιmιdιne-4-carboxamιde

Table 3

Example Compound Name N o.

55 6-{2-(((f?)-1 ,4-d(oxan-2-yl)methyl)-2W-tetrazol-5-yl)-λ/-(3-chloro-4- fluorobenzy!)-2-methylpyrιmιdιne-4-carboxamιde

56 6-(2-(((f?)-1 ,4-Dιoxan-2-yl)methyl)-2H-tetrazo!-5-yl)-λ/-(4-fluoro-3-(2 - nydroxyethoxy)benzyl)-2-methylpyπmιdιne-4-carboxamιde

57 6-(2-(((S)-1 ,4-dιoxan-2-y!)methyl)-2H-tetrazol-5-yl)-λ/-(3- methoxybenzyl)-2-methylpyrιmιdιne-4-carboxamιde

58 6-(2-(((S)-1 ,4-d(θxan-2-yl)methyl)-2W-tetrazol-5-yl)-λ/-(4-fluoro-3- methoxybenzyl)-2-methylpyrιmιdιne-4-carboxamιde

59 6-(2-(((S)-1 ,4-dtoxan-2-yl)methyl)-2H-tetrazol-5-yl)-λ/-(3-chloro-4- fluorobenzyl)-2-methylpyrιmιdιne-4-carboxamιde 0 6-(2-(((S)-1 ,4-dιoxan-2-yl)methyl)-2H-tetrazol-5-yl)-λ/-(4-fluoro-3-(2 - hydroxyethoxy)benzyl)-2-methylpyrιmιdιne-4-carboxamιde 1 rac-λ/-(3-Methoxybenzyl)-6-(2-(((2S*,5/?*)-5-(hydroxymethyl )-1 ,4-dιoxaπ-

2-yl)methyl)-2H-tetrazo!-5-yl)-2-methylpyrιmιdιne-4-ca rboxamιde 2 λ/-(3-Methoxybenzyl)-6-(2-(((2S,5f?)-5-(hydroxymethyl)-1 ,4-dιoxan-2- yl)me(hyl)-2W-tetrazol-5-yl)-2-me(hylpyπmιdιne-4-carboxam ιde 3 λ/-(3-Methoxybenzyl)-6-(2-(((2R,5S)-5-(hydroxymethy!)-1 ,4-dιoxan-2- yl)methyl)-2H-tetrazol-5-yl)-2-methylpyrιmιdιne-4-carboxa mιde 4 rac-/V-(4-F!uoro-3-methoxybenzyl)-6-(2-(((2S*,5f?*)-5-(hydro xymethyl)-

1 ,4-dιoxan-2-yl)methyl)-2/-/-tetrazol-5-yl)-2-methylpyrιmι dιne-4- carboxamide 5 λ/-(4-Fluoro-3-methoxybenzyl)-6-(2-(((2S,5/?)-5-(hydroxymet hyl)-1 ,4- dιoxan-2-yl)methyl)-2H-tetrazol-5-yl)-2-methylpyrιmιdιne -4- carboxamide 6 λ/-(4-F!uoro-3-methoxybenzyl)-6-(2-(((2R,5S)-5-(hydroxymeth yl)-1 ,4- dιoxan-2-yl)methyl)-2/-/-tetrazol-5-yl)-2-methylpyrιmιdι ne-4- carboxamide 7 / ^• ac-λ/-(4-Fluoro-3-methylbenzyl)-6-(2-(((2S*,5R*)-5-(hydroxy methy!)-1 ,4- dιoxan-2-yl)methyl)-2H-tetrazol-5-yl)-2-methylpyrιmιdιne -4- carboxamide 8 λ/-(4-Fluoro-3-methylbenzyl)-6-(2-(((2S,5/?)-5-(hydroxymeth yl)-1 ,4- dιoxan-2-yl)methyl)-2H-tetrazo!-5-yl)-2-methy!pyπmιdιne- 4- carboxamide 9 λ/-(4-Fluoro-3-methylbenzyl)-6-(2-(((2/?,5S)-5-(hydroxymeth yl)-1 ,4- dιoxan-2-yl)methyl)-2H-tetrazol-5-yl)-2-methylpyrιmιdιne -4- carboxamide 0 rac-λ/-(4-Fluoro-3-(trιfluoromethyl)benzyl)-6-(2-(((2S*,5R ^* )-5-

(hydroxymethyl)-1 ,4-dιoxan-2-y!)methyl)-2H-tetrazol-5-yl)-2- methylpyrιmιdιne-4-carboxamιde 1 rac-N-(3-Ethyl-4-fluorobenzy!)-6-(2-(((2S*,5R*)-5-(hydroxyme thy!)-1 ,4- dιoxan-2-yl)methyl)-2H-tetrazol-5-yl)-2-methylpyrιmιdιne -4- carboxamide 2 λ/-(3-Ethyl-4-fluorobenzyl)-6-(2-(((2S,5f?)-5-(hydroxymethy l)-1 ,4-dιoxan-

2-yl)methyl)-2H-tetrazol-5-yl)-2-methylpyπmιdιne-4-car boxamιde3 λ/-(3-Ethyl-4-fluorobenzyl)-6-(2-(((2R,5S)-5-(hydroxymethyl )-1 ,4-dιoxan-

2-y!)me(hyl)-2/-/-tetrazol-5-yl)-2-methylpyrιmιdιne-4-car boxam!de4 rac-λ/-(4-Fluoro-3-ιsopropylbenzyl)-6-(2-(((2S ^* ,5f? ^* )-5-(hydroxymethyl)-

1 ,4-dιoxan-2-y!)methyl)-2H-tetrazol-5-yl)-2-methylpyπmιdι ne-4- carboxamide

Table 3

Example Compound Name N o.

75 rac-/V-(3-Cyclopropyl-4-fluorobenzyl)-6-(2-(((2S*,5/? ^* )-5-

(hydroxymethyl)-1 ,4-dιoxan-2-yl)methyl)-2H-tetrazol-5-yl)-2- methylpyrιmιdιne-4-carboxamιde

76 rac-λ/-(3-Cyano-4-fluorobenzyl)-6-{2-({(2S ^* ,5R ^* )-5-(hydroxymethyl)-1 ,4- dιoxan-2-yl)methyl)-2H-tetrazol-5-yl)-2-methylpyrιmιdιne -4- carboxamide

77 rac-λ/-(4-Fluoro-3-(2-hydroxyethoxy)benzyl)-6-(2-(((2S ^* ,5/? ^* )-5-

(hydroxymethyl)-1 ,4-dιoxan-2-yl)methyl)-2H-tetrazol-5-yl)-2- methylpyrιmιdιne-4-carboxamιde

78 Aac-A/-(3-Chloro-4-fluorobenzyl)-6-(2-(((2S ^* ,5/?*)-5-(hydroxymethyl)-1 ,4- dιoxan-2-yl)methyl)-2/-/-tetrazol-5-yl)-2-methylpyrιmιdι ne-4- carboxamide

79 /V-(3-Chloro-4-fluorobenzyl)-6-(2-(((2S,5R)-5-(hydroxymethyl )-1 ,4- dιoxan-2-yl)methyl)-2H-tetrazol-5-yl)-2-methylpyrιmιdιne -4- carboxamide

80 λ/-(3-Bromo-4-fluorobenzyl)-6-(2-(((2S,5R)-5-(hydroxymethyl )-1 ,4- dιoxan-2-yl)methyl)-2/-/-tetrazol-5-yl)-2-methy!pyrιmιdι ne-4- carboxamide

81 λ/-(4-Fluoro-3-hydroxybenzyl)-6-(2-(((2S,5R)-5-(hydroxymeth y!)-1 ,4- dιoxan-2-yl)methyl)-2H-tetrazol-5-yl)-2-methylpyrιmιdιne -4- carboxamide

82 λ/-(4-Fluoro-3-methoxybenzyl)-6-(2-(((2R,5/?)-5-(hydroxymet hyl)-1 ,4- dιoxan-2-yl)methyl)-2H-tetrazol-5-y!)-2-methylpyrιmιdιne -4- carboxamide

83 λ/-(3-Chloro-4-fluorobenzyl)-6-(2-((5,5-bιs(hydroxymethyl) -1 ,4-dιoxan-2- yl)methyl)-2/-/-tetrazol-5-yl)-2-methylpyrιmιdιne-4-carbo xamιde

84 λ/-(3-Methoxybenzyl)-6-(2-((5,5-bιs(hydroxymethyl)-1 ,4-dιoxan-2- yl)methyl)-2/-/-tetrazol-5-yl)-2-methylpyrιmιdιne-4-carbo xamιde

85 rac-(2S ^* ,5S ^* )-Methyl 5-((5-(6-((3-methoxybenzyl)carbamoyl)-2- methylpyrιmιdιn-4-yl)-2/-/-tetrazol-2-yl)methyl)-1 ,4-dιoxane-2- carboxylate

86 rac-(2S*,5S ^* )-5-((5-(6-((3-Methoxybenzyl)carbamoyl)-2-methylpyrιmιdιn -

4-yl)-2/-/-tetrazol-2-yl)methyl)-1 ,4-dιoxane-2-carboxylιc acid

87 rac-(2S ^* ,5S ^* )-methyl 5-((5-(6-((4-fluoro-3-methoxybenzy!)carbamoyl)-2- methylpyπmιdιn-4-yl)-2H-tetrazol-2-yl)methyl)-1 ,4-dιoxane-2- carboxylate

88 rac-(2S ^* ,5S ^* )-5-((5-(6-((4-Flυoro-3-methoxybenzyl)carbamoyl)-2- methylpyrιmιdιn-4-yl)-2/-/-tetrazol-2-yl)methyl)-1 ,4-dιoxane-2- carboxyhc acid

89 (2S,5S)-5-((5-(6-((4-Fluoro-3-methoxybenzyl)carbamoy!)-2- methy!pyπmιdιn-4-yl)-2/-/-tetrazol-2-yl)methyl)-1 ,4-dιoxane-2- carboxyhc acid

90 (2S,5S)-Methyl 5-((5-(6-((4-Fluoro-3-methoxybenzyl)carbamoyl)-2- methylpyrιmιdιn-4-yl)-2H-tetrazo!-2-yl)methyl)-1 ,4-dιoxane-2- carboxylate

Table 3

Example Compound Name N o.

91 λ/-(4-Fluoro-3-methoxybenzyl)-6-(2-(((2S,5S)-5-(2-hydroxypr opan-2-yl)-

1 ,4-dιoxan-2-yl)methyl)-2/-/-tetrazol-5-yl)-2-methylpyrιmι dιne-4- carboxamide

90 (2S,5S)-Methyl 5-((5-(6-((4-Fluoro-3-methoxybenzyl)carbamoyl)-2- methylpyrιmιdιn-4-y!)-2/-/-tetrazol-2-yl)methyl)-1 ,4-dιoxane-2- carboxylate

91 λ/-(4-Fluoro-3-methoxybenzyl)-6-(2-(((2S,5S)-5-(2-hydroxypr opan-2-yl)-

1 ,4-dιoxan-2-yl)methyl)-2H-(etrazol-5-yl)-2-methylpyrιmιdÎ ¹ne-4- carboxamide 2 rac-(2S*,5S*)-Methy! 5-((5-(6-((3-chloro-4-fluorobenzyl)carbamoyl)-2- methylpyrιmιdιn-4-yl)-2H-tetrazol-2-yl)methyl)-1 ,4-dιoxane-2- carboxylate 3 rac-(2S*,5S*)-5-((5-(6-((3-Chloro-4-fluorobenzyl)carbamoy!)- 2- methylpyrιmιdιn-4-yl)-2H-tetrazol-2-yl)methyl)-1 ,4-dιoxane-2- carboxylic acid 4 rac-(2S*,5S*)-Methyl 5-((5-(6-((3-bromo-4-fluorobenzyl)carbamoyl)-2- methylpyrιmιdιn-4-yl)-2/-/-tetrazol-2-yl)methyl)-1 ,4-dιoxane-2- carboxylate 5 λac-(2S*,5S*)-5-((5-(6-((3-Bromo-4-fluorobenzyl)carbamoyl)- 2- methylpyrιmιdιn-4-yl)-2H-tetrazol-2-yl)methyl)-1 ,4-dιoxane-2- carboxylic acid 6 λac-W-(3-Methoxybenzyl)-6-(2-(((2S*,5/?*)-5-(amιnomethyl)- 1 ,4-dιoxan-

2-yl)methyl)-2H-tetrazol-5-yl)-2-methylpyrιmιdιne-4-carbo xamιde 7 rac-/V-(3-Methoxybenzyl)-6-(2-(((2S*,5f?*)-5-(acetamιdometh yl)-1 ,4- dιoxan-2-yl)methyl)-2H-tetrazol-5-yl)-2-methylpyπmιdιne- 4- carboxamide 8 rac-/\/-(3-Methoxybenzyl)-6-(2-(((2S ^* ,5R*)-5-(acetamidomethyl)-1 ,4- dιoxan-2-yl)methyl)-2H-tetrazol-5-yl)-2-methylpyrιmιdιne -4- carboxamide 9 λ/-(4-Fluoro-3-methoxybenzyl)-6-(2-(((2f?*,5R ^* )-5-(hydroxymethyl)- tetrahydro-2H-pyran-2-yl)methyl)-2/-/-tetrazol-5-yl)-2- methy!pyrιmιdιne-4-carboxamιde 00 /V-(4-Fluoro-3-methoxybenzyl)-6-(2-(((2R*,5R ^* )-5-(hydroxymethyl)- tetrahydro-2/-/-pyran-2-yl)methyl)-2H-tetrazol-5-yl)-2- methylpyπmιdιne-4-carboxamιde 01 /V-(4-Fluoro-3-methoxybenzyl)-6-(2-(((2S*,5R ^* )-5-(hydroxymethyl)- tetrahydro-2H-pyran-2-yl)methyl)-2H-tetrazol-5-yl)-2- methylpyrιmιdιne-4-carboxamιde

Table 3

Example Compound Name N o.

102 λ/-(4-fluoro-3-me(hoxyben2yl)-6-(2-(((2S ^* ,5/? ^* )-5-(hydroxymethyl)- tetrahydro-2H-pyran-2-yl)methyl)-2H-tetrazol-5-yl)-2- methylpyrιmιdιne-4-carboxamιde

103 W-(3-Methoxybenzyl)-6-(2-(((2f?*,5S ^* )-5-hydroxy-tetrahydro-2H-pyran-2- yl)methyl)-2H-tetrazol-5-yl)-2-methylpyrιmιdιne-4-carboxa mιde

104 λ/-(3-Methoxybenzyl)-6-(2-(((2f?*,5S*)-5-hydroxy-tetrahydro -2H-pyran-2- yl)methyl)-2H-tetrazol-5-yl)-2-methylpyrιmιdιne-4-carboxa mιde

105 (+)-A/-(4-Fluoro-3-methoxybenzy!)-6-(2-(((2R*,5S*)-5-hydroxy - tetrahydro-2H-pyran-2-yl)methyl)-2H-tetrazol-5-yl)-2- methylpyrιmιdιne-4-carboxamιde

106 (-)-λ/-(4-Fluoro-3-methoxybenzyl)-6-(2-(((2S ^* ,5R' ^r )-5-hydroxy-tetrahydro-

2H-pyran-2-yl)methyl)-2H-tetrazol-5-yl)-2-methylpyÏ€mιdÎ ¹ne-4- carboxamide

107 rac-λ/-(4-Fluoro-3-methoxybenzyl)-6-(2-(((2f? ^* ,5S ^* )-5-hydroxy-5-

(hydroxymethyl)-tetrahydro-2H-pyran-2-yl)methyl)-2H-tetra zo!-5- y!)-2-methylpyπmιdιne-4-carboxamιde

108 rac-/V-(4-Fluoro-3-methoxybenzyl)-6-(2-(((2R*,5/? ^* )-5-hydroxy-5-

(hydroxymethyl)-tetrahydro-2H-pyran-2-yl)methyl)-2/-/-tet razol-5- yl)-2-methylpyrιmιdιne-4-carboxamιde

109 rac-N-(3-Methoxybenzyl)-6-(1-(((2R*,5S*)-5-(hydroxymethyl)-1 ,4-dιoxan-

2-yl)methyl)-1 H- 1 ,2,4-trιazol-3-yl)-2-methylpyrιmιdιne-4- carboxamide

1 10 λ/-(3-Methoxybenzyl)-6-(1 -((frans-4-amιnocyclohexyl)methyl)-1 H-1 ,2,4- trιazol-3-yl)-2-methylpyrιmιdιne-4-carboxamιde

11 1 N-(3-Methoxybenzy!)-6-(1 -(((frans)-4-acetamιdocyclohexyl)methyl)-1 H-

1 ,2,4-trιazol-3-yl)-2-methylpyrιmιdιne-4-carboxamιde

112 /V-(3-Methoxybenzyl)-2-methyl-6-(1-(((<λaπs)-4-

(methylsulfonamιdo)cyclohexyl)methyl)-1 H-1 ,2,4-tπazol-3- yl)pyrιmιdιne-4-carboxamιde 13 2-((^aπs)-4-((3-(6-((3-methoxybenzyl)carbamoyl)-2-methylpyr ιmιdιn-4- yl)-1H-1 ,2,4-trιazol-1-yl)methyl)cyclohexylamιno)-2-oxoethyl acetate 14 λ/-(3-Methoxybenzyl)-6-(1 -(((frans)-4-(2- hydroxyacetamidojcyclohexyOmethyl^iH-i ^^-tnazol-S-yl)^- methylpyrιmιdιne-4-carboxamιde 15 rac-/V-(4-Fluoro-3-methoxybenzyl)-6-(1-(((2/?*,5S ^* )-5-(hydroxymethyl)-

1 ,4-dιoxan-2-yl)methyl)- 1 H- 1 ,2,4-tπazol-3-yl)-2- methylpyrιmιdιne-4-carboxamιde 16 λ/-(4-Fluoro-3-methoxybenzyl)-6-(1-(((rans-4-amιnocyclohex yl)methyl)-

1 H-1 ,2,4-tπazol-3-yl)-2-methylpyrιmιdιne-4-carboxamιde 17 N-(4-Fluoro-3-methoxybenzyl)-2-methyl-6-(1 -((/rans-4-

(methylsulfonamιdo)cyclohexyl)methyl)-1 H-1 ,2,4-tπazol-3- yl)pyrιmιdιne-4-carboxamιde

Table 3

Example Compound Name N o.

118 λ/-(4-fluoro-3-methoxybenzyl)-6-(1-((/λa/?s-4- acetamιdocyclohexyl)methyl)-1H-1 ,2,4-trιazol-3-yl)-2- methylpyrιmιdιne-4-carboxamιde

119 W-(4-Fluoro-3-methoxybenzy!)-6-(1-((frans-4-(2- hydroxyacetamιdo)cyclohexyl)methyl)-1H-1 ,2,4-trιazol-3-yl)-2- methylpyrιmιdιne-4-carboxamιde

120 λ/-(4-Fluoro-3-(2-hydroxyethoxy)benzyl)-2-methyl-6-( 1 -((trans-4-

(methy!sulfonamιdo)cyclohexyl)methyl)-1 H-1 ,2,4-trιazol-3- yl)pyrιmιdιne-4-carboxamιde

121 W-(4-Fluoro-3-(2-hydroxyethoxy)benzyl)-6-(1-((frans-4- acetamidocyclohexyl)methy!)-1H-1 ,2,4-triazol-3-y!)-2- methylpyπmιdιne-4-carboxamιde

122 λ/-(4-Fluoro-3-methoxybenzyl)-6-(5-((<rans-4-amιnocyclo hexyl)methyl)-

1 ,2,4-oxadιazol-3-yl)-2-methylpyrιmιdιne-4-carboxamιde

123 λ/-(4-fluoro-3-methoxybenzyl)-6-(5-((frans-4- acetamidocyclohexyl)methyl)-1 ,2,4-oxadiazol-3-yl)-2- methylpyrιmιdιne-4-carboxamιde

124 λ/-(4-Fluoro-3-methoxybenzyl)-2-methyl-6-(5-((fraπs-4-

(methylsulfonamιdo)cyclohexyl)methyl)-1 ,2,4-oxadιazol-3- yl)pyrιmιdιne-4-carboxamιde 25 λ/-(4-Fluoro-3-methoxybenzyl)-6-(2-(3-hydroxypropyl)-2H-te( razol-5-yl)-

2-methylpyrιmιdιne-4-carboxamιde 26 λ/-(4-Fluoro-3-methoxybenzyl)-6-(2-((S)-3-hydroxy-2-methylp ropyl)-2H-

(e(razol-5-yl)-2-methylpyrιmιdιne-4-carboxamιde 27 A/-(4-Fluoro-3-methoxybenzyl)-6-(2-((f?)-3-hydroxy-2-methylp ropy!)-2H- tetrazol-5-yl)-2-methylpyrιmιdιne-4-carboxamιde 28 Ay-(4-Fluoro-3-methoxybenzyl)-6-(1-(((2S,5R)-5-(hydroxymethy l)-1 ,4- dιoxan-2-yl)methyl)-1 /-/-1 ,2,3-trιazol-4-yl)-2-methylpyrιmιdιne-4- carboxamide 29 W-(4-Fluoro-3-methoxybenzyl)-6-(1 -(((S)-4-acetylmorpholin-2-yl)methyl)-

1 H- 1 ,2,3-tÏ€azol-4-yl)-2-methy!pyÏ€mιdιne-4-carboxamιde ₃₀ λ/-(3-Methoxybenzyl)-2-methyl-6-(1-((S)-morpholιn-2-ylmeth yl)-1 H-1 ,2,3- trιazol-4-yl)pyrιmιdιne-4-carboxamιde 31 λf-(3-Methoxybenzyl)-6-(1 -(((S)-4-acetylmorpholιn-2-yl)methyi)-1 H- 1 ,2,3- trιazol-4-yl)-2-methylpyrιmιdιne-4-carboxamιde 32 λ/-(3-Methoxybenzyl)-2-methyl-6-(1 -(((R)-4-(methylsulfonyl)morpholιn-2- yl)methyl)-1H-1 ,2,3-triazol-4-yl)pyrimidine-4-carboxamide 33 λ/-(3-Methoxybenzyl)-6-(1 -(((2S,5R)-5-(hydroxymethyl)-1 ,4-dιoxan-2- yl)methyl)-1H-1 ,2,3-trιazol-4-yl)-2-metnylpyrιmιdιne-4- carboxamtde 34 λ/-(4-Fluoro-3-methoxybenzyl)-6-(1 -(((/raÏ€s)-4-amιnocyclohexyl)methyl)-

1 H- 1 ,2,3-trιazol-4-yl)-2-methylpyrιmιdιne-4-carboxamιde

Table 3

Example Compound Name N o.

135 N-(4-Fluoro-3-methoxybenzyl)-6-(1 -(((trans)-A- acetamidocyclohexyl )methyl )- 1 H- 1 ,2 ,3-trιazol-4-yl)-2- methylpyrιmιdιne-4-carboxamιde

136 N-(4-Fluoro-3-methoxybenzyl)-6-(1-(((frans)-4-(2- hydroxyacetamιdo)cyclohexyl)methyl)-1 H-1 ,2,3-trιazol-4-y!)-2- methylpyrιmtdιne-4-carboxamιde

_{1 37} /V-(4-Fluoro-3-methoxybenzyl)-6-(1 -(((1/?,3S)-3- amιnocyclopentyl)methyl)-1 H-1 ,2,3-tπazol-4-yl)-2- methylpyrιmιdιne-4-carboxamιde

138 λ/-(4-Fluoro-3-methoxybenzyl)-6-(1-(((1 R,3S)-3- acetamιdocyclopentyl)methyl)-1/-/-1 ,2,3-trιazol-4-yl)-2- methylpyrιmιdιne-4-carboxamιde

139 λ/-(4-fluoro-3-methoxybenzyl)-6-(1-(((1 R,3S)-3-(2- hydroxyacetamιdo)cyclopentyl)methyl)-1 H-1 ,2,3-trιazol-4-yl)-2- methylpyπmιdιne-4-carboxamιde

140 N-(4-F!uoro-3-methoxybenzyl)-2-methyl-6-( 1 -((( 1 R,3S)-3-

(methylsulfonamιdo)cyclopentyl)methyl)-1 H-1 ,2,3-trιazol-4- yl)pyrιmιdιne-4-carboxamιde 4 ₁ W-(4-Fluoro-3-methoxybenzy!)-6-(1-(((1 S,3R)-3- amιnocyclopentyl)methyl)-1 H-1 ,2,3-trιazol-4-y!)-2- methylpyrιmιdιne-4-carboxamιde 42 λ/-(4-Fluoro-3-methoxybenzyl)-6-(1-(((1S,3/?)-3- acetamιdocyclopentyl)methyl)-1 H-1 ,2,3-trιazo!-4-yl)-2- methylpyÏ€mιdιne-4-carboxamιde 43 N-(4-FlÏ…oro-3-methoxybenzyl)-6-(1 -(((1 S,3R)-3-(2- hydroxyacetamιdo)cyclopentyl)methyl)-1H-1 ,2,3-trιazol-4-yl)-2- methylpyrιmιdιne-4-carboxamιde 44 W-(4-Fluoro-3-methoxybenzyl)-2-methyl-6-(1-(((1 S,3f?)-3-

(methylsulfonamιdo)cyclopentyl)methyl)-1 H-1 ,2,3-trιazol-4- yl)pyrιmιdιne-4-carboxamιde 45 6-(1-(((S)-1 ,4-Dioxan-2-yl)methyl)-1 H-1 ,2,3-tnazol-4-yl)-W-(4-fluoro-3- methoxybenzyl)-2-methylpyrιmιdιne-4-carboxamιde 46 6-(1-(((R)-1 ,4-Dιoxan-2-yl)methyl)-1 H-1 ,2,3-trιazol-4-yl)-λ'-(4-f)uoro-3- methoxybenzyl)-2-methylpyrιmιdιne-4-carboxamιde 4 ₇ λ/-(4-Fluoro-3-methoxybenzyl)-6-(1-(((2S,5R)-5-amιno-tetra hydro-2H- pyran-2-yl)methyl)-1H-1 ,2,3-tÏ€azol-4-yl)-2-methylpyÏ€mιdιne-4- carboxamide 48 N-(4-Fluoro-3-methoxybenzyl)-6-(1 -(((2S,5R)-5-acetamιdo-tetrahydro-

2H-pyran-2-yl)methyl)-1H-1 ,2,3-trιazol-4-yl)-2-methylpyπmιdιne- 4-carboxamιde

Table 3

Example Compound Name N o.

149 λ/-(4-Fluoro-3-methoxybenzyl)-6-(5-(((2S,5R)-5-(hydroxymeth yl)-1 ,4- dιoxan-2-yl)methyl)-1 ,2,4-oxadιazol-3-yl)-2-methylpyrιmιdιne-4- carboxamide

150 6-(5-((2/?)-1 ,4-Dιoxan-2-ylmethyl)-1 ,2,4-oxadιazol-3-yl)-W-(4-fluoro-3- methoxybenzy!)-2-methylpyrιrrudιne-4-carboxamιde

151 6-(5-((2S)- 1 ,4-Dioxan-2-ylmethyl)-1 ,2,4-oxadιazol-3-yl)-λ/-(4-fluoro-3- methoxybenzyl)-2-methylpynmιdιne-4-carboxamιde

152 λ/-(4-Fluoro-3-methoxybenzyl)-6-(3-(((fraπs)-4- acetamιdocyc!ohexy!)methyl)ιsoxazol-5-yl)-2-methylpyπmιd ιne- 4-carboxamιde

153 /V-(3-Methoxybenzyl)-4-(2-(((frans)-4-amιnocyclohexyl)methy l)-2/-/- tetrazol-5-yl)-6-methylpιcolιnamιde

154 λ/-(3-Methoxybenzyl)-6-methyl-4-(2-(((/rans)-4-

(methylsulfonamιdo)cyclohexyl)methyl)-2/-/-tetrazol-5- yl)pιcolιnamιde

155 /V-(3-Methoxybenzyl)-4-(2-(((tørts)-4-

(ethylsυlfonamιdo)cyclohexyl)methyl)-2/-/-tetrazol-5-yl )-6- methylpicohnamide

156 N-(3-Methoxybenzy\)-4-(2-(((trans}-4-

(cyclopropanesulfonamιdo)cyclohexyl)methyl)-2H-tetrazol- 5-yl)- 6-methylpιcolιnamιde

157 λ/-(3-Methoxybenzyl)-4-(2-(((/raπs)-4-

(butylsulfonamιdo)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6 - methylpicolinamide

158 N-(3-Methoxybenzyl)-4-(2-(((/rans)-4-acetamιdocyclohexyl)me thyl)-2H- tetrazol-5-yl)-6-methylpιcolιnamιde

159 N-(3-Methoxybenzyl)-4-(2-(((/raπs)-4-ιsobutyramιdocyclohe xyl)methyl)-

2H-tetrazol-5-yl)-6-methylpιcolιnamιde

160 2-((<rans)-4-((5-(2-((3-Methoxybenzyl)carbamoyl)-6-methyl pyrιdιn-4-yl)-

2/-/-tetrazol-2-yl)methyl)cyclohexylamιno)-2-oxoethyl acetate

161 λ/-(3-Methoxybenzyl)-4-(2-(((frans)-4-(2- hydroxyacetamιdo)cyclohexyl)methyl)-2H-tetrazo!-5-yl)-6- methylpicolinamide

162 λ/-(3-Methoxybenzyl)-4-(2-(((frans)-4-(2-hydroxy-2- methylpropanamιdo)cyclohexyl)methyl)-2/-/-tetrazol-5-yl)-6- methylpicolinamide

163 W-(3-Methoxybenzyl)-4-(2-((Urans)-4-((S)-2- hydroxypropanamιdo)cyclohexyl)methyl)-2/-/-tetrazol-5-yl)-6 - methylpicolinamide

164 λ/-(3-Methoxybenzyl)-4-(2-(((<rans)-4-(3- amιnopropanamιdo)cyclohexyl)methyl)-2/-/-tetrazol-5-yl)-6- methylpicolmamide

165 λ/-(3-Methoxybenzyl)-4-(2-(((/rans)-4-(2- methoxyacetamιdo)cyclohexyl)methyl)-2/-/-tetrazol-5-yl)-6- methylpicolmamide

166 λ/-(3-Methoxybenzyl)-4-(2-(((^ans)-4-(3- methoxypropanamιdo)cyclohexyl)methyl)-2/-/-tetrazol-5-yl)-6 - methylpicolinamide

Table 3

Example Compound Name N o.

167 /V-(3-Methoxybenzyl)-4-(2-(((tams)-4-(2- amιnoacetamιdo)cyclohexyl)methyl)-2/-/-tetrazol-5-yl)-6- methylpicolmamide

168 W-(3-Methoxybenzyl)-4-(2-(((to}/?s)-4-(3- hydroxypropanamιdo)cyclohexyl)methyl)-2/-/-tetrazol-5-yl)-6 - methylpicolinamide

169 1 -((^a/?s)-4-((5-(2-((3-methoxybenzyl)carbamoyl)-6-methylpyri din-4-yl)-

2H-tetrazol-2-yl)methyl)cyc!ohexyl)-3-methylurea

170 N-(4-Fluoro-3-methoxybenzyl)-4-(2-(((frans)-4-amιnocyclohex yl)methyl)-

2A7-tetrazol-5-yl)-6-methylpιcolιnamιde

171 λ/-(4-Fluoro-3-methoxybenzyl)-4-(2-(((frans)-4- acetamidocyclohexyOmethyl^H-tetrazol-δ-ylJ-e- methylpicolmamide

172 N-(4-Fluoro-3-methoxybenzyl)-4-(2-(((frans)-4-(3- amιnopropanamιdo)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6- methylpicolinamide

173 N-(4-Fluoro-3-methoxybenzyl)-4-(2-(((/rans)-4-(2- methoxyacetamιdo)cyclohexyl)methyl)-2/-/-tetrazol-5-yl)-6- methylpicolmamide

174 λ/-(4-Fluoro-3-methoxybenzyl)-4-(2-(((frans)-4-(3- methoxypropanamido)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6- methylpicolinamide

175 W-(4-Fluoro-3-methoxybenzyl)-4-(2-(((fra/7S)-4-(2- amιnoacetamιdo)cyclohexyl)methyl)-2/-/-tetrazol-5-yl)-6- methylpicolinamide

176 2-((<raπs)-4-((5-(2-((4-fluoro-3-methoxybenzyl)carbamoyl )-6- methylpyrιdιn-4-yl)-2H-tetrazol-2-yl)methyl)cyclohexylamι no)-2- oxoethyl acetate

177 λ/-(4-Fluoro-3-methoxybenzyl)-4-(2-(((/rans)-4-(2- hydroxyacetamιdo)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6- methylpicolinamide

178 N-(4-Fluoro-3-methoxybenzyl)-4-(2-(((<rans)-4-(3- hydroxypropanamidojcyclohexyOmethyO^H-tetrazol-S-yO-θ- methylpicolinamide

179 /V-(4-Fluoro-3-methoxybenzyl)-4-(2-(((frans)-4-(2-hydroxy-2- methylpropanamιdo)cyclohexyl)methyl)-2/-/-tetrazol-5-yl)-6- methylpicohnamide

180 /V-(3-Ethoxybenzyl)-6-methy!-4-(2-(((/ra/7s)-4-

(methylsυlfonamιdo)cyclohexyl)methyl)-2H-tetrazol-5- yl)pιcolιnamιde

181 W-(4-Fluoro-3-(hydroxymethyl)benzyl)-6-methyl-4-(2-(((/ra/7s )-4-

(methytsulfonamιdo)cyclohexyl)rrιethyl)-2H-tetrazol-5- yl)pιcolιnamιde

182 λ/-(4-Fluoro-3-methoxybenzyl)-6-methyl-4-(2-(((/rans)-4-

(methylsulfonamido)cyclohexyl)methyl)-2H-tetrazol-5- yt)pιcolιnamιde

183 W-(3-(Hydroxymethyl)benzyl)-6-methyl-4-(2-(((frans)-4-

(methylsulfonamιdo)cyclohexyl)methyl)-2H-tetrazol-5- yl)pιcolιnamιde

Table 3

Example Compound Name N o.

184 N-(3-(2-Hydroxyethoxy)benzyl)-6-melhyl-4-(2-(((/λaw)-4-

(methylsulfonamιdo)cyclohexyl)methyl)-2H-tetrazol-5- yl)pιcolιnamιde

185 /V-(4-Fluoro-3-methylbenzyl)-4-(2-(((Jraπs)-4-amιnocyclohe xyl)methyl)-

2H-tetrazol-5-yl)-6-methylpιcolιnamιde

186 N-(4-fluoro-3-methylbenzyl)-6-methyl-4-(2-(((<rans)-4-

(methylsulfonamιdo)cyclohexyl)methyl)-2H-tetrazol-5- yl)pιcolιnamιde

187 N-(4-Fluoro-3-methylbenzyl)-4-(2-(((<rans)-4- acetamιdocyclohexyl)methyl)-2/-/-tetrazol-5-yl)-6- methylpicohnamide

188 N-(4-Fluoro-3-methy!benzyl)-4-(2-(((frans)-4-(3- amιnopropanamιdo)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6- methylpicolmamide

189 λ/-(4-Fluoro-3-methylbenzyl)-4-(2-((((rans)-4-(2- methoxyacetamιdo)cyclohexyl)methyl)-2/-/-tetrazol-5-yl)-6- methylpicolmamide

190 2-((fraπs)-4-((5-(2-((4-Fluoro-3-methylbenzyl)carbamoyl)-6- methylpyrιdιn-4-yl)-2H-tetrazol-2-yl)methyl)cyclohexylamι no)-2- oxoethyl acetate

191 λ/-(4-Fluoro-3-methylbenzyl)-4-(2-(((<rans)-4-(2- hydroxyacetamιdo)cyclohexyl)methyl)-2/-/-tetrazol-5-yl)-6- methylpicolinamide

192 N-(4-Fluoro-3-methylbenzyl)-4-(2-(((<rans)-4-(3- methoxypropanamιdo)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6- methylpicolmamide

193 N-(4-fluoro-3-methy!benzy!)-4-(2-(((trans)-4-(2- amιnoacetamιdo)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6- methylpicolinamide

194 λ/-(3-Chloro-4-fluorobenzyl)-4-(2-(((frans)-4-amιnocyclohe xyl)methyl)-

2H-tetrazol-5-yl)-6-methylpιcolιnamιde

195 /V-(3-Chloro-4-fluorobeπzyl)-6-methyl-4-(2-(((f/-aπs)-4-

(methylsulfonamιdo)cyclohexyl)methyl)-2/-/-tetrazol-5- yl)picolinamide

196 λ/-(3-Chloro-4-fluorobeπzyl)-4-(2-{((frans)-4- acetamidocyclohexyl)methyl)-2H-tetrazol-5-yl)-6- methylpicolinamide

197 N-(3-Cb\oro-4-f\uorohenzy\)-4-(2-(((trans)-4-(3- amιnopropanamιdo)cyclohexyl)methyl)-2/-/-tetrazol-5-yl)-6- methylpicolmamide

198 λ/-(3-Chloro-4-fluorobenzyl)-4-(2-(((/rans)-4-(2- methoxyacetamιdo)cyclohexy!)methyl)-2H-tetrazol-5-yl)-6- methylpicolinamide

199 2-((^ans)-4-((5-(2-((3-Chloro-4-fluorobenzyl)carbamoyl)-6-me thylpyrιdιn-

4-yl)-2/-/-tetrazol-2-yl)methyl)cyclohexylamιno)-2-oxoet hy! acetate

200 λ/-(3-Chloro-4-fluorobenzyl)-4-(2-(((frans)-4-(2- hydroxyacetamιdo)cyc!ohexyl)methyl)-2/-/-tetrazol-5-yl)-6- methylpicolmamide

Table 3

Example Compound Name N o.

201 λ/-(3-Chloro-4-flυorobenzyl)-4-(2-(((frans)-4-(3- methoxypropanamιdo)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6- methylpicolmamide

202 /V-(3-Chloro-4-f!uorobenzyl)-4-(2-(((fraπs)-4-(2- amιnoacetamιdo)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6- methylpicolinamide

203 λ/-(4-Fluoro-3-((2-hydroxyethoxy)methyl)benzyl)-6-methyl-4- (2-(((^aπs)-

4-(methylsulfonamιdo)cyclohexyl)methyl)-2H-tetrazol-5- y!)pιcolιnamιde

204 4-(2-(((^a/7s)-4-Acetamιdocyclohexyl)methyl)-2H-tetrazol-5- yl)-λ/-((6- hydroxypyrιdιn-2-yl)methyl)-6-methylpιcolιnamιde

205 λ/-(3-(Hydroxymethyl)benzyl)-4-(2-(((fraπs)-4- acetamιdocyclohexyl)methyl)-2>-/-tetrazol-5-yl)-6- methylpicolinamide

206 λ/-(3-(2-Hydroxyethoxy)benzyl)-4-(2-(((fraA?s)-4- acetamιdocyclohexyl)methy!)-2H-tetrazol-5-yl)-6- methylpicohnamide

207 /V-(4-F!uoro-3-(hydroxymethyl)benzyl)-4-(2-(((frans)~4- acetamidocyclohexyOmethyO-^H-tetrazol-S-yO-θ- methylpicolinamide

208 N-(3-Ethoxybenzyl)-4-(2-(((/rans)~4-acetamidocyclohexyl)meth yl)-2H- tetrazol-5-yl)-6-methylpιcolιnamιde

209 λ/-(3-Methoxybenzyl)-4-(2-(((c/s)-4-amιnocyclohexyl)methyl )-2/-/-tetrazol-

5-yl)-6-methylpιcolιnamιde

210 N-(3-Methoxybenzyl)-6-methyl-4-(2-(((c/s)-4-

(methylsulfonamιdo)cyclohexyl)methyl)-2H-tetrazol-5- yl)pιcolιnamιde

211 A/-(3-Methoxybenzyl)-4-(2-(((αs)-4-acetamιdocyclohexyl)met hyl)-2H- tetrazol-5-yl)-6-methylpιcolιnamιde

212 λ/-(3-Methoxybenzyl)-4-(2-(((c/s)-4-(3- amιnopropanamιdo)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6- methylpicolinamide

213 N-(3-Methoxybenzyl)-4-(2-(((c/s)-4-(2- methoxyacetamιdo)cyclohexyl)methy!)-2/-/-tetrazol-5-yl)-6- methylpicolinamide

214 2-((c/s)-4-((5-(2-((3-methoxybenzyl)carbamoyl)-6-methylpyrι dιn-4-yl)-2H- tetrazol-2-yl)methyl)cyclohexylamιno)-2-oxoethyl acetate

215 λ/-(3-Methoxybenzyl)-4-(2-(((c/s)-4-(2- hydroxyacetamιdo)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6- methylpicolmamide

216 A/-(3-Methoxybenzyl)-4-(2-(((c/s)-4-(3- methoxypropanamidoJcyclohexyOmethyO^H-tetrazol-δ-yO-e- methylpicolmamide

217 N-(3-Methoxybenzyl)-4-(2-(((cιs)-4-(2- amιnoacetamιdo)cyclohexyl)methyl)-2/-/-tetrazol-5-yl)-6- methylpicolinamide

218 /V-(3-Methoxybenzyl)-4-(2-(((c/s)-4-(2-hydroxy-2- methylpropanamιdo)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6- methylpicolmamide

Table 3

Example Compound Name N o.

219 λ/-(4-Fluoro-3-methoxybenzyl)-4-(2-(((c/s)-4-amιnocyclohex yl)methyl)-

2H-tetrazo!-5-y!)-6-methylpιcolιnamιde

220 N-(4-Fluoro-3-methoxybenzyl)-4-(2-(((frans)-4-(2-hydroxy-2- methylpropanamιdo)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6- methylpicolinamide

221 N-(4-Fuoro-3-methoxybe^zyl)-4-(2-(((c/s)-4-(2- hydroxyacetamιdo)cyclohexyl)methyl)-2/-/-tetrazol-5-yl)-6- methylpicolmamide

222 N-(4-Fluoro-3-methoxybenzyl)-4-(2-(((c/s)-4- acetamιdocyclohexyl)methyl)-2/-/-tetrazol-5-yl)-6- methylpicolmamide

223 rac-λ/-(3-Methoxybenzyl)-4-(2-(((1 S*,3R*)-3-amιnocyc!ohexyl)methyl)-

2H-tetrazol-5-yl)-6-metnylpιcolιnamιde

224 rac-λ/-(3-Methoxybenzyl)-4-(2-(((1 S ^* ,3R ^* )-3-(3- amιnopropanamιdo)cyclohexyl)methyl)-2/-/-tetrazol-5-yl)-6- methylpicolmamide

225 rac-N-(3-Methoxybenzyl)-4-(2-(((1 S ^* ,3f? ^* )-3- acetamidocyclohexyOmethyO^H-tetrazol-S-yO-G- methylpicolmamide

226 λ/-(3-Methoxybenzy!)-4-(2-(((1 S ^* ,3R ^* )-3-acetamιdocyclohexyl)methyl)-

2/-/-tetrazol-5-yl)-6-methylpιcolιnamιde

227 λ/-(3-Methoxybenzyl)-4-(2-(((1f?*,3S*)-3-acetamιdocyclohex yl)methyl)-

2H-tetrazol-5-yl)-6-methylpιcolιnamιde

228 rac-λ/-(3-Methoxybenzyl)-4-(2-(((1 S ^* ,3R*)-3-(2- methoxyacetamιdo)cyclohexyl)methyl)-2/-/-tetrazol-5-yl)-6- methylpicolinamide

229 rac-2-((1 /? ^* ,3S ^* )-3-((5-(2-((3-methoxybenzyl)carbamoyl)-6- methylpyπdιn-4-yl)-2H-tetrazol-2-yl)methyl)cyclohexylamιn o)-2- oxoethyl acetate

230 rac-/V-(3-Methoxybenzyl)-4-(2-(((1 S ^* ,3R ^* )-3-(2- hydroxyacetamιdo)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6- methylpicolinamide

231 W-(3-Methoxybenzyl)-4-(2-(((1R*,3S ^* )-3-(2- hydroxyacetamιdo)cyclohexyl)methyl)-2/-/-tetrazol-5-yl)-6- methylpicolinamide

232 N-(3-Methoxybenzyl)-4-(2-(((1 S ^* ,3R ^* )-3-(2- hydroxyacetamιdo)cyclohexyl)methyl)-2/-/-tetrazol-5-yl)-6- methylpicolinamide

233 rac-λ/-(4-Fluoro-3-methoxybenzy!)-4-(2-(((1 S*,3R*)-3- amιnocyclohexyl)methyl)-2/-/-tetrazol-5-yl)-6-methylpιcolÎ ¹namιde

234 rac-2-((1f? ^* ,3S ^* )-3-((5-(2-((4-Fluoro-3-methoxybenzyl)carbamoyl)-6- methylpyrιdιn-4-yl)-2H-tetrazol-2-yl)methyl)cyclohexylamι no)-2- oxoethyl acetate

235 rac-λ/-(4-Fluoro-3-methoxybenzyl)-4-(2-(((1S ^* ,3fr)-3-(2- hydroxyacetamιdo)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6- methylpicolinamide

23 ₆ /V-(4-Fluoro-3-methoxybenzyl)-4-(2-(((1 S ^* ,3R*)-3-(2- hydroxyacetamιdo)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6- methylpicolmamide

Table 3

Example Compound Name N o.

237 /V-(4-Fluoro-3-methoxybenzyl)-4-(2-(((1 R*,3S*)-3-(2- hydroxyacetamιdo)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6- methylpicohnamide

238 rac-/V-(3-Methoxybenzyl)-4-(2-(((1 S' ,3R ^* )-3-(3- methoxypropanamιdo)cyclohexy!)methyl)-2H-tetrazol-5-yl)-6- methylpicolmamide

239 rac-/V-(3-Methoxybenzyl)-4-(2-(((1 S ^* ,3R ^* )-3-(2- amιnoacetamιdo)cyclohexyl)methy!)-2H-tetrazol-5-y!)-6- methylpicolmamide

240 rac-λ/-(3-Methoxybenzyl)-6-methyl-4-(2-(((1 S ^* ,3R ^* )-3-

(methylsulfonamιdo)cyclohexyl)methyl)-2H-tetrazo!-5- yl)pιcolιnamιde

241 rac-W-(3-Me(hoxybenzyl)-4-(2-(((1/?*,3/?*)-3-amιnocyclohexy l)methyl)-

2/-/-tetrazol-5-yl)-6-methylpιcolιnamιde

242 rac-/V-(3-Methoxybenzyl)-4-(2-(((1 R ^* ,3R ^* )-3-(2- metboxyacetamιdo)cyclohexyl)methy!)-2A7-tetrazol-5-yl)-6- methylpicolinamide

243 rac-N-(3-Methoxybenzyl)-4-(2-(((1 R*,3R*)-3- acetamιdocyclohexyl)methyl)-2H-tetrazol-5-yl)-6- methylpicolinamide

244 rac-2-((1 f? ^* ,3/? ^* )-3-((5-(2-((3-methoxybenzyl)carbamoyl)-6- methylpyrιdιn-4-yl)-2H-tetrazol-2-yl)methyl)cyclohexylamι no)-2- oxoethyl acetate

245 rac-W-(3-Methoxybenzyl)-4-(2-(((1R*,3R ^* )-3-(2- hydroxyacetamιdo)cyclohexyl)methyl)-2/-/-tetrazol-5-yl)-6- methylpicolinamide

246 λac-λ/-(3-Methoxybenzyl)-4-(2-(((1 R ^* ,3R ^* )-3-(3- methoxypropanamιdo)cyclohexyl)methyl)-2/-/-tetrazol-5-yl)-6 - methylpicolmamide

247 rac-λ/-(3-Methoxybenzyl)-4-(2-(((1tf ^* ,3R*)-3-(2- amιnoacetamιdo)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6- methylpicolinamide

248 rac-λ/-(3-Methoxybenzyl)-6-methyl-4-(2-(((1R*,3/ ^: ? ^* )-3-

(methylsulfonamιdo)cyclohexyl)methyl)-2/-/-tetrazol-5- yl)pιcolιnamιde

249 rac-λ/-(3-Methoxybenzyl)-4-(2-(((1 S*,3f?*)-3-amιnocyclopentyl)methyl)-

2H-tetrazol-5-yl)-6-methylpιcolιnamιde

250 rac-λ/-(3-Methoxybenzyl)-6-methyl-4-(2-(((1 S ^* ,3R ^* )-3-

(methylsulfoπamιdo)cyclopentyl)methyl)-2H-tetrazol-5- yl)pιcolιnamιde

251 rac-/V-(3-Methoxybenzyl)-4-(2-(((1 S ^* ,3/? ^* )-3-

(ethylsulfonamιdo)cyclopentyl)methyl)-2/-/-tetrazol-5-yl )-6- methylpicotinamide

252 rac-A/-(3-Methoxybenzyl)-4-(2-(((1 S ^* ,3R ^* )-3- acetamιdocyclopentyl)methyl)-2/-/-tetrazol-5-yl)-6- methylpicolinamide

253 rac-/V-(3-Methoxybenzyl)-4-(2-(((1 S* ,3R*)-3-(2- hydroxyacetamιdo)cyclopentyl)methyl)-2/-/-tetrazol-5-yl)-6- methylpicohnamide

Table 3

Example Compound Name N o.

254 rac-/V-(3-Methoxybenzyl)-4-(2-(((1 S ^* ,3/? ^* )-3-(3- hydroxypropanamιdo)cydopentyl)methyl)-2/-/-tetrazol-5-yl)-6 - methylpicolmamide

255 (trans)-Methyl 4-((5-(2-((4-fluorobenzyl)carbamoy!)-6-methylpyrιdιn-4- yl)-2H-tetrazo!-2-yl)methyl)cyclohexanecarboxylate

256 (/rans)-4-((5-(2-((4-Fluorobenzyl)carbamoyl)-6-methylpyrιdÎ ¹n-4-yl)-2H- tetrazol-2-yl)methyl)cyclohexanecarboxylιc acid

257 N-(4-Fluorobenzyl)-6-methyl-4-(2-(((frans)-4-

(methylsulfonylcarbamoyl)cydohexyl)methyl)-2H-tetrazol-5- yl)pιcolιnamιde

258 λ/-(4-Fluorobenzyl)-4-(2-(((/raπs)-4-(2-hydroxyacetyl)cycl ohexy!)methy!)-

2H-tetrazol-5-yl)-6-methylpιcolιnamιde

259 (trans)-Melhy\ 4-((5-(2-((3-(hydroxymethyl)benzyl)carbamoyl)-6- methylpyrιdιn-4-yl)-2/-/-tetrazol-2- yl)methyl)cyclohexanecarboxylate

260 (/λa/7s)-4-((5-(2-((3-(Hydroxymethyl)benzyl)carbamoyl)-6-me thylpyrιd!n-

4-yl)-2H-tetrazol-2-yl)methyl)cyclohexanecarboxylιc acιd

261 (frans)-Methyl 4-((5-(2-((3-hydroxybenzyl)carbamoyl)-6-methylpyrιdιn-4- yl)-2/-/-tetrazol-2-yl)methyl)cyclohexanecarboxylate

262 (/rans)-4-((5-(2-((3-Hydroxybenzyl)carbamoyl)-6-methylpyrιd ιn-4-yl)-2/-/- tetrazol-2-yl)methyl)cyclohexanecarboxylιc acid

263 (trans)-Methγ\ 4-((5-(2-((3-(3-methoxypropoxy)benzyl)carbamoyl)-6- methylpyrιdιn-4-yl)-2/-/-tetrazol-2- yl)methyl)cyclohexanecarboxylate

264 (frans)-4-((5-(2-((3-(3-Methoxypropoxy)benzyl)carbamoyl)-6- methylpyrιdιn-4-yl)-2H-tetrazol-2-yl)- methyl)cyclohexanecarboxylιc acid

265 (frans)-Methyl 4-((5-(2-((3,4-dιfluorobenzyl)carbamoyl)-6-methylpyrιdιn-

4-yl)-2H-tetrazol-2-yl)methyl)cyclohexanecarboxylate

266 (frans)-4-((5-(2-((3,4-Dιfluorobenzyl)carbamoyl)-6-methylpy rιdιn-4-yl)-

2H-tetrazol-2-yl)methy!)cyclohexanecarboxylιc acid

267 (fraπs)-Methyl 4-((5-(2-((3-methoxybenzyl)carbamoyl)-6-methylpyrιdιn-4- yl)-2H-tetrazol-2-yl)methyl)cyclohexanecarboxylate

268 (/raπs)-4-((5-(2-((3-Methoxybenzyl)carbamoyl)-6-methylpyπd ιn-4-yl)-2H- tetrazol-2-yl)methyl)cyclohexanecarboxylιc acid

269 λ/-(3-Methoxybenzyl)-6-methyl-4-(2-(((<rans)-4-(pιperι dιne-1 - carbonyl)cyclohexyl)methyl)-2H-tetrazol-5-yl)picolinamide

270 4-(2-(((^ans)-4-((2-Methoxyethyl)carbamoyl)cyclohexyl)methyl )-2H- tetrazol-5-yl)-λ/-(3-methoxybenzyl)-6-methylpιcolιnamιde

271 λ/-(3-Methoxybenzyl)-6-methyl-4-(2-(((<rans)-4-(morpholÎ ¹ne-4- carbonyl)cyclohexyl)methyl)-2/-/-tetrazol-5-yl)pιcolιnamι de

272 λ/-(3-Methoxybenzyl)-4-(2-(((<rans)-4-

(dιmethylcarbamoyl)cyclohexyl)methyl)-2/-/-tetrazol-5-yl )-6- methylpicolinamide

273 λ/-(3-Methoxybenzyl)-4-(2-(((^rans)-4-

(isopropylcarbamoyOcyclohexyOmethyO^W-tetrazol-S-yO-e- methylpicolinamide

274 4-(2-((((rans)-4-((2-Amιno-2-oxoethyl)carbamoyl)cyclohexyl) methyl)-2H- tetrazol-5-yl)-λ/-(3-methoxybenzyl)-6-methylpιcolιnamιde

Table 3

Example Compound Name N o.

275 /V-(3-Methoxybenzyl)-6-methyl-4-(2-(((fraπs)-4-

(methylcarbamoyOcyclohexyOmethyl^H-tetrazol-S- yl)pιcolιnamιde

276 /V-(3-Methoxybenzyl)-4-(2-(((fraπs)-4-

(ethylcarbamoyl)cyclohexyl)methyl)-2/-/-tetrazol-5-yl)-6- methylpicolinamide

277 4-(2-(((fraπs)-4-((2-Hydroxyethyl)carbamoyl)cyclohexyl)meth yl)-2H- tetrazol-5-yl)-N-(3-methoxybenzyl)-6-rnethylpιcolιnamιde

278 λ/-(3-Methoxybenzyl)-4-(2-(((/rans)-4-carbamoylcyclohexyl)m ethyl)-2/-/- tetrazol-5-yl)-6-methylpιcolιnamιde

279 λ/-(3-Methoxybenzyl)-4-(2-(((frans)-4-cyanocyclohexyl)methy l)-2H- tetrazol-5-yl)-6-methylpιcolιnamιde

280 /V-(3-Methoxybenzyl)-4-(2-(((^ar?s)-4-(2- hydroxyacetyOcyclohexyOmethyO^H-tetrazol-δ-yO-θ- methylpicolinamide

281 (trans)-Meihyl 4-((5-(2-((3-(Dιfluoromethoxy)benzyl)carbamoyl)-6- methylpyrιdιn-4-yl)-2H-tetrazol-2- yl)methyl)cyclohexanecarboxylate

282 (/ra/7s)-4-((5-(2-((3-(Difluoromelhoxy)benzyl)carbamoyl)-6-m ethylpyridin-

4-yl)-2/-/-tetrazol-2-yl)methyl)cyclohexanecarboxylιc acid

283 λ/-(3-(Dιfluoromethoxy)benzyl)-4-(2-(((<rans)-4-

(hydroxymethyl)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6- methylpicolinamide

284 (Zrans)-Methyl 4-((5-(2-((4-Fluoro-3-methylbenzyl)carbamoyl)-6- methylpyrιdιn-4-yl)-2/-/-tetrazol-2- yl)methyl)cyclohexanecarboxylate

285 (frans)-4-((5-(2-((4-Fluoro-3-methylbenzyl)carbamoyl)-6-meth ylpyrιdιn-4- yl)-2/-/-tetrazol-2-yl)methyl)cyclohexanecarboxylιc acid

286 λ/-(4-Fluoro-3-methy(benzyl)-4-(2-(((/rans)-4- carbamoylcyclohexyl)methyl)-2/-/-tetrazol-5-yl)-6- methylpicolmamide

287 λ/-(4-Fluoro-3-methylbenzyl)-4-(2-(((<rans)-4-cyanocyclo hexyl)methyl)-

2/-/-tetrazol-5-yl)-6-methylpιcolιnamιde

288 (frans)-Methy! 4-((5-(2-((3-Ethylbenzy!)carbamoyl)-6-methylpyπdιn-4-yl)-

2H-tetrazol-2-yl)methyl)cyclohexanecarboxylate

289 (frans)-4-((5-(2-((3-Ethylbenzyl)carbamoyl)-6-methylpyrιdι n-4-yl)-2A7- tetrazol-2-yl)methyl)cyclohexanecarboxylιc acid

290 λ/-(3-Ethylbenzyl)-4-(2-(((^ans)-4-carbamoylcyclohexyl)meth yl)-2H- tetrazol-5-yl)-6-methylpιcolιnamιde

291 (trans)-Me\by\ 4-((5-(2-((3-Cyanobenzyl)carbamoyl)-6-methylpyπdιn-4- yl)-2/-/-tetrazol-2-yl)methyl)cyclohexanecarboxylate

292 (frans)-4-((5-(2-((3-Cyanobenzyl)carbamoyl)-6-methylpyridin- 4-yl)-2H- tetrazol-2-yl)methyl)cyclohexanecarboxylιc acid

293 (frans)-Methyl 4-((5-(2-((3-Ethoxybenzyl)carbamoyl)-6-methylpyrιdιn-4- yl)-2H-tetrazol-2-yl)methyl)cyclohexanecarboxylate

294 (/rans)-4-((5-(2-((3-Ethoxybenzyl)carbamoyl)-6-methylpyridin -4-yl)-2H- tetrazol-2-yl)methyl)cyclohexanecarboxylιc acid

295 W-(3-Ethoxybenzyl)-4-(2-((((rans)-4-carbamoylcyclohexyl)meth yl)-2/-/- tetrazol-5-yl)-6-methylpιcolιnamιde

Table 3

Example Compound Name N o.

296 W-(3-Ethoxybenzyl)-4-(2-(((/λa/?s)-4-cyanocyclohexyl)methyl )-2H- tetrazol-5-yl)-6-methylpιcolιnamιde

297 (Zrans)-Methyl 4-((5-(2-((4-Fluoro-3-methoxybenzyl)carbamoyl)-6- methylpyrιdιn-4-yl)-2W-tetrazol-2- yl)methyl)cyclohexanecarboxylate

298 ((raπs)-4-((5-(2-((4-Fluoro-3-methoxybenzyl)carbamoyl)-6-me thylpyrιdιn-

4-yl)-2H-tetrazol-2-yl)methyl)cyclohexanecarboxylιc acid

299 N-(4-Fluoro-3-methoxybenzyl)-4-(2-(((frans)-4- carbamoylcyclohexyl )methyl )-2H-tetrazol-5-yl)-6- methylpicolinamide

300 N-(4-Fluoro-3-methoxybenzy!)-4-(2-((((rans)-4-cyanocyclohexy l)methyl)-

2H-tetrazol-5-yl)-6-methylpιcolιnamιde

301 (/raπs)-Methyl 4-((5-(2-((3-Chloro-4-f)uorobenzyl)carbamoyl)-6- methylpyπdιn-4-y!)-2H-tetrazol-2- yl)methyl)cyclohexanecarboxylate

302 (/raπs)-4-((5-(2-((3-Chloro-4-fluorobenzyl)carbamoyl)-6-met hylpyrιdιn-4- yl)-2H-tetrazo!-2-y!)methyl)cyclohexanecarboxylιc acid

303 λ/-(3-Chloro-4-fluorobenzyl)-4-(2-(((<rans)-4- carbamoylcyclohexyl)methyl)-2/-/-tetrazol-5-yl)-6- methylpicolmamide

304 λ/-(3-Chloro-4-fluorobenzyl)-4-(2-(((/rans)-4-cyanocyclohex yl)methyl)-

2AV-tetrazol-5-yl)-6-methy!pιcolιnamιde

305 (^rans)-Methyl 4-((5-(2-((4-Fluoro-3-(trιfluoromethyl)benzyl)carbamoyl)-

6-methylpyrιdιn-4-yl)-2H-tetrazol-2- yl)methyl)cyc!ohexanecarboxylate

306 (frans)-4-((5-(2-((4-Fluoro-3-(tnfluoromethyl)benzyl)carbamo yl)-6- methylpyrιdιn-4-yl)-2H-tetrazol-2- yl)methyl)cyclohexanecarboxylιc acid

307 λ/-((2,3-Dιhydrobenzofuran-5-yl)methyl)-4-(2-(((^aπs)-4-

(hydroxymethyl)cyclohexyl)methyl)-2/-/-tetrazol-5-yl)-6- methylpicohnamide

308 W-(3-(Trιfluoromethyl)benzyl)-4-(2-(((frans)-4-

(hydroxyme(hyl)cyclohexyl)methyl)-2/-/-tetrazol-5-yl)-6- methylpicolinamide

309 /V-(3-(TÏ€fluoromethoxy)benzy!)-4-(2-(((/rans)-4-

(hydroxymethyl)cyclohexyl)methyl)-2/-/-tetrazol-5-yl)-6- methylpicolinamide

310 W-(3-Ch!orobenzyl)-4-(2-(((^rans)-4-(hydroxymethyl)cyclohexy l)methyl)-

2/-/-tetrazol-5-yl)-6-methylpιco!ιnamιde

31 1 N-(3-Methylbenzyl)-4-(2-(((/rans)-4-(hydroxymethyl)cyclohexy l)methyl)-

2H-tetrazol-5-yl)-6-methylpιcolιnamιde

312 λ/-(3-Ethylbenzyl)-4-(2-(((frans)-4-(hydroxymethyl)cyclohex yl)methyl)-

2H-tetrazo!-5-yl)-6-methylpιcolιnamιde

313 W-(3-lsopropoxybenzyl)-4-(2-(((fraπs)-4-

(hydroxymethyl)cyc!ohexyl)methyl)-2/-/-tetrazol-5-yl)-6- methylpicolinamide

314 λ/-(3-Ethoxybenzyl)-4-(2-(((/λaπs)-4-(hydroxymethyl)cyclo hexyl)methyl)-

2H-tetrazol-5-yl)-6-methylpιcolιnamιde

Table 3

Example Compound Name N o.

315 /V-(3,4-Dιfluorobenzyl)-4-(2-(((frans)-4-

(hydroxymethyl)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6- methylpicolinamide

316 /V-(4-Fluoro-3-methylbenzyl)-4-(2-(((fraπs)-4-

(hydroxymethyl)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6- methylpicolmamide

317 N-(4-FlÏ…oro-3-(tnflÏ…oromethy\)benzy\)-4-(2-(((trans)-4-

(hydroxymethyl)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6- methylpicolmamide

318 λ/-(3-(Hydroxymethyl)benzyl)-4-(2-(((to3/?s)-4-

(hydroxymethyl)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6- methylpicolinamide

319 W-(3-Hydroxybenzy!)-4-(2-(((/λ3/7s)-4-

(hydroxymethyl)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6- methylpicolmamide

320 λ/-(3-Fluoro-5-methoxybenzyl)-4-(2-(((/rans)-4-

(hydroxymethyl)cyclohexy!)methy!)-2H-tetrazo!-5-yl)-6- methylpicolmamide

321 /V-((2,3-Dihydrobenzofuran-6-yl)methyl)-4-(2-(((<rans)-4-

(hydroxymethyl)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6- methylpicolmamide

322 λ/-(3-Methoxybenzyl)-4-(2-(((^ans)-4-

(hydroxymethyl)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6- methylpicolmamide

323 λ/-(4-Fluoro-3-methoxybenzyl)-4-(2-(((trans)-4-

(hydroxymethyl)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6- methylpicolinamide

324 λ/-(3-Bromobenzyl)-4-(2-(((fraπs)-4-(hydroxymethyl)cyclohe xyl)methyl)-

2/-/-tetrazol-5-yl)-6-methylpιcolιnamιde

325 λ/-(3-(2-Hydroxyethoxy)benzyl)-4-(2-(((^rans)-4-

(hydroxymethyl)cyclohexyl)methyl)-2/-/-tetrazol-5-yl)-6- methylpicolinamide

326 λ/-(3-Propoxybenzyl)-4-(2-(((<rans)-4-

(hydroxymethyl)cyclohexyl)methyl)-2/-/-tetrazol-5-yl)-6- methylpicolinamide

327 λ/-((2,3-Dιhydrobenzo[b][1 ,4]dιoxιn-6-yl)methyl)-4-(2-(((/raπs)-4-

(hydroxymethyl)cyclohexyl)methyl)-2/-/-tetrazol-5-yl)-6- methylpicolmamide

328 4-(2-(((frans)-4-(Hydroxymethyl)cyclohexyl)methyl)-2H-tetraz ol-5-yl)-W-

((2-methoxypyrιdιn-4-yl)methyl)-6-methylpιcolιnamιde

329 λ/-(4-Fluoroben2yl)-4-(2-(((^aπs)-4-(hydroxymethyl)cyclohe xyl)methyl)-

2/-/-tetrazol-5-yl)-6-methylpιco!ιnamιde

330 λ/-(3-Methoxybenzyl)-4-(2-(((c/s)-4-(hydroxymethyl)cyclohex yl)methyl)-

2W-tetrazol-5-yl)-6-methy!pιcolιnamιde

331 λ/-(3-Methoxybenzyl)-4-(2-(((fraÏ€s)-4-(2-hydroxypropan-2- yl)cyclohexyl)methy!)-2H-tetrazol-5-yl)-6-methylpιco!ιnamÎ ¹de

332 /V-(4-F!uoro-3-methoxybenzyl)-4-(2-(((frans)-4-(2-hydroxypro pan-2- yOcyclohexyOmethy^^H-tetrazol-S-yO-θ-methylpicolinamide

333 W-(3-Methoxybenzyl)-4-(2-(((frans)-4-hydroxycyclohexy!)methy l)-2H- tetrazol-5-yl)-6-methylpιcolιnamιde

Table 3

Example Compound Name N o.

334 W-(3-Methoxybenzyl)-4-(2-(((c/s)-4-hydroxycyclohexyl)methyl) -2AV- tetrazol-5-yl)-6-methylpιcolιnamιde

335 λ/-(4-Fluoro-3-methylbenzyl)-4-(2-(((/λans)-4-hydroxycyclo hexyl)methyl)-

2/-/-tetrazol-5-yl)-6-methylpιcolιnamιde

336 N-(4-Fluoro-3-methylbenzyl)-4-(2-(((cιs)-4-hydroxycyclohexy l)methyl)-

2f/-tetrazol-5-yl)-6-methylpιcolιnamιde

337 /V-(3-Chloro-4-fluorobenzyl)-4-(2-(((/rans)-4-hydroxycyclohe xyl)methyl)-

2H-tetrazol-5-y!)-6-methylpιcolιnamιde

338 λ/-(3-Chloro-4-fluorobenzyl)-4-(2-(((c/s)-4-hydroxycyclohex yl)methyl)-

2/-/-tetrazol-5-yl)-6-methylpιcolιnamιde

339 λ/-(3-Ethoxybenzyl)-4-(2-((((rans)-4-hydroxycyclohexyl)meth yl)-2H- tetrazol-5-yl)-6-methylpιcolιnamιde

340 A/-(4-Fluoro-3-methoxybenzyl)-4-(2-(((^aπs)-4- hydroxycyclohexyl)methyl)-2H-tetrazot-5-yt)-6- methylpicolinamide

341 rac-λ/-(4-Fluoro-3-methoxybenzyl)-6-methyl-4-(2-((3- oxocyclopentyl)methyl)-2/-/-tetrazol-5-yl)pιcolιnamιde

342 rac-λ/-(4-Fluoro-3-methoxybenzyl)-4-(2-(((1R ^* ,3R ^* )-3- hydroxycyclopentyl)methyl)-2H-tetrazol-5-yl)-6- methylpicolinamide

343 λac-λ/-(4-Fluoro-3-methoxybenzy!)-4-(2-(((1 R ^* ,3S ^* )-3- hydroxycyclopentyl)methyl)-2/-/-tetrazol-5-yl)-6- methylpicohnamide

344 λ/-(3-Methoxybenzyl)-4-(2-(((c/s)-4-hydroxy-4-

(hydroxymethyl)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6- methylpicolinamide

345 λ/-(3-Methoxybenzyl)-4-(2-(((<raπs)-4-hydroxy-4-

(hydroxymethyl)cyclohexyl)methyl)-2/7-tetrazol-5-yl)-6- methylpicolmamide

346 λ/-(3-(2-Hydroxyethoxy)benzyl)-6-methyl-4-(2-(((frans)-4-

(methylsulfonylmethyl)cyclohexyl)methyl)-2H-tetrazol-5- yl)pιcolιnamιde

347 λ/-(3-Hydroxybenzyl)-6-methyl-4-(2-(((/rans)-4-

(methylsulfonylmethyl)cyclohexyl)methyl)-2H-tetrazol-5- yl)picolinamide

348 W-(3-Chloro-4-fluorobenzyl)-6-methyl-4-(2-(((<rans)-4-

(methylsulfonylmethyl)cyclohexyl)methyl)-2/-/-tetrazol-5- yl)pιcolιnamιde

349 λ/-(4-Fluoro-3-methoxybenzyl)-6-methyl-4-(2-(((/rans)-4-

(methylsulfonylmethyl)cyclohexyl)methyl)-2H-tetrazol-5- yOpicolinamide

350 λ/-(3-(Hydroxymethyl)benzyl)-6-methyl-4-(2-(((frans)-4-

(methylsu!fony!methyl)cyc!ohexyl)methyl)-2H-tetrazol-5- yl)pιcolιnamιde

351 /V-(3-Methoxybenzyl)-4-(2-(((frans)-4-(amιnomethyl)cyclohex yl)methyl)-

2H-tetrazol-5-yl)-6-methylpιcolιnamιde

352 W-(3-Methoxybeπzyl)-4-(2-(((^aπs)-4-

(acetamidomethyOcyclohexyOmethyO^H-tetrazol-δ-yO-θ- methylpicolinamide

Table 3

Example Compound Name N o.

353 N-(3-Melhoxybenzy\)-6-methy\-4-(2-(((trans)-4-

(methylsulfonamιdomethyl)cyclohexyl)methyl)-2/-/-tetrazo l-5- yl)pιcolιnamιde

354 /V-(4-Fluoro-3-methoxybenzyl)-4-(2-(((//-3A7s)-4-

(aminomethyl)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6- methylpicolinamide

355 / ^• ac-λ/-(3-Methoxybenzyl)-4-(2-(((1/? ^* ,3S ^* )-3-

(hydroxymethyl)cyclopentyl)methyl)-2/-/-tetrazol-5-yl)-6- methylpicohnamide

356 rac-λ/-(3-Methoxybenzyl)-4-(2-(((1 R*,3S ^* )-3-

(amιnomethyl)cyclopentyl)methyl)-2/-/-tetrazol-5-yl)-6- methylpicolmamide

357 rac-/V-(3-Methoxybenzyl)-6-methyl-4-(2-(((1 FT ,3S ^* )-3-

(methy!su!fonamιdomethyl)cyclopentyl)methyl)-2H-tetrazol -5- yl)pιcolιnamιde

358 A/-(3-Methoxybenzyl)-6-methyl-4-(2-((S)-pιperιdιn-3-ylmet hyl)-2H- tetrazo!-5-yl)pιcolιnamιde

359 λ/-(3-Methoxybenzyl)-6-methyl-4-(2-(((f?)-1-(methylsulfonyl )pιperιdιn-3- yl)methyl)-2H-tetrazol-5-yl)pιcolιnamιde

360 λ/-(3-Methoxybenzyl)-4-(2-(((S)-1-acetylpιperιdιn-3-y!)Î ¹nnethy!)-2H- tetrazol-5-yl)-6-methylpιcolιnamιde

361 λ/-(3-Methoxybenzyl)-6-methyl-4-(2-((f?)-pιperιdιn-3-ylm ethyl)-2H- tetrazol-5-yl)pιcolιnamιde

362 λ/-(3-Methoxybenzyl)-6-methyl-4-(2-(((S)-1 -(methylsulfonyl)pιperιdιn-3- yl)methyl)-2H-tetrazol-5-yl)pιcolιnamιde

363 λ/-(3-Methoxybenzyl)-4-(2-(((R)-1-acetylpιperιdιn-3-yl)m ethyl)-2H- tetrazol-5-yl)-6-methylpιcolιnamιde

364 λ/-(4-Fluoro-3-methoxybenzyl)-6-methyl-4-(2-((S)-pιperιdÎ ¹n-3-ylmethyl)-

2/-/-tetrazol-5-yl)pιcolιnamιde

365 λ/-(4-Fluoro-3-methoxybenzyl)-6-methyl-4-(2-(((R)-1 -

(methylsulfonyl)pιperιdιn-3-yl)methyl)-2/-/-tetrazol-5 - yl)pιcolιnamιde

366 λ/-(4-Fluoro-3-methoxybenzyl)-4-(2-(((S)-1 -acetylpιperιdιn-3-yl)methy!)-

2/-/-tetrazol-5-yl)-6-methylpιcolιnamιde

367 A/-(4-Fluoro-3-methoxybenzyl)-6-methyl-4-(2-((R)-pipendin-3- ylmethyl)-

2/-/-tetrazol-5-yl)pιcolιnamιde

368 λ/-(4-Fluoro-3-methoxybenzyl)-6-methyl-4-(2-(((S)- 1 -

(methylsulfonyl)pιperιdιn-3-yl)methyl)-2/-/-tetrazol-5 - yl)pιcolιnamιde

369 N-(4-Fluoro-3-methoxybenzyl)-4-(2-(((R)-1 -acetylpιperιdιn-3-yl)methyl)-

2/-/-tetrazol-5-yl)-6-methylpιcolιnamιde

370 λ/-(4-Fluoro-3-methoxybenzyl)-6-methyl-4-(2-((f?)-pyrrolιd ιn-3-ylmethyl)-

2H-tetrazol-5-yl)pιcolιnamιde

371 λ/-(4-Fluoro-3-methoxybenzyl)-6-methyl-4-(2-(((S)-1-

(methylsulfonyl)pyrrolιdιn-3-yl)methyl)-2H-tetrazol-5- yl)pιcolιnamιde

372 W-(4-Fluoro-3-methoxybenzyl)-4-(2-(((f?)-1-acetylpyrrolιdι n-3-yl)methyl)-

2/-/-tetrazol-5-yl)-6-methylpιcolιnamιde

373 2-((f?)-3-((5-(2-((4-Fluoro-3-methoxybenzyl)carbamoyl)-6-met hylpyrιdιn-

4-yl)-2W-tetrazol-2-yl)methyl)pyrrolιdιn-1-yl)-2-oxoeth yl acetate

Table 3

Example Compound Name N o.

374 λ/-(4-Fluoro-3-methoxybenzyl)-4-(2-(((f?)-1-(2-hydroxyacety l)pyrrolιdιπ-3- yl)methyl)-2H-tetrazol-5-yl)-6-methylpιcolιnamιde

375 rac-λ/-(4-Fluoro-3-methoxybenzyl)-4-(2-((1-benzyl-5-oxopyrr olιdιn-3- yl)methyl)-2AY-tetrazol-5-yl)-6-rr)efhylpιcolιnamιde

376 N-(3-(2-Hydroxyethoxy)benzyl)-6-methyl-4-(2-((1 -

(methylsulfonyl)pιperιdιn-4-yl)methyl)-2/-/-tetrazol-5 - yl)pιcolιnamιde

377 λ/-(3-Ethoxybenzyl)-6-methyl-4-(2-((1-(methylsulfonyl)pιpe πdιn-4- yl)methyl)-2A7-tetrazol-5-yl)pιcolιnamιde

378 W-(4-Fluoro-3-methylbenzyl)-6-methyl-4-(2-((1-(methylsulfony l)pιperιdιn-

4-yl)methyl)-2H-tetrazol-5-yl)pιcolιnamιde

379 λ/-(3-Methoxybenzyl)-6-methyl-4-(2-(pιperιdιn-4-ylmethyl )-2/-/-tetrazol-5- yl)pιco!ιnamιde

380 λ/-(3-Methoxybenzyl)-4-(2-((1-(2-hydroxy-2-methylpropanoyl) pιperιdιn-4- yl)methyl)-2/-/-tetrazol-5-yl)-6-methylpιcolιnamιde

381 λ/-(3-Methoxybenzyl)-4-(2-((1-(3-amιnopropanoyl)pιperιdÎ ¹n-4-yl)methyl)-

2/-/-tetrazoϊ-5-yl)-6-methylpιcolιnamιde

382 λ/-(3-Methoxybenzyl)-4-(2-((1-(2-amιnoacetyl)pιperιdιn- 4-yl)methyl)-2H- tetrazol-5-yl)-6-methylpιcolιnamιde

383 λ/-(3-Me(hoxybenzyl)-4-(2-((1-acetylpιperιdιn-4-yl)methy l)-2/-/-tetrazol-5- yl)-6-methylpιcolιnamιde

384 W-(3-Methoxybenzy!)-6-methyl-4-(2-((1-(methylsulfony!)pιper ιdιn-4- yl)methyl)-2/-/-tetrazol-5-yl)pιcolιnamιde

385 λ/-(3-Methoxybenzyl)-4-(2-((1 -ιsobutyrylpιperιdιn-4-yl)methyl)-2/-/- tetrazol-5-yl)-6-methylpιcolιnamιde

386 λ/-(3-Methoxybenzyl)-6-methyl-4-(2-((1-(methylcarbamoyl)pι perιdιn-4- yl)methyl)-2H-tetrazol-5-yl)pιcolιnamιde

387 W-(3-Chloro-4-fluoroben2yl)-6-methyl-4-(2-(pιpeπdιn-4-ylm e»hyl)-2/-/- tetrazol-5-yl)pιcolιnamιde

388 λ/-(3-Chloro-4-fluorobenzyl)-6-methyl-4-(2-((1-(methylsulfo ny!)pιperιdιn-

4-yl)methy))-2H-tetrazol-5-yl)pιcolιnamιde

389 λ/-(4-Fluoro-3-(trιfluoromethyl)benzyl)-6-methyl-4-(2-(pι perιdιn-4- ylmethyl)-2/-/-tetrazol-5-yl)pιcolιnamιde

390 W-(4-F!uoro-3-(tπfluoromethyl)benzyl)-6-methyl-4-(2-((1-

(methylsulfonyl)pιperιdιn-4-yl)methyl)-2H-tetrazol-5- yl)pιcolιnamιde

391 /V-(4-Fluoro-3-methoxybenzyl)-6-methyl-4-(2-(pιpeπdιn-4-y lmethyl)-2/-/- tetrazol-5-yl)pιcolιnamιde

392 λ/-(4-Fluoro-3-methoxybenzyl)-6-methyl-4-(2-((1-

(methylsulfonyl)pιperιdιn-4-yl)methyl)-2W-tetrazol-5- yOpicolinamide

393 A/-(4-Fluoro-3-methoxybenzyl)-6-methyl-4-(2-((R)-morpholιn- 2-ylmethyl)-

2/-/-tetrazol-5-yl)pιcolιnamιde

394 /V-(4-Fluoro-3-methoxybenzyl)-4-(2-(((R)-4-acetylmorpholιn- 2-yl)methyl)-

2H-tetrazol-5-yl)-6-methylpιco!ιnamιde

395 /V-(4-Fluoro-3-methoxybenzyl)-6-methyl-4-(2-((S)-morpholιn- 2-y!methyl)-

2H-tetrazol-5-yl)pιcolιnamιde

396 A/-(4-F!uoro-3-methoxybenzyl)-4-(2-(((S)-4-acetylmorpholιn- 2-yl)methy!)-

2/-/-tetrazol-5-yl)-6-methylpιcolιnamιde

Table 3

Example Compound Name N o.

397 λ/-(4-Fluoro-3-methoxybenzyl)-6-methy!-4-(2-(((R)-4-

(methylsulfonyl)morpholιn-2-yl)methyl)-2H-tetrazol-5- yl)pιcolιnamιde

398 λ/-(3-Methoxybenzyl)-6-methyl-4-(2-((S)-morpholιn-2-ylmeth yl)-2AV- tetrazo!-5-yl)ptcolιnamιde

399 λ/-(3-Methoxybenzyl)-4-(2-(((S)-4-acetylmorpholιn-2-yl)met hyl)-2H- tetrazol-5-yl)-6-methylpιcolιnamιde

400 λ/-(3-Methoxybenzy!)-6-methyl-4-(2-(((R)-4-(methylsu!fonyl) morpholιn-2- yl)methyl)-2H-tetrazol-5-yl)pιcolιnamιde

401 rac-4-(2-((1 ,4-Dιoxan-2-yl)methyl)-2/ ^L /-tetrazol-5-yl)-A/-(4-fluoro-3- methoxybenzyl)-6-methylpιcolιnamιde

402 rac-4-(2-((1 ,4-Dιoxan-2-yl)methyl)-2/-/-tetrazol-5-yl)-λ/-(4-fluoro-3- methylbenzyl)-6-methylpιcolιnamιde

403 rac-λ/-(3-Methoxybenzyl)-4-(2-(((2S*,5R*)-5-(hydroxymethy!) -1 ,4-dιoxan-

2-yl)methyl)-2/-/-tetrazol-5-yl)-6-methylpιcolιnamιde

404 λ/-(3-Methoxybenzyl)-4-(2-(((2S,5R)-5-(hydroxymethyl)- 1 ,4-dιoxan-2- yl)methyl)-2/-/-tetrazol-5-y!)-6-methylpιcolιnamιde

405 λ/-(3-Methoxybenzyl)-4-(2-(((2f?,5S)-5-(hydroxymethyl)-1 ,4-dιoxan-2- yl)methyl)-2AV-tetrazol-5-yl)-6-methylpιcolιnamιde

406 rac-(2S ^* ,5S ^* )-Methyl 5-((5-(2-((3-methoxybenzyl)carbamoyl)-6- methylpyrιdιn-4-yl)-2/-/-tetrazol-2-yl)methyl)-1 ,4-dιoxane-2- carboxylate

407 rac-(2S*,5S*)-5-((5-(2-((3-Methoxybenzyl)carbamoy!)-6-methyl pyrιdιn-4- yl)-2H-tetrazol-2-yl)methyl)-1 ,4-dιoxane-2-carboxylιc acid

408 rac-/V-(3-Methoxybenzy!)-4-(2-(((2S*,5S*)-5-(2-hydroxypropan -2-yl)-1 ,4- dιoxan-2-yl)methyl)-2/-/-tetrazol-5-yl)-6-methylpιcolιnam ιde

409 rac-/V-(3-Methoxybenzyl)-4-(2-(((2S*,5S ^* )-5-carbamoyl-1 ,4-dιoxan-2- yl)methyl)-2H-tetrazol-5-yl)-6-methylpιcolιnamιde

410 rac-N-(3-Methoxybenzyl)-4-(2-(((2S*,5S ^* )-5-cyano-1 ,4-dιoxan-2- yl)methyl)-2/-/-tetrazol-5-y!)-6-methylpιcolιnamιde

41 1 rac-λ/-(3-Methoxybenzyl)-4-(2-(((2S*,5/?*)-5-cyano-1 ,4-dιoxan-2- yl)methyl)-2/-/-tetrazol-5-yl)-6-methylpιcolιnamιde

412 rac-λ/-(4-Fluoro-3-methoxybenzyl)-4-(2-(((2S*,5f? ^* )-5-(hydroxymethyl)-

1 ,4-dioxan-2-yl)methyl)-2W-(etrazol-5-yl)-6-methylpicolinamid e

413 rac-(2S ^* ,5S ^* )-Methyl 5-((5-(2-((4-fluoro-3-methoxybenzyl)carbamoyl)-6- methylpyrιdιn-4-yl)-2/-/-tetrazol-2-yl)methyl)-1 ,4-dιoxane-2- carboxylate 14 rac-(2S*,5S ^* )-5-((5-(2-((4-Fluoro-3-methoxybenzyl)carbamoyl)-6- methylpyrιdιn-4-yl)-2/-/-tetrazol-2-yl)methyl)-1 ,4-dιoxane-2- carboxylic acid 15 rac-λ/-(4-Fluoro-3-methoxybenzyl)-4-(2-(((2S*,5S ^* )-5-(2-hydroxypropan-

2-yl)-1 ,4-dιoxan-2-yl)methyl)-2H-tetrazol-5-yl)-6- methylpicolmamide 16 rac-A/-(4-Fluoro-3-methoxybenzyl)-4-(2-(((2S*,5S*)-5-carbamo yl-1 ,4- dιoxan-2-yl)methyl)-2/-/-tetrazol-5-yl)-6-methylpιcolιnam ιde 17 rac-λ/-(4-Fluoro-3-methoxybenzyl)-4-(2-(((2S*,5S*)-5-cyano- 1 ,4-dιoxan-

2-yl)methyl)-2H-tetrazol-5-yl)-6-methylpιcolιnamιde 18 rac-N-(4-F!uoro-3-methoxybenzy!)-4-(2-(((2S ^* ,5R ^* )-5-cyano-1 ,4-dιoxan-

2-yl)methyl)-2/-/-tetrazol-5-yl)-6-methylpιcolιnamιde

Table 3

Example Compound Name N o.

419 rac-λ/-(4-Fluoro-3-methoxybenzyl)-4-(2-(((2S*,5S ^* )-5-(2-hydroxyacetyl)-

1 ,4-dιoxan-2-yl)methyl)-2H-tetrazol-5-yl)-6-methylpιcolιna mιde

420 rac-(2S*,5S*)-Methyl 5-((5-(2-((3-chloro-4-fluorobenzyl)carbamoyl)-6- methylpyndin-4-yl)-2AV-tetrazol-2-yl)methyl)- 1 ,4-dιoxane-2- carboxylate

421 rac-(2S ^* ,5S ^* )-5-((5-(2-((3-Chloro-4-fluorobenzyl)carbamoyl)-6- methylpyπdιn-4-yl)-2W-tetrazol-2-yl)methyl)-1 ,4-dιoxane-2- carboxylic acid

422 rac-λ/-(3-Methoxybenzyl)-4-(2-(((2R*,5S ^* )-5-(amιnomethyl)-1 ,4-dιoxan-

2-yl)methyl)-2/-/-tetrazol-5-yl)-6-methylpιcolιnamιde

423 rac-N-(3-Methoxybenzyl)-6-methyl-4-(2-(((2R ^* ,5S ^* )-5-

(methylsulfonamιdomethyl)-1 ,4-dιoxan-2-yl)methyl)-2H-tetrazol- 5-yl)pιcolιnamιde

424 rac-λ/-(3-Methoxybenzyl)-4-(2-(((2/?*,5S*)-5-(acetamιdomet hyl)-1 ,4- dιoxan-2-yl)methyl)-2H-tetrazol-5-yl)-6-methylpιcolιnamι de 25 W-(3-Methoxybenzyl)-6-methyl-4-(2-((tetrahydrofuran-2-yl)met hyl)-2H- tetrazol-5-yl)pιcolιnamιde 26 λ/-(4-Fluoro-3-methylbenzyl)-6-methyl-4-(2-((tetrahydro-2H- pyran-4- yl)methyl)-2H-tetrazol-5-yl)pιcolιnamιde 27 rac-λ/-(3-Methoxybenzyl)-6-methyl-4-(2-((tetrahydro-2H-pyra n-2- yl)methyl)-2/-/-tetrazol-5-yl)pιcolιnamιde 28 (-)-λ/-(3-Methoxybenzyl)-6-methyl-4-(2-((tetrahydro-2A7-pyr an-2- yl)methyl)-2H-tetrazol-5-yl)pιcolιnamιde 29 (+)-λ/-(3-Methoxybenzyl)-6-methyl-4-(2-((tetrahydro-2/-/-py ran-2- yl)methyl)-2H-tetrazol-5-yl)pιcolιnamιde 30 rac-λ/-(4-Fluoro-3-methoxybenzyl)-6-methyl-4-(2-((tetrahydr o-2/-/-pyran-

2-yl)methyl)-2H-tetrazol-5-yl)pιcolιnamιde 31 rac-λ/-(4-Fluoro-3-methylbenzy!)-6-methyl-4-(2-((tetrahydro -2H-pyran-2- yl)methyl)-2H-tetrazol-5-yl)pιcolιnamιde 32 rac-λ/-(4-Fluoro-3-methoxybenzyl)-6-methyl-4-(2-((tetrahydr o-2/-/-pyran-

3-yl)methyl)-2H-tetrazol-5-yl)pιcolιnamtde 33 rac-λ/-(3-Methoxybenzyl)-6-methyl-4-(2-(( ⁽ etrahydro-2H-pyran-3- yl)methyl)-2H-tetrazol-5-yl)pιcolιnamιde 34 rac-/V-(4-Fluoro-3-methoxybenzyl)-4-(2-(((2S*,5/? ^* )-5-hydroxy- tetrahydro-2H-pyran-2-yl)methyl)-2H-tetrazol-5-yl)-6- methylpicolinamide 35 λ/-(4-Fluoro-3-methoxybenzyl)-4-(2-((1 S ^* ,2S*,4f? ^* )-7-oxa- bιcyclo[2 2 1]heptan-2-ylmethyl)-2H-tetrazol-5-yl)-6- methylpicolmamide 36 Ethyl 4-((5-(2-((3-Methoxybenzyl)carbamoyl)-6-methylpyÏ€dιn-4-yl) -2/-/- tetrazol-2-yl)methyl)bιcyclo[2 2 2]octane-1-carboxylate 37 4-((5-(2-((3-Methoxybenzyl)carbamoyl)-6-methylpyrιdιn-4-yl )-2H- tetrazol-2-yl)methyl)bιcyclo[2 2 2]octane-1-carboxylιc acid38 W-(3-Methoxybenzyl)-4-(2-((4-(hydroxymethyl)bιcyclo[2 2 2]octan-1- yl)methy!)-2H-tetrazol-5-yl)-6-methylpιcolιnamιde 39 4-(2-((4-(Hydroxymethyl)pentacyclo[4 2 0 O ²⁵ O ^{3 β} O ^{4 7} ]oct-1 -yl)methyl)-

2/-/-tetrazol-5-yl)-λ/-(3-methoxybenzyl)-6-methylpyrιdÎ ¹ne-2- carboxamide 40 4-((5-(2-(((3-Methoxybenzyl)amιno)carbonyl)-6-methylpyrιdÎ ¹n-4-yl)-2/-/- tetrazol-2-yl)methyl)cubane-1-carboxylιc acid

Table 3

Example Compound Name N o.

441 4-(2-((4-(Amιnocarbony!)pentacyclo[4 2 0 O ²⁵ O ^{3 8} O ^{4 7} ]oct-1-yl)methyl)-

2H-tetrazol-5-yl)-/V-(3-methoxybenzyl)-6-methylpyrιdιne -2- carboxamide

442 4-(2-((4-Cyanopentacyclo[4 2 0 O ^{2 5} O ^{3 8} O ^{4 7} ]oct-1-yl)methyl)-2H-tetrazol-

5-yl)-N-(3-methoxybenzyl)-6-methylpyπdιne-2-carboxamιd e

443 λ/-(3-Methoxybenzyl)-6-methyl-4-(2-((S)-3-methylbutan-2-yl) -2H- tetrazol-5-yl)pιcolιnamιde

444 λ/-(4-Fluoro-3-methoxybenzyl)-4-(2-((R)-3-hydroxy-2-methylp ropyi)-2H- tetrazol-5-yl)-6-methylpιcolιnamιde

445 W-(4-Fluoro-3-methoxybenzyl)-4-(2-((S)-3-hydroxy-2-methylpro pyl)-2H- tetrazol-5-yl)-6-methylpιcolιnamιde

446 λ/-(4-Fluoro-3-methylbenzyl)-4-(2-ιsobutyl-2H-tetrazol-5-y l)-6- mefhylpicolinamide

447 N-(4-Fluoro-3-methoxybenzyl)-4-(2-ιsobutyl-2H-tetrazol-5-yl )-6- methylpicolmamide

448 /V-(3-Methoxybenzyl)-4-(2-ιsobutyl-2AY-tetrazol-5-yl)-6- methylpicohnamide

449 6-((4-(2-lsobutyl-2/-/-tetrazol-5-yl)-2-methylpιcolιnamιd o)methyl)-1 /-/- ιndole-2-carboxamιde

450 λ/-(3-me(hoxybenzyl)-4-(1 -(((fraπs)-4-amιnocyclohexyl)methyl)-1 H-1 ,2,4- trιazol-3-yl)-6-methylpιcolιnamιde

451 λ/-(3-Methoxybenzyl)-6-methyl-4-(1-(((fraπs)-4-

(methylsulfonamιdo)cyclohexyl)methyl)-1 H- 1 ,2,4-trιazol-3- yl)pιcolιnamιde

452 λ/-(3-Methoxybenzyl)-4-(1 -(((<rans)-4-acetamιdocyclohexyl)methy!)-1/-/-

1 ,2,4-trιazol-3-yl)-6-methylpιcolιnamιde

453 2-((^ans)-4-((3-(2-((3-Methoxybenzyl)carbamoyl)-6-methylpyrÎ ¹dιn-4-yl)-

1H-1 ,2,4-trιazol-1 -yl)methyl)cyclohexylamιno)-2-oxoethyl acetate

454 λ/-(3-Methoxybenzyl)-4-(1-(((frans)-4-(2- hydroxyacetamιdo)cyc!ohexyl)methy!)-1 H-1 ,2,4-tπazol-3-yl)-6- methylpicohnamide

455 /V-(4-Fluoro-3-methoxybenzyl)-4-(1 -(((/rans)-4-amιnocyclohexyl)methyl)-

1H-1 ,2,4-trιazol-3-yl)-6-methylpιcolιnamιde 56 λ/-(4-Fluoro-3-methoxybenzyl)-6-methyl-4-(1-(((<rans)-4-

(methylsulfonamido)cyclohexyl)methy!)-1H-1 ,2,4-triazol-3- yOpicolmamide 57 W-(4-Fluoro-3-methoxybenzyl)-4-(1 -({(trans)-4- acetamιdocyclohexyl)methyl)-1 H-λ ,2,4-trιazol-3-yl)-6- methylpicolmamide 58 2-((frans)-4-((3-(2-((4-Fluoro-3-methoxybenzyl)carbamoyl)-6- methylpyrιdιn-4-y|)-1 H-1 ,2,4-trιazol-1 - yl)methyl)cyclohexylamιno)-2-oxoethyl acetate 59 Ay-(4-Fluoro-3-methoxybenzyl)-4-(1-(((^aπs)-4-(2- hydroxyacetamιdo)cyclohexyl)methyl)-1 H-1 ,2,4-trιazol-3-yl)-6- methylpicolinamide 60 W-(4-Fluoro-3-methylbenzyl)-4-(1 -((((rans)-4-amιnocyclohexyl)methyl)-

1 H-1 ,2,4-trιazol-3-yl)-6-methylpιcolιnamιde

Table 3

Example Compound Name N o.

461 λ/-(4-Fluoro-3-methylbenzyl)-6-methyl-4-(1-(((frans)-4-

(methylsulfonamιdo)cyclohexyl)methyl)-1 H- 1 ,2,4-trιazol-3- yl)picolinamide

462 λ/-(4-Fluoro-3-methylbenzyl)-4-(1-(((/λa/?s)-4- acetamidocyclohexyl)methyl)-1H-1 ,2,4-triazol-3-yl)-6- methylpicolinamide

463 2-((/rans)-4-((3-(2-((4-Fluoro-3-methylbenzyl)carbamoyl)-6- methylpyrιdιn-4-yl)-1H-1 ,2,4-trιazol-1- yl)methyl)cyclohexylamιno)-2-oxoethyl acetate

464 N-(4-Fluoro-3-methylbenzyl)-4-(1-(((/rans)-4-(2- hydroxyacetamιdo)cyclohexyl)methyl)-1H-1 ,2,4-trιazol-3-yl)-6- methylpicohnamidemide

465 λ/-(3-Methoxybenzyl)-4-(1-(((trans)-4-

(hydroxymethyl)cyclohexyl)methyl)-1 H- 1 ,2,4-trιazol-3-yl)-6- methylpicolmamide

466 rac-λ/-(3-Methoxybenzyl)-4-(1 -(((2S*,5/? ^* )-5-(hydroxymethyl)-1 ,4-dιoxan-

2-yl)methyl)-1H-1 ,2,4-trιazol-3-yt)-6-methylpιcolιnamιde

467 rac-λ/-(4-Fluoro-3-methoxybenzyl)-4-(1-(((2S* ₎ 5fr)-5-(hydroxymethyl)-

1 ,4-dιoxan-2-yl)methyl)-1H-1 ,2,4-trιazol-3-yl)-6- methylpicolinamide

468 rac-λ/-(4-Fluoro-3-methylbenzyl)-4-(1 -(((2S*,5R ^* )-5-(hydroxymethyl)-1 ,4- dιoxan-2-yl)methyl)-1H-1 ,2,4-trιazol-3-yl)-6-methylpιcolιnamιde

Another embodiment of the invention is a pharmaceutical composition comprising a compound as described heremabove, or a pharmaceutically acceptable salt thereof, admixed with a pharmaceutically acceptable carrier, excipient, or diluent Another embodiment of the invention is a method for inhibiting an MMP-13 enzyme in an animal, comprising administering to the animal an MMP-13 inhibiting amount of a compound described heremabove, or a pharmaceutically acceptable salt thereof

Another embodiment of the invention is a method for treating a disease mediated by an MMP- 13 enzyme, comprising administering to a patient suffering from such a disease a nontoxic effective amount of a compound described heremabove, or a pharmaceutically acceptable salt thereof

Another embodiment of the invention is a method for treating arthritis, comprising administering to a patient suffering from an arthritis disease a nontoxic antiarthritic effective amount of a compound described heremabove, or a pharmaceutically acceptable salt thereof

Another embodiment of the invention is a method for treating osteoarthritis, comprising administering to a patient suffering from osteoarthritis a nontoxic effective amount of a compound described heremabove, or a pharmaceutically acceptable salt thereof

Another embodiment of the invention is a method for treating rheumatoid arthritis, comprising administering to a patient suffering from rheumatoid arthritis a nontoxic effective amount of a compound described heremabove, or a pharmaceutically acceptable salt thereof

Another embodiment of the invention is a method for treating psoriatic arthritis, comprising administering to a patient suffering from psoriatic arthritis a nontoxic effective amount of a compound described hereinabove, or a pharmaceutically acceptable salt thereof

Another embodiment of the invention is a method for treating a cancer, comprising administering to a patient suffering from a cancer a nontoxic anti-cancer effective amount of a compound described hereinabove, or a pharmaceutically acceptable salt thereof

Another embodiment of the invention is a method for treating inflammation, comprising administering to a patient suffering from inflammation a nontoxic effective amount of a compound described hereinabove, or a pharmaceutically acceptable salt thereof Another embodiment of the invention is a method for treating chronic obstructive pulmonary disease, comprising administering to a patient suffering from chronic obstructive pulmonary disease a nontoxic effective amount of a compound described hereinabove, or a pharmaceutically acceptable salt thereof

Another embodiment of the invention is a method for treating psoriasis, comprising administering to a patient suffering from psoriasis a nontoxic effective amount of a compound described hereinabove, or a pharmaceutically acceptable salt thereof.

Another embodiment of the invention is a method for treating asthma, comprising administering to a patient suffering from asthma a nontoxic effective amount of a compound described hereinabove, or a pharmaceutically acceptable salt thereof Another embodiment of the invention is a method for treating inflammatory bowel disease, comprising administering to a patient suffering from inflammatory bowel disease a nontoxic effective amount of a compound described hereinabove, or a pharmaceutically acceptable salt thereof

For the purposes of this invention, the term "arthritis", which is synonymous with the phrase "arthritic condition", includes osteoarthritis, rheumatoid arthritis, degenerative joint disease, spondyloarthropathies, gouty arthritis, systemic lupus erythematosus, juvenile arthritis, and psoriatic arthritis An allosteric inhibitor of MMP-13 having an anti-arthritic effect is a compound as defined above that inhibits the progress, prevents further progress, or reverses progression, in part or in whole, of any one or more symptoms of any one of the arthritic diseases and disorders listed above

As used herein, the term "alkyl" refers to a straight or branched chain monovalent hydrocarbon radical For example, a C _1-6 alkyl radical is a straight or branched chain monovalent hydrocarbon radical having 1 to 6 carbon atoms Examples of C _1-6 alkyl radicals include methyl, ethyl, 1 -propyl, 2- propyl, 1 -butyl, 2-butyl, 2,2-dιmethylethyl, 1 -pentyl, 2-pentyl, 2,2-dιmethylpropyl, and 1 -hexyl

As used herein, the term "alkylene" refers to a straight or branched chain divalent hydrocarbon radical For example, a C ₁ ^ alkylene radical is a straight or branched chain divalent hydrocarbon radical having 1 to 6 carbon atoms Examples of C ₁ ^ alkylene radicals include methylene, ethylene, 1 - propylene, 2-propylene, 1 -butylene, 2-butylene, 2,2-dιmethylethylene, 1 -pentylene, 2-pentylene, 2,2- dimethylpropylene, and 1-hexylene

As used herein, the term "cycloalkyl" refers to a cyclic monovalent hydrocarbon radical For example, a C _3-6 cycloalkyl radical is a cyclic monovalent hydrocarbon radical having 1 to 6 carbon

atoms Examples of C _3-6 cycloalkyl radicals include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl

The term "IC ₅₀ " means the concentration of a compound, usually expressed as μM or nM, required to inhibit an enzyme's catalytic activity by 50% As used herein, the phrase "cartilage damage" means a disorder of hyaline cartilage and subchondral bone characterized by hypertrophy of tissues in and around the involved joints, which may or may not be accompanied by deterioration of hyaline cartilage surface

The phrase "treating", which is related to the terms "treat" and "treated", means administration of an invention combination as defined above that inhibits the progress, prevents further progress, or reverses progression, in part or in whole, of any one or more symptoms of any one of the diseases and disorders listed above

The phrase "invention compound" means a compound of Formula I, or a pharmaceutically acceptable salt thereof, as fully defined above

The term "NSAID" is an acronym for the phrase "nonsteroidal anti-inflammatory drug", which means any compound which inhibits cyclooxygenase-1 ("COX-1") and cyclooxygenase-2 Most NSAIDs fall within one of the following five structural classes (1 ) propionic acid derivatives, such as ibuprofen, naproxen, naprosyn, diclofenac, and ketoprofen, (2) acetic acid derivatives, such as tolmetin and sulindac, (3) fenamic acid derivatives, such as mefenamic acid and meclofenamic acid, (4) biphenylcarboxylic acid derivatives, such as diflunisal and flufenisal, and (5) oxicams, such as piroxim, peroxicam, sudoxicam, and isoxicam Other useful NSAIDs include aspirin, acetominophen, indomethacin, and phenylbutazone Selective inhibitors of cyclooxygenase-2 as described above may be considered to be NSAIDs also

A selective inhibitor of COX-2 is a compound that inhibits COX-2 selectively versus COX-1 such that a ratio of IC ₅₀ for a compound with COX-1 divided by a ratio of IC ₅₀ for the compound with COX-2 is greater than, or equal to, 5, where the ratios are determined in one or more assays All that is required to determine whether a compound is a selective COX-2 inhibitor is to assay a compound in one of a number of well know assays in the art

The term "drugs", which is synonymous with the phrases "active components", "active compounds", and "active ingredients", includes celecoxib, or a pharmaceutically acceptable salt thereof, valdecoxib, or a pharmaceutically acceptable salt thereof, and an allosteric inhibitor of MMP- 13, and may further include one or two of the other therapeutic agents described above

An allosteric inhibitor of MMP-13 is any compound of Formula I that binds allosterically into the S1 ' site of the MMP- 13 enzyme, including the S1 ' channel, and/or the S1 " site, without ligating, coordinating, or binding the catalytic zinc of the MMP-13 Certain of the invention compounds possess one or more chiral centers, and each center may exist in the R or S configuration The scope of the present invention encompasses any diastereomeric, enantiomeric, or epimeric form of invention compound, as well as mixtures thereof Compounds of Formula I may be prepared as single enantiomer or as a mixture of individual enantiomers which includes racemic mixtures Methods to obtain preferentially a single enantiomer from a mixture of individual enantiomers or a racemic mixture are well known to those ordinarily skilled in the art of

organic chemistry Such methods include but are not limited to preferential crystallization of diastereomeric salts (e g tartrate or camphor sulfonate), covalent denvatization by a chiral, non- racemic reagent followed by separation of the resulting diastereomers by common methods (e g crystallization, chromatographic separation, or distillation) and chemical reversion to scalemtc compound, Simulated Moving Bed technology, or high/mediÏ…m-pressure liquid chromatography employing a chiral stationary phase These techniques may be performed on the final compounds of Formula I or on any intermediates to compounds of Formula I which bear a stereogenic center Also, to facilitate separation by any of the methods described above, the compounds of Formula I or any intermediates to the compounds of Formula I which bear a stereogenic center may be transiently reacted with an achiral reagent, separated, and then reverted to scalemic compound by standard synthetic techniques

Additionally, certain invention compounds may exist as geometric isomers such as the entgegen (E) and zusammen (Z) isomers of 1 ,2-dιsubstιtuted alkenyl groups or cis and trans isomers of disubstituted cyclic groups Any cis, trans, syn, anti, entgegen (E), or zusammen (Z) isomer of a compound of Formula I, as well as mixtures thereof, is encompassed within the scope of the present invention

Certain invention compounds can exist as two or more tautomeric forms Tautomeric forms of the invention compounds may interchange, for example, via enolization/de-enolization, 1 ,2-hydrιde, 1 ,3-hydrιde, or 1 ,4-hydrιde shifts, and the like Any tautomeric form of a compound of Formula I, as well as mixtures thereof, Is encompassed within the scope of the present invention

Some compounds of the present invention have cycloalkyl groups, which may be substituted at more than one carbon atom, in which case all geometric forms thereof, both cis and trans, and mixtures thereof, are within the scope of the present invention

Encompassed within the scope of the present invention are isotopically-labelled compounds of Formula I, which are identical to those recited above, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as 2H, 3H, 13C, 14C, 15N, 180, 17O ₁ 31 P, 32P, 35S, 18F and 36Cl, respectively Compounds of the present invention and pharmaceutically acceptable salts of said compounds which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention Certain isotopically labelled compounds of the present invention, for example those into which radioactive isotopes such as 3H and 14C are incorporated, are useful in drug and/or substrate tissue distribution assays Tritiated, i e , 3H and carbon-14, i e , 14C, isotopes are particularly preferred for their ease of preparation and detectability Further, substitution with heavier isotopes such as deuterium, i e , 2H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances Isotopically labelled compounds of those described above in this invention can generally be prepared by carrying out the procedures incorporated by reference above

or disclosed in the Schemes and/or in the Examples and Preparations below, by substituting a readily available isotopically labelled reagent for a non-isotopically labelled reagent

Some of the invention compounds are capable of further forming nontoxic pharmaceutically acceptable salts, including, but not limited to, acid addition and/or base salts The acid addition salts are formed from basic invention compounds, whereas the base addition salts are formed from acidic invention compounds All of these forms are within the scope of the compounds useful in the invention

Pharmaceutically acceptable acid addition salts of the basic invention compounds include nontoxic salts derived from inorganic acids such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydroiodic, hydrofluoric, phosphorous, and the like, as well nontoxic salts derived from organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc Such salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, tnfluoroacetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, malate, tartrate, methanesulfonate, and the like Also contemplated are salts of amino acids such as arginate and the like and gluconate or galacturonate An acid addition salt of a basic invention compound is prepared by contacting the free base form of the compound with a sufficient amount of a desired acid to produce a nontoxic salt in the conventional manner The free base form of the compound may be regenerated by contacting the acid addition salt so formed with a base, and isolating the free base form of the compound in the conventional manner The free base forms of compounds prepared according to a process of the present invention differ from their respective acid addition salt forms somewhat in certain physical properties such as solubility, crystal structure, hygroscopicity, and the like, but otherwise free base forms of the invention compounds and their respective acid addition salt forms are equivalent for purposes of the present invention

A nontoxic pharmaceutically acceptable base addition salt of an acidic invention compound may be prepared by contacting the free acid form of the compound with a metal cation such as an alkali or alkaline earth metal cation, or an amine, especially an organic amine Examples of suitable metal cations include sodium cation (Na"), potassium cation (K ^* ), magnesium cation (Mg ²⁺ ), calcium cation (Ca ^2* ), and the like Examples of suitable amines are N,N'-dιbenzylethylenedιamιne, chloroprocaine, choline, diethanolamine, dicyclohexylamine, ethylenediamme, A/-methylglucamιne, and procaine

A base addition salt of an acidic invention compound may be prepared by contacting the free acid form of the compound with a sufficient amount of a desired base to produce the salt in the conventional manner The free acid form of the compound may be regenerated by contacting the salt form so formed with an acid, and isolating the free acid of the compound in the conventional manner The free acid forms of the invention compounds differ from their respective salt forms somewhat in

certain physical properties such as solubility, crystal structure, hygroscopicity, and the like, but otherwise the salts are equivalent to their respective free acid for purposes of the present invention

Certain invention compounds can exist in unsolvated forms as well as solvated forms, including hydrated forms In general, the solvated forms, including hydrated forms, are equivalent to unsolvated forms and are encompassed within the scope of the present invention

The invention also provides pharmaceutical compositions comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, as defined above, together with a pharmaceutically acceptable carrier, diluent, or excipient

The present invention also relates to the formulation of a compound of the present invention alone or with one or more other therapeutic agents which are to form the intended combination, including wherein said different drugs have varying half-lives, by creating controlled-release forms of said drugs with different release times which achieves relatively uniform dosing, or, in the case of non- human patients, a medicated feed dosage form in which said drugs used in the combination are present together in admixture in the feed composition There is further provided in accordance with the present invention co-administration in which the combination of drugs is achieved by the simultaneous administration of said drugs to be given in combination, including co-administration by means of different dosage forms and routes of administration, the use of combinations in accordance with different but regular and continuous dosing schedules whereby desired plasma levels of said drugs involved are maintained in the patient being treated, even though the individual drugs making up said combination are not being administered to said patient simultaneously

A therapeutically effective amount, or, simply, effective amount, of a compound of Formula I will generally be from about 1 to about 300 mg/kg of subject body weight of the compound of Formula I, or a pharmaceutically acceptable salt thereof Typical doses will be from about 10 to about 5000 mg/day for an adult subject of normal weight for each component of the combination In a clinical setting, regulatory agencies such as, for example, the Food and Drug Administration ("FDA") in the U S may require a particular therapeutically effective amount

In determining what constitutes a nontoxic effective amount or a therapeutically effective amount of a compound of Formula I for treating, preventing, or reversing one or more symptoms of any one of the diseases and disorders described above that are being treated according to the invention methods, a number of factors will generally be considered by the medical practitioner or veterinarian in view of the experience of the medical practitioner or veterinarian, including the Food and Drug Administration guidelines, or guidelines from an equivalent agency, published clinical studies, the subject's (e g , mammal's) age, sex, weight and general condition, as well as the type and extent of the disease, disorder or condition being treated, and the use of other medications, if any, by the subject As such, the administered dose may fall within the ranges or concentrations recited above, or may vary outside them, ιe, either below or above those ranges, depending upon the requirements of the individual subject, the severity of the condition being treated, and the particular therapeutic formulation being employed Determination of a proper dose for a particular situation is within the skill of the medical or veterinary arts Generally, treatment may be initiated using smaller dosages of the compound of Formula I that are less than optimum for a particular subject Thereafter,

the dosage can be increased by small increments until the optimum effect under the circumstance is reached For convenience, the total daily dosage may be divided and administered in portions during the day, if desired

Pharmaceutical compositions, described briefly here and more fully below, of an invention combination may be produced by formulating the invention combination in dosage unit form with a pharmaceutical carrier Some examples of dosage unit forms are tablets, capsules, pills, powders, aqueous and nonaqueous oral solutions and suspensions, and parenteral solutions packaged in containers containing either one or some larger number of dosage units and capable of being subdivided into individual doses Alternatively, the compounds of Formula I may be formulated separately

Some examples of suitable pharmaceutical carriers, including pharmaceutical diluents, are gelatin capsules, sugars such as lactose and sucrose, starches such as corn starch and potato starch, cellulose derivatives such as sodium carboxymethyl cellulose, ethyl cellulose, methyl cellulose, and cellulose acetate phthalate, gelatin, talc, stearic acid, magnesium stearate, vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil, and oil of theobroma, propylene glycol, glycerin, sorbitol, polyethylene glycol, water, agar, alginic acid, isotonic saline, and phosphate buffer solutions, as well as other compatible substances norrηally used in pharmaceutical formulations

The compositions to be employed in the invention can also contain other components such as coloring agents, flavoring agents, and/or preservatives These materials, if present, are usually used in relatively small amounts The compositions can, if desired, also contain other therapeutic agents commonly employed to treat any of the above-listed diseases and disorders

The percentage of the active ingredients of a compound of Formula I, or a pharmaceutically acceptable salt thereof, in the foregoing compositions can be varied within wide limits, but for practical purposes it is preferably present in a total concentration of at least 10% in a solid composition and at least 2% in a primary liquid composition The most satisfactory compositions are those in which a much higher proportion of the active ingredients are present, for example, up to about 95%

Preferred routes of administration of a compound of Formula I are oral or parenteral However, another route of administration may be preferred depending upon the condition being treated For exampled, topical administration or administration by injection may be preferred for treating conditions localized to the skin or a joint Administration by transdermal patch may be preferred where, for example, it is desirable to effect sustained dosing

It should be appreciated that the different routes of administration may require different dosages For example, a useful intravenous ("IV") dose is between 5 and 50 mg, and a useful oral dosage is between 20 and 800 mg, of a compound of Formula I, or a pharmaceutically acceptable salt thereof The dosage is within the dosing range used in treatment of the above-listed diseases, or as would be determined by the needs of the patient as described by the physician

Compounds of Formula I may be administered in any form Preferably, administration is in unit dosage form A unit dosage form of the compound of Formula I to be used in this invention may also comprise other compounds useful in the therapy of diseases described above A further description of

pharmaceutical formulations useful for administering the compounds of Formula I and invention combinations is provided below

The invention also provides combinations, comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, together with another pharmaceutically active component as described herein

The active components of the invention combinations, may be formulated together or separately and may be administered together or separately The particular formulation and administration regimens used may be tailored to the particular patient and condition being treated by a practitioner of ordinary skill in the medical or pharmaceutical arts For the treatment of rheumatoid arthritis, the compounds of the invention may be combined with agents such as TNF-σ inhibitors such as anti-TNF monoclonal antibodies and TNF receptor immunoglobulin molecules (such as Enbrel®), low dose methotrexate, lefunimide, hydroxychloroquine, d-penicillamine, auranofin or parenteral or oral gold

The compounds of the invention can also be used in combination with existing therapeutic agents for the treatment of osteoarthritis Suitable agents to be used in combination include standard non-steroidal anti-inflammatory agents (hereinafter NSAID's) such as piroxicam, diclofenac, propionic acids such as naproxen, flurbiprofen, fenoprofen, ketoprofen and ibuprofen, fenamates such as mefenamic acid, indomethacin, sulindac, apazone, pyrazolones such as phenylbutazone, salicylates such as aspirin, COX-2 inhibitors such as etoricoxib and rofecoxib, analgesics and intraarticular therapies such as corticosteroids and hyaluronic acids such as hyalgan and synvisc

The active ingredient of the present invention may be administered in combination with inhibitors of other mediators of inflammation, comprising one or more members selected from the group consisting essentially of the classes of such inhibitors and examples thereof which include, matrix metalloproteinase inhibitors, aggrecanase inhibitors, TACE inhibitors, leucotriene receptor antagonists, IL-1 processing and release inhibitors, ILra, H1 -receptor antagonists, kιnιn-B1 - and B2 - receptor antagonists, prostaglandin inhibitors such as PGD-, PGF- PGI2 - and PGE-receptor antagonists, thromboxane A2 (TXA2-) inhibitors, 5- and 12-lιpoxygenase inhibitors, leukotπene LTC4 - , LTD4/LTE4 - and LTB4 -inhibitors, PAF-receptor antagonists, gold in the form of an aurothio group together with various hydrophilic groups, immunosuppressive agents, e g , cyclospoπne, azathiopπne and methotrexate, anti-inflammatory glucocorticoids, penicillamine, hydroxychloroquine, anti-gout agents, e g , colchicine, xanthine oxidase inhibitors, e g , allopurinol and uricosuric agents, e g , probenecid, sulfinpyrazone and benzbromarone

The compounds of the present invention may also be used in combination with anticancer agents such as endostatin and angiostatin or cytotoxic drugs such as adriamycin, daunomycin, cis- platinum, etoposide, taxol, taxotere and alkaloids, such as vincristine and antimetabolites such as methotrexate

The compounds of the present invention may also be used in combination with antihypertensives and other cardiovascular drugs intended to offset the consequences of atherosclerosis, including hypertension, myocardial ischemia including angina, congestive heart failure and myocardial infarction, selected from vasodilators such as hydralazine, β-adrenergic receptor antagonists such as

propranolol, calcium channel blockers such as nifedipine, α2-adrenergιc agonists such as clonidine, α- adrenergic receptor antagonists such as prazosin and HMG-CoA-reductase inhibitors (anti- hypercholesterolemics) such as lovastatin or atorvastatin

The compounds of the present invention may also be administered in combination with one or more antibiotic, antifungal, antiprotozoal, antiviral or similar therapeutic agents

The compounds of the present invention may also be used in combination with CNS agents such as antidepressants (such as sertraline), anti-Parkinsonian drugs (such as L-dopa, requip, mirapex, MAOB inhibitors such as selegine and rasagiline, comP inhibitors such as Tasmar, A-2 inhibitors, dopamine reuptake inhibitors, NMDA antagonists, nicotine agonists, dopamine agonists and inhibitors of neuronal nitric oxide synthase) and anti-Alzheimer's drugs such as donepezil, tacrine, COX-2 inhibitors, propentofylline or metryfonate

The compounds of the present invention may also be used in combination with osteoporosis agents such as raloxifene, lasofoxifene, droloxifene or fosomax and immunosuppressant agents such as FK-506 and rapamycin Compounds of Formula I may be used in combination with a COX-2 selective inhibitor, more preferably celecoxib, valdecoxib, parecoxib, lumiracoxib, or rofecoxib, or with compounds such as etanercept, infliximab, leflunomide, or methotrexate, and the like

Compounds of Formula I may be used in combination with biological therapeutics useful for treating arthritic conditions, including CP-870, etanercept (a tumor necrosis factor alpha ("TNF-alpha") receptor immunoglobulin molecule, trade names ENBREL® and ENBREL ENTANERCEPT® by Immunex Corporation, Seattle, Washington), infliximab (an anti-TNF-alpha chimeric IgG 1 K monoclonal antibody, tradename REMICADE® by Centocor, lnc , Malvern, Pennsylvania), methotrexate (tradename RHEUMATREX® by American Cyanamid Company, Wayne, New Jersey), and adalimumab (a human monoclonal anti-TNF-alpha antibody, tradename HUMIRA® by Abbott Laboratories, Abbott Park, Illinois)

The invention also provides methods of inhibiting an MMP-13 enzyme in an animal, comprising administering to the animal a compound of Formula I ₁ or a pharmaceutically acceptable salt thereof

The invention also provides methods of treating a disease mediated by an MMP-13 enzyme in a patient, comprising administering to the patient a compound of Formula I, or a pharmaceutically acceptable salt thereof

The invention also provides methods of treating diseases such as heart disease, multiple sclerosis, osteo and rheumatoid arthritis, arthritis other than osteo- or rheumatoid arthritis, cardiac insufficiency, inflammatory bowel disease, heart failure, age-related macular degeneration, chronic obstructive pulmonary disease, asthma, periodontal diseases, psoriasis, atherosclerosis, and osteoporosis in a patient, comprising administering to the patient a compound of Formula I, or a pharmaceutically acceptable salt thereof

Other mammalian diseases and disorders which are treatable by administration of an invention combination alone, or contained in a pharmaceutical composition as defined below, include fever (including rheumatic fever and fever associated with influenza and other viral infections),

common cold, dysmenorrhea, menstrual cramps, inflammatory bowel disease, Crohn's disease, emphysema, acute respiratory distress syndrome, asthma, bronchitis, chronic obstructive pulmonary disease, Alzheimer's disease, organ transplant toxicity, cachexia, allergic reactions, allergic contact hypersensitivity, cancer (such as solid tumor cancer including colon cancer, breast cancer, lung cancer and prostrate cancer, hematopoietic malignancies including leukemias and lymphomas, Hodgkin's disease, aplastic anemia, skin cancer and familiar adenomatous polyposis), tissue ulceration, peptic ulcers, gastritis, regional enteritis, ulcerative colitis, diverticulitis, recurrent gastrointestinal lesion, gastrointestinal bleeding, coagulation, anemia, synovitis, gout, ankylosing spondylitis, restenosis, periodontal disease, epidermolysis bullosa, osteoporosis, loosening of artificial joint implants, atherosclerosis (including atherosclerotic plaque rupture), aortic aneurysm (including abdominal aortic aneurysm and brain aortic aneurysm), periarteritis nodosa, congestive heart failure, myocardial infarction, stroke, cerebral ischemia, head trauma, spinal cord injury, neuralgia, neurodegenerative disorders (acute and chronic), autoimmune disorders, Huntmgton's disease, Parkinson's disease, migraine, depression, peripheral neuropathy, pain (including low back and neck pain, headache and toothache), gingivitis, cerebral amyloid angiopathy, nootropic or cognition enhancement, amyotrophic lateral sclerosis, multiple sclerosis, ocular angiogenesis, corneal injury, macular degeneration, conjunctivitis, abnormal wound healing, muscle or joint sprains or strains, tendonitis, skin disorders (such as psoriasis, eczema, scleroderma and dermatitis), myasthenia gravis, polymyositis, myositis, bursitis, burns, diabetes (including types I and Il diabetes, diabetic retinopathy, neuropathy and nephropathy), tumor invasion, tumor growth, tumor metastasis, corneal scarring, scleritis, immunodeficiency diseases (such as AIDS in humans and FLV, FIV in cats), sepsis, premature labor, hypoprothrombmemia, hemophilia, thyroiditis, sarcoidosis, Behcet's syndrome, hypersensitivity, kidney disease, Rickettsial infections (such as Lyme disease, Erlichiosis), Protozoan diseases (such as malaria, giardia, coccidia), reproductive disorders (preferably in livestock), epilepsy, convulsions, and septic shock

One of ordinary skill in the art will appreciate that the compounds of the invention are useful in treating a diverse array of diseases. One of ordinary skill in the art will also appreciate that when using the compounds of the invention in the treatment of a specific disease that the compounds of the invention may be combined with various existing therapeutic agents used for that disease This invention also relates to a method of or a pharmaceutical composition for treating inflammatory processes and diseases comprising administering a compound of this invention to a mammal, including a human, cat, livestock or dog, wherein said inflammatory processes and diseases are defined as above and said inhibitory compound is used in combination with one or more other therapeutically active agents under the following conditions A) where a joint has become seriously inflamed as well as infected at the same time by bacteria, fungi, protozoa and/or virus, said inhibitory compound is administered in combination with one or more antibiotic, antifungal, antiprotozoal and/or antiviral therapeutic agents;

B) where a multi-fold treatment of pain and inflammation is desired, said inhibitory compound is administered in combination with inhibitors of other mediators of

inflammation, comprising one or more members independently selected from the group consisting essentially of

1 NSAIDs,

2 H ₁ -receptor antagonists, 3 kinin-B, - and B ₂ -receptor antagonists,

4 prostaglandin inhibitors selected from the group consisting of PGD-, PGF- PGI ₂ - and PGE-receptor antagonists,

5 thromboxane A ₂ (TXA ₂ -) inhibitors,

6 5-, 12- and 15-lιpoxygenase inhibitors, 7 leukotÏ€ene LTC ₄ -, LTD ₄ /LTE ₄ - and LTB ₄ -inhibitors,

8 PAF-receptor antagonists,

9 gold in the form of an aurothio group together with one or more hydrophilic groups,

10 immunosuppressive agents selected from the group consisting of cyclosporine, azathiopnne and methotrexate,

11 anti-inflammatory glucocorticoids,

12 penicillamine,

13 hydroxychloroquine,

14 anti-gout agents including colchicine, xanthine oxidase inhibitors including allopuπnol, and uricosuric agents selected from probenecid, sulfinpyrazone and benzbromarone, where older mammals are being treated for disease conditions, syndromes and symptoms found in geriatric mammals, said inhibitory compound is administered in combination with one or more members independently selected from the group consisting essentially of

1 cognitive therapeutics to counteract memory loss and impairment,

2 anti-hypertensives and other cardiovascular drugs intended to offset the consequences of atherosclerosis, hypertension, myocardial ischemia, angina, congestive heart failure and myocardial infarction, selected from the group consisting of a diuretics, b vasodilators, c β-adrenergic receptor antagonists, d angiotensm-ll converting enzyme inhibitors (ACE-inhibitors), alone or optionally together with neutral endopeptidase inhibitors, e angiotensin Il receptor antagonists, f renin inhibitors, g calcium channel blockers, h sympatholytic agents, 1 σ ₂ -adrenergιc agonists,

j σ-adrenergιc receptor antagonists, and k HMG-CoA-reductase inhibitors (anti-hypercholesterolemics),

3 vinca alkaloids selected from a vinblastine, and b vincristine,

4 growth hormone secretagogues,

5 strong analgesics,

6 local and systemic anesthetics, and

7 H ₂ -receptor antagonists, proton pump inhibitors and other gastroprotective agents

The invention method is useful in human and veterinary medicines for treating mammals suffering from one or more of the above-listed diseases and disorders

An allosteric inhibitor of MMP-13 may be readily identified by one of ordinary skill in the pharmaceutical or medical arts by assaying an alkyne test compound for inhibition of MMP-13 as described, for example, in Biological Methods 1 or 2 of International Patent Application Pub No WO 04/014366US200400488637179822, the content of which are herein incorporated by reference Allosteric inhibition of MMP-13 may be identified by one of ordinary skill in the pharmaceutical or medical arts by assaying the test invention compound for inhibition of MMP-13 in the presence of an inhibitor to the catalytic zinc of MMP-13 as described, for example, in Biological Methods 3 or 4 of International Patent Application Pub No WO 04/014366US200400488637179822, the content of which are herein incorporated by reference

Further, a compound having an anti-inflammatory, an analgesic, anti-arthritic, or a cartilage damage inhibiting effect, or any combination of these effects, may be readily identified by one of ordinary skill in the pharmaceutical or medical arts by assaying the compound in any number of well known assays for measuring determining the compound's effects on cartilage and or other joint tissue damage, arthritis, inflammation, or pain These assays include in vitro assays that utilize cartilage samples and in vivo assays in whole animals that measure cartilage degradation, inhibition of inflammation, or pain alleviation

For example with regard to assaying cartilage damage in vitro, an amount of a compound or control vehicle may be administered with a cartilage-damaging agent to cartilage such as IL- 1 , and the cartilage damage inhibiting effects in both tests studied by gross examination or histopathologic examination of the cartilage, or by measurement of biological markers of cartilage damage such as, for example, proteoglycan content or hydroxyprolme content, or by biomarkers of type Il collagen degradation such as CTX-II or TIINE (Sunyer et al , Osteo Cartilage 12 (2004) (Suppl B), p P84) Further, in vivo studies to assay cartilage damage and/or joint degeneration may be performed as follows an amount of a compound or control vehicle may be administered with a cartilage damaging agent to an animal or may be administered in the absence of cartilage damaging agents, to animals that have surgery-induced or spontaneous OA lesions in the knee Examples of surgery-induced animal models include the rat medial meniscus tear model or the dog anterior cruciate ligament transaction model The effects of the compound being assayed in the animals for effects on cartilage

integrity and/or joint structure may be evaluated by gross examination or histopathologic examination of the affected joιnt(s), and respose to compounds further characterized by measurement of biological markers of cartilage damage such as, for example, proteoglycan content or hydroxyprolme content or biomarkers of type Il collagen degradation such as CTX-II or TIINE in biological fluids such as urine, plasma, serum or synovial fluids Effect of the compounds may also be assessed by observation of the effects in an acute model on functional limitations of the affected joint

Several methods of identifying a compound with cartilage damage inhibiting properties are described below The amount to be administered in an assay is dependent upon the particular assay employed, but in any event is not higher than the well known maximum amount of a compound that the particular assay can effectively accommodate

Similarly, compounds having pain-alleviating properties may be identified using any one of a number of in vivo animal models of pain

Still similarly, compounds having anti-inflammatory properties may be identified using any one of a number of in vivo animal models of inflammation For example, for an example of inflammation models, see United States patent number 6,329,429, which is incorporated herein by reference

Still similarly, compounds having anti-arthritic properties may be identified using any one of a number of in vivo animal models of arthritis For example, for an example of arthritis models, see also United States patent number 6,329,429

Other embodiments of the present invention are compounds described herein, or a pharmaceutically acceptable salt thereof, that are >10, >20, >50, >100, or >1000 times more potent versus MMP-13 than versus at least two of any other MMP enzyme or TACE

Still other aspects of the present invention are compounds of Formula I ₁ or a pharmaceutically acceptable salt thereof, that are selective inhibitors of MMP-13 versus 2, 3, 4, 5, 6, or 7 other MMP enzymes, or versus TACE and 1 , 2, 3, 4, 5, 6, or 7 other MMP enzymes It should be appreciated that selectivity of a compound of Formula I, or a pharmaceutically acceptable salt thereof, is a multidimensional characteristic that includes the number of other MMP enzymes and TACE over which selectivity for MMP-13 inhibition is present and the degree of selectivity of inhibition of MMP-13 over another particular MMP or TACE, as measured by, for example, the IC ₅₀ in μM of the compound for the inhibition of the other MMP enzyme or TACE divided by the IC ₅₀ in μM of the compound for the inhibition of MMP-13

As discussed above, one aspect of the present invention is novel compounds that are selective inhibitors of the enzyme MMP-13 A selective inhibitor of MMP-13, as used in the present invention, is a compound that is 25X more potent in vitro versus MMP-13 than versus at least one other matrix metalloproteinase enzyme such as, for example, MMP-1 , MMP-2, MMP-3, MMP-7, MMP- 8, MMP-9, or MMP-14, or versus TACE A preferred aspect of the present invention is novel compounds that are selective inhibitors of MMP-13 versus MMP-1

The invention provides a compound of Formula I, or a pharmaceutically acceptable salt thereof, which has an IC _5O with any MMP enzyme that is less than or equal to 50 μM Preferred are compounds of Formula I ₁ or a pharmaceutically acceptable salt thereof, which have an IC ₅₀ with a human full-length MMP-13 ("hMMP-13FL") or a human MMP-13 catalytic domain ("hMMP-13CD") that

is less than or equal to 50 μM More preferred are compounds of Formula I, or a pharmaceutically acceptable salt thereof, which have an IC ₅₀ with a human full-length MMP-13 ("hMMP-13FL") or a human MMP-13 catalytic domain ("hMMP-13CD") that is less than or equal to 10 μM Examples of biological methods useful for determining IC ₅₀ S for compounds with an MMP are described herein The advantages of using an invention compound in a method of the instant invention include the nontoxic nature of the compounds at and substantially above therapeutically effective doses, their ease of preparation, the fact that the compounds are well-tolerated, and the ease of topical, IV, or oral administration of the drugs

Another important advantage is that the present invention compounds more effectively target a particular disease that is responsive to inhibition of MMP-13 with fewer undesirable side effects than similar compounds that inhibit MMP-13 that are not invention compounds This is so because the instant invention compounds of Formula I, or a pharmaceutically acceptable salt thereof, do not directly, or indirectly via a bridging water molecule, ligate, coordinate to, or bind to the catalytic zinc cation of MMP-13, but instead bind at a different location from where natural substrate binds to MMP- 13 The binding requirements of an allosteric MMP-13 binding site are unique to MMP-13, and account for the specificity of the invention compounds for inhibiting MMP-13 over any other MMP enzyme See J Chem Biol , 2005(12), 181 -189 Indeed, prior art inhibitors of MMP-13 bind to the catalytic zinc cations of other MMP enzymes as well as to the catalytic zinc cation of MMP-13, and are consequently significantly less selective inhibitors of MMP-13 enzyme The invention compounds which are invention compounds, and pharmaceutically acceptable salts thereof, are thus therapeutically superior to other inhibitors of MMP-13, or even TACE, because of fewer undesirable side effects from inhibition of the other MMP enzymes or TACE For example, virtually all prior art MMP inhibitors tested clinically to date have exhibited an undesirable side effect known as musculoskeletal syndrome ("MSS") MSS is associated with administering an inhibitor of multiple MMP enzymes or an inhibitor of a particular MMP enzyme such as MMP-1 MSS will be significantly reduced in type and severity by administering the invention compound instead of any prior art MMP-13 inhibitor, or a pharmaceutically acceptable salt thereof The invention compounds are superior to similar compounds that interact with the catalytic zinc cation of the MMP-13 enzyme as discussed above, even if similar compounds show some selectivity for the MMP-13

General Synthetic Procedures

Intermediates for the synthesis of a compound of Formula I, or a pharmaceutically acceptable salt thereof, may be prepared by one of ordinary skill in the art of organic chemistry by adapting various synthetic procedures incorporated by reference above or that are well-known in the art of organic chemistry These synthetic procedures may be found in the literature Alternatively, a skilled artisan may find methods useful for preparing the intermediates in the chemical literature by searching widely available databases such as, for example, those available from the Chemical Abstracts Service, Columbus, Ohio, or MDL Information Systems GmbH (formerly Beilstein Information Systems GmbH), Frankfurt, Germany

Preparations of the invention compounds may use starting materials, reagents, solvents, and catalysts that may be purchased from commercial sources or they may be readily prepared by adapting procedures in the references or resources cited above Commercial sources of starting materials, reagents, solvents, and catalysts useful in preparing invention compounds include, for example, The Aldrich Chemical Company, and other subsidiaries of Sigma-Aldrich Corporation, St Louis, Missouri, BACHEM, BACHEM A G , Switzerland, or Lancaster Synthesis Ltd, United Kingdom

Syntheses of some invention compounds may utilize starting materials, intermediates, or reaction products that contain a reactive functional group During chemical reactions, a reactive functional group may be protected from reacting by a protecting group that renders the reactive functional group substantially inert to the reaction conditions employed A protecting group is introduced onto a starting material prior to carrying out the reaction step for which a protecting group is needed Once the protecting group is no longer needed, the protecting group can be removed It is well within the ordinary skill in the art to introduce protecting groups during a synthesis of a compound of Formula I ₁ or a pharmaceutically acceptable salt thereof, and then later remove them Procedures for introducing and removing protecting groups are well known Thus, for example, protecting groups such as the following may be utilized to protect ammo, hydroxyl, and other groups carboxylic acyl groups such as, for example, formyl, acetyl, and trifluoroacetyl, alkoxycarbonyl groups such as, for example, ethoxycarbonyl, tert-butoxycarbonyl (BOC), /?,/?,/?-tÏ€chloroethoxycarbonyl (TCEC), and /?-ιodoethoxycarbonyl, aralkyloxycarbonyl groups such as, for example, benzyloxycarbonyl (CBZ), para-methoxybenzyloxycarbonyl, and 9-fluorenylmethyloxycarbonyl (FMOC), trialkylsilyl groups such as, for example, trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBDMS), and other groups such as, for example, triphenylmethyl (trityl), tetrahydropyranyl, vinyloxycarbonyl, ortho-nitrophenylsulfenyl, diphenylphosphinyl, para-toluenesulfonyl (Ts), mesyl, tÏ€fluoromethanesulfonyl, and benzyl Examples of procedures for removal of protecting groups include hydrogenolysis of CBZ groups using, for example, hydrogen gas at 50 psi in the presence of a hydrogenation catalyst such as 10% palladium on carbon, acidolysis of BOC groups using, for example, hydrogen chloride in dichloromethane, tÏ€fluoroacetic acid (TFA) in dichloromethane, and the like, reaction of silyl groups with fluoride ions, and reductive cleavage of TCEC groups with zinc metal

The following schemes are representative of the methods that can be used to prepare compounds of Formula I Starting materials may be obtained by procedures described in the schemes, by procedures well known to one of ordinary skill in organic chemistry, and/or may be obtained commercially

The following schemes are representative of the methods that can be used to prepare compounds of Formula I Starting materials may be obtained by procedures described in the schemes, by procedures well known to one of ordinary skill in organic chemistry, and/or may be obtained commercially

CHART A

A1 A2

Compounds of formula (I) wherein L is a tetrazole (U = N) or triazole (U = CH) may be prepared as described in Chart A A compound of formula A1 is reacted with an alcohol (G-OH) under Mitsunobu coupling conditions (e g Ph ₃ P, di-tert-butyl azodicarboxylate) wherein G is a group V-Z as described above and in which reactive functional groups may be protected Alternatively, a compound of formula A1 may be reacted with a compound G-X in the presence of a base (e g tertiary amine, sodium hydride) wherein X is Cl, Br, I, alkylsulfonate ester, or arylsulfonate ester The reagents G-OH or G-X are either commercially available or prepared as described below (Charts J - X) The above reaction conditions may afford one or more positional isomers about the five-membered heterocycle including A2 (Chart A), B1 , or B2 (Chart B) Determination of the structural isomer formed is readily possible by someone skilled in the art employing NMR techniques (e g H1 , gHSQC, gHMBC, gHMBC-N15, and 1d NOE experiments) or single crystal X-ray analysis

CHART B

B1 B2

CHART C

C4 C3

Compounds of the formula A1 employed in Chart A are prepared as described in Charts C - H below Hydrolysis of 4,6-dιchloropyÏ€mιdιnes of the formula C1 under strongly acidic conditions provide compounds of the formula C2 (Henze, H R J Org Chem 1952, 77, 1320-1326) Compounds of the formula C1 are commercially available (Y = H and CH ₃ ) or may be prepared by literature procedures wherein Y = (CH ₂ ) _L3 CH ₃ , CH(CH ₃ )C ₂ H ₅ , and CH ₂ CH(CHs) ₂ (Henze, H R J Org Chem 1952, 77, 1320-1326), Y = CH(CH ₃ ) ₂ (Gershon, H J Med Chem 1964, 7, 808-81 1 ), Y = CF ₃ (Inoue, S J Org Chem 1961 , 26, 4504-4508), Y = CH ₂ F (Elvidge, J A J Chem Soc , C, 1968, 2188-2198) or by analogous procedures to those described in these references Carbonylation of compounds C2 with carbon monoxide and an alcohol solvent (e g methanol) in the presence of a palladium catalyst provides esters of the formula C3 Subsequent chlorination of esters C3 followed by reaction with

tetraethylammonium cyanide provides compounds of the formula C5 The reaction of cyano derivatives with sodium azide in the presence of zinc bromide provides the tetrazoles C6 which subsequently are reacted with a primary amine of the formula W-NH ₂ to provide compounds of the formula C7 Alternatively, cyano derivatives C5 may be reacted with the amine W-NH ₂ first to provide C8 which subsequently is subjected to tetrazole formation to provide C7

CHART D

D4

Compounds of the formula A1 employed in Chart A wherein Q is N and U is CH may be prepared as described in Chart D starting from 4,6-dιchloropyrιmιdιnes of the formula C1 obtained as described above Carbonylation of compounds C1 with carbon monoxide and an alcohol solvent (e g methanol) in the presence of a palladium catalyst provides esters of the formula D1 Treatment of esters D1 with less than two equivalents of a primary amine of the formula W-NH ₂ affords amides D2 which are then subsequently reacted with ammonia to provide bis-amides of the formula D3 Condensation of D3 with dimethylformamide dimethylacetal followed by reaction with hydrazine (Mustazza, C J Heterocyclic Chem 2001 , 38, 1 1 19-1 129) affords tÏ€azoles of the formula D4 Alternatively as described in Chart E, triazoles of the formula D4 may be prepared by reacting nitriles of the formula C8 with hydrazine to provide E1 which is then heated with formic acid

CHART E

E1

CHART F

F7

Compounds of the formula A1 employed in Chart A wherein Q is CH and U is N may be prepared as described in Chart F Carboxylic acids of the formula F1 are commercially available (Y = H and CH ₃ ) or may be prepared by literature procedures wherein Y = CH ₂ CH ₃ (Tracy, A H J Org Chem 1941 , 6, 70-76), Y = CH ₂ CH ₂ CH ₃ , CH(CH ₃ ) ₂ , C(CH ₃ ) ₃ (Libermann, D Bull Soc Chim Fr 1958, 687-694) or by analogous procedures to those described in these references Compounds F1 may be chlorinated (e g POCI ₃ , PCI ₅ ) and then reacted with tert-butylamme to provide compounds of the formula F3 Further oxidation of secondary amides F3 by treatment with POCI ₃ affords the corresponding nitriles F4 The reaction of cyano derivatives F4 with sodium azide in the presence of zinc bromide provides the tetrazoles F5 Carbonylation of compounds F5 with carbon monoxide and an alcohol solvent (e g methanol) in the presence of a palladium catalyst provides esters of the formula F6 which are subsequently reacted with a primary amine of the formula W-NH ₂ to provide compounds of the formula F7

CHART G

Alternatively, compounds of the formula A1 employed in Chart A wherein Q is CH and U is N may be prepared as described in Chart G starting from compounds F1 obtained as described above Compounds F1 may be chlorinated (e g POCI ₃ , PCI ₅ ) and then reacted with an alkanol (e g methanol) to provide compounds of the formula G1 Cyanation of G1 in the presence of a palladium catalyst affords G2 which is subsequently hydrolyzed under basic conditions (e Q potassium hydroxide) to provide carboxylic acids of the formula G3 Esterification of carboxylic acids G3 with pentafluorophenyl trifluoroacetate affords diesters of the formula G4 The sequential addition of a primary amine of the formula W-NH ₂ followed by ammonia provides amides G5 Dehydration of the primary amide by treatment with POCI ₃ affords the corresponding nitriles G6 which react with sodium

azide to provide tetrazoles of the formula G7 Intermediates of the formula G5 may also be transformed to triazole derivatives useful in Chart A wherein Q is CH and U is CH as described in Chart H Condensation of primary carboxamides G5 with dimethylformamide dimethylacetal followed by reaction with hydrazine (Mustazza, C J Heterocyclic Chem 2001 , 38, 1 1 19-1 129) affords triazoles of the formula H1

CHART H

H1

CHART I

11 I2

I3

As described in Chart I, compounds of formula I3 may be prepared by reacting a compound of formula 11 (prepared as described in Chart C or Chart F) with an alcohol (G-OH) under Mitsunobu coupling conditions (e g Ph ₃ P, di-tert-butyl azodicarboxylate) to provide I2 wherein G is a group V-Z as described above and in which reactive functional groups may be protected Alternatively, a compound of formula 11 may be reacted with a compound G-X in the presence of a base (e g tertiary amine, sodium hydride) wherein X is Cl, Br, I, alkylsulfonate ester, or arylsulfonate ester The reagents G-OH or G-X are either commercially available or prepared as described below (Charts J - X) The resulting ester is then reacted with a primary amine of the formula W-NH ₂ to provide compounds of the formula I3

CHART J

J1 J2

CHART K

K1 K1

CHART L

The reagents G-X employed in Chart A and Chart I above wherein X is an alkylsulfonate ester or arylsulfonate ester are prepared by reaction of an alcohol G-OH with and alkyl- or arylsulfonyl chloride in the presence of a base (e g triethylamine or pyridine) Representative examples are shown in Charts J - L wherein the alcohol G-OH may be prepared by literature procedures, e g J1 , tert-butyl (f?)-2-(hydroxymethyl)morpholιne-4-carboxylate and tert-butyl (S)-2-(hydroxymethyl)morpholιne-4- carboxylate (Yanagisawa, H Heterocycles, 1993, 35, 105-109), K1 , (R)-(1 , 4-dιoxan-2-yl)methanol and (S)-(1.4-dιoxan-2-yl)methanol (Kim, H Y Bioorg Med Chem Lett 2005, -/5, 3207-321 1 ) Tosylation of trans-2,5-bιs-(hydroxymethyl)-1 ,4-dιoxane (L1 ) (Summerbell, R K J Am Chem Soc 1954, 76, 6401 -6407) affords rac-((2/? ^* ,5R ^* )-5-(hydroxymethyl)-1 ,4-dιoxan-2-yl)methyl 4- methylbenzenesulfonate (L2) which upon resolution by chiral supercritical fluid chromatography provides the corresponding (2R,5R)- and (2S,5S)-ιsomers

CHART M

M1 M2

CHART N

N1 N2

N3

Additional examples of G-X may be prepared as described below According to Chart M, (5,5- bιs(hydroxymethyl)-1 ,4-dιoxan-2-yl)methyl 4-methylbenzenesulfonate (M2) is prepared from rac- ((2R ^* ,5R ^* )-5-(hydroxymethyl)-1 ,4-dιoxan-2-yl)methyl 4-methylbenzenesulfonate (L2) by oxidation under Swern conditions to afford M1 which is then reacted with formaldehyde under basic conditions According to Chart N, rac-(2S*,5R ^* )-methyl 5-((tosyloxy)methyl)-1 ,4-dιoxane-2-carboxylate (N3) is prepared from trans-dimethyl 1 ,4-dιoxane-2,5-dιcarboxylate (N1 ) (Summerbell, R K J Am Chem Soc 1954, 76, 6401-6407) by first partial saponification to provide carboxylic acid N2 Subsequent reduction of the carboxylic acid functional group with borane dimethylsulfide followed by the reaction of the resulting alcohol with p-toluenesulfonyl chloride in pyridine affords N3

CHART O

01 02

O4 03

05 06

07

According to Chart O, (trans^-cyanocyclohexyOmethyl 4-methylbenzenesulfonate (07) is prepared by reacting 1 ,4-dιoxa-spιro[4 5]decan-8-one with tosyl-methyl-isocyanide in the presence of potassium t- butoxide to afford 1 ,4-dιoxa-spιro[4 5]decane-8-carbonιtrιle (O2) Acidic hydrolysis of the resulting ketal followed by Wittig olefination with methoxy methyl tπphenylphosphonium ylide and acid hydrolysis provides trans-4-formylcyclohexanecarbonιtrιle (05) Reduction of the aldehyde functional group with sodium borohydride and reaction of the resulting alcohol with p-toluenesulfonyl chloride in pyridine affords 07

CHART P

^HO v Tλ ^yo η _^ ^TSO W" ^~ Y° ^~

O'

P1 P2

P4 P3

P5

According to Chart P, cis- and trans-(4-hydroxy-4-(hydroxymethyl)cyclohexyl)methyl 4- methylbenzenesulfonate (P5) may be prepared by reacting 1 ,4-dιoxaspιro[4 5]dec-8-ylmethanol with p-toluenesulfonyl chloride in pyridine to afford P2 The resulting ketal is subjected to acidic hydrolysis to provide (4-oxocyclohexyl)methyl 4-methylbenzenesulfonate (P3) Epoxidation of ketone P3 with trimethylsulfoxonium ylide affords P4 which upon acid promoted oxirane ring opening provides P5

CHART Q

Q4 Q3

Q5 Q6

According to Chart Q, reagents of the formula G-X including 6-(iodomethyl)-tetrahydro-2H-pyran-3- yl)methanol (Q4) and (5-((tosyloxy)methyl)-tetrahydro-2/-/-pyran-2-yl)methyl acetate (Q6) may be prepared starting from diethylmalonate 6-(lodomethyl)-tetrahydro-2H-pyran-3-yl)methanol (Q4) is prepared analogous to previously described procedures in which diethylmalonate is alkylated with 1 - bromo-3-butene to afford Q2 (Deleπs, G Tetrahedron 1988, 44, 4243-4258) and then subsequently Q2 is reduced with lithium aluminium hydride to afford 2-(but-3-enyl)propane-1 ,3-dιol (Q3) (Ramos Tombo, G M Tetrahedron Lett 1986, 27, 5707-5710) Cyclization of Q3 by reaction with iodine and sodium bicarbonate provides Q4 as a mixture of diastereomers (PCT Application WO2005/080317) The individual isomers of Q4 may be obtained through separation by chiral supercritical fluid chromatography 6-(lodomethy!)-tetrahydro-2/-/-pyran-3-yl)methanol (Q4) may be further reacted with an acetate salt to afford Q5 The resulting alcohol is treated with p-toluenesulfonyl chloride in the presence of an amine base to provide (5-((tosyloxy)methyl)-tetrahydro-2/-/-pyran-2-yl)methyl acetate (06)

CHART R

R1 R2

R4 R3

R5 R6

According to Chart R, reagents of the formula G-X including rac-((2R*,5S ^* )-5-hydroxy-tetrahydro-2H- pyran-2-yl)methyl 4-methylbenzenesulfonate (R3) and (5-hydroxy-5-(hydroxymethyl)-tetrahydro-2/-/- pyran-2-yl)methyl 4-methylbenzenesulfonate (R6) may be prepared (3,4-Dιhydro-2H-pyran-2- yl)methanol (R1 ) is treated with p-toluenesulfonyl chloride in pyridine to afford sulfonylester R2 Analogous to literature precedent (Zhang, S Bioorg Med Chem 2006, 14, 3953-3966), reaction of R2 under hydroboration/oxidation conditions (BH ₃ , NaOH, H ₂ O ₂ ) affords rac-((2F? ^* ,5S ^* )-5-hydroxy- tetrahydro-2H-pyran-2-yl)methyl 4-methylbenzenesulfonate (R3) Oxidation of R3 under Swern conditions provides (5-oxo-tetrahydro-2H-pyran-2-yl)methyl 4-methylbenzenesulfonate (R4) Epoxidation of ketone R4 with trimethylsulfoxonium ylide affords R5 which upon acid promoted oxirane ring opening provides R6

CHART S

S1

S3 S2

S4 S5

According to Chart S, re/-(1 R,2S,4S)-7-oxa-bιcyclo[2 2 1]heptan-2-ylmethyl 4-methylbenzenesulfonate may be prepared by initially reacting furan with ethyl acrylate in the presence of zinc iodide to afford the cycloadduct S1 Alkene S1 is then treated with hydrogen and palladium on carbon in ethanol to provide a mixture of isomers which are separated by silica gel chromatography to afford S2 Saponification of S2 with aqueous sodium hydroxide provides carboxylic acid S3 which may be reacted with 1 ,1'-carbonyldιιmιdazole and sodium borohydride to afford alcohol S4 The desired tosylate S5 is provided by reacting the resulting alcohol with p-toluenesulfonyl chloride in the presence of an amine base By employing these same procedures and the other S2 isomer separated by chromatography, re/-(1 R,2S,4S)-7-oxa-bιcyc!o[2 2 1]heptan-2-y!methy! 4-methylbenzenesυlfonate may be prepared

CHART T

T1 T2

T4 T3

According to Chart T, (6-oxopιperιdιn-3-yl)methyl 4-methylbenzenesulfonate (T4) may be prepared by reacting 6-hydroxynιcotιnιc acid (T1 ) with hydrogen in the presence of a palladium catalyst to afford carboxylic acid T2 The resulting acid is treated with 1 ,1 '-carbonyldιιmιdazole and sodium borohydπde to provide alcohol T3 which is then reacted with p-toluenesulfonyl chloride in the presence of an amine base to provide tosylate T4

CHART U

According to Chart U, reagents of the formula G-X may be prepared where lactam carboxylic acids of the formula U1 (where R may include but is not limited to hydrogen, methyl, ethyl, and iso-propyl) obtained as described by E Valentin et al (Tetrahedron Asymmetry, 2001 , 12, 3241 -3249) are reacted with 1 ,1 '-carbonyldιιmιdazole and sodium borohydride to provide alcohols of the formula U2 The resulting alcohols are reacted with p-toluenesulfonyl chloride in the presence of an amine base to provide tosylates of the formula U3

CHART V

V1 V2

V3 V4

According to Chart V, (S)-λ/-Boc 3-(hydroxymethyl)pyrrolιdιne (V4) is prepared from (R)-1 - phenylethanamine by cyclization with dimethyl 2-oxosuccιnate in refluxing toluene to provide V2 Lactam V2 is then reduced with lithium aluminium hydride to provide ((S)-I -((S)-1 - phenylethyl)pyrrolιdιn-3-yl)methanol (V3) The alcohol is reacted with hydrogen gas in the presence of Pd(OH) ₂ on carbon, and the resulting amine is treated with di-tert-butyl dicarbonate to provide V4 In a similar manner, (R)-N-Boc 3-(hydroxymethyl)pyrrolιdιne is prepared from (S)-i -phenylethanamιne

CHART W

W1

W2 W3

W4

According to Chart W, reagents of the formula G-X specifically (tetrahydro-2/-/-thιopyran-4-yl)methyl 4- methylbenzenesulfonate (W4) may be prepared Tetrahydrothιopyran-4-one is reacted with lithium chloride and samarium diiodide to afford tetrahydro-2H-thιopyran-4-carbonιtrιle (W1 ) which is then hydrolyzed under basic conditions (e g NaOH) to provide the corresponding carboxylic acid W2 The carboxylic acid is reacted with 1 ,1 '-carbonyldιιmιdazole and sodium borohydride to provide alcohol W3 Tosylate W4 is then prepared by treating W3 with p-toluenesulfonyl chloride in the presence of an amine base

CHART X

X5

According to Chart X, reagents of the formula G-X as depicted in formula X5 may be prepared L- SeÏ€ne methyl ester is treated with benzaldehyde and NaBH(OAc) ₃ to afford benzylamme X1 which is subsequently coupled (BDP, 1 -HOBT, diisopropylethylamme) with λ/-(tert-butoxycarbonyl)glycιne to provide X2 The tert-butylcarbamate is removed under acidic conditions (HCI/chloroform) and the resulting product is cyclized under basic conditions (5% aq NaHCO ₃ ) to provide pιperιzιne-2,5-dιone X3 Piperizine X4 is then prepared by reduction of X3 with a metal hydride (e g lithium aluminium hydride) and the product is subsequently reacted with alkyl sulfonyl chlorides in the presence of an amine base to provide compounds of the formula X5 where R may be but is not limited to methyl, ethyl, propyl, and iso-propyl

CHART Y

Compounds of the general formula Y1 and Y2 (wherein J and K are independently CH ₂ or O) may be further elaborated as described in Chart Y Compounds of the formula Y1 may be oxidized to the carboxylic acid by reaction with an appropriate oxidizing agent (e g pyridinium dichromate) to provide Y3 (X = OH) Similarly, saponification of compounds of the formula Y2 under basic conditions (e g sodium hydroxide) may provide compounds of the formula Y3 (X = OH) Treatment of the resulting carboxylic acids Y3 with oxalyl chloride followed by reaction with ammonia affords the primary amides

Y3 (X = NH ₂ ) The primary amide may then be reacted with a strong dehydrating agent (e g POCI ₃ ) to provide nitriles of the formula Y4

CHART Z

Compounds of the general formula Z1 (wherein J and K are independently CH ₂ or O) may be further elaborated as described in Chart Z Alcohols of the formula Z1 (X = OH) may be reacted with p- toluenesulfonyl chloride in the presence of an amine base to afford compounds of the formula Z1 (Y = OTs) Subsequent reaction of Z1 (X = OTs) with ammonia in a solvent such as methanol provides amines of the formula Z2 The resulting amine may be reacted with alkyl halides or with alkanals in the presence of a reducing agent to provide compounds of the formula Z3 (R = C,. ₆ alkyl) Alternatively, the amine Z2 may be reacted with carboxylic acid halides to provide compounds of the formula Z3 (R = COR ²³ ) or with sulfonyl chlorides to provide compounds of the formula Z3 (R = SO ₂ R ³⁷ )

CHART AA

AA1 AA2

Compounds of the general formula AA1 may be further elaborated as described in Chart AA The amine may be reacted with alkyl halides or with alkanals in the presence of a reducing agent to provide compounds of the formula AA2 (R = C,. ₆ alkyl) Alternatively, the amine AA1 may be reacted with carboxylic acid halides to provide compounds of the formula AA2 (R = COR ⁹ ) or with sulfonyl chlorides to provide compounds of the formula AA2 (R = SO ₂ R ³⁶ )

CHART BB

BB1 BB2

Compounds of the general formula BB1 may be further elaborated as described in Chart BB The amine may be reacted with alkyl halides or with alkanals in the presence of a reducing agent to provide compounds of the formula BB2 (R = C _1-6 alkyl) Alternatively, the amine BB1 may be reacted with carboxylic acid halides to provide compounds of the formula BB2 (R = COR ⁹ ) or with sulfonyl chlorides to provide compounds of the formula BB2 (R = SO ₂ R ¹² )

CHART CC

CC1 CC2

Compounds of the general formula CC 1 (where X is CH ₂ or O) may be further elaborated as described in Chart CC The amine may be reacted with alkyl halides or with alkanals in the presence of a reducing agent to provide compounds of the formula CC2 (R = C _1-6 alkyl) Alternatively, the amine CC1 may be reacted with carboxylic acid halides to provide compounds of the formula CC2 (R = R ⁹ ) or with sulfonyl chlorides to provide compounds of the formula CC2 (R = R ¹² )

CHART DD

DD1 DD2

As described in Chart DD, compounds of the formula DD1 may be oxidized in the presence of oxone to provide tetrahydrothιopyran-1 ,1 -dιone derivatives of the formula DD2

CHART EE

EE4 EE3

Compounds of formula (I) in which L is an oxadiazole ring may be prepared as described in Chart EE Nitriles of the formula EE1 obtained as described in Chart C and Chart G above are treated with hydroxylamine hydrochloride under basic conditions (e g sodium hydroxide) to provide compounds of the formula EE2 Compounds EE2 are then reacted with compounds of the formula G-CO ₂ H in the presence of an activating agent (e g N-hydroxybenzotriazole) and a coupling reagent (e g polymer supported carbodiimide resin) to afford compounds of the formula EE3 which upon heating in the presence of a base provide EE4

CHART FF

Compounds of formula (I) in which L is a 1 ,2,3-trιazole ring, M is N, and Q is N may be prepared as described in Chart FF Esters of the formula C4 obtained as described in Chart C are reacted with trialkylsilylacetylene (where R may be but not limited to methyl, ethyl, isopropyl) under Sonogashira coupling conditions (e g catalytic CuI ₁ Ph ₃ P, and (Ph ₃ P) ₂ PdCI ₂ ) to provide alkynes FF1 which are subsequently treated with lithium hydroxide to afford carboxylic acids of the formula FF2 Treatment of FF2 with a primary amine of the formula W-NH ₂ in the presence of O-(7-azabenzotrιazol-1 -yl)- N,N,N',N'-tetramethyluronιum hexafluorophosphate provides amides of the formula FF3 Cyclization of FF3 with azides of the formula G-N ₃ in the presence of catalytic copper(ll) sulfate and sodium ascorbate provide 1 ,2,3-trιazoles of the formula FF4

CHART GG

Compounds of formula (I) in which L is a 1 ,2,3-trιazole ring, M is N, and Q is N may be prepared as described in Chart GG Esters of the formula C3 obtained as described in Chart C are reacted with a primary amine of the formula W-NH ₂ to provide amides of the formula GG1 Treatment of hydroxypyrimidmes GG 1 with oxalyl chloride/DMF affords chloropyrimidines of the formula GG2 Amides GG2 are reacted with trialkylsilylacetylene (where R may be but not limited to methyl, ethyl, isopropyl) under Sonogashira coupling conditions (e g catalytic CuI, Ph ₃ P, and (Ph ₃ P) ₂ PdCI ₂ ) to provide alkynes GG3, which are subsequently treated with a fluoride ion source (e g potassium fluoride) to afford terminal alkynes of the formula GG4 Cyclization of GG4 with azides of the formula G-N ₃ in the presence of catalytic copper(ll) sulfate and sodium ascorbate provide 1 ,2,3-trιazoles of the formula FF4

CHART HH

HH3 HH2

FF4

Compounds of formula (I) in which L is a 1 ,2,3-trιazole ring, M is N, and Q is N may be prepared as described in Chart HH Esters of the formula FF1 obtained as described in Chart FF are reacted with a fluoride ion source (e g potassium fluoride) to afford terminal alkynes of the formula HH 1 Cyclization of HH1 with azides of the formula G-N ₃ in the presence of catalytic copper(ll) sulfate and sodium ascorbate provide 1 ,2,3-trιazoles of the formula HH2 which are subsequently treated with lithium hydroxide to afford carboxylic acids of the formula HH3 Treatment of HH3 with a primary amine of the formula W-NH ₂ in the presence of O-(7-azabenzotrιazol-1 -yl)-N,N,N',N'- tetramethyluromum hexafluorophosphate provides amides of the formula FF4

CHART Il

113 112

FF4

Compounds of formula (I) in which L is a 1 ,2,3-trιazole ring, M is N, and Q is N may be prepared as described in Chart Il Esters of the formula C4 obtained as described in Chart C are reacted with trialkylsilylacetylene (where R may be but not limited to methyl, ethyl, isopropyl) under Sonogashira coupling conditions (e g catalytic CuI, Ph ₃ P, and (Ph ₃ P) ₂ PdCI ₂ ) to provide alkynes 111 , which are subsequently treated with lithium hydroxide to afford carboxylic acids of the formula II2 Cyclization of II2 with azides of the formula G-N ₃ in the presence of catalytic copper(ll) sulfate and sodium ascorbate provide 1 ,2,3-trιazoles of the formula II3 Treatment of 113 with a primary amine of the formula W-NH ₂ in the presence of O-(7-azabenzotrιazol-1 -yl)-N,N,N',N'-tetramethyluronιum hexafluorophosphate provides amides of the formula FF4

Azides of the formula G-N ₃ employed in Charts FF - Il may be prepared alcohols G-OH obtained commercially or prepared as described in Charts J - X For example, the alcohol G-OH may be converted to a sulfonate ester which is then subjected to substitution by a nucleophilic azide source (e g sodium azide)

CHART JJ

JJ3 JJ4 JJ5 JJ6

Reagents of the formula G-X such as ((2S,5R)-5-(hydroxymethyl)-1 ,4-dιoxan-2-yl)methyl 4- methylbenzenesulfonate (JJ6) may be prepared as described in Chart JJ /?-Epιchlorohydrιn, JJ 1 , was reacted with benzyl alcohol using boron trifluoride etherate as an acid catalyst to provide the alcohol of formula JJ2 The alcohol of formula JJ2 was reacted with the S-glycidol tosylate using boron trifluoride etherate as an acid catalyst to provide the alcohol of formula JJ3 The alcohol of formula JJ3 was cychzed under basic conditions (e g , aqueous sodium hydroxide) to provide the alcohol of formula JJ4 The alcohol of formula JJ4 was reacted with p-toluenesulfonyl chloride in the presence of an amine base (e g , pyridine) to provide the tosylate of formula JJ5 The benzyl ether of formula JJ5 was reacted with hydrogen gas in the presence of palladium on carbon to provide the alcohol of formula JJ6

CHART KK

FF3 KK1

Compounds of formula (I) in which L is an isoxazole ring, M is N, and Q is N may be prepared as described in Chart KK Alkynes of the formula FF3 described in Chart FF may be reacted with 2-

chloro-2-(hydroxyιmιno)-derιvatιves of the formula G-C(NOH)-CI in the presence of an amine base (e g triethylamine) in toluene at temperatures from 20 - 1 10 ⁰ C The chloro-hydroxyimines are readily prepared from the corresponding aldehydes by reaction with hydroxylamme hydrochloride and sodium acetate followed by chlorination by λ/-chlorosuccιnιmιde

CHART LL

Compounds of the general formula Y3 (wherein X is OH, J and K are independently CH ₂ or O) may be further elaborated as described in Chart LL Compounds of the formula Y3 (X = OH) may be reacted with an amine of the general formula HNR ³⁸ R39 in the presence of 1 ,1 '-carbonyldιιmιdazole (or other suitable carboxylic acid activating agent) to afford amides of the general formula LL1

CHART MM

MM1 MM2 MM3

Compounds of the general formula MM1 (wherein R is an alkyl group) may be elaborated as described in Chart MM Esters of the formula MM1 may be reacted with an inorganic base (e g sodium hydroxide, lithium hydroxide) in a mixture of water and an organic solvent (e g tetrahydrofuran) to afford carboxylic acids of the formula MM2 Carboxylic acids of the formula MM2 may be reacted with an amine of the formula W-NH ₂ in the presence of a suitable carboxylic acid activating agent (e g 1 ,1 '-carbonyldιιmιdazole, 1 -hydroxybenzotÏ€azole/1 -ethyl-3-(3'- dιmethylamιnopropyl)carbodιmιde hydrochloride) to afford amides of the formula MM3 Alternatively, esters of the formula MM1 (wherein R is methyl or ethyl) may be reacted with an amine of the formula W-NH ₂ at temperatures of 20 - 100 ⁰ C either neat or in a minimal amount of an organic solvent (e g

methanol, tetrahydrofuran, and λ/,λ/-dιmethylformamιde) to provide amides of the formula MM3 directly

CHART NN

Compounds of the general formula NN 1 (wherein R is alkyl, J and K are independently CH ₂ or O) may be further elaborated as described in Chart NN Alcohols of the formula NN 1 (X = OH) may be reacted with p-toluenesulfonyl chloride in the presence of an amine base to afford compounds of the formula NN1 (Y = OTs) Subsequent reaction of NN1 (X = OTs) with the sodium salt of thioalkoxides of the formula HSR ²³ to afford compounds of the formula NN2 Sulfides of the formula NN2 may be oxidized by 3-chloroperbenzoιc acid to provide sulfones of the formula NN3 Compounds of formula NN2 and NN3 may be further elaborated as described in Chart MM to afford amides of Formula (I)

The compounds of Formula (I) may be prepared as single enantiomer or as a mixture of individual enantiomers which includes racemic mixtures Methods to obtain preferentially a single enantiomer from a mixture of individual enantiomers or a racemic mixture are well known to those ordinarily skilled in the art of organic chemistry Such methods include but are not limited to preferential crystallization of diastereomeric salts (e g tartrate or camphor sulfonate), covalent deπvatization by a chiral, non- racemic reagent followed by separation of the resulting diastereomers by common methods (e g

crystallization, chromatographic separation, or distillation) and chemical reversion to scalemic compound, Simulated Moving Bed technology, or high/medium-pressure liquid chromatography or supercritical fluid chromatography employing a chiral stationary phase These techniques may be performed on the final compounds of Formula (I) or on any intermediates to compounds of Formula (I) which bear a stereogenic center Also, to facilitate separation by any of the methods described above, the compounds of Formula (I) or any intermediates to the compounds of Formula (I) which bear a stereogenic center may be transiently reacted with an achiral reagent, separated, and then reverted to scalemic compound by standard synthetic techniques

Detailed Preparative Methods

The detailed examples below illustrate preparation of compounds of this invention Other compounds of this invention may be prepared using the methods illustrated in these examples, either alone or in combination with techniques generally known in the art The following examples are merely illustrative, and not limiting to the remainder of this disclosure in any way

Example 1

/V-(4-Fluoro-3-methoxybenzyl)-6-(2-((frans-4-aminocyclohe xyl)methyl)-2H-tetrazol-5- yl)pyrimidine-4-carboxamide

Step 1 Preparation of methyl θ-cvanopyrimidine^-carboxylate

Commercially available methyl 6-chloropyrιmιdιne-4-carboxylate (1 00 g, 5 80 mmol) was taken up in dichloromethane (20 mL) and then treated with tetraethyl ammonium cyanide (0 996 g, 6 37 mmol) and 1 ,4-dιazabιcyclo[2 2 2]octane (0 13 g, 1 2 mmol) The reaction was allowed to stir at room temperature for 0 5 h The reaction was diluted with diethyl ether (40 mL) then washed with water (1 x 25 mL) and brine (1 x 40 mL) The organics were poured onto a silica plug (20 g) and eluted with diethyl ether (200 mL) to afford the title compound as an orange oil (0 85 g, 90%) LC/MS (5%- 95% CH ₃ CN/H ₂ O, 6 mm) 0 267 mm, m/z 164 (M+Na)

Step 2 Preparation of methyl 6-(2/-/-tetrazol-5-yl)pyrιmιdιne-4-carboxylate

Methyl θ-cyanopyÏ€midine^-carboxylate (1 43 g, 8 77 mmol) was taken up in methanol (40 mL) and treated with sodium azide (598 mg, 9 20 mmol) and zinc (II) bromide (1 97 g, 8 77 mmol) The reaction was stirred at room temperature for 15 h and then was concentrated This residue was diluted with water (8 mL) and 1 N aqueous hydrochloric acid (40 mL) and stirred one hour The resulting slurry was filtered with the solids washed with water (10 mL) and dried in vacuo to afford the title compound as a yellow solid (1 37 g, 76%) LC/MS (5%-95% CH ₃ CN/H ₂ O, 6 mm) 0 54 mm, m/z 207 (M+H) Step 3 Preparation of 4-fluoro-3-methoxybenzylamιne hydrochloride

A 2G Parr reactor (4842) was charged with 4-fluoro-3-methoxy-benzonιtrιle (133 0 g, 0 88 mol), ethano! (3550 mL), concentrated hydrochloric acid (396 ml, 4 75 mol) and 10% Pd/C with 50% water (13 3 g) The resulting mixture was stirred with heating at 30-33 ⁰ C under hydrogen pressure (40-50 psi, first 2 hours refill hydrogen every 20 mm) overnight The reaction mixture was cooled to room temperature, filtered through Celiteâ„¢ and the filtrate concentrated The residue obtained was treated with acetonitrile (250 mL) and the white solid was filtered, washed with cold acetonitrile and vacuum dried to afford the title compound (140 g, 83%) MS (ES+) m/z 156 (M+H) Elemental analysis found C, 49 97, H, 6 13, N, 7 59 Step 4 Preparation of λ/-(4-fluoro-3-methoxybenzyl)-6-(2H-tetrazol-5-yl)pyrιmιd ιne-4-carboxamιde

Methyl 6-(2H-tetrazol-5-yl)pyrιmιdιne-4-carboxylate (0 75 g, 3 64 mmol) was taken up in dimethylacetamide (5 mL) and then treated with 4-fluoro-3-methoxybenzylamιne hydrochloride (1 57 g, 8 19 mmol) and triethylamine (1 5 g, 14 mmol) and left to stir for 15 hours at room temperature The mixture was diluted with 1 N aqueous NaOH (15 mL) and then washed with diethyl ether (2 x 10 mL) The mixture was then adjusted to pH 3 with concentrated Hydrochloric acid and stirred with ethyl acetate ( 10 mL) After 1 h, the organic layer was separated and concentrated to an oil that solidified affording the title compound as a beige solid (1 05 g, 88%) LC/MS (5%-95% CH ₃ CN/H ₂ O, 6 mm) 2 26 mm, m/z 330 (M+H)

Step 5 Preparation of λ/-(4-fluoro-3-methoxybenzyl)-6-(2-((frans-4-amιnocvclohex yl)methyl)-2/-/- tetrazol-5-yl)pyrimidine-4-carboxamide

λ/-(4-Fluoro-3-methoxybenzyl)-6-(2/-/-tetrazol-5-yl)pyrιmÎ ¹dιne-4-carboxamιde (0 91 g, 2 8 mmol) and commercially available tert-butyl /rans-4-(hydroxymethyl)cyclohexylcarbamate (760 mg, 3 32 mmol) were taken up in tetrahydrofuran (20 mL) and treated with polymer supported triphenylphosphine (1 54 g, 3 32 mmol) After stirring for 30 mm at room temperature, di-tert-butyl azodicarboxylate (954 mg, 4 15 mmol) was added After 15 h at room temperature, the reaction was filtered to remove the resin The filtrate was concentrated to a crude oily residue The residue was purified via normal phase chromatography (silica, 0-75% ethyl acetate/heptane with a trace 1 % methanol ran through entire gradient) to afford the protected amine as a mixture of regioisomers ( 0 97 g, 65%, 1 80 mmol) which was subsequently dissolved in dichloromethane (5 mL) and treated with tÏ€fluoroacetic acid (2 0 mL, 15 mmol) After the reaction was stirred at ambient temperature for 3 h, the mixture was diluted with dichloromethane (5 mL) and neutralized with 2 5 N aqueous NaOH to achieve pH 7-8 The organic layer was separated and washed with water (3 mL), dried over sodium sulfate, and concentrated to afford the title compound (0 87 g, 72%) LC/MS (5%-95% CH ₃ CN/H ₂ O, 6 mm) 2 06 mm, m/z 441 (M+H)

Example 2

/V-(4-Fluoro-3-methoxybenzyl)-6-(2-(((rans-4-((methylsulf onyl)amino)cyclohexyl)methyl)-2H- tetrazol-5-yl)pyrimidine-4-carboxamide

λ/-(4-Fluoro-3-methoxybenzyl)-6-(2-((frans-4-amιnocyclohex yl)methyl)-2H-tetrazol-5- yl)pyrιmιdιne-4-carboxamιde (prepared as described in Example 1 ) (0 870 g, 1 98 mmol) was taken up in dichloromethane (5 mL) and treated with methane sulfonyl chloride ( 0 17 mL, 2 1 mmol) and tÏ€ethytamine (0 30 mL, 2 2 mmol) After 1 h at room temperature, the reaction was concentrated The residue was purified via reverse phase chromatography (4-60% acetonitrile/water over 45 minutes) with the first eluted compound was isolated to afford the title compound as a white solid (143 mg, 14%) LC/MS (5%-95% CH ₃ CN/H ₂ O, 6 mm) 3 98 mm, m/z 519 (M+H) ¹ H NMR (400 MHz, DMSOd ₆ ) δ ppm 1 04 - 1 25 (m, 4 H), 1 61 (br s , 2 H), 1 83 - 1 99 (m, 3 H), 2 83 (s, 3 H), 3 00 (br s , 1 H), 3 78 (s, 3 H), 4 46 (d, J=Q 0 Hz, 2 H), 4 66 (d, J=6 6 Hz, 2 H), 6 89 (d, J=I 3 Hz, 2 H), 7 03 - 7 21 (m, 2 H) ₁ 8 56 (s, 1 H), 9 46 (s, 1 H), 9 61 (t, J=6 1 Hz, 1 H)

Example 3

W-(3-Chloro-4-fluorobenzyl)-6-(2-((frans-4-aminocyclohexy l)methyl)-2H-tetrazol-5-yl)pyrimidine-

4-carboxamide

Step 1 Preparation of λ/-(3-chloro-4-fluorobenzyl)-6-(2H-tetrazol-5-yl)pyrιmιdÎ ¹ne-4-carboxamιde

Methyl 6-(2H-tetrazol-5-yl)pyrιmιdιne-4-carboxylate (prepared as described in step 2 of the synthesis of /V-(4-fluoro-3-methoxybenzyl)-6-(2-((frans-4-ammocyclohexyl) methyl)-2/-/-tetrazol-5- yl)pyrιmιdιne-4-carboxamιde, Example 1 ) (0 72 g, 3 49 mmol) was taken up in dimethylacetamide (5 mL), treated with commercially available (4-fluoro-3-chlorophenyl)methanamιne (1 23 g, 7 68 mmol) and triethylamine (1 95 g, 14 mmol), and left to stir for 15 hours at room temperature The mixture was diluted with 1 N aqueous NaOH (15 mL) and then washed with diethyl ether (2 x 10 mL) The mixture was then adjusted to pH 3 with concentrated Hydrochloric acid, stirred with ethyl acetate (10 mL), and filtered to afford the title compound as a pale yellow solid (0 71 g, 61 %) LC/MS (5%-95% CH ₃ CN/H ₂ O, 6 mm) 2 19 mm, m/z 334 (M+H)

Step 2 Preparation of Ay-(3-chloro-4-fluorobenzyl)-6-(2-((frans-4-amιnocvclohexyl )methyl)-2/-/-tetrazol- 5-yl)pyrιmιdιne-4-carboxamιde

λ/-(4-Fluoro-3-chlorobenzyl)-6-(2H-tetrazol-5-yl)pyπmι dιne-4-carboxamιde (0 71 g, 2 1 mmol) and commercially available tert-butyl frans-4-(hydroxymethyl)cyclohexylcarbamate (585 mg, 2 55 mmol) were taken up in tetrahydrofuran (20 mL) and treated with polymer supported triphenylphosphme (1 19 g, 2 55 mmol) After stirring for 30 mm at room temperature, di-tert-butyl azodicarboxylate (735 mg, 3 19 mmol) was added After 15 h at room temperature, the reaction was filtered to remove the resin The filtrate was concentrated to a crude oily residue The residue was purified via normal phase chromatography (silica, 0-75% ethyl acetate/heptane with a trace 1 % methanol ran through entire gradient) to afford the protected amine (1 08 g, 93%, 1 99 mmol) which was taken up in dichloromethane (5 mL) and treated with trifluoroacetic acid (2 0 mL, 15 mmol) After the reaction was stirred at ambient temperature for 3 h, the mixture was diluted with dichloromethane (5 mL) and neutralized with 2 5 N aqueous NaOH to achieve pH 7-8 The organic layer was

separated, washed with water (3 mL), then dried over sodium sulfate, and concentrated to afford the title compound as an amber oil (0 87 g, 92%) LC/MS (5%-95% CH ₃ CN/H ₂ O, 6 mm) 2 24 mm, m/z 445 (M+H)

Example 4

W-(3-Chloro-4-fluorobenzyl)-6-(2-(((rans-4-((methylsulfon yl)amino)cyclohexyl)methyl)-2H- tetrazol-5-yl)pyrimidine-4-carboxamide

λ/-(3-Chloro-4-fluorobenzyl)-6-(2-((frans-4-ammocyclohexyl) methyl)-2/-/-tetrazol-5- yl)pyrιmιdιne-4-carboxamιde (prepared as described in Example 3) (0 87 g, 2 0 mmol) was taken up in dichloromethane (5 mL) and treated with methane sulfonyl chloride (0 17 mL, 2 1 mmol) and triethylamine (0 30 mL, 2 2 mmol) After 1 h at room temperature, the reaction was concentrated to a crude residue The residue was purified via reverse phase chromatography (4-60% acetonitrile/water over 45 minutes) The first eluted compound was isolated to afford the title compound as a white solid (105 mg, 10%) LC/MS (5%-95% CH ₃ CN/H ₂ O, 6 mm) 4 22 mm, m/z 523 (M+H) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1 04 - 1 27 (m, 4 H), 1 59 (d, J=10 8 Hz, 2 H), 1 80 - 1 98 (m, 3 H), 2 83 (s, 3 H), 3 01 (d, J=6 8 Hz, 1 H), 4 48 (d, J=6 2 Hz, 2 H), 4 66 (d, J=6 8 Hz, 2 H), 6 89 (d, J=7 3 Hz, 1 H), 7 25 - 7 36 (m, 2 H), 7 48 - 7 58 (m, 1 H), 8 55 (d, J=1 3 Hz, 1 H), 9 46 (d, J=1 1 Hz, 1 H), 9 71 (t, J=6 3 Hz ₁ 1 H)

Example 5 W-(3-Methoxybenzyl)-6-(2-(((frans)-4-aminocyclohexyl)methyl) -2H-tetrazol-5-yl)-2- methylpyrimidine-4-carboxamide

Step 1 Preparation of 6-chloro-2-methylpyrιmιdιn-4-ol

HCk ^^ _^ CI

N^ . N

To a 0 ⁰ C solution of 13M sulfuric acid (1 2 L, 15 6 mol) was added portion-wise solid 4,6- dιchloro-2-methylpyrιmιdιne (475 g, 2 91 mol) The resulting mixture was allowed to warm to room temperature over 1 5 hours The solution was poured into a well stirred iced solution of 6N NaOH (3 6 L, 21 6 mol) The resulting solids were then collected by vacuum filtration and washed with warm

water (3 x 1 L) High vacuum drying at 35 ⁰ C provided the title compound as a white solid (393 4 g, 93%) LC/MS (5%-95% CH ₃ CN/H ₂ O, 6 mm) 0 95 mm, m/z 145 (M+H) ¹ H NMR (400 MHz, DMSO-^ ₆ ) δ ppm 12 81 (br s, 1 H), 6 30 (s, 1 H), 2 26 (s, 3 H)

Step 2 Preparation of methyl 6-hvdroxy-2-methylpyrιmιdιne-4-carboxylate

6-Chloro-2-methylpyrιmtdιn-4-ol (36 7 g, 254 mmol), [1 ,1'-bιs(dιphenylphosphιno)ferrocene]- palladιum(ll) dichloride (10 4 g, 12 7 mmol), and dnsopropylethylamine (49 2 g, 381 mmol) were combined in methanol (254 mL) The reaction was heated to 85 ⁰ C in the presence of carbon monoxide (10 7 g, 381 mmol, 50 psi) for 24 hours The reaction was allowed to cool to room temperature and the resulting solids collected by vacuum filtration The solids were rinsed with methanol (100 mL) and diethyl ether (2 x 100 mL) Vacuum drying provided the title compound as a brown solid (38 7 g, 91 %) LC/MS (5%-95% CH ₃ CN/H ₂ O, 3 mm 0 29 mm, m/z 169 (M+H) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 12 79 (br s, 1 H), 6 68 (s, 1 H), 3 79 (s, 3 H), 2 29 (s, 3 H)

Step 3 Preparation of methyl 6-chloro-2-methylpyrιmιdιne-4-carboxylate

Methyl 6-hydroxy-2-methylpyÏ€mιdme-4-carboxylate (30 O g, 178 mmol) was dissolved in dichloromethane (446 mL) Oxalyl chloride (18 6 mL, 1 2 equiv) was added followed by addition of λ/,λ/-dιmethylacetamιde (3 5 mL, 0 25 equiv) The mixture was heated to reflux for 2 hours After cooling to room temperature, the insolubles were removed by filtration and the filtrate partially concentrated Purification by silica gel chromatography (35/65, ethyl acetate/heptane) provided the title compound as a white solid (26 6 g, 80%) LC/MS (5%-95% CH ₃ CN/H ₂ O, 4 mm 1 59 mm, m/z 187 (M+H) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 7 90 (s, 1 H), 3 88 (s, 3 H), 2 65 (s, 3 H)

Step 4 Preparation of methyl 6-cyano-2-methylpyrιmιdιne-4-carboxylate

O

XN

O ^'

N •.\^ ^N'

Methyl 6-chloro-2-methylpyrimidine-4-carboxylate (30 O g, 161 mmol) was dissolved in dichloromethane (460 mL) Tetraethylammonium cyanide (27 6 g, 177 mmol) was added followed by 1 ,4-dιazabιcyclo[2 2 2]octane (3 60 g, 32 0 mmol) The reaction was stirred for 30 mm at room temperature The reaction mixture was washed with 1 N NaOH (3 x 100 mL), water (2 x 100 mL) and brine (200 mL) The organic layer was dried over sodium sulfate, filtered, and evaporated to give a

dark brown solid Purification by silica gel chromatography (2/1 , ethyl acetate/heptane) provided the title compound as a white crystalline solid (24 4 g, 86%) LC/MS (5%-95% CH ₃ CN/H ₂ O, 4 mm 0 96 mm, m/z 178 (M+H) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8 38 (s, 1 H), 3 88 (s, 3 H), 2 75 (s, 3 H)

Step 5 Preparation of 6-cvano-λ/-(3-methoxybenzyl)-2-methylpyrιmιdιne-4-carbox amιde

3-Methoxybenyzlamιne (9 68 g, 70 6 mmol) and methyl 6-cyano-2-methylpyrιmιdιne-4- carboxylate (10 0 g, 56 4 mmol) were dissolved in λ/,λ/-dιmethylacetamιde (1 13 mL) Diisopropylethylamine (25 5 g, 198 mmol) was added and the mixture heated to 100 ⁰ C for 2 hours After cooling to room temperature, the mixture was diluted with water (250 mL) and extracted with ethyl acetate (3 x 250 mL) The combined organics were then washed with brine (250 mL) and dried over sodium sulfate, filtered, and evaporated to give a red oil Purification by silica gel chromatography (20/80, ethyl acetate/heptane) provided the title compound as a white solid (14 6 g, 92%) LC/MS (5%- 95% CH ₃ CN/H ₂ O, 4 mm 2 49 mm, m/z 283 (M+H) ¹ H NMR (400 MHz, DMSOd ₆ ) 6 ppm 9 55 (t, J=Q 2 Hz, 1 H), 8 31 (s, 1 H), 7 19 (t, J=8 1 Hz, 1 H), 6 74 - 6 89 (m, 3 H), 4 44 (d, J=6 3 Hz, 2 H), 3 69 (s, 3 H), 2 75 (s, 3 H)

Step 6 Preparation of λ/-(3-methoxybenzyl)-2-methyl-6-(2H-tetrazol-5-vDpyrιmιdÎ ¹ne-4-carboxamιde

6-Cyano-λ/-(3-methoxybenzyl)-2-methylpyrιmιdιne-4-carbox amιde (14 2 g, 50 3 mmol), sodium azide (3 60 g, 55 3 mmol), and zinc bromide (1 1 3 g, 50 3 mmol) were suspended in water (1 12 mL) The reaction was heated to reflux for 16 hours After cooling to room temperature, 6N hydrochloric acid (180 mL) was added and the mixture stirred vigorously for 1 hour The solids were collected by vacuum filtration and rinsed with 6N hydrochloric acid (3 x 100 mL) and water (2 x 100 mL) High vacuum drying at 55 ⁰ C provided the title compound as a white solid (15 0 g, 92%) LC/MS (5%-95% CH ₃ CN/H ₂ O, 4 mm 2 38 mm, m/z 326 (M+H) ¹ H NMR (400 MHz, DMSO-d _δ ) δ ppm 9 53 (t, J=Q 4 Hz, 1 H), 8 42 (s, 1 H), 7 21 (t, J=8 2 Hz, 1 H), 6 86 - 6 91 (m, 2 H), 6 76 - 6 82 (m, 1 H), 4 48 (d, J=Q 6 Hz, 2 H), 3 70 (s, 3 H), 2 82 (s, 3 H)

Step 7 Preparation of (frans-4-((terf-butoxγcarbonyl)amιno)cvclohβxyl)methyl 4- methylbenzenesulfonate

p-Toluene sulfonyl chloride (1 68 g, 8 81 mmol) was added to a solution of tert-butyl trans-(4- hydroxymethyl)cyclohexylcarbamate (1 84 g, 8 02 mmol) in pyridine (10 mL) at 0 ⁰ C The reaction mixture was allowed to slowly warm to room temperature After 6 h, the mixture was cooled to 0 °C and treated with water (100 mL) The resulting precipitate was filtered, washed with cold water (2 x 20 mL), and dried in vacuo to afford the title compound as a white solid (2 91 g, 95%) ¹ H NMR (400 MHz, DMSOd ₆ ) δ ppm 7 78 (d, J=8 3 Hz, 2 H), 7 49 (d, J=8 2 Hz, 2 H), 6 69 (d, J=8 0 Hz, 1 H), 3 82 (d, J=6 2 Hz, 2 H), 3 04 - 3 14 (m, 1 H), 2 43 (s, 3 H), 1 69 - 1 76 (m, 2 H), 1 57 - 1 64 (m, 2 H), 1 42 - 1 53 (m, 1 H), 1 36 (s, 9 H), 1 01 - 1 12 (m, 2 H), 0 85 - 0 96 (m, 2 H)

Step 8 Preparation of tert-butyl frans-4-((5-(6-((3-methoxybenzyl)carbamoyl)-2-methylpyrιmι dιn-4-yl)- 2H-tetrazol-2-yl)methyl)cvclohexylcarbamate

Triethylamine (280 mg, 2 7 mmol) and (frans-4-((fert-butoxycarbonyl)amino)cyclohexyl)methyl 4-methylbenzenesulfonate (530 mg, 1 38 mmol) was added to a solution of λ/-(3-methoxybenzyl)-2- methyl-6-(2H-tetrazol-5-yl)pyrιmιdιne-4-carboxamιde (450 mg, 1 38 mmol) in anhydrous dimethylacetamide (0 5 mL) The reaction was stirred overnight at 85 ⁰ C in a capped vial The reaction mixture was purified by reverse phase preparative HPLC (water/acetonitrile) to afford the title compound as a white solid (342 mg)

Step 9 Preparation of /V-(3-methoxybenzyl)-6-(2-(((frans)-4-amιnocyclohexyl)methy l)-2/-/-tetrazol-5-yl)- 2-methylpyrιmιdtne-4-carboxamιde

4M Hydrochloric acid in dioxane (5 mL) was added to a solution of tert-butyl /rans-4-((5-(6-((3- methoxybenzyl)carbamoyl)-2-methylpyrιmιdιn-4-yl)-2H-tetra zol-2-yl)methyl)cyclohexylcarbamate (342 mg) in acetonitrile (1 5 mL) The reaction was stirred overnight at room temperature The solvent was removed under vacuum and the residue was slurried 2x in ether (ether decanted off each time) and

the resultant solid was dried under vacuum to afford the hydrochloride salt of the title compound as a white solid (418 mg)

Example 6

W-(3-Methoxybenzyl)-2-methyl-6-(2-(((frans-4-(methylsulfo namido)cyclohexyl)methyl)-2H- tetrazol-5-yl)pyrimidine-4-carboxamide

Triethylamine (60 mg, 0 6 mmol) and methane sulfonyl chloride (34 mg, 0 3 mmol) were added to a solution of λ/-(3-methoxybenzyl)-6-(2-(((frans)-4-amιnocyclohexyl)meth yl)-2H-tetrazol-5-yl)- 2-methylpyrιmιdιne-4-carboxamιde (prepared as described in Example 5) (100 mg, 0 19 mmol) in dichloromethane (1 mL) The reaction was stirred overnight at room temperature The reaction mixture was purified by reverse phase preparative HPLC (water/acetonitÏ€le) to afford the title compound as a white solid (41 mg) MS (ES+) m/z 515 (M+H) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9 49 (1 H, br s ), 8 41 (1 H, s), 7 56 (1 H, br s ), 7 22 - 7 30 (1 H, m), 6 93 (2 H, br s ), 6 84 (1 H, br s ), 4 70 (2 H, d, J=7 0 Hz), 4 51 (2 H, d, J=5 9 Hz), 3 74 (2 H, s), 3 05 (2 H, br s ), 2 86 (6 H, d, J=19 8 Hz), 1 90 (3 H, br s ), 1 64 (2 H, br s ), 1 20 (5 H, d, J=11 0 Hz)

Example 7

W-(3-Methoxybenzyl)-6-(2-((frans-4-acetamidocyclohexyl)me thyl)-2H-tetrazol-5-yl)-2- methylpyrimidine-4-carboxamide

Triethylamine (60 mg, 0 6 mmol) and acetic anhydride (31 mg, 0 3 mmol) were added to a solution of N-(3-methoxybenzyl)-6-(2-(((frans)-4-aminocyclohexyl)methy!) -2H-tetrazol-5-yl)-2- methylpyrιmιdιne-4-carboxamιde (prepared as described in Example 5) (100 mg, 0 19 mmol) in dichloromethane (1 mL) The reaction was stirred overnight at room temperature The reaction mixture was purified by reverse phase preparative HPLC (water/acetonitrile) and neutralized by passing through a small carbonate column to afford the title compound as a white solid (34 mg) MS (ES+) m/z 479 (M+H) ¹ H NMR (400 MHz, DMSO-d ₅ ) δ ppm 9 49 (1 H, br s ), 8 41 (1 H, s), 7 65 (1 H, d, J=7 7 Hz), 7 33 (1 H, br s ), 7 24 (1 H, s), 6 93 (1 H, br s ), 6 81 (1 H, br s ), 4 70 (2 H, d, J=6 6 Hz), 4 51 (2 H, d, J=6 6 Hz), 3 74 (3 H, s), 3 46 (1 H, br s ), 2 83 (3 H, s), 1 99 (1 H, br s ), 1 75 (5 H, s), 1 61 (2 H, br s ), 1 15 (5 H, d, J=10 2 Hz)

Example 8

W-(3-Methoxybenzyl)-6-(2-((((rans)-4-(2-hydroxyacetamido) cyclohexyl)methyl)-2H-tetrazol-5-y!)-

2-methylpyrimidine-4-carboxamide

λ/-(3-Methoxyben2yl)-6-(2-(((frans)-4-amιnocyclohexyl)meth yl)-2/-/-tetrazol-5-yl)-2- methylpyrιmιdιne-4-carboxannιde (prepared as described in Example 5) (146 mg, 0 287 mmol), triethylamine (102 mg, 1 OO mmol) and acetoxy acetyl chloride (47 mg, 0 344 mmol) were combined in dichloromethane (4 mL) After stirring for 10 mm, the mixture was concentrated and then treated with acetonitrile (2 mL) and 2 5 N sodium hydroxide (2 mL) After 1 h, the organics were removed under nitrogen stream and the aqueous was adjusted to pH 6 with 10% hydrogen chloride The mixture was extracted with ethyl acetate (2 x 5 mL) The combined organic layers were dried over magnesium sulfate, filtered, and concentrated to afford the title compound as a yellow solid (64 7 mg, 46%) LC/MS (10%-90% CH ₃ CN/H ₂ O, 6 mm) 4 44 mm m/z 495 (M+H) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9 47 (br, s, 1 H) 8 40 (s, 1 H), 7 37 (d, J = 8 05, 1 H), 7 17-7 30 (m, 1 H), 6 91 (br s, 2 H), 6 77 - 6 84 (m, 1 H), 5 38 (s, 1 H), 4 69 (d, J = 6 6 Hz, 2 H), 4 49 (d, J = 6 6 Hz, 2 H), 3 67 - 3 79 (m, 4 H), 3 56 (br s , 1 H), 2 81 (s, 3 H), 1 97 (br s , 1 H), 1 72 (br s , 2 H), 1 60 (d, J = 1 1 0 Hz, 2 H), 1 09 - 1 33 (m, 5 H)

Example 9

/V-(4-Fluoro-3-methoxybenzyl)-6-(2-(frans-4-aminocycIohex yl)methyl)-2H-tetrazol-5-yl)-2- methylpyrimidine-4-carboxamide

Step 1 Preparation of 6-cvano-λ/-(4-fluoro-3-methoxybenzyl)-2-methylpyrιmιdιne -4-carboxamιde

4-Fluoro-3-methoxybenzylamιne hydrochloride (prepared as described in step 3 of the synthesis of λ/-(4-fluoro-3-methoxybenzyl)-6-(2-((frans-4-amιnocyclohex yl)methyl)-2H-tetrazol-5- y!)pyrιmιdιne-4-carboxamιde, Example 1 ) (13 5 g, 70 6 mmol) was dissolved in methanol (56 mL) Diisopropylethylamine (29 2 g, 226 mmol) was added and the mixture stirred for 15 minutes at room temperature Methyl 6-cyano-2-methylpyrιmιdιne-4-carboxylate (prepared as described in step 4 of the

synthesis of λ/-(3-methoxybenzyl)-6-(2-(((frans)-4-amιnocyclohexyl)meth yl)-2/-/-tetrazol-5-yl)-2- methylpyrιmιdιne-4-carboxamιde, Example 5) (10 0 g, 56 4 mmol) was added and the reaction heated to 35 ⁰ C for 1 h The methanol was removed in vacuo and the crude material partitioned between ethyl acetate (500 mL) and 1 N hydrochloric acid (500 mL) The layers were separated and the aqueous layer extracted with ethyl acetate (2 x 250 mL) The combined organics were washed with saturated aqueous sodium bicarbonate (2 x 250 mL) and brine (250 mL) The organic layer was dried over sodium sulfate, filtered, and evaporated to give a brown solid Purification by silica gel chromatography (1/2, ethyl acetate/heptane) provided the title compound as a white solid (1 1 7 g, 69%) LC/MS (5%-95% CH ₃ CN/H ₂ O, 4 mm 2 67 mm, m/z 301 (M+H) ¹ H NMR (400 MHz, DMSOd ₆ ) δ ppm 9 58 (t, J=6 2 Hz, 1 H), 8 32 (s, 1 H), 7 04 - 7 19 (m, 2 H), 6 79 - 6 90 (m, 1 H), 4 44 (d, J=6 2 Hz, 2 H), 3 78 (s, 3 H), 2 76 (s, 3 H)

Step 2 Preparation of /V-(4-fluoro-3-methoxybenzyl)-2-methyl-6-(2/-/-tetrazol-5-yl )pyrιmιdιne-4- carboxamide

6-Cyano-/V-(4-fluoro-3-methoxybenzyl)-2-methylpyrιmιdιne- 4-carboxamιde (4 8O g, 16 0 mmol), sodium azide (1 14 g, 17 6 mmol), and zinc bromide (3 6O g, 16 0 mmol) were suspended in water (36 mL) The reaction was heated to reflux for 16 h After cooling to room temperature, 6N hydrochloric acid (180 mL) was added and the mixture stirred vigorously for 1 hour The solids were collected by vacuum filtration and rinsed with 6N hydrochloric acid (3 x 100 mL) and water (2 x 100 mL) High vacuum drying at 55 ⁰ C provided the title compound as a white solid (5 45 g, 99%) LC/MS (5%-95% CH ₃ CN/H ₂ O, 4 mm 2 56 mm, m/z 344 (M+H) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9 55 (t, J=6 4 Hz, 1 H), 8 42 (s, 1 H), 7 06 - 7 20 (m, 2 H), 6 81 - 6 94 (m, 1 H), 4 47 (d, J=6 4 Hz, 2 H), 3 79 (s, 3 H), 2 82 (s, 3 H)

Step 3 Preparation of terf-butyl <rans-4-((5-(6-((4-fluoro-3-methoxybenzyl)carbamoyl)-2- methylpyrιmιdιn-4-yl)-2H-tetrazol-2-yl)methyl)cvclohexylc arbamate

Triethylamine (176 mg, 1 7 mmol) and (/rans-4-((fe/t-butoxycarbonyl)amιno)cyclohexyl)methyl 4-methylbenzenesulfonate (prepared as described in step 7 of the synthesis of λ/-(3-methoxybenzyl)- 6-(2-(((frans)-4-amιnocyclohexyl)methyl)-2/-/-tetrazol-5-yl )-2-methylpyrιmιdιne-4-carboxamιde, Example 5) (335 mg, 0 87 mmol) was added to a solution of λ/-(4-f!uoro-3-methoxybenzyl)-2-methyl-6- (2H-tetrazol-5-yl)pyrιmιdιne-4-carboxamιde (300 mg, 0 87 mmol) in anhydrous λ/,λ/-dιmethylformamιde (0 6 mL) The reaction was stirred overnight at 85 °C in a capped vial The reaction mixture was

purified by reverse phase preparative HPLC (water/acetonitrile) to afford the title compound as a white solid (130 mg)

Step 4 Preparation of /V-(4-fluoro-3-methoxybenzyl)-6-(2-(frans-4-amιnocvclohexyl )methyl)-2/-/- tetrazol-5-yl)-2-methylpyrιmιdιne-4-carboxamιde

A mixture of 4 M hydrochloric acid in dioxane (5 mL) and tert-butyl frans-4-((5-(6-((4-fluoro-3- methoxybenzyl)carbamoyl)-2-methylpyrιmιdιn-4-yl)-2H-tetra zol-2-yl)methyl)cyclohexylcarbamate (130 mg) was stirred for 4 h at room temperature The solvent was removed under a stream of nitrogen The residue was slurried in ether (2x), decanting each time The resultant solid was dried under vacuum to afford the hydrochoride salt of the title compound as a white solid (135 mg)

Example 10

W-(4-Fluoro-3-methoxybenzyl)-2-methyl-6-(2-((fraπs-4-(me thylsulfonamido)cyclohexyl)methyl)-

2W-tetrazol-5-yl)pyrimidine-4-carboxamide

Triethylamine (60 mg, 0 6 mmol) and methane sulfonyl chloride (34 mg, 0 3 mmol) were added to a solution of λ/-(4-fluoro-3-methoxybenzyl)-6-(2-(frans-4-amιnocyclohexy l)methyl)-2H- tetrazol-5-yl)-2-methylpyrιmιdιne-4-carboxamιde (prepared as described in Example 9) (70 mg, 0 14 mmol) in dichloromethane (1 mL) The reaction was stirred overnight at room temperature The product was isolated by reverse phase preparative HPLC (water/acetonitrile) to afford the title compound as a white solid (37 mg) MS (ES+) m/z 533 (M+H) ¹ H NMR (400 MHz, DMSOd ₆ ) δ ppm 9 51 (1 H, t, J=6 0 Hz), 8 42 (1 H, s), 7 11 - 7 21 (1 H, m), 7 18 (1 H, d, J=9 2 Hz), 6 94 (2 H, d, J=7 3 Hz), 4 70 (2 H, d, J=7 0 Hz), 4 50 (2 H, d, J=5 9 Hz), 3 82 (3 H, s), 3 05 (1 H, br s ), 2 88 (3 H, s), 2 83 (3 H, s), 1 91 (3 H, d, J=10 2 Hz), 1 64 (2 H, br s ), 1 26 (1 H, br s ), 1 19 (3 H, d, J=10 6 Hz), 1 15 (1 H, br s )

Example 11

W^-Fluoro-S-methoxybenzyO-G^Z-^frans^-acetamidocyclohexyO methyO^H-tetrazol-S-yl)^- methylpyrimidine-4-carboxamide

Triethylamine (60 mg, 0 6 mmol) and acetic anhydride (31 mg, O 3 mmol) were added to a solution of λ/-(4-fluoro-3-methoxybenzyl)-6-(2-(frans-4-amιnocyclohexy l)methyl)-2/-/-tetrazol-5-yl)-2- methylpyrιmιdιne-4-carboxamιde (prepared as described in Example 9) (65 mg, 0 13 mmol) in dichloromethane (1 mL) The reaction was stirred overnight at room temperature The product was isolated by reverse phase preparative HPLC (water/acetonitrile) and neutralized by passing through a small carbonate column to afford the title compound as a white solid (51 mg) MS (ES+) m/z 497 (M+H) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9 51 (1 H, t, J=5 7 Hz), 8 42 (1 H, s), 7 66 (1 H, d, J=7 7 Hz), 7 11 - 7 21 (1 H, m), 7 18 (1 H, d, J=8 8 Hz), 6 90 (1 H, d, J=7 3 Hz), 4 70 (2 H, d, J=7 0 Hz), 4 50 (2 H, d, J=5 9 Hz), 3 82 (3 H, s), 3 46 (1 H, br s ), 2 83 (3 H, s), 1 99 (1 H, br s ), 1 75 (4 H, s), 1 80 (1 H, br s ), 1 61 (2 H, d, J=9 5 Hz), 1 25 (1 H, d, J=5 5 Hz), 1 15 (3 H, d, J=9 5 Hz), 1 10 - 1 21 (1 H, m)

Example 12

W-(4-Fluoro-3-methoxybenzyl)-6-(2-((((ra/7s)-4-(2-hydroxy acetamido)cyclohexyl)methyl)-2H- tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide

λ/-(4-Fluoro-3-methoxybenzyl)-6-(2-(<rans-4-amιnocycloh exyl)methyl)-2H-tetrazol-5-yl)-2- methylpyrιmιdιne-4-carboxamιde (prepared as described in Example 9) (108 mg, 0 238 mmol), triethylamine (84 2 mg, 0 832 mmol) and acetoxy acetyl chloride (38 9 mg, 0 285 mmol) were combined in dichloromethane (4 mL) and stirred for 10 mm The mixture was concentrated and then treated with acetonitrile (2 mL) and 2 5 N sodium hydroxide (2 mL) After 1 hour, the organics were removed under nitrogen stream and the aqueous solution was adjusted to pH 6 with 10% hydrogen chloride The mixture was extracted with ethyl acetate (2 x 5 mL) The combined organic layers were dried over magnesium sulfate, filtered and concentrated to afford the title compound as an white solid (76 mg, 62%) LC/MS (10%-90% CH ₃ CN/H ₂ O, 6 mm) 4 44 mm, m/z 495 (M+H) ¹ H NMR (400 MHz, DMSO-Cf ₆ ) 6 ppm 9 35 - 9 54 (m, 1 H), 8 40 (s, 1 H), 7 37 (d, J = 8 1 Hz, 1 H), 7 04-7 22 (m, 1 H), 6 89 (br s, 1 H), 5 34 (s, 1 H), 4 68 (d, J= 6 6 Hz, 2 H), 4 48 (d, J = 5 9 Hz, 2 H), 3 77 - 3 85 (m, 3 H), 3 73 (d, J = 5 9 Hz, 2 H), 3 53 (br s , 1 H), 2 81 (s, 3 H), 1 98 (br s , 1 H), 1 73 (d, J = 10 3 Hz, 2 H), 1 60 (d, J = 10 3 Hz, 2 H), 1 06 - 1 36 (m, 5 H)

Example 13 W-(3-(2-Hydroxyethoxy)benzyl)-6-(2-(((frans)-4-aminocyclohex yl)methyl)-2H-tetrazol-5-yl)-2- methylpyrimidine-4-carboxamide

Step 1 Preparation of 2-(3-((benzylanr)ino)methyl)phenoxy)ethanol

A solution of 3-(2-hydroxyethoxy) benzaldehyde (10 00 g, 60 18 mmol) in anhydrous THF (230 mL) was treated at room temperature with benzyl amine (6 90 ml, 63 19 mmol) as a bolus and the resulting yellow solution was stirred at room temperature for 1 h Acetic acid (3 45 ml, 60 18 mmol) was added as a bolus followed by the portion-wise addition of sodium triacetoxyborohydride (19 1 g, 90 27 mmol) After 1 5 h, the reaction was quenched by the addition of 1 N NaOH (200 ml) The phases were separated and the aqueous layer was extracted with ethyl acetate (2 x 100 mL) The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated in vacuo to afford the title compound as an oil (13 20 g, 86 9 %) MS (ES+) m/z 258 (M+H)

Step 2 Preparation of 2-(3-(amιnomethyl)phenoxy)ethanol (3-((Benzylamιno)methyl)phenoxy)ethanol (13 2 g) was dissolved with heating in absolute ethanol (500 mL) and ammonium formate (40 9 g, 648 mmol) was added The mixture was sparged with N ₂ for a short period before 10% Pd/C (1 5 g, 13 9 mmol) was added The slurry was heated to reflux (55 ⁰ C to 66 ⁰ C) and stirred for 2 h Additional catalyst (1 5 g) was added and heating at reflux (74 7 ⁰ C) was continued for 30 mm The reaction was filtered and concentrated in vacuo The crude material was chromatographed on a normal phase column eluting with 95/5/0 5, dιchloromethane/methanol/NH ₄ OH to afford the title compound (3 14 g)

Step 3 Preparation of λ/-(3-(2-hvdroxyethoxy)benzyl)-6-cvano-2-methylpyrιmιdιn e-4-carboxamιde

Methyl θ-cyano^-methylpyπmidine^-carboxylate (prepared as described in step 4 of the synthesis of λ/-(3-methoxybenzyl)-6-(2-(((frans)-4-amιnocyclohexyl)meth yl)-2/-/-tetrazol-5-yl)-2- methylpyrιmιdιne-4-carboxamιde, Example 5) (892 mg, 5 03 mmol), 2-(3-

(amιnomethyl)phenoxy)ethanol (894 mg, 5 35 mmol), and triethylamine (382 mg, 3 78 mmol) were combined in dimethylacetamide (6 mL) The mixture was stirred at 80 ⁰ C for 2 h The mixture was cooled and partitioned into ethyl acetate and water The aqueous layer was extracted with additional

ethyl acetate (15 mL) The organic extracts were combined, dried over magnesium sulfate, filtered and concentrated The product was purified by silica gel chromatography (dichloromethane/methanol, 100/0 - 95/5) The pure fractions were combined and concentrated to afford the title compound as an oil (950 mg, 60%) LC/MS (10%-90% CH ₃ CN H ₂ O ₁ 8 mm) 2 338 mm, m/z 313 (M+H)

Step 4 Preparation of λ/-(3-(2-hvdroxyethoxy)benzyl)-2-methyl-6-(2/-/-tetrazol-5- yl)pyrιmιdιne-4- carboxamide

λ/-(3-(2-Hydroxyethoxy)benzyl)-6-cyano-2-methylpyrιmιdιn e-4-carboxamιde (687 mg, 2 20 mmol), sodium azide (214 mg, 3 30 mmol), and zιnc(ll) bromide (248 mg, 1 10 mmol) were combined in methanol (10 mL) The resulting mixture was stirred at 60 °C until homogeneous, then cooled to 25 ⁰ C and stirred for 18 h The methanol was removed, the solution acidified to pH 3 (3N hydrochloric acid) and extracted with ethyl acetate (3 x 10 mL) The organic extracts were combined, dried over magnesium sulfate, filtered and concentrated to afford the title compound as a yellow solid (782 mg, 100%) LC/MS (10%-90% CH ₃ CN/H ₂ O, 8 mm) 3 58 mm, m/z 356 (M+H) Step 5 Preparation of λ/-(3-(2-hvdroxyethoxy)benzyl)-6-(2-(((<rans)-4-amιnocv clohexyl)methyl)-2/-/- tetrazol-5-yl)-2-methylpyrιmιdιne-4-carboxamιde

λ/-(3-(2-hydroxyethoxy)benzyl)-2-methyl-6-(2/-/-tetrazol-5- yl)pyrιmιdιne-4-carboxamιde (782 mg, 2 20 mmol), (frans-4-((/ert-butoxycarbonyl)amino)cyclohexyl)methyl 4-methylbenzenesulfonate (prepared as described in step 7 of the synthesis of λ/-(3-methoxybenzyl)-6-(2-(((frans)-4- aminocyclohexyOmethyO^H-tetrazol-S-yO^-methylpyÏ€midine^-car boxamide, Example 5) (844 mg, 2 20 mmol), and triethylamine (267 mg, 2 64 mmol) were combined in dimethylacetamide (12 mL) The resulting mixture was stirred at 85 ⁰ C for 18 h The mixture was partitioned into water/ethyl acetate and extracted with additional ethyl acetate (5 mL) The organic extracts were combined, dried over magnesium sulfate, filtered and concentrated Purification was accomplished by reverse phase high-pressure liquid chromatography The pure fractions were combined, extracted with ethyl acetate (2 x 20 mL), dried over magnesium sulfate, and concentrated to an oil The intermediate was dissolved in methylene chloride (2 mL) and trifluoroacetic acid (2 mL) was added The mixture was stirred 10 mm , concentrated, and neutralized to pH 8 (NaOH) The mixture was extracted with ethyl acetate (2 x 15 mL), dried over magnesium sulfate, filtered and concentrated to afford the title compound as a clear oil (100 mg, 8%) LC/MS (10%-90% CH ₃ CN/H ₂ O, 6 mm) 5 92 mm, m/z 467 (M+H)

Example 14

W-(3-(2-Hydroxyethoxy)benzyl)-6-(2-(((frans)-4-acetamidoc yclohexyl)methyl)-2H-tetrazol-5-yl)-2- methylpyrimidine-4-carboxamide

λ/-(3-(2-Hydroxyethoxy)benzyl)-6-(2-(((/rans)-4-amιnocyclo hexyl)methyl)-2H-tetrazol-5-yl)-2- methylpyrιmιdιne-4-carboxamιde (prepared as described in Example 13) (50 mg, 0 11 mmol), triethylamine (38 O mg, O 375 mmol) and acetyl chloride (10 1 mg, 0 129 mmol) were combined in dichloromethane (2 mL) After stirring for 18 h, the mixture was concentrated and then treated with acetonitrile (2 mL) and 2 5 N sodium hydroxide (2 mL) After 1 h, the organics were removed under a nitrogen stream and the aqueous layer was adjusted to pH 6 with 10% hydrogen chloride The mixture was extracted with ethyl acetate (2 x 5 mL) The combined organic layers were dried over magnesium sulfate, filtered and concentrated to afford the title compound as a white solid (6 mg, 1 1 %) LC/MS (10%-90% CH ₃ CN/H ₂ O, 4 mm) 2 45 mm, m/z 509 (M+H) ¹ H NMR (400 MHz, DMSO-c/ ₆ ) δ ppm 9 41 - 9 48 (m, 1 H), 8 39 (s, 1 H), 7 58-7 64 (m, 1 H), 7 14 - 7 24 (m, 1 H), 6 83 - 6 94 (m, 2 H), 6 77 - 6 84 (m, 1 H), 5 43 - 5 55 (m, 1 H), 4 64 - 4 71 (m, 1 H), 4 45 - 4 51 (m, 2 H), 3 97 (m, 1 H), 3 62 - 3 72 (m, 2 H), 3 37 - 3 48 (m, 1 H), 2 81 (s, 3 H), 1 88 - 2 03 (m, 2 H), 1 84 (m, 2 H), 1 72 (s, 3 H), 1 63 (m, 2 H), 0 95 - 1 26 (m, 5 H)

Example 15

/V-(3-(2-Hydroxyethoxy)benzyl)-2-methyl-6-(2-(((frans)-4- (methylsulfonamido)cyclohexyl)methyl)-2/-/-tetrazol-5-yl)pyr imidine-4-carboxamide

A/-(3-(2-Hydroxyethoxy)benzyl)-6-(2-(((frans)-4-aminocyclohe xyl)methyl)-2H-tetrazol-5-yl)-2- methylpyrιmιdιne-4-carboxamιde (prepared as described in Example 13) (184 mg, 0 409 mmol), triethylamine (200 μL) and methanesulfonyl chloride (46 9 mg, 0 409 mmol) were combined in dichloromethane (2 mL) After stirring for 18 h, the resulting mixture was stirred at 85 ⁰ C for 18 h The mixture was concentrated under a nitrogen stream Purification was accomplished by high-pressure liquid chromatography Pure fractions were combined and concentrated to afford the title compound as a white solid (6 5 mg, 2 9%) LC/MS (10%-90% CH ₃ CN/H ₂ O, 8 mm) 4 26 mm, m/z 545 (M+H) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9 48 (s, 1 H), 8 42 (s, 1 H), 7 23 (m, 1 H), 6 93 (m, 2 H), 6 83 (m, 1 H), 4 77 (m, 1 H), 4 70 (d, J = 6 6 Hz, 2 H), 4 51 (d, J = 6 22 Hz, 2 H), 3 96 (t, J = 4 9 Hz, 2 H), 3 69 (d,

J = 5 1 Hz, 2 H), 3 06 (m, 1 H), 2 85 (s, 3 H), 2 83 (s, 3 H), 1 90 (m, 3 H), 1 64 (m, 2 H), 1 20 (m, 4 H), 0 06 (m, 1 H)

Example 16

W-(3-(2-Hydroxyethoxy)benzyl)-6-(2-(((frans)-4-(2-hydroxy acetamido)cyclohexyl)methyl)-2H- tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide

λ/-(3-(2-Hydroxyethoxy)benzyl)-6-(2-(((frans)-4-amιnocyclo hexyl)methyl)-2H-tetrazol-5-yl)-2- methylpyrιmιdιne-4-carboxamιde (prepared as described in Example 13) (184 mg, 0 409 mmol), triethylamine (200 μL) and acetoxy acetyl chloride (55 9 mg, 0 409 mmol) were combined in dichloromethane (4 mL) After stirring for 10 mm , the mixture was concentrated then treated with acetonitrile (2 mL) and 2 5 N sodium hydroxide (2 mL) After 1 h, the organics were removed under a nitrogen stream and the aqueous layer was adjusted to pH 6 with 10% hydrogen chloride The mixture was extracted with ethyl acetate (2 x 5 mL) The combined organic layers were dried over magnesium sulfate, filtered and concentrated to afford the title compound as a white solid (79 9 mg, 37%) LC/MS (10%-90% CH ₃ CN/H ₂ O, 6 mm) 4 00 mm, m/z 525 (M+H) ¹ H NMR (400 MHz, DMSOd ₆ ) δ ppm 9 48 (s, 1 H), 8 31 (s, 1 H), 7 52 (s, 1 H), 7 38 - 6 94 (m, 4 H), 3 85 (s, 1 H), 3 72 (d, J = 1 1 4 Hz, 4 H), 3 47 (t, J = 1 1 0, 4 H), 2 60 (s, 3 H), 2 41 (d, J = 13 2, 4 H), 1 79 (m, 8 H), 0 06 (m, 1 H)

Example 17

/V-(4-Fluoro-3-(2-hydroxyethoxy)benzyl)-6-(2-(((frans)-4- acetamidocyclohexyl)methyl)-2H- tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide

Step 1 Preparation of methyl 2-methyl-6-(2/-/-tetrazol-5-yl)pyrιmιdιne-4-carboxylate

Methyl 6-cyano-2-methylpyrιmιdιne-4-carboxylate (prepared as described in step 4 of the synthesis of λ/-(3-methoxybenzyl)-6-(2-(((<λans)-4-amιnocyclohexyl) methyl)-2H-tetrazol-5-yl)-2- methylpyrιmιdιne-4-carboxamιde, Example 5) (5 00 g, 28 2 mmol), sodium azide (1 93 g, 29 6 mmol),

and zinc bromide (6 36 g, 28 2 mmol) were suspended in methanol (28 mL) The reaction was stirred at room temperature for 16 hours 1 N hydrochloric acid (75 mL) was added and the mixture was stirred vigorously for 1 hour The solids were collected by vacuum filtration and rinsed with 1 N hydrochloric acid (2 x 50 mL) and water (2 x 100 mL) High vacuum drying at 40 ⁰ C provided the title compound as a white solid (5 31 g, 85%) LC/MS (5%-95% CH ₃ CN/H ₂ O, 6 mm) 2 24 mm, m/z 221 (M+H) ¹ H NMR (400 MHz, DMSO-d _δ ) δ ppm 8 38 (s, 1 H), 3 94 (s, 3 H), 2 80 (s, 3 H)

Step 2 Preparation of methyl 6-(2-(((/rans)-4-amιnocyclohexyl)methyl)-2H-tetrazol-5-yl)- 2- methylpyrιmιdιne-4-carboxylate

Methyl 2-methyl-6-(2H-tetrazol-5-yl)pyrιmιdιne-4-carboxylate (2 00 g, 9 0 mmol), tert-butyl

(frans)-4-(hydroxymethyl)cyclohexylcarbamate (2 29 g, 9 99 mmol), resin-bound tÏ€phenylphosphine (4 84 g, 10 9 mmol) and di-tert-butyl azodicarboxylate (2 3 g, 9 99 mmol) were combined in tetrahydrofuran (30 mL) The mixture was stirred at 25 ⁰ C for 18 h The mixture was filtered and concentrated The residue was purified by reverse phase preparative high-pressure liquid chromatography Fractions containing methyl 6-(2-((trans-4-((tert- butoxycarbonyl)amιno)cyclohexyl)methyl)-2H-tetrazol-5-yl)-2 -methylpyrιmιdιne-4-carboxylate were combined, extracted with ethyl acetate (2 x 20 mL), dried over magnesium sulfate, and concentrated The residue was dissolved in methylene chloride (2 mL) and trifluoroacetic acid (2 mL) was added The mixture was stirred 10 mm, concentrated, and neutralized to pH 8 (NaOH) The organic layer was extracted with ethyl acetate (2 x 15 mL), dried with magnesium sulfate, filtered and concentrated to afford the title compound as a clear oil (400 mg, 7%) LC/MS (10%-90% CH ₃ CN/H ₂ O, 4 mm) 1 704 mm, m/z 332 (M+H)

Step 3 Preparation of 5-amιnomethyl-2-fluoro-phenol hydrobromide A mixture of 4-fluoro-3-methoxy-benzylamιne hydrochloride (133 g, 0 642 mol), 48% aqueous

HBr (1 L) and 30% HBr in acetic acid (1 L) was refluxed for 4 h and concentrated under vacuum Ethanol was added to the residue and evaporated to remove last remaining water The crystalline residue obtained was dissolved in a small amount of ethanol and ethyl ether was slowly added A heavy crystalline suspension formed and was filtered, washed with ethyl ether and dried in vacuum to afford the title compound (147 g, 95 4%)

Step 4 Preparation of tert-butyl 4-fluoro-3-hvdroxybenzylcarbamate

Triethylamine (13 7 g, 0 135 mol) and di-tert-butyl dicarbonate (29 5 g, 0 135 mol) were added to a solution of 5-amιnomethyl-2-fluorophenol hydrobromide (30 g, 0 135 mol) in dichloromethane (200 mL) at ice bath temperature The reaction mixture was stirred overnight at room temperature, diluted with water and adjusted to pH-5 with acetic acid The organic layer was separated, washed with water and concentrated under vacuum to afford the title compound as a clear viscous oil (31 5 g, 96%)

Step 5 fert-butyl 4-fluoro-3-(2-hvdroxyethoxy)benzylcarbamate

To a mixture of /erf-butyl 4-fluoro-3-hydroxybenzylcarbamate (31 5 g, 0 13 mol) in dimethylsulfoxide (300 mL) was added KOH (15 75 g), Kl (0 3 g) and bromoethanol (19 6 g, 0 157 mol) The mixture was stirred for 5 days until no starting material remained The mixture was diluted with excess dichloromethane and washed with water The organic solution was concentrated and the crude product purified by silica gel column chromatography (0-80% ethyl acetate in hexane) to afford the desired tert-butyl 4-fluoro-3-(2-hydroxyethoxy)benzyIcarbamate as an oil (14 g, 40%)

Step 6 Preparation of 2-(5-amιnomethyl-2-fluorophenoxy)ethanol hydrochloride tert-Butyl 4-fluoro-3-(2-hydroxyethoxy)benzylcarbamate (14 g, 0 05 mol) was dissolved in excess of 4N hydrochloric acid in dioxane (125 ml) and stirred for 5 h at room temperature The resulting solid was diluted with an additional amount of dioxane and then filtered, washed with cold dioxane and dried in vacuo to afford the title compound as the hydrochloride salt (8 5 g, 78%) MS (ES+) m/z 186 (M+H) Elemental analysis found C, 48 25, H, 6 09, N, 6 45

Step 7 Preparation of λ/-(4-fluoro-3-(2-hvdroxyethoxy)benzyl)-6-(2-((«rans)-4- acetamιdocvclohexyl)methyl)-2H-tetrazol-5-yl)-2-methylpyrι mιdιne-4-carboxamιde

Methyl 6-(2-(((frans)-4-aminocyclohexyl)methyl)-2/-/-tetrazol-5-yl) -2-methylpyrimidme-4- carboxylate (134 mg, 0 404 mmol), acetyl chloride (104 mg, 1 33 mmol) and triethylamine (200 μl_)

were combined in dichloromethane (2 mL) The resulting mixture was stirred at 25 ⁰ C for 30 mm The dichloromethane was removed under nitrogen stream The residue was dissolved in dimethylacetamide (2 mL) and 2-(5-(amιnomethyl)-2-fluorophenoxy)ethanol hydrochloride (178 mg,

0 808 mmol) and triethylamine (200 μL) were added The mixture was stirred at 25 C for 18 h Purification was accomplished by reverse phase preparative high-pressure liquid chromatography (acetonitrile/water, 5 - 95%, 30 mm) The pure fractions were combined, extracted with ethyl acetate (2 x 20 mL), dried (magnesium sulfate), and concentrated to an oil that solidified under reduced pressure to afford the title compound as a white solid (48 5 mg, 23%) LC/MS (10%-90% CH ₃ CN/H ₂ O, 4 mm) 2 53 mm, m/z 527 (M+H) ¹ H NMR (400 MHz, DMSOd ₆ ) δ ppm 9 47 (s, 1 H), 8 40 (s, 1 H), 7 61 (d, J = 8 05, 1 H), 7 18 (m, 2 H), 6 90 (m, 1 H), 4 81 (t, J = 5 68, 5 86, 1 H), 4 67 (d, J = 7 32, 2 H), 4 47 (d, J = 6 59, 2 H), 4 01 (m, 2 H), 3 71 (m, 2 H), 3 45 (m, 1 H), 2 81 (s, 3 H), 1 97 (m, 1 H),

1 78 (m, 2 H), 1 73 (s, 3 H), 1 58 (m, 2 H), 1 14 (m, 4 H)

Example 18

/V-(4-Fluoro-3-(2-hydroxyethoxy)benzyl)-2-methyl-6-(2-((( fraπs)-4- (methylsulfonamidoJcyclohexyOmethyO^H-tetrazol-S-yOpyrimidin e^-carboxamide

Methyl 6-(2-(((frans)-4-aminocyclohexyl)methyl)-2/-/-tetrazol-5-yl) -2-methylpynmidine-4- carboxylate (prepared as described in step 2 of the synthesis of λ/-(4-fluoro-3-(2- hydroxyethoxy)benzyl)-6-(2-(((frans)-4-acetamιdocyclohexyl) methyl)-2H-tetrazol-5-yl)-2- methylpyrιmιdιne-4-carboxamιde, Example 17) (134 mg, 0 404 mmol), methanesulfonyl chloride (152 mg, 1 33 mmol) and triethylamine (200 μL) were combined in dichloromethane (2 mL) The resulting mixture was stirred at 25 ⁰ C for 30 mm The dichloromethane was removed under nitrogen stream The residue was dissolved in dimethylacetamide (2 mL) and 2-(5-(amιnomethyl)-2- fluorophenoxy)ethanol (prepared as described in steps 3 - 6 of the synthesis of λ/-(4-fluoro-3-(2- hydroxyethoxy)benzyl)-6-(2-(((frans)-4-acetamιdocyclohexyl) methyl)-2H-tetrazol-5-yl)-2- methylpyrιmιdιne-4-carboxamιde, Example 17) (178 mg, 0 808 mmol) and triethylamine (200 μL) were added The mixture was stirred at 25 ⁰ C for 18 h Purification was accomplished by reverse phase preparative high-pressure liquid chromatography (acetonitrile/water, 5 - 95%, 30 mm) The pure fractions were combined, extracted with ethyl acetate (2 x 20 mL), dried over magnesium sulfate, and concentrated to an oil that solidified under reduced pressure to afford the title compound as an white solid (45 3 mg, 20%) LC/MS (10%-90% CH ₃ CN/H ₂ O, 4 mm) 2 64 mm, m/z 563 (M+H) ¹ H NMR (400 MHz, DMSOd ₆ ) δ PPm 9 47 (m, 1 H), 8 40 (s, 1 H), 7 13 (m, 2 H), 6 90 (m, 2 H), 4 79 (m, 1 H), 4 68 (m, 2 H), 4 47 (m, 2 H), 4 03 (m, 2 H), 3 70 (m, 2 H), 3 05 (m, 1 H), 2 86 (s, 3 H), 2 81 (s, 3 H), 1 93 (m, 3 H), 1 61 (m, 2 H), 1 18 (m, 4 H)

Example 19

W-(4-Fluoro-3-(2-hydroxyethoxy)benzyl)-6-(2-(((frans)-4-( 2- hydroxyacetamido)cyclohexyl)methyl)-2H-tetrazol-5-yl)-2-meth ylpyrimidine-4-carboxamide

Methyl 6-(2-(((frans)-4-amιnocyclohexyl)methyl)-2/-/-tetrazol-5-yl )-2-methylpyrιmιdιne-4- carboxylate (prepared as described in step 2 of the synthesis of λ/-(4-fluoro-3-(2- hydroxyethoxy)benzyl)-6-(2-(((frans)-4-acetamιdocyclohexyl) methyl)-2/-/-tetrazol-5-yl)-2- methylpyrιmιdιne-4-carboxamιde, Example 17) (134 mg, 0 404 mmol), acetoxy acetyl chloride (181 mg, 1 33 mmol) and tÏ€ethylamine (200 μl_) were combined in dichloromethane (2mL) The resulting mixture was stirred at 25 °C for 30 mm The dichloromethane was removed under nitrogen stream The residue was dissolved in dimethylacetamide (2 mL) and (2-(5-(amιnomethyl)-2- fluorophenoxy)ethanol (prepared as described in steps 3 - 6 of the synthesis of λ/-(4-fluoro-3-(2- hydroxyethoxy)benzyl)-6-(2-(((/rans)-4-acetamidocyclohexyl)m ethyl)-2H-tetrazol-5-yl)-2- methylpyrιmιdιne-4-carboxamιde, Example 17) (178 mg, 0 808 mmol) and triethylamine (200 μL) were added The mixture was stirred at 25 ⁰ C for 18 h Purification was accomplished by reverse phase preparative high-pressure liquid chromatography (acetonitrile/water, 5 - 95%, 30 mm) The pure fractions were combined, extracted with ethyl acetate (2 x 20 mL), dried over magnesium sulfate, and concentrated The residue was dissolved in acetonitrile (4 5 mL) and treated with 2 5N NaOH (2 5 mL) The acetonitrile was removed in vacuo and the aqueous layer was adjusted to pH 6 with 10% hydrochloric acid The mixture was extracted with ethyl acetate (2 x 20 mL), dried over magnesium sulfate, and concentrated to an oil the solidified under reduced pressure to give the title compound as an white solid (52 2 mg, 24%) LC/MS (10%-90% CH ₃ CN/H ₂ O, 4 mm) 2 43 mm, m/z 543 (M+H) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9 47 (s, 1 H), 8 40 (s, 1 H), 7 35 (m, 1 H), 7 09 - 7 18 (m, 2 H), 6 90 (m, 1 H), 5 30 (m, 1 H), 4 81 (m, 1 H), 4 68 (d, J = 7 32, 2 H), 4 47 (d, J = 6 59, 2 H), 4 02 (m, 2 H), 3 70 (m, 4 H), 3 53 (m, 1 H), 2 81 (s, 3 H), 1 97 (m, 1 H), 1 72 (m, 2 H), 1 62 (m, 2 H), 1 15 - 1 28 (m, 4 H)

Example 20 fraπs-Methyl 4-((5-(6-((4-fluoro-3-methoxybenzyl)carbamoyl)-2-methylpyrim idin-4-yl)-2H- tetrazol-2-yl)methyl)cyclohexanecarboxylate

Step 1 Preparation of frans-methyl 4-((methylsulfonyloxy)methyl)cvclohexanecarboxylate

Triethylamine (6 46 g, 63 9 mmol) was added to a solution of frans-methyl 4- (hydroxymethyl)cyclohexanecarboxylate (10 0 g, 58 1 mmol) in dichloromethane (100 mL) Methane sulfonylchloride (7 98 g, 69 7 mmol) was added drop-wise and then the mixture was stirred at room temperature for 2 days The mixture was diluted with brine The organic layer was separated, dried over sodium sulfate, filtered, and concentrated The resulting oil crystallized upon addition of petroleum ether and was filtered to afford the title compound (14 0 g)

Step 2 Preparation of frans-methyl 4-((5-(6-((4-fluoro-3-methoxybenzyl)carbamoyl)-2-methylpyrι mιdιn- 4-yl)-2H-tetrazol-2-yl)methyl)cvclohexanecarboxylate

frans-Methyl 4-((methylsulfonyloxy)methyl)cyclohexanecarboxylate (65 mg, 0 26 mmol) was added to a solution of λ/-(4-fluoro-3-methoxybenzyl)-2-methyl-6-(2H-tetrazol-5-yl) pyrιmιdιne-4- carboxamide (60 mg, 0 17 mmol) and triethylamine (34 mg, 0 34 mmol) in anhydrous dimethylacetamide (0 3 mL) The mixture was stirred at 80 - 90 ⁰ C in a capped vial overnight The reaction mixture was purified by reverse phase preparative HPLC (water/acetonitrile) to afford the title compound (43 mg)

Example 21

(rans-4-((5-(6-((4-Fluoro-3-methoxybenzyl)carbamoyl)-2-me thylpyrimidin-4-yl)-2H-tetrazol-2- yl)methyl)cyclohexanecarboxylic acid

Sodium hydroxide (2 pellets) were added to a mixture of frans-methyl 4-((5-(6-((4-fluoro-3- methoxybenzyl)carbamoyl)-2-methylpyrιmιdιn-4-yl)-2H-tetra zol-2-y!)methyl)cyclohexanecarboxylate (43 mg) in tetrahydrofuran (0 4 mL) and water (0 4 mL) The mixture was stirred at room temperature overnight The reaction mixture was acidified with trifluoroacetic acid and the product was purified by reverse phase preparative HPLC (water/acetonitrile) to afford the title compound as a white solid (28 mg) MS (ES+) m/z 484 (M+H) ¹ H NMR (400 MHz, DMSOd ₆ ) δ ppm 9 51 (1 H, t, J=6 0 Hz), 8 42 (1 H, s), 7 1 1 - 7 22 (1 H, m), 6 92 (1 H, br s ), 4 70 (3 H, d, J=6 6 Hz), 4 51 (3 H, d, J=5 9 Hz), 3 82 (3 H,

S), 2 83 (3 H, s), 2 14 (1 H, br s ), 1 99 (1 H, br s ), 1 90 (2 H, br s ), 1 64 (2 H, br s ), 1 30 (3 H, d, J=12 8 Hz), 1 08 - 1 19 (2 H, m)

Example 22

(fraπs)-Methyl 4-((5-(6-((3-methoxybenzyl)carbamoyl)-2-methylpyrimidin-4-yl )-2H-tetrazol-2- yOmethyOcyclohexanecarboxylate

frans-Methyl 4-((methylsulfonyloxy)methyl)cyclohexanecarboxylate (prepared as described in step 1 of the synthesis of /rans-methyl 4-((5-(6-((4-fluoro-3-methoxybenzyl)carbamoyl)-2- methylpyrιmιdιn-4-yl)-2/-/-tetrazol-2-yl)methyl)cyclohexa necarboxylate, Example 20) (56 mg, 0 22 mmol) was added to a solution of /V-(3-methoxybenzyl)-2-methyl-6-(2H-tetrazol-5-yl)pyÏ€mιdι ne-4- carboxamide (prepared as described in step 6 of the synthesis of λ/-(3-methoxybenzyl)-6-(2-(((frans)- 4-amιnocyclohexyl)methyl)-2/-/-tetrazol-5-yl)-2-methylpyrι mιdιne-4-carboxamιde, Example 5) (50 mg, 0 15 mmol) and triethylamine (56 mg, 0 22 mmol) in anhydrous dimethylacetamide (0 3 mL) The mixture was stirred at 80 - 90 ⁰ C in a capped vial overnight The reaction mixture was purified by reverse phase preparative HPLC (water/acetonitrile) to afford the title compound (37 mg)

Example 23

(<rans)-4-((5-(6-((3-Methoxybenzyl)carbamoyl)-2-methyl pyrimidin-4-yl)-2H-tetrazol-2- yl)methyl)cyclohexanecarboxylic acid

Sodium hydroxide (2 pellets) was added to mixture of (fraÏ€s)-methyl 4-((5-(6-((3- methoxybenzyl)carbamoyl)-2-methylpyrιmιdιn-4-yl)-2H-tetra zol-2-yl)methyl)cyclohexanecarboxylate (prepared as described in Example 22) in tetrahydrofuran (0 4 mL) and water (0 4 mL) The mixture was stirred at room temperature overnight The reaction mixture was acidified with trifluoroacetic acid and purified by reverse phase preparative HPLC (water/acetonitrile) The resulting residue was slurried and decanted from ethyl ether and dried in a vacuum desiccator to afford the title compound as an off-white solid (19 mg) MS (ES+) m/z 466 (M+H) ¹ H NMR (400 MHz, DMSO-Cy ₆ ) 6 ppm 9 49 (1 H, t, J=6 2 Hz), 8 41 (1 H,s), 7 24 (1 H, t, J=8 1 Hz), 6 93 (2 H, br s ), 6 83 (1 H, d, J=I 7 Hz), 4 70 (2 H, d, J=I 0 Hz), 4 51 (3 H, d, J=Q 2 Hz), 3 74 (3 H, s), 2 83 (3 H, s), 2 14 (1 H, br s ), 2 01 (1 H, br s ), 1 91 (2 H, d, J=12 1 Hz), 1 64 (2 H, br s ), 1 30 (3 H, d, J=12 4 Hz), 1 14 (2 H, t, J=1 1 3 Hz)

Example 24

W-P-Methoxybenzyl^e-^-^frans^-cyanocyclohexyOmethyl^H-tet razol-S-yO-Z- methylpyrimidine-4-carboxamide

Step 1 Preparation of 1 ,4-dιoxa-spιrof4 51decane-8-carbonitnle

tosyl-methyl-isocyanide (200 0 g, 1 024 mol) in DMF (2 2 L) and ethanol (85 mL), was added potassium f-butoxide (210 0 g, 1 87 mol) portion wise over a period of 2 h, and the temperature was maintained below -5 ⁰ C After complete addition, the mixture was brought to 0 ⁰ C and stirred another 1 h at 0 ⁰ C followed by room temperature for another 2 5 h The reaction mixture was diluted with ethyl acetate (3 5 L) and water (3 5 L) The mixture was stirred for 1 h The organic layer was separated and washed with water (3 x 1 5 L) followed by brine solution (1 5 L), dried over anhydrous sodium sulfate, and concentrated to afford the title compound as an oil (99 g, 75 %) Step 2 Preparation of 4-oxocvclohexanecarbonιtrιle

To a stirred solution of 1 ,4-dιoxa-spιro[4 5]decane-8-carbonιtrιle (100 g, 0 60 mol) in tetrahydrofuran (1 0 L) was added 2N hydrochloric acid (1 0 L) at room temperature and the mixture was stirred for 24 h The reaction mixture was diluted with ethyl acetate (1 0 L) The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2 x 700 mL) The combined organic layer was washed with water (1 5 L) followed by brine (1 0 L), dried over anhydrous sodium sulfate, and concentrated The crude material was purified by flash column chromatography over silica gel (230-400 mesh) eluting with 20% ethyl acetate in hexane to afford the title compound (50 g, 67 %)

Step 3 Preparation of 4-(methoxymethylene)cvclohexanecarbonιtrιle

MeO _/ — v N — '

To a cold (-30 ⁰ C) suspension of methoxy methyl triphenylphosphonium chloride (84 g, 163 mmol) in dry tetrahydrofuran (300 mL) was added drop-wise 1 6 M n-butyllithium (153 mL, 243 6 mmol) maintaining the temperature at -25 ⁰ C to -30 ⁰ C After complete addition, the mixture was allowed to stir for 1 h at -20 ⁰ C A solution of 4-oxocyclohexanecarbonιtrιle (20 g, 162 4 mmol) in tetrahydrofuran (150 mL) was added drop-wise at -20 ⁰ C and allowed to stir for 2 h at the same temperature Hexane (200 mL) was added, and the mixture was filtered The filtrate was concentrated

under reduced pressure and the crude material was purified by flash column chromatography over silica gel (230-400 mesh) eluting with 10% ethyl acetate in hexane to afford the title compound (9 g,

36%)

Step 4 Preparation of frans^-formylcvclohexanecarbomtrile

A mixture of 4-(methoxymethylene)cyclohexanecarbonιtrιle (9 g, 59 5 mmol) and tetrahydrofuran /2N hydrochloric acid (4 1 , 400 mL v/v) was heated to reflux for 30 minutes The reaction mixture was poured into water (300 mL) cold water and extracted with diethyl ether (3 x 300 mL) The combined organic layer was washed with water (400 mL), dried over anhydrous sodium sulfate and concentrated Recrystallization from hexane afforded the title compound (2 1 g, 25 %)

Step 5 Preparation of /rans^-divdroxymethvDcvclohexanecarbonitrile

A suspension of 600 mg (189 15 mmol) of sodium borohydride in methanol/diethyl ether (9 1 , 70 mL v/v) was treated drop-wise with a solution of frans-4-formylcyclohexanecarbonιtrιle (2 g, 14 6 mmol) in methanol/diethyl ether (9/1 , 30 mL v/v) within 10 minutes at 0 ⁰ C The reaction mixture was allowed to stir for 2 h at 10 °C, treated with 2N hydrochloric acid (35 mL) under ice-water cold condition, and extracted with dichloromethane (3 x 100 mL) The combined organic layers were dried over anhydrous sodium sulfate and concentrated to afford the title compound as an oil (1 45 g, 71 %) MS (ES+) m/z 162 (M+Na) Step 6 Preparation of «rans-4-cvanocvclohexyl)methyl 4-methylbenzenesulfonate

p-Toluene sulfonyl chloride (2 15 g, 1 1 3 mmol) was added portion-wise over 30 mm to a solution of <raπs-4-(hydroxymethyl)cyclohexanecarbonιtrιle (1 57 g, 11 3 mmol) in anhydrous pyridine (10 mL) at room temperature The reaction mixture was stirred for 4 h and then water (40 mL) was added drop-wise with ice bath cooling The mixture was extracted with dichloromethane The organic layer was washed with 3 M hydrochloric acid, dried over magnesium sulfate, and concentrated under vacuum to afford the title compound as a white solid (2 4 g)

Step 7 Preparation of λ/-(3-methoxybenzyl)-6-(2-(((frans-4-cvanocyclohexyl)methyl )-2H-tetrazol-5-yl)- 2-methylpyrιmιdιne-4-carboxamιde

(frans-4-Cyanocyclohexyl)methyl 4-methylbenzenesulfonate (232 mg, 0 79 mmol) was added to a solution of λ/-(3-methoxybenzyl)-2-methyl-6-(2H-tetrazol-5-yl)pyrιmιd ιne-4-carboxamιde (prepared as described in step 6 of the synthesis of λ/-(3-methoxybenzyl)-6-(2-(((frans)-4- amιnocyclohexyl)methyl)-2/-/-tetrazol-5-yl)-2-methylpyrιmÎ ¹dιne-4-carboxamιde, Example 5) (200 mg, 0 61 mmol) and triethylamine (186 mg, 1 8 mmol) in anhydrous dimethylacetamide (0 3 mL) The reaction was stirred overnight at 85 ⁰ C in a capped vial The reaction mixture was purified by reverse phase preparative HPLC (water/acetonitÏ€le) Fractions containing product were neutralized by passing through a small carbonate resin column and concentrated The residue was slurried and decanted from ethyl ether three times and dried in a vacuum desiccator to afford the title compound as a white solid (64 mg) MS (ES+) m/z 447 (M+H) ¹ H NMR (400 MHz, DMSO-d ₆ ) 6 ppm 9 48 (1 H, t, J=6 2 Hz), 8 41 (1 H, s), 7 24 (1 H, t, J=8 1 Hz), 6 93 (2 H, br s ), 6 83 (1 H, d, J=8 1 Hz), 4 71 (2 H, d, J=7 0 Hz), 4 51 (2 H, d, J=6 2 Hz), 3 74 (3 H, s), 2 83 (3 H, s), 2 63 (1 H, br s ), 2 08 (1 H, br s ), 2 02 (2 H, d, J=1 1 3 Hz), 1 65 (3 H, d, J=1 1 0 Hz), 1 51 (2 H, d, J=12 8 Hz), 1 15 (2 H, t, J=1 1 3 Hz)

Example 25

/V-(4-Fluoro-3-methoxybenzyl)-6-(2-(((<rans-4-cyanocyc lohexyl)methyl)-2H-tetrazol-5-yl)-2- methylpyrimidine-4-carboxamide

(frans-4-Cyanocyclohexyl)methyl 4-methylbenzenesulfonate (prepared as described in step 6 of the synthesis of λ/-(3-methoxybenzyl)-6-(2-(((frans-4-cyanocyclohexyl)methyl )-2H-tetrazol-5-yl)-2- methylpyrιmιdιne-4-carboxamιde, Example 24) (214 mg, 0 73 mmol) was added to a solution of /V-(4- fluoro-3-methoxybenzyl)-2-methyl-6-(2H-tetrazol-5-yl)pyrιmÎ ¹dιne-4-carboxamιde (prepared as described in step 2 of the synthesis of λ/-(4-fluoro-3-methoxybenzyl)-6-(2-(/rans-4- aminocyclohexyOmethyl^H-tetrazol-S-yl^-methylpyÏ€midine^-car boxamide, Example 9) (170 mg, 0 495 mol) and triethylamine (148 mg, 1 4 mmol) in anhydrous dimethylacetamide (0 4 mL) The mixture was stirred overnight at 85 ⁰ C in a capped vial The reaction mixture was purified by reverse phase preparative HPLC (water/acetonitrile) Fractions containing product were neutralized by passing through a small carbonate resin column and concentrated The residue was slurried and decanted from ethyl ether three times and dried in a vacuum desiccator to afford the title compound as a white

solid (65 mg) MS (ES+) m/z 465 (M+H) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9 50 (1 H, t, J=6 4 Hz), 8 42 (1 H, s), 7 19 (1 H, d, J=8 4 Hz), 7 14 (1 H, dd, J= 11 5, 8 6 Hz), 6 91 (1 H, br s ), 4 71 (2 H, d, J=7 0 Hz), 4 51 (2 H, d, J=6 2 Hz), 3 83 (3 H, s), 2 83 (3 H, s), 2 63 (1 H, br s ), 2 01 (3 H, br s ), 1 63 (3 H, br s ), 1 50 (2 H, br s ), 1 08 - 1 19 (2 H, m)

Example 26

W-(3-(2-Hydroxyethoxy)benzyl)-6-(2-(((frans)-4-cyanocyclo hexyl)methyl)-2W-tetrazol-5-yl)-2- methylpyrimidine-4-carboxamide

λ/-(3-(2-Hydroxyethoxy)benzyl)-2-methyl-6-(2H-tetrazol-5-yl )pyrιmιdιne-4-carboxamιde (prepared as described in steps 1 - 4 of the synthesis of λ/-(3-(2-hydroxyethoxy)benzyl)-6-(2-(((/rans)- 4-amιnocyclohexyl)methyl)-2/-/-tetrazol-5-yl)-2-methylpyÏ€m ιdιne-4-carboxamιde, Example 13) (180 mg, 0 614 mmol), (fr-ans-4-cyanocyclohexyl)methyl 4-methylbenzenesulfonate (prepared as described in steps 1 - 6 of the synthesis of λ/-(3-methoxybenzyl)-6-(2-(((fλans-4-cyanocyclohexyl)methy l)-2H- tetrazol-5-yl)-2-methylpyrιmιdιne-4-carboxamιde, Example 24) (150 mg, 0 423 mmol ), and triethylamine (400 μL) were combined in dimethylacetamide (100 μL) The resulting mixture was stirred at 85 ⁰ C for 18 h The mixture was concentrated under a nitrogen stream Purification was accomplished by reverse phase preparative high-pressure liquid chromatography Pure fractions were combined and concentrated to afford the title compound as a white solid (36 6 mg, 12%) MS (ES+) m/z 477 (M+H) ¹ H NMR (400 MHz, DMSOd ₆ ) ÏŒ ppm 9 48 (m, 1 H), 8 30 (s, 1 H), 7 24 (m, 1 H), 6 91 (m, 2 H), 6 79 (m, 1 H), 4 81 (m, 1 H), 4 71 (m , 2 H), 4 52 (m, 2 H), 3 96 (m, 2 H), 3 61 (m, 2 H), 2 80 (s, 3 H), 2 61 (m, 1 H), 2 40 (m, 1 H), 2 01 (m, 4 H), 1 62 (m, 2 H), 1 44 (m, 2 H), 1 05 (m, 2 H)

Example 27

/V-(4-Fluoro-3-(2-hydroxyethoxy)benzyl)-6-(2-(((frans-4-c yanocyclohexyl)methyl)-2H-tetrazol-5- yl)-2 -methylpyrimidine-4-carboxamide

Step 1 Preparation of /V-(4-fluoro-3-(2-hvdroxyethoxy)benzyl)-6-cvano-2-methylpyrÎ ¹mιdιne-4- carboxamide

Methyl δ-cyano-σ-methylpynmidine^-carboxylate (prepared as described in step 4 of the synthesis of λ/-(3-methoxybenzy!)-6-(2-(((frans)-4-amιnocyclohexyl)meth yl)-2/-/-tetrazol-5-yl)-2- methylpyrιmιdιne-4-carboxamιde, Example 5) (5 20 g, 29 0 mmol), 2-(5-(amιnomethyl)-2- fluorophenoxy)ethanol hydrochloride (prepared as described in steps 3 - 6 of the synthesis of W-(4- fluoro-3-(2-hydroxyethoxy)benzyl)-6-(2-(((<rans)-4-acetam ιdocyclohexyl)methyl)-2/-/-tetrazol-5-yl)-2- methylpyrιmιdιne-4-carboxamιde, Example 17) (8 30 g, 32 3 mmol), and triethylamine (5 94 g, 58 7 mmol) were combined in dimethylacetamide (50 mL) The mixture was stirred at 80 ⁰ C for 2 h The mixture was cooled and poured into 1 N hydrochloric acid (50 mL) and was extracted with ethyl acetate (3 x 30 mL) The combined organic layers dried over magnesium sulfate, filtered and concentrated to a crude oil The product was triturated with ethyl acetate to afford the title compound as a solid (1 5 g, 15%) LC/MS (10%-90% CH ₃ CN/H ₂ O, 4 mm) 2 437 mm, m/z 331 (M+H) Step 2 Preparation of λ/-(4-fluoro-3-(2-hvdroxyethoxy)benzyl)-2-methyl-6-(2H-tetr azol-5-yl)pyrιmιdιne- 4-carboxamιde

λ/-(4-Fluoro-3-(2-hydroxyethoxy)benzyl)-6-cyano-2-methylpyr ιmιdιne-4-carboxamιde (7 93 g, 24 0 mmol), sodium azide (2 34 g, 36 0 mmol), and zιnc(ll) bromide (2 70 g, 12 0 mmol) were combined in methanol (50 mL) The resulting mixture was stirred at 25 ⁰ C for 18 h The methanol was removed and the residue was acidified to pH 3 (3N hydrochloric acid) and extracted with ethyl acetate (2 x 50 mL) The combined organic layers were dried over magnesium sulfate, filtered and concentrated to afford the title compound as an off-white solid (4 25g, 47%) LC/MS (10%-90% CH ₃ CN/H ₂ O, 4 mm) 2 274 mm, m/z 374 (M+H)

Step 3 Preparation of λ/-(4-fluoro-3-(2-hvdroxyethoxy)benzyl)-6-(2-(((<rans-4- cvanocvclohexyl)methyl)- 2H-tetrazol-5-yl)-2-methylpyrιmιdιne-4-carboxamιde

(frans-4-cyanocyclohexyl)methyl 4-methylbenzenesulfonate (prepared as described in steps 1 - 6 of the synthesis of A/-(3-methoxybenzyl)-6-(2-(((frans-4-cyanocyclohexyl)methyl) -2/-/-tetrazol-5-yl)- 2-methylpyrιmιdιne-4-carboxamιde, Example 24) (1 14 mg, 0 389 mmol ) was added to a solution of N- (4-fluoro-3-(2-hydroxyethoxy)benzyl)-2-methyl-6-(2/-/-tetraz ol-5-yl)pyrιmιdιne-4-carboxamιde (100 mg,

0 268 mmol) and triethylamine (162 mg, 1 6 mmol) in anhydrous dimethylacetamide (0 2 mL) The mixture was stirred overnight at 85 ⁰ C in a capped vial The reaction mixture was purified by reverse phase preparative HPLC (water/acetonitrile) Fractions containing product were neutralized by passing through a small carbonate resin column and concentrated The residue was slurried and decanted from ethyl ether three times and dried in a vacuum desiccator to afford the title compound as a white solid (46 mg) MS (ES+) m/z 495 (M+H) ¹ H NMR (400 MHz, DMSOd ₆ ) ÏŒ ppm 7 63 (1 H, s), 7 53 - 7 57 (1 H, m), 7 40 - 7 51 (3 H, m), 7 34 (2 H, d, J=Q 2 Hz), 7 25 (1 H, br s ), 7 14 (2 H, br s ), 7 03 (1 H, br s ), 3 96 (1 H, s), 3 85 (4 H, d, J= 1 1 7 Hz), 3 58 (4 H, t, J=10 8 Hz), 2 55 - 2 66 (3 H, m), 1 85 -

1 96 (3 H, m)

Example 28

W-(3-Methoxybenzyl)-6-(2-(((frans)-4-hydroxy-4-(hydroxyme thyl)cyclohexyl)methyl)-2H-tetrazol-

5-yl)-2-methylpyrimidine-4-carboxamide

Step 1 Preparation of 1 ,4-dιoxaspιro[4 51dec-8-ylmethyl 4-methylbenzenesulfonate

p-Toluene sulfonylchloÏ€de (4 43 g, 23 24 mmol) was added portion-wise over 20 mm to a solution of 1 ,4-dιoxaspιro[4 5]dec-8-ylmethanol (Bioorg Med Chem 2005, 13, 6309-6323) (4 0 g, 23 0 mmol) in anhydrous pyridine (30 mL) The mixture was stirred at room temperature for 2 5 hours The reaction mixture was cooled to 0 ⁰ C and water (100 mL) was added drop-wise maintaining the temperature below 20 ⁰ C The mixture was extracted with dichloromethane The organic layer was

washed with water (4x), dried over magnesium sulfate, and concentrated under vacuum to afford the title compound as a clear oil (5 7 g)

Step 2 Preparation of 6-(2-(1 ,4-dιoxaspιrof4 51dec-8-ylmethyl)-2H-tetrazol-5-yl)-λ/-(3-methoxybenzyl)- 2-methylpyrιmιdιne-4-carboxamιde

1 ,4-Dιoxaspιro[4 5]dec-8-ylmethyl 4-methylbenzenesulfonate (552 mg, 1 69 mmol) was added to a solution of λ/-(3-methoxybenzyl)-2-methyl-6-(2/-/-tetrazol-5-yl)pyrιmÎ ¹dιne-4-carboxamιde (prepared as described in step 6 of the synthesis of λ/-(3-methoxybenzyl)-6-(2-(((frans)-4- aminocyclohexyOmethyO^H-tetrazol-δ-yO^-methylpyÏ€midine^-ca rboxamide, Example 5) (550 mg, 1 69 mmol) and triethylamine (171 mg, 1 7 mmol) in anhydrous dimethylacetamide (0 5 mL) The mixture was stirred overnight at 85 ⁰ C in a capped vial The reaction mixture was purified by reverse phase preparative HPLC (water/acetonitrile) to afford the title compound (271 mg)

Step 3 Preparation of λ/-(3-methoxybenzyl)-2-methyl-6-(2-((4-oxocvdohexyl)methyl) -2/-/-tetrazol-5- yl)pyrtmιdιne-4-carboxamιde

6-(2-(1 ,4-Dιoxaspιro[4 5]dec-8-ylmethyl)-2H-tetrazol-5-yl)-λ/-(3-methoxybenzyl)-2- methylpyrιmιdιne-4-carboxamιde (271 mg) was dissolved in tetrahydrofuran (3 mL) and 96% formic acid (4 mL) was added The mixture was stirred at room temperature overnight The solvent was removed under a stream of nitrogen and the residue was dissolved in dichloromethane The mixture was washed with saturated aqueous sodium bicarbonate solution The organic layer was dried over magnesium sulfate, filtered, and concentrated under vacuum to afford the title compound (218 mg)

Step 4 Preparation of λ/-(3-methoxybenzyl)-2-methyl-6-(2-(1-oxaspιro[2 51oct-6-ylmethyl)-2/-/-tetrazol- 5-yl)pyrιmιdιne-4-carboxamιde

A solution of λ/-(3-methoxybenzyl)-2-methyl-6-(2-((4-oxocyclohexyl)methyl )-2H-tetrazol-5- yl)pyrιmιdιne-4-carboxamιde (218 mg) in anhydrous dimethylsulfoxide (3 mL) was added to a solid mixture of trimethylsulfoxonium iodide (223 mg, 1 0 mmol) and potassium f-butoxιde(1 13 mg, 1 0

mmol) The mixture was stirred at room temperature for 40 mm Water (15 mL) was added and the resulting slurry was stirred an additional 20 mm The precipitate was filtered, washed with water, and dried under vacuum to afford the title compound (163 mg)

Step 5 Preparation of λ/-(3-methoxybenzyl)-6-(2-(((frans)-4-hvdroxy-4- (hvdroxymethyl)cvclohexyl)methyl)-2/-/-tetrazol-5-yl)-2-meth ylpyrιmιdιne-4-carboxamιde

Perchloric acid (70%, 0 3 mL) was added to a solution of λ/-(3-methoxybenzyl)-2-methyl-6-(2- (1 -oxaspιro[2 5]oct-6-ylmethyl)-2H-tetrazol-5-yl)pynmidine-4-carboxamide (163 mg) in a mixture of tetrahydrofuran (3 mL) and water (1 mL) The resulting slurry was warmed to afford a solution and the mixture was stirred at room temperature for 3 5 h The reaction mixture was purified by reverse phase preparative HPLC (water/acetonitrile) Fractions containing the first eluting product were neutralized by passing through a carbonate resin column and concentrated The residue was slurried and decanted from ethyl ether three times and dried in a vacuum desiccator to afford the title compound as a white solid (35 mg) MS (ES+) m/z 468 (M+H) ¹ H NMR (400 MHz, DMSO-d ₆ ) 6 ppm 9 48 (1 H, t, J=6 2 Hz), 8 42 (1 H, s), 7 24 (1 H, t, J=8 1 Hz), 6 90 - 6 95 (2 H, m), 6 83 (1 H, d, J=8 4 Hz), 4 75 (2 H, d, J=I 3 Hz), 4 51 (2 H, d, J=Q 2 Hz), 4 32 (1 H, t, J=5 9 Hz), 3 99 (1 H, s), 3 74 (3 H, s), 2 83 (3 H, s), 2 15 (1 H, br s ), 1 71 (2 H, d, J=10 2 Hz), 1 60 (2 H, d, J=10 2 Hz), 1 17 (3 H, d, J=9 9 Hz), 1 22 (3 H, d, J=12 8 Hz)

Example 29 W-(3-Methoxybenzyl)-6-(2-(((c/s)-4-hydroxy-4-(hydroxymethyl) cyclohexyl)methyl)-2H-tetrazol-5- yl)-2-methylpyrimidine-4-carboxamide

Isolation of the second eluting product by reverse phase preparative HPLC from the reaction mixture described in Example 28 afforded the title compound as a white solid (19 mg) MS (ES+) m/z 468 (M+H) ¹ H NMR (400 MHz, DMSOd ₆ ) ÏŒ ppm 9 47 (1 H, t, J=Q 2 Hz), 8 41 (1 H, s), 7 24 (1 H, t, J=8 1 Hz), 6 90 - 6 95 (2 H, m), 6 83 (1 H, d, J=Q 1 Hz), 4 69 (2 H, d, J=I 0 Hz), 4 51 (2 H, d, J=6 6 Hz), 4 41 (1 H, t, J=5 7 Hz), 3 82 (1 H, s), 3 74 (3 H, s), 3 13 (2 H, d, J=5 9 Hz), 2 83 (3 H, s), 1 95 (1 H, br s ), 1 37 (3 H, d, J=9 2 Hz), 1 43 (5 H, t, J=13 0 Hz), 1 33 (1 H, br s )

Example 30

/V-(3-chloro-4-fluorobenzyl)-6-(2-((frans-4-hydroxy-4-(hy droxymethyl)cyclohexyl)methyl)-2H- tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide

Step 1 Preparation of (4-oxocvclohexyl)methyl 4-methylbenzenesulfonate

Formic acid (8 mL) was added to a solution of 1 ,4-dιoxaspιro[4 5]dec-8-ylmethyl 4- methylbenzenesulfonate (prepared as described in step 1 of the synthesis of λ/-(3-methoxybenzyl)-6- (2-(((frans)-4-hydroxy-4-(hydroxymethyl)cyclohexyl)methyl)-2 /-/-tetrazol-5-yl)-2-methylpyrιmιdιne-4- carboxamide, Example 28) (1 0 g, 3 0 mmol) in tetrahydrofuran (5 mL) The reaction was stirred at room temperature overnight, and then solvent was removed under a stream of nitrogen The residue was dissolved in dichloromethane The organic layer was washed with water (1 x), dried over magnesium sulfate, and concentrated under vacuum to afford the title compound as an oil (852 mg)

Step 2 Preparation of 1-oxaspιro[2 51oct-6-ylmethyl 4-methylbenzenesulfonate

A solution of (4-oxocyclohexyl)methyl 4-methylbenzenesulfonate (852 mg) in anhydrous dimethylsulfoxide (1 1 mL) was added in one portion to a mixture of trimethylsulfoxonium iodide (1 32 g, 6 0 mmol) and potassium f-butoxide (673 mg, 6 0 mmol) The mixture was stirred at room temperature for 1 h and then water (50 mL) was added The reaction mixture was extracted with ethyl ether (3x) The combined organic layers were washed with water (4x), dried over magnesium sulfate, and concentrated under vacuum to afford the title compound as an oil (621 mg) consisting of cis and trans isomers

Step 3 Preparation of (frans-4-hvdroxy-4-(hvdroxymethyl)cvclohexyl)methyl A- methylbenzenesulfonate

Perchloric acid (0 5 mL) was added to a solution of 1-oxaspιro[2 5]oct-6-ylmethyl 4- methylbenzenesulfonate (621 mg) in a mixture of tetrahydrofuran (4 mL) and water (2 mL) The

mixture was stirred for 2 hours The reaction mixture was purified by reverse phase preparative HPLC (water/acetonitπle) afforded the title compound as a clear oil (105 mg)

Step 4 Preparation of λ/-(3-chloro-4-fluorobenzyl)-6-(2-((/rar7s-4-hydroxy-4- (hvdroxymethyl)cvclohexyl)methyl)-2/-/-tetrazol-5-yl)-2-meth ylpyrιmιdιne-4-carboxamιde

/rans-(4-Hydroxy-4-(hydroxymethyl)cyclohexyl)methyl 4-methylbenzenesulfonate (100 mg, 0 318 mmol) was added to a solution of λ/-(3-chloro-4-fluorobenzyl)-2-methyl-6-(2/-/-tetrazol-5- yl)pyrιmιdιne-4-carboxamιde (88 mg, 0 25 mmol) and triethylamine (140 mg, 1 38 mmol) in anhydrous dimethylacetamide (0 3 ml_) The mixture was stirred overnight at 85 ⁰ C in a capped vial The reaction mixture was purified by reverse phase preparative HPLC (water/acetonitrile) Fractions containing product were neutralized by passing through a carbonate resin column and concentrated The residue was slurried and decanted from ethyl ether three times and dried in a vacuum desiccator to afford the title compound as a white solid (35 mg) MS (ES+) m/z 490 (M+H) ¹ H NMR (400 MHz, DMSO-c/ ₆ ) δ ppm 9 61 (1 H, t, J=Q 2 Hz), 8 41 (1 H, s), 7 57 (1 H, d, J=I 0 Hz), 7 37 (2 H, d, J=I 7 Hz), 4 75 (2 H, d, J=I 7 Hz), 4 52 (2 H, d, J=6 2 Hz), 4 33 (1 H, t, «7=5 7 Hz), 4 00 (1 H, s), 3 30 (1 H, s), 2 83 (3 H, s), 2 15 (1 H, br s ), 1 71 (2 H, d, J=8 4 Hz), 1 60 (2 H, d, J= 10 2 Hz), 1 17 (2 H, d, J=9 5 Hz), 1 22 (3 H, d, J=12 8 Hz)

Example 31 rac-/V-(4-Fluoro-3-methoxybenzyl)-6-(2-(((1 S*,3R*)-3-aminocyclopentyl)methyl)-2H-tetrazol-5-yl)- 2-methylpyrimidine-4-carboxamide

Step 1 Preparation of tert-butyl rac-(1 f? ^* ,3S ^* )-3-((5-(6-((4-fluoro-3-methoxybenzyl)carbamoyl)-2- methylpyrιmιdιn-4-yl)-2/-/-tetrazol-2-yl)methyl)cvclopent ylcarbamate

In a 20 ml scintillation vial with a magnetic stir bar at room temperature, λ/-(4-fluoro-3- methoxybenzyl)-2-methyl-6-(2H-tetrazol-5-yl)pyrιmιdιne-4- carboxamιde (prepared as described in step

2 of the synthesis of λ/-(4-fluoro-3-methoxybenzyl)-6-(2-(^ans-4-amιnocyclohexyl )methyl)-2/-/-tetrazol- 5-yl)-2-methylpyrιmιdιne-4-carboxamιde, Example 9) (227 mg, 0 66 mmol) was combined with /erf- butyl rac-(1 S ^* ,3R ^* )-3-(hydroxymethyl)cyclopentylcarbamate (193 mg, 0 90 mmol), polymer supported triphenylphosphine (247 mg, 0 531 mmol), and anhydrous tetrahydrofuran (15 ml) and stirred for 1 hour The mixture was cooled to -10 ⁰ C Di-fert-buty! azodicarboxylate (174 mg, 0 76 mmol) was added After 2 h, the reaction mixture was allowed to warm to room temperature and continue to stir for 14 hours The reaction mixture was concentrated, dissolved in acetonitrile and water and chromatographed by reversed phase preparative HPLC (Gilson, Delta Pak column, 30%-80% acetonitrile, 10 mm hold, 45 mm run, 10 mm hold) The desired product fractions were collected, combine and concentrated under vacuum to afford the title compound as a white solid (80 mg) ¹ H NMR (400 MHz, CDCI ₃ ) δ ppm 1 17 - 1 29 (m, 1 H), 1 41 (s, 9 H), 1 44 - 1 59 (m, 1 H), 1 61 (s, 3 H) ₁ 1 70 (br s , 1 H), 2 01 (br s , 1 H), 2 16 (br s , 1 H), 2 59 (d, J=7 52 Hz, 1 H), 2 83 (s, 1 H), 3 88 (s, 3 H), 4 50 (br s , 1 H), 4 63 (d, J=6 18 Hz, 1 H), 4 97 (dd, J=7 52, 3 22 Hz, 2 H), 6 84 - 6 92 (m, 1 H), 6 98 (dd, J=Q 06, 1 88 Hz, 1 H), 7 05 (dd, J=U 01 , 8 32 Hz, 1 H), 8 18 - 8 30 (m, 1 H), 8 91 (s, 1 H) LC/MS (5%-95%, CH ₃ CN/H ₂ O,, 5 mm ) 3 428 mm, m/z 541 (M+H)

Step 2 Preparation of rac-λ/-(4-fluoro-3-methoxybenzyl)-6-(2-(((1 S ^* ,3f? ^* )-3-amιnocvclopentyl)methyl)- 2H-tetrazol-5-yl)-2-methylpyrιmιdιne-4-carboxamιde

Trifluoroacetic acid (21 1 mg, 0 19 mmol) was added to a solution of tert-butyl rac-(1 R ^* ,3S ^* )-3- ((5-(6-((4-fluoro-3-methoxybenzyl)carbamoyl)-2-methylpyrιmÎ ¹dm-4-yl)-2H-tetrazol-2- yl)methyl)cyclopentylcarbamate (80 mg, 0 15 mmol) in dichloromethane (10 mL) and the mixture was stirred at room temperature for 4 hours The reaction mixture was concentrated to afford the trifluoroacetic acid salt of the title compound (80 mg) LC/MS (5%-95%, CH ₃ CN/H ₂ O, 5 mm ) 2 383 mm, m/z 441 (M+H)

Example 32 rac-/V-(4-Fluoro-3-methoxybenzyl)-6-(2-(((1S*,3R*)-3-acetami docyclopentyl)methyl)-2H-tetrazol-

5-yl)-2-methylpyrimidine-4-carboxamide

In a 2 dram vial with a magnetic stir bar at room temperature, rac-λ/-(4-fluoro-3- methoxybenzyl)-6-(2-(((1 S ^* ,3f? ^* )-3-amιnocyclopentyl)methyl)-2H-tetrazol-5-yl)-2-methylpyrÎ ¹mιdιne-4- carboxamide trifluoroacetic acid salt (prepared as described in Example 31 ) (40 mg, 0 7 mmol) was

dissolved in λ/,λ/-dιmethyl formamide (2 0 ml) Acetic anhydrιde( 9 21 mg, 0 09 mmol) and N ₁ N- dnsopropylethylamine (37 3 mg, 0 28 mmol) were added The reaction mixture was concentrated, dissolved in acetonitÏ€le and water and chromatographed by reversed phase preparative HPLC (30% - 70% acetonitrile/water, 10 mm hold, 45 mm run, 10 mm hold) Fractions containing the desired product were collected and concentrated under vacuum to afford the title compound as a white solid (10 0 mg) ¹ H NMR (400 MHz, DMSOd ₆ ) S ppm 1 16 - 1 27 (m, 2 H), 1 43 - 1 55 (m, 2 H), 1 76 (s, 5 H), 2 01 (d, J=M 8 Hz, 1 H), 2 83 (s, 3 H), 3 82 (s, 3 H), 4 00 (d, J=I 3 Hz, 1 H), 4 51 (d, J=6 2 Hz, 2 H), 4 82 (br s , 1 H), 4 83 (d, J=2 2 Hz, 1 H), 6 92 (d, J=A 4 Hz, 1 H), 7 16 (td, J=M 0, 8 6 Hz, 2 H), 7 84 (br s , 1 H), 8 42 (s, 1 H), 9 48 - 9 54 (m, 1 H) LC/MS (5%-95%, CH ₃ CN/H ₂ O, 5 mm ) 2 842 mm, m/z 441 (M+H)

Example 33

(+)-N-(4-Fluoro-3-methoxybenzyl)-6-(2-(((1 S*,3R*)-3-acetamidocyclopentyl)methyl)-2H-tetrazol-

5-yl)-2-methylpyrimidine-4-carboxamide

rac-λ/-(4-Fluoro-3-methoxybenzy!)-6-(2-(((1 S\3R*)-3-acetamidocyclopentyl)methyl)-2H- tetrazol-5-yl)-2-methylpyrιmιdιne-4-carboxamιde (prepared as described in Example 32) was separated by supercritical fluid chiral chromatography (Chiralcel AD-H column, 30 x 250 mm, 20% 2- propanol, 70 mL/min) Isolation of the first eluting isomer afforded the title compound (49 4 mg) LC/MS (5%-95% CH ₃ CN/H ₂ O, 5 mm ) 2 813 mm , m/z 483 (M+H) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1 21 (br s , 1 H), 1 47 (d, J=5 49 Hz, 1 H), 1 70 (br s , 1 H), 1 76 (s, 3 H), 2 01 (br s , 1 H), 2 61 (br s , 1 H), 2 82 (s, 2 H), 3 37 (s, 9 H), 3 82 (s, 2 H), 4 00 (br s , 1 H), 4 50 (d, J=6 22 Hz, 1 H), 4 81 (dd, J=I 14, 2 01 Hz, 1 H), 6 90 (br s , 1 H), 7 16 (d, J=2 20 Hz, 1 H), 7 85 (br s , 1 H), 9 51 (s, 1 H) [σ] _D ^21'c = +3 7° (c = 0 7, dichloromethane)

Example 34 (-)-/V-(4-Fluoro-3-methoxybenzyl)-6-(2-(((1R*,3S*)-3-acetami docyclopentyl)methyl)-2H-tetrazol-5- yl)-2-methylpyrimidine-4-carboxamide

rac-W-(4-Fluoro-3-methoxybenzyl)-6-(2-(((1 S ^* ,3/ ^: ? ^* )-3-acetamιdocyclopentyl)methyl)-2/-/- tetrazol-5-yl)-2-rnethylpyπmιdιne-4-carboxamιde (prepared as described in Example 32) was separated by supercritical fluid chiral chromatography (Chiralcel AD-H column, 30 x 250 mm, 20% 2- propanol, 70 mL/min) Isolation of the second eluting isomer afforded the title compound (44 8 mg)

LC/MS (5%-95% CH ₃ CN/H ₂ O, 5 mm ) 2 813 mm , m/z 483 (M+H) ¹ H NMR (400 MHz, DMSOd ₆ ) 6 ppm 1 21 (br s , 1 H), 1 47 (d, J=5 89 Hz, 1 H), 1 70 (br s , 1 H), 1 76 (s, 3 H), 2 01 (br s , 1 H), 2 61 (br s , 1 H), 2 83 (s, 2 H), 3 37 (s, 9 H), 3 82 (s, 2 H), 4 10 (br s , 1 H), 4 51 (d, J=6 62 Hz, 1 H), 4 91 (dd, J=7 54, 2 01 Hz, 1 H), 6 90 (br s , 1 H), 7 18 (d, J=2 50 Hz, 1 H), 7 86 (br s , 1 H), 9 53 (s, 1 H) [σ] _D ^2rc = 4 6° (c = 0 7, dichloromethane)

Example 35 rac-W-(4-Fluoro-3-methoxybenzyl)-2-methyl-6-(2-(((1S*,3R*)-3 - (methylsulfonamido)cyclopentyl)methyl)-2H-tetrazol-5-yl)pyri midine-4-carboxamide

In a 2 dram vial with a magnetic stir bar at room temperature, rac-λ/-(4-fluoro-3- methoxybenzyl)-6-(2-(((1 S*,3R ^* )-3-ammocyclopentyl)methyl)-2/-/-tetrazol-5-yl)-2-methylpyÏ€ mιdιne-4- carboxamide trifluoroacetic acid salt (prepared as described in Example 31 ) (40 mg, 0 7 mmol) was dissolved in λ/,λ/-dιmethyl formamide (2 0 ml) λ/,λ/-Dιιsopropylethylamιne (28 0 mg, 0 216 mmol) and methane sulfonyl chloride (10 3 mg, 0 09 mmol) was added and the mixture was stirred for 1 h The reaction mixture was concentrated, dissolved in acetonitÏ€le and water and chromatographed by reversed phase preparative HPLC (Gilson, Delta Pak column, 30%-70% acetonitrile, 10 mm hold, 45 mm run, 10 mm hold) Fractions containing the desired product were collect and concentrated under vacuum to afford the title compound as a white solid (10 4 mg) LC/MS (5%-95%, CH ₃ CN/H ₂ O, 5 mm ) 2 925 mm, m/z 519 (M+H) ¹ H NMR (400 MHz, DMSOd ₆ ) ÏŒ ppm 9 48 (t, J=6 2 Hz, 1 H), 8 40 (s, 1 H), 7 06 - 7 19 (m, 3 H), 6 86 - 6 91 (m, 1 H), 4 80 (d, J=7 3 Hz, 2 H), 4 48 (d, J=6 2 Hz, 2 H), 3 80 (s, 3 H), 3 59 - 3 69 (m, 1 H), 2 85 (s, 3 H), 2 81 (s, 3 H), 2 54 - 2 63 (m, 1 H), 2 02 - 2 1 1 (m, 1 H), 1 83 - 1 94 (m, 1 H), 1 62 - 1 73 (m, 1 H), 1 43 - 1 60 (m, 2 H), 1 25 - 1 36 (m, 1 H)

Example 36

(+)-λ^4-Fluoro-3-methoxybenzyl)-2-methyl-6-(2-(((1R*,3S* )-3- (methylsulfonamido)cyclopentyl)methyl)-2H-tetrazol-5-yl)pyri midine-4-carboxamide

rac-λ/-(4-Fluoro-3-methoxybenzyl)-2-methyl-6-(2-(((1S\3R ^* )-3-

(methylsulfonamιdo)cyclopentyl)methyl)-2/-/-tetrazol-5-yl)p yÏ€mιdιne-4-carboxamιde (prepared as described in Example 35) was separated by supercritical fluid chiral chromatography (Chiralcel OJ-H column, 30 x 250 mm, 25% methanol, 70 mUmin) Isolation of the first eluting isomer afforded the title compound (34 1 mg) MS (ES+) m/z 519 (M+H) ¹ H NMR (400 MHz, DMSOd ₆ ) δ ppm 9 45 (t, J=Q 2

Hz, 1 H), 8 37 (s, 1 H), 7 03 - 7 16 (m, 3 H), 6 83 - 6 89 (m, 1 H), 4 77 (d, J=I 3 Hz, 2 H), 4 46 (d, J=6 2 Hz, 2 H), 3 78 (s, 3 H), 3 57 - 3 65 (m, 1 H), 2 83 (s, 3 H), 2 78 (s, 3 H), 2 51 - 2 60 (m, 1 H), 2 00 - 2 09 (m, 1 H), 1 82 - 1 91 (m, 1 H), 1 59 - 1 70 (m, 1 H), 1 41 - 1 58 (m, 2 H), 1 22 - 1 33 (m, 1 H) [O]D ^{21 C} = +2 9° (C = 0 7, dichloromethane)

Example 37

(.)-W-(4-Fluoro-3-methoxybenzyl)-2-methyl-6-(2-(((1 S*,3fr)-3- (methylsulfonamido)cyclopentyl)methyl)-2H-tetrazol-5-yl)pyri midine-4-carboxamide

rac-λ/-(4-Fluoro-3-methoxybenzyl)-2-methyl-6-(2-(((1 S ^* ,3R ^* )-3- (methylsulfonamιdo)cyclopentyl)methyl)-2/-/-tetrazol-5-yl)p yrιmιdιne-4-carboxamιde (prepared as described in Example 35) was separated by supercritical fluid chiral chromatography (Chiralcel OJ-H column, 30 x 250 mm, 25% methanol, 70 mL/min) Isolation of the second eluting isomer afforded the title compound (36 9 mg) MS (ES+) m/z 519 (M+H) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9 50 (t, J=Q 2 Hz, 1 H), 8 42 (s, 1 H), 7 08 - 7 21 (m, 3 H), 6 88 - 6 94 (m, 1 H), 4 82 (d, J=I 3 Hz, 2 H), 4 51 (d, J=Q 2 Hz, 2 H), 3 82 (s, 3 H), 3 62 - 3 70 (m, 1 H), 2 87 (s, 3 H), 2 83 (s, 3 H), 2 55 - 2 65 (m, 1 H), 2 04 - 2 13 ((H ₁ 1 H), 1 86 - 1 96 (m, 1 H), 1 65 - 1 74 (m, 1 H), 1 46 - 1 62 (m, 2 H), 1 27 - 1 37 (m, 1 H) [σ] _D ^21'C = -4 8° (c = 0 7, dichloromethane)

Example 38

/V-(3-Methoxybenzyl)-2-methyl-6-(2-((S)-morpholin-2-ylmet hyl)-2H-tetrazol-5-yl)pyrimidine-4- carboxamide

λ/-(3-Methoxybenzyl)-2-methyl-6-(2H-tetrazol-5-yl)pyrιm ιdιne-4-carboxamιde (prepared as described in step 6 of the synthesis of λ/-(3-methoxybenzyl)-6-(2-(((/rans)-4-amιnocyclohexyl)meth yl)- 2H-tetrazol-5-yl)-2-methylpynmidine-4-carboxamide, Example 5) (0 656 g, 2 02 mmol) and (S)-tert- butyl 2-(hydroxymethyl)morpholιne-4-carboxylate (438 mg, 2 02 mmol) were taken up in tetrahydrofuran (25 mL) and treated with polymer supported triphenylphosphine (1 34 g, 3 02 mmol) After stirring for 30 mm at room temperature, dι-/ert-butyl azodicarboxylate (557 mg, 2 42 mmol) was added After 36 h at room temperature, the reaction was filtered to remove the resin The filtrate was concentrated to a crude residue as a yellow oil The residue was purified via normal phase chromatography (silica, 0-75% ethyl acetate/heptane with a trace 1 % methanol ran through entire gradient) Fractions containing (2S)-ferf-butyl 2-((5-(6-((3-methoxybenzyl)carbamoyl)-2-

methylpyrιmιdιn-4-yl)-2H-tetrazol-2-yl)methyl)morpholιne -4-carboxylate were concentrated The residue was taken up in dichloromethane (5 mL) and stirred with trifluoroacetic acid (1 mL) After 3 h stirring at room temperature, additional dichloromethane (5 mL) was added and the reaction was neutralized with 2 5 N aqueous NaOH to pH 7-8 The organic layer was separated and washed with water, dried over sodium sulfate, and concentrated to afford a regioisomeric mixture of products (0 28 g) containing the title compound LC/MS (5%-95% CH ₃ CN/H ₂ O, 6 mm) 2 9 mm, m/z 525 (M+H)

Example 39

A/-(3-Methoxybenzyl)-6-(2-(((S)-4-acetylmorpholin-2-yl)me thyl)-2H-tetrazol-5-yl)-2- methylpyrimidine-4-carboxamide

.

A regioisomeric mixture (0 13 g) containing λ/-(3-methoxybenzyl)-2-methyl-6-(2-((S)- morpholιn-2-ylmethyl)-2H-tetrazol-5-yl)pyrιmιdιne-4-carb oxamιde (prepared as described in Example 38) was taken up in dichloromethane (2 mL) and treated with triethylamine (0 047 mL, 0 38 mmol) and a solution of acetyl chloride (0 033 mL, 0 46 mmol) in dichloromethane (1 mL) After stirring for 2 h at room temperature, the mixture was concentrated and purified via reverse phase chromatography (40- 60% acetonitrile/water, 45 mm) Under these conditions, isolation of the first compound to elute afforded the title compound as a white solid (31 mg, 20%) LC/MS (5%-95% CH ₃ CN/H ₂ O, 6 mm) 2 52 mm, m/z 467 (M+H) ¹ H NMR (400 MHz, DMSOd ₆ ) δ ppm 2 01 (3 H, d, J=17 0 Hz), 2 56 - 2 74 (1 H, m), 2 81 (3 H, s), 3 40 (1 H, d, J=11 O Hz), 3 63 (1 H, d, J=1 1 0 Hz), 3 71 (3 H, s), 3 79 (1 H, d, J=7 9 Hz), 3 88 - 4 13 (2 H, m), 4 37 (1 H, d, J=14 3 Hz), 4 49 (2 H, d, J=6 2 Hz), 4 85 - 5 07 (2 H, m), 6 80 (1 H, d, J=7 9 Hz), 6 91 (2 H, br s ), 7 14 - 7 29 (1 H, m), 8 40 (1 H, s), 9 47 (1 H, s)

Example 40

/V-(3-Methoxybenzyl)-2-methyl-6-(2-(((/?)-4-(methylsulfon yl)morpholin-2-yl)methyl)-2H-tetrazol-5- yl)pyrimidine-4-carboxamide

A regioisomeric mixture (0 13 g) containing λ/-(3-methoxybenzyl)-2-methyl-6-(2-((S)- morpholιn-2-ylmethyl)-2H-tetrazol-5-yl)pyrιmιdιne-4-carb oxamιde (prepared as described in Example 38) was taken up in dichloromethane (2 mL) and treated with triethylamine (0 047 mL, 0 38 mmol) and a solution of methane sulfonyl chloride (0 026 mL, 0 32 mmol) in dichloromethane (1 mL) After stirring for 2 h at room temperature, the mixture was concentrated and purified via reverse phase chromatography (40-60% acetonitrile/water, 45 mm) Under these conditions, isolation of the first

compound to elute afforded the title compound as a white solid (34 mg, 22%) LC/MS (5%-95% CH ₃ CN/H ₂ O, 6 mm) 3 99 mm, m/z 503 (M+H) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2 68 - 2 88 (5 H, m), 2 91 (3 H, s), 3 34 (1 H ₁ br s ), 3 50 (1 H, t, J=10 8 Hz), 3 67 (1 H, d, J=11 7 Hz), 3 71 (3 H, s), 3 89 (1 H, d, J=1 1 0 Hz), 4 13 (1 H, t, J=9 0 Hz), 4 49 (2 H, d, J=6 4 Hz), 4 89 - 5 00 (1 H, m), 5 03 - 5 13 (1 H, m), 6 80 (1 H ₁ d, J=6 6 Hz), 6 91 (2 H, br s ), 7 22 (1 H, t, J=8 1 Hz), 8 40 (1 H, s), 9 47 (1 H, s)

Example 41

W-(4-Fluoro-3-methoxybenzyl)-2-methyl-6-(2-((S)-morpholin -2-ylmethyl)-2H-tetrazol-5- yl)pyrimidine-4-carboxamide

λ/-(4-Fluoro-3-methoxybenzyl)-2-methyl-6-(2/-/-tetrazol-5-y l)pyÏ€mιdιne-4-carboxamιde (prepared as described in step 2 of the synthesis of λ/-(4-fluoro-3-methoxybenzyl)-6-(2-(/rans-4- aminocyclohexy^methyl^H-tetrazol-S-yl^-methylpyÏ€midine^-car boxamide, Example 9) (1 00 g, 2 91 mmol) and (S)-tert-buty! 2-(hydroxymethyl)morpholιne-4-carboxylate (633 mg, 2 91 mmol) were taken up in tetrahydrofuran (50 mL) and treated with polymer supported tÏ€phenylphosphine (1 94 g, 4 37 mmol) After stirring for 30 mm at room temperature, di-fert-butyl azodicarboxylate (895 mg, 3 50 mmol) was added After 15 h at room temperature, the reaction was filtered to remove the resin The filtrate was concentrated to a crude oily residue The residue was purified via normal phase chromatography (silica, 0-75% ethyl acetate/heptane with a trace 1% methanol ran through entire gradient) Fractions containing (2S)-tert-butyl 2-((5-(6-((4-fluoro-3-methoxybenzyl)carbamoyl)-2- methylpyrιmιdιn-4-yl)-2H-tetrazol-2-yl)methyl)morpholιne -4-carboxylate were concentrated The residue was taken up in dichloromethane (10 mL) and stirred with trifluoroacetic acid (3 mL) After 3 h stirring at room temperature, additional dichloromethane (5 mL) was added and the reaction was neutralized with 2 5 N aqueous NaOH to pH 7-8 The organic layer was separated and washed with water (2 mL), dried over sodium sulfate, and concentrated to afford a regioisomeric mixture of products (0 57 g) containing the title compound LC/MS (5%-95% CH ₃ CN/H ₂ O, 6 mm) 2 33 mm, m/z 443 (M+H)

Example 42

N-(4-fluoro-3-methoxybenzyl)-6-(2-(((S)-4-acetylmorpholin -2-yl)methyl)-2H-tetrazol-5-yl)-2- methylpyrimidine-4-carboxamide

A regioisomeric mixture (0 065 g) containing λ/-(4-fluoro-3-methoxybenzyl)-2-methyl-6-(2-((S)- morpholιn-2-ylmethyl)-2H-tetrazol-5-yl)pyrιmιdιne-4-carb oxamιde (prepared as described in Example 41 ) was taken up in dichloromethane (2 mL) and treated with triethylamine (0 033 ml_, 0 24 mmol) and a solution of acetyl chloride (0 016 mL, 0 23 mmol) in dichloromethane (1 mL) After stirring for 2 h at room temperature, the mixture was concentrated and the crude residue was purified via reverse phase chromatography (40-60% acetonitrile/water, 45 mm) Under these conditions, isolation of the first peak to elute afforded the title compound as a white solid (35 mg, 49%) LC/MS (5%-95% CH ₃ CN/H ₂ O, 6 mm) 3 75 mm, m/z 485 (M+H) ¹ H NMR (400 MHz, DMSO-c/ ₆ ) δ ppm 1 94 - 2 02 (3 H, m), 2 58 - 2 73 (1 H, m), 2 85 (3 H, s), 3 04 - 3 20 (1 H, m), 3 60 (1 H, d, J=13 2 Hz), 3 67 - 3 76 (1 H, m), 3 80 (3 H, s), 3 83 - 3 93 (1 H, m), 3 97 - 4 06 (1 H, m), 4 40 (1 H, d, J=13 2 Hz), 4 49 (2 H, d, J=6 4 Hz), 4 93 - 5 01 (1 H, m), 5 08 (1 H, d, J=9 7 Hz), 6 83 - 6 92 (1 H, m), 7 06 - 7 20 (2 H, m), 8 46 (1 H, s), 9 54 (1 H, t, J=6 0 Hz)

Example 43 λ/-(4-Fluoro-3-methoxybenzyl)-2-methyl-6-(2-(((/?)-4-(methy lsulfonyl)morpholin-2-yl)methyl)-2H- tetrazol-5-yl)pyrimidine-4-carboxamide

A regioisomeric mixture (0 15 g) containing λ/-(4-fluoro-3-methoxybenzyl)-2-methyl-6-(2-((S)- morpho!ιn-2-ylmethyl)-2H-tetrazol-5-yl)pyrιmιdιne-4-carb oxamιde (prepared as described in Example 41 ) was taken up in dichloromethane (3 mL) and treated with triethylamine (0 052 mL, 0 37 mmol) and a solution of methane sulfonyl chloride ( 0 029 mL, 0 34 mmol) in dichloromethane (1 mL) After stirring for 2 h at room temperature, the mixture was concentrated and purified via reverse phase chromatography (40-60% acetonitrile/water, 55 mm) Under these conditions, isolation of the first eluted compound afforded the title compound as a white solid (68 mg, 39%) LC/MS (5%-95% CH ₃ CN/H ₂ O, 6 mm) 3 94 mm m/z 521 (M+H) ¹ H NMR (400 MHz, DMSOd ₆ ) δ ppm 2 73 - 2 88 (5 H, m), 2 91 (3 H, s), 3 32 (1 H, d, J=1 1 3 Hz), 3 44 - 3 55 (1 H, m), 3 65 (1 H, s), 3 80 (3 H, s), 3 89 (1 H, d, J=1 1 7 Hz), 4 06 - 4 16 (1 H, m), 4 48 (2 H, d, J=6 4 Hz), 4 89 - 4 99 (1 H, m), 5 01 - 5 12 (1 H, m), 6 89 (1 H, br s ), 7 06 - 7 21 (2 H, m), 8 40 (1 H, s), 9 49 (1 H, t, J=6 4 Hz)

Example 44 W-(3-Methoxybenzyl)-2-methyl-6-(2-((R)-morpholin-2-ylmethyl) -2H-tetrazol-5-yl)pyrimidine-4- carboxamide

λ/-(3-Methoxybenzyl)-2-methyl-6-(2/-/-tetrazol-5-yl)pyrιmÎ ¹dιne-4-carboxamιde (prepared as described in step 6 of the synthesis of /V-(3-methoxybenzyl)-6-(2-(((frans)-4-amιnocyclohexyl)methy l)- 2/-/-tetrazol-5-yl)-2-methylpyrιmιdιne-4-carboxamιde, Example 5) (1 00 g, 3 07 mmol) and (R)-terf-butyl 2-(hydroxymethyl)morpholιne-4-carboxylate (801 mg, 3 69 mmol) were taken up in tetrahydrofuran (50 mL) and treated with polymer supported triphenylphosphine (2 05 g, 4 61 mmol) After stirring for 30 mm at room temperature, di-fert-butyl azodicarboxylate (849 mg, 3 69 mmol) was added After 15 h at room temperature, the reaction was filtered to remove the resin The filtrate was concentrated to a crude oily residue The residue was purified via normal phase chromatography (silica, 0-75% ethyl acetate/heptane with a trace 1 % methanol ran through entire gradient) Fractions containing (2R)-tert- butyl 2-((5-(6-((3-methoxybenzyl)carbamoyl)-2-methylpyrιmιdιn-4 -yl)-2H-tetrazol-2- yl)methyl)morpholιne-4-carboxylate were concentrated The residue was taken up in dichloromethane (10 mL) and stirred with trifluoroacetic acid (3 mL) After 3 h stirring at room temperature, additional dichloromethane (5 mL) was added and the reaction was neutralized with 2 5 N aqueous NaOH to pH 7-8 The organic layer was separated, washed with water, dried over sodium sulfate, and concentrated to afford a regioisomeÏ€c mixture of products (0 85 g) containing the title compound LC/MS (5%-95% CH ₃ CN/H ₂ O, 6 mm) 2 69 mm, m/z 425 (M+H)

Example 45

^-(S-MethoxybenzyO-e^Z-i^RJ^-acetylmorpholin^-yOmethyO-σ H-tetrazol-S-yl)^- methylpyrimidine-4-carboxamide

A regioisomeric mixture (0 42 g) containing λ/-(3-methoxybenzyl)-2-methyl-6-(2-((R)- morpholιn-2-ylmethyl)-2H-tetrazol-5-yl)pyrιmιdιne-4-carb oxamιde (prepared as described in Example 44) was taken up in dichloromethane (4 mL) and treated with tnethylamine (0 193 mL, 1 4 mmol) and a solution of acetyl chloride (0 077 mL, 0 1 1 mmol) in dichloromethane (1 mL) After stirring for 2 h at room temperature, the mixture was concentrated and purified via reverse phase chromatography (40- 60% acetonitÏ€le/water, 60 mm) Under these conditions, isolation of the first compound to elute afforded the title compound as a white solid (67 mg, 15%) LC/MS (5%-95% CH ₃ CN/H ₂ O, 6 mm) 3 66 mm, m/z 467 (M+H) ¹ H NMR (400 MHz, DMSOd ₆ ) δ ppm 2 01 (3 H, d, J=17 0 Hz), 2 59 - 2 73 (1 H, m), 2 81 (3 H, s), 3 42 (1 H, t, J=1 1 0 Hz), 3 63 (1 H, d, J=13 0 Hz), 3 71 (3 H, s), 3 80 (1 H, d, J=9 7 Hz), 3 89 - 4 13 (2 H, m), 4 37 (1 H, d, J=13 0 Hz), 4 49 (2 H, d, J=6 4 Hz), 4 86 - 5 09 (2 H, m), 6 80 (1 H, d, J=7 7 Hz), 6 91 (2 H, br s ), 7 22 (1 H, t, J=8 1 Hz), 8 40 (1 H, s), 9 47 (1 H, t, J=6 4 Hz)

Example 46

λ/-(3-Methoxybenzyl)-2-methyl-6-(2-(((S)-4-(methylsulfon yl)morpholιn-2-vπmethyl)-2H-tetrazol-5- yl)pyrιmιdιne-4-carboxamιde

A regioisomeric mixture (0 42 g) containing λ/-(3-methoxybenzyl)-2-methyl-6-(2-((R)- morpholιn-2-ylmethyl)-2H-tetrazol-5-yl)pyrιmιdιne-4-carb oxamιde (prepared as described in Example 44) was taken up in dichloromethane (5 mL) and treated with triethylamine (0 193 mL, 1 40 mmol) and a solution of methane sulfonyl chloride (0 087 mL, 1 1 mmol) in dichloromethane (1 mL) After stirring for 2 h at room temperature, the mixture was concentrated and purified via reverse phase chromatography (40-60% acetonitrile/water, 60 mm) Under these conditions, isolation of the first compound to elute afforded the title compound as a white solid (43 mg, 9%) LC/MS (5%-95% CH ₃ CN/H ₂ O, 6 mm) 3 95 mm, m/z 503 (M+H) ¹ H NMR (400 MHz, DMSOd ₆ ) δ ppm 2 71 - 2 88 (5 H, m), 2 91 (3 H, s), 3 32 (1 H, d, J=13 0 Hz), 3 42 - 3 54 (1 H, m), 3 67 (1 H, d, J=1 1 7 Hz), 3 71 (3 H, s), 3 89 (1 H, d, J=12 1 Hz), 4 13 (1 H, t, J=9 0 Hz), 4 49 (2 H, d, J=6 4 Hz), 4 85 - 5 01 (1 H, m), 5 01 - 5 12 (1 H, m), 6 80 (1 H, d, J=8 1 Hz), 6 91 (2 H, br s ), 7 22 (1 H, t, J=8 1 Hz), 8 40 (1 H, s), 9 47 (1 H, t, J=6 3 Hz)

Example 47

W-(3-Chloro-4-fluorobenzyl)-2-methyl-6-(2-((S)-morpholin- 2-ylmethyl)-2H-tetrazol-5- yl)pyrimidine-4-carboxamide

Step 1 Preparation of λ/-(3-chloro-4-fluorobenzyl)-2-methyl-6-(2/-/-tetrazol-5-yl )pyrιmιdιne-4- carboxamide

Methyl 2-methyl-6-(2H-tetrazol-5-yl)pyrιmιdιne-4-carboxylate (prepared as described in step 1 of the synthesis of λ/-(4-Fluoro-3-(2-hydroxyethoxy)benzyl)-6-(2-(((frans)-4- acetamιdocyclohexyl)methyl)-2H-tetrazol-5-yl)-2-methylpyrι mιdιne-4-carboxamιde, Example 17) (3 03 g, 13 8 mmol), 3-chloro-4-fluorobenzylamιne (2 31 g, 14 4 mmol) and triethylamine (2 78 g, 27 5

mmol) were combined in dimethylacetamide (30 mL) The resulting mixture was stirred at 25 ⁰ C for 18 h The solvent was removed and the product was slurried with 3N hydrochloric acid (100 mL) The precipitate was collected by suction filtration, washed with water (2 x 25 mL) and dried under vacuum to afford the title compound as a tan solid (2 08 mg, 44%) LC/MS (10%-90% CH ₃ CN/H ₂ O, 4 mm) 2 74 mm, m/z 348 (M+H)

Step 2 Preparation of (2SHert-butyl 2-((5-(6-((3-chloro-4-fluorobenzyl)carbamoyl)-2-methylpyrιm ιdιn- 4-yl)-2/-/-tetrazol-2-yl)methyl)morpholιne-4-carboxylate

λ/-(3-Chloro-4-fluorobenzyl)-2-methyl-6-(2/-/-tetrazol-5 -yl)pyπmιdιne-4-carboxamιde (750 mg, 2 16 mmol) and (S)-tert-butyl 2-(hydroxymethyl)morpholιne-4-carboxylate (562 mg, 2 59 mmol) were taken up in tetrahydrofuran (40 mL) and treated with polymer supported triphenylphosphine (1 44 g, 3 24 mmol) After stirring for 30 mm at room temperature, di-tert-butyl azodicarboxylate (596 mg, 2 59 mmol) was added After 36 h at room temperature, the reaction was filtered to remove the resin The filtrate was concentrated and the residue was purified via normal phase chromatography (silica, 0-75% ethyl acetate/heptane with a trace 1 % methanol ran through entire gradient) The resulting regioisomeπc mixture was further purified by reverse phase chromatography (40-65%, acetonitπle/water, 60 minutes) Isolation of the first compound to elute afforded the title compound (0 10 g, 8%)

Step 3 Preparation of λ/-(3-chloro-4-f1uorobenzyl)-2-methyl-6-(2-((S)-morpholιn- 2-ylmethyl)-2/-/- tetrazol-5-yl)pyrιmιdιne-4-carboxamιde

(2S)-tert-Butyl 2-((5-(6-((3-chloro-4-fluorobenzyl)carbamoyl)-2-methylpyrιm ιdιn-4-yl)-2H- tetrazol-2-yl)methyl)morpholme-4-carboxylate, (0 10 g, 0 18 mmol) was taken up in dichloromethane (1 mL) and stirred with trifluoroacetic acid (0 5 mL) After 3 h stirring at room temperature, additional dichloromethane (5 mL) was added and the reaction was neutralized with 2 5 N aqueous NaOH to pH 7-8 The organic layer was separated, washed with water, dried over sodium sulfate, and concentrated to afford the title compound as an oil (0 065 g, 7%) LC/MS (5%-95% CH ₃ CN/H ₂ O, 6 mm) 2 30 mm, m/z 447 (M+H)

Example 48

W-(3-Chloro-4-fluorobenzyl)-2-methyl-6-(2-(((R)-4-(methyl sulfonyl)morpholin-2-yl)methyl)-2H- tetrazol-5-yl)pyrimidine-4-carboxamide

λ/-(3-Chloro-4-fluorobenzyl)-2-methyl-6-(2-((S)-morpholιn- 2-ylmethyl)-2/-/-tetrazol-5- yl)pyrιmιdιne-4-carboxamιde (prepared as described in Example 47) (0 065 g, 0 15 mmol) was taken up in dichloromethane (2 mL) and treated with triethylamine (O 018 ml_, 0 1 1 mmol) and a solution of methane sulfonyl chloride (13 5 mg, 0 19 mmol) in dichloromethane (0 5 mL) After stirring for 2 h at room temperature, the mixture was concentrated The resulting residue was triturated with diethyl ether to afford the title compound as a beige solid (38 5 mg, 68%) LC/MS (5%-95% CH ₃ CN/H ₂ O, 6 mm) 4 23 mm, 525 (M+H) ¹ H NMR (400 MHz, DMSOd ₆ ) δ ppm 2 71 - 2 87 (5 H, m), 2 89 (3 H, s), 3 27 - 3 33 (1 H, m), 3 41 - 3 52 (1 H, m), 3 64 (1 H, d, J=1 1 5 Hz), 3 86 (1 H, d, J=9 2 Hz), 4 06 - 4 15 (1 H, m), 4 47 (2 H, d, J=6 2 Hz), 4 86 - 4 97 (1 H, m), 5 00 - 5 08 (1 H, m), 7 28 - 7 36 (2 H, m), 7 52 (1 H, d, J=7 9 Hz), 8 37 (1 H, s), 9 56 (1 H, t, J=6 2 Hz)

Example 49

λ/-(3-Ethyl-4-fluorobenzyl)-2-methyl-6-(2-((S)-morpholι n-2-ylmethyl)-2/-/-tetrazol-5-yl)pγrιmιdιne-4- carboxamide

Step 1 Preparation of ethyl 3-bromo-4-fluorobenzoate

To a solution of 3-bromo-4-fluorobenzoιc acid (48 g, 219 18 mmol) in ethanol (250 mL) was added cone H ₂ SO ₄ (15 mL) and the mixture was refluxed for 24 h The reaction mixture was concentrated under reduced pressure and the residue was extracted with dichloromethane (2 x 300 mL) The combined organic layers were washed with saturated NaHCO ₃ solution followed by brine solution, dried over sodium sulfate, and concentrated under reduced pressure to afford the title compound (50 5 g, 93 %)

Step 2 Preparation of ethyl 3-ethyl-4-fluorobenzoate

Ethylmagnesium bromide (2 0 M in ether, 137 61 mL, 275 23 mmol) was added slowly to a solution of anhydrous ZnCI ₂ (37 43 g, 275 23 mmol) in dry tetrahydrofuran (200 mL) under argon atmosphere The resulting white slurry was stirred at 50 ⁰ C for 3 h In a separate flask, a solution of ethyl 3-bromo-4-fluorobenzoate (17 g, 68 80 mmol) in dry tetrahydrofuran (50 mL) was sequentially treated with PdCI ₂ (dppf) (2 8 g, 3 44 mmol) and copper(l) iodide (0 78 g, 4 12 mmol) under an argon atmosphere and the mixture was stirred at room temperature for 30 mm The alkyl zinc slurry was added to the ester mixture at room temperature The resulting brown slurry was stirred in the dark at room temperature for 48 h The reaction mixture was concentrated under vacuum to give a dark brown residue which was taken up in ethyl acetate (75OmL) and washed sequentially with 1 N hydrochloric acid (300 mL) solution, sat NaHCO ₃ (200 mL) solution and brine (250 mL) solution The organic layer was concentrated in vacuo to obtain crude material which was purified by column chromatography over silica gel (100-200 mesh) using 5 % EtOAc in hexane as an eluent to afford the title compound (12 5 g, 93 %)

Step 3 Preparation of 3-ethyl-4-fluorobenzoιc acid

Ethyl 3-ethyl-4-fluorobenzoate (12 5 g, 63 7 mmol) and lithium hydroxide monohydrate were taken up in dioxane (250 mL) and water (1/1 ) and stirred overnight at room temperature The reaction mixture was concentrated under reduced pressure and the residue was acidified with 1 N hydrochloric acid under ice-water cold conditions The mixture was extracted with dichloromethane (2 x 150 mL) The combined organic layers were washed with brine solution, dried over sodium sulfate and concentrated to afford the title compound (10 g, 95 %)

Step 4 Preparation of 3-ethyl-4-fluorobenzamιde

3-Ethyl-4-fluorobenzoιc acid (10 3 g, 61 3 mmol) was taken up in SOCI ₂ (150 mL) and then refluxed for 4 h The SOCI ₂ was removed under reduced pressure and the residue was dissolved in dry acetonitrile (100 mL) Ammonia gas was passed through the solution at -78 ^° C for 10 mm and the reaction mixture was allowed to warm to room temperature very slowly and stirred overnight The reaction mixture was concentrated to a residue which was extracted with dichloromethane (2 x 100 mL) The combined organic layers were washed with sat NaHCO ₃ solution followed by brine solution,

dried over sodium sulfate, and concentrated The residue was washed with hexane to afford the title compound (9 0 g, 88 % )

Step 5 Preparation of (3-ethyl-4-fluorophenyl)methanamιne Borane dimethylsulfide complex (94%, 22 mL, 215 49 mmol) was added slowly to a solution of

3-ethyl-4-fluorobenzamιde (9 0 g, 53 87 mmol) in dichloromethane (200 mL) under ice-cold condition After the addition, the reaction mixture was stirred for 1 h at room temperature and then it was refluxed for 24 h The reaction mixture was cooled to 0 ⁰ C and washed with NaHCO ₃ solution followed by brine The organic layer was concentrated to a crude material which was purified by column chromatography over silica gel (100-200 mesh) using 15 % dichloromethane in hexane as an eluent to afford (3-ethyl- 4-fluorophenyl)methanamιne as a solid (4 8 g, 58 %) MS (ES+) m/z 154 (M+H) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1 23 (t, 3 H) 1 76 (br s , 1 H) 2 67 (q, 2 H), 3 77 (br s , 1 H), 3 88 (s, 2 H), 7 01 -7 15 (m, 3 H)

Step 6 Preparation of λ/-(3-ethyl-4-fluorobenzyl)-2-methyl-6-(2H-tetrazol-5-yl)py rιmιdιne-4- carboxamide

A solution of methyl 2-methyl-6-(2/-/-tetrazol-5-yl)pyrιmιdιne-4-carboxylate (prepared as described in step 1 of the synthesis of λ/-(4-fluoro-3-(2-hydroxyethoxy)benzyl)-6-(2-(((frans)-4- acetamιdocyclohexyl)methyl)-2H-tetrazol-5-yl)-2-methylpyrι mιdιne-4-carboxamιde, Example 17) (1 0 g, 4 54 mmol) in dimethylformamide (5 mL) was treated with (3-ethyl-4-fluorophenyl)methanamιne (2 09 g, 13 6 mmol) and heated to 65 ⁰ C for 3 days The mixture was cooled to room temperature Excess 2 5 N NaOH was added to the mixture The product mixture was washed with ethyl acetate (3 x 10 mL) Concentrated hydrochloric acid was added and the resulting precipitate was filtered, washed with water and dried in vacuo to afford the title compound (367 mg, 24%) Step 7 Preparation of (S)-tert-butyl 2-((tosyloxy)methyl)morpholιne-4-carboxylate

(S)-tert-Butyl 2-(hydroxymethyl)morpholιne-4-carboxylate (5 00 g, 23 0 mmol) was taken up in pyridine (10 mL) and then treated with p-toluene sulfonyl chloride (5 70 g, 29 9 mmo!) The reaction was allowed to stir at room temperature for 15 h The mixture was poured into cold water (50 mL) and

extracted with ethyl acetate (2 * 50 mL) The organic layers were washed with water (3 * 40 mL) followed by brine (40 mL), dried over sodium sulfate, and concentrated The residue was purified on normal phase silica (50 g, 0-75% ethyl acetate/heptane) to afford the title compound as a white solid (7 3 g, 85%) LC/MS (5%-95% CH ₃ CN/H ₂ O, 6 mm) 3 17 mm, m/z 394 (M+Na)

Step 8 Preparation of λ/-(3-ethyl-4-fluorobenzyl)-2-methyl-6-(2-((S)-morpholιn-2 -ylmethyl)-2/-/-tetrazol- 5-yl)pyrιmιdιne-4-carboxamιde

λ/-(3-Ethyl-4-fluorobenzyl)-2-methyl-6-(2/-/-tetrazol-5-yl) pyrιmιdιne-4-carboxamιde (430 mg, 1 26 mmol) and (S)-tert-butyl 2-((tosyloxy)methyl)morpholιne-4-carboxylate (515 mg, 1 39 mmol) were taken up in triethylamine (7 0 mL) and dimethylformamide (0 010 mL) The reaction was stirred at 80 ⁰ C for 15 h and was then concentrated This residue was purified on normal phase silica (20 g, 0-75% ethyl acetate/heptane with 1 % methanol trace running throughout gradient) Fractions containing (2S)- tert-butyl 2-((5-(6-((3-ethyl-4-fluorobenzyl)carbamoyl)-2-methylpyrιmÎ ¹dιn-4-yl)-2H-tetrazol-2- yl)methyl)morpholιne-4-carboxylate were concentrated The residue was taken up in dichloromethane (4 mL) and stirred with trifluoroacetic acid (1 mL) for 2 h at room temperature Additional dichloromethane (5 mL) was added and the reaction was neutralized with 2 5 N aqueous NaOH to pH 7-8 The organic layer was separated, dried over sodium sulfate, and concentrated to afford a regioisomeric mixture of products (0 41 g) containing the title compound LC/MS (5%-95% CH ₃ CN/H ₂ O, 6 mm) 2 46 mm, m/z 441 (M+H)

Example 50

λ/-(3-Ethyl-4-fluorobenzyl)-2-methyl-6-(2-(((f?)-4-(meth ylsulfonyl)morpholιn-2-yl)methyl)-2H-tetrazol-5- vl)pyrιmιdιne-4-carboxamιde

A regioisomeric mixture (0 40 g) containing λ/-(3-ethyl-4-fluorobenzyl)-2-methyl-6-(2-((S)- morpholιn-2-ylmethyl)-2/-/-tetrazol-5-yl)pyrιmιdιne-4-ca rboxamιde (prepared as described in Example 49) (0 40 g, 0 91 mmol) was taken up in dichloromethane (2 mL) and treated with triethylamine (0 512 mL, 1 09 mmol) and a solution of methane sulfonyl chloride (114 mg, 1 00 mmol) in dichloromethane (0 5 mL) After stirring for 2 h at room temperature, the mixture was concentrated and purified via reverse phase chromatography (40-65% acetonitrile/water, 60 minutes) to afford the title compound as a white solid (36 mg, 8%) LC/MS (5%-95% CH ₃ CN/H ₂ O, 6 mm) 4 41 mm, 519 (M+H) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1 06 - 1 16 (2 H, m), 1 21 (2 H, d, J=5 3 Hz), 2 55 (1 H, s), 2 70 - 2 83 (4 H,

m), 2 89 (3 H, s), 3 21 - 3 35 (1 H, m), 3 40 - 3 52 (1 H, m), 3 59 - 3 71 (1 H, m), 3 86 (1 H, d, J=1 1 0 Hz), 4 01 - 4 14 (1 H, m), 4 44 (2 H, d), 4 87 - 4 97 (1 H, m), 4 99 - 5 07 (1 H, m), 6 95 - 7 04 (2 H, m), 7 16 (1 H, d, J=5 5 Hz), 7 22 - 7 29 (1 H, m), 8 38 (1 H, s), 9 46 (1 H, t, J=6 5 Hz)

Example 51 rac-6-(2-((1 ,4-Dioxan-2-yl)methyl)-2H-tetrazol-5-yl)-/V-(3-methoxybenzyl )-2-methylpyrimidine-4- carboxamide

A mixture of /V-(3-methoxybenzyl)-2-me{hyl-6-(2H-tetrazol-5-yl)pyrιmιdÎ ¹ne-4-carboxamιde (prepared as described in step 6 of the synthesis of λ/-(3-methoxybenzyl)-6-(2-(((/rans)-4- amιnocyclohexy!)methyl)-2/-/-tetrazol-5-yl)-2-methylpyrιmÎ ¹dιne-4-carboxamιde, Example 5) (300 mg, 0 92 mmol), 2-ιodomethyl-1 ,4-dιoxane (421 mg, 1 84 mmol), triethylamine (0 51 mL, 3 69 mmol) and dimethylacetamide (0 5 mL) was stirred at 85 ⁰ C for 2 days The mixture was purified by reverse phase preparative HPLC Fractions containing the desired product were combined, isolated and concentrated to afford the title compound as a white solid (146 mg, 37%) LC/MS (5%-95% CH ₃ CN/H ₂ O, 4 mm , 95% CH ₃ CN, 1 mm ) 2 75 mm, m/z 426 (M+H) ¹ H NMR (400 MHz, DMSO-c/ ₆ ) δ ppm 2 83 (s, 3 H), 3 38 - 3 59 (m, 3 H), 3 65 (d, J=10 6 Hz, 1 H), 3 73 - 3 75 (m, 4 H), 3 91 (dd, J= 11 5, 2 38 Hz, 1 H), 4 11 - 4 20 (m, 1 H), 4 51 (d, J=6 2 Hz, 2 H), 4 93 (d, J=6 2 Hz, 2 H), 6 89 - 6 96 (m, 2 H), 7 24 (t, J=8 05 Hz, 1 H), 8 42 (s, 1 H), 9 49 (t, J=6 4 Hz, 1 H)

Example 52 rac-6-(2-((1 ,4-Dioxan-2-yl)methyl)-2H-tetrazol-5-yl)-/V-(4-fluoro-3-meth oxybenzyl)-2- methylpyrimidine-4-carboxamide

A mixture of λ/-(4-fluoro-3-methoxybenzyl)-2-methyl-6-(2H-tetrazol-5-yl) pyrιmιdιne-4- carboxamide (prepared as described in step 2 of the synthesis of λ/-(4-fluoro-3-methoxybenzyl)-6-(2- (/rans^-aminocyclohexyOmethyO^H-tetrazol-δ-yO^-methylpyrimi dine^-carboxamide, Example 9) (300 mg, 0 87 mmol), 2-ιodomethyl-1 ,4-dιoxane (399 mg, 1 75 mmol), triethylamine (0 97 mL, 6 99 mmol) and dimethylacetamide (0 5 mL) was stirred at 85 ⁰ C for 2 days The mixture was purified by reverse phase preparative HPLC Fractions containing the desired product were combined, isolated and concentrated to afford the title compound as a white solid (147 mg, 38%) LC/MS (5%-95% CH ₃ CN/H ₂ O, 4 mm , 95% CH ₃ CN, 1 mm ) 2 78 mm, m/z 444 (M+H) ¹ H NMR (400 MHz, DMSOd ₆ ) ÏŒ

ppm 2 83 (s, 3 H), 3 38 - 3 59 (m, 3 H), 3 65 (d, J=10 6 Hz, 1 H), 3 73 (d, J= 1 1 0 Hz, 1 H), 3 83 (s, 3 H), 3 91 (dd, J= 11 5, 2 4 Hz, 1 H), 4 09 - 4 21 (m, 1 H), 4 51 (d, J=6 2 Hz, 2 H), 4 93 (d, J=6 2 Hz, 2 H), 6 87 - 6 95 (m, 1 H), 7 09 - 7 22 (m, 2 H), 8 42 (s, 1 H), 9 51 (t, J=6 2 Hz, 1 H)

Example 53

6-(2-(((R)-1 ,4-dioxan-2-yl)methyl)-2H-tetrazol-5-yl)-/V-(3-methoxybenzyl )-2-methylpyrimidine-4- carboxamide

Step 1 Preparation of (R)-(1 ,4-dιoxan-2-yl)methanol S-Epichlorohydrin (8 00 g, 86 5 mmol) was added drop wise to a stirred solution of chloro-2- ethanol (20 90 g, 259 0 mmol) and boron trifluoride diethyl etherate (0 12 mL, 1 3 mmol) at 45 ⁰ C After 1 5 hours, the reaction mixture was allowed to cool and was diluted with ethyl ether (50 mL) The mixture was washed with water (25 mL) The organic layer was dried over sodium sulfate and concentrated under reduced pressure with no heating to afford the intermediate, (S)-2-((2- chloroethoxy)methyl)oxιrane The oxirane was added drop wise to a stirred solution of sodium hydroxide (8 65 g, 216 mmol) in water (12 mL) The reaction mixture was stirred at room temperature for 2 hours and then was heated at 90 ⁰ C for 2 hours The reaction mixture was extracted with dichloromethane (3 x 30 mL) The combined organic layers were concentrated to afford the title compound (5 1 g) Step 2 Preparation of (S)-(1 ,4-dιoxan-2-yl)methyl 4-methγlbenzenesulfonate

p-Toluene sulfonyl chloride (8 75 g, 45 9 mmol) was added to a solution of (R)-(1 ,4-dιoxan-2- yl)methanol (5 1 g) in pyridine (50 mL) The mixture was stirred at room temperature for 15 hours The reaction mixture was poured into ice cold water and then extracted with dichloromethane (3 x 50 mL) The combined organic layers were washed with water (5 x 20 mL), dried over sodium sulfate and concentrated in vacuo to afford the title compound as an amber oil (6 1 g) LC/MS (5%-95% CH ₃ CN/H ₂ O, 6 mm) 2 50 mm, m/z 273 (M+H)

Step 3 Preparation of 6-(2-(((ff)-1 ,4-dιoxan-2-yl)methyl)-2H-tetrazol-5-yl)-λ/-(3-methoxybenz yl)-2- methylpyrιmιdιne-4-carboxamιde

A mixture of λ/-(3-methoxybenzyl)-2-methyl-6-(2/-/-tetrazol-5-yl)pyÏ€mι dιne-4-carboxamιde (prepared as described in step 6 of the synthesis of λ/-(3-Methoxybenzyl)-6-(2-(((frans)-4- aminocyclohexyOmethyO^H-tetrazol-S-yO^-methylpyrimidine^-car boxamide, Example 5) (100 mg, O 307 mmol), (S)-(1 , 4-dιoxan-2-yl)methyl 4-methylbenzenesulfonate (167 mg, 0 615 mmol), tÏ€ethylamine (0 17 mL, 1 23 mmol) and dimethylacetamide (0 3 mL) was stirred at 85 ⁰ C for 18 hours The mixture was purified by reverse phase preparative HPLC Fractions containing the desired product were combined, isolated and concentrated to afford the title compound as a white solid (39 mg, 30%) LC/MS (5%-95% CH ₃ CN/H ₂ O, 4 mm , 95% CH ₃ CN, 1 mm ) 2 75, m/z 426 (M+H) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2 83 (s, 3 H), 3 38 - 3 58 (m, 3 H), 3 64 (d, J=10 8 Hz, 1 H), 3 70 - 3 77 (m, 4 H), 3 92 (dd, J=1 1 4, 2 4 Hz, 1 H), 4 10 - 4 19 (m, 1 H), 4 51 (d, J=6 5 Hz, 2 H), 4 92 (d, J=1 6 Hz, 2 H), 6 83 (dd, J=9 0, 1 6 Hz, 1 H), 6 90 - 6 95 (m, 2 H), 7 24 (t, J=8 1 Hz, 1 H), 8 42 (s, 1 H), 9 54 (t, J=6 4 Hz, 1 H)

Example 54

6-(2-(((R)-1 ,4-dioxan-2-yl)methyl)-2H-tetrazol-5-yl)-/V-(4-fluoro-3-meth oxybenzyl)-2- methylpyrimidine-4-carboxamide

A mixture of λ/-(4-fluoro-3-methoxybenzyi)-2-methyl-6-(2H-tetrazol-5-yl) pyrιmιdιne-4- carboxamide (prepared as described in step 2 of the synthesis of λ/-(4-fluoro-3-methoxybenzyl)-6-(2- (frans-4-amιnocyclohexyl)methyl)-2/-/-tetrazol-5-yl)-2-meth ylpyrιmιdιne-4-carboxamιde, Example 9) (100 mg, 0 291 mmol), (S)-(1 , 4-dιoxan-2-yl)methyl 4-methylbenzenesulfonate (prepared as described in step 2 of the synthesis of 6-(2-(((R)-1 ,4-dιoxan-2-yl)methy!)-2H-tetrazol-5-yl)-λ/-(3-methoxybenz yl)- 2-methylpyÏ€mιdιne-4-carboxamιde, Example 53) (159 mg, 0 583 mmol), triethylamine (0 16 mL, 1 17 mmol) and dimethylacetamide (0 3 mL) was stirred at 85 ⁰ C for 18 hours The mixture was purified by reverse phase preparative HPLC Fractions containing the desired product were isolated and concentrated to afford the title compound as a white solid (51 mg, 39%) LC/MS (5%-95% CH ₃ CN/H ₂ O, 4 mm , 95% CH ₃ CN, 1 mm ) 2 78 mm, m/z 444 (M+H) ¹ H NMR (400 MHz, DMSO-Cf ₆ ) δ ppm 2 83 (s, 3 H), 3 38 - 3 58 (m, 3 H), 3 65 (d, J=10 6 Hz, 1 H), 3 73 (d, J=11 4 Hz, 1 H), 3 83 (s, 3 H), 3 91 (dd, J= 1 1 5, 2 4 Hz, 1 H), 4 1 1 - 4 19 (m, 1 H), 4 51 (d, J=6 2 Hz, 2 H), 4 93 (d, J=6 2 Hz, 2 H), 6 88 - 6 94 (m, 1 H), 7 09 - 7 22 (m, 2 H), 8 42 (s, 1 H), 9 51 (t, J=6 4 Hz, 1 H)

Example 55

6-(2-(((/?)-1 ,4-dioxan-2-yl)methyl)-2H-tetrazol-5-yl)-/V-(3-chloro-4-fluo robenzyl)-2- methylpyrimidine-4-carboxamide

λ/-(3-Chloro-4-fluorobenzyl)-2-methyl-6-(2H-tetrazol-5-yl)p yrιmιdιne-4-carboxamιde (prepared as described in step 1 of the synthesis of λ/-(3-chloro-4-fluorobenzyl)-2-methyl-6-(2-((S)-morpholιn- 2- ylmethyl)-2H-tetrazol-5-yl)pyrιmιdιne-4-carboxamιde, Example 47) (150 mg, 0 43 mmol) and (S)-(1 , 4- dιoxan-2-yl)methyl 4-methylbenzenesulfonate (prepared as described in step 2 of the synthesis of 6- (2-(((f?)-1 ,4-dιoxan-2-yl)methyl)-2/-/-tetrazol-5-yl)-λ/-(3-methoxybe nzyl)-2-methylpyrιmιdιne-4- carboxamide, Example 53) (129 mg, 0 47 mmol) were taken up in triethylamine (2 00 mL) and dimethylformamide (0 033 mL) The reaction was heated at 90 ⁰ C while shaking on a reactor block for 15 h The mixture was concentrated and the residue was purified by reverse phase chromatography to afford the title compound as an oil (29 mg, 15%) LC/MS (5%-95% CH ₃ CN/H ₂ O, 6 mm) 4 25 mm, m/z 448 (M+H) ¹ H NMR (400 MHz, DMSO-d ₆ ) ÏŒ ppm 2 81 (3 H, s), 3 35 - 3 57 (3 H, m), 3 62 (1 H, d, J=10 6 Hz), 3 71 (1 H, d, J=1 1 2 Hz), 3 89 (1 H, dd, J=11 53, 2 4 Hz), 4 06 - 4 20 (1 H, m), 4 49 (2 H, d, J=6 4 Hz), 4 90 (2 H, d, J=6 4 Hz), 7 35 (2 H, d, J=7 1 Hz), 7 54 (1 H, d, J=7 3 Hz), 8 39 (1 H, s), 9 59 (1 H, t, J=6 2 Hz)

Example 56

6-(2-(((/?)-1 ,4-Dioxan-2-yl)methyl)-2H-tetrazol-5-yl)-W-(4-fluoro-3-(2-hy droxyethoxy)benzyl)-2- methylpyrimidine-4-carboxamide

λ/-(4-Fluoro-3-(2-hydroxyethoxy)benzyl)-2-methyl-6-(2H-tetr azol-5-yl)pyrιmιdιne-4- carboxamide (prepared as described in step 2 of the synthesis of λ/-(4-fluoro-3-(2- hydroxyethoxy)benzyl)-6-(2-(((<rans-4-cyanocyclohexyl)met hyl)-2/-/-tetrazol-5-yl)-2-methylpyrimidme-4- carboxamide, Example 27) (45 mg, 0 20 mmol) and (S)-(1 ,4-dιoxan-2-yl)methyl 4- methylbenzenesulfonate (prepared as described in step 2 of the synthesis of 6-(2-(((R)-1 ,4-dιoxan-2- yl)methyl)-2/-/-tetrazol-5-yl)-λ/-(3-methoxybenzyl)-2-methy lpyrιmιdιne-4-carboxamιde, Example 53) (60 mg, 0 22 mmo!) were taken up in triethylamine (1 00 mL) and dimethylformamide (0 12 mL) The reaction was heated at 90 ⁰ C while shaking on a reactor block for 15 h The mixture was concentrated and the residue was purified by reverse phase chromatography to afford the title compound as an oil (17 mg, 18%) LC/MS (5%-95% CH ₃ CN/H ₂ O, 6 mm) 3 43 mm, m/z 474 (M+H) ¹ H NMR (400 MHz, DMSO-CZ ₆ ) δ ppm 2 81 (3 H, s), 3 35 - 3 57 (3 H, m), 3 62 (1 H, d, J=10 8 Hz), 3 67 - 3 75 (3 H, m),

3 89 (1 H, dd, J=11 6, 2 5 Hz), 4 02 (2 H, t, J=5 0 Hz), 4 06 - 4 18 (1 H, m), 4 47 (2 H, d, J=6 2 Hz),

4 81 (1 H, t, J=5 4 Hz) ₁ 4 90 (2 H, d, J=6 6 Hz), 6 81 - 6 94 (1 H, m), 7 08 - 7 20 (2 H, m), 8 40 (1 H, s) 9 48 (1 H, t, J=6 3 Hz)

Example 57

6-(2-(((S)-1 ,4-dioxan-2-yl)methyl)-2H-tetrazol-5-yl)-W-(3-methoxybenzyl) -2-methylpyrimidine-4- carboxamide

Step 1 Preparation of (S)-(L 4-dιoxan-2-yl)methanol R-Epichlorohydrin (17 00 g, 180 mmol) was added drop wise to a stirred solution of chloro-2- ethanol (44 4 g, 551 mmol) and boron trifluoride diethyl etherate (1 05 g, 9 19 mmol) at 45 ⁰ C After 18 hours, the reaction was quenched by adding diethyl ether (100 mL) The organic layer was washed with water (100 mL), dried over magnesium sulfate, filtered and evaporated Purification was accomplished by vacuum distillation (10 torr) affording the desired intermediate as an oil (128-131 ⁰ C, 18 g, 57%) The intermediate was added drop-wise to a stirred solution of sodium hydroxide (10 4 g, 260 mmol) in water (15 mL) The reaction was stirred at room temperature for 1 h, diluted with water (15 mL) and heated at 90 ⁰ C for 2 h The reaction mixture was extracted with dichloromethane (3 x 30 mL) The organic extracts were combined, dried over magnesium sulfate, filtered and evaporated to afford the title compound as a clear oil (7 4 g, 35%) Step 2 Preparation of (ff)-(1 ,4-dιoxan-2-yl)methyl 4-methylbenzenesulfonate

(S)-(1 ,4-Dιoxan-2-yl)methanol (2 52 g, 21 3 mmol) was taken up in pyridine (30 mL) and treated with p-toluene sulfonyl chloride (4 1 1 g, 21 5 mmol) and stirred at 25 °C for 18 hours The reaction mixture was dripped into ice water, extracted with dichloromethane (3 x 50 mL) and washed with water (5 x 20 mL) The organic extracts were combined, dried over magnesium sulfate, filtered and concentrated to afford the title compound as a clear oil (2 48 g, 43%) LC/MS (5%-95% CH ₃ CN/H ₂ O, 4 mm) 2 60 mm, m/z 273 (M+H)

Step 3 Preparation of 6-(2-(((S)- 1 ,4-dιoxan-2-yl)methyl)-2H-tetrazol-5-yl)-λ/-(3-methoxybenz yl)-2- methylpyrιmιdιne-4-carboxamιde

A mixture of λ/-(3-methoxybenzyl)-2-methyl-6-(2/-/-tetrazol-5-yl)pyrιmÎ ¹dιne-4-carboxamιde (prepared as described in step 6 of the synthesis of λ/-(3-Methoxybenzyl)-6-(2-(((<rans)-4- aminocyclohexyOmethyO^H-tetrazol-S-yO^-methylpyÏ€midine^-car boxamide, Example 5) (100 mg, O 307 mmol), (R)-(1 , 4-dιoxan-2-yl)methyl 4-methylbenzenesulfonate (167 mg, 0 615 mmol), triethylamine (0 17 mL, 1 23 mmol) and dimethylacetamide (0 3 mL) was stirred at 85 X for 18 h The mixture was purified by reverse phase preparative HPLC Fractions containing the desired product were isolated and concentrated to afford the title compound as a white solid (46 mg, 35%) LC/MS (5%-95% CH ₃ CN/H ₂ O, 4 mm , 95% CH ₃ CN, 1 mm ) 2 75 mm, m/z 426 (M+H) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2 84 (s, 3 H), 3 38 - 3 59 (m, 3 H), 3 65 (d, J=10 8 Hz, 1 H), 3 70 - 3 76 (m, 4 H), 3 92 (dd, J= ^* \ 1 5, 2 5 Hz, 1 H), 4 1 1 - 4 20 (m, 1 H), 4 51 (d, J=Q 3 Hz, 2 H), 4 93 (d, J= 1 8 Hz, 2 H), 6 83 (dd, J=8 1 , 1 7 Hz, 1 H), 6 90 - 6 96 (m, 2 H), 7 25 (t, J=8 1 Hz, 1 H), 8 43 (s, 1 H), 9 54 (t, J= ^Q 5 Hz, 1 H)

Example 58

6-(2-(((S)-1 ,4-dioxan-2-yl)methyl)-2H-tetrazol-5-yl)-W-(4-fluoro-3-metho xybenzyl)-2- methylpyrimidine-4-carboxamide

A mixture of λ/-(4-fluoro-3-methoxybenzyl)-2-methyl-6-(2H-tetrazol-5-yl) pyrιmιdιne-4- carboxamide (prepared as described in step 2 of the synthesis of λ/-(4-fluoro-3-methoxybenzyl)-6-(2- (frans^-aminocyclohexyOmethyO-σH-tetrazol-S-yO-σ-methylpyn midine^-carboxamide, Example 9) (100 mg, 0 291 mmol), (R)-(1 ,4-dιoxan-2-yl)methy! 4-methylbenzenesulfonate (prepared as described in step 2 of the synthesis of 6-(2-(((S)- 1 ,4-dιoxan-2-yl)methyl)-2H-tetrazol-5-yl)-λ/-(3-methoxybenz yl)- 2-methylpyrιmιdιne-4-carboxamιde, Example 57) (159 mg, 0 583 mmol), triethylamine (0 16 mL, 1 17 mmol) and dimethylacetamide (0 3 mL) was stirred at 85 ⁰ C for 18 hours The mixture was purified by reverse phase HPLC Fractions containing the desired product were concentrated to afford the title compound as a white solid (41 mg, 32%) LC/MS (5%-95% CH ₃ CN/H ₂ O, 4 mm , 95% CH ₃ CN, 1 mm ) 2 78 mm, m/z 444 m/z (M+H) ¹ H NMR (400 MHz, DMSOd ₆ ) δ ppm 2 83 (s, 3 H) 3 38 - 3 59 (m, 3 H) 3 65 (d, J=10 6 Hz, 1 H) 3 73 (d, J=1 1 4 Hz, 1 H) 3 83 (s, 3 H) 3 91 (dd, J=1 1 5, 2 38 Hz, 1 H) 4 15 (q, J=Q 2 Hz, 1 H) 4 51 (d, J=Q 2 Hz, 2 H) 4 93 (d, J=5 5 Hz, 2 H) 6 88 - 6 95 (m, 1 H) 7 09 - 7 22 (m, 2 H) 8 42 (S, 1 H) 9 50 (t, J=Q 22 Hz, 1 H)

Example 59

6-(2-(((S)-1,4-dioxan-2-yl)methyl)-2H-tetrazol-5-yl)-W-(3 -chloro-4-fluorobenzyl)-2- methylpyrimidine-4-carboxamide

λ/-(3-Chloro-4-fluorobenzyl)-2-melhyl-6-(2/-/-tetrazol-5-yl )pyrιmιdιne-4-carboxamιde (prepared as described in step 1 of the synthesis of λ/-(3-chloro-4-fluorobenzyl)-2-methyl-6-(2-((S)-morpholιn- 2- ylmethyl)-2/-/-tetrazo!-5-yl)pyrιmιdιne-4-carboxamιde, Example 47) (100 mg, 0 288 mmol), (R)-(1 , 4- dιoxan-2-yl)methyl 4-methylbenzenesulfonate (prepared as described in step 2 of the synthesis of 6- (2-(((S)-1 ,4-dιoxan-2-yl)methyl)-2H-tetrazol-5-yl)-λ/-(3-methoxybenz yl)-2-methylpyrιmιdιne-4- carboxamide, Example 57) (78 3 mg, 0 288 mmol), and triethylamine (400 μL) were combined in dimethylacetamide (100 μL) The resulting mixture was stirred at 90 ⁰ C for 18 h The mixture was concentrated The residue was purified by reverse phase high-pressure liquid chromatography The pure fractions were combined, extracted with ethyl acetate (2 x 20 ml_), dried over magnesium sulfate, and concentrated to afford the title compound as a solid (8 mg, 6%) MS (ES+) m/z 448 (M+H) ¹ H NMR (400 MHz, DMSOd ₆ ) δ ppm 9 48 (m, 1 H), 8 40 (s, 1 H), 7 54(m, 1 H), 7 24 (m, 2 H), 4 91 (m, 2 H), 4 51 (m, 2 H), 4 18 (m, 1 H), 3 81 (m, 1 H), 3 42-3 72 (m, 5 H), 2 81 (s, 3 H)

Example 60

6-(2-(((S)-1 ,4-dioxan-2-yl)methyl)-2H-tetrazol-5-yl)-/V-(4-fluoro-3-(2-h ydroxyethoxy)benzyl)-2- methylpyrimidine-4 -carboxamide

λ/-(4-Fluoro-3-(2-hydroxyethoxy)benzyl)-2-methyl-6-(2H-tetr azol-5-yl)pyrιmιdιne-4- carboxamide (prepared as described in step 2 of the synthesis of λ/-(4-fluoro-3-(2- hydroxyethoxy)benzyl)-6-(2-(((/rans-4-cyanocyclohexyl)methyl )-2H-tetrazol-5-yl)-2-methylpyrιmιdιne-4- carboxamide, Example 27) (56 7 mg, 0 152 mmol), (R)-(1 , 4-dιoxan-2-yl)methyl 4- methylbenzenesulfonate (prepared as described in step 2 of the synthesis of 6-(2-(((S)-1 ,4-dιoxan-2- yl)methyl)-2/-/-tetrazol-5-yl)-λ/-(3-methoxybenzyl)-2-methy lpyrιmιdιne-4-carboxamιde, Example 57) (400 μL) and triethylamine (30 7 mg, 0 304 mmol) were combined in dimethylacetamide (100 μL) After heating the reaction at 90 ⁰ C for 18 h, the mixture was concentrated The residue was purified by reverse phase high-pressure liquid chromatography The pure fractions were combined, extracted with ethyl acetate (2 x 20 mL), dried over magnesium sulfate, and concentrated to afford the title compound as an oil (12 1 mg, 17%) MS (ES+) m/z 474 (M+H) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm

9 48 (m, 1 H) ₁ 8 41 (s, 1 H), 7 20 (m, 3 H), 6 84 (m, 1 H), 4 88 - 4 94 (m, 4 H), 4 81 (t, 1 H), 4 42 - 4 48 (m, 2 H), 4 10 - 4 16 (m, 1 H), 3 99 - 4 06 (m, 2 H), 3 84 - 3 93 (m, 2 H), 3 67 - 3 73 (m, 1 H), 3 57 - 3 65 (m, 1 H), 3 35 - 3 55 (m, 1 H), 2 81 (s, 3 H)

Example 61 rac-W-(3-Methoxybenzyl)-6-(2-(((2S*,5/?*)-5-(hydroxymethyl)- 1 ,4-dioxan-2-yl)methyl)-2H-tetrazol-

5-yl)-2-methylpyrimidine-4-carboxamide

Step 1 Preparation of trans-2, 5-bιs(ιodomethyl)-1 ,4-dιoxane Yellow mercury oxide (700 g, 3 23 mol) was dissolved in concentrated nitric acid (70%, 443 mL, 6 53 mol) and water (295 mL) To the solution was added water (1180 mL) and it was cooled to 0 ⁰ C AIIyI alcohol (445 mL, 6 53 mol) was added in portions while the temperature was at 0-10 ⁰ C After addition, the mixture was stirred for 6 h The precipitate was collected by filtration and washed with water The solid was dissolved in 10% NaOH (1 94 L, 4 85 mol) and the solution was basic Concentrated potassium iodide (805 g, 4 85 mol) in water (560 mL) was added until precipitation of the mercury intermediate was complete The precipitate was collected and washed with water The wet solid was mixed with iodine (1041 g, 1 11 mol) and potassium iodide (1492 g, 8 99 mol) in water (3 7 L) The mixture was heated to reflux for 24 h A few mL of benzene was added to wash back iodine that sublimed on the condenser After 24 hr, the mixture was cooled to room temperature The precipitate was filtered, washed with dilute NaHSO ₃ and water to provide the title compound (598 g, 25%)

Step 2 Preparation of /rans-2,5-bιs-(acetoxymethyl)-1 ,4-dιoxane

A mixture of trans-2, 5-bιs(ιodomethyl)-1 ,4-dιoxane (523 g, 1 42 mol) and potassium acetate (956 g, 9 74 mol) in acetic acid (3 35 L) was heated to reflux The solution was seeded with 7 g of potassium iodide The resulting mixture was heated to gently reflux for nine days The dark mixture was cooled down and filtered to remove the solid The filtrate was concentrated to remove half of the solvent and then diluted with ethyl acetate (5 L), and filtered The filtrate was concentrated, and the residue was triturated with water (5 L) and cooled in an ice bath to provide the title compound as brown solid (140 5 g)

Step 3 Preparation of trans-2, 5-bιs-(hydroxymethyl)-1 ,4-dιoxane

A mixture of trans-2, 5-bιs-(acetoxymethy1 )-1 ,4-dιoxane (213 g) in methanol (1065 mL) and 4N hydrochloric acid in dioxane (229 mL) was heated to reflux for 1 h About 30 g of decolorizing charcoal was added after cooling down The mixture was filtered through a pad of Celite™ The filtrate was concentrated, and the oily residue was dissolved in isopropyl alcohol/benzene (1/5, 600 mL) Crystals were obtained by filtration and washed with isopropyl alcohol/benzene (1/5) to provide the title compound as a solid (126 9)

Step 4 Preparation of rac-((2/? ^* ,5f?*)-5-(hydroxymethyl)-1 ,4-dιoxan-2-yl)methyl 4- methylbenzenesulfonate

<rans-2,5-bιs-(Hydroxymethyl)-1 ,4-dιoxane (342 9 g, 2 31 mol) and p-toluene sulfonylchloride (441 0 g, 2 31 mol), tÏ€ethylamine (471 5 g, 4 66 mol) and dichloromethane (3 L) were combined in a 5 L round-bottomed flask equipped with a mechanical stirrer under nitrogen The mixture was maintained at 35 ⁰ C for 30 mm with water bath cooling and than allowed to stir at room temperature overnight The mixture was diluted with 3 N hydrochloric acid (1 L), and the resulting solids were filtered The organic phase of the filtrate was separated, washed with 3 N hydrochloric acid (1 L) followed by saturated ammonium chloride solution (500 mL), dried over magnesium sulfate, and concentrated to afford the title compound (338 3 g) Step 5 Preparation of rac-λπS-MethoxybenzvO-θ-^-U^S'.SP'Vδ-fhvdroxymethyO-i ^-dioxan^- vOmethvO^H-tetrazol-δ-yO^-methylpyrimidine^-carboxamide

rac-((2R*,5R*)-5-(Hydroxymethy!)-1 ,4-dιoxan-2-yl)methyl 4-methylbenzenesulfonate (4 3 g, 14 0 mmol) was added to a solution of λ/-(3-methoxybenzyl)-2-methyl-6-(2H-tetrazo!-5-yl)pyrιmιd ιne-4- carboxamide (prepared as described in step 6 of the synthesis of λ/-(3-methoxybenzyl)-6-(2-(((frans)- 4-amιnocyclohexyl)methyl)-2H-tetrazol-5-yl)-2-methylpyrιmÎ ¹dιne-4-carboxamιde, Example 5) (3 2 g, 9 8 mmol) and triethylamine (2 O g, 19 7 mmol) in anhydrous dimethylacetamide (4 mL) The reaction was stirred at 85 ⁰ C in a capped vial overnight The mixture was purified by reverse phase preparative HPLC (water/acetonitrile) Fractions containing product were neutralized by passing through a carbonate resin column and concentrated The resulting product was slurried with diethyl ether, decanted, and dried in vacuo to afford the title compound as a white solid (1 38 g) MS (ES+) m/z 456 (M+H) ¹ H NMR (400 MHz, DMSOd ₆ ) & PPm 9 44 - 9 52 (1 H, m), 8 42 (1 H, s), 7 24 (1 H, t, J=8 1

Hz), 6 89 - 6 95 (2 H, m), 6 83 (1 H, d, J=8 1 Hz), 4 93 (1 H, d, J=3 3 Hz), 4 88 (1 H, d, J=I 7 Hz), 4 51 (3 H, d, J=5 9 Hz), 4 08 (1 H, d, J=3 3 Hz), 3 99 (1 H, d, J= 1 1 3 Hz), 3 78 (1 H, d, J= 11 3 Hz), 3 74 (3 H, s), 3 36 - 3 48 (4 H, m), 3 31 (1 H, d, J=2 2 Hz), 2 83 (3 H, s)

Example 62

W-(3-Methoxybenzyl)-6-(2-(((2S,5R)-5-(hydroxymethyl)-1,4- dioxan-2-yl)methyl)-2H-tetrazol-5-yl)-

2-methylpyrimidine-4-carboxamide

Step 1 Preparation of ((2ff,5ff)-5-(hvdroxymethyl)-1 ,4-dιoxan-2-yl)methyl 4-methylbenzenesulfonate

rac-((2R ^* ,5R*)-5-(Hydroxymethyl)-1 ,4-dιoxan-2-yl)methyl 4-methylbenzenesulfonate (prepared as described in step 4 of the synthesis of rac-λ/-(3-methoxybenzyl)-6-(2-(((2S ^* ,5R*)-5-(hydroxymethyl)- 1 ,4-dιoxan-2-yl)methyl)-2H-tetrazol-5-yl)-2-methylpyrιmιdÎ ¹ne-4-carboxamιde, Example 61 ) was chirally separated by supercritical fluid chromatography (AD-H, 30% methanol/dichloromethane, 10/1 , 200 mL/min) Isolation of the first eluting isomer afforded the title compound as a white solid Step 2 Preparation of λ/-(3-methoxybenzyl)-6-(2-(((2S,5R)-5-(hvdroxymethyl)-1 ,4-dιoxan-2-yl)methyl)- 2/-/-tetrazol-5-yl)-2-methylpyrιmιdιne-4-carboxamιde

((2f?,5R)-5-(Hydroxymethyl)-1 ,4-dιoxan-2-yl)methyl 4-methylbenzenesulfonate (5 2 g, 17 2 mmol) was added to a solution of λ/-(3-methoxybenzyl)-2-methyl-6-(2H-tetrazol-5-yl)pyrιmιd ιne-4- carboxamide (prepared as described in step 6 of the synthesis of λ/-(3-methoxybenzyl)-6-(2-(((frans)- 4-amιnocyclohexyl)methyl)-2H-tetrazol-5-yl)-2-methylpyrιmÎ ¹dιne-4-carboxamιde, Example 5) (4 0 g, 12 3 mmol) and triethylamine (3 1 g, 30 0 mmol) in anhydrous dimethylacetamide (4 ml.) The reaction was stirred at 85 ⁰ C in a capped vial overnight The mixture was purified by reverse phase preparative HPLC (water/acetonitrile), and fractions containing product were concentrated The residue was dissolved in dichloromethane and washed with dilute aqueous NaOH followed by water The organic layer was dried over magnesium sulfate, filtered, and concentrated under vacuum The crude product was further separated by supercritical fluid chromatography (OJ-H, 30 x 250 mm, 40% methanol, 70 mL/min) Fractions containing the desired product were concentrated and the resulting solid was

recrystallized from isopropanol to afford the title compound as a white solid (986 mg) MS (ES+) m/z 456 (M+H) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9 52 (1 H, t, J=Q 4 Hz), 8 39 (1 H, s), 7 24 (1 H, t, J=8 1 Hz), 6 86-6 92 (2 H, m), 6 77-6 82 (1 H, m), 4 80-4 95 (2 H, m), 4 69 (1 H, t, J=5 5 Hz), 4 47 (2 H, d, J=6 2 Hz) ₁ 3 93-4 09 (2 H, m), 3 71-3 77 (1 H ₁ m), 3 70 (3 H, s), 3 2-3 45 (5 H, m), 2 79 (3 H, s)

Example 63

W-(3-Methoxybenzyl)-6-(2-(((2R,5S)-5-(hydroxymethyl)-1,4- dioxan-2-yl)methyl)-2H-tetrazol-5-yl)-

2-methylpyrimidine-4-carboxamide

Step 1 Preparation of ((2S,5S)-5-(hydroxymethyl)-1 ,4-dιoxan-2-yl)methyl 4-methylbenzenesulfonate

rac-((2R ^* ,5R ^* )-5-(Hydroxymethyl)-1 ,4-dιoxan-2-yl)methyl 4-methylbenzenesulfonate (prepared as described in step 4 of the synthesis of rac-λ/-(3-methoxybenzyl)-6-(2-(((2S ^* ,5R ^* )-5-(hydroxymethyl)- 1 ,4-dιoxan-2-yl)methyl)-2H-tetrazol-5-yl)-2-methylpyrιmιdÎ ¹ne-4-carboxamιde, Example 61 ) was chirally separated by supercritical fluid chromatography (AD-H, 30% methanol/dichloromethane, 10/1 , 200 mL/min) Isolation of the second eluting isomer afforded the title compound as a white solid

Step 2 Preparation of λ/-(3-Methoxybenzyl)-6-(2-(((2R,5S)-5-(hydroxymethyl)-1 ,4-dιoxan-2-yl)methyl)- 2H-tetrazol-5-yl)-2-methylpyrιmιdιne-4-carboxamιde

((2S,5S)-5-(Hydroxymethyl)-1 ,4-dιoxan-2-yl)methyl 4-methylbenzenesulfonate (5 2 g, 17 2 mmol) was added to a solution of λ/-(3-methoxybenzyl)-2-methyl-6-(2/-y-tetrazol-5-yl)pyrιmÎ ¹dιne-4- carboxamide (prepared as described in step 6 of the synthesis of λ/-(3-methoxybenzyl)-6-(2-(((<rans)- 4-amιnocyclohexyl)methyl)-2H-tetrazol-5-yl)-2-methylpyrιmÎ ¹dιne-4-carboxamιde, Example 5) (4 0 g, 12 3 mmol) and triethylamine (3 1 g, 30 0 mmol) in anhydrous dimethylacetamide (4 mL) The reaction was stirred at 85 ⁰ C in a capped vial overnight The mixture was purified by reverse phase preparative HPLC (water/acetonitÏ€le), and fractions containing product were concentrated The residue was dissolved in dichloromethane and washed with dilute aqueous NaOH followed by water The organic layer was dried over magnesium sulfate, filtered, and concentrated under vacuum The crude product was further separated by supercritical fluid chromatography (OJ-H, 30 x 250 mm, 40% methanol, 70

mL/min) Fractions containing the desired product were concentrated and the resulting solid was recrystallized from isopropanol to afford the title compound as a white solid (576 mg) MS (ES+) m/z 456 (M+H) ¹ H NMR (400 MHz, DMSO-Cf ₆ ) δ ppm 9 52 (1 H, t, J=6 4 Hz), 8 39 (1 H, s), 7 24 (1 H, t, J=8 1 Hz), 6 86-6 92 (2 H, m), 6 77-6 82 (1 H, m), 4 80-4 95 (2 H, m), 4 69 (1 H, t, J=5 5 Hz), 4 47 (2 H, d, J=6 2 Hz), 3 93-4 09 (2 H, m), 3 71 -3 77 (1 H, m), 3 70 (3 H, s), 3 2-3 45 (5 H, m), 2 79 (3 H ₁ s)

Example 64 rac-N-(4-Fluoro-3-methoxybenzyl)-6-(2-(((2S*,5R*)-5-(hydroxy methyl)-1 ,4-dioxan-2-yl)methyl)- 2H-tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide

rac-((2R*,5R*)-5-(Hydroxymethyl)-1 ,4-dιoxan-2-yl)methyl 4-methylbenzenesulfonate (prepared as described in step 4 of the synthesis of rac-λ/-(3-methoxybenzyl)-6-(2-(((2S*,5R ^* )-5-(hydroxymethyl)- 1 ,4-dιoxan-2-yl)methyl)-2H-tetrazol-5-yl)-2-methylpyrιmιdÎ ¹ne-4-carboxamιde, Example 61 ) (2 64 g, 8 7 mmol) was added to a solution of λ/-(4-fluoro-3-methoxybenzyl)-2-methyl-6-(2H-tetrazol-5- yl)pyrιmιdιne-4-carboxamιde (prepared as described in step 2 of the synthesis of λ/-(4-Fluoro-3- methoxybenzyl)-6-(2-(ÏŠrans-4-amιnocyclohexyl)methyl)-2/-/- tetrazol-5-yl)-2-methylpyrιmιdιne-4- carboxamide, Example 9) (2 0 g, 5 8 mmol) and triethylamine (880 mg, 8 7 mmol) in anhydrous dimethylacetamide (2 mL) The reaction was stirred overnight at 85 °C in a capped vial The mixture was purified by reverse phase preparative HPLC (water/acetonitrile) Fractions containing product were neutralized by passing through a carbonate resin column and concentrated The resulting product was slurried with diethyl ether, decanted, and dried in vacuo to afford the title compound as a white solid (1 02 g) MS (ES+) m/z 474 (M+H) ¹ H NMR (400 MHz, DMSO-c/ ₆ ) δ ppm 9 50 (1 H, t, J=6 2 Hz), 8 42 (1 H, s), 7 15 (2 H, td, J=12 1 , 8 4 Hz), 6 92 (1 H, d, J=A 4 Hz), 4 93 (1 H, d, J=Z 7 Hz), 4 88 (1 H, d, J=I 7 Hz), 4 65 (1 H, t, J=5 5 Hz), 4 51 (3 H, d, J=6 2 Hz), 4 08 (1 H, d, J=2 9 Hz), 3 99 (1 H, dd, J=1 1 5, 2 0 Hz), 3 83 (3 H, s), 3 78 (1 H, d, J= 1 1 7 Hz), 3 36 - 3 48 (4 H, m), 3 31 (1 H, s), 2 83 (3 H, s)

Example 65

/V-(4-Fluoro-3-methoxybenzyl)-6-(2-(((2S,5R)-5-(hydroxyme thyl)-1,4-dioxan-2-yl)methyl)-2H- tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide

λ/-(4-Fluoro-3-methoxybenzyl)-2-methyl-6-(2/-/-tetrazol-5-y l)pyrιmιdιne-4-carboxamιde (prepared as described in step 2 of the synthesis of λ/-(4-fluoro-3-methoxybenzyl)-6-(2-(frans-4- amιnocyclohexyl)methyl)-2/-/-tetrazol-5-yl)-2-methylpyrιmÎ ¹dιne-4-carboxamιde, Example 9) (10 0 g, 29 1 mmol) was dissolved in tÏ€ethylamine (7 04 g, 69 7 mmol) and λ/,λ/-dιmethylacetamιde (31 mL) ((2R,5R)-5-(hydroxymethyl)-1 ,4-dιoxan-2-yl)methyl 4-methylbenzenesulfonate (prepared as described in step 1 of the synthesis of λ/-(3-methoxybenzyl)-6-(2-(((2S,5f?)-5-(hydroxymethyl)-1 ,4-dιoxan-2- yl)methyl)-2H-tetrazol-5-yl)-2-methylpyrιmιdιne-4-carboxa mιde, Example 62) (12 4 g, 41 0 mmol) was added and the reaction heated to 85 ⁰ C for 16 hours After cooling to room temperature, the mixture was diluted with water (300 mL) and extracted with dichloromethane (3 x 200 mL) The combined organics were washed with 1 N NaOH (2 x 100 mL), 1 M hydrochloric acid (2 x 100 mL), water (100 mL), and brine (250 mL) The organic layer was dried over sodium sulfate, filtered and evaporated to give a yellow oil Purification by silica gel chromatography using heptane, ethyl acetate and methanol provided a mixture of regioisomers as an opaque oil The mixture was separated by supercritical fluid chromatography (OJ-H, 30 x 250 mm, 40% methanol, 70 mL/min) and the desired isomer was recrystallized from ethyl acetate (80 mL) and ethanol (1 mL) to provide the title compound as a white crystalline solid (3 5 g, 25%) LC/MS (5%-95% CH ₃ CN/H ₂ O, 4 mm) 3 39 mm, m/z 474 (M+H) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9 53 (t, J=6 3 Hz, 1 H), 8 39 (s, 1 H), 7 06 - 7 19 (m, 2 H), 6 83 - 6 91 (m, 1 H), 4 78 - 4 98 (m, 2 H), 4 68 (t, J=5 7 Hz, 1 H), 4 47 (d, J=6 4 Hz, 2 H), 3 99 - 4 10 (m, 1 H), 3 96 (dd, J=1 1 4, 2 4 Hz, 1 H), 3 79 (s, 3 H), 3 74 (dd, J=1 1 4, 2 2 Hz, 1 H), 3 19 - 3 47 (m, 5 H), 2 80 (s, 3 H)

Example 66

/V-(4-F!uoro-3-methoxybenzyl)-6-(2-(((2R,5S)-5-(hydroxyme thyl)-1,4-dioxan-2-yl)methyl)-2H- tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide

((2S,5S)-5-(Hydroxymethyl)-1 ,4-dιoxan-2-yl)methyl 4-methylbenzenesulfonate (prepared as described in step 1 of the synthesis of λ/-(3-Methoxybenzyl)-6-(2-(((2R,5S)-5-(hydroxymethyl)-1 ,4- dιoxan-2-yl)methyl)-2H-tetrazol-5-yl)-2-methylpyrιmιdιne -4-carboxamιde, Example 63) (5 2 g, 17 2 mmol) was added to a solution of λ/-(4-Fluoro-3-methoxybenzyl)-2-methyl-6-(2H-tetrazol-5- yl)pyrιmιdιne-4-carboxamιde (prepared as described in step 2 of the synthesis of λ/-(4-fluoro-3-

methoxybenzyl)-6-(2-(frans-4-amιnocyclohexyl)rnethyl)-2/-/- tetrazol-5-yl)-2-methylpyrιmιdιne-4- carboxamide, Example 9) (4 22 g, 12 3 mmol) and triethylamine (3 1 g, 30 O mmol) in anhydrous dimethylacetamide (4 mL) The reaction was stirred at 85 ⁰ C in a capped vial overnight The mixture was purified by reverse phase preparative HPLC (water/acetonitrile), and fractions containing product were concentrated The residue was dissolved in dichloromethane and washed with dilute aqueous NaOH followed by water The organic layer was dried over magnesium sulfate, filtered, and concentrated under vacuum The crude product was further separated by supercritical fluid chromatography (OJ-H, 30 x 250 mm, 45% acetonitrile, 70 mL/min) Fractions containing the desired product were concentrated and the resulting solid was recrystallized from ethyl acetate (80 mL) to afford the title compound as a white solid (1 5 g) MS (ES+) m/z 474 (M+H) ¹ H NMR (400 MHz,

DMSO-CZ ₆ ) δ ppm 9 50 (1 H, t, J=Q 2 Hz), 8 42 (1 H, s), 7 08-7 17 (2 H, m), 6 85-6 9 (1 H, m), 4 80-4 95 (2 H, m), 4 69 (1 H, t, J=5 5 Hz), 4 47 (2 H, d, J=6 2 Hz), 3 93-4 09 (2 H, m), 3 79 (3 H, s), 3 71-3 77 (1 H, m), 3 2-3 45 (5 H, m), 2 79 (3 H, s)

Example 67 rac-W-(4-Fluoro-3-methylbenzyl)-6-(2-(((2S*,5R*)-5-(hydroxym ethyl)-1,4-dioxan-2-yl)methyl)-2H- tetrazol-5-y!)-2-methylpyrimidine-4-carboxamide

Step 1 Preparation of methyl rac-6-(2-(((2S ^* ,5R*)-5-(hvdroxymethyl)-1 ,4-dιoxan-2-yl)methyl)-2/-/- tetrazol-5-yl)-2-methylpyrιmιdιne-4-carboxylate

In a 30 mL scintillation vial with a magnetic stir bar at room temperature and standard pressure, methyl 2-methyl-6-(2H-tetrazol-5-yl)pyrιmιdιne-4-carboxylate (prepared as described in step 1 of the synthesis of λ/-(4-fluoro-3-(2-hydroxyethoxy)benzyl)-6-(2-(((frans)-4- acetamιdocyclohexyl)methyl)-2H-tetrazol-5-yl)-2-methylpyrι mιdιne-4-carboxamιde, Example 17) (1 57 g, 7 13 mmol) was dissolved in N,N-dιmethylformamιde (15ml) λ/,λ/-Dιιsopropylethylamιne (1 86 g, 14 40 mmol) was added and the mixture was stirred at room temperature for 30 mm rac-((2R ^* ,5R ^* )-5- (Hydroxymethyl)-1 ,4-dιoxan-2-yl)methyl 4-methylbenzenesulfonate (prepared as described in step 4 of the synthesis of rac-λ/-(3-methoxybenzyl)-6-(2-(((2S ^* ,5/? ^* )-5-(hydroxymethyl)-1 ,4-dιoxan-2-yl)methyl)- 2H-tetrazol-5-yl)-2-methylpyrιmιdιne-4-carboxamιde, Example 61 ) (4 41 g, 14 59 mmol) was added and the reaction mixture was heated to 80 ⁰ C with stirring for 14 hours The reaction mixture was

concentrated, dissolved in acetonitrile and water, and chromatographed by reversed phase preparative HPLC (Gilson, Delta Pak, 20%-35% acetonitrile, 20 mm hold, 40 mm gradient, 8 mm hold) Fractions corresponding to the first eluting peak (27 34 mm) were concentrated under vacuum to afford the title compound as a solid (1 4 g) LC/MS (5%-95% CH ₃ CN/H ₂ O, 6 mm) 1 856 mm, m/z 351 (M+H) ¹ H NMR (400 MHz, DMSO-Cf ₆ ) rf ppm 1 16 - 1 27 (m, 2 H), 2 25 (s, 1 H), 2 79 (s, 3 H), 3 11 (dd, J=7 4, 4 2 Hz, 1 H), 3 18 - 3 29 (m, 2 H), 3 29 - 3 46 (m, 2 H), 3 59 (d, J=3 8 Hz, 1 H), 3 74 (dd, J= 1 1 6, 2 4 Hz, 1 H), 4 80 - 4 88 (m, 1 H), 4 89 - 4 97 (m, 1 H), 7 08 (d, J=7 8 Hz, 1 H), 7 44 (d, J=8 1 Hz, 1 H), 8 36 (s, 1 H)

Step 2 Preparation of rac-λ/-(4-fluoro-3-methylbenzyl)-6-(2-(((2S*,5f?*)-5-(hvdro xymethyl)-1 ,4-dιoxan- 2-yl)methyl)-2H-tetrazol-5-yl)-2-methylpyrιmιdιne-4-carbo xamιde

A mixture of rac-methyl 6-(2-(((2S ^* ,5R*)-5-(hydroxymethyl)-1 ,4-dιoxan-2-yl)methyl)-2H- tetrazol-5-yl)-2-methylpyrιmιdιne-4-carboxylate (100 mg, 0 285 mmol), 4-fluoro-3-methylbenzylamιne (1 19 mg, 0 856 mmol), and dimethylacetamide (1 mL) was heated to 85 ⁰ C for 18 hours The title compound was isolated as a solid by reverse phase preparative HPLC (73 mg, 56%) MS (ES+) m/z 458 m/z (M+H) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2 22 (s, 3 H), 2 83 (s, 3 H), 3 34 - 3 55 (m, 5 H), 3 78 (dd, J= 1 1 5, 2 0 Hz, 1 H), 3 99 (dd, J= 1 1 5, 2 0 Hz, 1 H), 4 04 - 4 16 (m, 1 H), 4 48 (d, J=6 2 Hz, 2 H), 4 65 (t, J=5 7 Hz, 1 H), 4 80 - 5 00 (m, 2 H), 7 07 (t, J=9 2 Hz, 1 H), 7 16 - 7 24 (m, 1 H), 7 26 (d, J=7 3 Hz, 1 H), 8 42 (s, 1 H), 9 50 (t, J=6 2 Hz, 1 H)

Example 68

/V-(4-Fluoro-3-methylbenzyl)-6-(2-(((2S,5/ ^: ?)-5-(hydroxymethyl)-1 _l 4-dioxan-2-yl)methyl)-2H- tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide

Step 1 Preparation of λ/-(4-fluoro-3-methylbenzyl)-2-methyl-6-(2H-tetrazol-5-yl)p yrιmιdιne-4- carboxamide

A solution of methyl 2-methyl-6-(2H-tetrazol-5-yl)pyrιmιdιne-4-carboxylate (prepared as described in step 1 of the synthesis of λ/-(4-fluoro-3-(2-hydroxyethoxy)benzyl)-6-(2-(((rrans)-4- acetamιdocyclohexyl)methyl)-2H-tetrazol-5-yl)-2-methylpyrι mιdιne-4-carboxamιde, Example 17) (1 0 g, 4 54 mmol) in dimethylformamide (5 mL) was treated with 4-fluoro-3-methylbenzylamιne (1 9 g, 13 6 mmol) and heated to 65 ⁰ C for 3 days The mixture was cooled to room temperature Excess 2 5 N NaOH was added to the mixture The product mixture was washed with ethyl acetate (3 x 10 mL) Concentrated hydrochloric acid was added and the resulting precipitate was filtered, washed with water and dried in vacuo to afford the title compound (1 21 g, 75%)

Step 2 Preparation of N-(4-fluoro-3-methylbenzyl)-6-(2-(((2S,5f?)-5-(hvdroxymethyl )-1 ,4-dιoxan-2- yl)methyl)-2H-tetrazol-5-yl)-2-methylpyrιmιdιne-4-carboxa mιde

A mixture of λ/-(4-fluoro-3-methylbenzyl)-2-methyl-6-(2H-tetrazol-5-yl)p yÏ€mιdιne-4- carboxamide (96 mg, 0 293 mmol), ((2R,5R)-5-(hydroxymethyl)-1 ,4-dιoxan-2-yl)methyl 4- methylbenzenesulfonate (prepared as described in step 1 of the synthesis of λ/-(3-methoxybenzyl)-6- (2-(((2S,5R)-5-(hydroxymethyl)-1 ,4-dιoxan-2-yl)methyl)-2H-tetrazol-5-yl)-2-methylpyrιmιdÎ ¹ne-4- carboxamide, Example 62) (106 mg, 0 352 mmol), and triethylamine (0 16 mL, 1 17 mmol) was heated in dimethylformamide at 85 ⁰ C overnight The mixture was chromatographed by reverse phase preparative HPLC Fractions containing the desired product were passed through a carbonate cartridge and concentrated to afford the title compound (39 mg, 28%) MS (ES+) m/z 458 (M+H) ¹ H NMR (400 MHz, CDCI ₃ ) δ ppm 1 83 (t, J=5 9 Hz, 1 H), 2 28 (d, J=2 0 Hz, 3 H), 2 89 (s, 3 H), 3 47 - 3 62 (m, 3 H), 3 62 - 3 71 (m, 2 H), 3 82 (dd, J= 1 1 6, 2 3 Hz, 1 H), 3 99 (dd, J= 1 1 6, 2 4 Hz, 1 H), 4 17 - 4 26 (m, 1 H), 4 64 (d, J=6 1 Hz, 2 H), 4 68 - 4 88 (m, 2 H), 6 96 - 7 03 (m, 1 H), 7 14 - 7 23 (m, 2 H), 8 27 - 8 34 (m, 1 H), 8 80 (s, 1 H)

Example 69

λ/-(4-Fluoro-3-methylbenzyl)-6-(2-(((2R,5S)-5-(hydroxyme thyl)-1 ,4-dioxan-2-yl)methyl)-2H- tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide

A mixture of A/-(4-fluoro-3-methylbenzyl)-2-methyl-6-(2H-tetrazol-5-yl)py rιmιdιne-4- carboxamide (prepared as described in step 1 in the synthesis of λ/-(4-fluoro-3-methylbenzyl)-6-(2- (((2S,5R)-5-(hydroxymethyl)-1 ,4-dιoxan-2-yl)methyl)-2H-tetrazol-5-yl)-2-methylpyrιmιdÎ ¹ne-4- carboxamide, Example 68) (96 mg, 0 293 mmol), ((2S,5S)-5-(hydroxymethyl)-1 ,4-dιoxan-2-yl)methyl 4-methylbenzenesulfonate (prepared as described in step 1 of the synthesis of λ/-(3-Methoxybenzyl)- 6-(2-(((2R,5S)-5-(hydroxymethyl)-1 ,4-dιoxan-2-y!)methyl)-2H-tetrazo!-5-yl)-2-methylpyrιmιdÎ ¹ne-4- carboxamide, Example 63) (106 mg, 0 352 mmol), and triethylamine (0 16 mL, 1 17 mmol) was heated in dimethylformamide at 85 ⁰ C overnight The mixture was chromatographed by reverse phase preparative HPLC Fractions containing the desired product were passed through a carbonate cartridge and concentrated to afford the title compound (21mg, 16%)

MS (ES+) m/z 458 (M+H) ¹ H NMR (400 MHz, CDCI ₃ ) δ ppm 2 26 (d, J= 1 4 Hz, 3 H), 2 87 (s, 3 H), 3 43 - 3 70 (m, 6 H), 3 79 (dd, J= 11 6, 2 1 Hz, 1 H), 3 96 (dd, J= 11 5, 2 5 Hz, 1 H), 4 14 - 4 25 (m, 1 H), 4 61 (d, J=6 3 Hz, 2 H), 4 66 - 4 86 (m, 2 H), 6 97 (t, J=8 9 Hz, 1 H), 7 10 - 7 21 (m, 2 H), 8 29 (t, J=5 8 Hz, 1 H), 8 77 (s, 1 H)

Example 70 rac-W-(4-Fluoro-3-(trifluoromethyl)benzyl)-6-(2-(((2S*,5/?*) -5-(hydroxymethyl)-1,4-dioxan-2- yl)methyl)-2H-tetrazol-5-yl)-2-methylpyrimidine-4-carboxamid e

A mixture of rac-methyl 6-(2-(((2S\5R ^* )-5-(hydroxymethyl)-1 ,4-dιoxan-2-yl)methyl)-2H- tetrazol-5-yl)-2-methylpyrιmιdιne-4-carboxylate (prepared as described in step 1 of the synthesis of rac-λ/-(4-fluoro-3-methylbenzyl)-6-(2-(((2S ^* ,5R ^* )-5-(hydroxymethyl)-1 ,4-dιoxan-2-yl)methyl)-2H- tetrazol-5-yl)-2-methylpyÏ€mιdιne-4-carboxamιde, Example 67) (100 mg, 0 285 mmol), 4-fluoro-3- tÏ€fluoromethylbenzylamine (165 mg, 0 856 mmol), and dimethylacetamide (1 mL) was heated to 85 ⁰ C for 18 hours The title compound was isolated as a solid by reverse phase preparative HPLC (52 mg, 36%) MS (ES+) m/z 512 (M+H) ¹ H NMR (400 MHz, DMSO-Cf ₆ ) δ ppm 2 84 (s, 3 H), 3 31 - 3 52 (m, 5 H), 3 78 (dd, J= 11 4, 1 8 Hz, 1 H), 3 99 (dd, J= 11 4, 2 2 Hz, 1 H), 4 03 - 4 14 (m, 1 H), 4 59 (d, J=6 2 Hz, 2 H), 4 65 (t, J=5 7 Hz, 1 H), 4 81 - 5 00 (m, 2 H), 7 41 - 7 53 (m, 1 H), 7 69 - 7 83 (m, 2 H), 8 41 (s, 1 H), 9 66 (t, J=6 04 Hz, 1 H)

Example 71 rac-N-(3-Ethyl-4-fluorobenzyl)-6-(2-(((2S*,5f?*)-5-(hydroxym ethyl)-1,4-dioxan-2-yl)methyl)-2W- tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide

A mixture of methyl rac-6-(2-(((2S ^* ,5R*)-5-(hydroxymethyl)-1 ,4-dιoxan-2-yl)methyl)-2H- tetrazol-5-yl)-2-methylpyrιmιdιne-4-carboxylate (prepared as described in step 1 of the synthesis of rac-W-(4-fluoro-3-methylbenzyl)-6-(2-(((2S ^* ,5R ^* )-5-(hydroxymethyl)-1 ,4-dioxan-2-yl)methyl)-2H- tetrazol-5-yl)-2-methylpyrιmιdιne-4-carboxamιde, Example 67) (100 mg, 0 285 mmol), (3-ethyl-4- fluorophenyl)methanamιne (prepared as described in steps 1 - 5 of the synthesis of λ/-(3-ethyl-4- fluorobenzyl)-2-methyl-6-(2-((S)-morpholιn-2-ylmethyl)-2/-/ -tetrazol-5-yl)pyrιmιdιne-4-carboxamιde, Example 49) (131 mg, 0 856 mmol), and dimethylacetamide (1 mL) was heated to 85 ⁰ C for 18 hours The title compound was isolated as a solid by reverse phase preparative HPLC (57 mg, 42%) MS (ES+) m/z All (M+H) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1 12 (t, J=7 7 Hz, 3 H), 2 57 (q, J=7 3 Hz, 2 H), 2 79 (s, 3 H), 3 26 - 3 47 (m, 5 H), 3 74 (dd, J= 11 0, 2 2 Hz, 1 H), 3 95 (dd, J= 1 1 0, 2 2 Hz, 1 H), 4 00 - 4 10 (m, 1 H), 4 46 (d, J=6 6 Hz, 2 H), 4 62 (t, J=5 9 Hz, 1 H), 4 77 - 4 96 (m, 2 H), 6 97 - 7 09 (m, 1 H), 7 13 - 7 21 (m, 1 H), 7 25 (d, J=9 5 Hz, 1 H), 8 38 (s, 1 H), 9 46 (t, J=6 2 Hz, 1 H)

Example 72

W-(3-Ethyl-4-fluorobenzyl)-6-(2-(((2S,5R)-5-(hydroxymethy l)-1,4-dioxan-2-yl)methyl)-2H-tetrazol-

5-yl)-2-methylpyrimidine-4-carboxamide

A mixture of /V-(3-ethyl-4-fluorobenzyl)-2-methyl-6-(2H-tetrazol-5-yl)pyr ιmιdιne-4-carboxamιde (prepared as described in steps 1 - 6 of the synthesis of λ/-(3-ethyl-4-fluorobenzyl)-2-methyl-6-(2-((S)- morpholιn-2-ylmethyl)-2H-tetrazol-5-yl)pyrιmιdιne-4-carb oxamιde, Example 49) (100 mg, 0 293 mmol), ((2R,5R)-5-(hydroxymethyl)-1 ,4-dιoxan-2-yl)methy! 4-methylbenzenesulfonate (prepared as described in step 1 of the synthesis of λ/-(3-methoxybenzyl)-6-(2-(((2S,5R)-5-(hydroxymethyl)-1 ,4-dιoxan-2- yl)methyl)-2H-tetrazol-5-yl)-2-methylpyrιmιdιne-4-carboxa mιde, Example 62) (106 mg, 0 352 mmol), and triethylamine (0 16 mL, 1 17 mmol) was heated in dimethylformamide at 85 ⁰ C overnight The mixture was chromatographed by reverse phase preparative HPLC Fractions containing the desired product were passed through a carbonate cartridge and concentrated to afford the title compound (28 mg, 20%) MS (ES+) m/z 472 (M+H) ¹ H NMR (400 MHz, CDCI ₃ ) δ ppm 1 23 (t, J=7 5 Hz, 3 H), 1 80

(br s , 1 H), 2 67 (q, J=7 6 Hz, 2 H), 2 89 (s, 3 H), 3 41 - 3 73 (m, 5 H), 3 82 (dd, J=1 1 6, 2 3 Hz, 1 H), 3 99 (dd, J=1 1 5, 2 5 Hz, 1 H), 4 15 - 4 26 (m, 1 H), 4 65 (d, J=6 3 Hz, 2 H), 4 68 - 4 89 (m, 2 H), 7 00 (dd, J=9 7, 8 3 Hz, 1 H), 7 13 - 7 24 (m, 2 H), 8 32 (t, J=6 0 Hz, 1 H), 8 79 (s, 1 H)

Example 73

W-(3-Ethyl-4-fluorobenzyl)-6-(2-(((2/?,5S)-5-(hydroxymeth yl)-1,4-dioxan-2-yl)methyl)-2H-tetrazol-

5-yl)-2-methylpyrimidine-4-carboxamide

A mixture of λ/-(3-ethyl-4-fluorobenzyl)-2-methyl-6-(2H-tetrazol-5-yl)py rιmιdιne-4-carboxamιde (prepared as described in steps 1 - 6 of the synthesis of λ/-(3-ethyl-4-fluorobenzyl)-2-methyl-6-(2-((S)- morpholιn-2-ylmethyl)-2H-tetrazol-5-yl)pyrιmιdιne-4-carb oxamιde, Example 49) (100 mg, 0 293 mmol), ((2S,5S)-5-(hydroxymethyl)-1 ,4-dιoxan-2-yl)methyl 4-methylbenzenesulfonate (prepared as described in step 1 of the synthesis of λ/-(3-Methoxybenzyl)-6-(2-(((2R,5S)-5-(hydroxymethyl)-1 ,4-dιoxan-2- yl)methyl)-2H-tetrazol-5-yl)-2-methylpyrιmιdιne-4-carboxa mιde, Example 63} (106 mg, 0 352 mmol), and triethylamine (0 16 ml_, 1 17 mmol) was heated in dimethylformamide at 85 ⁰ C overnight The mixture was chromatographed by reverse phase preparative HPLC Fractions containing the desired product were passed through a carbonate cartridge and concentrated to afford the title compound (39 mg, 28%) MS (ES+) m/z All (M+H) ¹ H NMR (400 MHz, CDCI ₃ ) δ ppm 1 23 (t, J=I 5 Hz, 3 H), 1 72 (br s , 1 H), 2 67 (q, J=I 5 Hz, 2 H), 2 89 (s, 3 H), 3 46 - 3 70 (m, 5 H), 3 82 (dd, J=1 1 6, 2 3 Hz, 1 H), 3 98 (dd, 4 65 (d, J=Q 1 Hz, 2 H), 4 68 - 4 88 (m, 2 H), 7 00 (dd, J=9 6, 8 4 Hz, 1 H), 7 14 - 7 24 (m, 2 H), 8 32 (t, J=6 0 Hz, 1 H), 8 79 (s, 1 H)

Example 74 rac-/V-(4-Fluoro-3-isopropylbenzyl)-6-(2-(((2S*,5/?*)-5-(hyd roxymethyl)-1 ,4-dioxan-2-yl)methyl)- 2H-tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide

Step 1 Preparation of ethyl 4-fluoro-3-ιsopropylbenzoate

lsopropylmagnesium chloride (2 0 M in ether, 137 61 mL, 275 23 mmol) was added slowly to a solution of anhydrous ZnCI ₂ (37 43 g, 275 23 mmol) in dry tetrahydrofuran (200 mL) under an argon atmosphere The resulting white slurry was stirred at 50 ⁰ C for 3 h In a separate flask, a solution of ethyl 3-bromo-4-fluorobenzoate (prepared as described in step 1 of the synthesis of λ/-(3-ethyl-4- fluorobenzyl)-2-methyl-6-(2-((S)-morpholιn-2-ylmethyl)-2H-t etrazol-5-yl)pyrιmιdιne-4-carboxamιde, Example 49) (17 g, 68 80 mmol) in dry tetrahydrofuran (150 mL) was sequentially treated with PdCI ₂ (dppf) (2 8 g, 3 44 mmol) and copper(l) iodide (0 78 g, 4 12 mmol) under an argon atmosphere The alkyl zinc slurry was added to the ester mixture at room temperature The resulting brown slurry was stirred in the dark at room temperature for 48 h The reaction mixture was concentrated under vacuum to give a dark brown residue, which was taken up in ethyl acetate (750 mL) and washed sequentially with 1 N hydrochloric acid (300 mL) solution, sat NaHCO ₃ solution, and brine The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated The crude product was purified by column chromatography over silica gel (100-200 mesh) using 5 % ethyl acetate in hexane as an eluent to afford the title compound (12 5 g, 89%)

Step 2 Preparation of 4-fluoro-3-ιsopropylbenzoιc acid

Ethyl 4-fluoro-3-ιsopropylbenzoate (12 5 g, 59 46 mmol) and lithium hydroxide monohydrate (7 49 g, 178 40 mmol) were taken up in a mixture of dioxane/water (1/1 , 250 mL) and stirred overnight at room temperature The reaction mixture was concentrated under reduced pressure and the residue was acidified with 1 N hydrochloric acid under ice-water cold condition The mixture was extracted with dichloromethane (2 x 150 mL) The combined organic layers were washed with brine solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford the title compound (10 g, 92 %)

Step 3 Preparation of 4-fluoro-3-ιsopropylbenzamιde

4-Fluoro-3-ιsopropylbenzoιc acid (10 3g, 54 94 mmol) was taken up in SOCI ₂ (150 mL) and then refluxed for 4 h The SOCI ₂ was removed under reduced pressure and the resulting residue was dissolved in dry acetonitrile (125 mL) Ammonia gas was passed through the solution at -78 ⁰ C for 10 mm The reaction mixture was allowed to warm to room temperature very slowly and stirred for overnight The reaction mixture was concentrated to a residue which was extracted with

dichloromethane (2 x 100 mL) The combined dichloromethane layers were washed with sat NaHCO ₃ solution followed by brine, dried over sodium sulfate, and concentrated The resulting solid was washed with hexane (2 x 25 mL) to afford the title compound (9 g, 90%)

Step 4 Preparation of (4-fluoro-3-ιsopropylphenyl)methanamιne

Borane dimethylsulfide complex (94 %, 20 33 mL, 198 67 mmol) was added slowly to a solution of 4-fluoro-3-ιsopropylbenzamιde (9 g, 49 66 mmol) in dichloromethane (200 mL) at ice cold condition After the addition, the reaction mixture was stirred for 1 h at room temperature and then it was refluxed for 24 h The reaction mixture was cooled to 0 ⁰ C, washed with NaHCO ₃ solution followed by brine, and dried over sodium sulfate The organic layer was concentrated under reduced pressure The crude product was purified by column chromatography over silica gel (100-200 mesh) using 15 % CH ₂ CI ₂ in hexane as an eluent to afford the title compound (4 8 g, 54%) MS (ES+) m/z 168 (M+H)

Step 5 Preparation of rac-λy-(4-fluoro-3-ιsopropylbenzyl)-6-(2-(((2S*,5f?*)-5-(h vdroxymethyl)-1 A- dιoxan-2-yl)methyl)-2H-tetrazol-5-yl)-2-methylpyrιmιdιne -4-carboxamιde

A mixture of rac-methyl 6-(2-(((2S*,5R*)-5-(hydroxymethyl)-1 ,4-dιoxan-2-yl)methyl)-2H- tetrazol-5-yl)-2-methylpyrιmιdιne-4-carboxylate (prepared as described in step 1 of the synthesis of rac-λ/-(4-fluoro-3-methylbenzyl)-6-(2-(((2S*,5R*)-5-(hydrox ymethyl)-1 ,4-dιoxan-2-yl)methyl)-2H- tetrazol-5-yl)-2-methylpyrιmιdιne-4-carboxamιde, Example 67) (100 mg, 0 285 mmol), (4-fluoro-3- ιsopropylphenyl)methanamιne (143 mg, 0 856 mmol), and dimethylacetamide (1 mL) was heated to 85 ⁰ C for 18 hours The title compound was isolated as a solid by reverse phase preparative HPLC (49 mg, 35%) MS (ES+) m/z 486 (M+H) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1 21 (d, J=I 0 Hz, 6 H), 2 83 (s, 3 H), 3 07 - 3 20 (m, 1 H), 3 31 - 3 52 (m, 5 H), 3 78 (dd, J=11 4, 1 8 Hz, 1 H), 3 99 (dd, J=1 1 4, 2 2 Hz, 1 H), 4 04 - 4 14 (m, 1 H), 4 51 (d, J=6 2 Hz, 2 H), 4 66 (t, J=5 7 Hz, 1 H), 4 79 - 5 02 (m, 2 H), 7 07 (dd, J=10 4, 8 6 Hz, 1 H), 7 15 - 7 25 (m, 1 H), 7 28 - 7 37 (m, 1 H), 8 42 (s, 1 H), 9 50 (t, J=6 2 Hz, 1 H)

Example 75 rac-W^S-CyclopropyM-fluorobenzyO-β^Z-^IZ^.S/^J-S^hydroxymet hyO-i ^-dioxan-Z-y^methyl)- 2W-tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide

Step 1 Preparation of ethyl S-cyclopropyM-fluorobenzoate

Cyclopropylmagnesium bromide (2 O M in ether, 137 61 mL, 275 23 mmol) was added slowly to a solution of anhydrous ZnCI ₂ (37 43 g, 275 23 mmol) in dry tetrahydrofuran (200 mL) under an argon atmosphere The resulting white slurry was stirred at 50 ⁰ C for 3 h In a separate flask a solution of ethyl 3-bromo-4-fluorobenzoate (prepared as described in step 1 of the synthesis of λ/-(3-ethyl-4- fluorobenzyl)-2-methyl-6-(2-((S)-morpholιn-2-ylmethyl)-2/-/ -tetrazol-5-yl)pyrιmιdιne-4-carboxamιde, Example 49) (17 g, 68 80 mmol) in dry tetrahydrofuran (150 mL) was sequentially treated with PdCI ₂ (dppf) (2 8 g, 3 44 mmol) and copper(l) iodide (0 78 g, 4 12 mmol) under an argon atmosphere The alkyl zinc slurry was added to the ester mixture at room temperature The resulting brown slurry was stirred in the dark at room temperature for 48 h The reaction mixture was concentrated under vacuum to give a dark brown residue, which was taken up in ethyl acetate (750 mL) and washed sequentially with 1 N hydrochloric acid (300 mL) solution, sat NaHCO ₃ solution and brine The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated in vacuo to obtain a mixture of the desired product and bromo starting material (9 8 g of - 40/60 product/starting material ) The mixture was carried on to the next step without further purification

Step 2 Preparation of S-cyclopropyM-fluorobenzoic acid

A mixture containing ethyl 3-cyclopropyl-4-fluorobenzoate from step 1 (16 g) and lithium hydroxide monohydrate (9 68 g, 230 54 mmol) were taken up in a mixture of dioxane/water (1/1 , 300 mL) and stirred overnight at room temperature The reaction mixture was concentrated under reduced pressure and the residue was acidified with 1 N hydrochloric acid under ice-water cold condition The mixture was extracted with dichloromethane (2 x 150 mL) The combined organic layers were washed with brine solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford the title compound contaminated by 3-bromo-4-fluorobenzoιc acid (12 0 g)

Step 3 Preparation of 3-cvclopropyl-4-fluorobenzamιde

A mixture containing S-cyclopropyM-fluorobenzoic acid from step 2 (10 5 g) was taken up in SOCI ₂ (150 mL) and then refluxed for 4 h The SOCI ₂ was removed under reduced pressure and the residue was dissolved in dry acetonitrile (125 mL) Ammonia gas was passed through solution at -78 ⁰ C for 10 mm The reaction mixture was allowed to warm at room temperature very slowly and stirred overnight The reaction mixture was concentrated to a residue and extracted with dichloromethane (2 x 100 mL) The combined dichloromethane layers were washed with sat NaHCO ₃ solution followed by brine, dried over sodium sulfate and concentrated The crude product was washed with hexane (2 x 25 mL) to afford a mixture of the title compound and 3-bromo-4-fluorobenzamιde and bromo impurity (9 5 g)

Step 4 Preparation of (S-cvclopropyM-fluorophenvDmethanamine

Borane dimethylsulfide complex (94%, 21 70 mL, 212 05 mmol) was added slowly to a solution of the mixture containing 3-cyclopropyl-4-fluorobenzamιde from step 3 (9 5 g) in dichloromethane (200 mL) under ice-cold condition After the addition, the reaction mixture was stirred for 1 h at room temperature and then it was refluxed for 24 h The reaction mixture was cooled to 0 ⁰ C ₁ washed with NaHCO ₃ solution followed by brine, and dried over sodium sulfate The organic layer was concentrated under reduced pressure The crude product was purified by column chromatography over silica gel (100-200 mesh) using 25 % CH ₂ CI ₂ in hexane as an eluent to afford the title compound (1 8 g) MS (ES+) m/z 166 (M+H)

Step 5 Preparation of rac-λ/-(3-cvclopropyl-4-fluorobenzyl)-6-(2-(((2S*,5R*)-5-(h vdroxymethyl)-1 ,4- dιoxan-2-yl)methyl)-2H-tetrazol-5-yl)-2-methylpyrιmιdιne -4-carboxamιde

A mixture of rac-methyl 6-(2-(((2S ^* ,5/? ^* )-5-(hydroxymethyl)-1 ,4-dιoxan-2-yl)methyl)-2/-/- tetrazol-5-yl)-2-methylpyrιmιdιne-4-carboxylate (prepared as described in step 1 of the synthesis of rac-W-(4-fluoro-3-methylbenzyl)-6-(2-(((2S*,5/?*)-5-(hydroxy methyl)-1 ,4-dιoxan-2-yl)methy!)-2H- tetrazol-5-yl)-2-methylpyÏ€mιdιne-4-carboxamιde, Example 67) (100 mg, 0 285 mmol), (3-cyclopropyl- 4-fluoropheny!)methanamιne (141 mg, 0 856 mmol), and dimethylacetamide (1 mL) was heated to 85 ⁰ C for 18 hours The title compound was isolated as a solid by reverse phase preparative HPLC (58

mg, 42%) MS (ES+) m/z 484 (M+H) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0 60 - 0 75 (m, 2 H), 0 95 (d, J=10 3 Hz, 2 H), 1 91 - 2 07 (m, 1 H), 2 81 (s, 3 H), 3 18 - 3 46 (m, 5 H), 3 76 (d, J=1 1 4 Hz, 1 H), 3 97 (d, J=1 1 4 Hz, 1 H), 4 03 - 4 14 (m, 1 H), 4 45 (d, J=6 2 Hz, 2 H), 4 70 - 4 79 (m, 1 H), 4 78 - 4 97 (m, 2 H), 6 94 - 7 10 (m, 2 H), 7 10 - 7 20 (m, 1 H), 8 39 (s, 1 H), 9 47 (t, J=6 0 Hz, 1 H)

Example 76 rac-W-(3-Cyano-4-fluorobenzyl)-6-(2-(((2S*,5/?*)-5-(hydroxym ethyl)-1 ₎ 4-dioxan-2-yl)methyl)-2H- tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide

Step 1 Preparation of 2-fluoro-5-(hvdroxymethyl)benzonιtrιle

2-fluoro-5-formylbenzonιtrιle (7 0 g, 46 93 mmol) was dissolved in a mixture of methanol (30 mL) and dichloromethane (20 mL) Solid NaBH ₄ (1 8 g, 46 93 mmol) was added portion-wise, and the mixture was stirred at room temperature overnight The organic volatile was removed and the residue was dissolved in water (50 mL) and extracted with diethyl ether (2 x 50 mL) The combined organic layer was washed with saturated sodium bicarbonate solution followed by brine solution, dried over anhydrous sodium sulfate, and concentrated to afford the title compound (6 6 g, 93 %)

Step 2 Preparation of 5-(amιnomethyl)-2-fluorobenzonιtrιle 2-fluoro-5-(hydroxymethyl)benzonιtrιle (6 6 g, 43 66 mmol) was dissolved in dichloromethane (75 mL), and triethylamine (12 mL) was added Mesityl chloride (4 4 mL, 56 76 mmol) was added drop-wise under ice-cold condition and the reaction mixture was stirred for 2 h at room temperature The mixture was poured into cold water (50 mL) The organic layer was separated and was washed with saturated aqueous sodium bicarbonate solution, 1 % aqueous hydrochloric acid solution and brine solution The organic layer was dried over anhydrous sodium sulfate and concentrated The residue was dissolved in acetonitrile (50 mL), and aqueous NH ₄ OH (30 mL) was added to it The reaction mixture was stirred at room temperature for 3 h and was then concentrated under reduced pressure The crude product was purified by washing with hexane and then with ethyl acetate to afford the title compound as a solid (6 8 g, quantitative)

Step 3 Preparation of rac-λ/-(3-cvano-4-fluorobenzyl)-6-(2-(((2S\5ff*)-5-(hvdroxy methyl)-1 ,4-dιoxan- 2-yl)methyl)-2H-tetrazol-5-yl)-2-methylpyrιmιdιne-4-carbo xamιde

A mixture of rac-methyl 6-(2-(((2S*,5f?*)-5-(hydroxymethyl)-1 ,4-dιoxan-2-yl)methyl)-2H- tetrazol-5-yl)-2-methylpyrιmιdιne-4-carboxylate (prepared as described in step 1 of the synthesis of rac-λ/-(4-fluoro-3-methylbenzyl)-6-(2-(((2S*,5R*)-5-(hydrox ymethyl)-1 ,4-dιoxan-2-yl)methyl)-2H- tetrazol-5-yl)-2-methylpyrιmιdιne-4-carboxamιde, Example 67) (100 mg, 0 285 mmol), 5- (amιnomethyl)-2-fluorobenzonιtrι!e (129 mg, 0 856 mmol), and dimethylacetamide (1 mL) was heated to 85 ⁰ C for 18 hours The title compound was isolated as a solid by reverse phase preparative HPLC 51 mg, 38%) MS (ES+) m/z 469 (M+H) ¹ H NMR (400 MHz, DMSO-c/ ₆ ) δ ppm 2 54 (s, 1 H), 2 84 (s, 3 H), 3 29 - 3 51 (m, 4 H), 3 78 (dd, J=1 1 7, 2 2 Hz, 1 H), 3 99 (dd, J=1 1 35, 2 56 Hz, 1 H), 4 03 - 4 14 (m, 1 H), 4 56 (d, J=6 6 Hz, 2 H), 4 65 (t, J=5 5 Hz, 1 H), 4 80 - 5 01 (m, 2 H), 7 49 (t, J=9 2 Hz, 1 H), 7 72 - 7 83 (m, 1 H), 7 88 (dd, J=5 9, 2 2 Hz, 1 H), 8 41 (s, 1 H), 9 63 (t, J=6 2 Hz, 1 H)

Example 77 rac-N-(4-Fluoro-3-(2-hydroxyethoxy)benzyl)-6-(2-(((2S*,5/?*) -5-(hydroxymethyl)-1 ,4-dioxan-2- yl)methyl)-2tf-tetrazol-5-yl)-2-methylpyrimidine-4-carboxami de

λ/-(4-Fluoro-3-(2-hydroxyethoxy)benzyl)-2-methyl-6-(2H-tetr azol-5-yl)pyrιmιdιne-4- carboxamide (prepared as described in step 2 of the synthesis of λ/-(4-fluoro-3-(2- hydroxyethoxy)benzyl)-6-(2-(((frans-4-cyanocyclohexyl)methyl )-2H-tetrazol-5-yl)-2-methylpynmidine-4- carboxamide, Example 27) (491 mg, 1 32 mmol), rac-((2f?*,5R ^* )-5-(Hydroxymethyl)-1 ,4-dιoxan-2- yl)methyl 4-methylbenzenesulfonate (prepared as described in step 4 of the synthesis of rac-λ/-(3- methoxybenzyl)-6-(2-(((2S*,5R*)-5-(hydroxymethyl)-1 ,4-dιoxan-2-yl)methyl)-2/-/-tetrazol-5-yl)-2- methylpyrιmιdιne-4-carboxamιde, Example 61 ) (398 mg, 1 32 mmol) and 1 ,8-dιazabιcyclo[5 4 OJundec- 7-ene (240 mg, 1 58 mmol) were combined in dimethylacetamide (5 mL) After heating the reaction at 90 ⁰ C for 18 h, the reaction mixture was purified by reverse phase preparative high-pressure liquid chromatography The pure fractions were combined, extracted with ethyl acetate (2 x 20 mL), dried over magnesium sulfate, and concentrated to an oil which solidified under reduced pressure to give the title compound as an white solid (70 mg, 1 1 %) MS (ES+) m/z 504 ¹ H NMR (400 MHz, DMSOd ₆ ) δ ppm 9 48 (s, 1 H), 8 40 (s, 1 H), 7 14 (m, 2 H), 6 89 (m, 1 H), 4 74 (m, 2 H), 4 62 (m ,1 H), 4 41 (m ,

2 H) ₁ 4 15 (m, 1 H), 4 02 (m 2 H), 3 91 (m, 1 H), 3 78 - 3 95 (m, 2 H), 3 59 - 3 72 (m, 1 H), 3 72 (m, 1 H), 3 61 (m, 2 H), 3 65-3 79 (m, 4 H), 2 81 (s, 3 H)

Example 78 fac-W-(3-Chloro-4-fluorobenzyl)-6-(2-(((2S*,5R ^* )-5-(hydroxymethyl)-1 ,4-dioxan-2-yl)methyl)-2H- tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide

rac-((2R ^* ,5R ^* )-5-(Hydroxymethyl)-1 ,4-dιoxan-2-yl)methyl 4-methylbenzenesulfonate (prepared as described in step 4 of the synthesis of rac-λ/-(3-methoxybenzyl)-6-(2-(((2S ^* ,5R ^* )-5-(hydroxymethyl)- 1 ,4-dιoxan-2-yl)methyl)-2/-/-tetrazol-5-yl)-2-methylpyrιmι dιne-4-carboxamιde, Example 61 ) (224 mg, 0 741 mmol) was added to a mixture of λ/-(3-chloro-4-fluorobenzyl)-2-methyl-6-(2H-tetrazol-5- yl)pyÏ€mιdιne-4-carboxamιde (prepared as described in step 1 of the synthesis of λ/-(3-chloro-4- fluorobenzyl)-2-methyl-6-(2-((S)-morpholιn-2-ylmethyl)-2/-/ -tetrazol-5-yl)pyrιmιdιne-4-carboxamιde, Example 47) (200 mg, 0 575 mmol) and triethylamine (349 mg, 3 4 mmol) in anhydrous dimethylacetamide (0 3 mL) The reaction was stirred overnight at 85 ⁰ C in a capped vial The mixture was purified by reverse phase preparative HPLC (water/acetonitrile) Fractions containing product were neutralized by passing through a carbonate resin column and concentrated The resulting product was slurried with diethyl ether, decanted, and dried in vacuo to afford the title compound as a white solid (95 mg) MS (ES+) m/z 478 (M+H) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9 60 (1 H, t, J=6 2 Hz), 8 41 (1 H,s), 7 57 (1 H, d, J=7 0 Hz), 7 37 (2 H, d, J=7 7 Hz), 4 93 (1 H, d, J=Z 7 Hz), 4 88 (1 H, d, J=8 1 Hz) ₁ 4 66 (1 H, br s ), 4 52 (2 H, d, J=6 2 Hz), 4 08 (1 H, d, J=2 9 Hz), 3 99 (1 H, d,

J= 11 3 Hz), 3 78 (1 H, d, J=9 9 Hz), 3 36 - 3 48 (2 H, m), 3 45 (3 H, t, J=10 8 Hz), 3 30 - 3 34 (1 H, m), 2 84 (3 H, s)

Example 79

W-(3-Chloro-4-fluorobenzyl)-6-(2-(((2S,5R)-5-(hydroxymeth yl)-1,4-dioxan-2-yl)methyl)-2H- tetrazol-5-yl)-2-methylpyrimidine-4-carboxamιde

((2R,5R)-5-(Hydroxymethyl)-1 ,4-dιoxan-2-yl)methyl 4-methylbenzenesulfonate (prepared as described in step 1 of the synthesis of λ/-(3-methoxybenzyl)-6-(2-(((2S,5R)-5-(hydroxymethyl)-1 ,4- dιoxan-2-yl)methyl)-2H-tetrazol-5-yl)-2-methylpyrιmιdιne -4-carboxamιde, Example 62) (136 mg, 0 45

mmol) was added to a mixture of λ/-(3-chloro-4-fluorobenzyl)-2-methyl-6-(2H-tetrazol-5-yl)p yrιmιdιne- 4-carboxamιde (prepared as described in step 1 of the synthesis of λ/-(3-chloro-4-fluorobenzyl)-2- methyl-6-(2-((S)-morpholιn-2-ylmethyl)-2/-/-tetrazol-5-yl)p yÏ€mιdιne-4-carboxamιde, Example 47) (125 mg, 0 359 mmol) and triethylamine (153 mg, 1 5 mmol) in anhydrous dimethylacetamide (0 3 mL) The reaction was stirred overnight at 85 ⁰ C in a capped vial The mixture was purified by reverse phase preparative HPLC (water/acetonitrile) Fractions containing product were neutralized by passing through a carbonate resin column and concentrated The resulting product was slurried with diethyl ether, decanted, and dried in vacuo to afford the title compound as a white solid (49 mg) MS (ES+) m/z 478 (M+H) ¹ H NMR (400 MHz, DMSO-d ₆ ) ÏŒ ppm 9 60 (1 H, t, J=6 2 Hz), 8 41 (1 H,s), 7 57 (1 H, d, J=7 0 Hz), 7 37 (2 H, d, J=7 7 Hz), 4 93 (1 H, d, J=3 7 Hz), 4 88 (1 H, d, J=8 1 Hz), 4 66 (1 H, br s ), 4 52 (2 H, d, J=6 2 Hz), 4 08 (1 H, d, J=2 9 Hz), 3 99 (1 H, d, J=ÏŠ 1 3 Hz), 3 78 (1 H, d, J=9 9 Hz), 3 36 - 3 48 (2 H, m), 3 45 (3 H, t, J=10 8 Hz), 3 30 - 3 34 (1 H, m), 2 84 (3 H, s)

Example 80

W-(3-Bromo-4-fluorobenzyl)-6-(2-(((2S,5R)-5-(hydroxymethy l)-1 ,4-dioxan-2-yl)methyl)-2H- tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide

Step 1 Preparation of /V-(3-bromo-4-fluorobenzyl)-2-methyl-6-(2H-tetrazol-5-yl)pyr ιmιdιne-4- carboxamide

3-Bromo-4-fluorobenzylamιne (865 mg, 3 6 mmol) was added to a solution of methyl 2-methyl-

6-(2/-/-tetrazol-5-yl)pyrιmιdιne-4-carboxylate (229 mg, 1 04 mmol) (prepared as described in step 1 of the synthesis of AV-(4-Fluoro-3-(2-hydroxyethoxy)benzyl)-6-(2-(((frans)-4-ace tamιdocyclohexyl)methyl)- 2H-tetrazol-5-yl)-2-methylpyrιmιdιne-4-carboxamιde, Example 17) and triethylamine (316 mg, 3 1 mmol) in anhydrous dimethylacetamide (2 0 mL) The mixture was stirred at 65 ⁰ C for 2 5 days After cooling to room temperature, the reaction mixture was diluted with excess 2 5 N NaOH solution and washed with ethyl acetate (2x) The aqueous layer was acidified with concentrated hydrochloric acid The resulting precipitate was filtered, washed with water, and dried to afford the title compound as a light yellow solid (300 mg)

Step 2 Preparation of λ/-(3-bromo-4-f1uorobenzyl)-6-(2-(((2S,5R)-5-(hvdroxymethyl )-1 ,4-dιoxan-2- yl)methyl)-2H-tetrazol-5-yl)-2-methylpyrιmιdιne-4-carboxa mιde

((2f?,5R)-5-(Hydroxymethyl)-1 ,4-dιoxan-2-yl)methyl 4-methylbenzenesulfonate (prepared as described in step 1 of the synthesis of λ/-(3-methoxybenzyl)-6-(2-(((2S,5R)-5-(hydroxymethyl)-1 ,4- dιoxan-2-yl)methyl)-2H-tetrazol-5-yl)-2-methylpyrιmιdιne -4-carboxamιde, Example 62) (136 mg, O 45 mmol) was added to a mixture of λ/-(3-bromo-4-fluorobenzyl)-2-methyl-6-(2H-tetrazol-5-yl)py rιmιdιne- 4-carboxamιde (125 mg, 0 359 mmol) and triethylamine (153 mg, 1 5 mmol) in anhydrous dimethylacetamide (0 3 mL) The reaction was stirred overnight at 85 ⁰ C in a capped vial The mixture was purified by reverse phase preparative HPLC (water/acetonitrile) Fractions containing product were neutralized by passing through a carbonate resin column and concentrated The resulting product was slurried with diethyl ether, decanted, and dried in vacuo to afford the title compound as a white solid (61 mg) MS (ES+) m/z 522 (M+H) ¹ H NMR (400 MHz, DMSOd ₆ ) δ ppm 9 60 (1 H, t, J=6 0 Hz), 8 41 (1 H, s), 7 69 (1 H, d, J=5 5 Hz), 7 41 (1 H, d, J= 1 8 Hz), 7 33 (1 H, t, J=8 8 Hz), 4 93 (1 H, d, J=3 7 Hz), 4 88 (1 H, d, J=8 1 Hz), 4 66 (1 H, br s ), 4 52 (2 H, d, J=6 2 Hz), 4 08 (1 H, d, J=2 9 Hz), 3 99 (1 H, d, J= 1 1 3 Hz), 3 78 (1 H, d, J=9 9 Hz), 3 36 - 3 48 (2 H, m), 3 45 (2 H, t, J=10 8 Hz), 3 31 (1 H, br s ), 2 84 (3 H, s)

Example 81

/V-(4-Fluoro-3-hydroxybenzyl)-6-(2-(((2S,5R)-5-(hydroxyme thyl)-1,4-dioxan-2-yl)methyl)-2H- tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide

λ/-(4-Fluoro-3-methoxybenzyl)-6-(2-(((2S,5f?)-5-(hydroxymet hyl)-1 ,4-dιoxan-2-yl)methyl)-2H- tetrazol-5-yl)-2-methylpyrιmιdιne-4-carboxamιde (prepared as described in Example 65) (476 mg, 1 0 mmol) was dissolved in dichloromethane (20 mL) and the solution was cooled to -70 ⁰ C A solution of boron tribromide (4 0 mL, 1 0 M in dichloromethane, 4 0 mmol) was added After 30 mm, the mixture was allowed to warm to room temperature and was stirred for 2 hours The reaction mixture was poured into a mixture of ice and saturated aq sodium bicarbonate The mixture was extracted with dichloromethane (2 x 50 mL) The aqueous layer was acidified to pH 2 with 1 N hydrochloric acid and extracted with dichloromethane (50 mL) The combined organic layers were dried (sodium sulfate) and concentrated The residue was purified by silica gel column chromatography

(dichloromethane/methanol, 100/2, 100/3, 100/4) to afford the title compound as a foaming white solid (1 14 mg, 25%) MS (ES+) m/z 460 (M+H) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9 72 (s, 1 H), 9 50 (t, J=Q 4 Hz, 1 H), 8 37 (s, 1 H), 7 00 (dd, J= 1 1 3, 8 4 Hz, 1 H), 6 89 (dd, J=B 6, 2 1 Hz, 1 H), 6 72 - 6 68 (m, 1 H), 4 89 (dd, J= 14 3, 3 7 Hz, 1 H), 4 84 - 4 77 (m, J= 14 3, 8 0 Hz, 1 H), 4 65 (t, J=5 7 Hz, 1 H), 4 37 (d, J=6 4 Hz, 2 H), 4 06 - 3 98 (m, 1 H), 3 93 (dd, J= 11 5, 2 3 Hz, 1 H), 3 72 (dd, J= 1 1 5, 2 5 Hz, 1 H), 3 42 - 3 18 (m, 5 H), 2 78 (s, 3 H)

Example 82

W-(4-Fluoro-3-methoxybenzyl)-6-(2-(((2R,5R)-5-(hydroxymet hyl)-1 ,4-dioxan-2-yl)methyl)-2W- tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide

Step 1 Preparation of (2ff)-1 -(benzyloxy)-3-chloropropan-2-ol

To a flame-dried, three neck round bottomed flask was added dry 1 ,2-dιchloroethane (50 mL) and charged with f?-(-)-epιchlorohydrιn (3 8 mL, 49 mmol) and benzyl alcohol (10 mL, 100 mmol) The solution was cooled to 0 ⁰ C under nitrogen The stirring solution was then treated with boron tÏ€fluoÏ€de etherate (0 27 mL, 2 2 mmol) dropwise and allowed to warm to room temperature overnight The reaction mixture was then heated to reflux After about 2 hours, the mixture was cooled to room temperature The mixture was partitioned against 10% aqueous saturated sodium bicarbonate (25 mL) and the layers were separated The aqueous phase was extracted with dichloromethane (2 x 25 mL) The organic layers were combined and washed with brine (2 x 10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a viscous oil The oil was adsorbed onto silica and purified by silica column chromatography eluting with 20-30% ethyl acetate in heptanes to provide the title compound as a viscous oil (5 6 g, 57%) LCMS (5%-100% CH ₃ CN/H ₂ O, 5 mm) 2 7 mm, m/z 223 (M+Na) ¹ H NMR (400 MHz, CDCI ₃ ) δ ppm 7 29 - 7 41 (m, 5 H), 4 58 (s, 2 H), 3 98 - 4 07 (m, 1 H), 3 58 - 3 71 (m, 4 H), 2 49 (d, J=5 8 Hz, 1 H)

Step 2 Preparation of (2S)-3-((1 R)-2-(benzyloxy)-1 -(chloromethyl)ethoxy)-2-hvdroxypropyl 4- methylbenzenesulfonate

To a flask containing (2R)-1 -(benzyloxy)-3-chloropropan-2-ol (2 5 g, 12 5 mmol) was added S- glycidol tosylate (0 95 g, 0 33 mmol) and back-filled with nitrogen The flask was charged with dry 1 ,2- dichloroethane (50 mL) and the resulting stirring solution cooled to 0 ⁰ C The mixture was treated with boron trifluoride etherate (0 10 mL, 0 81 mmol) dropwise and the reaction mixture was allowed to slowly warm to room temperature overnight The mixture was diluted with dichloromethane (50 mL) and partitioned against 10% aqueous saturated sodium bicarbonate (100 mL) The layers were separated and the aqueous phase extracted with dichloromethane (2 x 50 mL) The organic layers were combined and washed with water (25 mL) and brine (25 mL) The organic layer was then dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a viscous oil The oil was adsorbed onto silica and purified by silica column chromatography eluting with 30-50% ethyl acetate in heptanes to provide the title compound as a viscous oil (0 80 gm, 45%) LCMS (5%-100% CH ₃ CN/H ₂ O, 5 mm) 4 0 mm, m/z 429 (M+H) ¹ H NMR (400 MHz, CDCI ₃ ) δ ppm 7 80 (d, «7=8 2 Hz, 2 H), 7 28 - 7 41 (m, 7 H), 4 54 (s, 2 H), 4 02 - 4 13 (m, 2 H), 3 69 - 3 76 (m, 2 H), 3 50 - 3 65 (m, 6 H), 2 95 (d, J=A 3 Hz, 1 H), 2 45 (s, 3 H)

Step 3 Preparation of ((2ff,5/?)-5-((benzyloxy)methyl)-1 ,4-dιoxan-2-yl)methanol To a flask containing (2S)-3-((1 R)-2-(benzyloxy)-1 -(chloromethyl)ethoxy)-2-hydroxypropyl 4- methylbenzenesulfonate (0 80 g, 1 9 mmol) was added 2 5 N aqueous sodium hydroxide solution (2 6 mL, 6 5 mmol) The resulting bi-phasic reaction mixture was vigorously stirred at room temperature After about 2 5 hours, the reaction mixture was heated to 90 ⁰ C After about 4 hours, the reaction mixture was cooled to room temperature and stirred overnight The mixture was then re-heated to 90 ⁰ C for about 2 hours and finally cooled to room temperature The reaction was neutralized with 1 N hydrochloric acid and solid sodium chloride was added to saturation The reaction mixture was partitioned against dichloromethane (10 mL) The aqueous layer was extracted with additional portions of dichloromethane (3 x 10 mL) The organic layers were combined and washed with saturated aqueous sodium bicarbonate, brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a viscous oil The oil was purified by silica column chromatography eluting with 1 -4% methanol in dichloromethane to provide the title compound as a viscous oil (0 20 gm, 45%) LCMS (5%-100% CH ₃ CN/H ₂ O, 5 mm) 2 6 mm, m/z 239 (M+H) ¹ H NMR (400 MHz, CDCI ₃ ) δ ppm 7 25 - 7 45 (m, 5 H), 4 59 (s, 2 H), 3 5 - 3 9 (m, 10 H), 2 3 (br S , 1 H)

Step 4 Preparation of ((2S,5f?)-5-((benzyloxy)methyl)-1 ,4-dιoxan-2-yl)methyl 4- methylbenzenesulfonate

To a solution of ((2R,5/?)-5-((benzyloxy)methyl)-1 ,4-dιoxan-2-yl)methanol (0 20 g, 0 59 mmol) in pyridine (3 mL) was added p-toluenesulfonyl chloride (0 38 g, 3 4 mmol) and a small crystal of 4- dimethylaminopyÏ€dine The reaction mixture was left to stir at room temperature overnight The mixture was then treated with additional p-toluenesulfonyl chloride (0 10 gm) and left to stir for about 8 hours The reaction mixture was treated with toluene (10 mL) and concentrated under reduced pressure using a cold bath The addition of toluene and concentration under reduced pressure was repeated (3x) The resulting residue was partitioned between water (20 mL) and ethyl acetate (20 mL) The layers were separated and the aqueous phase extracted with ethyl acetate (2 x 20 mL) The organic phases were combined and washed with saturated aqueous sodium bicarbonate solution, brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give a viscous oil This oil was adsorbed onto silica and purified by silica column chromatography eluting with 30-40% ethyl acetate in heptanes to provide the title compound as a viscous oil (0 19 gm, 82%) LCMS (50%- 100% CH ₃ CN/H ₂ O, 5 mm) 2 6 mm, m/z 393 (M+H) ¹ H NMR (400 MHz, CDCI ₃ ) δ ppm 7 81 (d, J=B 2 Hz, 2 H), 7 28 - 7 41 (m, 7 H), 4 54 (s, 2 H), 4 30 (dd, J=10 4, 7 0 Hz, 1 H), 4 12 (dd, J=10 4, 5 6 Hz, 1 H), 3 52 - 3 86 (m, 7 H), 3 42 - 3 50 (m, 1 H), 2 45 (s, 3 H)

Step 5 Preparation of ((2S,5ff)-5-(hvdroxymethyl)-1 ,4-dιoxan-2-yl)methyl 4-methylbenzenesulfonate

To a solution of ((2S,5/?)-5-((benzyloxy)methyl)-1 ,4-dιoxan-2-yl)methyl 4- methylbenzenesulfonate (0 19 g, 0 48 mmol) in ethanol (5 mL) under nitrogen was added palladium on carbon and back-filled with hydrogen gas The mixture was allowed to stir at room temperature overnight under a balloon of hydrogen gas The reaction mixture was filtered through Celiteâ„¢ with ethanol washes The combined filtrates were concentrated under reduced pressure to give the title compound as a viscous oil (0 13 gm, 89%) LCMS (5%-100% CH ₃ CN/H ₂ O, 5 mm) 2 8 mm, m/z 303 (M+H) ¹ H NMR (400 MHz, CDCI ₃ ) δ ppm 7 80 (d, J=8 2 Hz, 2 H), 7 35 (d, J=Q 2 Hz, 2 H), 4 21 - 4 30 (m, 1 H), 4 1 1 - 4 19 (m, 1 H), 3 76 - 3 85 (m, 1 H), 3 52 - 3 75 (m, 7 H), 2 45 (s, 3 H)

Step 6 Preparation of λ/-(4-fluoro-3-methoxybenzyl)-6-(2-(((2R5R)-5-(hvdroxymethy l)-1.4-dιoxan-2- yl)methyl)-2/-/-tetrazol-5-yl)-2-methylpyrιmιclιne-4-carb oxamιde

To a vial containing λ/-(4-fluoro-3-methoxybenzyl)-2-methyl-6-(2H-tetrazol-5-yl) pyrιmιdιne-4- carboxamide (prepared as described in step 2 of the synthesis of N-(4-flÏ…oro-3-methoxybenzyl)-6-(2- (fraÏ€s-4-amιnocyclohexyl)methy!)-2/-/-tetrazol-5-yl)-2-met hylpyrιmιdιne-4-carboxamιde, Example 9) (101 mg, 0 29 mmol) and ((2S,5R)-5-(hydroxymethyl)-1 ,4-dιoxan-2-yl)methyl 4- methylbenzenesulfonate (1 15 mg, 0 38 mmol) was added λ/,/V-dιmethylformamιde (0 3 mL) followed by triethylamine (1 0 mL) The vial was flushed with nitrogen, tightly capped and heated to 85 °C with stirring After about 2 days, the mixture was cooled to room temperature and concentrated under reduced pressure The resulting residue was diluted with dichloromethane (10 mL) and partitioned with water (10 mL) The layers were separated and the aqueous phase was extracted with dichloromethane (3 x 10 mL) The organic layers were combined and washed with 1 N hydrochloric acid solution (10 mL), water (10 mL), 1 N sodium hydroxide solution (10 mL), water (10 mL), brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure The residue was subjected to silica column chromatography eluting with 1 -3% methanol in ethyl acetate The crude product was further purified by reverse phase preparative HPLC (acetonitrile/water) to provide the title compound as a white solid (39 mg, 28%) LCMS (5%-100% CH ₃ CN/H ₂ O, 5 mm) 3 05 mm, m/z 474 (M+H) ¹ H NMR (400 MHz, DMSO-O ₆ ) δ ppm 9 58 (t, J=6 4 Hz, 1 H), 8 42 (s, 1 H), 7 09 - 7 24 (m, 2 H), 6 83 - 6 96 (m, 1 H), 5 35 (dd, J=14 2, 9 9 Hz, 1 H), 4 98 (dd, J=14 3, 4 0 Hz, 1 H), 4 70 - 4 82 (m, 1 H), 4 50 (d, J=Q 3 Hz, 2 H), 4 16 - 4 28 (m, 1 H), 3 82 (s, 3 H), 3 73 - 3 81 (m, 3 H), 3 43 - 3 58 (m, 4 H), 2 83 (s, 3 H)

Example 83

λ/-(3-Chloro-4-fluorobenzyl)-6-(2-((5,5-bis(hydroxymethy l)-1,4-dioxan-2-yl)methyl)-2H-tetrazol-5- yl)-2-methylpyrimidine-4-carboxamide

Step 1 Preparation of /rans-(5-formyl-1.4-dιoxan-2-yl)methyl 4-methylbenzenesulfonate

To a -78 ⁰ C solution of oxalyl chloride (6 43 g, 49 6 mmol) in dichloromethane (30 mL) was slowly added dimethyl sulfoxide (7 29 g, 93 3 mmol) The reaction was stirred at -78 ⁰ C for 20 mm at which time a solution of rac-((2f?*,5/?*)-5-(hydroxymethyl)-1 ,4-dιoxan-2-yl)methyl 4- methylbenzenesulfonate (prepared as described in step 4 of the synthesis of rac-λ/-(3- methoxybenzyl)-6-(2-(((2S ^* ,5R ^* )-5-(hydroxymethyl)-1 ,4-dioxan-2-yl)methyl)-2H-tetrazol-5-yl)-2- methylpyrιmιdιne-4-carboxamιde, Example 61 ) (6 0 g, 20 mmol) in dichloromethane (12 mL) was added drop-wise The resulting solution was stirred at -78 ⁰ C for 1 h and then quenched with triethylamine (1 1 O g, 109 mmol) forming a thick white precipitate The ice bath was removed and the reaction was slowly warmed to room temperature The mixture was diluted in dichloromethane (100 mL) and washed successively with 1 N hydrochloric acid (75 mL), sat sodium bicarbonate (75 mL), and brine (100 mL) The organic layer was dried over magnesium sulfate, filtered and evaporated to afford the title compound as a yellow oil (6 4 g, 100%) ¹ H NMR (400 MHz, DMSO-cfe) δ ppm 9 43 (s, 1 H), 7 75 (m, 2 H), 7 47 (m, 2 H), 3 63 - 4 08 (m, 5 H), 3 17 - 3 38 (m, 3 H), 2 39 (s, 3 H)

Step 2 Preparation of (5,5-bιs(hvdroxymethyl)-1 ,4-dιoxan-2-yl)methyl 4-methylbenzenesulfonate

2 5 N Sodium hydroxide (17 0 mL, 1 70 g, 42 6 mmol) was added to a solution of trans-((5- formyl-1 ,4-dιoxan-2-y!)methyl 4-methylbenzenesulfonate (6 4 g, 21 0 mmol) in 2 1 tetrahydrofuran/water (30 mL) To this reaction was added a 37% solution of formaldehyde (3 69 mL, 3 80 g, 46 9 mmol) and the mixture was stirred at 25 ⁰ C for 18 hours The reaction mixture was neutralized with formic acid (2 mL) The reaction was concentrated, washed with ethyl acetate (150 mL) and filtered The filtrate was concentrated to afford the title compound as a yellow oil that solidified upon standing (5 4 g, 76%) LC/MS (5%-95% CH ₃ CN H ₂ O, 6 mm) 3 69 mm, m/z 333 (M+H) ¹ H NMR (400 MHz, CDCI ₃ ) δ ppm 7 75 (m, 2 H), 7 33 (m, 2 H), 4 75 (m, 2 H), 3 95 - 3 49 (m, 3 H), 3 45 - 3 75 (m, 9 H), 2 43 (s, 3 H)

Step 3 λ/-(3-chloro-4-fluQrobenzyl)-6-(2-((5,5-bιs(hvclroxymethyl )-1.4-clιoxan-2-yl)methyl)-2H-tetrazol- 5-yl)-2-methylpyrιmιdιne-4-carboxamιde

λ/-(3-Chloro-4-fluorobenzyl)-2-methyl-6-(2/-/-tetrazol-5-yl )pyrιmιdιne-4-carboxamιde (prepared as described in step 1 of the synthesis of /V-(3-chloro-4-fluorobenzyl)-2-methyl-6-(2-((S)-morpholιn-2 - ylmethyl)-2/-/-tetrazol-5-yl)pyrιmιdιne-4-carboxamιde, Example 47) (50 mg, 0 144 mmol), (5,5- bιs(hydroxymethyl)-1 ,4-dιoxan-2-yl)methyl 4-methylbenzenesulfonate (47 8 mg, 0 144 mmol), and triethylamine (400 μL) were combined in dimethylacetamide (100 μl_) The resulting mixture was stirred at 90 ⁰ C for 18 h The mixture was concentrated The residue was purified by reverse phase high-pressure liquid chromatography The pure fractions were combined, extracted with ethyl acetate (2 x 20 mL), dried over magnesium sulfate, and concentrated to afford the title compound as a solid (12 mg, 16%) MS (ES+) m/z 508 (M+H) ¹ H NMR (400 MHz, DMSO-CZ ₆ ) δ ppm 9 61 (t, J = 6 2 Hz, 1 H), 7 57 d, J = 7 0 Hz, 1 H), 7 37 (d, J = 7 7 Hz, 2 H), 4 97 (s, 1 H), 4 95 (d, J = 3 3 Hz, 1 H), 4 44 - 4 54 (m, 1 H), 4 52 (d, J = 6 2 Hz, 3 H), 3 73 (d, J = 3 3 Hz, 1 H), 3 60 (t, J = 5 5 Hz, 1 H), 3 66 (m, 2 H), 3 39 (d, J = 4 4 Hz, 1 H), 3 35 - 3 44 (m, 1 H), 3 23 (s, 1 H), 3 25 (d, J = 5 5 Hz, 2 H), 2 84 (s, 3 H), 2 74 (s, 1 H)

Example 84

/V-(3-Methoxybenzyl)-6-(2-((5,5-bis(hydroxymethyl)-1,4-di oxan-2-yl)methyl)-2H-tetrazol-5-yl)-2- methylpyrimidine-4-carboxamide

λ/-(3-Methoxybenzyl)-2-methyl-6-(2H-tetrazol-5-yl)pyrιmιd ιne-4-carboxamιde (prepared as described in step 6 of the synthesis of /V-(3-methoxybenzyl)-6-(2-(((/rans)-4-amιnocyclohexyl)methy l)- 2H-tetrazol-5-yl)-2-methylpyrιmιdιne-4-carboxamιde, Example 5) (47 mg, 0 144 mmol), (5,5- bιs(hydroxymethyl)-1 ,4-dιoxan-2-yl)methyl 4-methylbenzenesulfonate (prepared as described in step 2 of the synthesis of λ/-(3-chloro-4-fluorobenzyl)-6-(2-((5,5-bιs(hydroxymethyl) -1 ,4-dιoxan-2-yl)methyl)- 2/-/-tetrazol-5-yl)-2-methylpyrιmιdιne-4-carboxamιde, Example 83) (48 mg, 0 144 mmol), and triethylamine (400 μL) were combined in dimethylacetamide (100 μL) The resulting mixture was stirred at 90 °C for 18 h The mixture was concentrated and the residue was purified by reverse phase high-pressure liquid chromatography The pure fractions were combined, extracted with ethyl acetate (2 x 20 mL), dried over magnesium sulfate, and concentrated to afford the title compound as a solid (12 mg, 16%) MS (ES+) m/z 486 (M+H) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9 49 (m, 1 H), 8 42 (s,

1 H), 7 24 (m, 1 H), 6 93 (m, 2 H), 6 81 (m, 2 H), 4 96 (m, 2 H), 4 53 (m, 3 H), 4 18 (m, 2 H), 3 74 (s, 3 H), 3 48 - 3 62 (m, 4 H), 3 42 (m, 2 H), 2 86 (s, 3 H)

Example 85 rac-(2S*,5S*)-Methyl 5-((5-(6-((3-methoxybenzyl)carbamoyl)-2-methylpyrimidin-4-yl )-2H-tetrazol- 2-yl)methyl)-1 ,4-dioxane-2-carboxylate

Step 1 Preparation of transλ ,4-dιoxane-2,5-dιcarboxylιc acid

A solution of trans-2, 5-bιs-(hydroxymethyl)-1 ,4-dιoxane (prepared as described in step 3 of the synthesis of rac-λ/-(3-methoxybenzyl)-6-(2-(((2S ^* ,5f? ^* )-5-(hydroxymethyl)-1 ,4-dιoxan-2-yl)methyl)-2H- tetrazol-5-yl)-2-methylpyrιmιdιne-4-carboxamιde, Example 61 ) (88 17 g) in water (458 mL) and HNO ₃ (1238 mL) was heated to reflux for 100 mm and then cooled to 5 ⁰ C The resulting precipitate was collected by filtration, washed with cold water (500 mL), and dried in vacuo at 50 ⁰ C overnight to provide the title compound (100 75 g) Step 2 Preparation of frans-dimethyl 1.4-dιoxane-2.5-dιcarboxylate frans-1 , 4-Dιoxane-2,5-dιcarboxylιc acid (90 g) was dissolved in hot methanol (1380 mL) The solution was cooled to 15 ⁰ C and HCI gas (approximately 45 g) was bubbled through the solution until saturated The reaction mixture was stirred at room temperature for 24 hours, and then cooled to 5 ⁰ C The resulting precipitate was collected by filtration, washed methanol and cold saturated sodium bicarbonate solution (500 mL) The solid was further washed with cold water (500 mL) until the wash was neutral The product was dried in a vacuo at 50 ⁰ C overnight to afford the title compound (97 g)

Step 3 Preparation of rac-(2ff ^* ,5S ^* )-5-(methoxycarbonyl)-1 ,4-dιoxane-2-carboxylιc acid A solution of /rans-dimethyl 1 ,4-dιoxane-2,5-dιcarboxylate (68 54 g, 336 mmol) in methanol

(3 2 L) and water (0 8 L) was slowly added to a solution of lithium hydroxide monohydrate (10 56 g, 252 mmol) in water (0 6 L) The reaction mixture was maintained at 20 ⁰ C during the addition by applying a water bath The resulting solution was stirred for 24 h and concentrated to remove most of the methanol in vacuo The remaining aqueous mixture was extracted with ethyl acetate (2 L) The aqueous layer was then acidified to pH 2 with 6 N hydrochloric acid and concentrated to a small

volume (ca 400 mL) The mixture was cooled to 0-5 ⁰ C and filtered The solids were washed with cold water and dried in a vacuum oven at 50 ⁰ C for 24 h to afford the title compound (33 34 g)

Step 4 Preparation of rac-(2S ^* .5S ^* )-methyl 5-(hγdroxymethyl)-1 ,4-dιoxane-2-carboxylate rac-(2R\5S ^* )-5-(Methoxycarbonyl)-1 ,4-dιoxane-2-carboxylιc acid (19 34 g, 102 mmol) was dissolved in tetrahydrofuran (800 mL) A solution of borane dimethylsulfide (10 M, 12 2 mL) was slowly added to the solution The mixture was stirred at room temperature for 3 h and then quenched with water (50 mL) The mixture was concentrated under vacuum The residue was suspended in ethyl acetate and filtered The filtrate was concentrated The residue was again suspended in chloroform, filtered, and the filtrate concentrated The crude product was purified by silica gel chromatography (dichloromethane/methanol, 99 5/0 5 - 98/2) to afford the title compound

Step 5 Preparation of rac-(2S ^* .5ff*)-methyl 5-((tosyloxy)methyl)-1 ,4-dιoxane-2-carboxylate

p-Toluene sulfonylchloride (3 46 g, 18 15 mmol) was added portion-wise over 30 mm to a solution of rac-(2S ^* ,5S ^* )-methyl 5-(hydroxymethyl)-1 ,4-dιoxane-2-carboxylate (3 2 g, 18 0 mmol) in anhydrous pyridine (24 mL) The mixture was stirred at room temperature for 3 5 h Water (100 mL) was added drop-wise at ice bath temperatures The resulting precipitate was filtered, washed with water, and dried to afford the title compound as a white solid (4 31 g)

Step 6 Preparation of rac-(2S ^* .5S*)-methyl 5-((5-(6-((3-methoxybenzyl)carbamoyl)-2-methylpyrιmιdιn- 4-yl)-2H-tetrazol-2-vDmethyl)-1 ,4-dιoxane-2-carboxylate

rac-(2S ^* ,5R ^* )-Methyl 5-((tosyloxy)methyl)-1 ,4-dιoxane-2-carboxylate (2 19 g, 6 6 mmol) was added to a solution of A/-(3-methoxybenzyl)-2-methyl-6-(2H-tetrazol-5-yl)pyrimidine -4-carboxamide (prepared as described in step 6 of the synthesis of λ/-(3-methoxybenzyl)-6-(2-(((<rans)-4- amιnocyclohexyl)methyl)-2H-tetrazol-5-yl)-2-methylpyrιmιd ιne-4-carboxamιde, Example 5) (2 16 g, 6 6 mmol) and triethylamine (1 33 g, 13 2 mmol) in anhydrous dimethylacetamide (4 mL) The mixture was stirred at 85 ⁰ C in a capped vial overnight The reaction mixture was purified by reverse phase preparative HPLC (water/acetonitrile) to afford the title compound (54 mg)

Example 86 rac-(2S*,5S*)-5-((5-(6-((3-Methoxybenzyl)carbamoyl)-2-methyl pyrimidin-4-yl)-2H-tetrazol-2- yl)methyl)-1 ,4-dioxane-2-carboxylic acid

Sodium hydroxide (10 pellets) was added to a mixture of rac-(2S ^* ,5S ^* )-methyl 5-((5-(6-((3- methoxybenzyl)carbamoyl)-2-methylpyrιmιdιn-4-yl)-2H-tetra zol-2-yl)methyl)-1 ,4-dιoxane-2-carboxylate (54 mg) in tetrahydrofuran (3 mL) and water (3 mL) The mixture was stirred overnight at room temperature The reaction mixture was acidified with trifluoroacetic acid and purified by reverse phase preparative HPLC (water/acetonitrile) Fractions containing the product were concentrated The residue was slurried and decanted from ethyl ether and dried in a vacuum desiccator to afford the title compound as a white solid (736 mg) MS (ES+) m/z 470 (M+H) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9 48 (1 H, t, J=Q 2 Hz), 8 42 (1 H, s), 7 24 (1 H, t, J=8 1 Hz), 6 93 (2 H, br s ), 6 83 (1 H, d, J=I 3 Hz), 4 96 (1 H, d, J=3 3 Hz), 4 92 (1 H, d, J=I 7 Hz), 4 51 (2 H, d, J=Q 2 Hz), 4 09 (2 H, t, J=10 4 Hz), 4 12 (1 H, d, J=12 8 Hz), 3 95 (1 H, dd. J=1 1 7, 2 6 Hz), 3 74 (3 H, s), 3 49 (2 H, dt, J=16 4, 10 8 Hz), 2 83 (3 H, s), 2 43 (1 H, s)

Example 87 rac-(2S*,5S*)-methyl 5-((5-(6-((4-fluoro-3-methoxybenzyl)carbamoyl)-2-methylpyrim idin-4-yl)-2H- tetrazol-2-yl)methyl)-1,4-dioxane-2-carboxylate

rac-(2S ^* ,5f? ^* )-Methyl 5-((tosyloxy)methyl)-1 ,4-dιoxane-2-carboxylate (prepared as described in step 1 of the synthesis of rac-(2S*,5S*)-methyl 5-((5-(6-((3-methoxybenzyl)carbamoyl)-2- methylpyrιmιdιn-4-yl)-2H-tetrazol-2-yl)methyl)-1 ,4-dιoxane-2-carboxylate, Example 85) (562 mg, 1 7 mmol) was added to a solution of λ/-(4-fluoro-3-methoxybenzyl)-2-methyl-6-(2H-tetrazol-5- yl)pyrιmιdιne-4-carboxamιde (prepared as described in step 2 of the synthesis of λ/-(4-fluoro-3- methoxybenzyl)-6-(2-(fλans-4-amιnocyclohexyl)methyl)-2H-te trazol-5-yl)-2-methylpyrιmιdιne-4- carboxamide, Example 9) (400 mg, 1 17 mmol) and triethylamine (233 mg, 2 3 mmol) in anhydrous dimethylacetamide (1 0 mL) The mixture was stirred at 85 ⁰ C in a capped vial overnight The reaction mixture was purified by reverse phase preparative HPLC (water/acetonitrile) to afford the title compound (210 mg)

Example 88 rac-(2S*,5S*)-5-((5-(6-((4-Fluoro-3-methoxybenzyl)carbamoyl) -2-methy!pyrimidin-4-yl)-2H- tetrazol-2-yl)methyl)-1 ,4-dioxane-2-carboxylic acid

Sodium hydroxide (2 pellets) was added to a mixture of rac-(2S ^* ,5S ^* )-methyl 5-((5-(6-((4- fluoro-S-methoxybenzyOcarbamoyO^-methylpyÏ€midin^-yO^H-tetra zol^-yOmethyO-i ^-dioxane-Z- carboxylate (prepared as described in Example 87) (34 mg, 0 068 mmol) in tetrahydrofuran (0 4 mL) and water (0 4 mL) The mixture was stirred overnight at room temperature The reaction mixture was acidified with tÏ€fluoroacetic acid and purified by reverse phase preparative HPLC (water/acetonitrile) Fractions containing the product were concentrated The residue was slurried and decanted from ethyl ether and dried in a vacuum desiccator to afford the title compound as a white solid (31 mg) MS (ES+) m/z 488 (M+H) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9 46 - 9 56 (1 H, m), 8 42 (1 H, s), 7 17 (1 H, dd, J=12 8, 8 8 Hz), 6 92 (1 H, br s ), 4 89 - 5 00 (2 H, m), 4 50 (2 H, d, J=5 9 Hz), 4 06 (3 H, br s ), 3 95 (1 H, d, J=1 1 7 Hz), 3 82 (3 H, s), 3 48 (2 H, dd, J=10 4, 7 5 Hz), 3 22 (2 H, br s ), 2 83 (2 H, s), 1 25 (2 H, d, J=5 1 Hz)

Example 89

(2S,5S)-5-((5-(6-((4-Fluoro-3-methoxybenzyl)carbamoyl)-2- methylpyrimidin-4-yl)-2H-tetrazol-2- yl)methyl)-1 ,4-dioxane-2-carboxylic acid

A mixture of λ/-(4-fluoro-3-methoxybenzyl)-6-(2-(((2S,5R)-5-(hydroxymeth yl)-1 ,4-dιoxan-2- yl)methyl)-2H-tetrazol-5-yl)-2-methylpyrιmιdιne-4-carboxa mιde (prepared as described in Example 65) (238 mg, 0 5 mmol) and pyridinium dichromate (1 15 g, 3 0 mmol) in DMF (5 0 mL) was shaken for 24 hours at room temperature The reaction mixture was diluted with dichloromethane (50 mL) and washed with 1 N hydrochloric acid solution (2 x 50 mL) The organic layer was extracted with 1 N sodium hydroxide solution (2 x 40 mL) The combined aqueous layers were acidified with concentrated hydrochloric acid and extracted with dichloromethane (2 x 50 mL) The combined organic layers were dried (sodium sulfate) and concentrated The residue was triturated with diethyl ether and filtered to afford the title compound as a white solid (79 mg, 32%) MS (ES+) m/z 488 (M+H) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9 58 (t, J=Q 6 Hz, 1 H), 8 41 (s, 1 H), 7 17 (dd, J=8 4, 2 2 Hz, 1 H), 7 13 (dd, J=1 1 7, 8 4 Hz, 1 H), 6 89 (ddd, J=Q 3, 4 5, 2 2 Hz, 1 H), 4 97 (dd, J=14 3, 3 7

Hz ₁ 1 H), 4 89 (dd, J=14 3, 7 7 Hz, 1 H), 4 49 (d, J=6 2 Hz, 2 H), 4 15 - 4 03 (m, 3 H), 3 93 (dd, J=1 1 5, 3 1 Hz, 1 H), 3 81 (s, 3 H), 3 53 - 3 41 (m, 2 H), 2 82 (s, 3 H)

Example 90

(2S,5S)-Methyl 5-((5-(6-((4-Fluoro-3-methoxybenzyl)carbamoyl)-2-methylpyπm idin-4-yl)-2H- tetrazol-2-yl)methyl)-1 ,4-dioxane-2-carboxylate

A mixture of W-(4-fluoro-3-methoxybenzyl)-6-(2-(((2S,5R)-5-(hydroxymethyl )-1 ,4-dιoxan-2- yl)methyl)-2/-/-tetrazol-5-yl)-2-methylpyrιmιdιne-4-carbo xamιde (prepared as described in Example 65) (952 mg, 2 0 mmol) and pyridinium dichromate (4 61 g, 12 0 mmol) in DMF (20 0 mL) was shaken for 36 h at room temperature The reaction mixture was poured into 1 N hydrochloric acid solution (100 mL) and extracted with ethyl acetate (4 x 50 mL) The combined organic layers were dried (sodium sulfate) and concentrated The residue was dissolved in methanol (50 mL) and a solution of hydrochloric acid (4M in dioxane, 25 mL) was added The mixture was allowed to stand for 18 h and was then concentrated The residue was mixed with dichloromethane (50 mL) and water (100 mL) The aqueous layer was further extracted with dichloromethane (2 x 50 mL) The combined organic layers were washed with brine (25 mL), dried (sodium sulfate), and concentrated The crude product was purified by silica gel column chromatography (dichloromethane/methanol, 100/1 , 100/2) to afford the title compound (711 mg, 71 %) MS (ES+) m/z 502 (M+H) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9 58 (t, J=6 2 Hz, 1 H), 8 41 (s, 1 H), 7 17 (dd, J=Q 1 , 2 2 Hz, 1 H), 7 13 ((Jd ₁ J=H 3, 8 1 Hz, 1 H) ₁ 6 89 (ddd, J=8 3, 4 5, 1 8 Hz, 1 H), 4 98 (dd, J=14 3, 3 7 Hz ₁ 1 H) ₁ 4 90 (dd, J=14 3, 7 7 Hz ₁ 1 H) ₁ 4 48 (d, J=6 6 Hz, 2 H) ₁ 4 24 (dd, J=10 2, 2 9 Hz ₁ 1 H) ₁ 4 17 - 4 10 (m, 1 H) ₁ 4 08 (dd, J= 1 1 5, 2 7 Hz, 1 H), 3 99 - 3 91 (m, 1 H) ₁ 3 81 (s, 3 H) ₁ 3 63 (s, 3 H) ₁ 3 56 - 3 44 (m, 2 H) ₁ 2 82 (s, 3 H)

Example 91

W-(4-Fluoro-3-methoxybenzyl)-6-(2-(((2S,5S)-5-(2-hydroxyp ropan-2-yl)-1,4-dioxan-2-yl)methyl)- 2H-tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide

(2S,5S)-Methyl 5-((5-(6-((4-Fluoro-3-methoxybenzyl)carbamoyl)-2-methylpyrι mιdιn-4-yl)-2/-/- tetrazo!-2-yl)methyl)-1 ,4-dιoxane-2-carboxylate (prepared as in Example 90) (251 mg, 0 5 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL) and the solution was cooled to -70 °C A solution of

methylmagnesium bromide (3 M in ethyl ether, 666 μl, 2 O mmol) was added and the mixture was allowed to warm to room temperature After 2 h, the reaction mixture was quenched with 1 N hydrochloric acid (5 mL) The mixture was poured into water (50 mL) and extracted with ethyl acetate (2 x 50 mL) The combined organic layers were dried (sodium sulfate) and concentrated The crude product was purified by silica gel column chromatography (dichloromethane/methanol, 100/1 , 100/2) to afford the title compound (51 7 mg, 21%) MS (ES+) m/z 502 (M+H) ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 9 57 (t, J=6 6 Hz, 1 H), 8 41 (s, 1 H), 7 20 - 7 10 (m, 2 H), 6 89 (ddd, J=Q 4, 4 4, 2 2 Hz, 1 H), 4 93 (dd, J=13 9, 3 7 Hz, 1 H), 4 88 - 4 82 (m, J=14 3, 7 7 Hz, 1 H), 4 49 (d, J=6 6 Hz, 2 H), 4 46 (S, 1 H), 4 07 - 3 98 (m, 2 H), 3 85 - 3 77 (m, 4 H), 3 39 (dt, J=16 8, 11 3 Hz, 2 H), 3 19 - 3 13 (m, J=10 2, 2 2 Hz, 1 H), 2 82 (s, 3 H), 1 06 (s, 3 H), 0 99 (s, 3 H)

Example 92 rac-(2S*,5S*)-Methyl 5-((5-(6-((3-chloro-4-fluorobenzyl)carbamoyl)-2-methylpyrimi din-4-yl)-2H- tetrazot-2-yl)methyl)-1 ,4-dioxane-2-carboxylate

rac-(2S*,5/? ^* )-Methyl 5-((tosyloxy)methyl)-1 ,4-dιoxane-2-carboxylate (prepared as described in step 1 of the synthesis of rac-(2S ^* ,5S ^* )-methyl 5-((5-(6-((3-methoxybenzyl)carbamoyl)-2- methylpyrιmιdιn-4-yl)-2/-/-tetrazol-2-yl)methyl)-1 ,4-dιoxane-2-carboxylate, Example 85) (244 mg, 0 74 mmol) was added to a solution of λ/-(3-chloro-4-fluorobenzyl)-2-methyl-6-(2H-tetrazol-5-yl)p yÏ€mιdιne- 4-carboxamιde (prepared as described in step 1 of the synthesis of λ/-(3-chloro-4-fluorobenzyl)-2- methyl-6-(2-((S)-morpholιn-2-ylmethyl)-2H-tetrazol-5-yl)pyr ιmιdιne-4-carboxamιde, Example 47) (200 mg, 0 575 mmol) and triethylamine (349 mg, 3 4 mmol) in anhydrous dimethylacetamide (0 3 mL) The mixture was stirred at 85 ⁰ C in a capped vial overnight The reaction mixture was purified by reverse phase preparative HPLC (water/acetonitrile) to afford the title compound (103 mg)

Example 93 rac-(2S*,5S*)-5-((5-(6-((3-Chloro-4-fluorobenzyl)carbamoyl)- 2-methylpyrimidin-4-yl)-2H-tetrazol-

2-yl)methyl)-1 ,4-dioxane-2-carboxylic acid

Sodium hydroxide (3 pellets) was added to a mixture of rac-(2S*,5S ^* )-methy! 5-((5-(6-((3- chloro^-fluorobenzyOcarbamoyl^-methylpynmidin^-yl^H-tetrazol ^-yl^ethyl^i ^-dioxane^- carboxylate (prepared as described in Example 92) (103 mg) in tetrahydrofuran (0 4 mL) and water (0 4 mL) The mixture was stirred overnight at room temperature The reaction mixture was acidified

with trifluoroacetic acid with ice bath cooling and purified by reverse phase preparative HPLC (water/acetonitrile) Fractions containing the product were concentrated The residue was slurried and decanted from ethyl ether and dried in a vacuum desiccator to afford the title compound as a white solid (88 mg) MS (ES+) m/z 492 (M+H) ¹ H NMR (400 MHz, DMSOd ₆ ) δ ppm 9 55 - 9 64 (1 H, m), 8 42 (1 H, s), 7 57 (1 H, d, J=7 3 Hz), 7 37 (2 H, d, J=I 0 Hz), 4 91 (1 H, br s ), 4 95 (1 H, d, J=12 8 Hz), 4 52 (2 H, d, J=5 9 Hz), 4 1 1 (3 H, d, J=12 8 Hz), 4 06 (1 H, br s ), 3 95 (1 H, d, J=11 7 Hz), 3 48 (1 H, t, J=1 1 0 Hz), 3 44 - 3 55 (1 H, m), 2 84 (3 H, s)

Example 94 rac-(2S*,5S*)-Methyl 5-((5-(6-((3-bromo-4-fluorobenzyl)carbamoyl)-2-methylpyrimid in-4-yl)-2H- tetrazol-2-yl)methyl)-1 ,4-dioxane-2-carboxylate

rac-(2S*,5R*)-Methyl 5-((tosyloxy)methyl)-1 ,4-dιoxane-2-carboxylate (prepared as described in step 1 of the synthesis of rac-(2S ^* ,5S*)-methyl 5-((5-(6-((3-methoxybenzyl)carbamoyl)-2- methylpyrιmιdιn-4-y!)-2H-tetrazol-2-yl)methyl)-1 ,4-dιoxane-2-carboxylate, Example 85) (150 mg, 0 454 mmol) was added to a solution of λ/-(3-bromo-4-fluorobenzyl)-2-methyl-6-(2H-tetrazol-5-yl)py rιmιdιne- 4-carboxamιde (prepared as described in step 1 of the synthesis of λ/-(3-bromo-4-fluorobenzyl)-6-(2- (((2S,5f?)-5-(hydroxymethyl)-1 ,4-dιoxan-2-yl)methyl)-2H-tetrazol-5-yl)-2-methylpyrιmιdÎ ¹ne-4- carboxamide, Example 80) (150 mg, 0 382 mmol) and triethylamine (153 mg, 1 5 mmol) in anhydrous dimethylacetamide (0 3 mL) The mixture was stirred at 85 ⁰ C in a capped vial overnight The reaction mixture was purified by reverse phase preparative HPLC (water/acetonitrile) to afford the title compound (70 mg)

Example 95 rac-(2S*,5S*)-5-((5-(6-((3-Bromo-4-fluorobenzyl)carbamoyl)-2 -methylpyrimidin-4-yl)-2H-tetrazol-

2-yl)methyl)-1 ,4-dioxane-2-carboxylic acid

Sodium hydroxide (3 pellets) was added to a mixture of rac-(2S*,5S*)-methyl 5-((5-(6-((3- bromo-4-fluorobenzyl)carbamoyl)-2-methylpyrιmιdιn-4-yl)-2 /-/-tetrazol-2-yl)methyl)-1 ,4-dιoxane-2- carboxylate (prepared as described in Example 94) (70 mg) in tetrahydrofuran (0 4 mL) and water (0 4 mL) The mixture was stirred overnight at room temperature The reaction mixture was acidified with trifluoroacetic acid with ice bath cooling and purified by reverse phase preparative HPLC

(water/acetonitrile) Fractions containing the product were concentrated The residue was slurried and

decanted from ethyl ether and dried in a vacuum desiccator to afford the title compound as a white solid (18 mg) MS (ES+) m/z 536 (M+H) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9 61 (1 H, t, J=6 2 Hz), 8 42 (1 H, s), 7 69 (1 H, d, J=7 0 Hz), 7 41 (1 H, t, J=5 7 Hz), 7 33 (1 H, t, J=8 6 Hz), 4 90 - 5 00 (2 H, m), 4 52 (3 H, d, J=6 2 Hz), 4 05 - 4 17 (3 H, m), 3 95 (1 H, dd, J=ÏŠ 1 9, 2 7 Hz), 3 50 (2 H, dt, J=16 3, 11 1 Hz), 2 84 (3 H, s)

Example 96 rac-rV-(3-Methoxybenzyl)-6-(2-(((2S*,5R*)-5-(aminomethyl)-1, 4-dioxan-2-yl)methyl)-2H-tβtrazol-5- yl)-2-methylpyrimidine-4-carboxamide

Step 1 Preparation of rac-((2S ^* ,5S ^* )-5-((5-(6-((3-methoxybenzyl)carbamoyl)-2-methylpyπmιdιn- 4-yl)- 2H-tetrazol-2-yl)methyl)-1 ,4-dιoxan-2-yl)methyl 4-methylbenzenesulfonate

In a 40 mL scintillation vial with a magnetic stir bar at room temperature and standard pressure, /V-(3-methoxybenzyl)-2-methyl-6-(2H-tetrazol-5-yl)pyÏ€mιdι ne-4-carboxamιde (prepared as described in step 6 of the synthesis of /V-(3-methoxybenzyl)-6-(2-(((frans)-4-amιnocyclohexyl)methy l)- 2H-tetrazol-5-yl)-2-methylpyrιmιdιne-4-carboxamιde, Example 5) (520 mg, 1 60 mmol) was combined with rac-((2R ^* ,5R ^* )-5-(hydroxymethyl)-1 ,4-dιoxan-2-yl)methyl 4-methylbenzenesulfonate (prepared as described in step 4 of the synthesis of rac-λ/-(3-methoxybenzyl)-6-(2-(((2S ^* ,5R*)-5-(hydroxymethyl)- 1 ,4-dιoxan-2-yl)methyl)-2/-/-tetrazol-5-yl)-2-methylpyrιmι dιne-4-carboxamιde, Example 61 ) (604 mg, 2 00 mmol), polymer supported triphenylphosphine (1490 mg, 3 20 mmol), and anhydrous tetrahydrofuran (15 ml) The reaction mixture was cooled to 0 ⁰ C and di-tert-butyl azodicarboxylate (736 mg, 3 20 mmol) was added The mixture was stirred at 0 ⁰ C for 2 hours and then was allowed to warm to room temperature for 12 hours The reaction mixture was filtered and concentrated to oil The oil was dissolved in acetonitrile and water and chromatographed by reversed phased preparative HPLC (Gilson prep, Delta Pak column, 30 to 40% acetonitrile, 10 mm hold, 40 mm run, 10 mm hold) Fractions containing the desired were combined and concentrated under vacuum to afford the title compound as a white solid (136 5 mg) ¹ H NMR (400 MHz, methanol-d ₄ ) 6 ppm 2 84 - 2 86 (m, 3 H), 3 03 (dd, J=13 3, 2 8 Hz, 1 H), 3 37 (dd, J=11 6, 10 2 Hz, 1 H), 3 60 (dd, .7=1 1 6, 10 5 Hz, 1 H), 3 74 - 3 77 (m, 3 H), 4 12 (dd, J=λ 1 7, 2 6 Hz, 1 H), 4 20 - 4 28 (m, 1 H), 4 57 - 4 62 (m, 2 H), 4 87 - 4 90 (m, 2 H), 6 81 (dd, J=7 9, 2 0 Hz, 1 H), 6 90 - 6 95 (m, 2 H), 7 22 (t, 1 H), 8 57 (s, 1 H), 9 50 (t, 1 H) LC/MS (5%-95% CH ₃ CN/H ₂ O, 8 mm) 6 47 mm, m/z 610 (M+H)

Step 2 Preparation of rac-λ/-(3-methoxybenzyl)-6-(2-(((2S\5ff ^* )-5-(amιnomethyl)-1 ,4-dιoxan-2- yl)methyl)-2H-tetrazol-5-yl)-2-methylpyrιmιdιne-4-carboxa mιde

In a 20 ml scintillation vial with a magnetic stir bar at room temperature and standard pressure, rac-((2S*,5S*)-5-((5-(6-((3-methoxybenzyl)carbamoyl)-2-methy lpyrιmιdιn-4-yl)-2H-tetrazol-2- yl)methyl)-1 ,4-dιoxan-2-yl)methyl 4-methylbenzenesulfonate (130 mg) was dissolved in dimethyl sulfoxide (5 mL) and ammonium hydroxide (31 5 mg, 0 898 mmol) was added The mixture was stirred at room temperature for 2 hours and then heated to 80 ⁰ C for 12 hours The reaction mixture was concentrated, dissolved in acetonitrile and water, acidified with acetic acid, and chromatographed by reversed phase preparative HPLC (Gilson, Delta Pak column, 30-60% acetonitrile, 5 mm hold, 30 mm run, 5 mm hold) Fractions containing the desired product were collected and concentrated under vacuum to afford the trifluoroacetic acid salt of the title compound as a clear oil (81 6 mg) ¹ H NMR (400 MHz, methanol-d,) δ ppm 2 85 (s, 3 H) ₁ 3 03 (dd, J=13 3, 2 8 Hz, 1 H), 3 37 (dd, J=11 4, 10 3 Hz, 1 H), 3 60 (dd, J=11 6, 10 5 Hz, 1 H), 3 76 (s, 3 H), 3 81 (dd, J=1 1 6, 2 4 Hz, 1 H), 4 12 (dd, J=11 7, 2 6 Hz, 1 H), 4 20 - 4 28 (m, 1 H), 4 58 - 4 61 (m, 2 H), 4 87 - 4 90 (m, 2 H), 6 79 - 6 83 (m, 1 H), 6 91 - 6 95 (m, 2 H), 7 22 (t, J=8 1 Hz, 1 H), 8 57 (s, 1 H), 9 50 (t, J=6 58 Hz, 1 H) LC/MS (5%-95% CH ₃ CN/H ₂ O, 5 mm) 2 241 mm, m/z 455 (M+H)

Example 97 rac-N-(3-Methoxybenzyl)-6-(2-(((2S*,5/?*)-5-(acetamidomethyl )-1,4-dioxan-2-yl)methyl)-2H- tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide

In a 20 mL scintillation vial with a magnetic stir bar at room temperature and standard pressure, rac-λ/-(3-methoxybenzyl)-6-(2-(((2S*,5R*)-5-(amιnomethyl)- 1 ,4-dιoxan-2-yl)methyl)-2H- tetrazol-5-yl)-2-methylpyrιmιdιne-4-carboxamιde trifluoroacetate (prepared as described in Example 96) (40 mg, 0 70 mmol) was combined with λ/,λ/-dιmethylformamιde (5 mL) and N,N- diisopropylethylamme (59 2 mg, 0 458 mmol) Acetic anhydride (19 1 mg, 0 187 mmol) was added and the mixture was stirred overnight The reaction mixture was concentrated, re-dissolved in acetonitrile and water, and chromatographed by reversed phase preparative HPLC (Gilson, Delta Pak column, 20- 60% acetonitrile, 10 mm hold, 20 mm run, 10 mm hold) Fractions containing the desired product were collected and concentrated to afford the title compound as a white solid (21 3 mg) ¹ H NMR (400 MHz, methanol-d ₄ ) 6 ppm 1 32 - 1 37 (m, 2 H), 1 91 (s, 3 H), 2 85 (s, 3 H) ₁ 3 09 - 3 16 (m, 1 H), 3 18 - 3 24

(m, 1 H), 3 49 - 3 60 (m, 1 H), 3 76 (s, 3 H), 4 01 (dd, J= 11 6, 2 4 Hz, 1 H), 4 14 - 4 22 (m, 1 H), 4 58 - 4 62 (m, 1 H), 6 81 (dd, J=8 1 , 1 9 Hz, 1 H), 6 92 - 6 95 (m, 2 H), 7 23 (t, J=8 1 Hz, 1 H), 8 58 (s, 1 H), 9 49 (t, J=6 6 Hz, 1 H) LC/MS (5%-95% CH ₃ CN/H ₂ O, 5 mm) 2 59 mm, m/z 497 (M+H)

Example 98 rac-W-(3-Methoxybenzyl)-6-(2-(((2S*,5/?*)-5-(acetamidomethyl )-1,4-dioxan-2-yl)methyl)-2H- tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide

In a 20 mL scintillation vial with a magnetic stir bar at room temperature and standard pressure, rac-λ/-(3-methoxybenzyl)-6-(2-(((2S*,5/? ^* )-5-(amιnomethyl)-1 ,4-dιoxan-2-yl)methyl)-2H- tetrazol-5-yl)-2-methylpyrιmιdιne-4-carboxamιde trifluoroacetate (prepared as described in Example 96) (115 mg, 0 253 mmol) was combined with λ/,λ/-dιmethylformamιde (5 mL) and N, N- dnsopropylethylamine (98 1 mg, 0 759 mmol) at room temperature After 30 mm, methane sulfonyl chloride was added and the reaction mixture was stirred for 12 hours The reaction mixture was concentrated, dissolved in acetonitrile and water, and chromatographed by reversed phased preparative HPLC (Gilson, Delta Pak column, 30-60% acetonitrile, 10 mm hold, 30 mm run, 5 mm hold) Fractions containing the desired product were collected and concentrated to afford the title compound as a white solid (10 mg) ¹ H NMR (400 MHz, methanol-d,) δ ppm 2 68 (s, 3 H), 2 84 (dd, J= 13 2, 9 4 Hz, 1 H), 3 03 (dd, J=13 3, 2 6 Hz, 1 H), 3 37 (dd, J= 1 1 6, 10 5 Hz, 1 H), 3 56 - 3 63 (m, 1 H), 3 76 (s, 3 H), 3 82 (dd, J= 11 4, 2 6 Hz, 1 H), 4 11 (dd, J=11 6, 2 4 Hz, 1 H), 4 18 - 4 26 (m, 1 H), 4 60 (s, 2 H), 6 81 (dd, J=9 0, 2 3 Hz, 1 H), 6 91 - 6 96 (m, 2 H), 7 23 (t, J=8 1 Hz, 1 H), 8 1 1 (d, J= 1 1 Hz, 1 H), 8 57 (s, 1 H) LC/MS (5%-95% CH ₃ CN/H ₂ O, 5 mm) 2 695 mm, m/z 533 (M+H)

Example 99

C->W-(4-Fuoro-3-methoxybenzyl)-6-(2-(((2/?*,5R*)-5-(hy droxymethyl)-tetrahydro-2H-pyran-2- yl)methyl)-2W-tetrazol-5-yl)-2-methylpyrimidine-4-carboxamid e

Step 1 Preparation of diethyl 2-(but-3-enyl)malonate

Small pieces of sodium (13 g, 565 mmol) were added to absolute ethanol (300 mL) slowly After complete consumption, diethylmalonate (100 g, 625 mmol) was added drop wise The reaction mixture was heated to 50 ⁰ C for 30 mm and then cooled to room temperature 1 -Bromo-3-butene (76 g, 565 mmol) was added and the mixture was refluxed overnight The ethanol was evaporated and the residue was diluted with water (500 mL) The mixture was extracted with ethyl acetate (3 x 500 mL) The combined ethyl acetate extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure The crude material was purified by vacuum (0 1mm) distillation (bath temp 125-135 0C and vapor temp 82-85 ⁰ C) to afford the title compound (110 g, 82%)

Step 2 Preparation of 2-(but-3-enyl)propane-1.3-dιol

To a suspension of lithium aluminum hydride (56 g, 1 47 mol) in tetrahydrofuran (800 mL) was added diethyl 2-(but-3-enyl)malonate (80 O g ₁ O 373 mol) dissolved in tetrahydrofuran (400 mL) drop- wise under ice-water cold condition Lithium bromide (3 2 g, 37 3 mmol) was added and the mixture was stirred at room temperature overnight under nitrogen atmosphere The mixture was cooled in an ice water bath and the reaction was cautiously quenched by the drop-wise addition of water (56 mL), then with 15% aqueous NaOH solution (168 mL) and finally with water (56 mL) The mixture was stirred for another 1 h and filtered The solid residue was thoroughly washed with tetrahydrofuran (3 x 500 mL) The combined filtrate was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford the title compound (41 5 g, 85 %)

Step 3 Preparation of (6-(ιodomethyl)-tetrahydro-2H-pyran-3-yl)methanol

To a suspension of iodine (98 g, 386 mmol) and NaHCO ₃ (32 6 g, 388 56 mmol) in ether (430 mL) and water (205 mL) was added a solution of 2-(bÏ…t-3-enyl)propane-1 ,3-dιol (33 5 g, 257 33 mmol) in ether (250 mL) at 0 °C The mixture was stirred at room temperature for 8-10 h and then was quenched by the addition of saturated aqueous Na ₂ S ₂ O ₃ at 0 ⁰ C The organic layer was separated and the aqueous layer was extracted with ether (2 x 350 mL) The combined organic layers were dried over anhydrous sodium sulfate and concentrated The crude material was purified by flash column chromatography over silica gel (230-400 mesh) using 40% ethyl acetate in hexane as an eluent to afford the title compound as an oil consisting of a mixture of cis/trans isomers (53 0 g, 80 5%) MS (ES+) m/z 256 (M+H)

Step 4 Preparation of λ)-((3f? ^* ,6ff*)-6-(ιodome(hyl)-tetrahvdro-2/-/-pyran-3-yl)methanol (Peak 1 )

An isomeric mixture of (6-(ιodomethyl)-tetrahydro-2H-pyran-3-yl)methanol (4 0 g) in ethanol (50 mL) was separated by supercritical-fluid chromatography (AD-H 30 x 250 mm, 15% ethanol, 70 mL/min, 0 5 mL/injection) The first eluting isomer was isolation and concentrated under vacuum to afford the title compound as a colorless oil (920 mg) ¹ H NMR (500 MHz, DMSOd ₆ ) δ ppm 1 07 - 1 28 (m, 2 H), 1 50 - 1 64 (m, 1 H), 1 67 - 1 80 (m, 2 H), 2 99 - 3 36 (m, 6 H), 3 89 - 4 00 (m, 1 H), 4 42 (t, J=5 1 Hz, 1 H) SFC (AD-H, 20% ethanol) 3 01 mm LC/MS (5% to 95%, CH ₃ CN/H ₂ O, 12 mm) 4 197 mm, m/z 257 (M+H) Ia] ^{224 0} _D = -0 380 (acetonitrile, 6 76) Step 5 Preparation of ^)-λy-(4-Fuoro-3-methoxybenzvO-6-(2-(((2ff\5f? ^* )-5-(hvdroxymethyl)-tetrahvdro- 2/-/-pyran-2-yl)methyl)-2/-/-tetrazol-5-yl)-2-methylpyrιmι dιne-4-carboxamιde

In a 20 ml scintillation vial with a magnetic stir bar at room temperature and standard pressure, λ/-(4-fluoro-3-methoxybenzyl)-2-methyl-6-(2H-tetrazol-5-yl) pyrιmιdιne-4-carboxamιde (prepared as described in step 2 of the synthesis of λ/-(4-fluoro-3-methoxybenzyl)-6-(2-(/rans-4- amιnocyclohexyl)methyl)-2/-/-tetrazol-5-yl)-2-methylpyrιmÎ ¹dιne-4-carboxamιde, Example 9) (600 mg, 1 75 mmol) was dissolved in λ/,λ/-dιmethyl acetamide (3 mL) A/,λ/-Dιιsopropylethylamιne (226 mg, 1 75 mmol) was added, and the mixture was stirred at room temperature for 30 mm A solution of (-)- ((3R*,6R*)-6-(ιodomethyl)-tetrahydro-2H-pyran-3-yl)methanol (Peak 1 ) (895 mg, 3 50 mmol) in N, N- dimethyl acetamide (2 mL) was added, and the mixture was warmed to 80 ⁰ C for 14 hours After cooling, the reaction mixture was concentrated, dissolved in acetonitrile and water, and chromatographed by reversed phase preparative HPLC (Gilson, Delta Pak column, 20-60% acetonitrile, 10 minute hold, 60 minutes run, 5 minute hold) The first eluting peak (49 mm) was isolated and concentrated under vacuum to afford the title compound as a clear, colorless oil (373 mg) ¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 1 14 - 1 25 (m, 1 H), 1 29 - 1 40 (m, 1 H), 1 54 - 1 65 (m, 1 H), 1 78 (d, J=9 9 Hz, 2 H), 2 06 (s, 3 H), 2 82 (s, 3 H), 3 00 (t, J=1 1 1 Hz, 1 H), 3 14 (dd, J=10 8, 7 20 Hz, 1 H), 3 23 (dd, J=10 7, 5 6 Hz, 1 H), 3 81 (s, 3 H), 3 86 (dd, J=11 1 , 3 9 Hz ₁ 2 H), 4 49 (d, J=6 3 Hz, 2 H), 4 80 - 4 92 (m, 2 H), 6 87 - 6 92 (m, 1 H), 7 10 - 7 20 (m, 2 H), 8 41 (s, 1 H), 9 53 (t, J=6 5 Hz, 1 H) LC/MS (5%-95% CH ₃ CN/H ₂ O, 5 mm ) 2 748 mm, m/z 472 (M+H) HPLC (5%-95% CH ₃ CN/H ₂ O, 40 mm) 19 509 mm [σ] ^{22 4 C} _D = -0 193 (acetonitrile, 0 27)

Example 100

(+ _/ )-W-(4-Fuoro-3-methoxybenzyl)-6-(2-(((2/?*,5/?*)-5-(hydroxym ethyl)-tetrahydro-2H-pyran-2- yl)methyl)-2H-tetrazol-5-yl)-2-methylpyrimidine-4-carboxamid e

Step 1 Preparation of / ^'• <-)-((3/ ^: ? ^* .6/? ^> )-6-(ιodomethyl)-tetrahvdro-2/-/-pyran-3-yl)fnethanol (Peak 2)

The second eluting isomer from the separation described in step 3 of Example 99 was isolated and concentrated under vacuum to afford the title compound as a clear, colorless oil (1 0 g) ¹ H NMR (500 MHz, DMSOd ₆ ) δ ppm 1 07 - 1 28 (m, 2 H), 1 50 - 1 64 (m, 1 H), 1 67 - 1 80 (m, 2 H), 2 99 - 3 36 (m, 6 H), 3 89 - 4 00 (m, 1 H), 4 42 (t, J=5 1 Hz, 1 H) SFC (AD-H, 20% ethanol) 3 18 mm LC/MS (5% -95%, CH ₃ CN/H ₂ O, 12 mm ) 4 210 mm, m/z 257(M+H) [O] ^{22 4 0} _D = 0 289 (acetonitrile, 2 56)

Step 2 Preparation of ^)-λy-(4-Fuoro-3-methoxybenzyl)-6-(2-(((2/ ^: ?*,5R ^t )-5-(hvdroxymethyl)- tetrahvdro-2H-pγran-2-yl)methyl)-2/-/-tetrazol-5-yl)-2-meth ylpyrιmιdιne-4-carboxamιde

In a 20 ml scintillation vial with a magnetic stir bar at room temperature and standard pressure, λ/-(4-fluoro-3-methoxybenzyl)-2-methyl-6-(2/-/-tetrazol-5-y l)pyrιmιdιne-4-carboxamιde (prepared as described in step 2 of the synthesis of /V-(4-flÏ…oro-3-methoxybenzyl)-6-(2-(/rans-4- amιnocyclohexyl)methyl)-2H-tetrazol-5-yl)-2-methylpyrιmιd ιne-4-carboxamιde, Example 9) (680 mg, 1 98 mmol) was dissolved in λ/,A/-dιmethyl acetamide (3 mL) λ/,/V-Dιιsopropylethylamιne (256 mg, 1 98 mmol) was added, and the mixture was stirred at room temperature for 30 mm A solution of (+)- ((3/? ^* ,6/? ^* )-6-(ιodomethyl)-tetrahydro-2/-/-pyran-3-yl)methanol (Peak 2) (1010 mg, 3 96 mmol) in N ₁ N- dimethyl acetamide (2 mL) was added, and the mixture was warmed to 80 ⁰ C for 14 hours After cooling, the reaction mixture was concentrated, dissolved in acetonitrile and water, and chromatographed by reversed phase preparative HPLC (Gilson, Delta Pak column, 20-60% acetonitrile, 10 minute hold, 60 minutes run, 5 minute hold) The first eluting peak (49 mm) was isolated and concentrated under vacuum to afford the title compound as a clear, colorless oil (344 mg) ¹ H NMR (500 MHz, DMSOd ₆ ) δ ppm 1 14 - 1 25 (m, 1 H), 1 29 - 1 40 (m, 1 H), 1 54 - 1 65 (m, 1

H), 1 78 (d, J=9 9 Hz, 2 H), 2 06 (s, 3 H), 2 82 (s, 3 H), 3 00 (t, J=11 1 Hz, 1 H), 3 14 (dd, J=IO 8, 7 2 Hz, 1 H), 3 23 (dd, J=10 7, 5 3 Hz, 1 H), 3 81 (s, 3 H), 3 86 (dd, J=11 1 , 3 9 Hz, 2 H), 4 49 (d, J=6 3 Hz, 2 H), 4 80 - 4 92 (m, 2 H), 6 87 - 6 92 (m, 1 H), 7 10 - 7 20 (m, 2 H), 8 41 (s, 1 H), 9 53 (t, J=6 5 Hz, 1 H) LC/MS (5%-95% CH ₃ CN/H ₂ O, 5 mm) 2 752 mm, m/z 472 (M+H) HPLC (5%-95% CH ₃ CN/H ₂ O, 40 mm) 19 501 mm [O] ^{22 4 0} _D = 0 200 (acetonitrile, 0 09)

Example 101

('->W-(4-Fuoro-3-methoxybenzyl)-6-(2-(((2S*,5/?*)-5-(h ydroxymethyl)-tetrahydro-2H-pyran-2- yl)methyl)-2H-tetrazol-5-yl)-2-methylpyrimidine-4-carboxamid e

Step 1 Preparation of ("-)-((3ff ^* ,6S ^* )-6-(ιodomethyl)-tetrahydro-2H-Dyran-3-yl)methanol (Peak 3)

The third eluting isomer from the separation described in step 3 of Example 99 was isolated and concentrated under vacuum to afford the title compound as a clear, colorless oil (440 mg) ¹ H NMR (500 MHz, DMSOd ₆ ) 6 ppm 1 07 - 1 27 (m, 2 H), 1 50 - 1 62 (m, 1 H), 1 66 - 1 80 (m, 2 H), 3 02 - 3 35 (m, 6 H), 3 89 - 4 00 (m, 1 H), 4 42 (t, J=5 1 Hz, 1 H) SFC (AD-H, 20% ethanol) 3 48 mm LC/MS (5% -95%, CH ₃ CN/H ₂ O, 12 mm ) 4 154 mm, m/z 257 (M+H) [σ] ^{22 4 C} _D = -1 469 (acetonitrile, 2 37)

Step 2 Preparation of ('-)-/V-(4-fluoro-3-methoxybenzyl)-6-(2-(((2S*,5/?*)-5-(hvdr oxymethyl)-tetrahvdro- 2/-/-pyran-2-yl)methyl)-2/-/-tetrazol-5-yl)-2-methylpyrιmι dιne-4-carboxamιde

In a 20 ml scintillation vial with a magnetic stir bar at room temperature and standard pressure, λ/-(4-fluoro-3-methoxybenzyl)-2-methyl-6-(2H-tetrazol-5-yl) pyrιmιdιne-4-carboxamιde (prepared as described in step 2 of the synthesis of λ/-(4-fluoro-3-methoxybenzyl)-6-(2-(frans-4- amιnocyclohexyl)methyl)-2/-/-tetrazol-5-yl)-2-methylpyrιmÎ ¹dιne-4-carboxamιde, Example 9) (296 mg, 0 862 mmol) was dissolved in λ/,λ/-dιmethyl acetamide (3 mL) λ/,λ/-Dιιsopropylethylamιne (1 1 1 mg,

0 862 mmol) was added, and the mixture was stirred at room temperature for 30 mm A solution of (-J- ((3R*,6S ^* )-6-(ιodomethyl)-tetrahydro-2H-pyran-3-yl)methanol (Peak 3) (442 mg, 1 72 mmol) in N ₁ N- dimethyl acetamide (2 ml.) was added, and the mixture was warmed to 80 ⁰ C for 14 hours After cooling, the reaction mixture was concentrated, dissolved in acetonitrile and water, and chromatographed by reversed phase preparative HPLC (Giison, Delta Pak column, 20-50% acetonitrile, 10 minute hold, 60 minutes run, 5 minute hold) The first eluting peak (47 mm) was isolated and concentrated under vacuum to afford the title compound as a clear, colorless oil (206 mg) ¹ H NMR (500 MHz, DMSOd ₆ ) δ ppm 1 41 - 1 71 (m, 3 H), 1 71 - 1 85 (m, 1 H), 2 47 - 2 52 (m, 1 H), 2 81 (s, 3 H), 3 34 - 3 43 (m, 1 H), 3 45 - 3 53 (m, 1 H), 3 69 - 3 77 (m, 1 H), 3 81 (s, 3 H), 3 92 - 4 06 (m, 1 H), 4 43 - 4 54 (m, 2 H), 4 77 - 4 97 (m, 2 H), 6 86 - 6 93 (m, 1 H), 7 13 (dd, J= 11 4, 8 4 Hz,

1 H), 7 17 (dd, J=8 5, 1 8 Hz, 1 H), 8 41 (s, 1 H), 9 52 (t, J=6 4 Hz, 1 H) LC/MS (5%-95% CH ₃ CN/H ₂ O, 5 mm) 2 753 mm m/z 472 (M+H) HPLC (5%-95% CH ₃ CN/H ₂ O, 40 mm) 19 582 mm [σ] ^{22 4 C} _D = -0 154 (acetonitrile, 0 39)

Example 102

C+j.λ/.(4.fluoro-3-methoxyberzyl)-6-(2-(((2S*,5R*)-5-(hy droxymethyl)-tetrahydro-2H-pyran-2- yl)methyl)-2»4-tetrazol-5-yl)-2-methylpyrimidine-4-carboxam ide

F

Step 1 Preparation of (+)-((3R*.6S ^* )-6-(ιodomethyl)-tetrahvdro-2/-/-pyran-3-yl)methanol (Peak 4)

The fourth eluting isomer from the separation described in step 3 of Example 99 was isolated and concentrated under vacuum to afford the title compound as a clear, colorless oil (390 mg) ¹ H NMR (500 MHz, DMSO-Cf ₆ ) δ ppm 1 07 - 1 27 (m, 2 H), 1 50 - 1 62 (m, 1 H), 1 66 - 1 80 (m, 2 H), 3 02 - 3 35 (m, 6 H), 3 89 - 4 00 (m, 1 H), 4 42 (t, J=5 12 Hz, 1 H) SFC (AD-H, 20% ethanol) 3 402 mm LC/MS (5%-95%, CH ₃ CN/H ₂ O, 12 mm ) 4 153 mm, m/z 257 (M+H) (σ) ^{22 4 C} _D = 0 194 (acetonitrile, 1 99)

Step 2 Preparation of ^)-λ/-(4-fluoro-3-methoxybenzyl)-6-(2-(((2S ^* ,5ff*)-5-(hvdroxymethyl)- tetrahvdro-2H-pyran-2-yl)methyl)-2/-/-tetrazol-5-yl)-2-methy lpyrιmιdιne-4-carboxamιde

In a 20 ml scintillation vial with a magnetic stir bar at room temperature and standard pressure, λ/-(4-fluoro-3-methoxybenzyl)-2-methyl-6-(2/-/-tetrazol-5-y l)pyrιmιdιne-4-carboxamιde (prepared as described in step 2 of the synthesis of λ/-(4-fluoro-3-methoxybenzyl)-6-(2-(frans-4- aminocyclohexyOmethyl^H-tetrazol-S-ylJ^-methylpyπmidine^-ca rboxamide, Example 9) (275 mg, 0 801 mmol) was dissolved in λ/,W-dιmethyl acetamide (3 mL) λ/,λ/-Dιιsopropylethylamιne (104 mg,

0 801 mmol) was added, and the mixture was stirred at room temperature for 30 mm A solution of (+)- ((3R*,6S*)-6-(ιodomethyl)-tetrahydro-2H-pyran-3-yl)methanol (Peak 4) (410 mg, 1 60 mmol) in N ₁ N- dimethyl acetamide (2 mL) was added, and the mixture was warmed to 80 ⁰ C for 14 hours After cooling, the reaction mixture was concentrated, dissolved in acetonitrile and water, and chromatographed by reversed phase preparative HPLC (Gilson, Delta Pak column, 30-50% acetonitrile, 10 minute hold, 60 minutes run, 5 minute hold) The first eluting peak (39 mm) was isolated and concentrated under vacuum to afford the title compound as a clear, colorless oil (130 mg) ¹ H NMR (500 MHz, DMSOd ₆ ) δ ppm 1 41 - 1 71 (m, 3 H), 1 71 - 1 85 (m, 1 H), 2 47 - 2 52 (m, 1 H), 2 81 (s, 3 H), 3 34 - 3 43 (m, 1 H), 3 45 - 3 53 (m, 1 H), 3 69 - 3 77 (m, 1 H), 3 81 (s, 3 H), 3 92 - 4 06 (m, 1 H), 4 43 - 4 54 (m, 2 H), 4 77 - 4 97 (m, 2 H), 6 86 - 6 93 (m, 1 H), 7 13 (dd, J=I ^{^} l 4, 8 4 Hz,

1 H) ₁ 7 17 (dd, J=8 5, 1 8 Hz, 1 H) ₁ 8 41 (s, 1 H), 9 52 (t, J=6 4 Hz, 1 H) LC/MS (5%-95% CH ₃ CN/H ₂ O, 5 mm ) 2 751 mm, m/z 472 (M+H) HPLC (5%-95% CH ₃ CN/H ₂ O, 40 mm ) 19 586 mm [O) ^{224 0} _D = 0 267 (acetonitrile, 0 45)

Example 103

W-(3-Methoxybenzyl)-6-(2-(((2R*,5S*)-5-hydroxy-tetrahydro -2H-pyran-2-yl)methyl)-2H-tetrazol-5- yl)-2-methylpyrimidine-4-carboxamide

Step 1 Preparation of rac-(3.4-dιhvdro-2H-pyran-2-yl)methyl 4-methylbenzenesulfonate

A mixture of (3,4-dιhydro-2H-pyran-2-yl)methanol (10 g, 87 6 mmol), p-toluenesulfonyl chloride (16 7 g, 87 6 mmol), and pyridine (20 mL) was stirred at room temperature overnight The reaction was cooled in an ice bath and water (50 mL) was added slowly while keeping the mixture cold The mixture was then extracted with dichloromethane (3 x 20 mL) The combined organic layers were washed with 3N hydrochloric acid, dried over magnesium sulfate, and concentrated to afford the title compound as an oil (20 2 g, 86%)

Step 2 Preparation of rac-((2ff*.5S*)-5-hvdroxy-tetrahvdro-2H-pyran-2-yl)methyl 4- methyl benzenesulfonate

To a solution of rac-(3,4-dιhydro-2/-/-pyran-2-yl)methyl 4-methylbenzenesulfonate (1 5 g, 5 6 mmol) in dry tetrahydrofuran (10 mL) cooled to 0 ⁰ C was added a 1 M BH ₃ TTHF solution (16 8 mL, 16 8 mmol) drop-wise After complete addition, the reaction was brought to room temperature and stirred overnight The reaction was treated with 2 5 N NaOH (13 4 mL) by careful drop-wise addition followed by H ₂ O ₂ (4 6 mL), and then the mixture was heated to 55 °C for 1 h The mixture was cooled in an ice bath and K ₂ CO ₃ was added until the aqueous layer was saturated (-7 g) The resulting mixture was stirred for 30 mm and then was extracted with ethyl acetate (3 x 20 mL) The combined organic layers were dried over magnesium sulfate, filtered, and concentrated to an oil The crude product mixture was purified by reverse phase preparative HPLC to afford the title compound as an oil (3 69 g, 97%) LC/MS (5%-95% CH ₃ CN/H ₂ O, 4 mm , 95% CH ₃ CN, 1 mm ) 2 37 mm, m/z 287 (M+H)

Step 3 Preparation of λ/-(3-methoxybenzyl)-6-(2-(((2fr.5S ^» )-5-hvdroxy-tetrahvdro-2H-pyran-2- yl)methyl)-2H-tetrazol-5-yl)-2-methylpyrιmιdιne-4-carboxa rnιde

A mixture of λ/-(3-methoxybenzyl)-2-methyl-6-(2H-tetrazol-5-yl)pyrιmιd ιne-4-carboxamιde

(prepared as described in step 6 of the synthesis of λ/-(3-methoxybenzyl)-6-(2-(((fra/7S)-4- amιnocyclohexyl)methyl)-2H-tetrazol-5-yl)-2-methylpyrιmιd ιne-4-carboxamιde, Example 5) (400 mg, 1 23 mmol), rac-((2R\5S ^* )-5-hydroxy-tetrahydro-2H-pyran-2-yl)methyl 4-methylbenzenesulfonate (704 mg, 2 46 mmol), triethylamine (1 37 mL, 9 84 mmol), and dimethylacetamide (2 mL) was stirred at 85 ⁰ C for 3 days The reaction mixture was purified by reverse phase preparative HPLC and the peak containing the desired regioisomer was isolated Further separation by supercritical fluid

chromatography (Chiralcel AS-H, 30 x 250 mm, 12% methanol, 70 mL/min) and isolation of the first eluting enantiomer afforded the title compound (40 mg) MS (ES+) m/z 439 (M+H) ¹ H NMR (400 MHz, DMSOd ₆ ) δ ppm 1 39 (d, J=10 3 Hz, 1 H), 1 78 - 1 90 (m, 1 H), 1 99 (d, J=8 4 Hz, 1 H), 2 83 (s, 3 H), 2 91 (t, J= 10 4 Hz, 1 H), 3 34 - 3 49 (m, 1 H), 3 68 - 3 78 (m, 4 H), 3 80 - 3 93 (m, 2 H), 4 51 (d, J=Q 6 Hz, 2 H), 4 77 (d, J=A 8 Hz, 1 H), 4 81 - 4 95 (m, 2 H) ₁ 6 83 (d, J=B 1 Hz, 1 H), 6 88 - 6 97 (m, 2 H), 7 24 (t, J=8 1 Hz, 1 H), 8 42 (s, 1 H), 9 48 (t, J=6 4 Hz, 1 H)

Example 104

λ/-(3-Methoxybenzyl)-6-(2-(((2R*,5S*)-5-hydroxy-tetrahyd ro-2H-pyran-2-yl)methyl)-2H-tetrazol-5- yl)-2-methylpyrimidine-4-carboxamide

Isolation of the second eluting enantiomer from the product mixture described in Example 103 afforded the title compound (40 mg) MS (ES+) m/z 439 (M+H) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1 25 - 1 52 (m, 2 H), 1 76 - 1 90 (m, 1 H), 1 99 (d, J=11 0 Hz, 1 H), 2 83 (s, 3 H) ₁ 2 85 - 2 96 (m, 1 H), 3 36 - 3 49 (m, 1 H), 3 68 - 3 79 (m, 4 H) ₁ 3 84 - 3 95 (m, 1 H), 4 52 (d, J=6 6 Hz, 2 H) ₁ 4 72 - 4 95 (m, 3 H) ₁ 6 84 (d, J=1 5 Hz, 1 H), 6 89 - 6 97 (m, 2 H), 7 24 (t, J=8 1 Hz, 1 H), 8 42 (s, 1 H), 9 48 (t, J=6 2 Hz, 1 H)

Example 105

(+)-W-(4-Fluoro-3-methoxybenzyl)-6-(2-(((2/?*,5S*)-5-hydr oxy-tetrahydro-2H-pyran-2-yl)methyl)- 2W-tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide

A mixture of λ/-(4-fluoro-3-methoxybenzyl)-2-methyl-6-(2H-tetrazol-5-yl) pyrιmιdιne-4- carboxamide (prepared as described in step 2 of the synthesis of λ/-(4-fluoro-3-methoxybenzyl)-6-(2- (/rans-4-aminocyclohexyl)methyl)-2H-tetrazol-5-yl)-2-methylp yrimidine-4-carboxamide, Example 9) (461 mg, 1 34 mmol), rac-((2ff,5S ^* )-5-hydroxy-tetrahydro-2H-pyran-2-yl)methyl A- methylbenzenesulfonate (prepared as described in step 2 of the synthesis of λ/-(3-methoxybenzyl)-6- (2-(((2/? ^* ,5S*)-5-hydroxy-tetrahydro-2H-pyran-2-yl)methyl)-2H-tetrazol -5-yl)-2-methylpyrιmιdιne-4- carboxamide, Example 103) (500 mg, 1 75 mmol), and triethylamine (1 50 mL, 10 7 mmol) was heated in λ/,W-dιmethylacetamιde (15 mL) at 85 ⁰ C for 18 hours The mixture was purified by reverse phase preparative HPLC The racemate was further separated by supercritical fluid chiral chromatography

(Chiralcel AD-H column, 30 x 250 mm, 50% 2-propanol, 70 mL/min) and the first eluting isomer was isolated to afford the title compound (25 mg, 4%) MS (ES+) m/z 458 (M+H) ¹ H NMR (400 MHz, DMSO-CZ ₆ ) δ ppm 1 26 - 1 48 (m, 2 H), 1 77 - 1 88 (m, 1 H), 1 91 - 2 03 (m, 1 H), 2 74 - 2 95 (m, 4 H), 3 38 - 3 46 (m, 1 H), 3 64 - 3 75 (m, 1 H), 3 76 - 3 92 (m, 4 H), 4 49 (d, J=6 59 Hz, 2 H), 4 74 - 4 98 (m, 3 H), 6 81 - 6 96 (m, 1 H), 7 06 - 7 23 (m, 2 H), 8 40 (s, 1 H), 9 50 - 9 64 (m, 1 H) [σ] _D ^21'c = +9 1 ° (c = 0 7, dichloromethane)

Example 106

(-)-λ/-(4-Fluoro-3-methoxybenzyl)-6-(2-(((2S*,5/?*)-5-hy droxy-tetrahydro-2W-pyran-2-yl)methyl)- 2H-tetrazol-5-yl)-2-methylpyrimidine-4-carboxamidβ

Isolation of the second eluting isomer by supercritical fluid chiral chromatography (Chiralcel

AD-H column, 30 x 250 mm, 50% 2-propanol, 70 mL/min) of the racemic mixture provided in Example 105 afforded the title compound (21 mg, 3%) ¹ H NMR (400 MHz ₁ DMSO-d ₆ ) δ ppm 1 27 - 1 48 (m, 2 H) ₁ 1 78 - 1 89 (m, 1 H) ₁ 1 92 - 2 03 (m, 1 H), 2 77 - 2 93 (m, 4 H) ₁ 3 38 - 3 48 (m, 1 H), 3 67 - 3 75 (m, 1 H), 3 77 - 3 93 (m, 4 H), 4 49 (d, J=6 59 Hz, 2 H), 4 74 - 4 96 (m, 3 H), 6 83 - 6 95 (m, 1 H), 7 08 - 7 23 (m, 2 H) ₁ 8 40 (s, 1 H), 9 50 - 9 64 (m, 1 H)

Example 107 rac-W-(4-Fluoro-3-methoxybenzyl)-6-(2-(((2/?*,5S*)-5-hydroxy -5-(hydroxymethyl)-tetrahydro-2H- pyran-2-yl)methyl)-2W-tetrazol-5-yl)-2-methylpyrimidine-4-ca rboxamide

Step 1 Preparation of (5-oxo-tetrahvdro-2H-pyran-2-yl)methyl 4-methylbenzenesulfonate

A solution of dichloromethane (40 mL) and dimethylsulfoxide (1 37 ml_, 19 3 mmol) was cooled to -78 ⁰ C and oxalyl chloride (0 84 mL, 9 64 mmol) was added drop-wise rac-((2R*,5S ^* )-5- hydroxy-tetrahydro-2H-pyran-2-yl)methyl 4-methylbenzenesulfonate (prepared as described in step 2 of the synthesis of rac-λ/-(3-Methoxybenzyl)-6-(2-(((2f? ^* ,5S ^* )-5-hydroxy-tetrahydro-2H-pyran-2-

yl)methyl)-2/-/-tetrazol-5-y!)-2-methylpyrιmιdιne-4-carbo xamιcle, Example 103) (2 51 g, 8 77 mmol) in dichloromethane (20 mL) was then added via pipette The mixture was stirred at -78 ⁰ C for 15 mm and then triethylamine (6 1 1 mL, 43 8 mmol) was added drop-wise After 5 mm, the dry ice bath was removed and the mixture allowed to warm to room temperature over 30 minutes The mixture was washed with sat NaHCO ₃ (2 x 20 mL), brine (2 x 20 mL), and water (20 mL) The organic layer was dried over magnesium sulfate, filtered, and concentrated to an oil The crude product was purified by reverse phase preparative HPLC to afford the title compound as an oil (2 43 g, 97%) MS (ES+) m/z 285 (M+H)

Step 2 Preparation of 1 ,5-dιoxaspιro[2 51oct-6-ylmethyl 4-methylbenzenesulfonate

5-Oxo-tetrahydro-2H-pyran-2-yl)methyl 4-methylbenzenesulfonate (2 4 g, 8 4 mmol) in dimethylsulfoxide (25 mL) was added to a dry mixture of tÏ€methylsulfoxoniÏ…m iodide (3 72 g, 16 9 mmol) and potassium f-butoxide (1 89 g, 16 9 mmol) The resulting mixture was stirred at room temperature for 3 hours The solution was poured into water (200 mL) and stirred for 30 mm Ethyl acetate and brine were added and the mixture extracted with ethyl acetate (3 x 20 mL) The organic extracts were combined, dried over magnesium sulfate and concentrated to afford the title compound as an oil (1 32 g) LC/MS (5%-95% CH ₃ CN/H ₂ O, 4 mm , 95% CH ₃ CN, 1 mm ) 2 72 mm, m/z 321 (M+Na)

Step 3 Preparation of (5-hvdroxy-5-(hvdroxymethyl)-tetrahvdro-2/-/-pyran-2-yl)meth yl 4- methylbenzenesulfonate

1 ,5-dιoxaspιro[2 5]oct-6-ylmethyl 4-methylbenzenesulfonate (1 3 g, 4 4 mmol) was taken up in tetrahydrofuran (6 mL) and water (3 mL) The resulting solution was treated with perchloric acid (1 mL) and the reaction stirred at room temperature for 3 hours The product mixture was purified by reverse phase preparative HPLC to afford the title compound LC/MS (5%-95% CH ₃ CN/H ₂ O, 4 mm , 95% CH ₃ CN, 1 mm ) 2 23 mm, m/z 317 (M+H)

Step 4 Preparation of rac-λ/-(4-fluoro-3-methoxybenzyl)-6-(2-(((2/? ^* ,5S ^* )-5-hvdroxy-5- (hvdroxymethylVtetrahvdro^H-pyran-σ-vOmethvO^H-tetrazol-δ- vπ^-methylpyrimidine^-carboxamide

A mixture of λ/-(4-fluoro-3-methoxybenzyl)-2-methyl-6-(2/-/-tetrazol-5-y l)pyrιmιdιne-4- carboxamide (prepared as described in step 2 of the synthesis of λ/-(4-fluoro-3-methoxybenzyl)-6-(2- (frans-4-amιnocyclohexyl)methyl)-2/-/-tetrazol-5-yl)-2-meth ylpyrιmιdιne-4-carboxamιde, Example 9) (116 mg, O 337 mmol), (5-hydroxy-5-(hydroxymethyl)-tetrahydro-2H-pyran-2-yl)methyl 4- methylbenzenesulfonate (160 mg, 0 506 mmol), tÏ€ethylamine (0 38 mL, 2 70 mmol), and dimethylacetamide (1 mL) was stirred at 85 °C overnight The reaction mixture was purified by reverse phase preparative HPLC to provide a mixture of isomers which was further separated by supercritical fluid chromatography (Pegasus, 30 x 250 mm, 20% n-butanol, 70 mUmm) / (Diol, 30 x 250 mm, 25% n-butanol, 70 mL/min) to afford the title compound (20 mg, 12%) LC/MS (5%-95% CH ₃ CN/H ₂ O, 6 mm) 2 545 mm, m/z 488 (M+H) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1 40 - 1 50 (m, 2 H), 1 74 (d, J=9 2 Hz, 1 H), 1 84 - 1 98 (m, 1 H), 2 83 (s, 3 H), 2 97 (d, J= 1 1 0 Hz, 1 H), 3 33 - 3 38 (m, 1 H), 3 40 - 3 46 (m, 1 H), 3 56 (d, J=11 0 Hz, 1 H), 3 82 (s, 3 H), 3 93 (d, J=5 9 Hz, 1 H), 4 51 (d, J=6 2 Hz, 3 H), 4 89 (d, J=5 5 Hz, 2 H), 6 87 - 6 94 (m, 1 H), 7 15 (td, J=12 2, 8 2 Hz, 2 H), 8 14 (s, 1 H), 8 42 (s, 1 H), 9 50 (t, J=6 4 Hz, 1 H)

Example 108 rac-W-(4-Fluoro-3-methoxybenzyl)-6-(2-(((2/?*,5/? ^* )-5-hydroxy-5-(hydroxymethyl)-tetrahydro-2H- pyran-2-yl)methyl)-2H-tetrazol-5-yl)-2-methylpyrimidine-4-ca rboxamide

Isolation of a second eluting isomer from the product mixture described in Example 107 afforded the title compound (30 mg, 18%) LC/MS (5%-95% CH ₃ CN/H ₂ O, 6 mm) 2 531 mm, m/z 488 (M+H) ¹ H NMR (400 MHz, DMSOd ₆ ) S ppm 1 24 (br s , 1 H), 1 44 - 1 84 (m, 6 H), 2 83 (s, 3 H), 3 14 (d, J= 1 8 Hz, 2 H), 3 41 - 3 53 (m, 1 H), 3 84 (s, 3 H) ₁ 3 85 - 3 94 (m, 1 H), 4 51 (d, J=6 2 Hz, 2 H), 4 82 - 4 93 (m, 2 H), 6 84 - 6 95 (m, 1 H), 7 15 (td, J= 12 0, 8 2 Hz, 2 H) ₁ 8 42 (s, 1 H), 9 50 (t, J=6 2 Hz, 1 H)

Example 109 rac-/V-(3-Methoxybenzyl)-6-(1 -(((2/?*,5S*)-5-(hydroxymethyl)-1 ,4-dioxan-2-yl)methyl)-1 H-1 ,2,4- triazol-3-yl)-2-methylpyrimidine-4-carboxamide

Step 1 Preparation of dimethyl 2-methylpyrιmιdιne-4,6-dιcarboxylate

4,6-Dιchloro-2-methylpyrιmιdιne (24 g, 147 mmol), Pd(Ph ₃ P) ₂ CI ₂ (1 03 g, 1 47 mmol), triethylamine (45 1 mL, 324 mmol), and methanol (400 mL) were added to a 1 L high-pressure vessel The vessel was pressurized to 500 psi with carbon monoxide and heated to 100 ⁰ C for 10 h The mixture was filtered and the filtrate concentrated The residue was suspended in a mixture of ethyl acetate/tetrahydrofuran (2/1 ) and the mixture was refluxed for 30 mm After cooling to below 40 ⁰ C, the mixture was filtered and the filtrate was concentrated The crude product was purified by silica gel chromatography eluting with ethyl acetate Fractions containing product were concentrated The residue was slurried in a mixture of acetone/hexanes (2/1 ), filtered and dried in vacuo at 45 ⁰ C to afford the title compound as a light yellow solid

Step 2 Preparation of λ/-(3-methoxybenzyl)-2-methylpyrιmιdιne-4,6-dιcarboxamÎ ¹de

Dimethyl 2-methylpyrιmιdιne-4,6-dιcarboxylate (5 0 g, 23 8 mmol), 3-methoxybenzylamιne (3 59 g, 26 2 mmol), and 2-methyltetrahydrofuran (31 7 mL) were combined in an 50 mL microwave reaction tube and heated to 90 ⁰ C for 15 mm The reaction mixture was filtered through a plug of silica gel, and the filtrate was concentrated The residue was suspended in methanol (25 mL) and a solution of ammonia in methanol (7 N, 3 0 mL) was added The mixture was stirred at room temperature overnight and then concentrated The crude product was purified by silica gel chromatography (ethyl acetate/heptane/methanol, 65/34/1 ) to afford the title compound as a white solid (2 2 g) MS (ES+) m/z 301 (M+H) ¹ H NMR (400 MHz, DMSOd ₆ ) d ppm 9 46 (t, J=6 3 Hz, 1 H), 8 27 (br s , 1 H), 8 22 (s, 1 H), 7 98 (br s , 1 H), 7 20 (t, J=B 1 Hz, 1 H), 6 85 - 6 90 (m, 2 H), 6 79 (dd, J=8 3, 2 1 Hz, 1 H), 4 45 (d, J=6 2 Hz, 2 H), 3 70 (s, 3 H), 2 77 (s, 3 H)

Step 3 Preparation of λ/-(3-methoxybenzyl)-2-methyl-6-(1H-1 ,2,4-trιazol-3-yl)pyrιmιdιne-4- carboxamide

λ/-(3-Methoxybenzyl)-2-methylpyrιmιdιne-4,6-dιcarboxamÎ ¹de (1 49 g, 4 96 mmol) was treated with dimethylformamide dimethylacetal (50 mL, 380 mmol) followed by heating at 101 ⁰ C for 2h A short path distillation was utilized to collect the generated methanol The solvent was then removed in vacuo to afford a crude residue The residue was dissolved in glacial acetic acid (20 ml ) and treated with monohydrazine hydrate (0 75 mL, 14 9 mmol) The mixture was heated at 90 ⁰ C for 2 hours and then allowed to cool to room temperature The mixture was poured into H ₂ O (75 mL) and left to stand at room temperature overnight The resulting solids were filtered and dried to afford the title compound (1 1 1 g, 69 %) LC/MS (5%-95% CH ₃ CN/H ₂ O, 6 mm) 3 95 mm, m/z 325 (M+H)

Step 4 Preparation of rac-λ/-(3-methoxybenzyl)-6-(1-(((2/? ^* ,5S*)-5-(hvdroxymethyl)-1 ,4-dιoxan-2- yl)methyl)-1/-/-1 ,2,4-trιazol-3-yl)-2-methylpyrιmιdιne-4-carboxamιde

W-(3-Methoxybenzyl)-2-methyl-6-(1/-/-1 ,2,4-trιazol-3-yl)pyrιmιdιne-4-carboxamιde (0 070 g,

0 22 mmol) was treated with rac-((2/?*,5R*)-5-(hydroxymethyl)-1 ,4-dιoxan-2-yl)methyl 4- methylbenzenesulfonate (prepared as described in step 4 of the synthesis of rac-λ/-(3- methoxybenzyl)-6-(2-(((2S*,5R*)-5-(hydroxymethyl)-1 ,4-dιoxan-2-yl)methyl)-2H-tetrazol-5-yl)-2- methylpyrιmιdιne-4-carboxamιde, Example 61 ) (0 085 g, 0 28 mmol) and 1 ,8- dιazabιcyclo[5 4 0]undec-7-ene (0 082 g, 0 54 mmol) in acetonitrile (5 mL) After the reaction was stirred for 12 h at 75 °C, the mixture was concentrated to a crude residue that was purified via reverse phase chromatography (40-60% acetonitrile/water, 55 mm) to afford the title compound as a white solid (30 mg, 31 %) LC/MS (5%-95% CH ₃ CN/H ₂ O, 6 mm) 3 83 mm, m/z 455 (M+H) 1 H NMR (400 MHz, DMSO-Of ₆ ) δ ppm 2 78 (3 H, s), 3 30 - 3 38 (4 H, m), 3 42 (1 H, d, J=5 9 Hz) ₁ 3 74 (3 H, s), 3 79 (1 H, br s ), 3 90 (2 H, d, J=9 2 Hz), 4 29 - 4 36 (1 H, m), 4 38 - 4 46 (1 H, m), 4 50 (2 H, d, J=6 2 Hz), 4 60 - 4 69 (1 H, m), 6 82 (1 H, d, J=7 7 Hz), 6 93 (2 H, br s ), 7 24 (1 H, t, J=8 1 Hz), 8 36 (1 H, s), 8 69 (1 H, s), 9 39 (1 H, t, J=6 2 Hz)

Example 110

/V^S-MethoxybenzyO-e^i-^frans^-aminocyclohexyOmethyO-IH-i ^^-triazol-S-yl)^- methylpyrimidine-4-carboxamide

Step 1 Preparation of (/raπs-4-((tert-butoxycarbonyDamιno)cvclohexyl)methyl 4-nιtrobenzenesulfonate

The commercially available tert-butyl (<raÏ€s)-4-(hydroxymethyl)cyclohexylcarbamate (0 30 g, 1 3 mmol) was taken up in dichloromethane (7 mL) and treated with pyridine (0 16 mL, 2 0 mmol) before dripping in a solution of 4-nιtrobenzene-1 -sulfonyl chloride (0 43 g, 1 96 mmol) in dichloromethane (3 0 mL) The reaction was allowed to stir at room temperature for 15 h The mixture was washed with water (5 mL), 5% aqueous hydrochloric acid (3 mL), followed by water ( 5 mL) before drying over sodium sulfate The organic layer was concentrated to a crude oily residue that crystallized to afford the title compound as a beige solid (0 44 g, 81%) LC/MS (5%-95% CH ₃ CN/H ₂ O, 6 mm) 5 48 mm, m/z 439 (M+Na)

Step 2 Preparation of terf-butyl (frans)-4-((3-(6-((3-methoxybenzyl)carbamoyl)-2-methylpyrιm ιdιn-4-yl)- 1 H- 1.2,4-trιazol-1 -vDmethvDcvclohexylcarbamate

(/rans-4-((/ert-Butoxycarbonyl)amιno)cyclohexyl)methyl 4-nιtrobenzenesulfonate (0 096 g,

0 23 mmol) and λ/-(3-methoxybenzyl)-2-methyl-6-(1H-1 ,2,4-trιazol-3-yl)pyrιmιdιne-4-carboxamιde (prepared as described in step 2 of the synthesis of rac-λ/-(3-methoxybenzyl)-6-(1-(((2R ^* ,5S*)-5- (hydroxymethyl)-1 ,4-dιoxan-2-yl)methyl)-1/-/-1 ,2,4-trιazol-3-yl)-2-methylpyrιmιdιne-4-carboxamιde, Example 109) (0 050 g, 0 15 mmol) were treated with 1 ,8-dιazabιcyclo[5 4 0]undec-7-ene (0 022 mL, 0 15 mmol) in acetonitrile ( 5mL) at 75 °C for 12 h The mixture was concentrated and the residue was purified via reverse phase chromatography (10-90% acetonitrile/water, 30 mm) to afford the title compound as a tan oil (0 057 mg, 69%) LC/MS (5%-95% CH ₃ CN/H ₂ O, 5 mm) 3 10 mm, m/z 536 (M+H)

Step 3 Preparation of λ/-(3-methoxybenzyl)-6-(1-(((/rans)-4-amιnocyclohexyl)meth yl)-1 H-1 ,2,4-trιazol- 3-yl)-2-methylpyrιmιdιne-4-carboxamιde

terf-Butyl (frans)-4-((3-(6-((3-methoxybenzyl)carbamoyl)-2-methylpyrimi dm-4-yl)-1 H- 1 ,2,4- trιazol-1 -yl)methyl)cyclohexylcarbamate (0 057 g, 0 1 1 mmol) was taken up in dichloromethane (2 mL) and treated with trifluoroacetic acid (1 0 mL, 7 7 mmol) The reaction was stirred at ambient temperature for 3 h, diluted with dichloromethane (5 mL), and then neutralized with 2 5 N aqueous NaOH to achieve pH 7-8 The organic layer was separated, washed with water (3 mL), dried over sodium sulfate, and concentrated to afford the title compound (0 037 g, 51%) LC/MS (5%-95% CH ₃ CN/H ₂ O, 6 mm) 3 78 mm, m/z 436 (M+H)

Example 111

/V-(3-Methoxybenzyl)-6-(1 -(((frans)-4-acetamidocyclohexyl)methyl)-1 W- 1 ,2,4-triazol-3-yl)-2- methylpyrimidine-4-carboxamide

λ/-(3-Methoxybenzyl)-6-(1-(((<rans)-4-amιnocyclohexyl)m ethyl)-1 /-/-1 ,2,4-trιazol-3-yl)-2- methylpyrιmιdιne-4-carboxamιde (prepared as described in Example 110) (0 034 g, 0 078 mmol) was taken up in dichloromethane (2 mL) and treated with acetyl chloride (0 006 mL, 0 086 mmol) and triethylamine (0 012 mL, 0 086 mmol) After 1 h, the reaction was concentrated, and the residue was purified via reverse phase chromatography (10-95% acetonitrile/water over 30 minutes) to afford the title compound as a clear oil (11 7 mg, 31%) LC/MS (5%-95% CH ₃ CN/H ₂ O, 6 mm) 4 07 mm, m/z 477 m/e 1 H NMR (400 MHz, DMSO-d6) d ppm 1 09 (4 H, br s ) 1 22 - 1 33 (1 H, m) 1 60 (2 H, br s ) 1 73 - 1 84 (2 H, m) 1 75 (3 H, s) 2 78 (3 H, s) 3 46 (1 H, br s ) 3 74 (3 H, s) 4 16 (2 H, d, J=6 95 Hz) 4 50 (2 H, d, J=6 22 Hz) 6 82 (1 H, d, J=8 05 Hz) 6 92 (2 H, br s ) 7 24 (1 H, t, J=8 05 Hz) 7 64 (1 H, d, J=7 69 Hz) 8 36 (1 H, s) 8 72 (1 H, s) 9 39 (1 H, t, J=6 04 Hz)

Example 112

λ/-(3-Methoxybenzyl)-2-methyl-6-(1 -(((frans)-4-{methylsulfonamido)cyclohexyl)methyl)-1 H-1 ,2,4- triazol-3-yl)pyrimidine-4-carboxamide

/V-(3-Methoxybenzyl)-6-(1-(((?rans)-4-amιnocyclohexyl)methy l)-1/-/-1 ,2,4-trιazol-3-yl)-2- methylpyrιmιdιne-4-carboxamιde (prepared as described in Example 1 10) (0 050 g, 0 115 mmol) was taken up in dichloromethane (1 mL) and treated with methane sulfonyl chloride (0 009 mL, 0 1 15 mmol) and triethylamine (0 018 mL, 0 126 mmol) After 1 h, the reaction was concentrated to a crude residue The residue was purified via reverse phase chromatography (10-95% acetonitrile/water over 25 minutes) to afford the title compound as a clear oil (38 1 mg, 64%) LC/MS (5%-95% CH ₃ CN/H ₂ O,

6 mm) 2 57 mm, m/z 514 (M+H) ¹ H NMR (400 MHz, DMSOd ₆ ) δ ppm 1 00 - 1 26 (5 H ₁ m), 1 58 (2 H, d), 1 79 (1 H, br s ), 1 88 (2 H, d, J=9 9 Hz) ₁ 2 76 (3 H, s), 2 86 (3 H, s), 3 02 (1 H, br s ), 3 71 (3 H, s), 4 14 (2 H, d, J=7 0 Hz), 4 48 (2 H, d, J=6 2 Hz), 6 80 (1 H, d, J=7 9 Hz), 6 90 (2 H ₁ br s ), 7 15 -

7 29 (1 H ₁ m), 8 33 (1 H, s), 8 70 (1 H, s), 9 37 (1 H, br s )

Example 113

2-((fraπs)-4-((3-(6-((3-methoxybenzyl)carbamoyl)-2-methy lpyrimidin-4-yl)-1 H-λ ,2,4-triazol-1 - yl)methyl)cyclohexylamino)-2-oxoethyl acetate

λ/-(3-Methoxybenzyl)-6-(1-(((/rans)-4-amιnocyclohexyl)meth yl)-1 /-/-1 ,2 _l 4-trιazol-3-yl)-2- methylpyrιmιdιne-4-carboxamιde (prepared as described in Example 1 10) (0 085 g, 0 195 mmol) was taken up in dichloromethane (2 mL) and treated with acetoxy acetyl chloride (0 025 mL, 0 234 mmol) and triethylamine (0 041 mL, 0 293 mmol) After stirring 2 hours at room temperature, the reaction was concentrated and the residue was purified via reverse phase chromatography (10-95% acetonitrile/water over 25 minutes) to afford the title compound (0 095 g, 91 %)

Example 114

^-(S-MethoxybenzyO-e^i^^^ransJ^^Z-hydroxyacetamidoJcycloh exyOmethyO-IH-i ^^-triazol-S- yl)-2-methylpyrimidine-4-carboxamide

2-((<rans)-4-((3-(6-((3-Methoxybenzyl)carbamoyl)-2-met hylpyrιmιdιn-4-yl)-1 /-/-1 ,2,4-trιazol-1 - yl)methyl)cyclohexylamιno)-2-oxoethyl acetate (prepared as described in Example 1 13) (0 095g, 0 18

mmol) was taken up in acetonitrile (3 mL) and stirred with 2 5 N aqueous NaOH (2 O mL) for 2 hours at room temperature The acetonitrile was removed in vacuo and the aqueous solution was acidified to pH 5 via 10% aqueous hydrochloric acid to afford a solid The solid was filtered, washed with water (2 x 3 mL), and dried to afford the title compound as a beige solid (11 1 mg, 11 3%) LC/MS (5%-95% CH ₃ CN/H ₂ O, 6 mm) 3 45 mm, m/z 494 (M+H) ¹ H NMR (400 MHz, DMSO-Cf ₆ ) δ ppm 1 00 - 1 16 (2 H, m), 1 16 - 1 30 (2 H, m), 1 58 (2 H, d, J=13 2 Hz), 1 73 (2 H, d, J=9 5 Hz), 2 52 (2 H, s), 2 76 (3 H, s), 3 42 - 3 59 (1 H, m), 3 66 - 3 78 (4 H, m), 4 15 (2 H, d, J=6 6 Hz), 4 48 (2 H, d, J=6 2 Hz), 5 30 (1 H, t, J=5 5 Hz), 6 80 (1 H, d, J=10 6 Hz), 6 86 - 6 95 (2 H, m), 7 16 - 7 26 (1 H, m), 7 35 (1 H, d, J=8 4 Hz), 8 34 (1 H, s), 8 71 (1 H, s), 9 29 - 9 40 (1 H, m)

Example 115 rac-W-(4-Fluoro-3-methoxybenzyl)-6-(1-(((2R*,5S*)-5-(hydroxy methyl)-1,4-dioxan-2-yl)methyl)- 1 W-1 ,2,4-triazol-3-yl)-2-methylpyrimidine-4-carboxamide

Step 1 Preparation of methyl 6-((4-fluoro-3-methoxybenzyl)carbamoyl)-2-methylpyrιmιdιn e-4- carboxylate

Dimethyl 2-methylpyÏ€mιdιne-4,6-dιcarboxylate (prepared as described in step 1 of the synthesis of rac-λ/-(3-Methoxybenzyl)-6-(1-(((2f? ^* ,5S*)-5-(hydroxymethyl)-1 ,4-dιoxan-2-yl)methyl)-1 H- 1 ,2,4-trιazol-3-yl)-2-methylpyrιmιdιne-4-carboxamιde, Example 109) (4 50 g, 21 4 mmol), 4-fluoro-3- methoxybenzylamine (prepared as described in step 3 of the synthesis of W-(4-fluoro-3- methoxybenzyl)-6-(2-((/rans-4-amιnocyclohexyl)methyl)-2H-te trazol-5-yl)pyrιmιdιne-4-carboxamιde, Example 1 ) (3 65 g, 23 6 mmol), and 2-methyltetrahydrofuran (21 4 mL) were combined in an 80 mL microwave reaction tube and heated to 110 ⁰ C for 30 mm The reaction mixture was filtered through a plug of silica gel eluting with 65/35, ethyl acetate/heptane The filtrate was concentrated and purified by silica gel chromatography (heptane/acetone, 4/1 ) to afford the title compound as a white solid (1 95 g) MS (ES+) m/z 334 (M+H) ¹ H NMR (400 MHz, DMSO-d ₆ ) 9 53 (t, J=6 3 Hz, 1 H), 8 20 (s, 1 H), 7 14 (dd, J=7 8, 1 9 Hz, 1 H), 7 07 - 7 13 (m, J=11 5, 8 2 Hz, 1 H), 6 85 (ddd, J=Q 3, 4 4, 1 9 Hz, 1 H), 4 45 (d, J=6 4 Hz, 2 H), 3 91 (s, 3 H), 3 78 (s, 3 H), 2 77 (s, 3 H)

Step 2 Preparation of /V-4-(4-fluoro-3-methoxybenzyl)-2-methylpyrιmιdιne-4.6-dÎ ¹carboxamιde

Methyl 6-((4-fluoro-3-methoxybenzyl)carbamoyl)-2-methylpyÏ€mιdιne -4-carboxylate (1 945 g, 5 84 mmol) was dissolved in a mixture of methanol (80 mL) and dichloromethane (15 mL) A solution of ammonia in methanol (7 N, 16 7 mL, 117 mmol) was added and the mixture was stirred at room temperature for 18 h The mixture was concentrated to minimal volume The resulting precipitate was filtered and washed with ethyl ether to afford the title compound as a white solid (1 785 g) MS (ES+) m/z 319 (M+H) ¹ H NMR (400 MHz, DMSO-cfe) 9 48 (t, J=6 4 Hz, 1 H), 8 27 (s, 1 H), 8 22 (s, 1 H), 7 98 (s, 1 H), 7 14 (dd, J=I 9, 1 7 Hz, 1 H), 7 1 1 (dd, J=1 1 5, 8 3 Hz, 1 H), 6 86 (ddd, J=8 2, 4 4, 1 9 Hz, 1 H), 4 45 (d, J=6 3 Hz, 2 H), 3 78 (s, 3 H), 2 77 (s, 3 H)

Step 3 Preparation of λ/-(4-fluoro-3-methoxybenzγl)-2-methyl-6-(1H-1 ,2,4-trιazol-3-yl)pyrιmιdιne-4- carboxamide

λ/-4-(4-Fluoro-3-methoxybenzyl)-2-methylpyrιmιdιne-4,6-d ιcarboxamιde (1 O g, 3 1 mmol) was dissolved in dimethylformamide dimethylacetal (25 mL), and the reaction was refluxed for approximately 2 h The reaction was concentrated under reduced pressure, and the residue was dissolved in acetic acid (20 mL) Hydrazine hydrate (1 0 mL) was added and the reaction mixture was heated at 90 ⁰ C for 1 h The reaction mixture was poured into water and left to sit overnight The resulting precipitate was collected by suction filtration and washed with water and diethyl ether to afford the title compound (702 mg, 65%) LC/MS (5%-95% CH ₃ CN/H ₂ O, 8 mm , 95% CH ₃ CN, 2 mm ) 4 60 mm, m/z 343 (M+H)

Step 4 Preparation of / ^• ac-λ/-(4-fluoro-3-methoxybenzyl)-6-(1-(((2ff*,5S*)-5-(hvdro xymethyl)-1 ,4- dιoxan-2-yl)methyl)-1 H-1 ,2,4-trιazol-3-yl)-2-methylpyrιmιdιne-4-carboxamιde

λ/-(4-Fluoro-3-methoxybenzyl)-2-methyl-6-(1 H-\ ,2,4-trιazol-3-yl)pyrιmιdιne-4-carboxamιde

(1 10 mg, 0 321 mmol) and rac-((2/? ^* ,5f?*)-5-(hydroxymethyl)-1 ,4-dιoxan-2-yl)methyl 4- methylbenzenesulfonate (prepared as described in step 4 of the synthesis of rac-λ/-(3- methoxybenzyl)-6-(2-(((2S ^* ,5R*)-5-(hydroxymethyl)-1 ,4-dιoxan-2-yl)methyl)-2H-tetrazol-5-yl)-2- methylpyrιmιdιne-4-carboxamιde, Example 61 ) (126 mg, 0 418 mmol) were stirred in acetonitrile (5

mL), and 1 ,8-dιazobιcyclo[5 4 0]Ï…ndec-7ene (73 4 mg, 0 482 mmol) was subsequently added The reaction was heated at 75 °C overnight before cooling to room temperature and concentrating under reduced pressure The residue was dissolved in acetonitrile (2 mL)/water (1 mL) and was purified by reverse phase HPLC (20-mιnute hold at 20% B followed by a 30 minute gradient from 20% B to 80% B (A = 0 1 % TFA / water and B = 0 1 % TFA / acetonitrile)) The combined fractions were lyophilized to afford the title compound (4 5 mg, 2 4%) as the TFA salt LC/MS (5%-95% CH ₃ CN/H ₂ O, 8 mm , 95% CH ₃ CN, 2 mm ) 4 73 mm, m/z 473 (M+H) ¹ H NMR (400 MHz, DMSOd ₆ ) δ ppm 9 48 (t, 1 H), 8 71 (s, 1 H), 8 33 (s, 1 H) ₁ 7 04 - 7 23 (m, 2 H), 6 87 (s, 1 H) 4 19 - 4 53 (m, 5 H), 3 56 - 4 05 (m, 6 H), 3 78 (s, 3 H), 3 19 - 3 49 (m, 2 H), 2 75 (s, 3 H)

Example 116

λ/-(4-Fluoro-3-methoxybenzyl)-6-(1-((<rans-4-aminocyc lohexyl)methyl)-1H-1,2,4-triazol-3-yl)-2- methylpyrimidine-4-carboxamide

Step 1 Preparation of terf-butyl <rans-4-((3-(6-((4-fluoro-3-methoxybenzyl)carbamoyl)-2-

λ/-(4-Fluoro-3-methoxybenzyl)-2-methyl-6-(1/-/-1 ,2,4-trιazol-3-yl)pyrιmιdιne-4-carboxamιde (prepared as described in step 2 of the synthesis of rac-/V-(4-fluoro-3-methoxybenzyl)-6-(1 -(((2R ^* ,5S ^* )- 5-(hydroxymethyl)-1 ,4-dioxan-2-yl)methyl)-1H-1 ,2,4-tnazol-3-yl)-2-methylpyrimidine-4-carboxamide, Example 115) (702 mg, 2 05 mmol) and (/rans-4-((/ert-butoxycarbonyl)amιno)cyclohexyl)methyl 4- methylbenzenesulfonate (prepared as described in step 7 of the synthesis of λ/-(3-methoxybenzyl)-6- (2-(((frans)-4-amιnocyclohexyl)methyl)-2/-/-tetrazol-5-yl)- 2-methylpyrιmιdιne-4-carboxamιde, Example 5) (786 mg, 2 05 mmol) were stirred in acetonitrile (40 mL), and 1 ,8-dιazobιcyclo[5 4 0]undec-7ene (480 mg, 3 15 mmol) was subsequently added The reaction was heated at 75 ⁰ C overnight before cooling to room temperature and concentrating under reduced pressure The residue was purified by reverse phase HPLC using a 40% B to 60% B, 30 minutes (A = 0 1% TFA / water and B = 0 1% TFA / acetonitrile) to afford the title compound (230 mg, 20%) LC/MS (5%-95% CH ₃ CN/H ₂ O, 8 mm , 95% CH ₃ CN ₁ 2 mm ) 6 28 mm, m/z 554 (M+H)

Step 2 Preparation of λ/-(4-fluoro-3-methoxybenzyl)-6-(1-((/rans-4-amιnocvclohex yl)methyl)-1 H-1 ,2,4- trιazol-3-yl)-2-methylpyrιmιdιne-4-carboxamιcle

tert-Butyl /rans-4-((3-(6-((4-fluoro-3-methoxybenzyl)carbamoyl)-2-methy lpyrimidin-4-yl)-1 H- 1 ,2,4-trιazol-1 -yl)methyl)cyclohexylcarbamate (230 mg, 0 415 mmol) was dissolved in 1 1 TFA / dichloromethane (2 mL each), and the reaction was stirred at room temperature for an hour The reaction was then concentrated under reduced pressure, and the residue was dissolved in water The pH was adjusted to 8, and the product was extracted into ethyl acetate The organic layer was washed with water and saturated sodium chloride before drying over anhydrous sodium sulfate Filtration and evaporation of the solvent under reduced pressure afforded the title compound (120 mg, 64% yield) LC/MS (5%-95% CH ₃ CN/H ₂ O, 8 mm , 95% CH ₃ CN, 2 mm ) 4 28 mm, m/z 454 (M+H)

Example 117

/V-(4-Fluoro-3-methoxybenzyl)-2-methyl-6-(1-((<rans-4- (methylsulfonamido)cyclohexyl)methyl)-

1 HA ,2,4-triazol-3-yl)pyrimidine-4-carboxamιde

λ/-(4-Fluoro-3-methoxybenzyl)-6-(1-((/rans-4-amιnocyclohex yl)methyl)-1 H-1 ,2,4-tÏ€azol-3-yl)-2- methylpyrιmιdιne-4-carboxamιde (prepared as described in Example 1 16) (60 mg, 0 13 mmol) was dissolved in dichloromethane (2 mL) Triethylamine (26 8 mg, 0 265 mmol) and methanesulfonyl chloride (18 2 mg, 0 159 mmol) were subsequently added, and the reaction was continued overnight at room temperature The solvent was then removed under reduced pressure, and the residue was dissolved in ethyl acetate The organic layer was washed with water (3x), 1 N hydrochloric acid (2x), and saturated sodium chloride before drying over anhydrous sodium sulfate Filtration and evaporation of the solvent under reduced pressure afforded the title compound as an off-white solid (60 mg, 85% yield) LC/MS (5%-95% CH ₃ CN/H ₂ O, 8 mm , 95% CH ₃ CN, 2 mm ) 5 19 mm, m/z 532 (M+H) ¹ H NMR (400 MHz, DMSOd ₆ ) δ ppm 9 38 (t, 1 H), 8 69 (s, 1 H), 8 31 (s, 1 H), 7 03 - 7 20 (m, 2 H), 6 83 - 7 00 (m, 2 H), 4 40 - 4 52 (m, 2 H), 4 09 - 4 23 (m, 2 H), 3 80 (s, 3 H), 2 94 - 3 12 (m, 1 H), 2 86 (s, 3 H), 2 75 (s, 3 H), 1 68 - 1 99 (m, 3 H), 1 50 - 1 66 (m, 2 H), 0 90 - 1 29 (m, 4 H)

Example 118

W-(4-fluoro-3-methoxybenzyl)-6-(1-((ffans-4-acetamidocycl ohexyl)methyl)-1H-1 ,2,4-tπazol-3-yl)- 2-methylpyrimidine-4-carboxamide

λ/-(4-Fluoro-3-methoxybenzyl)-6-(1-((/raÏ€s-4-amιnocyclohe xyl)methyl)-1 /-/-1 ,2,4-trιazol-3-yl)-2- methylpyrιmιdιne-4-carboxamιde (prepared as described in Example 1 16) (60 mg, 0 13 mmol) was dissolved in dichloromethane (2 mL) Triethylamine (26 8 mg, 0 265 mmol) and acetyl chloride (12 5 mg, 0 159 mmol) were subsequently added, and the reaction was continued overnight at room temperature The solvent was then removed under reduced pressure, and the residue was dissolved in ethyl acetate The organic layer was washed with water (3x), 1 N hydrochloric acid (2x), and saturated sodium chloride before drying over anhydrous sodium sulfate Filtration and evaporation of the solvent under reduced pressure afforded a crude solid which was dissolved in acetonitrile (1 mL), water (0 5 mL), and DMF (0 5 mL) and purified by reverse phase HPLC using a 30 - 60% B, 30 minutes (A = 0 1 % TFA / water and B = 0 1% TFA / acetonitrile) The product-containing fractions were combined and concentrated under reduced pressure to afford the title compound as a white solid (14 mg, 17% yield) LC/MS (5%-95% CH ₃ CN/H ₂ O, 8 mm , 95% CH ₃ CN, 2 mm ) 5 16 mm, 496 (M+H) 1H NMR (400 MHz, DMSOd ₆ ) δ ppm 9 37 (t, 1 H), 8 66 (s, 1 H), 8 33 (s, 1 H), 7 54 - 7 68 (m, 1 H), 7 04 - 7 22 (m, 2 H), 6 76 - 6 97 (m, 1 H), 4 41 - 4 53 (m, 2 H), 4 04 - 4 18 (m, 2 H), 3 78 (s, 3 H), 3 38 - 3 53 (m, 1 H), 2 76 (s, 3 H), 1 73 - 1 89 (m, 3 H), 1 73 (s, 3 H), 1 40 - 1 63 (m, 2 H), 0 95 - 1 17 (m, 4 H)

Example 119

/V-(4-Fluoro-3-methoxybenzyl)-6-(1 -(((rans-4-(2-hydroxyacetamido)cyclohexyl)methyl)-1 W-1 ,2,4- triazol-3-yl)-2-methylpyrimidine-4-carboxamide

Step 1 Preparation of 2-(frans-4-((3-(6-((4-fluoro-3-methoxybenzyl)carbamoyl)-2-me thylpyrιmιdιn-4- yl)-1/-/-1 ,2,4-trιazol-1-yl)methyl)cvclohexylamιno)-2-oxoethyl acetate

λ/-(4-Fluoro- -methoxybenzyl)-6-(1 -((frans-X4-amιnocyclohex ^N yrl)meth ^λ yl)-1 H- 1 ,2,4-trιazol-3-yl)-2- methylpyrιmιdιne-4-carboxamιde (prepared as described in Example 116) (60 mg, 0 13 mmol) was dissolved in dichloromethane (2 mL) Triethylamine (26 8 mg, 0 265 mmol) and acetoxyacetyl chloride

(21 7 mg, 0 159 mmol) were subsequently added, and the reaction was continued overnight at room temperature The solvent was then removed under reduced pressure, and the residue was dissolved in ethyl acetate The organic layer was washed with water (3x), 1 N hydrochloric acid (2x), and saturated sodium chloride before drying over anhydrous sodium sulfate Filtration and evaporation of the solvent under reduced pressure afforded the title compound (56 mg, 76%) LC/MS (5%-95% CH ₃ CN/H ₂ O, 8 mm , 95% CH ₃ CN, 2 mm ) 5 26 mm, m/z 554 (M+H)

Step 2 Preparation of /V-(4-fluoro-3-methoxybenzyl)-6-(1-((frans-4-(2- hvdroxyacetamιdo)cvclohexyl)methyl)-1/-/-1 ,2,4-trιazol-3-yl)-2-methylpyrιmιdιne-4-carboxamιde

2-(frans-4-((3-(6-((4-Fluoro-3-methoxybenzyl)carbamoyl)-2-me thylpyrιmιdιn-4-yl)-1 /-/-1 ,2,4- trιazol-1-yl)methyl)cyclohexylamιno)-2-oxoethy! acetate (56 mg, 0 10 mmol) was dissolved in acetonitrile (3 mL), and 2 5 N NaOH (1 5 mL) was added The reaction was continued overnight at room temperature The pH was adjusted with concentrated hydrochloric acid, and the product was extracted into ethyl acetate (2x) The organic layer was washed with water and saturated sodium chloride before drying over anhydrous sodium sulfate Filtration and evaporation of the solvent under reduced pressure afforded the title compound as a solid (26 mg, 50% yield) LC/MS (5%-95% CH ₃ CN/H ₂ O, 8 mm , 95% CH ₃ CN, 2 mm ) 4 82 mm, m/z 512 (M+H) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9 36 (t, 1 H) ₁ 8 72 (s, 1 H), 8 31 (s, 1 H), 7 29 - 7 41 (m, 1 H), 6 97 - 7 25 (m, 2 H), 6 79 - 7 00 (m, 1 H), 5 21 - 5 40 (m, 1 H), 4 40 - 4 55 (m, 2 H), 4 06 - 4 23 (m, 2 H), 3 80 (s, 3 H), 3 65 - 3 75 (m, 2 H), 3 40 - 3 60 (m, 1 H), 2 77 (s, 3 H), 1 66 - 1 85 (m, 3 H), 1 52 - 1 63 (m, 2 H), 0 99 - 1 31 (m, 4 H)

Example 120

W-(4-Fluoro-3-(2-hydroxyethoxy)benzyl)-2-methyl-6-(1 -((<rans-4- (methylsulfonamido)cyclohexyl)methyl)-1/-/-1,2,4-triazol-3-y l)pyrιmidιne-4-carboxamide

Step 1 Preparation of λ/-(3-(2-(fert-butyldιphenylsιlyloxytethoxy)-4-fluorobenz yl)-6-cvano-2- methvlpvrιmιdιne-4-carboxamιde

A/-(4-Fluoro-3-(2-hydroxyethoxy)benzyl)-6-cyano-2-methylpyrÎ ¹mιdιne-4-carboxamιde (prepared as described in step 1 of the synthesis of λ/-(4-fluoro-3-(2-hydroxyethoxy)benzyl)-6-(2-(((frans-4- cyanocyclohexyl)methyl)-2/-/-tetrazol-5-yl)-2-methylpyrιmι dιne-4-carboxamιde, Example 27) (2 2 g, 6 7 mmol) and imidazole (453 mg, 6 7 mmol) were dissolved in dry DMF (36 mL) After cooling to 0 ⁰ C, tert-butyldiphenylsilyl chloride (2 2 g, 8 0 mmol) was added The reaction was permitted to warm to room temperature with stirring for 2 days The reaction was then diluted with ethyl acetate and washed with water (3x) and saturated sodium chloride (1X) before drying over anhydrous sodium sulfate Filtration and evaporation of the solvent under reduced pressure afforded the title compound as an oil (3 g, 79%) LC/MS (5%-95% CH ₃ CN/H ₂ O, 8 mm , 95% CH ₃ CN, 2 mm ) 8 48 mm, 591 (M+Na)

Step 2 Preparation of λ/-(3-(2-(ferf-butyldιphenylsιlyloxy)ethoxy)-4-fluorobenz yl)-2-methylpyrιmιdιne- 4,6-dιcarboxamιde

To a solution of λ/-(3-(2-(tert-butyldιphenylsιlyloxy)ethoxy)-4-fluorobenz yl)-6-cyano-2- methylpyrιmιdιne-4-carboxamιde (3 g, 5 mmol) in acetone (21 mL) was added 2 5 N sodium hydroxide (1 1 mL) followed by 30% hydrogen peroxide (3 15 mL) The reaction was stirred at room temperature for 1 h The reaction mixture was diluted with ethyl acetate, and the organic layer was washed with water and saturated sodium chloride before drying over anhydrous sodium sulfate Filtration and evaporation of the solvent under reduced pressure afforded the title compound as an oil (2 95 g, 100%) LC/MS (5%-95% CH ₃ CN/H ₂ O, 8 mm , 95% CH ₃ CN, 2 mm ) 8 00 mm, m/z 609 (M+Na)

Step 3 Preparation of /V-(3-(2-(terf-butyldιphenylsιlyloxy)ethoxy)-4-fluorobenzy l)-2-methyl-6-(1 /-/-1 ,2,4- trιazol-3-yl)pyrιmιdιne-4-carboxamιde

λ/-(3-(2-(fert-butyldιphenylsιlyloxy)ethoxy)-4-fluorobenz yl)-2-methylpyrιmιdιne-4,6- dicarboxamide (2 95 g, 5 0 mmol) was dissolved in dimethylformamide dimethylacetal (45 mL), and the mixture was refluxed for approximately 2 h The reaction was concentrated under reduced pressure, and the residue was dissolved in acetic acid (30 mL) Hydrazine hydrate (1 5 mL) was then added and the mixture was heated at 90 ⁰ C for 1 h After cooling to room temperature, the reaction was poured into water The pH was adjusted to 7, and the product was extracted into ethyl acetate The organic layer was washed with water and saturated sodium chloride before drying over anhydrous sodium sulfate Filtration and evaporation of the solvent under reduced pressure afforded the title compound (1 7 g) LC/MS (5%-95% CH ₃ CN/H ₂ O, 8 mm , 95% CH ₃ CN, 2 mm ) 7 88 mm, m/z 611 (M+H)

Step 4 Preparation of terf-butyl trans-4-((3-(6-((3-(2-(tert-butyldιphenylsιlyloxy)ethoxy)- 4- fluorobenzyl Carbamoyl )-2-methylpyrιmιdιn-4-yl)-1 H-1.2,4-trιazol-1 -yl)methyl)cyclohexylcarbamate

λ/-(3-(2-(<ert-Butyldιphenylsιlyloxy)ethoxy)-4-fluorob enzyl)-2-methyl-6-(1 H-1 ,2,4-trιa2θl-3- yl)pyrιmιdιne-4-carboxamιde (1 73 g, 2 83 mmol) and (trans-4-((tert- butoxycarbonyl)amιno)cyclohexyl)methyl 4-methylbenzenesulfonate (prepared as described in step 7 of the synthesis of λ/-(3-methoxybenzyl)-6-(2-(((/rans)-4-amιnocydohexyl)methy l)-2H-tetrazol-5-yl)-2- methylpyrιmιdιne-4-carboxamιde, Example 5) (1 19 g, 3 12 mmol) were stirred in acetonitrile (50 mL), and 1 ,8-dιazobιcyclo[5 4 0]undec-7ene (647 mg, 4 25 mmol) was subsequently added The reaction was heated at 75 ⁰ C overnight before cooling to room temperature and concentrating under reduced pressure The residue was purified by reverse phase HPLC using a 40% B to 60% B, 30 minutes (A = 0 1 % TFA / water and B = 0 1 % TFA / acetonitrile) to afford the title compound (300 mg, 13%) LC/MS (5%-95% CH ₃ CN/H ₂ O, 8 mm , 95% CH ₃ CN, 2 mm ) 9 04 mm, 822 (M+H)

Step 5 Preparation of /V-(3-(2-(te^butyldιphenylsιlyloxy)ethoxy)-4-fluorobenzyl) -6-(1 -((frans-4- amιnocvclohexyl)methyl)-1 H-1.2,4-trιazol-3-yl)-2-methylpyrιmιclιne-4-carboxamιcl e

tert-Butyl /rans-4-((3-(6-((3-(2-(tert-butyldιphenylsιlyloxy)ethoxy)- 4-fluorobenzyl)carbamoyl)-2- (300 mg, O 365 mmol) was dissolved in 1 1 TFA / dichloromethane (3 mL each), and the reaction was stirred at room temperature for 1 h The reaction was concentrated under reduced pressure, and the residue was dissolved in water The pH was adjusted to 8, and the product was extracted into ethyl acetate The organic layer was washed with water followed by saturated sodium chloride and concentrated to afford title compound (60 mg, 23%) LC/MS (5%-95% CH ₃ CN/H ₂ O, 8 mm , 95% CH ₃ CN, 2 mm ) 7 07 mm, 722 (M+H)

Step 6 Preparation of /V-(3-(2-(teft-butyldιphenylsιlyloxy)ethoxy)-4-fluorobenzy l)-2-methyl-6-(1 -((frans- 4-(methylsulfonamιdo)cvclohexyl)methyl)-1H-1 ,2,4-trιazol-3-yl)pyrιmιdιne-4-carboxamιde

λ/-(3-(2-(tert-Butyldιphenylsιlyloxy)ethoxy)-4-flÏ…oroben zyl)-6-(1 -((trans-4- amιnocyclohexyl)methyl)-1 /-/-1 ,2,4-trιazol-3-yl)-2-methylpyrιmιdιne-4-carboxamιde (60 mg, 0 0 83 mmol) was dissolved in dichloromethane (3 mL) Triethylamine (16 8 mg, 0 166 mmol) and methanesulfonyl chloride (1 1 4 mg, 0 0997 mmol) were subsequently added, and the reaction was continued overnight at room temperature The solvent was then removed under reduced pressure, and the residue was dissolved in ethyl acetate The organic layer was washed with water (3X) and saturated sodium chloride (1X) before drying over anhydrous sodium sulfate Filtration and evaporation of the solvent under reduced pressure afforded the title compound as a solid (60 mg, 90%) LC/MS (5%-95% CH ₃ CN/H ₂ O, 8 mm , 95% CH ₃ CN, 2 mm ) 7 97 mm, 800 (M+H)

Step 7 Preparation of /V-(4-fluoro-3-(2-hvdroxyethoxy)benzyl)-2-methyl-6-(1-((fran s-4- (methylsulfonamιdo)cvdohexyl)methyl)-1H-1.2,4-trιazol-3-yl )pyrιmιdιne-4-carboxamιde

λ/-(3-(2-(/ert-Butyldιphenylsιlyloxy)ethoxy)-4-fluorobenz yl)-2-methyl-6-(1-((fraÏ€s-4- (methylsulfonamιdo)cyclohexyl)methyl)-1/-/-1 ,2,4-trιazol-3-yl)pyrιmιdιne-4-carboxanrιιde (60 mg, 075 mmol) was dissolved in THF (2 mL) Tetrabutylammonium fluoride in THF (1 M) (19 6 mg, 0 075 mmol) was subsequently added and the mixture stirred for a couple of hours The reaction mixture was purified by reverse phase chromatography using an acetonitrile gradient in water (10% - 85% over 30 minutes) The product-containing fractions were combined and neutralized with 2 5 N sodium hydroxide The product was extracted into ethyl acetate, and the organic layer was washed with saturated sodium chloride before drying over anhydrous sodium sulfate Filtration and evaporation of the solvent under reduced pressure The residue was redissolved in ethyl acetate and washed with saturated ammonium chloride and saturated sodium chloride before drying over anhydrous sodium sulfate Filtration and evaporation of the solvent under reduced pressure afforded the title compound as a solid (5 mg, 10%) LC/MS (5%-95% CH ₃ CN/H ₂ O, 8 mm , 95% CH ₃ CN, 2 mm ) 4 57 mm, 562

(M+H) ¹ H NMR (400 MHz, DMSO-d ₆ ) 6 ppm 9 40 (t, 1 H), 8 70 (s, 1 H), 8 33 (s, 1 H), 7 58 - 7 76 (m,1 H), 7 05 - 7 23 (m, 2 H), 6 83 - 6 98 (m, 1 H), 4 82 (t, 1 H), 4 41 - 4 53 (m, 2 H), 4 08 - 4 21 (m, 2 H), 3 98 - 4 08 (m, 2 H), 3 61 - 3 78 (m, 2 H), 3 02 - 3 12 (m, 1 H), 2 87 (s, 3 H), 2 76 (s, 3 H), 1 77 - 1 92 (m, 3 H), 1 51 - 1 65 (m, 2 H), 0 98 - 1 33 (m, 4 H)

Example 121

W-(4-Fluoro-3-(2-hydroxyethoxy)benzyl)-6-(1-((frans-4-ace tamidocyclohexyl)methyl)-1H-1 ,2,4- triazol-3-yl)-2-methylpyrimidine-4-carboxamide

Step 1 Preparation of λ/-(4-fluoro-3-(2-hvdroxyethoxy)benzyl)-6-(carbamιmιdoyl) -2-methylpyrιmιdιne- 4-carboxamιde

λ/-(4-Fluoro-3-(2-hydroxyethoxy)benzyl)-6-cyano-2-methylpyr ιmιdιne-4-carboxamιde (prepared as described in step 1 of the synthesis of λ/-(4-fluoro-3-(2-hydroxyethoxy)benzyl)-6-(2-(((frans-4- cyanocyclohexyl)methyl)-2/-/-tetrazol-5-yl)-2-methylpyrιmι dιne-4-carboxamιde, Example 27) (700 mg, 2 12 mmol) was dissolved in absolute ethanol (20 mL) Hydrazine hydrate (2 33 g, 46 6 mmol) was added, and the reaction was refluxed for 3 h The reaction mixture was allowed to cool to room temperature The reaction was diluted with ethyl acetate and washed with water (3X) and saturated sodium chloride (1X) before drying over anhydrous sodium sulfate Filtration and evaporation of the solvent under reduced pressure afforded the title compound as an oil (300 mg, 39%) LC/MS (5%-95% CH ₃ CN/H ₂ O, 8 mm , 95% CH ₃ CN, 2 mm ) 3 19 mm , m/z 363 (M+H)

Step 2 Preparation of λ/-(4-fluoro-3-(2-hydroxyethoxy)benzyl)-2-methyl-6-(1 H-1.2,4-trιazol-3- yl)pyπmιdιne-4-carboxamιde

λ/-(4-Fluoro-3-(2-hydroxyethoxy)benzyl)-6-(carbamιmιdo yl)-2-methylpyrιmιdιne-4-carboxamιde

(300 mg, 0 83 mmol) was dissolved in formic acid (3 mL), and the reaction was refluxed overnight The reaction was then cooled and concentrated under reduced pressure The residue was partitioned between saturated sodium bicarbonate and ethyl acetate The layers were separated, and the organic layer was washed with saturated sodium bicarbonate and saturated sodium chloride before drying over anhydrous sodium sulfate Filtration and evaporation of the solvent under reduced pressure afforded the title compound as an oil (80 mg, 26%) LC/MS (5%-95% CH ₃ CN/H ₂ O, 8 mm , 95% CH ₃ CN, 2 mm ) 4 77 mm, m/z 373 (M+H)

Step 3 Preparation of (fraπs-4-amιnocyclohexyl)methyl 4-methylbenzenesulfonate

(frans-4-((^ert-Butoxycarbonyl)amιno)cyclohexyl)methyl 4-methylbenzenesυlfonate (prepared as described in step 7 of the synthesis of λ/-(3-methoxybenzyl)-6-(2-(((frans)-4- aminocyclohexyOmethyl^H-tetrazol-S-yl^-methylpyrimidine^-car boxamide, Example 5) (1 0 g, 2 6

mmol) was dissolved in 1 1 TFA / dichloromethane (5 mL each), and the reaction was stirred at room temperature for an hour The reaction was then concentrated under reduced pressure, and the residue was dissolved in water The pH was adjusted to 8, and the product was extracted into ethyl acetate The organic layer was washed with water followed by saturated sodium chloride, dried over anhydrous sodium sulfate, filtration and concentrated to afforded the title compound (450 mg, 61 % yield) LC/MS (5%-95% CH ₃ CN/H ₂ O, 8 mm , 95% CH ₃ CN, 2 mm ) 3 99 mm , m/z 284 (M+H)

Step 4 Preparation of (/rans^-acetamidocvclohexyOmethyl 4-methylbenzenesulfonate

(/rans-4-Amιnocyclohexyl)methyl 4-methylbenzenesulfonate (450 mg, 1 59 mmol) was dissolved in dichloromethane (10 mL) Triethylamine (321 mg, 3 18 mmol) and acetyl chloride (150 mg, 1 91 mmol) were subsequently added, and the reaction was continued overnight at room temperature The solvent was then removed under reduced pressure, and the residue was dissolved in ethyl acetate The organic layer was washed with water (3x), 1 N hydrochloric acid (2x), and saturated sodium chloride solution before drying over anhydrous sodium sulfate Filtration and evaporation of the solvent under reduced pressure afforded the title compound as an oil (450 mg) LC/MS (5%-95% CH ₃ CN/H ₂ O, 8 mm , 95% CH ₃ CN, 2 mm ) 5 23 mm, m/z 326 (M+H)

Step 5 Preparation of λ/-(4-fluoro-3-(2-hvdroxyethoxy)benzyl)-6-(1-((frans-4- acetamιdocvclohexyl)methyl)-1 /-/-1 ,2,4-trιazol-3-yl)-2-methylpyrιmιdιne-4-carboxamιde

λ/-(4-F!uoro-3-(2-hydroxyethoxy)benzyl)-2-methyl-6-(1 H-1 ,2,4-trιazol-3-yl)pyrιmιdιne-4- carboxamide (80 mg, 0 21 mmol) and ((?rans-4-acetamιdocyclohexyl)methyl 4- methylbenzenesulfonate (76 9 mg, 0 236 mmol) were stirred in acetonitrile (5 mL), and 1 ,8- dιazobιcyclo[5 4 0]undec-7ene (DBU) (49 1 mg, 0 322 mmol) was subsequently added The reaction was heated at 75 ⁰ C overnight before cooling to room temperature and diluting with ethyl acetate The organic layer was washed with water (3X) and saturated sodium chloride (1X) before drying over anhydrous sodium sulfate Filtration and evaporation of the solvent under reduced pressure afforded an oil which was purified by reverse phase HPLC using a 20% B to 60% B, 40 minutes (A = 0 1 % TFA / water and B = 0 1% TFA / acetonitrile) The product-containing fractions were combined, and the pH was made basic with 2 5 N sodium hydroxide The product was extracted into ethyl acetate, and the combined organic layer was washed with saturated sodium chloride before drying over anhydrous sodium sulfate Filtration and evaporation of the solvent under reduced pressure afforded the title compound (3 9 mg, 3 5%) LC/MS (5%-95% CH ₃ CN/H ₂ O, 8 mm , 95% CH ₃ CN, 2 mm ) 4 56 mm, m/z

326 (M+H) ¹ H NMR (400 MHz, DMSO-Cf ₆ ) δ ppm 9 39 (t, 1 H), 8 73 (s, 1 H) ₁ 8 32 (s, 1 H), 7 54 - 7 72 (m,1 H), 7 04 - 7 26 (m, 2 H), 6 84 - 6 96 (m, 1 H), 4 80 (t, 1 H), 4 41 - 4 54 (m, 2 H), 4 11 - 4 22 (m, 2 H), 3 96 - 4 09 (m, 2 H), 3 63 - 3 80 (m, 2 H), 3 33 - 3 52 (m, 1 H), 2 76 (s, 3 H), 1 78 - 2 05 (m, 3 H), 1 71 (s, 3 H), 1 48 - 1 65 (m, 2 H), 1 09 - 1 34 (m, 4 H)

Example 122

/V-(4-Fluoro-3-methoxybenzyl)-6-(5-((<rans-4-aminocycl ohexyl)methyl)-1 ,2,4-oxadiazol-3-yl)-2- methylpyrimidine-4-carboxamide

Step 1 Preparation of λ/-(4-fluoro-3-methoxybenzyl)-6-cvano-2-methylpyrιmιdιne -4-carboxamιde

A mixture of methyl 6-cyano-2-methylpyrιmιdιne-4-carboxylate (prepared as described in step 4 of the synthesis of λ/-(3-methoxybenzyl)-6-(2-(((<rans)-4-amιnocyclohexyl)m ethyl)-2/-/-tetrazol-5-yl)-2- methylpyrιmιdιne-4-carboxamιde, Example 5) (10 0 g, 56 4 mmol), 4-fluoro-3-methoxybenzylamιne hydrochloride (prepared as described in step 3 of the synthesis of λ/-(4-fluoro-3-methoxybenzyl)-6-(2- ((^ans^-aminocyclohexyOmethyl^H-tetrazol-S-yOpyπmidine^-car boxamide, Example 1 ) (13 5 g, 70 6 mmol), /V,λ/-dιιsopropylethylamιne (39 3 mL, 226 mmol), and methanol (56 4 mL) was heated to 35 °C for 1 h The mixture was concentrated and the residue was partitioned between ethyl acetate (500 mL) and 1 N hydrochloric acid (500 mL) The aqueous layer was extracted with ethyl acetate (2 x 250 mL) The combined organic layers were washed with saturated sodium bicarbonate solution (2 x 250 mL) followed by brine, dried over sodium sulfate, and concentrated The crude product was purified by silica gel chromatography (2/1 , heptane/ethyl acetate) to afford the title compound as a white solid (1 1 7 g) MS (ES+) m/z 301 (M+H)

Step 2 Preparation of λ/-(4-f1uoro-3-methoxybenzyl)-6-(carbamιmιdovO-2-methylpy rιmιdιne-4- carboxamide

λ/-(4-Fluoro-3-methoxybenzyl)-6-cyano-2-methylpyrιmιdÎ ¹ne-4-carboxamιde (1 0 g, 3 3 mmol) was dissolved in ethanol / water (20 mL / 5 mL) Hydroxylamine hydrochloride (255 mg, 3 66 mmol)

and sodium hydroxide (213 mg, 3 66 mmol) were subsequently added, and the reaction was heated at 75 ⁰ C for 2 hours After cooling to room temperature, the reaction was diluted with ethyl acetate and washed with water and saturated sodium chloride before drying over anhydrous sodium sulfate Filtration and evaporation of the solvent under reduced pressure afforded the title compound as an off- white solid (1 0 g, 90% yield) LC/MS (5%-95% CH ₃ CN/H ₂ O, 8 mm , 95% CH ₃ CN, 2 mm ) 4 65 mm, m/z 334 (M+H)

Step 3 Preparation of tert-butyl (4-(2-((((1Z)-amino(6-(((4-fluoro-3-methoxybenzyl)amιno)car bonyl)-2- methylpyrιmιdιn-4-yl)methylene)amιno)oxy)-2-oxoeth yl )cvclohexyl Carbamate

λ/^-fluoro-S-methoxybenzyO-θ^carbamimidoyO^-methylpynmidin e^-carboxamide (500 mg,

1 50 mmol), 2-(/rans-4-(tert-butoxycarbonyl)cyclohexyl)acetιc acid (386 mg, 1 50 mmol), N- hydroxybenzotnazole (230 mg, 1 50 mmol), and dnsopropyethylamine (582 mg, 4 50 mmol) were dissolved in acetonitrile (20 mL) and dimethylacetamide (2 mL) PS-carbodiimide resin (3 49 g, 4 50 mmol) was subsequently added, and the reaction was agitated at 40 °C overnight The reaction was filtered to remove the resin, and the resin was washed with dimethylformamide The filtrate was diluted with ethyl acetate, and the organic layer was washed with water and saturated sodium chloride before drying over anhydrous sodium sulfate Filtration and evaporation of the solvent under reduced pressure afforded the title compound as a white solid (700 mg, 82%) LC/MS (5%-95% CH ₃ CN/H ₂ O, 8 mm , 95% CH ₃ CN, 2 mm ) 6 23 mm, m/z 517 (M+H-f-butyl) Step 4 Preparation of fert-butyl (frans)-4-((3-(6-((4-fluoro-3-methoxybenzyl)carbamoyl)-2-

tert-Butyl (4-(2-((((12)-amιno(6-(((4-fluoro-3-methoxybenzyl)amιno)ca rbonyl)-2- methylpyrιmιdιn-4-yl)methylene)amιno}oxy)-2-oxoethyl)cyc lohexyl)carbamate (400 mg, 0 70 mmol) was dissolved in acetonitrile (8 mL) and dimethylacetamide (4 mL) MP-carbonate resin (732 mg, 2 1 mmol) was added, and the reaction was microwaved for 15 mm at 120 ⁰ C at 200W The reaction was filtered to remove the resin, and the filtrate was diluted with ethyl acetate The organic layer was washed with water (3X) and saturated sodium chloride (1X) before drying over anhydrous sodium sulfate Filtration and evaporation of the solvent under reduced pressure afforded the title compound

as a solid (388 mg, 95%) LC/MS (5%-95% CH ₃ CN/H ₂ O, 8 mm , 95% CH ₃ CN, 2 mm ) 6 76 mm, m/z 577 (M+Na)

Step 5 Preparation of /V-(4-fluoro-3-methoxybenzyl)-6-(5-((frans-4-aminocvclohexy0 methyl)-1 ,2,4- oxadiazol-3-yl)-2-methylpyrimidine-4-carboxarnide

fert-BÏ…tyl (frans)-4-((3-(6-((4-fluoro-3-methoxybenzyl)carbamoyl)-2-met hylpyrιmιdιn-4-yl)-1 ,2,4- oxadιazol-5-yl)methyl)cyclohexylcarbamate (370 mg, 0 67 mmol) was dissolved in a mixture of tnfluoroacetic acid (5 mL) and dtchloromethane (5 mL) The reaction mixture was stirred at room temperature for several hours before being concentrated under reduced pressure The residue was treated with saturated sodium bicarbonate, and the product was extracted into ethyl acetate The organic layer was washed with saturated sodium bicarbonate and saturated sodium chloride before drying over anhydrous sodium sulfate Filtration and evaporation of the solvent under reduced pressure afforded the title compound LC/MS (5%-95% CH ₃ CN/H ₂ O, 8 mm, 2 mm) 4 53 mm, m/z 455 (M+H)

Example 123

/V-(4-fluoro-3-methoxybenzyl)-6-(5-((frans-4-acetamidocyc lohexyl)methyl)-1,2,4-oxadiazol-3-yl)-

2-methylpyrimidine-4-carboxamide

/V-(4-Fluoro-3-methoxybenzyl)-6-(5-((/rans-4-amιnocyclohexy l)methyl)-1 ,2,4-oxadιazol-3-yl)-2- methylpyÏ€mιdιne-4-carboxamιde (prepared as described in Example 122) (10 mg, 0 022 mmol) was dissolved in dichloromethane (2 mL) Triethylamine (4 45 mg, 0 0440 mmol) and acetyl chloride (1 90 mg, 0 0242 mmol) were subsequently added, and the reaction was continued overnight at room temperature The solvent was then removed under reduced pressure, and the residue was dissolved in ethyl acetate The organic layer was washed with water (3x), 1 N hydrochloric acid (3x), and saturated sodium chloride solution before drying over anhydrous sodium sulfate Filtration and evaporation of the solvent under reduced pressure afforded the title compound (9 mg, 83% yield) LC/MS (5%-95% CH ₃ CN/H ₂ O, 8 mm , 95% CH ₃ CN, 2 mm ) 5 61 mm, m/z 497 (M+H) ¹ H NMR (400 MHz, DMSO-de) δ ppm 9 46 (t, 1 H), 8 28 (s, 1 H), 8 08 (s, 1 H), 7 49 - 7 67 (m,1 H), 7 02 - 7 19 (m, 1 H), 6 81 - 6 94 (m, 1 H), 4 39 - 4 52 (m, 2 H), 3 76 (s, 3 H), 3 31 - 3 50 (m, 1 H), 2 89 - 2 99 (m, 2 H), 2 78 (s, 3 H), 1 70 - 1 91 (m, 2 H), 1 71 (s, 3 H), 1 10- 1 28 (m, 7 H)

Example 124

W-(4-Fluoro-3-methoxybenzyl)-2-methyl-6-(5-((fraπs-4-(me thylsulfonamido)cyclohexyl)methyl)-

1 ,2,4-oxadιazol-3-yl)pyrimidine-4-carboxamide

λ/-(4-Fluoro-3-methoxybenzyl)-6-(5-((fraÏ€s-4-amιnocyclohe xyl)methyl)-1 ,2,4-oxadιazol-3-yl)-2- methylpyrιmιdιne-4-carboxamιde (prepared as described in Example 122) (15 mg, 0 033 mmol) was dissolved in dichloromethane (2 mL) Triethylamine (6 69 mg, 0 0661 mmol) and methanesulfonyl chloride (4 55 mg, 0 0397 mmol) were subsequently added, and the reaction was continued overnight at room temperature The solvent was then removed under reduced pressure, and the residue was dissolved in ethyl acetate The organic layer was washed with water (3x), 1 N hydrochloric acid (3x), and saturated sodium chloride solution before drying over anhydrous sodium sulfate Filtration and evaporation of the solvent under reduced pressure afforded the title compound (6 5 mg, 37% yield) LC/MS (5%-95% CH ₃ CN/H ₂ O, 8 mm , 95% CH ₃ CN, 2 mm ) 5 70 mm, m/z 534 (M+H) ¹ H NMR (400 MHz, DMSO-Cf ₆ ) δ ppm 9 47 (t, 1 H), 8 28 (s, 1 H), 7 55 - 7 72 (m,1 H), 7 02 - 7 21 (m, 2 H), 6 81 - 6 97 (m, 1 H), 4 40 - 4 52 (m, 2 H), 3 76 (s, 3 H), 2 99 - 3 08 (m, 1 H), 2 89 - 2 99 (m, 2 H), 2 85 (s, 3 H), 2 75 (s, 3 H), 1 62 - 2 02 (m, 2 H), 1 1 1 - 1 31 (m, 7 H)

Example 125

W-(4-Fluoro-3-methoxybenzyl)-6-(2-(3-hydroxypropyl)-2H-te trazol-5-yl)-2-methylpyrimidine-4- carboxamide

λ/-(4-Fluoro-3-methoxybenzyl)-2-methyl-6-(2/-/-tetrazol-5-y l)pyrιmιdιne-4-carboxamιde (prepared as described in step 2 of the synthesis of λ/-(4-fluoro-3-methoxybenzyl)-6-(2-(frans-4- aminocyclohexyOmethyO^H-tetrazol-S-yO^-methylpyÏ€midine^-car boxamide, Example 9) (355 mg, 1 03 mmol), 2-bromoethanol (194 mg, 1 55 mmol), triethylamine (400 μL) and dimethylacetamide (400 μL) were combined The resulting mixture was stirred at 130 °C for 2 h The mixture was cooled and purification was accomplished by reverse phase preparative high-pressure liquid chromatography The pure fractions were combined, extracted with ethyl acetate (2 x 20 mL), dried over magnesium sulfate, and concentrate to afford a residue that upon methanol trituration provided the title compound as a white solid (25 mg, 6 2%) LC/MS (10%-90% CH ₃ CN/H ₂ O, 8 mm) 4 94 mm, m/z 388 (M+H) ¹ H NMR (400 MHz, DMSO-CZ ₆ ) δ ppm 9 54 (m, 1 H), 8 42 (s, 1 H), 7 15 (td, J = 12 3, 8 4 Hz, 2 H), 6 92 (br s, 1 H), 4 87 (t, J = 6 8 Hz, 2 H), 4 69 (br s , 1 H), 4 51 (d, J = 5 9 Hz, 2 H), 3 82 (s, 3 H), 3 49 (d, J = 5 1 Hz, 2 H), 2 83 (s, 3 H), 2 1 1 (m, 2 H)

Example 126

W-(4-Fluoro-3-methoxybenzyl)-6-(2-((S)-3-hydroxy-2-methyl propyl)-2H-tetrazol-5-yl)-2- methylpyrimidine-4-carboxamide

λ/-(4-Fluoro-3-methoxybenzyl)-2-methyl-6-(2/-/-tetrazol-5-y l)pyrιmιdιne-4-carboxamιde

(prepared as described in step 2 of the synthesis of A/-(4-fluoro-3-methoxybenzyl)-6-(2-(frans-4- amιnocyclohexyl)methyl)-2/-/-tetrazol-5-yl)-2-methylpyrιmÎ ¹dιne-4-carboxamιde, Example 9) (104 mg, 0 303 mmol), (R)-3-bromo-2-methylpropan-1 -ol (46 4 mg, 0 303 mmol), triethylamine (400 μL) and dimethylacetamide (100 μL) were combined The resulting mixture was stirred at 130 ⁰ C for 2 h The mixture was cooled and purification was accomplished by reverse phase preparative high-pressure liquid chromatography The pure fractions were combined, extracted with ethyl acetate (2 x 20 mL), dried over magnesium sulfate, and concentrated to afford a residue that upon methanol trituration provided the title compound as a white solid (10 mg, 7 9%) MS (ES+) m/z 416 (M+H) ¹ H NMR (400 MHz, DMSO-Cf ₆ ) δ ppm 9 50 (s, 1 H), 8 42 (s, 1 H), 7 18 (dd, J = 8 4, 1 8 Hz, 1 H), 7 14 (dd, J = 1 1 7, 8 4 Hz, 1 H), 6 91 (br s, 1 H), 4 87 (dd, J = 13 5, 5 9 Hz, 1 H), 4 77 (t, J = 5 1 Hz ₁ 1 H), 4 65 (dd, J = 13 5, 8 1 , 1 H), 4 50 (d, J = 6 2 Hz, 2 H), 3 82 (s, 3 H), 3 38 (dt, J = 10 0, 5 1 Hz, 2 H), 2 83 (s, 3 H), 2 33 (s, 1 H), 0 86 (d, J = 7 0 Hz, 3H)

Example 127

/V-(4-Fluoro-3-methoxybenzyl)-6-(2-((/?)-3-hydroxy-2-meth ylpropyl)-2H-tetrazol-5-yl)-2- methylpyrimidine-4-carboxamide

λ/-(4-Fluoro-3-methoxybenzyl)-2-methyl-6-(2/-/-tetrazol-5-y l)pyrιmιdιne-4-carboxamιde (prepared as described in step 2 of the synthesis of λ/-(4-fluoro-3-methoxybenzyl)-6-(2-(frans-4- amιnocyclohexyl)methyl)-2/-/-tetrazol-5-yl)-2-methylpyrιmÎ ¹dιne-4-carboxamιde, Example 9) (104 mg, 0 303 mmol), (S)-3-bromo-2-methylpropan-1-ol (46 4 mg, 0 303 mmol), triethylamine (400 μL) and dimethylacetamide (100 μL) were combined The resulting mixture was stirred at 130 ⁰ C for 2 h The mixture was cooled and purification was accomplished by reverse phase preparative high-pressure liquid chromatography The pure fractions were combined, extracted with ethyl acetate (2 x 20 mL), dried over magnesium sulfate, and concentrated to afford a residue that upon methanol trituration provided the title compound as a white solid (10 mg, 7 9%) MS (ES+) m/z 416 (M+H) ¹ H NMR (400 MHz, DMSO-CZ ₆ ) δ ppm 9 51 (s, 1 H), 8 42 (s, 1 H), 7 15 (td, J = 1 1 7, 8 4, Hz, 2 H), 6 91 (br s, 1 H), 4 87 (dd, J = 13 5, 5 9 Hz, 1 H), 4 77 (t, J = 5 1 Hz, 1 H), 4 65 (dd, J = 13 5, 8 1 , 1 H), 4 50 (d, J = 6 2

Hz, 2 H), 3 82 (s, 3 H) ₁ 3 38 (dt, J = 10 0, 5 1 Hz, 2 H), 2 83 (s, 3 H), 2 33 (s, 1 H), 0 86 (d, J = 7 0 Hz, 3H)

Example 128

W-(4-Fluoro-3-methoxyben2yl)-6-(1-(((2S,5f?)-5-(hydroxyme thyl)-1 ,4-dioxan-2-yl)methyl)-1H- 1 ,2,3-triazol-4-yl)-2-methylpyrimidine-4-carboxamide

Step 1 Preparation of λ/-(4-fluoro-3-methoxybenzyl)-6-hvdroxy-2-methylpyrιmιdι ne-4-carboxamιde

Methyl 6-hydroxy-2-methylpyrιmιdιne-4-carboxy!ate (prepared as described in step 2 of the synthesis of λ/-(3-methoxybenzy1 )-6-(2-(((frans)-4-amιnocyclohexyl)methyl)-2/-/-tetrazol-5- y1 )-2- methylpyrιmιdιne-4-carboxamιde, Example 5) (10 0 g, 59 5 mmol), 4-fluoro-3-methoxybenzylamιne hydrochloride (prepared as described in step 3 of the synthesis of λ/-(4-fluoro-3- methoxybenzy1 )-6-(2- ((frans-4-amιnocyclohexyl)methyl)-2/-/-tetrazol-5-y1 )pyrιmιdιne-4-carboxamιde, Example 1 ) (13 7 g, 71 4 mmol, 1 20 equiv ), and λ/,/V-dιιsopropylethylamιne (26 mL, 149 mmol, 2 50 equiv ) were combined in methanol (120 mL) After stirring for 2 hours at reflux, the mixture was cooled to room temperature, and diluted with 1 0 N aqueous hydrochloric acid (150 mL) and water (100 mL) The resulting solid was collected by suction filtration, and the filter cake was washed with water (2 x 100 mL) and air dried for 1 h The solid was dried under vacuum at 40 ⁰ C to provide the title compound as a tan solid (13 9 g, 80%) MS (ES+) m/z 292 (M+H) ¹ H NMR (400 MHz, DMSO-CZ ₆ ) δ ppm 12 75 (1 H, br s ), 9 09 (1 H, t, J=6 2 Hz), 7 04 - 7 21 (2 H, m), 6 78 - 6 90 (1 H ₁ m), 6 67 (1 H ₁ s), 4 40 (2 H, d, J=6 2 Hz) ₁ 3 81 (3 H, s), 2 35 (3 H, s)

Step 2 Preparation of λ/-(4-fluoro-3-methoxybenzyl)-6-chloro-2-methylpyrιmιdιn e-4-carboxamιde

λ/-(4-Fluoro-3-methoxybenzyl)-6-hydroxy-2-methylpyrιmιdι ne-4-carboxamιde (10 0 g, 34 3 mmol) and W,λ/-dιmethylformamιde (0 66 mL, 8 58 mmol, 0 25 equiv ) were combined in tetrahydrofuran (137 mL) and the mixture was heated to 60 ⁰ C To the mixture was added dropwise oxalyl chloride (5 1 mL, 58 4 mmol, 1 70 equiv ) After stirring for 1 hour at 60 ⁰ C, the mixture was cooled to room temperature, water (25 mL) was added dropwise, the mixture was filtered through

Celiteâ„¢, the filter cake was washed with tetrahydrofuran (100 mL), and the filtrate was evaporated to one-third the original volume Water (150 mL) was added and the mixture was concentrated under reduced pressure to induce precipitation of the product The solid was collected by suction filtration, the filter cake was washed with water (3 x 100 mL), and the solid was air dried for 15 hours to provide the title compound as a red solid (9 50 g, 89%) MS (ES+) m/z 310 (M+H) ¹ H NMR (400 MHz,

DMSO-d ₆ ) δ ppm 9 50 ( 1 H, t, J=6 2 Hz), 7 88 (1 H, s), 7 07 - 7 19 (2 H, m), 6 82 - 6 92 (1 H, m), 4 45 (2 H ₁ d, J=6 4 Hz), 3 81 (3 H, s), 2 71 (3 H, s)

Step 3 Preparation of /V-(4-fluoro-3-methoxybenzyl)-2-methyl-6-(2-(trιmethylsιly l)ethvnyl)pyrιmιdιne-4- carboxamide

A solution of tetrahydrofuran (10 0 mL) and triethylamine (15 0 mL) was sparged with nitrogen gas for 5 minutes To this solution was added sequentially λ/-(4-fluoro-3-methoxybenzyl)-6-chloro-2- methylpyrιmιdιne-4-carboxamιde (3 00 g, 9 69 mmol), dιchlorobιs(trιphenylphosphιne)palladιum(ll) (68 mg, 97 μmol, 0 01 equiv ), triphenylphosphine (51 mg, 0 19 mmol, 0 02 equiv ), copper (I) iodide (37 mg, 0 19 mmol, 0 02 equiv ), and trimethylsilylacetylene (2 2 mL, 15 5 mmol, 1 60 equiv ) After stirring for 3 hours at 50 ⁰ C, the mixture was cooled to room temperature, diluted with ethyl acetate (100 mL), filtered, and concentrated under reduced pressure to give a red oil Purification by silica gel chromatography (gradient 5 1 heptane/EtOAc to 2 1 heptane/EtOAc) provided the title compound as a viscous, yellow oil (2 60 g, 72%) LC/MS (5%-100% CH ₃ CN/H ₂ O, 5 mm) 4 12 mm, m/z 372 (M+H) Step 4 Preparation of λ/-(4-fluoro-3-methoxybenzyl)-6-ethvnyl-2-methylpyrιmιdι ne-4-carboxamιde

To a solution of /V-(4-fluoro-3-methoxybenzyl)-2-methyl-6-(2-(trιmethylsιly l)ethynyl)pyrιmιdιne- 4-carboxamιde (2 60 g, 7 00 mmol) in tetrahydrofuran (20 mL) and water (10 mL) was added potassium fluoride (447 mg, 7 70 mmol, 1 10 equiv ) After stirring for 2 hours at room temperature, the mixture was concentrated under reduced pressure to remove the tetrahydrofuran, diluted with ethyl acetate (50 mL), and washed with pH 7 0 aqueous phosphate buffer The layers were separated and the aqueous layer was washed with ethyl acetate (1x) The organic layers were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound as a brown solid (2 06 g, >95%) LC/MS (5%-100% CH ₃ CN/H ₂ O, 5 mm) 3 24 mm, m/z 300 (M+H)

Step 5 Preparation of ((2S,5ff)-5-((trιfluoromethylsulfonyloxy)methyl)-1 ,4-dιoxan-2-yl)methγl 4- methylbenzenesulfonate

((2S,5S)-5-(Hydroxymethyl)-1 ,4-dιoxan-2-yl)methyl 4-methylbenzenesulfonate (prepared as described in step 1 of the synthesis of λ/-(3-methoxybenzy1 )-6-(2-(((2S,5f?)-5-(hydroxymethyl)-1 ,4- dιoxan-2-yl)methyl)-2/-/-tetrazol-5-yl)-2-methylpyrιmιdι ne-4-carboxamιde, Example 62) (5 0 g, 16 5 mmol) and pyridine (1 4 mL, 17 3, 1 05 equiv ) were combined in 70 mL dichloromethane, the resulting solution was cooled in a methanol/ice bath, and a solution of trifluoromethanesulfonic anhydride (2 9 mL, 17 3 mmol, 1 05 equiv ) in dichloromethane (10 mL) was added dropwise via cannula After warming to room temperature, the mixture was diluted with dichloromethane (150 mL) and treated with 1 0 N aqueous hydrochloric acid (40 mL) The layers were separated and the aqueous layer was washed with dichloromethane (3 x 10 mL) The organic layers were combined, washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound as a light yellow solid (6 89 g, >95%) Step 6 Preparation of ((2S,5S)-5-((4-(6-((4-fluoro-3-methoxybenzyl)carbamoyl)-2-me thylpyrιmιdιn-4- yl)-1 /-/-1.2,3-triazol-1 -yl)methyl)-1.4-dιoxan-2-yl)methyl 4-methylbenzenesulfonate

((2S,5f?)-5-((Trιfluoromethylsulfonyloxy)methyl)-1 ,4-dιoxan-2-yl)methyl 4- methylbenzenesulfonate (100 mg, 0 23 mmol) and sodium azide (16 mg, 0 24 mmol, 1 05 equiv ) were combined in tetrahydrofuran (0 8 mL), tert-butano! (0 4 mL), and water (0 4 mL) After stirring for 1 hour at room temperature, the reaction vessel was charged sequentially with λ/-(4-fluoro-3- methoxybenzyl)-6-ethynyl-2-methylpyrιmιdιne-4-carboxamιd e (69 mg, 0 23 mmol, 1 00 equiv ), 1 0 M aqueous sodium ascorbate (23 μL, 0 023 mmol, 0 10 equiv ), and 0 30 M aqueous copper (II) sulfate (17 μL, 0 005 mmol, 0 02 equiv ) After stirring for 15 hours at room temperature, the mixture was diluted with ethyl acetate and washed with 50% aqueous sodium chloride The layers were separated and the aqueous layer was washed with ethyl acetate (3x) The organic layers were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure to give a dark, orange oil Purification by silica gel chromatography (gradient 1 1 heptane/EtOAc to 100% EtOAc) provided the title compound as a white solid (142 mg, >95%) LC/MS (10%-90% CH ₃ CN/H ₂ O, 5 mm) 3 07 mm, m/z 627 (M+H)

Step 7 Preparation of λ/-(4-fluoro-3-methoxybenzyl)-6-(1 -(((2S.5R)-5-(hvdroxymethyl)-1 ,4-dιoxan-2- v0methyl)-1 /-/-1 ,2,3-trιazol-4-yl)-2-methylpyrιmιdιne-4-carboxamιde

((2S,5S)-5-((4-(6-((4-Fluoro-3-methoxybenzyl Carbamoyl )-2-methylpyrιmιdιn-4-yl)-1 H-1 , 2, 3- trιazol-1 -yl)methyl)-1 ,4-dιoxan-2-yl)methyl 4-methylbenzenesulfonate (75 mg, 0 12 mmol) and tetrabutylammonium acetate (40 mg, 0 13 mmol, 1 10 equiv ) were combined in dimethylformamide (1 0 mL) After stirring for 1 hour at 65 ⁰ C, the mixture was cooled to room temperature, and the reaction vessel was charged sequentially with water (250 //L) and 1 0 N aqueous sodium hydroxide (144 μL, 0 144 mmol, 1 20 equiv ) After stirring for 20 minutes at room temperature, the mixture was diluted with ethyl acetate (10 mL) and washed with 50% aqueous sodium chloride (2 x 3 mL) The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give an orange oil Purification by silica gel chromatography (gradient 100% EtOAc to 5% MeOH/EtOAc) provided the title compound as a white solid (40 mg, 71 %) LC/MS (10%-90% CH ₃ CN/H ₂ O, 5 mm) 2 01 mm, m/z 473 (M+H) ¹ H NMR (400 MHz, CD ₃ OD) 6 ppm 8 65 (1 H, s), 8 47 (1 H, s), 7 13 (1 H, dd, J=8 3, 1 8 Hz), 7 03 (1 H, dd, J= 1 1 4, 8 3 Hz), 6 86 - 6 97 (1 H, m), 4 60 - 4 70 (1 H, m), 4 58 (3 H, s), 4 45 - 4 55 (1 H, m), 3 92 - 4 01 (2 H, m), 3 88 (1 H, d, J=11 1 Hz) ₁ 3 86 (3 H, s), 3 51 - 3 59 (1 H, m), 3 47 - 3 51 (2 H, m), 3 41 - 3 48 (1 H, m), 3 33 - 3 41 (1 H, m), 2 77 (3 H, s)

Example 129

/V-(4-Fluoro-3-methoxybenzyl)-6-(1-(((S)-4-acetylmorpholi n-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-2- methylpyrimidine-4-carboxamide

Step 1 Preparation of methyl 2-methyl-6-(2-(trιmethylsιlyl)ethvnyl)pyrιmιdιne-4-carb oxylate

The title compound was prepared in a similar manner to λ/-(4-fluoro-3-methoxybenzyl)-2- methyl-6-(2-(trιmethylsιlyl)ethynyl)pyrιmιdιne-4-carbox amιde (step 3, Example 128) by reaction of methyl 6-chloro-2-methylpyrιmιdιne-4-carboxylate (prepared as described in step 3 of the synthesis of λ/-(3-methoxybenzy1 )-6-(2-(((frans)-4-amιnocyclohexyl)methyl)-2/-/-tetrazol-5- y1 )-2-methylpyrιmιdιne-

4-carboxamιde, Example 5) (1 00 g, 5 36 mmol), dιchlorobιs(trιphenylphosphιne)palladιum(!l) (38 mg, 54 μmol, 0 01 equiv ), triphenylphosphine (28 mg, 0 1 1 mmol, 0 02 equiv ), copper (I) iodide (20 mg, 0 11 mmol, 0 02 equiv ), and tÏ€methylsilylacetylene (1 2 mL, 8 50 mmol, 1 60 equiv ) Purification by silica gel chromatography (gradient 3 1 heptane/EtOAc to 2 1 heptane/EtOAc) provided the title compound as a tan solid (1 15 g, 86%) LC/MS (10%-90% CH ₃ CN/H ₂ O, 5 mm) 2 91 mm, m/z 249 (M+H)

Step 2 Preparation of methyl 6-ethvnyl-2-methylpyrιmιdιne-4-carboxylate

The title compound was prepared in a similar manner to λ/-(4-fluoro-3-methoxybenzyl)-6- ethynyl-2-methylpyrιmιdιne-4-carboxamιde (step 4, Example 128) by reaction of methyl 2-methyl-6-(2- (trιmethylsιlyl)ethynyl)pyrιmιdιne-4-carboxylate (100 mg, 0 40 mmol) and potassium fluoride (26 mg, 0 44 mmol, 1 10 equiv ) to afford the title compound as an orangish-brown solid (70 mg, >95%) LC/MS (10%-90% CH ₃ CN/H ₂ O, 5 mm) 1 20 mm, m/z 177 (M+H)

Step 3 Preparation of (9H-fluoren-9-yl)methyl (S)-2-(hvdroxymethyl)morpholιne-4-carboxylate

terf-Butyl (S)-2-(hydroxymethyl)morpholιne-4-carboxylate (1 0 g, 4 60 mmol) and 4 0 M hydrochloric acid in 1 ,4-dιoxane (50 mL, 20 0 mmol, 4 35 equiv ) were combined and the solution was stirred at room temperature for 30 minutes The solvent was evaporated and to the crude residue was added sequentially tetrahydrofuran (10 mL), water (5 0 mL), sodium bicarbonate (1 16 g, 13 8 mmol, 3 0 equiv ), and 9-fluorenylmethyl chloroformate (1 19 g, 4 60 mmol, 1 00 equiv ) After stirring for 15 h at room temperature, the tetrahydrofuran was evaporated under reduced pressure and the mixture was diluted with ethyl acetate (25 mL) The layers were separated and the aqueous layer was washed with ethyl acetate (3x) The organic layers were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound as a white solid (1 56 g, >95%)

Step 4 Preparation of (9H-fluoren-9-yl)methyl (S)-2-((trιfluoromethylsulfonyloxy)methyl)morpholιne-4- carboxylate

The title compound was prepared in a similar manner to ((2S,5R)-5- ((trιfluoromethylsulfonyloxy)methyl)-1 ,4-dιoxan-2-yl)methyl 4-methylbenzenesulfonate (step 5,

Example 128) by reaction of (9H-fluoren-9-yl)methyl (S)-2-(hydroxymethyl)morpholιne-4-carboxylate (1 25 g, 3 68 mmol), pyridine (313 μL, 3 87 mmol, 1 05 equiv ), and trifluoromethanesulfonic anhydride (0 65 mL, 3 87 mmol, 1 05 equiv ) to afford the title compound as a light tan solid (1 68 g, >95%)

Step 5 Preparation of methyl 6-(1-(((S)-4-(((9/-/-fluoren-9-yl)methoxy)carbonyl)morpholι n-2-yl)methyl)- 1 H- 1.2.3-trιazol-4-yl)-2-methylpyrιmιdιne-4-carboxylate

The title compound was prepared in a similar manner to ((2S,5S)-5-((4-(6-((4-fluoro-3- methoxybenzyl)carbamoyl)-2-methylpyrimidin-4-yl)-1 H-1 ,2,3-triazol-1-yl)methyl)-1 ,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate (step 6, Example 128) by reaction of (9H-fluoren-9-y!)methyl (S)-2- ((tÏ€fluoromethylsulfonyloxy)methyl)morpholιne-4-carboxylat e (140 mg, 0 30 mmol), sodium azide (20 mg, 0 31 mmol, 1 05 equiv ), methyl 6-ethynyl-2-methylpyrιmιdιne-4-carboxylate (52 mg, 0 30 mmol, 1 00 equiv ), 1 0 M aqueous sodium ascorbate (30 μL, 0 030 mmol, 0 10 equiv ), and 0 30 M aqueous copper (II) sulfate (20 μL, 0 006 mmol, 0 02 equiv ) Purification by silica gel chromatography (gradient 1 1 heptane/EtOAc to 100% EtOAc) provided the title compound as a tan solid (1 13 mg, 71 %) LC/MS (10%-90% CH ₃ CN/H ₂ O, 5 mm) 2 99 mm, m/z 541 (M+H)

Step 6 Preparation of λ/-(4-fluoro-3-methoxybenzyl)-6-(1-(((S)-4-acetylmorpholιn -2-yl)methyl)-1 H- 1.2,3-trιazol-4-yl)-2-methylpyrιmιdιne-4-carboxamιde

Methyl 6-(1-(((S)-4-(((9/-/-fluoren-9-yl)methoxy)carbonyl)morpholι n-2-yl)methyl)-1 H-1 , 2,3- trιazol-4-yl)-2-methylpyrιmιdιne-4-carboxylate (49 mg, 91 μmol), 4-fluoro-3-methoxybenzylamιne hydrochloride (prepared as described in step 3 of the synthesis of λ/-(4-fluoro-3- methoxybenzy1 )-6-(2- ((/raπs^-aminocyclohexyOmethyO^H-tetrazol-S-y^pyπmidine^-c arboxamide, Example 1 ) (52 mg,

0 27 mmol, 3 00 equiv ), and triethylamine (51 μL, O 36 mmol, 4 OO equiv ) were combined in N ₁ N- dimethylacetamide (1 O mL) After stirring for 1 hour at 65 ⁰ C, the mixture was cooled to room temperature, and to the mixture was added sequentially dichloromethane (1 0 mL), triethylamine (76 μL, 0 54 mmol, 6 00 equiv ), and acetyl chloride (32 μL, 0 45 mmol, 5 00 equiv ) After stirring for 1 hour at room temperature, the mixture was concentrated under reduced pressure, diluted with ethyl acetate {5 mL), and washed with pH 7 0 aqueous phosphate buffer (2 mL) The layers were separated and the aqueous layer was washed with ethyl acetate (3 x 1 mL) The organic layers were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure Partial purification by silica gel chromatography (gradient 1 2 heptane/EtOAc to 100% EtOAc to 5% MeOH/EtOAc) provided an oily residue, which was further purified by reverse-phase HPLC to afford the title compound as a white solid (7 mg, 16%) MS (ES+) m/z 484 (M+H) ¹ H NMR (400 MHz, DMSO-CZ ₆ ) δ 9 39 (1 H, t, J=5 9 Hz), 8 80 (1 H, d, J=11 9 Hz), 8 34 (1 H, s), 7 17 - 7 21 (1 H, m), 7 14 (1 H, dd, J= 1 1 7, 8 6 Hz), 6 81 - 6 98 (1 H, m), 4 63 - 4 77 (1 H, m), 4 54 - 4 63 (1 H, m), 4 49 (2 H, d, J=6 2 Hz), 4 21 (1 H, dd, J=86 2, 13 0 Hz), 3 85 - 3 98 (2 H ₁ m), 3 82 (3 H, s), 3 39 - 3 71 (1 H, m), 2 92 - 3 23 (1 H, m), 2 75 (3 H, s), 2 52 - 2 73 (1 H, m), 2 02 (3 H, d, J= 1 1 3 Hz)

Example 130

^-(a-MethoxybenzyO^-methyl-e^i-IISJ-morpholin^-ylmethyO-I W-i ^.a-triazoM-yOpyrimidine^- carboxamide

Step 1 Preparation of 6-(1-(((S)-4-(((9/-/-fluoren-9-yl)methoxy)carbonyl)morpholι n-2-yl)methyl)-1 H- 1 ,2,3-trιazol-4-yl)-2-methylpyrιmιdιne-4-carboxylιc acid

Methyl 2-methy!-6-(2-(trιmethylsιlyl)ethynyl)pyrιmιdιne-4-carb oxylate (prepared as described in step 4 of the synthesis of λ/-(4-fluoro-3-methoxybenzyl)-6-(1-(((S)-4-acetylmorpholιn -2-yl)methyl)-1H- 1 ,2,3-trιazol-4-yl)-2-methylpyrιmιdιne-4-carboxamιde, Example 129) (200 mg, 0 81 mmol) was dissolved in tetrahydrofuran (0 90 mL), tert-bυtanol (0 90 mL), and water (0 90 mL), and to this mixture was added 2 0 N aqueous lithium hydroxide (423 μL, 0 85 mmol, 1 05 equiv ) In a separate reaction vessel, (9/-/-fluoren-9-yl)methyl (S)-2-((trιfluoromethylsulfonyloxy)methyl)morpholιne-4-car boxylate (prepared as described in step 4 of the synthesis of λ/-(4-fluoro-3-methoxybenzyl)-6-(1 -(((S)-4- acetylmorpholιn-2-yl)methyl)-1/-M ,2,3-trιazol-4-yl)-2-methylpyrιmιdιne-4-carboxamιde, Example 129)

(380 mg, 0 81 mmol, 1 00 equiv ) and sodium azide (55 mg, 0 85 mmol, 1 05 equiv ) were combined in tetrahydrofuran (0 90 mL), tert-butanol (0 90 mL), and water (0 90 mL) After stirring for 2 hours at room temperature, both crude reaction mixtures were combined into a single reaction vessel To this mixture was added sequentially 1 0 M aqueous sodium ascorbate (81 μL, 0 081 mmol, 0 10 equiv ), and 0 30 M aqueous copper (II) sulfate (54 μL, 0 016 mmol, 0 02 equiv ) After stirring for 15 hours at room temperature, the mixture was diluted with ethyl acetate (4 mL) and washed with 2 0 N aqueous sodium hydroxide (0 5 mL) The layers were separated, the aqueous layer was acidified with 1 0 N aqueous hydrochloric acid (1 2 mL), and extracted with ethyl acetate (3 x 2 mL) and dichloromethane (3 x 2 mL) The organic layers were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure to provide the crude title compound as a purple solid (424 mg) that was used in subsequent reactions without further purification LC/MS (10%-90% CH ₃ CN/H ₂ O, 5 mm) 2 60 mm, m/z 527 (M+H)

Step 2 Preparation of (2S)-(9/-/-fluoren-9-yl)methyl 2-((4-(6-((3-methoxybenzyl)carbamoyl)-2- methylpyrιmιdιn-4-yl)-1 /-/-1 ,2,3-trιazol-1-yl)methyl)morpholιne-4-carboxylate

6-(1-(((S)-4-(((9H-Fluoren-9-yl)methoxy)carbonyl)morpholιn- 2-yl)methyl)-1 H-1 ,2,3-trιazol-4-yl)- 2-methylpyrιmιdιne-4-carboxylιc acid (200 mg, 0 38 mmol), 3-methoxybenzylamιne (54 μL, 0 42 mmol, 1 10 equiv ), /V,W-diisopropylethylamine (79 μL, 0 42 mmol, 1 20 equiv ), and O-(7-azabenzotÏ€azol-1- yl)-λ/,λ/,/\r,λ/'-tetramethyluronιum hexafluorophosphate (188 mg, 0 49 mmol, 1 30 equiv ) were combined in λ/,λ/-dιmethylformamιde (2 5 mL) After stirring for 15 hours at room temperature, the mixture was diluted with ethyl acetate (10 mL), and washed with pH 7 0 aqueous phosphate buffer (3 mL) The layers were separated and the aqueous layer was washed with ethyl acetate (3 x 2 mL) The organic layers were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure to give an oily residue Purification by silica gel chromatography (gradient 1 1 heptane/EtOAc to 100% EtOAc) provided the title compound as a white solid (192 mg, 78%) LC/MS (10%-90% CH ₃ CN/H ₂ O, 5 mm) 3 43 mm, m/z 646 (M+H)

Step 3 Preparation of /V-(3-methoxybenzyl)-2-methyl-6-(1-((S)-morpholιn-2-ylmethy l)-1 H-1 ,2,3-trιazol- 4-vQpyrιmιdιne-4-carboxamtde

(2SH9H-Fluoren-9-yl)methyl 2-((4-(6-((3-methoxybenzyl)carbamoyl)-2-methylpyrιmιdιn-4 -yl)- 1 H-1 ,2,3-trιazol-1 -y!)methyl)morpholιne-4-carboxylate (192 mg, 0 30 mmol) and piperidine (60 μL,

0 60 mmol, 2 0 equiv ) were combined in λ/,λ/-dιmethylformamιde (1 2 mL) After stirring for 5 minutes at room temperature, the mixture was concentrated under reduced pressure to afford the crude title compound as an oil that was used in subsequent reactions without further purification LC/MS (10%- 90% CH ₃ CN/H ₂ O, 5 mm) 1 62 mm, m/z 424 (M+H)

Example 131

W-(3-Methoxybenzyl)-6-(1 -(((S)-4-acetylmorpholin-2-yl)methyl)-1 H-1 ,2,3-triazol-4-yl)-2- methylpyrJmidine-4-carboxamide

λ/-(3-Methoxybenzyl)-2-methyl-6-(1-((S)-morpholιn-2-ylmeth yl)-1 H-1 ,2,3-trιazol-4- yl)pyrιmιdιne-4-carboxamιde (prepared as described in Example 130) (63 mg, 0 15 mmol), triethylamine (83 μL, 0 60 mmol, 4 00 equiv ), and acetyl chloride (32 μL, 0 45 mmol, 3 00 equiv ) were combined in dichloromethane (1 5 mL) After stirring for 1 hour at room temperature, methanol (0 5 mL) was added and the mixture was concentrated under reduced pressure to give a salty slurry Purification by silica gel chromatography (gradient 100% EtOAc to 10% MeOH/EtOAc) provided the title compound as an off-white foam (41 mg, 60%) MS (ES+) m/z 466 (M+H) ¹ H NMR (400 MHz, DMSO-d _β ) (J 9 38 (1 H, t, J=6 3 Hz), 8 80 (1 H, d, J=M 3 Hz), 8 34 (1 H ₁ s), 7 24 (1 H, t, J=Q 1 Hz), 6 89 - 6 98 (2 H, m), 6 82 (1 H, dd, J=B 3, 1 9 Hz), 4 65 - 4 79 (1 H, m), 4 52 - 4 64 (1 H, m), 4 50 (2 H, d, J=Q 2 Hz), 4 21 (1 H, dd, J=86 1 , 12 7 Hz), 3 77 - 3 99 (3 H, m), 3 74 (3 H, s), 3 65 (1 H, d, J=14 3 Hz), 3 33 - 3 51 (1 H, m), 2 94 - 3 21 (1 H ₁ m), 2 75 (3 H, s), 2 02 (3 H, d, J=1 1 5 Hz)

Example 132

N-(3-Methoxybenzyl)-2-methyl-6-(1 -(((R)-4-(methylsulfonyl)morpholin-2-yl)methyl)-1 H-1 ,2,3- triazol-4-y!)pyrιmidine-4-carboxamide

The title compound was prepared in a similar manner to λ/-(3-methoxybenzyl)-6-(1-(((S)-4- acetylmorpholιn-2-yl)methyl)-1 H-1 ,2,3-trιazol-4-yl)-2-methylpyrιmιdιne-4-carboxamιde (Example 131 ) by reaction of λ/-(3-methoxybenzyl)-2-methyl-6-(1-((S)-morpholιn-2-ylmeth yl)-1 H-1 ,2, 3-trιazol-4- yl)pyÏ€mιdιne-4-carboxamιde (prepared as described in Example 130) (63 mg, 0 15 mmol), triethylamine (83 μL, 0 60 mmol, 4 00 equiv ), and methanesulfonyl chloride (34 μL, 0 45 mmol, 3 00 equiv ) to afford the title compound as an off-white foam (48 mg, 65%) MS (ES+) m/z 502 (M+H) ¹ H NMR (400 MHz, DMSO-Cf ₆ ) δ 9 38 (1 H, t, J=6 4 Hz), 8 84 (1 H, s), 8 34 (1 H, s), 7 24 (1 H, t, J=8 1 Hz), 6 88 - 6 98 (2 H, m), 6 82 (1 H, dd, J=Q 2, 2 0 Hz), 4 68 - 4 76 (1 H, m), 4 55 - 4 65 (1 H, m), 4 50

(2 H, d, J=6 2 Hz), 3 98 - 4 08 (1 H ₁ m), 3 95 (1 H, d, J=11 0 Hz), 3 74 (3 H, s), 3 48 - 3 63 (2 H, m), 3 32 - 3 40 (1 H, m), 2 92 (3 H, s), 2 80 - 2 90 (1 H, m), 2 75 (3 H, s), 2 68 (1 H, dd, .7=1 1 4, 10 2 Hz)

Example 133

W-(3-Methoxybenzyl)-6-(1 -(((2S,5R)-5-(hydroxymethyl)-1 ,4-dioxan-2-yl)methyl)-1 W-1 ,2,3-triazol-4- yl)-2-methylpyrimidine-4-carboxamide

Step 1 Preparation of methyl 2-methyl-6-(1-(((2S.5S)-5-((tosyloxy)methyl)-1 ,4-dιoxan-2-yl)methyl)-1 H- 1.2.3-trιazol-4-yl)pyrιmιdιne-4-carboxylate

Methyl 2-methyl-6-(2-(trιmethylsιlyl)ethynyl)pyrιmιdιne-4-carb oxylate (prepared as described in step 4 of the synthesis of /V-(4-fluoro-3-methoxybenzyl)-6-(1-(((S)-4-acetylmorpholin-2 -yl)methyl)-1 H- 1 ,2,3-trιazol-4-yl)-2-methylpyrιmιdιne-4-carboxamιde, Example 129) (30 mg, 0 12 mmol) was dissolved in tetrahydrofuran (0 20 mL), terf-butanol (0 20 mL), and water (0 20 mL), and to this mixture was added potassium fluoride (7 mg, 0 12 mmol, 1 00 equiv ) In a separate reaction vessel, ((2S,5f?)-5- ((trιfluoromethy!sulfonyloxy)methyl)-1 ,4-dιoxan-2-yl)methyl 4-methylbenzenesulfonate (prepared as described in step 5 of the synthesis of /V-(4-fluoro-3-methoxybenzyl)-6-(1 -(((2S,5R)-5-(hydroxymethyl)- 1 ,4-dιoxan-2-yl)methyl)-1 H- 1 ,2,3-trιazol-4-yl)-2-methylpyrιmιdιne-4-carboxamιde, Example 128) (50 mg, 0 12 mmol, 1 00 equiv ) and sodium azide (8 mg, 0 12 mmol, 1 00 equiv ) were combined in tetrahydrofuran (0 2 mL), tert-butanol (0 2 mL), and water (0 2 mL) After stirring for 1 hour at room temperature, both crude reaction mixtures were combined into a single reaction vessel To this mixture was added sequentially 1 0 M aqueous sodium ascorbate (12 μt, 0 012 mmol, 0 10 equiv ), and 0 30 M aqueous copper (II) sulfate (8 μL, 0 002 mmol, 0 02 equiv ) After stirring for 15 hours at room temperature, the mixture was diluted with ethyl acetate (4 mL) and washed with saturated aqueous sodium chloride (1 mL) The layers were separated and the aqueous layer was washed with ethyl acetate (2 mL) The organic layers were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure to provide an orange oil Purification by silica gel chromatography (gradient 1 1 heptane/EtOAc to 100% EtOAc) provided the title compound as a yellow solid (59 mg, >95%) LC/MS (10%-90% CH ₃ CN/H ₂ O, 5 mm) 2 50 mm, m/z 504 (M+H)

Step 2 Preparation of 2-methyl-6-(1-(((2S,5S)-5-(((osyloxy)methyl)-1 ,4-dιoxan-2-yl)methyl)-1H-1 , 2, 3- triazol^-vDpyrimidine^-carboxylic acid

Methyl 2-methyl-6-(1-(((2S,5S)-5-((tosyloxy)methyl)-1 ,4-dιoxan-2-yl)methy!)-1 H-1 ,2,3-trιazol-4- yl)pyrιmιdιne-4-carboxy!ate (59 mg, 0 12 mmol) was dissolved in tetrahydrofuran (0 80 mL), and water (0 40 mL), and to this mixture was added 2 0 N aqueous lithium hydroxide (65 μL, 0 13 mmol, 1 08 equiv ) After stirring for 5 minutes at room temperature, the solution was neutralized with 1 0 N aqueous hydrochloric acid (130 μL, 0 13 mmol, 1 08 equiv ) The mixture was concentrated under reduced pressure, the residue was dissolved in ethyl acetate (4 mL) and methanol (2 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to afford the crude title compound as an orange solid (57 mg) that was used in subsequent reactions without further purification LC/MS (10%-90% CH ₃ CN/H ₂ O, 5 mm) 2 13 mm, m/z 490 (M+H)

Step 3 Preparation of ((2S,5S)-5-((4-(6-((3-methoxybenzyl)carbamoyl)-2-methylpyrι mιdιn-4-yl)-1 /-/- 1 ,2,3-trιazol-1 -yl)methyl)-1 ,4-dιoxan-2-yl)methyl 4-methylbenzenesulfonate

2-Methyl-6-(1 -(((2S,5S)-5-((tosyloxy)methyl)-1 ,4-dιoxan-2-yl)methyl)-1 H-1 ,2,3-trιazol-4- yl)pyrιmιdιne-4-carboxylιc acid (108 mg, 0 22 mmol), 3-methoxybenzylamιne (30 μL, 0 23 mmol, 1 05 equiv ), λ/,λ/-dιιsopropylethylamιne (40 μL, 0 23 mmol, 1 05 equiv ), and O-(7-azabenzotrιazol-1-yl)- λ/,λ/,λ/',/V-tetramethyluronιum hexafluorophosphate (88 mg, 0 23 mmol, 1 05 equiv ) were combined in λ/,λ/-dιmethylformamιde (1 5 mL) After stirring for 15 hours at room temperature, the mixture was diluted with ethyl acetate (10 mL) and washed with 10% aqueous sodium bisulfate (3 mL) The layers were separated and the aqueous layer was washed with ethyl acetate (3 x 2 mL) The organic layers were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure to give an oily residue Purification by silica gel chromatography (gradient 1 2 heptane/EtOAc to 100% EtOAc to 10% MeOH/EtOAc) provided the title compound as a white solid (131 mg, >95%) LC/MS (10%- 90% CH ₃ CN/H ₂ O, 5 mm) 3 02 mm, m/z 609 (M+H)

Step 4 Preparation of A7-(3-methoxybenzyl)-6-(1 -(((2S,5ff)-5-(hvdroxymethyl)-1.4-dιoxan-2-yl)methyl)- 1 H- 1 ,2,3-trιazol-4-yl)-2-methylpyrιmιdιne-4-carboxamιde

The title compound was prepared in a similar manner to λ/-(4-fluoro-3-methoxybenzyl)-6-(1 - (((2S,5R)-5-(hydroxymethyl)-1 ,4-dιoxan-2-yl)methyl)-1 H-1 ,2,3-trιazol-4-yl)-2-methylpyrιmιdιne-4- carboxamide (step 7, Example 128) by reaction of ((2S,5S)-5-((4-(6-((3-methoxybenzyl)carbamoyl)-2- methylpyrιmιdιn-4-yl)-1 H-1 ,2,3-tÏ€azol-1-yl)methyl)-1 ,4-dιoxan-2-yl)methyl 4-methylbenzenesulfonate (131 g, 0 22 mmol), tetrabutylammonium acetate (71 mg, 0 24 mmol, 1 10 equiv ), and 1 0 N aqueous sodium hydroxide (260 μL, 0 26 mmol, 1 20 equiv ) Purification by silica gel chromatography (gradient 100% EtOAc to 10% MeOH/EtOAc) provided the title compound as a white solid (50 mg, 51 %) MS (ES+) m/z 455 (M+H) ¹ H NMR (400 MHz, DMSOd ₆ ) δ 9 38 (1 H, t, J=6 4 Hz), 8 80 (1 H ₁ s), 8 33 (1 H, s), 7 24 (1 H, t, J=S 1 Hz), 6 88 - 6 99 (2 H, m), 6 82 (1 H, dd, J=8 1 , 2 0 Hz), 4 67 (1 H, t, J=5 6 Hz), 4 55 - 4 63 (1 H, m), 4 43 - 4 54 (3 H ₁ m), 3 87 - 4 01 (2 H, m), 3 77 - 3 85 (1 H, m), 3 74 (3 H ₁ s), 3 32 - 3 47 (4 H, m), 2 75 (3 H ₁ s)

Example 134

W^-Fluoro-S-methoxybenzylJ-e^i^^fransJ^-aminocyclohβxyOm ethyO-I H-I .σ.S-triazol^-yO-σ- methylpyrimidine-4-carboxamide

Step 1 Preparation of ((fransM-ftert-butoxycarbonvOcvclohexyQmethyl 2.2.2-trιfluoroethanesulfonate

Commercially available tert-butyl fraÏ€s-4-(hydroxymethyl)cyclohexylcarbamate (2 00 g, 8 72 mmol), 2,2,2-trιfluoroethanesulfonyl chloride (1 2 mL, 11 0 mmol, 1 20 equiv ), and N ₁ N- dnsopropylethylamine (2 0 mL, 11 0 mmol, 1 20 equiv ) were combined in dichloromethane (35 mL) After stirring for 1 hour at 0 ⁰ C, the mixture was concentrated under reduced pressure, and the salty residue was partitioned between ethyl acetate (100 mL) and 1 0 N aqueous hydrochloric acid (20 mL) The layers were separated and the organic layer was washed with 1 0 N aqueous hydrochloric acid (10 mL), saturated aqueous sodium bicarbonate (20 mL), and brine (20 mL) The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure Purification by

recrystallization (1 2 heptane/EtOAc) provided the title compound as a white needles (2 29 g, 70%) ¹ H NMR (400 MHz, CDCI ₃ ) δ 4 40 (1 H, br s ), 4 15 (2 H, d, J=6 5 Hz), 3 89 (2 H, q, J=S 7 Hz), 3 40 (1 H, br s ), 1 98 - 2 16 (2 H, m), 1 80 - 1 93 (2 H, m), 1 66 - 1 79 (1 H, m), 1 44 (9 H, s), 1 05 - 1 20 (4 H, m)

Step 2 Preparation of /ert-butyl (fransM-((4-(6-((4-fluoro-3-methoxybenzyl)carbamoyl)-2- methylpyrιmιdιn-4-yl)-1/-/-1 ,2,3-trιazol-1 -yl)methyl)cvclohexylcarbamate

((/raÏ€s)-4-(fert-Butoxycarbonyl)cyclohexyl)methyl 2,2,2-trιfluoroethanesulfonate (450 mg, 1 20 mmol) and sodium azide (80 mg, 1 22 mmol, 1 02 equiv ) were combined in λ/,λ/-dιmethylformamιde (1 0 mL) After stirring for 18 hours at room temperature, the reaction vessel was charged sequentially with λ/,/V-dιmethylformamιde (3 0 mL), water (1 0 mL), λ/-(4-fluoro-3-methoxybenzyl)-6-ethynyl-2- methylpyrιmιdιne-4-carboxamιde (prepared as described in step 4 of the synthesis of /V-(4-fluoro-3- methoxybenzyl)-6-(1-(((2S,5R)-5-(hydroxymethyl)-1 ,4-dιoxan-2-yl)methyl)-1 H-1 ,2,3-trιazol-4-yl)-2- methylpyrιmιdιne-4-carboxamιde, Example 128) (305 mg, 1 20 mmol, 1 00 equiv ), 1 0 M aqueous sodium ascorbate (120 μl, 0 12 mmol, 0 10 equiv ), and 0 30 M aqueous copper (II) sulfate (80 μL, 0 024 mmol, 0 02 equiv ) After stirring for 23 hours at room temperature, to the reaction mixture was added sequentially λ/,λ/-dιmethylformamιde (2 0 mL), 1 0 M aqueous sodium ascorbate (120 μL, 0 12 mmol, 0 10 equiv ), and 0 30 M aqueous copper (II) sulfate (80 μl, 0 024 mmol, 0 02 equiv ) After stirring for 6 hours at room temperature, the mixture was poured with vigorous stirring into ice-cold water (150 mL) The precipitate was collected by suction filtration, washed with water (3x), dissolved in ethyl acetate, dried over sodium sulfate, filtered, and concentrated under reduced pressure The reddish-orange amorphous solid was dissolved in 5% methanol/ethyl acetate, filtered through a short pad of silica, and concentrated under reduced pressure Purification by recrystallization (2 3 heptane/EtOAc) provided the title compound as a pale orange solid (504 mg, 76%) LC/MS (5%- 100% CH ₃ CN/H ₂ O, 5 mm) 3 71 mm, m/z 554 (M+H) Step 3 Preparation of /V-(4-f1uoro-3-methoxybenzyl)-6-(1 -(((frans)-4-aminocvclohexyl)methyl)-1 /-/- 1.2,3-trιazol-4-yl)-2-methylpyrιmιdιne-4-carboxamιde

tert-Butyl (<rans)-4-((4-(6-((4-fluoro-3-methoxybenzyl)carbamoyl)-2- methylpynmidin-4-yl)-1 H- 1 ,2,3-tnazol-1 -yl)methyl)cyclohexylcarbamate (497 mg, 0 90 mmol) and 4 0 N hydrochloric acid in 1 ,4- dioxane (3 6 mL, 14 4 mmol, 16 0 equiv ) were combined in 1 ,4-dιoxane (4 0 mL) After stirring for 18 hours at room temperature, the mixture was concentrated under reduced pressure The residue was dissolved in methanol, concentrated under reduced pressure, and dried under high vacuum to afford

the hydrochloride salt form of title compound as a white solid (440 mg, >95%) that was used in subsequent reactions without further purification LC/MS (5%-100% CH ₃ CN/H ₂ O, 5 mm) 2 74 mm, m/z 454 (M+H)

Example 135

W-(4-Fluoro-3-methoxybenzyl)-6-(1 -((((ransJ^-acetamidocyclohexylJmethyO-i H-1 ,2,3-triazol-4- yl)-2-methylpyrimidine-4-carboxamide

The hydrochloride salt form of λ/-(4-fluoro-3-methoxybenzyl)-6-(1-(((frar?s)-4-amιnocyclo hexyl)- methyl)-1H-1 ,2,3-trιazol-4-yl)-2-methylpyrιmιdιne-4-carboxamιde (prepared as described in Example 134) (440 mg, 0 90 mmol), triethylamine (376 μl, 2 70 mmol, 3 00 equiv ), and acetyl chloride (77 μL, 1 08 mmol, 1 20 equiv ) were combined in dichloromethane (5 0 mL) After stirring for 1 hour at room temperature, methanol (2 mL) was added and the mixture was diluted with dichloromethane (20 mL) and water (5 mL) The layers were separated and the organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure Purification by silica gel chromatography (gradient 100% EtOAc to 20% MeOH/EtOAc) provided the title compound as a white solid (353 mg, 79%) LC/MS (5%-100% CH ₃ CN/H ₂ O, 5 mm) 3 17 mm, m/z 496 (M+H) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9 46 (1 H, t, J=Q 4 Hz), 8 90 (1 H, s), 8 33 (1 H, s), 7 71 (1 H, d, J=I 9 Hz), 7 10 - 7 23 (2 H, m), 6 84 - 6 95 (1 H, m), 4 49 (2 H, d, J=Q 3 Hz), 4 33 (2 H, d, J=I 2 Hz), 3 82 (3 H, s), 2 75 (3 H, s), 1 82 - 1 94 (1 H, m), 1 75 - 1 82 (2 H ₁ m), 1 75 (3 H, s), 1 47 - 1 63 (2 H, m), 1 00 - 1 18 (4 H, m)

Example 136

/V-(4-Fluoro-3-methoxybenzyl)-6-(1 -(((frans)-4-(2-hydroxyacetamido)cyclohexyl)methyl)-1 H- 1 ,2,3-triazol-4-yl)-2-methylpyrimidine-4-carboxamide

The hydrochloride salt form of λ/-(4-fluoro-3-methoxybenzyl)-6-(1 -(((frans)-4-amιnocyclohexyl)- methyl)-1H-1 ,2,3-tπazol-4-yl)-2-methylpyrιmιdιne-4-carboxamιde (prepared as described Example 134) (224 mg, 0 46 mmol), triethylamine (160 μL, 1 14 mmol, 2 50 equiv ), and 2-acetoxyacetyl chloride (59 μL, 0 55 mmol, 1 20 equiv ) were combined in dichloromethane (10 mL) After stirring for 1 hour at room temperature, the mixture was concentrated under reduced pressure To the salty residue were added sequentially tetrahydrofuran (4 0 mL) and 2 0 N aqueous lithium hydroxide (2 0 mL, 4 00 mmol, 8 70 equiv ) After stirring for 1 hour at room temperature, the mixture was diluted with ethyl acetate (20 mL) and water (5 mL) The layers were separated and the organic layer was dried

over sodium sulfate, filtered, and concentrated under reduced pressure Purification by silica gel chromatography (gradient 100% EtOAc to 10% MeOH/EtOAc) provided the title compound as a white solid (185 mg, 81 %) MS (ES+) m/z 512 (M+H) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9 47 (1 H, t, J=6 3 Hz), 8 90 (1 H, s), 8 33 (1 H, s), 7 47 (1 H, d, J=8 2 Hz), 7 1 1 - 7 21 (2 H, m), 6 90 (1 H, ddd), 5 41 (1 H, t, J=5 8 Hz), 4 49 (2 H, d, J=6 4 Hz), 4 34 (2 H, d, J=I 1 Hz), 3 82 (3 H, s), 3 75 (2 H, d, J=5 7 Hz), 3 48 - 3 64 (1 H, m), 2 74 (3 H, s), 1 80 - 1 98 (1 H, m), 1 73 (2 H, d, J= 11 2 Hz), 1 56 (2 H, d, J= 1 1 9 Hz), 1 19 - 1 36 (2 H, m), 1 00 - 1 19 (2 H, m)

Example 137

N-(4-Fluoro-3-methoxybenzyl)-6-(1 -(((1 R,3S)-3-aminocyclopentyl)methyl)-1 H-1 ,2,3-triazol-4-yl)-2- methylpyrimidine-4-carboxamide

Step 1 Preparation of ((1 f?,3S)-3-(/eff-butoxycarbonyl)cvclopentyl)methyl 2,2,2- tnfluoroethanesulfonate terf-Butyl (1 S,3f?)-3-(hydroxymethyl)cyclopentylcarbamate (prepared from commercially available 1-(R)-( — )-2-azabιcyclo[2 2 1]hept-5-en-3-one according to the method described by Shuto and coworkers, see Kudoh, T et al J Am Chem Soc 2005, 127, 8846-8855) (150 mg, 0 70 mmol), 2,2,2-trιfluoroethanesulfonyl chloride (82 μL, 0 73 mmol, 1 05 equiv ), and λ/,/V-dιιsopropylethylamιne (140 μL, 0 80 mmol, 1 15 equiv ) were combined in dichloromethane (3 0 mL) After stirring for 30 minutes at 0 ⁰ C, the mixture was diluted with dichloromethane (15 mL) and 10% aqueous sodium bisulfate (5 mL) The layers were separated and the aqueous layer was washed with dichloromethane (1 x) The organic layers were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure Purification by silica gel chromatography (gradient 4 1 heptane/EtOAc to 2 1 heptane/EtOAc) provided the title compound as a white solid (206 mg, 82%) ¹ H NMR (400 MHz, CDCI ₃ ) δ 4 50 (1 H, br s ), 4 28 (2 H, d, J=6 4 Hz), 3 97 (1 H, br s ), 3 90 (2 H, q, J=8 8 Hz), 2 33 - 2 46 (1 H, m), 2 20 - 2 32 (1 H, m), 1 95 - 2 09 (1 H, m), 1 77 - 1 91 (1 H, m), 1 46 - 1 58 (2 H, m), 1 45 (9 H, s), 1 10 - 1 23 (1 H, m)

Step 2 Preparation of terf-butyl (1 S,3ff)-3-(azιdomethyl)cvclopentylcarbamate ((1 R,3S)-3-(fert-Butoxycarbonyl)cyclopentyl)methyl 2,2,2-trιfluoroethanesulfonate (125 mg,

0 35 mmol) and sodium azide (35 mg, 0 54 mmol, 1 54 equiv ) were combined in N ₁ N-

dimethylformamide (0 90 mL) After stirring for 1 hour at 60 ⁰ C, the mixture was cooled to room temperature and diluted with ethyl acetate (10 mL) and 50% aqueous sodium chloride (2 mL) The layers were separated and the aqueous layer was washed with ethyl acetate (3 x 1 mL) The organic layers were combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure Purification by silica gel chromatography (gradient 4 1 heptane/EtOAc to 2 1 heptane/EtOAc) provided the title compound as a colorless oil (83 mg, >95%)

Step 3 Preparation of tert-butyl (1 S,3R)-3-((4-(6-((4-fluoro-3-methoxybenzyl)carbamoyl)-2-

tert-Butyl (I S.S^-S^azidomethyOcyclopentylcarbamate (75 mg, 0 31 mmol), λ/-(4-fluoro-3- methoxybenzyl)-6-ethynyl-2-methylpyrιmιdιne-4-carboxamιd e (prepared as described in step 4 of the synthesis of λ/-(4-fluoro-3-methoxybenzyl)-6-(1-(((2S,5R)-5-(hydroxymeth yl)-1 ,4-dιoxan-2-yl)methyl)- 1 H-1 ,2,3-trιazol-4-yl)-2-methylpyrιmιdιne-4-carboxamιde, Example 128) (93 mg, 0 31 mmol, 1 00 equiv ), 1 0 M aqueous sodium ascorbate (31 μL, 0 031 mmol, 0 10 equiv ), and 0 30 M aqueous copper (II) sulfate (20 μL, 0 006 mmol, 0 02 equiv ) were combined in tetrahydrofuran (0 50 mL), tert- butanol (0 50 mL), and water (0 50 mL) After stirring for 15 hours at room temperature, the mixture was diluted with ethyl acetate (10 mL) and saturated aqueous sodium chloride (2 mL) The layers were separated and the aqueous layer was washed with ethyl acetate (3 x 1 mL) The organic layers were combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure Purification by silica gel chromatography (gradient 4 1 heptane/EtOAc to 100% EtOAc) provided the title compound as an off-white solid (136 mg, 81%) LC/MS (5%-100% CH ₃ CN/H ₂ O, 5 mm) 3 78 mm, m/z 484 (M - 2-Me-propene + H)

Step 4 Preparation of λ/-(4-fluoro-3-methoxybenzyl)-6-(1 -(((1 ff,3S)-3-amιnocvclopentyl)methyl)-1 H- 1 ,2,3-trιazol-4-yl)-2-methylpyrιmιdιne-4-carboxamιde

tert-Butyl (1 S,3R)-3-((4-(6-((4-fluoro-3-methoxybenzyl)carbamoyl)-2-methy lpyrιmιdιn-4-yl)-1 H- 1 ,2,3-triazol-1 -yl)methyl)cyclopentylcarbamate (136 mg, 0 25 mmol) was dissolved in 4 0 N hydrochloric acid in methanol (1 5 mL, 6 00 mmol, 24 2 equiv ) After stirring for 18 hours at room temperature, the mixture was concentrated under reduced pressure The residue was dissolved in methanol, concentrated under reduced pressure, and dried under high vacuum to afford the hydrochloride salt form of title compound as a white solid (1 18 mg, >95%) that was used in

subsequent reactions without further purification LC/MS (5%-100% CH ₃ CN/H ₂ O, 5 mm) 2 73 mm, m/z 440 (M+H)

Example 138

N-(4-Fluoro-3-methoxybenzyl)-6-(1-(((1R,3S)-3-acetamidocy clopentyl)methyl)-1H-1 ,2,3-triazol-4- yl)-2-methylpyrimidine-4-carboxamide

The title compound was prepared in a similar manner to /V-(3-methoxybenzyl)-6-(1 -(((S)-4- acetylmorpholιn-2-yl)methyl)-1 H- 1 ,2,3-trιazol-4-yl)-2-methylpyrιmιdιne-4-carboxamιde (Example 131 ) by reaction of the hydrochloride salt form of λ/-(4-fluoro-3-methoxybenzyl)-6-(1-(((1f?,3S)-3- (prepared as described in Example 137) (39 mg, 0 089 mmol), triethylamine (35 μl, 0 25 mmol, 2 80 equiv ), and acetyl chloride (15 μL, 0 21 mmol, 2 40 equiv ) Purification by silica gel chromatography (gradient 100% EtOAc to 10% MeOH/EtOAc) provided the title compound as a light yellow foam (27 mg, 63%) MS (ES+) m/z 482 (M+H) ¹ H NMR (400 MHz, DMSO-c/ ₆ ) δ 9 39 (1 H, t, J=Q 2 Hz), 8 89 (1 H, s), 8 34 (1 H, s), 7 81 (1 H, d, J=I 3 Hz), 7 18 (1 H, dd, J=8 6, 1 6 Hz), 7 14 (1 H, dd, .7=12 0, 8 5 Hz), 6 85 - 6 96 (1 H, m), 4 50 (2 H, d, J=Q 2 Hz), 4 46 (2 H, d, J=I 3 Hz), 3 92 - 4 05 (1 H, m), 3 83 (3 H, s), 2 75 (3 H, s), 1 91 - 2 01 (1 H, m), 1 78 - 1 88 (1 H, m), 1 76 (3 H, s), 1 57 - 1 70 (1 H, m), 1 37 - 1 54 (2 H, m), 1 07 - 1 22 (1 H, m)

Example 139 W-(4-fluoro-3-methoxybenzyl)-6-(1 -(((1 /?,3S)-3-(2-hydroxyacetamido)cyclopentyl)methyl)-1 H-

1 ,2,3-triazol-4-yl)-2-methylpyrimidine-4-carboxamide

The title compound was prepared in a similar manner to /V-(4-fluoro-3-methoxybenzyl)-6-(1 - (((/rans)-4-(2-hydroxyacetamιdo)cyclohexyl)methyl)-1 /-/-1 ,2,3-trιazol-4-yl)-2-methylpyÏ€mιdιne-4- carboxamide (Example 136) by reaction of the hydrochloride salt form of λ/-(4-fluoro-3- methoxybenzyl)-6-(1-(((1 R,3S)-3-amιnocyclopentyl)methyl)-1 /-/-1 ,2,3-trιazol-4-yl)-2-methylpyrιmιdιne- 4-carboxamιde (prepared as described in Example 137) (39 mg, 0 089 mmol), triethylamine (35 μL, 0 25 mmol, 2 80 equiv ), 2-acetoxyacetyl chloride (20 μL, 0 19 mmol, 2 10 equiv ), and 2 0 N aqueous lithium hydroxide (0 45 mL, 0 89 mmol, 10 0 equiv ) Purification by silica gel chromatography (gradient 100% EtOAc to 10% MeOH/EtOAc) provided the title compound as a light yellow foam (25 mg, 56%) MS (ES+) m/z 498 (M+H) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9 39 (1 H, t, J=Q 2 Hz), 8 89 (1

H, s), 8 34 (1 H, s), 7 61 (1 H, d, J=I 5 Hz), 7 18 (1 H, dd, J=Q 6, 1 5 Hz), 7 14 (1 H, dd, J=1 1 6, 8 3 Hz), 6 82 - 6 96 (1 H, m), 5 31 (1 H, t, J=5 9 Hz), 4 50 (2 H, d, J=Q 4 Hz), 4 46 (2 H, dd, J=I 0, 2 1 Hz), 4 02 - 4 16 (1 H, m), 3 82 (3 H, s), 3 77 (2 H, d, J=5 9 Hz), 2 75 (3 H, s), 1 90 - 2 01 (1 H, m), 1 75 - 1 90 (1 H, m), 1 42 - 1 70 (4 H, m), 1 21 - 1 35 (1 H, m)

Example 140

W-(4-Fluoro-3-methoxybenzyl)-2-methyl-6-(1 -(((1 f?,3S)-3- (methylsulfonamidoJcyclopentyOmethyO-IH-i ^ _j S-triazoM-yOpyrimidine^-carboxamide

The title compound was prepared in a similar manner to λ/-(3-methoxybenzyl)-6-(1 -(((S)-4- acetylmorpholιn-2-yl)methyl)-1 /-/-1 ,2,3-trιazol-4-yl)-2-methylpyrιmιdιne-4-carboxamιde (Example 131 ) by reaction of the hydrochloride salt form of λ/-(4-fluoro-3-methoxybenzyl)-6-(1 -(((1 R,3S)-3- amιnocyclopentyl)methyl)-1 H- 1 ,2,3-trιazol-4-yl)-2-methylpyrιmιdιne-4-carboxamιde (prepared as described in Example 137) (39 mg, 0 089 mmol), triethylamine (35 μL, 0 25 mmol, 2 80 equiv ), and methanesulfonyl chloride (15 μL, 0 19 mmol, 2 10 equiv ) Purification by silica gel chromatography (gradient 100% EtOAc to 10% MeOH/EtOAc) provided the title compound as a light yellow foam (33 mg, 72%) MS (ES+) m/z 518 (M+H) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9 39 (1 H, t, J=Q 5 Hz), 8 89 (1 H, s), 8 34 (1 H, s), 7 18 (1 H, dd, J=Q 6, 1 6 Hz), 7 1 1 - 7 17 (1 H, m), 7 09 (1 H, d, J=I 3 Hz), 6 83 - 6 96 (1 H, m), 4 50 (2 H, d, J=Q 2 Hz), 4 45 (2 H, d, J=I 3 Hz), 3 82 (3 H, s), 3 51 - 3 71 (1 H, m), 2 88 (3 H, s), 2 75 (3 H, s), 1 97 - 2 09 (1 H, m), 1 82 - 1 96 (1 H, m), 1 35 - 1 72 (4 H, m), 1 19 - 1 34 (1 H, m)

Example 141

/V-(4-Fluoro-3-methoxybenzyl)-6-(1 -(((1 S,3R)-3-aminocyclopentyl)methyl)-1 H-1 ,2,3-triazol-4-yl)-2- methylpyrimidine-4-carboxamide

Step 1 Preparation of ((I S.Sffϊ-S-^ert-butoxycarbonvOcyclopentvDmethyl methanesulfonate tert-Butyl (1 R,3S)-3-(hydroxymethyl)cyclopentylcarbamate (prepared from commercially available 1 -(S)-(+)-2-azabιcyclo[2 2 1]hept-5-en-3-one according to the method described by Shuto

and coworkers, see Kudoh, T et al J Am Chem. Soc 2005, 127, 8846-8855) (250 mg, 1 16 mmol), methanesulfonyl chloride (108 μL, 1 39 mmol, 1 20 equiv ), and λ/,λ/-dιιsopropylethylamιne (263 μL, 1 51 mmol, 1 30 equiv ) were combined in dichloromethane (5 0 mL) After stirring for 30 minutes at 0 ⁰ C, the mixture was diluted with dichloromethane (15 mL) and 10% aqueous sodium bisulfate (5 mL) The layers were separated and the aqueous layer was washed with dichloromethane (3 x 2 mL) The organic layers were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure to afford the title compound as an off-white solid (341 mg, >95%)

Step 2 Preparation of terf-butyl (1 R,3S)-3-(azιdomethyl)cvclopentylcarbamate ((1 S,3R)-3-(^erf-Butoxycarbonyl)cyclopentyl)methyl methanesulfonate (100 mg, 0 34 mmol) and sodium azide (69 mg, 1 07 mmol, 3 15 equiv ) were combined in λ/,λ/-dιmethylformamιde (0 60 mL) After stirring for 15 hours at 50 ⁰ C, the mixture was cooled to room temperature, diluted with ethyl acetate (10 mL), and washed with water (3 x 2 mL) The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure Purification by silica gel chromatography (gradient 4 1 heptane/EtOAc to 2 1 heptane/EtOAc) provided the crude title compound as a pale orange oil (82 mg, >95%) that was used in subsequent reactions without further purification

Step 3 Preparation of tert-butyl (1 f?,3S)-3-((4-(6-((4-fluoro-3-methoxybenzyl)carbamoyl)-2- methylpyrιmιdιn-4-yl)-1 /-/-1 ,2,3-trιazol-1 -yl)methyl)cvclopentylcarbamate

The title compound was prepared in a similar manner to tert-butyl (1 S,3R)-3-((4-(6-((4-fluoro-

3-methoxybenzyl)carbamoyl)-2-methylpyrιmιdιn-4-yl)-1 /-M ,2,3-trιazol-1 - yl)methyl)cyclopentylcarbamate (step 3, Example 137) by the reaction of tert-butyl (1 R,3S)-3- (azιdomethyl)cyclopentylcarbamate (82 mg, 0 34 mmol), /V-(4-fluoro-3-methoxybenzyl)-6-ethynyl-2- methylpyrιmιdιne-4-carboxamιde (prepared as described in step 4 of the synthesis of λ/-(4-fluoro-3- methoxybenzy!)-6-(1 -(((2S,5R)-5-(hydroxymethyl)-1 ,4-dιoxan-2-yl)methyl)-1 H-1 ,2,3-trιazol-4-yl)-2- methylpyrιmιdιne-4-carboxamιde, Example 128) (102 mg, 0 34 mmol, 1 00 equiv ), 1 0 M aqueous sodium ascorbate (34 μL, 0 034 mmol, 0 10 equiv ), and 0 30 M aqueous copper (II) sulfate (23 μL, 0 007 mmol, 0 02 equiv ) to afford title compound as a light yellow foam (128 mg, 70%) LC/MS (5%- 100% CH ₃ CN/H ₂ O, 5 mm) 3 78 mm, m/z 484 (M - 2-Me-propene + H)

Step 4 Preparation of λ/-(4-fluoro-3-methoxybenzyl)-6-(1 -(((1 S.3f?)-3-amιnocvclopentyl)methyl)-1 /-/- 1 ,2,3-trιazol-4-yl)-2-methylpyrιmιdιne-4-carboxamιde

The title compound was prepared in a similar manner to /V-(4-fluoro-3-methoxybenzyl)-6-(1 - (((1 R,3S)-3-amιnocyclopentyl)methyl)-1 H-1 ,2,3-trιazol-4-yl)-2-methylpyrιmιdιne-4-carboxamιde (step 4, Example 137) by the reaction of tert-butyl (1 R,3S)-3-((4-(6-((4-fluoro-3-methoxybenzyl Carbamoyl )-2- methylpyÏ€mιdιn-4-yl)-1 H-1 ,2,3-trιazol-1-yl)methyl)cyclopentylcarbamate (128 mg, 0 24 mmol) and 4 0 N hydrochloric acid in methanol (1 5 mL, 6 00 mmol, 25 Oequiv ) to afford the hydrochloride salt form of title compound as a white solid (1 14 mg, >95%) that was used in subsequent reactions without further purification LC/MS (5%-100% CH ₃ CN/H ₂ O, 5 mm) 2 73 mm, m/z 440 (M+H)

Example 142

/V-(4-Fluoro-3-methoxybenzyl)-6-(1 -(((1 S,3/?)-3-acetamidocyclopentyl)methyl)-1 H-1 ,2,3-triazol-4- yl)-2-methylpyrimidine-4-carboxamide

The title compound was prepared in a similar manner to λ/-(3-methoxybenzyl)-6-(1-(((S)-4- acetylmorpholιn-2-yl)methyl)-1 H- 1 ,2,3-trιazol-4-yl)-2-methylpyrιmιdιne-4-carboxamιde (Example 131 ) by reaction of the hydrochloride salt form of λ/-(4-fluoro-3-methoxybenzyl)-6-(1 -(((1 S,3/?)-3- aminocyclopentyOmethyO-I H-I .σ.S-tÏ€azoM-yl^-methylpyÏ€midine^-carboxamide (prepared as described in Example 141 ) (38 mg, 0 079 mmol), triethylamine (35 μL, 0 25 mmol, 3 16 equiv ), and acetyl chloride (1 1 μL, 0 16 mmol, 2 02 equiv ) Purification by reverse phase HPLC provided the title compound as a white solid (15 mg, 39%) MS (ES+) m/z 482 (M+H) ¹ H NMR (400 MHz, DMSO-Cy ₆ ) δ 9 39 (1 H, t, J=Q 2 Hz), 8 89 (1 H, s), 8 34 (1 H, s), 7 81 (1 H, d, J=I 0 Hz), 7 18 (1 H, dd, J=Q 5, 1 6 Hz), 7 14 (1 H, dd, J= 1 1 6, 8 3 Hz), 6 84 - 6 95 (1 H, m), 4 50 (2 H, d, J=Q 4 Hz), 4 45 (2 H, d, J=I 1 Hz), 3 91 - 4 05 (1 H, m), 3 82 (3 H, s), 2 75 (3 H, s), 1 90 - 2 02 (1 H, m), 1 78 - 1 88 (1 H, m), 1 76 (3 H, s), 1 57 - 1 70 (1 H, m), 1 37 - 1 53 (2 H, m), 1 09 - 1 21 (1 H, m)

Example 143

/V-(4-Fluoro-3-methoxybenzyl)-6-(1 -(((1 S,3R)-3-(2-hydroxyacetamido)cyclopentyl)methyl)-1 H- 1 ,2,3-triazol-4-yl)-2-methylpyrimidine-4-carboxamide

The title compound was prepared in a similar manner to λ/-(4-fluoro-3-methoxybenzyl)-6-(1- (((/λans)-4-(2-hydroxyacetamιdo)cyclohexyl)methyl)-1 /-/-1 ,2,3-trιazol-4-yl)-2-methylpyrιmιdιne-4- carboxamide (Example 136) by reaction of the hydrochloride salt form of λ/-(4-fluoro-3- methoxybenzyl)-6-(1 -(((1 S,3R)-3-amιnocyc!opentyl)methyl)-1 H-1 ,2,3-trιazol-4-yl)-2-methylpyrιmιdιne- 4-carboxamιde (prepared as described in Example 141 ) (38 mg, 0 079 mmol), triethylamine (35 μL,

0 25 mmol, 3 16 equiv ), 2-acetoxyacetyl chloride (17 μL, 0 16 mmol, 2 02 equiv ), and 2 0 N aqueous lithium hydroxide (0 40 mL, 0 80 mmol, 10 1 equiv ) Purification by reverse phase HPLC provided the title compound as a white solid (16 mg, 41 %) MS (ES+) m/z 498 (M+H) ¹ H NMR (400 MHz, DMSO- d _β ) δ 9 39 (1 H, t, J=Q 4 Hz), 8 89 (1 H, s), 8 34 (1 H, s), 7 61 (1 H, d, J=I 7 Hz), 7 18 (1 H, dd, J=8 5,

19 Hz), 714(1 H, dd, J=116, 83 Hz), 687 - 696 (1 H, m), 532 (1 H, t, J=57 Hz), 450 (2 H, d, J=Q 2 Hz), 439 - 448 (2 H, m), 404 - 416 (1 H, m), 382 (3 H, s), 377 (2 H, d, J=59 Hz), 275 (3 H, s), 190 - 203 (1 H, m), 177 - 190 (1 H, m), 141 - 170 (4 H, m), 121 - 135 (1 H, m)

Example 144 N-(4-Fluoro-3-methoxybenzyl)-2-methyl-6-(1-(((1S,3f?)-3-

(methylsulfonamido)cyclopentyl)methyl)-1H-1,2,3-triazol-4 -yl)pyrimidine-4-carboxamide

The title compound was prepared in a similar manner to /V-(3-methoxybenzyl)-6-(1 -(((S)-4- acetylmorpholιn-2-yl)methyl)-1 /-/-1 ,2,3-trιazol-4-yl)-2-methylpyrιmιdιne-4-carboxamιde (Example 131 ) by reaction of the hydrochloride salt form of λ/-(4-fluoro-3-methoxybenzyl)-6-(1 -(((1 S,3R)-3- amιnocyclopentyl)methyl)-1 H- 1 ,2,3-trιazol-4-yl)-2-methylpyrιmιdιne-4-carboxamιde (prepared as described in Example 141 ) (38 mg, 0 079 mmol), triethylamine (35 μL, 0 25 mmol, 3 16 equiv ), and methanesulfonyl chloride (12 μL, 0 16 mmol, 2 02 equiv ) Purification by reverse phase HPLC provided the title compound as a white solid (12 mg, 29%) MS (ES+) m/z 518 (M+H) ¹ H NMR (400 MHz, DMSO-ds) δ 9 38 (1 H, t, J=Q 3 Hz), 8 89 (1 H, s), 8 33 (1 H, s), 7 18 (1 H, dd, J=Q 4, 1 8 Hz), 7 13 (1 H, dd, J=1 1 7, 8 4 Hz), 7 09 (1 H, d, J=I 1 Hz), 6 86 - 6 95 (1 H, m), 4 49 (2 H, d, J=Q 2 Hz), 4 45 (2 H, d, J=I 3 Hz), 3 82 (3 H, s), 3 56 - 3 70 (1 H, m), 2 87 (3 H, s), 2 74 (3 H, s), 1 97 - 2 09 (1 H, m), 1 83 - 1 95 (1 H, m), 1 39 - 1 69 (3 H, m), 1 20 - 1 33 (1 H, m)

Example 145 6-(1 -(((S)-1 ,4-Dioxan-2-yl)methyl)-1 H-1 ,2,3-triazol-4-yl)-/V-(4-f luoro-3-methoxybenzyl)-2- methylpyrimidine-4-carboxamide

Step 1 Preparation of (R)-C\ ,4-dιoxan-2-vl)methvl tπfluoromethanesulfonate

The title compound was prepared in a similar manner to ((2S,5R)-5- ((trιfluoromethylsulfonyloxy)methyl)-1 ,4-dιoxan-2-yl)methyl 4-methylbenzenesulfonate (step 5, Example 128) by reaction of (S)-(1 , 4-dιoxan-2-y!)methanol (prepared as described in step 1 of the synthesis of 6-(2-(((S)- 1 ,4-dιoxan-2-yl)methyl)-2H-tetrazol-5-yl)-λ/-(3-methoxybenz yl)-2- methylpyrιmιdιne-4-carboxamιde, Example 57) (100 mg, 0 85 mmol), pyridine (72 μL, 0 89 mmol, 1 05 equiv ), and trifluoromethanesulfonic anhydride (150 μL, 0 89 mmol, 1 05 equiv ) to afford the title compound as a tan oil (185 mg, 87%) ¹ H NMR (400 MHz, CDCI ₃ ) δ 4 40 - 4 54 (2 H, m), 3 90 - 3 97 (1 H, m), 3 72 - 3 90 (4 H, m), 3 59 - 3 70 (1 H, m), 3 48 (1 H, dd, J=11 4, 10 0 Hz)

Step 2 Preparation of 6-(1 -(((S)-1 ,4-dιoxan-2-yl)methyl)-1 /-/-1 ,2,3-trιazol-4-yl)-λ/-(4-fluoro-3- methoxybenzyl)-2-methylpyrιmιdιne-4-carboxamιde

The title compound was prepared in a similar manner to ((2S,5S)-5-((4-(6-((4-fluoro-3- methoxybenzyl)carbamoyl)-2-methylpyrιmιdιn-4-yl)-1 H-1 ,2,3-trιazol-1-yl)methyl)-1 ,4-dιoxan-2-yl)methyl 4-methylbenzenesulfonate (step 6, Example 128) by reaction of (R)-(1 ,4-dιoxan-2-yl)methyl trifluoromethanesulfonate (175 mg, 0 70 mmol, 1 20 equiv ), sodium azide (38 mg, 0 58 mmol, 1 00 equiv ), λ/-(4-fluoro-3-methoxybenzyl)-6-ethynyl-2-methylpyrιmιdι ne-4-carboxamιde (prepared as described in step 4 of the synthesis of λ/-(4-fluoro-3-methoxybenzyl)-6-(1-(((2S,5R)-5-(hydroxymeth yl)- 1 ,4-dιoxan-2-yl)methyl)-1 H-1 ,2,3-trιazol-4-yl)-2-methylpyrιmιdιne-4-carboxamιde, Example 128) (174 mg, 0 58 mmol), 1 0 M aqueous sodium ascorbate (58 μL, 0 058 mmol, 0 10 equiv ), and 0 30 M aqueous copper (II) sulfate (40 μL, 0 012 mmol, 0 02 equiv ) Purification by silica gel chromatography (gradient 1 2 heptane/EtOAc to 100% EtOAc) provided the title compound as a white solid (258 mg, >95%) MS (ES+) m/z 443 (M+H) ¹ H NMR (400 MHz, DMSOd ₆ ) δ 9 47 (1 H, t, J=6 4 Hz), 8 82 (1 H, s), 8 33 (1 H, s), 7 10 - 7 24 (2 H, m), 6 90 (1 H, ddd, J=8 1 , 4 3, 1 8 Hz), 4 50 - 4 65 (2 H, m), 4 49 (2 H, d, J=6 8 Hz), 3 94 - 4 06 (1 H, m), 3 80 - 3 87 (4 H, m), 3 75 (1 H, d, J=11 3 Hz), 3 64 (1 H, d, J=1 1 0 Hz), 3 51 - 3 59 (1 H, m), 3 40 - 3 50 (1 H, m), 3 24 - 3 33 (1 H, m), 2 75 (3 H, s)

Example 146

6-(1 -(((R)-1 ,4-Dioxan-2-yl)methyl)-1 H-1 ,2,3-triazol-4-yl)-N-(4-f luoro-3-methoxybenzyl)-2- methylpyrimidine-4-carboxamide

Step 1 Preparation of (S)-(1 ,4-dιoxan-2-yl)methyl trifluoromethanesulfonate

The title compound was prepared in a similar manner to ((2S,5R)-5-

((trιfluoromethylsulfonyloxy)methyl)-1 ,4-dιoxan-2-yl)methyl 4-methylbenzenesulfonate (step 5, Example 128) by reaction of (f?)-(1 ,4-dιoxan-2-yl)methanol (prepared as described in step 1 of the synthesis of 6-(2-(((f?)-1 ,4-dιoxan-2-yl)methyl)-2H-tetrazol-5-y1 )-λ/-(3-methoxybenzyl)-2- methylpyrιmιdιne-4-carboxamιde, Example 53) (54 mg, 0 46 mmol), pyridine (41 μL, 0 50 mmol, 1 10 equiv ), and tπfluoromethanesulfonic anhydride (85 μL, 0 50 mmol, 1 10 equiv ) to afford the title compound as a tan oil (96 mg, 84%)

Step 2 Preparation of 6-(1 -(((/?)-1 ,4-dιoxan-2-yl)methyl)-1 /-/-1 ,2,3-trιazol-4-yl)-λ/-(4-fluoro-3- methoxybenzyl)-2-methylpyrιrnιdιne-4-carboxamιde

The title compound was prepared in a similar manner to ((2S,5S)-5-((4-(6-((4-fluoro-3- methoxybenzyl)carbamoyl)-2-methylpyrιmιdιn-4-yl)-1 H-1 ,2,3-trιazol-1 -yl)methyl)-1 ,4-dιoxan-2-yl)methyl 4-methylbenzenesulfonate (step 6, Example 128) by reaction of (S)-(1 , 4-dιoxan-2-yl)methyl trifluoromethanesulfonate (96 mg, 0 38 mmol, 1 30 equiv ), sodium azide (20 mg, 0 31 mmol, 1 05 equiv ), λ/-(4-fluoro-3-methoxybenzyl)-6-ethynyl-2-methylpyrιmιdι ne-4-carboxamιde (prepared as described in step 4 of the synthesis of λ/-(4-fluoro-3-methoxybenzyl)-6-(1-(((2S,5R)-5-(hydroxymeth yl)- 1 ,4-dιoxan-2-yl)methyl)-1 H-1 ,2,3-trιazol-4-yl)-2-methylpyrιmιdιne-4-carboxamιde, Example 128) (88 mg, 0 30 mmol), 1 0 M aqueous sodium ascorbate (30 μL, 0 030 mmol, 0 10 equiv ), and 0 30 M aqueous copper (II) sulfate (20 μL, 0 006 mmol, 0 02 equiv ) Purification by silica gel chromatography (gradient 1 2 heptane/EtOAc to 100% EtOAc) provided the title compound as a white solid (95 mg, 73%) MS (ES+) m/z 443 (M+H) ¹ H NMR (400 MHz, DMSOd ₆ ) δ 9 47 (1 H, t, J=Q 2 Hz), 8 82 (1 H, s), 8 33 (1 H, s), 7 1 1 - 7 22 (2 H, m), 6 85 - 6 94 (1 H, m), 4 51 - 4 63 (2 H, m), 4 49 (2 H, d, J=6 6

Hz), 3 96 - 4 05 (1 H, m), 3 79 - 3 87 (4 H, m), 3 75 (1 H, d, J=1 1 5 Hz), 3 64 (1 H, d, J= 1 1 2 Hz), 3 51 - 3 59 (1 H, m), 3 41 - 3 49 (1 H, m), 3 25 - 3 32 (1 H, m), 2 75 (3 H, s)

Example 147

W-(4-Fluoro-3-methoxybenzyl)-6-(1-(((2S,5/?)-5-amιno-tet rahydro-2W-pyran-2-yl)methyl)-1H-1 ,2,3- trιazol-4-yl)-2-methylpyrimidine-4-carboxamide

Step 1 Preparation of ((2S,5f?)-5-(terf-butoxycarbonyl)-tetrahvdro-2/-/-pyran-2-yl )methyl 2,2,2- trifluoroethanesulfonate

terf-Butyl (3f?,6S)-6-(hydroxymethyl)-tetrahydro-2/-/-pyran-3-ylcarbama te (prepared from commercially available tri-O-acetyl-D-glucal according to the method described by Overkleeft and coworkers, see KÏ€ek, N M A J et al Eur J Org Chem 2003, 2418-2427) (75 mg, 0 32 mmol), 2,2,2-trιfluoroethanesulfonyl chloride (43 μl, 0 39 mmol, 1 20 equiv ), and triethylamine (59 μL, 0 42 mmol, 1 30 equiv ) were combined in dichloromethane (2 0 mL) After stirring for 2 hours at 0 ⁰ C, the mixture was diluted with dichloromethane (10 mL) and 10% aqueous sodium bisulfate (3 mL) The layers were separated and the aqueous layer was washed with dichloromethane (3 x 1 mL) The organics were combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a faint yellow residue Purification by silica gel chromatography (gradient 2 1 heptane/EtOAc to 100% EtOAc) provided the title compound as a white solid (1 11 mg, 91 %) ¹ H NMR (400 MHz, CDCI ₃ ) δ 4 33 (2 H, d, J=4 8 Hz), 4 27 (1 H, br s ), 3 88 - 4 19 (3 H, m), 3 48 - 3 70 (2 H, m), 3 03 (1 H, t, J=10 8 Hz), 2 06 - 2 25 (1 H, m), 1 65 - 1 79 (1 H, m), 1 46 - 1 58 (1 H, m), 1 45 (9 H, s), 1 24 - 1 40 (1 H, m)

Step 2 Preparation of tert-butyl (3R6S)-6-((4-(6-((4-fluoro-3-methoxybenzyl)carbamoyl)-2- methylpyrιmιdιn-4-yl)-1 /-/-1 ,2,3-trιazol-1 -yl)methyl)-tetrahvdro-2/-/-pyran-3-ylcarbamate

((2S,5f?)-5-(fer -Butoxycarbonyl)-tetrahydro-2H u-pyraon-2-yl)methyl 2,2,2- tπfluoroethanesulfonate (97 mg, 0 26 mmol) and sodium azide (18 mg, 0 28 mmol, 1 10 equiv ) were combined in λ/,λ/-dιmethylformamιde (0 50 mL) After stirring for 18 hours at room temperature, the

reaction vessel was charged sequentially with λ/,λ/-dιmethylformamιde (1 0 mL), water (0 50 mL), N- (4-fluoro-3-methoxybenzyl)-6-ethynyl-2-methylpyrιmιdιne-4 -carboxamιde (prepared as described in step 4 of the synthesis of λ/-(4-fluoro-3-methoxybenzyl)-6-(1-(((2S,5/?)-5-(hydroxymet hyl)-1 ,4-dιoxan- 2-yl)methyl)-1 /-/-1 ,2,3-trιazol-4-yl)-2-methylpyrιmιdιne-4-carboxamιde, Example 128) (77 mg, 0 26 mmol, 1 00 equiv ), 1 0 M aqueous sodium ascorbate (26 μl_, 0 026 mmol, 0 10 equiv ), and 0 30 M aqueous copper (II) sulfate (17 μl_, 0 005 mmol, 0 02 equiv ) After stirring for 15 hours at room temperature, water (15 mL) was added, the precipitate was collected by suction filtration, and the filter cake was washed with water (3x) The solid was dissolved in ethyl acetate, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a solid residue Purification by silica gel chromatography (gradient 1 1 heptane/EtOAc to 100% EtOAc) provided the title compound as a pale yellow solid (95 mg, 66%) LC/MS (5%-100% CH ₃ CN H ₂ O, 5 mm) 3 61 mm, m/z 556 (M+H)

Step 3 Preparation of λ/-(4-fluoro-3-methoxybenzyl)-6-(1 -(((2S,5ff)-5-amιno-tetrahvdro-2/-/-pyran-2- yl)methylH H-1 ,2,3-trιazol-4-yl)-2-methylpyrιmιdιne-4-carboxamιde

tert-Butyl (3R,6S)-6-((4-(6-((4-fluoro-3-methoxybenzyl)carbamoyl)-2-met hylpyrιmιdιn-4-yl)-1 H-

1 ,2,3-trιazol-1 -yl)methyl)-tetrahydro-2H-pyran-3-ylcarbamate (95 mg, 0 17 mmol) was dissolved in 4 0 N hydrochloric acid in 1 ,4-dιoxane (1 0 mL, 4 00 mmol, 23 5 equiv ) After stirring for 2 hours at room temperature, the mixture was concentrated under reduced pressure The residue was dissolved in methanol, concentrated under reduced pressure, and dried under high vacuum to afford the title compound as the hydrochloride salt (84 mg, >95%)

Example 148

W-(4-Fluoro-3-methoxybenzyl)-6-(1-(((2S,5/?)-5-acetamido- tetrahydro-2W-pyran-2-yl)methyl)-1 H- 1 ,2,3-triazol-4-yl)-2-methylpyrimidine-4-carboxamide

The hydrochloride salt of λ/-(4-fluoro-3-methoxybenzyl)-6-(1 -(((2S,5R)-5-amιno-tetrahydro-2/-/- pyran-2-yl)methyl)-1 /-/-1 ,2,3-trιazol-4-yl)-2-methylpyrιmιdιne-4-carboxamιde (prepared as described in Example 147) (84 mg), triethylamine (71 μL, 0 51 mmol, 3 00 equiv ), and acetyl chloride (24 μL, 0 34 mmol, 2 00 equiv ) were combined in dichloromethane (1 2 mL) After stirring for 15 hours at room temperature, methanol (2 mL) was added and the mixture concentrated under reduced pressure to give a salty residue Purification by silica gel chromatography (gradient 100% EtOAc to 10%

MeOH/EtOAc) provided the title compound as a white solid (60 mg, 71 %) MS (ES+) m/z 498 (M+H)

¹ H NMR (400 MHz, DMSO-c/ ₆ ) δ 9 47 (1 H, t, J=Q 3 Hz), 8 77 (1 H, s), 8 33 (1 H, s), 7 74 (1 H, d, J=7 1 Hz), 7 08 - 7 24 (2 H, m), 6 82 - 6 96 (1 H, m), 4 55 - 4 64 (1 H, m), 4 43 - 4 54 (3 H, m), 3 70 - 3 86 (5 H, m), 3 52 - 3 67 (1 H, m), 2 92 (1 H, t, J=10 6 Hz), 2 75 (3 H, s), 1 83 - 1 95 (1 H, m), 1 68 - 1 82 (4 H, m), 1 20 - 1 50 (2 H, m)

Example 149

/V-(4-Fluoro-3-methoxybenzyl)-6-(5-(((2S,5/?)-5-(hydroxym ethyl)-1 ,4-dioxan-2-yl)methyl)-1,2,4- oxadiazol-3-yl)-2-methylpyrimidine-4-carboxamide

Step 1 Preparation of ((2S,5S)-5-(cvanomethyl)-1 ,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate

Potassium cyanide (580 mg, 8 91 mmol) was added to a solution of ((2S,5R)-5-

((tπfluoromethylsulfonyloxy)methyl)-1 ,4-dιoxan-2-yl)methyl 4-methylbenzenesulfonate (prepared as described in step 5 of the synthesis of λ/-(4-fluoro-3-methoxybenzyl)-6-(1 -(((2S,5/ ^: ?)-5-(hydroxymethyl)- 1 ,4-dιoxan-2-yl)methyl)-1 /-/-1 ,2,3-tπazol-4-yl)-2-methylpyrιmιdιne-4-carboxamιde, Example 128) (3 87 g, 8 91 mmol) in acetonitrile (30 ml_) and water (3 ml) The mixture was stirred for 2 hours at room temperature and then was concentrated The residue washed with water and dried to afford the title compound as a solid (2 17 g, 78%)

Step 2 Preparation of ((2S,5S)-5-(2-oxoethyl)-1 ,4-dιoxan-2-yl)methyl 4-methylbenzenesulfonate

A diisobutylaluminum hydride solution (1 M in dichloromethane, 17 4 mL, 17 4 mmol) was added to a solution of ((2S,5S)-5-(cyanomethyl)-1 ,4-dιoxan-2-yl)methyl 4-methylbenzenesulfonate (2 17 g, 6 97 mmol) in dichloromethane (60 mL) cooled in a dry ice/acetone bath The mixture was stirred at -78 ⁰ C for 1 hour 1 N Hydrochloric acid solution (25 mL) was added and the mixture was allowed to warm to room temperature The mixture was poured into water (100 mL) and extracted with ethyl acetate (3x) The combined organic layers were dried over magnesium sulfate and concentrated The residue was purified by reverse phase preparative HPLC to afford the title compound (553 mg, 25%) ¹ H NMR (400 MHz, CDCI ₃ ) δ ppm 2 32 - 2 42 (m, 1 H), 2 44 (s, 3 H), 2 47 - 2 58 (m, 1 H), 3 25

- 3 48 (m, 2 H), 3 67 - 3 83 (m, 3 H), 3 89 - 4 03 (m, 3 H), 7 34 (d, J=8 01 Hz, 2 H), 7 77 (d, J=8 40 Hz, 2 H), 9 57 - 9 80 (m, 1 H)

Step 3 Preparation of ((2S,5S)-5-((((4-methylphenyl)sulfonyl)oxy)methv0-1 ,4-dioxan-2-yl)acetic acid

((2S,5S)-5-(2-oxoethyl)-1 ,4-dιoxan-2-yl)methyl 4-methylbenzenesulfonate (390 mg, 1 24 mmol) was dissolved in f-butanol (20 mL) A 2M solution of 2-methyl-2-butene (12 4 mL, 24 8 mmol) was added to the stirring mixture followed by a solution of sodium chlorite (1 12 g, 10 mmol) and mono-sodium phosphate (monobasic) monohydrate (2 23 g, 13 0 mmol) in water (10 mL) The mixture was stirred at room temperature for 18 hours The reaction mixture was diluted with dichloromethane and saturated aqueous ammonium chloride The layers were separated and the aqueous layer was extracted with dichloromethane (3x) The combined organic layers were dried over magnesium sulfate and concentrated to afford the title compound as an oil which crystallized upon standing (515 mg) MS (ES+) m/z 331 (M+H)

Step 5 Preparation of ((2S,5S)-5-(2-(((6-(((4-fluoro-3-methoxybenzyl)amιno)carbon yl)-2- methylpyrιmιdιn-4-yl)(hγdroxyιmιno)methyl)amιno)-2-ox oethyl)-1 ,4-dιoxan-2-yl)methyl 4- methylbenzenesulfonate

A mixture of λ/-(4-fluoro-3-methoxybenzyl)-6-(carbamιmιdoyl)-2-methylp yrιmιdιne-4- carboxamide (prepared as described in step 2 of the synthesis of λ/-(4-fluoro-3-methoxybenzyl)-6-(5- ((/rans-4-ammocyclohexyl)methyl)-1 ,2,4-oxadiazol-3-yl)-2-methylpyrimidine-4-carboxamide, Example 122) (353 mg, 1 06 mmol), ((2S,5S)-5-((((4-methylphenyl)sulfonyl)oxy)methyl)-1 ,4-dιoxan-2-yl)acetιc acid (350 mg, 1 06 mmol), 1 -hydroxybenzotrιazole ( 143 mg, 1 06 mmol), dnsopropylethylamine (0 55 mL, 3 18 mmol), and polymer supported-carbodiimide resin (2 86 g, 3 18 mmol) in acetonitrile (10 mL) was stirred at 40 ⁰ C for 42 hours The reaction mixture was filtered and the resin was washed with acetonitrile The filtrate was concentrated and the residue was purified by reverse phase preparative HPLC to afford the title compound as a solid (155 mg, 23%)

Step 6 Preparation of λλ(4-fluoro-3-methoxybenzyl)-6-(5-(((2S,5R)-5-(hvdroxymeth yl)-1 ,4-dιoxan-2- yl)methyl)-1 ,2,4-oxadιazol-3-yl)-2-methylpyrιmιdιne-4-carboxamιde

A solution of ((2S,5S)-5-(2-(((6-(((4-fluoro-3-methoxybenzyl)amιno)carbon yl)-2- methylpyrιmιdιn-4-yl)(hydroxyιmιno)methyl)amιno)-2-oxo ethyl)-1 ,4-dιoxan-2-yl)methyl A- methylbenzenesulfonate (134 mg, 0 209 mmol) in acetonitrile (5 mL) was treated with MP-carbonate resin and heated to 65 ⁰ C for 18 hours The resin was filtered and washed with acetonitrile The filtrate was concentrated to a volume of 5 mL Tetrabutyl ammonium acetate (126 mg, 0 418 mmol) was added and the mixture was heated to 65 ⁰ C for 5 hours The mixture was then treated with a 2 5 M sodium hydroxide solution (1 mL) and the solution was stirred at room temperature for 18 hours After reaction mixture was purified by reverse phase preparative HPLC The crude product was dissolved in ethyl acetate and washed several times with a saturated solution of ammonium chloride The organic layer was dried over magnesium sulfate and concentrated to afford the title compound as an oil (22 mg, 11 %) MS (ES+) m/z 474 (M+H) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1 25 (d, J=5 49 Hz, 2 H), 2 83 (s, 3 H), 3 07 - 3 22 (m, 2 H), 3 31 - 3 54 (m, 4 H), 3 74 - 3 87 (m, 4 H), 4 50 (d, J=Q 22 Hz, 2 H), 4 60 - 4 72 (m, 1 H), 5 28 (dd, 1 H), 6 80 - 6 98 (m, 1 H), 7 06 - 7 25 (m, 2 H), 8 33 (s, 1 H), 9 43 - 9 60 (m, 1 H)

Example 150

6-(5-((2R)-1 ,4-Dioxan-2-ylmethyl)-1,2,4-oxadiazol-3-yl)-/V-(4-fluoro-3-m ethoxybenzyl)-2- methylpyrimidine-4-carboxamide

Step 1 Preparation of (2R)- 1 ,4-dιoxan-2-ylacetonιtrιle

Potassium cyanide (2 27 g) was added to (S)-(1 , 4-dιoxan-2-yl)methyl tπfluoromethanesulfonate (prepared as describe in step 1 of the synthesis of 6-(1 -(((R)-1 ,4-dιoxan-2- yl)methyl)-1H-1 ,2,3-trιazol-4-yl)-λ/-(4-fluoro-3-methoxybenzyl)-2-methylp yrιmιdιne-4-carboxamιde, Example 146) (7 3 g, 29 0 mmol) in a mixture of acetonitrile (60 mL) and water (6 mL) The mixture was stirred at room temperature for 18 hours and was then concentrated The residue was taken up

in ethyl acetate and washed with water (2x) The organic layer was dried over sodium sulfate to afford the title compound as an oil (3 23 g, 87%) MS (ES+) m/z 128 (M+H)

Step 2 Preparation of methyl (2/?)-1 ,4-dιoxan-2-ylacetate (2R)-1 ,4-dιoxan-2-ylacetonιtrιle (3 2 g, 25 0 mmol) was dissolved in methanol (10 mL) and HCI gas was bubbled through the mixture for several minutes The resulting solution was stirred at room temperature for 1 hour Water (2 mL) was added and most of the solvent was removed in vacuo The residue was taken up in ethyl acetate and washed with a saturated sodium bicarbonate solution The organic layer was dried over magnesium sulfate, and concentrated to afford the title compound as an oil MS (ES+) m/z 161 (M+H)

Step 3 Preparation of (2ff)-1 ,4-dιoxan-2-ylacetιc acid

A mixture of methyl (2/?)-1 ,4-dιoxan-2-ylacetate (300 mg, 1 87 mmol), tetrahydrofuran (5 mL), water (1 mL), and lithium hydroxide (359 mg, 15 0 mmol) was stirred at room temperature for 18 hours The mixture was acidified with the addition of 3N hydrochloric acid and then passed through a Chem Elute extraction column eluting with ethyl acetate The eluant was concentrated to afford the title compound as a solid (262 mg, 96%) MS (ES+) m/z 147 (M+H)

Step 4 Preparation of 6-(5-((2R)- 1 ,4-dιoxan-2-ylmethyl)-1 ,2,4-oxadιazol-3-yl)-λ/-(4-fluoro-3- methoxybenzyl)-2-methylpyrιmιdιne-4-carboxamιde

A mixture of λ/-(4-fluoro-3-methoxybenzyl)-6-(carbamιmιdoyl)-2-methylp yrιmιdιne-4- carboxamide (prepared as described in step 2 of the synthesis of λ/-(4-fluoro-3-methoxybenzyl)-6-(5- ((/rans^-aminocyclohexyOmethylJ-i ^^-oxadiazol-S-yO^-methylpyÏ€midine^-carboxamide, Example 122) (100 mg, 0 30 mmol), (2R)-1 ,4-dιoxan-2-ylmethanol (87 mg, 0 60 mmol), 1 -hydroxybenzotrιazole (61 mg, 0 45 mmol), polymer supported-carbodiimide resin (81 1 mg, 0 90 mmol), and diisopropylamine (0 16 mL, 0 90 mmol) in acetonitrile (5 mL) was heated to 40 °C for 3 days The reaction mixture was filtered and the resin was washed with a minimal amount of acetonitrile The filtrate was then treated with MP-carbonate resin (523 mg, 1 5 mmol) and heated to 65 ⁰ C for 18 hours The mixture was filtered and the resin was washed with acetonitrile The filtrate was concentrated and the residue was purified by reverse phase preparative HPLC to afford the title compound as a solid (16 mg, 12%) MS (ES+) m/z 444 (M+H) ¹ H NMR (400 MHz, DMSO-Cf ₆ ) δ ppm 2 82 (s, 3 H), 3 13 - 3 20 (m, 1 H), 3 22 - 3 31 (m, 2 H), 3 42 - 3 50 (m, 1 H), 3 54 - 3 66 (m, 2 H), 3 68

- 3 73 (m, 1 H), 3 77 - 3 89 (m, 4 H), 4 00 - 4 08 (m, 1 H), 4 48 (d, J=6 22 Hz, 2 H), 6 88 (ddd, J=& 33, 4 30, 2 01 Hz, 1 H), 7 09 - 7 19 (m, 2 H), 8 32 (s, 1 H), 9 55 - 9 62 (m, 1 H)

Example 151

6-(5-((2S)-1 ,4-Dioxan-2-ylmethyl)-1 ,2,4-oxadiazol-3-yl)-/V-(4-fluoro-3-methoxybenzyl)-2- methylpyrimidine-4-carboxamide

The title compound was prepared in a similar manner to 6-(5-((2R)-1 ,4-dιoxan-2-ylmethyl)- 1 ,2,4-oxadιazol-3-yl)-λ/-(4-fluoro-3-methoxybenzyl)-2-methy lpyrιmιdιne-4-carboxamιde (Example 150) starting from (S)- 1 ,4-dιoxan-2-ylmethanol (prepared as described in step 1 of the synthesis of 6-(2- (((S)-1 ,4-dιoxan-2-yl)methyl)-2H-tetrazol5-yl)-/V-(3-methyoxybenzy l)-2-methylpyrιmιdιne-4- carboxamide, Example 57) to afford 75 mg (56%) MS (ES+) m/z 444 (M+H) ¹ H NMR (400 MHz, DMSO-Cf ₆ ) δ ppm 2 82 (s, 3 H), 3 12 - 3 21 (m, 1 H), 3 22 - 3 30 (m, 1 H), 3 42 - 3 50 (m, 1 H), 3 55 (d, J=2 56 Hz, 1 H), 3 57 - 3 66 (m, 2 H), 3 68 - 3 73 (m, 1 H), 3 77 - 3 90 (m, 4 H), 4 00 - 4 08 (m, 1 H), 4 48 (d, J=Q 22 Hz, 2 H), 6 88 (ddd, J=8 33, 4 30, 2 01 Hz, 1 H), 7 09 - 7 19 (m, 2 H), 8 32 (s, 1 H), 9 55 - 9 62 (m, 1 H)

Example 152

W-(4-Fluoro-3-methoxybenzyl)-6-(3-(((frans)-4-acetamidocy clohexyl)methyl)isoxazol-5-yl)-2- methylpyrimidine-4-carboxamide

Step 1 Preparation of tert-butyl (frans)-4-((E)-2-(hvdroxyimino)ethyl)cyclohexylcarbamate

tert-Butyl (frans)-4-(2-oxoethyl)cyclohexylcarbamate (403 mg, 1 67 mmol) was dissolved in a mixture of ethanol (12 ml) and water (8 mL) Sodium acetate (407 mg, 4 96 mmol) was added and the mixture was stirred for 30 mm at room temperature Hydroxylamine hydrochloride (363 mg, 5 01 mmol) was added and the mixture was heated to 60 ⁰ C for 1 5 hours The reaction mixture was concentrated to obtain the title compound as a white solid (70 mg)

Step 2 Preparation of tert-butyl (fraπs)-4-((Z)-2-chloro-2-mvdroxyιmιno)ethyl)cycloheχylc arbamate

/V-Chlorosuccinimide (51 5 mg, 0 38 mmol) was added to a solution of tert-butyl (trans)-4-((E)- 2-(hydroxyιmιno)ethyl)cyclohexylcarbamate (99 mg, 0 38 mmol) in acetonιtrιle( 5 mL) and the mixture was stirred at room temperature for 18 hours Additional λ/-chlorosuccιnιmιde was added (25 7 mg,

0 19 mmol) After 4 hours, the reaction mixture was concentrated The residue was suspended in dichloromethane and filtered The filtrate was concentrated to afford the title compound as a white solid (177 mg) LC/MS (5%-95% CH ₃ CN/H ₂ O, 5 mm ) 2 621 mm , m/z 338 (M+H) ¹ H NMR (400 MHz, CDCI ₃ ) δ ppm 1 09 (d, J= 10 16 Hz, 2 H), 1 43 (s, 9 H), 1 77 (d, J=10 94 Hz, 2 H), 2 77 (s, 5 H), 2 92 (s, 1 H), 5 30 (s, 1 H)

Step 3 Preparation of /erf-butyl (fraπs)-4-((5-(6-((4-fluoro-3-methoxybenzyl)carbamoyl)-2- methylpyrimidin^-vDisoxazol-S-yQmethvDcyclohexylcarbamate

tert-Butyl (/rans)-4-((Z)-2-chloro-2-(hydroxyιmιno)ethyl)cyclohexylca rbamate (48 6 mg, 0 16 mmol) was added to a mixture of λ/-(4-fluoro-3-methoxybenzyl)-6-ethynyl-2-methylpyrιmιdι ne-4- carboxamide (prepared as described in step 4 of the synthesis of λ/-(4-fluoro-3-methoxybenzyl)-6-(1 - (((2S,5R)-5-(hydroxymethyl)-1 ,4-dιoxan-2-yl)methyl)-1 H-1 ,2,3-trιazol-4-yl)-2-methylpyrιmιdιne-4- carboxamide, Example 128) (50 1 mg, 0 16 mmol) and tÏ€ethylamine (0 023 mL, 0 16 mmol) in toluene (5 mL) The mixture was stirred at room temperature for 2 hours, then heated to 1 10 ⁰ C for 2 hours, and finally allowed to stir at room temperature for 18 hours The reaction mixture was concentrated and the residue was purified by reverse phase preparative HPLC to afford the title compound as an orange solid (51 7 mg, 46%) LC/MS (5%-95% CH ₃ CN/H ₂ O, 5 mm ) 3 72 mm , m/z 498 (M-C ₄ H ₉ ) ¹ H NMR (400 MHz, CDCI ₃ ) δ ppm 1 02 - 1 20 (m, 4 H), 1 22 - 1 27 (m, 1 H), 1 36 - 1 51 (m, 9 H), 1 58 -

1 72 (m, 1 H), 1 80 (d, J=10 55 Hz, 2 H), 1 94 - 2 06 (m, 2 H), 2 64 (d, J=7 04 Hz, 2 H), 2 74 - 2 82 (m, 3 H), 3 36 (br s , 1 H), 3 84 - 3 91 (m, 3 H), 4 62 (d, J=5 86 Hz, 2 H), 5 28 (s, 1 H), 6 83 - 6 91 (m, 1

H), 6 92 - 6 99 (m, 2 H), 6 99 - 7 07 (m, 1 H), 8 29 - 8 37 (m, 1 H), 8 38 (s, 1 H)

Step 4 Preparation of λ/-(4-fluoro-3-methoxybenzyl)-6-(3-(((frar?s)-4- acetamιdocvclohexvl)methvl)ιsoxazol-5-vl)-2-methvlpvrιmι dιne-4-carboxamιde

Trifluoroacetic acid (1 mL) was added to a solution of fert-butyl (frans)-4-((5-(6-((4-fluoro-3- methoxybenzyl)carbamoyl)-2-methylpyrιmιdιn-4-yl)ιsoxazol -3-yl)methyl)cyclohexylcarbamate (51 mg, 0 076 mmol) in dichloromethane (40 mL) and the mixture was stirred at room temperature for 6 hours The reaction mixture was concentrated and the residue was dissolved in λ/,λ/-dιmethylformamιde (10 mL) Diisopropylethylamine (0 05 mL, 0 30 mmol) and acetic anhydride (0 015 mL, 0 152 mmol) were added and the mixture was stirred at room temperature under nitrogen for 16 hours The reaction mixture was concentrated and the residue was purified by reverse phase preparative HPLC to afford the title compound as a white solid (32 3 mg) LC/MS (5%-95% CH ₃ CN/H ₂ O, 5 mm ) 3 062 mm , m/z 496 (M+H) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1 03 - 1 15 (m, 4 H), 1 17 (d, J=O 73 Hz, 1 H), 1 69 (d, J=1 1 71 Hz, 3 H), 1 73 - 1 79 (m, 5 H), 2 61 (d, J=6 95 Hz, 2 H), 2 79 (s, 3 H), 3 31 (br s , 1 H), 3 44 (dt, J=I 05, 3 61 Hz, 1 H), 3 81 (s, 3 H), 4 48 (d, J=6 59 Hz, 2 H), 6 89 (ddd, J=Q 33, 4 30, 2 01 Hz, 1 H), 7 09 - 7 20 (m, 2 H), 7 41 (s, 1 H), 7 71 (d, J=I 69 Hz, 1 H), 8 20 (s, 1 H), 9 50 - 9 57 (m, 1 H)

Example 153

/V-(3-Methoxybenzyl)-4-(2-(((fraπs)-4-aminocyclohexyl)me thyl)-2H-tetrazol-5-yl)-6- methylpicolinamide

Step 1 Preparation of λ/-terf-butyl-2-chloro-6-methylιsonιcotιnamιde

Oxalyl chloride (95 mL, 1 10 mol) was added to 2-chloro-6-methylιsonιcotιnιc acid (95 g, 0 55 mol) in dichloromethane (950 mL, anhydrous) The mixture was cooled in an ice/water bath and DMF (2 0 mL) was slowly added When gas evolution subsided, the ice/water bath was removed and the mixture was allowed to reach ambient temp and stir for 15 hours The solution was then concentrated in vacuo and azeotroped with toluene (2 x 200 mL) The residue was taken into dichloromethane (800 mL, anhydrous), cooled in an ice/water bath, and a solution of tert-butylamine (175 mL, 1 7 mol) in

dichloromethane (300 mL, anhydrous) was added drop wise The mixture was allowed to reach ambient temp and stir for 15 hours Water (250 mL) was added The organic layer was washed with water (200 mL) followed by brine (200 mL), dried over magnesium sulfate, filtered, and concentrated to afford the title compound as a beige solid (12O g, 96%) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 7 39 (s, 1 H), 7 38 (s, 1 H), 6 05 (s, 1 H), 2 59 (s, 3 H), 1 5 (s, 9 H)

Step 2 Preparation of 2-chloro-6-methylιsonιcotιnonιtrιle

To AZ-tert-butyl^-chloro-β-methylisonicotinamide (120 g, 0 53 mol) in toluene (2 5 L, anhydrous) was added POCI ₃ (572 mL, 6 26 mol) The resulting mixture was refluxed 15 h, cooled to ambient temperature, and concentrated in vacuo The residue was dissolved in dichloromethane (1 0 L) and aqueous saturated sodium bicarbonate (500 mL) was carefully added Solid sodium bicarbonate was then added portion wise until the aqueous layer was basic The organic layer was washed with brine (300 mL), dried (magnesium sulfate), filtered, and concentrated to afford the title compound as a pale tan solid (76 g, 94%) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 7 41 (s, 1 H), 7 37 (s, 1 H), 2 61 (s, 3 H)

Step 3 Preparation of 2-chloro-6-methyl-4-(2/-/-tetrazol-5-yl)pyrιdιne hydrochloride

Triethylamine hydrochloride (72 g, 0 52 mol) and sodium azide (34 g, 0 52 mol) were added to a solution of 2-chloro-6-methylιsonιcotιnonιtrιle (76 g, 0 50 mol) in toluene (1 2 L, anhydrous) The mixture was refluxed for 4 hours behind a blast shield After cooling to ambient temperature, water (1 5 L) was added and the layers were separated The toluene layer was washed with water (500 mL) and the combined aqueous layers were acidified with 6N hydrochloric acid (100 mL) The resulting precipitate was filtered and dried in vacuo (60 ⁰ C) to afford the title compound (105 g) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 7 92 (s, 1 H), 7 89 (s, 1 H), 2 79 (s, 3 H) Step 4 Preparation of methyl 6-methyl-4-(2/-/-tetrazol-5-yl)pιcolιnate

Triethylamine (120 mL), 1 ,1 '-bιs(dιphenylphosphιno)ferrocene (8 0 g, 14 mmol), and Pd(OAc) ₂ (9 2 g, 40 mmol) were added to a solution of 2-chloro-6-methyl-4-(2H-tetrazol-5-yl)pyndine hydrochloride (88 g, 380 mmol) in methanol (1 5 L, anhydrous) in a pressure reactor The reactor was evacuated and purged with carbon monoxide gas twice and finally pressurized to 120 PSI and heated

to 100 ⁰ C for 24 hr (190 PSI reached) An aliquot was taken and analyzed by HPLC revealing consumption of the starting material After cooling to ambient temp, the mixture was filtered through Celiteâ„¢ and concentrated in vacuo Water (700 mL) and aq saturated NaHCO ₃ (200 mL) were added to provide an almost clear solution 3N hydrochloric acid was added until a pH of 2 was reached The resulting solid was filtered and dried in vacuo (50 ⁰ C) until constant weight (78 g, 94%) ¹ H NMR (400 MHz, DMSO-CZ ₆ ) δ ppm 8 48 (s, 1 H), 8 15 (s, 1 H), 3 95 (s, 3 H), 2 67 (s, 3 H)

Step 5 Preparation of /V-(3-methoxybenzyl)-6-methyl-4-(2/-/-tetrazol-5-yl)pιcolι namιde

A mixture of methyl 6-methyl-4-(2H-tetrazo!-5-yl)pιcolιnate (3 29 g, 15 0 mmol) and 3- methoxybenzylamine (6 17 g, 45 0 mmol) was heated at 100 ⁰ C with removal of methanol in a stream of nitrogen for 1 hour A solution of 1 N hydrochloric acid (50 mL) was added The resulting precipitate was filtered and washed with ethyl ether The solid was suspended in a solution of 2 5 N sodium hydroxide (30 mL)/water (50 mL) and extracted with ethyl acetate ( 2 x 50 mL) The aqueous layer was cooled in an ice bath and acidified to pH 1 with concentrated hydrochloric acid The resulting precipitate was filtered and dried to afford the title compound as a white solid (4 69 g, 96%) MS (ES+) m/z 325 (M+H) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9 28 (t, J=Q 3 Hz, 1 H), 8 49 (d, J= 0 8 Hz, 1 H), 8 13 (d, J=1 2 Hz, 1 H), 7 24 (t, J=8 1 Hz, 1 H), 6 94-6 90 (m, 2 H), 6 82 (dd, J=Q 0, 2 1 Hz, 1 H), 4 51 (d, J=& 3 Hz, 2 H), 3 73 (s, 3 H), 2 68 (s, 3 H)

Step 6 Preparation of terf-butyl (frans)-4-((5-(2-((3-methoxybenzyl)carbamoyl)-6-methylpyrιd ιn-4-yl)- 2/-/-tetrazol-2-yl)methyl)cvclohexylcarbamate

λ/-(3-Methoxybenzyl)-6-methyl-4-(2/-/-tetrazol-5-yl)pιcolÎ ¹namιde (1 62 g, 5 0 mmol), polymer supported tÏ€phenylphosphine (3 49 g, 7 5 mmol), and terf-butyl trans-{4- hydroxymethyl)cyclohexylcarbamate (1 38 g, 6 0 mmol) were suspended in tetrahydrofuran (100 mL) Di-tert-butyl azodicarboxylate (1 73 g, 7 5 mmol) was added The mixture was allowed to stir for 18 hours The reaction mixture was filtered and the resin washed with THF (100 mL) The filtrate was concentrated The crude product was purified by silica column chromatography (CH ₂ CI ₂ /methanol, 100/1 , 100/2) Combined fractions were concentrated onto silica and repurified by silica column chromatography (heptane/EtOAc, 2/1 , 1/1 ) Combined fractions were concentrated The resulting solid was slurried in heptane and filtered to afford the title compound as a white solid (1 824 g, 68%) MS (ES+) m/z 536 (M+H) ¹ H NMR (400 MHz, DMSO-Cf ₆ ) δ ppm 9 23 (t, J=Q 3 Hz, 1 H), 8 40 (d, J=O 8 Hz,

1 H), 8 05 (d, J=1 1 Hz, 1 H), 7 21 (t, J=8 1 Hz, 1 H), 6 86 - 6 90 (m, 2 H), 6 79 (dd, J=Q 2, 1 9 Hz, 1 H), 6 68 (d, J=I 8 Hz, 1 H), 4 63 (d, J=I 0 Hz, 2 H), 4 48 (d, J=6 3 Hz, 2 H), 3 70 (s, 3 H), 3 13 (br s , 1 H), 2 64 (s, 3 H), 1 90 (br s , 1 H), 1 71 - 1 77 (m, 2 H), 1 53 - 1 59 (m, 2 H), 1 33 (s, 9 H), 1 06 - 1 14 (m, 4 H)

Step 7 Preparation of λ/-(3-methoxybenzyl)-4-(2-(((/rans)-4-amιnocvdohexyl)methy l)-2H-tetrazol-5-yl)- 6-methylpιcolιnamιde

terf-Butyl (frans)-4-((5-(2-((3-methoxybenzyl)carbamoyl)-6-methylpyrιd ιn-4-yl)-2H-tetrazol-2- yOmethyOcyclohexylcarbamate (1 82 g, 3 40 mmol) was dissolved in dichloromethane (20 mL) and trifluoroacetic acid (5 05 mL, 68 0 mmol) was added The mixture was allowed to stand for 2 hours and was then concentrated The residue was dissolved in dichloromethane (150 mL) and washed with 1 N NaOH solution (2 x 40 mL) The organic layer was dried over sodium sulfate and concentrated The residue was triturated with heptane and filtered to afford the title compound as a white solid (1 407 g, 95%) MS (ES+) m/z 436 (M+H) ¹ H NMR (400 MHz, DMSO-Cf ₆ ) δ ppm 9 23 (t, J=6 3 Hz, 1 H), 8 39 (d, J=O 8 Hz, 1 H), 8 05 (d, J= 1 2 Hz, 1 H), 7 21 (t, J=8 1 Hz, 1 H), 6 90 - 6 86 (m, 2 H), 6 79 (dd, J=8 2, 1 9 Hz, 1 H), 4 62 (d, J=7 1 Hz, 2 H), 4 48 (d, J=6 3 Hz, 2 H), 3 70 (s, 3 H), 2 64 (s, 3 H), 2 45 - 2 37 (m, 1 H), 1 96 - 1 84 (m, 1 H), 1 71 (d, J=12 0 Hz, 2 H), 1 53 (d, J=12 2 Hz, 2 H), 1 37 (br s , 2 H), 1 07 (q, J=12 8 Hz, 2 H), 1 01 - 0 88 (m, J=10 6, 10 6, 10 6 Hz, 2 H)

Example 154 N^S-MethoxybenzyO-e-methyM^Z^^fraπsJ^^methylsulfonamidoJcyc lohexyOmethyO^H- tetrazol-5-yl)picolinamide

Triethylamine (0 096 mL, 0 690 mmol) and methane sulfonyl chloride (0 021 mL, 0 276 mmol) were added to a solution of /V-(3-methoxybenzy!)-4-(2-(((frans)-4-amιnocyclohexyl)methy l)-2H-tetrazol- 5-yl)-6-methylpιcolιnamιde (prepared as described in Example 153) (100 0 mg, 0 230 mmol) in dichloromethane (2 mL) The mixture was stirred for 2 hours at room temperature Volatiles were removed under a nitrogen stream The residue was purified by reverse phase preparative HPLC (5%- 95% CH ₃ CN/H ₂ O, 8 mm) to afford the title compound as a solid (28 2 mg, 24%) LC/MS (5%-95% CH ₃ CN/H ₂ O, 4 5 mm , 95% CH ₃ CN, 1 5 mm ) 3 148 mm , m/z 514 (M+H) ¹ H NMR (400 MHz, DMSO- d _β ) δ ppm 0 95 - 1 32 (m, 4 H), 1 49 - 1 69 (m, 2 H), 1 78 - 2 04 (m, 3 H), 2 65 (s, 3 H), 2 86 (s, 3 H),

3 71 (s, 3 H), 4 49 (d, J=5 9 Hz, 2 H), 4 64 (d, J=I 3 Hz, 2 H), 6 77 - 6 82 (m, 1 H), 6 90 (m, 2 H), 6 93 (s, 1 H), 7 12 - 7 29 (m, 1 H), 8 05 (s, 1 H), 8 41 (s, 1 H), 9 04 - 9 31 (m, 1 H)

Example 155

W-(3-Methoxybenzyl)-4-(2-(((frans)-4-(ethylsulfonamido)cy clohexyl)methyl)-2W-tetrazol-5-yl)-6- methylpicolinamide

Triethylamine (0 096 mL, 0 690 mmol) and ethane sulfonyl chloride (44 3 mg, 0 344 mmol) were added to a solution of λ/-(3-methoxybenzyl)-4-(2-(((frans)-4-amιnocyclohexyl)meth yl)-2/-/-tetrazol- 5-yl)-6-methylpιcolιnamιde (prepared as described in Example 153) (100 0 mg, 0 230 mmol) in tetrahydrofuran (2 mL) The mixture was stirred overnight at room temperature Volatiles were removed under a nitrogen stream The residue was purified by reverse phase preparative HPLC (5%- 95% CH ₃ CN/H ₂ O, 8 mm) to afford the title compound as a solid (9 9 mg, 8%) LC/MS (5%-95% CH ₃ CN/H ₂ O, 4 5 mm , 95% CH ₃ CN, 1 5 mm ) 3 252 mm , m/z 528 (M+H) ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 0 96 - 1 36 (m, 7 H), 1 52 - 1 70 (m, 2 H), 1 78 - 1 90 (m, 2 H), 1 89 - 2 10 (m, 1 H), 2 65 (s, 3 H), 2 94 - 3 09 (m, 1 H), 3 71 (s, 3 H), 4 49 (d, J=6 6 Hz, 2 H), 4 63 (d, J=6 6 Hz, 2 H), 6 73 - 6 84 (m, 1 H), 6 86 - 6 92 (m, 2 H), 6 92 - 7 01 (m, 1 H), 7 15 - 7 27 (m, 1 H), 8 05 (s, 1 H), 8 40 (s, 1 H), 9 10 - 9 25 (m, 1 H)

Example 156

W-(3-Methoxybenzyl)-4-(2-(((frans)-4-(cyclopropanesulfona mido)cyclohexyl)methyl)-2H-tetrazol- 5-yl)-6-methylpicolinamide

The title compound was prepared in a similar manner to λ/-(3-methoxybenzyl)-4-(2-(((frans)-4- (ethylsulfonamidoJcyclohexyOmethyO^H-tetrazol-S-yO-θ-methyl picolinamide (Example 155) by reaction with cyclopropane sulfonyl chloride and afforded 22 3 mg (18%) as a solid LC/MS (5%-95% CH ₃ CN/H ₂ O, 4 5 mm , 95% CH ₃ CN, 1 5 mm ) 3 310 mm , m/z 540 (M+H) ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 0 80 - 0 95 (m, 4 H), 1 04 - 1 33 (m, 4 H), 1 51 - 1 68 (m, 2 H), 1 83 - 2 01 (m, 2 H), 2 41 - 2 55 (m, 1 H), 2 65 (s, 3 H), 2 96 - 3 14 (m, 1 H), 3 71 (s, 3 H), 4 49 (d, J=5 9 Hz, 2 H), 4 64 (d, J=6 6 Hz, 2 H), 6 73 - 6 84 (m, 1 H), 6 86 - 6 93 (m, 2 H), 6 93 - 7 02 (m, 1 H), 7 13 - 7 29 (m, 1 H), 8 05 (s, 1 H), 8 40 (S, 1 H), 9 11 - 9 27 (m, 1 H)

Example 157

W-(3-Methoxybenzyl)-4-(2-(((frans)-4-(butylsulfonamido)cy clohexyl)methyl)-2W-tetrazol-5-yl)-6- methytpicolinamide

The title compound was prepared in a similar manner to λ/-(3-methoxybenzyl)-4-(2-(((frans)-4-

(ethylsulfonamido)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6-met hylpicolmamide (Example 155) by reaction with butane sulfonyl chloride and afforded 45 6 mg (36%) as a solid LC/MS (5%-95% CH ₃ CN/H ₂ O, 4 5 mm, 95% CH ₃ CN, 1 5 mm ) 3 574 mm , 556 (M+H) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0 77 - 0 91 (m) 1 07 - 1 47 (m) 1 48 - 1 91 (m) 1 91 - 2 05 (m, 1 H), 2 65 (s, 3 H), 2 83 - 3 01 (m) 3 48 - 3 65 (m, 1 H), 3 71 (s, 3 H), 4 49 (d, J=Q 59 Hz, 2 H), 4 66 (d, J=I 32 Hz, 2 H), 6 76 - 6 82 (m, 1 H), 6 87 - 6 97 (m) 7 17 - 7 26 (m, 1 H), 8 05 (s, 1 H), 8 41 (s, 1 H), 9 15 - 9 25 (m)

Example 158

^-(S-MethoxybenzylM-^-Mfrans^-acetamidocyclohexylJmethyl^ H-tetrazol-S-yO-β- methylpicolinamide

Acetic anhydride (0 033 mL, 0 344 mmol) and silica-bound 4-(dιmethylamιno)pyrιdιne (833 0 mg, 0 575 mmol, 0 69 mmol/g loading) were added to a solution of λ/-(3-methoxybenzyl)-4-(2-(((frans)- 4-ammocyclohexyl)methyl)-2H-tetrazol-5-yl)-6-methylpιcolιn amιde (prepared as described in Example 153) (50 1 mg, 0 1 15 mmol) in dichloromethane (2 mL) The reaction mixture was agitated overnight at room temperature, filtered, and washed with λ/,λ/-dιmethylformamιde The filtrate was concentrated under a stream of nitrogen The residue was purified by reverse phase preparative HPLC (5%-95% CH ₃ CN/H ₂ O, 8 mm) to afford the title compound (22 4 mg, 41 %) LC/MS (5%-95% CH ₃ CN/H ₂ O, 4 5 mm , 95% CH ₃ CN, 1 5 mm ) 2 994 mm , m/z 478 (M+H) ¹ H NMR (400 MHz, DMSOd ₆ ) δ ppm 0 99 - 1 28 (m, 4 H), 1 60 (m, 2 H), 1 73 (s, 3 H), 1 74 - 1 81 (m, 3 H), 1 89 - 2 06 (m, 1 H), 2 65 (s, 3 H), 3 71 (s, 3 H), 4 49 (d, J=5 9 Hz, 2 H), 4 64 (d, J=I 3 Hz, 2 H), 6 75 - 6 83 (m, 1 H), 6 86 - 6 98 (m, 2 H), 7 13 - 7 30 (m, 1 H), 7 63 (s, 1 H), 8 05 (s, 1 H), 8 41 (s, 1 H), 9 06 - 9 25 (m, 1 H)

Example 159

W-(3-Methoxybenzyl)-4-(2-(((frans)-4-isobutyramidocyclohe xyl)methyl)-2H-tetrazol-5-yl)-6- methylpicolinamide

The title compound was prepared in a similar manner to λ/-(3-Methoxybenzyl)-4-(2-(((/rans)-4- acetamιdocyclohexyl)methyl)-2/-/-tetrazol-5-yl)-6-methylpι colιnamιde (Example 158) by reaction with isobutyric anhydride and afforded 22 6 mg (39%) as a solid LC/MS (5%-95% CH ₃ CN/H ₂ O, 4 5 mm , 95% CH ₃ CN, 1 5 mm ) 3 325 mm , m/z 506 (M+H) ¹ H NMR (400 MHz, DMSO-Cf ₆ ) δ ppm 0 93 (s, 3 H), 0 94 (s, 3 H), 1 02 - 1 26 (m, 4 H), 1 54 - 1 66 (m, 2 H), 1 69 - 1 81 (m, 2 H), 1 86 - 2 04 (m, 1 H), 2 18 - 2 36 (m, 1 H) ₁ 2 65 (s, 3 H), 3 71 (s, 3 H), 4 49 (d, J=5 9 Hz, 2 H), 4 65 (d, J=7 3 Hz, 1 H), 6 71 - 6 83 (m, 1 H), 6 86 - 6 98 (m, 2 H), 7 13 - 7 30 (m, 1 H), 7 38 - 7 55 (m, 1 H), 8 05 (s, 1 H), 8 41 (s, 1 H), 9 12 - 9 26 (m, 1 H)

Example 160

2-((<rans)-4-((5-(2-((3-Methoxybenzyl)carbamoyl)-6-met hylpyridin-4-yl)-2H-tetrazol-2-yl)methyl)- cyclohexylamino)-2-oxoethyl acetate

Triethylamine (651 μL, 6 43 mmol), 4-(dιmethylamιno)pyrιdιne (78 5 mg, 0 64 mmol), and acetoxyacetyl chloride (415 μL, 3 86 mmol) were added to a solution of λ/-(3-methoxybenzyl)-4-(2- ((((rans)-4-amιnocyclohexyl)methyl)-2H-tetrazol-5-yl)-6-met hylpιcolιnamιde (prepared as described in Example 153) (1 400 g, 3 21 mmol) in dichloromethane (60 mL) The mixture was allowed to stir at room temperature for 1 hour The reaction mixture was diluted with dichloromethane (150 mL) and washed with saturated aq sodium bicarbonate solution (2 x 40 mL) The organic layer was dried over sodium sulfate and concentrated The crude product was purified by silica column chromatography (CH ₂ CI ₂ /methanol, 100/1 , 100/2) Fractions were concentrated and the oily residue was partially concentrated from a mixture of dichloromethane/heptane/ethyl ether The resulting slurry was filtered to afford the title compound as a white solid (1 513 g, 88%) MS (ES+) m/z 536 (M+H) ¹ H NMR (400 MHz, DMSOd ₆ ) 6 ppm 9 24 (t, J=6 4 Hz, 1 H), 8 40 (d, J=O 8 Hz, 1 H), 8 06 (d, J= 1 2 Hz, 1 H), 7 82 (d, J=7 9 Hz, 1 H), 7 21 (t, J=8 1 Hz, 1 H), 6 90 - 6 86 (m, 2 H), 6 79 (dd, J=7 9, 2 0 Hz, 1 H), 4 65 (d, J=7 0 Hz, 2 H), 4 48 (d, J=6 4 Hz, 2 H), 4 35 (s, 2 H), 3 70 (s, 3 H), 3 49 (br s , 1 H), 2 65 (s, 3 H), 2 03 (s, 3 H), 1 95 (br s , 1 H), 1 78 - 1 71 (m, 2 H), 1 63 - 1 56 (m, 2 H), 1 21 - 1 1 1 (m, 4 H)

Example 161

N-(3-Methoxybenzyl)-4-(2-((((rans)-4-(2-hydroxyacetamido) cyclohexyl)methyl)-2H-tetrazol-5-yl)- 6-methylpicolinamide

2-((frans)-4-((5-(2-((3-Methoxybenzyl)carbamoyl)-6-methylpyÏ €dιn-4-yl)-2H-tetrazol-2- yl)methyl)cyclohexylamιno)-2-oxoethyl acetate (prepared as described in Example 160) (1 50 g, 2 80 mmol) was dissolved in tetrahydrofuran (100 mL) Lithium hydroxide (201 mg, 8 40 mmol) followed by water (35 mL) were added The mixture was stirred for 1 hour and then the tetrahydrofuran was removed in vacuo The residue was added to dichloromethane (100 mL) and washed with water (2 x 20 mL) The organic layer was dried over sodium sulfate and concentrated to afford a foaming solid The residue was dissolved in methanol (10 mL) and seeded The resulting slurry was filtered to afford the title compound as a white crystalline solid (1 233 g, 89%) MS (ES+) m/z 494 (M+H) ¹ H NMR (400 MHz, DMSO-c/ ₆ ) δ ppm 9 23 (t, J=6 4 Hz, 1 H), 8 40 (s, 1 H), 8 06 (d, J= 1 2 Hz, 1 H), 7 41 (d, «7=8 3 Hz, 1 H), 7 21 (t, J=8 1 Hz, 1 H), 6 90 - 6 86 (m, 2 H), 6 79 (dd, J=8 2, 1 9 Hz, 1 H), 5 36 (t, J=5 8 Hz, 1 H), 4 65 (d, J=7 0 Hz, 2 H), 4 48 (d, J=6 4 Hz, 2 H), 3 72 (d, J=5 8 Hz, 2 H), 3 70 (s, 3 H), 3 59 - 3 48 (m, 1 H), 2 65 (s, 3 H), 2 00 - 1 89 (m, 1 H), 1 71 (d, J= 10 6 Hz, 2 H), 1 59 (d, J=13 6 Hz, 2 H), 1 32 - 1 09 (m, 4 H)

Example 162

W-(3-Methoxybenzyl)-4-(2-((((rans)-4-(2-hydroxy-2-methylp ropanamido)cyclohexyl)methyl)-2H- tetrazol-5-yl)-6-methylpicolinamide

A mixture of 2-hydroxy isobutyric acid (10 mg, 0 10 mmol) and 1 -hydroxybenzatrιazole (15 mg, 0 1 1 mmol) in 2- methyl tetrahydrofuran (2 mL) for was stirred for 5 minutes λ/-(3-

Methoxybenzyl)-4-(2-(((frans)-4-amιnocyclohexyl)methyl)-2/- /-tetrazol-5-yl)-6-methylpιcolιnamιde (prepared as described in Example 153) (0 050 g, 0 09 mmol), tÏ€ethylamine (0 015 mL, 0 11 mmol), and polymer supported carbodiimide (0 1 1 g, 0 14 mmol) were added The mixture was stirred for 18 hours at room temperature and was then filtered The filtrate was washed with water (3 x 5 mL) followed by brine (5 mL), dried over anhydrous sodium sulfate, and concentrated The residue was purified by reverse phase preparative HPLC to afford the title compound (21 mg, 45%) ¹ H NMR (400 MHz, DMSO-Cf ₆ ) δ ppm 9 19 (t, J=6 2 Hz, 1 H), 8 41 (s, 1 H), 8 05 (s, 1 H), 7 22 (t, J=8 1 Hz, 2 H), 6 90 (br s , 2 H), 6 80 (d, J=8 8 Hz, 1 H), 4 65 (d, J=6 6 Hz, 2 H), 4 49 (d, J=5 9 Hz, 2 H), 3 71 (s, 3 H), 3 21 - 3 35 (m, 1 H), 2 65 (s, 3 H), 1 91 - 2 05 (m, 1 H), 1 72 (d, J= 1 1 7 Hz, 2 H), 1 60 (d, J= 1 1 7 Hz, 2 H), 1 06 - 1 33 (m, 10 H)

Example 163

/V-(3-Methoxybenzyl)-4-(2-(((<rans)-4-((S)-2-hydroxypr opanamido)cyclohexyl)methyl)-2H- tetrazol-5-yl)-6-methylpicolinamide

A mixture of (S)-2-acetoxypropanoιc acid (13 mg, 0 10 mmol) and 1-hydroxybenzatrιazole (16 mg, 0 12 mmol) in 2-methyl tetrahydrofuran (2 ml_) was stirred for 5 minutes A/-(3-Methoxybenzyl)-4- (2-(((/raÏ€s)-4-amιnocyclohexyl)methyl)-2H-tetrazol-5-yl)-6 -methylpιcolιnamιde (prepared as described in Example 153) (0 055 g, 0 10 mmol), tÏ€ethylamme (0 017 mL, 0 12 mmol), and polymer supported carbodiimide (0 12 g, 0 15 mmol) were added The mixture was stirred for 18 hours at room temperature and was then filtered The filtrate was concentrated, and the residue was dissolved in acetonitrile (5 mL) Aqueous sodium hydroxide solution (2 5 N, 1 0 mL) was added and the mixture was stirred for 18 hours at room temperature The acetonitrile was removed in vacuo and the aqueous phase was acidified to pH 6 with an aqueous 10% solution of hydrochloric acid The mixture was extracted with ethyl acetate (3 x 5 mL) The combined organic layers were washed with water (2 x 5 mL) followed by brine (5 mL), dried over anhydrous sodium sulfate, and concentrated The residue was purified by reverse phase preparative HPLC to afford the title compound (23 mg, 45%) ¹ H NMR (400 MHz, DMSO-Cf ₆ ) δ ppm 9 19 (t, J=6 2 Hz, 1 H), 8 41 (s, 1 H), 8 05 (s, 1 H), 7 31 (d, J=8 1 Hz, 1 H), 7 22 (t, J=8 1 Hz, 1 H), 6 90 (br s , 2 H), 6 80 (d, J=I 3 Hz, 1 H), 5 32 (d, J=5 1 Hz, 1 H), 4 65 (d, J=Q 6 Hz, 2 H), 4 49 (d, J=Q 6 Hz, 2 H), 3 83 - 3 96 (m, 1 H), 3 71 (s, 3 H), 3 42 - 3 55 (m, 1 H), 2 65 (s, 3 H), 1 97 (d, J=2 9 Hz, 1 H), 1 72 (d, J=Q Q Hz, 2 H), 1 61 (d, J=12 4 Hz, 2 H), 0 97 - 1 34 (m, 7 H)

Example 164

/V-(3-Methoxybenzyl)-4-(2-(((frans)-4-(3-aminopropanamido )cyclohexyl)methyl)-2H-tetrazol-5-yl)-

6-methylpicolinamide

A solution of 1 -hydroxybenzotrιazole (3 2 mg, 0 024 mmol) in λ/,/V-dιmethylformamιde (2 mL) was added to 3-(tert-butoxycarbonyl)propanoιc acid (27 2 mg, 0 144 mmol) Carbodiimide resin (138 mg, 0 18 mmol, 1 30 mmol/g loading), dichloromethane (2 mL), λ/-(3-methoxybenzyl)-4-(2-(((/rans)-4- amιnocyclohexyl)methyl)-2/-/-tetrazol-5-yl)-6-methylpιcolÎ ¹namιde (prepared as described in Example 153) (52 3 mg, 0 120 mmol), and /V-methylmorpholine (0 066 mL, 0 60 mmol) were added The mixture was agitated at room temperature overnight The reaction mixture was filtered washing with

λ/,λ/-dιmethylformamιde followed by dichloromethane, and volatiles were removed under a stream of nitrogen The residue was purified by reverse phase preparative HPLC (5%-95% CH ₃ CNZH ₂ O, 8 mm) After concentration, the resulting intermediate was dissolved in a mixture of tnfluoroacetic acid/dichloromethane (1/1 ) and stirred for 1 hour The reaction mixture was filtered and concentrated The residue was suspended in dichloromethane and neutralized using MP-carbonate resin to afford the title compound (10 mg, 16%) LC/MS (5%-95% CH ₃ CN/H ₂ O, 4 5 mm , 95% CH ₃ CN, 1 5 mm ) 2 642 mm , m/z 507 (M+H)

Example 165

/V-(3-Methoxybenzyl)-4-(2-(((ffans)-4-(2-methoxyacetamido )cyclohexyl)methyl)-2H-tetrazol-5-yl)- 6-methylpicolinamide

The title compound was prepared in a similar manner to /V-(3-methoxybenzyl)-4-(2-(((<rans)-4- (3-amιnopropanamιdo)cyclohexyl)methyl)-2/-/-tetrazol-5-yl) -6-methylpιcolιnamιde (Example 164) by reaction with 2-methoxyacetιc acid to afford 25 6 mg (42%) LC/MS (5%-95% CH ₃ CN/H ₂ O, 4 5 mm , 95% CH ₃ CN, 1 5 mm ) 3 162 mm , m/z 508 (M+H)

Example 166

/V-(3-Methoxybenzyl)-4-(2-(((frans)-4-(3-methoxypropanami do)cyclohexyl)methyl)-2H-tetrazol-5- yl)-6-methylpicolinamide

The title compound was prepared in a similar manner to A/-(3-methoxybenzyl)-4-(2-(((frans)-4-

(3-amιnopropanamιdo)cyclohexyl)methy!)-2/-/-tetrazol-5-yl) -6-methylpιcolιnamιde (Example 164) by reaction with 3-methoxypropanoιc acid to afford 24 3 mg (39%) LC/MS (5%-95% CH ₃ CN/H ₂ O, 4 5 mm , 95% CH ₃ CN, 1 5 mm ) 3 087 mm , m/z 522 (M+H)

Example 167 /V-(3-Methoxybenzyl)-4-(2-((((rans)-4-(2-aminoacetamido)cycl ohexyl)methyl)-2H-tetrazol-5-yl)-6- methylpicolinamide

The title compound was prepared in a similar manner to λ/-(3-methoxybenzyl)-4-(2-(((frans)-4- (S-aminopropanamidoJcyclohexy^methyO-ZH-tetrazol-δ-yO-θ-me thylpicolinamide (Example 164) by reaction with 2-(tert-butoxycarbonyl)acetιc acid to afford 10 0 mg (17%) LC/MS (5%-95% CH ₃ CN/H ₂ O, 4 5 mm , 95% CH ₃ CN, 1 5 mm ) 2 631 mm , m/z 493 (M+H)

Example 168

/V-(3-Methoxybenzyl)-4-(2-((((raπs)-4-(3-hydroxypropanam ido)cyclohexyl)methyl)-2H-tetrazol-5- yl)-6-methylpicolinamide

Step 1 Preparation of methyl 4-(2-(((/rans)-4-amιnocvclohexyl)methyl)-2H-tetrazol-5-yl)- 6- methylpicolinate

A mixture of methyl 6-methyl-4-(2H-tetrazol-5-yl)picolinate (prepared as described in step 4 of the synthesis of λ/-(3-methoxybenzyl)-4-(2-(((/rans)-4-amιnocyclohexyl)meth yl)-2/-/-tetrazol-5-yl)-6- methylpicolinamide, Example 153) (1 5 g, 6 8 mmol), fert-butyl trans-(4- hydroxymethyl)cyclohexylcarbamate (3 14 g, 13 7 mmol), and polymer supported triphenylphosphine resin (6 37 g, 13 7 mmol, 2 15 mmol/g loading) in tetrahydrofuran (75 mL) was cooled in an ice bath Di-fert-butylazodicarboxylate (3 15 g, 13 7 mmol) was added and the mixture was stirred with cooling for 30 minutes The mixture was then allowed to warm to room temperature and stir for 18 hours The reaction mixture was filtered and the resin was washed with tetrahydrofuran and methanol The filtrate was concentrated The residue was dissolved in methanol (25 mL) and treated with 4N hydrochloric acid in dioxane (10 2 mL, 40 8 mmol) for 18 hours at room temperature The reaction mixture was concentrated and the residue washed with ethanol to afford the hydrochloride salt of the product as a solid (2 09 g, 84%) MS (ES+) m/z 331 (M+H) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1 18 (s, 2 H), 1 26 - 1 42 (m, 2 H), 1 65 (d, J= 1 1 28 Hz, 2 H), 1 97 (s, J=9 94 Hz, 3 H), 2 64 (s, 3 H), 2 89 (br s , 1 H), 3 91 (s, 3 H), 4 67 (d, J=6 71 Hz, 2 H), 8 1 1 (s, J= 1 34 Hz, 1 H), 8 25 (br s , 2 H), 8 39 (s, 1 H)

Step 2 Preparation of 4-(2-(((frans)-4-(3-hvdroxypropanamιdo)cvclohexyl)methyl)-2 H-tetrazol-5-yl)-6- methylpicolinic acid

2-(1 /-/-Benzotrιazole-1 -yl)-1 ,1 ,3,3-tetramethyluronιum hexafluorophosphate (775 mg, 2 04 mmol) was added to a solution of methyl 4-(2-(((frans)-4-amιnocyclohexyl)methyl)-2H-tetrazol-5-yl)- 6- methylpicolinate (500 mg, 1 36 mmol), 3-hydroxypropanoιc acid (147 mg, 1 63 mmol), and tπethylamine (0 23 mL, 1 63 mmol) in λ/,λ/-dιmethylformamιde (20 mL) The reaction mixture was allowed to stir at room temperature for 2 days and was then treated with lithium hydroxide (326 mg, 13 6 mmol) The mixture was stirred for 18 hours The reaction mixture was acidified with the addition of 3 N hydrochloric acid and then extracted with ethyl acetate The organic layer was dried over magnesium sulfate and concentrated to afford the title compound as a solid

Step 3 Preparation of λ/-(3-methoxybenzyl)-4-(2-(((/rans)-4-(3- hvdroxypropanamιdo)cvclohexyl)methyl)-2/-/-tetrazol-5-yl)-6 -methylpιcolιnamιde

2-(1 H-BenzotÏ€azole-1 -yl)-1 ,1 ,3,3-tetramethyluronιum hexafluorophosphate (109 mg, 0 289 mmol) was added to a solution of 4-(2-(((/rans)-4-(3-hydroxypropanamido)cyclohexyl)methyl)-2H - tetrazol-5-yl)-6-methylpιcolιnιc acid (50 mg, 0 13 mmol), 3-methoxyphenylmethanamιne (50 mg, 0 36 mmol), and triethylamine (0 07 mL, 0 48 mmol) in λ/,λ/-dιmethylformamιde (1 mL), and the mixture was stirred at room temperature for 18 hours The reaction mixture was purified by reverse phase preparative HPLC Fractions containing the product were passed through a carbonate cartridge eluting with methanol and then concentrated to afford the title compound as a white solid (16 mg, 24%) MS (ES+) m/z 508 (M+H) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0 99 - 1 23 (m, 4 H), 1 53 -

1 64 (m, 2 H), 1 68 - 1 81 (m, 2 H), 1 86 - 2 03 (m, 2 H), 2 15 (t, J=6 59 Hz, 2 H), 2 44 - 2 48 (m, 1 H),

2 64 (s, 3 H), 3 54 (t, J=Q 22 Hz, 2 H), 3 70 (s, 3 H), 4 48 (d, J=Q 59 Hz, 2 H), 4 63 (d, J=Q 59 Hz, 2 H), 6 78 (d, J=8 05 Hz, 1 H), 6 85 - 6 91 (m, 1 H), 7 12 - 7 25 (m, 2 H), 7 58 (d, J=Q 05 Hz, 1 H), 8 04 (s, 1

H), 8 39 (s, 1 H), 9 18 (t, J=Q 22 Hz, 1 H)

Example 169

1 -(((rans)-4-((5-(2-((3-methoxybenzyl)carbamoyl)-6-methylpyri din-4-yl)-2H-tetrazol-2- yl)methyl)cyclohexyl)-3-methylurea

Methyl isocyanate (1 mL, 4M solution in dichloromethane) and silica-bound 4- (dιmethylamιno)pyrιdιne (833 0 mg, 0 575 mmol, 0 69 mmol/g loading) were added to a solution of λ/- (3-rnethoxybenzyl)-4-(2-(((/rans)-4-amιnocyclohexyl)methyl) -2/-/-tetrazol-5-yl)-6-methylpιcolιnamιde (prepared as described in Example 153) (50 0 mg, 0 115 mmol) in dichloromethane (1 mL) The mixture was agitated overnight at room temperature and was then filtered washing with N, N- dimethylformamide The filtrate was concentrated under a stream of nitrogen The residue was purified by reverse phase preparative HPLC (5%-95% CH ₃ CN/H ₂ O, 8 mm) to afford the title compound as a solid (22 8 mg, 40%) LC/MS (5%-95% CH ₃ CN/H ₂ O, 4 5 mm , 95% CH ₃ CN, 1 5 mm ) 2 963 mm , m/z 493 (M+H) ¹ H NMR (400 MHz, DMSOd ₆ ) ÏŒ ppm 0 87 - 1 30 (m, 4 H), 1 48 - 1 68 (m, 2 H), 1 71 -

1 85 (m, 2 H), 1 95 (s, 1 H), 2 38 - 2 53 (m, 3 H), 2 65 (s, 3 H), 3 71 (s, 3 H), 4 49 (d, J=6 6 Hz, 2 H),

464 (d, J=73 Hz, 2 H), 542 - 555 (m, 1 H), 558 - 572 (m, 1 H), 671 - 684 (m, 1 H), 686 - 695 (m,

2 H), 714 - 732 (m, 1 H), 805 (s, 1 H), 840 (s, 1 H), 919 (s, 1 H)

Example 170 W-(4-Fluoro-3-methoxybenzyl)-4-(2-(((frans)-4-aminocyclohexy l)methyl)-2W-tetrazol-5-yl)-6- methylpicolinamide

Step 1 Preparation of 6-methyl-4-(2/-/-tetrazol-5-γl)pιcolιnιc acid

A solution of lithium hydroxide monohydrate (4 1 g, 100 mmol) in water (100 mL) was added to a suspension of methyl 6-methyl-4-(2H-tetrazol-5-yl)picolinate (prepared as described in step 4 of the synthesis of λ/-(3-methoxybenzyl)-4-(2-(((frans)-4-amιnocyclohexyl)meth yl)-2/-/-tetrazol-5-yl)-6- methylpicolmamide, Example 153) in tetrahydrofuran (300 mL) The mixture was heated to reflux overnight, concentrated in vacuo, and dissolved in water The mixture was cooled in an ice/water bath and acidified with 1 N hydrochloric acid The resulting precipitate was filtered, washed with water, and air dried to afford the title compound as an odd-white solid (10 35 g, 100%) MS (ES+) m/z 206

(M+H) ¹ H NMR (400 MHz, DMSOd ₆ ) δ ppm 8 41 (d, J=O 8 Hz, 1 H), 8 06 (d, J= 1 1 Hz, 1 H), 2 62 (s, 3 H)

Step 2 Preparation of λ/-(4-fluoro-3-methoxybenzyl)-6-methyl-4-(2/-/-tetrazol-5-y l)pιcolι namide

A mixture of 6-methyl-4-(2H-tetrazol-5-yl)pιcolιnιc acid (27 g, 0 132 mol), 4-fluoro-3- methoxybenzylamine hydrochloride (prepared as described in step 3 of the synthesis of λ/-(4-fluoro-3- methoxybenzyl)-6-(2-(((rans-4-arnιnocyclohexyl)methyl)-2/-/ -tetrazol-5-yl)pyrιmιdιne-4-carboxamιde, Example 1 ) (26 5 g, 0 138 mol), tetrahydrofuran (445 mL), and 1 -hydroxybenzotrιazole (18 6 g, 0 138 mmol) was cooled in an ice bath λ/-Methylmorpholιne (43 5 mL, 0 396 mmol) followed by dimethylsulfoxide (335 mL) and 1-ethyl-3-(3'-dιmethylamιnopropyl)carbodιιmιde hydrochloride (26 5 g, 0 138 mmol) were added The mixture was allowed to warm to room temperature overnight Dimethylsulfoxide (100 mL) was added followed by 1 N hydrochloric acid (400 mL) with ice bath cooling After stirring for 45 mm, the precipitate was filtered The resulting solid was slurried in ethyl acetate, filtered, and dried in vacuo to afford the title compound (31 98 g) MS (ES+) m/z 343 (M+H) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9 30 (t, J=6 4 Hz, 1 H), 8 47 (d, J= 1 1 Hz, 1 H), 8 09 (d, J= 1 2 Hz, 1 H), 7 18 (dd, J=8 5, 1 9 Hz, 1 H), 7 14 (dd, J= 1 1 7, 8 3 Hz, 1 H), 6 90 (ddd, J=8 2, 4 4, 2 0 Hz, 1 H), 4 50 (d, J=6 3 Hz, 2 H), 3 82 (s, 3 H), 2 68 (s, 3 H)

Step 3 Preparation of tert-butyl (frans)-4-((5-(2-((4-fluoro-3-methoxybenzyl)carbamoyl)-6- methylpyridin^-vO^H-tetrazol^-vQmethvDcvclohexylcarbamate

λ/-(4-Fluoro-3-methoxybenzyl)-6-methyl-4-(2/-/-tetrazol-5-y l)pιcolιnamιde (1 71 g, 5 0 mmol), polymer supported triphenylphosphine (3 49 g, 7 5 mmol), and tert-butyl trans-(4- hydroxymethyl)cyclohexylcarbamate (1 38 g, 6 0 mmol) were suspended in tetrahydrofuran (100 mL) Di-terf-butyl azodicarboxylate (1 73 g, 7 5 mmol) was added The mixture was allowed to stir for 18 hours The reaction mixture was filtered and the resin washed with tetrahydrofuran (100 mL) The filtrate was concentrated The crude product was purified by silica column chromatography (CH ₂ C! ₂ /methanol, 100/1 , 100/2) Combined fractions were concentrated onto silica and repurified by silica column chromatography (heptane/EtOAc, 2/1 , 1/1 ) Combined fractions were concentrated and triturated with heptane to afford the title compound as a white solid (1 903 g, 69%) MS (ES+) m/z 554 (M+H) ¹ H NMR (400 MHz, DMSOd ₆ ) δ ppm 9 26 (t, J=6 4 Hz, 1 H), 8 40 (d, J=O 8 Hz, 1 H), 8 05 (d, J= 1 2 Hz, 1 H), 7 15 (dd, J=8 7, 1 9 Hz, 1 H), 7 11 (dd, J=11 7, 8 3 Hz, 1 H), 6 87 (ddd, J=8 3, 4 3, 2 0

Hz, 1 H), 6 68 (d, J=I 7 Hz, 1 H), 4 63 (d, J=7 0 Hz, 2 H), 4 47 (d, J=6 4 Hz, 2 H), 3 79 (s, 3 H), 3 14 (br s , 1 H), 2 64 (s, 3 H), 1 89 (br s , 1 H), 1 78 - 1 70 (m, 2 H), 1 59 - 1 53 (m, 2 H), 1 33 (s, 9 H) ₁ 1 16 - 1 04 (m, 4 H)

Step 3 Preparation of A/-(4-fluoro-3-methoxybenzyl)-4-(2-(((frans)-4-amιnocvclohe xyl)methyl)-2H- tetrazol-5-yl)-6-methylpιcolιnamιde

terf-Butyl (frans)-4-((5-(2-((4-fluoro-3-methoxybenzyl)carbamoyl)-6-met hylpyridin-4-yl)-2H- tetrazol-2-yl)methyl)cyclohexylcarbamate (1 90 g, 3 43 mmol) was dissolved in dichloromethane (20 mL) and tÏ€fluoroacetic acid (5 1 mL, 68 6 mmol) was added The mixture was allowed to stand for 2 hours and was then concentrated The residue was dissolved in dichloromethane (150 mL) and washed with 1 N NaOH solution (2 x 40 mL) The organic layer was dried over sodium sulfate and concentrated to afford the title compound as a glass (1 541 g, 98%) MS (ES+) m/z 454 (M+H) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9 25 (t, J=Q 4 Hz, 1 H), 8 39 (s, 1 H), 8 05 (d, J=1 1 Hz, 1 H), 7 15 (dd, J=Q 5, 1 9 Hz, 1 H), 7 1 1 (dd, J= 1 1 7, 8 3 Hz, 1 H), 6 87 (ddd, J=Q 3, 4 4, 2 0 Hz, 1 H), 4 62 (d, J=I 0 Hz, 2 H), 4 47 (d, J=6 4 Hz, 2 H), 3 79 (s, 3 H), 2 64 (s, 3 H), 2 42 (tt, J= 10 9, 3 4 Hz, 1 H), 1 95 - 1 84 (m, 1 H), 1 71 (d, J= 1 1 1 Hz, 2 H), 1 53 (d, J=12 5 Hz, 2 H), 1 37 (br s , 2 H), 1 07 (q, J=12 1 Hz, 2 H), 0 94 (q, J=1 1 5 Hz, 2 H)

Example 171

/V^-Fluoro-S-methoxybenzyO^^Z-l^fransJ^-acetamidocyclohex yOmethyO^H-tetrazol-S-yO-e- methylpicolinamide

Triethylamine (944 μl, 6 77 mmol), 4-(dιmethylamιno)pyrιdιne (83 mg, 0 68 mmol), and acetyl chloride (289 μL, 4 06 mmol) was added to a solution of N-(4-fluoro-3-methoxybenzyl)-4-(2-(((?rans)-4- amιnocyclohexyl)methyl)-2/-/-tetrazol-5-yl)-6-methylpιcolÎ ¹namιde (prepared as described in Example 170) (1 535 g, 3 39 mmol) in dichloromethane (60 mL) The mixture was allowed to stir at room temperature for 1 hour The reaction mixture was diluted with dichloromethane (150 mL) and washed with saturated aq sodium bicarbonate solution (2 x 40 mL) The organic layer was dried over sodium sulfate and concentrated The crude product was purified by silica column chromatography (CH ₂ CI ₂ /methanol, 100/1 , 100/2, 100/4) Fractions were concentrated The resulting solid was

triturated with ethyl ether and filtered to afford the title compound as a white solid (1 370 g, 82%) MS (ES+) m/z 496 (M+H) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9 26 (t, J=6 4 Hz, 1 H), 8 40 (d, J=O 8 Hz, 1 H), 8 05 (d, J=1 2 Hz, 1 H), 7 67 (d, J=I 8 Hz, 1 H), 7 15 (dd, J=8 5, 1 9 Hz, 1 H), 7 1 1 (dd, J=1 1 6, 8 4 Hz, 1 H), 6 87 (ddd, J=Q 3, 4 4, 2 0 Hz, 1 H), 4 64 (d, J=7 1 Hz, 2 H), 4 47 (d, J=6 3 Hz, 2 H), 3 79 (s, 3 H), 3 47 - 3 38 (m, 1 H), 2 65 (s, 3 H), 1 98 - 1 90 (m, 1 H), 1 78 - 1 72 (m, 2 H), 1 72 (s, 3 H), 1 62 - 1 55 (m, 2 H), 1 19 - 1 03 (m, 4 H)

Example 172

W^-Fluoro-S-methoxybenzyO^-IZ^^fransJ^-IS-aminopropanamid oJcyclohexyOmethyO^H- tetrazol-5-yl)-6-methylpicolinamide

O-(7-Azabenzotrιazole-1-yl)-λ/,W,λfλT-tetramethyluronιu m hexafluorophosphate (75 0 mg, 0 198 mmol), 3-(tert-butoxycarbonyl)propanoιc acid (31 2 mg, 0 165 mmol), and dnsopropylethylamine (0 057 mL, 0 330 mmol) were added to a solution of λ/-(4-fluoro-3-methoxybenzyl)-4-(2-(((fraÏ€s)-4- aminocyclohexyOmethyl^H-tetrazol-S-yO-θ-methylpicolmamide (prepared as described in Example 170) (74 8 mg, 0 165 mmol) in λ/,λ/-dιmethylformamιde (2 mL) The mixture was stirred overnight at room temperature Volatiles were removed under a stream of nitrogen The residue was purified by reverse phase preparative HPLC (5%-95% CH ₃ CN/H ₂ O, 8 mm) to afford the title compound (30 5mg, 35%) LC/MS (5%-100% CH ₃ CN/H ₂ O, 10 0 mm ) 3 69 mm , m/z 525 (M+H) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0 96 - 1 28 (m), 1 50 - 1 84 (m), 1 88 - 2 05 (m), 2 10 (t, J=6 6 Hz, 2 H), 2 65 (s, 3 H), 2 69 (t, J=Q 6 Hz, 2 H), 3 27 (br s ), 3 46 (br s ), 3 80 (s, 3 H), 4 48 (d, J=5 9 Hz, 2 H), 4 65 (d,

J=66 Hz, 2 H), 678 - 695 (m), 704 - 721 (m), 766 - 775 (m, 1 H), 805 (s, 1 H), 840 (s, 1 H), 914 - 927(m, 1 H)

Example 173

W-(4-Fluoro-3-methoxybenzyl)-4-(2-((((rans)-4-(2-methoxya cetamido)cyclohexyl)methyl)-2H- tetrazol-5-yl)-6-methylpicolinamide

The title compound was prepared in a similar manner to /V-(4-fluoro-3-methoxybenzyl)-4-(2- (((frans)-4-(3-ammopropanamιdo)cyclohexyl)methyl)-2/-/-tetr azol-5-yl)-6-methylpιcolιnamιde (Example 172) by reaction with 2-methoxyacetιc acid to afford 41 5 mg (48%) LC/MS (5%-100% CH ₃ CN/H ₂ O,

10 0 mm ) 4 71 min , m/z 526 (M+H) ¹ H NMR (400 MHz, DMSOd ₆ ) δ ppm 1 07 - 1 35 (m, 4 H), 1 55 - 1 80 (m, 4 H), 1 87 - 2 03 (m, 1 H), 2 65 (s, 3 H), 3 44 - 3 63 (m, 1 H), 3 72 (s, 3 H), 3 80 (s, 3 H), 4 48 (d, J=6 6 Hz, 2 H), 4 65 (d, J=6 6 Hz, 2 H), 6 84 - 6 92 (m, 1 H), 7 06 - 7 20 (m, 2 H), 7 42 - 7 50 (m, 1 H), 8 05 (s, 1 H), 8 41 (s, 1 H), 9 1 1 - 9 27 (m, 1 H)

Example 174

W-(4-Fluoro-3-methoxybenzyl)-4-(2-(((frans)-4-(3-methoxyp ropanamido)cyclohexyl)methyl)-2H- tetrazol-5-yl)-6-methylpicolinamide

The title compound was prepared in a similar manner to λ/-(4-fluoro-3-methoxybenzyl)-4-(2- (((fransH^S-aminopropanamidoJcyclohexyOmethyO^H-tetrazol-S-y O-θ-methylpicolinamide (Example 172) by reaction with 3-methoxypropanoιc acid to afford 52 7 mg (59%) LC/MS (5%-100% CH ₃ CN/H ₂ O, 10 0 mm ) 4 61 mm , m/z 540 (M+H) ¹ H NMR (400 MHz, DMSOd ₆ ) δ ppm 1 02 - 1 25 (m, 4 H), 1 56 - 1 83 (m, 4 H), 1 90 - 2 02 (m, 1 H), 2 23 (t, J=6 2 Hz, 2 H), 2 65 (s, 3 H), 3 28 (s), 3 47 (t, J=6 6 Hz, 2 H), 3 80 (s, 3 H), 4 48 (d, J=6 6 Hz, 2 H), 4 65 (d, J=6 6 Hz, 2 H), 6 84 - 6 92 (m, 1 H), 7 05 - 7 20 (m, 2 H), 7 61 - 7 68 (m, 1 H), 8 05 (s, 1 H), 8 41 (s, 1 H), 9 18 - 9 26 (m, 1 H)

Example 175 W-(4-Fluoro-3-methoxybenzyl)-4-(2-(((fraπs)-4-(2-aminoaceta mido)cyclohexyl)methyl)-2H- tetrazol-5-yl)-6-methylpicolinamide

NH ₂ The title compound was prepared in a similar manner to /V-(4-fluoro-3-methoxybenzyl)-4-(2-

(((frans)-4-(3-amιnopropanamιdo)cyclohexyl)methyl)-2/-/-te trazol-5-yl)-6-methylpιcolιnamιde (Example 172) by reaction with 2-(tert-butoxycarbony!)acetιc acid to afford 34 5 mg (41%) LC/MS (5%-100% CH ₃ CN/H ₂ O, 10 0 mm ) 3 66 mm , m/z 511 (M+H) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1 07 - 1 27 (m, 4 H), 1 53 - 1 84 (m, 4 H), 1 91 - 2 03 (m, 1 H), 2 65 (s, 3 H), 3 01 (s, 2 H), 3 28 (br s ), 3 41 - 3 58 (m, 1 H), 3 80 (s, 3 H), 4 48 (d, J=δ 6 Hz, 2 H), 4 65 (d, J=6 6 Hz, 2 H), 6 85 - 6 91 (m, 1 H), 7 06 - 7 20 (m, 2 H), 7 53 - 7 61 (m, 1 H), 8 05 (s, 1 H), 8 41 (s, 1 H), 9 16 - 9 27 (m, 1 H)

Example 176

2-((<rans)-4-((5-(2-((4-fluoro-3-methoxybenzyl)carbamo yl)-6-methylpyridin-4-yl)-2H-tetrazol-2- yl)methyl)cyclohexylamino)-2-oxoethyl acetate

The title compound was prepared in a similar manner to λ/-(4-fluoro-3-methoxybenzyl)-4-(2-

(((frans)-4-(3-ammopropanamido)cyclohexyl)methyl)-2H-tetrazo l-5-yl)-6-methylpicolinamide (Example 172) by reaction with 2-acetoxyacetιc acid to afford 48 0 mg (53%) LC/MS (5%-100% CH ₃ CN/H ₂ O, 10 0 mm ) 4 76 mm , m/z 554 (M+H) ¹ H NMR (400 MHz, DMSO-c/ ₆ ) δ ppm 1 07 - 1 26 (m, 4 H), 1 56 - 1 81 (m, 4 H), 1 90 - 2 02 (m, 1 H), 2 04 (s, 3 H), 2 65 (s, 3 H), 3 42 - 3 56 (m, 1 H), 3 80 (s, 3 H), 4 36 (s, 2 H), 4 48 (d, J=5 9 Hz, 2 H), 4 65 (d, J=6 6 Hz, 2 H), 6 84 - 6 93 (m, 1 H), 7 06 - 7 20 (m, 2 H), 7 74 - 7 82 (m, 1 H), 8 05 (s, 1 H), 8 40 (s, 1 H), 9 17 - 9 25 (m, 1 H)

Example 177

/V-(4-Fluoro-3-methoxybenzyl)-4-(2-(((frans)-4-(2-hydroxy acetamido)cyclohexyl)methyl)-2H- tetrazol-5-yl)-6-methylpicolinamide

The title compound was prepared in a similar manner to λ/-(4-fluoro-3-methoxybenzyl)-4-(2- (((frans)-4-(3-amιnopropanamιdo)cyclohexyl)methyl)-2/-/-te trazol-5-yl)-6-methylpιcolιnamιde (Example 172) by reaction with 2-hydroxyacetιc acid to afford 41 0 mg (49%) LC/MS (5%-100% CH ₃ CN/H ₂ O, 10 0 mm ) 4 41 mm , m/z 512 (M+H) ¹ H NMR (400 MHz, DMSO-Cf ₆ ) δ ppm 1 07 - 1 39 (m, 4 H), 1 53 - 1 79 (m, 4 H), 1 88 - 2 05 (m, 1 H), 2 65 (s, 3 H), 3 48 - 3 61 (m, 1 H), 3 73 (s, 3 H), 3 80 (s, 2 H), 4 48 (d, J=6 6 Hz, 2 H), 4 65 (d, J=I 3 Hz, 2 H), 6 85 - 6 92 (m, 1 H), 7 06 - 7 19 (m, 2 H), 7 33 - 7 40 (m, 1 H), 8 05 (s, 1 H), 8 41 (s, 1 H), 9 17 - 9 26 (m, 1 H)

Example 178

/V-(4-Fluoro-3-methoxybenzyl)-4-(2-(((frans)-4-(3-hydroxy propanamido)cyclohexyl)methyl)-2H- tetrazol-5-yl)-6-methylpicolinamide

The title compound was prepared in a similar manner to λ/-(3-methoxybenzyl)-4-(2-(((frans)-4- (S-hydroxypropanamidoJcyclohexyOmethyO^H-tetrazol-δ-yO-θ-m ethylpicolinamide (Example 168) by reaction with 4-fluoro-3-methoxybenzylamιne hydrochloride (prepared as described in step 3 of the synthesis of λ/-(4-fluoro-3-methoxybenzyl)-6-(2-((/rans-4-amιnocyclohex yl)methyl)-2H-tetrazol-5- yl)pyrιmιdιne-4-carboxamιde, Example 1 ) to afford 25 mg (37%) of a white solid MS (ES+) m/z 526 (M+H) ¹ H NMR (400 MHz, DMSO-c/ ₆ ) δ ppm 1 05 - 1 25 (m, 4 H), 1 57 - 1 68 (m, 2 H), 1 73 - 1 84 (m,

2 H), 1 92 - 2 04 (m, 1 H), 2 19 (t, J=6 59 Hz, 2 H), 2 54 (s, 2 H), 2 67 (s, 3 H), 3 53 - 3 62 (m, 2 H),

382 (s, 3 H), 451 (d, J=586 Hz, 2 H), 467 (d, J=I 32 Hz, 2 H), 686 - 695 (m, 1 H), 706 - 725 (m, 2 H), 762 (d, J=I 32 Hz, 1 H), 807 (s, 1 H), 843 (s, 1 H), 924 (t, J=622 Hz, 1 H)

Example 179

/V-(4-Fluoro-3-methoxybenzyl)-4-(2-((((rans)-4-(2-hydroxy -2- methylpropanamido)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6-met hylpicolinamide

Step 1 Preparation of methyl 4-(2-(((frans)-4-(2-hydroxy-2-methylpropanamιdo)cyclohexyl) methyl)-2/-/- tetrazol-5-yl)-6-methylpιcohnate

A mixture of 2-hydroxy isobutyric acid (25 mg, 0 24 mmol) and 1 -hydroxybenzatrιazole (37 mg, 0 27 mmol) in 2- methyl tetrahydrofuran (2 mL) was stirred for 5 minutes 4-(2-(((frans)-4- Amιnocyclohexyl)methyl)-2H-tetrazol-5-yl)-6-methylpιcolιn ate (prepared as described in step 1 of the synthesis of /V-(3-methoxybenzyl)-4-(2-(((frans)-4-(3-hydroxypropanamido) cyclohexyl)methyl)-2H- tetrazol-5-yl)-6-methylpιcolιnamιde, Example 168) (0 10 g, 0 23 mmol), triethylamine (0 038 mL, 0 27 mmol), and polymer supported carbodiimide (0 27 g, 0 34 mmol) were added The mixture was stirred for 18 hours at room temperature The reaction mixture was filtered The filtrate was washed with water (3 x 5 mL) followed by brine (5 mL), dried over anhydrous sodium sulfate, and concentrated

The residue was purified by silica column chromatography (0-50% ethyl acetate/heptane) to afford the title compound (65 mg, 69%)

Step 2 Preparation of 4-(2-(((/rans)-4-(2-hvdroxy-2-methylpropanamιdo)cvclohexyl) methyl)-2/-/- tetrazol-5-yl)-6-methylpιcolιnιc acid

Aqueous sodium hydroxide (2 5 N, 1 0 mL) was added to a solution of methyl 4-{2-(((trans)-4- (2-hydroxy-2-methylpropanamιdo)cyclohexyl)methyl)-2/-/-tetr azol-5-yl)-6-methylpιcolιnate (65 mg, 0 16 mmol) in acetonitrile (2 mL), and the mixture was stirred for 1 hour at room temperature The acetonitπle was removed in a stream of nitrogen Water (1 mL) was added to the residue and the mixture was acidified to pH 6 with 10% aqueous hydrochloric acid The resulting solid was collected by filtration, washed with water (2 x 2 mL), and dried to afford the title compound (53 mg, 84%) MS (ES+) m/z 403 (M+H)

Step 3 Preparation of λ/-(4-Fluoro-3-methoxybenzyl)-4-(2-(((fraπs)-4-(2-hydroxy- 2- methylpropanamido^vclohexyDmethvD^H-tetrazol-δ-vD-e-methylp icolinamide

A mixture of 4-(2-(((frans)-4-(2-hydroxy-2-methylpropanamιdo)cyclohexyl) methyl)-2H-tetrazol-

5-yl)-6-methylpιcolιnιc acid (0 040 g, 0 10 mmol) and 1 -hydroxybenzatrιazole (21 mg, 0 12 mmol) in λ/,λ/-dιmethylformamιde was stirred for 15 minutes 4-Fluoro-3-methoxybenzy!amιne hydrochloride (prepared as described in step 3 of the synthesis of λ/-(4-fluoro-3-methoxybenzyl)-6-(2-((frans-4- amιnocyclohexyl)methyl)-2/-/-tetrazol-5-yl)pyÏ€mιdιne-4-c arboxamιde, Example 1 ) (27 mg, 0 16 mmol) was then added followed by polymer supported carbodiimide (0 135 g, 0 15 mmol) The mixture was stirred for 18 hours at room temperature The reaction mixture was filtered, and the filtrate was extracted by ethyl acetate (3 x 5 mL) The combined organic layers were washed with water (2 x 5 mL) followed by brine (5 mL), dried over anhydrous sodium sulfate, and concentrated The residue was purified by reverse phase preparative HPLC to afford the title compound (8 3 mg, 15%) ¹ H NMR (400 MHz, DMSO-cfe) δ ppm 9 21 (s, 1 H), 8 41 (br s , 1 H), 8 06 (br s , 1 H), 7 06 - 7 28 (m, 2 H), 6 88 (d, J=8 8 Hz, 1 H), 6 43 (br s , 1 H), 5 25 (br s , 1 H), 4 67 (d, J=3 7 Hz, 2 H), 4 48 (d, J=5 9 Hz, 2 H), 3 80 (s, 3 H), 3 60 (d, J=9 5 Hz, 1 H), 2 66 (s, 3 H), 2 05 (s, 1 H), 1 72 (d, J= 1 1 7 Hz, 2 H), 1 60 (d, J=7 3 Hz, 2 H), 1 10 - 1 34 (m, 9 H)

Example 180

/V^S-EthoxybenzylJ-e-methyl^^Z^^fransJ^^methylsulfonamido JcyclohexyOmethyO-σH- tetrazol-5-yl)picolinamide

Step 1 Preparation of 6-methyl-4-(2-(((/rans)-4-(methylsulfonamιdo)cvclohexyl)met hyl)-2H-tetrazol-5- vDpicolinic acid

Diisopropylethylamine (O 59 mL, 3 4 mmol) and methanesulfonyl chloride (0 16 mL, 2 1 mmol) were added to a solution of methyl 4-(2-(((<rans)-4-amιnocyclohexyl)methyl)-2/-/-tetrazol-5 -yl)-6- methylpicolinate (prepared as described in step 1 of the synthesis of λ/-(3-methoxybenzyl)-4-(2- (((frans)-4-(3-hydroxypropanamιdo)cyclohexyl)methyl)-2H-tet razol-5-yl)-6-methylpιcolιnamιde, Example 168) (125 mg, 0 34 mmol) in λ/,λ/-dιmethylformamιde (1 mL) The mixture was allowed to stir at room temperature overnight The reaction mixture was concentrated and the residue was dissolved in tetrahydrofuran (8 mL) A 4N aqueous solution of lithium hydroxide (2 mL) was added and the mixture was allowed to stir for 4 hours The reaction mixture was concentrated and purified by reverse phase preparative HPLC (20-60% acetonitrile/water) to afford the title compound (42 mg, 25%)

Step 2 Preparation of (3-ethoxyphenyl)methanamιne

Lithium aluminum hydride (59 5 g) was added to anhydrous ethyl ether (900 mL) cooled to 10 ⁰ C A solution of 3-ethoxybenzonιtrιle (35 5 g) in anhydrous ethyl ether (100 mL) was added over 1 25 hours, and the mixture was stirred for 4 5 hours The reaction mixture was quenched with water (60 mL) and was stirred for 1 25 hours A 15% aqueous solution of sodium hydroxide (60 mL) was added followed by ether (500 mL) and water (180 mL) The slurry was filtered The filtrate was dried over sodium sulfate and concentrated to afford the title compound as an oil (35 3 g) MS (ES+) m/z 152 (M+H) ¹ H NMR (400 MHz, CDCI ₃ ) δ ppm 7 20 (t J=8 1 , 1 H), 6 87-6 72 (m, 3 H), 4 00 (q, J=6 9, 2 H), 3 78 (s, 2 H), 1 38 (t, J=7 2, 3 H)

Step 3 Preparation of λ/-(3-ethoxybenzyl)-6-methyl-4-(2-(((frans)-4- (methylsulfonamιdo)cvclohexyl)methyl)-2/-/-tetrazol-5-yl)pÎ ¹colιnamιde

In a 2 dram vial with a magnetic stir bar, 6-methyl-4-(2-(((frans)-4- (methylsulfonamido)cyclohexyl)methyl)-2/-/-tetrazol-5-yl)pic olinic acid (70 mg, 0 177 mmol) was dissolved in λ/,λ/-dιmethylformamιde (2 mL) Dnsopropylethylamine (0 19 mL, 1 06 mmol) and (3- ethoxyphenyl)methanamιne (33 4 mg, 0 221 mmol) were added and the mixture was stirred for 30 minutes O-(1 H-Benzotrιazol-1 -yl)-λ/,W,λ/\ λ/Metramethyluronium tetrafluoroborate (128 mg, 0 398 mmol) was added and stirring continued at room temperature overnight The reaction mixture was purified by reverse phase preparative HPLC to afford the title compound (27 2 mg) LC/MS (5%-95% CH ₃ CN/H ₂ O, 5 mm ) 3 54 mm, m/z 514 (M+H) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1 06 - 1 33 (m, 8 H), 1 54 - 1 65 (m, 3 H), 1 82 - 1 98 (m, 3 H), 2 45 - 2 50 (m, 1 H), 2 50 - 2 53 (m, 1 H), 2 61 - 2 68 (m, 3 H), 2 80 - 2 88 (m, 3 H), 2 97 - 3 08 (m, 1 H), 3 94 - 3 98 (m, 2 H), 4 43 - 4 52 (m, 2 H), 4 58 - 4 69 (m, 2 H), 6 73 - 6 80 (m, 1 H), 6 83 - 6 97 (m, 2 H), 7 15 - 7 26 (m, 1 H), 8 02 - 8 07 (m, 1 H), 8 38 - 8 43 (m, 1 H), 9 14 - 9 23 (m, 1 H)

Example 181

W-(4-Fluoro-3-(hydroxymethyl)benzyl)-6-methyl-4-(2-((((ra ns)-4- (methylsulfonamidoJcyclohexyOmethyO-ZH-tetrazol-S-yOpicolina mide

Step 1 Preparation of (5-(amιnomethyl)-2-fluorophenyl)methanol

In a 250 round bottomed flask with a magnetic stir bar, 4-fluoro-3-formylbenzonιtrιle (1 50 g, 10 06 mmol) was dissolved in tetrahydrofuran (30 mL) The mixture was cooled in an ice bath to 0 ⁰ C and lithium aluminum hydride (573 mg, 15 1 mmol) was added The reaction mixture was stirred at 0 ⁰ C for 3 hours and then was allowed to warm to room temperature and stir overnight The mixture was concentrated and the residue was purified by reverse phase preparative HPLC to afford the title compound as a white solid (478 mg, 30%) MS (ES+) m/z 156 (M+H) ¹ H NMR (400 MHz, methanol- d ₄ ) δ ppm 4 09 (s, 2 H), 4 68 (s, 2 H), 7 13 (dd, J=9 67, 8 59 Hz, 1 H), 7 31 - 7 44 (m, 1 H), 7 56 (dd, J=6 85, 2 28 Hz, 1 H)

Step 2 Preparation of λ/-(4-fluoro-3-(hvdroxymethyl)benzyl)-6-methyl-4-(2-(((fran s)-4- (methylsulfonamidotovclohexyOmethvO^H-tetrazol-δ-vQpicolina mide

The title compound was prepared in a similar manner to λ/-(3-ethoxybenzyl)-6-methyl-4-(2-(((frans)-4- (methylsulfonamιdo)cyclohexyl)methyl)-2H-tetrazol-5-yl)pιc olιnamιde (Example 180) by reaction with (5-(amιnomethyl)-2-fluorophenyl)methanol to afford 14 1 mg ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 1 28 (d, ./=1 1 6 Hz, 4 H), 1 34 (d, 1 H), 1 73 (s, 2 H), 2 67 (s, 3 H), 3 12 - 3 22 (m, 1 H), 4 59 - 4 64 (m, 6 H), 7 02 (s, 1 H), 7 26 - 7 34 (m, 1 H), 7 45 - 7 51 (m, 1 H), 8 09 (d, J=1 1 Hz, 1 H)

Example 182 /V^-Fluoro-S-methoxybenzyO-e-methyM-l∑-^lfransJ^^methylsul fonamidoJcyclohexyOmethyl)-

2H-tetrazol-5-yl)picolinamide

The title compound was prepared in a similar manner to /V-(3-ethoxybenzyl)-6-methyl-4-(2- (((frans)-4-(methylsulfonamido)cyclohexyl)methyl)-2H-tetrazo l-5-yl)picolinamide (Example 180) by reaction with 4-fluoro-3-methoxybenzylamιne hydrochloride (prepared as described in step 3 of the synthesis of λ/-(4-fluoro-3-methoxybenzyl)-6-(2-((frans-4-amιnocyclohex yl)methyl)-2/-/-tetrazol-5- yl)pyrιmιdιne-4-carboxamιde, Example 1 ) to afford 15 9 mg ¹ H NMR (400 MHz, DMSO-Cf ₆ ) δ ppm

1 07 - 1 27 (m, 5 H), 1 61 (d, J=10 3 Hz, 2 H), 1 89 (d, J=10 3 Hz, 2 H), 2 51 (s, 1 H), 2 65 (s, 3 H),

286 (s, 3 H), 296 - 311 (m, 2 H), 327 (s, 1 H), 380 (s, 3 H), 448 (d, J=59 Hz, 2 H), 464 (d, J=66 Hz, 2 H), 685 - 695 (m, 2 H), 705 - 719 (m, 2 H), 803 - 807 (m, 1 H), 837 - 843 (m, 1 H), 915 -

925(m, 1 H)

Example 183

/V-(3-(Hydroxymethyl)benzyl)-6-methyl-4-(2-(((frans)-4-(m ethylsulfonamido)cyclohexyl)methyl)-

2H-tetrazol-5-yl)picolinamide

Step 1 Preparation of (3-(amιnomethyl)phenyl)methanol

To a refluxing (33 8 ⁰ C) suspension of lithium aluminum hydride (20 0 g) in anhydrous ethyl ether (300 mL) under nitrogen was added portionwise of 3-cyanobenzaldehyde (10 51 g) over a 2 mm period The resulting slurry was heated at reflux for 10 hours The reaction mixture was cooled in an ice bath and water (20 mL) was added in 1 mL increments while keeping the temperature < 20 ⁰ C A 15 % sodium hydroxide solution (20 mL) was added in a similar fashion, followed by water (60 mL) The resulting solids were filtered off and washed The filtrate was concentrated in vacuo The residue was dissolved in a mixture of dichloromethane/methanol/ammonium hydroxide (95/5/0 5, 10 mL), filtered, and purified by silica column chromatography eluting with the same to afford the title compound as a light yellow oil (4 25 g)

Step 2 Preparation of λ/-(3-(hvdroxymethyl)benzyl)-6-methyl-4-(2-(((frans)-4- (methylsulfonamido)cvclohexyl)methyl)-2H-tetrazol-5-yl)picol inamide

The title compound was prepared in a similar manner to λ/-(3-ethoxybenzyl)-6-methyl-4-(2-

(((<rans)-4-(methylsulfonamιdo)cyclohexyl)methyl)-2/-/-t etrazol-5-yl)pιcolιnamιde (Example 180) by reaction with (3-(amιnomethyl)phenyl)methanol to afford 27 2 mg ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1 07 - 1 28 (m, 5 H), 1 61 (d, J=10 3 Hz, 3 H), 1 89 (d, J= 1 1 0 Hz, 2 H), 2 65 (s, 3 H), 2 85 (s, 3 H), 2 97 - 3 08 (m, 1 H), 3 32 (s, 1 H), 4 45 (d, J=5 1 Hz, 2 H), 4 51 (d, J=6 6 Hz, 2 H), 4 64 (d, J=7 3 Hz, 2 H), 6 92 (d, J=I 3 Hz, 1 H), 7 13 - 7 21 (m, 1 H), 7 22 - 7 30 (m, 2 H), 8 05 (s, 1 H), 8 41 (s, 1 H), 9 20 (t, _/=6 2 Hz, 1 H)

Example 184

/V-(3-(2-Hydroxyethoxy)benzyl)-6-methyl-4-(2-(((frans)-4- (methylsulfonamido)cyclohexyl)methyl)-2/-/-tetrazol-5-yl)pic olinamide

The title compound was prepared in a similar manner to λ/-(3-ethoxybenzyl)-6-methyl-4-(2- (((frans)-4-(methylsulfonamιdo)cyclohexyl)methyl)-2H-tetraz ol-5-yl)pιcolιnamιde (Example 180) by reaction with 2-(3-(amιnomethyl)phenoxy)ethanol (prepared as described in step 2 of the synthesis of λ/-(3-(2-hydroxyethoxy)benzy!)-6-(2-(((<rans)-4-amιnocy clohexyl)methyl)-2/-/-tetrazol-5-yl)-2-

methylpyrιmιdιne-4-carboxamιde, Example 13) to afford 10 6 mg ¹ H NMR (400 MHz, DMS0-c/ ₆ ) δ ppm 1 08 - 1 27 (m, 5 H), 1 61 (d, J=10 3 Hz, 2 H), 1 89 (d, J=9 5 Hz, 2 H), 2 51 (s, 1 H), 2 65 (s, 3 H), 2 86 (s, 3 H), 3 03 (s, 1 H), 3 67 (t, J=4 8 Hz, 2 H), 3 93 (t, J=5 1 Hz, 2 H), 4 49 (d, J=6 6 Hz, 2 H), 4 64 (d, J=7 3 Hz, 2 H), 6 79 (d, J=7 3 Hz, 1 H), 6 86 - 6 95 (m, 3 H), 7 20 (t, J=8 1 Hz, 1 H), 8 05 (s, 1 H), 8 41 (s, 1 H), 9 19 (t, J=6 2 Hz, 1 H)

Example 185

/V-(4-Fluoro-3-methylbenzyl)-4-(2-(((frans)-4-aminocycloh exyl)methyl)-2W-tetrazol-5-yl)-6- methylpicolinamide

Step 1 Preparation of λ/-(4-fluoro-3-methylbenzyl)-6-methyl-4-(2/-/-tetrazol-5-yl )pιcolιnamιde

Tetrahydrofuran (2 mL) and 4-fluoro-3-methy!benzylamιne (3 5 g) was added to methyl 6- methyl-4-(2/-/-tetrazol-5-yl)pιcolιnate (prepared as described in step 4 of the synthesis of λ/-(3- methoxybenzyl)-4-(2-(((/rans)-4-amιnocyclohexyl)methyl)-2/- /-tetrazol-5-yl)-6-methylpιcolιnamιde, Example 153) (2 69 g) The resultant slurry was treated with λ/,/V-dιmethylacetamιde (2 mL) and heated to 90 ⁰ C After 3 h, the mixture was allowed to cool to room temperature, treated with 1 N hydrochloric acid, diluted with water and filtered The crude product was triturated with methanol, (50 mL) to provided the title compound as a solid (2 06 g, 51 %) MS(ES+) m/z 327 (M+H), ¹ H NMR (400 MHz, DMSOd ₆ ) δ ppm 2 18 (d, J=1 6 Hz, 3 H), 2 65 (s, 3 H), 4 45 (d, J=6 2 Hz, 2 H), 7 05 (t, 1 H), 7 13 - 7 20 (m, 1 H), 7 22 (d, J=7 5 Hz, 1 H), 8 06 (d, J=1 3 Hz, 1 H), 8 45 (d, J=1 1 Hz, 1 H), 9 27 (t, J=6 3 Hz, 1 H)

Step 2 Preparation of tert-butyl (frans)-4-((5-(2-((4-fluoro-3-methylbenzyl)carbamoyl)-6-meth ylpyridm- 4-yl)-2H-tetrazol-2-yl)methyl)cvclohexylcarbamate

To λ/-(4-fluoro-3-methylbenzyl)-6-methyl-4-(2H-tetrazol-5-yl)p ιcolιnamιde (1 95 g) was added fert-butyl-frans-(4-hydroxymethyl)cyclohexylcarbamate (1 65 g), polymer supported triphenylphosphine (7 00 g, Argonaut, 2 15 mmol/g) and anhydrous THF (60 mL) The stirred mixture was cooled in an ice-water bath and treated with di-tert-butyl azodicarboxylate (2 76 g) The mixture was concentrated in vacuo and the residue was purified by silica column chromatography (40% ethyl acetate/hexanes) to afford the title compound as a white, crystalline solid (2 00 g, 62%) MS(ES+) 538 (M+H), ¹ H NMR (400 MHz, CDCI ₃ ) δ ppm 1 02 - 1 30 (m, 4 H), 1 42 (s, 9 H), 1 56 - 1 65 (m, 1 H), 1 71 (d, J=13 2 Hz, 2 H), 2 00 - 2 12 (m, 3 H), 2 26 (d, J= 1 9 Hz, 3 H), 2 63 (s, 3 H), 4 37 (s, 1 H), 4 52 (d, J=7 3 Hz, 2 H), 4 61 (d, J=6 2 Hz, 2 H), 6 96 (t, 1 H), 7 1 1 - 7 23 (m, 2 H), 8 04 (d, J= 1 1 Hz, 1 H), 8 40 (t, 1 H), 8 71 (s, 1 H)

Step 3 Preparation of λ/-(4-fluoro-3-methylbenzyl)-4-(2-(((trans)-4-amιnocvdohex yl)methyl)-2/-/- tetrazol-5-yl)-6-methylpιcolιnamιde

TÏ€fluoroacetic acid (5 mL) was added to a solution of tert-butyl (frans)-4-((5-(2-((4-fluoro-3- methylbenzyl)carbamoyl)-6-methylpyrιdιn-4-yl)-2H-tetrazol- 2-yl)methyl)cyclohexylcarbamate (849 5 mg, 1 58 mmol) in dichloromethane (5 mL), and the mixture was stirred for 30 minutes The reaction mixture was concentrated under a stream of nitrogen The residue was dissolved in dichloromethane and neutralized with MP-carbonate resin The mixture was filtered, washed with dichloromethane followed by methanol, and concentrated under a stream of nitrogen to afford the title compound (781 mg) LC/MS (5%-95% CH ₃ CN/H ₂ O, 4 5 mm , 95% CH ₃ CN, 1 5 mm ) 2 625 mm , m/z 438 (M+H)

Example 186 N-(4-fluoro-3-methylbenzyl)-6-methyl-4-(2-(((<rans)-4-(me thylsulfonamido)cyclohexyl)methyl)-

2H-tetrazol-5-yl)picolinamide

Triethylamine (0 071 mL, 0 513 mmol) and methane sÏ…lfonyl chloride (0 020 mL, 0 257 mmo!) was added to a solution of λ/-(4-fluoro-3-methylbenzyl)-4-(2-(((<rans)-4-amιnocydo hexyl)methyl)-2H- tetrazol-5-yl)-6-methylpιcolιnamιde (prepared as described in Example 185) (75 0 mg, 0 171 mmol) in tetrahydrofÏ…ran (2 mL) The mixture was stirred for approximately 30 mm at room temperature and was then concentrated under a stream of nitrogen The residue was purified by reverse phase preparative HPLC (5%-95% CH ₃ CN/H ₂ O, 8 mm) to afford the title compound as a solid (29 mg, 33%) LC/MS (5%-95% CH ₃ CN/H ₂ O, 4 5 mm , 95% CH ₃ CN, 1 5 mm ) 3 365 mm , m/z 516 (M+H) ¹ H NMR (400 MHz, DMSO-Cf ₆ ) δ ppm 0 91 - 1 35 (m, 4 H), 1 49 - 1 68 (m, 2 H), 1 75 - 2 02 (m, 3 H), 2 19 (s, 3 H), 2 65 (s, 3 H), 2 85 (s, 3 H), 2 94 - 3 13 (m, 1 H), 4 45 (d, J=6 6 Hz, 2 H), 4 64 (d, J=7 3 Hz, 2 H), 6 88 - 6 97 (m, 1 H), 6 99 - 7 09 (m, 1 H), 7 12 - 7 21 (m, 1 H), 7 21 - 7 27 (m, 1 H), 8 00 - 8 08 (m, 1 H), 8 35 - 8 45 (m, 1 H), 9 14 - 9 25 (m, 1 H)

Example 187

/V-(4-Fluoro-3-methylbenzyl)-4-(2-(((fraπs)-4-acetamidoc yclohexyl)methyl)-2H-tetrazol-5-yl)-6- methylpicolinamide

Acetic anhydride (0 065 mL, 0 687 mmol) and 4-(dιmethylamιno)pyrιdιne Si bound (1 659 g, 1 145 mmol, 0 69 mmol/g loading) was added to a solution of λ/-(4-fluoro-3-methylbenzyl)-4-(2- (((fraÏ€s)-4-amιnocyclohexyl)methyl)-2H-tetrazol-5-yl)-6-me thylpιcolιnamιde (prepared as described in Example 185) (100 0 mg, 0 229 mmol) in dichloromethane (2 mL) The mixture was agitated overnight at room temperature, filtered, and λ/,λ/-dιmethylformamιde The filtrate was concentrated under a stream of nitrogen The residue was purified by reverse phase preparative HPLC (5%-95% CH ₃ CN/H ₂ O, 8 mm) to afford the title compound as a solid (33 mg, 30%) LC/MS (5%-100% CH ₃ CN/H ₂ O, 10 0 mm ) 4 82 mm , m/z 480 (M+H) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0 95 - 1 29 (m), 1 53 - 1 82 (m), 1 90 - 2 04 (m, 1 H), 2 19 (s, 3 H), 3 35 - 3 52 (m, 1 H), 4 46 (d, J=5 9 Hz, 2 H), 4 64 (d, J=6 6 Hz, 2 H), 6 99 - 7 08 (m, 1 H), 7 13 - 7 21 (m, 1 H), 7 21 - 7 28 (m, 1 H), 7 59 - 7 67 (m, 1 H), 8 05 (s, 1 H), 8 40 (s, 1 H), 9 16 - 9 24 (m, 1 H)

Example 188

W-(4-Fluoro-3-methylbenzyl)-4-(2-((((rans)-4-(3-aminoprop anamido)cyclohexyl)methyl)-2H- tetrazol-5-yl)-6-methylpicolinamide

O-(7-Azabenzotrιazole-1-yl)-λ/,λ/,λ/α/'-tetramethyluron ιum hexafluorophosphate (78 0 mg,

0 205 mmol), 3-(tert-butoxycarbonyl)propanoιc acid (32 4 mg, 0 171 mmol), and dnsopropylethylamine (0 060 mL, 0 342 mmol) was added to a solution of λ/-(4-fluoro-3-methylbenzyl)-4-(2-(((/rans)-4- aminocyclohexyOmethyO^H-tetrazol-S-ylJ-β-methylpicolinamide (prepared as described in Example 185) (100 0 mg, 0 229 mmol) (75 0 mg, 0 171 mmol) in λ/,λ/-dιmethylformamιde (2 mL) The mixture was stirred overnight at room temperature and was then concentrated under a stream of nitrogen The residue was purified by reverse phase preparative HPLC (5%-95% CH ₃ CN/H ₂ O, 8 mm) The resulting intermediate was dissolved in dichloromethane and trifluoroacetic acid was added The mixture was stirred for approximately 30 mm and then concentrated under a stream of nitrogen The residue was dissolved in dichloromethane and stirred with MP-carbonate resin for approximately 30 minutes The mixture was filtered and washed with dichloromethane followed by methanol The filtrate was concentrated under a stream of nitrogen to afford the title compound as a solid (15 mg, 17%) LC/MS (5%-95% CH ₃ CN/H ₂ O, 4 5 mm , 95% CH ₃ CN, 1 5 mm ) 2 833 mm , m/z 509 (M+H) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0 98 - 1 20 (m, 4 H), 1 49 - 1 65 (m, 2 H), 1 67 - 1 82 (m, 2 H), 1 94 (s, 3 H), 2 06 - 2 14 (m, 2 H), 2 17 (s, 3 H), 2 49 - 2 56 (m, 2 H), 2 60 (s, 3 H), 4 43 (d, J=6 6, Hz, 2 H), 4 59 (d, J=6 6 Hz, 2 H), 6 95 - 7 07 (m, 1 H), 7 10 - 7 19 (m), 7 21 (m, 1 H), 7 70 (m, 1 H), 7 96 (s, 1 H), 8 34 (s, 1 H), 9 08 - 9 18 (m, 1 H)

Example 189

W-(4-Fluoro-3-methylbenzyl)-4-(2-(((frans)-4-(2-methoxyac etamido)cyclohexyl)methyl)-2H- tetrazol-5-yl)-6-methylpicolinamide

The title compound was prepared in a similar manner to λ/-(4-fluoro-3-methylbenzyl)-4-(2- (((fλansH^S-aminopropanamido^yclohexyOmethyO^H-tetrazol-S-y O-θ-methylpicolmamide (Example 188) by reaction with 2-methoxyacetιc acid to afford 42 2 mg (48%) as a solid LC/MS (5%-95% CH ₃ CN/H ₂ O, 4 5 mm, 95% CH ₃ CN, 1 5 mm ) 3 356 mm , m/z 510 (M+H) ¹ H NMR (400 MHz, DMSO- Of ₆ ) ÏŒ ppm 0 99 - 1 39 (m, 4 H), 1 51 - 1 81 (m, 4 H), 1 83 - 2 07 (m, 2 H), 2 19 (s, 3 H), 2 65 (s, 3 H),

3 43 - 3 63 (m, 2 H), 3 72 (s, 3 H), 4 45 (d, J=Q 6 Hz, 2 H), 4 65 (d, J=I 3 Hz, 2 H), 6 96 - 7 10 (m, 1 H), 7 12 - 7 21 (m, 1 H), 7 20 - 7 29 (m, 1 H), 7 39 - 7 50 (m, 1 H), 8 05 (s, 1 H), 8 40 (s, 1 H), 9 13 - 9 26 (m, 1 H)

Example 190

2-((fraπs)-4-((5-(2-((4-Fluoro-3-methylbenzyl)carbamoyl) -6-methylpyridin-4-yl)-2W-tetrazol-2- yl)methyl)cyclohexylamino)-2-oxoethyl acetate

The title compound was prepared in a similar manner to /V-(4-fluoro-3-methylbenzyl)-4-(2- (((fransH^S-ammopropanamidoJcyclohexyOmethyO^H-tetrazol-S-yO -e-methylpicolinamide (Example 188) by reaction with 2-acetoxyacetιc acid to afford 49 2 mg (54%) as a solid LC/MS (5%-95%

CH ₃ CN/H ₂ O, 4 5 mm, 95% CH ₃ CN, 1 5 mm ) 3 353 mm 538 (M+H) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1 00 - 1 31 (m, 4 H), 1 49 - 1 84 (m, 4 H), 1 87 - 2 01 (m, 1 H), 2 03 (s, 3 H), 2 19 (s, 3 H), 2 65 (s, 3 H), 3 39 - 3 61 (m, 1 H), 4 36 (s, 2 H), 4 45 (d, J=5 9 Hz, 2 H), 4 65 (d, J=I 3 Hz, 2 H), 6 96 - 7 10 (m, 1 H) ₁ 7 12 - 7 21 (m, 1 H), 7 21 - 7 28 (m, 1 H), 7 71 - 7 84 (m, 1 H), 8 05 (s, 1 H), 8 40 (s, 1 H), 9 16 - 9 25 (m, 1 H)

Example 191

W-(4-Fluoro-3-methylbenzyl)-4-(2-(((frans)-4-(2-hydroxyac etamido)cyclohexyl)methyl)-2H- tetrazol-5-yl)-6-methylpicolinamide

The title compound was prepared in a similar manner to λ/-(4-fluoro-3-methylbenzyl)-4-(2-

(((^λaÏ€s^^S-aminopropanamido^yclohexy^methylJ^H-tetrazol-Î ´-yO-θ-methylpicolinamide (Example 188) by reaction with 2-hydroxyacetιc acid to afford 37 5 mg (44%) as a solid LC/MS (5%-95% CH ₃ CN/H ₂ O, 4 5 mm , 95% CH ₃ CN, 1 5 mm ) 3 080 mm , m/z 496 (M+H) ¹ H NMR (400 MHz, DMSO-c/ ₆ ) δ ppm 1 04 - 1 42 (m, 4 H), 1 50 - 1 83 (m, 4 H), 1 85 - 2 07 (m, 1 H), 2 19 (s, 3 H), 2 65 (s, 3 H), 3 41 - 3 64 (m, 1 H), 3 73 (s, 2 H), 4 45 (d, J=Q 6 Hz, 2 H), 4 65 (d, J=I 3 Hz, 2 H), 6 97 - 7 11 (m, 1 H), 7 13 - 7 21 (m, 1 H), 7 21 - 7 27 (m, 1 H), 7 32 - 7 43 (m, 1 H), 8 05 (s, 1 H), 8 40 (s, 1 H), 9 13 - 9 26 (m, 1 H)

Example 192

/V-(4-Fluoro-3-methylbenzyl)-4-(2-((((rans)-4-(3-methoxyp ropanamido)cyclohexyl)methyl)-2H- tetrazol-5-yl)-6-methylpicolinamide

The title compound was prepared in a similar manner to λ/-(4-fluoro-3-methylbenzyl)-4-(2-

(((/rans)-4-(3-amιnopropanamιdo)cyclohexyl)methyl)-2H-tetr azol-5-yl)-6-methylpιcolιnamιde (Example 188) by reaction with 3-methoxypropanoιc acid to afford 39 7 mg (44%) as a solid LC/MS (5%-95% CH ₃ CN/H ₂ O, 4 5 mm , 95% CH ₃ CN, 1 5 mm ) 3 298 mm , m/z 524 (M+H) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1 00 - 1 22 (m, 4 H), 1 52 - 1 82 (m, 4 H), 1 87 - 2 03 (m, 1 H), 2 19 (s, 3 H), 2 23 (t, J=6 6 Hz, 2 H), 2 65 (br s , 6 H), 3 35 - 3 54 (m, 3 H), 4 45 (d, J=6 6 Hz, 2 H), 4 64 (d, J=I 3 Hz, 2 H) ₁ 6 96 - 7 09 (m, 1 H), 7 1 1 - 7 20 (m, 1 H), 7 20 - 7 27 (m, 1 H), 7 55 - 7 75 (m, 1 H), 7 97 - 8 09 (m, 1 H), 8 35 - 8 46 (m, 1 H), 9 15 - 9 27 (m, 1 H)

Example 193

N-(4-fluoro-3-methylbenzyl)-4-(2-((((rans)-4-(2-aminoacet amido)cyclohexyl)methyl)-2H-tetrazol- 5-yl)-6-methylpicolinamide

The title compound was prepared in a similar manner to λ/-(4-fluoro-3-methylbenzyl)-4-(2- (((/rans)-4-(3-amιnopropanamιdo)cyclohexyl)methyl)-2H-tetr azol-5-yl)-6-methylpιcolιnamιde (Example 188) by reaction with 2-(tert-butoxycarbonyl)acetιc acid to afford 33 7 mg (40%) LC/MS (5%-95% CH ₃ CN/H ₂ O, 4 5 mm , 95% CH ₃ CN, 1 5 mm ) 2 790 mm , m/z 495 (M+H) ¹ H NMR (400 MHz,

DMSO-d ₆ ) 6 ppm 1 08 - 1 28 (m, 4 H), 1 52 - 1 83 (m, 4 H), 1 89 - 2 04 (m, 1 H), 2 19 (s, 3 H), 2 65 (s, 3 H), 3 01 (s, 2 H), 3 38 - 3 57 (m, 1 H), 4 45 (d, J=5 9 Hz, 1 H), 4 65 (d, J=I 3 Hz, 1 H), 7 00 - 7 09 (m, 1 H), 7 1 1 - 7 19 (m, 1 H), 7 21 - 7 28 (m, 1 H), 7 51 - 7 62 (m, 1 H), 8 05 (s, 1 H), 8 40 (s, 1 H), 9 17 - 9 26 (m, 1 H)

Example 194

/V-(3-Chloro-4-fluorobenzyl)-4-(2-((((rans)-4-aminocycloh exyl)methyl)-2H-tetrazol-5-yl)-6- methylpicolinamide

Step 1 Preparation of λ/-(3-chloro-4-fluorobenzyl)-6-methyl-4-(2/-/-tetrazol-5-yl )pιcolιnamιde

4-Fluoro-3-chlorobenzylamιne (3 52 g) was added to a solution of methyl 6-methyl-4-(2H- tetrazol-5-yl)pιcolιnate (prepared as described in step 4 of the synthesis of λ/-(3-methoxybenzyl)-4-(2- (((frans)-4-amιnocyclohexyl)methyl)-2/-/-tetrazol-5-yl)-6-m ethylpιcolιnamιde, Example 153) (2 20 g) in λ/,λ/-dιmethylacetamιde (4 mL) The mixture was heated to 90 ⁰ C for 2 hours The reaction mixture was allowed to cool, treated with water and filtered The solids were triturated with methanol (50 mL) overnight to afford the title compound as an off-white solid (2 00 g, 47%) MS(ES+) m/z 347 (M+H) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2 66 (s, 3 H), 4 49 (d, J=Q 4 Hz, 2 H), 7 30 - 7 39 (m, 1 H), 7 53 (d,

J=I 8 Hz, 1 H), 8 07 (d, J=1 1 Hz, 1 H), 8 44 (s, 1 H), 9 40 (t, J=G 4 Hz, 1 H) 19 F NMR (376 MHz, DMSO-c/ ₆ ) δ ppm -1 19 66 (q)

Step 2 Preparation of tert-butyl (^ans)-4-((5-(2-((3-chloro-4-fluorobenzyl)carbamoyl)-6-methy lpyrιdιn- 4-yl)-2/-/-tetrazol-2-yl)methyl)cvclohexylcarbamate

fert-Butyl-trans-(4-hydroxymethyl)cyclohexylcarbamate (1 46 g), polymer supported triphenylphosphine (Argonaut, 2 15 mmol/g, 6 17 g), and anhydrous tetrahydrofuran (55 mL) were added to λ/-(3-chloro-4-fluorobenzyl)-6-methyl-4-(2H-tetrazol-5-yl)p ιcolιnamιde (1 84 g) The stirred mixture was cooled in an ice-water bath and treated with di-tert-butyl azodicarboxylate (2 45 g) After 30 mm, the ice bath was removed and the mixture allowed to stir overnight at room temperature The mixture was concentrated in vacuo and the residue was purified by silica column chromatography (40% ethyl acetate/hexanes) to afford the title compound as a yellow, crystalline solid (0 83 g, 28%) MS(ES+) m/z 558 (M+H) ¹ H NMR (400 MHz, CDCI ₃ ) δ ppm 1 02 - 1 29 (m, 4 H), 1 42 (s, 9 H), 1 71 (d, J=12 6 Hz, 2 H), 2 00 - 2 14 (m, 3 H), 2 62 - 2 68 (m, 3 H), 3 31 - 3 50 (m, 1 H), 4 34 - 4 45 (m, 1 H), 4 52 (d, J=I 3 Hz, 2 H), 4 63 (d, J=6 4 Hz, 2 H), 7 10 (t, J=B 6 Hz, 1 H), 7 21 - 7 29 (m, 1 H), 7 42

(dd, J=I 0, 2 2 Hz, 1 H), 8 06 (d, J=1 1 Hz, 1 H), 8 51 (t, J=6 2 Hz, 1 H), 8 71 (d, J= 1 1 Hz, 1 H) ¹⁹ F NMR (376 MHz, CDCI ₃ ) δ ppm -1 17 85 (br s)

Step 3 Preparation of λ/-(3-chloro-4-fluorobenzyl)-4-(2-(((frans)-4-amιnocvdohex yl)methyl)-2/-/- tetrazol-5-yl)-6-methylpιcolιnamιde

Trifluoroacetic acid (5 mL) was added to a solution of tert-butyl (frans)-4-((5-(2-((3-chloro-4- fluorobenzyl)carbamoyl)-6-methylpyrιdιn-4-yl)-2H-tetrazol- 2-yl)methyl)cyclohexylcarbamate (199 8 mg, 0 358 mmol) in dichloromethane (5 mL), and the mixture was stirred for 30 mm at room temperature The reaction mixture was concentrated under a stream of nitrogen The residue was dissolved in dichloromethane and neutralized for approximately 30 mm with MP-carbonate resin The mixture was filtered and washed with dichloromethane and methanol The filtrate was concentrated under a stream of nitrogen for a quantitative yield LC/MS (5%-95% CH ₃ CN/H ₂ O, 4 5 mm , 95% CH ₃ CN, 1 5 mm ) 2 687 mm , m/z 458 (M+H)

Example 195 /^-(S-Chloro^-fluorobenzyO-β-methyM^Z^^fransJ^^methylsulfon amidoJcyclohexyOmethyl)-

2H-tetrazol-5-yl)picolinamide

Triethylamine (0 068 mL, 0 492 mmol) and methane sulfonyl chloride (0 019 mL, 0 246 mmol) were added to a solution of λ/-(3-chloro-4-fluorobenzyl)-4-(2-(((/rans)-4-amιnocyclohe xyl)methyl)-2H- tetrazol-5-yl)-6-methylpιcolιnamιde (prepared as described in Example 194) (75 1 mg, 0 164 mmol) in tetrahydrofuran (5 mL), and the mixture was stirred for 30 mm at room temperature The reaction mixture was concentrated and the residue was purified by reverse phase preparative HPLC (5%-95% CH ₃ CN/H ₂ O, 8 mm) to afford the title compound as a solid (45 6 mg, 52%) LC/MS (5%-95% CH ₃ CN/H ₂ O, 4 5 mm , 95% CH ₃ CN, 1 5 mm ) 3 384 mm , m/z 536 (M+H) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0 98 - 1 31 (m, 4 H), 1 53 - 1 67 (m, 2 H), 1 78 - 2 03 (m, 3 H), 2 66 (s, 3 H), 2 85 (s, 3 H), 2 95 - 3 12 (m, 1 H), 4 49 (d, J=6 6 Hz, 2 H), 4 64 (d, J=6 6 Hz, 2 H), 6 86 - 6 96 (m, 1 H), 7 26 - 7 39 (m, 2 H), 7 49 - 7 56 (m, 1 H), 8 02 - 8 10 (m, 1 H), 8 36 - 8 42 (m, 1 H), 9 29 - 9 38 (m, 1 H)

Example 196

W-(3-Chloro-4-fluorobenzyl)-4-(2-(((frans)-4-acetamidocyc lohexyl)methyl)-2H-tetrazol-5-yl)-6- methylpicolinamide

Acetic anhydride (0 037 mL, 0 393 mmol) and 4-(dιmethylamιno)pyrιdιne Si bound (949 0 mg,

0 655 mmol, 0 69 mmol/g loading) were added to a solution of N-(3-chloro-4-fluorobenzyl)-4-(2- (((/rans)-4-amιnocyclohexyl)methyl)-2/-/-tetrazol-5-yl)-6-m ethylpιcolιnamιde (prepared as described in Example 194) (60 0 mg, 0 131 mmol) in dichloromethane (2 mL), and the mixture was agitated overnight at room temperature The reaction mixture was filtered and washed with N ₁ N- dimethylformamide The filtrate was concentrated under a stream of nitrogen and purified by reverse phase preparative HPLC (5%-95% CH ₃ CN/H ₂ O, 8 mm) to afford the title compound as a solid (23 mg, 35%) LC/MS (5%-100% CH ₃ CN/H ₂ O, 10 0 mm ) 4 93 mm , m/z 500 (M+H) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0 94 - 1 27 (m), 1 54 - 1 83 (m), 1 89 - 2 04 (m, 1 H), 2 66 (s, 3 H), 3 28 (s), 3 35 - 3 52 (m, 1 H), 4 49 (d, J=5 9 Hz, 2 H), 4 64 (d, J=I 3 Hz, 2 H), 7 26 - 7 38 (m, 2 H), 7 46 - 7 57 (m, 1 H), 7 59 - 7 67 (m, 1 H), 8 06 (s, 1 H), 8 40 (s, 1 H), 9 30 - 9 39 (m, 1 H)

Example 197

W-(3-Chloro-4-fluorobenzyl)-4-(2-(((frans)-4-(3-aminoprop anamido)cyclohexyl)methyl)-2H- tetrazol-5-yl)-6-methylpicolinamide

O-(7-Azabenzotrιazole-1-yl)-λ/,λ/,λ/\λ/'-tetramethyluro nιum hexafluorophosphate (65 0 mg,

0 170 mmol), 3-(tert-butoxycarbonyl)propanoιc acid (26 9 mg, 0 142 mmol), and dnsopropylethylamine (0 049 mL, 0 284 mmol) were added to a solution of λ/-(3-chloro-4-fluorobenzyl)-4-(2-(((frans)-4- amιnocyclohexyl)methyl)-2/-/-tetrazol-5-yl)-6-methylpιcolÎ ¹namιde (prepared as described in Example 194) (65 0 mg, 0 142 mmol) in λ/,λ/-dιmethylformamιde (2 mL), and the mixture was overnight at room temperature The reaction mixture was concentrated, treated with trifluoroacetic acid, and purified by reverse phase preparative HPLC (5%-95% CH ₃ CN/H ₂ O, 8 mm) to afford the title compound as a solid (24 0 mg, 32%) LC/MS (5%-100% CH ₃ CN/H ₂ O, 10 0 mm ) 3 86 mm , m/z 529 (M+H) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1 05 - 1 23 (m, 4 H), 1 53 - 1 81 (m, 4 H), 1 90 - 2 03 (m, 1 H), 2 10 (t, J=6 6 Hz, 2 H), 2 66 (s, 3 H), 2 69 (t, J=6 6 Hz, 2 H), 3 28 (br s ), 3 40 - 3 53 (m, 1 H), 4 49 (d, J=5 9 Hz, 2

H), 4 65 (d, J=6 6 Hz, 2 H), 7 23 - 7 38 (m, 2 H), 7 48 - 7 57 (m, 1 H), 7 66 - 7 75 (m, 1 H), 8 06 (s, 1 H), 8 40 (s, 1 H), 9 30 - 9 39 (m, 1 H)

Example 198

/V-(3-Chloro-4-fluorobenzyl)-4-(2-(((frans)-4-(2-methoxya cetamido)cyclohexyl)methyl)-2H- tetrazol-5-yl)-6-methylpicolinamide

The title compound was prepared in a similar manner to λ/-(3-Chloro-4-fluorobenzyl)-4-(2- (((/rans)-4-(3-amιnopropanamιdo)cyclohexyl)methyl)-2H-tetr azol-5-yl)-6-methylpιcolιnamιde (Example 197) by reaction with 2-methoxyacetιc acid to afford 35 mg (46%) as a solid LC/MS (5%-100% CH ₃ CN/H ₂ O, 10 0 mm ) 5 13 mm , m/z 530 (M+H) ¹ H NMR (400 MHz, DMSOd ₆ ) ÏŒ ppm 1 06 - 1 34 (m, 4 H), 1 54 - 1 78 (m, 4 H), 1 86 - 2 05 (m, 1 H), 2 66 (s), 3 23 - 3 33 (m), 3 45 - 3 62 (m, 1 H), 3 72 (S, 3 H), 4 49 (d, J=5 9 Hz, 2 H), 4 65 (d, J=7 3 Hz, 2 H), 7 29 - 7 39 (m, 2 H), 7 43 - 7 49 (m, 1 H), 7 50 - 7 58 (m, 1 H), 8 06 (s, 1 H), 8 40 (s, 1 H), 9 30 - 9 37 (m, 1 H)

Example 199 2-((frans)-4-((5-(2-((3-Chloro-4-fluorobenzyl)carbamoyl)-6-m ethylpyridin-4-yl)-2H-tetrazol-2- yl)methyl)cyclohexylamino)-2-oxoethyl acetate

The title compound was prepared in a similar manner to A/-(3-Chloro-4-fluorobenzyl)-4-(2- (((frans)-4-(3-amιnopropanamιdo)cyclohexyl)methyl)-2/-/-te trazol-5-yl)-6-methylpιcolιnamιde (Example 197) by reaction with 2-acetoxyacetιc acid to afford 31 2 mg (39%) as a solid LC/MS (5%-100%

CH ₃ CN/H ₂ O, 10 0 mm ) 5 06 mm , m/z 558 (M+H) ¹ H NMR (400 MHz, DMSOd ₆ ) δ ppm 1 06 - 1 29 (m, 4 H), 1 55 - 1 84 (m, 4 H), 1 89 - 2 01 (m, 1 H), 2 04 (s, 3 H), 2 66 (s, 3 H), 3 41 - 3 59 (m, 1 H), 4 36 (s, 2 H), 4 49 (d, J=5 9 Hz, 2 H), 4 65 (d, J-I 3 Hz, 2 H), 7 30 - 7 38 (m, 2 H), 7 50 - 7 55 (m, 1 H), 7 75 - 7 82 (m, 1 H), 8 06 (s, 1 H), 8 40 (s, 1 H), 9 30 - 9 38 (m, 1 H)

Example 200

W-(3-Chloro-4-fluorobenzyl)-4-(2-((((rans)-4-(2-hydroxyac etamido)cyclohexyl)methyl)-2H- tetrazol-5-yl)-6-methylpicolinamide

The title compound was prepared in a similar manner to λ/-(3-Chloro-4-fluorobenzyl)-4-(2- (((frans)-4-(3-amιnopropanamιdo)cyclohexyl)methyl)-2/-/-te trazol-5-yl)-6-methylpιcolιnamιde (Example 197) by reaction with 2-hydroxyacetιc acid to afford 48 2 mg (66%) as a solid LC/MS (5%-100% CH ₃ CN/H ₂ O, 10 0 mm ) 4 74 mm , m/z 516 (M+H) ¹ H NMR (400 MHz, DMSOd ₆ ) ÏŒ ppm 1 05 - 1 35 (m, 4 H), 1 55 - 1 79 (m, 4 H), 1 88 - 2 03 (m, 1 H), 2 66 (s, 3 H), 3 28 (br s ), 3 47 - 3 61 (m, 1 H), 3 73 (s, 2 H), 4 49 (d, J=Q 6 Hz, 2 H), 4 65 (d, J=Q 6 Hz, 2 H), 7 24 - 7 44 (m, 3 H), 7 48 - 7 58 (m, 1 H), 8 06 (s, 1 H), 8 40 (s, 1 H), 9 27 - 9 41 (m, 1 H)

Example 201

W-(3-Chloro-4-fluorobenzyl)-4-(2-((((rans)-4-(3-methoxypr opanamido)cyclohexyl)methyl)-2H- tetrazol-5-yl)-6-methylpicolinamide

The title compound was prepared in a similar manner to λ/-(3-Chloro-4-fluorobenzyl)-4-(2- (((frans)-4-(3-aminopropanamido)cyclohexyl)methyl)-2/-/-tetr azol-5-yl)-6-methylpicolinamide (Example 197) by reaction with 3-methoxypropanoιc acid to afford 49 1 mg (64%) as a solid LC/MS (5%-100% CH ₃ CN/H ₂ O, 10 0 mm ) 5 01 mm , m/z 544 (M+H) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1 01 - 1 25 (m, 4 H), 1 50 - 1 81 (m, 4 H), 1 86 - 2 05 (m, 1 H), 2 23 (t, J=Q 6 Hz, 2 H), 2 66 (s, 3 H), 3 24 - 3 32 (m), 3 47 (t, J=Q 2 Hz, 2 H), 4 49 (d, J=5 9 Hz, 2 H), 4 64 (d, J=Q 6 Hz, 2 H), 7 29 - 7 39 (m, 2 H), 7 49 - 7 55 (m, 1 H), 7 60 - 7 68 (m, 1 H), 8 06 (s, 1 H), 8 40 (s, 1 H), 9 30 - 9 38 (m, 1 H)

Example 202

/V-(3-Chloro-4-fluorobenzyl)-4-(2-(((frans)-4-(2-aminoace tamido)cyclohexyl)methyl)-2H-tetrazol-

5-yl)-6-methylpicolinamide

The title compound was prepared in a similar manner to λ/-(3-Chloro-4-fluorobenzyl)-4-(2- (((frans)-4-(3-aminopropanamido)cyclohexyl)methyl)-2/-y-tetr azol-5-yl)-6-methylpicolinamide (Example 197) by reaction with 2-(tert-butoxycarbonyl)acetιc acid to afford 45 6 mg (62%) as a solid LC/MS (5%-100% CH ₃ CN/H ₂ O, 10 0 mm ) 3 81 mm , m/z 515 (M+H) ¹ H NMR (400 MHz, DMSOd ₆ ) δ ppm 1 03 - 1 27 (m, 4 H), 1 50 - 1 84 (m, 4 H), 1 89 - 2 05 (m, 1 H), 2 66 (s, 3 H), 3 04 (s), 3 27 (br s ), 3 41 - 3 57 (m, 1 H), 4 49 (d, J=5 9 Hz, 2 H), 4 65 (d, J=I 3 Hz, 2 H), 7 26 - 7 39 (m, 2 H), 7 50 - 7 55 (m, 1 H), 7 58 - 7 65 (m, 1 H), 8 06 (s, 1 H), 8 40 (s, 1 H), 9 30 - 9 38 (m, 1 H)

Example 203 W-(4-Fluoro-3-((2-hydroxyethoxy)methyl)benzyl)-6-methyl-4-(2 -(((frans)-4-(methylsulfonamido)- cyclohexyl)methyl)-2H-tetrazol-5-yl)picolinamide

λ/-(4-Fluoro-3-(hydroxymethyl)benzyl)-6-methyl-4-(2-(((fran s)-4- (methylsulfonamιdo)cyclohexyl)methyl)-2/-/-tetrazol-5-yl)pÎ ¹colιnamιde (prepared as described in Example 181 ) (38 mg, 0 059 mmol), potassium carbonate (8 13 mg, 0 59 mmol), and ethanol (5 mL) were combined in a 20 mL scintillation vial with a magnetic stir bar and reflux for 2 hours The reaction mixture was cooled in an ice bath and ethylene oxide (7 13 mg, 0 162 mmol) was added The mixture was slowly warmed to room temperature and stirred for 36 hours The reaction mixture was concentrated and purified by preparative reverse phase preparative HPLC to afford the title compound as a white solid (30 8 mg, 76%) LC/MS (5%-95% CH ₃ CN/H ₂ O, 5 mm ) 2 71 mm , m/z 576 (M+H) ¹ H NMR (400 MHz, DMSOd ₆ ) δ ppm 9 25 (t, J=6 22 Hz, 1 H), 8 41 (s, 1 H), 8 05 (s, 1 H), 7 44 (d, J=7 32 Hz, 1 H), 7 19 - 7 28 (m, J=6 59 Hz, 1 H), 7 06 (t, 1 H), 6 92 (d, J=7 32 Hz, 1 H), 5 20 (t, J=5 49 Hz, 1 H), 4 64 (d, J=6 59 Hz, 2 H), 4 50 (d, J=5 12 Hz, 3 H), 3 28 (d, J=5 12 Hz, 1 H), 2 97 - 3 1 1 (m, J=6 59 Hz, 1 H), 2 79 - 2 91 (m, 2 H), 2 65 (s, 2 H), 2 43 - 2 53 (m, 1 H), 1 75 (dd, J=1 11 63, 10 61 Hz, 4 H), 1 05 - 1 28 (m, 3 H)

Example 204

4-(2-(((fra/7s)-4-Acetamidocyclohexyl)methyl)-2H-tetrazol -5-yl)-W-((6-hydroxypyridin-2- yl)methyl)-6-methylpicolinamide

Step 1 Preparation of 4-(2-((4-acetamιdocvclohexyl)methyl)-2/-/-tetrazol-5-v0-6-m ethylpιcolιnιc acid

Tπethylamine (0 95 mL, 6 81 mmol) and acetic anhydride (0 52 ml_, 5 45 mmol) were added to a solution of methyl 4-(2-(((frans)-4-amιnocyclohexyl)methyl)-2/-/-tetrazol-5-yl )-6-methylpιcolιnate (prepared as described in step 1 of the synthesis of N-(3-methoxybenzyl)-4-(2-(((frans)-4-(3- hydroxypropanamιdo)cyclohexyl)methyl)-2/-/-tetrazol-5-yl)-6 -methylpιcolιnamιde, Example 168) (500 mg, 1 36 mmol) in dichloromethane (20 mL) and the mixture was stirred at room temperature for two days The reaction mixture was filtered and washed with dichloromethane The filtrate was concentrated and the residue was dissolved in a mixture of tetrahydrofuran/water (12 mL, 5/1 ) Lithium hydroxide (131 mg, 5 45 mmol) was added and the mixture was stirred at room temperature for 18 hours The reaction mixture was concentrated and the residue was purified by reverse phase preparative HPLC to afford the title compound as a white solid (165 mg, 34%) MS (ES+) m/z 359 (M+H) Step 2 Preparation 4-(2-(((rrans)-4-acetamιdocvclohexyl)rnethyl)-2H-tetrazol-5 -yl)-N-((6- hvdroxypyrιdιn-2-yl)methyl)-6-methylpιcolιnamιde

λ/,λ/,λ/',λ/'-Tetramethyl-O-(1 H-benzotrιazol-1 -yl)uronιum hexafluorophosphate (254 mg, 0 67 mmol) was added to a mixture of 4-(2-((4-acetamιdocyclohexyl)methyl)-2/-/-tetrazol-5-yl)-6- methylpicolinic acid (160 mg, 0 446 mmol), 6-(amιnomethyl)pyrιdιn-2(1 H)-one (Bronn, W R US 4,555,573, 1985) (191 mg, 0 67 mmol), and triethylamine (0 22 mL, 1 56 mmol) in W ₁ N- dimethylformamide (2 mL) The mixture was stirred at room temperature for 18 hours The reaction mixture was purified by reverse phase preparative HPLC to afford the title compound as a solid (106 mg, 51%) MS (ES+) m/z 465 (M+H) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0 99 - 1 21 , (m, 4 H), 1 58 (s, J=9 52 Hz, 2 H), 1 67 - 1 81 (m, 5 H), 1 87 - 2 00 (m, 2 H), 2 66 (s, 3 H), 3 36 - 3 48 (m, 1 H), 4 33 (d, J=5 86 Hz, 2 H), 4 63 (d, J=7 32 Hz, 2 H), 5 98 - 6 10 (m, 1 H), 6 17 (d, J=9 52 Hz, 1 H), 7 24 - 7 37 (m, 1 H), 7 61 (d, J=8 05 Hz, 1 H), 8 07 (s, 1 H), 8 38 (s, 1 H), 9 24 (t, J=B 95 Hz, 1 H)

Example 205

W-(3-(Hydroxymethyl)benzyl)-4-(2-(((frans)-4-acetamidocyc lohexyl)methyl)-2W-tetrazol-5-yl)-6- methylpicolinamide

λ/,λ/,λ/',λ/'-Tetramethyl-O-(1/-/-benzotrιazol-1-yl)uro nιum hexafluorophosphate (159 mg, 0 42 mmol) was added to a mixture of 4-(2-((4-acetamιdocyclohexyl)methyl)-2H-tetrazol-5-yl)-6- methylpicolinic acid (prepared as described in step 1 of the synthesis of 4-(2-(((frans)-4- acetamιdocyclohexyl)methyl)-2/-/-tetrazol-5-yl)-λ/-((6-hyd roxypyrιdιn-2-yl)methyl)-6-methylpιcolιnamιde, Example 204) (50 mg, 0 14 mmol), (3-(amιnomethyl)pheny!)methanol (prepared as described in step 1 of the synthesis of λ/-(3-(hydroxymethyl)benzyl)-6-methyl-4-(2-(((/rans)-4-

(methylsulfonamιdo)cydohexyl)methyl)-2H-tetrazol-5-yl)pιco lιnamιde, Example 183) (29 mg, 0 21 mmol), and triethylamine (0 03 mL, 0 21 mmol) in λ/,λ/-dιmethylformamιde (2 mL) The mixture was stirred at room temperature for 18 hours The reaction mixture was purified by reverse phase preparative HPLC Fractions containing desired product were combined and concentrated The resulting residue was taken up in methanol and passed through a carbonate cartridge The filtrate was concentrated to afford the title compound as a solid (22 mg, 33%) MS (ES+) m/z 478 (M+H) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1 04 - 1 26 (m, 6 H), 1 56 - 1 67 (m, 2 H), 1 71 - 1 85 (m, 5 H), 1 91 - 2 03 (m, 1 H), 2 67 (s, 3 H), 3 25 - 3 35 (m, 1 H), 4 48 (s, 2 H), 4 54 (d, J=6 59 Hz, 2 H), 4 67 (d, J=I 32 Hz, 2 H), 7 14 - 7 34 (m, 3 H), 7 66 (d, J=I 32 Hz, 1 H), 8 08 (s, 1 H), 8 44 (s, 1 H), 9 22 (t, J=5 86 Hz, 1 H)

Example 206

/V-(3-(2-Hydroxyethoxy)benzyl)-4-(2-((((rans)-4-acetamido cyclohexyl)methyl)-2W-tetrazol-5-yl)-6- methylpicolinamide

Ay,λ/,/V',λ/'-Tetramethyl-O-(1H-benzotrιazol-1-yl)uronιu m hexafluorophosphate (159 mg, 0 42 mmol) was added to a mixture of 4-(2-((4-acetamιdocyclohexyl)methyl)-2H-tetrazol-5-yl)-6- methylpicolinic acid (prepared as described in step 1 of the synthesis of 4-(2-(((/rans)-4- acetamιdocyclohexyl)methyl)-2H-tetrazol-5-yl)-/V-((6-hydrox ypyrιdιn-2-yl)methyl)-6-methylpιcolιnamιde, Example 204) (50 mg, 0 14 mmol), 2-(3-(amιnomethyl)phenoxy)ethanol (prepared as described in step 2 of the synthesis of λ/-(3-(2-hydroxyethoxy)benzyl)-6-(2-(((frans)-4-amιnocyclo hexyl)methyl)-2H- tetrazol-5-yl)-2-methylpyπmιdιne-4-carboxamιde, Example 13) (35 mg, 0 21 mmol), and triethylamine

(0 03 mL, 0 21 mmol) in λ/,λ/-dιmethylformamιde (2 mL) The mixture was stirred at room temperature for 18 hours The reaction mixture was purified by reverse phase preparative HPLC Fractions containing desired product were combined and concentrated The resulting residue was taken up in methanol and passed through a carbonate cartridge The filtrate was concentrated to afford the title compound as a solid (26 mg, 37%) MS (ES+) m/z 508 (M+H) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1 04 - 1 24 (m, 5 H), 1 58 - 1 68 (m, 2 H), 1 72 - 1 84 (m, 5 H), 1 92 - 2 05 (m, 2 H), 2 68 (s, 3 H), 3 69 (t, J=5 12 Hz, 2 H), 3 96 (t, J=5 12 Hz, 2 H), 4 51 (d, J=5 86 Hz, 2 H), 4 67 (d, J=I 32 Hz, 2 H), 6 82 (d, J=I 32 Hz, 1 H), 6 88 - 6 96 (m, 1 H), 7 23 (t, J=Q 05 Hz, 1 H), 7 66 (d, J=I 32 Hz, 1 H), 8 08 (s, 1 H), 8 43 (s, 1 H), 9 22 (t, J=6 59 Hz, 1 H)

Example 207

W-(4-Fluoro-3-(hydroxymethyl)benzyl)-4-(2-((((rans)-4-ace tamidocyclohexyl)methyl)-2H-tetrazol-

5-yl)-6-methylpicolinamide

λ/,λ/,λ/',λ/'-Tetramethyl-0-(1 /-/-benzotrιazol-1 -yl)uronιum hexafluorophosphate (476 mg, 1 26 mmol) was added to a mixture of 4-(2-((4-acetamιdocyclohexyl)methyl)-2H-tetrazol-5-yl)-6- methylpicolimc acid (prepared as described in step 1 of the synthesis of 4-(2-(((trans)-4- acetamιdocyclohexyl)methyl)-2H-tetrazol-5-yl)-λ/-((6-hydro xypyrιdιn-2-yl)methyl)-6-methylpιcolιnamιde, Example 204) (150 mg, 0 42 mmol), (5-(amιnomethyl)-2-fluorophenyl)methanol (prepared as described in step 1 of the synthesis of λ/-(4-fluoro-3-(hydroxymethyl)benzyl)-6-methyl-4-(2-(((/raÏ €s)-4- (methylsulfonamido)cyclohexyl)methyl)-2H-tetrazol-5-yl)picol inamide, Example 181 ) (120 mg, 0 63 mmol), and tÏ€ethylamine (0 15 mL, 1 05 mmol) in λ/,λ/-dιmethylformamιde (6 mL) The mixture was stirred at room temperature for 18 hours The reaction mixture was purified by reverse phase preparative HPLC Fractions containing desired product were combined and concentrated The resulting residue was taken up in methanol and passed through a carbonate cartridge The filtrate was concentrated to afford the title compound as a solid (1 12 mg, 54%) MS (ES+) m/z 496 (M+H) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1 04 - 1 27 (m, 4 H), 1 55 - 1 68 (m, Hz, 2 H), 1 71 - 1 84 (m, 5 H), 1 91 - 2 06 (m, 2 H), 2 67 (s, 3 H), 3 82 (s, 3 H), 4 51 (d, J=5 86 Hz, 2 H), 4 67 (d, J=I 32 Hz, 2 H), 6 82 - 6 96 (m, 1 H), 7 05 - 7 26 (m, 2 H), 7 65 (d, J=I 32 Hz, 1 H), 8 07 (s, 1 H), 8 43 (s, 1 H), 9 24 (t, J=Q 22 Hz, 1 H)

Example 208

/V-(3-Ethoxybenzyl)-4-(2-(((frans)-4-acetamidocyclohexyl) methyl)-2H-tetrazol-5-yl)-6- methylpicolinamide

λ/,λ/,λ/',λ/'-Tetramethyl-O-(1 /-/-benzotrιazol-1 -yl)uronιum hexafluorophosphate (159 mg, 0 42 mmol) was added to a mixture of 4-(2-((4-acetamιdocyclohexyl)methyl)-2H-tetrazol-5-yl)-6- methylpicolinic acid (prepared as described in step 1 of the synthesis of 4-(2-(((frans)-4- acetamιdocyclohexyl)methyl)-2H-tetrazol-5-yl)-λ/-((6-hydro xypyrιdιn-2-yl)methyl)-6-methylpιcolιnamιde, Example 204) (50 mg, 0 14 mmol), (3-ethoxyphenyl)methanamιne (prepared as described in step 2 of the synthesis of λ/-(3-ethoxybenzyl)-6-methyl-4-(2-(((frans)-4-(methylsulfon amιdo)cyclohexyl)methyl)- 2/-/-tetrazo!-5-yl)pιcolιnamιde, Example 180) (31 mg, 0 21 mmol), and tÏ€ethylamine (0 03 mL, 0 21 mmol) in λ/,λ/-dιmethylformamιde (2 mL) The mixture was stirred at room temperature for 18 hours The reaction mixture was purified by reverse phase preparative HPLC Fractions containing desired product were combined and concentrated The resulting residue was taken up in methanol and passed through a carbonate cartridge The filtrate was concentrated to afford the title compound as a solid (39 mg, 57%) MS (ES+) m/z 492 (M+H) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1 02 - 1 25 (m, 4 H), 1 30 (t, J=6 95 Hz, 3 H), 1 53-1 68(m, 2H), 1 72 - 1 85 (m, 5 H), 1 98 (m, 2 H), 2 68 (s, 3 H), 4 00 (q, J=6 83 Hz, 2 H), 4 50 (d, J=6 59 Hz, 2 H), 4 67 (d, J=6 59 Hz, 2 H), 6 77 - 6 83 (m, 1 H), 6 87 - 6 94 (m, 2 H), 7 17 - 7 26 (m, 8 05 Hz, 1 H), 7 60 - 7 70 (m, 1 H), 8 08 (s, 1 H), 8 43 (s, 1 H), 9 21 (t, J=6 22 Hz, 1 H)

Example 209

W-(3-Methoxybenzyl)-4-(2-(((c/s)-4-aminocyclohexyl)methyl )-2H-tetrazol-5-yl)-6- methylpicolinamide

Step 1 Preparation of tert-butyl (c/s)-4-((5-(2-((3-methoxybenzyl)carbamoyl)-6-methylpyridin- 4-yl)-2/-/- tetrazol-2-yl)methyl)cvclohexylcarbamate

A mixture of λ/-(3-methoxybenzyl)-6-methyl-4-(2H-tetrazol-5-yl)pιcolιn amιde (prepared as described in step 5 of the synthesis of λ/-(3-methoxybenzyl)-4-(2-(((/rans)-4-amιnocyclohexyl)meth yl)- 2H-tetrazol-5-yl)-6-methylpιcolιnamιde, Example 153) (1 0 g, 3 08 mmol), tert-butyl cιs-(4-

hydroxymethyl)cyclohexyl carbamate (1 41 g, 6 17 mmol), and polymer supported-triphenylphosphine (3 580 g, 7 07 mmol) in anhydrous tetrahydrofuran (60 mL) was cooled to 0 ⁰ C in an ice bath and then di-tert-butyl azodicarboxylate (1 42 g, 3 08 mmol) was added The reaction was allowed to warm to room temperature while stirring over 15 hours The reaction mixture was filtered and the filtrate was concentrated The residue was purified by reverse phase preparative HPLC (5%-95% CH ₃ CN/H ₂ O) to afford the title compound

Step 2 Preparation of λ/-(3-methoxybenzyl)-4-(2-(((c<5)-4-amιnocvclohexyl)met hyl)-2/-/-tetrazol-5-yl)-6- methylpicolinamide

Trifluoroacetic acid was added to a solution of tert-butyl (c;s)-4-((5-(2-((3-methoxybenzyl)- carbamoyl)-6-methylpyrιdιn-4-yl)-2H-tetrazol-2-yl)methyl)c yclohexylcarbamate in dichloromethane and the mixture was allowed to stir for 30 mm at room temperature The reaction mixture was concentrated The residue was dissolved in dichloromethane and MP-carbonate resin was added The mixture was agitated for 1 h, filtered, and washed with dichloromethane and methanol The filtrate was concentrated to afford the title compound as a solid (1 091 g, 81 %) LC/MS (5%-95% CH ₃ CN/H ₂ O, 4 5 mm , 95% CH ₃ CN, 1 5 mm ) 2 479 mm , m/z 436 (M+H) ¹ H NMR (400 MHz, DMSO-c/ ₆ ) δ ppm 1 33 - 1 86 (m, 8 H), 2 17 - 2 31 (m, 1 H), 2 65 (s, 3 H), 3 18 - 3 28 (m, 1 H), 3 70 (s, 3 H), 4 48 (d, J=6 4 Hz, 2 H), 4 72 (d, J=7 3 Hz, 2 H), 6 76 - 6 84 (m, 1 H), 6 85 - 6 93 (m, 2 H), 7 17 - 7 27 (m, 1 H), 7 93 (br s , 2 H), 8 03 - 8 09 (m, 1 H), 8 41 (s, 1 H), 9 19 - 9 28 (m, 1 H)

Example 210

W-(3-Methoxybenzyl)-6-methyl-4-(2-(((c/s)-4-(methylsulfon amido)cyclohexyl)methyl)-2H-tetrazol-

5-yl)picolinamide

Triethylamine (0 048 mL, 0 345 mmol) and methane sulfonyl chloride (0 013 mL, 0 173 mmol) were added to a solution of λ/-(3-methoxybenzyl)-4-(2-(((c/s)-4-amιnocyclohexyl)methyl )-2H-tetrazol-5- yl)-6-methy!pιcolιnamιde (prepared as described in (Example 209) (50 1 mg, 0 1 15 mmol) in tetrahydrofuran (1 5 mL) and the mixture was stirred 2 hours at room temperature The reaction mixture was concentrated and purified by reverse phase preparative HPLC (5%-95% CH ₃ CN/H ₂ O) to afford the title compound as a solid (33 7 mg, 57%) LC/MS (5%-95% CH ₃ CN/H ₂ O, 4 5 mm , 95% CH ₃ CN, 1 5 mm ) 3 188 mm , m/z 514 (M+H) ¹ H NMR (400 MHz, DMSOd ₆ ) δ ppm 1 29 - 1 79 (m), 1 99 - 2 22 (m), 2 65 (s, 3 H), 2 87 (s, 3 H), 3 36 - 3 48 (m), 3 71 (s, 3 H), 4 49 (d, J=6 6 Hz, 2 H), 4 67

(d, _/=6 6 Hz, 2 H), 6 73 - 6 84 (m, 1 H), 6 84 - 6 97 (m, 3 H), 7 13 - 7 28 (m, 1 H), 8 05 (s, 1 H), 8 41 (s, 1 H), 9 12 - 9 25 (m, 1 H)

Example 211

W-(3-Methoxybenzyl)-4-(2-(((c/s)-4-acetamidocyclohexyl)me thyl)-2W-tetrazol-5-yl)-6- methylpicolinamide

Acetic anhydride (0 033 mL, 0 345 mmol) and 4-(dιmethylamιno)pyrιdιne Si bound (833 0 mg, 0 575 mmol, 0 69 mmol/g loading) were added to a solution of λ/-(3-methoxybenzyl)-4-(2-(((c/s)-4- amιnocyclohexyl)methyl)-2H-tetrazol-5-yl)-6-methylpιcolιn amιde (prepared as described in Example 209) (50 0 mg, 0 1 15 mmol) in dichloromethane (2 mL) and the mixture was agitated overnight at room temperature The reaction mixture was filtered, washed with λ/,λ/-dιmethylformamιde, and concentrated The residue was purified by reverse phase preparative HPLC (5%-95% CH ₃ CN/H ₂ O) to afford the title compound as a solid (27 1 mg, 49%) LC/MS (5%-100% CH ₃ CN/H ₂ O, 10 0 mm ) 4 64 mm , m/z 478 (M+H) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1 31 - 1 66 (m), 1 80 (s, 3 H), 2 07 - 2 21 (m, 1 H), 2 62 - 2 69 (m, 3 H), 3 23 - 3 31 (m), 3 71 (s, 3 H), 3 74 - 3 82 (m, 1 H), 4 49 (d, J=6 6 Hz, 2 H), 4 68 (d, J= 7 3 Hz, 2 H), 6 76 - 6 82 (m, 1 H), 6 86 - 6 94 (m, 2 H), 7 17 - 7 25 (m, 1 H), 7 60 - 7 68 (m, 1 H), 8 05 (s, 1 H), 8 41 (s, 1 H), 9 14 - 9 23 (m, 1 H)

Example 212

W-(3-Methoxybenzyl)-4-(2-(((c/s)-4-(3-aminopropanamido)cy clohexyl)methyl)-2H-tetrazol-5-yl)-6- methylpicolinamide

O-(7-Azabenzotrιazole-1 -yl)-N,N,/V,/V-tetramethyluronιum hexafluorophosphate (52 0 mg, 0 138 mmol), 3-(tert-butoxycarbonyl)propanoιc acid (21 6 mg, 0 1 15 mmol), and dnsopropylethylamine (0 040 mL, 0 230 mmol) were added to a solution of λ/-(3-methoxybenzyl)-4-(2-(((c/s)-4- aminocyclohexyOmethyO^H-tetrazol-S-yO-e-methylpicolinamide (prepared as described in Example 209) (50 1 mg, 0 1 15 mmol) in λ/,λ/-dιmethylformamιde (2 mL) and the mixture was stirred overnight at room temperature The reaction mixture was concentrated, treated with trifluoroacetic acid, and the residue was purified by reverse phase preparative HPLC (5%-95% CH ₃ CN/H ₂ O) to afford the title compound as a solid (16 3 mg, 28%) LC/MS (5%-95% CH ₃ CN/H ₂ O, 4 5 mm , 95% CH ₃ CN, 1 5 mm ) 2 665 mm , m/z 507 (M+H) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1 27 - 1 69 (m), 2 14 (t, J=6 6 Hz, 2

H), 2 18 - 2 27 (m, 1 H), 2 65 (s, 3 H), 2 70 (t, J=6 6 Hz, 2 H), 3 71 (s, 3 H), 3 80 (br s), 4 49 (d, J=6 6 Hz, 2 H), 4 68 (d, J=I 3 Hz, 2 H), 6 74 - 6 82 (m, 1 H), 6 84 - 6 93 (m, 2 H), 7 14 - 7 25 (m, 1 H), 7 80 - 7 87 (m, 1 H), 8 05 (s, 1 H), 8 40 (s, 1 H), 9 13 - 9 23 (m, 1 H)

Example 213 /V-(3-Methoxybenzyl)-4-(2-(((c/s)-4-(2-methoxyacetamido)cycl ohexyl)methyl)-2H-tetrazol-5-yl)-6- methylpicolinamide

The title compound was prepared in a similar manner to λ/-(3-methoxybenzyl)-4-(2-(((c/s)-4-(3- amιnopropanamιdo)cyclohexyl)methyl)-2/-/-tetrazol-5-yl)-6- methylpιcolιnamιde (Example 212) by reaction with 2-methoxyacetιc acid and afforded 26 8 mg (46%) as a solid LC/MS (5%-95% CH ₃ CN/H ₂ O, 4 5 mm , 95% CH ₃ CN, 1 5 mm ) 3 151 mm , m/z 508 (M+H) ¹ H NMR (400 MHz, DMSO-Cf ₆ ) δ ppm 1 22 - 1 75 (m), 2 13 - 2 28 (m), 2 52 (s), 2 65 (s, 3 H), 3 71 (s, 3 H), 3 77 (s), 3 78 - 3 86 (m), 4 49 (d, J=6 6 Hz, 2 H), 4 76 (d, J=I 3 Hz, 2 H), 6 75 - 6 83 (m, 1 H), 6 86 - 6 94 (m, 2 H), 7 17 - 7 25 (m, 1 H), 7 38 - 7 45 (m, 1 H), 8 05 (s, 1 H), 8 41 (s, 1 H), 9 15 - 9 24 (m, 1 H)

Example 214

2-((c/s)-4-((5-(2-((3-methoxybenzyl)carbamoyl)-6-methylpy ridin-4-yl)-2H-tetrazol-2-yl)methyl)- cyclohexylamino)-2-oxoethyl acetate

The title compound was prepared in a similar manner to λ/-(3-methoxybenzyl)-4-(2-(((c/s)-4-(3- amιnopropanamιdo)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6-me thylpιcolιnamιde (Example 212) by reaction with 2-acetoxyacetιc acid and afforded 20 9 mg (34%) as a solid LC/MS (5%-95% ^ CH ₃ CNZH ₂ O, 4 5 mm , 95% CH ₃ CN, 1 5 mm ) 3 163 mm , m/z 536 (M+H) ¹ H NMR (400 MHz, DMSOd ₆ ) δ ppm 1 27 - 1 71 (m), 2 04 (s, 3 H), 2 1 1 - 2 26 (m, 1 H), 2 65 (s, 3 H), 3 71 (s, 3 H), 3 74 - 3 84 (m, 1 H), 4 43 (s, 2 H), 4 49 (d, J=Q 6 Hz, 2 H), 4 70 (d, J=I 3 Hz, 2 H), 6 74 - 6 83 (m, 1 H), 6 85 - 6 98 (m, 2 H), 7 15 - 7 27 (m, 1 H), 7 70 - 7 82 (m, 1 H), 8 05 (s, 1 H), 8 41 (s, 1 H), 9 12 - 9 24 (m, 1 H)

Example 215

W-(3-Methoxybenzyl)-4-(2-(((c/s)-4-(2-hydroxyacetamido)cy clohexyl)methyl)-2H-tetrazol-5-yl)-6- methylpicolinamide

The title compound was prepared in a similar manner to λ/-(3-methoxybenzyl)-4-(2-(((c/s)-4-(3- amιnopropanamιdo)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6-me thylpιcolιnamιde (Example 212) by reaction with 2-hydroxyacetιc acid and afforded 27 4 mg (48%) as a solid LC/MS (5%-95% CH ₃ CN/H ₂ O, 4 5 mm , 95% CH ₃ CN, 1 5 mm ) 2 897 mm , m/z 494 (M+H) ¹ H NMR (400 MHz,

DMSO-dg) δ ppm 1 26 - 1 76 (m), 2 14 - 2 29 (m), 2 65 (s, 3 H), 3 71 (s, 3 H), 3 78 (s), 3 80 - 3 90 (m, 1 H), 4 49 (d, J=5 9 Hz, 2 H), 4 76 (d, J=I 3 Hz, 2 H), 6 74 - 6 84 (m, 1 H), 6 84 - 6 97 (m, 2 H), 7 16 - 7 28 (m, 1 H), 7 34 - 7 46 (m, 1 H), 8 05 (s, 1 H), 8 41 (s, 1 H), 9 12 - 9 25 (m, 1 H)

Example 216

W-(3-Methoxybenzyl)-4-(2-(((c/s)-4-(3-methoxypropanamido) cyclohexyl)methyl)-2H-tetrazol-5- yl)-6-methylpicolinamide

The title compound was prepared in a similar manner to λ/-(3-methoxybenzyl)-4-(2-(((c/s)-4-(3- ammopropanamιdo)cyclohexyl)methyl)-2/-/-tetrazol-5-yl)-6-me thylpιcolιnamιde (Example 212) by reaction with 3-methoxypropanoιc acid and afforded 23 7 mg (40%) as a solid LC/MS (5%-95% CH ₃ CN/H ₂ O, 4 5 mm , 95% CH ₃ CN, 1 5 mm ) 3 1 1 1 mm , m/z 522 (M+H) ¹ H NMR (400 MHz, DMSO-CZ ₆ ) δ ppm 1 28 - 1 71 (m), 2 06 - 2 21 (m, 1 H), 2 31 (t, J=6 2 Hz, 2 H), 2 65 (s), 3 49 (t, J=6 6 Hz, 2 H), 3 71 (s), 3 75 - 3 83 (m, 1 H), 4 49 (d, J=6 6 Hz, 2 H), 4 68 (d, J=I 3 Hz, 2 H), 6 74 - 6 84 (m, 1 H), 6 84 - 6 96 (m, 2 H), 7 13 - 7 30 (m, 1 H), 7 56 - 7 68 (m, 1 H), 8 05 (s, 1 H), 8 41 (s, 1 H), 9 12 - 9 25 (m, 1 H)

Example 217

W-(3-Methoxybenzyl)-4-(2-(((c/s)-4-(2-aminoacetamido)cycl ohexyl)methyl)-2H-tetrazol-5-yl)-6- methylpicolinamide

The title compound was prepared in a similar manner to λ/-(3-methoxybenzyl)-4-(2-(((c/s)-4-(3- aminopropanamido^yclohexyOmethyO^H-tetrazol-S-yO-θ-methylpi colinamide (Example 212) by

reaction with 2-(tert-butoxycarbonyl)acetιc acid and afforded 13 6 mg (24%) as a solid LC/MS (5%- 95% CH ₃ CN/H ₂ O, 4 5 mm , 95% CH ₃ CN, 1 5 mm ) 2 628 mm , m/z 493 (M+H) ¹ H NMR (400 MHz, DMSO-d ₆ ) ÏŒ ppm 1 19 - 1 73 (m), 2 10 - 2 25 (m, 1 H), 2 60 - 2 66 (m), 2 65 (s, 3 H), 3 05 (s), 3 28 (s) 3 71 (s, 3 H), 3 76 - 3 88 (m, 1 H), 4 49 (d, J=Q 6 Hz, 2 H), 4 72 (d, J=I 3 Hz, 2 H), 6 73 - 6 84 (m, 1 H), 6 85 - 6 95 (m, 2 H), 7 14 - 7 26 (m, 1 H), 7 62 - 7 70 (m, 1 H), 8 05 (s, 1 H), 8 41 (s, 1 H), 9 13 - 9 23 (m, 1 H)

Example 218

/V-(3-Methoxybenzyl)-4-(2-(((c/s)-4-(2-hydroxy-2-methylpr opanamido)cyclohexyl)methyl)-2H- tetrazol-5-yl)-6-methylpicolinamide

A mixture of 2-hydroxy isobutyric acid (19 mg, 0 19 mmol) and 1 -hydroxybenzatrιazole (25 mg, 0 19 mmol) in 2- methyl tetrahydrofuran (2 mL) was stirred for 5 minutes λ/-(3-Methoxybenzyl)-4- (2-(((c/s)-4-amιnocyclohexyl)methyl)-2H-tetrazol-5-yl)-6-me thylpιcolιnamιde (prepared as described in Example 209) (0 085 g, 0 15 mmol), triethylamine (0 026 mL, 0 19 mmol), and polymer supported carbodiimide (0 18 g, 0 23 mmo!) were then added The mixture was allowed to stir for 18 hours at room temperature and then filtered The filtrate was washed with water (3 x 5 mL) followed by brine (5 mL), dried over anhydrous sodium sulfate, and concentrated The residue was purified by reverse phase preparative HPLC to afford the title compound (20 mg, 25%) ¹ H NMR (400 MHz, DMSO-d ₅ ) δ ppm 9 19 (t, J=6 6 Hz, 1 H), 8 41 (s, 1 H), 8 05 (s, 1 H), 7 29 (d, J=8 05 Hz, 1 H), 7 22 (t, J=8 1 Hz, 1 H), 6 90 (br s , 2 H), 6 80 (d, J=8 1 Hz, 1 H), 5 35 (s, 1 H), 4 77 (d, J=I 3 Hz, 2 H), 4 49 (d, J=6 6 Hz, 2 H), 3 71 (s, 3 H), 2 65 (s, 3 H), 2 17 - 2 30 (m, 1 H), 1 61 - 1 74 (m, 2 H), 1 42 - 1 55 (m, 4 H), 1 30 - 1 41 (m, 2 H), 1 22 (s, 6 H)

Example 219

W-(4-Fluoro-3-methoxybenzyl)-4-(2-(((c/s)-4-aminocyclohex yl)methyl)-2H-tetrazol-5-yl)-6- methylpicolJnamide

Step 1 Preparation of methyl 4-(2-(((c<s)-4-(tert-butoxycarbonyl)cvclohexyl)methyl)-2H -tetrazol-5-yl)-6- methylpicolinate

A mixture of methyl 6-methyl-4-(2/-/-tetrazol-5-yl)pιcolιnate (prepared as described in step 4 of the synthesis of λ/-(3-methoxybenzyl)-4-(2-(((<rans)-4-amιnocyclohexyl)m ethyl)-2H-tetrazol-5-yl)-6- methylpicolinamide, Example 153) (0 23 g, 1 1 mmol), tert-butyl c/s-(4-hydroxymethyl)cyclohexyl carbamate (0 24 g, 1 1 mmol), and polymer supported-tÏ€phenylphosphine (0 70 g, 1 6 mmol) in anhydrous tetrahydrofuran (15 mL) was cooled to 0 ⁰ C in an ice bath for 15 mm and then di-tert-butyl azodicarboxylate (0 29 g, 1 3 mmol) was added The reaction was allowed to warm to room temperature while stirring over 15 hours The reaction mixture was filtered and the filtrate was concentrated to afford the title compound

Step 2 Preparation of 4-(2-(((c;s)-4-(tert-butoxycarbonyl)cvclohexyl)methyl)-2H-te trazol-5-yl)-6- methylpicolimc acid

An aqueous solution of sodium hydroxide (2 5 N, 1 0 mL) was added to a mixture of 4-(2-

(((c/s)-4-(tert-butoxycarbonyl)cyclohexyl)methyl)-2H-tetr azol-5-yl)-6-methylpιcolιnate in acetonitπle (3 mL), and the mixture was stirred 2 hours The acetonitrile was removed in vacuo and the aqueous residue was acidified to pH 6 with a 10% aqueous solution of hydrochloric acid This mixture was extracted with ethyl acetate (3 x 5 mL) The combined organic layers were washed with water (2 x 5mL) followed by brine (5 mL), dried over sodium sulfate, and concentrated to afford the title compound

Step 3 Preparation of tert-butyl (c/s)-4-((5-(2-((4-fluoro-3-methoxybenzyl)carbamoyl)-6-methy lpyrιdιn- 4-yl)-2/-/-tetrazol-2-yl)methγl)cyclohexylcarbamate

A mixture of 4-(2-(((c/s)-4-(tert-butoxycarbonyl)cyclohexyl)methyl)-2H-te trazol-5-yl)-6- methylpicolinic acid and 1 -hydroxybenzatπazole (97 mg, 0 72 mmol) in λ/,λ/-dιmethylformamιde (2 mL) was stirred for 5 minutes 4-Fluoro-3-methoxybenzylamιne hydrochloride (prepared as described in step 3 of the synthesis of λ/-(4-fluoro-3-methoxybenzyl)-6-(2-((^ans-4-amιnocyclohexy l)methyl)-2/-/-

tetrazol-5-yl)pyrιmιdιne-4-carboxamιde, Example 1 ) (0 13g, 0 66 mmol), triethylamine (O 10 mL, O 72 mmol), and polymer supported carbodiimide (0 88 g, 0 98 mmol) were added The mixture was stirred for 18 hours at room temperature and then was filtered The filtrate was washed with water (3 x 5 mL) followed by brine (5 mL), dried over anhydrous sodium sulfate, and concentrated The residue was purified by silica column chromatography (0-50%, ethyl acetate/heptane) to afford the title compound as a beige oil

Step 4 Preparation of λ/-(4-fluoro-3-methoxybenzyl)-4-(2-(((c<s)-4-amιnocyclo hexyl)methyl)-2H- tetrazol-5-yl)-6-methylpιcolιnamιde

Trifluoroacetic acid (1 0 mL) was added to a solution of tert-butyl (c/s)-4-((5-(2-((4-fluoro-3- methoxybenzyl^arbamoyO-θ-methylpyÏ€din^-ylJ^H-tetrazol-σ-y OmethyOcyclohexylcarbamate in dichloromethane (5 mL), and the mixture was stirred for 3 hours at room temperature The reaction mixture was concentrated and then triturated with diethyl ether to afford the title compound as a trifluoroacetate salt (0 12 g) LC/MS (5-100% CH ₃ CN/H ₂ O, 6 mm) 5 33 mm, m/z 454 (M+H)

Example 220

/V-(4-Fluoro-3-methoxybenzyl)-4-(2-(((frans)-4-(2-hydroxy -2- methylpropanamido)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6-met hylpicolinamide

A mixture of 2-hydroxy isobutyric acid (10 mg, 0 09 mmol) and 1 -hydroxybenzatrιazole (1 1 mg, 0 08 mmol) in 2- methyl tetrahydrofuran (2 mL) was stirred for 5 minutes λ/-(4-Fluoro-3- methoxybenzy!)-4-(2-(((c/s)-4-amιnocyc!ohexy!)methyl)-2H-te trazol-5-yl)-6-methylpιco!ιnamιde (prepared as described in Example 219) (0 040 g, 0 07 mmol), triethylamine (0 012 mL, 0 085 mmol), and polymer supported carbodiimide (0 082 g, 0 1 1 mmol) were added The mixture was stirred for 18 hours at room temperature and was then filtered The filtrate was washed with water (3 x 5 mL) followed by brine (5 mL), dried over anhydrous sodium sulfate, and concentrated The residue was purified by reverse phase preparative HPLC to afford the title compound (10 mg, 29%) ¹ H NMR (400 MHz, DMSOd ₆ ) δ ppm 9 21 (t, J=6 2 Hz, 1 H), 8 41 (s, 1 H), 8 05 (s, 1 H), 7 29 (d, J=7 3 Hz, 1 H), 7 05 - 7 20 (m, 2 H), 6 89 (d, J=3 7 Hz, 1 H), 5 35 (s, 1 H), 4 77 (d, J=Q 1 Hz, 2 H), 4 48 (d, J=5 9 Hz, 2

H), 3 80 (s, 3 H), 3 71 (br s , 1 H), 2 61 - 2 70 (m, 3 H), 2 21 (d, J=3 7 Hz, 1 H), 1 61 - 1 74 (m, 2 H), 1 48 (dd, J=W 3, 3 7 Hz, 3 H), 1 27 - 1 40 (m, 2 H), 1 14 - 1 28 (m, 6 H)

Example 221

/V-(4-Fuoro-3-methoxybenzyl)-4-(2-(((c/s)-4-(2-hydroxyace tamido)cyclohexyl)methyl)-2H- tetrazol-5-yl)-6-methylpicolinamide

A mixture of 2-acetoxyacetιc acid (1 1 mg, 0 092 mmol) and 1 -hydroxybenzatrιazole (1 1 mg, 0 08 mmol) in 2- methyl tetrahydrofuran (2 mL) was stirred for 5 minutes λ/-(4-Fluoro-3- methoxybenzyl)-4-(2-(((c/s)-4-amιnocyclohexyl)methyl)-2/-/- tetrazol-5-yl)-6-methylpιcolιnamιde (prepared as described in Example 219) (0 040 g, 0 07 mmol), triethylamine (0 012 mL, 0 085 mmol), and polymer supported carbodiimide (0 082 g, 0 11 mmol) were added The mixture was stirred for 18 hours at room temperature and was then filtered The filtrate was washed with water (3 x 5 mL) followed by brine (5 mL), dried over anhydrous sodium sulfate, and concentrated The residue was dissolved in tetrahydrofuran (2 mL) and stirred with an aqueous solution of sodium hydroxide (2 5 N, 0 5 mL) for 2 hours at room temperature The tetrahydrofuran was removed in vacuo and the aqueous residue was acidified with a 10% aqueous solution of hydrochloric acid The mixture was extracted with ethyl acetate (3 x 5 mL) The combined organic layers were washed with water (5 mL) followed by brine (5 mL), dried over anhydrous sodium sulfate, and concentrated The residue that was purified by reverse phase preparative HPLC to afford the title compound (7 3 mg, 20%) ¹ H NMR (400 MHz, DMSO-Cf ₆ ) δ ppm 9 22 (t, J=Q 22 Hz, 1 H), 8 41 (s, 1 H), 8 05 (s, 1 H), 7 39 (d, J=Q 8 Hz ₁ 1 H), 7 04 - 7 23 (m, 2 H), 6 89 (d, J=Q Q Hz, 1 H), 5 35 (t, J=5 9 Hz, 1 H), 4 76 (d, J=I 3 Hz, 2 H), 4 48 (d, J=5 9 Hz, 2 H), 3 69 - 3 93 (m, 5 H), 2 65 (s, 3 H), 2 21 (br s , 1 H), 1 65 (br s , 2 H), 1 41 - 1 55 (m, 4 H), 1 36 (d, J=8 8 Hz, 2 H)

Example 222 W-(4-Fluoro-3-methoxybenzyl)-4-(2-(((c/s)-4-acetamidocyclohe xyl)methyl)-2H-tetrazol-5-yl)-6- methylpicolinamide

Triethylamine (0 012 mL, 0 085 mmol) and a solution of acetyl chloride (6 3 mg in 0 5 mL dichloromethane) were added to a solution of λ/-(4-fluoro-3-methoxybenzyl)-4-(2-(((c/s)-4-

aminocyclohexyOmethyO^H-tetrazol-S-yO-θ-methylpicolinamide (prepared as described in Example 219) (O 040 g, O 07 mmol) in 2-methyltetrahydrofuran (2 mL) The reaction mixture was stirred for 1 hour at room temperature and was then concentrated The residue was purified by reverse phase preparative HPLC (10-90 % acetonitrile/water) to afford the title compound (1 1 mg, 31 %) ¹ H NMR (400 MHz, DMSO-cfe) δ ppm 9 22 (t, J=6 2 Hz, 1 H), 8 41 (s, 1 H), 8 05 (s, 1 H), 7 63 (d, J= 7 3 Hz, 1 H), 7 03 - 7 25 (m, 2 H), 6 75 - 6 95 (m, 1 H), 4 68 (d, J=I 3 Hz, 2 H), 4 48 (d, J=5 9 Hz, 2 H), 3 80 (s, 4 H), 2 65 (s, 3 H), 2 06 - 2 24 (m, 1 H), 1 79 (s, 3 H), 1 52 - 1 62 (m, 2 H), 1 31 - 1 52 (m, 6 H)

Example 223 rac-W-(3-Methoxybenzyl)-4-(2-(((1 S*,3R*)-3-aminocyclohexyl)methyl)-2H-tetrazol-5-yl)-6- methylpicolinamide

Step 1 Preparation of rac-terf-butyl (1 /? ^* ,3S ^* )-3-((5-(2-((3-methoxybenzyl)carbamoyl)-6-methylpyπdιn- 4-yl)-2H-tetrazol-2-yl)methyl)cvclohexylcarbamate

A solution of λ/-(3-methoxybenzyl)-6-methyl-4-(2H-tetrazol-5-yl)pιcolιn amιde (prepared as described in step 5 of the synthesis of λ/-(3-methoxybenzyl)-4-(2-(((/rans)-4-amιnocyclohexyl)meth yl)- 2H-tetrazol-5-yl)-6-methylpιcolιnamιde, Example 153) (500 0 mg, 1 54 mmol) in anhydrous tetrahydrofuran (30 mL) and triphenylphosphine resin (1 790 g, 3 85 mmol, 2 15 mmol/g loading) was added to a vial containing rac-tert-butyl (1 R\3S ^* )-3-(hydroxymethyl)cyclohexylcarbamate (707 0 mg, 3 08 mmol) The mixture was cooled in an ice bath and di-tert-butylazodicarboxylate (710 0 mg, 3 08 mmol) was added The reaction mixture was agitated overnight at room temperature and then concentrated The residue was purified by reverse phase preparative HPLC (5%-95% CH ₃ CN/H ₂ O, 8 mm) to afford the title compound

Step 2 Preparation of rac-/V-(3-methoxybenzyl)-4-(2-(((1 S\3ff*)-3-amιnocyclohexyl)methyl)-2H- tetrazol-5-yl)-6-methylpιcolιnamιde

rac-tert-butyl (1f?*,3S*)-3-((5-(2-((3-methoxybenzyl)carbamoyl)-6-methylpyr ιdιn-4-yl)-2/-/- tetrazol-2-yl)methyl)cyclohexylcarbamate obtained in step 1 was dissolved in dichloromethane and trifluoroacetic acid and stirred for approximately 30 minutes The mixture was concentrated and the residue was dissolved in dichloromethane MP-carbonate resin was added to the solution and the mixture was agitated for approximately 1 hour The mixture was filtered and the resin was washed with dichloromethane and methanol The filtrate was concentrated under a stream of nitrogen and dried under high vacuum overnight to afford the title compound as a solid (456 mg, 68%) LC/MS (5%-95% CH ₃ CN/H ₂ O, 4 5 mm , 95% CH ₃ CN, 1 5 mm ) 2 531 mm , m/z 436 (M+H) ¹ H NMR (400 MHz, DMSO-CZ ₆ ) δ ppm 0 86 - 1 99 (m, 8 H), 2 04 - 2 24 (m, 1 H), 2 66 (s, 3 H), 2 91 - 3 11 (m, 1 H), 3 71 (s, 3 H), 4 48 (d, J=Q 44 Hz, 2 H), 4 65 - 4 88 (m, 2 H), 6 74 - 6 83 (m, 1 H), 6 86 - 6 93 (m, 2 H), 7 17 - 7 26 (m, 1 H), 7 86 (br s , 2 H), 8 00 - 8 1 1 (m, 1 H), 8 41 (s, 1 H), 9 19 - 9 30 (m, 1 H)

Example 224 rac-W-(3-Methoxybenzyl)-4-(2-(((1 S*,3/?*)-3-(3-aminopropanamido)cyclohexyl)methyl)-2W- tetrazol-5-yl)-6-methylpicolinamide

O-(7-Azabenzotrιazo!e-1 -yl)-/V,λ/,λ/,/V-tetramethyluronιum hexafluorophosphate (52 0 mg, 0 138 mmol), 3-(terf-butoxycarbonyl)propanoιc acid (21 6 mg, 0 115 mmol), and dnsopropylethylamine (0 040 mL, 0 230 mmol) were added to a solution of rac-λ/-(3-methoxybenzyl)-4-(2-(((1 S ^* ,3R ^* )-3- amιnocyclohexyl)methyl)-2/-/-tetrazol-5-yl)-6-methylpιcolÎ ¹namιde (prepared as described in Example 223) (50 1 mg, 0 1 15 mmol) in dimethylformamide (2 mL) The mixture was stirred overnight at room temperature The reaction mixture was concentrated and the residue was purified by reverse phase preparative HPLC (5%-95% CH ₃ CN/H ₂ O, 8 mm) The resulting intermediate was added to a mixture of dichloromethane and trifluoroacetic acid and stirred approximately 30 minutes The mixture was concentrated and the residue was dissolved in dichloromethane MP-carbonate resin was added and the mixture was agitated for approximately 30 minutes The mixture was filtered and the resin was washed with dichloromethane and methanol The filtrate was concentrated and dried overnight under high vacuum to afford the title compound as a solid (19 1 mg, 33%) LC/MS (5%-95% CH ₃ CN/H ₂ O, 4 5 mm , 95% CH ₃ CN, 1 5 mm ) 2 669 mm , m/z 507 (M+H) ¹ H NMR (400 MHz, DMSO-c/ _β ) δ ppm 0 83 - 1 79 (m), 2 01 - 2 19 (m), 2 65 (s, 3 H), 3 51 (s), 3 71 (s, 3 H), 4 49 (d, J=6 59 Hz, 2 H), 4 68 (m,

2 H), 6 76 - 6 83 (m, 1 H), 6 86 - 6 94 (m, 2 H), 7 18 - 7 26 (m, 1 H), 7 69 - 7 77 (m, 1 H), 8 05 (s, 1 H), 8 40 (s, 1 H), 9 13 - 9 24 (m, 1 H)

Example 225 rac-W-(3-Methoxybenzyl)-4-(2-(((1 S*,3/?*)-3-acetamidocyclohexyl)methyl)-2H-tetrazol-5-yl)-6- methylpicolinamide

Acetic anhydride (0 033 mL, 0 345 mmol) and 4-(dιmethylamιno)pyrιdιne Si bound (833 0 mg, 0 575 mmol, 0 69 mmol/g loading) were added to a solution of rac-λ/-(3-methoxybenzyl)-4-(2- (((1 S'.SR^-S-aminocyclohexyOmethyO^H-tetrazol-δ-yO-θ-methylpic olinamide (prepared as described in Example 223) (50 0 mg, 0 1 15 mmol) in dichloromethane (2 mL) The mixture was agitated overnight at room temperature The reaction mixture was filtered, and the resin was washed with dimethylformamide The filtrate was concentrated and the residue was purified by reverse phase preparative HPLC (5%-95% CH ₃ CN/H ₂ O, 8 mm) to afford the title compound as a solid (28 0 mg, 51 %) LC/MS (5%-100% CH ₃ CN/H ₂ O, 10 0 mm ) 4 61 mm , m/z 478 (M+H) ¹ H NMR (400 MHz, DMSO-Of ₆ ) δ ppm 0 83 - 1 82 (m), 2 01 - 2 18 (m, 1 H), 3 40 - 3 61 (m, 1 H), 3 71 (s, 3 H), 4 49 (d, J=5 9 Hz, 2 H), 4 61 - 4 75 (m), 6 76 - 6 83 (m, 1 H), 6 86 - 6 93 (m, 2 H), 7 17 - 7 26 (m, 1 H), 7 63 - 7 71 (m, 1 H), 8 05 (s, 1 H), 8 40 (s, 1 H), 9 14 - 9 23 (m, 1 H)

Example 226

W-(3-Methoxybenzyl)-4-(2-(((1 S*,3f?*)-3-acetamidocyclohexyl)methyl)-2H-tetrazol-5-yl)-6- methylpicolinamide

rac-W-(3-Methoxybenzyl)-4-(2-(((1 S ^* ,3R ^* )-3-acetamιdocyclohexyl)methyl)-2H-tetrazol-5-yl)-6- methylpicolinamide (prepared as described in Example 225) was resolved by chiral supercritical-fluid chromatography (OJ-H, 30 x 250 mm, 15% methanol, 70 mL/min) The first eluting enantiomer was isolated to provide 22 mg (8%) of the title compound ¹ H NMR (400 MHz, DMSOd ₆ ) δ ppm 9 20 (t, J=Q 6 Hz, 1 H), 8 42 (s, 1 H), 8 07 (s, 1 H), 7 68 (d, J=I 3 Hz, 1 H), 7 23 (t, J=Q 1 Hz, 1 H), 6 92 (br s , 2 H), 6 81 (d, J=8 8 Hz, 1 H), 4 62 - 4 78 (m, 2 H), 4 51 (d, J=5 9 Hz, 2 H), 3 73 (s, 3 H), 3 42 - 3 57 (m, 1 H), 2 67 (s, 3 H), 2 53 (s, 1 H), 2 1 1 (br s , 1 H), 1 64 - 1 80 (m, 5 H), 1 59 (d, J=\ 1 7 Hz, 1 H), 1 20 - 1 34 (m, 1 H), 0 82 - 1 09 (m, 3 H)

Example 227

A/-(3-Methoxybenzyl)-4-(2-(((1R*,3S*)-3-acetamidocyclohex yl)methyl)-2H-tetrazol-5-yl)-6- methylpicolinamide

rac-λ/-(3-Methoxybenzyl)-4-(2-(((1 S*,3R*)-3-acetamιdocyclohexyl)methyl)-2H-tetrazol-5-yl)-6- methylpicolinamide (prepared as described in Example 225) was resolved by chiral supercritical-fluid chromatography (OJ-H, 30 x 250 mm, 15% methanol, 70 mL/min) The second eluting enantiomer was isolated to provide 23 mg (9%) of the title compound ¹ H NMR (400 MHz, DMSO-c/ ₆ ) δ ppm 9 18 (t, J=6 6 Hz, 1 H), 8 41 (s, 1 H), 8 05 (s, 1 H), 7 66 (d, J=I 3 Hz, 1 H), 7 22 (t, J=& 1 Hz, 1 H), 6 90 (br s , 2 H), 6 80 (d, J=7 3 Hz, 1 H), 4 62 - 4 77 (m, 2 H), 4 49 (d, J=6 6 Hz, 2 H), 3 71 (s, 3 H), 3 41 - 3 55 (m, 1 H), 2 60 - 2 73 (m, 3 H), 2 51 (s, 1 H), 2 07 (d, J=19 76 Hz, 1 H), 1 64 - 1 81 (m, 5 H), 1 55 (br s , 1 H), 1 19 - 1 36 (m, 2 H), 0 80 - 1 08 (m, 2 H)

Example 228 rac-W-(3-Methoxybenzyl)-4-(2-(((1 S*,3/?*)-3-(2-methoxyacetamido)cyclohexyl)methyl)-2H- tetrazol-5-yl)-6-methylpicolinamide

The title compound was prepared in a similar manner to rac-λ/-(3-methoxybenzyl)-4-(2- (((1 S ^* ,3f? ^* )-3-(3-amιnopropanamιdo)cyclohexyl)methyl)-2/-/-tetrazol-5 -yl)-6-methylpιcolιnamιde (Example 224) by reaction with 2-methoxyacetιc acid and afforded 33 9 mg (58%) as a solid LC/MS (5%-95% CH ₃ CN/H ₂ O, 4 5 mm , 95% CH ₃ CN, 1 5 mm ) 3 169 mm , m/z 508 (M+H) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0 81 - 1 80 (m), 2 03 - 2 20 (m), 2 65 (s, 3 H), 3 50 - 3 66 (m, 1 H), 3 71 (s, 3 H), 4 49 (d, J=6 6 Hz, 2 H), 4 59 - 4 77 (m, 2 H), 6 74 - 6 83 (m, 1 H), 6 86 - 6 94 (m, 2 H), 7 17 - 7 25 (m, 1 H), 7 51 - 7 58 (m, 1 H), 8 06 (s, 1 H), 8 41 (s, 1 H), 9 13 - 9 26 (m, 1 H)

Example 229 rac-2-((1/?* ₎ 3S*)-3-((5-(2-((3-methoxybenzyl)carbamoyl)-6-methylpyridin-4 -yl)-2H-tetrazol-2- yl)methyl)cyclohexylamino)-2-oxoethyl acetate

The title compound was prepared in a similar manner to rac-/V-(3-methoxybenzyl)-4-(2- (((1 S ^* ,3/? ^* )-3-(3-amιnopropanamιdo)cyclohexyl)methyl)-2/-/-tetrazol-5 -yl)-6-methylpιcolιnamιde (Example 224) by reaction with 2-acetoxyacetιc acid and afforded 32 7 mg (53%) as a solid LC/MS (5%-95% CH ₃ CN/H ₂ O, 4 5 mm , 95% CH ₃ CN, 1 5 mm ) 3 174 mm , m/z 536 (M+H) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0 85 - 1 80 (m), 2 03 (s, 3 H), 2 06 - 2 24 (m, 1 H), 2 65 (s, 3 H), 3 46 - 3 64 (m, 1 H), 3 71 (s, 3 H), 4 34 (s, 2 H), 4 49 (d, J=6 6 Hz, 2 H), 4 69 (d, J=5 9 Hz, 2 H), 6 74 - 6 84 (m, 1 H), 6 86 - 6 93 (m, 2 H), 7 17 - 7 26 (m, 1 H), 7 76 - 7 85 (m, 1 H), 8 05 (s, 1 H), 8 41 (s, 1 H), 9 14 - 9 25 (m, 1 H)

Example 230 rac-W-(3-Methoxybenzyl)-4-(2-(((1 S*,3R*)-3-(2-hydroxyacetamido)cyclohexyl)methyl)-2H- tetrazol-5-yl)-6-methylpicolinamide

The title compound was prepared in a similar manner to rac-/V-(3-methoxybenzyl)-4-(2- (((I S'.SR^-S^S-aminopropanamido^yclohexyOmethy^^H-tetrazol-S-yO- θ-methylpicolmamide (Example 224) by reaction with 2-hydroxyacetιc acid and afforded 32 1 mg (57%) as a solid LC/MS (5%-95% CH ₃ CN/H ₂ O, 4 5 mm , 95% CH ₃ CN, 1 5 mm ) 2 902 mm , m/z 493 (M+H) ¹ H NMR (400 MHz, DMSO-d ₆ ) 6 ppm 0 82 - 1 77 (m), 1 99 - 2 20 (m, 1 H), 2 52 (s), 2 65 (s, 3 H), 3 27 - 3 39 (m), 3 71 (s, 3 H), 4 49 (d, J=5 9 Hz, 2 H), 4 57 - 4 77 (m, 2 H), 5 23 - 5 37 (m), 6 74 - 6 82 (m, 1 H), 6 86 - 6 94 (m, 2 H), 7 17 - 7 25 (m, 1 H), 7 39 - 7 48 (m, 1 H), 8 05 (s, 1 H), 8 40 (s, 1 H), 9 11 - 9 24 (m, 1 H)

Example 231

W-(3-Methoxybenzyl)-4-(2-(((1/?*,3S*)-3-(2-hydroxyacetami do)cyclohexyl)methyl)-2H-tetrazol-5- yl)-6-methylpicolinamide

rac-λ/-(3-Methoxybenzyl)-4-(2-(((1 S ^* ,3R ^* )-3-(2-hydroxyacetamιdo)cyclohexyl)methyl)-2H- tetrazol-5-yl)-6-methylpιcolιnamιde (prepared as described in Example 230) was resolved by chiral supercritical-fluid chromatography (OJ-H, 30 x 250 mm, 15% methanol, 70 mL/min) The first eluting enantiomer was isolated to provide 23 mg (10%) of the title compound ¹ H NMR (400 MHz, DMSOd ₆ ) δ ppm 9 18 (t, J=6 2 Hz, 1 H), 8 41 (s, 1 H), 8 05 (s, 1 H), 7 43 (d, J=8 1 Hz, 1 H), 7 22 (t, J=B 1 Hz, 1 H), 6 90 (br s , 2 H), 6 80 (d, J=I 3 Hz, 1 H), 5 28 (t, J=5 5 Hz, 1 H), 4 68 (dd, J=6 2, 3 3 Hz, 2 H),

4 49 (d, J=Q 6 Hz, 2 H), 3 71 (s, 3 H), 3 59 (d, >13 9 Hz, 1 H), 2 65 (s, 3 H), 2 51 (s, 1 H), 2 1 1 (br s 1 H), 1 63 (dd, J=34 8, 20 1 Hz, 4 H), 0 90 - 1 35 (m, 5 H)

Example 232

W-(3-Methoxybenzyl)-4-(2-(((1S*,3/?*)-3-(2-hydroxyacetami do)cyclohexyl)methyl)-2H-tetrazol-5- yl)-6-methylpicolinamide

rac-A/-(3-Methoxybenzyl)-4-(2-(((1 S*,3f?*)-3-(2-hydroxyacetamido)cyclohexyl)methyl)-2/-/- tetrazol-5-yl)-6-methylpιcolιnamιde (prepared as described in Example 230) was resolved by chiral supercritical-fluid chromatography (OJ-H, 30 x 250 mm, 15% methanol, 70 mL/min) The second eluting enantiomer was isolated to provide 21 mg (10%) of the title compound ¹ H NMR (400 MHz, DMSO-cfe) δ ppm 9 18 (t, J=6 6 Hz ₁ 1 H), 8 41 (s, 1 H), 8 05 (s, 1 H), 7 43 (d, J=8 1 Hz, 1 H), 7 22 (t, J=8 1 Hz, 1 H), 6 90 (br s , 2 H), 6 80 (d, J=8 1 Hz, 1 H), 5 28 (t, J=5 9 Hz, 1 H), 4 63 - 4 76 (m, 2 H), 4 49 (d, J=6 6 Hz, 2 H), 3 71 (s, 3 H), 3 60 (d, J= 1 1 0 Hz, 1 H), 2 65 (s, 3 H), 2 51 (s, 1 H), 2 1 1 (br s , 1 H), 1 54 - 1 78 (m, 4 H), 0 84 - 1 37 (m, 5 H)

Example 233 rac-W-(4-Fluoro-3-methoxybenzyl)-4-(2-(((1 S*,3R*)-3-aminocyclohexyl)methyl)-2H-tetrazol-5-yl)-

6-methylpicolinamide

λ/-(4-fluoro-3-methoxybenzyl)-6-methyl-4-(2/-/-tetrazol-5-y l)pιcolιnamιde (prepared as described in step 2 of the synthesis of λ/-(4-fluoro-3-methoxybenzyl)-4-(2-(((/rans)-4- amιnocyclohexyl)methyl)-2H-tetrazol-5-yl)-6-methylpιcolιn amιde, Example 170) (1 00 g, 2 64 mmol), t- butyl cιs-(3-hydroxymethyl)cyclohexylcarbamate (0 73 g, 3 2 mmol), and polymer supported- tÏ€phenylphosphine (1 76 g, 4 0 mmol) were suspended in anhydrous tetrahydrofuran (50 mL) The mixture was cooled to 0 ⁰ C in an ice bath for 15 mm and then di-tert-butyl azodicarboxylate (0 73 g, 3 2 mmol) was added The reaction mixture was allowed to warm to room temperature while stirring over 15 hours The mixture was filtered and the filtrate was concentrated The crude residue was purified on silica (20 g, 0-2% methanol/dichloromethane) to afford the protected amine The intermediate was dissolved in dichloromethane (5 mL) and trifluoroacetic acid (2 mL) was added After 2 hours at room temperature, the reaction mixture was diluted with dichloromethane (10 mL) and neutralized with an aqueous solution of sodium hydroxide (2 5 N) for pH 7 The organic layer was

separated, dried over anhydrous sodium sulfate, filtered and concentrated to afford the title compound as a beige oil (689 mg, 58%) LC/MS (5-100% CH ₃ CN/H ₂ O, 8 mm) 3 90-4 15 mm, m/z 454 (M+H)

Example 234 rac-2-((1/?*,3S*)-3-((5-(2-((4-Fluoro-3-methoxybenzyl)carbam oyl)-6-methylpyridin-4-yl)-2H- tetrazol-2-yl)methyl)cyclohexylamino)-2-oxoethyl acetate

rac-A/-(4-Fluoro-3-methoxybenzyl)-4-(2-(((1 S ^* ,3/?*)-3-aminocyclohexyl)methyl)-2H-tetrazol-5- yl)-6-methylpιcolιnamιde (prepared as described in Example 233) (1 00 g, 2 20 mmol) was dissolved in dichloromethane (10 mL) Triethylamine (0 19 mL, 2 6 mmol) and a solution of acetoxy acetyl chloride (336 mg) in dichloromethane (1 0 mL) was added The mixture was stirred for 4 hours at room temperature and was then concentrated The residue was purified by reverse phase preparative HPLC (10-90 % acetonitrile/water) to afford the title compound (190 mg)

Example 235 rac-/V-(4-Fluoro-3-methoxybenzyl)-4-(2-(((1S*,3R*)-3-(2-hydr oxyacetamido)cyclohexyl)methyl)- 2W-tetrazol-5-yl)-6-methylpicolinamide

rac-2-((1 f? ^* ,3S ^* )-3-((5-(2-((4-Fluoro-3-methoxybenzyl)carbamoyl)-6-methylpyr ιdιn-4-yl)-2H- tetrazol-2-yl)methyl)cyclohexylamιno)-2-oxoethyl acetate (190 mg) was dissolved in acetonitrile ( 10 mL) An aqueous solution of sodium hydroxide (2 5 N, 4 0 mL) was added and the mixture was stirred for 2 hours The reaction mixture was concentrated and the aqueous residue was acidified to pH 7 with a 10% solution of hydrochloric acid in water The neutralized mixture was extracted with ethyl acetate (3 x 1 OmL) The combined organics were washed with brine (2 x 10 mL), dried over anhydrous sodium sulfate, and filtered, and concentrated The residue was purified by reverse phase preparative HPLC to afford the title compound (150 mg) MS (ES+) m/z 512 (M+H)

Example 236

W-(4-Fluoro-3-methoxybenzyl)-4-(2-(((1S*,3/?*)-3-(2-hydro xyacetamido)cyclohexyl)methyl)-2H- tetrazol-5-yl)-6-methylpicolinamide

rac-λ/-(4-Fluoro-3-methoxybenzyl)-4-(2-(((1 S\3/? ^* )-3-(2- hydroxyacetamιdo)cyclohexyl)methyl)-2/-/-tetrazol-5-yl)-6-m ethylpιcolιnamιde (prepared as described in Example 235) was resolved by chiral supercritical-fluid chromatography (OJ-H, 30 x 250 mm, 15% methanol, 70 ml_/mιn) The first eluting enantiomer was isolated to provide 120 mg (21 %) of the title compound ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9 20 (t, J=6 6 Hz, 1 H), 8 41 (s, 1 H), 8 05 (s, 1 H) ₁ 7 42 (d, J=Q 1 Hz, 1 H), 7 05 - 7 20 (m, 2 H), 6 88 (d, J=8 1 Hz, 1 H), 5 27 (t, J=5 9 Hz, 1 H), 4 59 - 4 72 (m, 2 H), 4 48 (d, J=5 9 Hz, 2 H), 3 77 - 3 84 (m, 3 H), 3 71 (d, J=5 1 Hz, 2 H), 3 53 - 3 64 (m, 1 H), 2 65 (s, 3 H), 2 51 (s, 1 H), 2 06 - 2 19 (m, 1 H), 1 49 - 1 75 (m, 3 H), 0 88 - 1 33 (m, 4 H)

Example 237

/V-(4-Fluoro-3-methoxybenzyl)-4-(2-(((1/?*,3S*)-3-(2-hydr oxyacetamido)cyclohexyl)methyl)-2H- tetrazol-5-yl)-6-methylpicolinamide

rac-λ/-(4-Fluoro-3-methoxybenzyl)-4-(2-(((1 S ^* ,3/?*)-3-(2- hydroxyacetamido^yclohexyOmethyl^H-tetrazol-δ-yO-θ-methylp icolinamide (prepared as described in Example 235) was resolved by chiral supercritical-fluid chromatography (OJ-H, 30 x 250 mm, 15% methanol, 70 mL/min) The second eluting enantiomer was isolated to provide 107 mg (19%) of the title compound ¹ H NMR (400 MHz, DMSO-c/ ₆ ) δ ppm 9 20 (t, J=5 9 Hz, 1 H), 8 41 (s, 1 H), 8 05 (s, 1 H), 7 42 (d, J=8 8 Hz, 1 H), 7 05 - 7 22 (m, 2 H), 6 89 (br s , 1 H), 5 27 (t, J=5 9 Hz, 1 H), 4 68 (d, J=2 9 Hz, 2 H), 4 48 (d, J=5 9 Hz, 2 H), 3 80 (s, 3 H), 3 71 (d, J=5 1 Hz, 2 H), 3 60 (d, J=1 1 7 Hz, 1 H), 2 65 (s, 3 H), 2 51 (s, 1 H), 2 1 1 (br s , 1 H), 1 59 (d, J=20 5 Hz, 3 H), 0 84 - 1 36 (m, 4 H)

Example 238 rac-A/-(3-Methoxybenzyl)-4-(2-(((1S*,3/?*)-3-(3-methoxypropa namido)cyclohexyl)methyl)-2H- tetrazol-5-yl)-6-methylpicolinamide

The title compound was prepared in a similar manner to rac-λ/-(3-methoxybenzyl)-4-(2- (((1 S ^* ,3R ^* )-3-(3-amιnopropanamιdo)cyclohexyl)methyl)-2/-/-tetrazol-5 -yl)-6-methylpιcolιnamιde

(Example 224) by reaction with 3-methoxypropanoιc acid and afforded 35 2 mg (59%) as a solid LC/MS (5%-95% CH ₃ CN/H ₂ O, 4 5 mm , 95% CH ₃ CN, 1 5 mm ) 3 1 15 mm , m/z 522 (M+H) ¹ H NMR (400 MHz, DMSOd ₆ ) δ ppm 0 84 - 1 79 (m), 2 01 - 2 17 (m, 1 H), 2 22 (t, J=6 6 Hz, 2 H), 2 65 (s, 3 H), 3 37 - 3 60 (m), 3 71 (s, 3 H), 4 49 (d, J=5 9 Hz, 2 H), 4 61 - 4 77 (m, 2 H), 6 76 - 6 83 (m, 1 H), 6 87 - 6 93 (m, 2 H), 7 18 - 7 25 (m, 1 H), 7 64 - 7 72 (m, 1 H), 8 05 (s, 1 H), 8 40 (s, 1 H), 9 14 - 9 22 (m, 1 H)

Example 239 rac-A/-(3-Methoxybenzyl)-4-(2-(((1 S*,3R*)-3-(2-aminoacetamido)cyclohexyl)methyl)-2W-tetrazol-5 - yl)-6-methylpicolinamide

The title compound was prepared in a similar manner to rac-λ/-(3-methoxybenzyl)-4-(2-

(((I S'.SR^-S^S-aminopropanamidoJcyclohexyl^ethyO^H-tetrazol-δ-y O-e-methylpicolinamide (Example 224) by reaction with 2-(tert-bÏ…toxycarbonyl)acetιc acid and afforded 23 0 mg (41 %) as a solid LC/MS (5%-95% CH ₃ CN/H ₂ O, 4 5 mm , 95% CH ₃ CN, 1 5 mm ) 2 634mιn , m/z 493 (M+H) ¹ H NMR (400 MHz, DMSO-tf ₆ ) δ ppm 0 80 - 1 83 (m), 2 02 - 2 21 (m), 2 65 (s, 3 H), 2 98 (s, 1 H), 3 45 - 3 61 (m, 1 H), 3 71 (s, 3 H), 4 49 (d, J=6 6 Hz, 2 H), 4 61 - 4 73 (m, 2 H), 6 75 - 6 83 (m, 1 H), 6 86 - 6 94 (m, 2 H), 7 17 - 7 26 (m, 1 H), 7 54 - 7 62 (m, 1 H), 8 05 (s, 1 H), 8 40 (s, 1 H), 9 13 - 9 25 (m, 1 H)

Example 240 rac-W-(3-Methoxybenzyl)-6-methyl-4-(2-(((1S*,3/?*)-3-(methyl sulfonamido)cyclohexyl)methyl)-

2W-tetrazol-5-yl)picolinamide

Triethylamine (0 048 mL, 0 345 mmol) and methane sulfonyl chloride (0 013 mL, 0 173 mmol) were added to a solution of rac-λ/-(3-methoxybenzyl)-4-(2-(((1 S ^* ,3f? ^* )-3-amιnocyclohexyl)methyl)-2H- tetrazol-5-yl)-6-methylpιcolιnamιde (prepared as described in Example 223) (50 1 mg, 0 1 15 mmol) in tetrahydrofuran (1 5 mL) The mixture was stirred for 2 hours at room temperature The reaction mixture was concentrated and the residue was purified by reverse phase preparative HPLC (5%-95% CH ₃ CN/H ₂ O, 8 mm) to afford the title compound as a solid (26 0 mg, 44%) LC/MS (5%-95% CH ₃ CN/H ₂ O, 4 5 mm , 95% CH ₃ CN, 1 5 mm ) 3 188 mm , m/z 514 (M+H) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9 12 - 9 24 (m, 1 H), 8 41 (s, 1 H),8 05 (s, 1 H), 7 16 - 7 26 (m, 1 H), 6 95 - 7 03 (m, 1 H), 6 86 - 6 93 (m, 2 H), 6 75 - 6 83 (m, 1 H), 4 68 (d, J=6 6 Hz, 2 H), 4 49 (d, J=5 9 Hz, 2 H), 3 71

(s, 3 H), 2 85 (s, 3 H), 2 65 (s, 3 H), 2 03 - 2 20 (m), 1 81 - 1 92 (m), 1 63 - 1 74 (m), 1 43 - 1 58 (m), 0 82 - 1 37 (m)

Example 241 rac-/V-(3-Methoxybenzyl)-4-(2-(((1R*,3/?*)-3-aminocyclohexyl )methyl)-2H-tetrazol-5-yl)-6- methylpicolinamide

Step 1 Preparation of rac-tert-butyl (1 R ^> ,3P ^* )-3-((5-(2-((3-methoxybenzyl)carbamoyl)-6- methylpyrιdιn-4-yl)-2/-/-tetrazol-2-yl)methyl)cvclohexylca rbamate

A solution of λ/-(3-methoxybenzyl)-6-methyl-4-(2H-tetrazol-5-yl)pιcolιn amιde (prepared as described in step 5 of the synthesis of λ/-(3-methoxybenzyl)-4-(2-(((frans)-4-amιnocyclohexyl)meth yl)- 2H-tetrazol-5-yl)-6-methylpιcolιnamιde, Example 153) (500 0 mg, 1 54 mmol) in anhydrous tetrahydrofuran (30 mL) and triphenylphosphine resin (1 790 g, 3 85 mmol, 2 15 mmol/g loading) was added to a vial containing rac-tert-butyl (IR'^fO-S^hydroxymethyOcyclohexylcarbamate (707 0 mg, 3 08 mmol) The mixture was cooled in an ice bath and di-tert-butylazodicarboxylate (710 0 mg, 3 08 mmol) was added The reaction mixture was agitated overnight at room temperature and then concentrated The residue was purified by reverse phase preparative HPLC (5%-95% CH ₃ CN/H ₂ O, 8 mm) to afford the title compound

Step 2 Preparation of rac-/V-(3-methoxybenzyl)-4-(2-(((1 f? ^* ,3ff*)-3-amιnocvclohexyl)methyl)-2/-/- tetrazol-5-yl)-6-methylpιcolιnamιde

rac-tert-bυtyl (1 f? ^* ,3R*)-3-((5-(2-((3-methoxybenzyl)carbamoyl)-6-methylpyrιdι n-4-yl)-2H- tetrazol-2-yl)methyl)cyclohexylcarbamate obtained in step 1 was dissolved in dichloromethane and trifluoroacetic acid and stirred for approximately 30 minutes The mixture was concentrated and the residue was dissolved in dichloromethane MP-carbonate resin was added to the solution and the mixture was agitated for approximately 1 hour The mixture was filtered and the resin was washed

with dichloromethane and methanol The filtrate was concentrated under a stream of nitrogen and dried under high vacuum overnight to afford the title compound as a solid (460 mg, 68%) LC/MS (5%-95% CH ₃ CN/H ₂ O, 4 5 mm , 95% CH ₃ CN, 1 5 mm ) 2 514 mm , m/z 436 (M+H) ¹ H NMR (400 MHz, DMSOd ₆ ) δ ppm 9 21 - 9 29 (m, 1 H), 8 41 (s, 1 H), 8 05 - 8 08 (m, 1 H), 7 93 (br s , 2 H), 7 17 - 7 26 (m, 1 H), 6 85 - 6 94 (m, 2 H), 6 75 - 6 83 (m, 1 H), 4 68 - 4 86 (m, 2 H), 4 48 (d, J=6 4 Hz, 2 H), 3 70 (s, 3 H), 3 37 - 3 49 (m, 1 H), 2 66 (s, 3 H), 2 45 - 2 56 (m, 1 H), 1 12 - 1 78 (m)

Example 242 rac-W-(3-Methoxybenzyl)-4-(2-(((1/?*,3/?*)-3-(2-methoxyaceta mido)cyclohexyl)methyl)-2W- tetrazol-5-yl)-6-methylpicolinamide

O-(7-Azabenzotrιazole-1 -yl)-λ/,λ/,λ/\/V-tetramethyluronιum hexafluorophosphate (52 0 mg, 0 138 mmol), 2-methoxyacetιc acid (10 4 mg, 0 115 mmol), and dnsopropylethylamine (0 040 mL,

0 230 mmol) were added to a solution of rac-λ/-(3-methoxybenzyl)-4-(2-(((1 R ^* ,3R ^* )-3- amιnocyclohexyl)methyl)-2/-V-tetrazol-5-yl)-6-methylpιcolÎ ¹namιde (prepared as described in Example 241 ) (50 1 mg, 0 115 mmol) in λ/,λ/-dιmethylformamιde (2 mL) The mixture was allowed to stir at room temperature overnight and was then concentrated The residue was purified by reverse phase preparative HPLC (5%-95% CH ₃ CN/H ₂ O, 8 mm) to afford the title compound as a solid (31 9 mg, 55%) LC/MS (5%-95% CH ₃ CN/H ₂ O, 4 5 mm , 95% CH ₃ CN, 1 5 mm ) 3 196 mm , m/z 508 (M+H) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9 05 - 9 24 (m, 1 H), 8 40 (s, 1 H), 8 05 (s, 1 H), 7 41 - 7 50 (m, 1 H), 7 16 - 7 26 (m, 1 H), 6 86 - 6 93 (m, 2 H), 6 76 - 6 84 (m, 1 H), 4 70 (d, J=I 32 Hz, 2 H), 4 49 (d, J=5 86 Hz, 2 H), 4 01 (br s ), 3 76 (s, 3 H), 3 71 (s, 3 H), 2 62 - 2 70 (s, 3 H), 2 32 - 2 45 (m, 1 H),

1 04 - 1 74 (m)

Example 243 rac-W-(3-Methoxybenzyl)-4-(2-(((1R*,3f?*)-3-acetamidocyclohe xyl)methyl)-2H-tetrazol-5-yl)-6- methylpicolinamide

Acetic anhydride (0 033 mL, 0 345 mmol) and 4-(dιmethylamιno)pyπdιne Si bound (833 0 mg, 0 575 mmol, 0 69 mmol/g loading) were added to a solution of rac-λ/-(3-methoxybenzyl)-4-(2- (((IR'.SR'J-S-aminocyclohexyOmethylJ^H-tetrazol-S-yO-β-meth ylpicolinamide (prepared as described in Example 241 ) (50 0 mg, 0 1 15 mmol) in dichloromethane (2 mL) The mixture was agitated overnight and then filtered The filtrate was concentrated and the residue was purified by reverse

phase preparative HPLC (5%-95% CH ₃ CN/H ₂ O, 8 mm) to afford the title compound (30 0 mg, 55%) LC/MS (5%-100% CH ₃ CN/H ₂ O, 10 0 mm ) 4 57 mm , m/z 478 (M+H) ¹ H NMR (400 MHz, DMSOd ₆ ) δ ppm 9 14 - 9 23 (m, 1 H), 8 41 (s, 1 H), 8 06 (s, 1 H), 7 65 - 7 73 (m, 1 H), 7 18 - 7 26 (m, 1 H), 6 86 - 6 94 (m, 2 H), 6 75 - 6 83 (m, 1 H), 4 66 (d, J=I 32 Hz, 2 H), 4 49 (d, J=5 86 Hz, 2 H), 3 92 - 4 02 (m, 1 H), 3 71 (s, 3 H), 2 65 (s, 3 H), 3 28 (s), 2 32 - 2 45 (m, 1 H), 1 78 (s, 3 H), 0 95 - 1 70 (m)

Example 244 rac-2-((1/?*,3/?*)-3-((5-(2-((3-methoxybenzyl)carbamoyl)-6-m ethylpyridin-4-yl)-2H-tetrazol-2- yl)methyl)cyclohexylamino)-2-oxoethyl acetate

The title compound was prepared in a similar manner to rac-λ/-(3-methoxybenzyl)-4-(2-

(((1/? ^* ,3/? ^* )-3-(2-methoxyacetamιdo)cyclohexyl)methyl)-2/-/-tetrazol-5- yl)-6-methylpιcolιnamιde (Example 242) by reaction with 2-acetoxyacetιc acid to afford 23 7 mg (38%) as a solid LC/MS (5%- 95% CH ₃ CN/H ₂ O, 4 5 mm , 95% CH ₃ CN, 1 5 mm ) 3 188 mm , m/z 536 (M+H) ¹ H NMR (400 MHz, DMSO-Cf ₆ ) ÏŒ ppm 0 99 - 1 73 (m) 2 01 (s, 3 H), 2 26 - 2 46 (m, 1 H), 2 65 (s, 3 H) ₁ 3 71 (s, 3 H), 3 99 (br s ) 4 41 (s, 2 H), 4 49 (d, J=6 59 Hz, 1 H), 4 68 (d, J=I 32 Hz, 2 H), 6 74 - 6 83 (m, 1 H), 6 86 - 6 95 (m, 2 H), 7 16 - 7 25 (m, 1 H), 7 79 - 7 87 (m, 1 H), 8 05 (s, 1 H), 8 41 (s, 1 H), 9 14 - 9 23 (m, 1 H)

Example 245 rac-W-(3-Methoxybenzyl)-4-(2-(((1R*,3R*)-3-(2-hydroxyacetami do)cyclohexyl)methyl)-2H- tetrazol-5-yl)-6-methylpicolinamide

The title compound was prepared in a similar manner to rac-λ/-(3-methoxybenzyl)-4-(2- (((1 R ^* ,3R ^* )-3-(2-methoxyacetamιdo)cyclohexyl)methyl)-2H-tetrazol-5-yl )-6-methylpιcolιnamιde (Example 242) by reaction with 2-hydroxyacetιc acid to afford 26 1 mg (46%) as a solid LC/MS (5%- 95% CH ₃ CN/H ₂ O, 4 5 mm , 95% CH ₃ CN, 1 5 mm ) 2 927 mm , m/z 494 (M+H) ¹ H NMR (400 MHz, DMSO-Cf ₆ ) δ ppm 1 02 - 1 75 (m) 2 27 - 2 43 (m, 1 H), 2 52 (s, 3 H), 2 65 (s, 3 H), 3 71 (s, 3 H), 3 77 (br s ) 4 01 (br s ) 4 49 (d, J=5 86 Hz, 2 H), 4 70 (d, J=I 32 Hz, 2 H), 6 72 - 6 83 (m, 1 H), 6 86 - 6 93 (m, 2 H), 7 17 - 7 26 (m, 1 H), 7 32 - 7 39 (m, 1 H), 8 05 (s, 1 H), 8 40 (s, 1 H), 9 15 - 9 24 (m, 1 H)

Example 246 fac-W-(3-Methoxybenzyl)-4-(2-(((1/?*,3/7*)-3-(3-methoxypropa namido)cyclohexyl)methyl)-2H- tetrazol-5-yl)-6-methylpicolinamide

The title compound was prepared in a similar manner to rac-λ/-(3-methoxybenzyl)-4-(2-

(((I R'.SR^-S^Z-methoxyacetamido^yclohexyOmethyO^H-tetrazol-δ-yO -β-methylpicolinamide (Example 242) by reaction with 3-methoxypropanoιc acid to afford 33 O mg (55%) as a solid LC/MS (5%-95% CH ₃ CN/H ₂ O, 4 5 mm , 95% CH ₃ CN, 1 5 mm ) 3 152 mm , m/z 522 (M+H) ¹ H NMR (400 MHz, DMSO-CZ ₆ ) δ ppm 0 98 - 1 70 (m) 2 30 (t, J=6 22 Hz, 2 H), 2 39 (br s ) 2 65 (s, 3 H), 3 46 (t, J=6 59 Hz, 2 H), 3 71 (s, 3 H), 3 97 (br s ) 4 49 (d, J=6 59 Hz, 2 H), 4 66 (d, J=I 32 Hz, 2 H), 6 76 - 6 83 (m, 1 H), 6 85 - 6 93 (m, 2 H), 7 18 - 7 26 (m, 1 H), 7 65 - 7 73 (m, 1 H), 8 05 (s, 1 H), 8 41 (s, 1 H), 9 14 - 9 24 (m, 1 H)

Example 247 rac-/V-(3-Methoxybenzyl)-4-(2-(((1R*,3R*)-3-(2-aminoacetamid o)cyclohexyl)methyl)-2H-tetrazol- 5-yl)-6-methylpicolinamide

The title compound was prepared in a similar manner to rac-λ/-(3-methoxybenzyl)-4-(2- (((1 f? ^* ,3/ ^: ? ^* )-3-(2-methoxyacetamιdo)cyclohexyl)methyl)-2/-/-tetrazol-5- yl)-6-methylpιcolιnamιde (Example 242) by reaction with 2-(tert-butoxycarbonyl)acetιc acid to afford 19 8 mg (41 %) as a solid LC/MS (5%-95% CH ₃ CN/H ₂ O, 4 5 mm , 95% CH ₃ CN, 1 5 mm ) 2 653 mm , m/z 493 (M+H) ¹ H NMR (400 MHz, DMSOd ₆ ) δ ppm 0 97 - 1 69 (m) 2 34 (br s ) 2 65 (s, 3 H), 3 27 (br s ) 3 71 (s, 3 H), 3 99 (br s ) 4 49 (d, J=5 86 Hz, 2 H), 4 57 - 4 77 (m, 2 H), 6 72 - 6 84 (m, 1 H), 6 85 - 6 94 (m, 2 H), 7 13 - 7 27 (m, 1 H), 7 63 - 7 72 (m, 1 H), 8 04 - 8 08 (m, 1 H), 8 39 - 8 47 (m, 1 H), 9 13 - 9 23 (m, 1 H)

Example 248 rac-W-(3-Methoxybenzyl)-6-methyl-4-(2-(((1/?*,3R*)-3-(methyl sulfonamido)cyclohexyl)methyl)-

2H-tetrazol-5-yl)picolinamide

Triethylamine (0 048 mL, 0 345 mmol) and methane sulfonyl chloride (0 013 mL, 0 173 mmol) were added to a solution of rac-λ/-(3-methoxybenzyl)-4-(2-(((1 R*,3R*)-3-amιnocyclohexyl)methyl)-2/-y- tetrazol-5-yl)-6-methylpιcolιnamιde (prepared as described in Example 241 ) (50 1 mg, 0 1 15 mmol) in tetrahydrofuran (1 5 mL) The mixture was stirred for 2 hours at room temperature and was then concentrated The residue was purified by reverse phase preparative HPLC (5%-95% CH ₃ CN/H ₂ O, 8 mm) to afford the title compound as a solid (29 2 mg, 49%) LC/MS (5%-95% CH ₃ CN/H ₂ O, 4 5 mm , 95% CH ₃ CN, 1 5 mm ) 3 198 mm , m/z 514 (M +H) ¹ H NMR (400 MHz, DMSO-Cf ₆ ) δ ppm 9 09 - 9 25 (m, 1 H), 8 41 (s, 1 H), 8 05 (s, 1 H), 7 15 - 7 28 (m, 1 H), 6 92 - 6 99 (m, 1 H), 6 86 - 6 93 (m, 2 H), 6 73 - 6 83 (m), 4 68 (d, J=7 3 Hz, 2 H), 4 49 (d, J=6 6 Hz, 2 H), 3 71 (s, 3 H), 3 52 - 3 63 (m), 2 84 (s, 3 H), 2 65 (s, 3 H), 2 32 - 2 46 (m), 1 30 - 1 75 (m), 0 86 - 1 21 (m)

Example 249 rac-W-(3-Methoxybenzyl)-4-(2-(((1 S*,3R*)-3-aminocyclopentyl)methyl)-2H-tetrazol-5-yl)-6- methylpicolinamide

Step 1 Preparation of (erf-butyl rac-(1 /?*,3S*)-3-((5-(2-((3-methoxybenzyl)carbamoyl)-6-methylpyrι dιn- 4-yl)-2/-/-tetrazol-2-yl)methyl)cvclopentylcarbamate

tert-Butyl (c7s)-3-(hydroxymethyl)cyclopentylcarbamate (1 66 g, 6 166 mmol) and polymer supported-triphenylphosphine (5 74 g, 12 3 mmol) was added to a solution of /V-(3-methoxybenzyl)-6- methyl-4-(2/-/-tetrazol-5-yl)pιcolιnamιde (prepared as described in step 5 of the synthesis of λ/-(3- methoxybenzyl)-4-(2-((((rans)-4-amιnocyclohexyl)methyl)-2H- tetrazol-5-yl)-6-methylpιcolιnamιde, Example 153) in THF (25 mL) cooled to -20 ⁰ C Di-tert-butylazodicarboxylate (2 84 g, 12 3 mmol) was added and the mixture was stirred at -20 ⁰ C for 2 hours The reaction mixture was allowed to warm and stir overnight The mixture was filtered and the resin was washed with tetrahydrofuran The filtrate was concentrated and the residue was purified by reverse phase preparative HPLC to afford the title compound (1 759 g) LC/MS (5%-95% CH ₃ CN/H ₂ O, 5 mm ) 3 647 mm , m/z 522 (M+H) ¹ H NMR

(400 MHz, CDCI ₃ ) δ ppm 1 17 - 1 29 (m, 1 H), 1 37 - 1 46 (m, 9 H), 1 46 - 1 62 (m, 1 H), 1 75 - 1 86 (m, 1 H), 1 86 - 1 96 (m, 1 H), 1 97 - 2 09 (m, 1 H), 2 17 - 2 30 (m, 1 H), 2 57 - 2 73 (m, 3 H), 3 75 - 3 84 (m, 3 H), 3 96 (br s , 1 H), 4 54 (d, J=5 6 Hz, 1 H), 4 65 (t, J=7 3 Hz, 3 H), 6 82 (dd, J=8 2, 2 3 Hz, 1 H), 6 88 - 7 01 (m, 1 H), 7 20 - 7 34 (m, 1 H), 8 03 (s, 1 H), 8 42 (t, J=5 8 Hz, 1 H), 8 70 (s, 1 H)

Step 2 Preparation of rac-λ/-(3-methoxybenzyl)-4-(2-(((1 S*,3f?*)-3-amιnocvclopentyl)nnethyl)-2/-/- tetrazol-5-yl)-6-methylpιcolιnamιde

Trifluoroacetic acid (0 73 mL, 9 84 mmol) was added to a solution of /ert-butyl rac-(1 R ^* ,3S ^* )-3- ((5-(2-((3-methoxybenzyl)carbamoyl)-6-methylpyrιdιn-4-yl)- 2H-tetrazol-2- yl)methyl)cyclopentylcarbamate (1 475 g, 1 968 mmol) in dichloromethane (25 mL) The mixture was allowed to stir at room temperature overnight and was then concentrated to afford the title compound as a clear, yellow oil (1 59 g, 100% yield) LC/MS (5%-95% CH ₃ CN/H ₂ O, 5 mm ) 2 484 mm , m/z 422 (M+H) ¹ H NMR (400 MHz, CDCI ₃ ) δ ppm 1 62 - 1 75 (m, 2 H), 1 79 - 1 95 (m, 2 H), 2 02 - 2 13 (m, 1 H), 2 21 - 2 32 (m, 1 H), 2 70 (s, 3 H), 3 50 (br s , 1 H), 3 76 (s, 3 H), 4 62 (d, J=5 9 Hz, 2 H), 4 64 - 4 81 (m, 2 H), 5 28 (s, 2 H), 6 78 - 6 92 (m, 2 H), 6 95 (br s , 2 H), 7 23 - 7 27 (m, 1 H), 7 72 (br s , 1 H), 8 15 (s, 1 H), 8 63 (s, 1 H)

Example 250 rac-/V-(3-Methoxybenzyl)-6-methyl-4-(2-(((1 S*,3/?*)-3-(methylsulfonamido)cyclopentyl)methyl)-

2/-/-tetrazol-5-yl)picolinamide

Diisopropylethylamine (0 64 ml, 13 4 mmol) was added to a solution of rac-/V-(3- methoxybenzyl)-4-(2-(((1 S ^* ,3R ^* )-3-amιnocyclopentyl)methyl)-2H-tetrazol-5-yl)-6-methylpιc olιnamιde (prepared as described in Example 249) (1 16 mg, 0 275 mmol) in DMF (5 0 mL) After 20 minutes, methanesulfonyl chloride (158 mg, 1 38 mmol) was added and the mixture was allowed to stir overnight The reaction mixture was concentrated and the residue was purified by preparative reverse phase preparative HPLC to afford the title compound as an oil (62 8 mg, 49%) LC/MS (5%-95% CH ₃ CN/H ₂ O, 5 mm ) 3 156 mm , m/z 500 (M+H) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm9 19 (t, J=6 22 Hz, 1 H), 8 41 (br s , 1 H), 8 06 (s, 1 H), 7 22 (t, J=8 05 Hz, 1 H), 7 09 (d, J=7 32 Hz, 1 H), 6 90 (br s , 2 H), 6 80 (d, J=8 05 Hz, 1 H), 4 77 (d, J=7 32 Hz, 2 H), 4 49 (d, J=5 86 Hz, 2 H), 3 71 (s, 3 H), 2 85 (s, 3 H), 2 65 (s, 3 H), 2 01 - 2 13 (m, 2 H), 1 82 - 1 96 (m, 2 H), 1 69 (br s , 2 H), 1 44 - 1 60 (m, 2 H), 1 23 - 1 37 (m, 2 H)

Example 251 rac-W-(3-Methoxybenzyl)-4-(2-(((1 S*,3R*)-3-(ethylsulfonamido)cyclopentyl)methyl)-2H-tetrazol- 5- yl)-6-methylpicolinamide

Diisopropylethylamine (0 23 ml_, 1 31 mmol) was added to a solution of rac-λ/-(3- methoxybenzyl)-4-(2-(((1 S ^* ,3R ^* )-3-amιnocyclopentyl)methyl)-2/-/-tetrazol-5-yl)-6-methylpÎ ¹colιnamιde (prepared as described in Example 249) (100 rng, 0 131 mmol) in DMF (5 0 mL) After 20 minutes, ethanesulfonyl chloride (101 mg, 0 786 mmol) was added and the mixture was allowed to stir overnight The reaction mixture was concentrated and the residue was purified by preparative reverse phase preparative HPLC to afford the title compound as an oil (25 3 mg, 26%) MS (ES+) m/z 514 (M+H) ¹ H NMR (400 MHz, methanol-d ₄ ) δ ppm 1 28 (t, J=7 38 Hz, 3 H), 1 34 - 1 45 (m, 1 H), 1 55 - 1 69 (m, 1 H), 1 79 (d, J=6 71 Hz, 1 H), 1 96 - 2 07 (m, 1 H), 2 14 - 2 24 (m, 1 H), 2 67 (s, 3 H), 3 01 (q, J=7 25 Hz, 2 H), 3 76 (s, 3 H), 4 59 (s, 2 H), 4 74 (d, J=I 52 Hz, 2 H), 6 80 (dd, J=8 06, 2 42 Hz, 1 H), 6 90 - 6 96 (m, 1 H), 7 22 (t, J=Q 19 Hz, 1 H), 8 10 (d, J= 1 07 Hz, 1 H), 8 57 (s, 1 H)

Example 252 rac-W-(3-Methoxybenzyl)-4-(2-(((1 S*,3R*)-3-acetamidocyclopentyl)methyl)-2H-tetrazol-5-yl)-6- methylpicolinamide

Diisopropylethylamine (128 mg, 1 00 mmol) was added to a solution of rac-λ/-(3- methoxybenzyl)-4-(2-(((1 S ^* ,3R ^* )-3-amιnocyclopentyl)methyl)-2H-tetrazol-5-yl)-6-methylpιc olιnamιde (prepared as described in Example 249) (100 mg, 0 131 mmol) in dichloromethane (5 mL) After 20 minutes, acetic anhydride (40 mg, 0 40 mmol) was added The mixture was allowed to stir at room temperature overnight The reaction mixture was concentrated and the residue was purified by preparative reverse phase preparative HPLC to afford the title compound (58 3 mg, 43%) LC/MS (5%-95% CH ₃ CN/H ₂ O, 5 mm ) 3 071 mm , m/z 464 (M+H) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9 20 (t, J=6 22 Hz, 1 H), 8 40 (s, 1 H), 8 05 (s, 1 H), 7 82 (d, J=5 86 Hz, 1 H), 7 21 (t, J=8 05 Hz, 1 H), 6 90 (br s , 1 H), 6 79 (d, J=7 32 Hz, 2 H), 4 76 (d, J=6 59 Hz, 2 H), 4 49 (d, J=5 86 Hz, 2 H), 3 98 (dd, J=14 64, 7 32 Hz, 1 H), 3 71 (s, 3 H), 2 65 (s, 3 H), 2 50 - 2 60 (m, 1 H), 2 48 (br s , 1 H), 1 94 - 2 07 (m, 1 H)1 61 - 1 87 (m, 4 H), 1 37 - 1 56 (m, 2 H), 1 13 - 1 26 (m, 1 H)

Example 253 rac-A/-(3-Methoxybenzyl)-4-(2-(((1S*,3/?*)-3-(2-hydroxyaceta mido)cyclopentyl)methyl)-2H- tetrazol-5-yl)-6-methylpicolinamide

Diisopropylethylamine (118 mg, 0 917 mmol) and glycolic acid (19 9 mg, 0 262 mmol) were added to a solution of rac-λ/-(3-methoxybenzyl)-4-(2-(((1 S ^* ,3f? ^* )-3-amιnocyclopentyl)methyl)-2/-/- tetrazol-5-yl)-6-methylpιcolιnamιde (prepared as described in Example 249) (100 mg, 0 131 mmol) in λ/,λ/-dιmethylformamιde (5 mL) After 20 mm, O-(1 H-benzotrιazol-1-yl)-λ/,λ/,A/',λ/"-tetramethyluronιum tetrafluoroborate (116 mg, 0 360 mmol) was added and the mixture was allowed to stir for 72 hours The reaction mixture was concentrated and the residue was purified by reverse phase preparative HPLC to afford the title compound (30 5 mg, 33%) LC/MS (5%-95% CH ₃ CN/H ₂ O, 5 mm ) 2 958 mm , m/z 480 (M+H) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9 19 (t, J=6 22 Hz, 1 H), 8 41 (br s , 1 H), 8 06 (s, 1 H), 7 22 (t, J=8 05 Hz, 1 H), 6 90 (br s , 1 H), 6 80 (d, J=8 05 Hz, 1 H), 5 29 (br s , 1 H), 4 49 (d, J=5 86 Hz, 2 H), 4 03 - 4 18 (m, 1 H), 3 67 - 3 80 (m, 3 H), 2 65 (s, 3 H), 2 50 - 2 62 (m, 1 H), 2 48 (br s , 1 H), 1 76 - 1 88 (m, 1 H), 1 61 - 1 73 (m, 1 H), 1 53 (d, J=6 59 Hz, 2 H), 1 22 - 1 39 (m, 1 H)

Example 254 rac-/V-(3-Methoxybenzyl)-4-(2-(((1S*,3/?*)-3-(3-hydroxypropa namido)cyclopentyl)methyl)-2H- tetrazol-5-yl)-6-methylpicolinamide

Diisopropylethylamine (130 mg, 1 01 mmol) and 3-hydroxypropιonιc acid (26 mg, 0 288 mmol) were added to a solution of rac-λ/-(3-methoxybenzyl)-4-(2-(((1 S ^* ,3R ^* )-3-amιnocyclopentyl)methyl)-2H- tetrazol-5-yl)-6-methylpιcolιnamιde (prepared as described in Example 249) (1 10 mg, 0 144 mmol) in λ/,λ/-dιmethylformamιde (5 mL) After 20 mm, O-(1 H-benzotrιazol-1-yl)-λ/,λ/,λ/',λ/"-tetramethyluronιum tetrafluoroborate (127 mg, 0 396 mmol) was added and the mixture was allowed to stir for 72 hours The reaction mixture was concentrated and the residue was purified by reverse phase preparative HPLC to afford the title compound (16 1 mg, 15%) LC/MS (5%-95% CH ₃ CN/H ₂ O, 5 mm ) 2 936 mm , m/z 494 (M+H) ¹ H NMR (400 MHz, CD ₃ OD) ÏŒ ppm 9 20 (s, 1 H), 8 55 (s, 1 H), 8 10 (s, 1 H), 7 23 (t, J=Q 19 Hz, 1 H), 6 91 - 6 96 (m, 2 H), 6 78 - 6 83 (m, 1 H), 4 73 - 4 81 (m, 2 H), 4 59 (s, 2 H), 3 74 - 3 79 (m, 3 H), 2 66 - 2 70 (m, 3 H), 2 35 (t, J=6 31 Hz, 1 H), 2 13 - 2 22 (m, 1 H), 1 99 (d, J=6 18 Hz, 1 H), 1 81 (s, 1 H), 1 51 - 1 67 (m, 2 H), 1 28 - 1 38 (m, 1 H)

Example 255

(frans)-Methyl 4-((5-(2-((4-fluorobenzyl)carbamoyl)-6-methylpyridin-4-yl)-2 H-tetrazol-2- yl)methyl)cyclohexanecarboxylate

Step 1 Preparation of λ/-(4-fluorobenzγl)-6-methyl-4-(2H-tetrazol-5-yl)pιcolιn amιde

A solution of trimethyl aluminum (2M in toluene, 91 25 ml_, 0 183 mol) was added to a solution of 4-fluorobenzylamιne (22 84 g, 0 183 mol) in anhydrous tetrahydrofuran (400 mL) The reaction mixture was stirred at room temperature for 4 h, at which time the solution was cannulated into a suspension of methyl 6-methyl-4-(2/-/-tetrazol-5-yl)pιcolιnate (prepared as described in step 4 of the synthesis of λ/-(3-methoxybenzyl)-4-(2-(((fraπs)-4-amιnocyclohexyl)met hyl)-2/-/-tetrazol-5-yl)-6- methylpicolinamide, Example 153) (20 0 g, 0 0913 mol) in anhydrous tetrahydrofuran (400 mL) The reaction mixture was then stirred overnight The mixture was quenched slowly with methanol and was poured into a 2 L Erlenmeyer containing methanol (500 mL) The mixture was filtered through Celite™ and concentrated in vacuo The crude product was purified by silica column chromatography

(CH ₂ CI ₂ /tetrahydrofuran, 9/1 ) The desired fractions were combined and concentrated to afford the title compound (25 4 g, 89%) ¹ H NMR (400 MHz, DMSO-CZ ₆ ) δ ppm 9 33 (t, J= 6 34, 1 H), 8 43 (s, 1 H), 8 05 (s, 1 H), 7 34 (dd, J= 8 5, 2 H) ₁ 7 1 1 (dd, J= 8 9, 2 H), 4 48 (d, J= 6 6, 2 H), 2 64 (s, 3 H)

Step 2 Preparation of (frans)-methyl 4-((5-(2-((4-fluorobenzyl)carbamoyl)-6-methylpyrιdιn-4-yl) -2H- tetrazol^-vDmethvQcvclohexanecarboxylate

Triethylamine (9 12 g, 0 09 mol)was added to a suspension of the λ/-(4-fluorobenzyl)-6- methyl-4-(2H-tetrazol-5-yl)pιcolιnamιde (12 8 g, 0 04 mol) in acetonitrile (400 mL, anhydrous) trans- methyl 4-((methylsulfonyloxy)methyl)cyclohexanecarboxylate (prepared as described in step 1 of the synthesis of frans-methyl 4-((5-(6-((4-fluoro-3-methoxybenzyl)carbamoyl)-2-methylpyrι mιdιn-4-yl)-2H- tetrazol-2-yl)methyl)cyclohexanecarboxylate, Example 20) (10 77 g, 0 04 mol) was then added and the reaction mixture was stirred over night at 60 ⁰ C The mixture was concentrated under reduced pressure and the crude product was purified by silica column chromatography

(CH ₂ CI ₂ /tetrahydrofuran, 9/1 ) The desired fractions were combined and concentrated to afford the title compound (1 1 g, 58%) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9 29 (t, J= 6 34, 1 H), 8 39 (s, 1 H) ₁ 8 04 (s, 1 H), 7 36 (m, 2H), 7 1 1 (m, 2H), 4 64 (d, J= 7 1 , 2H), 4 49 (d, J= 6 6, 2H), 3 30 (s, 3H), 2 64 (s, 3H), 2 1 (m, 1 H), 1 96 (m, 1 H), 1 89 (m, 2H), 1 64 (m, 2H), 1 26 (m, 2H), 1 09 (m, 2H)

Example 256

(fra/7s)-4-((5-(2-((4-Fluorobenzyl)carbamoyl)-6-methylpyr idin-4-yl)-2H-tetrazol-2- yl)methyl)cyclohexanecarboxylic acid

To a solution of (frans)-methyl 4-((5-(2-((4-fluorobenzyl)carbamoyl)-6-methylpyrιdιn-4-yl) -2H- tetrazol-2-yl)methyl)cyclohexanecarboxylate (prepared as described in Example 255) (10 g, 0 021 mol) in tetrahydrofuran (300 mL) was added water (300 mL) and then sodium hydroxide (4 3 g, 0 107 mol) The mixture was stirred vigorously overnight The tetrahydrofuran was removed under reduced pressure and the resulting alkaline solution was acidified drop wise with 1 M hydrochloric acid until the solution reached pH 5 The mixture was left sitting in a refrigerator overnight The resulting precipitate was isolated by filtration and washed with water (pH 5) The solid was dried in a vacuum oven overnight to afford the title compound (7 5 g, 77%) Mp 122-124 ⁰ C, ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1 1 96 (s, 1 H), 9 27 (t, J= 6 4, 1 H), 8 36 (s, 1 H), 8 02 (s, 1 H), 7 33 (dd, J= 8 5, 2H), 7 09 (dd, J= 9 0, 2H), 4 61 (d, J= 6 8, 2H), 4 45 (d, J= 6 3, 2H), 2 61 (s, 3H), 2 07 (m, 1 H), 1 93 (m, 1 H), 1 85 (d, J= 11 , 2H), 1 58 (d, J= 10 8, 2H), 1 25 (m, 2H), 1 07 (m, 2H)

Example 257

/V-(4-Fluorobenzyl)-6-methyl-4-(2-(((frans)-4-(methylsulf onylcarbamoyl)cyclohexyl)methyl)-2H- tetrazol-5-yl)picolinamide

4-(Dιmethylamιno)pyrιdιne (5 4mg, 0 041 mmol) was added to a mixture of (/rans)-4-((5-(2-((4- fluorobenzyl)carbamoyl)-6-methylpyrιdιn-4-yl)-2H-tetrazol- 2-yl)methyl)cyclohexanecarboxylιc acid

(prepared as described in Example 256) (0 20 g, 0 442 mmol), dι-(λ/,/V-succιnιmιdyl)carbonate (0 14g, 0 53 mmol), and triethylamine (0 092 mL, 0 66 mmol) in λ/,N-dιmethylacetamιde (2 mL) After 5 minutes, methanesulfonamide (51 mg, 0 53 mmol) was added The reaction mixture was allowed to stir at room temperature for 24 hours and then purified by reverse phase preparative HPLC to afford the title compound as a solid (0 040 g, 17%) ¹ H NMR (400 MHz, DMSOd ₆ ) δ ppm 9 29 (t, J=6 31 Hz,

1 H), 8 39 (s, 1 H), 8 05 (s, 1 H), 7 26 - 7 44 (m, 2 H), 7 02 - 7 18 (m, 2 H), 4 66 (d, J=6 99 Hz, 2 H), 4 48 (d, J=6 45 Hz, 2 H), 3 31 (br s , 1 H), 2 76 (s, 3 H), 2 61 - 2 69 (m, 4 H), 1 92 - 2 13 (m, 3 H), 1 68 (d, J= 12 90 Hz, 2 H), 1 33 - 1 50 (m, 2 H), 1 10 - 1 29 (m, 2 H)

Example 258

A/-(4-Fluorobenzyl)-4-(2-(((fraπs)-4-(2-hydroxyacetyl)cy clohexyl)methyl)-2H-tetrazol-5-yl)-6- methylpicolinamide

Oxalyl chloride (3 mL) was added to a solution of (/rans)-4-((5-(2-((4-fluorobenzyl)carbamoyl)- 6-methylpyrιdιn-4-yl)-2H-tetrazol-2-yl)methyl)cyclohexanec arboxylιc acid (prepared as described in Example 256) (380 mg, 0 84 mmol) in dichloromethane (2 mL) and the mixture was stirred at room temperature for 18 hours The reaction mixture was concentrated and the residue was treated with trιs(trιmethylsιloxy)ethylene (541 mg, 1 85 mmol) The mixture was heated to 90 °C for 3 hours and then was stirred at room temperature for 2 days The mixture was treated with several drops of 4 N hydrochloric acid until gas stopped evolving The reaction mixture was purified by reverse phase preparative HPLC The crude product was taken up in methanol and passed through a carbonate cartridge The filtrate was concentrated to afford the title compound as a white solid (79 mg, 20%) LCMS (ES+) m/z 467(M+H) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1 02 - 1 40 (m, 4 H), 1 61 - 1 73 (m, J=10 98 Hz, 2 H), 1 91 (s, J= 10 98 Hz, 2 H), 1 96 - 2 08 (m, 1 H), 2 20 - 2 32 (m, 1 H), 2 67 (s, 3 H), 3 26 - 3 33 (m, J=2 20 Hz, 1 H), 3 57 (s, 2 H), 4 52 (d, J=5 86 Hz, 2 H), 4 58 - 4 72 (m, 3 H), 7 14 (s, J=8 78, 8 78 Hz, 1 H), 7 39 (dd, J=Q 05, 5 86 Hz, 2 H), 8 07 (s, 1 H), 8 42 (s, 1 H), 9 28 (t, J=6 59 Hz, 1 H)

Example 259

(frans)-Methyl 4-((5-(2-((3-(hydroxymethyl)benzyl)carbamoyl)-6-methylpyridi n-4-yl)-2H-tetrazol- 2-yl)methyl)cyclohexanecarboxylate

Step 1 Preparation of (frans)-methyl 4-((3-nιtrophenylsulfonyloxy)methyl)cvclohexanecarboxylate

A mixture of /rans-methyl 4-(hydroxymethyl)cyclohexanecarboxylate (22 O g, 128 mmol) and 3-nιtrobenzene-1 -sulfonyl chloride (35 7 g, 161 mmol) in dichloromethane (130 mL) was cooled in an ice bath and triethylamine (23 7 mL, 170 mmol) was added by addition funnel maintaining the temperature below 7°C The mixture was stirred at this temperature for 1 hour and then quenched with water (1 mL) The reaction mixture was diluted with saturated aqueous sodium bicarbonate solution and extracted with dichloromethane The organic layer was dried over magnesium sulfate, filtered, and concentrated The residue was slurried in methanol, filtered, and dried in a vacuum oven to afford the title compound as a white solid (40 66 g, 89%)

Step 2 Preparation of methyl 4-(2-(((frans)-4-(methoxycarbonyl)cvclohexyl)methyl)-2H-tetr azol-5-yl)-6- methylpicolinate

Diisopropylethylamine (20 7 mL, 1 18 6 mmol) was added by addition funnel to a mixture of (frans)-methyl 4-((3-nιtrophenylsulfonyloxy)methyl)cyclohexanecarboxylate (35 9 g, 100 4 mmol) and methyl 6-methyl-4-(2/-/-tetrazol-5-yl)pιcolιnate (prepared as described in step 4 of the synthesis of /V- (3-methoxybenzyl)-4-(2-(((/rans)-4-amιnocyclohexyl)methyl)- 2/-/-tetrazol-5-yl)-6-methylpιcolιnamιde, Example 153) (20 g, 91 2 mmol) in acetonitrile (120 mL) The mixture was heated at reflux for 7 hours and then was concentrated in vacuo The residue was suspended in dichloromethane and washed with 1 N aqueous sodium hydroxide solution The organic layer was dried over magnesium sulfate, filtered, and concentrated The crude product was purified by silica gel column chromatography (heptane/ethyl acetate, 65/35, 50/50) to afford the title compound as a white solid (27 g, 79%)

Step 3 Preparation of (frans)-methyl 4-((5-(2-((3-(hvdroxymethyl)benzyl)carbamoyl)-6-methylpyrιd ιn-4- vO-2H-tetrazol-2-yl)methyl)cvclohexanecarboxvlate

(3-(Amιnomethyl)phenyl)methanol (prepared as described in step 1 of the synthesis of λ/-(3- (hydroxymethyl)benzyl)-6-methyl-4-(2-(((frans)-4-(methylsulf onamido)cyclohexyl)methyl)-2H-tetrazol- 5-yl)pιcolιnamιde, Example 183) (1 15 mg, 0 838 mmol) was added to a solution of methyl 4-(2- (((trans )-4-(methoxycarbonyl)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6- methylpιcolιnate (75 mg, 0 201

mmol) in λ/,λ/-dιmethylformamιde (6 mL) and the mixture was heated at 60 ⁰ C for 3 days The reaction mixture was purified by reverse-phase preparative HPLC to afford the title compound as a solid (50 mg, 65%) LC/MS (0%-25% CH ₃ CN/H ₂ O, 5 mm ) 3 010 mm , m/z 479 (M+H) ¹ H NMR (400 MHz, methanol-^) δ ppm 1 10 - 1 24 (m, 2 H), 1 34 - 1 49 (m, 2 H), 1 74 (dd, ,7=13 7, 3 0 Hz, 2 H), 1 99 (dd, .7=13 8, 3 1 Hz, 2 H), 2 03 - 2 16 (m, 1 H), 2 23 - 2 35 (m, 1 H), 2 65 - 2 71 (m, 3 H), 3 62 (s, 3 H), 3 96 (s, 1 H), 4 62 (d, J=7 0 Hz, 2 H), 4 74 (s, 2 H), 7 77 (d, J=8 1 Hz, 1 H), 8 03 (dd, .7=8 2, 1 5 Hz, 1 H), 8 09 (d, J= 1 1 Hz, 1 H), 8 54 (s, 1 H), 8 72 (d, J= 1 6 Hz, 1 H)

Example 260

((rans)-4-((5-(2-((3-(Hydroxymethyl)benzyl)carbamoyl)-6-m ethylpyridin-4-yl)-2H-tetrazol-2- yl)methyl)cyclohexanecarboxylic acid

(fraÏ€s)-Methyl 4-((5-(2-((3-(hydroxymethyl)benzyl)carbamoyl)-6-methylpyrιd ιn-4-yl)-2H- tetrazol-2-yl)methyl)cyclohexanecarboxylate (50 mg, 0 13 mmol) was dissolved in tetrahydrofuran (1 0 mL) and a 4 N aqueous solution of lithium hydroxide (1 0 mL) was added The mixture was allowed to stir at room temperature overnight The reaction mixture was concentrated to afford the title compound (16 7 mg, 18%) ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 1 12 - 1 25 (m, 2 H), 1 35 - 1 48 (m, 2 H), 1 70 - 1 78 (m, 2 H), 1 95 - 2 03 (m, 2 H), 2 05 - 2 14 (m, 1 H), 2 25 - 2 35 (m, 1 H), 2 67 (s, 3 H), 3 33 (s, 1 H), 3 62 (s, 3 H), 3 85 (s, 3 H), 4 62 (d, J=7 25 Hz, 2 H), 4 67 (s, 2 H), 6 90 - 6 97 (m, 1 H), 6 97 - 7 08 (m, 2 H), 8 09 (s, 1 H), 8 55 (s, 1 H)

Example 261

(frans)-Methyl 4-((5-(2-((3-hydroxybenzyl)carbamoyl)-6-methylpyridin-4-yl)- 2H-tetrazol-2- yl)methyl)cyclohexanecarboxylate

A mixture of 3-(amιnomethyl)phenol (1 01 g, 8 21 mmol) and methyl 4-(2-(((trans)-4- (methoxycarbonyl)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6-meth ylpιcolιnate (prepared as described in step 2 of the synthesis of (frans)-methyl 4-((5-(2-((3-(hydroxymethyl)benzyl)carbamoyl)-6- methylpyridm-4-yl)-2/-/-tetrazol-2-yl)methyl)cyclohexanecarb oxylate, Example 260) (1 0 g, 2 05 mmol) in methanol (25 mL) was heated at 60 ⁰ C for 4 days The reaction mixture was allowed to cool to room temperature and filtered The resulting solids were washed with methanol to afford the title compound (770 mg, 80%) MS (ES+) m/z 465 (M+H) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1 06 -

1 22 (m, 2 H), 1 24 - 1 41 (m, 2 H), 1 58 - 1 71 (m, 2 H), 1 85 - 1 95 (m, 2 H), 1 96 - 2 08 (m, 1 H), 2 20 - 2 32 (m, 1 H), 2 67 (s, 3 H), 3 57 (s, 3 H), 4 45 (d, J=6 44 Hz, 2 H), 4 67 (d, J=6 98 Hz, 2 H), 6 62 (d, 1 H), 6 72 - 6 80 (m, 2 H), 7 10 (t, J=I 92 Hz, 1 H), 8 08 (d, J= 1 34 Hz, 1 H), 8 43 (s, 1 H), 9 22 (t, J=6 31 Hz, 1 H), 9 32 (s, 1 H)

Example 262

((rans)-4-((5-(2-((3-Hydroxybenzyl)carbamoyl)-6-methylpyr idin-4-yl)-2W-tetrazol-2-yl)methyl)- cyclohexanecarboxylic acid

A mixture of (frans)-methyl 4-((5-(2-((3-hydroxybenzyl)carbamoyl)-6-methylpyrιdιn-4-yl )-2H- tetrazol-2-yl)methyl)cyclohexanecarboxylate (prepared as described in Example 261 ) (50 mg, 0 1 1 mmol) and lithium hydroxide (15 mg, 0 65 mmol) in a mixture of tetrahydrofuran/water (5/1 , 3 mL) was stirred at room temperature for 3 days The reaction mixture was concentrated and the aqueous residue was treated dropwise with 3N hydrochloric acid until a precipitate formed The precipitate was taken up in a mixture of dichloromethane and methanol and then passed through an lsolute SPE 103 cartridge eluting with dichloromethane/methanol (9/1 ) The filtrate was concentrated The residue was washed with water and dried to afford the title compound as a white solid (38 mg, 76%) MS (ES+) m/z 451 (M+H) ¹ H NMR (400 MHz, DMSOd ₆ ) 6 ppm 1 04 - 1 20 (m, 2 H), 1 21 - 1 38 (m, 2 H), 1 65 (d, J=10 74 Hz, 2 H), 1 90 (d, J= 1 1 01 Hz, 2 H), 1 99 (s, J=7 12, 3 89 Hz, 1 H), 2 08 - 2 20 (m, 1 H), 2 68 (s, 3 H), 4 46 (d, J=6 18 Hz, 2 H), 4 67 (d, J=6 98 Hz, 2 H), 6 58 - 6 66 (m, 1 H), 6 71 - 6 79 (m, 1 H), 7 10 (t, J=8 06 Hz, 1 H), 8 08 (d, J= 1 34 Hz, 1 H), 8 43 (s, 1 H), 9 15 - 9 27 (m, 1 H), 9 30 (s, 1 H), 12 03 (s, 1 H)

Example 263

(fraπs)-Methyl 4-((5-(2-((3-(3-methoxypropoxy)benzyl)carbamoyl)-6-methylpyr ϊdin-4-yl)-2H- tetrazol-2-yl)methyl)cyclohexanecarboxylate

A mixture of (/ra/7s)-methyl 4-((5-(2-((3-hydroxybenzyl)carbamoyl)-6-methylpyrιdιn-4-yl )-2H- tetrazo!-2-yl)methyl)cyclohexanecarboxylate (prepared as described in Example 261 ) (50 mg, 0 11 mmol), 1 -bromo-3-methoxypropane (33 mg, 0 22 mmol), potassium carbonate (37 mg, 0 27 mmol), and tetrabutylammonium iodide (4 mg, 0 01 mmol) in λ/,λ/-dιmethylformamιde (2 mL) was heated at 60 ⁰ C for 18 hours Additional potassium carbonate (30 mg) was added and heating was continued for

18 hours The reaction mixture was purified by reverse phase preparative HPLC to afford the title compound as an oil (26 mg, 45%) MS (ES+) m/z 537 (M+H) ¹ H NMR (400 MHz, CDCI ₃ ) δ ppm 1 08 - 1 24 (m, 2 H), 1 37 - 1 55 (m, 2 H), 1 74 - 1 85 (m, 2 H), 1 96 - 2 21 (m, 5 H), 2 22 - 2 35 (m, 1 H), 2 67 (s, 3 H), 3 35 (d, J= 1 61 Hz, 3 H), 3 55 (t, J=5 91 Hz, 2 H), 3 67 (s, 3 H), 4 06 (t, J=6 31 Hz, 2 H) ₁ 4 56 (d, J=6 71 Hz, 2 H), 4 68 (d, J=6 18 Hz, 2 H), 6 77 - 6 89 (m, J=& 32 Hz, 1 H), 6 91 - 7 03 (m, 2 H), 7 21 - 7 33 (m, 1 H), 8 08 (s, 1 H), 8 46 - 8 60 (m, 1 H), 8 76 (s, 1 H)

Example 264

((raπs)-4-((5-(2-((3-(3-Methoxypropoxy)benzyl)carbamoyl) -6-methylpyridin-4-yl)-2H-tetrazol-2- yl)methyl)cyclohexanecarboxylic acid

A mixture of (Zrans)-methyl 4-((5-(2-((3-(3-methoxypropoxy)benzyl)carbamoyl)-6- methylpyÏ€din^-yl^H-tetrazol^-yOmethyOcyclohexanecarboxylate (prepared as described in Example 263) (25 mg, 0 05 mmol) and lithium hydroxide (5 mg, 0 2 mmol) in a mixture of tetrahydrofuran/water (5/1 , 3 mL) was stirred at room temperature for 18 hours The reaction mixture was acidified with a few drops of 4N hydrochloric acid and purified by reverse phase preparative HPLC to afford the title compound (17 mg, 57%) MS (ES+) m/z 523 (M+H) ¹ H NMR (400 MHz, CDCI ₃ ) δ ppm 1 1 1 - 1 25 (m, 2 H), 1 41 - 1 55 (m, 2 H), 1 77-1 86 (m, 2 H), 2 00 - 2 19 (m, 6 H), 2 26 â–  2 37 (m, 1 H), 2 65 (s, 3 H), 3 35 (s, 3 H), 3 46-3 56 (m, 1 H), 3 56 (t, J=6 18 Hz, 2 H), 4 06 (t, J=6 18 Hz, 2 H), 4 56 (d, J=Q 98 Hz, 2 H), 4 68 (d, J=5 91 Hz, 2 H), 6 85 (t, J=8 19, 2 28 Hz, 1 H), 6 91 - 7 00 (m, 2 H), 8 06 (d, J= 1 07 Hz, 1 H), 8 46 (t, J=6 04 Hz, 1 H), 8 74 (s, 1 H)

Example 265

(fraπs)-Methyl 4-((5-(2-((3,4-difluorobenzyl)carbamoyl)-6-methylpyridin-4-y l)-2H-tetrazol-2- yl)methyl)cyclohexanecarboxylate

A mixture of (3,4-dιfluorophenyl)methanamιne (153 mg, 1 07 mmol) and 4-(2-(((frans)-4-

(methoxycarbonyl)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6-meth ylpιcolιnate (prepared as described in step 2 of the synthesis of (Zrans)-methyl 4-((5-(2-((3-(hydroxymethyl)benzyl)carbamoyl)-6- methylpyrιdιn-4-yl)-2H-tetrazol-2-yl)methyl)cyclohexanecar boxylate, Example 260) (100 mg, 0 27 mmol) in tetrahydrofuran (0 5 mL) was heated at 60 ⁰ C for 3 days The reaction mixture was purified by reverse phase preparative HPLC The fractions containing the desired product were combined and

concentrated The residue was taken up in methanol and passed through a carbonate cartridge The filtrate was concentrated to afford the title compound as a white solid (87 mg, 61 %) MS (ES+) m/z 485 (M+H) ¹ H NMR (400 MHz, CDCI ₃ ) δ ppm 1 08 - 1 25 (m, 2 H), 1 38 - 1 53 (m, 2 H), 1 79 (dd, J= 13 70, 2 95 Hz, 2 H), 1 99 - 2 19 (m, 3 H), 2 22 - 2 35 (m, 1 H), 2 66 (s, 3 H), 3 67 (s, 3 H), 4 56 (d, J=6 98 Hz, 2 H), 4 66 (d, J=6 44 Hz, 2 H), 7 07 - 7 26 (m, 3 H), 8 08 (d, J=1 07 Hz, 1 H), 8 43 - 8 54 (m, 1 H), 8 73 (s, 1 H)

Example 266

((rans)-4-((5-(2-((3,4-Difluorobenzyl)carbamoyl)-6-methyl pyridin-4-yl)-2H-tetrazol-2-yl)methyl)- cyclohexanecarboxylic acid

A mixture of (Zrans)-methyl 4-((5-(2-((3,4-dιfluorobenzyl)carbamoyl)-6-methylpyrιdιn- 4-yl)-2H- tetrazol-2-y!)methyl)cyc!ohexanecarboxylate (prepared as described in Example 265) (50 mg, 0 1 1 mmol) _, and lithium hydroxide (8 mg, 0 33 mmol) in a mixture of tetrahydrofuran/water (5/1 , 6 mL) was stirred at room temperature for 18 hours The reaction mixture was purified by reverse phase preparative HPLC The fractions containing the desired product were combined and concentrated The residue was taken up in dichloromethane and saturated sodium chloride solution (2 mL) and passed through a VaÏ€an ChemElute column eluting with dichloromethane The filtrate was concentrated to afford the title compound as a white solid (35 mg, 72%) _MS (ES+) m/z 471 (M+H) ¹ H NMR (400 MHz, CDCI ₃ ) ÏŒ ppm 1 11 - 1 29 (m, 2 H), 1 40 - 1 56 (m, 2 H), 1 74 - 1 86 (m, 2 H), 2 02 - 2 22 (m, 3 H), 2 25 - 2 38 (m, 2 H), 2 67 (s, 3 H), 4 56 (d, J=6 98 Hz, 2 H), 4 66 (d, J=6 18 Hz, 2 H), 7 07 - 7 26 (m, 3 H), 8 09 (s, 1 H), 8 44 - 8 63 (m, 1 H), 8 73 (s, 1 H)

Example 267

(frans)-Methyl 4-((5-(2-((3-methoxybenzyl)carbamoyl)-6-methylpyridin-4-yl)- 2H-tetrazol-2- yl)methyl)cyclohexanecarboxylate

A mixture of λ/-(3-methoxybenzyl)-6-methyl-4-(2H-tetrazol-5-yl)pιcolιn amιde (prepared as described in step 5 of the synthesis of λ/-(3-methoxybenzyl)-4-(2-(((frans)-4-amιnocyclohexyl)meth yl)- 2/-/-tetrazol-5-yl)-6-methylpιcolιnamιde, Example 153) (2 0 g, 6 17 mmol), (frans)-methyl 4- (hydroxymethyl)cyclohexanecarboxylate (2 12 g, 12 33 mmol), and polymer supported triphenylphosphine resin (7 18 g, 15 43 mmol, 2 15 mmol/g loading) m tetrahydrofuran (100 mL) was

cooled in an ice bath and di-tert-butylazodicarbxylate (2 84 g, 12 33 mmol) was added The mixture was stirred for 10 minutes in the ice bath, allowed to warm to room temperature, and stirred an additional 2 hours The reaction mixture was filtered and the resin was washed with tetrahydrofuran and methanol The filtrate was concentrated and the residue was purified by reverse phase preparative HPLC to afford the title compound as a white solid (1 58 g, 54%) MS (ES+) m/z 479

(M+H) ¹ H NMR (400 MHz, DMSO-c/ ₆ ) 6 ppm 1 06 - 1 21 (m, 2 H), 1 25 - 1 39 (m, 2 H), 1 58 - 1 70 (m, 2 H), 1 84 - 1 95 (m, 2 H), 1 95 - 2 08 (m, 1 H), 2 19 - 2 31 (m, 1 H), 2 67 (s, 3 H), 3 57 (s, 3 H), 3 73 (s, 3 H), 4 51 (d, J=6 18 Hz, 2 H), 4 67 (d, J=6 98 Hz, 2 H), 6 77 - 6 86 (m, 1 H), 6 88 - 6 97 (m, 2 H), 7 24 (t, J=8 19 Hz, 1 H), 8 07 (s, 1 H), 8 42 (s, 1 H), 9 26 (t, J=6 44 Hz, 1 H)

Example 268

((rans)-4-((5-(2-((3-Methoxybenzyl)carbamoyl)-6-methylpyr idin-4-yl)-2H-tetrazol-2-yl)methyl)- cyclohexanecarboxylic acid

A mixture of (frans)-methyl 4-((5-(2-((3-methoxybenzyl)carbamoyl)-6-methylpyridin-4-yl)- 2H- tetrazol-2-yl)methyl)cyclohexanecarboxylate (prepared as described in Example 267) (2 729 g, 5 697 mmol), aqueous 2 5 N sodium hydroxide solution (28 515 mmol, 5 equiv ), water (114 ml_), and tetrahydrofuran (1 14 ml_) was stirred overnight at room temperature The reaction mixture was concentrated and the aqueous residue was acidified The precipitate was filtered, washed with water, and dried under high vacuum to afford the title compound as a solid (2 598 g, 98%) LC/MS (5%-95% CH ₃ CN/H ₂ O, 4 5 mm , 95% CH ₃ CN, 1 5 mm ) 3 217 mm , m/z 465 (M+H) ¹ H NMR (400 MHz, acetone-d ₆ ) δ ppm 1 15 - 1 32 (m, 2 H), 1 33 - 1 50 (m, 2 H), 1 72 - 1 83 (m, 2 H), 1 99 - 2 02 (m, J=3 22 Hz, 2 H), 2 07 - 2 18 (m, 1 H), 2 20 - 2 33 (m, 1 H), 2 64 (s, 3 H), 3 77 (s, 3 H), 4 64 (d, J=6 44 Hz, 2 H), 4 68 (d, J=6 98 Hz, 2 H), 6 82 (dd, J=Q 32, 1 61 Hz, 1 H), 6 93 - 7 02 (m, 2 H), 7 24 (t, J=I 92 Hz, 1 H), 8 06 (d, J=1 07 Hz, 1 H), 8 61 (s, 1 H), 8 88 (s, 1 H)

Example 269

/V^S-MethoxybenzyO-β-methyM^Z-l^fransJ^^piperidine-i-car bonyOcyclohexyOmethyO^H- tetrazol-5-yl)picolinamide

To a vial containing piperidine, (13 79 mg, 0 162 mmol) added a solution of (/rans)-4-((5-(2-((3- methoxybenzyl)carbamoyl)-6-methylpyrιdιn-4-yl)-2H-tetrazol -2-yl)methyl)cyclohexanecarboxy!ιc acid

(prepared as described in Example 268) (51 0 mg, 0 108 mmol) and 1-hydroxybenzotπazole (2 9 mg,

0 022 mmol) in λ/,λ/-dιmethylformamιde (2 ml_), followed by carbodiimide resin (125 mg, 0 162 mmol,

1 30 mmol/g loading), dichloromethane (2 ml_), and λ/-methylmorpholιne (54 54 mg, 0 54 mmol) The mixture was agitated on an orbital shaker overnight at room temperature The mixture was filtered and the resin was washed with λ/,λ/-dιmethylformamιde and dichloromethane The filtrate was concentrated and the residue was purified by reverse phase preparative HPLC (5%-95% CH ₃ CN/H ₂ O, 8 mm ) to afford the title compound (34 5 mg, 60%) LC/MS (5%-95% CH ₃ CN/H ₂ O, 4 5 mm , 95% CH ₃ CN, 1 5 mm ) 3 705 mm , m/z 532 (M+H)

Example 270 4-(2-(((frans)-4-((2-Methoxyethyl)carbamoyl)cyclohexyl)methy l)-2H-tetrazol-5-yl)-W-(3- methoxybenzyl)-6-methylpicolinamide

The title compound (34 1 mg, 61 %) was prepared in a similar manner to λ/-(3-methoxybenzyl)- 6-methyl-4-(2-(((/rans)-4-(pιperιdιne-1 -carbonyl)cyclohexyl)methyl)-2/-/-tetrazol-5-yl)pιcolιnamÎ ¹de (Example 269) by reaction with 2-methoxyethanamιne LC/MS (5%-95% CH ₃ CN/H ₂ O, 4 5 mm , 95% CH ₃ CN, 1 5 mm ) 3 183 mm , m/z 522 (M+H)

Example 271

/V-(3-Methoxybenzyl)-6-methyl-4-(2-(((frans)-4-(morpholin e-4-carbonyl)cyclohexyl)methyl)-2W- tetrazol-5-yl)picolinamide

The title compound (32 9 mg, 57%) was prepared in a similar manner to λ/-(3-methoxybenzyl)- 6-methyl-4-(2-(((frans)-4-(pιperιdιne-1-carbonyl)cyclohex yl)methyl)-2H-tetrazol-5-yl)pιcolιnamιde (Example 269) by reaction with morpholine LC/MS (5%-95% CH ₃ CN/H ₂ O, 4 5 mm , 95% CH ₃ CN, 1 5 mm ) 3 259 mm , m/z 534 (M+H)

Example 272

/V-(3-Methoxybenzyl)-4-(2-((((rans)-4-(dimethylcarbamoyl) cyclohexyl)methyl)-2H-tetrazol-5-yl)-6- methylpicolinamide

The title compound (37 O mg, 70%) was prepared in a similar manner to λ/-(3-methoxybenzyl)- 6-methyl-4-(2-(((frans)-4-(pipendine-1-carbonyl)cyclohexyl)m ethyl)-2H-tetrazol-5-yl)picolinamide (Example 269) by reaction with dimethylamine LC/MS (5%-95% CH ₃ CN/H ₂ O, 4 5 mm , 95% CH ₃ CN, 1 5 mm ) 3 295 mm , m/z 492 (M+H)

Example 273

W-(3-Methoxybenzyl)-4-(2-(((frans)-4-(isopropylcarbamoyl) cyclohexyl)methyl)-2H-tetrazol-5-yl)-

6-methylpicolinamide

The title compound (16 6 mg, 30%) was prepared in a similar manner to λ/-(3-methoxybenzyl)-

6-methyl-4-(2-(((frans)-4-(piperidine-1-carbonyl)cyclohexyl) methyl)-2H-tetrazol-5-yl)picolmamide (Example 269) by reaction with propan-2-amιne LC/MS (5%-95% CH ₃ CN/H ₂ O, 4 5 mm , 95% CH ₃ CN, 1 5 mm ) 3 422 mm , m/z 506 (M+H)

Example 274

4-(2-(((frans)-4-((2-Amino-2-oxoethyl)carbamoyl)cyclohexy l)methyl)-2H-tetrazol-5-yl)-W-(3- methoxybenzyl)-6-methylpicolinamide

The title compound (29 9 mg, 53%) was prepared in a similar manner to λ/-(3-methoxybenzyl)- 6-methyl-4-(2-(((/rans)-4-(pιperιdιne-1 -carbonyl)cyclohexyl)methyl)-2/-/-tetrazol-5-yl)pιcolιnamÎ ¹de (Example 269) by reaction with 2-amιnoacetamιde LC/MS (5%-95% CH ₃ CN/H ₂ O, 4 5 mm , 95% CH ₃ CN, 1 5 mm ) 2 861 mm , m/z 521 (M+H)

Example 275

/V-(3-Methoxybenzyl)-6-methyl-4-(2-(((frans)-4-(methylcar bamoyl)cyclohexyl)methyl)-2H- tetrazol-5-yl)picolinamide

O-(7-Azabenzotrιazole-1-yl)-λ/,λ/,λPλ/'-tetramethyluron ιurn hexafluorophosphate (49 0 mg, 0 130 mmol), methylamine (0 054 ml_ of a 2M solution in tetrahydrofuran, 0 108 mmol), and diisopropylethylamine (0 038 mL, 0 216 mmol) was added to a solution of (/rans)-4-((5-(2-((3- methoxybenzyl)carbamoyl)-6-methylpyÏ€dιn-4-yl)-2/-/-tetrazo l-2-yl)methyl)cyclohexanecarboxylιc acid (prepared as described in Example 268) (50 0 mg, 0 108 mmol) in λ/,λ/-dιmethylformamιde (1 mL), and the mixture was stirred overnight at room temperature The reaction mixture was concentrated and the residue was purified by reverse phase preparative HPLC (5%-95% CH ₃ CN/H ₂ O, 8 mm ) to afford the title compound as a solid (47 4 mg, 92%) LC/MS (5%-95% CH ₃ CN/H ₂ O, 4 5 mm , 95% CH ₃ CN, 1 5 mm ) 2 996 mm , m/z 478 (M+H) ¹ H NMR (400 MHz, DMSOd ₆ ) δ ppm 0 95 - 1 18 (m, 2 H), 1 21 - 1 43 (m, 2 H), 1 53 - 1 80 (m, 4 H), 1 87 - 2 13 (m, 1 H), 2 51 (d, J=A 39 Hz, 3 H), 2 65 (s, 3 H), 3 71 (s, 3 H), 4 49 (d, J=6 59 Hz, 2 H), 4 65 (d, J=I 32 Hz, 2 H), 6 74 - 6 83 (m, 1 H), 6 90 (m, 2 H), 7 15 - 7 29 (m, 1 H), 7 48 - 7 64 (m, 1 H), 8 05 (s, 1 H), 8 40 (s, 1 H), 9 1 1 - 9 29 (m, 1 H)

Example 276 W-(3-Methoxybenzyl)-4-(2-(((frans)-4-(ethylcarbamoyl)cyclohe xyl)methyl)-2H-tetrazol-5-yl)-6- methylpicolinamide

The title compound (45 2 mg, 85%) was prepared in a similar manner to λ/-(3-methoxybenzyl)- 6-methyl-4-(2-(((frans)-4-(methylcarbamoyl)cyclohexyl)methyl )-2H-tetrazol-5-yl)pιcolιnamιde (Example 275) by reaction with ethylamine LC/MS (5%-95% CH ₃ CN/H ₂ O, 4 5 mm , 95% CH ₃ CN, 1 5 mm ) 3 163 mm , m/z 492 (M+H) ¹ H NMR (400 MHz, DMSOd ₆ ) δ ppm 0 95 (t, J=I 32 Hz, 3 H), 1 00 - 1 15 (m, 2 H), 1 22 - 1 41 (m, 2 H), 1 52 - 1 82 (m, 4 H), 1 87 - 2 13 (m, 1 H), 2 65 (s, 3 H), 2 89 - 3 09 (m, 2 H), 3 71 (s, 3 H), 4 49 (d, J=6 59 Hz, 2 H), 4 65 (d, J=6 59 Hz, 2 H), 6 74 - 6 85 (m, 1 H), 6 90 (m, 2 H), 7 13 - 7 29 (m, 1 H), 7 51 - 7 68 (m, 1 H), 8 05 (s, 1 H), 8 40 (s, 1 H), 9 08 - 9 26 (m, 1 H)

Example 277

4-(2-(((frans)-4-((2-Hydroxyethyl)carbamoyl)cyclohexyl)me thyl)-2H-tetrazol-5-yl)-N-(3- methoxybenzyl)-6-methylpicolinamide

The title compound (45 2 mg, 85%) was prepared in a similar manner to /V-(3-methoxybenzyl)- 6-methyl-4-(2-(((/rans)-4-(methylcarbamoyl)cyclohexyl)methyl )-2H-tetrazol-5-yl)pιcolιnamιde (Example 275) by reaction with 2-amιnoethanol LC/MS (5%-95% CH ₃ CN/H ₂ O, 4 5 mm , 95% CH ₃ CN, 1 5 mm ) 2 835 mm 508 (M+H) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0 96 - 1 19 (m, 2 H), 1 21 - 1 44 (m, 2 H), 1 54 - 1 80 (m, 4 H), 1 88 - 2 16 (m, 3 H), 2 65 (s, 3 H), 2 96 - 3 14 (m, 2 H), 3 71 (s, 3 H), 4 49 (d, J=5 86 Hz, 2 H), 4 65 (d, J=6 59 Hz, 2 H), 6 73 - 6 85 (m, 1 H), 6 90 (m, 2 H), 7 10 - 7 33 (m, 1 H), 7 50 - 7 68 (m, 1 H), 8 06 (s, 1 H), 8 41 (s, 1 H)

Example 278 /V-(3-Methoxybenzyl)-4-(2-(((frans)-4-carbamoylcyclohexyl)me thyl)-2H-tetrazol-5-yl)-6- methylpicolinamide

Formamide (120 mg) was added to a solution of (Zrans)-methyl 4-((5-(2-((3-methoxybenzyl)- carbamoyl)-6-methylpyrιdιn-4-yl)-2H-tetrazol-2-yl)methyl)c yclohexanecarboxylate (prepared as described in Example 267) (100 mg, 0 2 mmol) in anhydrous tetrahydrofuran (1 mL) and the mixture was heated to reflux A 25% sodium methoxide solution in methanol (120 mg) was added and the reaction was stirred at reflux for 2 hours The reaction mixture was allowed to cool to room temperature and then diluted with methanol (2 mL) The resulting precipitate was filtered, washed with a small amount of methanol and the solid was dried in a vacuum desiccator to afford the title compound as a white solid (77 5 mg) MS (ES+) m/z 464 (M+H)

Example 279

W-(3-Methoxybenzyl)-4-(2-((((rans)-4-cyanocyclohexyl)meth yl)-2H-tetrazol-5-yl)-6- methylpicolinamide

Polymer supported triphenylphosphine (Argonaut, 2 15 mmol/g, 500 mg) was added to λ/-(3- methoxybenzyl)-4-(2-((((rans)-4-carbamoylcyclohexyl)methyl)- 2/-/-tetrazol-5-yl)-6-methylpιcolιnamιde

(Example 278) (77 5 mg, 0 16 mmol) in a mixture of carbon tetrachloride (0 5 mL) and dichloroethane (4 5 mL) and the mixture was heated at 80 ⁰ C for 2 hours The reaction mixture was filtered and the resin was washed with dichloroethane The filtrate was concentrated and the residue was recrystallized from methanol to afford the title compound as a white solid (33 6 mg) MS (ES+) m/z 446 (M+H) ¹ H NMR (400 MHz, DMSO-c/ ₆ ) δ ppm 9 29 (t, J=6 6 Hz, 1 H), 8 43 (s, 1 H), 8 09 (s, 1 H), 7 25 (t, J=8 0 Hz, 1 H), 6 90 - 6 94 (m, 2 H), 6 83 (dd, J=& 1 , 2 3 Hz, 1 H), 4 69 (d, J=6 8 Hz, 2 H), 4 51 (d, J=S 5 Hz, 2 H), 3 74 (s, 3 H), 2 68 (s, 3 H), 2 59 - 2 67 (m, 1 H), 1 98 - 2 13 (m, 3 H), 1 65 (d, J=13 1 Hz, 2 H), 1 45 - 1 56 (m, 2 H), 1 07 - 1 19 (m, 2 H)

Example 280 W-(3-Methoxybenzyl)-4-(2-(((<rans)-4-(2-hydroxyacetyl)cyc lohexyl)methyl)-2H-tetrazol-5-yl)-6- methylpicolinamide

Oxalyl chloride (10 mL) was added to a solution of (trans)-4-((5-{2-((3- methoxybenzyl)carbamoyl)-6-methylpyrιdιn-4-yl)-2/-/-tetraz ol-2-yl)methyl)cyclohexanecarboxylιc acid (prepared as described in Example 268) (1 4 g, 3 0 mmol) in dichloromethane (10 mL) and the mixture was stirred at room temperate for 3 hours The reaction mixture was concentrated The residue was taken up in dioxane (15 mL) and treated with trιs(trιmethylsιloxy)ethylene (1 94 g, 6 63 mmol) The mixture was heated to 90 ⁰ C for 3 hours and then stirred at room temperate for 18 hours The mixture was treated with several drops of 4 N hydrochloric acid until gas stopped evolving The reaction mixture was purified by reverse phase preparative HPLC The crude product was taken up in methanol and passed through a carbonate cartridge The filtrate was concentrated to afford the title compound as a white solid (24 mg, 2%) LCMS (ES+) m/z 479 (M+H) ¹ H NMR (400 MHz, DMSOd ₆ ) δ ppm 1 06 - 1 41 (m, 4 H), 1 60 - 1 71 (m, J=10 98 Hz, 2 H), 1 85 - 1 96 (m, J=10 98 Hz, 2 H), 1 96 - 2 07 (m, 1 H), 2 20 - 2 31 (m, J=12 08, 12 08 Hz, 1 H), 2 67 (s, 3 H), 3 28 - 3 34 (m, 1 H), 3 57 (s, 2 H), 3 73 (s, 3 H), 4 51 (d, J=5 86 Hz, 2 H), 4 67 (d, J=Q 59 Hz, 2 H), 6 82 (d, J=Q 05 Hz, 1 H), 6 88 - 6 98 (m, 2 H), 7 24 (t, J=& 05 Hz, 1 H), 8 07 (s, 1 H), 8 43 (s, 1 H), 9 21 (t, J=Q 22 Hz, 1 H)

Example 281

(frans)-Methyl 4-((5-(2-((3-(Difluoromethoxy)benzyl)carbamoyl)-6-methylpyri din-4-yl)-2H- tetrazol-2-yl)methyl)cyclohexanecarboxylate

A mixture of (3-(dιfluoromethoxy)phenyl)methanamιne (380 mg, 2 2 mmol) and 4-(2-(((fraπs)- 4-(methoxycarbonyl)cyclohexyl)methyl)-2/-/-tetrazol-5-yl)-6- methylpιcolιnate (prepared as described in step 2 of the synthesis of (frans)-methyl 4-((5-(2-((3-(hydroxymethyl)benzyl)carbamoyl)-6- methylpyridin^-yl^H-tetrazol^-y^methyOcyclohexanecarboxylate , Example 260) (205 mg, 0 54 mmol) in λ/,λ/-dιmethylacetamιde (0 5 ml.) was allowed to stir at room temperature for 3 days The reaction mixture was purified by reverse phase preparative HPLC The product containing fractions were passed through a carbonate resin column and concentrated The residue was slurried with ethyl ether, decanted, and the solid was dried to afford the title compound (135 mg) MS (ES+) m/z 515 (M+H)

Example 282

(ffans)-4-((5-(2-((3-(Difluoromethoxy)benzyl)carbamoyl)-6 -methylpyridin-4-yl)-2H-tetrazol-2- yl)methyl)cyclohexanecarboxylic acid

Sodium hydroxide (1 pellet) was added to a solution of (frans)-methyl 4-((5-(2-((3-

(dιfluoromethoxy)benzyl)carbamoyl)-6-methylpyπdιn-4-yl )-2H-tetrazol-2- yl)methyl)cyclohexanecarboxylate (prepared as described in Example 281 ) (40 mg, 0 077 mmol) in a mixture of tetrahydrofuran/water (0 6 mL, 1/1 ) and the mixture was stirred at room temperature overnight The reaction mixture was acidified with trifluoroacetic acid and purified by reverse phase preparative HPLC The crude product was slurried in ethyl ether, decanted, and the solid was dried to afford the title compound as a white solid (29 mg) MS (ES+) m/z 502 (M+H)

Example 283

^-(S-IDifluoromethoxyJbenzyO^^Z^^fransJ^^hydroxymethylJcy clohexyOmethyO^H-tetrazol-S- yl)-6-methylpicolinamide

Lithium aluminum hydride (50 mg) was added to a solution of (frans)-methyl 4-((5-(2-((3- (dιfluoromethoxy)benzyl)carbamoyl)-6-methylpyrιdιn-4-yl)- 2/-/-tetrazol-2- yl)methyl)cyclohexanecarboxylate (prepared as described in Example 281 ) (53 mg, 0 1 mmol) in anhydrous tetrahydrofuran (1 mL) cooled in an ice bath The mixture was stirred at room temperature for 1 hour Water (1 mL) was slowly added followed by acetonitrile (1 mL) The reaction mixture was filtered and the filtrate was concentrated The residue was purified by reverse phase preparative HPLC Fractions containing the product were passed through a carbonate resin column The crude product was slurried and decanted from ethyl ether several times, and dried in a vacuum desiccator to afford the title compound as a white solid (28 mg) MS (ES+) m/z 487 (M+H) ¹ H NMR (400 MHz, DMSOd ₆ ) 6 ppm 9 39 (t, J=6 4 Hz, 1 H), 8 43 (s, 1 H), 8 10 (s, 1 H), 7 36 - 7 41 (m, 1 H), 7 21 - 7 24 (m, 1 H), 7 16 (s, 1 H), 7 03 - 7 09 (m, 2 H), 4 67 (d, J=7 0 Hz, 2 H), 4 55 (d, J=6 3 Hz, 2 H), 4 37 (t, J=5 2 Hz, 1 H), 3 19 (t, J=5 8 Hz, 2 H), 2 69 (s, 3 H), 1 91 - 2 03 (m, 1 H), 1 74 (d, J= 1 1 4 Hz, 2 H), 1 62 (d, J=10 9 Hz, 2 H), 1 25 - 1 36 (m, 1 H), 1 02 - 1 15 (m, 2 H), 0 81 - 0 94 (m, 2 H)

Example 284

(frans)-Methyl 4-((5-(2-((4-Fluoro-3-methylbenzyl)carbamoyl)-6-methylpyridi n-4-yl)-2H-tetrazol-2- yl)methyl)cyclohexanecarboxylate

The title compound was prepared in a similar manner to (frans)-methyl 4-((5-(2-((3- (dιfluoromethoxy)benzyl)carbamoyl)-6-methylpyrιdιn-4-yl)- 2H-tetrazol-2- yl)methyl)cyclohexanecarboxylate (Example 281 ) by reaction with 4-fluoro-3-methylbenzylamιne to afford 172 mg as a solid MS (ES+) m/z 481 (M+H) ¹ H NMR (400 MHz, DMSOd ₆ ) δ ppm 9 30 (t, J=6 4 Hz, 1 H), 8 43 (s, 1 H), 8 09 (d, J=O 9 Hz, 1 H), 7 26 (d, J=I 9 Hz, 1 H), 7 17 - 7 22 (m, 1 H), 7 05 - 7 1 1 (m, 1 H), 4 68 (d, J=Q 8 Hz, 2 H), 4 48 (d, J=6 5 Hz, 2 H), 3 58 (s, 3 H), 2 68 (s, 3 H), 2 22 2 31 (m, 1 H), 2 21 (d, J= 1 5 Hz, 3 H), 1 95 - 2 07 (m, 1 H), 1 91 (d, J=1 1 1 Hz, 2 H), 1 66 (d, J=13 0 Hz, 2 H), 1 26 - 1 39 (m, 2 H), 1 07 - 1 21 (m, 2 H)

Example 285

(frans)-4-((5-(2-((4-Fluoro-3-methylbenzyl)carbamoyl)-6-m ethylpyridin-4-yl)-2H-tetrazol-2- yl)methyl)cyclohexanecarboxylic acid

Sodium hydroxide (1 pellet) was added to a solution of (frans)-methyl 4-((5-(2-((4-fluoro-3- methylbenzyl)carbamoyl)-6-methylpyrιdιn-4-yl)-2H-tetrazol- 2-yl)methyl)cyclohexanecarboxylate (prepared as described in Example 284) (81 mg, 0 168 mmol) in a mixture of tetrahydrofuran/water (0 6 mL, 1/1 ) and the mixture was stirred at room temperature overnight The reaction mixture was acidified with trifluoroacetic acid and purified by reverse phase preparative HPLC The crude product was slurried in ethyl ether, decanted, and the solid was dried to afford the title compound as a white solid (71 mg) MS (ES+) m/z 467 (M+H) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 12 12 (br s , 1 H), 9 30 (t, J=6 4 Hz, 1 H), 8 43 (s, 1 H), 8 09 (s, 1 H), 7 26 (d, J=7 7 Hz, 1 H), 7 17 - 7 22 (m, 1 H), 7 08 (t, J=9 6 Hz, 1 H), 4 68 (d, J=I 0 Hz, 2 H), 4 48 (d, J=6 3 Hz, 2 H), 2 68 (s, 3 H), 2 21 (d, J= 1 4 Hz, 3 H), 2 08 - 2 17 (m, 1 H), 1 94 - 2 05 (m, 1 H), 1 90 (d, J=10 8 Hz, 2 H), 1 65 (d, J=12 5 Hz, 2 H), 1 22 - 1 36 (m, 2 H), 1 06 - 1 18 (m, 2 H)

Example 286

W-(4-Fluoro-3-methylbenzyl)-4-(2-(((frans)-4-carbamoylcyc lohexyl)methyl)-2H-tetrazol-5-yl)-6- methylpicolinamide

Formamide (60 mg) was added to a solution of (frans)-methyl 4-((5-(2-((4-fluoro-3- methylbenzyl)carbamoyl)-6-methylpyrιdιn-4-yl)-2H-tetrazol- 2-yl)methyl)cyclohexanecarboxylate (prepared as described in Example 284) (50 mg, 0 1 mmol) in anhydrous tetrahydrofuran (0 6 mL) and the mixture was heated to reflux A 25% sodium methoxide solution in methanol (60 mg) was added and the reaction was stirred at reflux for 2 hours The reaction mixture was allowed to cool to room temperature, diluted with excess methanol, and then concentrated Methanol (2 mL) was added to the residue The resulting precipitate was filtered, washed with a small amount of methanol and the solid was dried in a vacuum desiccator to afford the title compound as a white solid (25 4 mg) MS (ES+) m/z 466 (M+H) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9 30 (t, J=6 4 Hz, 1 H), 8 43 (s, 1 H), 8 09 (s, 1 H), 7 26 (d, J=7 7 Hz, 1 H), 7 16 - 7 22 (m, 2 H), 7 08 (t, J=9 1 Hz, 1 H), 6 67 (br s , 1 H), 4 68 (d, J=6 8 Hz, 2 H), 4 48 (d, J=6 3 Hz, 2 H), 2 68 (s, 3 H), 2 22 (d, J= 1 0 Hz, 3 H), 2 02 (t, J=12 0 Hz, 2 H), 1 76 (d, J=10 9 Hz, 2 H), 1 65 (d, J=1 1 8 Hz, 2 H), 1 25 - 1 37 (m, 2 H), 1 03 - 1 15 (m, 2 H)

Example 287

W-(4-Fluoro-3-methylbenzyl)-4-(2-(((fraπs)-4-cyanocycloh exyl)methyl)-2W-tetrazol-5-yl)-6- methylpicolinamide

Polymer supported triphenylphosphine (Argonaut, 2 15 mmol/g) was added to λ/-(4-fluoro-3- methylbenzyl)-4-(2-(((^rans)-4-carbamoylcyclohexyl)methyl)-2 /-/-tetrazol-5-yl)-6-methylpicolinamide (Example 286) (20 mg, 0 043 mmol) in a mixture of carbon tetrachloride (0 16 mL) and dichloroethane (1 5 mL) and the mixture was heated at 80 ⁰ C for 2 hours The reaction mixture was filtered and the resin was washed with dichloroethane The filtrate was concentrated to afford the title compound as a white solid (9 7 mg) MS (ES+) m/z 448 (M+H) ¹ H NMR (400 MHz, DMSOd ₆ ) <$ PPm 9 30 (t, J=6 3 Hz, 1 H), 8 43 (s, 1 H), 8 09 (d, J=O 9 Hz, 1 H), 7 26 (d, J=7 3 Hz, 1 H), 7 17 - 7 22 (m, 1 H), 7 08 (t, J=9 1 Hz, 1 H), 4 69 (d, J=7 0 Hz, 2 H), 4 48 (d, J=6 3 Hz, 2 H), 2 68 (s, 3 H), 2 59 - 2 67 (m, 1 H), 2 22 (d, J= 1 4 Hz, 3 H), 1 98 - 2 11 (m, 3 H), 1 65 (d, J=13 3 Hz, 2 H), 1 44 - 1 58 (m, 2 H), 1 05 - 1 19 (m, 2 H)

Example 288

(frans)-Methyl 4-((5-(2-((3-Ethylbenzyl)carbamoyl)-6-methylpyridin-4-yl)-2H -tetrazol-2- yl)methyl)cyclohexanecarboxylate

The title compound was prepared in a similar manner to (frans)-methyl 4-((5-(2-((3- (dιfluoromethoxy)benzyl)carbamoyl)-6-methylpyrιdιn-4-yl)- 2H-tetrazol-2- yl)methyl)cyclohexanecarboxylate (Example 281 ) by reaction with 3-ethylbenzylamιne to afford 155 mg MS (ES+) m/z 477 (M+H)

Example 289

(<rans)-4-((5-(2-((3-Ethylbenzyl)carbamoyl)-6-methylpy ridin-4-yl)-2H-tetrazol-2- yl)methyl)cyclohexanecarboxylic acid

The title compound was prepared in a similar manner to (/rans)-4-((5-(2-((3-(dιfluoromethoxy)- benzyl)carbamoyl)-6-methylpyrιdιn-4-yl)-2/-/-tetrazol-2-yl )methyl)cyclohexanecarboxylιc acid (Example 282) by reaction wιth(frans)-methyl 4-((5-(2-((3-ethylbenzyl)carbamoyl)-6-methylpyrιdιn-4-yl)- 2H- tetrazol^-ylJmethyOcyclohexanecarboxylate (Example 288) to afford 45 mg as a white solid MS (ES+) m/z 463 (M+H) ¹ H NMR (400 MHz, DMSOd ₆ ) δ ppm 12 1 1 (br s , 1 H), 9 27 (t, J=6 5 Hz, 1 H) ₁ 8 44 (s, 1 H), 8 09 (s, 1 H), 7 08 - 7 26 (m, 4 H), 4 68 (d, J=Q 8 Hz, 2 H), 4 52 (d, J=6 3 Hz, 2 H), 2 68 (s, 3 H), 2 59 (q, J=7 6 Hz, 2 H), 2 09 - 2 17 (m, 1 H), 1 95 - 2 05 (m, 1 H), 1 90 (d, J= 1 1 1 Hz, 2 H), 1 65 (d, J=10 6 Hz, 2 H), 1 23 - 1 36 (m, 2 H), 1 06 - 1 19 (m, 5 H)

Example 290

/V-(3-Ethylbenzyl)-4-(2-(((fraπs)-4-carbamoylcyclohexyl) methyl)-2H-tetrazol-5-yl)-6- methylpicolinamide

Formamide (120 mg) was added to a solution of (frans)-methyl 4-((5-(2-((3- ethylbenzyl)carbamoyl)-6-methylpyrιdιn-4-yl)-2H-tetrazol-2 -yl)methyl)cyclohexanecarboxylate

(prepared as described in Example 288) (80 mg, 0 16 mmol) in anhydrous tetrahydrofÏ…ran (1 mL) and the mixture was heated to reflux A 25% sodium methoxide solution in methanol (120 mg) was added and the reaction was stirred at reflux for 2 hours The reaction mixture was allowed to cool to room temperature and was diluted with methanol (2 mL) The mixture was stirred for 15 minutes and then the resulting precipitate was filtered, washed with a small amount of methanol and dried in a vacuum desiccator to afford the title compound as a white solid (41 mg) MS (ES+) m/z 462 (M+H) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9 17 (t, J=Q 2 Hz, 1 H), 8 41 (s, 1 H), 8 05 (s, 1 H), 7 03 - 7 25 (m, 5 H), 6 58 (br s , 1 H), 4 65 (d, J=I 0 Hz, 2 H), 4 50 (d, J=Q 2 Hz, 2 H), 2 65 (s, 3 H), 2 56 (q, J=7 4 Hz, 2 H), 1 90 - 2 05 (m, 2 H), 1 74 (d, J= 1 1 3 Hz, 2 H), 1 63 (d, J= 11 0 Hz, 2 H), 1 22 - 1 36 (m, 2 H), 1 01 - 1 18 (m, 5 H)

Example 291

(frans)-Methyl 4-((5-(2-((3-Cyanobenzyl)carbamoyl)-6-methylpyridin-4-yl)-2W -tetrazol-2- yl)methyl)cyclohexanecarboxylate

The title compound was prepared in a similar manner to (frans)-methyl 4-((5-(2-((3- (dιfluoromethoxy)benzyl)carbamoyl)-6-methylpyrιdιn-4-yl)- 2H-tetrazol-2- yl)methyl)cyclohexanecarboxylate (Example 281 ) by reaction with 3-(amιnomethyl)benzonιtrιle to afford 157 mg as a white solid MS (ES+) m/z 474 (M+H) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9 47 (t, J=6 3 Hz, 1 H), 8 43 (s, 1 H), 8 10 (s, 1 H), 7 79 (s, 1 H), 7 74 (d, J=7 7 Hz, 1 H), 7 70 (d, J=I 9 Hz, 1 H), 7 56 (t, J=I 8 Hz, 1 H), 4 68 (d, J=6 8 Hz, 2 H), 4 58 (d, J=Q 1 Hz, 2 H), 3 58 (s, 3 H), 2 69 (s, 3 H), 2 22 - 2 31 (m, 1 H), 1 96 - 2 06 (m, 1 H), 1 91 (d, J=1 1 1 Hz, 2 H), 1 65 (d, J= ^* \0 8 Hz, 2 H), 1 33 (q, J=12 6 Hz, 2 H), 1 07 - 1 21 (m, 2 H)

Example 292

(frans)-4-((5-(2-((3-Cyanobenzyl)carbamoyl)-6-methylpyrid in-4-yl)-2W-tetrazol-2- yl)methyl)cyclohexanecarboxylic acid

Sodium hydroxide (1 pellet) was added to a solution of (frans)-methyl 4-((5-(2-((3- cyanobenzyl)carbamoyl)-6-methylpyrιdιn-4-yl)-2H-tetrazol-2 -yl)methyl)cyclohexanecarboxylate

(prepared as described in Example 291 ) (81 mg, 0 17 mmol) in a mixture of tetrahydrofuran/water (0 6 mL, 1/1 ) and the mixture was stirred at room temperature overnight The reaction mixture was acidified with trifluoroacetic acid and purified by reverse phase preparative HPLC The crude product was slurried in ethyl ether, decanted, and the solid was dried to afford the title compound as a white solid (45 mg) MS (ES+) m/z 460 (M+H) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9 46 (t, J=6 4 Hz, 1 H), 8 43 (S, 1 H), 8 10 (d, J=O 9 Hz, 1 H), 7 79 (s, 1 H), 7 67 - 7 76 (m, 2 H), 7 56 (t, J=I 7 Hz, 1 H), 4 66 (d, J=7 0 Hz, 2 H), 4 58 (d, J=6 5 Hz, 2 H), 2 69 (s, 3 H), 1 92 - 2 02 (m, 2 H), 1 87 (d, J=10 9 Hz, 2 H), 1 61 (d, J=10 8 Hz, 2 H), 1 18 - 1 31 (m, 2 H) ₁ 1 01 - 1 15 (m, 2 H)

Example 293 (frans)-Methyl 4-((5-(2-((3-Ethoxybenzyl)carbamoyl)-6-methylpyridin-4-yl)-2 H-tetrazol-2- yl)methyl)cyclohexanecarboxylate

The title compound was prepared in a similar manner to (/rans)-methyl 4-((5-(2-((3- (dιfluoromethoxy)benzyl)carbamoyl)-6-methylpyrιdιn-4-yl)- 2/-/-tetrazol-2- yl)methyl)cyclohexanecarboxylate (Example 281 ) by reaction with (3-ethoxyphenyl)methanamιne (prepared as described in step 2 of the synthesis of λ/-(3-ethoxybenzyl)-6-methyl-4-(2-(((/rans)-4- (methylsulfonamιdo)cyclohexyl)methyl)-2/-/-tetrazol-5-yl)pÎ ¹colιnamιde, Example 180) to afford 182 mg as a white solid MS (ES+) m/z 493 (M+H) ¹ H NMR (400 MHz, DMS0-d ₆ ) δ ppm 9 28 (t, J=6 4 Hz, 1 H), 8 43 (s, 1 H), 8 09 (d, J=O 9 Hz, 1 H), 7 23 (t, J=8 0 Hz, 1 H), 6 89 - 6 92 (m, 2 H), 6 80 (dd, J=Q 0, 1 9 Hz, 1 H), 4 68 (d, J=I 0 Hz, 2 H), 4 50 (d, J=6 5 Hz, 2 H), 4 00 (q, J=Q 9 Hz, 2 H), 3 58 (s, 3 H), 2 68 (s, 3 H), 2 21 - 2 31 (m, 1 H), 1 97 - 2 07 (m, 1 H), 1 91 (d, J=10 6 Hz, 2 H), 1 66 (d, J=10 6 Hz, 2 H), 1 27 - 1 39 (m, 5 H), 1 09 - 1 21 (m, 2 H)

Example 294

((rans)-4-((5-(2-((3-Ethoxybenzyl)carbamoyl)-6-methylpyri din-4-yl)-2H-tetrazol-2- yl)methyl)cyclohexanecarboxylic acid

Sodium hydroxide (1 pellet) was added to a solution of (trans )-methyl 4-((5-(2-((3- ethoxybenzyl)carbamoyl)-6-methylpyπdιn-4-yl)-2H-tetrazol-2 -yl)methyl)cyclohexanecarboxylate (prepared as described in Example 293) (78 mg, 0 15 mmol) in a mixture of tetrahydrofuran/water (0 6 mL, 1/1 ) and the mixture was stirred at room temperature overnight The reaction mixture was acidified with tπfluoroacetic acid and purified by reverse phase preparative HPLC The crude product was slurried in ethyl ether, decanted, and the solid was dried to afford the title compound as a white solid (7 mg) MS (ES+) m/z 479 (M+H)

Example 295

N-(3-Ethoxybenzyl)-4-(2-(((frans)-4-carbamoylcyclohexyl)m ethyl)-2H-tetra2ol-5-yl)-6- methylpicolinamide

Formamide (120 mg) was added to a solution of (frans)-methyl 4-((5-(2-((3- ethoxybenzyl)carbamoyl)-6-methylpyridin-4-yl)-2H-tetrazol-2- yl)methyl)cyclohexanecarboxylate (prepared as described in Example 293) (85 mg, 0 17 mmol) in anhydrous tetrahydrofuran (1 mL) and the mixture was heated to reflux A 25% sodium methoxide solution in methanol (120 mg) was added and the reaction was stirred at reflux for 2 hours The reaction mixture was allowed to cool to room temperature, diluted with excess methanol, and was concentrated Methanol (2 mL) was added to the residue The resulting precipitate was filtered, washed with a small amount of methanol and the solid was dried in a vacuum desiccator to afford the title compound as a white solid (33 mg) MS (ES+) m/z 478 (M+H)

Example 296

/V-P-EthoxybenzylM-^-^fransM-cyanocyclohexyOmethyO-aH-tet razol-S-yO-e- methylpicolinamide

Polymer supported tÏ€phenylphosphine (Argonaut, 2 15 mmol/g, 200 mg) was added to λ/-(3- ethoxybenzyl)-4-(2-(((/rans)-4-carbamoylcyclohexyl)methyl)-2 /-/-tetrazol-5-yl)-6-methylpιcolιnamιde (Example 295) (30 mg, 0 062 mmol) in a mixture of carbon tetrachloride (0 25 mL) and dichloroethane (2 25 mL) and the mixture was heated at 80 ⁰ C for 2 hours The reaction mixture was filtered and the resin was washed with dichloroethane The filtrate was concentrated and the residue was purified by reverse phase preparative HPLC Fractions containing product were passed through a carbonate resin column and were concentrated The product was slurried and decanted several times from ether and the solid was dried in a vacuum desiccator to afford the title compound as a white solid (18 3 mg) MS (ES+) m/z 460 (M+H) ¹ H NMR (400 MHz, DMSOd ₆ ) δ ppm 9 18 (t, J=6 2 Hz, 1 H), 8 40 (s, 1 H), 8 05 (s, 1 H), 7 20 (t, J=8 1 Hz, 1 H), 6 85 - 6 90 (m, 2 H), 6 78 (d, J=8 8 Hz, 1 H), 4 65 (d, J=I 3 Hz, 2 H), 4 48 (d, J=5 9 Hz, 2 H), 3 97 (q, J=7 3 Hz, 2 H), 2 65 (s, 3 H), 2 56 - 2 64 (m, 1 H), 1 95 - 2 1 1 (m, 3 H), 1 63 (d, J=1 1 O Hz, 2 H), 1 49 (q, J= 12 7 Hz, 2 H), 1 28 (t, J=7 0 Hz, 3 H), 1 05 - 1 17 (m, 2 H)

Example 297

(frans)-Methyl 4-((5-(2-((4-Fluoro-3-methoxybenzyl)carbamoyl)-6-methylpyrid ιn-4-yl)-2H-tetrazol-

2-yl)methyl)cyclohexanecarboxylate

The title compound was prepared in a similar manner to (frans)-methyl 4-((5-(2-((3- (dιfluoromethoxy)benzyl)carbamoyl)-6-methylpyrιdιn-4-yl)- 2H-tetrazol-2- yl)methyl)cyclohexanecarboxylate (Example 281 ) by reaction with 4-fluoro-3-methoxybenzylamιne (prepared as described in step 3 of the synthesis of A/-(4-fluoro-3-methoxybenzyl)-6-(2-((frans-4- amιnocyclohexyl)methyl)-2/-/-tetrazol-5-yl)pyrιmιdιne-4- carboxamιde, Example 1 ) to afford 121 mg as a white solid MS (ES+) m/z 497 (M+H) ¹ H NMR (400 MHz, DMSOd ₆ ) δ ppm 9 31 (t, J=6 3 Hz, 1 H), 8 43 (s, 1 H), 8 09 (d, J=O 9 Hz, 1 H), 7 19 (dd, J=8 5, 1 9 Hz, 1 H), 7 15 (dd, J=1 1 6, 8 4 Hz, 1 H), 6 87 - 6 93 (m, 1 H), 4 68 (d, J=7 0 Hz, 2 H), 4 50 (d, J=6 5 Hz, 2 H), 3 82 (s, 3 H), 3 58 (s, 3 H), 2 68 (s, 3 H), 2 21 - 2 31 (m, 1 H), 1 98 (br s , 1 H), 1 92 (d, J=13 3 Hz, 2 H), 1 65 (d, J=10 6 Hz, 2 H), 1 26 - 1 39 (m, 2 H), 1 09 - 1 20 (m, 2 H)

Example 298

(frans)-4-((5-(2-((4-Fluoro-3-methoxybenzyl)carbamoyl)-6- methylpyridin-4-yl)-2H-tetrazol-2- yl)methyl)cyclohexanecarboxylic acid

Sodium hydroxide (1 pellet) was added to a solution of (frans)-methyl 4-((5-(2-((4-fluoro-3- methoxybenzyl)carbamoyl)-6-methylpyrιdιn-4-yl)-2H-tetrazol -2-yl)methyl)cyclohexanecarboxylate (prepared as described in Example 297) (63 mg, 0 13 mmol) in a mixture of tetrahydrofuran/water (0 6 mL, 1/1 ) and the mixture was stirred at room temperature overnight The reaction mixture was acidified with trifluoroacetic acid and purified by reverse phase preparative HPLC The crude product was slurried in ethyl ether, decanted, and the solid was dried to afford the title compound as a white solid (30 mg) MS (ES+) m/z 483 (M+H) ¹ H NMR (400 MHz, DMSO-c/ ₆ ) δ ppm 9 30 (t, J=6 3 Hz, 1 H), 8 43 (s, 1 H), 8 09 (s, 1 H), 7 19 (dd, J=9 0, 2 1 Hz, 1 H), 7 15 (dd, J=11 6, 8 4 Hz, 1 H), 6 88 - 6 93 (m, 1 H), 4 67 (d, J=6 8 Hz, 2 H), 4 50 (d, J=Q 3 Hz, 2 H), 3 82 (s, 3 H), 2 68 (s, 3 H), 1 93 - 2 12 (m, 2 H), 1 89 (d, J=10 9 Hz, 2 H), 1 63 (d, J=10 9 Hz, 2 H), 1 28 (q, J=12 5 Hz, 2 H), 1 05 - 1 18 (m, 2 H)

Example 299

W-(4-Fluoro-3-methoxybenzyl)-4-(2-(((frans)-4-carbamoylcy clohexyl)methyl)-2H-tetrazol-5-yl)-6- methylpicolinamide

Formamide (720 mg) was added to a solution of (frans)-methyl 4-((5-(2-((4-fIuoro-3- methoxybenzyl)carbamoyl)-6-methylpyrιdιn-4-yl)-2H-tetrazol -2-yl)methyl)cyclohexanecarboxylate (prepared as described in Example 297) (476 mg (0 95 mmol) in anhydrous tetrahydrofuran (6 mL) and the mixture was heated to reflux A 25% sodium methoxide solution in methanol (720 mg) was added and the reaction was stirred at reflux for 2 hours The reaction mixture was allowed to cool to room temperature, diluted with methanol (6 mL), and then concentrated Methanol (3 mL) was added to the residue The resulting precipitate was filtered, washed with methanol and the solid was dried in a vacuum desiccator to afford the title compound as a white solid (262 mg) MS (ES+) m/z 482 (M+H) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9 31 (t, J=Q 4 Hz, 1 H), 8 43 (s, 1 H), 8 09 (s, 1 H), 7 12 - 7 23 (m, 3 H), 6 91 (dd, J=Q 1 , 3 9 Hz, 1 H), 6 67 (br s , 1 H), 4 68 (d, J=I 0 Hz, 2 H), 4 51 (d, J=Q 1 Hz, 2 H), 3 83 (s, 3 H), 2 68 (s, 3 H), 1 94 - 2 07 (m, 2 H), 1 76 (d, J=12 1 Hz, 2 H), 1 65 (d, J=M 1 Hz, 2 H), 1 24 - 1 38 (m, 2 H), 1 03 - 1 16 (m, 2 H)

Example 300 /V-(4-Fluoro-3-methoxybenzyl)-4-(2-(((frans)-4-cyanocyclohex yl)methyl)-2H-tetrazol-5-yl)-6- methylpicolinamide

Polymer supported triphenylphosphine (Argonaut, 2 15 mmol/g, 1 g) was added to λ/-(4-fluoro- 3-methoxybenzyl)-4-(2-(((frans)-4-carbamoylcyclohexyl)methyl )-2/-/-tetrazol-5-yl)-6-methylpιcolιnamιde (Example 299) (223 mg, 0 46 mmol) in a mixture of carbon tetrachloride (1 5 mL) and dichloroethane (13 5 mL) and the mixture was heated at 80 ⁰ C for 2 hours The reaction mixture was filtered and the resin was washed with dichloroethane The filtrate was concentrated and the residue was purified by reverse phase preparative HPLC The product was slurried and decanted several times from ether and the solid was dried in a vacuum desiccator to afford the title compound as a white solid (139 mg) MS (ES+) m/z 464 (M+H) ¹ H NMR (400 MHz, DMSOd ₆ ) δ ppm 9 31 (t, J=Q 4 Hz, 1 H), 8 43 (s, 1 H), 8 09 (d, J=O 9 Hz, 1 H), 7 19 (dd, J=Q 5, 1 7 Hz, 1 H), 7 15 (dd, J= ¹ 1 1 6, 8 2 Hz, 1 H), 6 87 - 6 93 (m, 1 H), 4 69 (d, J=Q 8 Hz, 2 H), 4 50 (d, J=Q 3 Hz, 2 H), 3 83 (s, 3 H), 2 68 (s, 3 H), 2 58 - 2 67 (m, 1 H), 1 98 - 2 12 (m, 3 H), 1 65 (dd, J=13 2, 2 6 Hz, 2 H), 1 44 - 1 57 (m, 2 H), 1 07 - 1 19 (m, 2 H)

Example 301

(frans)-Methyl 4-((5-(2-((3-Chloro-4-fluorobenzyl)carbamoyl)-6-methylpyridi n-4-yl)-2W-tetrazol-2- yl)methyl)cyclohexanecarboxylate

The title compound was prepared in a similar manner to (frans)-methyl 4-((5-(2-((3-

(dιfluoromethoxy)benzyl)carbamoyl)-6-methylpyrιdιn-4-yl)- 2/-y-tetrazol-2- yl)methyl)cyclohexanecarboxylate (Example 281 ) by reaction with 3-chloro-4-fluorobenzylamιne to afford 123 mg as a white solid MS (ES+) m/z 501 (M+H) ¹ H NMR (400 MHz, DMSOd ₆ ) δ ppm 9 43 (t, J=6 4 Hz, 1 H), 8 42 (s, 1 H), 8 10 (d, J=O 7 Hz, 1 H), 7 56 (d, J=7 9 Hz, 1 H), 7 35 - 7 40 (m, 2 H), 4 68 (d, J=I 0 Hz, 2 H), 4 51 (d, J=Q 3 Hz, 2 H), 3 58 (s, 3 H), 2 69 (s, 3 H), 2 21 - 2 31 (m, 1 H), 1 96 - 2 07 (m, 1 H), 1 91 (d, J= 1 1 1 Hz, 2 H), 1 65 (d, J=10 8 Hz, 2 H) ₁ 1 27 - 1 38 (m, 2 H), 1 09 - 1 21 (m, 2 H)

Example 302

(frans)-4-((5-(2-((3-Chloro-4-fluorobenzyl)carbamoyl)-6-m ethylpyridin-4-yl)-2W-tetrazol-2- yl)methyl)cyclohexanecarboxylic acid

Sodium hydroxide (1 pellet) was added to a solution of (frans)-methyl 4-((5-(2-((3-chloro-4- fluorobenzyl)carbamoyl)-6-methylpyrιdιn-4-yl)-2/-/-tetrazo l-2-yl)methyl)cyclohexanecarboxylate (prepared as described in Example 301 ) (65 mg, 0 13 mmol) in a mixture of tetrahydrofuran/water (0 6 mL, 1/1 ) and the mixture was stirred at room temperature overnight The reaction mixture was acidified with trifluoroacetic acid and purified by reverse phase preparative HPLC The crude product was slurried in ethyl ether, decanted, and the solid was dried to afford the title compound as a white solid (41 mg) MS (ES+) m/z 487 (M+H) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9 49 (t, J=6 2 Hz, 1 H), 8 42 (s, 1 H), 8 10 (s, 1 H), 7 78 (d, J=7 0 Hz, 1 H), 7 71 - 7 75 (m, 1 H), 7 45 - 7 52 (m, 1 H), 4 68 (d, J=6 8 Hz, 2 H), 4 58 (d, J=6 3 Hz, 2 H), 3 58 (s, 3 H), 2 69 (s, 3 H), 2 20 - 2 30 (m, 1 H), 1 96 - 2 04 (m, 1 H), 1 91 (d, J=13 0 Hz, 2 H), 1 66 (d, J=12 8 Hz, 2 H), 1 26 - 1 39 (m, 2 H), 1 08 - 1 20 (m, 2 H)

Example 303

W-(3-Chloro-4-fluorobenzyl)-4-(2-(((frans)-4-carbamoylcyc lohexyl)methyl)-2W-tetrazol-5-yl)-6- methylpicolinamide

Formamide (720 mg) was added to a solution of (frans)-methyl 4-((5-(2-((3-chloro-4- fluorobenzyl)carbamoyl)-6-methylpyrιdιn-4-yl)-2H-tetrazol- 2-yl)methyl)cyclohexanecarboxylate (prepared as described in Example 301 ) (268 mg, 0 53 mmol) in anhydrous tetrahydrofuran (6 mL) and the mixture was heated to reflux A 25% sodium methoxide solution in methanol (720 mg) was added and the reaction was stirred at reflux for 2 hours The reaction mixture was allowed to cool to room temperature, diluted with methanol (6 mL), and then concentrated Methanol (3 mL) was added to the residue The resulting precipitate was filtered, washed with a small amount of methanol and the solid was dried in a vacuum desiccator to afford the title compound as a white solid (135 mg) MS (ES+) m/z 486 (M+H) ¹ H NMR (400 MHz, DMSOd ₆ ) δ ppm 9 43 (t, J=6 4 Hz, 1 H), 8 42 (s, 1 H), 8 10 (s, 1 H), 7 56 (d, J=7 0 Hz, 1 H), 7 37 (d, J=7 9 Hz, 2 H), 7 17 (br s , 1 H), 6 67 (br s , 1 H), 4 68 (d, J=Q 8 Hz, 2 H), 4 51 (d, J=6 5 Hz, 2 H), 2 69 (s, 3 H), 1 92 - 2 07 (m, 2 H), 1 76 (d, J= 1 1 1 Hz, 2 H), 1 64 (d, J=10 8 Hz, 2 H), 1 25 - 1 38 (m, 2 H), 1 03 - 1 15 (m, 2 H)

Example 304

W-(3-Chloro-4-fluorobenzyl)-4-(2-((((rans)-4-cyanocyclohe xyl)methyl)-2H-tetrazol-5-yl)-6- methylpicolinamide

Polymer supported triphenylphosphine (Argonaut, 2 15 mmol/g, 1 g) was added to λ/-(3- chloro-4-fluorobenzyl)-4-(2-(((frans)-4-carbamoylcyclohexyl) methyl)-2/-/-tetrazol-5-yl)-6- methylpicolinamide (Example 303) (100 mg, 0 2 mmol) in a mixture of carbon tetrachloride (1 5 mL) and dichloroethane (13 5 mL) and the mixture was heated at 80 ⁰ C for 2 hours The reaction mixture was filtered and the resin was washed with methanol The filtrate was concentrated and the residue was purified by reverse phase preparative HPLC Fractions containing product were passed through a carbonate resin column and then concentrated The product was slurried and decanted several times from ether and the solid was dried in a vacuum desiccator to afford the title compound as a white solid (33 9 mg) MS (ES+) m/z 468 (M+H) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9 43 (t, J=6 4 Hz, 1 H), 8 42 (s, 1 H), 8 09 (d, J= 1 0 Hz, 1 H), 7 53 - 7 59 (m, 1 H), 7 35 - 7 41 (m, 2 H), 4 69 (d, J=6 8 Hz, 2 H), 4 51 (d, J=6 3 Hz, 2 H), 2 69 (s, 3 H), 2 58 - 2 67 (m, 1 H), 1 98 - 2 13 (m, 3 H), 1 60 - 1 69 (m, 2 H), 1 45 - 1 57 (m, 2 H), 1 07 - 1 19 (m, 2 H)

Example 305

(fraπs)-Methyl 4-((5-(2-((4-Fluoro-3-(trifluoromethyl)benzyl)carbamoyl)-6-m ethylpyridin-4-yl)-2H- tetrazol-2-yl)methyl)cyclohexanecarboxylate

The title compound was prepared in a similar manner to (frans)-methyl 4-((5-(2-((3-

(dιfluoromethoxy)benzyl)carbamoyl)-6-methylpyrιdιn-4-yl)- 2/-/-tetrazol-2- yl)methyl)cyclohexanecarboxylate (Example 281 ) by reaction with (4-fluoro-3- (trιfluoromethyl)phenyl)methanamιne to afford 143 mg as a white solid MS (ES+) m/z 535 (M+H) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9 49 (t, J=6 2 Hz, 1 H), 8 42 (s, 1 H), 8 10 (s, 1 H), 7 76 - 7 79 (m, 1 H), 7 71 - 7 76 (m, 1 H), 7 48 (dd, J=10 5, 8 5 Hz, 1 H), 4 68 (d, J=6 8 Hz, 2 H), 4 58 (d, J=6 3 Hz, 2 H), 3 58 (s, 3 H), 2 69 (s, 3 H), 2 20 - 2 31 (m, 1 H), 1 91 (d, J= 1 1 9 Hz, 2 H), 1 65 (d, J=U 7 Hz, 2 H), 1 26 - 1 39 (m, 2 H), 1 08 - 1 21 (m, 2 H)

Example 306

((rans)-4-((5-(2-((4-Fluoro-3-(trifluoromethyl)benzyl)car bamoyl)-6-methylpyridin-4-yl)-2H- tetrazol-2-yl)methyl)cyclohexanecarboxylic acid

Sodium hydroxide (1 pellet) was added to a solution of (rans)-methyl 4-((5-(2-((4-fluoro-3- (trιfluoromethyl)benzyl)carbamoyl)-6-methylpyrιdιn-4-yl)- 2H-tetrazol-2- yl)methyl)cyclohexanecarboxylate (prepared as described in Example 305) (68 mg, 0 13 mmol) in a mixture of tetrahydrofuran/water (0 6 mL, 1/1 ) and the mixture was stirred at room temperature overnight The reaction mixture was acidified with tÏ€fluoroacetic acid and purified by reverse phase preparative HPLC The crude product was slurried in ethyl ether, decanted, and the solid was dried to afford the title compound as a white solid (46 mg) MS (ES+) m/z 521 (M+H) ¹ H NMR (400 MHz, DMSO-c/ ₆ ) ÏŒ ppm 9 49 (t, J=6 3 Hz, 1 H), 8 42 (s, 1 H), 8 10 (s, 1 H), 7 76 - 7 80 (m, 1 H), 7 71 - 7 75 (m, 1 H), 7 48 (dd, J=10 7, 8 8 Hz, 1 H), 4 67 (d, J=6 8 Hz, 2 H), 4 58 (d, J=6 3 Hz, 2 H), 2 69 (s, 3 H), 2 06 - 2 15 (m, 1 H), 1 94 - 2 03 (m, 1 H), 1 86 - 1 93 (m, 2 H), 1 64 (d, J=12 5 Hz, 2 H), 1 22 - 1 35 (m, 2 H), 1 05 - 1 18 (m, 2 H)

Example 307

/V-((2,3-Dihydrobenzofuran-5-yl)methyl)-4-(2-((((rans)-4- (hydroxymethyl)cyclohexyl)methyl)-2H- tetrazol-5-yl)-6-methylpicolinamide

Step 1 Preparation of methyl 4-(2-(((frans)-4-(hvdroxymethyl)cvclohexyl)methyl)-2H-tetraz ol-5-yl)-6- methylpicolinate

Methyl 6-methyl-4-(2H-tetrazol-5-yl)pιcolιnate (prepared as described in step 4 of the synthesis of λ/-(3-methoxybenzyl)-4-(2-(((frans)-4-amιnocyclohexyl)meth yl)-2/-/-tetrazol-5-yl)-6- methylpicolinamide, Example 153) (2 19 g, 10 0 mmol), polymer supported triphenylphosphine (9 3 g, 20 0 mmol), and trans-cyclohexane-1 ,4-dιmethanol (2 88 g, 20 0 mmol) were suspended in tetrahydrofuran (200 mL) The mixture was cooled to 0 ⁰ C Di-tert-butyl azodicarboxylate (4 6 g, 20 0 mmol) was added The mixture was allowed to warm to room temperature and stir for 18 hours The reaction mixture was filtered and the resin washed with tetrahydrofuran (100 mL) The filtrate was concentrated The residue was dissolved in ethyl acetate (200 mL) and washed with water (50 mL) The organic layer was dried over sodium sulfate and concentrated The crude product was purified by silica column chromatography (C^C^/methanol, 100/1 , 100/2, 100/4) to afford the title compound as an oil (2 3 g, 67%) MS (ES+) m/z 346 (M+H) ¹ H NMR (400 MHz, DMSOd ₆ ) δ ppm 8 40 (d, J=O 8 Hz, 1 H), 8 12 (d, J= 1 1 Hz, 1 H), 4 67 (d, J=7 0 Hz, 2 H), 4 35 (t, J=5 3 Hz, 1 H), 3 93 (s, 3 H), 3 19 (t, J=5 8 Hz, 2 H), 2 66 (s, 3 H), 2 04 - 1 90 (m, 1 H), 1 74 (d, J=10 6 Hz, 2 H), 1 61 (d, J=10 6 Hz, 2 H), 1 37 - 1 23 (m, 1 H), 1 08 (dq, J=12 6, 2 7 Hz, 2 H), 0 87 (dq, J=12 8, 3 1 Hz, 2 H)

Step 2 Preparation of 4-(2-(((<rans)-4-(hvdroxymethyl)cvclohexyl)methyl)-2H-tet razol-5-yl)-6- methylpicolinic acid

Methyl 4-(2-(((/rans)-4-(hydroxymethyl)cyclohexyl)methyl)-2H-tetraz ol-5-yl)-6-methylpιcolιnate (2 3 g, 6 68 mmol) was dissolved in a mixture of tetrahydrofuran/water (40 mL, 1/1 ) Lithium hydroxide (479 mg, 20 0 mmol) was added and the mixture was stirred at room temperature for 3 hours The solvent was removed in vacuo and the residue was diluted with water (20 mL) The solution was made acidic with 1 N hydrochloric acid solution (20 mL) and the resulting precipitate was filtered to afford the title compound as a white solid (1 03 g, 47%) MS (ES+) m/z 332 (M+H) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 13 36 (br, 1 H), 8 40 (d, J=O 8 Hz, 1 H), 8 09 (d, J=1 1 Hz, 1 H), 4 66 (d, J=7 1

Hz, 2 H), 4 35 (br, 1 H), 3 19 (d, J=6 2 Hz, 2 H), 2 65 (s, 3 H), 2 03 - 1 90 (m, 1 H), 1 74 (d, J= 10 5 Hz, 2 H), 1 61 (d, J=10 9, 2 H), 1 35 - 1 25 (m, 1 H), 1 08 (dg, J=12 6, 2 8 Hz, 2 H), 0 87 (dg, J=12 8, 3 2 Hz, 2 H)

Step 3 Preparation of /V-((2,3-dιhvdrobenzofuran-5-yl)methyl)-4-(2-(((ffans)-4- (hvdroxymethvDcvclohexyDmethvD^H-tetrazol-δ-vD-S-methylpico linamide

A mixture of 4-(2-(((/rans)-4-(hydroxymethyl)cyclohexyl)methyl)-2/-/-tetr azol-5-yl)-6- methylpicolinic acid (33 mg, 0 10 mmol) and 1-hydroxybenzotÏ€azole (18 9 mg, 0 14 mmol) in N, N- dimethylformamide (0 5 mL) was shaken for 15 minutes λ/-Methylmorpholιne (44 μL, 0 40 mmol) was added followed by (2,3-dιhydrobenzofuran-5-yl)methanamιne (17 9 mg, 0 12 mmol) in N ₁ N- dimethylformamide (0 5 mL) 1-Ethyl-3-(3'-dιmethylamιnopropyl)carbodιιmιde hydrochloride (26 8 mg, 0 14 mmol) was then added and the mixture was shaken for 18 hours The reaction mixtures were purified by preparative reverse phase preparative HPLC to afford the title compound (33 mg) MS (ES+) m/z 463 (M+H) ¹ H NMR (400 MHz, DMSOd ₆ ) δ ppm 10 48 (s, 0 5 H), 9 1 1 (t, J=6 2 Hz, 1 H), 8 37 (s, 1 H), 8 02 (s, 1 H), 7 18 (s, 1 H), 7 03 (d, J=7 7 Hz, 1 H), 6 64 (d, J=8 1 Hz, 1 H), 4 61 (d, J=7 0 Hz, 2 H), 4 44 (t, J=8 8 Hz, 2 H), 4 39 (d, J=6 6 Hz, 2 H), 4 32 (t, J=5 1 Hz, 1 H), 3 14 (t, J=5 5 Hz, 2 H), 3 09 (t, J=8 8 Hz, 2 H), 2 61 (s, 3 H), 1 99 - 1 84 (m, 1 H), 1 69 (d, J=12 8 Hz, 2 H), 1 56 (d, J= 1 1 7 Hz, 2 H), 1 30 - 1 19 (m, 1 H), 1 03 (q, J=1 1 7 Hz, 2 H), 0 82 (q, J=12 2 Hz, 2 H)

Example 308 λ/-(3-(Trifluoromethyl)benzyl)-4-(2-(((frans)-4-(hydroxymet hyl)cyclohexyl)methyl)-2H-tetrazol-5- yl)-6-methylpicolinamide

3-Trιfluoromethylbenzylamιne was reacted according to procedures described in Example 307 to afford the title compound (37 mg) MS (ES+) m/z 489 (M+H) ¹ H NMR (400 MHz, DMSOd ₆ ) δ ppm 9 43 (t, J=6 2 Hz, 1 H), 8 37 (s, 1 H), 8 04 (s, 1 H), 7 69 - 7 48 (m, 4 H), 4 61 (d, J=7 0 Hz, 2 H), 4 56 (d, J=6 2 Hz, 2 H), 4 31 (t, J=5 1 Hz, 1 H), 3 13 (t, J=5 7 Hz, 2 H), 2 63 (s, 3 H), 1 98 - 1 85 (m, 1 H), 1 68 (d, J= 1 1 7 Hz, 2 H), 1 56 (d, J= 1 1 3 Hz, 2 H), 1 31 - 1 19 (m, 1 H), 1 02 (q, J=12 8 Hz, 2 H), 0 82 (q, J=12 4 Hz, 2 H)

Example 309

/V-(3-(Trifluoromethoxy)benzyl)-4-(2-(((frans)-4-(hydroxy methyl)cyclohexyl)methyl)-2H-tetrazol-

5-yl)-6-methylpicolinamide

3-Trιfluoromethoxybenzylamιne was reacted according to procedures described in Example

307 to afford the title compound (31 mg) MS (ES+) m/z 527 (M+H) ¹ H NMR (400 MHz, DMSO-d ₆ ) 6 ppm 9 40 (t, J=6 4 Hz, 1 H), 8 38 (s, 1 H), 8 05 (s, 1 H), 7 43 (t, J= 7 9 Hz, 1 H), 7 34 (d, J=I 7 Hz, 1 H), 7 29 (s, 1 H), 7 21 (d, J=Q 1 Hz, 1 H), 4 62 (d, J=I 0 Hz, 2 H), 4 53 (d, J=Q 2 Hz, 2 H), 4 32 (t, J=5 3 Hz, 1 H), 3 14 (t, J=5 7 Hz, 2 H), 2 64 (s, 3 H), 1 97 - 1 87 (m, 1 H) ₁ 1 70 (d, J=12 4 Hz, 2 H), 1 57 (d, J= 1 1 7 Hz, 2 H), 1 31 - 1 20 (m, 1 H), 1 03 (q, J= 13 2 Hz, 2 H), 0 83 (q, J=12 8 Hz, 2 H)

Example 310

W-(3-Chlorobenzyl)-4-(2-(((frans)-4-(hydroxymethyl)cycloh exyl)methyl)-2W-tetrazol-5-yl)-6- methylpicolinamide

3-Chlorobenzylamιne was reacted according to procedures described in Example 307 to afford the title compound (16 mg) MS (ES+) m/z 455 (M+H) ¹ H NMR (400 MHz, DMSO-Cf ₆ ) 6 ppm 9 37 (t, J=6 4 Hz, 1 H), 8 38 (s, 1 H), 8 05 (s, 1 H), 7 26 - 7 37 (m, 4 H), 4 62 (d, J=7 0 Hz, 2 H), 4 49 (d, J=6 6 Hz, 2 H), 4 33 (t, J=5 3 Hz, 1 H), 3 14 (t, J=5 7 Hz, 2 H), 2 64 (s, 3 H), 1 97 - 1 87 (m, 1 H), 1 70 (d, J=10 6 Hz, 2 H), 1 57 (d, J= 1 1 3 Hz, 2 H), 1 31 - 1 21 (m, 1 H), 1 03 (q, J=12 4 Hz, 2 H), 0 83 (q, J=12 4 Hz, 2 H)

Example 311

/V-(3-Methylbenzyl)-4-(2-(((frans)-4-(hydroxymethyl)cyclo hexyl)methyl)-2H-tetrazol-5-yl)-6- methylpicolinamide

3-Methylbenzylamιne was reacted according to procedures described in Example 307 to afford the title compound (33 mg) MS (ES+) m/z 435 (M+H) ¹ H NMR (400 MHz, DMSO-Cf ₆ ) δ ppm 9 21 (t, J=6 4 Hz, 1 H), 8 39 (s, 1 H), 8 04 (s, 1 H), 7 17 (t, J=I 5 Hz, 1 H), 7 07 - 7 13 (m, 2 H), 7 02 (d, J=7 3 Hz, 1 H), 4 62 (d, J=I 0 Hz, 2 H), 4 46 (d, J=Q 2 Hz, 2 H), 4 32 (t, J=5 1 Hz, 1 H), 3 14 (t, J=5 9 Hz, 2 H), 2 63 (s, 3 H), 2 24 (s, 3 H), 1 97 - 1 87 (m, 1 H), 1 70 (d, J=1 1 0 Hz, 2 H), 1 57 (d, J=\ 1 3 Hz, 2 H), 1 30 - 1 20 (m, 1 H), 1 04 (q, J=13 2 Hz, 2 H), 0 83 (q, J=12 2 Hz, 2 H)

Example 312

W-(3-Ethylbenzyl)-4-(2-(((rrans)-4-(hydroxymethyl)cyclohe xyl)methyl)-2W-tetrazol-5-yl)-6- methylpicolinamide

3-Ethylbenzylamιne was reacted according to procedures described in Example 307 to afford the title compound (32 mg) MS (ES+) m/z 449 (M+H) ¹ H NMR (400 MHz, DMSO-d ₆ ) ÏŒ ppm 9 21 (t, J=6 2 Hz, 1 H), 8 38 (s, 1 H), 8 03 (s, 1 H), 7 21 - 7 02 (m, 4 H), 4 61 (d, J=I 0 Hz, 2 H), 4 46 (d, J=6 6 Hz, 2 H), 4 32 (t, J=5 3 Hz, 1 H), 3 14 (t, J=5 7 Hz, 2 H), 2 62 (s, 3 H), 2 53 (q, J=7 6 Hz, 2 H), 1 97 - 1 87 (m, 1 H), 1 69 (d, J=\ 1 0 Hz, 2 H), 1 56 (d, J=10 2 Hz, 2 H), 1 30 - 1 20 (m, 1 H), 1 1 1 (t, J=I 7 Hz, 3 H), 1 03 (q, J=12 4 Hz, 2 H), 0 82 (q, J=12 1 Hz, 2 H)

Example 313

/V-(3-lsopropoxybenzyl)-4-(2-(((frans)-4-(hydroxymethyl)c yclohexyl)methyl)-2H-tetrazol-5-yl)-6- methylpicolinamide

3-lsopropoxybenzylamιne was reacted according to procedures described in Example 307 to afford the title compound (37 mg) MS (ES+) m/z 479 (M+H) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9 22 (t, J=6 2 Hz, 1 H), 8 38 (s, 1 H), 8 04 (s, 1 H), 7 16 (t, J=8 1 Hz, 1 H), 6 87 - 6 72 (m, 3 H), 4 61 (d, J=7 0 Hz, 2 H), 4 52 (qq, J=5 9 Hz, 1 H), 4 44 (d, J=6 2 Hz, 2 H), 4 31 (t, J=5 1 Hz, 1 H), 3 14 (t,

J=5 7 Hz, 2 H), 2 63 (s, 3 H), 1 98 - 1 86 (m, 1 H), 1 69 (d, J= 1 1 3 Hz, 2 H), 1 56 (d, J= 1 1 0 Hz, 2 H), 1 30 - 1 19 (m, 1 H), 1 19 (d, J=5 9 Hz, 6 H), 1 03 (q, J=12 8 Hz, 2 H), 0 82 (q, J= 12 4 Hz, 2 H)

Example 314

W-(3-Ethoxybenzyl)-4-(2-(((frans)-4-(hydroxymethyl)cycloh exyl)methyl)-2H-tetrazol-5-yl)-6- methylpicolinamide

(3-Ethoxyphenyl)methanamιne (prepared as described in step 2 of the synthesis of λ/-(3- ethoxybenzyl)-6-methy!-4-(2-(((frans)-4-(methylsulfonamιdo) cyclohexyl)methyl)-2H-tetrazol-5- yl)pιcolιnamιde, Example 180) was reacted according to procedures described in Example 307 to afford the title compound (36 mg) MS (ES+) m/z 465 (M+H) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9 22 (t, J=6 2 Hz, 1 H), 8 38 (s, 1 H), 8 04 (s, 1 H), 7 18 (t, J=8 1 Hz, 1 H), 6 88 - 6 83 (m, 2 H), 6 76 (d, J=8 4 Hz, 1 H), 4 62 (d, J=7 0 Hz, 2 H), 4 46 (d, J=6 2 Hz, 2 H), 4 33 (t, J=5 3 Hz, 1 H), 3 95 (q, J=7 0 Hz, 2 H), 3 14 (t, J=5 7 Hz, 2 H), 2 63 (s, 3 H), 1 97 - 1 87 (m, 1 H), 1 69 (d, J=12 4 Hz, 2 H), 1 57 (d, J=12 4 Hz, 2 H), 1 26 (t, J=7 0 Hz, 3 H), 1 28 - 1 20 (m, 1 H), 1 04 (q, J=12 4 Hz, 2 H), 0 83 (q, J=1 1 3 Hz, 2 H)

Example 315 rV-(3,4-Difluorobenzyl)-4-(2-(((frans)-4-(hydroxymethyl)cycl ohexyl)methyl)-2H-tetrazol-5-yl)-6- methylpicolinamide

3,4-Dιfluorobenzylamιne was reacted according to procedures described in Example 307 to afford the title compound (33 mg) MS (ES+) m/z 457 (M+H) ¹ H NMR (400 MHz, DMSOd ₆ ) ÏŒ ppm 9 36 (t, J=6 4 Hz, 1 H), 8 38 (s, 1 H), 8 05 (s, 1 H), 7 39 - 7 30 (m, J=8 5, 8 5, 8 5 Hz, 2 H), 7 13 - 7 18 (m, 1 H), 4 62 (d, J=7 0 Hz, 2 H), 4 47 (d, J=6 6 Hz, 2 H), 4 32 (t, J=5 3 Hz, 1 H), 3 14 (t, J=5 9 Hz, 2 H), 2 64 (s, 3 H), 1 97 - 1 87 (m, 1 H), 1 70 (d, J= 1 1 0 Hz, 2 H), 1 57 (d, J=12 1 Hz, 2 H), 1 30 - 1 18 (m, 1 H), 1 03 (q, J=12 8 Hz, 2 H), 0 83 (q, J= 1 1 3 Hz, 2 H)

Example 316

/V-(4-Fluoro-3-methylbenzyl)-4-(2-(((frans)-4-(hydroxymet hyl)cyclohexyl)methyl)-2H-tetrazol-5- yl)-6-methylpicolinamide

4-Fluoro-3-methylbenzylamιne was reacted according to procedures described in Example 307 to afford the title compound (35 mg) MS (ES+) m/z 453 (M+H) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9 25 (t, J=6 2 Hz, 1 H), 8 38 (s, 1 H), 8 04 (s, 1 H), 7 21 (d, J=7 3 Hz, 1 H), 7 17 - 7 13 (m, 1 H), 7 03 (t, J=9 2 Hz, 1 H), 4 62 (d, J=7 0 Hz, 2 H), 4 43 (d, J=6 2 Hz, 2 H), 4 32 (t, J=5 1 Hz, 1 H), 3 14 (t, J=5 7 Hz, 2 H), 2 63 (s, 3 H), 2 17 (s, 3 H), 1 97 - 1 87 (m, 1 H), 1 70 (d, J= 1 1 0 Hz, 2 H), 1 57 (d, J=13 2 Hz, 2 H), 1 30 - 1 20 (m, 1 H), 1 03 (q, J=10 6 Hz, 2 H), 0 83 (q, J=M 4 Hz, 2 H)

Example 317

/V-(4-Fluoro-3-(trifluoromethyl)benzyl)-4-(2-(((frans)-4- (hydroxymethyl)cyclohexyl)methyl)-2H- tetrazol-5-yl)-6-methylpicolinamide

4-Fluoro-3-trιfluorobenzylamιne was reacted according to procedures described in Example 307 to afford the title compound (30 mg) MS (ES+) m/z 507 (M+H) ¹ H NMR (400 MHz, DMSOd ₆ ) S ppm 9 43 (t, J=Q 2 Hz, 1 H), 8 37 (s, 1 H), 8 05 (s, 1 H), 7 73 (d, J=6 2 Hz, 1 H), 7 71 - 7 66 (m, 1 H), 7 47 - 7 40 (m, 1 H), 4 62 (d, J=I 0 Hz, 2 H), 4 53 (d, J=6 2 Hz, 2 H), 4 32 (t, J=5 3 Hz, 1 H), 3 14 (t, J=5 5 Hz, 2 H), 2 64 (s, 3 H), 1 97 - 1 87 (m, 1 H), 1 69 (d, .7=10 6 Hz, 2 H), 1 57 (d, J= 1 1 3 Hz, 2 H), 1 30 - 1 20 (m, 1 H), 1 03 (q, J=12 8 Hz, 2 H), 0 83 (q, J=12 4 Hz, 2 H)

Example 318

/V-(3-(Hydroxymethyl)benzyl)-4-(2-((((rans)-4-(hydroxymet hyl)cyclohexyl)methyl)-2H-tetrazol-5- yl)-6-methylpicolinamide

(3-(Amιnomethyl)phenyl)methanol was reacted according to procedures described in Example 307 to afford the title compound (34 mg) MS (ES+) m/z 451 (M+H) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9 24 (t, J=6 4 Hz, 1 H), 8 39 (s, 1 H), 8 04 (s, 1 H), 7 12 - 7 29 (m, 4 H), 5 13 (t, J=5 7 Hz, 1 H), 4 62 (d, J=7 0 Hz, 2 H), 4 49 (d, J=6 2 Hz, 2 H), 4 43 (d, J=5 5 Hz, 2 H), 4 33 (t, J=5 1 Hz, 1 H), 3 14

(t, J=5 7 Hz, 2 H), 2 63 (s, 3 H), 1 97 - 1 87 (m, 1 H), 1 70 (d, J=11 0 Hz, 2 H), 1 57 (d, J=λ 1 0 Hz, 2 H), 1 30 - 1 20 (m, 1 H), 1 03 (q, J=M 1 Hz, 2 H), 0 83 (q, J=12 1 Hz, 2 H)

Example 319

^-(S-HydroxybenzyO^^Z^^fransJ^^hydroxymethyOcyclohexyOmet hyO^W-tetrazol-S-yO-e- methylpicolinamide

3-Hydroxybenzylamιne was reacted according to procedures described in Example 307 to afford the title compound (34 mg) MS (ES+) m/z 437 (M+H) ¹ H NMR (400 MHz, DMSO-d ₆ ) ÏŒ ppm 9 27 (s, 1 H), 9 18 (t, J=6 0 Hz, 1 H), 8 38 (s, 1 H), 8 04 (s, 1 H), 7 06 (t, J=7 9 Hz, 1 H), 6 73 - 6 67 (m, 2 H), 6 57 (d, J=8 8 Hz, 1 H), 4 62 (d, J=I 0 Hz, 2 H), 4 40 (d, J=Q 2 Hz, 2 H), 4 32 (t, J=5 1 Hz, 1 H), 3 14 (t, J=5 5 Hz, 2 H), 2 63 (s, 3 H), 1 98 - 1 86 (m, 1 H), 1 69 (d, J=1 1 3 Hz, 2 H), 1 56 (d, J=1 1 0 Hz, 2 H), 1 31 - 1 20 (m, 1 H), 1 03 (q, J=12 8 Hz, 2 H), 0 82 (q, J=12 8 Hz, 2 H)

Example 320

/V-(3-Fluoro-5-methoxybenzyl)-4-(2-((((rans)-4-(hydroxyme thyl)cyclohexyl)methyl)-2H-tetrazol-5- yl)-6-methylpicolinamide

Step 1 Preparation of (3-fluoro-5-methoxyphenyl)methanamιne

To a suspension of lithium aluminum hydride ( 3 3 mL, 2 0 M in tetrahydrofuran) was added dropwise a solution of 3-fluoro-5-methoxybenzonιtrιle (0 20 g, 1 34 mmol) in tetrahydrofuran (5 0 mL) at 0 ⁰ C After 2 h, a saturated solution of sodium sulfate (2-3 mL) was added dropwise until hydrogen gas evolution ceased The precipitate was filtered off and the filtrate was diluted with ethyl acetate ( 10 mL) The organic layer was separated, washed with water (2 x 5 mL), brine (5 mL), dried over sodium sulfate, and concentrated to afford the title compound (0 14 g, 69%) ¹ H NMR (400 MHz, DMSO-Cf ₆ ) ÏŒ ppm 6 68 - 6 74 (m, 2 H), 6 54 - 6 61 (m, 1 H), 3 72 (s, 3 H), 3 64 (s, 2 H), 1 68 - 1 87 (m, 2 H)

Step 2 Preparation of λ/-(3-fluoro-5-methoxybenzyl)-4-(2-(((frans)-4- (hvdroxymethyl)cvclohexyl)methyl)-2H-tetrazol-5-yl)-6-methyl picolinamide

(3-Fluoro-5-methoxyphenyl)methanamιne was reacted according to procedures described in Example 307 to afford the title compound (22 mg) ¹ H NMR (400 MHz, DMSOd ₆ ) δ ppm 9 27 (t, J=6 2 Hz, 1 H), 8 40 (s, 1 H), 8 06 (s, 1 H), 6 55 - 6 84 (m, 3 H), 4 63 (d, J=7 3 Hz, 2 H), 4 48 (d, J=6 6 Hz, 2 H), 4 29 (t, J=5 1 Hz, 1 H), 3 60 - 3 80 (m, 3 H), 2 66 (s, 3 H), 2 40 - 2 54 (m, 1 H), 1 88 - 2 06 (m, 1 H), 1 72 (d, J=1 1 0 Hz, 2 H), 1 60 (d, J=1 1 0 Hz, 2 H), 1 27 (d, J=1 1 7 Hz, 1 H), 0 96 - 1 14 (m, 2 H), 0 74 - 0 98 (m, 2 H)

Example 321

W-((2,3-Dιhydrobenzofuran-6-yl)methyl)-4-(2-(((rrans)-4- (hydroxymethyl)cyclohexyl)methyl)-2H- tetrazol-5-yl)-6-methylpicolinamide

Step 1 Preparation of (2, 3-dιhydrobenzofuran-5-yl)methanamιne

To a suspension of lithium aluminum hydride (0 38 mL, 2 0 M in tetrahydrofuran) was added dropwise a solution of 2,3-dιhydrobenzofuran-6-carbonιtrιle (0 10 g, 0 61 mmol) in tetrahydrofuran (2 0 mL) at 0 ⁰ C The reaction was allowed to warm to room temperature and then was heated at 70 ⁰ C for 3 hours A saturated solution of sodium sulfate (1-2 mL) was added dropwise until hydrogen gas evolution ceased The precipitate was filtered off and the filtrate was diluted with ethyl acetate (10 mL) The organic layer was separated, washed with water (2 x 5 mL) followed by brine (5 mL), dried over sodium sulfate, and concentrated The residue was taken up in acetonitrile and filtered through a Celiteâ„¢ pad The filtrate was concentrated to afford the title compound as an oil (65 mg, 61%) LC/MS (5-100% CH ₃ CN/H ₂ O, 5 mm) 0 73 mm, m/z 150 (M+H)

Step 2 Preparation of λ/-((2,3-dιhydrobenzofuran-6-yl)methyl)-4-(2-(((frans)-4- (hvdroxymethyl)cvclohexyl)methyl)-2/-/-tetrazol-5-yl)-6-meth ylpιcolιnamιde

(2,3-Dιhydrobenzofuran-5-yl)methanamιne was reacted according to procedures described in Example 307 to afford the title compound (33 mg) ¹ H NMR (400 MHz, DMSOd ₆ ) δ ppm 9 13 (t, J=6 6 Hz, 1 H) ₁ 8 39 (s, 1 H), 8 04 (s, 1 H), 7 13 (d, J=7 3 Hz, 1 H), 6 61 - 6 84 (m, 3 H), 4 63 (d, J=7 3 Hz ₁ 2 H) ₁ 4 37 - 4 56 (m, 4 H) ₁ 4 29 (t, J=5 1 Hz, 1 H) ₁ 3 00 - 3 19 (m, 1 H), 2 64 (s, 3 H), 2 46 - 2 58 (m, 2 H) ₁ 1 84 - 2 04 (m, 1 H), 1 72 (d, J=10 3 Hz, 2 H), 1 60 (d, J=1 1 0 Hz, 2 H) ₁ 1 29 (d, J=5 9 Hz, 1 H), 0 93 - 1 18 (m, 2 H), 0 72 - 0 97 (m, 2 H)

Example 322

λ/-(3-Methoxybenzyl)-4-(2-((((rans)-4-(hydroxymethyl)cyc lohexyl)methyl)-2H-tetrazol-5-yl)-6- methylpicolinamide

(3-Methoxyphenyl)methanamιne was reacted according to procedures described in Example 307 to afford the title compound (46 mg) LC/MS (5%-95% CH ₃ CN/H ₂ O, 4 5 mm , 95% CH ₃ CN, 1 5 mm ) 3 261 mm , m/z 451 (M+H) ¹ H NMR (400 MHz, DMSOd ₆ ) δ ppm 9 23 (m, 1 H), 8 39 (s, 1 H), 8 05 (s, 1 H), 7 12 - 7 28 (m, 1 H), 6 94 - 6 84 (m, 2 H), 6 82 - 6 72 (m, 1 H), 4 63 (d, J=7 0 Hz ₁ 2 H), 4 47 (d, J=6 4 Hz ₁ 2 H), 3 70 (s, 3 H), 3 21 - 3 08 (m, 2 H) ₁ 2 64 (s, 3 H), 2 04 - 1 81 (m, 1 H), 1 78 - 1 50 (m, 4 H), 1 43 - 1 16 (m), 1 15 - 0 71 (m, 4 H)

Example 323

/V-(4-Fluoro-3-methoxybenzyl)-4-(2-(((trans)-4-(hydroxyme thyl)cyclohexyl)methyl)-2W-tetrazol-5- yl)-6-methylpicolinamide

4-Fluoro-3-methoxybenzylamιne hydrochloride (prepared as described in step 3 of the synthesis of λ/-(4-fluoro-3-methoxybenzyl)-6-(2-((/rans-4-amιnocyclohex yl)methyl)-2H-tetrazol-5-

yl)pyÏ€mιdιne-4-carboxamιde, Example 1 ) (133 mg, 0 857 mmol) and dnsopropylethylamine (0 5 ml_, 0 308 mmol) was added to a solution of 4-(2-(((frans)-4-(hydroxymethyl)cyclohexyl)methyl)-2/-/- tetrazol-5-yl)-6-methylpιcolιnιc acid (prepared as described in step 2 of the synthesis of λ/-((2,3- dihydrobenzofuran-5-yl)methyl)-4-(2-(((/rans)-4-(hydroxymeth yl)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6- methylpicolinamide, Example 307) (102 mg, 0 308 mmol) in DMF (10 mL), and the mixture was stirred at room temperature for 10 minutes (Benzotrιazol-1 -yloxy)- dιmethylamιnomethylene]dιmethylammonιum tetrafluoroborate (254 mg, 0 79 mmol) was added and stirring continued for 30 minutes The reaction mixture was concentrated and purified by reverse phase preparative HPLC followed by neutralization using a carbonate column to afford the title compound (50 mg, 28%) LC/MS (5%-95% CH ₃ CN/H ₂ O, 5 mm ) 3 331 mm , m/z 469 (M+H) ¹ H NMR (400 MHz, CDCI ₃ ) δ ppm 0 91 - 1 04 (m, 2 H), 1 05 - 1 19 (m, 2 H), 1 39 - 1 54 (m, 1 H), 1 66 - 1 90 (m, 4 H), 2 00 - 2 14 (m, 1 H), 2 61 (s, 3 H), 3 38 - 3 48 (m, 3 H), 3 86 (s, 3 H), 4 52 (d, J=I 0 Hz, 2 H), 4 62 (d, J=6 4 Hz, 2 H), 6 85 - 6 92 (m, 1 H), 6 94 - 7 06 (m, 2 H), 8 03 (d, J=1 3 Hz, 1 H), 8 42 (t, J=6 2 Hz, 1 H), 8 70 (s, 1 H)

Example 324

/V-(3-Bromobenzyl)-4-(2-(((frans)-4-(hydroxymethyl)cycloh exyl)methyl)-2H-tetrazol-5-yl)-6- methylpicolinamide

Triethylamine (0 16 mL, 1 18 mmol) and 3-bromobenzylamιne hydrochloride (55 mg, 0 245 mmol) were added to a solution of 4-(2-(((frans)-4-(hydroxymethyl)cyclohexyl)methyl)-2H-tetraz ol-5- yl)-6-methylpιcolιnιc acid (prepared as described in step 2 of the synthesis of λ/-((2,3- dιhydrobenzofuran-5-yl)methyl)-4-(2-(((/rans)-4-(hydroxymet hyl)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6- methylpicolinamide, Example 307) (65 mg, 0 196 mmol) in λ/,λ/-dιmethylformamιde (2 mL), and the mixture was stirred for 30 minutes O-(1 H-Benzotrιazol-1 -yl)-/V,/V,W,λf-tetramethyluronιum hexafluorophosphate (186 mg, 0 49 mmol) was added and stirring continued overnight The reaction mixture was purified by reverse phase preparative HPLC to afford the title compound (1 5 mg, 1 5%) ¹ H NMR (400 MHz, CDCI ₃ ) δ ppm 1 13 - 1 31 (m, 4 H), 1 74 - 1 98 (m, 3 H), 2 01 - 2 23 (m, 3 H), 2 64 (s, 2 H), 4 35 (d, J=6 7 Hz, 2 H ₁ ) 4 56 (d, J=I 0 Hz, 2 H), 4 66 (d, J=6 2 Hz, 2 H), 7 14 - 7 27 (m, 1 H), 7 30 (d, J=I 8 Hz, 1 H), 7 34 - 7 44 (m, 2 H), 7 44 - 7 57 (m, 2 H), 8 02 (d, J=β 6 Hz, 1 H), 8 07 (d, J=1 1 Hz, 1 H), 8 52 (t, J=6 2 Hz, 1 H), 8 71 (s, 1 H)

Example 325

W-(3-(2-Hydroxyethoxy)benzyl)-4-(2-(((frans)-4-(hydroxyme thyl)cyclohexyl)methyl)-2H-tetrazol-

5-yl)-6-methylpicolinamide

2-(1 H-Benzotrιazole-1-yl)-1 ,1 ,3,3-tetramethyluronιum hexafluorophosphate (137 mg, 0 362 mmol) was added to a mixture of 4-(2-(((frans)-4-(hydroxymethyl)cydohexyl)methyl)-2/-/-tetra zol-5-yl)- 6-methylpιcolιnιc acid (prepared as described in step 2 of the synthesis of λ/-((2,3-dιhydrobenzofuran- 5-yl)methyl)-4-(2-(((frans)-4-(hydroxyrnethyl)cyclohexyl)met hyl)-2H-tetrazol-5-yl)-6-methylpιcolιnamιde, Example 307) (100 mg, 0 302 mmol), 2-(3-(amιnomethyl)phenoxy)ethanol (prepared as described in step 2 of the synthesis of λ/-(3-(2-hydroxyethoxy)benzyl)-6-(2-(((frans)-4-amιnocyclo hexyl)methyl)-2H- tetrazol-5-yl)-2-methylpyrιmιdιne-4-carboxamιde, Example 13) (60 55 mg, 0 362 mmol), and triethylamine (0 09 mL, 0 664 mmol) in tetrahydrofuran (1 mL) The mixture was stirred at room temperature for 18 hours and then purified by reverse phase preparative HPLC Fractions containing the desired product were combined, passed through a carbonate cartridge to neutralize, and concentrated to afford the title compound as a white solid (32 mg, 22%) MS (ES+) m/z 481 (M+H) ¹ H NMR (400 MHz, CDCI ₃ ) δ ppm 0 89 - 1 32 (m, 4 H), 1 40 - 1 58 (m, 1 H), 1 65 - 2 01 (m, 6 H), 1 99 - 2 19 (m, 1 H), 2 64 (s, 3 H), 3 47 (d, J=6 18 Hz, 2 H), 3 89 - 4 01 (m, 2 H), 4 03 - 4 15 (m, 2 H), 4 54 (d, J=6 98 Hz, 2 H), 4 67 (d, J=6 18 Hz, 2 H), 6 79 - 6 89 (m, 1 H), 6 91 - 7 04 (m, 2 H), 7 21 - 7 34 (m, 1 H), 8 06 (s, 1 H), 8 48 (t, J=5 77 Hz, 1 H), 8 73 (s, 1 H)

Example 326

W-(3-Propoxybenzyl)-4-(2-(((frans)-4-(hydroxymethyl)cyclo hexyl)methyl)-2W-tetrazol-5-yl)-6- methylpicolinamide

Step 1 Preparation of 3-propoxybenzonιtrιle

A mixture of potassium hydroxide (18 8 g, 85 %, crushed) in dimethylsulfoxide (80 mL) was stirred for 5 minutes at ambient temperature To this white slurry was added 3-cyanophenol (10 0 g) and iodopropane (28 5 g) The mixture was stirred for 2 5 hours at room temperature The reaction mixture was poured into 1 L of ice water and then extracted with dichloromethane (5 x 300 mL) The combined organic layers were washed with water (5 x 500 mL) and dried over anhydrous sodium sulfate Filtration and concentration in vacuo afforded the title compound (13 23 g, 97 8%)

Step 2 Preparation of (3-propoxyphenyl)methanamιne

3-Propoxybenzonιtrιle (13 2 g) was dissolved in absolute ethanol (100 mL) and the solution was sparged with nitrogen gas Palladium on carbon catalyst (4 0 g) was added and the mixture was shaken under hydrogen gas for 2 hours The mixture was sparged, filtered, and concentrated in vacuo The residue was purified by silica gel chromatography (dιchloromethane/methanol/NH ₄ OH, 97/3/0 3, 94/6/0 6, 90/10/1 ) to afford the title compound (8 47 g)

Step 3 Preparation of λ/-(3-propoxybenzyl)-4-(2-(((frans)-4-(hvdroxymethyl)cvcloh exyl)methyl)-2/-y- tetrazol-5-yl)-6-methylpιcolιnamιde

(3-Propoxyphenyl)methanamιne (59 8 mg, 0 362 mmol) was reacted according to procedures described in Example 325 to afford the title compound as a solid (44mg, 30%) MS (ES+) m/z 479 (M+H) ¹ H NMR (400 MHz, CDCI ₃ ) δ ppm 0 91 - 1 06 (m, 5 H), 1 08 - 1 25 (m, 3 H), 1 43 - 1 56 (m, 1 H), 1 71 - 1 91 (m, 6 H), 2 04 - 2 18 (m, 1 H), 2 66 (s, 3 H), 3 43 - 3 50 (m, 2 H), 3 93 (t, J=6 58 Hz, 2 H), 4 55 (d, J=I 25 Hz, 2 H), 4 68 (d, J=Q 18 Hz, 2 H), 6 84 (dd, J=Q 19, 2 28 Hz, 1 H), 6 91 - 7 01 (m, 2 H), 7 22 - 7 32 (m, 1 H), 8 07 (d, J=λ 34 Hz, 1 H), 8 49 (t, J=5 91 Hz, 1 H), 8 75 (s, 1 H)

Example 327

W-((2,3-Dihydrobenzo[b][1 ,4]dioxin-6-yl)methyl)-4-(2-(((trans)-4- (hydroxymethyl)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6-methyl picolinamide

(2,3-Dιhydrobenzo[b][1 ,4]dιoxιn-6-yl)methanamιne (37 4 mg, 0 226 mmol) was reacted according to procedures described in Example 325 to afford the title compound as a solid (3 2 mg, 9%) MS (ES+) m/z 479 (M+H) ¹ H NMR (400 MHz, CDCI ₃ ) δ ppm 0 92 - 1 32 (m, 8 H), 1 71 - 1 93 (m, 4 H), 2 02 - 2 17 (m, 1 H), 2 70 (s, 2 H), 3 48 (d, J=6 18 Hz, 2 H), 4 26 (s, 3 H), 4 58 (dd, J=17 19, 6 44 Hz, 4 H), 6 80 - 6 95 (m, 3 H), 8 10 (d, J= 1 34 Hz, 1 H), 8 62 (br s , 1 H), 8 77 (s, 1 H)

Example 328

4-(2-((((rans)-4-(Hydroxymethyl)cyclohexyl)methyl)-2H-tet razol-5-yl)-W-((2-methoxypyridin-4- yl)methyl)-6-methylpicolinamide

(2-Methoxypyrιdιn-4-yl)methanamιne (39 5 mg, 0 226 mmol) was reacted according to procedures described in Example 325 to afford the title compound as a solid (5 4 mg, 7%) MS (ES+) m/z 452 (M+H) ¹ H NMR (400 MHz, CDCI ₃ ) δ ppm 0 93 - 1 30 (m, 5 H), 1 41 - 1 56 (m, 1 H), 1 76 (d, J=12 89 Hz, 2 H), 1 87 (d, J=10 47 Hz, 2 H), 2 04 - 2 17 (m, 1 H), 2 68 (s, 3 H), 3 48 (d, J=Q 18 Hz, 2 H), 3 96 (S, 3 H), 4 55 (d, J=6 98 Hz, 2 H), 4 69 (d, J=Q 18 Hz, 2 H), 6 77 (s, 1 H), 6 92 (d, J=5 10 Hz, 1 H), 8 10 (s, 1 H), 8 15 (d, J=5 37 Hz, 1 H), 8 54 (t, J=Q 31 Hz, 1 H), 8 73 (s, 1 H)

Example 329

/V-(4-Fluorobenzyl)-4-(2-(((frans)-4-(hydroxymethyl)cyclo hexyl)methyl)-2H-tetrazol-5-yl)-6- methylpicolinamide

A mixture of λ/-(4-fluorobenzyl)-6-methyl-4-(2H-tetrazol-5-yl)pιcolιna mιde (prepared as described in step 1 of the synthesis of (frans)-Methyl 4-((5-(2-((4-fluorobenzyl)carbamoyl)-6- methylpyridm-4-yl)-2/-/-tetrazol-2-yl)methyl)cyclohexanecarb oxylate, Example 255) (50 mg, 0 16 mmol), polymer supported triphenylphosphine (186 mg, 0 4 mmol), and rrans-cyclohexane-1 ,4- dimethanol (46 mg, 0 32 mmol) in tetrahydrofuran (3 mL) was cooled in an ice bath and di-fert-butyl azodicarboxylate (74 mg, 0 32 mmol) was added The mixture was allowed to warm to room temperature and stir for 2 hours The reaction mixture was acidified with trifluoroacetic acid and filtered The filtrate was concentrated and the residue was purified by reverse phase preparative HPLC The product was dissolved in dichloromethane and passed through a carbonate resin column The filtrate was concentrated to afford the title compound as a white solid (36 7 mg) MS (ES+) m/z 439 (M+H) ¹ H NMR (400 MHz, DMSOd ₆ ) δ ppm 9 35 (t, J=Q 4 Hz, 1 H), 8 43 (s, 1 H), 8 09 (s, 1 H), 7 39 (dd, J=8 4, 5 7 Hz, 2 H), 7 16 (t, J=Q 9 Hz, 2 H), 4 67 (d, J=I 0 Hz, 2 H), 4 52 (d, J=Q 3 Hz, 2 H), 4 37 (t, J=5 3 Hz, 1 H), 3 19 (t, J=5 7 Hz, 2 H), 2 68 (s, 3 H), 1 91 - 2 02 (m, 1 H), 1 71 - 1 78 (m, 2 H), 1 58 - 1 64 (m, 2 H), 1 24 - 1 37 (m, 1 H), 1 02 - 1 14 (m, 2 H), 0 81 - 0 94 (m, 2 H)

Example 330

W-(3-Methoxybenzyl)-4-(2-(((c/s)-4-(hydroxymethyl)cyclohe xyl)methyl)-2H-tetrazol-5-yl)-6- methylpicolinamide

λ/-(3-Methoxybenzyl)-6-methyl-4-(2/-/-tetrazol-5-yl)pιcolÎ ¹namιde (prepared as described in step

5 of the synthesis of λ/-(3-methoxybenzyl)-4-(2-(((/rans)-4-amιnocyclohexyl)meth yl)-2/-/-tetrazol-5-yl)-6- methylpicolinamide, Example 153) (100 mg, 0 31 mmol), polymer supported tÏ€phenylphosphine (287 mg, 0 62mmol), and cis-cyclohexane-i ^-dimethanol (89 mg, 0 62 mmol) (Kuroda, C , Murase, A , Suzuki, hours , Endo, T , Anzai, S Bull Chem Soc Jpn 1998, 71 , 1639-1647 ) were suspended in tetrahydrofuran (10 mL) The mixture was cooled to 0 ⁰ C Di-tert-butyl azodicarboxylate (142 mg, 0 62 mmol) was added The mixture was allowed to warm to room temperature and stir for 36 hours The reaction mixture was filtered and the resin washed with tetrahydrofuran (20 mL) The filtrate was concentrated The crude product was purified by silica column chromatography (CH ₂ CI ₂ /methanol, 100/1 , 100/2) to afford the title compound as an oil (62 mg, 45%) MS (ES+) m/z 351 (M+H) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9 26 (t, J=6 4 Hz, 1 H), 8 42 (d, J=O 9 Hz, 1 H), 8 08 (d, J= 1 1 Hz, 1 H), 7 24 (t, J=B 1 Hz, 1 H), 6 93 - 6 90 (m, 2 H), 6 82 (ddd, J=8 2, 2 5, 0 9 Hz, 1 H), 4 76 (d, J=7 7 Hz, 2 H), 4 51 (d, J=6 4 Hz, 2 H), 4 37 (t, J=5 4 Hz, 1 H), 3 73 (s, 3 H), 3 33 (dd, J=6 4, 5 5 Hz, 2 H), 2 68 (s, 3 H), 2 31 - 2 21 (m, 1 H), 1 65 - 1 27 (m, 9 H)

Example 331 W-(3-Methoxybenzyl)-4-(2-(((frans)-4-(2-hydroxypropan-2-yl)c yclohexyl)methyl)-2H-tetrazol-5-yl)-

6-methylpicolinamide

A mixture of /V-(3-methoxybenzyl)-6-methyl-4-(2/-/-tetrazol-5-yl)pιcolι namιde (prepared as described in step 5 of the synthesis of λ/-(3-methoxybenzyl)-4-(2-(((frans)-4-amιnocyclohexyl)meth yl)- 2H-tetrazol-5-yl)-6-methylpιcolιnamιde, Example 153) (105 mg), 2-((trans)-4-

(hydroxymethyl)cyclohexyl)propan-2-ol (Aust J Chem 1993, 46, 1869-1879) (98 7 mg), and polymer supported triphenylphosphine (740 mg) in anhydrous tetrahydrofuran (10 mL) was cooled in an ice bath Di-tert-butyl azodicarboxylate (126 mg) was added and the mixture was placed in an ultrasonic bath for 30 minutes The reaction mixture was filtered and the resin was washed with tetrahydrofuran and methanol The filtrate was concentrated and the residue was purified by reverse phase preparative HPLC (acetonitrile/water, 50/50 - 80/20) The fractions containing product were

concentrated The aqueous residue was made basic with 5% aqueous sodium bicarbonate (3 mL) and extracted with dichloromethane (3 x 10 mL) The combined organic layers were dried over magnesium sulfate, filtered and concentrated to afford the title compound (1 18 mg) MS (ES+) m/z 479 (M+H) ¹ H NMR (400 MHz, DMSO-c/ ₆ ) δ ppm 9 21 (t, J=6 2 Hz, 1 H), 8 42 (s, 1 H), 8 07 (s, 1 H), 7 24 (t, J=Q 1 Hz, 1 H), 6 90 - 6 94 (m, 2 H), 6 82 (d, J=I 7 Hz, 1 H), 4 65 (d, J=I 0 Hz, 2 H), 4 51 (d, J=6 6 Hz, 2 H), 3 94 (s, 1 H), 3 73 (s, 3 H), 2 67 (s, 3 H), 1 95 (s, 1 H), 1 80 (d, J=12 1 Hz, 2 H), 1 65 (d, J= 1 1 3 Hz, 2 H), 1 13 (d, J=8 1 Hz, 1 H), 0 97 - 1 07 (m, 10 H)

Example 332

/V-(4-Fluoro-3-methoxybenzyl)-4-(2-(((frans)-4-(2-hydroxy propan-2-yl)cyclohexyl)methyl)-2H- tetrazol-5-yl)-6-methylpicolinamide

The title compound was prepared in a similar manner to λ/-(3-methoxybenzyl)-4-(2-(((frans)-4- (2-hydroxypropan-2-yl)cyclohexyl)methyl)-2H-tetrazol-5-yl)-6 -methylpιcolιnamιde (Example 331 ) by reaction with λ/-(4-fluoro-3-methoxybenzyl)-6-methyl-4-(2H-tetrazol-5-yl) pιcolιnamιde (prepared as described in step 2 of the synthesis of λ/-(4-fluoro-3-methoxybenzyl)-4-(2-(((frans)-4-amιnocycloh exyl)methyl)-2/-/- tetrazol-5-yl)-6-methylpιcolιnamιde, Example 170) and afforded 53 8 mg as an oil MS (ES+) m/z 497 (M+H) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9 21 (t, J=6 2 Hz, 1 H), 8 40 (s, 1 H), 8 05 (s, 1 H), 7 16 (d, J=8 4 Hz, 1 H), 7 1 1 (dd, J= 11 5, 8 2 Hz, 1 H), 6 85 - 6 92 (m, 1 H), 4 62 (d, J=6 6 Hz, 2 H), 4 48 (d, J=6 2 Hz, 2 H), 3 92 (s, 1 H), 3 80 (s, 3 H), 2 65 (s, 3 H), 1 87 - 1 98 (m, 1 H), 1 78 (d, J=11 7 Hz, 2 H), 1 63 (d, J= 1 1 3 Hz, 2 H), 0 90 - 1 23 (m, 11 H)

Example 333

W-(3-Methoxybenzyl)-4-(2-(((frans)-4-hydroxycyclohexyl)me thyl)-2H-tetrazol-5-yl)-6- methylpicolinamide

Step 1 Preparation of 4-(hydroxymethyl)cyclohexanol

A solution of 2M lithium aluminum hydride in tetrahydrofuran (70 mL) was added to diethyl ether (100 mL) in a mechanically stirred 2L flask A solution of ethyl 4- hydroxycyclohexanecarboxylate (24 92 g) in diethyl ether (100 mL) was added dropwise over 50 minutes The mixture was heated at reflux for 1 hour and then stirred overnight at room temperature Ethyl acetate (5 mL) was carefully added and the mixture was acidified with 12 N hydrochloric acid (50 mL) with ice bath cooling The organic layer was decanted and the aqueous layer was extracted with a mixture of tetrahydrofuran (150 mL) and ether (100 mL) The aqueous layer was neutralized with sodium bicarbonate (75 g) and extracted with ethyl acetate (4 x 400 mL) The combined organic layers were dried over magnesium sulfate, filtered and concentrated The resulting oil was distilled under reduced pressure to afford the title compound as a colorless oil (15 07 g)

Step 2 Preparation of A/-(3-methoxybenzyl)-4-(2-(((fraf7S)-4-hvdroxycvclohexyl)met hyl)-2/-/-tetrazol-5- yl)-6-methylpιcolιnamιde

A mixture of λ/-(3-methoxybenzyl)-6-methyl-4-(2H-tetrazol-5-yl)pιcolιn amιde (prepared as described in step 5 of the synthesis of λ/-(3-methoxybenzyl)-4-(2-(((/rans)-4-amιnocyclohexyl)meth yl)- 2/-/-tetrazol-5-yl)-6-methylpιcolιnamιde, Example 153) (986 mg), 4-(hydroxymethyl)cyclohexanol (614 mg), and polymer supported triphenylphosphine (3 55 g, 7 5 mmol) in tetrahydrofuran (60 mL) was cooled in an ice bath Di-terf-butylazodicarboxylate (1 046 g) was added and the mixture was placed in an ultrasonic bath for 50 minutes The mixture was filtered and the resin was washed with tetrahydrofuran The filtrate was concentrated and the residue was purified by reverse phase preparative HPLC (acetonitrile/water, 35/65 - 55/45) Fractions containing the first eluting isomer were combined and concentrated The residue was dissolved in dichloromethane and washed with 5% aqueous sodium bicarbonate (3 mL) The organic layer was dried over magnesium sulfate, filtered, and concentrated to afford the title compound (298 mg) MS (ES+) m/z 437 (M+H) ¹ H NMR (400 MHz, DMSOd ₆ ) δ ppm 9 19 (t, J=Q 4 Hz, 1 H), 8 40 (s, 1 H), 8 05 (s, 1 H), 7 22 (t, J=Q 1 Hz, 1 H), 6 87 - 6 92 (m, 2 H), 6 77 - 6 82 (m, 1 H), 4 63 (d, J=I 0 Hz, 2 H), 4 49 (d, J=Q 2 Hz, 2 H), 3 71 (s, 3 H), 2 65 (s, 3 H), 2 52 (s, 1 H), 1 89 - 1 98 (m, 1 H), 1 77 - 1 85 (m, 2 H), 1 53 - 1 61 (m, 2 H), 1 37 (d, J=I 3 Hz, 2 H), 1 03 - 1 17 (m, 2 H)

Example 334

W-(3-Methoxybenzyl)-4-(2-(((c/s)-4-hydroxycyclohexyl)meth yl)-2H-tetrazol-5-yl)-6- methylpicolinamide

Isolation of the second eluting isomer by reverse phase preparative HPLC from the reaction mixture described in Example 333 afforded the title compound (520 mg) MS (ES+) m/z 437 (M+H) ¹ H NMR (400 MHz, DMSO-c/ ₆ ) δ ppm 9 19 (t, J=6 4 Hz, 1 H), 8 40 (s, 1 H), 8 05 (s, 1 H), 7 21 (t, J=8 1 Hz, 1 H), 6 87 - 6 92 (m, 2 H), 6 79 (dd, J=8 4, 1 5 Hz, 1 H), 4 65 (d, J=I 0 Hz, 2 H), 4 48 (d, J=6 6 Hz, 2 H), 4 30 (br s , 1 H), 3 73 (br s , 1 H), 3 71 (s, 3 H), 2 65 (s, 3 H), 2 52 (s, 1 H), 2 04 (br s , 1 H), 1 54 - 1 63 (m, 2 H), 1 27 - 1 48 (m, 5 H)

Example 335

W-(4-Fluoro-3-methylbenzyl)-4-(2-(((<rans)-4-hydroxycy clohexyl)methyl)-2W-tetrazol-5-yl)-6- methylpicolinamide

Step 1 Preparation of methyl 4-(2-(((frans)-4-hvdroxycvclohexyl)methyl)-2H-tetrazol-5-yl) -6- methylpicolinate

A mixture of methyl 6-methyl-4-(2H-tetrazol-5-yl)pιcolιnate (prepared as described in step 4 of the synthesis of λ/-(3-methoxybenzyl)-4-(2-(((/rans)-4-amιnocyclohexyl)meth yl)-2H-tetrazol-5-yl)-6- methylpicolmamide, Example 153) (5 0 g, 28 8 mmol), 4-(hydroxymethyl)cyclohexanol (prepared as described in step 1 of the synthesis of λ/-(3-methoxybenzyl)-4-(2-(((frans)-4- hydroxycyclohexyOmethyO^H-tetrazol-δ-yO-θ-methylpicolinami de, Example 333) (3 71 g, 28 5 mmol), and polymer supported-triphenylphosphine (21 2 g, 45 6 mmol) in tetrahydrofuran (100 mL) was cool to 0 ⁰ C in an ice bath Di-tert-butyl azodicarboxylate (10 5 g, 45 6 mmol) was added and stirring was continued for 60 minutes in an ice bath The mixture was allowed to warm to room temperature and stir overnight The reaction mixture was filtered and the resin was washed with tetrahydrofuran The filtrate was concentrated and the residue was purified by reverse phase preparative HPLC Isolation of the first eluting isomer afforded the title compound as a clear, light yellow colored oil (1 48 g) LC/MS (5%-95% CH ₃ CN/H ₂ O, 5 mm ) 3 22 mm , m/z 332 (M+H) ¹ H NMR (500 MHz, DMSOd ₆ ) δ ppm 1 04 - 1 16 (m, 3 H), 1 57 (d, J=I 07 Hz, 2 H), 1 78 - 1 84 (m, 2 H), 1 89 - 1 97 (m, 1 H), 2 63 (s, 3

H), 3 29 - 3 36 (m, 1 H), 3 91 (s, 3 H), 4 63 (d, J=I 07 Hz, 2 H), 4 70 (d, J=7 07 Hz, 1 H), 8 08 (d, J=λ 63 Hz, 1 H), 8 36 (d, J=1 36 Hz, 1 H)

Step 2 Preparation of A/-(4-fluoro-3-methylbenzyl)-4-(2-(((frans)-4-hvdroxycvclohe xyl)methyl)-2/-/- tetrazol-5-yl)-6-methylpιcohnamιde

Diisopropylethylamine (77 9 mg, 0 603 mmol) and (4-fluoro-3-methylphenyl)methanamιne (125 9 mg, 0 905 mmol) were added to a solution of methyl 4-(2-(((<rans)-4-hydroxycyclohexyl)methyl)- 2H-tetrazol-5-yl)-6-methylpιcolιnate (100 mg, 0 301 mmol) in λ/,λ/-dιmethylformamιde (2 ml_) The mixture was stirred for 30 minutes and then heated to 60 ⁰ C overnight The reaction mixture was purified by reverse-phase preparative HPLC to afford the title compound (18 5 mg, 12%) ¹ H NMR (400 MHz, DMSO-cfe) δ ppm 1 09 (t, J= 10 25 Hz, 3 H), 1 57 (s, 2 H), 1 79 (s, 2 H), 1 93 (s, 1 H), 2 19 (s, 2 H), 2 65 (s, 2 H), 4 46 (d, J=6 59 Hz, 2 H), 4 63 (d, J=6 59 Hz, 2 H), 6 99 - 7 09 (m, 1 H), 7 12 - 7 28 (m, 2 H), 8 05 (s, 1 H), 8 40 (s, 1 H), 9 21 (t, J=Q 59 Hz, 1 H)

Example 336 /V-(4-Fluoro-3-methylbenzyl)-4-(2-(((c/s)-4-hydroxycyclohexy l)methyl)-2H-tetrazol-5-yl)-6- methylpicolinamide

Step 1 Preparation of methyl 4-(2-(((c<s)-4-hvdroxycvclohexyl)methyl)-2/-/-tetrazol-5- yl)-6- methylpicolinate

Isolation of the second eluting isomer from reverse phase preparative HPLC of the reaction mixture obtained in step 1 of the synthesis of λ/-(4-fluoro-3-methylbenzyl)-4-(2-((((λans)-4- hydroxycyclohexyOmethyO^H-tetrazol-S-yO-θ-methylpicolmamide (Example 335) afforded the title compound as a clear, light yellow colored oil (2 41 g) LC/MS (5%-95% CH ₃ CN/H ₂ O, 5 mm ) 3 34 mm , m/z 332 (M+H) ¹ H NMR (500 MHz, DMSO-cfe) δ ppm 1 29 - 1 35 (m, 2 H), 1 37 - 1 47 (m, 3 H), 1 60 (dd, J=9 65, 3 67 Hz, 2 H), 1 89 - 2 10 (m, 1 H), 2 64 (s, 3 H), 3 75 (br s , 1 H), 3 91 (s, 3 H), 4 67 (d, J=I 07 Hz, 2 H), 4 74 (d, J=I 07 Hz, 1 H), 8 1 1 (s, 1 H), 8 39 (s, 1 H)

Step 2 Preparation of λ/-(4-fluoro-3-methylbenzyl)-4-(2-(((c/s)-4-hvdroxycvclohex yl)methyl)-2/-/- tetrazol-5-yl)-6-methylpιcolιnamιde

Diisopropylethylamine (0 5 mL, 0 287 mmol) and (4-fluoro-3-methylphenyl)methanamιne (41 7 mg, 0 30 mmol) were added to a solution of methyl 4-(2-(((c/s)-4-hydroxycyclohexyl)methyl)-2H- tetrazol-5-yl)-6-methylpιcolιnate (25 mg, 0 075 mmol) in /V,N-dιmethylacetamιde (2 mL) The mixture was stirred for 30 minutes and then heated to 60 ⁰ C overnight The reaction mixture was purified by reverse-phase preparative HPLC to afford the title compound (21 5 mg, 65%) ¹ H NMR (400 MHz, DMSO-Cy ₆ ) δ ppm 1 09 (t, J=10 25 Hz, 4 H), 1 57 (s, 2 H), 1 79 (s, 2 H), 1 93 (s, 2 H), 2 19 (s, 3 H), 2 65 (s, 3 H), 3 27 (s, 1 H), 4 43 - 4 49 (m, 2 H), 7 01 - 7 08 (m, 1 H), 7 14 - 7 21 (m, 1 H), 7 23 (d, J=6 59 Hz ₁ 1 H), 8 05 (s, 1 H), 8 40 (s, 1 H), 9 21 (t, J=Q 22 Hz, 1 H)

Example 337

/V-(3-Chloro-4-fluorobenzyl)-4-(2-(((frans)-4-hydroxycycl ohexyl)methyl)-2H-tetrazol-5-yl)-6- methylpicolinamide

The title compound (18 7 mg, 13%) was prepared in a similar manner to λ/-(4-fluoro-3- methylbenzyl)-4-(2-(((frans)-4-hydroxycyclohexyl)methyl)-2H- tetrazol-5-yl)-6-methylpιcolιnamιde (Example 335) by reaction with (3-chloro-4-fluorophenyl)methanamιne ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1 09 (t, J=9 88 Hz, 5 H), 1 57 (s, 2 H), 1 79 (s, 2 H), 1 91 (d, J=13 91 Hz, 2 H), 2 66 (s, 3 H), 4 43 - 4 53 (m, 3 H), 4 63 (d, J=Q 59 Hz, 2 H), 7 34 (d, J=I 32 Hz, 2 H), 7 53 (d, J=7 32 Hz, 1 H), 8 05 (S, 1 H), 8 39 (s, 1 H), 9 34 (t, J=Q 22 Hz, 1 H)

Example 338

/V-(3-Chloro-4-fluorobenzyl)-4-(2-(((c/s)-4-hydroxycycloh exyl)methyl)-2H-tetrazol-5-yl)-6- methylpicolinamide

The title compound (18 8 mg, 55%) was prepared in a similar manner to λ/-(4-fluoro-3- methylbenzyl)-4-(2-(((c/s)-4-hydroxycyclohexyl)methyl)-2/-/- tetrazol-5-yl)-6-methylpιcolιnamιde

(Example 336) by reaction with (3-chloro-4-fluorophenyl)methanamιne ¹ H NMR (400 MHz, DMSOd ₆ ) δ ppm 1 01 - 1 18 (m, 4 H), 1 57 (s, 3 H), 1 79 (s, 2 H), 1 91 (d, J=13 91 Hz, 1 H), 2 66 (s, 3 H), 4 43 - 4 54 (m, 3 H), 4 63 (d, J=6 59 Hz, 2 H), 7 34 (d, J= 7 32 Hz, 2 H), 7 53 (d, J=8 05 Hz, 1 H), 8 05 (s, 1 H), 8 39 (s, 1 H), 9 34 (t, J=6 22 Hz, 1 H)

Example 339

W-(3-Ethoxybenzyl)-4-(2-((((rans)-4-hydroxycyclohexyl)met hyl)-2H-tetrazol-5-yl)-6- methylpicolinamide

The title compound (18 5 mg, 13%) was prepared in a similar manner to λ/-(4-fluoro-3- methylbenzyl)-4-(2-(((<rans)-4-hydroxycyclohexyl)methyl)- 2H-tetrazol-5-yl)-6-methylpιcolιnamιde

(Example 335) by reaction with (3-ethoxyphenyl)methanamιne (prepared as described in step 2 of the synthesis of λ/-(3-ethoxybenzyl)-6-methyl-4-(2-(((frans)-4-(methylsulfon amιdo)cyclohexyl)methyl)-2H- tetrazol-5-yl)pιcohnamιde, Example 180) ¹ H NMR (400 MHz, DMSOd ₆ ) δ ppm 1 09 (t, J=9 88 Hz, 5 H), 1 28 (t, J=6 95 Hz, 3 H), 1 57 (s, 2 H), 1 79 (s, 2 H), 1 93 (s, 1 H), 2 65 (s, 3 H), 3 27 (s, 1 H), 3 97 (q, J=6 59 Hz, 2 H), 4 41 - 4 53 (m, 2 H), 4 63 (d, J=6 59 Hz, 2 H), 6 78 (d, J=8 05 Hz, 1 H), 6 87 (s, 2 H), 7 20 (t, J=8 05 Hz, 1 H), 8 05 (s, 1 H), 8 40 (s, 1 H), 9 18 (t, J=6 59 Hz, 1 H)

Example 340

W-(4-Fluoro-3-methoxybenzyl)-4-(2-(((frans)-4-hydroxycycl ohexyl)methyl)-2H-tetrazol-5-yl)-6- methylpicolinamide

The title compound (20 9 mg, 15%) was prepared in a similar manner to λ/-(4-fluoro-3- methylbenzyl)-4-(2-(((/rans)-4-hydroxycyclohexyl)methyl)-2H- tetrazol-5-yl)-6-methylpιcolιnamιde (Example 335) by reaction with 4-fluoro-3-methoxybenzylamιne hydrochloride (prepared as described in step 3 of the synthesis of λ/-(4-fluoro-3-methoxybenzyl)-6-(2-((frans-4-amιnocyclohex yl)methyl)-2/-/- tetrazol-5-yl)pyrιmιdιne-4-carboxamιde, Example 1 ) ¹ H NMR (400 MHz, DMSOd ₆ ) δ ppm 1 31 (d, J=Q 78 Hz, 2 H), 1 43 (t, J=10 25 Hz, 3 H), 1 59 (dd, J=10 25, 4 39 Hz, 2 H), 2 05 (s, 1 H), 2 51 (s, 1 H), 2 65 (s, 3 H), 3 72 (d, J= 10 25 Hz, 1 H), 3 80 (s, 3 H), 4 27 (d, J=2 93 Hz, 1 H), 4 48 (d, J=6 59 Hz, 2 H), 4 65 (d, J=7 32 Hz, 2 H), 6 89 (s, 1 H), 7 07 - 7 13 (m, 1 H), 7 13 - 7 19 (m, 1 H), 8 05 (s, 1 H), 8 40 (s, 1 H), 9 17 - 9 25 (m, 1 H)

Example 341 rac-/V-(4-Fluoro-3-methoxybenzyl)-6-methyl-4-(2-((3-oxocyclo pentyl)methyl)-2H-tetrazol-5- yl)picolinamide

Step 1 Preparation of (3, 3-dιmethoxycvclopentyl)methanol

/ O

O

A solution of methyl S.S-dimethoxycyclopentanecarboxylate (Tetrahedron 1977, 33, 1 1 13) (6 22 g) in anhydrous tetrahydrofuran (60 mL) was added dropwise to a solution of 2 M lithium aluminum hydride (20 mL) in anhydrous tetrahydrofuran (240 mL) and the mixture was heated at 40 ⁰ C for 18 hours The reaction mixture was cooled in an ice bath and water (7 mL) was added slowly, followed by 10% aqueous sodium hydroxide (2 0 mL) The mixture was heated to 40 ⁰ C for an hour The mixture was filtered through a pad of neutral alumina and rinsed with tetrahydrofuran The filtrate was concentrated to afford the title compound as an oil (4 77 g) ¹ H NMR (400 MHz, CDCI ₃ ) ÏŒ ppm 3 47 - 3 56 (m, 2 H), 3 18 (s, 3 H), 3 18 (s, 3 H), 2 19 - 2 29 (m, 1 H), 1 97 (dd, J=13 2, 8 9 Hz, 1 H), 1 92 (s, 1 H), 1 72 - 1 84 (m, 3 H), 1 51 - 1 58 (m, 1 H), 1 36 - 1 47 (m, 1 H)

Step 2 Preparation of rac-λ/-(4-fluoro-3-methoxybenzyl)-6-methyl-4-(2-((3-oxocvcl opentyl)methyl)-2/-/- tetrazol-5-yl)pιcolιnamιde

A mixture of λ/-(4-fluoro-3-methoxybenzyl)-6-methyl-4-(2H-tetrazol-5-yl) pιcolιnamιde (prepared as described in step 2 of the synthesis of λ/-(4-fluoro-3-methoxybenzyl)-4-(2-(((/rans)-4- amιnocyclohexyl)methy!)-2/-/-tetra2θl-5-yl)-6-methylpιcol ιnamιde, Example 170) (500 mg), (3,3- dιmethoxycyclopentyl)methanol (350 mg), polymer support triphenylphosphine (1 388 g, 3 0 mmol) in anhydrous tetrahydrofuran (50 mL) was cooled in an ice bath Di-tert-butylazodicarboxylate (403 mg) was added and the mixture was placed in an ultrasonic bath for one hour After standing overnight, the mixture was filtered and the resin was washed with tetrahydrofuran and methanol The filtrate was acidified with tπfluoroacetic acid and concentrated The residue was purified by reverse phase preparative HPLC (acetonitrile/water, 50/50 - 75/25) The product containing fractions were concentrated The aqueous residue was made basic with 5% aqueous sodium bicarbonate and extracted with dichloromethane (3 x 5 mL) The combined organic layers were dried over magnesium

sulfate, filtered and concentrated to afford the title compound (435 mg) MS (ES+) m/z 439 (M+H) ¹ H NMR (400 MHz, DMSO-c/ ₆ ) δ ppm 9 24 (t, J=Q 2 Hz, 1 H), 8 43 (s, 1 H), 8 08 (s, 1 H), 7 09 - 7 21 (m, 2 H), 6 90 (s, 1 H), 4 91 (d, J=I 3 Hz, 2 H), 4 50 (d, J=6 2 Hz, 2 H), 3 82 (s, 3 H), 2 88 - 2 97 (m, 1 H), 2 68 (s, 3 H), 2 27 - 2 37 (m, 1 H), 2 18 - 2 24 (m, 2 H), 1 99 - 2 17 (m, 2 H), 1 67 - 1 77 (m, 1 H)

Example 342 rac-/V-(4-Fluoro-3-methoxybenzyl)-4-(2-(((1/?*,3/?*)-3-hydro xycyclopentyl)methyl)-2H-tetrazol-5- yl)-6-methylpicolinamide

A 2 M solution of lithium aluminum hydride in tetrahydrofuran (0 20 ml_) was added to a cooled solution (ice/acetone bath) of rac-λ/-(4-fluoro-3-methoxybenzyl)-6-methyl-4-(2-((3- oxocyclopentyOmethyO^H-tetrazol-δ-yOpicolinamide (prepared as described in Example 341 ) (272 mg) in anhydrous tetrahydrofuran (5 0 mL) under nitrogen The mixture was allowed to stir for 5 minutes and was then quenched with methanol (1 mL) The reaction mixture was concentrated and the residue was purified by reverse phase preparative HPLC (acetonitrile/water, 40/60 - 60/40) Fractions containing the first eluting isomer were combined and concentrated The aqueous residue was extracted with dichloromethane (3 x 5 mL) The organic layer was dried over magnesium sulfate, filtered, and concentrated to afford the title compound (83 mg) MS (ES+) m/z 441 (M+H) ¹ H NMR (400 MHz, DMSO-Cy ₆ ) δ ppm 9 23 (t, J=5 9 Hz, 1 H), 8 43 (s, 1 H), 8 08 (s, 1 H), 7 15 - 7 20 (m, 1 H), 7 09 - 7 15 (m, 1 H), 6 86 - 6 93 (m, 1 H), 4 73 (d, J=I 3 Hz, 2 H), 4 50 (d, J=Q 2 Hz, 2 H), 4 43 (s, 1 H), 4 16 (s, 1 H), 3 82 (s, 3 H), 2 75 - 2 83 (m, 1 H), 2 67 (s, 3 H), 1 77 - 1 86 (m, 2 H), 1 62 (d, J=Q 6 Hz, 1 H), 1 43 - 1 52 (m, 2 H), 1 28 - 1 38 (m, 1 H)

Example 343 rac-W-(4-Fluoro-3-methoxybenzyl)-4-(2-(((1/?*,3S*)-3-hydroxy cyclopentyl)methyl)-2W-tetrazol-5- yl)-6-methylpicotinamide

Isolation of the second eluting isomer by reverse phase preparative HPLC from the reaction mixture described in Example 342 afforded the title compound as a white solid (122 mg) MS(ES+) m/z 441 (M+H) ¹ H NMR (400 MHz, DMSO-CZ ₆ ) δ ppm 9 23 (t, J=Q 2 Hz, 1 H), 8 43 (s, 1 H), 8 07 (s, 1 H), 7 15 - 7 20 (m, 1 H), 7 10 - 7 15 (m, 1 H), 6 87 - 6 93 (m, 1 H), 4 78 (d, J=I 3 Hz, 2 H), 4 56 (d, J=3 7 Hz, 1 H), 4 50 (d, J=Q 2 Hz, 2 H), 4 10 - 4 16 (m, 1 H), 3 82 (s, 3 H), 2 67 (s, 3 H), 2 55 - 2 62 (m, 1 H), 1 86 - 1 94 (m, 1 H), 1 62 - 1 70 (m, 2 H), 1 52 - 1 62 (m, 2 H), 1 31 - 1 38 (m, 1 H)

Example 344

A/-(3-Methoxybenzyl)-4-(2-(((c/s)-4-hydroxy-4-(hydroxymet hyl)cyclohexyl)methyl)-2H-tetrazol-5- yl)-6-methylpicolinamide

Step 1 Preparation of 4-(2-(1 ,4-dιoxaspιro[4 51dec-8-ylmethyl)-2H-tetrazol-5-yl)-λ/-(3-methoxybenzyl)- 6-methylpyrιdιne-2-carboxamιde

1 ,4-Dιoxaspιro[4 5]dec-8-ylmethyl 4-methylbenzenesulfonate (prepared as described in step 1 of the synthesis of λ/-(3-methoxybenzyl)-6-(2-(((<rans)-4-hydroxy-4-(hydroxy methyl)cyclohexyl)methyl)- 2H-tetrazol-5-yl)-2-methylpyrιmιdιne-4-carboxamιde, Example 28) (1 4 g, 4 3 mmol) is added to a mixture of /V-(3-methoxybenzyl)-6-methyl-4-(2H-tetrazol-5-yl)pιcolιna mιde (prepared as described in step 5 of the synthesis of λ/-(3-methoxybenzyl)-4-(2-(((frans)-4-amιnocyc!ohexyl)meth yl)-2/-/-tetrazol-5- yl)-6-methylpιcolιnamιde, Example 153) (1 39 g, 4 3 mmol) and triethylamine (434 mg) in anhydrous /V,λ/-dιmethylacetamιde (2 mL) The mixture was stirred at 85 ⁰ C for 64 hours The reaction mixture is purified by reverse phase preparative HPLC to afford the title compound as an oil (1 7 g)

Step 2 Preparation of λ/-(3-methoxybenzyl)-6-methyl-4-(2-((4-oxocvclohexyl)methyl )-2H-tetrazol-5- vQpicolinamide

Formic acid (96%, 20 mL) was added to a solution of 4-(2-(1 ,4-dιoxaspιro[4 5]dec-8-ylmethyl)- 2/-/-tetrazol-5-yl)-λ/-(3-methoxybenzyl)-6-methylpyrιdιne -2-carboxamιde (1 6 g, 3 3 mmol) in tetrahydrofuran (13 mL) and the mixture is stirred overnight at room temperature The reaction mixture is concentrated and the residue is dissolved in dichloromethane The mixture was washed with saturated aqueous sodium bicarbonate solution The organic layer was dried over magnesium sulfate and concentrated to afford the title compound as a white solid (1 6 g)

Step 3 Preparation of λ/-(3-methoxybenzyl)-6-methyl-4-(2-(1-oxaspιrof2 51oct-6-ylmethyl)-2H-tetrazol- 5-yl)pyrιdιne-2-carboxamιde

A solution of λ/-(3-methoxybenzyl)-6-methyl-4-(2-((4-oxocyclohexyl)methyl )-2H-tetrazol-5- yl)pιcolιnamιde (445 mg, 1 0 mmol) in anhydrous dimethylsulfoxide (4 mL) was added to a solid mixture of trimethylsulfoxonium iodide (445 mg, 2 0 mmol) and potassium t-butoxide (225 mg, 2 0 mmol) The mixture was allowed to stir at room temperature for 30 minutes Water (25 mL) was then added and the slurry was stirred at room temperature for 20 minutes The resulting precipitate was filtered, washed with water and dried under vacuum to afford the title compound (266 mg) Step 4 Preparation of λ/-(3-methoxybenzyl)-4-(2-(((c<s)-4-hvdroxy-4-

(hvdroxymethyl)cvclohexyl)methyl)-2H-tetrazol-5-yl)-6-met hylpιcolιnamιde

Perchloric acid (70%, 0 4 mL) was added to λ/-(3-methoxybenzyl)-6-methyl-4-(2-(1 - oxaspιro[2 5]oct-6-ylmethyl)-2H-tetrazol-5-yl)pyrιdιne-2-carboxamιde (260 mg, 0 58 mmol) in a mixture of tetrahydrofuran (4 ml) and water (1 2 mL) The mixture was allowed to stir at room temperature for 3 5 hours The reaction mixture was purified by reverse phase preparative HPLC followed by elution through a carbonate resin column The resulting mixture of isomers were separated by supercritical fluid chiral chromatography (OJ-H column, 30 x 250 mm, 20% 2-propanol, 70 mL/min) and the first eluting isomer was isolated to afford the title compound as a white solid (32 mg) MS (ES+) m/z 467 (M+H) ¹ H NMR (400 MHz, DMSO-Cf ₆ ) δ ppm 9 19 (t, J=6 4 Hz, 1 H), 8 41 (s, 1 H), 8 06 (s, 1 H), 7 22 (t, J=& 1 Hz, 1 H), 6 88 - 6 92 (m, 2 H), 6 80 (d, J=& 8 Hz, 1 H), 4 64 (d, J=I 0 Hz, 2 H), 4 49 (d, J=Q 2 Hz, 2 H), 4 39 (t, J=5 3 Hz, 1 H), 3 80 (s, 1 H), 3 71 (s, 3 H), 3 10 (d, J=5 5 Hz, 2 H), 2 65 (s, 3 H), 1 87 - 1 97 (m, 1 H), 1 25 - 1 49 (m, 8 H)

Example 345 W-(3-Methoxybenzyl)-4-(2-((((rans)-4-hydroxy-4-(hydroxymethy l)cyclohexyl)methyl)-2H-tetrazol-

5-yl)-6-methylpicolinamide

Isolation of the second eluting isomer by supercritical fluid chiral chromatography (OJ-H column, 30 x 250 mm, 20% 2-propanol, 70 mUmin) from the reaction mixture described in Example 344 afforded the title compound as a white solid (54 mg) MS (ES+) m/z 467 (M+H)

Example 346

W-(3-(2-Hydroxyethoxy)benzyl)-6-methyl-4-(2-(((frans)-4- (methylsulfonylmethyl)cyclohexyl)methyl)-2/-/-tetrazol-5-yl) picolinamide

Step 1 Preparation of ((frans)-4-(hvdroxymethyl)cvclohexyl)methyl 4-methylbenzenesulfonate

4-Methylbenzenesulfonyl chloride (19 O g, 100 mmol) was added to a solution of fraπs- 1 ,4- cyclohexane dimethanol (14 4 g, 100 mmol) in anhydrous pyridine (50 mL) cooled in an ice bath The mixture was allowed to warm to room temperature and was stirred for 18 hours The reaction mixture was diluted with ether (300 mL), poured into water (400 mL), and filtered The separated aqueous layer was further extracted with ether (2 x 200 mL) The combined organic layers were washed with water (200 mL), 1 N hydrochloric acid (2 x 200 mL), water (200 mL), and saturated aqueous sodium bicarbonate solution (200 mL) The organic layer was dried over magnesium sulfate and concentrated to afford the title compound as an oil (14 8 g)

Step 2 Preparation of methyl 6-methyl-4-(2-(((frans)-4-((tosyloxy)methyl)cvclohexyl)methy l)-2/-/- tetrazol-5-yl)pιcolιnate

In a 100 ml round-bottomed flask under nitrogen at room temperature, methyl 6-methyl-4-(2H- tetrazol-5-yl)pιcolιnate (prepared as described in step 4 of the synthesis of /V-(3-methoxybenzy!)-4-(2- (((<raπs)-4-amιnocyclohexyl)methyl)-2/-/-tetrazol-5-yl) -6-methylpιcolιnamιde, Example 153) (0 835 mg,

3 81 mmol) was combined with ((fra/7s)-4-(hydroxymethyl)cyclohexyl)methyl 4- methylbenzenesulfonate (1 25 g, 4 19 mmol), polymer supported-tÏ€phenylphosphine (4 87 g, 10 5 mmol) and tetrahydrofuran (30 mL) The mixture was cool to 0 ⁰ C in a dry ice bath for 20 minutes and di-terf-butyl azodicarboxylate (1 75 g, 7 62 mmol) was added The mixture was stirred in a dry ice bath for 1 hour and then allowed to warm to room temperature and stir overnight The reaction mixture was filtered and the resin was washed with tetrahydrofuran The residue was purified by reverse phase preparative HPLC to afford the title compound (1 295 g) LC/MS (5%-95% CH ₃ CN/H ₂ O, 5 mm ) 3 565 mm , m/z 500 (M+H) ¹ H NMR (400 MHz, CDCI ₃ ) δ ppm 0 88 - 1 18 (m, 3 H), 1 55 - 1 82 (m, 4 H), 1 95 - 2 12 (m, 1 H), 2 38 - 2 46 (m, 3 H), 2 91 (s, 3 H), 3 79 (d, J=6 18 Hz, 2 H), 4 04 (s, 3 H), 4 56 (d, J=I 25 Hz, 2 H), 7 31 (d, J=8 06 Hz, 2 H), 7 67 - 7 79 (m, 2 H), 8 44 (s, 1 H), 8 85 (s, 1 H), 13 80 (s, 2 H)

Step 3 Preparation of methyl 6-methyl-4-(2-(((frans)-4-(methylthιomethyl)cvclohexyl)meth yl)-2/-/- tetrazol-5-yl)pιcolιnate

Sodium thiomethoxide (0 363 g, 5 18 mmol) was added to a solution of methyl 6-methyl-4-(2-

(((<rans)-4-((tosyloxy)methyl)cyclohexyl)methyl)-2H-tetra zol-5-yl)pιcolιnate (1 295 g, 2 592 mmol) in dimethylsulfoxide (20 mL) and the mixture was heated at 50 ⁰ C for 2 hours The reaction mixture was passed through a silica plug, eluted with ethyl acetate, and concentrated The residue was purified by reverse phase preparative HPLC to afford the title compound as a clear, light yellow colored oil (0 973 g) LC/MS (5%-95% CH ₃ CN/H ₂ O, 5 mm ) 3 536 mm , m/z 376 (M+H)

Step 4 Preparation of methyl 6-methyl-4-(2-((((rans)-4-(methylsulfonylmethyl)cvclohexyl)m ethyl)-2H- tetrazol-5-yl)pιcolιnate

3-Chloroperoxybenzoιc acid (772 mg, 4 47 mmol) was added to a solution of methyl 6-methyl- 4-(2-(((frans)-4-(methylthιomethyl)cyclohexyl)methyl)-2H-te trazol-5-yl)pιcolιnate (381 4 mg, 1 016 mmol) in dichloromethane (10 mL) and the mixture was allowed to stir overnight A saturated aqueous sodium bicarbonate solution (5 mL) was added The organic layer was separated, dried over magnesium sulfate, filtered, and concentrated to afford the title compound as a clear, colorless oil (415 mg) LC/MS (5%-95% CH ₃ CN/H ₂ O, 5 mm ) 2 626 mm , m/z 408 (M+H)

Step 5 Preparation of 6-methyl-4-(2-(((/rans)-4-(methylsulfonylmethyl)cvclohexyl)m ethyl)-2H-tetrazol- 5-yl)pιcolιnιc acid

A solution of lithium hydroxide (1 M, 1 ml, 1 0 mmol) was added to a solution of methyl 6- methyl-4-(2-(((^ans)-4-(methylsulfonylmethyl)cyclohexyl)meth yl)-2/-/-tetrazol-5-yl)pιcolιnate (414 mg, 1 02 mmol) in tetrahydrofuran (10 mL) The mixture was allowed to stir at room temperature overnight and was then concentrated to afford the title compound LC/MS (5%-95% CH ₃ CN/H ₂ O, 5 mm ) 2 090 mm , m/z 394 (M+H) ¹ H NMR (400 MHz, CDCI ₃ ) δ ppm 1 08 - 1 29 (m, 4 H), 1 99 (s, 1 H), 2 00 - 2 17 (m, 4 H), 2 86 - 3 00 (m, 8 H), 4 60 (d, J=6 98 Hz, 2 H), 8 48 (s, 1 H), 8 87 (s, 1 H), 12 53 (br s , 2 H) Step 6 Preparation of λ/-(3-(2-hvdroxyethoxy)benzyl)-6-methyl-4-(2-((((rans)-4-(m ethylsulfonylmethyl)- cvclohexyl)methyl)-2/-/-tetrazol-5-yl)pιcolιnamιde

A mixture of 6-methyl-4-(2-(((frans)-4-(methylsulfonylmethyl)cyclohexyl)m ethyl)-2/-/-tetrazol-5- yl)pιcolιnιc acid (50 0 mg, 0 130 mmol), dnsopropylethylamine (150 mg, 1 10 mmol), and 2-(3- (amιnomethyl)phenoxy)ethanol (prepared as described in step 2 of the synthesis of λ/-(3-(2- hydroxyethoxy)benzyl)-6-(2-(((/rans)-4-amιnocyclohexyl)meth yl)-2H-tetrazol-5-yl)-2-methylpyrιmιdιne- 4-carboxamιde, Example 13) (42 0 mg, 0 250 mmol) in λ/,λ/-dιmethylformamιde (2 0 mL) was stirred for 20 minutes O-(1 H-Benzotrιazol-1-yl)-W,W,/V,W-tetramethyluronιum tetrafluoroborate (102 mg,

0 318 mmol) was added and the mixture was stirred for 3 hours The reaction mixture was purified by reverse phase preparative HPLC to afford the title compound as the trifluoroacetate salt (38 0 mg,

55% yield) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1 05 - 1 16 (m, 14 H), 1 61 (d, J= 10 25 Hz, 9 H),

1 90 (d, J=10 98 Hz, 11 H), 2 65 (s, 9 H), 2 90 - 2 96 (m, 10 H), 2 99 (d, J=6 59 Hz, 7 H), 3 67 (d, J=A 39 Hz, 7 H), 3 93 (t, J=5 12 Hz, 8 H), 4 49 (d, J=6 59 Hz, 9 H), 4 64 (d, J=I 32 Hz, 8 H), 6 85 - 6 93 (m, 6 H)

Example 347

/V^S-HydroxybenzyO-β-methyM^Z^^ffansJ^^methylsulfonylmet hyOcyclohexyOmethyO^H- tetrazol-5-yl)picolinamide

The title compound (49 O mg, 77%) was prepared in a similar manner to λ/-(3-(2- hydroxyethoxy)benzyl)-6-methyl-4-(2-(((^rans)-4-(methylsulfo nylmethyl)cyclohexyl)methyl)-2/-y-tetrazol- 5-yl)pιcolιnamιde (Example 346) by reaction with 3-(amιnomethyl)phenol ¹ H NMR (400 MHz, DMSO- d ₆ ) <5 ppm 1 05 - 1 16 (m, 17 H), 1 61 (d, J=10 98 Hz, 1 1 H), 1 82 - 1 93 (m, 14 H), 2 65 (s, 12 H), 2 90 - 2 97 (m, 12 H), 2 99 (d, J=5 86 Hz, 8 H), 4 44 (d, J=6 59 Hz, 10 H), 4 64 (d, J=6 59 Hz, 9 H), 6 70 - 6 77 (m, 7 H)

Example 348

^-(S-Chloro^-fluorobenzylJ-β-methyM-IZ^^fransJ^^methylsu lfonylmethyOcyclohexyOmethyl)- 2H-tetrazol-5-yl)picolinamide

The title compound (48 0 mg, 58%) was prepared in a similar manner to λ/-(3-(2- hydroxyethoxy)benzyl)-6-methyl-4-(2-(((frans)-4-(methylsulfo nylmethyl)cyclohexyl)methyl)-2H-tetrazol- 5-yl)pιcolιnamιde (Example 346) by reaction with (3-chloro-4-fluorophenyl)methanamιne ¹ H NMR (400 MHz, DMSO-Cf ₆ ) δ ppm 1 04 - 1 15 (m, 18 H), 1 61 (d, J=1 1 71 Hz, 12 H), 1 81 - 1 93 (m, 16 H), 2 66 (s, 13 H), 2 89 - 2 95 (m, 12 H), 2 99 (d, J=5 86 Hz, 9 H), 4 49 (d, J=5 86 Hz, 10 H), 4 64 (d, J=6 59 Hz, 10 H)

Example 349

W-(4-Fluoro-3-methoxybenzyl)-6-methyl-4-(2-(((frans)-4- (methylsulfonylmethy^cyclohexylJmethyl^H-tetrazol-S-yOpicoli namide

The title compound (76 5 0 mg, 56%) was prepared in a similar manner to λ/-(3-(2- hydroxyethoxy)benzyl)-6-methyl-4-(2-(((frans)-4-(methylsulfo nylmethyl)cyclohexyl)methyl)-2H-tetrazol- 5-yl)pιcolιnamιde (Example 346) by reaction with 4-fluoro-3-methoxybenzylamιne hydrochloride (prepared as described in step 3 of the synthesis of λ/-(4-fluoro-3-methoxybenzyl)-6-(2-((frans-4- amιnocyclohexyl)methyl)-2H-tetrazol-5-yl)pyrιmιdιne-4-ca rboxamιde, Example 1 ) ¹ H NMR (400 MHz, DMSO-(Z ₆ ) S PPm 1 08 - 1 16 (m, 12 H), 1 61 (d, J=10 26 Hz, 10 H), 1 82 - 1 93 (m, 12 H), 1 97 (s, 7

H), 2 65 (s, 9 H), 2 92 (s, 9 H), 2 99 (d, J=5 86 Hz, 8 H), 3 80 (s, 8 H), 4 48 (d, J=5 86 Hz, 9 H), 4 64 (d, J=5 86 Hz, 8 H), 7 06 - 7 18 (m, 7 H)

Example 350

N-(3-(Hydroxymethyl)benzyl)-6-methyl-4-(2-(((frans)-4- (methylsulfonylmethyOcyclohexyOmethyO-σH-tetrazol-δ-yOpico linamide

The title compound (45 O mg, 69%) was prepared in a similar manner to λ/-(3-(2- hydroxyethoxy)benzyl)-6-methyl-4-(2-(((frans)-4-(methylsulfo nylmethyl)cyclohexyl)methyl)-2H-tetrazol- 5-yl)pιcolιnamιde (Example 346) by reaction with (3-(amιnomethyl)phenyl)methanol ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1 04 - 1 16 (m, 17 H), 1 61 (d, J=11 71 Hz, 11 H), 1 81 - 1 93 (m, 14 H), 2 65 (s, 12 H), 2 89 - 2 95 (m, 12 H), 2 99 (d, J=5 86 Hz, 8 H), 4 45 (s, 7 H), 4 48 - 4 56 (m, 10 H), 4 64 (d, J=I 32 Hz, 9 H)

Example 351

W-(3-Methoxybenzyl)-4-(2-(((frans)-4-(aminomethyl)cyclohe xyl)methyl)-2H-tetrazol-5-yl)-6- methylpicolinamide

Step 1 Preparation of terf-butyl ((fransM-ihydroxymethvDcyclohexyDrnethylcarbarnate

A solution of trans 4-(fert-butyloxycarbonylamιno)methylcyclohexanecarboxylιc acid (5 O g, 19 mmol) in a mixture of 1 ,4-dιoxane/tetrahydrofuran (1 /1 , 20 mL) was added drop wise to a cooled suspension of lithium aluminum hydride (2 1 g, 57 mmol) and the resulting mixture was stirred at room temperature for 15 hours The excess of lithium aluminum hydride was destroyed by drop wise addition of water (2 mL) The suspension was filtered and the filter cake was washed with tetrahydrofuran (10 mL) and methanol (2 x 10 mL) The filtrate was concentrated in vacuo and extracted with ethyl acetate ( 3 x 15 mL) The combined organic layers were dried with sodium sulfate and concentrated to afford the title compound as a light amber oil which solidified on standing (3 7 g, 80%) LC/MS (5-100% CH ₃ CN/H ₂ O, 8 mm) 4 79 mm, m/z 266 (M+Na)

Step 2 Preparation of λ/-(3-methoxybenzyl)-4-(2-(((frans)-4-(amιnomethyl)cvclohe xyl)methyl)-2H- tetrazol-δ-vP-β-methylpicolinamide

A mixture of tert-butyl ((/ransH^hydroxymethyOcyclohexyOmethylcarbamate (O 75 g, 3 1 mmol), /V-(3-methoxybenzyl)-6-methyl-4-(2/-/-tetrazol-5-yl)pιcolι namιde (prepared as described in step 5 of the synthesis of λ/-(3-methoxybenzyl)-4-(2-(((<λans)-4-amιnocyclohexyl) methyl)-2/-/-tetrazol-5-yl)-6- methylpicolinamide, Example 153) (0 50 g, 1 5 mmol), and polymer supported-tÏ€phenylphosphine (1 85 g, 2 65 mmol) in tetrahydrofuran (25 0 mL) was cooled to 0 ⁰ C in an ice bath for 15 minutes Di- fert-butyl azodicarboxylate (755 mg, 3 08 mmol) was added and the mixture was allowed to warm to room temperature and stir for 48 hours The reaction mixture was filtered and the filtrate was concentrated The residue was dissolved in dichloromethane (4 mL) and tÏ€fluoroacetic acid (2 mL) was added The mixture was stirred for 30 minutes at room temperature and then concentrated in vacuo The residue was triturated with diethyl ether and further purified by reverse phase preparative HPLC (10-90% acetonitrile/water) to afford the title compound as a white solid (0 24 g, 52%) LC/MS (5-100% CH ₃ CN/H ₂ O, 8 mm) 4 59 mm, m/z 450 (M+H)

Example 352

W-(3-Methoxybenzyl)-4-(2-(((frans)-4-(acetamidomethyl)cyc lohexyl)methyl)-2H-tetrazol-5-yl)-6- methylpicolinamide

Triethylamine (0 031 ml) and acetyl chloride (0 010 mL) was added to a solution of λ/-(3- methoxybenzyl)- 4-(2-(((frans)-4-(amιnomethyl)cyclohexyl)methyl)-2/-/-tetra zol-5-yl)-6- methylpicohnamide (prepared as described in Example 351 ) (0 050 g, 0 010 mmol) in λ/,λ/- dimethylformamide (1 mL) and the mixture was stirred at room temperature for 4 hours The reaction mixture was diluted with water (2 mL) and extracted with ethyl acetate (2 x 5 mL) The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated The residue was purified by reverse phase preparative HPLC to afford the title compound as a solid (19 mg, 39%) ¹ H NMR (400 MHz, DMSOd ₆ ) δ ppm 9 13 - 9 25 (m, 1 H), 8 40 (s, 1 H), 8 05 (s, 1 H), 7 69 (s, 1 H), 7 17 - 7 26 (m, 1 H), 6 90 (s, 2 H), 6 80 (d, J=Q 05 Hz, 1 H), 4 64 (d, J=6 59 Hz, 2 H), 4 49 (d, J=6 59 Hz, 2 H), 3 71 (s, 3 H), 2 84 (t, J=5 86 Hz, 2 H), 2 65 (s, 3 H), 1 96 (d, J=2 93 Hz, 1 H), 1 76 (s, 3 H), 1 68 (d, J=11 71 Hz, 2 H), 1 60 (d, J=M 45 Hz, 2 H), 1 30 (s, 1 H), 0 98 - 1 12 (m, 2 H), 0 79 - 0 94 (m, 2 H)

Example 353

/V-(3-Methoxybenzyl)-6-methyl-4-(2-(((frans)-4-(methylsul fonamidomethyl)cyclohexyl)methyl)-

2H-tetrazol-5-yl)picolinamide

Triethylamine (0 031 ml) and methane sulfonylchloπde (0 010 mL) was added to a solution of

λ/-(3-methoxybenzyl)- 4-(2-(((/rans)-4-(amιnomethyl)cyclohexyl)methyl)-2/-/-tetra zol-5-yl)-6- methylpicolinamide (prepared as described in Example 351 ) (0 050 g, 0 010 mmol) in N, N- dimethylformamide (1 mL) and the mixture was stirred at room temperature for 4 hours The reaction mixture was diluted with water (2 mL) and extracted with ethyl acetate (2 x 5 mL) The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated The residue was purified by reverse phase preparative HPLC to afford the title compound as a solid (15 mg, 28%) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9 14 - 9 25 (m, 1 H), 8 41 (s, 1 H), 8 06 (s, 2 H), 7 16 - 7 27 (m, 1 H), 6 87 - 6 96 (m, 2 H), 6 80 (d, J=I 32 Hz, 1 H), 4 64 (d, J=I 32 Hz, 2 H), 4 49 (d, J=Q 59 Hz, 2 H), 3 71 (s, 3 H), 2 82 (s, 3 H), 2 74 (t, J=Q 59 Hz, 2 H), 2 65 (s, 3 H), 1 97 (s, 1 H), 1 75 (d, J=13 18 Hz, 2 H), 1 61 (d, J=1 1 71 Hz, 2 H), 1 34 (s, 1 H), 0 98 - 1 17 (m, 2 H), 0 79 - 0 95 (m, 2 H)

Example 354

/V-(4-Fluoro-3-methoxybenzyl)-4-(2-((((rans)-4-(aminometh yl)cyclohexyl)methyl)-2H-tetrazol-5- yl)-6-methylpicolinamide

Step 1 Preparation of methyl 4-(2-(((frans)-4-((feft-butoxycarbonyl)methyl)cvclohexyl)met hyl)-2/-/- tetrazol-5-yl)-6-methylpιcolιnate

A mixture of methyl 6-methyl-4-(2H-tetrazol-5-yl)pιcolιnate (prepared as described in step 4 of the synthesis of λ/-(3-methoxybenzyl)-4-(2-(((^rans)-4-amιnocyclohexyl)meth yl)-2H-tetrazol-5-yl)-6- methylpicolmamide, Example 153) (1 5Og, 6 85 mmol), te/t-butyl ((trans)-4-

(hydroxymethyl)cyclohexyl)methylcarbamate (prepared as described in step 1 of the synthesis of λ/-(3- methoxybenzyl)-4-(2-(((frans)-4-(amιnomethyl)cyclohexyl)met hyl)-2H-tetrazol-5-yl)-6-

methylpicolinamide, Example 351 ) (3 00 g, 12 3 mmol), and polymer supported-triphenylphosphine (7 78 g, 17 1 mmol) in tetrahydrofuran (150 mL) was cooled to 0 ⁰ C in an ice bath for 15 minutes Di- tert-butyl azodicarboxylate (3 15 g, 13 7 mmol) was added and the mixture was allowed to warm to room temperature and stir for 15 hours The reaction mixture was filtered and the filtrate was concentrated The residue was purified by silica gel chromatography (0-50% ethyl acetate/heptane) to afford the title compound as an beige solid (2 15 g, 71 %) LC/MS (5-100% CH ₃ CN/H ₂ O, 8 mm) 5 84 mm, m/z 445 (M+H)

Step 2 Preparation of 4-(2-(((frans)-4-((tert-butoxycarbonyl)methyl)cvclohexyl)met hyl)-2H-tetrazol-5- yl)-6-methylpιcolιnιc acid

An aqueous solution of sodium hydroxide (2 5 N, 5 0 mL) was added to a solution of methyl 4- (2-(((frans)-4-((/ert-butoxycarbonyl)methyl)cyclohexyl)methy l)-2H-tetrazol-5-yl)-6-methylpιcolιnate (0 50 g, 1 1 mmol) in tetrahydrofuran (5 mL) and water (2 mL) and the mixture was stirred at room temperature for 15 hours The tetrahydrofuran was removed in vacuo and the aqueous residue was acidified with aqueous hydrochloric acid to pH 7 The resulting white solid was filtered and dried to afford the title compound (0 45g, 92%) LC/MS (5-100% CH ₃ CN/H ₂ O, 8 mm) 5 10 mm, m/z 431 (M+H)

Step 3 Preparation of tert-butyl ((frans)-4-((5-(2-((4-fluoro-3-methoxybenzyl)carbamoyl)-6- methylpyrιdιn-4-yl)-2/-/-tetrazol-2-yl)methyl)cvclohexyl)m ethylcarbamate

A mixture of 4-(2-(((<rans)-4-((fert-butoxycarbonyl)methyl)cyclohexyl) methyl)-2H-tetrazol-5-yl)- 6-methylpιcolιnιc acid ( 0 080 g, 0 19 mmol) and 1-hydroxybenzatrιazole (30 mg, 0 22 mmol) in N ₁ N- dimethylacetamide (2 mL) was stirred for 5 minutes Triethylamine (0 028 g, 0 28 mmol), 4-fluoro-3- methoxybenzylamine hydrochloride (prepared as described in step 3 of the synthesis of /V-(4-fluoro-3- methoxybenzyl)-6-(2-((frans-4-amιnocyclohexyl)methyl)-2H-te trazol-5-yl)pyrιmιdιne-4-carboxamιde, Example 1 ) (35 mg, 0 22 mmol), and 1-(3-dιmethylamιnopropyl)-3-ethylcarbodιιmιde hydrochloride (53 mg, 0 28 mmol) were added, and the mixture was stirred at room temperature for 18 hours The reaction mixture was purified by reverse phase preparative HPLC to afford the title compound as solid (100 mg, 95%) LC/MS (5-100% CH ₃ CN/H ₂ O, 8 mm) 5 72 mm, m/z 568 (M+H)

Step 4 Preparation of λ/-(4-fluoro-3-methoxybenzyl)-4-(2-(((/rans)-4-(amιnomethy l)cvclohexyl)methyl)- 2H-tetrazol-5-yl)-6-methylpιcolιnamιde hydrochloride

A solution of hydrochloric acid in dioxane (4 N, 6 0 mL) was added to a solution of tert-butyl ((<rans)-4-((5-(2-((4-fluoro-3-methoxybenzyl)carbamoyl)-6 -methylpyridin-4-yl)-2H-tetrazol-2- yOmethylJcyclohexyOmethylcarbamate (105 mg, 0 185 mmol) in dichloromethane (2 mL) and the mixture was stirred for 1 5 hours The reaction mixture was concentrated and the residue was triturated with diethyl ether to afford the title compound as the hydrochloride salt (41 mg, 44%) ¹ H NMR (400 MHz, DMSOd ₆ ) 6 ppm 9 26 (br s , 1 H), 8 40 (br s , 1 H), 8 05 (br s , 1 H), 7 97 (br s , 1 H), 7 04 - 7 19 (m, 1 H), 6 87 (br s , 1 H), 4 65 (br s , 2 H), 4 47 (br s , 2 H), 3 79 (br s , 2 H), 3 54 (s, 3 H), 3 35 (br s , 1 H), 2 65 (br s , 3 H), 2 59 (br s , 1 H), 1 98 (br s , 1 H), 1 77 (d, J=9 94 Hz, 2 H), 1 61 (d, J=10 47 Hz, 2 H), 1 50 (br s , 1 H), 1 06 (br s , 2 H), 0 92 (d, J=Q 32 Hz, 2 H)

Example 355 fac-N^S-MethoxybenzyO^^Z-i^i/r.aS^J-a-lhydroxymethyOcyclopen tyOmethyO^H-tetrazol-S- yl)-6-methylpicolinamide

A mixture of λ/-(3-methoxybenzyl)-6-methyl-4-(2/-/-tetrazol-5-yl)pιcolÎ ¹namιde (prepared as described in step 5 of the synthesis of λ/-(3-methoxybenzyl)-4-(2-(((/rans)-4-amιnocyclohexyl)meth yl)- 2H-tetrazol-5-yl)-6-methylpιcolιnamιde, Example 153) (325 mg), c/s-cyclopentane-1 ,3-dιmethanol (Bioorg Med Chem Lett 2005, 15, 2685-2688) (203 mg), and polymer supported triphenylphosphine (1 27 g) in anhydrous tetrahydrofuran (15 mL) was cooled in an ice bath Dι-fert-butyl azodicarboxylate (345 mg) was added and the mixture was placed in an ultrasonic bath for 30 minutes The mixture was filtered and the resin was washed with tetrahydrofuran The filtrate was concentrated and the residue was purified by reverse phase preparative HPLC (acetonitÏ€le/water, 40/60 - 70/30) The product was dissolved in dichloromethane (20 mL) and stirred with Argonaut MP- CO ₃ H resin (2 62 mmol/g, 0 9 g) and eluting through a Stratosphere MP-CO ₃ H SPE column The eluent was concentrated to afford the title compound as an oil (245 mg) MS (ES+) m/z 437 (M+H) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9 19 (t, J=6 2 Hz, 1 H), 8 40 (s, 1 H), 8 05 (s, 1 H), 7 22 (t, J=8 2 Hz, 1 H), 6 87 - 6 92 (m, 2 H), 6 79 (dd, J=8 1 , 1 5 Hz, 1 H), 4 67 - 4 77 (m, 2 H), 4 49 (d, J=6 6 Hz, 2 H), 4 41 (t, J=5 1 Hz, 1 H), 3 71 (s, 3 H), 3 23 - 3 32 (m, 2 H), 2 65 (s, 3 H), 2 50 - 2 59 (m, 1 H), 1 96 - 2 07 (m, 1 H), 1 74 - 1 84 (m, 1 H), 1 57 - 1 71 (m, 2 H), 1 31 - 1 42 (m, 2 H), 0 96 - 1 06 (m, 1 H)

Example 356 rac-W-(3-Methoxybenzyl)-4-(2-(((1/?* ₎ 3S*)-3-(aminomethyl)cyclopentyl)methyl)-2H-tetrazol-5-yl)-

6-methylpicolinamide

Step 1 Preparation of rac-((1 S ^* .3/? ^* )-3-((5-(2-((3-methoxybenzyl)carbannoyl)-6-methylpyrιdιn-4 -yl)-2H- tetrazol-2-yl)methvDcvclopentyl)methyl methanesulfonate

Methanesulfonyl chloride (0 160 mL) was added to a solution of rac-λ/-(3-methoxybenzyl)-4- (2-(((1 /? ^* ,3S ^* )-3-(hydroxymethyl)cyclopentyl)methyl)-2H-tetrazol-5-yl)-6-m ethylpιcolιnamιde (prepared as described in Example 355) (742 mg) in pyridine (15 mL) cooled in an ice bath The mixture was allowed to warm to room temperature and was stirred for 3 hours The reaction mixture was concentrated and the residue was purified by reverse phase preparative HPLC (acetonitrile/water, 50/50 - 80/20) The combined fractions were made basic with 5% aqueous sodium bicarbonate (3 mL) and extracted with dichloromethane (3 x 10 mL) The combined organic layers were dried over magnesium sulfate, filtered, and concentrated to afford the title compound (752 mg) MS (ES+) m/z 515 (M+H) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9 19 (t, J=Q 4 Hz, 1 H), 8 41 (s, 1 H), 8 05 (s, 1 H), 7 22 (t, J=Q 1 Hz, 1 H), 6 87 - 6 92 (m, 2 H), 6 80 (d, J=8 1 Hz, 1 H), 4 76 (d, J=I 3 Hz, 2 H), 4 49 (d, J=6 2 Hz, 2 H), 4 05 - 4 14 (m, 2 H), 3 71 (s, 3 H), 2 65 (s, 3 H), 2 56 - 2 64 (m, 1 H), 2 52 (s, 3 H), 2 25 - 2 36 (m, 1 H), 1 85 - 1 94 (m, 1 H), 1 67 - 1 77 (m, 2 H), 1 38 - 1 48 (m, 2 H), 1 04 - 1 15 (m, 1 H)

Step 2 Preparation of rac-λ/-(3-methoxybenzyl)-4-(2-(((1 ff ^* ,3S*)-3-(amιnomethyl)cvclopentyl)methyl)- 2H-tetrazol-5-yl)-6-methylpιcolιnamιde

Ammonium hydroxide (2 mL) was added to a solution of rac-((1 S ^* ,3R ^* )-3-((5-(2-((3- methoxybenzyOcarbamoyO-θ-methylpyπdin^-yO^H-tetrazol-σ-yO methyOcyclopentyOmethyl methanesulfonate (227 mg) in DMSO (2 mL) and the mixture was heated to 70 °C overnight The mixture was poured into water (10 mL) and extracted with dichloromethane (2 x 5 mL) The combined organic layers were washed with water (5 mL), dried over magnesium sulfate, filtered and

concentrated The residue was purified by reverse phase preparative HPLC (acetonitrile/water, 30/70

- 60/40) The product containing fractions were concentrated The aqueous residue was made basic with 5% aqueous sodium bicarbonate and extracted with dichloromethane (5 x 10 mL) The combined organic layers were dried over magnesium sulfate, filtered and concentrated to afford the title compound as an oil (1 10 mg) MS (ES+) m/z 436 (M+H) ¹ H NMR (400 MHz, DMSO-c/ ₆ ) δ ppm 9 19 (t, J=Q 2 Hz, 1 H), 8 40 (s, 1 H), 8 05 (s, 1 H), 7 22 (t, J=8 1 Hz, 1 H), 6 90 (br s , 2 H), 6 80 (d, J=Q 1 Hz, 1 H), 4 72 (d, J=I 3 Hz, 2 H), 4 49 (d, J=Q 2 Hz, 2 H), 3 71 (s, 3 H), 2 65 (s, 3 H), 2 50 - 2 59 (m, 1 H), 1 78 - 1 94 (m, 2 H), 1 62 - 1 72 (m, 2 H), 1 23 - 1 44 (m, 2 H), 0 90 - 1 02 (m, 1 H)

Example 357 rac-N-(3-Methoxybenzyl)-6-methyl-4-(2-(((1 /?\3S*)-3-

(methylsulfonamidomethyOcyclopentylJmethyO-ZH-tetrazol-S- yOpicolinamide

Methanesulfonyl chloride (1 1 4 μL) was added to a mixture of rac-λ/-(3-methoxybenzyl)-4-(2- (((1 R*,3S*)-3-(amιnomethyl)cyclopentyl)methyl)-2H-tetrazol-5-yl )-6-methylpιcolιnamιde (prepared as described in Example 356) (53 mg) and diisopropylethylamme (30 μL) in anhydrous tetrahydrofuran (3 mL) The mixture was stirred at room temperature for 1 hour and was then concentrated The residue was purified by reverse phase preparative HPLC (acetonitrile/water, 50/50 - 75/25) The product containing fractions were concentrated The aqueous residue was made basic with 5% aqueous sodium bicarbonate and extracted with dichloromethane (3 x 10 mL) The combined organic layers were dried over magnesium sulfate, filtered and concentrated to afford the title compound as an oil (63 mg) MS (ES+) m/z 514 (M+H) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9 19 (t, J=Q 2 Hz, 1 H), 8 41 (s, 1 H), 8 05 (S, 1 H), 7 22 (t, J=8 1 Hz, 1 H), 6 87 - 6 95 (m, 3 H), 6 80 (d, J=8 1 Hz, 1 H), 4 74 (d, J=I 3 Hz, 2 H), 4 49 (d, J=Q 2 Hz ₁ 2 H), 3 71 (s, 3 H), 2 87 (t, J=Q Q Hz, 2 H), 2 83 (s, 3 H), 2 65 (s, 3 H), 2 52

- 2 62 (m, 1 H), 2 00 - 2 1 1 (m, 1 H), 1 82 - 1 92 (m, 1 H), 1 65 - 1 74 (m, 2 H), 1 28 - 1 47 (m, 2 H), 0 95 - 1 06 (m, 1 H)

Example 358 /V-(3-Methoxybenzyl)-6-methyl-4-(2-((S)-piperidin-3-ylmethyl )-2W-tetrazol-5-yl)picolinamide

Step 1 Preparation of (3S)-terf-butyl 3-((5-(2-((3-methoxybenzyl)carbamoyl)-6-methylpyrιdιn-4-yl )-2/-/- tetrazol-2-yl)methyl)pιperιdιne-1-carboxylate

λ/-(3-Methoxybenzyl)-6-methyl-4-(2/-/-tetrazol-5-y!)pιcolÎ ¹namιde (prepared as described in step 5 of the synthesis of λ/-(3-Methoxybenzyl)-4-(2-(((frans)-4-amιnocyclohexyl)meth yl)-2H-tetrazol-5-yl)-6- methylpicolinamide, Example 153) (324 mg, 1 0 mmol), polymer supported triphenylphosphine (698 mg, 1 5 mmol), and (S)-1-Boc-3-(hydroxymethyl)pιperιdιne (258 mg, 1 2 mmol) were suspended in tetrahydrofuran (16 mL) Di-tert-butyl azodicarboxylate (345 mg, 1 5 mmol) was added The mixture was allowed to stir for 18 hours The reaction mixture was filtered and the resin washed with tetrahydrofuran (20 mL) The filtrate was concentrated The crude product was purified by silica column chromatography (heptane/EtOAc, 2/1 , 1/1 ) Fractions containing the product were concentrated to afford the title compound as an oil (461 mg, 88%) MS (ES+) m/z 522 (M+H) ¹ H NMR (400 MHz, DMSO-CZ ₆ ) ppm 9 24 (t, J=6 4 Hz, 1 H), 8 41 (d, J=O 8 Hz, 1 H), 8 07 (d, J= 1 1 Hz, 1 H), 7 21 (t, J=8 1 Hz, 1 H), 6 90 - 6 87 (m, 2 H), 6 79 (dd, J=8 0, 2 1 Hz, 1 H), 4 77 - 4 66 (m, 2 H), 4 48 (d, J=6 6 Hz, 2 H), 3 70 (s, 3 H), 3 78 - 3 62 (m, 2 H), 2 82 (br s , 1 H), 2 65 (s, 3 H), 2 12 (br s , 1 H), 1 75 - 1 56 (m, 2 H), 1 37 - 1 17 (m, 12 H)

Step 2 Preparation of λ/-(3-methoxybenzyl)-6-methyl-4-(2-((S)-pιperιdιn-3-ylme thyl)-2/-/-tetrazol-5- vQpicolinamide

(3S)-tert-Butyl 3-((5-(2-((3-methoxybenzyl)carbamoyl)-6-methylpyrιdιn-4-yl )-2H-tetrazo!-2- yl)methyl)pιperιdιne-1-carboxylate (455 mg, 0 72 mmol) was dissolved in dichloromethane (5 0 mL) TÏ€fluoroacetic acid (1 0 mL, 13 0 mmol) was added and the solution was shaken for 2 hours at room temperature The solvent was removed in vacuo and the residue was dissolved in dichloromethane (100 mL) The mixture was washed with 1 N NaOH solution (2 x 10 mL) The organic layer was dried over sodium sulfate and concentrated to afford the title compound as an oil (349 mg, 94%) MS (ES+) m/z 422 (M+H) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9 24 (t, J=6 4 Hz, 1 H), 8 40 (d, J=O 8 Hz, 1 H), 8 05 (d, J= 1 1 Hz, 1 H), 7 21 (t, J=8 1 Hz, 1 H), 6 90 - 6 86 (m, 2 H), 6 79 (dd, J=7 9, 2 1 Hz, 1 H), 4 74 - 4 62 (m, 2 H), 4 47 (d, J=6 4 Hz, 2 H), 3 70 (s, 3 H), 2 83 - 2 74 (m, 2 H), 2 65 (s, 3 H), 2 47 - 2 40 (m, 1 H), 2 35 (dd, J=12 1 , 9 5 Hz, 1 H), 2 18 - 2 07 (m, 1 H), 1 68 - 1 52 (m, 2 H), 1 40 - 1 27 (m, 1 H), 1 16 (qd, J=11 1 , 3 2 Hz, 1 H)

Example 359

W-(3-Methoxybenzyl)-6-methyl-4-(2-(((R)-1-(methylsulfonyl )piperidin-3-yl)methyl)-2W-tetrazol-5- yl)picolinamide

λ/-(3-Methoxybenzyl)-6-rnethyl-4-(2-((S)-pιpeπdιn-3-ylme thyl)-2/-/-tetrazol-5-yl)pιcolιnamιde

(prepared as described in Example 358) (165 mg, 0 35 mmol) was dissolved in dichloromethane (5 mL) Triethylamine (98 μL, 0 71 mmol) and methanesulfonyl chloride (41 μl, 0 53 mmol) were added The reaction mixture was shaken at room temperature for 1 hour and then diluted with dichloromethane (50 mL) The mixture was washed with saturated aq sodium bicarbonate (10 mL) The organic layer was dried over sodium sulfate and concentrated The crude product was purified by silica column chromatography (heptane/EtOAc, 1/1 , 1/2, 1/4) to afford the title compound as a foaming solid (1 16 mg, 66%) MS (ES+) m/z 500 (M+H) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9 26 - 9 20 (m, 1 H), 8 43 (s, 1 H), 8 07 (s, 1 H), 7 24 (t, J=7 9 Hz, 1 H), 6 94 - 6 89 (m, 2 H), 6 81 (d, J=7 7 Hz, 1 H), 4 86 - 4 73 (m, 2 H), 4 51 (d, J=5 9 Hz, 2 H), 3 73 (s, 3 H), 3 48 - 3 36 (m, 2 H), 2 84 (s, 3 H), 2 83 - 2 75 (m, 1 H), 2 72 (t, J=9 9 Hz, 1 H), 2 67 (s, 3 H), 2 35 (br s , 1 H), 1 80 - 1 68 (m, 2 H), 1 57 - 1 46 (m, 1 H), 1 29 - 1 18 (m, 1 H)

Example 360

W-(3-Methoxybenzyl)-4-(2-(((S)-1-acetylpiperidin-3-yl)met hyl)-2H-tetrazol-5-yl)-6- methylpicolinamide

λ/-(3-Methoxybenzyl)-6-methyl-4-(2-((S)-pιperιdιn-3-ylme thyl)-2/-/-tetrazol-5-yl)pιcolιnamιde (prepared as described in Example 358) (165 mg, 0 35 mmol) was dissolved in dichloromethane (5 0 mL) Triethylamine (98 μL, 0 71 mmol), 4-(dιmethylamιno)pyrιdιne (8 6 mg, 0 07 mmol), and acetyl chloride (30 μL, 0 42 mmol) was added The mixture was allowed to stir at room temperature for 20 hours The reaction mixture was diluted with dichloromethane (50 mL) and washed with saturated aq sodium bicarbonate solution (20 mL) The organic layer was dried over sodium sulfate and concentrated The crude product was purified by silica column chromatography (CH ₂ CI ₂ /methanol, 100/1 , 100/2) to afford the title compound as an oil (160 mg, 100%) MS (ES+) m/z 464 (M+H) ¹ H NMR (400 MHz, DMSO-Cf ₆ ) δ ppm 9 24 (t, J=6 4 Hz, 1 H), 8 40 (s, 1 H), 8 06 (d, J=1 2 Hz, 1 H), 7 21 (t, J=8 1 Hz, 1 H), 6 91 - 6 86 (m, 2 H), 6 79 (dd, J=Q 2, 2 1 Hz, 1 H), 4 85 - 4 66 (m, 2 H), 4 48 (d, J=6 4 Hz, 2 H), 4 12 (dd, J=M 6, 3 4 Hz, 0 5 H), 4 01 (d, J=13 0 Hz, 0 5 H), 3 70 (s, 3 H), 3 64 (d, J=13 2 Hz, 0 5 H), 3 52 - 3 43 (m, 0 5 H), 3 00 (dd, J=13 4, 10 3 Hz, 1 H), 2 75 - 2 68 (m, 0 5 H), 2 65

(s, 3 H), 2 59 (dd, J=12 7, 10 3 Hz, 0 5 H), 2 26 - 2 18 (m, 0 5 H), 2 13 - 2 06 (m, 0 5 H), 1 95 (s, 1 5 H), 1 93 (s, 1 5 H), 1 74 - 1 53 (m, 2 H), 1 44 - 1 19 (m, 2 H)

Example 361 W-(3-Methoxybenzyl)-6-methyl-4-(2-((/?)-piperidin-3-y!methyl )-2H-tetrazol-5-yl)picolinamide

Step 1 Preparation of (3f?)-tert-butyl 3-((5-(2-((3-methoxybenzyl)carbamoyl)-6-methylpyrιdιn-4-yl )-2/-/- tetrazol-2-yl)methyl)pιperιdιne-1 -carboxylate

λ/-(3-Methoxybenzyl)-6-methyl-4-(2H-tetrazol-5-yl)pιcolιn amιde (prepared as described in step 5 of the synthesis of λ/-(3-Methoxybenzyl)-4-(2-(((frans)-4-amιnocyclohexyl)meth yl)-2H-tetrazol-5-yl)-6- methylpicolinamide, Example 153) (324 mg, 1 0 mmol), polymer supported triphenylphosphine (698 mg, 1 5 mmol), and (/?)-1-Boc-3-(hydroxymethyl)pιperιdιne (258 mg, 1 2 mmol) were suspended in tetrahydrofuran (16 mL) Di-tert-butyl azodicarboxylate (345 mg, 1 5 mmol) was added The mixture was allowed to stir for 18 hours The reaction mixture was filtered and the resin washed with tetrahydrofuran (20 mL) The filtrate was concentrated The crude product was purified by silica column chromatography (heptane/EtOAc, 2/1 , 1/1 ) Fractions containing product were concentrated and repurified by silica column chromatography (CH ₂ CI ₂ /methanol, 100/1 ) to afford the title compound as a foaming solid (352 mg, 67%) MS (ES+) m/z 522 (M+H) ¹ H NMR (400 MHz, DMSOd ₆ ) ÏŒ ppm 9 24 (t, J=6 4 Hz, 1 H), 8 41 (d, J=O 8 Hz, 1 H), 8 07 (d, J= 1 2 Hz, 1 H), 7 21 (t, J=8 1 Hz, 1 H), 6 90 - 6 87 (m, 2 H), 6 79 (dd, J=8 1 , 1 8 Hz, 1 H), 4 78 - 4 66 (m, 2 H), 4 48 (d, J=6 4 Hz, 2 H), 3 70 (s, 3 H), 3 66 (br s , 2 H), 2 82 (br s , 1 H), 2 65 (s, 3 H), 2 13 (br s , 1 H), 1 74 - 1 67 (m, 1 H), 1 64 - 1 57 (m, 1 H), 1 35 - 1 21 (m, 12 H)

Step 2 Preparation of λ/-(3-methoxybenzyl)-6-methyl-4-(2-((ff)-pιperιdιn-3-ylm ethyl)-2/-/-tetrazol-5- vQpicolinamide

(3R)-fert-Butyl 3-((5-(2-((3-methoxybenzyl)carbamoyl)-6-methylpyrιdιn-4-yl )-2H-tetrazol-2- yl)methyl)pιperιdιne-1 -carboxylate (348 mg, 0 65 mmol) was dissolved in dichloromethane (5 0 mL) Trifluoroacetic acid (1 0 mL, 13 0 mmol) was added and the solution was shaken for 2 hours at room temperature The solvent was removed in vacuo and the residue was dissolved in dichloromethane (100 mL) The mixture was washed with 1 N NaOH solution (2 x 10 mL) The organic layer was dried over sodium sulfate and concentrated to afford the title compound as an oil (283 mg, 96%) MS (ES+) m/z 422 (M+H) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9 24 (t, J=6 4 Hz, 1 H), 8 40 (d, J=O 8 Hz, 1 H), 8 05 (d, J= 1 2 Hz, 1 H), 7 21 (t, J=8 1 Hz, 1 H), 6 90 - 6 86 (m, 2 H), 6 79 (dd, J=7 9, 2 1 Hz, 1 H), 4 74 - 4 62 (m, 2 H), 4 47 (d, J=6 4 Hz, 2 H), 3 70 (s, 3 H), 2 81 - 2 74 (m, 2 H), 2 65 (s, 3 H), 2 46 - 2 39 (m, 1 H), 2 34 (dd, J= 1 1 9, 9 5 Hz, 1 H), 2 15 - 2 07 (m, 1 H), 1 66 - 1 52 (m, 2 H), 1 38 - 1 26 (m, 1 H), 1 16 (qd, J=10 5, 3 8 Hz, 1 H)

Example 362

/V-(3-Methoxybenzyl)-6-methyl-4-(2-(((S)-1-(methylsulfony l)piperidin-3-yl)methyl)-2H-tetrazol-5- yl)picolinamide

λ/-(3-Methoxybenzyl)-6-methyl-4-(2-((R)-pιperιdιn-3-ylme thyl)-2H-tetrazol-5-yl)pιcolιnamιde (prepared as described in Example 361 ) (135 mg, 0 35 mmol) was dissolved in dichloromethane (5 mL) Triethylamine (83 μL, 0 60 mmol) and methanesulfonyl chloride (35 μL, 0 48 mmol) were added The reaction mixture was shaken at room temperature for 1 hour and then diluted with dichloromethane (50 mL) The mixture was washed with saturated aq sodium bicarbonate (10 mL) The organic layer was dried over sodium sulfate and concentrated The crude product was purified by silica column chromatography (heptane/EtOAc, 1/1 , 1/2, 1/4) to afford the title compound as a foaming solid (99 mg, 66%) MS (ES+) m/z 500 (M+H) ¹ H NMR (400 MHz, DMSOd ₆ ) δ ppm 9 22 (t, J=6 2 Hz, 1 H), 8 43 (s, 1 H), 8 08 (s, 1 H), 7 24 (t, J=8 1 Hz, 1 H), 6 95 - 6 89 (m, 2 H), 6 82 (d, J=8 1 Hz, 1 H), 4 87 - 4 74 (m, 2 H), 4 51 (d, J=6 2 Hz, 2 H), 3 73 (s, 3 H), 3 48 - 3 36 (m, 2 H), 2 85 (s, 3 H), 2 79 (t, J=10 4 Hz, 1 H), 2 72 (t, J= 10 2 Hz, 1 H), 2 67 (s, 3 H), 2 36 (br s , 1 H), 1 80 - 1 68 (m, 2 H), 1 58 - 1 47 (m, 1 H), 1 29 - 1 19 (m, 1 H)

Example 363

A/-(3-Methoxybenzyl)-4-(2-(((/?)-1-acetylpiperidin-3-yl)m ethyl)-2H-tetrazol-5-yl)-6- methylpicolinamide

λ/-(3-Methoxybenzyl)-6-methyl-4-(2-((R)-pιperιdιn-3-ylme thyl)-2/-/-tetrazol-5-yl)pιcolιnamιde

(prepared as described in Example 361 ) (135 mg, 0 30 mmol) was dissolved in dichloromethane (5 0 mL) Triethylamine (83 μL, 0 60 mmol), 4-(dιmethylamιno)pyÏ€dιne (7 3 mg, 0 06 mmol), and acetyl chloride (25 μL, 0 36 mmol) was added The mixture was allowed to stir at room temperature for 20 hours The reaction mixture was diluted with dichloromethane (50 mL) and washed with saturated aq sodium bicarbonate solution (20 mL) The organic layer was dried over sodium sulfate and concentrated The crude product was purified by silica column chromatography (CH ₂ CI ₂ /methanol, 100/1 , 100/2) Fractions were concentrated to afford the title compound as an oil (123 mg, 88%) MS (ES+) m/z 464 (M+H) ¹ H NMR (400 MHz, DMSO-d ₅ ) δ ppm 9 21 (t, J=6 2 Hz, 1 H), 8 44 (s, 1 H), 8 09 (s, 1 H), 7 24 (t, J=8 1 Hz, 1 H), 6 95 - 6 89 (m, 2 H), 6 82 (d, J=8 1 Hz, 1 H), 4 88 - 4 68 (m, 2 H), 4 51 (d, J=6 2 Hz, 2 H), 4 17 - 4 12 (m, 0 5 H), 4 06 - 4 00 (m, 0 5 H), 3 79 - 3 73 (m, 0 5 H), 3 73 (s, 3 H), 3 71 - 3 64 (m, 0 5 H), 3 08 - 3 00 (m, 1 H), 2 80 - 2 72 (m, 0 5 H), 2 68 (s, 3 H), 2 65 - 2 60 (m, 0 5 H), 2 29 - 2 23 (m, 0 5 H), 2 17 - 2 10 (m, 0 5 H), 1 98 (s, 1 5 H), 1 96 (s, 1 5 H), 1 77 - 1 59 (m, 2 H), 1 46 - 1 25 (m, 2 H)

Example 364 W-(4-Fluoro-3-methoxybenzyl)-6-methyl-4-(2-((S)-piperidin-3- ylmethyl)-2H-tetrazol-5- yl)picolinamide

Step 1 Preparation of (3S)-tert-butyl 3-((5-(2-((4-f1uoro-3-methoxybenzyl)carbamoyl)-6-rnethylpyri din- 4-yl)-2H-tetrazol-2-yl)methyl)pιperιdιne-1 -carboxylate

/V-(4-Fluoro-3-methoxybenzyl)-6-methyl-4-(2H-tetrazol-5-yl)p ιcolιnamιde (prepared as described in step 2 of the synthesis of λ/-(4-fluoro-3-methoxybenzyl)-4-(2-(((frans)-4- aminocyclohexyOmethyO^H-tetrazol-S-yO-θ-methylpicolinamide, Example 170) (342 mg, 1 0 mmol), polymer supported triphenylphosphine (698 mg, 1 5 mmol), and (S)-1-Boc-3-(hydroxymethyl)pιperιdιne (258 mg, 1 2 mmol) were suspended in tetrahydrofuran (16 mL) Di-tert-butyl azodicarboxylate (345 mg, 1 5 mmol) was added The mixture was allowed to stir for 18 hours The reaction mixture was filtered and the resin washed with tetrahydrofuran (20 mL) The filtrate was concentrated The crude product was purified by column chromatography (heptane/EtOAc, 2/1 , 1/1 ) Fractions containing the product were concentrated to afford the title compound as an oil (455 mg, 84%) MS (ES+) m/z 540 (M+H) ¹ H NMR (400 MHz, DMSO-CZ ₆ ) δ ppm 9 26 (t, J=6 4 Hz ₁ 1 H), 8 40 (d, J=O 8 Hz, 1 H), 8 07 (d, J= 1 1 Hz, 1 H), 7 15 (dd, J=8 5, 1 9 Hz, 1 H), 7 1 1 (dd, J=11 7, 8 3 Hz, 1 H), 6 87 (ddd, J=8 3, 4 4, 1 9 Hz, 1 H), 4 77 - 4 66 (m, 2 H) ₁ 4 47 (d, J=5 9 Hz ₁ 2 H), 3 79 (s, 3 H) ₁ 3 72 - 3 62 (m, 2 H) ₁ 2 85 - 2 79 (m, 1 H), 2 65 (s, 3 H), 2 17 - 2 09 (m, 1 H), 1 76 - 1 50 (m, 2 H), 1 36 - 1 21 (m, 12 H)

Step 2 Preparation of /V-(4-fluoro-3-methoxybenzyl)-6-methyl-4-(2-((S)-pιperιdι n-3-ylmethyl)-2H- tetrazol-5-yl)pιcolιnamιde

(3S)-tert-Butyl 3-((5-(2-((4-fluoro-3-methoxybenzyl)carbamoyl)-6-methylpyrι dιn-4-yl)-2H- tetrazol-2-yl)methyl)pιperιdιne-1-carboxylate (450 mg, 0 63 mmol) was dissolved in dichloromethane (5 0 mL) TÏ€fluoroacetic acid (1 0 mL, 13 0 mmol) was added and the solution was shaken for 2 hours at room temperature The solvent was removed in vacuo and the residue was dissolved in dichloromethane (100 mL) The mixture was washed with 1 N NaOH solution (2 x 10 mL) The organic layer was dried over sodium sulfate and concentrated to afford the title compound as an oil (331 mg, 97%) MS (ES+) m/z 440 (M+H) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9 26 (t, J=6 4 Hz, 1 H) ₁ 8 39 (d, J=O 9 Hz, 1 H) ₁ 8 05 (d, J= 1 2 Hz ₁ 1 H) ₁ 7 15 (dd, J=8 5, 1 9 Hz, 1 H), 7 1 1 (dd, J=1 1 6, 8 4 Hz, 1 H), 6 87 (ddd, J=8 2, 4 4, 1 9 Hz, 1 H), 4 73 - 4 62 (m, 2 H), 4 47 (d, J=6 4 Hz, 2 H), 3 79 (s, 3 H), 2 81 - 2 74 (m, 2 H), 2 65 (s, 3 H), 2 46 - 2 39 (m, 1 H), 2 34 (dd, J=12 O ₁ 9 5 Hz ₁ 1 H) ₁ 2 15 - 2 07 (m, 1 H), 1 67 - 1 52 (m, 2 H), 1 38 - 1 26 (m, 1 H), 1 16 (qd, J=10 7, 3 5 Hz, 1 H)

Example 365

W-(4-Fluoro-3-methoxybenzyl)-6-methyl-4-(2-(((R)-1-(methy lsulfonyl)piperidin-3-yl)methyl)-2H- tetrazol-5-yl)picolinamide

λ/-(4-Fluoro-3-methoxybenzyl)-6-methyl-4-(2-((S)-pιperιdÎ ¹n-3-ylmethyl)-2/-/-tetrazol-5- yOpicolinamide (prepared as described in Example 364) (160 mg, O 34 mmol) was dissolved in dichloromethane (5 mL) TÏ€ethylamine (95 μL, 0 68 mmol) and methanesulfonyl chloride (40 μL, 0 51 mmol) were added The reaction mixture was shaken at room temperature for 1 hour and then diluted with dichloromethane (50 mL) The mixture was washed with saturated aq sodium bicarbonate (10 mL) The organic layer was dried over sodium sulfate and concentrated The crude product was purified by silica column chromatography (heptane/EtOAc, 1/1 , 1/2, 1/4) to afford the title compound as a foaming solid (1 1 1 mg, 63%) MS (ES+) m/z 518 (M+H) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9 24 (t, J=6 4 Hz, 1 H), 8 44 (s, 1 H), 8 09 (s, 1 H), 7 19 (d, J=8 4 Hz, 1 H), 7 14 (dd, J= 11 5, 8 2 Hz, 1 H), 6 91 (d, J=2 2 Hz, 1 H), 4 88 - 4 75 (m, 2 H), 4 51 (d, J=6 2 Hz, 2 H), 3 82 (s, 3 H), 3 49 - 3 37 (m, 2 H), 2 85 (S, 3 H), 2 83 - 2 77 (m, 1 H), 2 72 (t, J=9 9 Hz, 1 H), 2 68 (s, 3 H), 2 42 - 2 31 (m, 1 H), 1 80 - 1 69 (m, 2 H), 1 59 - 1 47 (m, 1 H), 1 30 - 1 19 (m, 1 H)

Example 366

W-(4-Fluoro-3-methoxybenzyl)-4-(2-(((S)-1-acetylpiperidin -3-yl)methyl)-2W-tetrazol-5-yl)-6- methylpicolinamide

λ/-(4-Fluoro-3-methoxybenzyl)-6-methyl-4-(2-((S)-pιperιdÎ ¹n-3-ylmethyl)-2H-tetrazol-5- yOpicolmamide (prepared as described in Example 364) (160 mg, 0 34 mmol) was dissolved in dichloromethane (5 0 mL) Triethylamine (95 μL, 0 68 mmol), 4-(dιmethylamιno)pyrιdιne (8 4 mg, 0 07 mmol), and acetyl chloride (29 μL, 0 41 mmol) was added The mixture was allowed to stir at room temperature for 20 hours The reaction mixture was diluted with dichloromethane (50 mL) and washed with saturated aq sodium bicarbonate solution (20 mL) The organic layer was dried over sodium sulfate and concentrated The crude product was purified by silica column chromatography (CH ₂ CI ₂ /methanol, 100/1 , 100/2) Fractions were concentrated to afford the title compound as a foaming solid (123 mg, 77%) MS (ES+) m/z 482 (M+H) ¹ H NMR (400 MHz, DMSO-cfe) δ ppm 9 26 (t, J=Q 4 Hz, 1 H), 8 40 (s, 1 H), 8 06 (d, J= 1 2 Hz, 1 H), 7 15 (dd, J=8 5, 1 9 Hz, 1 H) ₁ 7 1 1 (dd, J=11 6, 8 4 Hz, 1 H), 6 87 (ddd, J=8 2, 4 3, 1 9 Hz, 1 H), 4 85 - 4 66 (m, 2 H), 4 47 (d, J=6 4 Hz, 2 H), 4 1 1 (dd, J=12 6, 3 5 Hz, 0 5 H), 4 01 (d, J=13 4 Hz, 0 5 H) ₁ 3 79 <s, 3 H), 3 73 (d, J=14 0 Hz, 0 5 H) ₁ 3 64 (d,

J=12 8 Hz, 0 5 H), 3 00 (dd, J= 13 2, 10 1 Hz, 1 H), 2 76 - 2 67 (m, 0 5 H), 2 65 (s, 3 H), 2 59 (dd, J=12 7, 10 4 Hz, 0 5 H), 2 26 - 2 19 (m, 0 5 H), 2 13 - 2 05 (m, 0 5 H), 1 95 (s, 1 5 H), 1 93 (s, 1 5 H), 1 75 - 1 54 (m, 2 H), 1 46 - 1 19 (m, 2 H)

Example 367

/V-(4-Fluoro-3-methoxybenzyl)-6-methyl-4-(2-((/ ^: ?)-piperidin-3-ylmethyl)-2H-tetrazol-5- yl)picolinamide

Step 1 Preparation of (3f?)-/ert-butyl 3-((5-(2-((4-fluoro-3-methoxybenzyl)carbamoyl)-6-methylpyrι dιn- 4-yl)-2/-/-tetrazol-2-yl)methyl)pιperιdιne-1-carboxylate

λ/-(4-Fluoro-3-methoxybenzyl)-6-methyl-4-(2/-/-tetrazol-5-y l)pιcolιnamιde (prepared as described in step 2 of the synthesis of λ/-(4-fluoro-3-methoxybenzyl)-4-(2-(((/rans)-4- amιnocyclohexy!)methyl)-2/-/-tetrazol-5-yl)-6-methy!pιcolÎ ¹namιde, Example 170) (342 mg, 1 0 mmol), polymer supported triphenylphosphine (698 mg, 1 5 mmol), and (/?)-1-Boc-3- (hydroxymethyl)pιperιdιne (258 mg, 1 2 mmol) were suspended in tetrahydrofuran (16 mL) Di-tert- butyl azodicarboxylate (345 mg, 1 5 mmol) was added The mixture was allowed to stir for 18 hours The reaction mixture was filtered and the resin washed with tetrahydrofuran (20 mL) The filtrate was concentrated The crude product was purified by silica column chromatography (heptane/EtOAc, 2/1 , 1/1 ) Fractions containing the product were concentrated to afford the title compound as a foaming solid (472 mg, 87%) MS (ES+) m/z 540 (M+H) ¹ H NMR (400 MHz, DMSOd ₆ ) 6 ppm 9 26 (t, J=6 4 Hz, 1 H), 8 40 (d, J=O 8 Hz, 1 H), 8 07 (d, J= 1 1 Hz, 1 H) ₁ 7 15 (dd, J=8 5, 1 9 Hz, 1 H), 7 1 1 (dd, J=11 5, 8 3 Hz, 1 H), 6 87 (ddd, J=8 3, 4 4, 1 9 Hz, 1 H), 4 77 - 4 66 (m, 2 H), 4 47 (d, J=6 0 Hz, 2 H), 3 79 (s, 3 H), 3 70 - 3 62 (m, 2 H), 2 81 (br s , 1 H), 2 65 (s, 3 H), 2 12 (br s , 1 H), 1 74 - 1 56 (m, 2 H), 1 27 (br s , 12 H)

Step 2 Preparation of λ/-(4-fluoro-3-methoxybenzyl)-6-methyl-4-(2-((R)-pιperιdÎ ¹n-3-ylmethyl)-2H- tetrazol-5-vDpιcolιnamιde

(3R)-tert-Butyl 3-((5-(2-((4-fluoro-3-methoxybenzyl)carbamoyl)-6-methylpyrι dιn-4-yl)-2H- tetrazol-2-yl)methyl)pιperιdιne-1 -carboxylate (465 mg, 0 67 mmol) was dissolved in dichloromethane (5 0 mL) Trifluoroacetic acid (1 0 ml_, 13 0 mmol) was added and the solution was shaken for 2 hours at room temperature The solvent was removed in vacuo and the residue was dissolved in dichloromethane (100 mL) The mixture was washed with 1 N NaOH solution (2 x 10 mL) The organic layer was dried over sodium sulfate and concentrated to afford the title compound as an oil (362 mg, 96%) MS (ES+) m/z 440 (M+H) ¹ H NMR (400 MHz, DMSOd ₆ ) δ ppm 9 26 (t, J=6 4 Hz, 1 H), 8 40 (d, J=O 8 Hz, 1 H), 8 05 (d, J=1 1 Hz, 1 H), 7 15 (dd, J=8 5, 1 9 Hz, 1 H), 7 11 (dd, J=11 7, 8 3 Hz, 1 H), 6 87 (ddd, J=8 2, 4 4, 2 0 Hz, 1 H), 4 73 - 4 62 (m, 2 H), 4 47 (d, J=6 4 Hz, 2 H), 3 79 (s, 3 H), 2 80 - 2 74 (m, 2 H), 2 65 (s, 3 H), 2 46 - 2 39 (m, 1 H), 2 33 (dd, J= 1 1 9, 9 5 Hz, 1 H), 2 10 (br s , 1 H), 1 66 - 1 51 (m, 2 H), 1 39 - 1 26 (m, 1 H), 1 15 (qd, J=10 6, 3 5 Hz, 1 H)

Example 368

W-(4-Fluoro-3-methoxybenzyl)-6-methyl-4-(2-(((S)-1 -(methylsulfonyl)piperidin-3-yl)methyl)-2W- tetrazol-5-yl)picolinamide

λ/-(4-Fluoro-3-methoxybenzyl)-6-methyl-4-(2-((R)-pιperιdÎ ¹n-3-ylmethyl)-2W-tetrazol-5- yl)pιcolιnamιde (prepared as described in Example 367) (175 mg, 0 36 mmol) was dissolved in dichloromethane (5 mL) Triethylamine (101 μL, 0 73 mmol) and methanesulfonyl chloride (42 μL, 0 54 mmol) were added The reaction mixture was shaken at room temperature for 1 hour and then diluted with dichloromethane (50 mL) The mixture was washed with saturated aq sodium bicarbonate (10 mL) The organic layer was dried over sodium sulfate and concentrated The crude product was purified by silica column chromatography (CH ₂ CI ₂ /methanol, 100/1 , 100/2, 100/4) The resulting impure product was further purified by silica column chromatography (heptane/EtOAc, 1/1 , 1/2, 1/4) to afford the title compound as a foaming solid (99 mg, 53%) MS (ES+) m/z 518 (M+H) ¹ H NMR (400 MHz, DMSO-CZ ₆ ) δ ppm 9 24 (t, J=6 2 Hz, 1 H), 8 44 (s, 1 H), 8 08 (s, 1 H), 7 18 (d, J=8 4 Hz, 1 H), 7 13 (dd, J= 1 1 5, 8 2 Hz, 1 H), 6 94 - 6 88 (m, 1 H), 4 87 - 4 74 (m, 2 H), 4 51 (d, J=6 2 Hz, 2 H), 3 82 (s, 3 H), 3 49 - 3 37 (m, 2 H), 2 85 (s, 3 H), 2 84 - 2 76 (m, 1 H), 2 75 - 2 69 (m, 1 H), 2 68 (s, 3 H), 2 36 (br s , 1 H), 1 81 - 1 68 (m, 2 H), 1 58 - 1 47 (m, 1 H), 1 30 - 1 18 (m, 1 H)

Example 369

λ/-(4-Fluoro-3-methoxybenzyl)-4-(2-(((R)-1-acetylpiperid in-3-yl)methyl)-2H-tetrazol-5-yl)-6- methylpicolinamide

λ/-(4-Fluoro-3-methoxybenzyl)-6-methyl-4-(2-((R)-pιperιdÎ ¹n-3-ylmethyl)-2H-tetrazol-5- yl)pιcolιnamιde (prepared as described in Example 367) (175 mg, 0 36 mmol) was dissolved in dichloromethane (5 0 mL) TÏ€ethylamine (73 μL, 0 73 mmol), 4-(dιmethylamιno)pyrιdιne (8 9 mg, 0 06 mmol), and acetyl chloride (31 μL, 0 36 mmol) was added The mixture was allowed to stir at room temperature for 20 hours The reaction mixture was diluted with dichloromethane (50 mL) and washed with saturated aq sodium bicarbonate solution (20 mL) The organic layer was dried over sodium sulfate and concentrated The crude product was purified by silica column chromatography (CH ₂ CI ₂ /methanol, 100/1 , 100/2) to afford the title compound as a foaming solid (134 mg, 79%) MS (ES+) m/z 482 (M+H) ¹ H NMR (400 MHz, DMSOd ₆ ) δ ppm 9 24 (t, J=Q 2 Hz, 1 H), 8 43 (s, 1 H), 8 08 (s, 1 H), 7 18 (d, J=8 4 Hz, 1 H), 7 13 (dd, J=11 7, 8 4 Hz, 1 H), 6 93 - 6 88 (m, 1 H), 4 88 - 4 69 (m, 2 H), 4 50 (d, J=Q 2 Hz, 2 H), 4 17 - 4 12 (m, 0 5 H), 4 06 - 4 00 (m, 0 5 H), 3 82 (s, 3 H), 3 79 - 3 73 (m, 0 5 H), 3 70 - 3 64 (m, 0 5 H), 3 04 (t, .7=12 8 Hz, 1 H), 2 80 - 2 72 (m, 0 5 H), 2 68 (s, 3 H), 2 67 - 2 60 (m, 0 5 H), 2 30 - 2 22 (m, 0 5 H), 2 18 - 2 09 (m, 0 5 H), 1 98 (s, 1 5 H), 1 96 (s, 1 5 H), 1 77 - 1 59 (m, 2 H), 1 47 - 1 24 (m, 2 H)

Example 370 W-(4-Fluoro-3-methoxybenzyl)-6-methyl-4-(2-((/?)-pyrrolidin- 3-ylmethyl)-2W-tetrazol-5- yl)picolinamide

Step 1 Preparation of (3/?)-tert-butyl 3-((5-(2-((4-fluoro-3-methoxybenzyl)carbamoyl)-6-methylpyrid in- 4-yl)-2/-/-tetrazol-2-yl)methyl)pyrrolιdιne-1-carboxylate

A mixture of λ/-(4-fluoro-3-methoxybenzyl)-6-methyl-4-(2/-/-tetrazol-5-y l)pιcolιnamιde (prepared s described in step 2 of the synthesis of λ/-(4-fluoro-3-methoxybenzyl)-4-(2-(((frans)-4-

amιnocyclohexyl)methyl)-2/-/-tetrazo!-5-yl)-6-methylpιcolÎ ¹namιde, Example 170) (0 45 g, 1 3 mmol), (R)-tert-butyl 3-(hydroxymethyl) pyrrolιdιne-1 -carboxylate (O 27 g, 1 3 mmol), and polymer supported- tnphenylphosphine (0 73 g, 1 6 mmol) in anhydrous tetrahydrofuran (15 mL) was cooled to 0 ⁰ C in an ice bath for 15 mm and then di-tert-butyl azodicarboxylate (0 45 g, 2 0 mmol) was added The mixture was allowed to warm to room temperature while stirring over 15 hours The reaction mixture was filtered and the filtrate was concentrated The residue was purified by silica column chromatography (0-50%, ethyl acetate/heptane) to afford the title compound

Step 2 Preparation of λ/-(4-fluoro-3-methoxybenzyl)-6-methyl-4-(2-((ff)-pyrrolιd ιn-3-ylmethyl)-2/-/- tetrazol-5-yl)pιcolιnamιde

Trifluoroacetic acid (3 mL) was added to a solution of (3R)-tert-butyl 3-((5-(2-((4-fluoro-3- methoxybenzyl)carbamoyl)-6-methylpyrιdιn-4-yl)-2/-/-tetraz ol-2-yl)methyl)pyrrolιdιne-1 -carboxylate in dichloromethane (5 mL) After 30 mm at ambient temperature, the reaction mixture was neutralized to pH 7 with 2 5 N aqueous sodium hydroxide The mixture was extracted with ethyl acetate (3 x 10 mL) The combined organic layers were washed with water (2 x 10 mL) followed by brine (10 mL), dried over sodium sulfate, and concentrated to afford the title compound (0 35g, 63%) LC/MS (5-100% CH ₃ CN/H ₂ O, 5 mm) 2 05 mm, m/z 426 (M+H)

Example 371

/V-(4-Fluoro-3-methoxybenzyl)-6-methyl-4-(2-(((S)-1-(meth ylsulfonyl)pyrrolidin-3-yl)methyl)-2H- tetrazol-5-yl)picolinamide

Triethylamine (0 037 mL) and methane sulfonyl chloride (0 028 mg, 0 21 mmol) were added to a solution of λ/-(4-fluoro-3-methoxybenzyl)-6-methyl-4-(2-((R)-pyrrolιdÎ ¹n-3-ylmethyl)-2/-/-tetrazol-5- y!)pιcolιnamιde (prepared as described in Example 370) (0 075 g, 0 18 mmol) in dichloromethane (3 mL) The mixture was stirred at ambient temperature for 4 hours The reaction mixture was concentrated in vacuo and the residue was purified via reverse phase preparative HPLC to afford the title compound as an oil (15 mg, 17%) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9 24 (br s , 1 H), 8 44 (s, 1 H), 8 08 (s, 1 H), 7 10 - 7 21 (m, 2 H), 6 91 (br s , 1 H), 4 90 (d, J=I 0 Hz, 2 H), 4 51 (d, J=5 9 Hz, 2 H), 3 82 (s, 3 H), 3 46 (br s , 1 H), 3 07 - 3 17 (m, 1 H), 2 91 (s, 5 H), 2 68 (s, 4 H), 2 05 (br s , 1 H), 1 81 (d, J=7 7 Hz, 1 H)

Example 372

W-(4-Fluoro-3-methoxybenzyl)-4-(2-(((R)-1-acetylpyrrolidi n-3-yl)methyl)-2H-tetrazol-5-yl)-6- methylpicolinamide

Triethylamine (0 037 mL) and acetyl chloride (0 017 mg, 0 21 mmol) were added to a solution of /V-(4-fluoro-3-methoxybenzyl)-6-methyl-4-(2-((f?)-pyrrolιdÎ ¹n-3-ylmethyl)-2H-tetrazol-5-yl)pιcolιnamιde (prepared as described in Example 370) (0 075 g, 0 18 mmol) in dichloromethane (3 mL) The mixture was stirred at ambient temperature for 4 hours The reaction mixture was concentrated in vacuo and the residue was purified via reverse phase preparative HPLC to afford the title compound as an oil (15 mg, 18%) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9 24 (br s , 1 H), 8 44 (s, 1 H), 8 08 (s, 1 H), 7 14 (d, J=2 9 Hz, 1 H), 7 10 - 7 21 (m, 1 H), 6 91 (br s , 1 H), 4 88 (t, 2 H), 4 51 (d, J=6 2 Hz, 2 H), 3 82 (s, 3 H), 3 42 - 3 51 (m, 3 H), 3 12 - 3 18 (m, 1 H), 2 83 - 2 99 (m, 1 H), 2 68 (s, 3 H), 1 97 - 2 13 (m, 1 H), 1 92 (br s , 3 H), 1 64 - 1 86 (m, 1 H)

Example 373 2-((/?)-3-((5-(2-((4-Fluoro-3-methoxybenzyl)carbamoyl)-6-met hylpyridin-4-yl)-2H-tetrazol-2- yl)methyl)pyrrolidin-1 -yl)-2-oxoethyl acetate

Triethylamine (0 037 mL) and acetoxy acetyl chloride (0 029 mg, 0 21 mmol) were added to a solution of λ/-(4-fluoro-3-methoxybenzyl)-6-methyl-4-(2-((f?)-pyrrolιd ιn-3-ylmethyl)-2H-tetrazol-5- yl)pιcolιnamιde (prepared as described in Example 370) (0 075 g, 0 18 mmol) in dichloromethane (3 mL) The mixture was stirred at ambient temperature for 4 hours The reaction mixture was concentrated in vacuo and the residue was purified by reverse phase preparative HPLC to afford the title compound

Example 374 λ/-(4-Fluoro-3-methoxybenzyl)-4-(2-(((R)-1-(2-hydroxyacetyl )pyrrolidin-3-yl)methyl)-2H-tetrazol-

5-yl)-6-methylpicolinamide

A mixture of 2-((R)-3-((5-(2-((4-fluoro-3-methoxybenzyl)carbamoyl)-6-meth ylpyrιdιn-4-yl)-2AY- tetrazol-2-yl)methyl)pyrrolιdιn-1 -yl)-2-oxoethyl acetate (prepared as described in Example 373) and 2 5 N aqueous sodium hydroxide (1 mL) in acetonitrile (3 mL) was stirred for 2 hours at room temperature The acetonitrile was removed in vacuo and the aqueous residue was acidified to pH 5 with 10% aqueous hydrochloric acid The resulting solid was filtered and dried to afford 9 mg (10%) of the title compound as a white solid ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9 24 (br s , 1 H), 8 44 (s, 1 H), 8 08 (s, 1 H), 7 17 (br s , 1 H), 7 1 1 (s, 1 H), 6 91 (br s , 1 H), 4 89 (d, J=6 2 Hz, 2 H), 4 51 (d, J=6 2 Hz, 3 H), 3 97 (br s , 2 H), 3 82 (s, 3 H), 3 57 (br s , 2 H), 3 37 (br s , 2 H), 2 82 - 3 07 (m, 1 H), 2 68 (s, 3 H), 1 98 - 2 12 (m, 1 H)

Example 375 rac-W-(4-Fluoro-3-methoxybenzyl)-4-(2-((1-benzyl-5-oxopyrrol idin-3-yl)methyl)-2H-tetrazol-5-yl)-

6-methylpicolinamide

A mixture of λ/-(4-fluoro-3-methoxybenzyl)-6-methyl-4-(2/-/-tetrazol-5-y l)pιcolιnamιde (prepared as described in step 2 of the synthesis of λ/-(4-fluoro-3-methoxybenzyl)-4-(2-(((frans)-4- amιnocyclohexyl)methyl)-2/-/-tetrazol-5-yl)-6-methylpιcolÎ ¹namιde, Example 170) (0 17 g, 0 48 mmol), 1- benzyl-4-(hydroxymethy!)pyrrolιdιn-2-one (0 99 g, 0 48 mmol) (Org Lett 1999, 7, 799-801 ), and polymer supported-tÏ€phenylphosphine (0 32 g, 0 72 mmol) in anhydrous tetrahydrofuran (10 mL) was cooled to 0 ⁰ C in an ice bath for 15 minutes Di-tert-butyl azodicarboxylate (0 13 g, 0 58 mmol) was added and the reaction was allowed to warm to room temperature over 15 hours The reaction mixture was filtered and the filtrate was concentrated The residue was purified by reverse phase preparative HPLC (5-95% acetonitrile/water) to afford the title compound as a beige oil (0 18 g, 71 %) ¹ H NMR (400 MHz, DMSOd ₆ ) δ ppm 9 19 - 9 29 (m, 1 H), 8 41 (s, 1 H), 8 04 (s, 1 H), 7 32 (t, J=I 69 Hz, 2 H), 7 20 (d, J=6 95 Hz, 2 H), 7 17 - 7 27 (m, 1 H), 7 14 (dd, J=11 71 , 8 42 Hz, 1 H), 6 91 (d,

J=6 22 Hz, 1 H), 4 89 (d, J=Q 95 Hz, 2 H), 4 51 (d, J=6 22 Hz, 2 H) ₁ 4 35 (s, 2 H), 3 82 (s, 3 H), 3 40 (t, J=8 97 Hz, 1 H), 3 13 - 3 19 (m, 1 H), 2 67 (s, 3 H), 2 57 (d, J=I 69 Hz, 1 H), 2 35 (dd, J=16 65, 6 77 Hz, 1 H), 1 37 (d, J=15 37 Hz, 1 H), 1 24 (dd, J=12 63, 5 67 Hz, 1 H)

Example 376 yV-(3-(2-Hydroxyethoxy)benzyl)-6-methyl-4-(2-((1-(methylsulf onyl)piperidin-4-yl)methyl)-2H- tetrazol-5-yl)picolinamide

Step 1 Preparation of methyl 6-methyl-4-(2-(pιperιdιn-4-ylmethyl)-2/-/-tetrazol-5-yl)p ιcolιnate trifluoroacetate

Methyl 6-methyl-4-(2H-tetrazol-5-yl)pιcolιnate (prepared as described in step 4 of the synthesis of /V-(3-methoxybenzyl)-4-(2-(((frans)-4-amιnocyclohexyl)methy l)-2/-/-tetrazol-5-yl)-6- methylpicolinamide, Example 153) (1 99 g, 9 08mmol) and tert-butyl 4-(hydroxymethyl)pιperιdιne-1- carboxylate (1 95 g, 9 08 mmol) were suspended in anhydrous tetrahydrofuran (50 mL) along with polymer supported-tÏ€phenylphosphine (6 05 g, 13 6 mmol) The mixture was cooled to 0 ⁰ C in an ice bath for 15 minutes and then di-tert-butyl azodicarboxylate (2 51 g, 10 9 mmol) was added The mixture was allowed to warm to room temperature while stirring over 15 hours The reaction mixture was filtered and the filtrate was concentrated The residue was purified on silica (70 g, 0-50 % ethyl acetate/heptane) The resulting intermediate was dissolved in dichloromethane (15 mL) and stirred with trifluoroacetic acid (5 0 mL) for 1 hour at room temperature The reaction mixture was concentrate to 1/3 volume and tert-butyl methyl ether (5 mL) was slowly added to cause precipitation The resulting solids were collected by filtration, washed with diethyl ether (3 x 5 mL) and dried to afford the title compound as a beige solid (3 3 g, 84%) MS (ES+) m/z 317 (M+H) ¹ H NMR (400

MHz, DMSO-c/ ₆ ) δ ppm 8 72 (br s , 1 H), 8 37 (s, 1 H), 8 09 (s, 1 H) ₁ 4 78 (d, J=6 7 Hz, 2 H), 3 90 (s, 3 H), 3 27 (d, J=12 4 Hz, 2 H), 2 87 (d, J=10 8 Hz, 2 H), 2 63 (s, 3 H), 2 22 - 2 41 (m, 1 H), 1 66 - 1 82 (m, 2 H), 1 30 - 1 57 (m, 2 H)

Step 2 Preparation of methyl 6-methyl-4-(2-((1-(methylsulfonyl)pιperιdιn-4-yl)methyl)- 2H-tetrazol-5- vDpicolinate

Triethylamine (0 34 mL, 2 4 mmol) was added to a solution of methyl 6-methyl-4-(2-(pιperιdιn- 4-ylmethyl)-2H-tetrazol-5-yl)pιcolιnate trifluoroacetate (0 50 g, 1 2 mmol) in 2-methyltetrahydrofuran (5 mL) A solution of methane sulfonyl chloride (0 16 mL) in 2-methyltetrahydrofuran (2 mL) was added

and the mixture was allowed to stir at room temperature for 2 hours The reaction mixture was concentrated and the residue was purified by silica gel chromatography (0-50 % ethyl acetate/heptane) to afford the title compound (0 46 g, 100%) MS (ES+) m/z 395 (M+H)

Step 3 Preparation of 6-methyl-4-(2-((1 -(methylsulfonylbiperidin-4-yl)methyl)-2H-tetrazol-5-yl)pico linic acid

An aqueous sodium hydroxide solution (2 5 N, 2 5 mL) was added to a solution of methyl 6- methyl-4-(2-((1-(methylsulfonyl)pιperιdιn-4-yl)methyl)-2H -tetrazol-5-yl)pιcolιnate (0 46g, 1 2 mmol) in tetrahydrofuran (5 mL) The mixture was stirred at room temperature for 3 hours The tetrahydrofuran was removed in vacuo and the aqueous residue was acidified with concentrated hydrochloric acid to pH 6 The resulting precipitate was filtered, washed with water (3 x 10 mL), and then dried to afford the title compound (0 41 g, 93%) MS (ES+) m/z 381 (M+H)

Step 4 Preparation of /V-(3-(2-hvdroxyethoxy)benzyl)-6-methyl-4-( ^' 2-(( ^' 1-('methylsulfonvπpιperιdιn-4- yl)methyl)-2H-tetrazol-5-yl)pιcolιnamιde

1-HydroxybenzatÏ€azole (22 mg, 0 16 mmol) was added to a solution of 6-methyl-4-(2-((1- (methylsulfonyl)pιperιdιn-4-yl)methyl)-2H-tetrazol-5-yl)p ιcolιnιc acid ( 0 050 g, 0 13 mmol) in 2-methyl tetrahydrofuran (5 mL) After 15 minutes, 2-(3-(amιnomethyl)phenoxy) ethanol (27 mg, 0 16 mmol) and polymer supported carbodiimide (0 16 g, 0 20 mmol) were added The mixture was stirred for 18 hours at room temperature The reaction mixture was filtered and the filtrate was concentrated The residue was purified via reverse phase preparative HPLC to afford the title compound (25 mg, 36%) ¹ H NMR (400 MHz, DMSOd ₆ ) δ ppm 9 20 (t, J=Q 6 Hz ₁ 1 H), 8 41 (s, 1 H), 8 06 (s, 1 H), 7 20 (t, J=Q 1 Hz, 1 H), 6 85 - 6 96 (m, 2 H), 6 79 (d, J=I 3 Hz, 1 H), 4 76 (d, J=I 3 Hz, 2 H), 4 49 (d, J=6 6 Hz, 2 H), 3 93 (t, J=5 1 Hz, 2 H), 3 67 (q, J=5 1 Hz, 2 H), 3 55 (d, J=11 7 Hz, 2 H), 2 81 (s, 3 H), 2 59 - 2 77 (m, 5 H), 2 07 - 2 27 (m, 1 H), 1 67 (d, J=12 4 Hz ₁ 2 H), 1 25 - 1 46 (m, 2 H)

Example 377

W-(3-Ethoxybenzyl)-6-methyl-4-(2-((1 -(methylsulfonyl)piperidin-4-yl)methyl)-2H-tetrazol-5- yOpicotinamide

The title compound was prepared in a similar manner to λ/-(3-(2-hydroxyethoxy)benzyl)-6- methy!-4-(2-((1 -(methylsulfonyl)pιperιdιn-4-y!)methyl)-2H-tetrazol-5-yl) pιcolιnamιde (Example 376, step 4) by reaction with (3-ethoxyphenyl)methanamιne (prepared as described in step 2 of the synthesis of W-(3-ethoxybenzyl)-6-methyl-4-(2-(((frans)-4-(methylsulfonam ido)cyclohexyl)methyl)-2H-tetrazol-5- yl)pιcolιnamιde, Example 180) to afford 28 mg (42%) ¹ H NMR (400 MHz, DMSOd ₆ ) δ ppm 9 19 (t, J=Q 2 Hz, 1 H), 8 41 (s, 1 H), 8 06 (s, 1 H), 7 20 (t, J=Q 1 Hz, 1 H), 6 88 (d, J=5 9 Hz, 2 H), 6 78 (d, J=Q 8 Hz, 1 H), 4 76 (d, J=I 3 Hz, 2 H), 4 48 (d, J=Q 6 Hz, 2 H), 3 97 (q, J=Q 8 Hz, 2 H), 3 55 (d, J=1 1 7 Hz, 2 H), 2 81 (s, 3 H), 2 58 - 2 77 (m, 5 H), 2 10 - 2 28 (m, 1 H), 1 67 (d, J=1 1 7 Hz, 2 H), 1 31 - 1 44 (m, 2 H), 1 28 (t, J=I 0 Hz, 3 H)

Example 378

/V-(4-Fluoro-3-methylbenzyl)-6-methyl-4-(2-((1-(methylsul fonyl)piperidin-4-yl)methyl)-2H- tetrazol-5-yl)picolinamide

The title compound was prepared in a similar manner to λ/-(3-(2-hydroxyethoxy)benzyl)-6- methyl-4-(2-((1-(methylsulfonyl)pιperιdιn-4-yl)methyl)-2H -tetrazol-5-yl)pιcolιnamιde (Example 376, step 4) by reaction with (4-fluoro-3-methylphenyl)methanamιne to afford 25 mg (39%) ¹ H NMR (400 MHz, DMSO-cfe) δ ppm 9 21 (t, J=Q 2 Hz, 1 H), 8 41 (s, 1 H), 8 05 (s, 1 H), 7 23 (d, J=Q 6 Hz, 1 H), 7 12 - 7 20 (m, 1 H), 6 99 - 7 10 (m, 1 H), 4 76 (d, J=6 6 Hz, 2 H), 4 46 (d, J=Q 6 Hz, 2 H), 3 55 (d, J=11 7 Hz, 2 H), 2 81 (s, 3 H), 2 59 - 2 75 (m, 5 H), 2 07 - 2 27 (m, 4 H), 1 67 (d, J=13 2 Hz, 2 H), 1 26 - 1 45 (m, 2 H)

Example 379 λ/-(3-Mβthoxybenzyl)-6-methyl-4-(2-(piperidin-4-ylmethyl)- 2H-tetrazol-5-yl)picolinamide

Step 1 Preparation of tert-butyl 4-((5-(2-((3-methoxybenzyl)carbamoyl)-6-methylpyrιdιn-4-yl )-2/-/- tetrazol-2-yl)methyl)pιperιdιne-1 -carboxylate

A mixture of λ/-(3-methoxybenzyl)-6-methyl-4-(2H-tetrazol-5-yl)pιcolιn amιde (prepared as described in step 5 of the synthesis of A/-(3-methoxybenzyl)-4-(2-(((<rans)-4-amιnocyclohexyl)me thyl)- 2H-tetrazol-5-yl)-6-methylpιcolιnamιde, Example 153) (1 00 g, 3 10 mmol), tert-butyl 4-(hydroxymethyl) pιperιdιne-1-carboxylate (0 81 g, 3 8 mmol), and polymer supported-tnphenylphosphine (2 90 g, 6 21 mmol) were suspended in anhydrous tetrahydrofuran (32 mL) The mixture was cooled to 0 ⁰ C in an ice bath for 15 minutes and then di-tert-butyl azodicarboxylate (1 1 1 g, 4 82 mmol) was added The mixture was allowed to warm to room temperature while stirring over 15 hours The reaction mixture was filtered and the filtrate was concentrated The residue was purified by silica gel chromatography (20 g, 0-50% gradient ethyl acetate/heptane) to afford the title compound as a white solid (1 52 g, 94%) LC/MS (5-100% CH ₃ CN/H ₂ O, 8 mm) 6 24 mm, m/z 544 (M+Na)

Step 2 Preparation of λ/-(3-methoxybenzyl)-6-methyl-4-(2-(pιperιdιn-4-ylmethyl )-2/-/-tetrazol-5- yQpicolinamide

Trifluoroacetic acid (6 mL) was added to a solution of tert-butyl 4-((5-(2-((3-methoxybenzyl)- carbamoyl)-6-methylpyrιdιn-4-yl)-2H-tetrazol-2-yl)methyl)p ιperιdιne-1-carboxylate (1 51 g, 2 89 mmol) in dichloromethane (20 mL) The reaction mixture was stirred for 1 hour at room temperature and was then concentrated The residue was purified by reverse phase preparative HPLC to afford the title compound as the tÏ€fluoroacetate salt (0 83 g, 56%) LC/MS (5-100% CH ₃ CN/H ₂ O, 8 mm) 5 33 mm, m/z 422 (M+H)

Example 380

λ/-(3-Methoxybenzyl)-4-(2-((1 -(2-hydroxy-2-methylpropanoyl)piperidin-4-yl)methyl)-2H-tetr azol- 5-yl)-6-methylpicolinamide

Triethylamine (31 mg, 0 31 mmol) and 1 -chloro-2-methyl-1-oxopropan-2-yl acetate (O 023 g, O 14 mmol) were added to a solution of λ/-(3-methoxybenzyl)-6-methyl-4-(2-(pιperιdιn-4-ylmethyl )-2/-/- tetrazol-5-yl)pιcolιnamιde (prepared as described in Example 379) (75 mg, 0 14 mmol) in N ₁ N- dimethylacetamide (2 mL), and the mixture was stirred for 1 hour at room temperature The reaction mixture was diluted with water (2 mL) and extracted with ethyl acetate (3 x-5 mL) The organic layer was washed with water (3 x 5 mL) followed by brine (5 mL), dried over anhydrous sodium sulfate, and concentrated The residue was purified by silica gel chromatography (10 g, 0-50% ethyl acetate/heptane) The intermediate was dissolved in a mixture of methanol/water (4 mL, 3/1 )and potassium carbonate (41 mg, 0 30 mmol) was added The mixture was stirred for 10 hours at 6O ⁰ C The methanol was removed in vacuo and the aqueous residue was acidified with a 10% aqueous solution of hydrochloric acid This mixture was extracted with ethyl acetate (3 x 5 mL) The combined organic layers were washed with water (5 mL) followed by brine (5 mL), dried over anhydrous sodium sulfate, and concentrated The residue that was purified by reverse phase preparative HPLC to afford the title compound (21 mg, 30%) MS (ES+) m/z 508 (M+H) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9 19 (t, J=Q 2 Hz, 1 H), 8 41 (s, 1 H), 8 06 (s, 1 H), 7 22 (t, J=Q 1 Hz, 1 H), 6 90 (br s , 2 H), 6 80 (d, J=8 1 Hz, 1 H), 5 26 (s, 1 H), 4 71 (d, J=I 3 Hz, 2 H), 4 49 (d, J=Q 6 Hz, 2 H), 3 71 (s, 3 H), 2 65 (s, 3 H), 2 30 (d, J=2 9 Hz, 1 H), 1 58 (d, J=13 2 Hz, 4 H), 1 22 - 1 33 (m, 6 H), 1 19 (br s , 4 H)

Example 381 /V-(3-Methoxybenzyl)-4-(2-((1-(3-aminopropanoyl)piperidin-4- yl)methyl)-2H-tetrazol-5-yl)-6- methylpicolinamide

1 -Hydroxybenzotrιazole (3 2 mg, 0 024 mmol) was added to a solution of 3-(tert- butoxycarbonyl)propanoιc acid (27 2 mg, 0 144 mmol) in λ/,λ/-dιmethylformamιde (2 mL) Carbodiimide resin (138 mg, 0 18 mmol, 1 30 mmol/g loading), λ/-(3-methoxybenzyl)-6-methyl-4-(2- (pιperιdιn-4-ylmethyl)-2H-tetrazol-5-yl)pιcolιnamιde (prepared as described in Example 379) (50 6 mg, 0 120 mmol), and λ/-methylmorpholιne (0 066 mL, 0 60 mmol) were added with dichloromethane (2 mL), and the mixture was agitated overnight at room temperature The reaction mixture was filtered and the resin was washed with λ/,W-dιmethylformamιde followed by dichloromethane The filtrate was concentrated and the residue was purified by reverse phase preparative HPLC (5%-95% CH ₃ CN/H ₂ O, 8 mm ) The intermediate was added to a 1 1 mixture of trifluoroacetic acid and dichloromethane and

stirred for 1 hour The reaction mixture was concentrated The residue was dissolved in dichloromethane, neutralized with MP-carbonate resin, and concentrated to afford the title compound (10 mg, 17%) LC/MS (5%-95% CH ₃ CN/H ₂ O, 4 5 mm , 95% CH ₃ CN, 1 5 mm ) 2 572 mm , m/z 493 (M+H)

Example 382

N-(3-Methoxybenzyl)-4-(2-((1-(2-aminoacetyl)piperidin-4-y l)methyl)-2H-tetrazol-5-yl)-6- methylpicolinamide

The title compound was prepared in a similar manner to λ/-(3-methoxybenzyl)-4-(2-((1-(3- amιnopropanoyl)pιperιdιn-4-yl)methyl)-2/-/-tetrazol-5-yl )-6-methylpιcolιnamιde (Example 381 ) by reaction with 2-(tert-butoxycarbonyl)acetιc acid to afford 10 mg (17%) LC/MS (5%-95% CH ₃ CN/H ₂ O, 4 5 mm , 95% CH ₃ CN, 1 5 mm ) 2 543 mm , m/z 479 (M+H)

Example 383 N-(3-Methoxybenzyl)-4-(2-((1-acetylpiperidin-4-yl)methyl)-2H -tetrazol-5-yl)-6-methylpicolinamide

Acetic anhydride (0 034 ml_, 0 356 mmol) and 4-(dιmethy!amιno)pyÏ€dιne Si bound (862 0 mg, 0 595 mmol, 0 69 mmol/g loading) were added to a solution of λ/-(3-methoxybenzyl)-6-methyl-4-(2- (pιperιdιn-4-ylmethyl)-2/-/-tetrazol-5-yl)pιcolιnamιde (prepared as described in Example 379) (50 2 mg, 0 119 mmol) in dichloromethane (2 mL), and the mixture was agitated overnight at room temperature The reaction mixture was filtered and the resin was washed with λ/,W-dιmethylformamιde The filtrate was concentrated and the residue was purified by reverse phase preparative HPLC (5%-95% CH ₃ CN/H ₂ O, 8 mm ) to afford the title compound as a solid (24 5 mg, 44%) LC/MS (5%-95% CH ₃ CN/H ₂ O, 4 5 mm , 95% CH ₃ CN, 1 5 mm ) 2 959 mm , m/z 464 (M+H) ¹ H NMR (400 MHz, DMSOd ₆ ) δ ppm 0 98 - 1 35 (m, 4 H), 1 57 (m, 2 H), 1 94 (s, 3 H), 2 16 - 2 37 (m, 1 H), 2 44 - 2 57 (m, 2 H), 2 65 (s, 3 H), 3 71 (s, 3 H), 4 49 (d, J=6 6 Hz, 2 H), 4 71 (d, J=I 3 Hz, 2 H), 6 80 (m, 1 H), 6 86 - 6 95 (m, 2 H), 7 14 - 7 28 (m, 1 H), 8 05 (s, 1 H), 8 41 (s, 1 H), 9 1 1 - 9 27 (m, 1 H)

Example 384

λ/-(3-Methoxybenzyl)-6-methyl-4-(2-((1-(methylsulfonyl)p iperidin-4-yl)methyl)-2H-tetrazol-5- yl)picolinamide

The title compound was prepared in a similar manner to λ/-(3-methoxybenzyl)-4-(2-((1 -acetyl- pιperιdιn-4-yl)methyl)-2/-/-tetrazol-5-yl)-6-methylpιcol ιnamιde (Example 383) by reaction with methane sulfonylchloride to afford 32 5 mg (55%) LC/MS (5%-95% CH ₃ CN/H ₂ O, 4 5 mm , 95% CH ₃ CN, 1 5 mm ) 3 154 mm , m/z 500 (M+H) ¹ H NMR (400 MHz ₁ DMSO-cfe) δ ppm 1 24 - 1 48 (m, 4 H), 1 61 - 1 72 (m, 2 H), 2 07 - 2 27 (m, 1 H), 2 65 (s, 3 H), 2 81 (s, 3 H), 3 47 - 3 60 (m, 2 H), 3 71 (s, 3 H), 4 49 (d, J=6 6 Hz, 2 H), 4 76 (d, J=I 3 Hz, 2 H), 6 73 - 6 83 (m, 1 H), 6 86 - 6 95 (m, 2 H), 7 15 - 7 27 (m, 1 H), 8 05 (S, 1 H), 8 41 (s, 1 H), 9 19 (s, 1 H)

Example 385 N-(3-Methoxybenzyl)-4-(2-((1 -isobutyrylpiperidin-4-yl)methyl)-2H-tetrazol-5-yl)-6- methylpicolinamide

The title compound was prepared in a similar manner to /V-(3-methoxybenzyl)-4-(2-((1 -acetyl- pιperιdιn-4-yl)methyl)-2/-/-tetrazol-5-yl)-6-methylpιcol ιnamιde (Example 383) by reaction with isobutyryl chloride to afford 37 2 mg (63%) LC/MS (5%-95% CH ₃ CN/H ₂ O, 4 5 mm , 95% CH ₃ CN, 1 5 mm )

3 296 mm , m/z 492 (M+H) ¹ H NMR (400 MHz, DMSO-c/ ₆ ) δ ppm 1 00 - 1 37 (m, 6 H), 1 47 - 1 72 (m, 2 H), 2 28 (s, 1 H), 2 65 (s, 3 H) ₁ 2 74 - 2 90 (m, 1 H), 2 90 - 3 10 (m, 2 H) ₁ 3 71 (s, 3 H) ₁ 4 49 (d, J=6 6 Hz, 2 H) ₁ 4 72 (d, J=I 3 Hz, 2 H), 6 80 (s, 1 H), 6 86 - 6 97 (m, 2 H), 7 22 (s, 1 H), 8 05 (s, 1 H), 8 41 (S ₁ 1 H), 9 19 (s, 1 H)

Example 386

W-(3-Methoxybenzyl)-6-methyl-4-(2-((1-(methylcarbamoyl)pi peridin-4-yl)methyl)-2H-tetrazol-5- yl)picolinamide

Methylisocyanate (4M solution in dichloromethane, 1 mL) and 4-(dιmethy!amιno)pyrιdιne Si bound (862 0 mg, 0 595 mmol, 0 69 mmol/g loading) were added to a solution of λ/-(3-methoxybenzyl)-6- methyl-4-(2-(pιperιdιn-4-ylmethyl)-2/-/-tetrazol-5-yl)pι colιnamιde (prepared as described in Example

379) in dichloromethane (1 m!_), and the mixture was agitated overnight at room temperature The reaction mixture was filtered and the resin was washed with λ/,λ/-dιmethylformamιde The filtrate was concentrated and the residue was purified by reverse phase preparative HPLC (5%-95% CH ₃ CN/H ₂ O, 8 mm ) to afford the title compound (35 5 mg, 62%) LC/MS (5%-95% CH ₃ CN/H ₂ O, 4 5 mm , 95% CH ₃ CN , 1 5 mm ) 2 887 mm , m/z 479 (M+H) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1 01 - 1 24 (m, 4 H), 1 44 - 1 55 (m, 2 H), 2 20 (s, 1 H), 2 50 - 2 54 (m, 3 H), 2 56 - 2 63 (m, 2 H), 2 65 (s, 3 H), 3 71 (s, 3 H), 4 49 (d, J=6 6 Hz, 2 H), 4 70 (d, J=6 6 Hz, 2 H), 6 30 (s, 1 H), 6 80 (m, 1 H), 6 85 - 6 95 (m, 2 H), 7 22 (s, Hz, 1 H), 8 05 (s, 1 H), 8 40 (s, 1 H), 9 09 - 9 26 (m, 1 H)

Example 387 W-(3-Chloro-4-fluorobenzyl)-6-methyl-4-(2-(piperidin-4-ylmet hyl)-2H-tetrazol-5-yl)picolinamide

Step 1 Preparation of 4-(2-((1-(teff-butoxycarbonyl)piperιdιn-4-yl)methyl)-2/-/- tetrazol-5-yl)-6- methylpicolinic acid

A flask was charged with methyl 6-methyl-4-(2/-/-tetrazol-5-yl)pιcolιnate (prepared as described in step 4 of the synthesis of λ/-(3-methoxybenzyl)-4-(2-(((frans)-4-amιnocyclohexyl)meth yl)- 2/-/-tetrazol-5-yl)-6-methylpιcolιnamιde, Example 153) (1 0 g, 4 6 mmol), tert-butyl 4-(hydroxymethyl) pιperιdιne-1 -carboxylate (2 0 g, 9 1 mmol), polymer supported triphenylphosphine resin (4 2 g, 9 1 mmol, 2 15 mmol/g loading) and tetrahydrofuran (60 mL) The mixture was cooled in an ice bath and di-tert-butylazodicarbxylate (2 1 g, 9 1 mmol) was added The mixture was stirred for 30 minutes and then allowed to warm to room temperature over 18 hours The reaction mixture was filtered and the resin was washed with methanol The filtrate was concentrated and the residue was dissolved in a mixture of tetrahydrofuran/water (25 ml_/5 mL) LiOH (660 mg, 28 0 mmol) was added and the resulting mixture was stirred at room temperature over 3 days The tetrahydrofuran was removed in vacuo and the aqueous residue was treated with 4N hydrochloric acid carefully until pH 5-6 The mixture was extracted with dichloromethane The organic layer was dried over magnesium sulfate and concentrated The residue was purified by reverse phase preparative HPLC and then recrystallized from methanol/water to afford the title compound as a white solid (1 21 g, 65%) MS (ES+) m/z 508 (M+H) ¹ H NMR (400 MHz, DMSOd ₆ ) δ ppm 1 12 - 1 24 (m, 2 H), 1 34 - 1 43 (m, 1 1 H), 1 55 (m, 2 H), 2 14 - 2 28 (m, 1 H), 2 65 (s, 3 H), 3 89 - 3 98 (m, 2 H) ₁ 4 73 (d, J=6 98 Hz, 2 H), 8 09 (d, J= 1 07 Hz, 1 H), 8 39 (s, 1 H), 8 55 - 8 64 (m, 1 H)

Step 2 Preparation of fert-butyl 4-((5-(2-((3-chloro-4-fluorobenzyl)carbamoyl)-6-methylpyrιd ιn-4-yl)-2H- tetrazol-2-yl)methyl)pιperιdιne-1-carboxylate

2-(1H-Benzotrιazo!e-1-yl)-1 ,1 ,3,3-tetramethyluronιum hexafluorophosphate (141 mg, 0 37 mmol) was added to a mixture of 4-(2-((1-(tert-butoxycarbonyl)pιperιdιn-4-yl)methyl)-2H-t etrazol-5-yl)- 6-methylpιcolιnιc acid (100 mg, 0 25 mmol), (3-chloro-4-fluorophenyl)methanamιne (47 mg, 0 30 mmol), and triethylamine (0 05 mL, 0 37 mmol) in /V,/V-dιmethylformamιde (2 mL), and the mixture was stirred at room temperature for 18 hours The reaction mixture was purified by reverse phase preparative HPLC The product was dissolved in methanol, passed through a carbonate cartridge, and concentrated to afford the title compound as a solid (59 mg, 43%) LCMS (ES+) m/z 544 (M+H)

Step 3 Preparation of λ/-(3-chloro-4-fluorobenzyl)-6-methyl-4-(2-(pιperιdιn-4- ylmethyl)-2/-/-tetrazol-5- vDpicolinamide

A vial was charged with terf-butyl 4-((5-(2-((3-chloro-4-fluorobenzyl)carbamoyl)-6- methylpyrιdιn-4-yl)-2/-/-tetrazol-2-yl)methyl)pιperιdιn e-1 -carboxylate (59 mg, 0 12 mmol), methanol (1 mL), and a 4N solution of hydrochloric acid in dioxane (0 5 mL) The resulting solution was stirred at room temperature for 18 hours The reaction mixture was then passed through a carbonate cartridge eluting with methanol and concentrated to afford the title compound as a solid (49 mg, 95%) MS (ES+) m/z 444 (M+H) ¹ H NMR (400 MHz, CDCI ₃ ) δ ppm 1 38 - 1 53 (m, 2 H), 1 69 (s, J=12 08 Hz, 2 H), 2 20 - 2 34 (m, 1 H), 2 60 - 2 72 (m, 5 H), 3 17 - 3 25 (m, 2 H), 4 57 (d, J=6 98 Hz, 2 H), 4 63 (d, J=Q 44 Hz, 2 H), 7 10 (t, J=8 59 Hz, 1 H), 7 21 - 7 28 (m, 1 H), 7 41 (dd, J=6 98, 2 15 Hz, 1 H), 8 05 (d, J=1 34 Hz, 1 H), 8 46 (t, J=6 31 Hz, 1 H), 8 70 (s, 1 H)

Example 388

W-(3-Ch!oro-4-fluorobenzyl)-6-methyl-4-(2-((1-(methylsulf onyl)piperidin-4-yl)methyl)-2H-tetrazol- 5-yl)picolinamide

Methane sulfonylchlonde (0 007 mL, 0 08 mmol) was added to a mixture of λ/-(3-ch!oro-4- fluorobenzyl)-6-methyl-4-(2-(pιperιdιn-4-ylmethyl)-2/-/-t etrazol-5-yl)pιcolιnamιde (prepared as described in Example 387) (25 mg, 0 06 mmol) and triethylamine (0 016 mL, 0 11 mmol) in dichloromethane (1 mL), and the mixture was stirred at room temperature for 2 hours The reaction mixture was purified by reverse phase preparative HPLC Fractions containing desired product were combined and concentrated The residue was dissolved in methanol and passed through a carbonate cartridge Concentration of the resulting solution afforded the title compound as a solid (16 mg, 55%) MS (ES+) m/z 522 (M+H) ¹ H NMR (400 MHz ₁ DMSOd ₆ ) δ ppm 1 01 - 1 27 (m, 3 H), 1 51 (d, J= 11 71 Hz, 2 H), 1 93 - 2 10 (m, 2 H), 2 51 - 2 60 (m, 1 H), 2 65 (s, 3 H), 3 05 - 3 16 (m, 1 H), 3 38 (d, J=1 1 71 Hz, 3 H), 4 33 (d, J=5 86 Hz, 2 H), 4 60 (d, J=7 32 Hz, 2 H), 7 18 (d, J=7 32 Hz, 2 H), 7 31 - 7 44 (m, J=8 05 Hz, 1 H), 7 90 (S, 1 H), 8 24 (s, 1 H), 9 18 (t, J=6 59 Hz, 1 H)

Example 389

λ/-(4-Fluoro-3-(trifluoromethyl)benzyl)-6-methyl-4-(2-(p iperidin-4-ylmethyl)-2H-tetrazol-5- yl)picolinamide

Step 1 Preparation of tert-butyl 4-((5-(2-((4-fluoro-3-(trιfluoromethyl)benzyl)carbamoyl)-6- methylpyrιdιn-4-yl)-2H-tetrazol-2-yl)methyl)pιperιdιne- 1-carboxylate

2-(1H-Benzotrιazole-1-yl)-1 ,1 ,3,3-tetramethyluronιum hexafluorophosphate (141 mg, 0 37 mmol) was added to a mixture of 4-(2-((1-(tert-butoxycarbonyl)pιperιdιn-4-y!)methyl)-2/-/ -tetrazol-5-yl)- 6-methylpιcotιnιc acid (prepared as described in step 1 of the synthesis of λ/-(3-chloro-4-fluorobenzyl)- 6-methyM-(2-(pιperιdιn-4-ylmethyl)-2H-tetrazol-5-yl)pιco lιnamιde, Example 387) (100 mg, 0 25 mmol), (4-fluoro-3-(trιfluoromethyl)phenyl)methanamιne (58 mg, 0 30 mmol), and triethylamine (0 05 mL, 0 37 mmol) in λ/,λ/-dιmethylformamιde (2 mL), and the mixture was stirred at room temperature for 18 hours The reaction mixture was purified by reverse phase preparative HPLC The product was

dissolved in methanol, passed through a carbonate cartridge, and concentrated to afford the title compound as a solid (61 mg, 43%) LCMS (ES+) m/z 578 (M+H)

Step 2 Preparation of λ/-(4-fluoro-3-(trιfluoromethyl)benzyl)-6-methyl-4-(2-(pι perιdιn-4-ylmethyl)-2/-/- tetrazol-5-yl)pιcolιnamιde

A vial was charged with tert-butyl 4-((5-(2-((4-fluoro-3-(trιflÏ…oromethyl)benzyl)carbamoyl)-6 - methylpyrιdιn-4-yl)-2H-tetrazol-2-yl)methyl)pιperιdιne- 1-carboxylate (63 mg, 0 12 mmol), methanol (1 mL), and a 4N solution of hydrochloric acid in dioxane (0 5 mL) The resulting solution was stirred at room temperature for 18 hours The reaction mixture was then passed through a carbonate cartridge eluting with methanol and concentrated to afford the title compound as a solid (49 mg, 100%) MS (ES+) m/z 478 (M+H) ¹ H NMR (400 MHz, DMSO-cfe) 6 ppm 1 11 - 1 24 (m, 3 H), 1 50 (d, J= 1 1 72 Hz, 2 H), 2 04 - 2 17 (m, 1 H), 2 42 - 2 50 (m, 2 H), 2 64 (s, 3 H), 2 95 (d, J=11 72 Hz, 2 H), 4 54 (d, J=I 33 Hz, 2 H) ₁ 4 66 (d, J=5 86 Hz, 2 H), 7 34 - 7 49 (m, 1 H), 7 63 - 7 79 (m, J=19 78, 6 59 Hz, 2 H), 8 05 (S, 1 H), 8 38 (s, 1 H), 9 39 (t, J=6 59 Hz ₁ 1 H)

Example 390

W-(4-Fluoro-3-(trιfluoromethyl)benzyl)-6-methyl-4-(2-((1 -(methylsulfonyl)piperidin-4-yl)methyl)-

2H-tetrazol-5-yl)pιcolinamide

Methane sulfonylchloride 0 006 mL, 0 07 mmol) was added to a mixture of λ/-(4-fluoro-3- (trιfluoromethyl)benzyl)-6-methyl-4-(2-(pιperιdιn-4-ylme thyl)-2H-tetrazol-5-yl)pιcolιnamιde (prepared as described in Example 389) (23 mg, 0 05 mmol) and triethylamine (0 013 mL, 0 10 mmol) in dichloromethane (1 mL), and the mixture was stirred at room temperature for 2 hours The reaction mixture was purified by reverse phase preparative HPLC Fractions containing desired product were combined and concentrated The residue was dissolved in methanol and passed through a carbonate cartridge Concentration of the resulting solution afforded the title compound as a solid (16 mg, 58%) MS (ES+) m/z 556 (M+H) ¹ H NMR (400 MHz, DMSO-Of ₆ ) δ ppm 1 19 - 1 43 (m, 3 H), 1 67 (d, J= 11 71 Hz, 2 H) ₁ 2 08 - 2 24 (m, 2 H), 2 66 - 2 75 (m, 2 H) ₁ 2 81 (s, 3 H) ₁ 3 54 (d, J=11 71 Hz ₁ 3 H), 4 55 (d, J=5 86 Hz, 2 H), 4 75 (d, J=7 32 Hz ₁ 2 H), 7 38 - 7 51 (m, 1 H) ₁ 7 64 - 7 81 (m, 2 H), 8 06 (s, 1 H), 8 40 (S, 1 H), 9 40 (t, J=6 22 Hz, 1 H)

Example 391 W-(4-Fluoro-3-methoxybenzyl)-6-methyl-4-(2-(piperidin-4-ylme thyl)-2H-tetrazol-5-yl)picolinamide

Step 1 Preparation of tert-butyl 4-((5-(2-((4-fluoro-3-methoxybenzyl)carbamoyl)-6-methylpyrid in-4-yl)- 2/-/-tetrazol-2-yl)methyl)pιperιdιne-1-carboxylate

2-(1H-Benzotrιazole-1-yl)-1 ,1 ,3,3-tetramethyluronιum hexafluorophosphate (141 mg, 0 37 mmol) was added to a mixture of 4-(2-((1-(tert-butoxycarbonyl)pιperιdιn-4-yl)methyl)-2H-t etrazol-5-yl)- 6-methylpιcolιnιc acid (prepared as described in step 1 of the synthesis of λ/-(3-chloro-4-fluorobenzyl)- 6-methyl-4-(2-(pιperιdιn-4-ylmethyl)-2H-tetrazol-5-yl)pι colιnamιde, Example 387) (100 mg, 0 25 mmol), 4-fluoro-3-methoxybenzylamιne hydrochloride (prepared as described in step 3 of the synthesis of N- (4-fluoro-3-methoxybenzyl)-6-(2-((<rans-4-amιnocyclohexy l)methyl)-2H-tetrazol-5-yl)pyrιmιdιne-4- carboxamide, Example 1 ) (46 mg, 0 30 mmol), and triethylamine (0 05 mL, 0 37 mmol) in N, N- dimethylformamide (2 mL), and the mixture was stirred at room temperature for 18 hours The reaction mixture was purified by reverse phase preparative HPLC The product was dissolved in methanol, passed through a carbonate cartridge, and concentrated to afford the title compound as a solid (63 mg, 47%) MS (ES+) m/z 540(M+H)

Step 2 Preparation of /V-(4-fluoro-3-methoxybenzyl)-6-methyl-4-(2-(pιperιdιn-4- ylmethyl)-2/-/-tetrazol- 5-yl)pιcolιnamιde

A vial was charged with tert-butyl 4-((5-(2-((4-fluoro-3-methoxybenzyl)carbamoyl)-6- methylpyrιdιn-4-yl)-2/-/-tetrazol-2-yl)methyl)pιperιdιn e-1-carboxylate (53 mg, 0 10 mmol), methanol (1 mL), and a 4N solution of hydrochloric acid in dioxane (0 5 mL) The resulting solution was stirred at room temperature for 18 hours The reaction mixture was then passed through a carbonate cartridge eluting with methanol and concentrated to afford the title compound as a solid (43 mg, 100%) MS (ES+) m/z 440 (M+H) ¹ H NMR (400 MHz, DMSO-Cf ₆ ) δ ppm 1 07 - 1 26 (m, 3 H), 1 49 (d, J= 1 1 72 Hz, 2 H), 2 03 - 2 18 (m, 2 H), 2 44 - 2 52 (m, 2 H), 2 65 (s, 3 H), 2 94 (d, J= 1 1 72 Hz, 2 H), 3 80 (s, 3 H),

4 48 (d, J=T 33 Hz, 2 H), 4 67 (d, J=5 86 Hz, 2 H), 6 85 - 6 93 (m, 1 H), 7 04 - 7 22 (m, 2 H), 8 05 (s, 1 H), 8 40 (s, 1 H), 9 21 (t, J=5 86 Hz, 1 H)

Example 392

A/-(4-Fluoro-3-methoxybenzyl)-6-methyl-4-(2-((1-(methylsu lfonyl)piperidin-4-yl)methyl)-2H- tetrazol-5-yl)picolinamide

Methane sulfonylchloride 0 006 mL, 0 07 mmol) was added to a mixture of λ/-(4-fluoro-3- methoxybenzyl)-6-methyl-4-(2-(pιperιdιn-4-ylmethyl)-2/-/- tetrazol-5-yl)pιcolιnamιde (prepared as described in Example 391 ) (20 mg, 0 05 mmol) and triethylamine (0 013 mL, 0 10 mmol) in dichloromethane (1 mL), and the mixture was stirred at room temperature for 2 hours The reaction mixture was purified by reverse phase preparative HPLC Fractions containing desired product were combined and concentrated The residue was dissolved in methanol and passed through a carbonate cartridge Concentration of the resulting solution afforded the title compound as a solid (15 mg, 61 %) MS (ES+) m/z 518 (M+H) ¹ H NMR (400 MHz, DMSOd ₆ ) δ ppm 1 18 - 1 43 (m, 3 H), 1 67 (d, J=11 71 Hz, 2 H), 2 09 - 2 24 (m, 2 H), 2 62 - 2 76 (m, 2 H) ₁ 2 81 (s, 3 H), 3 54 (d, J=12 45 Hz, 3 H), 3 80 (s, 3 H), 4 48 (d, J=5 86 Hz, 2 H), 4 76 (d, J=6 59 Hz, 2 H), 6 82 - 6 92 (m, 1 H), 7 05 - 7 20 (m, 2 H), 8 06 (S, 1 H), 8 41 (s, 1 H), 9 22 (t, J=6 22 Hz, 1 H)

Example 393

W-(4-Fluoro-3-methoxybenzyl)-6-methyl-4-(2-((/?)-morpholi n-2-ylmethyl)-2H-tetrazol-5- yl)picolinamide

Step 1 Preparation of (2R)-tert-butyl 2-((5-(2-((4-fluoro-3-methoxybenzyl)carbamoyl)-6-methylpyrι dιn- 4-yl)-2H-tetrazol-2-yl)methyl)morpholιne-4-carboxylate

A mixture of λ/-(4-fluoro-3-methoxybenzyl)-6-methyl-4-(2H-tetrazol-5-yl) pιcolιnamιde (prepared as described in step 2 of the synthesis of λ/-(4-fluoro-3-methoxybenzyl)-4-(2-(((frans)-4- amιnocyclohexyl)methyl)-2/-/-tetrazol-5-yl)-6-methylpιcolÎ ¹namιde, Example 170) (0 070 g, 0 19 mmol), (R)-tert-butyl 2-(hydroxymethyl)morpholιne-4-carboxylate (0 050 g, 0 23 mmol), and polymer supported-tÏ€phenylphosphine (0 60 g, 0 29 mmol) in anhydrous tetrahydrofuran (5 mL) was cooled to 0 ⁰ C in an ice bath for 15 mm and then di-tert-butyl azodicarboxylate (0 053 g, 0 23 mmol) was added The mixture was allowed to warm to room temperature while stirring over 15 hours The reaction mixture was filtered and the filtrate was concentrated The residue was purified by silica column chromatography (0-2% methanol/dichloromethane) to afford the title compound as a beige oil (65 mg, 62%) LC/MS (5-100% CH ₃ CN/H ₂ O, 8 mm) 5 58 mm, m/z 564 (M+Na)

Step 2 Preparation of λ/-(4-fluoro-3-methoxybenzyl)-6-methyl-4-(2-((R)-morpholιn -2-ylmethyl)-2H- tetrazol-5-yl)pιcolιnamιde

Trifluoroacetic acid (0 5 mL) was added to a solution of (2R)-tert-butyl 2-((5-(2-((4-fluoro-3- methoxybenzyl)carbamoyl)-6-methylpyrιdιn-4-yl)-2/-/-tetraz ol-2-yl)methyl)morpholιne-4-carboxylate in dichloromethane (2 mL), and the mixture was stirred for 1 hour at room temperature The reaction mixture was concentrated, and the residue was triturated with diethyl ether (4 x 5 mL) to afford the title compound

Example 394

W-(4-Fluoro-3-methoxybenzyl)-4-(2-(((/?)-4-acetylmorpholi n-2-yl)methyl)-2H-tetrazol-5-yl)-6- methylpicolinamide

Triethylamine (0 037 mL, 0 26 mmol) and a solution of acetyl chloride (13 mg in 0 5 mL dichloromethane) were added to a solution of λ/-(4-fluoro-3-methoxybenzyl)-6-methyl-4-(2-((/?)- morpholιn-2-ylmethyl)-2/-/-tetrazol-5-yl)pιcolιnamιde (prepared as described in Example 393) (0 065 g, 0 12 mmol) in dichloromethane (2 mL) The mixture was stirred for 1 hour at room temperature and then was concentrated The residue was purified by reverse phase preparative HPLC (10-90 % acetonitÏ€le/water) to afford the title compound (26 mg, 45%) ¹ H NMR (400 MHz ₁ DMSO-d ₆ ) δ ppm 9 22 (br s , 1 H), 8 41 (br s , 1 H), 8 06 (br s , 1 H), 7 13 (dd, J=23 4, 10 3 Hz, 1 H), 6 89 (d, J=5 1 Hz, 1 H), 4 82 - 5 04 (m, 2 H), 4 48 (d, J=6 6 Hz, 2 H), 4 37 (d, J= 1 1 7 Hz, 1 H), 3 97 (br s , 2 H), 3 80 (s, 3 H), 3 61 (br s , 1 H), 3 39 (br s , 1 H), 3 11 (br s , 1 H), 2 66 (s, 5 H), 2 01 (d, J=16 1 Hz, 3 H)

Example 395

λ/-(4-Fluoro-3-methoxybenzyl)-6-methyl-4-(2-((S)-morphol in-2-ylmethyl)-2H-tetrazol-5- yl)picolinamide

Step 1 Preparation of (2S)-tert-butyl 2-((5-(2-((4-fluoro-3-methoxybenzyl)carbamoyl)-6-methylpyrι dιn- 4-yl)-2/-/-tetrazol-2-yl)methyl)morpholιne-4-carboxylate

A mixture of λ/-(4-fluoro-3-methoxybenzyl)-6-methyl-4-(2H-tetrazol-5-yl) pιcolιnamιde (prepared as described in step 2 of the synthesis of /V-(4-fluoro-3-methoxybenzyl)-4-(2-(((frans)-4- amιnocyclohexyl)methyl)-2/-/-tetrazol-5-yl)-6-methylpιcolÎ ¹namιde, Example 170) (0 070 g, 0 19 mmol), (S)-tert-butyl 2-(hydroxymethyl)morpholιne-4-carboxylate (0 050 g, 0 23 mmol), and polymer supported-tnphenylphosphine (0 60 g, 0 29 mmol) in anhydrous tetrahydrofuran (5 mL) was cooled to 0 ⁰ C in an ice bath for 15 mm and then di-tert-butyl azodicarboxylate (0 053 g, 0 23 mmol) was added The mixture was allowed to warm to room temperature while stirring over 15 hours The reaction mixture was filtered and the filtrate was concentrated The residue was purified by silica column

chromatography (0-2% methanol/dichloromethane) to afford the title compound as a beige oil (63 mg, 61 %) LC/MS (5-100% CH ₃ CN/H ₂ O, 8 mm) 5 57 mm, m/z 564 (M+Na)

Step 2 Preparation of λ/-(4-fluoro-3-methoxybenzyl)-6-methyl-4-(2-((S)-morpholιn -2-ylmethyl)-2H- tetrazol-5-yl)pιcolιnamιde

Trifluoroacetic acid (0 5 mL) was added to a solution of (2S)-tert-butyl 2-((5-(2-((4-fluoro-3- methoxybenzyl)carbamoyl)-6-methylpyrιdιn-4-yl)-2H-tetrazol -2-yl)methyl)morpholιne-4-carboxylate in dichloromethane (2 mL), and the mixture was stirred for 1 hour at room temperature The reaction mixture was concentrated, and the residue was triturated with diethyl ether (4 x 5 mL) to afford the title compound

Example 396

/V-(4-Fluoro-3-methoxybenzyl)-4-(2-(((S)-4-acetylmorpholi n-2-yl)methyl)-2H-tetrazol-5-yl)-6- methylpicolinamide

Triethylamine (0 037 mL, 0 26 mmol) and a solution of acetyl chloride (13 mg in 0 5 mL dichloromethane) was added to a solution of λ/-(4-fluoro-3-methoxybenzyl)-6-methyl-4-(2-((S)- morpholιn-2-ylmethyl)-2H-tetrazol-5-yl)pιcolιnamιde (prepared as described in Example 395) (0 063 g, 0 12 mmol) in dichloromethane (2 mL) The mixture was stirred for 1 hour at room temperature and then was concentrated The residue was purified by reverse phase preparative HPLC (10-90 % acetonitrile/water) to afford the title compound (29 mg, 50%) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9 21 (d, J=5 9 Hz, 1 H) ₁ 8 41 (br s , 1 H), 8 06 (br s , 1 H), 7 05 - 7 22 (m, 2 H), 6 80 - 6 95 (m, 1 H), 4 80 - 5 08 (m, 2 H), 4 48 (d, J=6 6 Hz, 3 H), 4 37 (d, J=13 9 Hz, 1 H), 3 90 - 4 15 (m, 2 H), 3 80 (s, 3 H), 3 63 (d, J=13 2 Hz, 1 H), 3 33 - 3 47 (m, 1 H), 3 02 - 3 20 (m, 1 H), 2 66 (s, 3 H), 2 02 (d, J=16 8 Hz, 3 H)

Example 397

W-(4-Fluoro-3-methoxybenzyl)-6-methyl-4-(2-(((R)-4-(methy lsulfonyl)morpholin-2-yl)methyl)-2H- tetrazol-5-yl)picolinamide

Triethylamine (0 037 ml_, 0 26 mmol) and a solution of methanesulfonyl chloride (18 mg in 0 5 mL dichloromethane) was added to a solution of λ/-(4-fluoro-3-methoxybenzyl)-6-methyl-4-(2-((S)- morpholιn-2-ylmethyl)-2H-tetrazol-5-yl)pιcolιnamιde (prepared as described in Example 395) (0 075 g, 0 18 mmol) in dichloromethane (2 mL) The mixture was stirred for 1 hour at room temperature and then was concentrated The residue was purified by reverse phase preparative HPLC (10-90 % acetonitrile/water) to afford the title compound (18 mg, 20%) ¹ H NMR (400 MHz, DMSO-Cf ₆ ) δ ppm 9 22 (t, J=6 2 Hz, 1 H), 8 42 (s, 1 H), 8 07 (s, 1 H), 7 06 - 7 22 (m, 2 H), 6 89 (br s , 1 H), 5 04 (dd, J=14 3, 3 3 Hz, 1 H), 4 91 (dd, J=13 9, 8 1 Hz, 1 H), 4 48 (d, J=6 6 Hz, 2 H), 4 06 - 4 17 (m, 1 H), 3 89 (d, J=12 4 Hz, 1 H), 3 80 (s, 3 H), 3 67 (d, J= 1 1 7 Hz, 1 H), 3 44 - 3 55 (m, 1 H), 3 32 (d, J= 1 1 0 Hz, 1 H), 2 91 (s, 3 H), 2 73 - 2 88 (m, 2 H), 2 66 (s, 3 H)

Example 398 W-(3-Methoxybenzyl)-6-methyl-4-(2-((S)-morpholin-2-ylmethyl) -2H-tetrazol-5-yl)picolinamide

Step 1 Preparation of (2S)-tert-butyl 2-((5-(2-((3-methoxybenzyl)carbamoγl)-6-methylpyrιdιn-4-y l)-2H- tetrazol-2-yl)methyl)morpholιne-4-carboxylate

A mixture of λ/-(3-methoxybenzyl)-6-methyl-4-(2W-tetrazol-5-yl)pιcolιn amιde (prepared as described in step 5 of the synthesis of /V-(3-methoxybenzyl)-4-(2-(((frans)-4-amιnocyclohexyl)methy l)- 2/-/-tetrazol-5-yl)-6-methylpιcolιnamιde, Example 153) (0 75 g, 2 3 mmol), (S)-tert-butyl 2- (hydroxymethyl)morpholιne-4-carboxylate (0 53 g, 2 4 mmol), and polymer supported- tÏ€phenylphosphine (1 29 g, 2 77 mmol) in anhydrous tetrahydrofuran (20 mL) was cooled to 0 ⁰ C in an ice bath for 15 mm and then di-tert-butyl azodicarboxylate (0 80 g, 3 5 mmol) was added The reaction mixture was filtered and the filtrate was concentrated The residue was purified by silica column chromatography (0-2% methanol/dichloromethane) to afford the protected amine as a beige oil

Step 2 Preparation of λ/-(3-methoxybenzyl)-6-methyl-4-(2-((S)-morpholιn-2-ylmeth yl)-2H-tetrazol-5- vQpicolinamide

Tnfluoroacetic acid (1 0 mL) was added to a solution of (2S)-tert-buty! 2-((5-(2-((3- methoxybenzyOcarbamoyO-β-methylpyridin^-yl^H-tetrazol^-yOme thyOmorpholine^-carboxylate in dichloromethane (5 mL), and the mixture was stirred for 1 hour at room temperature The reaction mixture was concentrated, and the residue was triturated with diethyl ether (4 x 5 mL) to afford the title compound The reaction mixture was diluted with dichloromethane (10 mL) and neutralized to pH 7 with a 2 5 N aqueous solution of sodium hydroxide The organic phase was separated and washed with water (10 mL) followed by brine (10 mL), dried over anhydrous sodium sulfate, and concentrated to afford the title compound (0 43 g, 44%)

Example 399

W-(3-Methoxybenzyl)-4-(2-(((S)-4-acetylmorpholin-2-yl)met hyl)-2H-tetrazol-5-yl)-6- methylpicolinamide

Triethylamine (0 037 mL, 0 26 mmol) and a solution of acetyl chloride (17 mg in 0 5 mL dichloromethane) was added to a solution of λ/-(3-methoxybenzyl)-6-methyl-4-(2-((S)-morpholιn-2- ylmethyl)-2W-tetrazol-5-yl)pιcolιnamιde (prepared as described in Example 398) (0 075 g, 0 18 mmol) in dichloromethane (2 mL) The mixture was stirred for 1 hour at room temperature and then was concentrated The residue was purified by reverse phase preparative HPLC (10-90 % acetonitrile/water) to afford the title compound (44 mg, 54%) ¹ H NMR (400 MHz, DMSOd ₆ ) δ ppm 9 19 (t, J=5 9 Hz, 1 H), 8 41 (s, 1 H), 8 06 (s, 1 H), 7 22 (t, J=Q 1 Hz, 1 H), 6 90 (br s , 2 H), 6 80 (d, J=Q 1 Hz, 1 H), 4 95 - 5 04 (m, 1 H), 4 85 - 4 95 (m, 1 H), 4 49 (d, J=6 6 Hz, 2 H), 3 90 - 4 13 (m, 2 H), 3 79 (d, J=10 3 Hz, 1 H), 3 71 (s, 3 H), 3 43 (d, J=9 5 Hz, 1 H), 3 05 - 3 20 (m, 2 H), 2 62 - 2 73 (m, 4 H), 2 01 (d, J=16 8 Hz, 3 H)

Example 400

W-(3-Methoxybenzyl)-6-methyl-4-(2-(((R)-4-(methylsulfonyl )morpholin-2-yl)methyl)-2H-tetrazol-5- yOpicolinamide

Triethylamine (0 022 mL, 0 16 mmol) and a solution of methanesulfonyl chloride (15 mg in 0 5 mL dichloromethane) was added to a solution of /V-(3-methoxybenzyl)-6-methyl-4-(2-((S)-morpholιn-2- ylmethyl)-2/-/-tetrazol-5-yl)pιcolιnamιde (prepared as described in Example 398) (0 045 g, 0 11 mmol) in dichloromethane (2 mL) The mixture was stirred for 1 hour at room temperature and then was concentrated The residue was purified by silica column chromatography (0-75%ethyl acetate/heptane) to afford the title compound (20 mg, 37%) ¹ H NMR (400 MHz, DMSO-d ₆ ) 6 ppm 9 19 (t, J=6 2 Hz, 1 H), 8 42 (s, 1 H), 8 07 (s, 1 H), 7 22 (t, J=8 1 Hz, 1 H), 6 90 (br s , 2 H), 6 80 (d, J=I 3 Hz, 1 H), 4 98 - 5 09 (m, 1 H), 4 91 (dd, J=14 6, 8 1 Hz, 1 H), 4 49 (d, J=6 6 Hz, 2 H), 4 1 1 (d, J=9 5 Hz, 1 H), 3 89 (d, J= 1 1 7 Hz, 1 H), 3 71 (s, 3 H), 3 67 (d, J= 1 1 0 Hz, 1 H), 3 50 (t, J=10 3 Hz, 1 H), 3 32 (d, J= 11 7 Hz, 1 H), 2 91 (s, 3 H), 2 75 - 2 88 (m, 2 H), 2 66 (s, 3 H)

Example 401 rac-4-(2-((1 ,4-Dioxan-2-yl)methyl)-2W-tetrazol-5-yl)-/V-(4-fluoro-3-meth oxybenzyl)-6- methylpicolinamide

rac-2-(lodomethyl)-1 ,4-dιoxane (57 mg, 0 25 mmol) was added to a mixture of N-(4-fluoro-3- methoxybenzyl)-6-methyl-4-(2/-/-tetrazol-5-yl)pιcolιnamιd e (prepared as described in step 2 of the synthesis of λ/-(4-fluoro-3-methoxybenzyl)-4-(2-(((frans)-4-amιnocycloh exyl)methyl)-2H-tetrazol-5-yl)- 6-methylpιcolιnamιde, Example 170) (79 mg, 0 23 mmol) and triethylamine (23 mg, 0 23 mole) in anhydrous acetonitrile (1 mL) The mixture was stirred at reflux temperature in a capped vial for two days and then was purified by reverse phase preparative HPLC (water/acetonitrile) Fractions containing the product were passed through a carbonate resin column and the filtrate was concentrated The residue was slurried with ether, decanted, and dried in a vacuum desiccator to afford the title compound as a white solid (39 mg) MS (ES+) m/z 443 (M+H) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9 24 (t, J=6 0 Hz, 1 H), 8 43 (s, 1 H) ₁ 8 08 (s, 1 H), 7 10-7 24 (m, 2 H), 6 91 (br s, 1 H), 4 85-4 95 (m, 2 H), 4 52 (d, J=6 2 Hz, 2 H), 4 05-4 20 (m, 1 H), 3 85-3-95 (m, 1 H), 3 82 (s, 3 H), 3 30-3-80 (m, 5 H), 2 68 (s, 3 H)

Example 402 rac-4-(2-((1,4-Dioxan-2-yl)methyl)-2H-tetrazol-5-yl)-W-(4-fl uoro-3-methylbenzyl)-6- methylpicolinamide

rac-2-(lodomethyl)-1 ,4-dιoxane (1 14 mg, 0 5 mmol) was added to a mixture of λ/-(4-fluoro-3- methylbenzyl)-6-methyl-4-(2H-tetrazol-5-yl)pιcolιnamιde (prepared as describe in step 1 of the synthesis of λ/-(4-fluoro-3-methylbenzyl)-4-(2-(((/rans)-4-amιnocyclohe xyl)methyl)-2H-tetrazol-5-yl)-6- methylpicolinamide, Example 185) (150 mg, 0 46 mmol) and triethylamine (46 mg, 0 46 mmol) in anhydrous acetonitrile (2 mL) The mixture was stirred at reflux temperature in a capped vial for two days and then was purified by reverse phase preparative HPLC (water/acetonitrile) Fractions containing the product were passed through a carbonate resin column and the filtrate was concentrated The residue was slurried with ether, decanted, and dried in a vacuum desiccator to afford the title compound as a white solid (61 mg) MS (ES+) m/z 427 (M+H) ¹ H NMR (400 MHz,

DMSO-d ₆ ) δ ppm 9 24 (t, J=6 0 Hz, 1 H), 8 43 (s, 1 H), 8 08 (s, 1 H), 7 00-7 30 (m, 3 H), 4 85-4 95 (m, 2 H), 4 52 (d, J=Q 2 Hz, 2 H), 4 05-4 20 (m, 1 H), 3 85-3-95 (m, 1 H), 3 30-3-80 (m, 5 H), 2 68 (s, 3 H), 2 20 (s, 3 H)

Example 403 rac-W-(3-Methoxybenzyl)-4-(2-(((2S*,5/?*)-5-(hydroxymethyl)- 1 ₎ 4-dioxan-2-yl)methyl)-2H-tetrazol-

5-yl)-6-methylpicolinamide

rac-((2/?*,5/?*)-5-(Hydroxymethyl)-1 ,4-dιoxan-2-yl)methyl 4-methylbenzenesulfonate (prepared as described in step 4 of the synthesis of rac-λ/-(3-methoxybenzyl)-6-(2-(((2S ^* ,5R*)-5-(hydroxymethyl)- 1 ,4-dιoxan-2-yl)methyl)-2/-/-tetrazol-5-yl)-2-methylpyrιmι dιne-4-carboxamιde, Example 61 ) (1 4 g, 4 3 mmol) was added to a mixture of /V-(3-methoxybenzyl)-6-methyl-4-(2H-tetrazol-5-yl)picolinami de (prepared as described in step 5 of the synthesis of λ/-(3-methoxybenzyl)-4-(2-(((fraÏ€s)-4- amιnocyclohexyl)methyl)-2/-/-tetrazol-5-yl)-6-methylpιcolÎ ¹namιde, Example 153) (1 O g, 3 1 mmol) and triethylamine (0 4 g, 4 0 mmole) in anhydrous W,λ/-dιmethylacetamιde (1 mL) The mixture was stirred at 85°C in a capped vial overnight and then was purified by reverse phase preparative HPLC

(water/acetonitrile) Fractions containing the product were passed through a carbonate resin column and the filtrate was concentrated The residue was slurried with ether, decanted, and dried in a vacuum desiccator to afford the title compound as a white solid (1 04 g) MS (ES+) m/z 455 (M+H) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9 20 (t, J=6 2 Hz, 1 H), 8 43 (s, 1 H), 8 08 (s, 1 H), 7 24 (t, J=8 1 Hz, 1 H), 6 93 (br s , 2 H), 6 83 (d, J=1 5 Hz, 1 H), 4 80-4 95 (m, 2 H), 4 65 (t, J=5 7 Hz, 1 H), 4 52 (d, J=6 2 Hz, 2 H), 4 05-4 15 (m, 1 H), 3 99 (dd, J=1 1 3, 1 8 Hz, 1 H), 3 77 (d, J=1 1 3Hz, 1 H), 3 73 (s, 3 H), 3 30-3 50 (m, 4 H), 2 68 (s, 3 H)

Example 404

W-(3-Methoxybenzyl)-4-(2-(((2S,5R)-5-(hydroxymethyl)-1,4- dioxan-2-yl)methyl)-2H-tetrazol-5-yl)-

6-methylpicolinamide

rac-/V-(3-Methoxybenzyl)-4-(2-(((2S ^* ,5f? ^* )-5-(hydroxymethyl)-1 ,4-dioxan-2-yl)methyl)-2H- tetrazol-5-yl)-6-methylpιcolιnamιde (prepared as described in Example 403) was separated by chiral supercritical-fluid chromatography (AS-H, 30 x 250 mm, 20% methanol, 70 mUmin) and the first eluting isomer was isolated to afford the title compound (50 mg) MS (ES+) m/z 455 (M+H) ¹ H NMR (400 MHz, DMSO-Of ₆ ) δ ppm 9 20 (t, J=Q 2 Hz, 1 H), 8 43 (s, 1 H), 8 08 (s, 1 H), 7 24 (t, J=Q 1 Hz, 1 H), 6 93 (br s , 2 H), 6 83 (d, J=\ 5 Hz, 1 H), 4 80-4 95 (m, 2 H), 4 65 (t, J=5 7 Hz, 1 H), 4 52 (d,

J=6 2 Hz, 2 H), 4 05-4 15 (m, 1 H), 3 99 (dd, J=1 1 3, 1 8 Hz, 1 H), 3 77 (d, J=1 1 3 Hz, 1 H), 3 73 (s, 3 H) ₁ 3 30-3-50 (m, 4 H), 2 68 (s, 3 H)

Example 405

W-(3-Methoxybenzyl)-4-(2-(((2/?,5S)-5-(hydroxymethyl)-1,4 -dioxan-2-yl)methyl)-2H-tetrazol-5-yl)- 6-methylpicolinamide

rac-λ/-(3-Methoxybenzyl)-4-(2-(((2S*,5f? ^* )-5-(hydroxymethyl)-1 ,4-dιoxan-2-yl)methyl)-2/-/- tetrazol-5-yl)-6-methylpιcolιnamιde (prepared as described in Example 403) was separated by chiral supercritical-fluid chromatography (AS-H, 30 x 250 mm, 20% methanol, 70 mUmin) and the second eluting isomer was isolated to afford the title compound (50 mg) MS (ES+) m/z 455 (M+H) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9 20 (t, J=6 2 Hz, 1 H), 8 43 (s, 1 H), 8 08 (s, 1 H), 7 24 (t, J=Q 1 Hz, 1 H), 6 93 (br s , 2 H), 6 83 (d, J=1 5 Hz, 1 H), 4 80-4 95 (m, 2 H), 4 65 (t, J=5 7 Hz, 1 H), 4 52 (d, J=Q 2 Hz, 2 H), 4 05-4 15 (m, 1 H), 3 99 (dd, J=1 1 3, 1 8 Hz, 1 H), 3 77 (d, J=11 3 Hz, 1 H), 3 73 (s, 3 H), 3 30-3-50 (m, 4 H), 2 68 (s, 3 H)

Example 406 rac-(2S*,5S*)-Methyl 5-((5-(2-((3-methoxybenzyl)carbamoyl)-6-methylpyridin-4-yl)- 2H-tetrazol-2- yl)methyl)-1 ,4-dioxane-2-carboxylate

rac-(2S ^* ,5/? ^* )-Methyl 5-((tosyloxy)methyl)-1 ,4-dιoxane-2-carboxylate (prepared as described in step 1 of the synthesis of rac-(2S*,5S ^* )-methyl 5-((5-(6-((3-methoxybenzyl)carbamoyl)-2- methylpyrιmιdιn-4-yl)-2H-tetrazol-2-yl)methyl)-1 ,4-dιoxane-2-carboxylate, Example 85) (1 22 g, 3 7 mmol) was added to a mixture of λ/-(3-methoxybenzyl)-6-methyl-4-(2/-/-tetrazol-5-y!)pιcolÎ ¹namιde (prepared as described in step 5 of the synthesis of λ/-(3-methoxybenzyl)-4-(2-(((/rans)-4- amιnocyclohexyl)methyl)-2H-tetrazol-5-yl)-6-methylpιcolιn amιde, Example 153) (1.2 g, 3 7 mmol) and triethylamine (749 mg, 7 4 mmol) in anhydrous N,N-dιmethylacetamιde (2.3 mL) The mixture was stirred at 85 ⁰ C in a capped vial overnight and then was purified by reverse phase preparative HPLC (water/acetonitrile) to afford the title compound as a white solid (1 7 g)

Example 407 fac-(2S*,5S*)-5-((5-(2-((3-Methoxybenzyl)carbamoyl)-6-methyl pyridin-4-yl)-2H-tetrazol-2- yl)methyl)-1 ,4-dioxane-2-carboxylic acid

Sodium hydroxide (10 pellets) was added to rac-(2S*,5S ^* )-methyl 5-((5-(2-((3-methoxybenzyl)- carbamoyl)-6-methylpyrιdιn-4-yl)-2/-/-tetrazol-2-yl)methyl )-1 ,4-dιoxane-2-carboxylate (prepared as described in Example 406) (1 35 g, 2 8 mmol) in a mixture of tetrahydrofuran/water (6 mL, 1/1 ) and the mixture was stirred at room temperature overnight The reaction mixture was acidified with trifluoroacetic acid and purified by reverse-phase preparative HPLC (water/ acetonitrile). The resulting product was slurried and decanted from ether several times and dried in a vacuum desiccator to afford the title compound as a white solid (1.09 g) MS (ES+) m/z 469 (M+H). ¹ H NMR (400 MHz, DMSOd ₆ ) δ ppm 9 20 (t, J=6.2 Hz, 1 H), 8.43 (s, 1 H), 8 08 (s, 1 H), 7.24 (t, J=B 1 Hz, 1 H), 6 93 (br. s , 2 H), 6 83 (d, J=1 5 Hz, 1 H), 4 85-4.99 (m, 2 H), 4 52 (d, J=6.2 Hz, 2 H), 4 05-4.20 (s, 3 H), 3 90-3.99 (m, 1 H), 3 73 (s, 3 H), 3 45-3-60 (m, 2 H), 2.68 (s, 3 H)

Example 408 rac-N-(3-Methoxybenzyl)-4-(2-(((2S*,5S*)-5-(2-hydroxypropan- 2-yl)-1,4-dioxan-2-yl)methyl)-2H- tetrazol-5-yl)-6-methylpicolinamide

A solution of methyl magnesium iodide (3M in ether, 0 16 mL, 0 48 mmol) was added dropwise at room temperature to a solution of rac-(2S ^* ,5S*)-methyl 5-((5-(2-((3- methoxybenzyl)carbamoyl)-6-methylpyrιdιn-4-yl)-2/-/-tetraz ol-2-yl)methyl)-1 ,4-dιoxane-2-carboxylate (prepared as described in Example 406) (75 mg, 0 15 mmol) in anhydrous tetrahydrofuran (1 mL) Additional tetrahydrofuran (0 5 mL) was added and the mixture was stirred at room temperature for 2 hours The reaction mixture was cooled to ice bath temperature and saturated aqueous ammonium chloride solution (0 5 mL) was added dropwise The product was purified by reverse phase preparative HPLC (water/ acetonitrile) Fractions containing the product were passed through a carbonate resin column and the filtrate was concentrated The residue was slurried and decanted from ether several times and then dried in a vacuum desiccator to afford the title compound as a white solid (25 mg) MS (ES+) m/z 483 (M+H) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9 22 (t, J=6 2 Hz, 1 H), 8 43 (s, 1 H), 8 08 (s, 1 H), 7 24 (t, J=8 1 Hz, 1 H), 6 93 (br s , 2 H), 6 83 (d, J=1 5 Hz, 1 H), 4 80- 4 99 (m, 2 H), 4 52 (d, J=Q 2 Hz, 2 H), 4 00-4 15 (m, 2 H), 3 90-3 99 (m, 1 H), 3 73 (s, 3 H), 3 33-3 45 (m, 2 H), 3 12-3 19 (m, 1 H), 2 68 (s, 3 H), 1 07 (s, 3 H), 1 01 (s, 3 H)

Example 409 rac-W-(3-Methoxybenzyl)-4-(2-(((2S*,5S*)-5-carbamoyl-1 ,4-dioxan-2-yl)methyl)-2H-tetrazol-5-yl)-

— 6-methylpicolinamide

Formamide (300 mg) was added to a solution of rac-(2S*,5S ^* )-methyl 5-((5-(2-((3- methoxybenzyl)carbamoyl)-6-methylpyrιdιn-4-yl)-2AY-tetrazo l-2-yl)methyl)-1 ,4-dιoxane-2-carboxylate (prepared as described in Example 406) (149 mg, 0 3 mmol) in anhydrous tetrahydrofuran (3 mL) at reflux temperature A solution of sodium methoxide (25% in methanol, 300 mg) was added and the mixture was stirred at reflux for 1 5 hours The reaction mixture was purified by reverse phase preparative HPLC (water/ acetonitrile) Fractions containing the product were passed through a carbonate resin column and the filtrate was concentrated The residue was slurried and decanted from ether several times and then dried in a vacuum desiccator to afford the title compound as a white solid (106 mg) MS (ES+) m/z 468 (M+H) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9 20 (t, J=6 2 Hz, 1 H), 8 43 (s, 1 H), 8 08 (s, 1 H), 7 24 (t, J=8 1 Hz, 1 H), 6 93 (br s , 2 H), 6 83 (d, J=1 5 Hz, 1 H), 4 85- 4 99 (m, 2 H), 4 52 (d, J=6 2 Hz, 2 H), 4 05-4 20 (m, 3 H), 3 90-3 99 (m, 1 H), 3 73 (s, 3 H), 3 45-3-60 (m, 2 H), 2 68 (S ₁ 3 H)

Example 410 rac-W-(3-Methoxybenzyl)-4-(2-(((2S*,5S*)-5-cyano-1,4-dioxan- 2-yl)methy|)-2H-tetrazol-5-yl)-6- methylpicolinamide

Polymer supported triphenylphosphine (Argonaut, 2 15 mmol/g, 300 mg) was added to rac-N-

(3-methoxybenzyl)-4-(2-(((2S ^* ,5S ^* )'5-carbamoyl-1 ,4-dιoxan-2-yl)methyl)-2H-tetrazol-5-yl)-6- methylpicolinamide

(Example 409) (85 mg, 0 18 mmol) in a mixture of carbon tetrachloride (0 5 mL) and dichloroethane (4 5 mL) and the mixture was heated at 80 ⁰ C for 3 hours The reaction mixture was filtered and the resin was washed with dichloroethane The filtrate was concentrated and the residue was purified by reverse phase preparative HPLC Fractions containing the first eluting isomer were passed through a carbonate resin column and were concentrated The product was slurried and decanted several times from ether and the solid was dried in a vacuum desiccator to afford the title compound as a white solid (23 mg) MS (ES+) m/z 450 (M+H) ¹ H NMR (400 MHz ₁ DMSO-^ ₆ ) δ ppm 9 29 (t, J=Q 4 Hz, 1 H), 8 44 (s, 1 H), 8 11 (s, 1 H), 7 25 (t, J=8 1 Hz, 1 H), 6 90 - 6 94 (m, 2 H), 6 83 (dd, J=Q 1 , 2 0 Hz, 1 H), 5 04 (d, J=2 7 Hz, 1 H), 4 99 (br s , 1 H), 4 97 (d, J=3 6 Hz, 1 H), 4 51 (d, J=Q 3 Hz, 2 H), 4 24 - 4 31 (m, 1 H), 4 08 (dd, J=11 9, 2 6 Hz, 1 H), 3 95 (d, J=12 5 Hz, 1 H), 3 81 (dd, J=12 5, 3 2 Hz, 1 H), 3 74 (s, 3 H), 3 71 - 3 75 (m, 1 H), 2 69 (s, 3 H)

Example 411 rac-A/-(3-Methoxyben2yl)-4-(2-(((2S*,5R*)-5-cyano-1 ,4-dioxan-2-yl)methy|)-2H-tetrazol-5-yl)-6- methylpicolinamide

Isolation of the second eluting isomer by reverse phase preparative HPLC from the reaction mixture described in Example 410 afforded the title compound as a white solid (24 mg) MS (ES+) m/z 450 (M+H) ¹ H NMR (400 MHz, DMSOd ₆ ) δ ppm 9 20 (t, J=6 4 Hz, 1 H), 8 41 (s, 1 H), 8 06 (s, 1 H), 7 22 (t, J=Q 1 Hz, 1 H), 6 87 - 6 93 (m, 2 H), 6 80 (d, J=Q 1 Hz, 1 H), 4 92 - 5 02 (m, 2 H), 4 77 (dd, J=Q 4, 2 9 Hz, 1 H), 4 49 (d, J=6 2 Hz, 2 H), 4 21 - 4 30 (m, 1 H), 4 05 - 4 13 (m, 2 H), 3 71 (s, 3 H), 3 64 (ddd, J=22 0, 12 0, 8 4 Hz, 2 H), 2 66 (s, 3 H)

Example 412 rac-W-(4-Fluoro-3-methoxybenzyl)-4-(2-(((2S*,5R*)-5-(hydroxy methyl)-1 ,4-dιoxan-2-yl)methyl)-

2H-tetrazol-5-yl)-6-methylpicolinamide

rac-((2/? ^* ,5R ^* )-5-(Hydroxymethyl)-1 ,4-dιoxan-2-yl)methyl 4-methylbenzenesulfonate (prepared as described in step 4 of the synthesis of rac-λ/-(3-methoxybenzyl)-6-(2-(((2S*,5/?*)-5-(hydroxymethyl )- 1 ,4-dιoxan-2-yl)methyl)-2H-tetrazol-5-yl)-2-methylpyrιmιdÎ ¹ne-4-carboxamιde, Example 61 ) (3 03 g, 10 0 mmol) was added to a mixture of λ/-(4-fluoro-3-methoxybenzyl)-6-methyl-4-(2/-/-tetrazol-5- yOpicolmamide (prepared as described in step 2 of the synthesis of /V-(4-fluoro-3-methoxybenzyl)-4-(2- (((frans)-4-amιnocyclohexyl)methyl)-2/-/-tetrazol-5-yl)-6-m ethylpιcolιnamιde, Example 170) (1 9 g, 5 0 mmol) and triethylamine (2 8 g, 27 0 mmol) in anhydrous DMA (3 mL) The mixture was stirred at 9O ⁰ C in a capped vial overnight The reaction mixture is allowed to cool, diluted with excess dichloromethane, and washed with 2N aqueous sodium hydroxide solution (2x) and water (4x) The organic layer was concentrated and the residue was crystallized from a mixture of methanol/ethyl acetate (70/30) over 48 hours in a refrigerator to afford the title compound as a white solid (1 03 g) MS (ES+) m/z 473 (M+H) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9 24 (t, J=6 0 Hz, 1 H), 8 43 (s, 1 H), 8 08 (s, 1 H), 7 10-7 24 (m, 2 H), 6 91 (br s 1 H), 4 80-4 95 (m, 2 H), 4 65 (t, J=5 7 Hz, 1 H), 4 52 (d, J=6 2 Hz, 2 H), 4 05-4 15 (m, 1 H), 3 99 (dd, J= 1 1 3, 1 8 Hz, 1 H), 3 77 (d, J=11 3 Hz, 1 H), 3 82 (s, 3 H), 3 30-3-50 (m, 4 H), 2 68 (s, 3 H)

Example 413 rac-(2S*,5S*)-Methyl 5-((5-(2-((4-fluoro-3-methoxybenzyl)carbamoyl)-6-methylpyrid in-4-yl)-2H- tetrazol-2-yl)methyl)-1 ,4-dioxane-2-carboxylate

rac-(2S ^* ,5R ^* )-Methyl 5-((tosyloxy)methyl)-1 ,4-dιoxane-2-carboxylate (prepared as described in step 1 of the synthesis of rac-(2S ^* ,5S ^* )-methyl 5-((5-(6-((3-methoxybenzyl)carbamoy!)-2- methylpyrιmιdιn-4-yl)-2/-/-tetrazol-2-yl)methyl)-1 ,4-dιoxane-2-carboxylate, Example 85) (77 mg, 0 23 mmol) was added to a mixture of λ/-(4-fluoro-3-methoxybenzyl)-6-methyl-4-(2/-/-tetrazol-5- yOpicolmamide (prepared as described in step 2 of the synthesis of λ/-(4-fluoro-3-methoxybenzyl)-4-(2- (((<rans)-4-amιnocyclohexyl)methyl)-2/-/-tetrazol-5-yl)- 6-methylpιcolιnamιde, Example 170) (80 mg, 0 23 mmol) and triethylamine (24 mg, 0 23 mmol) in anhydrous acetonitÏ€le (2 mL) The mixture was stirred at 80 ⁰ C in a capped vial overnight and then was purified by reverse phase preparative HPLC (water/acetonitrile) to afford the title compound as a white solid (65 mg)

Example 414 rac-(2S*,5S*)-5-((5-(2-((4-Fluoro-3-methoxybenzyl)carbamoyl) -6-methylpyridin-4-yl)-2H-tetrazol-

2-yl)methyl)-1 ,4-dioxane-2-carboxylic acid

Sodium hydroxide (2 pellets) was added to rac-(2S*,5S ^* )-methyl 5-((5-(2-((4-fluoro-3- methoxybenzyl)carbamoyl)-6-methylpyrιdιn-4-yl)-2/-/-tetraz ol-2-yl)methyl)-1 ,4-dιoxane-2-carboxylate (prepared as described in Example 413) (65 mg, 0 13 mmol) in a mixture of tetrahydrofuran/water (1 mL, 1/1 ) and the mixture was stirred at room temperature for 3 hours The reaction mixture was acidified with tÏ€fluoroacetic acid and purified by reverse-phase preparative HPLC (water/ acetonitrile) The resulting product was slurried and decanted from ether several times and then dried in a vacuum desiccator to afford the title compound as a white solid (50 mg) MS (ES+) m/z 487 (M+H) ¹ H NMR (400 MHz, DMSO-CZ ₆ ) δ ppm 9 24 (t, J=6 0 Hz, 1 H), 8 43 (s, 1 H), 8 08 (s, 1 H) ₁ 7 10-7 24 (m, 2 H) ₁ 6 91 (br S , 1 H), 4 85-4 99 (m, 2 H), 4 52 (d, J=6 2 Hz ₁ 2 H) ₁ 4 05-4 20 (m, 3 H) ₁ 3 90-3 99 (m, 1 H), 3 82 (s, 3 H), 3 45-3-60 (m, 2 H), 2 68 (s, 3 H)

Example 415 rac-W-(4-Fluoro-3-methoxybenzyl)-4-(2-(((2S*,5S*)-5-(2-hydro xypropan-2-yl)-1 ,4-dioxan-2- yl)methyl)-2H-tetrazol-5-yl)-6-methylpicolinamide

A solution of methyl magnesium iodide (3M in ether, 0 1 mL, 0 3 mmol) was added dropwise at room temperature to a solution of rac-(2S ^* ,5S ^* )-methyl 5-((5-(2-((4-fluoro-3- methoxybenzyl)carbamoyl)-6-methylpyrιdιn-4-yl)-2/-/-tetraz ol-2-yl)methyl)-1 ,4-dιoxane-2-carboxylate (prepared as described in Example 413) (35 mg, 0 07 mmol) in anhydrous tetrahydrofuran (1 mL) Additional tetrahydrofuran (0 5 mL) was added and the mixture was stirred at room temperature for 2 hours The reaction mixture was cooled to ice bath temperature and saturated aqueous ammonium chloride solution (0 5 mL) was added dropwise The product was purified by reverse phase preparative HPLC (water/ acetonitrile) Fractions containing the product were passed through a carbonate resin column and the filtrate was concentrated The residue was slurried and decanted from ether several times and then dried in a vacuum desiccator to afford the title compound as a white solid (21 mg) MS (ES+) m/z 501 (M+H) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9 24 (t, J=6 2 Hz, 1 H), 8 43 (s, 1 H), 8 08 (s, 1 H), 7 1 -7 25 (m, 2 H), 6 91 (br s , 1 H), 4 80-4 99 (m, 2 H ₁ m), 4 52 (d,

J=6 2 Hz, 2 H), 4 00-4 15 (m, 2 H), 3 90-3 99 (m, 1 H), 3 82 (s, 3 H), 3 33-3 45 (m, 2 H), 3 12-3 19 (m, 1 H), 2 68 (S ₁ 3 H) ₁ 1 07 (s, 3H) ₁ 1 01 (S ₁ 3H)

Example 416 rac-λ/-(4-Fluoro-3-methoxybenzyl)-4-(2-(((2S*,5S*)-5-carbam oyl-1,4-dioxan-2-yl)methyl)-2W- tetrazol-5-yl)-6-methylpicolinamιde

Formamide (200 mg) was added to a solution of rac-(2S*,5S*)-methyl 5-((5-(2-((4-fluoro-3- methoxybenzyl)carbamoyl)-6-methylpyrιdιn-4-yl)-2/-/-tetraz ol-2-yl)methyl)-1 ,4-dιoxane-2-carboxylate (prepared as described in Example 413) (123 mg, 0 3 mmol) in anhydrous tetrahydrofuran (1 5 ml) at reflux temperature A solution of sodium methoxide (25% in methanol, 200 mg) was added and the mixture was stirred at reflux for 1 5 hours The reaction mixture was purified by reverse phase preparative HPLC (water/ acetonitÏ€le) Fractions containing the product were passed through a carbonate resin column and the filtrate was concentrated The residue was slurried and decanted from ether several times and then dried in a vacuum desiccator to afford the title compound as a white solid (78 mg) MS (ES+) m/z 486 (M+H) ¹ H NMR (400 MHz, DMSO-cfe) <* PPm 9 24 (t, J=6 0 Hz, 1 H), 8 43 (s, 1 H), 8 08 (s, 1 H), 7 10-7 24 (m, 2 H), 6 91 (br S , 1 H), 4 85-4 99 (m, 2 H), 4 52 (d, J=6 2 Hz, 2 H), 4 05-4 20 (m, 3 H), 3 90-3 99 (m, 1 H), 3 82 (s, 3 H), 3 45-3-60 (m, 2 H), 2 68 (s, 3 H)

Example 417 rac-λ/-(4-Fluoro-3-methoxybenzyl)-4-(2-(((2S*,5S*)-5-cyano- 1,4-dioxan-2-yl)methyl)-2H-tetrazol-5- yl)-6-methylpicolinamide

Polymer supported triphenylphosphine (Argonaut, 2 15 mmol/g, 200 mg) was added to rac-λ/-

(4-fluoro-3-methoxybenzyl)-4-(2-(((2S ^* ,5S ^* )-5-carbamoyl-1 ,4-dιoxan-2-yl)methyl)-2H-tetrazol-5-yl)-6- methylpicolinamide (Example 416) (65 2 mg, 0 13 mmol) in a mixture of carbon tetrachloride (0 25 mL) and dichloroethane (2 25 mL) and the mixture was heated at 80 ⁰ C for 3 hours The reaction mixture was filtered and the resin was washed with dichloroethane The filtrate was concentrated and the residue was purified by reverse phase preparative HPLC Fractions containing the first eluting isomer were passed through a carbonate resin column and were concentrated The product was slurried and decanted several times from ether and the solid was dried in a vacuum desiccator to afford the title compound as a white solid (23 mg) MS (ES+) m/z 468 (M+H) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9 31 (t, J=6 3 Hz, 1 H), 8 44 (s, 1 H), 8 11 (d, J=1 O Hz, 1 H), 7 19 (dd, J=9 1 , 2 5 Hz, 1 H), 7 15 (dd, J= 11 7, 8 4 Hz, 1 H), 6 87 - 6 94 (m, 1 H), 5 04 (d, J=2 7 Hz, 1 H), 4 99 (br s , 1 H), 4 97 (d, J=4 1 Hz,

1 H), 4 51 (d, J=6 3 Hz, 2 H), 4 23 - 4 31 (m, 1 H), 4 08 (dd, J= 11 9, 2 6 Hz, 1 H), 3 95 (d, J=12 5 Hz, 1 H), 3 83 (s, 3 H), 3 71 - 3 82 (m, 2 H), 2 69 (s, 3 H)

Example 418 rac-W-(4-Fluoro-3-methoxybenzyl)-4-(2-(((2S*,5/?*)-5-cyano-1 ,4-dioxan-2-yl)methyl)-2H-tetrazol- 5-yl)-6-methylpicolinamide

Isolation of the second eluting isomer by reverse phase preparative HPLC from the reaction mixture described in Example 417 afforded the title compound as a white solid (18 mg) MS (ES+) m/z 468 (M+H) ¹ H NMR (400 MHz, DMSO-d ₆ ) 6 ppm 9 22 (t, J=Q 0 Hz, 1 H), 8 41 (s, 1 H), 8 06 (s, 1 H), 7 87 (s, 1 H), 7 16 (d, J=8 1 Hz, 1 H), 7 1 1 (dd, J= 1 1 5, 8 2 Hz, 1 H), 6 85 - 6 91 (m, 1 H), 4 74 - 5 00 (m, 2 H) ₁ 4 48 (d, J=Q 2 Hz ₁ 2 H), 4 05 - 4 17 (m, 2 H), 4 02 (d, J=8 1 Hz, 1 H) ₁ 3 89 (dd, J= 1 1 5, 2 7 Hz, 1 H), 3 80 (s, 3 H), 3 62 - 3 72 (m, 1 H), 2 65 (s, 3 H)

Example 419 rac-λ/-(4-Fluoro-3-methoxybenzyl)-4-(2-(((2S*,5S*)-5-(2-hyd roxyacetyl)-1 ,4-dioxan-2-yl)methyl)- 2H-tetrazol-5-yl)-6-methylpicolinamide

Oxalyl chloride (10 mL) was added to a stirred solution of rac-(2S*,5S*)-5-((5-(2-((4-fluoro-3- methoxybenzyl)carbamoyl)-6-methylpyrιdιn-4-yl)-2/-/-tetraz ol-2-yl)methyl)-1 ,4-dιoxane-2-carboxylιc acid (prepared as described in Example 414) (820 mg, 1 69 mmol) in dichloromethane (10 mL) The mixture was stirred at room temperature for 18 hours and then concentrated The residue was repeatedly taken up in dichloromethane and concentrated to remove excess oxalyl chloride The resulting residue was then taken up in dioxane (5 mL) and treated with trιs(trιmethylsι!oxy)ethylene (5 O g, 17 0 mmol) The mixture was heated to 95 ⁰ C for 18 hours Additional trιs(trιmethylsιloxy)ethylene (5 O g, 17 0 mmol) was added and heating at 95°C was continued for 1 week The mixture was treated with several drops of 3 N hydrochloric acid until gas evolution stopped The reaction mixture was purified by reverse phase preparative HPLC Fractions containing desired product were combined and concentrated The residue was dissolved in methanol and passed through a carbonate cartridge The filtrate was concentrated to afford the title compound as a solid (29 mg, 3%) MS (ES+) m/z 501 (M+H) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2 66 (s, 3 H), 3 43 - 3 58 (m, 2 H), 3 63 (s, 2 H), 3 80 (s, 3 H), 3 90 - 4 00 (m, 1 H), 4 02 - 4 19 (m, 2 H), 4 19 - 4 27 (m, 1

H), 4 48 (d, J=5 86 Hz, 2 H), 4 79 - 4 99 (m, 3 H), 6 83 - 6 94 (m, 1 H), 7 06 - 7 20 (m, 2 H), 8 06 (br s , 1 H), 8 41 (br s , 1 H), 9 16 - 9 26 (m, 1 H)

Example 420 rac-(2S*,5S ^* )-Methyl 5-((5-(2-((3-chloro-4-fluorobenzyl)carbamoyl)-6-methylpyridi n-4-yl)-2H- tetrazol-2-yl)methyl)-1,4-dioxane-2-carboxylate

rac-(2S ^* ,5/? ^* )-Methyl 5-((tosyloxy)methyl)-1 ,4-dιoxane-2-carboxylate (prepared as described in step 1 of the synthesis of rac-(2S ^* ,5S*)-methyl 5-((5-(6-((3-methoxybenzyl)carbamoyl)-2- methylpyrιmιdιn-4-yl)-2H-tetrazol-2-yl)methyl)-1 ,4-dιoxane-2-carboxylate, Example 85) (83 mg, O 25 mmol) was added to a mixture of /V-(3-chloro-4-fluorobenzyl)-6-methyl-4-(2W-tetrazol-5-yl)pÎ ¹colιnamιde (prepared as described in step 1 of the synthesis of λ/-(3-chloro-4-fluorobenzyl)-4-(2-(((<rans)-4- amιnocyclohexyl)methyl)-2/-/-tetrazol-5-yl)-6-methylpιcolÎ ¹namιde, Example 194) (75 mg, 0 22 mmol) and tÏ€ethylamine (109 mg, 1 0 mmol) in anhydrous λ/,λ/-dιmethylacetamιde (0 3 mL) The mixture was stirred at 85 ⁰ C in a capped vial overnight and then was purified by reverse phase preparative HPLC (water/acetonitrile) to afford the title compound as a white solid (99 mg)

Example 421 rac-(2S*,5S*)-5-((5-(2-((3-Chloro-4-fluorobenzyl)carbamoyl)- 6-methylpyridin-4-yl)-2H-tetrazol-2- yl)methyl)-1 ,4-dioxane-2-carboxylic acid

Sodium hydroxide (3 pellets) was added to rac-(2S*,5S*)-methyl 5-((5-(2-((3-chloro-4- (prepared as described in Example 420) (99 mg, 0 2 mmol) in a mixture of tetrahydrofuran/water (0 8 mL, 1/1 ) and the mixture was stirred at room temperature overnight The reaction mixture was acidified with trifluoroacetic acid and purified by reverse-phase preparative HPLC (water/acetonitrile) The resulting product was slurried and decanted from ether several times and then dried in a vacuum desiccator to afford the title compound as a white solid (68 mg) MS (ES+) m/z 491 (M+H) ¹ H NMR (400 MHz, DMSO-cfe) δ ppm 9 36 (t, J=6 0 Hz, 1 H), 8 42 (s, 1 H), 8 09 (s, 1 H), 7 55-7 6 (m, 1 H), 7 35-7 45 (m, 2 H), 4 85-4 99 (m, 2 H), 4 52 (d, J=6 2 Hz, 2 H), 4 05-4 20 (m, 3 H), 3 90-3 99 (m, 1 H), 3 45-3-60 (m, 2 H), 2 68 (s, 3 H)

Example 422 rac-/V-(3-Methoxybenzyl)-4-(2-(((2/?*,5S*)-5-(aminomethyl)-1 ,4-dioxan-2-yl)methyl)-2H-tetra2ol-5- yl)-6-methylpicolinamide

Step 1 Preparation of rac-((2/? ^* .5f? ^* )-5-((5-(2-((3-methoxyben2yl)carbamoyl)-6-methylpγrιdιn-4 -yl)-2H- tetrazol-2-yl)methyl)-1 ,4-dιoxan-2-yl)methyl methanesulfonate

Methane sulfonyl chloride (172 mg, 1 5 mmol) was added to a solution of rac-λ/-(3- methoxybenzyl)-4-(2-(((2S ^* ,5/? ^* )-5-(hydroxymethyl)-1 ₎ 4-dιoxan-2-yl)methyl)-2H-tetrazol-5-yl)-6- methylpicolinamide (prepared as described in Example 403) (620 mg, 1 36 mmol) in anhydrous pyridine (2 ml) at 0 ⁰ C The mixture was allowed to stir at room temperature overnight The reaction mixture was cooled to 0 ⁰ C, diluted with water, and extracted with dichloromethane The organic layer was dried over magnesium sulfate and concentrated to afford the title compound (546 mg)

Step 2 Preparation of rac-A/-(3-methoxybenzyl)-4-(2-(((2f? ^* .5S ^* )-5-(aminomethyl)-1.4-dioxan-2- yl)methyl)-2/-/-tetrazol-5-yl)-6-methylpιcolιnamιde

Concentrated ammonium hydroxide (50 mg, 1 40 mmol) was added to a solution of rac- ((2f? ^* ,5R ^* )-5-((5-(2-((3-methoxybenzyl)carbamoyl)-6-methylpyridin-4-yl )-2H-tetrazol-2-yl)methyl)-1 ,4- dιoxan-2-yl)methyl methanesulfonate (140 mg, 0 263 mmol) in tetrahydrofuran (5 mL) and the mixture was heated to 100 ⁰ C overnight The reaction mixture was concentrated and the residue was purified by reverse phase preparative HPLC to afford the title compound as a white solid (25 mg, 16%) LC/MS (5%-95% CH ₃ CN/H ₂ O, 5 mm ) 3 690 mm , m/z 568 (M+H) ¹ H NMR (400 MHz, methanol-^) 6 ppm 2 65 - 2 69 (m, 2 H), 2 78 - 2 90 (m, 2 H), 2 94 - 3 10 (m, 2 H), 3 32 - 3 46 (m, 1 H), 3 55 - 3 68 (m, 1 H), 3 74 - 3 77 (m, 3 H), 3 78 - 3 84 (m, 1 H), 4 07 - 4 14 (m, 1 H), 4 17 - 4 27 (m, 1 H), 4 56 - 4 63 (m, 2 H), 6 81 (dd, J=I 79, 2 15 Hz, 1 H), 6 77 - 6 83 (m, 1 H), 6 90 - 6 96 (m, 2 H), 7 22 (t, J=8 19 Hz, 1 H), 8 09 (s, 1 H), 8 56 (s, 1 H)

Example 423 rac-/V-(3-Methoxybenzyl)-6-methyl-4-(2-(((2/?*,5S*)-5-(methy lsulfonamidomethyl)-1,4-dioxan-2- yl)methyl)-2W-tetrazol-5-yl)picolinamide

Diisopropylethylamine (157 mg, 1 21 mmol) was added to a solution of rac-N-(3- methoxybenzyl)-4-(2-(((2R ^* ,5S*)-5-(amιnomethyl)-1 ,4-dιoxan-2-yl)methyl)-2H-tetrazol-5-yl)-6- methylpicolinamide (prepared as described in Example 422) (55 mg, O 12 mmol) in N, N- dimethylformamide (5 O mL) After 20 minutes, methanesulfonyl chloride (69 5 mg, O 606 mmol) was added and the mixture was stirred at room temperature overnight The reaction mixture was concentrated, and the residue was purified by reverse phase preparative HPLC to afford the title compound as a solid (36 4 mg, 46%) LCMS (5%-95% CH ₃ CN/H ₂ O, 5 mm ) 4 923 mm , m/z 532 (M+H) ¹ H NMR (400 MHz, DMSO-Of ₆ ) δ ppm 2 66 (s, 3 H), 2 87 (s, 3 H), 2 94 (t, J=5 86 Hz, 3 H), 3 46 (d, J=IO 98 Hz, 4 H), 3 42 (br s , 1 H), 3 71 (s, 3 H), 3 76 (d, J=11 71 Hz, 3 H), 4 49 (d, J=6 59 Hz, 4 H), 4 78 - 4 94 (m, 5 H)

Example 424 rac-W-(3-Methoxybenzyl)-4-(2-(((2R*,5S*)-5-(acetamidomethyl) -1,4-dioxan-2-yl)methyl)-2H- tetrazol-5-yl)-6-methylpicolinamide

Diisopropylethylamine (0 45 mL, 0 97 mmol) was added to a solution of rac-N-(3- methoxybenzyl)-4-(2-(((2/? ^* ,5S ^* )-5-(amιnomethyl)-1 ,4-dιoxan-2-yl)methyl)-2/-/-tetrazol-5-yl)-6- methylpicolinamide (prepared as described in Example 422) (55 mg, 0 12 mmol) in N ₁ N- dimethylformamide (5 0 mL) After 20 minutes, acetic anhydride (0 34 mL, 0 364 mmol) was added and the mixture was stirred at room temperature overnight The reaction mixture was concentrated, and the residue was purified by reverse phase preparative HPLC to afford the title compound as a solid (36 7 mg, 50%) LC/MS (5%-95% CH ₃ CN/H ₂ O, 5 mm ) 3 17 mm , m/z 496 (M+H) ¹ H NMR (400 MHz, DMSO-Oe) δ ppm 1 78 (s, 3 H), 2 49 (s, 1 H), 2 67 (s, 1 H), 2 97 - 3 08 (m, 1 H), 3 38 - 3 51 (m, 3 H), 3 65 - 3 75 (m, 4 H), 3 92 - 4 02 (m, 2 H), 4 02 - 4 09 (m, 2 H), 4 44 - 4 53 (m, 3 H), 4 75 - 4 95 (m, 4 H), 6 76 - 6 82 (m, 1 H), 6 85 - 6 93 (m, 1 H), 7 16 - 7 26 (m, 1 H), 7 78 - 7 89 (m, 1 H), 8 05 (s, 1 H), 8 40 (S, 1 H), 9 12 - 9 25 (m, 1 H)

Example 425

W-(3-Methoxybenzyl)-6-methyl-4-(2-((tetrahydrofuran-2-yl) methyl)-2H-tetrazol-5-yl)picolinamide

Di-tert-butylazodicarboxylate (74 0 mg, 0 320 mmol) was added to a cooled (ice bath) mixture of (tetrahydrofuran-2-yl)methanol (32 68 mg, 0 320 mmol), N-(3-methoxybenzyl)-6-methyl-4-(2H- tetrazol-5-yl)pιcolιnamιde (52 0 mg, 0 160 mmol) (prepared as described in step 5 of the synthesis of λ/-(3-methoxybenzyl)-4-(2-(((^ans)-4-amιnocyclohexyl)methy l)-2H-tetrazol-5-yl)-6-methylpιcolιnamιde, Example 153), and triphenylphosphine resin (186 0 mg, 0 400 mmol, 2 15 mmol/g loading) in anhydrous tetrahydrofuran (3 mL) The mixture was allowed to warm to room temperature and agitated overnight Trifluoroacetic acid (2 mL) was added and the mixture was agitated for 1 hour The reaction mixture was filtered and the resin was washed with trifluoroacetic acid (1 mL) The filtrate was concentrated and the residue was purified by reverse phase preparative HPLC (5%-95% CH ₃ CN/H ₂ O, 8 mm ) to afford the title compound as a solid (30 8 mg, 47%) LC/MS (5%-95% CH ₃ CN/H ₂ O, 4 5 mm , 95% CH ₃ CN, 1 5 mm ) 3 198 mm , m/z 409 (M+H)

Example 426

W-(4-Fluoro-3-methylbenzyl)-6-methyl-4-(2-((tetrahydro-2H -pyran-4-yl)methyl)-2H-tetrazol-5- yl)picolinamide

4-(Bromomethyl)-tetrahydro-2H-pyran (90 mg, 0 5 mmol) was added to a mixture of λ/-(4- fluoro-3-methylbenzyl)-6-methyl-4-(2H-tetrazol-5-yl)pιcolι namιde (prepared as describe in step 1 of the synthesis of λ/-(4-fluoro-3-methylbenzyl)-4-(2-(((/rans)-4-amιnocyclohe xyl)methyl)-2/-/-tetrazol-5-yl)-6- methylpicolinamide, Example 185) (150 mg, 0 46 mmol) and triethylamine (46 mg, 0 46 mmol) in anhydrous acetonitrile (2 mL) The mixture was stirred at reflux temperature in a capped vial for two days and then was purified by reverse phase preparative HPLC (water/acetonitrile) Fractions containing the product were passed through a carbonate resin column and the filtrate was concentrated The residue was slurried with ether, decanted, and dried in a vacuum desiccator to afford the title compound as a white solid (135 mg) MS (ES+) m/z 425 (M+H)

Example 427 rac-W-(3-Methoxybenzyl)-6-methyl-4-(2-((tetrahydro-2H-pyran- 2-yl)methyl)-2H-tetrazol-5- yl)picolinamide

To a vial containing tetrahydropyran-2-methanol (0 348 ml_, 3 08 mmol), a solution of N-(Z- methoxybenzyl)-6-methyl-4-(2/-/-tetrazol-5-yl)pιcolιnamιd e (prepared as described in step 5 of the synthesis of /V-(3-methoxybenzyl)-4-(2-(((frans)-4-aminocyclohexyl)methyl )-2H-tetrazol-5-yl)-6- methylpicolinamide, Example 153) (500 0 mg, 1 54 mmol) in anhydrous tetrahydrofuran (25 mL) and triphenylphosphine resin (1 791 g, 3 85 mmol, 2 15 mmol/g loading) was added The reaction mixture was chilled in an ice bath, and di-tert-butylazodicarboxylate (709 0 mg, 3 08 mmol) was added The ice bath was removed and the reaction mixture was agitated (orbital) overnight at room temperature Volatiles were removed under a nitrogen stream The residue was purified by silica gel chromatography to afford the title compound as a solid (350 mg, 54%) LC/MS (5%-95% CH ₃ CN/H ₂ O, 4 5 mm , 95% CH ₃ CN ₁ I 5 mm ) 3 506 mm , m/z 423 (M+H) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9 23 (m, 1 H), 8 40 (s, 1 H), 8 05 (s, 1 H), 7 23 - 7 19 (m, 1 H), 6 89 - 6 87 (m, 2 H), 6 80 - 6 77 (m, 1 H), 4 79 - 4 74 (m, 2 H), 4 48 (d, J=6 0 Hz, 2 H), 3 93 - 3 75 (m), 3 70 (s, 3 H), 2 65 (s, 3 H), 1 80 - 1 25 (m)

Example 428

(-)-W-(3-Methoxybenzyl)-6-methyl-4-(2-((tetrahydro-2H-pyr an-2-yl)methyl)-2H-tetrazol-5- yl)picolinamide

rac-λ/-(3-Methoxybenzyl)-6-methyl-4-(2-((tetrahydro-2/-/-py ran-2-yl)methyl)-2H-tetrazol-5- yl)pιcolιnamιde was resolved by supercritical fluid chromatography (Chiralcel OD-H, 30 x 250 mm, 25/75 ethanol/C0 ₂ , 70 mUmin) to afford the title compound as an oil (0 25 g) Chiralcel OD-H analytical column (4 6 x 250 mm, 20/80, ethanol/CO ₂ ), 8 06 mm, > 99% ee, [σ] _D ^21'c = 22 7° (c = 8 3, DMF)

Example 429 (+)-W-(3-Methoxybenzyl)-6-methyl-4-(2-((tetrahydro-2H-pyran- 2-yl)methyl)-2H-tetrazol-5- yl)picolinamide

rac-λ/-(3-Methoxybenzyl)-6-methyl-4-(2-((tetrahydro-2H-pyra n-2-yl)methyl)-2/-/-tetrazol-5- yl)pιcolιnamιde was resolved by supercritical fluid chromatography (Chiralcel OD-H, 30 x 250 mm, 25/75 ethanol/CO ₂ , 70 mUmm) to afford the title compound as an oil (0 26 g) Chiralcel OD-H analytical column (4 6 x 250 mm, 20/80, ethanol/CO ₂ ), 9 99 mm, > 99% ee, (σ] _D ^2rc = 19 0° (c = 9 8, DMF)

Example 430 rac-W-(4-Fluoro-3-methoxybenzyl)-6-methyl-4-(2-((tetrahydro- 2H-pyran-2-yl)methyl)-2H-tetrazol-

5-yl)picolinamide

Step 1 Preparation of methyl 6-methyl-4-(2-((tetrahvdro-2H-pyran-2-yl)methyl)-2H-tetrazol -5- vDpicohnate

Methyl 6-methyl-4-(2/-/-tetrazot-5-yl)pιcolιnate (prepared as described in step 4 of the synthesis of λ/-(3-methoxybenzyl)-4-(2-(((frans)-4-amιnocyclohexyl)meth yl)-2H-tetrazol-5-yl)-6- methylpicolinamide, Example 153) (0 50 g, 2 0 mmol), tetrahydropyran-2- methanol (0 27 g, 2 28 mmol), and polymer supported-tÏ€phenylphosphine (2 65 g, 5 70 mmol) were suspended in tetrahydrofuran (100 mL) The mixture was cooled to 0 ⁰ C in an ice bath for 15 mm and then dι-tert- butyl azodicarboxylate (1 05 g, 4 56 mmol) was added The reaction was allowed to warm to room temperature and was stirred for 15 hours The mixture was filtered through a Celiteâ„¢ pad and washed with tetrahydrofuran (15 mL) The filtrate was concentrated and purified by silica gel column chromatography (0-50 % ethyl acetate/hexanes) to afford the title compound as an oil (0 58 g, 81%) LC/MS (5-100% CH ₃ CN/H ₂ O, 8 mm) 4 88 mm, m/z 318 (M+H)

Step 2 Preparation of 6-methyl-4-(2-((tetrahvdro-2H-pyran-2-yl)methyl)-2H-tetrazol -5-yl)pιcolιnιc acid

6-Methyl-4-(2-((tetrahydro-2H-pyran-2-yl)methyl)-2H-tetrazol -5-yl)pιcolιnate (0 54 g, 1 84 mmol) was dissolved in tetrahydrofuran (5 mL) and then treated with an aqueous sodium hydroxide solution (2 5 N) The mixture was stirred at ambient temperature for 2 hours and then the tetrahydrofuran was removed in a stream of nitrogen The aqueous residue was acidified to pH 3 with concentrated hydrochloric acid and extracted with ethyl acetate (2 x 15 mL) The combined organic layers were dried over anhydrous sodium sulfate and concentrated to afford the title compound (0 48 g, 86%) LC/MS (5-100% CH ₃ CN/H ₂ O, 8 mm) 3 88 mm, m/z 304 (M+H) Step 3 Preparation of rac-/V-(4-fluoro-3-methoxybenzyl)-6-methyl-4-(2-((tetrahvdro -2/-/-pyran-2- yl)methyl)-2H-tetrazol-5-yl)pιcolιnamιde

1-Hydroxybenzatrιazole (22 mg, 0 16 mmol) was added to a solution of 6-methyl-4-(2- ((tetrahydro-2H-pyran-2-yl)methyl)-2/-/-tetrazol-5-yl)pιcol ιnιc acid (0 035g, 0 12 mmol) in N ₁ N- dimethylformamide (0 5 mL) After being stirred for 5 mm, λ/-methylmorpholιne (0 051 mL, 0 46 mmol) was then added followed by a solution of 4-fluoro-3-methoxybenzylamιne hydrochloride (prepared as described in step 3 of the synthesis of λ/-(4-fluoro-3-methoxybenzyl)-6-(2-((frans-4- aminocyclohexyOmethyl^H-tetrazol-S-yOpyrimidine^-carboxamide , Example 1 ) (18 mg, 0 12 mmol) in AZ.AZ-dimethylformamide (0 5 mL) 1 -Ethyl-3-(3'-dιmethylamιnopropyl)carbodιιmιde hydrochloride (31 mg, 0 16 mmol) was then added The mixture was stirred at room temperature for 18 hours and then purified by reverse phase preparative HPLC to afford the title compound as an oil (6 5 mg, 13%) ¹ H NMR (400 MHz, DMSOd ₆ ) δ ppm 9 21 (t, J=Q 2 Hz ₁ 1 H) ₁ 8 40 (s, 1 H) ₁ 8 06 (s, 1 H), 7 21 - 7 06 (m, 2 H) ₁ 6 89 (s, 1 H), 4 72 - 4 86 (m, 2 H), 4 48 (d, J=5 9 Hz ₁ 2 H) ₁ 3 92 (dd, J= 11 0, 5 1 Hz, 1 H), 3 84 - 3 74 (m, 3 H), 2 66 (s, 3 H), 1 80 (d, J=12 5 Hz, 2 H), 1 71 (d, J= 11 7 Hz ₁ 2 H) ₁ 1 58 - 1 16 (m, 4 H)

Example 431 rac-ZV-(4-Fluoro-3-methylbenzyl)-6-methyl-4-(2-((tetrahydro- 2W-pyran-2-yl)methyl)-2W-tetrazol-5- yl)picolinamide

1 -Hydroxybenzatrιazole (22 mg, 0 16 mmol) was added to a solution of 6-methyl-4-(2- ((tetrahydro-2H-pyran-2-yl)methyl)-2H-tetrazol-5-yl)pιcolι nιc acid (prepared as described in step 2 of the synthesis of rac-λ/-(4-Fluoro-3-methoxybenzyl)-6-methyl-4-(2-((tetrahydr o-2/-/-pyran-2-yl)methyl)- 2H-tetrazo!-5-y!)pιco!ιnamιde, Example 430) (0 035g, 0 12 mmol) in λ/,λ/-dιmethylformamιde (0 5 mL) After being stirred for 5 mm, λ/-methylmorpholιne (0 051 mL, 0 46 mmol) was then added followed by a solution of (4-fluoro-3-methylphenyl)methanamιne ( 16 mg, 0 12 mmol) in λ/,λ/-dιmethylformamιde (0 5 mL) 1 -Ethyl-3-(3'-dιmethylamιnopropyl)carbodιιmιde hydrochloride (31 mg, 0 16 mmol) was then added The mixture was stirred at room temperature for 18 hours and then purified by reverse phase preparative HPLC to afford the title compound as an oil (5 1 mg, 10%) ¹ H NMR (400 MHz, DMSOd ₆ ) δ ppm 9 18 (t, J=6 2 Hz, 1 H), 8 40 (s, 1 H), 8 06 (s, 1 H), 7 20 (t, J=8 1 Hz, 1 H), 6 87 (s, 2 H), 6 77 (d, J=Q 8 Hz, 1 H), 4 68 - 4 90 (m, 2 H), 4 48 (d, J=6 6 Hz, 2 H), 3 86 - 4 06 (m, 4 H), 3 78 (d, J= 1 1 0 Hz, 1 H), 2 65 (s, 3 H), 1 75 (dd, J=34 8, 12 8 Hz, 2 H), 1 13 - 1 58 (m, 4 H)

Example 432 rac-/V-(4-Fluoro-3-methoxybenzyl)-6-methyl-4-(2-((tetrahydro -2W-pyran-3-yl)methyl)-2H-tetrazol-

5-yl)picolinamide

Step 1 Preparation of rac-(tetrahvdro-2H-pyran-3-yl)methanol Tetrahydro-2/-/-pyran-3-carbaldehyde (0 40 g, 3 5 mmol) was dissolved in anhydrous methanol (7 mL) and cooled to -10 ⁰ C Sodium borohydride (0 53 g, 14 mmol) was added in three portions The reaction was stirred 1 hour at 0 ⁰ C and was then quenched with a saturated aqueous solution of ammonium chloride (5 mL) The mixture was filtered and the filtrate was concentrated to aqueous in vacuo without heat The residue was then diluted with water (5 mL) and ethyl acetate (15 mL), and the mixture was again filtered The filtrate was transferred to a separatory funnel and the phases separated The aqueous layer was re-extracted with ethyl acetate (2 x 10 mL) The combined organic layers were washed with water (4 x 10 mL) followed by brine (10 mL), dried over sodium sulfate, and concentrated at 30 ⁰ C under vacuum to afford the title compound as an oil (0 31 g, 76%) LC/MS (5-100% CH ₃ CN/H ₂ O, 8 mm) 0 85 mm, m/z 117 (M+H)

Step 2 Preparation of rac-(tetrahvdro-2/-/-pyran-3-yl)methyl 4-nιtrobenzenesulfonate

4-Nιtrobenzene-1 -sulfonyl chloride (0 62 g, 2 8 mmol) and pyridine (253 mg, 3 20 mmol) were added to a solution of rac-(tetrahydro-2/-/-pyran-3-yl)methanol (0 31 g, 2 67 mmol) in dichloromethane (5 mL), and the mixture was stirred at room temperature for 15 hours The reaction mixture was diluted with dichloromethane (10 mL) and washed with water (2 x 10 mL), brine (10 mL), dried over sodium sulfate, and concentrating The residue was purified on silica gel column chromatography (0- 50% ethyl acetate/heptane) to afford the title compound as an oil (0 65 g, 81 %) LC/MS (5-100% CH ₃ CN/H ₂ O, 5 mm) 2 56 mm, m/z 302 (M+H) Step 3 Preparation of rac-λ/-(4-fluoro-3-methoxybenzyl)-6-methyl-4-(2-((tetrahvdr o-2H-pyran-3- yl)methyl)-2H-tetrazol-5-yl)pιcolιnamιde

A mixture of λ/-(4-fluoro-3-methoxybenzyl)-6-methyl-4-(2/-/-tetrazol-5-y l)pιcolιnamιde (prepared as described in step 2 of the synthesis of λ/-(4-fluoro-3-methoxybenzyl)-4-(2-(((/raÏ€s)-4- aminocyclohexyOmethyO^H-tetrazol-δ-yO-e-methylpicolinamide, Example 170) (79 mg, 0 23 mmol), rac-(tetrahydro-2/-/-pyran-3-yl)methyl 4-nιtrobenzenesulfonate (77 mg, 0 25 mmol), and triethylamine (0 40 mL) in λ/,λ/-dιmethylacetamιde (0 1 mL) was stirred at 85 ⁰ C for 15 hours The reaction mixture was purified by reverse phase preparative HPLC to afford the title compound as a beige solid (68 mg, 69%) ¹ H NMR (400 MHz, DMSOd ₆ ) δ ppm 9 22 (t, J=Q 2 Hz, 1 H), 8 43 (s, 1 H), 8 08 (s, 1 H), 7 12 (d, J=8 4 Hz, 1 H), 7 16 (dd, J=13 4, 8 2 Hz, 2 H), 6 91 (d, J=A 0 Hz, 1 H), 4 74 (dd, J=12 6, 7 1 Hz, 2 H), 4 51 (d, J=Q 2 Hz, 2 H), 3 82 (s, 3 H), 3 72 (t, J=M 4 Hz, 2 H), 3 39 (t, J=9 0 Hz, 1 H), 2 68 (s, 3 H), 2 28 (br s , 1 H), 1 74 (d, J=12 4 Hz, 1 H), 1 63 (d, J=A 0 Hz, 1 H), 1 49 (dd, J=9 5, 4 0 Hz, 1 H), 1 35 (d, J=9 5 Hz, 1 H)

Example 433 rac-W-(3-Methoxybenzyl)-6-methyl-4-(2-((tetrahydro-2H-pyran- 3-yl)methyl)-2H-tetrazol-5- yl)picolinamide

A mixture of W-(3-methoxybenzy!)-6-methyl-4-(2H-tetrazol-5-yl)pιcolιnam ιde (prepared as described in step 5 of the synthesis of λ/-(3-methoxybenzyl)-4-(2-(((rrans)-4-amιnocyclohexyl)meth yl)-

2/-/-tetrazol-5-yl)-6-methy!pιcolιnamιde, Example 153) (79 mg, 0 23 mmol), rac-(tetrahydro-2/-/-pyran-3- yl)methyl 4-nιtrobenzenesulfonate (prepared as described in step 2 of the synthesis of rac-λ/-(4-fluoro- 3-methoxybenzyl)-6-methyl-4-(2-((tetrahydro-2/-/-pyran-3-yl) methyl)-2/-/-tetrazol-5-yl)pιcolιnamιde, Example 432) (77 mg, 0 25 mmol), and triethylamine (0 40 mL) in λ/,λ/-dιmethylacetamιde (0 1 mL) was stirred at 85 ⁰ C for 15 hours The reaction mixture was purified by reverse phase preparative HPLC to afford the title compound as a beige solid (62 mg, 61%) ¹ H NMR (400 MHz, DMSOd ₆ ) δ ppm 9 20 (br s , 1 H), 8 08 (s, 1 H), 7 24 (t, J=8 1 Hz, 1 H), 6 93 (br s , 2 H), 6 82 (d, J=I 7 Hz, 1 H), 4 75 <dq, ./=13 0, 6 8 Hz, 2 H), 4 51 (d, J=Q 2 Hz, 2 H), 3 73 (s, 5 H), 3 68 (br s , 1 H), 3 41 (br s , 1 H), 3 37 (d, J=2 2 Hz, 1 H), 2 68 (s, 3 H), 2 28 (br s , 1 H), 1 74 (br s , 1 H), 1 62 (br s , 1 H), 1 50 (d, J=Q 8 Hz, 1 H), 1 35 (d, J=9 5 Hz, 1 H)

Example 434 fac-/V-(4-Fluoro-3-methoxybenzyl)-4-(2-(((2S*,5R*)-5-hydroxy -tetrahydro-2H-pyran-2-yl)methyl)-

2H-tetrazol-5-yl)-6-methylpicolinamide

Step 1 Preparation of rac-(3f? ^* ,6S ^* )-6-(hvdroxymethyl)-tetrahvdro-2/-/-pyran-3-ol

Tetrabutylammonium fluoride (23 0 g, 88 0 mmol) was added to a suspension of rac- (3/? ^* ,6S ^* )-6-((fert-butyldιphenylsιlyloxy)methyl)-tetrahydro-2H-pyr an-3-ol (Bioorg Med Chem 2006, 14, 3953-3966) (16 3 g, 44 0 mmol) in tetrahydrofuran (700 mL) The mixture was allowed to stir at room temperature for 6 hours and was then concentrated The residue was purified by silica gel column chromatography (hexanes/ethyl acetate, 2/1 , ethyl acetate/ethanol, 40/1) The crude product was further purified by silica gel chromatography (ethyl acetate) to afford a waxy solid which was repeatedly triturated with chloroform and then filtered to provide the title compound as a white solid (2 44 g, 42%) Step 2 Preparation of rac-λ/-(4-fluoro-3-methoxybenzyl)-4-(2-(((2S ^* ,5f?*)-5-hvdroxy-tetrahvdro-2/-/- pyran-2-yl)methyl)-2H-tetrazol-5-yl)-6-methylpιcolιnamιde

A mixture of A/-(4-fluoro-3-methoxybenzyl)-6-methyl-4-(2/-/-tetrazol-5-yl )pιcolιnamιde (prepared s described in step 2 of the synthesis of W-(4-flυoro-3-methoxybenzyl)-4-(2-(((fraπs)-4-

aminocyclohexyOmethyl^H-tetrazol-S-yO-θ-methylpicolinamide, Example 170) (1 50 g, 3 96 mmol), rac-(3/?*,6S*)-6-(hydroxymethyl)-tetrahydro-2/-/-pyran-3-ol (1 05 g, 7 92 mmol), and polymer supported tÏ€phenylphosphine resin (3 68 g, 7 92 mmol) in tetrahydrofuran (20 mL) was cooled in an ice bath Di- terf-butyl-azodicarboxylate (1 82 g, 7 92 mmol) was added and the resulting mixture was stirred in the ice bath for 30 mm The ice bath was removed and the mixture stirred at room temperature for 18 hours TÏ€fluoroacetic acid (5 mL) was added and the reaction mixture was filtered The resin washed with tetrahydrofuran, methanol, and acetonitrile The filtrate was concentrated and the residue was purified by reverse phase preparative HPLC to afford the title compound as a white solid (251 mg, 1 1 %) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1 27 - 1 47 (m, 2 H), 1 78 - 1 88 (m, 1 H), 1 93 - 2 04 (m, 1 H), 2 68 (s, 3 H), 2 90 (t, J=10 25 Hz, 1 H), 3 37 - 3 47 (m, 1 H), 3 68 - 3 77 (m, 1 H), 3 78 - 3 92 (m, 4 H), 4 51 (d, J=6 59 Hz, 2 H), 4 74 - 4 93 (m, 3 H), 6 85 - 6 95 (m, 1 H), 7 08 - 7 24 (m, 2 H), 8 08 (s, 1 H), 8 43 (s, 1 H), 9 24 (t, J=Q 22 Hz, 1 H)

Example 435

W-(4-Fluoro-3-methoxybenzyl)-4-(2-((1 S*,2S*,4/?*)-7-oxa-bicyclo[2.2.1]heptan-2-ylmethyl)-2H- tetrazol-5-yl)-6-methylpicolinamide

Step 1 Preparation of (1 S*,2S ^* ,4ff ^* )-7-oxa-bιcvclof2 2 11heptan-2-ylmethanol

A mixture of (1 S*,2f?*,4/? ^* )-7-oxa-bιcyclo[2 2 1]heptane-2-carboxylιc acid {J Med Chem 1971 , 14, 698-702) (0 25 g, 1 8 mmol) and carbodiimidazole ( 0 29 g, 1 8 mmol) in tetrahydrofuran (5 mL) was stirred for 15 minutes A solution of sodium borohydride (0 11 g, 2 8 mmol) in water (1 mL) was slowly added and the mixture was allowed to stir at room temperature for 15 hours The reaction mixture was diluted with an aqueous 10% hydrochloric acid solution (2 mL) and brine (2 mL) and then extracted with ethyl acetate (3 x 10 mL) The combined organic layers were washed with brine (2 x 5 mL), dried over sodium sulfate and concentrated to afford the title compound as an oil ¹ H NMR (400 MHz, DMSOd ₆ ) δ ppm 3 29 (br s , 1 H), 2 94 - 3 13 (m, 2 H), 1 68 - 1 82 (m, 2 H), 1 40 - 1 60 (m, 4 H), 1 28 - 1 40 (m, 2 H), 0 89 - 1 01 (m, 1 H)

Step 2 Preparation of λ/-(4-fluoro-3-rnethoxybenzyl)-4-(2-((1 S ^* .2S ^* .4f? ^* )-7-oxa-bιcvclof2 2 Hheptan-2- ylmethyl)-2H-tetrazol-5-yl)-6-methylpιcolιnamιde

A mixture of (1 S\2S ^* ,4R*)-7-oxa-bιcyclo[2 2 1]heptan-2-ylmethanol (0 13 g, 0 98 mmol), N-(4- fluoro-3-methoxybenzyl)-6-methyl-4-(2/-/-tetrazol-5-yl)pιco lιnamιde (prepared as described in step 2 of the synthesis of λ/-(4-fluoro-3-methoxybenzyl)-4-(2-(((<rans)-4-amιnocyc lohexyl)methyl)-2H-tetrazol-5- yl)-6-methylpιcolιnamιde, Example 170) (0 31 g, 0 81 mmol), and polymer supported- tÏ€phenylphosphine (0 58 g, 1 22 mmol) in anhydrous tetrahydrofuran (10 mL) was cooled to 0 ⁰ C in an ice bath for 15 minutes Di-tert-butyl azodicarboxylate (0 23 g, 0 98 mmol) was added and the mixture was allowed to warm to room temperature and stir for 15 hours The reaction mixture was filtered and the filtrate was concentrated The residue was purified by reverse phase preparative HPLC (5-95% acetonitrile/water) to afford the title compound as a beige oil (66 mg, 18%) ¹ H NMR (400 MHz, DMSO-CZ ₆ ) δ ppm 9 08 - 9 26 (m, 1 H), 8 40 (br s , 1 H), 8 05 (br s , 1 H), 7 05 - 7 21 (m, 2 H), 6 88 (br s , 1 H), 4 64 (dd, J=13 18, 8 05 Hz, 1 H), 4 42 - 4 56 (m, 4 H), 4 33 (d, J=5 12 Hz, 1 H), 3 79 (s, 3 H), 3 22 (br s , 1 H), 2 64 (s, 3 H), 1 63 (dd, J= 11 35, 8 42 Hz, 1 H), 1 49 - 1 57 (m, 2 H), 1 38 - 1 48 (m, 2 H), 1 34 (d, J=13 18 Hz, 1 H)

Example 436

Ethyl 4-((5-(2-((3-Methoxybenzyl)carbamoyl)-6-methylpyridin-4-yl)- 2H-tetrazol-2- yl)methyl)bicyclo[2.2.2]octane-1-carboxylate

A mixture of λ/-(3-methoxybenzyl)-6-methyl-4-(2/-/-tetrazol-5-yl)pιcolÎ ¹namιde (prepared as described in step 5 of the synthesis of λ/-(3-methoxybenzyl)-4-(2-(((frans)-4-amιnocyclohexyl)meth yl)- 2H-tetrazol-5-yl)-6-methylpιcolιnamιde, Example 153) (130 mg), ethyl 4- ((tosyloxy)methyl)bιcyclo[2 2 2]octane-1-carboxylate (J Amer Chem Soc 1965, 87, 2404) (147 mg), and dnsopropylethylamine (0 090 mL) in dimethylsulfoxide (2 0 mL) was heated to 115 ⁰ C for 5 days The reaction mixture was purified by reverse phase preparative HPLC (acetonitrile/water, 70/30 - 90/10) Fractions containing the product were concentrated and extracted with dichloromethane (3 x 8 mL) The combined organic layers were dried over magnesium sulfate, filtered, and concentrated to afford the title compound (1 18 mg) MS (ES+) m/z 519 (M+H) ¹ H NMR (400 MHz, DMSO-c/ ₆ ) δ ppm 9 20 (t, J=6 4 Hz, 1 H), 8 40 (s, 1 H), 8 05 (s, 1 H), 7 22 (t, J=8 1 Hz, 1 H), 6 88 - 6 92 (m, 2 H), 6 80 (d, J=8 4 Hz, 1 H), 4 54 (s, 2 H), 4 49 (d, J=6 2 Hz, 2 H), 3 98 (q, J=7 0 Hz, 2 H), 3 71 (s, 3 H), 2 65 (s, 3 H), 1 63 - 1 71 (m, 6 H), 1 43 - 1 50 (m, 6 H), 1 1 1 (t, J=7 0 Hz, 3 H)

Example 437

4-((5-(2-((3-Methoxybenzyl)carbamoyl)-6-methylpyridin-4-y l)-2H-tetrazol-2- yl)methyl)bicyclo[2.2.2]octane-1 -carboxylic acid

Water (0 5 mL) and lithium hydroxide-monohydrate (21 4 mg) was added to a solution of ethyl 4-((5-(2-((3-methoxybenzyl)carbamoyl)-6-methylpyrιdιn-4-yl )-2/-/-tetrazol-2- yl)methyl)bιcyclo[2 2 2]octane-1 -carboxylate (prepared as described in Example 436) (75 mg) in tetrahydrofuran (1 0 mL) The mixture was heated at reflux for 3 days and then allowed to cool to room temperature The reaction mixture was filtered and the pH was adjusted to 4 with 1 N aqueous hydrochloric acid The resulting slurry was filtered, washed with water, and dried to afford the title compound as a white solid (54 mg) MS (ES+) m/z 491 (M+H) ¹ H NMR (400 MHz, DMSOd ₆ ) δ ppm 9 19 (t, J=6 4 Hz, 1 H), 8 40 (s, 1 H), 8 05 (s, 1 H), 7 22 (t, J=8 1 Hz, 1 H), 6 87 - 6 92 (m, 2 H), 6 80 (d, J=Q 1 Hz, 1 H), 4 54 (s, 2 H), 4 49 (d, J=Q 6 Hz, 2 H), 3 71 (s, 3 H), 2 65 (s, 3 H), 1 61 - 1 70 (m, 6 H), 1 41 - 1 50 (m, 6 H)

Example 438

W-(3-Methoxybenzyl)-4-(2-((4-(hydroxymethyl)bicyclo[2.2.2 ]octan-1 -yl)methyl)-2H-tetrazol-5-yl)-

6-methylpicolinamide

A solution of 4-((5-(2-((3-methoxybenzyl)carbamoyl)-6-methylpyrιdιn-4-yl )-2H-tetrazol-2- yl)methyl)bιcyclo[2 2 2]octane-1 -carboxylic acid (prepared as described in Example 437) (102 mg) in 2-methyltetrahydrofuran (5 mL) was cooled in an ice bath and a solution of lithium aluminum hydride (1 M in tetrahydrofuran, 0 30 mL) was added After 5 minutes the reaction was quenched with water The layers were separated and the aqueous layer was extracted with 2-methyltetrahydrofuran (2 x 3 mL) The combined organic layers were dried over magnesium sulfate and concentrated The residue was purified by reverse phase preparative HPLC to afford the title compound (30 7 mg) MS (ES+) m/z All (M+H) ¹ H NMR (400 MHz, DMSO-cfe) <5 ppm 9 19 (t, J=6 2 Hz, 1 H), 8 40 (s, 1 H), 8 05 (s, 1 H), 7 22 (t, J=Q 1 Hz, 1 H), 6 90 (br s , 2 H), 6 80 (dd, J=I 7, 1 5 Hz, 1 H), 4 47 - 4 53 (m, 4 H), 4 24 (t, J=5 5 Hz, 1 H), 3 71 (s, 3 H), 2 99 (d, J=5 1 Hz, 2 H), 2 65 (s, 3 H), 1 26 - 1 45 (m, 12 H)

Example 439

4-(2-((4-(Hydroxymethyl)pentacyclo[4.2.0.0 ² ' ⁵ .0 ^{3 β} .0 ^4J ]oct-1-yl)methyl)-2H-tetrazol-5-yl)-W-(3- methoxybenzyl)-6-methylpyridine-2-carboxamide

A mixture of λ/-(3-methoxybenzyl)-6-methyl-4-(2H-tetrazol-5-yl)pιcolιn amιde (prepared as described in step 5 of the synthesis of /V-(3-methoxybenzyl)-4-(2-(((<rans)-4-amιnocyclohexyl)me thyl)- 2/-/-tetrazol-5-yl)-6-methylpιcolιnamιde, Example 153) (52 mg, 0 16 mmol), 1 ,4- bιs(hydroxymethyl)cÏ…bane (J Amer Chem Soc 1991 , 113, 7692) (52 mg, 0 32 mmol), and polymer supported triphenylphosphine (190 mg, 0 4 mmol) in anhydrous tetrahydrofuran (3 mL) was cooled in an ice bath and di-terf-butyl azodicarboxylate (74 mg, 0 32 mmol) was added The mixture was placed in an ultrasonic bath for 10 mm and then filtered The filtrate was concentrated and the residue was purified by reverse phase preparative HPLC to afford the title compound (14 6 mg) MS (ES+) m/z 471 (M+H) ¹ H NMR (400 MHz, DMSO-Qf ₆ ) δ ppm 9 24 (t, J=Q 4 Hz, 1 H), 8 38 (s, 1 H), 8 04 (s, 1 H), 7 2 (t, J= 8 1 Hz, 1 H), 6 88 (s, 2 H), 6 78 (d, J=8 1 Hz, 1 H), 5 01 (s, 2 H), 4 46 (d, J=6 2 Hz, 3 H), 3 79 - 3 74 (m, 3 H), 3 71 - 3 64 (m, 6 H), 3 46 (d, J=5 5 Hz, 2 H), 2 63 (s, 3 H)

Example 440

4-((5-(2-(((3-Methoxybenzyl)amino)carbonyl)-6-methylpyrid in-4-yl)-2H-tetrazol-2- yl)methyl)cubane-1 -carboxylic acid

A mixture of λ/-(3-methoxybenzyl)-6-methyl-4-(2/-/-tetrazol-5-yl)pιcolÎ ¹namιde (prepared as described in step 5 of the synthesis of λ/-(3-methoxybenzyl)-4-(2-(((fraÏ€s)-4-amιnocyclohexyl)met hyl)- 2/-/-tetrazol-5-yl)-6-methylpιcolιnamιde, Example 153) (155 mg), methyl 4- hydroxymethylcubanecarboxylate (136 mg), and polymer supported triphenylphosphine (453 mg) in anhydrous tetrahydrofuran (10 mL) was cooled in an ice bath and di-tert-butyl azodicarboxylate (165 mg) was added The mixture was placed in an ultrasonic bath for 30 mm and then filtered The filtrate was acidified with trifluoroacetic acid (0 5 mL) and then concentrated The residue was purified by reverse phase preparative HPLC (acetonitrile/water, 50/50 - 80/20) The fractions containing product were concentrated and extracted with methylene chloride (3 x 5 mL) The combined organic layers were dried over magnesium sulfate, filtered and concentrated to afford the title compound as a white solid (146 mg) MS (ES+) m/z 485 (M+H) ¹ H NMR (400 MHz, DMSO-Cf ₆ ) δ ppm 12 26 (S, 1 H), 9 24 (t, J=S 4 Hz, 1 H), 8 39 (s, 1 H), 8 05 (d, J=1 3 Hz, 1 H), 7 21 (t, J=Q 1 Hz, 1 H), 6 87 - 6 90 (m, 2 H),

6 79 (dd, J=8 1 , 2 1 Hz, 1 H), 5 06 (s, 2 H), 4 47 (d, J=6 4 Hz, 2 H), 4 01 - 4 05 (m, 3 H), 3 88 - 3 92 (m, 3 H), 3 70 (s, 3 H), 2 65 (s, 3 H)

Example 441

4-(2-((4-(Aminocarbonyl)pentacyclo[4.2.0.0 ^{2 5} .0 ³ ' ⁸ .0 ⁴ ' ⁷ ]oct-1-yl)methyl)-2H-tetrazol-5-yl)-W-(3- methoxybenzyl)-6-methylpyridine-2-carboxamide

4-((5-(2-(((3-Methoxybenzyl)amιno)carbonyl)-6-methylpyÏ€dι n-4-yl)-2H-tetrazol-2- yl)methyl)cubane-1-carboxylιc acid (prepared as described in Example 440) (92 mg) was dissolved in anhydrous tetrahydrofuran (5 mL) under nitrogen and oxalyl chloride (0 100 ml_) was added followed by λ/,/V-dιmethylformamιde (one drop) The mixture was stirred at room temperature for 30 minutes and then concentrated The residue was dissolved in anhydrous tetrahydrofuran (4 0 mL) and a solution of 7N ammonia in methanol (0 30 mL) was added in one portion The mixture was diluted with water (5 mL), acidified with trifluoroacetic acid, and concentrated The residue was purified by reverse phase preparative HPLC (acetonitrile/water, 40/60 - 65/35) to afford the title compound as a white solid (52 mg) MS (ES+) m/z 484 (M+H) ¹ H NMR (400 MHz, DMSOd ₆ ) δ ppm 9 22 (t, J=6 0 Hz, 1 H), 8 43 (s, 1 H), 8 07 (s, 1 H), 7 24 (t, J=Q 1 Hz, 1 H), 7 17 (br s , 1 H), 6 93 (br s , 2 H), 6 87 (br s , 1 H), 6 82 (d, J=6 2 Hz, 1 H), 5 07 (s, 2 H), 4 51 (d, J=6 2 Hz, 2 H), 4 00 - 4 05 (m, 3 H), 3 86 - 3 91 (m, 3 H), 3 73 (s, 3 H), 2 68 (S ₁ 3 H)

Example 442

4-(2-((4-Cyanopentacyclo[4.2.0.0 ^{2 5} .0 ^{3 8} .0 ⁴ ' ⁷ ]oct-1-yl)methyl)-2H-tetra2ol-5-yl)-W-(3- methoxybenzyl)-6-methylpyridine-2-carboxamide

Phosphorus oxychloride (0 030 mL) was added to a solution of 4-(2-((4-(amιnocarbonyl)- pentacyclo[4 2 0 O ^{2 5} O ^{3 8} O ⁴ ^oct-i-yOmethyl^H-tetrazol-δ-yO-λHS-methoxybenzyO-e-methyl pyridine- 2-carboxamιde (prepared as described in Example 441 ) (32 mg) in DMF (0 8 mL) The mixture was stirred for 2 minutes and then a solution of 5% aqueous sodium bicarbonate (2 mL) was slowly added The liquid was decanted and the solid was stirred with water (2 mL) and placed in an ultrasonic bath for 1 hour The resulting slurry was filtered, washed with water, and dried to afford the title compound as a white solid (26 mg) MS (ES+) m/z 466 (M+H) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9 22 (t, J=5 5 Hz, 1 H), 8 42 (s, 1 H), 8 06 (s, 1 H), 7 24 (t, J=B 1 Hz, 1 H), 6 93 (br s , 2 H), 6 82 (d, J=8 4 Hz,

1 H), 5 09 (s, 2 H) ₁ 4 51 (d, J=Q 2 Hz, 2 H), 4 25 - 4 29 (m, 3 H), 4 01 - 4 06 (m, 3 H), 3 73 (s, 3 H),

2 68 (S, 3 H)

Example 443 λ/-(3-Methoxybenzyl)-6-methyl-4-(2-((S)-3-methylbutan-2-yl) -2H-tetrazol-5-yl)picolinamide

A mixture of /V-(3-methoxybenzyl)-6-methyl-4-(2H-tetrazol-5-yl)pιcolιna mιde (prepared as described in step 5 of the synthesis of W-(3-methoxybenzyl)-4-(2-(((frans)-4-amιnocyclohexyl)methyl )- 2/-/-tetrazol-5-yl)-6-methylpιcolιnamιde, Example 153) (100 mg, 0 31 mmol), polymer supported triphenylphosphine (287 mg, 0 62 mmol), and (/?)-(-)-3-methyl-2-butanol(54 mg, 0 62 mmol) in tetrahydrofuran (100 mL) was cooled to 0 ⁰ C and di-tert-butyl azodicarboxylate (142 mg, 0 62 mmol) was added The mixture was allowed to warm to room temperature and stir for 18 hours The reaction mixture was filtered and the resin washed with tetrahydrofuran (20 mL) The filtrate was concentrated The crude product was purified by silica column chromatography (hexane/EtOAc, 8/1 , 4/1 ) Fractions containing product were concentrated and further purified by reverse phase preparative HPLC (acetonitrile/water, 0 05% TFA, 15/85 - 85/15) Combined fractions were neutralized with 2 5 N NaOH solution and acetonitrile was removed in vacuo The remaining aqueous solution was extracted with EtOAc (50 mL) The organic layer was dried over sodium sulfate and concentrated to afford the title compound as an oil (16 mg, 13%) MS (ES+) m/z 395 (M+H) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9 26 (t, J=Q 4 Hz ₁ 1 H), 8 43 (d, J=O 9 Hz, 1 H), 8 09 (d, J=1 1 Hz, 1 H), 7 24 (t, J=8 1 Hz, 1 H), 6 90 - 6 93 (m, 2 H), 6 82 (ddd, J=B 2, 2 5, 0 8 Hz, 1 H), 4 95 (qd, J=Q 9, 6 8 Hz, 1 H), 4 51 (d, J=Q 4 Hz, 2 H), 3 73 (s, 3 H), 2 68 (s, 3 H), 2 31 - 2 18 (m, 1 H), 1 62 (d, J=Q 9 Hz ₁ 3 H), 0 97 (d, J=Q 9 Hz, 3 H), 0 78 (d, J=6 7 Hz, 3 H)

Example 444

W-(4-Fluoro-3-methoxybenzyl)-4-(2-((R)-3-hydroxy-2-methyl propyl)-2H-tetrazol-5-yl)-6- methylpicolinamide

A mixture of λ/-(4-fluoro-3-methoxybenzyl)-6-methyl-4-(2/-/-tetrazol-5-y l)pιcolιnamιde (prepared as described in step 2 of the synthesis of λ/-(4-fluoro-3-methoxybenzyl)-4-(2-(((<rans)-4- aminocyclohexyl)methyl)-2/-/-tetrazol-5-yl)-6-methylpicolmam ide, Example 170) (45 mg, 0 13 mmol), (S)-(+)-3-bromo-2-methyl-1 -propanol (33 mL, 0 20 mmol), and triethylamine (33 mL, 0 24 mmol) in

acetonitrile (3 ml.) was stirred at 80 ⁰ C for 15 hours The reaction mixture was concentrated and the residue was purified by reverse-phase preparative HPLC to afford the title compound as a beige solid (35 mg, 65%) ¹ H NMR (400 MHz, DMSO-cfe) 6 ppm 9 12 - 9 34 (m, 1 H), 8 45 (s, 1 H), 8 19 (s, 1 H), 8 05 (s, 1 H), 7 90 (s, 1 H), 7 06 - 7 21 (m, 2 H), 6 88 (d, J=I 3 Hz, 1 H), 4 59 (dd, J=14 3, 6 2 Hz, 1 H), 4 49 (d, J=5 9 Hz ₁ 2 H), 4 31 (dd, ./=13 9, 8 1 Hz, 1 H), 3 80 (s, 3 H), 3 32 (s, 1 H), 2 65 (d, J=3 7 Hz, 3 H), 2 02 - 2 22 (m, 1 H), 0 75 (d, J=6 6 Hz, 3 H)

Example 445

A/-(4-Fluoro-3-methoxybenzyl)-4-(2-((S)-3-hydroxy-2-methy lpropyl)-2H-tetrazol-5-yl)-6- methylpicolinamide

A mixture of /V-(4-fluoro-3-methoxybenzyl)-6-methyl-4-(2/-/-tetrazol-5-yl )pιcolιnamιde (prepared as described in step 2 of the synthesis of λ/-(4-fluoro-3-methoxybenzyl)-4-(2-(((frans)-4- amιnocyclohexyl)methyl)-2/-/-tetrazol-5-yl)-6-methylpιcolÎ ¹namιde, Example 170) (45 mg, 0 13 mmol), (/?)-(-)-3-bromo-2-methyl-1 -propanol (33 ml_, 0 20 mmol), and triethylamine (33 mL, 0 24 mmol) in acetonitrile (3 mL) was stirred at 80 ⁰ C for 15 hours The reaction mixture was concentrated and the residue was purified by reverse-phase preparative HPLC to afford the title compound as a beige solid (38 mg, 70%) ¹ H NMR (400 MHz, DMSOd ₆ ) δ ppm 9 12 - 9 33 (m, 1 H), 8 19 (s, 1 H), 7 90 (s, 1 H), 7 02 - 7 24 (m, 2 H), 6 89 (d, J=5 86 Hz, 1 H), 4 59 (dd, J=14 3, 6 2 Hz, 1 H), 4 48 (d, J=5 9 Hz, 2 H), 4 31 (dd, J= 14 3, 7 7 Hz, 1 H), 3 80 (s, 3 H), 3 29 (s, 1 H), 2 62 - 2 74 (m, 3 H), 2 52 (s, 2 H), 2 1 1 (dd, J=13 5, 6 2 Hz, 1 H) ₁ 0 75 (d, J=6 6 Hz, 3 H)

Example 446 W-(4-Fluoro-3-methylbenzyl)-4-(2-isobutyl-2H-tetrazol-5-yl)- 6-methylpicolinamide

Step 1 preparation methyl 4-(2-ιsobutyl-2H-tetrazol-5-yl)-6-methylpιcolιnate

A suspension of methyl 6-methyl-4-(2H-tetrazol-5-yl)pιcolιnate (prepared as described in step

4 of the synthesis of A/-(3-methoxybenzyl)-4-(2-(((^ans)-4-amιnocyclohexyl)methyl )-2/-/-tetrazol-5-yl)-6-

methylpicolinamide, Example 153) (1 00 g, 4 56 mmol), 2-methylpropan-1 -ol (0 34 g, 4 6 mmol), and polymer supported-triphenylphosphine (3 04 g, 6 84 mmol) in anhydrous tetrahydrofuran (25 mL) was cooled to 0 ⁰ C in an ice bath for 15 mm and then di-tert-butyl azodicarboxylate (1 26 g, 5 47 mmol) was added The mixture was allowed to warm to room temperature while stirring over 15 hours The reaction mixture was filtered and the filtrate was concentrated The residue was purified by silica chromatography (0-50% ethyl acetate /heptane) to afford the title compound as a beige oil

Step 2 Preparation of 4-(2-ιsobutyl-2/-/-tetrazol-5-yl)-6-methylpιcolιnιc acid

A mixture of methyl 4-(2-ιsobutyl-2H-tetrazol-5-yl)-6-methylpιcolιnate and an aqueous solution of sodium hydroxide ( 2 5N, 4 0 mL) in tetrahydrofuran (10 mL) was stirred for 2 hours at room temperature Tetrahydrofuran was removed in vacuo and the aqueous residue was acidified to pH 6 with concentrated hydrochloric acid The mixture was extracted with ethyl acetate (3 x 15 mL) The combined organic layers were washed with water (2 x 10 mL) followed by brine (10 mL), dried over anhydrous sodium sulfate, and concentrated to afford the title compound (1 05 g, 88%) LC/MS (5- 100% CH ₃ CN/H ₂ O, 8 mm) 4 03 mm, m/z 262 (M+H)

Step 3 Preparation of λ/-(4-fluoro-3-methylbenzyl)-4-(2-ιsobutyl-2H-tetrazol-5-y l)-6-methylpιcolιnamιde

A mixture of 4-(2-ιsobutyl-2H-tetrazol-5-yl)-6-methylpιcolιnιc acid (0 050 g, 0 19 mmol) and 1- hydroxybenzatnazole (31 mg, 0 23 mmol) in tetrahydrofuran (5 mL) was stirred for 5 mm (4-FlÏ…oro-3- methylphenyl)methanamιne (27 mg, 0 19 mmol) and polymer supported carbodiimide (0 23 g, 0 29 mmol) were then added The mixture was stirred for 18 hours at room temperature and was then filtered The filtrate was concentrated and the residue was purified by reverse phase preparative HPLC to afford the title compound (23 mg, 32%) ¹ H NMR (400 MHz, DMSOd ₆ ) δ ppm 9 20 (t, J=Q 6 Hz, 1 H), 8 41 (s, 1 H), 8 05 (s, 1 H), 7 23 (d, J=7 3 Hz, 1 H), 7 12 - 7 20 (m, 1 H), 6 93 - 7 10 (m, 1 H), 4 61 (d, J=6 6 Hz, 2 H), 4 46 (d, J=5 9 Hz, 2 H), 2 65 (s, 3 H), 2 27 - 2 40 (m, 1 H), 2 19 (s, 3 H), 0 92 (d, J=6 6 Hz, 6 H)

Example 447 λ/-(4-Fluoro-3-methoxybenzyl)-4-(2-isobutyl-2H-tetrazol-5-y l)-6-methylpicolinamide

A mixture of 4-(2-ιsobutyl-2/-/-tetrazol-5-yl)-6-methylpιcolιnιc acid (prepared as described in step 2 of the synthesis of λ/-(4-fluoro-3-methylbenzyl)-4-(2-ιsobutyl-2H-tetrazol-5-y l)-6- methylpicolinamide, Example 446) (0.050 g, 0.19 mmol) and 1 -hydroxybenzatrιazole (31 mg, 0 23 mmol) in tetrahydrofuran ( 5 mL) was stirred for 5 minutes 4-Fluoro-3-methoxybenzylamιne hydrochloride (prepared as described in step 3 of the synthesis of λ/-(4-fluoro-3-methoxybenzyl)-6-(2- ((frans^-aminocyclohexyOmethyO^H-tetrazol-S-yOpyÏ€midine^-ca rboxamide, Example 1 ) (31 mg, 0.19 mmol) and polymer supported carbodiimide (0.23 g, 0.29 mmol) were added. The mixture was stirred for 18 hours at room temperature and was then filtered. The filtrate was concentrated and the residue was purified by reverse phase preparative HPLC to afford the title compound (18 mg, 24%). ¹ H NMR (400 MHz, DMSOd ₆ ) δ ppm 9 21 (t, J=6.22 Hz, 1 H), 8.41 (s, 1 H), 8.06 (s, 1 H), 7.05 - 7 21 (m, 2 H), 6.89 (d, J=2.9 Hz, 1 H), 4.61 (d, J=6.6 Hz, 2 H), 4 48 (d, J=5.9 Hz, 2 H), 3.80 (s, 3 H), 2.65 (s, 3 H), 2.19 - 2 40 (m, 1 H), 0 92 (d, J=7.3 Hz, 6 H).

Example 448 W-(3-Methoxybenzyl)-4-(2-isobutyl-2H-tetrazol-5-yl)-6-methyl picolinamide

The title compound was prepared in a similar manner to λ/-(3-methoxybenzyl)-6-methyl-4-(2- ((tetrahydrofuran-2-yl)methyl)-2/-/-tetrazol-5-yl)pιcolιna mιde (Example 425) by reaction with 2- methylpropan-1 -ol and afforded 20.9 mg (34%) as a solid. LC/MS (5%-95% CH ₃ CN/H ₂ O, 4.5 mm.; 95% CH ₃ CN, 1.5 mm.): 3.638 mm., m/z 381 (M+H).

Example 449 6-((4-(2-lsobutyl-2H-tetrazol-5-yl)-2-methylpicolinamido)met hyl)-1 H-indole-2-carboxamide

Step 1 Preparation of methyl 6-((4-(2-isobutyl-2H-tetrazol-5-yl)-2-methylpicolinamido)met hyl)-1 H- ιndole-2-carboxylate

A mixture of 4-(2-ιsobutyl-2H-tetrazol-5-yl)-6-methylpιcolιnιc acid (prepared as described in step 2 of the synthesis of /V-(4-flÏ…oro-3-methylbenzyl)-4-(2-ιsobutyl-2H-tetrazol-5-y l)-6- methylpicohnamide, Example 446) (0 090 g, 0 34 mmol) and 1-hydroxybenzatrιazole (56 mg, 0 41 mmol) in N,/V-dιmethylacetamιde (3 mL) was stirred for 5 minutes Methyl 6-(amιnomethyl)-1 H-ιndole- 2-carboxylate (71 mg, 0 34 mmol) was then added followed by triethylamine (0 106 mL, 0 758 mmol) and 1-(3-dιmethylamιnopropyl)-3-ethylcarbodιιmιde hydrochloride (99 mg, 0 52 mmol) The mixture was stirred at room temperature for 18 hours The reaction mixture was diluted with water (3 mL) and extracted with ethyl acetate (3 x 5 mL) The combined organic layers were washed with water (2 x 5 mL) followed by brine (5 mL), dried over anhydrous sodium sulfate and concentrated The residue was purified by silica column chromatography (0-50% ethyl acetate/heptane) to afford the title compound (140 mg, 93%) ¹ H NMR (400 MHz, DMSO-c/ ₆ ) δ ppm 9 25 (t, J=Q 22 Hz, 1 H), 8 52 (br s , 2 H), 8 43 (S, 1 H), 8 06 (s, 1 H), 7 58 (d, J=8 78 Hz ₁ 1 H), 7 41 (s, 1 H), 6 97 - 7 16 (m, 1 H), 4 62 (d, J=I 32 Hz, 4 H), 3 83 (s, 3 H), 2 65 (s, 3 H), 2 26 - 2 38 (m, 1 H), 0 92 (d, J=Q 59 Hz, 6 H)

Step 2 Preparation of methyl 6-((4-(2-ιsobutyl-2H-tetrazol-5-yl)-2-methylpιcolιnamιdo )methyl)-1^/- ιndole-2-carboxylate

A solution of ammonia in methanol (7 N, 15 mL) was added to methyl 6-((4-(2-ιsobutyl-2H- tetrazol-5-yl)-2-methylpιcolιnamιdo)methyl)-1 /-/-ιndole-2-carboxylate (0 13 g, 0 29 mmol) and the mixture was heated to 60 ⁰ C in a sealed vial for 30 hours The reaction mixture was concentrated and the residue was purified by reverse phase preparative HPLC to afford the title compound (15 mg, 10%) ¹ H NMR (400 MHz, DMSOd ₆ ) δ ppm 11 40 (s, 1 H), 9 19 (t, J=Q 59 Hz, 1 H), 8 42 (s, 1 H), 8 11 (s, 1 H), 8 06 (s, 1 H), 7 84 (br s , 1 H), 7 52 (d, J=B 05 Hz, 1 H), 7 39 (s, 1 H), 7 23 (br s , 1 H), 6 93 - 7 10 (m, 1 H), 4 61 (t, J=I 69 Hz, 4 H), 2 64 (s, 3 H), 2 22 - 2 42 (m, 1 H), 0 92 (d, J=Q 59 Hz, 6 H)

Example 450

W-(3-methoxybenzyl)-4-(1-(((frans)-4-aminocyclohexyl)meth yl)-1H-1 ,2,4-triazol-3-yl)-6- methylpicolinamide

Step 1 Preparation of β-methylpyπdine^^-dicarboxylic acid

A solution of ammonia in ethanol (2 M, 400 mL) was cooled to 0 ⁰ C Pyruvic acid (29 6 mL, 425 mmol) was added dropwise maintaining the temperature below 5 ⁰ C After complete addition, the mixture was stirred for 30 mm and then filtered The resulting solid was washed with cold ethanol and immediately transferred to a 2 L Erlenmeyer The above procedures are repeated and the resulting solids were combined and dissolved in water (100 mL) The mixture was heated to reflux for 30 mm and then diluted with 1 N hydrochloric acid (200 mL) The mixture was cooled in an ice bath and further acidified until acidic The resulting precipitate was filtered and washed with ethyl ether to afford the title compound as a solid (10 97 g, 27%) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 13 52 (br, 2 H), 8 20 (d, J=O 7 Hz, 1 H), 7 90 (d, J=1 0 Hz, 1 H), 2 62 (s, 3H)

Step 2 Preparation of bιs(perfluorophenvD 6-methylpyrιdιne-2.4-dιcarboxvlate

6-Methylpyrιdιne-2,4-dιcarboxylιc acid (10 87 g, 60 0 mmol) and 1 ,3-dιcyclohexylcarbodιιmιde (27 24 g, 132 0 mmol) were dissolved in λ/,λ/-dιmethylformamιde (400 mL) Pentafluorophenol (33 13 g, 180 mmol) was added in λ/,λ/-dιmethylformamιde (25 mL) The mixture was allowed to stir at room temperature for 18 hours and then the solvent was removed in vacuo The residue was diluted with dioxane (500 mL) and filtered The filtrate was concentrated, dissolved in dichloromethane/hexane (2/1 , 100 mL), and filtered through a silica plug (5 cm x 8 cm) eluting with dichloromethane/hexane (2/1 ) The filtrate was concentrated, dissolved in ethyl acetate (500 mL), and washed with saturated aqueous sodium bicarbonate (2 x 50 mL) The organic layer was dried over sodium sulfate and concentrated The residue was purified by silica column chromatography (CH ₂ CI ₂ /hexane, 1/2, 1/1 ) After concentration, the residue was triturated with hexanes and filtered to afford the title compound as a solid (8 45 g, 27%) MS (ES+) m/z 514 (M+H)

Step 3 Preparation of λ/-(3-methoxybenzyl)-6-methylpyrιdιne-2.4-dιcarboxamιde

A solution of bιs(perfluorophenyl) 6-methylpyrιdιne-2,4-dιcarboxylate (4 23 g, 8 24 mmol) in dichloromethane (150 mL) was cooled to -78 ⁰ C A solution of 3-methoxybenzylamιne (1 24 g, 9 07 mmol) and diisopropylethylamine (1 12 mL, 9 07 mL) in dichloromethane (10 mL) was added The mixture was allowed to slowly warm to room temperature over 20 hours The solvent was removed in vacuo and the residue was dissolved in tetrahydrofuran (50 mL) A solution of ammonia (0 5 M in dioxane, 18 1 mL, 9 07 mmol) was added followed by diisopropylethylamine (1 12 mL, 9 07 mmol) The mixture was stirred at room temperature for 2 h, and then the solvent was removed in vacuo The resulting residue was suspended in ethyl acetate and filtered to afford the title compound as a white solid (2 36 g, 96%) MS (ES+) m/z 300 (M+H) ¹ H NMR (400 MHz, DMSO-Cf ₆ ) 6 ppm 9 16 (t, J=6 4 Hz, 1 H), 8 31 (s, 1 H), 8 22 (d, J=O 8 Hz, 1 H), 7 81 (d J= 1 1 Hz, 1 H), 7 70 (s, 1 H), 7 20 (t, J=8 1 Hz, 1 H), 6 89-6 85 (m, 2 H), 6 78 (dd, J=8 2, 1 9 Hz, 1 H), 4 46 (d, J=6 4, 2 H), 3 69 (s, 3 H), 2 59 (s, 3 H)

Step 4 Preparation of /V-(3-methoxybenzyl)-6-methyl-4-(1 H-1.2,4-trιazol-3-yl)pιcoltnamιde

λ/-(3-Methoxybenzyl)-6-methylpyrιdιne-2,4-dιcarboxamιde (599 mg, 2 0 mmol) and N,N- dimethylformamide dimethylacetal (26 5 mL) was heated at 1 10 ⁰ C such that any methanol formed is collected through a short path condenser After 2 h, the remaining ,λ/-dιmethylformamιde dimethylacetal was removed in vacuo The residue was dissolved in glacial acetic acid (20 mL) and hydrazine hydrate (344 μL, 6 0 mmol) was added The mixture was heated at 90 ⁰ C for 2 hours and then allowed to cool to room temperature The reaction mixture was poured into water (20 mL), cooled in an ice bath, and adjusted to pH 7 with 2 5 N sodium hydroxide solution The mixture was extracted with ethyl acetate (3 x 50 mL) The combined organic layers were washed with brine (25 mL), dried over sodium sulfate, and concentrated The residue was crystallized from ethyl acetate/ether ether/hexane to afford the title compound as a white solid (486 mg, 75%) MS (APCI+) m/z 324 (M+H) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 14 48 (s, 1 H), 9 19 (t, J=6 1 Hz, 1 H), 8 74 (s, 1 H), 8 44 (s, 1 H), 8 02 (s, 1 H), 7 24 (t, J=8 1 Hz ₁ 1 H), 6 94-6 89 (m, 2 H), 6 82 (dd, J=8 1 , 1 9 Hz, 1 H), 4 50 (d, J=6 4 Hz, 2 H), 3 73 (s, 3 H), 2 64 (s, 3 H)

Step 5 Preparation of tert-butyl (fran5)-4-((3-(2-((3-methoxybenzyl)carbamoylV6-methylpyrιdÎ ¹n-4-yl)- 1/-/-1 ,2.4-tÏ€azol-1 -yl)methyl)cvclohexylcarbamate

Ay-(3-Methoxybenzyl)-6-methyl-4-(1H-1 ,2,4-trιazol-3-yl)pιcolιnamιde (323 mg, 1 OO mmol), polymer supported triphenylphosphine (698 mg, 1 50 mmol), and tert-butyl trans-(4- hydroxymethyl)cyclohexylcarbamate (275 mg, 1 20 mmol) were suspended in THF (16 ml) Dι-tert- butyl azodicarboxylate (345 mg, 1 50 mmol) was added The mixture was allowed to warm to room temperature and stir for 18 hours The reaction mixture was filtered and the resin washed with THF (20 mL) The filtrate was concentrated The crude product was purified by silica column chromatography (CH ₂ CI ₂ /methanol, 100/1 , 100/2, 100/4) Combined fractions were concentrated to afford the title compound as a foaming white solid (491 mg, 92%) MS (ES+) m/z 535 (M+H) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9 18 (t, J=6 4 Hz, 1 H), 8 69 (s, 1 H), 8 39 (s, 1 H), 7 97 (d, J=1 1 Hz, 1 H), 7 24 (t, J=Q 1 Hz, 1 H), 6 93 - 6 89 (m, 2 H), 6 82 (dd, J=8 1 , 1 9 Hz ₁ 1 H), 6 70 (d, J=I 8 Hz, 1 H), 4 50 (d, J=64 Hz, 2 H), 4 12 (d, J=I 0 Hz, 2 H), 3 73 (s, 3 H), 3 21 - 3 11 (m, 1 H), 2 63 (s, 3 H), 1 82 - 1 71 (m, 3 H), 1 59 - 1 53 (m, 2 H) ₁ 1 36 (s, 9 H), 1 15 - 1 01 (m, 4 H)

Step 6 Preparation of λ/-(3-methoxybenzyl)-4-(1-(((/rans)-4-amιnocvclohexyl)meth yl)-1/-/-1.2,4-trιazol- 3-yl)-6-methylpιcolιnamιde

tert-Butyl (frans)-4-((3-(2-((3-methoxybenzyl )carbamoyl )-6-methylpyrιdιn-4-yl)-1 H- 1 ,2,4-trιazol- i-y^methyOcyclohexylcarbamate (380 mg, 0 71 mmol) was dissolved in dichloromethane (5 mL) and tÏ€fluoroacetic acid (1 06 mL, 14 2 mmol) was added The mixture was allowed to stand for 2 hours and was then concentrated The residue was dissolved in dichloromethane (100 mL) and washed with 1N NaOH solution (2 x 10 mL) The organic layer was dried over sodium sulfate and concentrated to afford the title compound as a glass which slowly solidified (276 mg, 89%) MS (ES+) m/z 435 (M+H) ¹ H NMR (400 MHz, DMSOd ₆ ) δ ppm 9 17 (t, J=Q 4 Hz, 1 H), 8 68 (s, 1 H), 8 39 (d, J=O 9 Hz, 1 H), 7 97 (d, J=1 2 Hz, 1 H), 7 24 (t, J=8 1 Hz, 1 H), 6 93 - 6 89 (m, 2 H), 6 82 (ddd, J=Q 2, 2 5, 0 8 Hz, 1 H), 4 50 (d, J=Q 4 Hz, 2 H), 4 1 1 (d, J=I 1 Hz, 2 H), 3 73 (s, 3 H) ₁ 2 63 (s, 3 H) ₁ 2 48 - 2 40 (m, 1 H), 1 84 - 1 71 (m, 3 H), 1 57 - 1 51 (m, 2 H), 1 40 (br s , 1 H), 1 09 - 0 90 (m, 4 H)

Example 451 N-(3-Methoxybenzyl)-6-methyl-4-(1 -(((trans)-4-(methylsulfonamido)cyclohexyl)methyl)-1 H-1 ,2,4- triazol-3-yl)picolιnamide

λ/-(3-Methoxybenzyl)-4-(1-(((^rans)-4-amιnocyclohexyl)meth yl)-1H-1 ,2,4-trιazol-3-yl)-6- methylpicolinamide (prepared as described in Example 450) (135 mg, 0 31 mmol) was dissolved in dichloromethane (5 mL) Triethylamine (86 6 μL, 0 62 mmol) and methanesulfonyl chloride (28 9 μL, 0 37 mmol) were added The reaction mixture was shaken at room temperature for 1 hour and then diluted with dichloromethane (50 mL) The mixture was washed with saturated aq sodium bicarbonate (10 mL) The organic layer was dried over sodium sulfate and concentrated on to silica The crude product was purified by silica column chromatography (CH ₂ Cl ₂ /methanol, 100/1 , 100/2, 100/4) to afford the title compound as a white solid (115 mg, 72%) MS (ES+) m/z 513 (M+H) ¹ H NMR (400 MHz, DMSO-Cf ₆ ) δ ppm 9 17 (t, J=6 4 Hz, 1 H), 8 69 (s, 1 H), 8 39 (s, 1 H), 7 97 (d, J=1 1 Hz, 1 H),

7 24 (t, J=8 1 Hz, 1 H), 6 98 (d, J=I 4 Hz, 1 H), 6 93 - 6 89 (m, 2 H), 6 82 (dd, J=8 2, 1 7 Hz, 1 H), 4 50 (d, J=6 4 Hz, 2 H), 4 13 (d, J=I 0 Hz, 2 H), 3 73 (s, 3 H), 3 09 - 3 00 (m, 1 H), 2 88 (s, 3 H), 2 63 (s, 3 H), 1 90 (d, J=12 1 Hz, 2 H), 1 85 - 1 76 (m, 1 H), 1 59 (d, J=12 0 Hz ₁ 2 H), 1 26 - 1 02 (m, 4 H)

Example 452 W-(3-Methoxybenzyl)-4-(1 -(((frans)-4-acetamidocyclohexyl)methyl)-1 H- 1 ,2,4-trιazol-3-yl)-6- methylpicolinamide

λ/-(3-Methoxybenzyl)-4-(1-(((<rans)-4-amιnocyclohexyl)m ethyl)-1 /-/-1 ,2,4-trιazol-3-yl)-6- methylpicolinamide (prepared as described in Example 450) (135 mg, 0 31 mmol) was dissolved in dichloromethane (5 mL) Triethylamine (86 6 μL, 0 62 mmol), DMAP (7 6 mg, 0 062 mmol), and acetyl chloride (26 5 μL, 0 37 mmol) was added The reaction mixture was shaken at room temperature for 1 hour and then diluted with dichloromethane (50 mL) The mixture was washed with saturated aq sodium bicarbonate (10 mL) The organic layer was dried over sodium sulfate and concentrated onto silica The crude product was purified by silica column chromatography (CH ₂ CI ₂ /methanol, 100/1 , 100/2, 100/4, 100/5) to afford the title compound as a white foaming solid (105 mg, 71%) MS (ES+) m/z 477 (M+H) ¹ H NMR (400 MHz, DMSO-Cf ₆ ) δ ppm 9 18 (t, J=6 4 Hz, 1 H), 8 69 (s, 1 H), 8 40 (s, 1 H), 7 97 (s, 1 H), 7 69 (d, J=I 7 Hz, 1 H), 7 24 (t, J=B 1 Hz, 1 H), 6 94 - 6 90 (m, 2 H), 6 82 (dd, J=8 1 , 2 1 Hz, 1 H), 4 50 (d, J=6 3 Hz, 2 H), 4 13 (d, J=I 0 Hz, 2 H), 3 73 (s, 3 H), 3 46 (br s , 1 H), 2 63 (s, 3 H), 1 88 - 1 72 (m, 6 H), 1 62 - 1 55 (m, 2 H), 1 15 - 1 02 (m, 4 H)

Example 453

2-(((rans)-4-((3-(2-((3-Methoxybenzyl)carbamoyl)-6-methyl pyridin-4-yl)-1 H-1 ,2,4-triazol-1 - yl)methyl)cyclohexylamino)-2-oxoethyl acetate

A/-(3-Methoxybenzyl)-4-(1-(((/rans)-4-aminocyclohexyl)methyl )-1 /-/-1 ,2,4-triazo!-3-yl)-6- methylpicolinamide (prepared as described in Example 450) (335 mg, 0 77 mmol) was dissolved in dichloromethane (20 mL) TÏ€ethylamine (215 μL, 1 54 mmol), DMAP (18 8 mg, 0 15 mmol), and acetoxyacetyl chloride (99 5 μl_, 0 93 mmol) were added The mixture was allowed to stir at room temperature for 18 hours The reaction mixture was diluted with dichloromethane (80 mL) and washed with saturated aq sodium bicarbonate solution (2 x 20 mL) The organic layer was dried over sodium sulfate and concentrated The crude product was purified by silica column chromatography (CH ₂ CI ₂ /methanol, 100/1 , 100/2, 100/4) Fractions were concentrated, and upon addition of EtOAc, the product crystallized The resulting slurry was filter to afford the title compound as a white crystalline solid (288 mg, 70%) MS (ES+) m/z 535 (M+H) ¹ H NMR (400 MHz, DMSO-cfe) δ ppm 9 19 (t, J=6 4 Hz, 1 H), 8 70 (s, 1 H), 8 40 (s, 1 H), 7 97 (d, J=1 1 Hz, 1 H), 7 85 (d, J=7 9 Hz, 1 H), 7 24 (t, J=8 1 Hz, 1 H), 6 94 - 6 88 (m, 2 H), 6 82 (dd, J=8 1 , 2 1 Hz, 1 H), 4 50 (d, J=6 4 Hz, 2 H), 4 38 (s, 2 H), 4 14 (d, J=7 0 Hz, 2 H), 3 73 (s, 3 H), 3 55 - 3 46 (m, 1 H), 2 63 (s, 3 H), 2 06 (s, 3 H), 1 89 - 1 73 (m, 3 H), 1 63 - 1 57 (m, 2 H), 1 24 - 1 04 (m, 4 H)

Example 454 N-(3-Methoxybenzyl)-4-(1 -(((frans)-4-(2-hydroxyacetamido)cyclohexyl)methyl)-1 H-1 ,2,4-triazol-3- yl)-6-methylpicolinamide

2-((frans)-4-((3-(2-((3-Methoxybenzyl)carbamoyl)-6-methylpyr ιdιn-4-yl)-1 /-/-1 ,2,4-trιazol-1- yl)methyl)cyclohexylamιno)-2-oxoethyl acetate (prepared as described in Example 453) (200 mg, 0 375 mmol) was dissolved in THF (15 mL) Lithium hydroxide (26 9 mg, 1 12 mmol) followed by water (5 0 mL) were added The mixture was stirred for 1 hour and then the THF was removed in vacuo The residue was added to dichloromethane (100 mL) and washed with water (2 x 20 mL) The organic layer was dried over sodium sulfate and concentrated to afford an oil The residue was dissolved in ethyl acetate/methanol (4/1 ) and partially concentrated until solids formed The suspension was filtered to afford the title compound as a white solid (165 mg, 89%) MS (ES+) m/z 493 (M+H) ¹ H NMR (400 MHz, DMSOd ₆ ) 6 ppm 9 19 (t, J=6 4 Hz, 1 H), 8 70 (s, 1 H), 8 40 (d, J=O 8 Hz, 1 H), 7 97 (d, J= 1 2 Hz, 1 H), 7 44 (d, J=8 3 Hz, 1 H), 7 24 (t, J=8 1 Hz, 1 H), 6 89 - 6 93 (m, 2 H), 6 82 (dd,

J=8 1 , 1 8 Hz, 1 H), 5 39 (t, J=5 6 Hz, 1 H), 4 50 (d, J=6 3 Hz, 2 H), 4 14 (d, J=7 0 Hz ₁ 2 H), 3 75 (d, J=5 6 Hz, 2 H), 3 73 (s, 3 H), 3 61 - 3 51 (m, 1 H), 2 63 (s, 3 H) ₁ 1 88 - 1 77 (m, 1 H), 1 74 (d, J=12 5 Hz, 2 H), 1 59 (d, J= 12 5 Hz, 2 H), 1 27 (qd, J= 12 4, 2 6 Hz, 2 H), 1 10 (qd, J=12 7, 2 4 Hz, 2 H)

Example 455

W-(4-Fluoro-3-methoxybenzyl)-4-(1-(((fraπs)-4-aminocyclo hexyl)methyl)-1H-1,2,4-triazol-3-yl)-6- methylpicolinamide

Step 1 Preparation of λ/-(4-fluoro-3-methoxybenzyl)-6-methylpyrιdιne-2,4-dιcar boxamιde

A solution of bιs(perfluorophenyl) 6-methy!pyrιdιne-2,4-dιcarboxylate (prepared as described in step 2 of the synthesis of λ/-(3-methoxybenzyl)-4-(1-(((^ans)-4-amιnocyclohexyl)nneth yl)-1 H-1 ,2,4- trιazol-3-y!)-6-methylpιcolιnamιde, Example 450) (104 g) in dichloromethane (945 mL) was cooled to - 70 ⁰ C A solution of 4-fluoro-3-methoxybenzylamιne hydrochloride (prepared as described in step 3 of the synthesis of λ/-(4-fluoro-3-methoxybenzyl)-6-(2-((<rans-4-amιnocyclo hexyl)methyl)-2H-tetrazol-5- yl)pyrιmιdιne-4-carboxamιde, Example 1 ) (23 5 g, 123 mmol) and triethylamine (33 4 mL, 240 mmol) in dichloromethane (140 mL) was added The mixture was allowed to slowly warm to room temperature over 20 hours The solvent was removed in vacuo and the residue was dissolved in tetrahydrofÏ…ran (575 mL) Triethylamine (18 4 mL, 132 mmol) was added followed by a solution of ammonia (0 5 M in dioxane, 260 mL, 130 mmol) The mixture was stirred at room temperature for 20 h, and then the solvent was removed in vacuo The resulting residue was suspended in ethyl acetate and filtered The resulting solid was again suspended in methanol and filtered to afford the title compound as a white solid (27 7 g, 75%) MS (ES+) m/z 318 (M+H) ¹ H NMR (400 MHz, DMSOd ₆ ) δ ppm 9 19 (t, J=6 4 Hz, 1 H), 8 32 (br s , 1 H), 8 22 (d, J=O 8 Hz, 1 H), 7 81 (d, J=1 2 Hz, 1 H), 7 71 (br s , 1 H), 7 14 (dd, J=8 5, 1 9 Hz, 1 H), 7 10 (dd, J=1 1 5, 8 3 Hz, 1 H), 6 82 - 6 87 (m, 1 H), 4 45 (d, J=6 4 Hz, 2 H), 3 78 (S, 3 H), 2 59 (s, 3 H)

Step 2 Preparation of λ/-(4-fluoro-3-methoxybenzyl)-6-methyl-4-(1 H-1 ,2.4-trιazol-3-yl)pιcolιnamιde

λ/-(4-Fluoro-3-methoxybenzyl)-6-methylpyrιdιne-2,4-dιcar boxamιde (27 67 g, 87 mmol) and λ/,λ/-dιmethylformamιde dimethylacetal (290 mL) was heated at 1 10 ⁰ C such that any methanol formed is collected through a short path condenser After 2 h, the remaining ,λ/-dιmethylformamιde dimethylacetal was removed in vacuo The residue was dissolved in glacial acetic acid (293 mL) and hydrazine hydrate (15 6 mL, 323 mmol) was added The mixture was heated at 90 ⁰ C for 2 hours and then allowed to cool to room temperature The reaction mixture was poured into water (250 mL) and filtered to afford the title compound as a solid (24 1 g, 81 %) MS (ES+) m/z 342 (M+H) ¹ H NMR (400 MHz, DMSOd ₆ ) δ ppm 14 47 (br s , 1 H), 9 19 (t, J=6 4 Hz, 1 H), 8 67 (br s , 1 H), 8 41 (s, 1 H), 7 98 (d, J=1 2 Hz, 1 H), 7 15 (dd, J=8 3, 1 9 Hz, 1 H), 7 11 (dd, J=11 7, 8 5 Hz, 1 H), 6 89 - 6 84 (m, 1 H), 4 46 (d, J=Q 4 Hz, 2 H), 3 79 (s, 3 H), 2 60 (s, 3 H)

Step 3 Preparation of /erf-butyl (frans)-4-((3-(2-((4-f1uoro-3-methoxybenzyl)carbamoyl)-6-

λ/-(4-Fluoro-3-methoxybenzyl)-6-methyl-4-(1H-1 ,2,4-trιazol-3-yl)pιcolιnamιde (683 mg, 2 00 mmol), polymer supported triphenylphosphine (1 40 g, 3 00 mmol), and tert-butyl trans-(4- hydroxymethyl)cyclohexylcarbamate (550 mg, 2 40 mmol) were suspended in tetrahydrofuran (32 mL) Di-tert-butyl azodicarboxylate (691 mg, 3 00 mmol) was added The mixture was allowed to warm to room temperature and stir for 18 hours The reaction mixture was filtered and the resin washed with tetrahydrofuran (40 mL) The filtrate was concentrated The crude product was purified by silica column chromatography (CH ₂ CI ₂ /methanol, 100/1 , 100/2, 100/4) Combined fractions were concentrated to afford the title compound as a foaming white solid (955 mg, 86%) MS (ES+) m/z 533 (M+H) ¹ H NMR (400 MHz, DMSO-c/ ₆ ) δ ppm 9 18 (t, J=6 4 Hz, 1 H), 8 66 (s, 1 H), 8 36 (d, J=O 8 Hz, 1 H), 7 94 (d, J=1 1 Hz ₁ 1 H), 7 15 (dd, J=8 5, 1 9 Hz, 1 H), 7 11 (dd, J=1 1 7, 8 3 Hz, 1 H), 6 86 (ddd, J=Q 3, 4 4, 1 9 Hz, 1 H), 6 67 (d, J=I 9 Hz, 1 H), 4 46 (d, J=6 4 Hz, 2 H), 4 09 (d, J=I 0 Hz, 2 H), 3 79 (s, 3 H), 3 12 (br s , 1 H), 2 60 (s, 3 H), 1 74 (br s , 3 H), 1 57 - 1 50 (m, 2 H), 1 33 (s, 9 H), 1 12 - 0 98 (m, 4 H)

Step 4 Preparation of λ/-(4-fluoro-3-methoxybenzyl)-4-(1 -^((rans)-4-amιnocvclohexyπmethyl)-1 H- 1 ,2,4-trιazol-3-yl)-6-methylpιcolιnamιde

tert-Butyl (^ans)-4-((3-(2-((4-fluoro-3-methoxybenzy!)carbamoyl)-6-meth ylpyrιdιn-4-yl)-1 /-/- 1 ,2,4-trιazol-1 -yl)methyl)cyclohexylcarbamate (950 mg, 1 72 mmol) was dissolved in dichloromethane (10 mL) and trifluoroacetic acid (2 55 mL, 34 4 mmol) was added The mixture was allowed to stand for 2 hours and was then concentrated The residue was dissolved in dichloromethane (100 mL) and washed with 1 N NaOH solution (2 x 20 mL) The organic layer was dried over sodium sulfate and concentrated to afford the title compound as a foaming solid (730 mg, 94%) MS (ES+) m/z 453 (M+H) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9 18 (t, J=6 4 Hz, 1 H), 8 65 (s, 1 H), 8 36 (d, J=O 8 Hz,

1 H), 7 94 (d, J= 1 1 Hz, 1 H), 7 15 (dd, J=8 6, 2 0 Hz, 1 H), 7 1 1 (dd, J= 1 1 7, 8 3 Hz ₁ 1 H), 6 86 (ddd, J=8 3, 4 4, 2 0 Hz, 1 H), 4 46 (d, J=6 4 Hz, 2 H), 4 08 (d, J=7 0 Hz, 2 H), 3 79 (s, 3 H), 2 60 (s, 3 H),

2 44 - 2 38 (m, 1 H), 1 81 - 1 61 (m, 3 H), 1 55 - 1 34 (m, 4 H), 1 06 - 0 82 (m, 4 H)

Example 456 /V^-Fluoro-S-methoxybenzyO-e-methyM^I-t^fransJ^^methylsulfon amidoJcyclohexylJmethyl)-

1 H-1 ,2,4-triazol-3-yl)picolinamide

λ/-(4-Fluoro-3-methoxybenzyl)-4-(1-(((^rans)-4-amιnocycloh exyl)methyl)-1H-1 ,2,4-trιazol-3-yl)- 6-methylpιcolιnamιde (prepared as described in Example 455) (725 mg, 1 6 mmol) was dissolved in dichloromethane (30 mL) Triethylamine (447 μl, 3 2 mmol) and methanesulfonyl chloride (149 μL, 1 92 mmol) were added The reaction mixture was stirred at room temperature for 1 hour and then diluted with dichloromethane (100 mL) The mixture was washed with saturated aq sodium bicarbonate (20 mL) The organic layer was dried over sodium sulfate and concentrated onto silica The crude product was purified by silica column chromatography (CH ₂ C! ₂ /methanol, 100/1 , 100/2, 100/4) Fractions were concentrated and the resulting oil crystallized from ethyl acetate to afford the title compound as a white solid (623 mg, 73%) MS (ES+) m/z 531 (M+H) ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 9 18 (t, J=6 4 Hz, 1 H), 8 66 (s, 1 H), 8 36 (d, J=O 8 Hz, 1 H), 7 94 (d, J=1 1 Hz, 1 H), 7 15 (dd, J=8 5, 1 7 Hz, 1 H), 7 11 (dd, J=11 5, 8 3 Hz, 1 H), 6 95 (d, J=7 4 Hz, 1 H), 6 86 (ddd, J=8 4, 4 3, 1 9 Hz, 1 H), 4 46 (d, J=6 3 Hz, 2 H), 4 10 (d, J=6 8 Hz, 2 H), 3 79 (s, 3 H), 3 05 - 2 97 (m, 1 H), 2 85

(s, 3 H), 2 60 (s, 3 H), 1 87 (d, J= ¹ IQ 5 Hz, 2 H), 1 82 - 1 71 (m, 1 H), 1 56 (d, J=12 4 Hz, 2 H), 1 22 - 1 00 (m, 4 H)

Example 457

N-(4-Fluoro-3-methoxybenzyl)-4-(1 -(((frans)-4-acetamidocyclohexyl)methyl)-1 HA ,2,4-triazol-3- yl)-6-methylpicolinamide

λ/-(4-Fluoro-3-methoxybenzy!)-4-(1 -(((<rans)-4-amιnocyclohexyl)methyl)-1 H-1 ,2,4-trιazol-3-yl)- 6-methylpιcolιnamιde (prepared as described in Example 455) ( 115 mg, 0 25 mmol) was dissolved in dichloromethane (5 mL) Triethylamine (70 8 μL, 0 51 mmol), DMAP (6 2 mg, 0 051 mmol), and acetyl chloride (21 7 μL, 0 31 mmol) was added The reaction mixture was shaken at room temperature for 1 hour and then diluted with dichloromethane (50 mL) The mixture was washed with saturated aq sodium bicarbonate (10 mL) The organic layer was dried over sodium sulfate and concentrated on to silica The crude product was purified by silica column chromatography (Biotage 4OS, CH ₂ CI ₂ /methanol, 100/2 x 0 75 L, 100/4 x 0 75 L, 100/5 x 0 75 L) to afford the title compound as a white foaming solid (109 mg, 87%) MS (ES+) m/z 495 (M+H) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9 20 (t, J=Q 4 Hz, 1 H), 8 69 (s, 1 H), 8 40 (s, 1 H), 7 97 (s, 1 H), 7 69 (d, J=7 8 Hz, 1 H), 7 18 (dd, J=8 5, 1 7 Hz, 1 H), 7 17 - 7 11 (m, J=1 1 6, 8 3 Hz, 1 H), 6 89 (ddd, J=Q 2, 4 3, 1 9 Hz, 1 H), 4 49 (d, J=Q 3 Hz, 2 H), 4 13 (d, J=I 0 Hz, 2 H), 3 82 (s, 3 H), 3 45 (br s , 1 H), 2 63 (s, 3 H), 1 88 - 1 73 (m, 6 H), 1 62 - 1 56 (m, 2 H), 1 17 - 1 02 (m, 4 H)

Example 458

2-(((rans)-4-((3-(2-((4-Fluoro-3-methoxybenzyl)carbamoyl) -6-methylpyridin-4-yl)-1H-1,2,4-triazol-

1 -yl)methyl)cyclohexylamino)-2-oxoethyl acetate

W-(4-Rluoro-3-methoxybenzyl)-4-(1 -(((frans)-4-amιnocyclohexyl)methy!)-1 H-1 ,2,4-trιazol-3-yl)- 6-methylpιcolιnamιde (prepared as described in Example 455) (349 mg, 0 77 mmol) was dissolved in dichloromethane (20 mL) Triethylamine (215 μL, 1 54 mmol), DMAP (18 8 mg, 0 15 mmol), and acetoxyacetyl chloride (99 5 μL, 0 93 mmol) were added The mixture was allowed to stir at room temperature for 18 hours The reaction mixture was diluted with dichloromethane (80 mL) and washed with saturated aq sodium bicarbonate solution (2 x 20 mL) The organic layer was dried over sodium

sulfate and concentrated The crude product was purified by silica column chromatography (CH ₂ CI ₂ /methanol, 100/1 , 100/2, 100/4) Fractions were concentrated, and upon addition of EtOAc, the product crystallized The resulting slurry was filter to afford the title compound as a white solid (290 mg, 68%) MS (ES+) m/z 553 (M+H) ¹ H NMR (400 MHz, DMSOd ₆ ) δ ppm 9 21 (t, J=Q 4 Hz, 1 H), 8 70 (s, 1 H), 8 40 (s, 1 H), 7 97 (s, 1 H), 7 85 (d, J=I 9 Hz, 1 H), 7 18 (dd, J=Q 1 , 1 7 Hz, 1 H), 7 14 (dd, J=1 1 5, 8 3 Hz, 1 H), 6 89 (ddd, J=8 1 , 4 6, 1 9 Hz, 1 H), 4 49 (d, J=6 3 Hz, 2 H), 4 38 (s, 2 H), 4 14 (d, J=I 0 Hz, 2 H), 3 82 (s, 3 H), 3 55 - 3 46 (m, 1 H), 2 63 (s, 3 H), 2 06 (s, 3 H), 1 88 - 1 74 (m, 3 H), 1 63 - 1 56 (m, 2 H), 1 24 - 1 03 (m, 4 H)

Example 459 W-(4-Fluoro-3-methoxybenzyl)-4-(1 -(((<raπs)-4-(2-hydroxyacetamido)cyclohexyl)methyl)-1 H-

1,2,4-triazol-3-yl)-6-methylpicolinamide

2-((frans)-4-((3-(2-((4-Fluoro-3-methoxybenzyl)carbamoyl)-6- methylpyrιdιn-4-yl)-1 /-/-1 ,2,4- trιazol-1 -yl)methyl)cyclohexylamιno)-2-oxoethyl acetate (prepared as described in Example 458) (207 mg, 0 375 mmol) was dissolved in THF (15 mL) Lithium hydroxide (26 9 mg, 1 12 mmol) followed by water (5 0 mL) were added The mixture was stirred for 1 hour and then the tetrahydrofuran was removed in vacuo The residue was added to dichloromethane (100 mL) and washed with water (2 x 20 mL) The organic layer was dried over sodium sulfate and concentrated to afford an oil The residue was dissolved in acetonitrile and partially concentrated, and upon standing, the product crystallizes The slurry was filtered to afford 63 mg of a white solid The filtrate was concentrated, dissolved in a minimum amount of acetonitrile, and seeded to afford a second crop of 79 mg The two crops were combined to afford the title compound as a white solid (142 mg, 74%) MS (ES+) m/z 51 1 (M+H) ¹ H NMR (400 MHz, DMSOd ₆ ) δ ppm 9 21 (t, J=Q 4 Hz, 1 H), 8 70 (s, 1 H), 8 40 (s, 1 H), 7 97 (d, J=O 9 Hz, 1 H), 7 44 (d, J=Q 3 Hz, 1 H), 7 18 (dd, J=Q 5, 1 7 Hz, 1 H), 7 14 (dd, J=\ 1 7, 8 3 Hz, 1 H), 6 89 (ddd, J=8 3, 4 5, 1 9 Hz, 1 H), 5 40 (t, J=5 7 Hz, 1 H) ₁ 4 49 (d, J=6 3 Hz, 2 H), 4 14 (d, J=I 0 Hz, 2 H), 3 82 (s, 3 H), 3 75 (d, J=5 6 Hz, 2 H), 3 60 - 3 52 (m, 1 H), 2 63 (s, 3 H), 1 88 - 1 77 (m, 1 H), 1 74 (d, J=10 1 Hz, 2 H), 1 59 (d, J=\7 8 Hz, 2 H), 1 27 (dq, J=12 4, 2 3 Hz, 2 H), 1 10 (qd, J=M 5, 2 0 Hz, 2 H)

Example 460 N-(4-Fluoro-3-methylbenzyl)-4-(1 -(((frans)-4-aminocyclohexyl)methyl)-1 H-1 ,2,4-triazol-3-yl)-6- methylpicolinamide

Step 1 Preparation of λ/-(4-fluoro-3-methylbenzyl)-6-methylpyrιdιne-2,4-dιcarb oxamιde

A solution of bιs(perfluorophenyl) 6-methylpyrιdιne-2,4-dιcarboxylate (prepared as described in step 2 of the synthesis of λ/-(3-methoxybenzyl)-4-(1-(((frans)-4-amιnocyclohexyl)meth yl)-1 H-1 ,2,4- tnazol-3-yl)-6-methylpιco!ιnamιde, Example 450) (104 g) in dichloromethane (945 mL) was cooled to - 70 ⁰ C A solution of 4-fluoro-3-methylbenzylamιne (16 92 g, 122 mmol) and triethylamine (17 0 mL, 122 mmol) in dichloromethane (140 mL) was added The mixture was allowed to slowly warm to room temperature over 20 hours The solvent was removed in vacuo and the residue was dissolved in tetrahydrofuran (575 mL) Triethylamine (19 2 mL, 138 mmol) was added followed by a solution of ammonia (0 5 M in dioxane, 271 mL, 135 mmol) The mixture was stirred at room temperature for 20 h, and then the solvent was removed in vacuo The resulting residue was suspended in ethyl acetate and filtered to afford the title compound as a white solid (35 4 g, 62%) MS (ES+) m/z 302 (M+H) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9 18 (t, J=6 3 Hz, 1 H), 8 32 (br s , 1 H), 8 22 (d, J=O 9 Hz, 1 H), 7 81 (d, J= 1 2 Hz, 1 H), 7 71 (br s , 1 H), 7 20 (d, J=7 7 Hz, 1 H), 7 12 - 7 17 (m, 1 H), 7 04 (t, J=9 7 Hz, 1 H), 4 42 (d, J=6 4 Hz, 2 H), 2 58 (s, 3 H), 2 17 (d, J=1 6 Hz, 3 H)

Step 2 Preparation of λ/-(4-fluoro-3-methylbenzyl)-6-methyl-4-(1/-/-1.2.4-trιazo l-3-vπpιcolιnamιde

A/-(4-Fluoro-3-methylbenzyl)-6-methylpyrιdιne-2,4-dιcarbo xamιde (35 O g, 116 mmol) and N ₁ N- dimethylformamide dimethylacetal (387 mL) was heated at 110 ⁰ C such that any methanol formed is collected through a short path condenser After 2 h, the remaining ,λ/-dιmethylformamιde dimethylacetal was removed in vacuo The residue was dissolved in glacial acetic acid (370 mL) and hydrazine hydrate (21 5 mL, 430 mmol) was added The mixture was heated at 90 ⁰ C for 2 hours and then allowed to cool to room temperature The reaction mixture was poured into water (375 mL) and filtered to afford the title compound as a white solid (20 7 g, 55%) MS (ES+) m/z 326 (M+H)

Step 3 Preparation of tert-butyl (frans)-4-((3-(2-((4-fluoro-3-methylbenzyl)carbamoyl)-6-meth ylpyridin- 4-yl)-1 /-/-1.2.4-trιazol-1 -yl)methyl)cvclohexylcarbamate

λ/-(4-Fluoro-3-methylbenzyl)-6-methyl-4-(1 H-1 ,2,4-tÏ€azol-3-yl)pιcolmamιde (2 50 g, 7 68 mmol), tert-butyl frans-(4-hydroxymethyl)cyclohexyl carbamate (2 29 g, 10 0 mmol), and polymer supported-triphenylphosphine (5 12g, 11 5 mmol) were suspended in anhydrous tetrahydrofuran (100 mL) The mixture was cooled to 0 ⁰ C in an ice bath for 15 mm and then di-tert-butyl azodicarboxylate (2 12 g, 9 22 mmol) was added The reaction was allowed to warm to room temperature while stirring over 15 hours The reaction was filtered and the filtrate was concentrated The crude residue was purified by silica gel column chromatography (50 g, 0-2% methanol/dichloromethane) to afford the title compound as a beige oil

Step 4 Preparation of λ/-(4-fluoro-3-methylbenzyl)-4-(1-(((frans)-4-amιnocyclohe xyl)methyl)-1 /-H .2.4- trιazol-3-yl)-6-methylpιcolιnamιde

tert-Butyl (fra/is)-4-((3-(2-((4-fluoro-3-methylbenzyl)carbamoyl)-6-met hylpyrιdιn-4-yl)-1H-1 ,2,4- trιazol-1-yl)methyl)cyclohexylcarbamate was dissolved in dichloromethane (15 mL) and stirred with trifluoroacetic acid (4 mL) for 1 hour at room temperature The reaction was concentrated and then triturated with diethyl ether to afford the title compound (2 76 g, 65%) LC/MS (5-95% CH ₃ CN/H ₂ O, 6 mm) 3 99 mm, m/z 437 (M+H)

Example 461

W-(4-Fluoro-3-methylbenzyl)-6-methyl-4-(1-(((frans)-4-(me thylsulfonamido)cyclohexyl)methyl)-

1 H-1 ,2,4-triazol-3-yl)picolinamide

Triethylamine (0 1 1 mL, 0 77 mmol) was added to a solution of λ/-(4-fluoro-3-methylbenzyl)-4- (1 -(((/ransH-aminocyclohexyOmethyO-i H- 1 ,2,4-trιazol-3-yl)-6-methylpιcolιnamιde (prepared as described in Example 460) (96 mg, 0 22 mmol) in dichloromethane (2 mL) A solution of methane sulfonyl chloride (30 mg) in dichloromethane (0 5 mL) was then added The reaction mixture was stirred for 1 hour at room temperature and then was concentrated The residue was purified by reverse phase preparative HPLC (10-90 % acetonitrile/water) to afford the title compound (17 mg, 15%) ¹ H NMR (400 MHz, DMSOd ₆ ) 6 ppm 9 01 - 9 20 (m, 1 H), 8 65 (s, 1 H), 8 37 (s, 1 H), 7 94 (br s , 1 H), 6 99 - 7 30 (m, 3 H), 6 92 (d, J=7 3 Hz, 1 H), 4 45 (d, J=5 9 Hz, 2 H), 4 11 (d, J=7 3 Hz, 2 H) ₁ 3 03 (s, 1 H), 2 86 (s, 3 H), 2 60 (s, 3 H), 2 19 (s, 3 H), 1 88 (d, J=IO 3 Hz, 2 H), 1 79 (s, 1 H), 1 58 (d, J= 13 2 Hz, 2 H), 0 96 - 1 29 (m, 4 H)

Example 462

W-(4-Fluoro-3-methylbenzyl)-4-(1-(((frans)-4-acetamidocyc lohexyl)methyl)-1H-1,2,4-triazol-3-yl)-

6-methylpicolinamide

Triethylamine (0 22 mL, 1 5 mmol) was added to a solution of λ/-(4-fluoro-3-methylbenzyl)-4- (^(((fransH-aminocyclohexyOmethyO-IH-i ^^-tÏ€azol-S-yO-θ-methylpicolinamide (prepared as described in Example 460) (96 mg, 0 22 mmol) in dichloromethane (2 mL) A solution of acetyl chloride (21 mg) in dichloromethane (0 5 mL) was then added The mixture was stirred for 1 hour at room temperature and was then concentrated The residue was purified by reverse phase preparative HPLC (10-90 % acetonitrile/water) to afford the title compound (18 mg, 17%) ¹ H NMR (400 MHz, DMSOd ₆ ) δ ppm 9 13 (t, J=5 9 Hz, 1 H), 8 65 (s, 1 H), 8 37 (br s , 1 H), 7 94 (s, 1 H), 7 63 (d, J=8 1 Hz, 1 H), 7 19 (dd, J=26 7, 6 2 Hz, 2 H), 6 92 - 7 11 (m, 1 H), 4 45 (d, J=5 9 Hz, 2 H), 4 11 (d, J=6 6 Hz, 2 H), 3 43 (br s , 1 H), 2 60 (s, 3 H), 2 19 (s, 3 H), 1 69 - 1 88 (m, 5 H), 1 58 (br s , 2 H), 0 95 - 1 20 (m, 5 H)

Example 463

2-(((rans)-4-((3-(2-((4-Fluoro-3-methylbenzyl)carbamoyl)- 6-methylpyridin-4-yl)-1 H-1,2,4-tπazol-1- yl)methyl)cyclohexylamino)-2-oxoethyl acetate

Triethylamine (0 22 ml_, 1 5 mmol) was added to a solution of /V-(4-fluoro-3-methylbenzyl)-4- (1 -(((^rans)-4-amιnocyclohexyl)methyl)-1/-/-1 ,2,4-tπazol-3-yl)-6-methylpιcolιnamιde (prepared as described in Example 460) (96 mg, 0 22 mmol) in dichloromethane (2 mL) A solution of acetoxy acetyl chloride (36 mg) in dichloromethane (0 5 mL) was added The mixture was stirred for 1 hour at room temperature and was then concentrated The residue was purified by reverse phase preparative HPLC (10-90 % acetonitrile/water) to afford the title compound (26 mg)

Example 464

N^-FJuoro-S-methylbenzyO^I-^fransJ^^-hydroxyacetamidoJcyc lohexylJmethyO-IW-i ,2,4- triazol-3-yl)-6-methylpicolinamidemide

2-((rraÏ€s)-4-((3-(2-((4-Fluoro-3-methylbenzyl)carbamoyl)-6- methylpyrιdιn-4-yl)-1 /-/-1 ,2,4-trιazol- 1-yl)methyl)cyclohexylamιno)-2-oxoethyl acetate (prepared as described in Example 464) (26 mg) was dissolved in acetonitrile (amount) A 2 5N sodium hydroxide solution (amount) was added and the mixture was stirred for 2 hours The mixture was acidified to ph 6-7 and extracted with ethyl acetate The organic layer was washed with brine, dried over sodium sulfate, and concentrated to 18 mg of the title compound ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9 13 (t, J=6 2 Hz, 1 H), 8 66 (s, 1 H), 8 37 (br s , 1 H), 7 94 (s, 1 H), 7 36 (d, J=8 8 Hz, 1 H), 6 94 - 7 26 (m, 3 H), 5 32 (d, J=5 1 Hz, 1 H), 4 45 (d, J=6 6 Hz, 2 H), 4 11 (d, J= 7 3 Hz, 2 H), 3 73 (d, J=5 1 Hz, 3 H), 3 53 (d, J=8 8 Hz, 1 H), 2 60 (s, 3 H), 2 19 (s, 2 H), 1 81 (br s , 1 H), 1 73 (d, J=11 0 Hz, 2 H), 1 58 (d, J=11 7 Hz, 2 H), 1 17 - 1 34 (m, 2 H), 0 99 - 1 17 (m, 2 H)

Example 465

/V-(3-Methoxybenzyl)-4-(1-(((trans)-4-(hydroxymethyl)cycl ohexyl)methyl)-1W-1,2,4-tria2ol-3-yl)-6- methylpicolinamide

λ/-(3-Methoxyben2yl)-6-methyl-4-(1 /-/-1 ,2,4-trιazol-3-yl)pιcolιnamιde (prepared as described in step 4 of the synthesis of λ/-(3-methoxybenzyl)-4-(1-(((/rans)-4-amιnocyclohexyl)meth yl)-1/-/-1 ,2,4- trιazol-3-y!)-6-methylpιcolιnamιde, Example 450) (0 20 g, 0 6 mmol), fraÏ€s-1 ,4 cyclohexylenedimethanol (0 18 g, 1 24 mmol), and polymer supported-tÏ€phenylphosphine (0 72 g, 1 6 mmol) were suspended in anhydrous tetrahydrofuran (5 mL) The mixture was cooled to 0 °C in an ice bath for 15 mm and then di-tert-butyl azodicarboxylate (0 29 g, 1 2 mmol) was added The reaction was allowed to warm to room temperature while stirring over 15 hours The reaction was filtered and the filtrate was concentrated The crude residue was purified by reverse phase preparative HPLC (5- 95% gradient acetonitrile/water) to afford the title compound as a white solid (97 mg, 35%) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9 1 1 (t, J=6 2 Hz, 1 H), 8 65 (s, 1 H), 8 37 (s, 1 H), 7 94 (s, 1 H), 7 22 (t, J=8 1 Hz, 1 H) ₁ 6 90 (br s , 2 H), 6 80 (d, J=8 1 Hz, 1 H), 4 48 (d, J=5 9 Hz, 2 H), 4 24 - 4 32 (m, 1 H), 4 19 (d, J=5 9 Hz, 1 H), 4 01 - 4 15 (m, 2 H), 3 71 (s, 3 H), 2 60 (s, 3 H), 1 81 (dd, J=11 4, 4 0 Hz, 1 H), 1 71 (d, J=11 7 Hz, 2 H), 1 58 (d, J=13 2 Hz, 2 H), 1 20 - 1 35 (m, 1 H), 0 91 - 1 06 (m, 2 H), 0 74 - 0 91 (m, 2 H)

Example 466 rac-/V-(3-Methoxybenzyl)-4-(1 -(((2S*,5/?*)-5-(hydroxymethyl)-1 ,4-dioxan-2-yl)methyl)-1 H-1 ,2,4- triazol-3-yl)-6-methylpicolinamide

λ/-(3-Methoxybenzyl)-6-methyl-4-(1 H-1 ,2,4-trιazol-3-yl)pιcolιnamιde (prepared as described in step 4 of the synthesis of λ/-(3-methoxybenzyl)-4-(1-(((frans)-4-amιnocyclohexyl)meth yl)-1 /-/-1 ,2,4- trιazol-3-yl)-6-methylpιcolιnamιde, Example 450) (32 mg, 0 10 mmol), /raÏ€s-2, 5-bιs-(hydroxymethyl)- 1 ,4-dιoxane (prepared as described in step 3 of the synthesis of rac-/V-(3-methoxybenzyl)-6-(2- (((2S ^* ,5f? ^* )-5-(hydroxymethyl)-1 ,4-dιoxan-2-yl)methyl)-2H-tetrazol-5-yl)-2-methylpyrιmιdÎ ¹ne-4- carboxamide, Example 61 ) ( 22 mg, 0 15 mmol), and polymer supported-tÏ€phenylphosphine (0 071 g, 0 15 mmol) were suspended in anhydrous tetrahydrofuran (2 mL) The mixture was cooled to 0 ⁰ C in an ice bath for 15 mm and then di-tert-butyl azodicarboxylate (28 mg, 0 12 mmol) was added The reaction was allowed to warm to room temperature while stirring over 15 hours The reaction was filtered and the filtrate was concentrated The crude residue was purified by reverse phase preparative HPLC (5-95% gradient acetonitrile/water) to afford the title compound as a white solid (15 mg, 33%) ¹ H NMR (400 MHz, DMSOd ₆ ) δ ppm 9 12 (t, J=6 2 Hz, 1 H), 8 63 (s, 1 H), 8 37 (s, 1 H), 7 95 (s, 1 H),

7 22 (t, J=8 1 Hz, 1 H), 6 90 (br s , 2 H), 6 80 (d, J=8 8 Hz, 1 H), 4 60 - 4 70 (m, 1 H), 4 48 (d, J=6 6 Hz, 2 H), 4 18 - 4 39 (m, 5 H), 3 88 (d, J=9 5 Hz, 2 H), 3 78 (d, J= 1 1 0 Hz, 1 H), 3 71 (s, 3 H), 2 56 - 2 71 (m, 4 H), 1 32 - 1 44 (m, 1 H)

Example 467 rac-λ/^-Fluoro-S-methoxybenzyO^I^^Z^.S^-S-ihydroxymethyO-i^ -dioxan^-yOmethyl)-

1 H-1 ,2,4-triazol-3-yl)-6-methylpicolinamide

λ/-(4-Fluoro-3-methoxybenzyl)-6-methyl-4-(1/-/-1 ,2,4-trιazol-3-y!)pιcolιnamιde (prepared as described in step 1 of the preparation of λ/-(4-fluoro-3-methoxybenzyl)-4-(1 -(((fraÏ€s)-4- aminocyclohexyOmethyO-I H-i ^^-triazol-S-yO-β-methylpicolinamide, Example 455) (34 mg, 0 10 mmol), frans-2, 5-bιs-(hydroxymethyl)-1 ,4-dιoxane (prepared as described in step 3 of the synthesis of rac-λ/-(3-methoxybenzyl)-6-(2-(((2S ^* ,5R*)-5-(hydroxymethyl)-1 ,4-dιoxan-2-yl)methyl)-2H-tetrazol-5-yl)- 2-methylpyrιmιdιne-4-carboxamιde, Example 61 ) (22 mg, 0 15 mmol), and polymer sÏ…pported- tÏ€phenylphosphine (0 071 g, 0 15 mmol) were suspended in anhydrous tetrahydrofuran (2 mL) The mixture was cooled to 0 ⁰ C in an ice bath for 15 mm then di-tert-butyl azodicarboxylate (28 mg, 0 12 mmol) was added The reaction was allowed to warm to room temperature while stirring over 15 hours The reaction was filtered and the filtrate was concentrated The crude residue was purified by reverse phase preparative HPLC (5-95% gradient acetonitrile/water) to afford the title compound as a white solid (22 mg, 47%) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9 14 (t, J=6 6 Hz, 1 H), 8 63 (s, 1 H), 8 37 (s, 1 H), 7 95 (s, 1 H), 7 05 - 7 22 (m, 2 H), 6 88 (br s , 1 H), 4 64 (t, J=5 1 Hz, 1 H), 4 47 (d,

J=6 6 Hz, 2 H), 4 18 - 4 40 (m, 5 H), 3 88 (d, J=9 5 Hz, 2 H), 3 67 - 3 83 (m, 5 H) ₁ 2 61 <s. 3 H), 1 30 - 1 45 (m, 1 H)

Example 468 rac-W-(4-Fluoro-3-methylbenzyl)-4-(1 -(((2S*,5R*)-5-(hydroxymethyl)-1 ,4-dioxan-2-yl)methyl)-1 H- 1 ,2,4-triazol-3-yl)-6-methylpicolinamide

λ/-(4-F!uoro-3-methylbenzyl)-6-methyl-4-(1 H- 1 ,2,4-trιazol-3-y!)pιcolιnamιde (prepared as described in step 2 of the synthesis of λ/-(4-fluoro-3-methylbenzyl)-4-(1 -(((?rans)-4- amιnocydohexyl)methyl)-1 H-1 ,2,4-trιazol-3-yl)-6-methylpιcolιnamιde, Example 460) (33 mg, 0 10

mmol), trans-2, 5-bιs-(hydroxymethyl)-1 ,4-dιoxane (prepared as described in step 3 of the synthesis of rac-/V-(3-methoxybenzyl)-6-(2-(((2S*,5f? ^* )-5-(hydroxymethyl)-1 ,4-dιoxan-2-yl)methyl)-2H-tetrazol-5-yl)- 2-methylpyrιmιdιne-4-carboxamιde, Example 61 ) (22 mg, 0 15 mmol), and polymer supported- tÏ€phenylphosphine (0 071 g, 0 15 mmol) were suspended in anhydrous tetrahydrofuran (2 mL) The mixture was cooled to 0 ⁰ C in an ice bath for 15 mm and then di-tert-butyl azodicarboxylate (28 mg, 0 12 mmol) was added The reaction was allowed to warm to room temperature while stirring over 15 hours The reaction mixture was filtered and the filtrate was concentrated The crude residue was purified by reverse phase preparative HPLC (5-95% gradient acetonitrile/water) to afford the title compound as a white solid (20 mg, 44%) ¹ H NMR (400 MHz, DMSO-Cf ₆ ) δ ppm 9 13 (t, J=6 2 Hz, 1 H), 8 63 (s, 1 H), 8 37 (s, 1 H), 7 94 (s, 1 H), 7 19 (dd, J=27 1 , 6 6 Hz, 2 H), 7 04 (t, J=9 2 Hz, 1 H), 4 64 (t, J=5 1 Hz, 1 H), 4 45 (d, J=6 6 Hz, 2 H), 4 18 - 4 40 (m, 5 H), 3 88 (d, J=9 5 Hz, 2 H), 3 78 (d, J=11 7 Hz, 2 H), 2 60 (s, 3 H), 2 19 (s, 3 H), 1 37 (br s , 1 H)

In Vitro MMP Inhibition Analysis

Matrix Metalloproteinase inhibitor compounds were analyzed in in vitro MMP Inhibition assays to determine their ability to inhibit the MMP cleavage of peptide substrates Inhibition constants (K ₁ ) were calculated from the assayed compound-MMP interactions

Human recombinant MMP-1 , MMP-2, MMP-3, MMP-7, MMP-9, MMP-12, MMP-13, MMP-14 and MMP-15 were used in these assays The enzymes are prepared following known laboratory procedures Protocols for the preparation and use of these enzymes are available in the scientific literature See, for example, Fnje et al , J Biol Chem , 269(24), 16766-73 (1994)

In addition, many MMPs may be purchased from suppliers For example, MMP-1 , MMP-2, MMP-3, MMP-7, MMP-8, MMP-9, MMP-10, MMP-11 , MMP-12, MMP-13, MMP-14, MMP-15, MMP-16, MMP-24, MMP-25, and MMP-26 are commercially available from R&D Systems in their 2006 catalog Available in the 2006 Millipore Chemicon catalog are MMP-1 , MMP-2, MMP-3, MMP-7, MMP-8, MMP- 9, MMP-13, MMP-14, MMP-15, MMP-16, MMP-17 and MMP-24

The MMP-1 proenzyme may be purified from spent media of MMP-1 -transfected HT-1080 cells and the protein purified on a zinc chelating column The MMP-2 proenzyme may be purified by gelatin Sepharose chromatography from MMP-2-transfected p2AHT2 cells The MMP-9 proenzyme may be purified by gelatin Sepharose chromatography from spent media of MMP-9-transfected HT1080 cells

The catalytic domain MMP-3 cDNA may be used to express the catalytic domain enzyme in E coli inclusion bodies Then the enzyme is solubihzed in urea, purified on a preparative C-14 reverse phase HPLC column, and refolded in the presence of zinc acetate and purified for use

The MMP-7 cDNA may be used to express the enzyme in E coli inclusion bodies Then the enzyme is solubihzed in urea, purified on a preparative C-14 reverse phase HPLC column, and refolded in the presence of zinc acetate and purified for use

The MMP-13 may be obtained as a proenzyme from a full-length cDNA clone using baculovirus expression The expressed proenzyme was first purified over a heparin agarose column,

and then over a chelating zinc chloride column Further details on baculovirus expression systems may be found in, for example, Luckow et al , J. Virol , 67, 4566-79 (1993)

The MMP-14 cDNA may be used to express the catalytic domain enzyme in E coli inclusion bodies Then the enzyme is solubihzed in urea, purified on a preparative C-14 reverse phase HPLC column, and refolded in the presence of zinc acetate and purified for use

The catalytic domain of MMP-12 and MMP-15 enzymes were purchased commercially for these assays

All full length MMPs were activated using 4-amιnophenylmercυrιc acetate ("APMA", Sigma Chemical, St Louis, Mo ) or trypsin MMP-9 also was activated using human recombinant MMP-3 following standard cloning and purification techniques

The fluorogenic, methoxycoumarin-containing polypeptide substrate MCA-

ArgProLeuGlyLeuDpaAlaArgGluArgNH ₂ was used as the MMP substrate in the MMP inhibition assays for human recombinant MMP-1 , MMP-2, MMP-7, MMP-9, MMP-12, MMP-13, MMP-14 and MMP-15 Here, "MCA" is 7-methoxycoumaÏ€n-4-yl acetyl and "Dpa" is 3-(2,4-dιnιtrophenyl)-L-2,3-dι- aminopropionyl group In the absence of MMP inhibitory activity, the substrate is cleaved at the GIy- Leu peptide bond The cleavage separates the highly fluorogenic peptide from the 2,4-dιnιtrophenyl quencher, resulting in an increase of fluorescent intensity

For the human MMP-1 , MMP-2, MMP-7, MMP-9, MMP-12, MMP-13, MMP-14 and MMP-15 assays, dilutions of the inhibitors (or salts thereof) were prepared in 100% dimethyl sulfoxide (DMSO) The stock solutions were diluted in Buffer A (100 mM Tris-HCI, 100 mM NaCI, 10 mM CaCI ₂ , 0 005% polyoxyethylene 23 lauryl ether, pH 7 5) to obtain solutions with different compound concentrations, i e , assay solutions with different concentrations of the assayed MMP inhibitory compound in 1% DMSO The experiment controls contained the same amount of Buffer A /DMSO as the assayed sample, but contained no inhibitor The fluorogenic, methoxycoumarin-containing polypeptide substrate Mca-Arg-Pro-Lys-Pro-

Val-Glu-Nva-Trp-Arg-Lys(Dnp)-NH ₂ (Bachem catalog number M-2110) was used as the MMP substrate in the MMP inhibition assays for catalytic domain of human recombinant MMP-3 (which refers to the catalytic domain of stromelysin) Here, "MCA" is 7-methoxycoumarιn-4-yl acetyl and "Dpa" is 3-(2,4-dιnιtrophenyl)-L-2,3-dι- aminopropionyl group In the absence of MMP inhibitory activity, the substrate is cleaved at the Gly-Leu peptide bond The cleavage separates the highly fluorogenic peptide from the 2,4-dιnιtrophenyl quencher, resulting in an increase of fluorescent intensity

For the human MMP-3 assay, dilutions of the inhibitors (or salts thereof) were prepared in 100% DMSO The stock solutions were diluted in Buffer B (50 mM λ/-morpholιnoethane sulfonate ("MES"), 100 mM NaCI, 10 mM CaCI ₂ , 0 005% polyoxyethylene 23 lauryl ether, pH 6 0) ) to obtain solutions with different compound concentrations, i e , assay solutions with different concentrations of the assayed MMP inhibitory compound in 1 % DMSO The experiment controls contained the same amount of Buffer B /DMSO as the assayed sample, but contained no inhibitor

To determine K ₁ , the inhibitor samples are incubated at room temperature for 1 hr in the presence of enzyme and then 4 μM of appropriate MMP substrate was added, and samples were

analyzed on a Tecan SpectraFlour Plus plate reader The excitation wavelength is 330 nm, and the emission (fluorescence) wavelength is 420 nm In the absence of MMP inhibitory activity, the substrate is cleaved at the Gly-Leu bond resulting in an increase of relative fluorescence Inhibition is observed as a reduced rate of increase in relative fluorescence

The inhibitors are analyzed using a single low enzyme concentration with a single substrate concentration fixed at or below the K _m This protocol is a modification of method by Knight et al , FEBS Lett , 296(3), 263-266 (1992) Apparent inhibitory constants are determined by non-linear regression of reaction velocity as a function of inhibitor and enzyme concentration using Morrison's equation, as described by Kuzmic, Anal Biochem 286, 45-50 (2000) Modifications were made in the non-linear regression method to allow a common control reaction rate and effective enzyme concentration to be shared between all dose-response relationships on a given assay plate Since the substrate concentration was chosen to be at or below the K _n ,, the apparent K,'s from this analysis were reported as K,'s without correction for the influence of substrate

Cartilage damage in vitro assay

Human articular cartilage (HAC) was dissected from knees obtained from Asterand from patients undergoing knee replacement Apparently normal (not fibrillated) cartilage was cut in small pieces (- 2 mm) and cultured in 96 well plates with 200 μl of DMEM media (Gibco BRL high glucose, 25 mM Hepes, containing 2 mM L-glutamine and 1 mM Sodium Pyruvate) freshly supplemented with 1x HL-1 (Bio Whitaker) and 5 μg/ml ascorbic acid (Sigma), and with or without 0 1 ng/ml IL-1/? (R &D Systems, Minneapolis, MN) + 50 μg/ml Oncostatin M (R & D Systems) Some cartilage wells were incubated in the presence of serially diluted MMP inhibitors, tested in quadruplicate at 6 concentrations Media were replaced every 3 to 5 days and cartilage was cultured for a total of 18-22 days Conditioned media were frozen and analyzed later for hydroxyproline content (or type Il collagen degradation biomarker TIINE)

TIINE sandwich immunoassay for culture media.

A chemiluminescent sandwich immunoassay was developed with the neoepitope 9A4 antibody (recognizing the conserved sequence at the C-terminus of the V* type Il collagen fragment GPPGPQG following collagenase cleavage) and the capture 5109 antibody (recognizing the type Il collagen specific epitope GEPGDDGPS) as detailed elsewhere (Nemirovskiy et al , Anal Biochem 2007,361 (1 ) 93-101 ) utilizing the proprietary, chemiluminescent Bioveπs technology (Biovens Corporation, Gaithersburg, MD) This immunoassay utilizes a sandwich format on a paramagnetic bead support phase in which the sandwich complex is bound to the bead in suspension, passed through a flow cell, and captured by a magnet The process effectively separates the analyte from the

sample, decreasing background interference and eliminating wash steps required in other formats Briefly, serially diluted culture supernatant samples were assayed in a 96-well plate In this one step assay, 25 μl of sample, 25 μl of streptavidin beads (0 4 mg/mL), 25 μl of each antibody at 1/yg/mL (Biotin conjugated mouse 5109 anti-capture and BVTAG labeled 9A4 anti-neoepitope) and 10O pL of assay buffer (DPBS, 0 1 % BSA, 0 05% Tween 20, pH 7 4) were incubated for 2 hours at room temperature before reading on the Bioveπs M384 Analyzer Values were calculated from a standard curve prepared from either human 45-mer or bovine 30-mer (0 14-100 ng/ml) neoepitope peptide

Cartilage damage and/or joint degeneration in vivo assay: surαical-inducβ medial meniscus tear rat OA model Adult male Sprague Dawley rats (Charles River, Wilmington, MA) weighing 275-300 g were allowed to acclimate for 1 week prior to surgery OA was surgically induced as described (Bendele, "Animal models of osteoarthritis," J. Musculoskelet Neuronal. Interact. 1 (2001 ) (4), pp 363-376) Briefly, animals were anesthetized with isoflurane and the right knee joint prepped for surgery The medial collateral ligament (MCL) was exposed by blunt dissection and transected to reflect the meniscus toward the femur The joint space was visualized and the meniscus was cut through the full thickness at its narrowest point to simulate a complete tear. The skin was closed with stainless steel staples Compound or vehicle treatment started the day of surgery and continued for 3 to 4 weeks The animals are then sacrificed, the femoro-tibial joint space lavaged with 100ul sterile saline to collect synovial fluid, and the total joint removed and fixed in 10% formalin for histology Scoring was performed by hispopathology quantification