BIARYL-CONTAINING COMPOUNDS AS INVERSE AGONISTS OF ROR-gamma

RECEPTORS

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of United States Provisional Patent Application Serial Nos. 61/667,334, filed July 2, 2012 and 61/799,894, filed March 15, 2013, the disclosures of which are incorporated herein by reference in their entireties.

TECHNICAL FIELD OF THE INVENTION

[0002] The present invention relates to biaryl-containing inverse agonists of ROR-gamma receptors. The invention also provides pharmaceutical compositions comprising these inverse agonists. Also provided are methods of using these inverse agonists to treat ROR- gamma mediated diseases.

BACKGROUND OF THE INVENTION

[0003] Dysregulation of the immune system is a common cause of human disease.

Autoimmune diseases occur when the immune system attacks and destroys healthy body tissue. Other inflammatory diseases, such as asthma, do not necessarily result from a direct attack on healthy tissue but rather from improper or uncontrolled immune responses. Agents that modulate the development and function of cells of the immune system can be useful as therapies for such diseases.

[0004] One method of achieving such modulation is by targeting the function of nuclear receptors expressed in the immune system. Nuclear receptors are a superfamily of ligand- regulated DNA-binding transcription factors that are expressed by many cell types and control a broad spectrum of physiological processes. Drugs that target nuclear receptors are used in the treatment of numerous human diseases. Pharmaceutical nuclear receptor agonists or antagonists, such as tamoxifen for oestrogen receptors (targeted in breast cancer), thiazolidinediones for peroxisome proliferator-activated receptor-γ (PPARy) (targeted in type II diabetes), or dexamethasone for the glucocorticoid receptor (targeted in inflammatory diseases), are among the most commonly used drugs. The nuclear receptor, RAR-related orphan receptor C (RORC, ROR-gamma, ROR-gamma-t, RORy), is expressed in cells of the immune system and plays an important role in immune system function. Disclosed herein are biaryl-containing compounds that are useful as inverse agonists of ROR-gamma. SUMMARY OF THE INVENTION

[0005] In one aspect, the invention provides biaryl-containing inverse agonists

gamma receptors, wherein the inverse agonists are compounds of Formula I:

Formula I

or pharmaceutically acceptable salts thereof,

wherein:

R ^la and R ^lb are each independently H, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heterocycloalkyl-alkyl, optionally substituted cycloalkyl-alkyl,

or R ^la and R ^lb taken together form an optionally substituted 4- to 7-membered heterocyclic ring;

R ^2a , R ^2b , R ^2c , and R ^2d are each independently H, halogen, Ci_ ₄ alkyl, OCi_ ₄ alkyl, or CF ₃ ; R ³ is H, optionally substituted alkyl, optionally substituted cycloalkyl, OR ⁴ , halogen, SR ⁴ ,

S(0) ₂ R ⁴ , NR ⁵ R ⁶ , an optionally substituted heteroaryl, or an optionally substituted heterocycloalkyl;

R ⁴ , R ⁵ , and R ⁶ are each independently optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted heterocycloalkyl;

R ⁷ is Ci_ ₄ alkyl, or

R ³ and R ⁷ may be taken together to form an optionally substituted 4- to 7-membered

heterocyclic ring;

R ^8a , R ^8b , R ^8c , R ^8d , and R ^8e are each independently H, halogen, Ci_ ₄ alkyl, OR ⁴ , NR ⁵ R ⁶ , CF ₃ , or CN, or any 2 adjacent substituents of R ^8a , R ^8b , R ^8c , R ^8d , and R ^8e may be taken together to form an optionally substituted 4- to 7-membered cycloaliphatic or optionally substituted 4- to 7-membered heterocyclic ring;

X is CH or N; and,

J is a bond or C _1-4 alkylene.

[0006] In some embodiments of this aspect, R ³ and R ⁷ taken together form an optionally substituted 5- to 7-membered heterocyclic ring; and, J is a bond. In some of these embodiments, the compound of Formula I is a compound of Formula I-a:

Formula I-a

wherein:

W is CR ^7c R ^7d , O, or NR ^7a ;

R ^7a and R ^7b are each independently H or Ci_ ₄ alkyl,

R ^7c and R ^7d are each independently H, C _1-4 alkyl, or halogen; and,

n is 1, 2, or 3.

[0007] In some embodiments, R ³ is H, alkyl, substituted alkyl, halogen, NR ⁵ R ⁶ , or an optionally substituted heterocycloalkyl; and R ⁷ is alkyl.

[0008] In other embodiments of this aspect, R ³ is OR ⁴ .

[0009] In other embodiments of this aspect, R ³ is SR ⁴ , or S(0) ₂ R ⁴ .

[0010] In some embodiments of Formula I, 2 adjacent substituents of R ^8a , R ^8b , R ^8c , R ^8d , and R ^8e may be taken together to form an optionally substituted 4- to 7-membered cycloaliphatic or optionally substituted 4- to 7-membered heterocyclic ring.

[0011] In some embodiments, the compound is a compound of Formula I-b:

Formula I-b

or pharmaceutically acceptable salts thereof, wherein:

R ^la and R ^lb are each independently H, optionally substituted alkyl, optionally

substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heterocycloalkyl-alkyl, optionally substituted cycloalkyl-alkyl,

or R ^la and R ^lb taken together form an optionally substituted 4- to 7- membered heterocyclic ring;

R ^2a , R ^2b , R ^2c , and R ^2d are each independently H, halogen, Ci_ ₄ alkyl, OCi_ ₃ alkyl _, or CF ₃ ;

R ³ is H, optionally substituted alkyl, OR ⁴ , halogen, SR ⁴ , S(0) ₂ R ⁴ , NR ⁵ R ⁶ , or an

optionally substituted heterocycloalkyl;

R ⁴ , R ⁵ , and R ⁶ are each independently optionally substituted alkyl, optionally

substituted cycloalkyl, or optionally substituted heterocycloalkyl; R ⁷ is Ci_ ₄ alkyl, or

R ³ and R ⁷ may be taken together to form an optionally substituted 4- to 7- membered heterocyclic ring;

R ^8a , R ^8b , R ^8c , R ^8d , and R ^8e are each independently H, halogen, Ci_ ₄ alkyl, OR ⁴ , NR ⁵ R ⁶ ,

CF ₃ , or CN;

X is CH or N; and,

a bond or Ci_ ₄ alkylene.

L2] In another aspect, the invention includes a compound of Formula II:

Fonnula II

or pharmaceutically acceptable salts thereof, wherein:

J is a bond or C _1-4 alkylene;

hydroxyl;

X ¹ is CH or N;

X ² is C-R ^2a or N;

X ³ is C-R ^2b or N;

X ⁴ is C-R ^2d or N;

X ⁵ is S, or O;

Z ¹ and Z ² are each independently H or optionally substituted alkyl;

R ^2a , R ^2b , R ^2c , and R ^2d are each independently H, halogen, Ci_ ₄ alkyl, OC _]-4 alkyl, or

CF ₃ ;

R is H, optionally substituted alkyl, optionally substituted cycloalkyl, OR , halogen, SR ⁴ , S(0) ₂ R ⁴ , NR ⁵ R ⁶ , an optionally substituted heteroaryl, or an optionally substituted heterocycloalkyl; each R ⁴ is independently optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heteroaryl, or optionally substituted

heterocycloalkyl;

R ⁵ and R ⁶ are each independently hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted heterocycloalkyl;

R ⁷ is Ci_ ₄ alkyl, or

R ³ and R ⁷ may be taken together to form an optionally substituted 5- to 7- membered heterocyclic ring;

R ^8a , R ^8b , R ^8c , R ^8d , and R ^8e are each independently H, halogen, Ci_ ₄ alkyl, OR ⁴ , NR ⁵ R ⁶ , CF ₃ , or CN;

R ⁹ is a bond, optionally substituted alkylene, or optionally substituted cycloalkylene;

R ¹⁰ is NR ^la R ^lb , hydroxyl, or optionally substituted alkyl;

R ^12a and R ^12b are each independently optionally substituted alkyl,

or R ^12a and R ^12b may be taken together to form an optionally substituted 4- to 7-membered heterocyclic ring; and

R ^la and R ^lb are each independently H, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heterocycloalkyl-alkyl, optionally substituted cycloalkyl- alkyl,

or R ^la and R ^lb taken together form an optionally substituted 4- to 7-membered heterocyclic ring.

[0013] In another aspect, the invention includes a pharmaceutical composition comprising a compound of Formula I, Formula I-a, Formula I-b, Formula II, Formula II-ki or Formula II- k ₂ or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or adjuvant.

[0014] In another aspect, the invention includes a method of modulating the activity of an ROR-gamma receptor with an inverse agonist, comprising contacting the receptor with a compound of Formula I, Formula I-a, Formula I-b, Formula II, Formula II-ki or Formula II- k ₂ , or a pharmaceutically acceptable salt thereof.

[0015] In one embodiment of this aspect, the compound of Formula I, Formula I-a, Formula I-b, Formula II, Formula II-ki or Formula II-k ₂ or a pharmaceutically acceptable salt thereof, modulates the activity of an ROR-gamma receptor in vitro. In another embodiment, the compound of Formula I, Formula I-a, Formula I-b, Formula II, Formula II-ki or Formula II- k ₂ , or a pharmaceutically acceptable salt thereof, modulates the activity of an ROR-gamma receptor in vivo. In one embodiment, the compound of Formula I, Formula I-a, Formula I-b, Formula II, Formula II-ki, Formula II-k ₂ , or a pharmaceutically acceptable salt thereof, is an inverse agonist of the ROR-gamma receptor.

[0016] In yet another aspect, the invention includes a method of treating or reducing the severity of an ROR-gamma receptor mediated disease in a patient comprising administering a compound of Formula I, Formula I-a, Formula I-b, Formula II, Formula II-ki, Formula II-k ₂ , or a pharmaceutically acceptable salt thereof, to a patient in need thereof.

[0017] In one embodiment of this aspect, an ROR-gamma receptor mediated disease can include an automimmune disease. In some embodiments, an autoimmune disease is selected from the group consisting of Ankylosing spondylitis, Asthma, Behcet's disease, Chronic obstructive pulmonary disease, Crohn's disease, Diabetes Mellitus Type 1, Multiple Sclerosis, Neuromyelitis optica, Polymyalgia Rheumatica, Psoriasis, Psoriatic Arthritis, Rheumatoid Arthritis, Scleroderma, Sjogren's syndrome, Systemic Lupus Erythematosus, Systemic sclerosis, Transplant rejection, Inflammatory Bowel Disease, Ulcerative Colitis, and Uveitis.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

[0018] As used herein, the following definitions shall apply unless otherwise indicated. For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed. Additionally, general principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausolito: 1999, and "March's Advanced Organic Chemistry", 5th Ed., Ed. : Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.

[0019] As used herein the term "aliphatic' encompasses the terms alkyl, alkenyl, alkynyl. Unless otherwise stated, aliphatic can include both substituted and unsubstituted alkyl, alkenyl, and alkynyl.

[0020] As used herein, an "alkyl" group refers to a saturated aliphatic hydrocarbon group containing 1-8 (e.g., 1-6, 1-4, or 1, 2, 3, 4, 5, 6, 7, or 8) carbon atoms. As used herein, the terminology C _1-n alkyl refers to an alkyl group containing 1-n carbon atoms. For example, Ci-5 alkyl refers to an alkyl group containing 1, 2, 3, 4, or 5 carbon atoms. An alkyl group can be straight or branched. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-heptyl, or 2- ethylhexyl.

[0021] As used herein, the term "alkylene" refers to an alkyl group, as defined above, wherein one of the alkyl group's hydrogen atoms has been replaced with a bond. The alkylene group can be linear or branched. Non-limiting examples of alkylene groups include -CH ₂ - -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH(CH ₃ )CH ₂ CH ₂ - and - CH ₂ CH(CH ₃ )CH2-. As used herein, the term "cycloalkylene" refers to a cycloalkyl substituent having a hydrogen replaced with a bond at the same carbon atom or a different carbon atom, for example, ^¾ or ^v . In other examples a "heterocycloalkylene" is a heterocycloalkyl substituent having a hydrogen replaced with a bond, etc.

[0022] As used herein, an "alkenyl" group refers to an aliphatic carbon group that contains 2-8 (e.g., 2-6 or 2-4) carbon atoms and at least one double bond. Like an alkyl group, an alkenyl group can be straight or branched. Examples of an alkenyl group include, but are not limited to, allyl, isoprenyl, 2-butenyl, and 2-hexenyl.

[0023] As used herein, an "alkynyl" group refers to an aliphatic carbon group that contains 2-8 (e.g., 2-6 or 2-4) carbon atoms and at least one triple bond. Like an alkyl group, an alkynyl group can be straight or branched.

[0024] As used herein, an "amino" group refers to -NR ^X R ^Y wherein each of R ^x and R ^Y is independently hydrogen, alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, aralkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, heteroaryl, or carbonyl each of which are defined herein. Examples of amino groups include alkylcarbonylamino, alkylsulfonylamino, alkoxycarbonylamino, (azacycloalkylcarbonyl)amino, heteroaralkylcarbonylamino, heteroarylcarbonylamino, carbonylamino, (heterocycloalkyl)carbonylamino, (heterocycloalkyl)alkylcarbonylamino, heteroarylcarbonylamino, arylcarbonylamino, aralkylcarbonylamino,

(cycloalkyl)alkylcarbonylamino, cycloalkylcarbonylamino. When the term "amino" is not the terminal group (e.g., alkylcarbonylamino), it is represented by -NR -. R has the same meaning as defined above. A nonexhaustive list of possible R ^x and R ^Y includes

sulfonylamino, alkylamino, carbonylamino, carboxy, oxo, hydroxyl, sulfo, mercapto, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, aminocarbonyl, alkylcarbonyl, cycloalkylcarbonyl, cycloalkylalkylcarbonyl, arylcarbonyl, aralkylcarbonyl, heterocycloalkylcarbonyl, heterocycloalkylalkylcarbonyl, heteroarylcarbonyl, or heteroaralkylcarbonyl.

[0025] As used herein, a "carbonyl" group, when used alone or as part of another structure refers to -(CO)R ^x , where R ^x is defined above. When the term "carbonyl" is not the terminal group (e.g., arylaminoalkylcarbonyl) it is represented by -C(0)R ^x . Without limitation, carbonyl groups can include optionally substituted aminocarbonyl, alkoxyalkoxycarbonyl, alkylaminocarbonyl, arylcarbonyl (e.g., haloarylcarbonyl), heterocycloalkylcarbonyl, heterocycloalkenylcarbonyl, arylaminocarbonyl (e.g., haloarylaminocarbonyl),

cyanoalkylarylcarbonyl, heterocycloalkoxycarbonyl, alkynyloxycarbonyl,

cycloalkoxycarbonyl, heterobicycloarylcarbonyl, alkylheteroarylaminocarbonyl,

alkoxy arylcarbonyl (e.g., haloalkoxyarylcarbonyl), (alkylheterocyclo)alkenylcarbonyl, heteroarylcarbonyl, arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl (e.g.,

haloalkoxycarbonyl), alkylarylcarbonyl, cycloalkylcarbonyl, alkylheteroarylcarbonyl, arylsulfonylcarbonyl, aminocarbonyl, sulfonylcarbonyl, alkylcarbonyl,

alkylsulfonylcarbonyl, alkylcarbonyl, arylaminocarbonyl, or the like. A nonexhaustive list of possible R ^x and R ^Y includes sulfonylaminocarbonyl, alkylcarbonyl, carbonylamino, carboxy, oxo, hydroxyl, sulfo, mercapto, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, aminocarbonyl, alkylcarbonyl, cycloalkylcarbonyl, cycloalkylalkylcarbonyl, arylcarbonyl, aralkylcarbonyl, heterocycloalkylcarbonyl, heterocycloalkylalkylcarbonyl, heteroarylcarbonyl, or

heteroaralkylcarbonyl.

[0026] As used herein, an "aryl" group used alone or as part of a larger moiety as in "aralkyl", "aralkoxy", or "aryloxyalkyl" refers to an aromatic monocyclic (e.g., phenyl); an aromatic bicyclic (e.g., indenyl, naphthalenyl, tetrahydronaphthyl, tetrahydroindenyl); an aromoatic tricyclic (e.g., fluorenyl, tetrahydrofluorenyl, anthracenyl, or

tetrahydroanthracenyl); or a benzofused group having 2-3 carbocyclic rings in which one or more of the rings are aromatic. For example, a benzofused group includes phenyl fused with two or more C ₄ _8 carbocyclic moieties.

[0027] As used herein, an "aralkyl" group refers to an alkyl group (e.g., a C _1-4 alkyl group) that is substituted with an aryl group. Both "alkyl" and "aryl" are defined herein. An example of an aralkyl group is benzyl.

[0028] A "heteroaralkyl" group refers to an alkyl group that is substituted with a heteroaryl. Both "alkyl" and "heteroaryl" are defined herein.

[0029] The term "cycloaliphatic" means a saturated or partially unsaturated monocyclic, bicyclic, or tricyclic hydrocarbon ring that has a single point of attachment to the rest of the molecule. Cycloaliphatic rings are 3-8 membered monocyclic rings (e.g., 3-6 membered rings). Cycloaliphatic rings also include 8-12 membered bicyclic hydrocarbon rings, (e.g., 10 membered bicyclic hydrocarbon rings). A cycloaliphatic group encompasses a "cycloalkyl" group and a "cycloalkenyl" group.

[0030] As used herein, a "cycloalkyl" group refers to a saturated carbocyclic mono-, bi-, tri- , or multicyclic (fused, spiro, or bridged) ring of 3-10 (e.g., 4-6, 5-10, 3, 4, 5, 6, 7, 8, 9, or 10) carbon atoms. Without limitation, examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or the like. Without limitation, examples of bicyclic cycloalkyl groups include octahydro-indenyl, decahydro- naphthyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, bicyclo[3.3.1]nonyl, bicyclo[3.3.2.]decyl, bicyclo[2.2.2]octyl, bicycle[2.2.1]heptanyl, bicycle[3.1.1]heptanyl, or the like. Without limitation, multicyclic groups include adamantyl, cubyl, norbornyl, or the like.

[0031] A "cycloalkenyl" group, as used herein, refers to a non-aromatic carbocyclic ring of 3-10 (e.g., 4-8) carbon atoms having one or more double bonds. Examples of cycloalkenyl groups include cyclopentenyl, 1 ,4-cyclohexa-di-enyl, cycloheptenyl, cyclooctenyl, hexahydro-indenyl, octahydro-naphthyl, cyclohexenyl, cyclopentenyl, bicyclo[2.2.2]octenyl, and bicyclo[3.3.1]nonenyl.

[0032] As used herein, the term "heterocycloaliphatic" and "heterocyclic" encompasses a heterocycloalkyl group and a heterocycloalkenyl group.

[0033] As used herein, a "heterocycloalkyl" group refers to a 3-10 membered mono or bicyclic (fused, spriro, or bridged) (e.g., 4-6, 5-10, 3, 4, 5, 6, 7, 8, 9, or 10-membered mono or bicyclic) saturated ring structure, in which one or more of the ring atoms is a heteroatom (e.g., N, O, S, or combinations thereof). Examples of a heterocycloalkyl group include piperidyl, piperazyl, tetrahydropyranyl, tetrahydrofuryl, 1 ,4-dioxolanyl, 1 ,4-dithianyl, 1,3- dioxolanyl, oxazolidyl, isoxazolidyl, morpholinyl, thiomorpholyl, octahydro-benzofuryl, octahydro-chromenyl, octahydro-thiochromenyl, octahydro-indolyl, octahydro-pyrindinyl, decahydro-quinolinyl, octahydro-benzo[^]thiopheneyl, 2-oxa-bicyclo[2.2.2]octyl, 1-aza- bicyclo[2.2.2]octyl, 3-aza-bicyclo[3.2.1]octanyl, 2,6-dioxa-tricyclo[3.3.1.0 ³ ' ⁷ ]nonyl, tropane.

[0034] A monocyclic heterocycloalkyl group may be fused with a phenyl moiety such as tetrahydroisoquinoline. Heterocycloalkyl ring structures can be optionally substituted at any chemically viable position on the ring or rings.

[0035] A "heterocycloalkenyl" group, as used herein, refers to a mono- or bicylic (e.g., 5- to 10-membered mono- or bicyclic) non-aromatic ring structure having one or more double bonds, and wherein one or more of the ring atoms is a heteroatom (e.g., N, O, or S).

[0036] Examples of heterocycloalkenyls include 2-pyrrolyl, 3-pyrrolyl, 2-imidazolyl, or 2- pyrazolyl. Monocyclic heteroaliphatics are numbered according to standard chemical nomenclature. For instance:

2-Pyrazoline

[0037] A "heteroaryl" group, as used herein, refers to a monocyclic, bicyclic, or tricyclic ring structure having 4 to 15 (e.g., 5-9, 6-13, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15) ring atoms wherein one or more of the ring atoms is a heteroatom (e.g., N, O, S, or combinations thereof), and wherein one or more rings of the bicyclic or tricyclic ring structure is aromatic. A heteroaryl group includes a benzofused ring system having 2 to 3 rings. For example, a benzofused group includes benzo fused with one or two C ₄ _8 heterocyclic moieties (e.g., indolizyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo[^]furyl, benzoyl thiophenyl, quinolinyl, or isoquinolinyl). Some examples of heteroaryl are azetidinyl, pyridyl, 1H- indazolyl, furyl, pyrrolyl, thienyl, thiazolyl, oxazolyl, imidazolyl, tetrazolyl, benzofuryl, isoquinolinyl, benzthiazolyl, xanthene, thioxanthene, phenothiazine, dihydroindole, benzo[l,3]dioxole, benzo[^]furyl, benzo[^]thiophenyl, indazolyl, benzimidazolyl, benzthiazolyl, puryl, cinnolyl, quinolyl, quinazolyl,cinnolyl, phthalazyl, quinazolyl, quinoxalyl, isoquinolyl, 4H-quinolizyl, benzo-l ,2,5-thiadiazolyl, or 1,8-naphthyridyl.

[0038] Without limitation, monocyclic heteroaryls include furyl, thiophenyl, 2H-pyrrolyl, pyrrolyl, oxazolyl, thazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, 1 ,3,4-thiadiazolyl, 2H-pyranyl, 4-H-pranyl, pyridyl, pyridazyl, pyrimidyl, pyrazolyl, pyrazyl, or 1,3,5-triazyl. Monocyclic heteroaryls are numbered according to standard chemical nomenclature. For instance:

Furan Thiazole Pyrimidine

[0039] Without limitation, bicyclic heteroaryls include indolizyl, indolyl, isoindolyl, 3H- indolyl, indolinyl, benzo[Z?]furyl, benzo[Z?]thiophenyl, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, indolizyl, isoindolyl, indazolyl, benzimidazyl, benzthiazolyl, purinyl, 4H-quinolizyl, quinolyl, isoquinolyl, cinnolyl, phthalazyl, quinazolyl, quinoxalyl, 1,8-naphthyridyl, indolizinyl, imidazopyridinyl, tetrahydrobenzoazepinyl, tetrahydrobenzooxazepinyl, benzo[ 1 ,4]oxazinyl, benzodihydro[ 1 ,4]oxazinyl,

benzo[l,3]oxazinyl, benzodihydro[l,3]oxazinyl, fused pyrido[l,4]oxazinyl, fused pyrido[l,3]oxazinyl, fused pyrido[l,4]dihydrooxazinyl, fused pyrido[l,3]dihydrooxazinyl, fused pyrimido[l,4]oxazinyl, fused pyrimido[l,3]oxazinyl, fused

pyrimido[l,4]dihydrooxazinyl, fused pyrimido[l,3]dihydrooxazinyl, fused

pyrizo[l,4]oxazinyl, fused pyrizo[l,3]oxazinyl, fused pyrizo[l,4]dihydrooxazinyl or fused pyrizo[l,3]dihydrooxazinyl or pteridyl. Bicyclic heteroaryls are numbered according to standard chemical nomenclature. For instance:

Quinoxaline

[0040] A "heteroaralkyl" group, as used herein, refers to an alkyl group (e.g., a C _1-4 alkyl group) that is substituted with a heteroaryl group. Both "alkyl" and "heteroaryl" have been defined above.

[0041] As used herein, "cyclic moiety" includes cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, or heteroaryl, each of which has been defined previously.

[0042] As used herein, an "acyl" group refers to a formyl group or alkyl-C(=0)- (also referred to as "alkylcarbonyl") where "alkyl" has been defined previously. Acetyl and pivaloyl are examples of acyl groups.

[0043] As used herein, a "carbamoyl" group refers to a group having the structure -O-CO- NR ^x R ^y or -NR ^x -CO-0-R ^z wherein R ^x and R ^y have been defined above and R ^z can be alkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl, or heteroaralkyl.

[0044] As used herein, a "carboxy" (or "carboxyl") and a "sulfo" group refer to -COOH or -COOR ^x and -S0 ₃ H or -S0 ₃ R ^x , respectively.

[0045] As used herein, a "hydroxy" or "hydroxyl" group refers to -OH.

[0046] As used herein, an "alkoxy" or "alkoxyl" group refers to an alkyl-O- group where "alkyl" has been defined previously. Moreover an alkoxy group includes structures comprising two alkoxy groups on the same atom or adjacent atoms that form a ring together with the atom(s) to which they are bound.

[0047] As used herein, a "sulfoxy" group refers to -0-SO-R ^x or -SO-0-R ^x , where R ^x has been defined above.

[0048] As used herein, a "mercapto" group refers to -SH.

[0049] As used herein, a "sulfonyl" group refers to -S(0) ₂ -R ^x , wherein R ^x has been defined above. Examples of sulfonyls include optionally substituted alkylsulfonyl, arylsulfonyl (e.g., haloarylsulfonyl), heteroarylsulfonyl (e.g., alkylheteroarylsulfonyl), or the like.

[0050] As used herein a "sulfinyl" group refers to -S(0)-R ^x , wherein R ^x has been defined above. Examples of sulfinyls include alkylsulfinyl.

[0051] As used herein a "sulfanyl" group refers to -S-R ^x , wherein R ^x has been defined above. Examples of sulfanyls include alkylsulfanyl.

[0052] As used herein, a "halogen" or "halo" group refers to fluorine, chlorine, bromine or iodine.

[0053] As used herein, a "haloaliphatic" group refers to an aliphatic group substituted with 1-3 halogen. For instance, the term haloalkyl includes the group -CF ₃ .

[0054] As used herein, a "sulfamoyl" group refers to the structure -S(0) ₂ -NR ^x R ^y or -NR ^X - S(0) ₂ -R ^z wherein R ^x , R ^y , and R ^z have been defined above.

[0055] As used herein, a "sulfamide" group refers to the structure -NR ^X -S(0) ₂ -NR ^Y R ^z wherein R ^x , R ^Y , and R ^z have been defined above.

[0056] As used herein, a "carbonylamino" group used alone or in connection with another group refers to an amido group such as Rx-C(0)-NR ^x -. For instance an alkylcarbonylamino includes alkyl-C(0)-NR ^x -, wherein R ^x has been defined above.

[0057] As used herein, a "aminocarbonyl" group used alone or in connection with another group refers to an amido group such as N(Rx)2-C(0)-.

[0058] As used herein, an "alkoxycarbonyl" used alone or in connection with another group refers to a carbonyl group such as alkyl-O-C(O)-.

[0059] As used herein, a "carboxyalkoxy" group used alone or in connection with another group refers to a carboxy (COOH-) bonded to an alkoxy group -C-0-( C ₂ _ ₄ alkyl), for example, -CO(C ₂ - ₄ alkyl)COOH

[0060] As used herein, an "alkoxyalkyl" refers to an alkyl group such as alkyl-O-alkyl-, wherein alkyl has been defined above.

[0061] As used herein, an "aminocarbonyl" refers to an amido group such as -NR ^x -C(0)-, wherein R ^x has been defined above.

[0062] As used herein, an "aminosulfonyl" refers to the structure -N(R ^x ) ₂ -S(0) ₂ -, wherein R ^x has been defined above.

[0063] As used herein, an "oxo" refers to =0.

[0064] As used herein, an "aminoalkyl" refers to the structure N(RX)2-alkyl-.

[0065] As used herein, a "cyanoalkyl" refers to the structure (CN)-alkyl-.

[0066] As used herein, an "alkylsulfonyl' group refers to the structure alkyl-S(0)2-.

[0067] As used herein, a "sulfonylamino" group refers to the structure Rx-S(0)2-N(RX)2-, wherein Rx has been defined above.

[0068] As used herein, a "urea" group refers to the structure -NRX-CO-NRYRZ and a "thiourea" group refers to the structure -NRX-CS-NRYRZ. RX, RY, and RZ have been defined above.

[0069] As used herein, pictured substituents drawn with a single, unattached wavy line drawn perpendicular to a bond of the substituent is meant to show the attachment point of the substituent. For example, the pyrrole substituent, ^ ⁵ */ , is shown as attached to the main core structure by the ring nitrogen, while the pyrrole substituent, , is shown as attached to the main core structure by the carbon atom adjacent to the ring nitrogen.

[0070] As used herein, pictured ring structures drawn with a substituent' s bond overlayed on one of the ring bonds shows that the substituent can be at any substitutable atom of the entire ring structure, whether the ring structure is monocyclic or multicyclic. For example,

the R substituent on the structure, , can be substituted on any atom of the piperidine

ring, and the R substituent on the structure, , can be substituted on any atom of the benzene ring or piperidine ring.

[0071] As used herein, pictured structures having methyl substituents ar drawn to show

those methyl substituents as an external bond. Specifically, the structure, , is identical

to the structure .

[0072] As depicted herein, divalent substituents, such as an amide, shown as -C(0)N(Rx)-, are meant to include the substituent in both directions. For example, the generic structure herein X is an unsubstituted amide can be or . Some examples of generic divalent substituents include, but are not limited to -CO-, -CS-, -CONQ2-, -C02-, -OCO-, -NQ2-, -NQ2C02-, -0-, -NQ2CONQ2- , -OCONQ2-, -NQ2CO-, -S-, -SO-, -S02-, -S02NQ2-, -NQ2S02-, and -NQ2S02NQ2-.

[0073] In general, the term "substituted," whether preceded by the term "optionally" or not, includes, but is not limited to, the replacement of radicals (for example, hydrogen radicals) in a given structure with the radical of a specified substituent or addition of the specified radical substituent to an atom (for example, sulfur or phosphorous). For instance, sulfur can be optionally substituted with one or more oxo substituents. Specific substituents are described above in the definitions and below in the description of compounds and examples thereof. Unless otherwise indicated, an optionally substituted group may have a substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. The substituents can be bound to the same atom (C, S, N, or O) or two or more different atoms. A ring substituent, such as a heterocycloalkyl, may be bound to another ring, such as a cycloalkyl, to form a spiro-bicyclic ring system, e.g., both rings share one common atom. As one of ordinary skill in the art will recognize, combinations of substituents envisioned by this invention are those combinations that result in the formation of stable or chemically feasible compounds.

[0074] Substituents can include, but are not limited to, alkyl, cycloalkyl, alkenyl, amino, carbonyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, heteroaryl, heteroaralkyl, acyl, carbamoyl, carboxy, hydroxyl, alkoxy, sulfoxy, mercapto, sulfo, sulfonyl, sulfinyl, sulfanyl, halogen, haloaliphatic, sulfamoyl, sulfamide,

carbonylamino, aminocarbonyl, alkoxycarbonyl, carboxyalkoxy, alkoxyallkyl,

aminocarbonyl, alkylcarbonylamino, alkylsulfonylamino, aminosulfonyl, oxo, cyano, aminoalkyl, cyanoalkyl, alkylsulfonyl, and sulfonylamino, wherein the cycloalkyl, cycloalkyl portion thereof, alkyl or alkyl portion of any of the foregoing substituents can be further substituted with at least one, preferably 1 to 3, of amino, halogen, hydroxyl, carboxy, sulfo, sulfonyl, oxo, cyano, and carbonyl.

[0075] In general, the term "unsubstituted" refers to a chemical moiety that includes no substituents.

[0076] The phrase "stable or chemically feasible," as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and preferably their recovery, purification, and use for one or more of the purposes disclosed herein. In some embodiments, a stable compound or chemically feasible compound is one that is not substantially altered when kept at a temperature of 40°C or less, in the absence of moisture or other chemically reactive conditions, for at least a week. [0077] As used herein, an effective amount is defined as the amount required to confer a therapeutic effect on the treated patient, and is typically determined based on age, surface area, weight, and condition of the patient. The interrelationship of dosages for animals and humans (based on milligrams per meter squared of body surface) is described by Freireich et al., Cancer Chemother. Rep., 50: 219 (1966). Body surface area may be approximately determined from height and weight of the patient. See, e.g., Scientific Tables, Geigy Pharmaceuticals, Ardsley, New York, 537 (1970). As used herein, "patient" refers to a mammal, including a human.

[0078] Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, single

stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention.

[0079] The compounds disclosed herein also include all pharmaceutically acceptable isotopic variations, in which at least one atom is replaced by an atom having the same atomic number, but an atomic mass different from the atomic mass most prevalent in nature.

Examples of isotopes suitable for inclusion in the disclosed compounds include, without

2 3 13 14 limitation, isotopes of hydrogen, such as H and H; isotopes of carbon, such as C and C;

15 17 18

isotopes of nitrogen, such as N; isotopes of oxygen, such as O and O; isotopes of phosphorus, such as ³¹ P and ³² P; isotopes of sulfur, such as ³⁵ S; isotopes of fluorine, such as ¹⁸ F; and isotopes of chlorine, such as ³⁶ C1. Certain isotopic variations of the disclosed compounds may incorporate a radioactive isotope (e.g., tritium, ³ H, or ¹⁴ C), which may be useful in drug and/or substrate tissue distribution studies.

[0080] Additionally, unless otherwise stated, isotopically labeled structures included in the invention are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the isotopically labeled structures; for example, the R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, single stereochemical isomers of isotopically labeled structures as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the isotopically labeled structures are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the isotopically labeled structures of the invention are within the scope of the invention.

Biar l-Containing Inverse Agonists of ROR-gamma receptors

[0081] In one aspect, the invention provides biaryl-containing inverse agonists of ROR- gamma receptors, wherein the inverse agonists are compounds of Formula I:

Formula I

or pharmaceutically acceptable salts thereof,

wherein:

R ^la and R ^lb are each independently H, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heterocycloalkyl-alkyl, optionally substituted cycloalkyl-alkyl,

or R ^la and R ^lb taken together form an optionally substituted 4- to 7-membered heterocyclic ring;

R ^2a , R ^2b , R ^2c , and R ^2d are each independently H, halogen, Ci_ ₄ alkyl, OCi_ ₄ alkyl, or CF ₃ ; R ³ is H, optionally substituted alkyl, optionally substituted cycloalkyl, OR ⁴ , halogen, SR ⁴ ,

S(0) ₂ R ⁴ , NR ⁵ R ⁶ , an optionally substituted heteroaryl, or an optionally substituted heterocycloalkyl;

R ⁴ , R ⁵ , and R ⁶ are each independently optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted heterocycloalkyl;

R ⁷ is Ci_ ₄ alkyl, or

R ³ and R ⁷ may be taken together to form an optionally substituted 4- to 7-membered

heterocyclic ring; R ^8a , R ^8b , R ^8c , R ^8d , and R ^8e are each independently H, halogen, Ci_ ₄ alkyl, OR ⁴ , NR ⁵ R ⁶ , CF ₃ , or CN, or any 2 adjacent substituents of R ^8a , R ^8b , R ^8c , R ^8d , and R ^8e may be taken together to form an optionally substituted 4- to 7-membered cycloaliphatic or optionally substituted 4- to 7-membered heterocyclic ring;

X is CH or N; and,

J is a bond or C _1-4 alkylene.

[0082] In another embodiment of this aspect, the invention includes a compound of Formula I, wherein:

R ^la and R ^lb are each independently H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heterocycloalkyl- alkyl, optionally substituted cycloalkyl-alkyl,

or R ^la and R ^lb taken together form an optionally substituted 4- to 7-membered heterocyclic ring;

R ^2a , R ^2b , R ^2c , and R ^2d are each independently H, halogen, Ci_ ₄ alkyl, OCi_ ₃ alkyl _, or

CF ₃ ;

R ³ is H, optionally substituted alkyl, OR ⁴ , halogen, SR ⁴ , S(0) ₂ R ⁴ , NR ⁵ R ⁶ , or an optionally substituted heterocycloalkyl;

R ⁴ , R ⁵ , and R ⁶ are each independently optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted heterocycloalkyl;

R ⁷ is Ci_ ₄ alkyl, or

R ³ and R ⁷ may be taken together to form an optionally substituted 4- to 7-membered heterocyclic ring;

R ^8a , R ^8b , R ^8c , R ^8d , and R ^8e are each independently H, halogen, Ci_ ₄ alkyl, OR ⁴ , NR ⁵ R ⁶ , CF ₃ , or CN;

X is CH or N; and,

J is a bond or C _1-4 alkylene.

[0083] In some embodiments of Formula I, R ³ and R ⁷ taken together form an optionally substituted 5- to 7-membered heterocyclic ring; and, J is a bond. In some of these embodiments, the compound of Formula I is a compound of Formula I-a:

Formula I-a

wherein:

W is CR ^7c R ^7d , O, or NR ^7a ;

R ^7a and R ^7b are each independently H or C1-4 alkyl,

R ^7c and R ^7d are each independently H, C1-4 alkyl, or halogen; and,

n is 1, 2, or 3.

[0084] In some embodiments, R ³ is H, alkyl, substituted alkyl, halogen, NR ⁵ R ⁶ , or an optionally substituted heterocycloalkyl; and R ⁷ is alkyl.

[0085] In other embodiments of this aspect, R ³ is OR ⁴ .

[0086] In other embodiments of this aspect, R ³ is SR ⁴ , or S(0) ₂ R ⁴ .

[0087] In another aspect, the invention includes a compound of Formula I-b:

Formula I-b

or pharmaceutically acceptable salts thereof, wherein:

R ^la and R ^lb are each independently H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heterocycloalkyl-alkyl, optionally substituted cycloalkyl-alkyl,

or R ^la and R ^lb taken together form an optionally substituted 4- to 7- membered heterocyclic ring;

R ^2a , R ^2b , R ^2c , and R ^2d are each independently H, halogen, Ci_ ₄ alkyl, OCi_ ₃ alkyl _, or CF ₃ ;

R ³ is H, optionally substituted alkyl, OR ⁴ , halogen, SR ⁴ , S(0) ₂ R ⁴ , NR ⁵ R ⁶ , or an

optionally substituted heterocycloalkyl;

R ⁴ , R ⁵ , and R ⁶ are each independently optionally substituted alkyl, optionally

substituted cycloalkyl, or optionally substituted heterocycloalkyl;

R ⁷ is Ci_ ₄ alkyl, or

R ³ and R ⁷ may be taken together to form an optionally substituted 4- to 7- membered heterocyclic ring;

R ^8a , R ^8b , R ^8c , R ^8d , and R ^8e are each independently H, halogen, Ci_ ₄ alkyl, OR ⁴ , NR ⁵ R ⁶ ,

CF ₃ , or CN;

X is CH or N; and,

J is a bond or Ci_ ₄ alkylene. In another aspect, the invention includes a compound of Formula II

Formula II

or pharmaceutically acceptable salts thereof, wherein:

J is a bond or Ci_ ₄ alkylene;

hydroxyl;

X ¹ is CH or N;

X ² is C-R ^2a or N;

X ³ is C-R ^2b or N;

X ⁴ is C-R ^2d or N;

X ⁵ is S, or O;

Z ¹ and Z ² are each independently H or optionally substituted alkyl;

R ^2a , R ^2b , R ^2c , and R ^2d are each independently H, halogen, Ci_ ₄ alkyl, OCi_ ₄ alkyl _, or

CF ₃ ;

R ³ is H, optionally substituted alkyl, optionally substituted cycloalkyl, OR ⁴ , halogen, SR ⁴ , S(0) ₂ R ⁴ , NR ⁵ R ⁶ , an optionally substituted heteroaryl, or an optionally substituted heterocycloalkyl; each R ⁴ is independently optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heteroaryl, or optionally substituted heterocycloalkyl;

R ⁵ and R ⁶ are each independently hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted heterocycloalkyl;

R ⁷ is Ci_ ₄ alkyl, or

R ³ and R ⁷ may be taken together to form an optionally substituted 5- to 7- membered heterocyclic ring;

R ^8a , R ^8b , R ^8c , R ^8d , and R ^8e are each independently H, halogen, Ci_ ₄ alkyl, OR ⁴ , NR ⁵ R ⁶ , CF ₃ , or CN;

R ⁹ is a bond, optionally substituted alkylene, or optionally substituted cycloalkylene; R ¹⁰ is NR ^la R ^lb , hydroxyl, or optionally substituted alkyl; R ^a and R are each independently optionally substituted alkyl, or R ^12a and R ^12b may be taken together to form an optionally substituted 4- to 7-membered heterocyclic ring; and

R ^la and R ^lb are each independently H, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heterocycloalkyl-alkyl, optionally substituted cycloalkyl- alkyl,

[0089] or R ^la and R ^lb taken together form an optionally substituted 4- to 7-membered heterocyclic ring.In another aspect, the invention includes a compound of Formula II-ki

Formula Il-k

or pharmaceutically acceptable salts thereof, wherein:

J is a bond or C _1-4 alkylene;

B is

X ¹ is CH or N;

X ² is C-R ^2a or N;

X ³ is C-R ^2b or N;

X ⁴ is C-R ^2d or N; X ⁵ is S, or O;

R ^2a , R ^2b , R ^2c , and R ^2d are each independently H, halogen, Ci_ ₄ alkyl, OCi_ ₄ alkyl _, or CF ₃ ;

R ³ is H, optionally substituted alkyl, OR ⁴ , halogen, SR ⁴ , S(0) ₂ R ⁴ , NR ⁵ R ⁶ , an optionally substituted heteroaryl, or an optionally substituted heterocycloalkyl;

each R ⁴ is independently optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heteroaryl, or optionally substituted heterocycloalkyl

R ⁵ , and R ⁶ are each independently hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted heterocycloalkyl;

R ⁷ is Ci_ ₄ alkyl, or

R ³ and R ⁷ may be taken together to form an optionally substituted 5- to 7-membered heterocyclic ring;

R ^8a , R ^8b , R ^8c , R ^8d , and R ^8e are each independently H, halogen, Ci_ ₄ alkyl, OR ⁴ , NR ⁵ R ⁶ , CF ₃ , or CN;

R ⁹ is a bond, optionally substituted alkylene, or optionally substituted cycloalkylene; R ¹⁰ is NR ^la R ^lb , or hydroxyl; and

R ^la and R ^lb are each independently H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heterocycloalkyl- alkyl, optionally substituted cycloalkyl-alkyl,

or R ^la and R ^lb taken together form an optionally substituted 4- to 7-membered heterocyclic ring.

[0090] In another embodiment, the invention includes a compound of Formula II-k ₂ :

Formula II-k ₂

or pharmaceutically acceptable salts thereof, wherein: J is a bond;

X ¹ is CH or N;

X ² is C-R ^2a or N;

X ³ is C-R ^2b or N;

X ⁴ is C-R ^2d or N;

X ⁵ is S, or O;

Z ¹ and Z ² are each independently H or optionally substituted alkyl;

R ^2a , R ^2b , R ^2c , and R ^2d are each independently H, halogen, Ci_ ₄ alkyl, OCi_ ₄ alkyl _, or

CF ₃ ;

R ³ is H, optionally substituted alkyl, optionally substituted cycloalkyl, OR ⁴ , halogen, SR ⁴ , S(0) ₂ R ⁴ , NR ⁵ R ⁶ , an optionally substituted heteroaryl, or an optionally substituted heterocycloalkyl; each R ⁴ is independently optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heteroaryl, or optionally substituted heterocycloalkyl;

R ⁵ and R ⁶ are each independently hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted heterocycloalkyl;

R ⁷ is Ci_ ₄ alkyl, or

R ³ and R ⁷ may be taken together to form an optionally substituted 5- to 7- membered heterocyclic ring;

R ^8a , R ^8b , R ^8c , R ^8d , and R ^8e are each independently H, halogen, Ci_ ₄ alkyl, OR ⁴ , NR ⁵ R ⁶ , CF ₃ , or CN;

R ⁹ is a bond, optionally substituted alkylene, or optionally substituted cycloalkylene;

R ¹⁰ is NR ^la R ^lb , hydroxyl, or optionally substituted alkyl;

R ^12a and R ^12b are each independently optionally substituted alkyl,

or R ^12a and R ^12b may be taken together to form an optionally substituted 4- to 7-membered heterocyclic ring; and

R ^la and R ^lb are each independently H, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heterocycloalkyl-alkyl, optionally substituted cycloalkyl- alkyl,

or R ^la and R ^lb taken together form an optionally substituted 4- to 7-membered heterocyclic ring.

[0091] In some embodiments of Formula II, R ⁵ and R ⁶ are each independently optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted heterocycloalkyl.

[0092] In some embodiments of Formula I or Formula II, R ³ and R ⁷ taken together form an optionally substituted 4- to 7-membered heterocyclic ring; and, J is a bond. In these aspects, a representative compound of Formula I is Formula I-a:

Formula I-a

wherein:

W is CR ^7c R ^7d , O, or NR ^7a ;

R ^7a and R ^7b are each independently H or C ₁ -4 alkyl,

R ^7c and R ^7d are each independently H, C ₁ -4 alkyl, or halogen; and, n is 1, 2, or 3.

[0093] In the following embodiments, recitation and definitions of the following substituents: R ^la , R ^lb , R ^2a , R ^2b , R ²⁰ , R ^2d , R ⁴ , R ⁵ , R ⁶ , R ^8a , R ^8b , R ^8c , R ^8d , and R ^8e , and X can be applicable to the compounds of Formula I, Formula II, Formula II-ki, Formula II-k ₂ and Formula I-a, as provided herein before and herein after. In the following embodiments, recitation and definitions of the following substituents: R ³ , and R ⁷ , can be applicable to the compounds of Formula I or Formula II, Formula II-ki, and Formula II-k ₂ , as provided herein before and herein after. In the following embodiments, recitation and definitions of the following substituents: R ^7a , R ^7b , R ^7c , R ^7d and W, can be applicable to the compounds of Formula I-a, as provided herein before and herein after.

[0094] In some embodiments, R ^la and R ^lb are each independently: H, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heterocycloalkyl-alkyl, optionally substituted cycloalkyl-alkyl, or R ^la and R ^lb taken together form an optionally substituted 4- to 7- membered heterocyclic ring.

[0095] In some embodiments, R ^la and R ^lb are each independently: H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted

heterocycloalkyl-alkyl, optionally substituted cycloalkyl-alkyl,

or R ^la and R ^lb taken together form an optionally substituted 4- to 7- membered heterocyclic ring.

[0096] In some embodiments, R ^la and R ^lb are each independently an optionally substituted alkyl, wherein the alkyl may be optionally substituted with one to three of hydroxyl, carboxy, amino, sulfonyl, sulfo, alkoxy, C ₂ _ ₄ carboxyalkoxy, C ₂ _ ₄ alkoxycarbonyl, aminocarbonyl, Ci_ ₄ alkyl, and heteroaryl. In some embodiments, the amino substituted Ci_ ₄ alkyl is Ci_ ₄ alkyl substituted with an alkylcarbonylamino, N(CH ₃ ) ₂ , or NH ₂ .

[0097] In some embodiments, R ^la and R ^lb taken together form an optionally substituted 4- to 7- membered heterocyclic ring, wherein the 4- to 7- membered heterocyclic ring is optionally substituted with one to three of: OH, amino, alkyl, carboxy, and alkoxy. In some embodiments, the 4- to 7- membered heterocyclic ring optionally substituted with an alkyl is a 4- to 7- membered heterocyclic ring substituted with an alkyl, wherein the alkyl is further substituted with hydroxyl. In some embodiments, the 4- to 7- membered heterocyclic ring is optionally substituted with Ci_ ₄ alkyl further substituted with hydroxyl. In some

embodiments, the 4- to 7- membered heterocyclic ring optionally substituted with an amino is a 4- to 7- membered heterocyclic ring substituted with NH ₂ , alkylsulfonylamino, or alkylcarbonylamino. In some embodiments, the 4- to 7- membered heterocyclic ring optionally substituted with an alkoxy is a 4- to 7- membered heterocyclic ring substituted with alkoxy, wherein the alkoxy is further substituted with hydroxyl.

[0098] In some embodiments, R ^la and R ^lb are each independently: H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted

heterocycloalkyl-alkyl, optionally substituted cycloalkyl-alkyl,

or R ^la and R ^lb taken together form an optionally substituted 4- to 7- membered heterocyclic ring, wherein the 4- to 7- membered heterocyclic ring is substituted by one or

[0099] In some of these embodiments , R ^la and R ^lb are each independently:

H, Ci_6 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, oxetane, tetrahydrofuran, tetrahydropyran, azetidine, pyrrolidine, piperidine, pyrrolidone,

piperidinone, diazetidine, piperazine, morpholine, thietane, tetrahydrothiopene,

tetrahydrothiopyran, tetrahydrofuran, tetrahydropyran, thietane dioxide, tetrahydrothiopene dioxide, tetrahydrothiopyran dioxide, tetrazole, Ci_6 aralkyl, furyl-Ci-6 alkyl, thiophenyl-Ci-6 alkyl, 2H-pyrrolyl-Ci_6 alkyl, pyrrolyl-Ci-6 alkyl, oxazolyl-Ci-6 alkyl, thazolyl-Ci-6 alkyl, imidazolyl-Ci_6 alkyl, pyrazolyl-Ci_ ₆ alkyl, isoxazolyl-Ci_6 alkyl, isothiazolyl-Ci_6 alkyl,

I, 3,4-thiadiazolyl-Ci_6 alkyl, 2H-pyranyl-Ci_6 alkyl, 4-H-pranyl-Ci_6 alkyl, pyridyl-Ci-6 alkyl,

and R taken together form azetidine, pyrrolidine, piperidine, pyrrolidone, piperidinone, morpholine, diazetidine, or piperazine;

wherein each of the foregoing non-H moieties is optionally substituted with one or more unsubstituted substituents selected from the group consisting of alkyl, cycloalkyl,

[00100] In some of these embodiments , R ^la and R ^lb are each independently:

H, Ci-6 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, oxetane,

tetrahydrofuran, tetrahydropyran, azetidine, pyrrolidine, piperidine, pyrrolidone, piperidinone, diazetidine, piperazine, morpholine, thietane, tetrahydrothiopene, tetrahydrothiopyran, thietane dioxide, tetrahydrothiopene dioxide, tetrahydrothiopyran dioxide, Ci_6 aralkyl, furyl-Ci-6 alkyl, thiophenyl-Ci-6 alkyl, 2H-pyrrolyl-Ci_6 alkyl, pyrrolyl-Ci-6 alkyl, oxazolyl-Ci-6 alkyl, thazolyl-Ci-6 alkyl, imidazolyl-Ci-6 alkyl, pyrazolyl-Ci-6 alkyl, isoxazolyl-Ci-6 alkyl, isothiazolyl-Ci_6 alkyl, 1 ,3,4-thiadiazolyl- Ci_6 alkyl, 2H-pyranyl-C _1-6 alkyl, 4-H-pranyl-Ci_ ₆ alkyl, pyridyl-Ci_ ₆ alkyl, pyridazyl- Ci-6 alkyl, pyrimidyl-Ci-6 alkyl, pyrazyl-Ci_6 alkyl, l ,3,5-triazyl-Ci_6 alkyl; or,

R ^la and R ^lb taken together form azetidine, pyrrolidine, piperidine, pyrrolidone, piperidinone, morpholine, diazetidine, or piperazine;

wherein each of the foregoing non-H moieties is optionally substituted with one or more unsubstituted substituents selected from the group consisting of alkyl, cycloalkyl,

[00102] In some of these embodiments , R ^la and R ^lb are each independently:

H, Ci-6 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, oxetane, tetrahydrofuran, tetrahydropyran, azetidine, pyrrolidine, piperidine, pyrrolidone,

piperidinone, diazetidine, piperazine, morpholine, thietane, tetrahydrothiopene,

tetrahydrothiopyran, tetrahydrofuran, tetrahydropyran, thietane dioxide, tetrahydrothiopene dioxide, tetrahydrothiopyran dioxide, tetrazole, Ci_6 aralkyl, furyl-Ci-6 alkyl, thiophenyl-Ci-6 alkyl, 2H-pyrrolyl-Ci_6 alkyl, pyrrolyl-Ci-6 alkyl, oxazolyl-Ci-6 alkyl, thazolyl-Ci-6 alkyl, imidazolyl-Ci-6 alkyl, pyrazolyl-Ci-6 alkyl, isoxazolyl-Ci-6 alkyl, isothiazolyl-Ci-6 alkyl,

I , 3,4-thiadiazolyl-Ci_6 alkyl, 2H-pyranyl-Ci_6 alkyl, 4-H-pranyl-Ci_6 alkyl, pyridyl-Ci_6 alkyl, pyridazyl-Ci-6 alkyl, pyrimidyl-Ci-6 alkyl, pyrazyl-Ci_6 alkyl, l,3,5-triazyl-Ci_6 alkyl,

HCT^^- , 0 , 0 , HCT^^* , and O _{; or} ,

R ^la and R ^lb taken together form azetidine, pyrrolidine, piperidine, pyrrolidone, piperidinone, morpholine, diazetidine, or piperazine;

wherein each of the foregoing azetidine, pyrrolidine, piperidine, pyrrolidone, piperidinone, morpholine, diazetidine, or piperazine is optionally substituted with one or more of:

OH, NH ₂ , C¾, ,

^{^} -N^ HN^

\ and , \ .

[00103] In some embodiments, R ^la and R ^lb may be taken to form a 4- to 7- membered heterocyclic ring optionally substituted with one or more of OH, OR ^lc , NR ^lc R ^ld and optionally substituted alkyl, wherein R ^lc and R ^ld are each independently H, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted heterocycloalkyl.

[00104] In some embodiments, R ^la and R ^lb taken together form an azetidine ring optionally substituted by one or more of OH, OR ^lc , NR ^lc R ^ld and optionally substituted alkyl, wherein R ^lc and R ^ld are each independently H, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted heterocycloalkyl.

[00105] In some embodiments, R ^la and R ^lb taken together form a piperidine ring optionally substituted by one or more of OH, OR ^lc , NR ^lc R ^ld and optionally substituted alkyl, wherein R ^lc and R ^ld are each independently H, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted heterocycloalkyl.

[00106] In some embodiments, R ^la and R ^lb taken together form a pyrrolidine ring optionally substituted by one or more of OH, OR ^lc , NR ^lc R ^ld and optionally substituted alkyl, wherein R ^lc and R ^ld are each independently H, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted heterocycloalkyl.

[00107] In some embodiments, R ^la and R ^lb taken together form a morpholine ring optionally substituted by one or more of OH, OR ^lc , NR ^lc R ^ld and optionally substituted alkyl, wherein R ^lc and R ^ld are each independently H, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted heterocycloalkyl.

[00108] In some embodiments, R ^la and R ^lb taken together form a piperazine ring optionally substituted by one or more of OH, OR ^lc , NR ^lc R ^ld and optionally substituted alkyl, wherein R ^lc and R ^ld are each independently H, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted heterocycloalkyl.

[00111] In one embodiment, R ^la and R ^lb are each independently:

H, Ci-4 alkyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetane, tetrahydrofuran, tetrahydropyran, azetidine, pyrrolidine, piperidine, tetrahydrothiopene dioxide, C _1-4 aralkyl, pyrrolyl- Ci-4 alkyl, imidazolyl-Ci-4 alkyl, pyrazolyl-Ci-4 alkyl, pyridyl-Ci-4 alkyl,

pyridazyl-Ci-4 alkyl, pyrimidyl-Ci-4 alkyl, pyrazyl-Ci-4 alkyl; or,

R ^la and R ^lb taken together form azetidine, pyrrolidine, piperidine, morpholine, diazetidine, or piperazine;

wherein each of the foregoing non-H moieties is optionally substituted with one or more unsubstituted substituents selected from the group consisting of C _1-4 alkyl, oxetane, tetrahydrofuran, tetrahydropyran, azetidine, pyrrolidine, piperidine, pyrrolidone, piperidinone, diazetidine, piperazine, morpholine, thietane, tetrahydrothiophene, tetrahydrothiopyran, thietane dioxide, tetrahydrothiophene dioxide,

tetrahydrothiopyran dioxide, hydroxyl, OC1-4 alkyl, Ci-4 carboxyl, and N(C _1-4 alkyl)(Ci_ ₄ alkyl).

[00112] In another embodiment, R ^la and R ^lb are each independently:

H, CH ₃ , C2H5, C ₃ H7, cyclopentyl, cyclohexyl, oxetane, tetrahydrofuran, tetrahydropyran, piperidine, tetrahydrothiophene dioxide, phenyl, or pyridyl; or,

R ^la and R ^lb taken together form azetidine, pyrrolidine, morpholine, or piperazine;

wherein each of the foregoing non-H moieties is optionally substituted with one or more unsubstituted substituents selected from the group consisting of CH ₃ , C2H5, OH, OCH ₃ , OC2H5, CH2COOH, C2H4COOH, C ₃ H ₆ COOH, N(Me)(Me), N(Me)(Et),

N(Et)(Et), tetrahydrofuran, tetrahydropyran, morpholine, pyrrolidine, and pyrrolidone.

[00113] In some embodiments, at least one of R ^la and R ^lb is an unsubstituted, non-H moiety; or, R ^la and R ^lb taken together form an unsubstituted hetercyclic ring.

[00114] In other embodiments, at least one of R ^la and R ^lb is a substituted non-H moiety; or, R ^la and R ^lb taken together form a substituted hetercyclic ring.

[00115] In some embodiments, R ^la and R ^lb are each independently selected from the group consisting of H, CH ₃ , C2H5, C ₃ H7, cyclopentyl, cyclohexyl, oxetane, tetrahydrofuran, tetrahydropyran, piperidine, tetrahydrothiophene dioxide, phenyl, 2-pyridyl, 3 -pyridyl, 4- pyridyl,

[00116] In one embodiment, R ^la and R ^lb are H. In another embodiment, R ^la and R ^lb are each independently H, CH ₃ , C2H5, or C ₃ H7.

[00117] In yet another embodiment, one of R ^la and R ^lb is H, and the other of R ^la and R ^lb is

[00118] In yet another embodiment, one of R ^la and R ^lb is CH ₃ , and the other of R ^la and R HO'

HO HO HO- is HO^ "^ ^" ^ >V OH

[00119] In yet another embodiment, one of R ^la and R ^lb is H, and the other of R ^la and R ^lb is

[00120] In still another embodiment, one of R ^la and R ^lb is H, and the other of R ^la and R ^lb is

[00121] In still another embodiment, one of R ^la and R ^lb is H, and the other of R ^la and R ^lb is [00122] In another embodiment, one of R ^la and R ^lb is H, and the other of R ^la and R ^lb is

cyclopentyl, cyclohexyl, or

[00123] In yet another embodiment, one of R ^la and R ^lb is H, and the other of R ^la and R ^lb is oxetane, tetrahydrofuran, tetrahydropyran, piperidine, tetrahydrothiophene dioxide, or

[00124] In still another embodiment, R ^la and R is H, and the other of R ^la and R is phenyl,

[00125] In one embodiment, one of R ^la and R ^lb is H, and the other of R ^la and R ^lb is 2- pyridyl, 3-pyridyl, 4-pyridyl.

[00126] In some embodiments, R ^2a , R ^2b , R ^2c , and R ^2d are each independently H, halogen, C _1-4 alkyl, OC _M alkyl _, or CF ₃ . In other embodiments, R ^2a , R ^2b , R ²⁰ , and R ^2d are each

independently H, halogen, C _1-4 alkyl, OC _1-3 alkyl, or CF ₃ .

[00127] In other embodiments, R ^2a , R ^2b , R ^2c , and R ^2d are each independently H, F, CI, CH ₃ , C ₂ H ₅ , OCH ₃ , OC ₂ H ₅ , OC ₃ H ₇ , or CF ₃ . In other embodiments, R ^2a , R ^2b , R ²⁰ , and R ^2d are each independently H, F, CI, CH ₃ , C ₂ H ₅ , OCH ₃ , OC ₂ H ₅ , or CF ₃ . In still other embodiments, R ^2a , R ²⁰ , and R ^2d are each independently H or F; and, R ^2b is H, F, CI, CH ₃ , C ₂ H ₅ , OCH ₃ , or OC ₂ H5. In some exemplary embodiments:

R ^2a , R ^2b , R ^2c , and R ^2d are each H;

R ^2a , R ²⁰ , and R ^2d are each H, and R ^2b is F;

R ^2a , R ^2b , and R ^¾ are each H, and R ^2d is F;

R ^2a , R ²⁰ , and R ^2d are each H, and R ^2b is OCH ₃ ;

R ^2a , R ²⁰ , and R ^2d are each H, and R ^2b is CH ₃ ;

R ^2a , R ²⁰ , and R ^2d are each H, and R ^2b is CI;

R ^2a , R ^2b , and R ^2d are each H, and R ^¾ is F;

R ^2a and R ^2b are each F, and R ^¾ and R ^2d are each H; or,

R ^2a and R ^2c are each H, R ^2c is CI, and R ^2d is F.

[00128] In some embodiments, R ^8a , R ^8b , R ^8c , R ^8d , and R ^8e are each independently H, F, CI, Ci_4 alkyl, OCi_ ₄ alkyl, NR ⁵ R ⁶ , CF ₃ , or CN. In other embodiments, R ^8a , R ^8b , R ^8c , R ^8d , and R* are each independently F, CI, CH ₃ , CH ₂ CH ₃ , OCH ₃ , OCH ₂ CH ₃ , or CF ₃ . In still other embodiments, R ^8a and R ^8e are each independently H, F, CI, or CH ₃ ; R ^8b and R ^8d are each independently H, CI, F, CH ₃ , OCH ₃ , or CF ₃ ; and, R ^8c is H, CI, CH ₃ , or OCH ₃ . In some exemplary embodiments:

R ^8c , R ^8d , and R ^8e are each H;

R ^8d , and R ^8e are each H, and R ^8c is CI;

R ^8d , and R ^8e are each H, and R ^8c is CH ₃ ;

R ^8d , and R ^8e are each H, and R ^8c is OCH ₃ ;

R ^8d , and R ^8e are each H, and R ^8b is CI;

R ^8d , and R ^8e are each H, and R ^8b is CF ₃ ;

R ^8d , and R ^8e are each H, and R ^8b is CH ₃ ;

R ^8d , and R ^8e are each H, and R ^8b is OCH ₃ ;

R ^8d , and R ^8e are each H and R ^8b is F;

R ^8d , and R ^8e are each H, and R ^8a is CI;

R ^8d , and R ^8e are each H, and R ^8a is CH ₃ ;

and R ^8d are each H, R ^8a is F, and R ^8e is CI;

and R ^8e are each H, and R ^8b and R ^8c are each CI;

and R ^8e are each H, and R ^8a and R ^8c are each CI; or,

and R ^8d are each H, and R ^8a and R ^8e are each F.

[00129] In some embodiments, X is N. In other embodiments, X is CH.

[00130] In some embodiments of Formula I-a, R ^7a and R ^7b are each independently H or Ci_ ₃ alkyl. In one embodiment, R ^7a and R ^7b are each independently H or CH ₃ , or CH ₂ CH ₃ . In another embodiment, R ^7a and R ^7b are each independently H or CH ₃ .

[00131] In some embodiments of Formula I-a, W is CR °R . In some of these

embodiments, R ^7c and R ^7d are each independently H, Ci_ ₃ alkyl, or F. In other of these embodiments, R ^7c and R ^7d are each independently H, CH ₃ , or F. For example, R ^7c and R ^7d are both H, both CH , or both F.

[00132] In some embodiments of Formula I-a, W is O. In other embodiments, W is NR ^7a ; and, R ^7a is Ci_ ₃ alkyl, such as CH ₃

[00133] In some embodiments of Formula I-a, n is 1. In other embodiments, n is 2. In still other embodiments, n is 3. [00134] In some embodiments:

R ^la and R ^lb are each independently:

H, Ci-6 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, oxetane,

tetrahydrofuran, tetrahydropyran, azetidine, pyrrolidine, piperidine,

pyrrolidone, piperidinone, diazetidine, piperazine, morpholine, thietane,

tetrahydrothiopene, tetrahydrothiopyran, thietane dioxide, tetrahydrothiopene dioxide, tetrahydrothiopyran dioxide, Ci_6 aralkyl, furyl-Ci-6 alkyl, thiophenyl- Ci-6 alkyl, 2H-pyrrolyl-Ci_6 alkyl, pyrrolyl-Ci_6 alkyl, oxazolyl-Ci_6 alkyl, thazolyl-Ci-6 alkyl, imidazolyl-Ci-6 alkyl, pyrazolyl-Ci_6 alkyl, isoxazolyl-Ci-6 alkyl, isothiazolyl-Ci_6 alkyl, l,3,4-thiadiazolyl-Ci_6 alkyl, 2H-pyranyl-Ci_6 alkyl, 4-H-pranyl-Ci_6 alkyl, pyridyl-Ci-6 alkyl, pyridazyl-Ci_6 alkyl,

pyrimidyl-Ci-6 alkyl, pyrazyl-Ci-6 alkyl, l,3,5-triazyl-Ci_6 alkyl; or,

R ^la and R ^lb taken together form azetidine, pyrrolidine, piperidine, pyrrolidone,

piperidinone, morpholine, diazetidine, or piperazine;

wherein each of the foregoing non-H moieties is optionally substituted with one or

more unsubstituted substituents selected from the group consisting of alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, carboxyl, amino, and halogen;

R ^2a , R ^2b , R ^2c , and R ^2d are each independently H, halogen, Ci_ ₄ alkyl, OCi_ ₄ alkyl _, or CF ₃ ; and, R ^8a , R ^8b , R ^8c , R ^8d , and R ^8e are each independently H, F, CI, Ci_ ₄ alkyl, OC^ alkyl, NR ⁵ R ⁶ , CF ₃ , or CN.

[00135] In other embodiments:

R ^la and R ^lb are each independently:

H, Ci^ alkyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetane, tetrahydrofuran,

tetrahydropyran, azetidine, pyrrolidine, piperidine, tetrahydrothiophene

dioxide; Ci_ ₄ aralkyl, pyrrolyl-Ci_ ₄ alkyl, imidazolyl-Ci^ alkyl, pyrazolyl-Ci_ ₄ alkyl, pyridyl-Ci^ alkyl, pyridazyl-Ci_ ₄ alkyl, pyrimidyl-Ci_ ₄ alkyl, pyrazyl-Ci- 4 alkyl; or,

R ^la and R ^lb taken together form azetidine, pyrrolidine, piperidine, morpholine,

diazetidine, or piperazine;

wherein each of the foregoing non-H moieties is optionally substituted with one or

more unsubstituted substituents selected from the group consisting of Ci_ ₄ alkyl, oxetane, tetrahydrofuran, tetrahydropyran, azetidine, pyrrolidine,

piperidine, pyrrolidone, piperidinone, diazetidine, piperazine, morpholine, thietane, tetrahydrothiophene, tetrahydrothiopyran, thietane dioxide, tetrahydrothiophene

dioxide, tetrahydrothiopyran dioxide, hydroxyl, OC ₁ -4 alkyl, Ci-4 carboxyl, and N(C _1-4 alkyl)(Ci_4 alkyl);

R ^2a , R ^2b , R ^2c , and R ^2d are each independently H, F, CI, CH ₃ , C ₂ H ₅ , OCH ₃ , OC ₂ H ₅ , or CF ₃ ;

R ^7a and R ^7b are each independently H or C _1-3 alkyl;

R ^7c and R ^7d are each independently H, C _1-3 alkyl, or F; and,

R ^8a , R ^8b , R ^8c , R ^8d , and R ^8e are each independently F, CI, CH ₃ , CH ₂ CH ₃ , OCH ₃ , OCH ₂ CH ₃ , or CF _3.

[00136] In still other embodiments:

R ^la and R ^lb are each independently:

H, CH ₃ , C ₂ H5, C ₃ H7, cyclopentyl, cyclohexyl, oxetane, tetrahydrofuran,

tetrahydropyran, piperidine, tetrahydrothiophene dioxide, phenyl, or pyridyl;

or,

R ^la and R ^lb taken together form azetidine, pyrrolidine, morpholine, or piperazine;

wherein each of the foregoing non-H moieties is optionally substituted with one or more unsubstituted substituents selected from the group consisting of CH ₃ , C ₂ H ₅ , OH, OCH ₃ , OC ₂ H ₅ , CH ₂ COOH, C ₂ H ₄ COOH, C ₃ H ₆ COOH,

N(Me)(Me), N(Me)(Et), N(Et)(Et), tetrahydrofuran, tetrahydropyran,

morpholine, pyrrolidine, and pyrrolidone;

R ^2a , R ²⁰ , and R ^2d are each independently H or F;

R ^2b is H, F, CI, CH ₃ , C ₂ H ₅ , OCH ₃ , or OC ₂ H ₅ ;

R ^7a and R ^7b are each independently H or CH ₃ , or CH ₂ CH ₃ ;

R ^7c and R ^7d are each independently H, CH ₃ , or F;

R ^8a and R ^8e are each independently H, F, CI, or CH ₃ ;

R ^8b and R ^8d are each independently H, CI, F, CH ₃ , OCH ₃ , or CF ₃ ;

R ^8c is H, CI, CH ₃ , or OCH ₃ ; and,

X is CH.

[00137] In other embodiments,

R ^la and R ^lb are each independently selected from the group consisting of H, CH ₃ , C ₂ Hs,

C ₃ H7, cyclopentyl, cyclohexyl, oxetane, tetrahydrofuran, tetrahydropyran, piperidine,

R ^la and R ^lb taken together

R ^2a , R ^2b , R ^2c , and R ^2d are each selected from the group consisting of H, F, CI, CH ₃ , and OCH3; wherein:

R ^2a , R ^2b , R ^2c , and R ^2d are each H;

2b ·

R ^a , and R ^2d are each H, and R ^ZD is F;

R ^2a , R ^2b , and R ^¾ are each H, and R ^2d is F;

,2d 2b ·

R ^2a , R ² ", and R ^a are each H, and R ^ZD is OCH ₃ ;

_> 2d 2b ·

R ^2a , R ² ", and R ^fl are each H, and R ^D is CH ₃ ;

2b■

R ^za , and R ^2d are each H, and R ^ZD is CI;

R ^2a , R ^2b , and R ^2d are each H, and R ² " is F;

R ^ia and R ^Zb are each F, and R and R ,2 ^a d a . re each H; or,

R ^2a and R ^2c are each H, R ^c is CI, and R ^2d is F;

R ^7a and R ^7b are each independently H or CH ₃ ;

R ^7c and R ^7d are each independently H, CH ₃ , or F; wherein:

R ^7c and R ^7d are both H;

R ^7c and R ^7d are both CH ₃ ; or

R ^7c and R ^7d are both F; and,

R ^8a , R ^8b , R ^8c , R ^8d and R ^8e are each selected from the group consisting of H, F, CI, CH ₃ , OCH ₃ , and CF ₃ , wherein:

R ^8a , R ^8b , R ^8c , R ⁸ , and R ^8e are each H;

R ^8a , R ^8b , R ^8d , and R ^8e are each H, and R ^8c is CI;

8c

R ^8a , R ^8b , R ^8d , and R ^ee are each H, and R ^a is CH ₃ ; R , R , R , and R ^5e are each H, and R ^5C is OCH ₃ ;

R ^8a , R ^8c , R ^8d , and R ^8e are each H, and R ^8b is CI;

R ^8a , R ^8c , R ^8d , and R ^8e are each H, and R ^8b is CF ₃ ;

R ^8a , R ^8c , R ^8d , and R ^8e are each H, and R ^8b is CH ₃ ;

R ^8a , R ^8c , R ^8d , and R ^8e are each H, and R ^8b is OCH ₃ ;

R ^8a , R ^8c , R ^8d , and R ^8e are each H and R ^8b is F;

R ^8b , R ^8c , R ^8d , and R ^8e are each H, and R ^8a is CI;

R ^8b , R ^8c , R ^8d , and R ^8e are each H, and R ^8a is CH ₃ ;

R ^8b , R ^8c , and R ^8d are each H, R ^8a is F, and R ^8e is CI;

R ^8a , R ^8d , and R ^8e are each H, and R ^8b and R ^8c are each CI;

R ^8b , R ^8d , and R ^8e are each H, and R ^8a and R ^8c are each CI; or,

R ^8b , R ^8c , and R ^8d are each H, and R ^8a and R ^8e are each F.

[00138] In one embodiment, R ^la and R ^lb are each H. In another embodiment, R ^la and R ^lb are each independently H, CH ₃ , C2H5, or C ₃ H7.

[00139] In yet another embodiment, one of R ^la and R ^lb is H, and the other of R ^la and R ^lb is

00140 In one embodiment, one of R ^la and R ^lb is H, and the other of R ^la and R ^lb is

[00141] In another embodiment, one of R ^la and R ^lb is H, and the other of R ^la and R ^lb is

cyclopentyl, cyclohexyl, or .

[00142] In another embodiment, one of R ^la and R ^lb is H, and the other of R ^la and R ^lb is oxetane, tetrahydrofuran, tetrahydropyran, piperidine, tetrahydrothiophene dioxide, or

[00143] In yet another embodiment, one of R ^la and R ^lb is H, and the other of R ^la and R ^lb is phenyl,

[00144] In still another embodiment, one of R ^la and R ^lb is H, and the other of R ^la and R ^lb is 2-pyridyl, 3-pyridyl, 4-pyridyl.

[00146] In some embodiments:

R ^la and R ^lb are each independently H or CH ₃ ;

R ^2a , R ²⁰ , and R ^2d are each H;

R ^2b is CI;

R ^7a and R ^7b are each H;

W is CR ^7c R ^7d ;

R ^7c and R ^7d are each H;

R ^8a , R ^8b , R ^8c , R ^8d and R ^8e are each selected from the group consisting of H, F, CI, CH ₃ , OCH ₃ , and CF ₃ ;

X is CH; and,

n is 2.

[00147] In some embodiments, the compound is a compound of Formula I-b, wherein:

R ^la and R ^lb are each independently H, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl;

R ^2a , R ^2b , R ^2c , and R ^2d are each independently H, halogen, C _M alkyl, OC _M alkyl, or CF ₃ ; R ³ are each independently H, or optionally substituted alkyl;

R ⁷ are each independently H, F, or optionally substituted alkyl;

R ^8a , R ^8b , R ^8c , R ^8d , and R ^8e are each independently H, F, CI, optionally substituted alkyl, or

OR ⁴ ; or any 2 adjacent groups of R ^a , R and R ⁰ together form a 4 to 7 membered optionally substituted cycloalkyl ring or a 4 to 7 membered optionally substituted heterocycloalkyl ring; wherein R ⁴ is optionally substituted alkyl, optionally substituted cycloalkyl or optionally substituted heterocycloalkyl; and

X is CH.

[00148] In some embodiments, the compound is a compound of Formula I-b, wherein:

R ^la and R ^lb are each independently H;

R ^2a , R ^2b , R ^2c , and R ^2d are each independently H, or halogen;

R ³ are each independently H, or optionally substituted alkyl;

R ⁷ are each independently H, F, or optionally substituted alkyl;

R ^8a , R ^8b , R ^8c , R ^8d , and R ^8e are each independently H, F, CI, optionally substituted alkyl, or OCi-4 alkyl optionally substituted with halogen;

or any 2 adjacent groups of R ^8a , R ^8b and R ^8c together form a 4 to 7 membered optionally substituted cycloalkyl ring or a 4 to 7 membered optionally substituted heterocycloalkyl ring; and

X is CH.

[00149] In some embodiments, the compound of Formula I-a can be a compound as shown in Table 1 or a pharmaceutically acceptable salt thereof.

Table 1. Exem lar Embodiments of the Com ound of Formula I-a

-y enzam e

D

4-chloro-3-(l-(2-chloro-6-fluorobenzoyl)-l, 2,3,4- tetrahydroquinolin-6-yl)-N-methylbenzamide

D

-chloro-4'-(2-chloro-6-fluoro-N-methylbenzamido)-3'-ethox y- [l,l'-biphenyl]-3-carboxamide

B

4-chloro-3-(l-(2-chloro-6-fluorobenzoyl)-l, 2,3,4- tetrahydroquinolin-6-yl)-N,N-dimethylbenzamide

D

4-chloro-3-(l-(2-chloro-6-fluorobenzoyl)-l, 2,3,4- tetrahydroquinolin-6-yl)-N-(2-hydroxyethyl)benzamide

D

4-chloro-3-(l-(2-chloro-6-fluorobenzoyl)-l, 2,3,4- tetrahydroquinolin-6-yl)-N-cyclopentylbenzamide A

(4-chloro-3-(l-(2-chloro-6-fluorobenzoyl)-l,2,3,4- tetrahydroquinolin-6-yl)phenyl)(morpholino)methanone

B

(4-chloro-3-(l-(2-chloro-6-fluorobenzoyl)-l,2,3,4- tetrahydroquinolin-6-yl)phenyl)(4-methylpiperazin- 1 - yl)methanone

B

4-chloro-3-(l-(2-chloro-6-fluorobenzoyl)-l, 2,3,4- tetrahydroquinolin-6-yl)-N-(2-methoxyethyl)benzamide

B

4-chloro-3-(l-(2-chloro-6-fluorobenzoyl)-l, 2,3,4- tetrahydroquinolin-6-yl)-N-(3-hydroxy-2,2- dimethylpropyl)benzamide

C

4-chloro-3-(l-(2-chloro-6-fluorobenzoyl)-l, 2,3,4- tetrahydroquinolin- 6-yl)-N- (3 -hydroxy- 3 - methylbutyl)benzamide

tetra y roquno n- -y - - - y roxypropy enzam e

[00150] In the foregoing Table 1, IC ₅₀ data is represented as follows: greater than or equal to 10 microMolar is designated at A; less than 10 microMolar but greater than or equal to 1 microMolar is designated as B; less than 1 microMolar but greater than or equal to 500 nanoMolar is designated at C; less than 500 nanoMolar but greater or equal to 100 nanoMolar is designated as D; less than 100 nanoMolar is designated at E. Methods for the determination of the IC ₅₀ data of Table 1 are provided in the description of Assay 1 below. [00151] In some embodiments, the compound of Formula I-a can include:

or a pharmaceutically acceptable salt thereof.

[00152] In various embodiments, R ³ is H, optionally substituted alkyl, optionally substituted cycloalkyl, OR ⁴ , halogen, SR ⁴ , S(0) ₂ R ⁴ , NR ⁵ R ⁶ , an optionally substituted heteroaryl, or an optionally substituted heterocycloalkyl.

[00153] In still further embodiments, R ³ is H, optionally substituted alkyl, OR ⁴ , halogen, SR ⁴ , S(0) ₂ R ⁴ , NR ⁵ R ⁶ , or an optionally substituted heterocycloalkyl.

[00154] In still further embodiments, R ³ is H, optionally substituted alkyl, OR ⁴ , halogen, or NR ⁵ R ⁶ , SR ⁴ , S(0) ₂ R ⁴ , or an optionally substituted heterocycloalkyl; and, R ⁷ is alkyl.

[00155] In some embodiments, R ³ is H, optionally substituted alkyl, OR ⁴ , halogen, NR ⁵ R ⁶ , SR ⁴ , S(0) ₂ R ⁴ or an optionally substituted heterocycloalkyl; and, R ⁷ is alkyl. In some of these embodiments, R ³ is H, optionally substituted alkyl, halogen, NR ⁵ R ⁶ , SR ⁴ , S(0) ₂ R ⁴ or an optionally substituted heterocycloalkyl.

[00156] In one embodiment of this aspect, R ³ is H, optionally substituted alkyl, halogen, or NR ⁵ R ⁶ .

[00157] In another aspect, R ³ is H, optionally substituted alkyl, optionally substituted heteroaryl, OR ⁴ , halogen, NR ⁵ R ⁶ , SR ⁴ , S(0) ₂ R ⁴ , or an optionally substituted

heterocycloalkyl; and R ⁷ is alkyl.

[00158] In one embodiment of this aspect, R ⁴ is an optionally substituted alkyl or an optionally substituted cycloalkyl.

[00159] In another embodiment, R ⁴ is alkyl, which is optionally substutued with halogen, aryl, heteroaryl, heterocycloalkyl, or cycloalkyl.

[00160] In another embodiment, R ⁴ is cycloalkyl which is optionally substituted with halogen, alkyl, halogen, aryl, heteroaryl, heterocycloalkyl, or cycloalkyl.

[00161] In a further embodiment, R ⁴ is selected from the group consisting of ^ ,

[00162] In another embodiment of this aspect, R ³ is optionally substituted alkyl, optionally substituted heteroaryl, NR ⁵ R ⁶ , or an optionally substituted heterocycloalkyl.

[00163] In a further embodiment, R ³ is an optionally substituted alkyl.

[00164] In one embodiment, R ³ is methyl, ethyl, propyl, isopropyl, butyl, t-butyl, or pentyl.

[00165] In still a further embodiment, R ³ is -CD ₃ .

[00166] In another embodiment of this aspect, R ³ is NR ⁵ R ⁶ , and wherein R ⁵ and R ⁶ are each independently optionally substituted alkyl.

[00167] In a further embodiment, R ³ is NR ⁵ R ⁶ , wherein R ⁵ and R ⁶ are each independently methyl, ethyl, propyl, isopropyl, butyl, t-butyl, or pentyl, each of which is optionally substituted with halogen.

[00169] In one embodiment this aspect, R ³ is an optionally substituted heterocycloalkyl.

[00170] In a further embodiment, R ³ is an optionally substituted monocyclic

heterocycloalkyl, selected from the group consisting of azetidyl, pyrollidyl, piperidyl, morpholyl, piperazyl, tetrahydrofuranyl, each of which is optionally substituted with halogen, cyano, oxo, -CF ₃ , alkyl, and cycloalkyl.

[00171] In still a further embodiment, R ³ is selected from the group consisting of

[00172] In another embodiment, R ³ is an optionally substituted bicyclic heterocycloalkyl.

[00174] In another embodiment of this aspect, R ³ is an optionally substituted heteroaryl.

[00175] In a further embodiment, R ³ is an optionally substutued pyrollyl, pyrazolyl, immidazolyl, pyridyl, pyrazyl, furanyl, thiophenyl, and thiazolyl. In a further embodiment, the pyrollyl, pyrazolyl, immidazolyl, pyridyl, pyrazyl, furanyl, thiophenyl, and thiazolyl is optionally substituted with halogen.

[00176] In still a further embodiment, R ³ is

[00177] In some embodiments, R ^la and R ^lb are each independently H, Ci_6 alkyl, C1-7 cycloalkyl, or Ci_6 aralkyl; wherein each of the foregoing non-H moieties is optionally substituted with one or more unsubstituted substituents selected from the group consisting of alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, carboxyl, amino, and halogen.

[00178] In other embodiments, R ^la and R ^lb are each independently H or Ci^ alkyl; wherein the Ci-4 alkyl is optionally substituted with one or more unsubstituted substituents selected from the group consisting of C1-3 alkyl, hydroxyl, and OC1-3 alkyl.

[00179] In still other embodiments, R ^la and R ^lb are each independently H or unsubstituted Ci-3 alkyl. In other embodiments, R ^la and R ^lb are each H.

[00180] In some embodiments, R ^2a , R ^2b , R ^2c , and R ^2d are each independently H, halogen, C1-4 alkyl, OC^ alkyl _, or CF ₃ . In other embodiments, R ^2a , R ^2b , R ²⁰ , and R ^2d are each

independently F, CI, CH ₃ , C ₂ H ₅ , OCH ₃ , OC ₂ H ₅ , or CF ₃ . In still other embodiments, R ^2a , R ^2c , and R are each independently H; and, R is H, F, or CI. In some exemplary embodiments, R ^2a , R ²⁰ , and R ^2d are each H; and, R ^2b is CI.

[00181] In some embodiments, R ³ is H, C1-4 alkyl, or halogen; wherein the C1-4 alkyl is optionally substituted with one or more unsubstituted substituents selected from the group consisting of C1-3 alkyl, halogen, hydroxyl, alkoxyl, carboxyl, and amino.

[00182] In other embodiments, R ³ is C1-3 alkyl, F, CI, or Br; wherein the C1-3 alkyl is optionally substituted with one or more unsubstituted substituents selected from the group consisting of C1-2 alkyl, halogen, hydroxyl, OC1-3 alkyl, carboxyl, and amino.

[00183] In still other embodiments, R ³ is CH ₃ , C ₂ H ₅ , CF ₃ , F, CI or Br; wherein the CH ₃ and C2H5 are each optionally substituted with one or more halogen.

[00184] In some exemplary embodiments, R ³ is CH ₃ , C2H5 _, CF ₃ , F, CI, or Br.

[00185] In some exemplary embodiments, R ³ is NR ⁵ R ⁶ , SR ⁴ , S(0) ₂ R ⁴ or an optionally substituted heterocycloalkyl.

[00186] In some embodiments, R ⁷ is Ci_6 alkyl. In other embodiments, R ⁷ is C1-4 alkyl. In still other embodiments, R ⁷ is C1-3 alkyl. In some exemplary embodiments, R ⁷ is CH ₃ or

[00187] In some embodiments, R ^8a , R ^8b , R ^8c , R ^8d , and R ^8e are each independently H, halogen, Ci_4 alkyl, OCi_ ₄ alkyl, NR ⁵ R ⁶ , CF ₃ , or CN. In other embodiments, R ^8a , R ^8b , R ^8c , R ^8d , and R ^8e are each independently H, F, CI, CH ₃ , C ₂ H ₅ , OCH ₃ , OC ₂ H ₅ , or CN. In still other

embodiments, R ^8a and R ^8e are each independently H, F, or CI; R ^8b and R ^8d are each independently H, F, OCH ₃ , or CN; and, R ^8c is H, F, or CI. In some exemplary embodiments:

R ^8a , R ^8c , R ^8d , and R ^8e are each H, and R ^8b is CN;

R ^8a , R ^8c , R ^8d , and R ^8e are each H, and R ^8b is OCH ₃ ;

R ^8b , R ^8c , and R ^8d are each H, and R ^8a and R ^8e are each F or CI;

R ^8b , R ^8d , and R ^8e are each H, R ^8a is CI, and R ^8c is F; or

R ^8b and R ^8e are each H, R ^8a and R ^8d are each F, and R ^8c is CI.

[00188] In some embodiments, J is a bond or CH2.

[00189] In some embodiments:

R ^la and R ^lb are each independently H, Ci_6 alkyl, C1-7 cycloalkyl, or Ci_6 aralkyl; wherein each of the foregoing non-H moieties is optionally substituted with one or more unsubstituted substituents selected from the group consisting of alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, carboxyl, amino, and halogen;

R ^2a , R ^2b , R ^2c , and R ^2d are each independently H, halogen, Ci_ ₄ alkyl, OCi_ ₄ alkyl _, or CF ₃ ; R ³ is H, CM alkyl, halogen, or NR ⁵ R ⁶ ;

wherein the C _1-4 alkyl is optionally substituted with one or more unsubstituted

substituents selected from the group consisting of C _1-3 alkyl, halogen,

hydroxyl, alkoxyl, carboxyl, and amino

R ⁷ is Ci-6 alkyl; and,

R ^8a , R ^8b , R ^8c , R ^8d , and R ^8e are each independently H, halogen, Ci_ ₄ alkyl, OC _M alkyl, NR ⁵ R ⁶ , CF ₃ , or CN.

[00190] In other embodiments:

R ^la and R ^lb are each independently H or C _1-4 alkyl;

wherein the C _1-4 alkyl is optionally substituted with one or more unsubstituted

substituents selected from the group consisting of C _1-3 alkyl, hydroxyl, and

Od_ ₃ alkyl;

R ^2a , R ^2b , R ^2c , and R ^2d are each independently F, CI, CH ₃ , C ₂ H ₅ , OCH ₃ , OC ₂ H ₅ , or CF ₃ ;

R ³ is C 1-3 alkyl, F, CI, or Br;

wherein the C _1-3 alkyl is optionally substituted with one or more unsubstituted

substituents selected from the group consisting of C _1-2 alkyl, halogen,

hydroxyl, OCi_ ₃ alkyl, carboxyl, and amino;

R ⁷ is Ci_ ₄ alkyl;

R ^8a , R ^8b , R ^8c , R ^8d , and R ^8e are each independently H, F, CI, CH ₃ , C ₂ H ₅ , OCH ₃ , OC ₂ H ₅ , or CN; and,

J is a bond or CH ₂ .

[00191] In still other embodiments:

R ^la and R ^lb are each independently H or unsubstituted C _1-3 alkyl;

R ^2a , R ²⁰ , and R ^2d are each independently H;

R ^2b is H, F, or CI;

R ³ is CH ₃ , C ₂ H ₅ , CF ₃ , F, CI or Br; wherein the CH ₃ and C2H5 are each optionally substituted with one or more halogen;

R ⁷ is Ci_3 alkyl;

R ^8a and R ^8e are each independently H, F, or CI;

R ^8b and R ^8d are each independently H, F, OCH ₃ , or CN; and,

R ^8c is H, F, or CI.

In some exemplary embodiments:

R ^la and R ^lb are each H;

R ^2a , R ^¾ , and R ^2d are each H;

R ^2b is CI;

R ³ is CH ₃ , C ₂ H _5, CF ₃ , F, CI, or Br;

R ⁷ is CH ₃ or C ₂ H ₅ ; and,

R ^8a , R ^8b , R ^8c , R ^8d and R ^8e are each selected from the group consisting of H, CN, OCH ₃ , F, and CI wherein:

R ^8a , R ^8c , R ^8d , and R ^8e are each H, and R ^8b is CN;

R ^8a , R ^8c , R ^8d , and R ^8e are each H, and R ^8b is OCH ₃ ;

R ^8b , R ^8c , and R ^8d are each H, and R ^8a and R ^8e are each F or CI;

R ^8b , R ^8d , and R ^8e are each H, R ^8a is CI, and R ^8c is F; or

R ^8b and R ^8e are each H, R ^8a and R ^8d are each F, and R ^8c is CI.

[00192] In some embodiments, R ³ is OR ⁴ .

[00193] In some embodiments, R ^la and R ^lb are each independently H, Ci_6 alkyl, C1-7 cycloalkyl, or Ci_6 aralkyl; wherein each of the foregoing non-H moieties is optionally substituted with one or more unsubstituted substituents selected from the group consisting of alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, carboxyl, amino, and halogen.

[00194] In other embodiments, R ^la and R ^lb are each independently H or Ci^ alkyl; wherein the Ci-4 alkyl is optionally substituted with one or more unsubstituted substituents selected from the group consisting of C1-3 alkyl, hydroxyl, and OC1-3 alkyl.

[00195] In still other embodiments, R ^la and R ^lb are each independently H or unsubstituted Ci-3 alkyl. In yet other embodiments, R ^la and R ^lb are each H.

[00196] In some embodiments, R ^2a , R ^2b , R ^2c , and R ^2d are each independently H, halogen, C1-4 alkyl, OCi_ ₃ alkyl _, or CF ₃ . In other embodiments, R ^2a , R ^2b , R ²⁰ , and R ^2d are each

independently F, CI, CH ₃ , C ₂ H ₅ , OCH ₃ , OC ₂ H ₅ , or CF ₃ . In still other embodiments, R ^2a , R ^2c , and R are each independently H; and, R is H, F, or CI. In some exemplary embodiments, R ^2a , R ²⁰ , and R ^2d are each H; and, R ^2b is CI.

[00197] In some embodiments, R ⁴ is C1-5 alkyl; wherein the C1-5 alkyl is optionally substituted with: one or more unsubstituted substituents selected from the group consisting of halogen, C1-4 alkyl, C1-4 alkoxy, cycloalkyl, and heterocycloalkyl; or substituted heterocycloalkyl.

[00198] In other embodiments, R ⁴ is C1-4 alkyl; wherein the C1-4 alkyl is optionally substituted with: one or more unsubstituted substituents selected from the group consisting of CI, F, Ci-2 alkyl, C1-2 alkoxy, cyclopropyl, cyclobutyl, cyclopentyl, oxetane, and tetrahydrofuran; substituted oxetane; or substituted tetrahydrofuran.

[00199] In still other embodiments, R ⁴ is C1-4 alkyl; wherein the Ci^ alkyl is optionally substituted with: one or more unsubstituted substituents selected from the group consisting of F, CH ₃ , OCH ₃ , cyclopropyl, cyclobutyl, and oxetane; or substituted oxetane.

[00200] In some exemplary embodiments, R ⁴ is CH ₃ , C2H5,

[00201] In some embodiments, R ⁷ is Ci_6 alkyl. In other embodiments, R ⁷ is C1-4 alkyl. In still other embodiments, R ⁷ is C1-3 alkyl. In some exemplary embodiments, R ⁷ is CH ₃ or

[00202] In some embodiments, R ^8a , R ^8b , R ^8c , R ^8d , and R ^8e are each independently H, halogen, Ci_4 alkyl, OCi_ ₄ alkyl, NR ⁵ R ⁶ , CF ₃ , or CN. In other embodiments, R ^8a , R ^8b , R ^8c , R ^8d , and R ^8e are each independently H, F, CI, CH ₃ , C ₂ H ₅ , OCH ₃ , OC ₂ H ₅ , or CN. In still other

embodiments, R ^8a and R ^8e are each independently H, F, or CI; R ^8b and R ^8d are each independently H, F, OCH ₃ , or CN; and R ^8c is H, F, or CI. In some exemplary embodiments:

R ^8a , R ^8c , R ^8d , and R ^8e are each H, and R ^8b is CN;

R ^8a , R ^8c , R ^8d , and R ^8e are each H, and R ^8b is OCH ₃ ;

R ^8b , R ^8c , and R ^8d are each H, and R ^8a and R ^8e are each F or CI;

R ^8b , R ^8d , and R ^8e are each H, R ^8a is CI, and R ^8c is F; or R and R ^5e are each H, R and R are each F, and ^c is CI.

[00203] In some embodiments, J is a bond. In other embodiments, J is a Ci_ ₄ alkylene.

[00204] In some embodiments:

R ^la and R ^lb are each independently H, Ci_6 alkyl, C1-7 cycloalkyl, or Ci_6 aralkyl;

wherein each of the foregoing non-H moieties is optionally substituted with one or

more unsubstituted substituents selected from the group consisting of alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, carboxyl, amino, and halogen;

R ^2a , R ^2b , R ^2c , and R ^2d are each independently H, halogen, Ci_ ₄ alkyl, OCi_ ₃ alkyl _, or CF ₃ ; R ⁴ is Ci_5 alkyl;

wherein the C1-5 alkyl is optionally substituted with: one or more unsubstituted

substituents selected from the group consisting of halogen, Ci_ ₄ alkyl, Ci^

alkoxy, cycloalkyl, and heterocycloalkyl; or substituted heterocycloalkyl;

R ⁷ is Ci_6 alkyl;

R ^8a , R ^8b , R ^8c , R ^8d , and R ^8e are each independently H, halogen, Ci_ ₄ alkyl, OC _M alkyl, NR ⁵ R ⁶ , CF ₃ , or CN; and,

J is a bond.

[00205] In other embodiments:

R ^la and R ^lb are each independently H or Ci_ ₄ alkyl;

wherein the Ci_ ₄ alkyl is optionally substituted with one or more unsubstituted

substituents selected from the group consisting of C1-3 alkyl, hydroxyl, and

Od_ ₃ alkyl;

R ^2a , R ^2b , R ^2c , and R ^2d are each independently F, CI, CH ₃ , C ₂ H ₅ , OCH ₃ , OC ₂ H ₅ , or CF ₃ ;

R ⁴ is Ci_ ₄ alkyl;

wherein the Ci_ ₄ alkyl is optionally substituted with: one or more unsubstituted

substituents selected from the group consisting of CI, F, Ci_ ₂ alkyl, Ci_ ₂

alkoxy, cyclopropyl, cyclobutyl, cyclopentyl, oxetane, and tetrahydrofuran;

substituted oxetane; or substituted tetrahydrofuran;

R ⁷ is Ci_ ₄ alkyl; and,

R ^8a , R ^8b , R ^8c , R ^8d , and R ^8e are each independently H, F, CI, CH ₃ , C ₂ H ₅ , OCH ₃ , OC ₂ H ₅ , or CN. [00206] In still other embodiments:

R ^la and R ^lb are each independently H or unsubstituted C _1-3 alkyl;

R ^2a , R ²⁰ , and R ^2d are each independently H;

R ^2b is H, F, or CI;

R ⁴ is Ci_4 alkyl;

wherein the C _1-4 alkyl is optionally substituted with: one or more unsubstituted

substituents selected from the group consisting of F, CH ₃ , OCH ₃ , cyclopropyl, cyclobutyl, and oxetane; or substituted oxetane;

R ⁷ is Ci_3 alkyl;

R ^8a and R ^8e are each independently H, F, or CI;

R ^8b and R ^8d are each independently H, F, OCH ₃ , or CN; and,

R ^& is H, F, or CI.

[00207] In some exemplary embodiments:

R ^la and R ^lb are each H;

R ^2a , R ²⁰ , and R ^2d are each H;

2 ^b is CI;

R ⁷ is CH ₃ or C ₂ H ₅ ; and,

R ^8a , R ^8b , R ^8c , R ^8d and R ^8e are each selected from the group consisting of H, CN, OCH ₃ , F, or CI wherein:

R ^8a , R ^8c , R ^8d , and R ^8e are each H, and R ^8b is CN;

R ^8a , R ^8c , R ^8d , and R ^8e are each H, and R ^8b is OCH ₃ ;

R ^8b , R ^8c , and R ^8d are each H, and R ^8a and R ^8e are each F or CI;

R ^8b , R ^8d , and R ^8e are each H, R ^8a is CI, and R ^8c is F; or

R ^8b and R ^8e are each H, R ^8a and R ^8d are each F, and R ^8c is CI.

[00208] In some embodiments, the compound of Fonnula I is a compound as shown in Table 2 or a pharmaceutically acceptable salt thereof, the compound of Formula I-b is a compound as shown in Table 3 or a pharmaceutically acceptable salt thereof, the compound of Formula II is a compound shown in Tables 4 and 5 or a pharmaceutically acceptable salt thereof.

[00208] Table 2. Exemplary Embodiments of the Compound of Formula I

N-(5-(5-carbamoyl-2-chlorophenyl)-3-(3-

or a pharmaceutically acceptable salt thereof.

Table 3. Exem lar Embodiments of the Com ound of Formula I-b:

463 A

6-chloro-4'-(2-fluoro-N,3-dimethylbenzamido)-3'- (trifluoromethyl)- [1,1 '-biphenyl] -3-carboxamide

464 A

6-chloro-3'-(trifluoromethyl)-4'-(N,2,3-trimethylbenzamid o)- [1,1 '-biphenyl] -3-carboxamide

465 A

N-(5'-carbamoyl-2'-chloro-3-(trifluoromethyl)-[l, - biphenyl]-4-yl)-N-methyl-2,3-dihydrobenzofuran-7- carboxamide

or a pharmaceutically acceptable salt thereof.

Table 4. Exemplary Embodiments of the Compound of Formula II:

80

82

83

84

85

89

94

96

100

101

102

105

108

110 Table 5. Exem lary Embodiments of the Compounds of Formula II:

Example # Structure ICso (μΜ)

285 D

286 E

287 E

288 E

289 E Example # Structure ICso (μΜ)

310 E

311 E

312 E

313 E

314 E

Example # Structure ICso (μΜ)

315 E

316 E

317 D

318 E

319 E Example # Structure ICso (μΜ)

325 E

0 C,

326 E

327 E

328 E

329 E Example # Structure ICso (μΜ)

330 E

331 E

332 E

333 E

334 E Example # Structure ICso (μΜ)

335 E

336 E

337 E

338 E

339 E

Example # Structure ICso (μΜ)

344 E

345 E

346 E

347 E o ci

348 E Example # Structure ICso (μΜ)

349 E

350 E

351 E

352 E

353 E Example # Structure ICso (μΜ)

354 E

355 E

356 E

0 CI

357 E

358 E Example # Structure ICso (μΜ)

359 E

360 E

361 E

362 E

363 E

0 C, Example # Structure ICso (μΜ)

369 E

CI

370 D

H ₂ N j^ i ⁱ

371 E

0 C,

372 E

373 E

0 CI Example # Structure ICso (μΜ)

384 D

385 D

386 D

387 E

388 E Example # Structure ICso (μΜ)

399 E

400 E

401 E

402 E

403 E Example # Structure ICso (μΜ)

404 E

405 E

406 E

407 E

408 E Example # Structure ICso (μΜ)

409 E

410 E

411 E

412 C

413 E

Example # Structure ICso (μΜ)

429 D

430 D

431 E

432 E Example # Structure ICso (μΜ)

441 E

442 E

443 E

444 E

445 E Example # Structure ICso (μΜ)

446 E

447 E

448 E

449 E

450 E

Example # Structure ICso (μΜ)

451 E

452 E

453 D

OH

454 E

455 E

[00209] In the foregoing Tables 2-5, IC ₅₀ data is represented as follows: greater than or equal to 10 microMolar is designated at A; less than 10 microMolar but greater than or equal to 1 microMolar is designated as B; less than 1 microMolar but greater than or equal to 500 nanoMolar is designated at C; less than 500 nanoMolar but greater or equal to 100 nanoMolar is designated as D; less than 100 nanoMolar is designated at E. Methods for the determination of the IC ₅₀ data of Tables 2-5are provided in the description of Assay 1 below.

[00210] In some embodiments, the compound of Formula I or Formula II can include:

or a pharmaceutically acceptable salt thereof.

[00211] In some embodiments of the compounds of Formula II, one or both of the R ³ or R ⁷ substituents contain at least one deuterium. [00212] In a further embodiment of the compounds of Formula II, both the R ³ and R ⁷ substituents each contain at least one deuterium.

[00213] In some embodiments of the compounds of Formula II, the R ⁷ substituent is alkyl, and wherein the alkyl contains at least one deuterium.

[00214] In further embodiments of the compounds of Formula II, the R ⁷ substituent is methyl, and wherein the methyl contains at least one deuterium.

[00215] In still further embodiments of the compounds of Formula II, the R ⁷ substituent is - CD ₃ .

[00216] In some embodiments of the compounds of Formula II, the R ³ substituent is optionally substituted alkoxy or optionally substituted heterocycloalkyl, and wherein the R substituent contains at least one deuterium.

[00217] In a further embodiments of the compounds of Formula II, the R ³ substituent is 2- methylpropoxy, 2,2-dimethylpropoxy, cyclopropylmethoxy, cyclobutylmethoxy, pyrollidinyl, or piperidinyl, and wherein the R substituent contains at least one deuterium.

[00218] In still a further embodiments of the compounds of Formula II, the R ³ substituent is selected from:

[00219] In some embodiments of the compounds of Formula II, the compound of Formula II is selected from the group consisting of:

159

160

162

163

164

165

166

167

168

169

171

172

173

174

176

177

180

181

182

183

184

185

186

189

190

SUBSTITUTE SHEET (RLILE 26)

191

192

193

194

or a pharmaceutically acceptable salt thereof.

[00220] In a further embodiment of the compounds of Formula II, the compound is selected from the group consisting of:

196

198

199

200

202

, or a pharmaceutically acceptable salt thereof.

[00221] In some embodiments of the compounds of Formula II, the compound has the Formula Ila:

or a pharmaceutically acceptable salt thereof.

Formula Ila

[00222] In some embodiments of the compounds of Formula Ila, the compound has the Formula Ila^

Formula Ilai

or a pharmaceutically acceptable salt thereof.

[00223] In still a further embodiments of the compounds of Formula II, the compound is Compound 240:

Compound 240

or a pharmaceutically acceptable salt thereof.

[00224] In some embodiments of the compounds of Formula II, the compound has the Formula lib:

Formula lib

or a pharmaceutically acceptable salt thereof.

[00225] In a further embodiments of the compounds of Formula II, the compound has the Formula Hb^

Formula Ilbi

or a pharmaceutically acceptable salt thereof.

[00226] In still a further embodiments of the compounds of Formula II, the compound is Compound 241:

Compound 241

or a pharmaceutically acceptable salt thereof.

[00227] In some embodiments of the compounds of Formula II, the compound has the Formula lie:

Formula lie or a pharmaceutically acceptable salt thereof.

[00228] In a further embodiments of the compounds of Formula II, the compound is Compound 242:

Compound 242

or a pharmaceutically acceptable salt thereof.

[00229] In some embodiments of the compounds of Formula II, the compound has the Formula lid:

Formula lid

or a pharmaceutically acceptable salt thereof.

[00230] In a further embodiments of the compounds of Formula II, the compound has the Formula Ildi:

Formula Ildi or a pharmaceutically acceptable salt thereof.

[00231] In some embodiments of the compounds of Formula II, the compound has the Formula He:

Formula He

or a pharmaceutically acceptable salt thereof,

wherein R ^7e is CH ₃ or CD ₃ .

[00232] In some embodiments of the compounds of Formula II, the compound has the Formula Ilf:

Formula Ilf

or a pharmaceutically acceptable salt thereof.

[00233] In some embodiments of the compounds of Formula II, the compound has the Formula Ilg:

Formula Ilg

or a pharmaceutically acceptable salt thereof.

[00234] In some embodiments of the compounds of Formula II, the compound has the Formula Hgi:

Formula Ilgi

or a pharmaceutically acceptable salt thereof.

[00235] In some embodiments of the compounds of Formula II, and Formula He, the compound is selected from the group consisting of:

210

212

or a pharmaceutically acceptable salt thereof.

[00236] In some embodiments of the compounds of Formula II, the compound is selected from the group consisting of:

SUBSTITUTE SHEET (RLILE 26)

217

or a pharmaceutically acceptable salt thereof.

[00237] In some embodiments of the compounds of Formula II, the compound is selected from the group consisting of:

445

448

or a pharmaceutically acceptable salt thereof.

[00238] In some embodiments of Formula II, R ¹⁰ is NR ^la R ^lb , R ³ is OR ⁴ or optionally substituted heterocycloalkyl and R is an optionally substituted alkyl. In some embodiments of Formula II, R ¹⁰ is NR ^la R ^lb wherein NR ^la R ^lb is NH ₂ or, wherein at least one of R ^la R ^lb is H and the other of R ^la R ^lb is optionally substituted alkyl, R ³ is optionally substituted heterocycloalkyl or OR ⁴ , wherein R ⁴ is optionally substituted alkyl or an optionally substituted cycloalkyl, and R is CH ₃ , CF or CD . In some embodiments, at least one position on R 3 and R 7 may have a deuterium atom replacing an H atom. In some

embodiments, R ³ is OR ⁴ , wherein R ⁴ is optionally substituted alkyl. In some embodiments, R ³ is OR ⁴ , wherein R ⁴ is optionally substituted cycloalkyl. In some embodiments, R ³ is optionally substituted heterocycloalkyl. In some embodiments, at least one position on R

7 Q

and R may have a deuterium atom replacing an H atom. In some embodiments, R is a

7

deuterated heterocycloalkyl. In some embodiments, R is CD ₃ .

[00239] In some embodiments of Formula II, when B is ₅ and J is C _1-4 alkylene R ¹⁰ is not hydroxyl. In other embodiments of Formula II, J is a bond and R ¹⁰ is NR ^la R ^lb , hydroxyl, or optionally substituted alkyl. In some embodiments of Formula II, B is

, J is a bond, or a C _1-4 alkylene, and R ¹⁰ is NR ^la R ^lb , hydroxyl, or optionally substituted alkyl.

[00240] In some embodiments of Formula II, R ¹⁰ is NR ^la R ^lb , or hydroxyl.

[00241] In some embodiments of Formula II, R ¹⁰ is OH. In other embodiments, R ¹⁰ is NR ^la R ^lb . In still further embodiments of Formula II, R ¹⁰ is NR ^la R ^lb . In some embodiments, R is a hydroxyl, amino or an optionally substituted alkyl when bonded to a -(S0 ₂ )- group. In some embodiments, R ¹⁰ is NH ₂ .

[00242] In some embodiments of Formula II, R ⁷ is methyl. In other embodiments, R ⁷ is

7 7

ethyl. In other embodiments, R is propyl. In other embodiments, R is butyl.

[00243] In some embodiments of Formula II, R ^la or R ^lb is N-methylazetidin-3-yl, 2- methoxy-2-methylpropyl, 2-hydroxy-2-methylpropyl, and 2-hydroxyethyl. In other embodiments, one of R ^la or R ^lb is H and the other of R ^la or R ^lb is N-methylazetidin-3-yl, 2- methoxy-2-methylpropyl, 2-hydroxy-2-methylpropyl, and 2-hydroxyethyl.

[00244] In some embodiments of Formula II, X ¹ is CH. In other embodiments, X ¹ is N. In some embodiments, X ² is C-R ^2a . In other embodiments, X ² is N. In some embodiments, X ³ is C-R ^2b . In other embodiments, X ³ is N. In some embodiments, X ⁴ is C-R ^2d . In other embodiments, X ⁴ is N. In some embodiments, X ⁵ is O. In other embodiments, X ⁵ is S. In some embodiments of Formula II, X ⁶ is C-R ^2b . In some embodiments, X ⁷ is C-R ^2b .

[00245] In some embodiments of Formula II, R ⁴ is alkoxyalkyl, cycloalkylalkyl, haloalkyl, a bicyclic cycloalkyl, heterocycloalkyl, or cycloalkyl.

[00246] In some embodiments of Formula II, R ⁴ is 2-methoxyethyl, cyclopentylmethyl, 2- fluoropropyl, bicyclo[3.1.0]hexane-3-yl, tetrahydrofuran-3-yl, pyran-4-yl, 2,2- dimethylpropyl, or cyclobutyl.

[00247] In some embodiments of Formula II, R ³ is heteroaryl, haloheteroaryl,

alkylheteroaryl, monocyclic heterocycloalkyl, bicyclic heterocycloalkyl, bridged bicyclic heterocycloalkyl, haloheterocycloalkyl, haloalkylheterocycloalkyl, alkoxyheterocycloalkyl, alkylheterocycloalkyl, monocyclic cycloalkyl, bicyclic cycloalkyl,

(halo)(alkoxy)heterocycloalkyl, or hydroxyheterocycloalkyl.

[00248] In some embodiments of Formula II, R ³ is 4-fluoropyrazol-l-yl, 8-oxa-3- azabicyclo[3.2.1]octane-3-yl, 3-trifluoromethylazetidine-l-yl, 7-oxa-2- azabicyclo[3.1.1]heptane-2-yl, 4-chloropyrazol-l-yl, 2-oxa-6-azaspiro[3.3]heptane-6-yl, 3- fluoroazetidine- 1-yl, 2,2-difluoropyrolidin- 1-yl, 2-oxa-5-azabicyclo[2.2. l]heptane-5-yl, piperidin-l-yl, pyrolidin-l-yl, pyrazole-l-yl, morpholin-3-one-l-yl, 3-methoxyazetidine-l-yl, 3,3-difluoroazetidine-l-yl, 3,3-difluoropyrolidine-l-yl, 3-azabicyclo[3.1.0]hexane-3-yl, 3- fluoro-4-methoxypyrolidine-l-yl, 4-methylpyrazol-l-yl, 4-fluoropiperidine-l-yl, 2- azabicyclo[3.1.0]hexane-2-yl, 2,6-dimethylmorpholin-l-yl, 4-methylpiperazine-l-yl, 4- hydroxypiperidine-l-yl, 4-fluoropiperidine-l-yl, 4,4-difluoropiperidine-l-yl, thiomorpholine-

I- yl, pyran-4-yl, or tetrahydrofuran-2-yl.

[00249] In another aspect, the invention includes pharmaceutically acceptable salts of the compound of Formula I, Formaula I-a, Formula I-b, Formula II, Formula Il-kl and Formula

II- k2 such as pharmaceutically acceptable salts of the compounds of Table 1, Table 2,Table 3, Table 4, and Table 5.

Formulations, Administrations, and Uses

[00250] In another aspect, the invention includes a pharmaceutical composition comprising a compound of Formula I, Formula II, Formula II-ki and Formula II-k ₂ or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or adjuvant. In some embodiments of this aspect, the invention includes pharmaceutically acceptable salts of the compounds of Table 1, Table 2, Table 3, Table 4, or Table 5. In some other embodiments of this aspect, the invention includes a pharmaceutical composition comprising a compound of Table 1, Table 2, Table 3, Table 4, or Table 5, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or adjuvant.

[00251] The present invention includes within its scope pharmaceutically acceptable prodrugs of the compounds of the present invention. A "pharmaceutically acceptable prodrug" means any pharmaceutically acceptable salt, ester, salt of an ester, or other derivative of a compound of the present invention which, upon administration to a recipient, is capable of providing (directly or indirectly) a compound of this invention or an active metabolite or residue thereof. In some embodiments, the prodrugs increase the

bioavailability of the compounds of this invention when such compounds are administered to a mammal or which enhance delivery of the parent compound to a biological compartment relative to the parent species.

[00252] The term "pharmaceutically acceptable carrier, adjuvant, or vehicle" refers to a nontoxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose- based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.

[00253] Pharmaceutically acceptable salts of the compounds of this invention include those derived from pharmaceutically acceptable inorganic and organic acids and bases. Examples of suitable acid salts include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate,

glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hydrochloride,

hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, salicylate, succinate, sulfate, tartrate, thiocyanate, tosylate and undecanoate. Other acids, such as oxalic, while not in themselves pharmaceutically acceptable, may be employed in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their

pharmaceutically acceptable acid addition salts.

[00254] Salts derived from appropriate bases include alkali metal (e.g., sodium and potassium), alkaline earth metal (e.g., magnesium), ammonium and N ⁺ (C _1-4 alkyl) ₄ salts. This invention also envisions the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Water or oil-soluble or dispersible products may be obtained by such quaternization.

[00255] The compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intra- articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. In some embodiments, the compositions are administered orally, intraperitoneally or intravenously. Sterile injectable forms of the compositions of this invention may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium.

[00256] For this purpose, any bland fixed oil may be employed including synthetic mono- or di-glycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions. Other commonly used surfactants, such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation. [00257] The pharmaceutically acceptable compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.

[00258] Alternatively, the pharmaceutically acceptable compositions of this invention may be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols.

[00259] The pharmaceutically acceptable compositions of this invention may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.

[00260] Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically- transdermal patches may also be used.

[00261] For topical applications, the pharmaceutically acceptable compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water.

Alternatively, the pharmaceutically acceptable compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol,

2-octyldodecanol, benzyl alcohol and water.

[00262] For ophthalmic use, the pharmaceutically acceptable compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with or without a preservative such as benzylalkonium chloride. Alternatively, for ophthalmic uses, the pharmaceutically acceptable compositions may be formulated in an ointment such as petrolatum.

[00263] The pharmaceutically acceptable compositions of this invention may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.

[00264] In some exemplary embodiments, the pharmaceutically acceptable compositions of this invention are formulated for oral administration.

[00265] The amount of the compounds of the present invention that may be combined with the carrier materials to produce a composition in a single dosage form will vary depending upon the host treated and the particular mode of administration. In some embodiments, the compositions should be formulated so that a dosage of between about 0.01 to about 100 mg/kg body weight/day of the modulator can be administered to a patient receiving these compositions.

[00266] It should also be understood that a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated. The amount of a compound of the present invention in the composition will also depend upon the particular compound in the composition.

[00267] Depending upon the particular condition, or disease, to be treated or prevented, additional therapeutic agents, which are normally administered to treat or prevent that condition, may also be present in the compositions of this invention. As used herein, additional therapeutic agents that are normally administered to treat or prevent a particular disease, or condition, are known as "appropriate for the disease, or condition, being treated."

Methods

[00268] The compound of Formula I, Formula I-a, Formula I-b, Formula II, Formula Il-ki and Formula II-k ₂ , or a pharmaceutically acceptable salt thereof, can inhibit the activity of an ROR-gamma receptor. For example, the compound of Formula I, Formula I-a, Formula I-b, Formula II, Formula Il-ki and Formula II-k ₂ , or a pharmaceutically acceptable salt thereof can inhibit the activity of an ROR-gamma receptor in vitro. The compound of Formula I, Formula I-a, Formula I-b, or Formula II, Formula Il-ki and Formula II-k ₂ , also can inhibit the activity of an ROR-gamma receptor in vivo.

[00269] In one aspect, thus, the invention includes a method of inhibiting the activity of an ROR-gamma receptor, comprising contacting the receptor with a compound of Formula I, Formula I-a, Formula I-b, Formula II, Formula Il-ki, Formula II-k ₂ or a pharmaceutically acceptable salt thereof. In one embodiment of this aspect, the compound of Formula I, Formula I-a, Formula I-b, or Formula II, Formula Il-ki, or Formula II-k ₂ , or a

pharmaceutcally acceptable salt thereof, inhibits the activity of an ROR-gamma receptor in vitro. In another embodiment, the compound of Formula I, Formula I-a, Formula I-b, Formula II, or a pharmaceutically acceptable salt thereof, inhibits the activity of an ROR- gamma receptor in vivo. In some embodiments, the compound of Formula I, Formula I-a, Formula I-b, Formula II, Formula Il-ki, Formula II-k _2> or pharmaceutically acceptable salt thereof is an inverse agonist of the ROR-gamma receptor.

[00270] In another aspect, the invention includes a method of treating or reducing the severity of an ROR-gamma receptor mediated disease in a patient comprising administering a compound of Formula I, Formula I-a, Formula I-b, Formula II, Formula Il-ki, Formula II-k _2> or a pharmaceutically acceptable salt thereof, to a patient in need thereof.

[00271] In another aspect, the invention includes a method of treatment of inflammatory diseases that associated with the overexpression or up regulation of "type- 17"

proinflammatory cytokines including IL-17a, IL-17f, IL-22, IL-26, IL-21 and GMCSF.

[00272] In one embodiment, an ROR-gamma receptor mediated disease can include an automimmune disease. In some embodiments, an autoimmune disease is selected from the group consisting of Ankylosing spondylitis, Asthma, Behcet's disease, Chronic obstructive pulmonary disease, Crohn's disease, Diabetes Mellitus Type 1, Multiple Sclerosis,

Neuromyelitis optica, Polymyalgia Rheumatica, Psoriasis, Psoriatic Arthritis, Rheumatoid Arthritis, Scleroderma, Sjogren's syndrome, Systemic Lupus Erythematosus, Systemic sclerosis, Transplant rejection, Inflammatory Bowel Disease, Ulcerative Colitis and Uveitis.

[00273] In another aspect, the invention includes a method of modulating the activity of an ROR-gamma receptor with an inverse agonist, comprising contacting the receptor with a compound of Formula I, Formula I-a, Formula I-b, Formula II, Formula II-k ₁ , Formula II-k ₂ , or a pharmaceutically acceptable salt thereof. In one embodiment of this aspect, the compound of Formula I, Formula I-a, Formula I-b, Formula II, Formula Il-lq, Formula II-k ₂ , or a pharmaceutically acceptable salt thereof modulates the activity of an ROR-gamma receptor in vitro. In another embodiment, the compound of Formula I, Formula I-a, Formula I-b, Formula II, or a pharmaceutically acceptable salt thereof modulates the activity of an ROR-gamma receptor in vivo. In one embodiment, the compound of Formula I, Formula I-a, Formula I-b, or Formula II, is an inverse agonist of the ROR-gamma receptor.

[00274]

Synthetic Procedures

[00275] The compounds of Formula I, Formula I-a, Formula I-b, or Formula II, Formula II- k _1; Formula II-k ₂ may be readily synthesized from commercially available starting materials using methods known in the art. Exemplary synthetic routes to produce compounds of Formula I, Formula I-a, Formula I-b, Formula II, Formula Il-ki, or Formula II-k _2> are provided in the general schemes and examples below. The general schemes and examples below are given to provide a better understanding of the synthetic procedures of the invention and are not meant to be limiting in any way.

General Scheme I: Synthesis of Compounds of Formula I or Formula II when R 3 and R 7 are taken together to form an optionally substituted 4- to 7-membered heterocyclic ring.

Formula l-a

[00276] Some compounds of Formula I or Formula II may be synthesized utilizing the process outlined in General Scheme I. The commercially available or synthesized bromo- intermediate I.l is first acylated with a variety of acid chloride 1.2 to form the amide 1.3. Treatment of 1.3 under Suzuki coupling conditions with boronic acid 1.4a affords the advanced acid Intermediate L5. The carboxylic acid functional group in L5 is further converted to an. acid chloride, which subsequently reacts with suitable amino-reagents 1,6 to provide compounds of Formula 1-a. Alternatively, intermediate 1.3 can react with amide boronic acid 1.4b directly under Suzuki coupling conditions to afford compounds of Formula

l b

I -a where R ^5:i and R ' ^:, are both hvdroeen

General Scheme 11: Synthesis of Compounds of Formula I or Formula Ii when i Is Π. aikyi. substituted alkyl haloeen, or NR 5 ^" rRvf>

Formuia i-b

(00277] Some compounds of Formula I or Formula II, where R ³ and R ^'' are not joined together to form a fully saturated heterocyclic ring system, can be synthesized according to General Scheme II. The general synthetic process is very similar to that described in General Scheme I. As a first step, the anilno-brouio intermediate ΪΙ.Ϊ is acylaied using an acid chloride Ϊ.2 to generate a secondary amide 11.2. The amide nitrogen is further alkylated with

2?9 a suitable halide under basic condition to provide intermediate II.3. Upon treatment of this intermediate with boronic acid I.4b under Suzuki coupling condition, compounds of Formula I-b is obtained where R ^la and R ^lb are both hydrogen. When boronic acid 1.4a is used, the Suzuki coupling reaction will result in the formation of an acid intermediate II.5; this acid is further converted to an acid chloride, and reacts with a variety of amines to provide compounds of Formula I-b.

General Scheme III: Synthesis of Compounds of Formula I or Formula II when R ³ is OR ⁴ .

Formula l-c

[00278] For some compounds of Formula I or Formula II, the synthetic route described in General Scheme III can be applied. The aryl amino-alcohol intermediate III.l is acylated at the amino group to provide intermediate III.2. Any bis-acylated by product can be converted to the desired mono-acylated compound III.2 after a simple hydrolysis upon treatment of aqueous NaOH (IN) at room temperature. The hydroxyl group in III.2 is then

chemo selectively alkylated to form III.3 with either a halide (R ⁴ X) or an electrophile with a suitable leaving group in place (R ⁴ -lvg). Under Suzuki coupling conditions, using boronic acid I.4b, compounds of formula I-c where R ^la and R ^lb are hydrogen is synthesized from intermediate III.3. Similarly as in General Scheme I and II, intermediate III.3 can be converted to an acid intermediate III.5 after treatment with boronic acid I.4a under Suzuki coupling conditions. The acid intermediate III.5 is further transformed to an acid chloride which subsequently reacts with suitable amines to provide compounds of Formula I-c.

[00279] The amidation of acid intermediates such as 1.5 (General Scheme I), II.5 (General Scheme II), III.5 (General Scheme III), can also be accomplished under common coupling conditions such as HOBt, amines and mild base.

Examples

[00280] Example 1: Synthesis of 3-(l-(2-chloro-6-fluorobenzoyl)-l,2,3,4- tetrahydroquinolin-6-yl)-4-fluorobenzamide

Ex.1

[00281] Step 1. To a stirred solution of 6-bromo-tetrahydroquinoline 1-A (5 g, 23.7 mmol) in 100 mL of CH ₂ CI ₂ at room temperature was added triethyl amine (2.8 g, 27.7 mmol) followed by 2-chloro-6-fluorobenzoyl chloride 1-B (4.6 g, 23.7 mmol). The reaction mixture was stirred for 3 h, then diluted with H ₂ 0 (50 mL). The organic phase was separated, washed with brine (50 mL), dried over anhydrous Na ₂ S0 ₄ , and concentrated in vacuo to give amide 1-C as a grayish solid (7.6 g, 86%). LC-MS: m/z = 368.0 [M+H] ⁺ .

[00282] Step 2. To a mixture of 1-C (150 mg, 0.41 mmol), obtained from step 1 above, with Pd(dppf)Cl ₂ (34 mg, 0.041 mmol) and K ₂ C0 ₃ (170 mg, 1.23 mmol) in 5 mL of dioxane and 1 mL of H ₂ 0 was added 5-carbamoyl-2-fluorophenylboronic acid 1-D (90 mg, 0.49 mmol). The resulting mixture was heated at 90 ^° C under a nitrogen atmosphere for 24 h. After cooling, the mixture was diluted with H ₂ 0 (20 mL), and extracted with EtOAc (20 mL x 3). The combined organic extracts were washed with brine (20 mL), dried over anhydrous Na ₂ S0 ₄ , and concentrated. The residue was purified by preparative TLC to provide the titled compound as a white solid (82 mg, 47%). 1H NMR (300 MHz, CD ₃ OD): δ 8.26 - 7.76 (m, 2H), 7.71 - 6.94 (m, 6H), 6.78 - 6.75 (m, 1H), 4.07 - 3.58 (m, 2H), 3.00 - 2.90 (m, 2H), 2.21 - 1.96 (m, 2H). HPLC = 100% (214 nm), 100% (254 nm), t _R = 6.14 min. LC-MS: m/z = 427.1 [M+H] ⁺ .

[00283] Example 2: Synthesis of 3-(l-(2-chloro-6-fluorobenzoyl)-l,2,3,4- tetrahydroquinolin-6-yl)-benzamide

[00284] To a mixture of 1-C (150 mg, 0.41 mmol), obtained from step 1 above, with Pd(dppf)Cl ₂ (34 mg, 0.041 mmol) and K ₂ C0 ₃ (113 mg, 0.82 mmol) in 5 mL of DMF was added 3-carbamoyl-phenylboronic acid 2-A (69 mg, 0.45 mmol). The resulting mixture was heated at lOO C under microwave condition for 1 h. Solvent was removed in vacuo, the residue was purified by preparative TLC and preparative HPLC to provide the titled compound as a colorless solid (30 mg, 17.9%). 1H NMR (300 MHz, CD ₃ OD): δ 8.17 - 6.63 (m, 10H), 3.93 - 3.51 (m, 2H), 2.96 - 2.85 (m, 2H), 2.11 - 1.83 (m, 2H). HPLC = 100% (214 nm), 100% (254 nm), t _R = 4.17 min. LC-MS: m/z = 409.1 [M+H] ⁺ .

[00285] Example 3: Synthesis of 5-(l-(2-chloro-6-fluorobenzoyl)-l,2,3,4- tetrahydroquinolin-6-yl)-2-fluorobenzamide

[00286] To a stirred mixture of intermetidate 1-C (0.1 g, 0.28 mmol), Pd(dppf)Cl ₂ (0.024 g, 0.03 mmol), and K ₂ C0 ₃ (0.082 mg, 0.59 mmol) in 5 mL of DMF was added 3-carbamoyl-4- fluorophenyl boronic acid (0.054 mg, 0.28 mmol). The mixture was heated overnight at 100°C. Solvent was removed in vacuo, and the residue was purified by preparative TLC and preparative HPLC to provide the titled compound as a colorless solid (33 mg, 27.7%). 1H NMR (300 MHz, CD ₃ OD): δ 8.06 - 6.92 (m, 9H), 3.97 - 3.48 (m, 2H), 2.89 - 2.80 (m, 2H), 2.08 - 1.93 (m, 2H). HPLC = 98.9% (214 nm), 98.6% (254 nm), t _R = 6.49 min. LC-MS: mJz = 427.1 [M+H] ⁺ .

[00287] Example 4: Synthesis of 3-(l-(2-chloro-6-fluorobenzoyl)-l,2,3,4- tetrahydroquinolin-6-yl)-2,4-difluorobenzamide

[00288] Step 1. A stirred mixture of amide 1-C (0.5 g, 1.4 mmol), 4,4,4',4 ^, ,5,5,5 ^, ,5'- octamethyl-2,2'-bi(l,3,2-dioxaborolane) (0.38 g, 1.5 mmol), Pd(dppf)Cl ₂ (0.11 g, 0.14 mmol) and NaOAc (0.335 g, 4.1 mmol) in 10 mL of dioxane and 2 mL of H ₂ 0 was heated at 80°C under nitrogen overnight. The mixture was diluted with H ₂ 0, extracted with EtOAc (20 mL x 3). The combined extracts were washed with brine (20 mL), dried over Na ₂ S0 ₄ , then concentrated. The residue was purified by column chromatography eluting with PE/EA (10: 1, v/v) to provide boronic ester 4-A as a yellowish solid (0.5 g, 85%). LC-MS: m/z = 416.1 [M+H] ⁺ .

[00289] Step 2. To a stirred mixture of boronic ester 4-A (0.12 g, 0.29 mmol), Pd(dppf)Cl ₂ (47 mg, 0.06 mmol) and Na ₂ C0 ₃ in 8 mL of dioxane and 2 mL of H ₂ 0 was added 3-bromo- 2,4-difluorobenzoic acid 4-B (68 mg, 0.29 mmol). The mixture was heated at 80°C under nitrogen overnight. Solid materials were filtered, the filtrate was basified with a 3N aqueous NaOH solution (10 mL) and washed with EtOAc (20 mL x 3). The combined organic layers were dried over anhydrous Na ₂ S0 ₄ , concentrated to provide the acid 4-Cas a yellowish solid (100 mg, 78%). LC-MS: m/z = 446.1 [M+H] ⁺ .

[00290] Step 3. To a solution of the acid 4-C (100 mg, 0.22 mmol) in 15 mL of anhydrous CH ₂ C1 ₂ was added oxalyl chloride (57 mg, 0.45 mmol). The mixture was stirred at room temperature for 2h, then added with NH H ₂ 0 (10 mL). Reaction mixture was stirred for a further 2 h, and then concentrated. The residue was purified by preparative TLC to provide the titled compound as a colorless solid (60 mg, 60%). 1H NMR (300 MHz, CD ₃ OD): δ 8.09 - 6.65 (m, 8H), 4.02 - 3.48 (m, 2H), 2.88 - 2.78 (m, 2H), 2.09 - 1.91 (m, 2H); HPLC = 100% (214 nm), 100% (254 nm), t _R = 6.26 min. LC-MS: m/z = 445.1 [M+H] ⁺ .

[00291] Example 5: Synthesis of 3-(l-(2-chloro-6-fluorobenzoyl)-l,2,3,4- tetrahydroquinolin-6-yl)-4-methoxy benzamide

[00292] A mixture of boronic ester 4-A (0.15 g, 0.36 mmol), 3-bromo-4-methoxybenzamide (0.091 g, 0.4 mmol), Pd(dppf)Cl ₂ (0.029 g, 0.036 mmol) and K ₂ C0 ₃ (0.335 g, 4.1 mmol) in 10 mL of DMF was heated at 85°C with stirring overnight. H ₂ 0 was added (20 mL), the mixture was extracted with EtOAc (20 mL x 3). The combined extracts were washed with brine (20 mL), dried over anhydrous Na ₂ S0 ₄ , and concentrated. The residue was purified by preparative TLC to give the titled compound as a colorless solid (0.06 g, 38%). 1H NMR

(300 MHz, d ₆ -DMSO): δ 8.25 - 6.75 (m, 9H), 6.68 - 6.50 (m, 1H), 4.09 - 3.67 (m, 3H), 3.58 - 3.48 (m, 2H), 2.92 - 2.73 (m, 2H), 2.06 - 1.92 (m, 2H). HPLC = 98.6% (214 nm), 99.7% (254 nm), t _R = 4.12 min. LC-MS: m/z = 439.0 [M+H] ⁺ .

[00293] Example 6: Synthesis of 3-(l-(2-chloro-6-fluorobenzoyl)-l,2,3,4- tetrahydroquinolin-6-yl)-4-methyl benzamide

[00294] Following the procedure described in Example 5, by substituting bromo-benzamide 5-A with 6-A (150 mg), the titled compound was obtained as a colorless solid (40 mg, 26%). ¹ H NMR (300 MHz, CD ₃ OD): δ 8.37 - 6.46 (m, 9H), 4.11 - 3.57 (m, 2H), 2.99 - 2.88 (m, 2H), 2.39 - 2.03 (m, 5H). HPLC = 99.8% (214 nm), 99.8% (254 nm), t _R = 4.19 min. LC-MS: m/z = 423.0 [M+H] ⁺ .

[00295] Example 7: Synthesis of 4-chloro-5-(l-(2-chloro-6-fluorobenzoyl)-l,2,3,4- tetrahydroquinolin-6-yl)-2-fluorobenzamide

[00296] Following the procedure described in Example 5, by substituting bromo-benzamide 5-A with 7-A (130 mg), the titled compound was obtained as a colorless solid (13 mg, 10%). 1H NMR (300 MHz, CD ₃ OD): δ 8.18 - 6.65 (m, 8H), 4.09 - 3.58 (m, 2H), 2.98 - 2.89 (m, 2H), 2.30 - 2.02 (m, 2H). HPLC = 100% (214 nm), 100% (254 nm), t _R = 6.98 min. LC-MS: m/z = 461.1 [M+H] ⁺ .

[00297] Example 8: Synthesis of 4-chloro-3-(l-(2-chloro-6-fluorobenzoyl)-l,2,3,4- tetrahydroquinolin-6-yl)benzamide

[00298] Step 1. To a stirred mixture of amine 8-A (0.44 g, 1.59 mmol) and H ₂ S0 ₄ (0.78 g, 7.96 mmol) in 20 mL of H ₂ 0 was added dropwise a solution of NaN0 ₂ (0.16 g, 2.34 mmol) in 5 mL of H ₂ 0 at -10°C. A solution of KI (0.8 g, 4.82 mmol) in H20 (5mL) was added dropwise. The suspension was filtered, and the filter cake was dissolved in EtOAc (20 mL). The organic solution was washed with brine (10 mL), dried over anhydrous Na ₂ S0 ₄ , and then concentrated. The residue was purified by column chromatography, eluting with PE/EA (10: 1, v/v) to afford the iodo intermediate 8-B as a yellow oil (0.25 g, 66%). 1H NMR (300 MHz, CDC1 ₃ ): δ 7.62 - 7.26 (m, 2H), 7.04 - 6.99 (m, 1H), 3.76 - 3.69 (m, 2H), 1.77 - 1.70 (m, 2H), 1.53 - 1.52 (m, 9H), 1.29 (d, J = 1.5 Hz, 6H).

[00299] Step 2. To a stirred solution of iodo intermediate 8-B (0.16 g, 0.41 mmol)in 5 mL of EtOAC was added dropwise a Sat. solution of HC1 in EtOAc (5 mL) at 0C. The reaction progress was monitored by TLC. Once the reaction was complete, the mixture was quenched by a Sat. NaHC0 ₃ aqueous solution, extracted with EtOAc (20 mL x 3). The combined organic extracts were concentrated; the residue was dissolved in 10 mL of CH2C12, treated with triethyl amine (0.12 g, 1.23 mmol) and 2-chloro-6-fluorobenzoyl chloride 1-B (0.12 g, 0.62 mmol). The mixture was stirred at room temperature for 2h, then diluted with EtOAc (20 mL), washed with H ₂ 0 (10 mL), brine (10 mL), dried over anhydrous Na ₂ S0 ₄ . Removal of solvent afforded amide 8-C a colorless oil (0.15 g, 82%). 1H NMR (300 MHz, CD ₃ OD): δ 7.99 - 6.33 (m, 6H), 4.18 - 3.53 (m, 2H), 1.96 - 1.82 (m, 2H), 1.38 - 1.31 (m, 6H). [00300] Step 3. Following a procedure similar to Step 2, Example 1, the iodo amide intermediate 8-C (150 mg, 0.34 mmol) was converted to the titled compound (50 mg, 31%, colorless solid) with Pd(dppf)Cl ₂ (56 mg, 0.07 mmol), 5-carbamoyl-2-chlorophenyl boronic acid 8-D (68 mg, 0.34 mmol), and Na ₂ C0 ₃ (73 mg, 0.68 mmol) in 10 mL of dioxane and 2 mL of H ₂ 0. 1H NMR (300 MHz, CD ₃ OD): δ 8.13 - 6.66 (m, 9H), 4.24 - 3.60 (m, 2H), 2.03 - 1.92 (m, 2H), 1.43 - 1.39 (m, 6H); HPLC = 100% (214 nm), 100% (254 nm), t _R = 3.44 min. LC-MS: m/z = 471.1 [M+H] ⁺ .

[00301] Example 9: Synthesis of 4-chloro-3-(l-(2-chloro-6-fluorobenzoyl)-4,4-difluoro- l,2,3,4-tetrahydroquinolin-6-yl)benzamide

EX.9

[00302] Following the procedures set forth in preparative example 8, by using l-Boc-4,4- difluoro amino tetrahydroquinoline 9-A, the titled compound was obtained as a colorless solid. 1H NMR (300 MHz, CD ₃ OD): δ 8.41 - 6.76 (m, 9H), 4.35 (t, J = 5.9 Hz, 1H), 3.84 (t, J = 5.9 Hz, 1H), 2.75 - 2.51 (m, 2H). HPLC = 100% (214 nm), 100% (254 nm), t _R = 4.55 min. LC-MS: m/z = 479.1 [M+H] ⁺ .

[00303] Example 10: Synthesis of 4-chloro-3-(4-(2-chloro-6-fluorobenzoyl)-3,4-dihydro- 2H-benzo[b][l,4]oxazin-7-yl)benzamide

EX.10

[00304] Following the procedures set forth in preparative example 1, by using 7-bromo-3,4- dihydro-2H-benzo[b][l,4]oxazine 10-A, the titled compound was obtained as a colorless solid. 1H NMR (300 MHz, CD ₃ OD): δ 8.43 - 7.74 (m, 3H), 7.65 - 7.36 (m, 3H), 7.32 - 7.22 (m, 1H), 7.17 - 7.01 (m, 2H), 6.66 - 6.51 (m, 1H), 4.61 - 4.09 (m, 3H), 3.79 - 3.67 (m, 1H). HPLC = 100% (214 nm), 100% (254 nm), t _R = 6.62 min. LC-MS: m/z = 445.0 [M+H] ⁺ .

[00305] Example 11: Synthesis of 4-chloro-3-(l-(2-chloro-6-fluorobenzoyl)indolin-5- yl)benzamide

EX.1 1

[00306] Following the procedures set forth in preparative example 1, by using 5-bromo- indoline 11-A, the titled compound was obtained as a colorless solid. 1H NMR (300 MHz, CD ₃ OD): δ 8.29 - 5.88 (m, 9H), 4.35 - 3.87 (m, 2H), 3.26 - 2.31 (m, 2H). HPLC = 99.9% (214 nm), 99.8% (254 nm), t _R = 7.38 min. LC-MS: m/z = 429.1 [M+H] ⁺ .

[00307] Example 12: Synthesis of 4-chloro-3-(l-(2,6-difluorobenzoyl)indolin-5- yl)benzamide

EX.12

[00308] Following the procedures set forth in preparative example 1, by using 5-bromo- indoline 11-A in step 1 and 2,6-difluorobenzoic acid chloride in step 2, the titled compound was obtained as a colorless solid. 1H NMR (300 MHz, DMSO-d6): δ 8.23 (d, J = 8.3, 1H), 8.11 (br, s, 1H), 7.94-7.83 (m, 2H), 7.71-7.59 (m, 2H), 7.50-7.27 (m, 5H), 3.94 (t, J = 8.3, 2H), 3.23 (t, J = 8.3, 2H). LC-MS: m/z = 413.0 [M+H] ⁺ .

[00309] Example 13: Synthesis of 4-chloro-3-(l-(2-chloro-6-fluorobenzoyl)-2-methyl- 1,2,3,4- tetrahydroquinolin-6-yl)benzamide

[00310] Step 1. To a stirred solution of compound 13-A (2.5 g, 17 mmol) in 30 mL of CHCI ₃ was added Br2 (5.4 g, 17 mmol) dropwise. The mixture was stirred at room temperature for 3 h. Solvent was removed under reduced pressure, and the residue was washed with EtOAc (20 mL x 3) to provide a crude product of 13-B as a yellowish solid (4.5 g), used in the next step directly. 1H NMR (300 MHz, CD ₃ OD): δ 7.38 (m, 3H), 3.55 - 3.49 (m, 2H), 2.97 - 2.85 (m, 2H), 1.45 - 1.37 (m, 3H); LC-MS: m/z = 226.1 [M+H] ⁺ .

[00311] Step 2. Following the procedure described in preparative example 1, step 1, the bromo intermediate 13-B (1 g, 3.3 mmol) was converted to the amide 13-C (1.2 g, 95%) after reacting with acid chloride 1-B.

[00312] Step 3. Following the procedure set forth in preparative example 3, the amide intermediate 13-B (0.12 g, 0.31 mmol) was reacted with boronic acid 8-D to give the titled compound as a colorless solid (0.03 g, 21%). 1H NMR (300 MHz, CD ₃ OD): δ 7.98 - 6.65 (m, 9H), 4.92 - 4.00 (m, 1H), 3.20 - 2.45 (m, 3H), 1.74 - 1.02 (m, 4H). HPLC = 99.6% (214 nm), 99.6% (254 nm), t _R = 4.48 min. LC-MS: m/z = 457.1 [M+H] ⁺ .

[00313] Example 14: Synthesis of 4-chloro-3-(l-(2-chloro-6-fluorobenzoyl)-3, 3- dimethyl-l,2,3,4-tetrahydroquinolin-6-yl)benzamide

[00314] Step 1. To a stirred solution of 2,2-dimethyl malonic acid 14-A (3.0 g, 22.7 mmol) in 40 mL of THF was added SOCl ₂ (3.2 g, 27.2 mmol). The mixture was heated at reflux for 2 h and cooled in an ice bath. 4-Bromobenzenamine (7.7 g, 45.4 mmol) was added drop wise and the reaction mixture was stirred at room temperature for 2 h. Solvent was removed under reduced pressure. 50 mL of EtOAc was added, the mixture was extracted with aqueous NaOH (1.0 M, 50 mL x 3). The combined aqueous extracts were acidified with concentrated aqueous hydrochloric acid, extracted with EtOAc (80 mL x 3). The organic extracts were combined, washed with brine and concentrated in vacuo to afford 14-B as a colorless solid (4.2 g, 65%). 1H NMR (300 MHz, CD ₃ OD): δ 7.40 - 7.31 (m, 4H), 1.41 (s, 6H). LC-MS: m/z = 286.1 [M+H] ⁺ .

[00315] Step 2. Intermediate 14-B (1.0 g, 3.5 mmol) was added to a stirred solution of P205 (0.3 g, 2.1 mmol) in 10 mL of methane sulfonic acid under a nitrogen atmosphere. The mixture was heated at 70C overnight. After cooling to room temperature, the mixture was poured into ice water (50 mL) and extracted with EtOAc (40mL x 2). The organic extracts were washed with brine, dried over anhydrous Na2S04, and concentrated to give

intermediate 14-C as a colorless solid (0.5 g, 54%). 1H NMR (300 MHz, CD ₃ OD): δ 7.83 (d, J = 2.3 Hz, 1H), 7.60 - 7.57 (m, 1H), 6.91 (d, J = 8.6 Hz, 1H), 1.33 (s, 6H). LC-MS: m/z = 268.0 [M+H] ⁺ .

[00316] Step 3. A mixture of lithium aluminum hydride (0.142 g, 3.74 mmol) and aluminum chloride (0.54 g, 4.14 mmol) in 20 mL of THF was stirred vigorously for 20 minutes at room temperature. A solution of intermediate 14-C (0.5 g, 1.87 mmol) in THF (10 mL) was added slowly to the above mixture during a 10 minutes period. The mixture was stirred overnight at room temperature, and then heated at reflux for 16 h. After cooling to room temperature, the mixture was quenched carefully with H ₂ 0 while cooling in an ice bath. Stirring was continued for 10 min. A 1.0 M NaOH aqueous solution (8 mL) was added. The resulting aqueous mixture was extracted with EtOAc (30 mL x 3), and the combined organic extracts were washed with brine, dried over anhydrous Na ₂ S0 ₄ , concentrated in vacuo to give the bromo-4,4-dimethyl-tetrahydroquinone 14-D as a yellow oil (0.11 g, 25%). LC-MS: m/z = 240.1 [M+H] ⁺ .

[00317] Step 4. Following the procedure described in preparative example 1, step 1, the bromo-4,4-dimethyl-tetrahydroquinone 14-D (0.11 g, 0.46 mmol) was converted to the amide 14-E as a yellow oil (0.2 g).

[00318] Step 5. Following the procedure set forth in preparative example 3, the amide intermediate 14-E (0.2 g, 0.5 mmol) was reacted with boronic acid 8-D to give the titled compound as a colorless solid (20 mg, 8.5%). ¹ H NMR (300 MHz, CD ₃ OD): δ 8.34 - 6.69 (m, 9H), 4.12 - 3.51 (m, 1H), 2.78 - 2.74 (m, 2H), 1.29 - 1.02 (m, 7H). HPLC = 99.6% (214 nm), 99.2% (254 nm), t _R = 7.70 min. LC-MS: m/z = 471.1 [M+H] ⁺ .

[00319] Example 15: Synthesis of 4-chloro-3-(l-(2-chloro-6-fluorobenzoyl)-2,3,4,5 tetrahydro-lH-benzo[b]azepin-7-yl)benzamide

[00320] Step 1. To a solution of ethyl 2-aminobenzoate 15-A (5.0 g, 30.27 mmol) and triethyl amine (4.59 g, 45.41 mmol) in 100 mL of CH ₂ C1 ₂ was added ethyl 4-chloro-4- oxobutanoate (5.48 g, 33.29 mmol). The mixture was stirred at room temperature overnight. Water (120 mL) was added. The aqueous mixture was extracted with CH ₂ C1 ₂ (100 mL x 2). The combined organic extracts were dried over anhydrous Na ₂ S0 ₄ , concentrated in vacuo to give intermediate 15-B as a yellow solid (9.2g, 77%). 1H NMR (300 MHz, CDC1 ₃ ): ^ 11.19 (s, 1H), 8.85 - 8.55 (m, 1H), 8.04 (dd, J = 8.0, 1.7 Hz, 1H), 7.65 - 7.43 (m, 1H), 7.19 - 6.96 (m, 1H), 4.39 (q, J = 7.1 Hz, 2H), 4.20 - 4.13 (m, 2H), 2.79 - 2.75 (m, 4H), 1.43 (t, J = 7.1 Hz, 3H), 1.33 - 1.17 (m, 3H). LC-MS: m/z = 294.2 [M+H] ⁺ .

[00321] Step 2. Intermediate 15-B (1.0 g, 3.4 mmol) and sodium acetate (0.42 g, 5.08 mmol) were dissolved in 20 mL of acetic acid. Bromine (2.0 g, 12.7 mmol) was added drop wise. The mixture was stirred overnight. Solvent was removed in vacuo, and the residue was purified by flash column chromatography (PE/EA=10:/1, v/v) to afford the bromide 15-C as a yellowish solid (1.2 g, 95.2%). 1H NMR (300 MHz, CDC1 ₃ ): δ 11.11 (s, 1H), 8.62 (d, J = 9.0 Hz, 1H), 8.14 (d, J = 2.3 Hz, 1H), 7.60 (d, J = 9.0 Hz, 1H), 4.39 (q, J = 7.2 Hz, 2H), 4.16 (q, J = 7.1 Hz, 2H), 2.75 (s, 4H), 1.43 (t, J = 1.1 Hz, 3H), 1.26 (t, J = 7.1 Hz, 3H). LC-MS: m/z = 372.0 [M+H] ⁺ .

[00322] Step 3. To a stirred solution of bromide 15-C (0.22 g, 9.18 mmol) in 30 mL of THF was added Sodium hydride (0.22 g, 9.18 mmol). The mixture was heated at 70°C for 2 h, then cooled to room temperature, and filtered. The solid collected by filtration was the desired intermediate 15-D (0.5 g, 57%). LC-MS: m/z = 325.9 [M+H] ⁺ .

[00323] Step 4. To a solution of intermediate 15-D (l.Og, 3.1 mmol) in 10 mL of DMF was added 1 drop of water. The mixture was heated under microwave condition at 130°C for 10 minutes. Solvents wee removed under reduced pressure, the residue was purified by flash column chromatography (PE/EA= 1: 1) to provide the keto lactam 15-E as a yellow solid (0.6 g, 76.9%. LC-MS: m/z = 254.0 [M+H] ⁺ .

[00324] Step 5. A solution of keto lactam intermediate 15-E (0.6 g, 2.37 mmol) in 5 mL of THF was added dropwise to a stirred mixture of lithium alumimum hydride (0.5 g, 13.0 mmol) and aluminum chloride (2.1 g, 15.5 mmol) in 25 mL of THF at room temperature. The resulting mixture was heated at 65°C for 5 h. After cooling, the precipitation was filtered off, the filtrate was concentrated, and the residue was purified by preparative TLC to give bromo-benzoazepine 15-F as a yellow oil (0.25 g, 47.2%). LC-MS: m/z = 226.0 [M+H] ⁺ .

[00325] Step 6. Following the procedure described in preparative example 1, step 1, bromo- benzoazepine 15-F (0.25 g) was converted to the amide 15-G (0.3 g, 71.4%). LC-MS: m/z = 382.0 [M+H] ⁺ .

[00326] Step 7. Following the procedure set forth in preparative example 3, the amide intermediate 15-G (0.1 g) was reacted with boronic acid 8-D to give the titled compound (10 mg, 8.4%). 1H NMR (300 MHz, CD ₃ OD): δ 8.26 - 6.86 (m, 9H), 3.32 - 2.76 (m, 4H), 2.23 - 1.39 (m, 4H); HPLC = 100% (214 nm), 100% (254 nm), t _R = 4.56 min. LC-MS: m/z = 457.1 [M+H] ⁺ .

[00327] Example 16: Synthesis of 4-chloro-3-(l-(2-chloro-6-fluorobenzoyl)-4-methyl- 1,2,3,4, tetrahydroquinoxalin-6-yl)benzamide

EX.16

[00328] Step 1. 4-Bromo-2-fluoro- 1 -nitrobenzene 16-A (5.5 g, 25 mmol) was added to a solution of methyl amine in THF (37.5 mL, 2 M). The mixture was stirred at room temperature for 10 min, quenched with a sat. NFLCl aqueous solution (10 mL). The aqueous mixture was extracted with EtOAc (30 mL x 3), and the combined organic extracts were washed with brine (20 mL), dried over anhydrous Na ₂ S0 ₄ , concentrated to provide the intermediate 16-B as a yellow oil (5.6 g, 97%). LC-MS: m/z = 231.0 [M+H] ⁺ .

[00329] Step 2. To a stirred solution of 16-B (5.5 g, 23.9 mmol) in 50 mL of anhydrous THF was added K ₂ C0 ₃ (6.6 g, 47.8 mmol) and 2-chloroacetyl chloride (4.05 g, 35.9 mmol). The mixture was heated at 80°C for 2 h. After cooling, the mixture was diluted with EtOAc (50 mL), washed with H ₂ 0 (20 mL), brine (20 mL), dried over anhydrous Na ₂ S0 ₄ , and concentrated to provide the amide 16-C as a yellow solid (7.3 g, 99%). LC-MS: m/z = 307.0 [M+H] ⁺ .

[00330] Step 3. A mixture of amide 16-C (0.4 g, 1.30 mmol) in 10 mL of a 1.0 M

B ₂ H6/THF solution was stirred at room temperature for 48 h. The reaction was quenched with 10 mL of methanol. Removal of solvents provided the amine product 16-D as a yellow oil (0.35g, 92%). LC-MS: m/z = 292.9 [M+H] ⁺ .

[00331] Step 4. To a stirred mixture of the intermediate 16-D (0.35 g, 5.97 mmol) in 10 mL of acetic acid was added Fe (0.33 g, 5.97 mmol). The mixture was stirred for 2 h at room temperature, basified to pH8 with a sat. NaHC0 ₃ aqueous solution, and then extracted with EtOAc (20 mL x 3). The combined organic extracts were washed with brine (20 mL), dried over anhydrous Na ₂ S0 ₄ , and concentrated in vacuo to give the reduced product 16-E as a yellow oil (0.22 g, 70%).

[00332] Step 5. A mixture of phenyl amine 16-E (0.22 g, 0.84 mmol), K ₂ C0 ₃ (0.35 g, 2.51 mmol), and KI (0.28 g, 1.67 mmol) in 10 mL of DMF was heated at 80°C with stirring for 3h. The mixture was diluted with EtOAc (50 mL), washed with H ₂ 0 (20 mL x 3), brine (20 mL), and then dried over anhydrous Na ₂ S0 ₄ . Removal of solvents afforded tetrahydroquinoxalin 16-F as a yellow solid (0.19 g, 100%). LC-MS: m/z = 263.1 [M+H] ⁺ .

[00333] Step 6. Following the procedure described in preparative example 1, step 1, bromo- tetrahydroquinoxalin 16-F (0.19 g, 0.84 mmoL) was converted to the amide 16-G (0.28 g, 88%). LC-MS: m/z = 383.0 [M+H] ⁺ .

[00334] Step 7. Following the procedure described in preparative example 1, step 2, bromo- tetrahydroquinoxalin amide 16-G (0.28 g) was reacted with 5-carbamoyl-2-chlorophenyl boronic acid 8-D to provide the titled compound as a colorless solid (0.060g, 18%). 1H NMR (300 MHz, CD ₃ OD): δ 7.89 - 6.17 (m, 9H), 4.13 - 3.92 (m, 2H), 3.60 - 3.34 (m, 2H), 2.93 (s, 2H), 2.89 (s, 1H). HPLC = 98.7% (214 nm), 99.1% (254 nm), t _R = 6.41 min. LC-MS: m/z = 458.1 [M+H] ⁺ .

[00335] Example 17: Synthesis of 4-chloro-3-(l-(4-chlorobenzoyl)-l,2,3,4- tetrahydroquinolin-6-yl)benzamide

Ex.17

[00336] Step 1. To a stirred solution of bromo-tetrahydroquinoline 1-A (5 g, 23.7 mmol) in 60 mL of THF was added a solution of NaOH (lg, 25 mmol) in H ₂ 0 (30 mL). Ditertbutyl dicarbonate (5.37 g, 25 mmol) was added. The mixture was stirred for 12 hours at room temperature. Solvent was removed in vacuo, and the aqueous mixture was extracted with EtOAc (50 mL x 3). The combined organic extracts were washed with brine, dried over anhydrous Na ₂ S0 ₄ , concentrated and purified with column chromatography to provide the boc-protected compound 17-A as a colorless solid (3 g, 40.7%). 1H NMR (300 MHz, CDC13): δ 7.56 - 7.53 (m, 1H), 7.24 - 7.19 (m, 2H), 3.70 - 3.66 (m, 2H), 2.75 - 2.71 (m, 2H), 1.92 - 1.88 (m, 2H), 1.52 (s, 9H).

[00337] Step 2. 5-Carbamoyl-2-chlorophenylboronic acid 8-D (0.7g, 3.5 mmol) was added to a stirred mixture of 17-A (l.Og, 3.2 mmol), Pd(dppf)Cl ₂ (0.26 g, 0.32 mmol) and K ₂ C0 ₃ (0.88 g, 6.4 mmol) in DMF (40 mL). The mixture was heated at 100°C overnight. Solvent was removed under reduced pressure, and the residue was purified by column

chromatography eluting with PE/EA (1: 1) to afford the intermediate 17-B as a colorless solid (0.76 g, 56%). 1H NMR (300 MHz, CD ₃ OD): δ 7.87 - 7.21 (m, 6H), 3.91 - 3.51 (m, 2H), 2.84 (dd, J = 10.8, 4.3 Hz, 2H), 2.00 - 1.81 (m, 2H), 1.55 (s, 9H).

[00338] Step 3. The intermediate 17-B (0.76 g, 19.1 mmol) synthesized from Step 2 above was added to a 10 mL solution of 4N HC1 in dioxane. The mixture was stirred for 3 h at room temperature, concentrated under reduced pressure to give the deprotected compound 17-C as a yellow solid (0.8 g). 1H NMR (300 MHz, CD30D): δ 7.92 - 7.37 (m, 6H), 3.62 - 3.56 (m, 2H), 3.04 (t, J = 6.2 Hz, 2H), 2.34 - 2.09 (m, 2H). LC-MS: m/z = 287.1 [M+H]+ [00339] Step 4. Following the procedure described in preparative example 1, step 1, the intermediate 17-C (100 mg, 0.31 mmol) was reacted with 4-chlorobenzoyl chloride (108.5 mg, 0.62 mmol) to provide the titled product as a colorless solid (20 mg, 15.2 %). ^l H NMR (300 MHz, CD ₃ OD): δ 7.85 - 6.83 (m, 10H), 3.94 - 3.89 (m, 2H), 2.96 - 2.92 (m, 2H), 2.14 - 2.03 (m, 2H). HPLC = 100% (214 nm), 100% (254 nm), t _R = 6.94 min. LC-MS: m/z = 427.0 [M+H] ⁺ .

[00340] Examples 18 to 31, 101. The following compounds of the present invention listed in Table were prepared following the procedures described in Example 1, step 1, when the intermediate 17-C (available from preparative example 17) was reacted with suitable acid chlorides

17-C Ex.18 - Ex. 31 , Ex. 101

[00341] Example 32: Synthesis of 4-chloro-3-(l-(2-chloro-6-fluorobenzoyl)-l,2,3,4- tetrahydroquinolin-6-yl)-N-methylbenzamide.

[00342] Step 1: To a stirred mixture of compound 1-C (1 g, 2.72 mmol), available from Example 1, and 3-brono-4-chlorobenzoic acid (2-C, 0.6 g, 3 mmol) in 20 mL of 1,4-dioxane and 5 mL of H ₂ 0 under nitrogen atmosphere was added Pd(dppf)Cl ₂ (0.4 g, 0.54 mmol) followed by sodium carbonate (0.57 g, 5.4 mmol). The mixture was heated at 80°C for 16h. 1,4-Dioxane was removed in vacuo, the residue aqueous was extracted with EtOAc (20 mL x 3). The organic extract was dried over anhydrous Na ₂ S0 ₄ , concentrated, and purified by column chromatography, eluting with MeOH -CH ₂ C1 ₂ (1: 10, v/v), to provide acid 32-A as a colorless solid (0.5g, 41%). LC-MS m/z = 444.0 [M+H] ⁺ .

[00343] Step 2: To a solution of acid 32-A (0.12 g, 0.27 mmol), prepared from Step 1 above, in 5 mL of DMF was added methylamine hydrochloride (0.023 g, 0.34 mmol), HBTU (0.2 g, 0.53 mmol) and diisopropylethyl amine (DIPEA, 0.1 g, 0.77 mmol). The mixture was stirred at room temperature for 4 hours, then concentrated in vacuo to remove majority of DMF solvent. The residue was diluted with 10 mL of EtOAc and 10 mL of H ₂ 0, and two phases were separated. The organic phase was washed with Sat. NH ₄ C1 (10 mL x 1), Sat. NaHC0 ₃ (10 mL), brine (10 mL), and dried over anhydrous Na ₂ S0 ₄ . Removal of solvent, further purified by preparative TLC, the titled compound Ex.32 was obtained as a colorless solid (28 mg, 23%). 1H NMR (300 MHz, CD ₃ OD) δ: 8.05 - 6.60 (m, 9H), 3.95 - 4.45 (m, 2H), 2.83 - 2.77 (m, 5H), 2.07 - 1.918 (m, 2H). HPLC = 99.5% (214 nm), 100% (254 nm), t _R = 4.53 min. LC-MS m/z = 457.0 [M+H] ⁺ .

[00344] Examples 33 to 71, and 100: Following the procedure described in Ex.32, step 2, or a slightly modified alternative (Method B), by using appropriate R ^la R ^lb NH, the

compounds of the present invention listed in Table 7 were prepared.

Table 7.

Ex # Structure Characterization Data Ex # Structure Characterization Data

lH NMR (300 MHz, CD ₃ OD): δ 8.47 - 6.71 (m, 13H), 4.67 (d, J = 9.9 Hz, 2H), 4.07 - 3.56 (m, 2H), 2.94 - 2.87 (m, 2H), 2.15 - 2.06 (m,

100

2H). HPLC = 99.6% (214 nm), 99.7% (254 nm), t _R = 4.83 min. LC-MS: m/z = 534.1 [M+H] ⁺ .

[00345] General ester hydrolysis conditions for examples 60, 61, and 62 in Table 5. For examples 60, 61 and 62 where an additional acid hydrolysis step was required to generate the target compound, the following procedure was used: A mixture of the corresponding ester precursor (1 molar equivalent) and a 2 N LiOH aqueous solution (2 molar equivalent) in THF (20 mL) was stirred at room temperature for 2h, acidified with a IN HC1 aqueous solution to pH: 3 ~4. The aqueous mixture was extracted with EtOAc, washed with brine, dried over anhydrous Na ₂ S0 ₄ , and concentrated in vacuo to give the crude material, which was purified by preparative TLC to afford the examples of 60, 61 and 62.

[00346] Example 63: Synthesis of 6-chloro-4'-(2-chloro-6-fluoro-N-methylbenzamido) - [1,1 ' -biphenyl] -3-carboxamide

Ex.63 [00347] Step 1. To a stirred solution of 4-bromophenyl methyl amine 63-A (0.098 mL, 0.78 mmol) in 5 mL of CH ₂ CI ₂ was added triethyl amine (0.217 mL, 1.55 mmol) followed by 2- chloro-6-fluoro-benzoyl chloride 1-B (0.116 mL, 0.881 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate, and then washed with a sat. NaHC0 ₃ aqueous solution, H ₂ 0, and brine. The organic layer was dried over anhydrous Na ₂ S0 ₄ . Solvents were removed in vacuo, the residue was purified by gradient column chromatography eluting with EtOAc / Heptanes to give the amide intermediate 63-B (270 mg, 100%). LC-MS: m/z = 341.9 [M+H ^]+ .

[00348] Step 2. The amide intermediate 63-B (270 mg, 0.7881 mmol) obtained from step 1 above was dissolved in a mixture of 1,4-dioxane (4 mL) and a 2 M Na ₂ C0 ₃ aqueous solution (1 mL) in a vial. Boronic acid 8-D (143 mg, 0.717 mmol), Pd(dppf) ₂ CI ₂ -CH ₂ CI ₂ complex (70.2 mg, 0.086 mmol) were added to the above mixture. The reaction mixture was heated under microwave condition at 80°C for 30 minutes. The mixture was diluted with EtOAc, then washed with sat. NaHC0 ₃ aqueous solution, H ₂ 0, and brine. The organic layer was dried over anhydrous Na ₂ S0 ₄ , and concentrated in vacuo to an oily residue, which was purified by preparative HPLC to afford the titled product Ex.63 as a colorless solid (130.8 mg, 44%). 1H NMR (300 MHz, CD ₃ OD): <Π.83 (dd, J = 2.27, 8.31 Hz, 1H), 7.78 (d, J = 2.27 Hz, 1H), 7.55 - 7.60 (m, 1H), 7.37 - 7.42 (m, 3H), 7.24 - 7.34 (m, 1H), 7.15 (d, J = 8.31 Hz, 1H), 6.93 - 7.04 (m, 1H), 3.53 - 3.57 (m, 3H). LC-MS: m/z = 417.0 [M+H ^]+ .

[00349] Examples 64 to 81. The following compounds of the present invention listed in Table 8 were prepared following the procedures set forth in Example 63, by using appropriately substituted phenyl amines I or pyridyl amines II in place of 63-A. A few examples were prepared by further changing the acid chloride from 1-B to III.

Ex.80 - Ex.81

[00350] Example 82: Synthesis of 6-chloro-4'-(2-chloro-6-fluoro-N-methylbenzamido) - [1,1 ' -biphenyl] -3-carboxamide

[00351] Step 1. To a stirred solution of 2-amino-5-bromophenol 82-A (400 mg, 2.13 mmol) in 14 mL of CH ₂ CI ₂ was added pyridine (0.189 mL, 2.34 mmol) followed by 2-chloro-6- fluoro-benzoyl chloride 1-B (0.309 mL, 2.34 mmol). The mixture was stirred at room temperature for 48 h, diluted with EtOAc. The organic solution was washed with a sat.

NaHC0 ₃ aq. solution, H ₂ 0, and brine. The organic layer was dried over anhydrous Na ₂ S0 ₄ , and concentrated in vacuo to an oily residue. The crude product was purified by column chromatography eluting with EtOAc / Heptanes to provide compound 82-B as a tan solid (719 mg, 79%). LC-MS: mJz = 343.8 [M+H] ⁺ .

[00352] Step 2. Compound 82-B (100 mg, 0.29 mmol) prepared from step 1 above was dissolved in DMF (2 mL). Potassium carbonate (60.2 mg, 0.435 mmol) and iodoethane (0.232 mL, 0.29 mmol) were added. The mixture was stirred at room temperature overnight. Ethyl acetate was added. The organic solution was washed with a sat. NaHC0 ₃ aq. solution, H ₂ 0, and brine. The organic layer was dried over anhydrous Na ₂ S0 ₄ , and concentrated in vacuo to an oily residue. The crude product was purified by column chromatography eluting with EtOAc / Heptanes to provide compound 82-C as a colorless solid (96.4 mg, 89%). LC- MS: m/z = 371.8 [M+H] ⁺ .

[00353] Step 3. To a solution of the secondary amide 82-C (96.4 mg, 0.26 mmol) in 1.78 mL of DMF was added sodium hydride (60% dispersed in mineral oil, 10.4 mg, 0.259 mmol). The mixture was stirred for 30 minutes, and then added with iodomethane (0.032 mL, 0.517 mmol) dropwise. Reaction was continued at room temperature overnight. The mixture was diluted with EtOAc, washed with a sat. NaHC0 ₃ aq. solution, H ₂ 0, and brine. The organic layer was dried over anhydrous Na ₂ S0 ₄ , and concentrated in vacuo to an oily residue. The crude product was purified by chromatography eluting with EtOAc / heptanes (gradient, 0 to 40%) to afford the key intermediate 82-D as a yellow oil (102.9 mg). LC-MS: mJz = 385.8 [M+H] ⁺ .

[00354] Step 4. Following the procedure described in preparative example 63, step 2, the bromo-phenyl amide intermediate 82-D (100 mg, 0.259 mmol) from step 3 above was reacted with boronic acid 8-D (57 mg, 0.2844 mmol) to provide the titled product Ex. 82 as an off white solid (68.7 mg, 58%). 1H NMR (400 MHz, DMSO-d6): 8.04 - 8.17 (m, 1H), 7.01 - 8.00 (m, 9H), 6.85 (t, J = 6.27 Hz, 1H), 3.94 - 4.25 (m, 2H), 3.03 - 3.37 (m, 3H), 1.30 - 1.44 (m, 3H). LC-MS: mJz = 460.9 [M+H] ⁺ .

[00355] Examples 83 to 88. The following compounds of the present invention listed in Table 9 were prepared following the procedures set forth in Example 80, steps 2 to 4, starting with intermedia -B by reacting with a variety of R ⁴ X.

Ex. 81 - Ex. 86 Table 9.

[00356] Example 89: Synthesis of N-(5-(5-carbamoyl-2-chlorophenyl)-3-ethoxpyridin-2- yl)-2-chloro-6-fluoro-N-methylbenzamide

89-A 89-B 89-C 89-D

[00357] Step 1. To a stirred solution of 2-nitro-3-hydroxy pyridine 89-A (5.0 g, 35.7 mmol) in 50 mL of DMF was added K ₂ C0 ₃ (9.9 g, 71.4 mmol) followed by iodoethane (6.7 g, 42.8 mmol). The mixture was heated at 50°C for 16 h and diluted with 100 mL of EtOAC. The organic layer was washed with brine (100 mL x 2), concentrated in vacuo to give compound 89-B as a yellow oil (6.0 g, 100%). ¹ H NMR (400 MHz, CDC1 ₃ ) δ: 8.07-8.06 (m, 1H), 7.54- 7.49 (m, 2H), 4.21 (q, J = 6.8 Hz, 2H), 1.47 (t, J = 6.8 Hz, 3H). LC-MS: m/z = 169.1

[M+H] ⁺ .

[00358] Step 2. The nitro intermediate 89-B (6.0 g, 35.7 mmol) prepared in step 1 above was dissolved in a mixture of 50 mL of EtOH and 2 mL of acetic acid. Fe powder (10.0 g, 178.5 mmol) and NH ₄ C1 (9.5 g, 178.5 mmol) were added. The resulting mixture was heated at 80 C with stirring for 1 h. The mixture was filtered and the filterate was concentrated in vacuo to a residue, which was dissolved in 100 mL of EtOAc. The organic solution was washed with H ₂ 0 (100 mL x 2), then concentrated in vacuo to provide the amino pyridine 89- C as a yellow oil (3.2 g, 65%). 1H NMR (400 MHz, CDC13) δ: 7.65 (d, J = 4.8 Hz, IH), 6.88 (d, J = 7.6 Hz, IH), 6.59 (dd, J = 4.8 Hz, 7.6 Hz, IH), 4.68 (br s, 2H), 4.04 (q, J = 7.2 Hz, 2H), 1.44 (t, J = 7.2 Hz, 3H). LC-MS: m/z = 139.1 [M+H] ⁺ .

[00359] Step 3. To a stirred solution of the amino pyridine 89-C (3.2 g, 23.2 mmol) in 20 mL of acetic acid was added bromine (1.2 mL, 23.2 mmol) over a 10 min period at room temperature. The resulting mixture was stirred for 16 h, concentrated under reduced pressure to a residue. The crude product was neutralized with a sat. NaHC0 ₃ aq. solution, the aqueous mixture was extracted with EtOAc (30 mL x 3). The combined organic extracts were washed with brine (60 mL), dried over anhydrous Na ₂ S0 ₄ , filtered, and concentrated in vacuo to provide the bromo-intermediate 89-D as a yellow oil (3.6 g, 72%), used in the next step without purification. LC-MS: m/z = 217.1 [M+H] ⁺ .

[00360] Step 4. To a stirred solution of the bromo intermediate 89-D (0.6 g, 2.8 mmol) in 10 mL of pyridine was added acid chloride 1-B (0.535 g, 2.8 mmol) at -15°C. The reaction mixture was stirred at room temperature for 16 h and concentrated. The residue was dissolved in 20 mL of EtOAc, and washed with brine (20 mL x 2), then concentrated. The residue was purified by reversed phase preparative HPLC (MeCN/H ₂ 0 = 5% to 95%) to afford the amide compound 89-E as a yellow oil (0.27 g, 26%). LC-MS: m/z = 373.1

[M+H] ⁺ .

[00361] Step 5. To a solution of the amide 89-E (0.27 g, 0.73 mmol) prepared in step 4 above in 3 mL of DMF at 0°C was added sodium hydride (0.060 g, 1.46 mmol) followed by iodomethane (0.125 g, 0.88 mmol). The mixture was stirred at 0°C for lh, then purified directly by reversed phase preparative HPLC (MeCN/H ₂ 0 = 5% to 95%) to give intermediate 89-F as a colorless solid (0.25 g, 89%). 1H NMR (400 MHz, CDC1 ₃ ): a mixture of conformers, δ 8.20 (s, 0.2 H), 7.84 (s, 0.8H), 7.24-7.22 (m, IH), 7.14-7.08 (m, IH), 6.99-6.97 (m, IH), 6.84-6.29 (m, IH), 4.11 (q, J = 6.8 Hz, 0.4H), 4.02 (q, J = 6.8 Hz, 1.6H), 3.45 (s, 2.4H), 3.22 (s, 0.6 H), 1.46 (t, J = 6.8 Hz, 3H). LC-MS: m/z = 378.2 [M+H] ⁺ .

[00362] Step 6. A mixture of amide intermediate 89-F (0.25 g, 0.65 mmol), 3-bromo-4- chlorobenzoic acid (0.156 g, 0.78 mmol), Cs ₂ C0 ₃ (0.422 g, 1.3 mmol), and Pd(dppf)Cl ₂ (0.050 g, 0.06 mmol) in DMF-H ₂ 0 (2 mL, 3/1, v/v) was heated at 100°C under a nitrogen atmosphere with stirring for 12 h. The mixture was diluted with 3 mL of MeOH and filtered. The filtrate was purified by reversed phase preparative HPLC (MeCN/H ₂ 0 = 5% to 95%) to provide the acid intermediate 89-G (0.12 g, 40%). LC-MS: m/z = 463.1 [M+H] ⁺ .

[00363] Step 7. To a stirred solution of acid 89-G (0.12 g, 0.26 mmol) in 2 mL of THF was added NH ₄ C1 (0.070 g, 1.3 mmol), HATU (0.198 mg, 0.52 mmol) and Et ₃ N (0.13 g, 1.3 mmol). The resulting mixture was heated at 45°C for 30 min, concentrated, and purified by reversed phase preparative HPLC (MeCN/H ₂ 0 = 5% to 95%) to afford the titled product as a yellow solid (35 mg, 29%). 1H NMR (400 MHz, CDC1 ₃ ): a mixture of conformers, δ: 8.21- 7.82 (m, 3H), 7.72-7.45 (m, 2.6H), 7.28-7.23 (m, 1.0H), 7.09-6.94 (m, 1.4H), 4.25 (q, J = 6.8 Hz, 0.6H), 4.15 (q, J = 6.8 Hz, 1.4H), 3.49 (s, 2.1H), 3.28 (s, 0.9 H), 1.47 (t, J = 6.8 Hz, 3H). LC-MS: m/z = 462.1 [M+H] ⁺ .

[00364] Example 90: Synthesis of N-(5-(5-carbamoyl-2-chlorophenyl)-3-(2,2,2- trifluoroethoxy)pyridin-2-yl)-2-chloro-6-fluoro-N-methylbenz amide

[00365] Step 1. Following a similar procedure described in preparative example 89, step 1, 3-trifluoroethoxy-2-nitro-pyridine 90-A (1.8 g, 90%) was prepared from 89-A and

CF ₃ CH ₂ OTf. . 1H NMR (400 MHz, CDC13) δ: 8.26 (dd, J = 2.0 Hz, 3.6 Hz, 1H), 7.62-7.60 (m, 2H), 4.53 (q, J = 8.0 Hz, 2H). LC-MS: m/z = 223.0 [M+H] ⁺ .

[00366] Steps 2 to 7. Following the procedure set forth in preparative example 89, steps 2 to 7, compound 90-A from step 1 above was converted to the titled product Ex.90 as a light yellow solid. 1H NMR (400 MHz, CD ₃ OD): a mixture of conformers, δ 8.36 (d, J = 2.0 Hz, 0.3H), 8.02-7.83 (m, 3H), 7.72-7.51 (m, 2H), 7.45-6.94 (m, 2.7H), 4.78-4.73 (m, 2H), 3.50 (s, 2.1 H), 3.30 (s, 0.9H). LC-MS: m/z = 516.2 [M+H] ⁺ .

[00367] Example 91: Synthesis of N-(5-(5-carbamoyl-2-chlorophenyl)-3- (cyclopropylmethoxy)pyridin-2-yl)-2-chloro-6-fluoro-N-methyl benzamide

[00368] Step 1. Following a similar procedure described in preparative example 89, step 1, 3-cyclopropylmethoxy-2-nitro-pyridine 91-A was prepared from 89-A and cyclopropyl methyl bromide.

[00369] Steps 2 to 7. Following the procedure set forth in preparative example 89, steps 2 to 7, compound 91-A from step 1 above was converted to the titled product as a colorless solid. ¹ H NMR (400 MHz, CD ₃ OD): a mixture of conformers, δ 8.21-7.81 (m, 3H), 7.70- 7.43 (m, 2.5H), 7.32-6.95 (m, 2.5H), 4.04-3.94 (m, 2H), 3.52 (s, 2.2H), 3.29 (s, 0.8H), 1.36- 1.29 (m, 1H), 0.69-0.63 (m, 2H), 0.43-0.40 (m, 2H). LC-MS: m/z = 448.1 [M+H] ⁺ .

[00370] Example 92: Synthesis of 6-chloro-4'-((2-chloro-6-fluoro-N- methylbenzamido)methyl)-3'-methyl-[l,l'-biphenyl]3-carboxami de

[00371] Step 1. To a stirred mixture of (4-bromo-2-methylphenyl)methyl amine

hydrochloride 92-A (160 mg, 0.68 mmol) and triethyl amine (207 mg, 2.04 mmol) in 10 mL of CH ₂ CI ₂ at room temperature was added acid chloride 1-B (170 mg, 0.88 mmol). Reaction was continued for 2h, and the mixture was concentrated. The residue was purified by preparative TLC to provide amide intermediate 92-B as a colorless solid (150 mg, 62%). 1H NMR (400 MHz, CDC1 ₃ ) δ: Ί .35-126 (m, 3H), 7.21 (d, J = 8.4 Hz, 2H), 7.04 (t, J = 8.4 Hz, 1H), 5.88 (br, 1H), 4.61 (d, J = 5.6 Hz, 2H), 2.37 (s, 3H). LC-MS: m/z = 356.0 [M+H] ⁺ . [00372] Step 2. To a solution of the amide intermediate 92-B (115 mg, 0.32 mmol) in 3 mL of DMF at room temperature was added sodium hydride ( 26 mg, 0.64 mmol). Iodomethane (92 mg, 0.64 mmol) was added. The mixture was stirred for 2h and purified directly by reverse phase preparative HPLC (CH ₃ CN/H ₂ O = 5% to 95%) to afford the methylated amide 92-C as a colorless solid (130 mg, 86%). 1H NMR (400 MHz, CDC1 _3, a mixture of conformers) δ: 7.36-7.35 (m, 1H), 7.34-7.32 (m, 1H), 7.32-7.28 (m, 1H), 7.26-7.23 (m, 1H), 7.21-7.16 (m, 1H), 7.10-7.02 (m, 1H), 4.78 (AB, 1.5H), 4.33 (s, 0.5H), 3.04 (s, 0.75H), 2.75 (s, 2.25H), 2.35 (s, 2.25H), 2.16 (s, 0.75H). LC-MS: m/z = 370.0 [M+H] ⁺ .

[00373] Step 3. To a mixture of amide 92-C (120 mg, 0.32 mmol) obtained from Step 2 above in 3 mL of DMF and 1 mL of H ₂ 0 was added 3-borono-4-chlorobenzoic acid (78 mg, 0.39 mmol), cesium carbonate (212 mg, 0.65 mmol) and Pd(dppf)Cl ₂ (27 mg, 0.03 mmol). The resulting mixture was heated under a N ₂ atmosphere at 100°C with stirring for 16 h. After cooling, the mixture was diluted with methanol (3 mL) and filtered. The filtrate was purified by reversed phase preparative HPLC (CH ₃ CN/H ₂ 0 = 5% to 95%) to provide the acid intermediate 92-D as a yellow solid (60 mg, crude product). LC-MS: m/z = 446.1 [M+H] ⁺ .

[00374] Step 4. To a mixture of acid 92-D (60 mg, 0.14 mmol) available from Step 3 above in 1 mL of THF was added NH ₄ C1 (37 mg, 0.70 mmol) and HATU (103 mg, 0.28 mmol). The mixture was stirred at room temperature for 2 h, diluted with MeOH (2 mL), and filtered. The filtrate was purified by reversed phase preparative HPLC (CH ₃ CN/H ₂ 0 = 5% to 95%) to give the titled product as a light yellow solid (8 mg, 13%). 1H NMR (400 MHz, CD ₃ OD, a mixture of conformers) δ: 7.89-7.81 (m, 2H), 7.60-7.58 (m, 1H), 7.51-7.47 (m, 1H), 7.43- 7.31 (m, 3H), 7.28-7.24 (m, 2H), 4.92 (AB, 1.5H), 4.54 (s, 0.5H), 3.12 (s, 0.75H), 2.85 (s, 2.25H), 2.45 (s, 2.25H), 2.23 (s, 0.75H). LC-MS: m/z = 445.1 [M+H] ⁺ .

[00375] Examples 93 to 97. The following compounds of the present invention listed in Table 10 were prepared following the procedures set forth in Example 1, step 2, using Suzuki coupling reaction to couple bromo intermediate 1-C with commercially available aryl boronic acids.

Table 10. Ex # Structure Characterization Data

LC-MS: m/z = 497.1 [M+H] ⁺ .

97

F

[00376] Example 98: Synthesis of 6-chloro-4'-(2-ch] oro-6-fluoro-N-methylbenzamido)-3'-

(cyclopropylmethoxy)-[l, l'-biphenyl]-3-carboxamide.

[00377] See Table 9 above.

[00378] Example 99: Synthesis of N-(5-(5-carbamoyl-2-chlorophenyl)-3-((2,2- difluorocyclopropyl)methoxy)pyridin-2-yl)-2-chloro-6-fluoro- N-methylbenzamide.

[00379] See Table 11 below.

[00380] Example 103: Synthesis of 6-chloro-4'-(2-chloro-6-fluoro-N-methylbenzamido)-3'- (2,2-difluoropropoxy)-[l, l '-biphenyl]-3-carboxamide.

[00381] Step 1. To a stirred solution of 4-bromo-2-fluoro- l-nitro-benzene (208.2 mg, 0.946 mmol) and 2,2-difluoropropan- l-ol (100 mg, 1.041 mmol) in DMF (6 mL, 77.5 mmol) was added cesium carbonate (244 mg, 0.75 mmol). The reaction mixture was stirred for 48 h at 40°C. The mixture was diluted with EtOAc, then washed with aq. Sat. NaHC0 ₃ , H ₂ 0, and brine. The organic layer was dried over sodium sulfate and solvent was removed in vacuo. The crude product was purified by flash column chromatography using gradient elution (EtOAc in Heptanes, 0 to 40%). Removal of solvents afforded 168.3 mg of intermediate 103- B as a yellow solid (60%). LC-MS: m/z = 295.9 [M+H] ⁺ . [00382] Step 2. To a stirred solution of 103-B (168.3 mg, 0.5684 mmol) in methanol (16 mL) was added Raney Nickel (1:9, nickel: water, 1.668 g, 2.842 mmol). The reaction mixture was stirred at room temperature for 2 h, filtered, and solvent was removed in vacuo. The residue was dissolved in EtOAc, washed with aq. Sat. NaHC0 ₃ , H ₂ 0, and brine. The organic layer was dried over sodium sulfate and concentrated. The crude product was purified by column chromatography eluting with EtOAc in heptanes (0 to 50%). Removal of solvents afforded 64.6 mg of 103-C as a yellow oil (97.7%). LC-MS: m/z = 265.9 [M+H] ⁺ .

[00383] Step 3. To a stirred solution of 103-C (97.7 mg, 0.367 mmol) in CH ₂ C1 ₂ (2.4 mL) was added acid chloride 1-B (0.065 mL, 0.492 mmol) and pyridine (0.060 mL, 0.742 mmol). The reaction mixture was stirred at room temperature for 48 h, diluted with EtOAc, washed with aq. Sat. NaHC0 ₃ , H ₂ 0, and brine. The organic layer was dried over sodium sulfate and concentrated. The crude product was purified by column chromatography eluting with EtOAc in heptanes (0 to 50%). Removal of solvents afforded 148.5 mg of 103-D as a colorless solid (96%). LC-MS: m/z = 421.8 [M+H] ⁺ .

[00384] Step 4. To a solution of 103-D (148.5 mg, 0.3514 mmol) in DMF (2.4 mL) was added sodium hydride in 60% mineral oil (14.05 mg, 0.3514 mmol). The mixture was pre- activated for 30 min at room temperature. The resultant mixture was added with

iodomethane (0.044 mL, 0.703 mmol) dropwise at room temperature. The mixture was stirred overnight, added with EtOAc, then washed with a sat. NaHC0 ₃ aq. solution, H ₂ 0, brine. The organic layer was dried over sodium sulfate and solvent was removed in vacuo. The crude product was purified by column chromatography eluting with EtOAc / heptanes (0 to 30%). Removal of solvents afforded 172.5 mg of 103-E as a colorless oil (100%). LC- MS: m/z = 435.8 [M+H] ⁺ .

[00385] Step 5. To a microwave vial was added Boronic acid 8-D (110.3 mg, 0.5531 mmol), 103-E (172.5 mg, 0.3950 mmol), PdC12(dppf) ₂ -CH ₂ Cl ₂ (1: 1) complex (43 mg, 0.053 mmol), and a 2M aqueous solution of Na ₂ C0 ₃ (0.5926 mmol, 1.185 mmol). Reaction was proceeded under microwave condition (300 watts) at 105 C for 35 minutes. After cooling, the mixture was diluted with EtOAc, washed with NaHC0 ₃ aq. solution, H ₂ 0, and brine. The organic layer was dried over sodium sulfate and concentrated in vacuo to an oily residue. The crude product was purified by HPLC to provide the titled product Ex.103 as a colorless solid (76.2 mg, 38%). 1H NMR (400 MHz, DMSO-d ₆ ) δ 6.77 - 8.21 (m, 11H), 4.21 - 4.53 (m, 2H), 3.35 (d, J = 4.52 Hz, 2H), 3.11 (s, 1H), 1.70 - 1.87 (m, 3H). LC-MS: m/z = 511.1 [M+H] ⁺ . LC-MS: m/z

[00386] Examples 98 and 115-126. The following compounds of the present invention listed in Table 11 are prepared following the procedures set forth in Example 80, steps 2 to 4, starting with intermediate 89-A by reacting with a variety of R ⁴ X.

[00387] Example 127: Synthesis of N-(5-(5-carbamoyl-2-chlorophenyl)-3- morpholinopyridin-2-yl)-2-chloro-6-fluoro-N-methylbenzamide

[00388] Step 1. To a solution of 3,5-dibromo-2-aminopyridine 127-A (1 g, 4 mmol) in 5 mL of THF at room temperature was added morpholine (520 mg, 6 mmol), chloro(X-Phos)[2-(2- aminoethyl)phenyl]-palladium(II) (118 mg, 0.16 mmol) and LHMDS (10 mL, 10 mmol, 1.0 M in THF). The mixture was heated under N ₂ at 65°C for 16 h. After cooling to room temperature, 200 mL of EtOAc was added, the mixture was washed with brine (100 mL x 3), dried over Na2S04, and concentrated in vacuo to give a black oil, which was purified by preparative HPLC (MeCN: H ₂ 0 = 1: 1) to give 127-B as a yellow solid (300 mg, 29%). ¹ H NMR (400 MHz, DMSO- ₆ ) δ: 7.74 (d, J = 2.0 Hz, 1H), 7.25 (d, J = 2.0 Hz, 1H), 5.89 (br s, 2H), 3.75-3.73 (m, 4H), 2.81-2.79 (m, 4H). LC-MS: m/z = 258.0 [M+H] ⁺ .

[00389] Step 2. To a solution of 127-B (250 mg, 1 mmol) in 2 mL of pyridine was added acid chloride 1-B (580 mg, 3 mmol). The reaction mixture was heated at 90°C with stirring for 2h and concentrated. The residue was dissolved in EtOAC (20 mL), washed with brine (20 mL x 2). The organic layer was concentrated in vacuo to give 220 mg of a crude product of 127-C as yellow oil. LC-MS: m/z = 570.1 [M+H] ⁺ . [00390] Step 3. A mixture of 127-C (220 mg, crude) and K ₂ C0 ₃ (106 mg, 0.8 mmol) in 20 mL of methanol was heated at reflux for 2h and then concentrated. The residue was diluted with EtOAc (100 mL) and washed with water (100 mL) and brine (100 mL). The organic layer was dried and concentrated to provide 100 mg of the amide 127-D (63%) as a yellow solid. 1H NMR (400 MHz, CDC1 ₃ ) δ: 8.66 (br s, 1H), 7.55 (s, 1H), 7.40-7.35 (m, 2H), 7.25- 7.24 (m, 1H), 7.11-7.05 (m, 1H), 3.88-3.87 (m, 4H), 2.97-2.95 (m, 4H). LC-MS: m/z = 414.0 [M+H] ⁺ .

[00391] Step 4. To a stirred solution of amide 127-D (100 mg, 0.24 mmol) in 5 mL of anhydrous DMF was added NaH (19 mg, 60% in mineral oil, 0.48 mmol) at 0°C under N2. lodomethane (70 mg, 0.48 mmol) was added. After lh, the mixture was quenched with a sat. NH ₄ CI aq. (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic extracts were washed with brine (100 mL), dried over Na ₂ S0 ₄ , and concentrated to afford 100 mg of a tertiary amide 127-E (100%). LC-MS: m/z = 428.0 [M+H] ⁺ .

[00392] Step 5. A stirred mixture of amide 127-E (100 mg, 0.23 mmol), PdCl ₂ (dppf) ₂ (10 mg, 0.01 mmol), boronic acid 8-D (92 mg, 0.46 mmol), and Na ₂ C0 ₃ (50 mg, 0.46 mmol) in 2 mL of DMF was heated under N2 at 90°C for 16 h. The mixture was filtered and the filtrate was purified by preparative HPLC (MeCN: H ₂ 0 = 3:2) to give 40 mg of the titled product Ex. 127 as a yellow solid (34%). HPLC: 100%. 1H NMR (400 MHz, CD ₃ OD) δ: 8.35 (s, 0.5H), 8.05-7.83 (m, 3H), 7.69-7.54 (m, 1.5H), 7.46-7.44 (m, 0.5H), 7.44 (s, 0.5H), 7.40-7.25 (m, 1H), 7.09-7.07 (m, 0.5H), 6.99-6.95 (m, 0.5H), 3.87-3.85 (m, 4H), 3.59 (s, 1.5H), 3.32- 3.31 (m, 1.5H), 2.93-2.87 (m, 4H). LC-MS: m/z = 503.1 [M+H] ⁺ .

[00393] Example 128: Synthesis of N-(5-(5-carbamoyl-2-chlorophenyl)-3- (propylthio)pyridin-2yl)-2-chloro-6-fluoro-N-methylbenzamide

[00394] Step 1. To a solution of 3-hydroxy 2-nitro pyridine 89-A (5 g, 35.7 mmol) in 50 mL of CH ₂ CI ₂ was added triethyl amine (10.7 g, 107.1 mmol) followed by triflic anhydride (11.9 g, 42.8 mmol). The mixture was stirred at r.t. for 4 h. The organic layer was washed with brine (100 mL x 2) and concentrated in vacuo to give 6 g of the triflate intermediate 128-A as a yellow oil (62.5%). 1H NMR (400 MHz, CDC1 ₃ ) δ: 8.63 (dd, J =1.2 Hz, 4.4 Hz, 1H), 7.97 (dd, J = 1.2 Hz, 8.4 Hz, 1H), 7.80 (dd, J = 4.8 Hz, 8.4 Hz, 1H). LC-MS: m/z = 273.0

[M+H] ⁺ .

[00395] Step 2. To a solution of 128-A (6.0 g, 22.0 mmol) in 50 mL of THF was added triethyl amine (6.8 g, 66.1 mmol) and propane- 1 -thiol (2.0 g, 26.4 mmol). The mixture was heated at 60°C for 20 h, then concentrated. The residue was purified by column

chromatography eluting with Petroleum ether / EtOAc (5: 1) to afford 2.0 g of thioether 128-B as a yellow solid (46%). 1H NMR (400 MHz, CDC1 ₃ ) δ: 8.34 (dd, J = 1.6 Hz, 4.4 Hz, 1H), 7.88 (dd, J = 1.2 Hz, 8.0 Hz, 1H), 7.54 (dd, J = 4.8 Hz, 8.4 Hz, 1H), 2.94 (t, J = 7.2 Hz, 2H), 1.80- 1.75 (m, 2H), 1.10 (t, J = 7.6 Hz, 3H). LC-MS: m/z = 199.0 [M+H] ⁺ .

[00396] Step 3. A stirred mixture of the nitro thioether 128-B (2.0 g, 10.1 mmol), Fe powder (2.8 g, 50.5 mmol), NH4C1 (2.7 g, 50.5 mmol) and HOAc (1 mL) in 20 mL of methanol was heated at 80°C for lh. The mixture was filtered, and the filtrate was concentrated in vacuo to give a residue which was dissolved in 100 mL of EtOAc. The organic solution was washed with water (100 mL x 2). Removal of solvent gave 1.0 g of the amino pyridine intermediate 128-C as a yellow oil (60%). LC-MS: m/z = 169.1 [M+H] ⁺ .

[00397] Step 4. To a stirred solution of 128-C (1.0 g, 5.9 mmol) in 10 mL of acetic acid was added bromine (0.95 g, 5.9 mmol) over a 10 minutes period at room temperature. The resulting mixture was stirred for 16 h at room temperature, concentrated in vacuo. The residue was neutralized with a sat. aq. NaHC0 ₃ to pH 7. The aqueous mixture was extracted with EtOAc (40 mL x 3). The organic extracts were washed with brine (60 mL), dried over Na ₂ S0 ₄ , filtered, and concentrated to give the bromo pyridine 1.0 g 128-D as a yellow oil (70%). LC-MS: m/z = 247.0 [M+H] ⁺ .

[00398] Step 5. To a solution of 128-D (1.0 g, 2.8 mmol) in 4 mL of pyridine was added acid chloride 1-B (535 mg, 2.8 mmol) at -15°C. The reaction mixture was stirred at room temperature for 16 h and concentrated. The residue was dissolved in EtOAC (20 mL), washed with brine (20 mL x 2). The organic layer was concentrated in vacuo and the residue was purified by preparative HPLC (MeCN / water = 5 to 95%) to give 902 mg of 128-E as a yellow oil. LC-MS: m/z = 559.0 [M+H] ⁺ .

[00399] Step 6. A mixture of 128-E (902 mg, 1.6 mmol) and K ₂ C0 ₃ (441 mg, 2.4 mmol) in 5 mL of methanol was heated at 70°C for 3h with stirring. The mixture was filtered, and concentrated to give a residue which was purified by reversed phase preparative HPLC (MeCN / water = 5 to 95%) to give 360 mg of 128-F as a yellow solid. LC-MS: m/z = 403.0 [M+H] ⁺ .

[00400] Step 7. To a stirred solution of 128-F (360 mg, 0.89 mmol) in 3 mL of anhydrous DMF was added NaH (71 mg, 60% in mineral oil, 1.79 mmol) at 0°C under N2.

Iodomethane (151 mg, 1.06 mmol) was added. The mixture was stirred for lh at 0°C, then purified directly by reversed phase preparative HPLC (MeCN / water = 5 to 95%) to give 260 mg of 128-G as a white solid. LC-MS: m/z = 417.0 [M+H] ⁺ .

[00401] Step 8. A stirred mixture of amide 128-G (260 mg, 0.62 mmol), PdCl ₂ (dppf) ₂ (50 mg, 0.06 mmol), boronic acid 8-D (150 mg, 0.75 mmol), and CS ₂ C0 ₃ (422 mg, 1.30 mmol) in 2 mL of a mixture of DMF-H ₂ 0 (3: 1) was heated under N2 at 100°C for 12 h. The mixture was diluted with methanol (3 mL) and filtered. The filtrate was purified by reversed preparative HPLC (MeCN: H ₂ 0 = 3:2) to give 153 mg of the titled product Ex. 128 as a colorless solid (52%). HPLC: 100%. 1H NMR (400 MHz, CD ₃ OD _> a mixture of conformers) δ: 8.44 (s, 0.5H), 8.06 (d, J = 2.0 Hz, 1H), 8.01 (d, J = 2.4 Hz, 0.5H), 7.95 (dd, J = 2.4 Hz, 8.8 Hz, 0.5H), 7.89 (dd, J = 2.4 Hz, 8.8Hz, 0.5H), 7.83 (d, J = 2.0 Hz, 1H), 7.71 (d, J = 8.0 Hz, 0.5H), 7.63 (d, J = 8.0 Hz, 0.5H), 7.59-7.53 (m, 0.5H), 7.44 (d, J = 8.0 Hz, 0.5H), 7.31 (t, J = 8.4 Hz, 0.5H), 7.28-7.23 (m, 0.5H), 7.12 (d, J = 8.0 Hz, 0.5H), 6.94 (t, J = 8.4 Hz, 0.5H), 3.50 (s, 1.5H), 3.27 (s, 1.5H), 3.05-3.00 (m, 2H), 1.76- 1.71 (m, 2H), 1.07 (t, J = 7.6 Hz, 3H). LC-MS: m/z = 492.0 [M+H] ⁺ .

[00402] Example 129: Synthesis of N-(5-(5-carbamoyl-2-chlorophenyl)-3- (pro lsulfonyl)pyridin-2yl)-2-chloro-6-fluoro-N-methylbenzamide

Ex. 128 Ex. 129

[00403] A mixture of thioether Ex. 128 (50 mg, 0.1 mmol), prepared in Example 128, and H ₂ 0 ₂ (17 mg, 0.5 mmol) in 1 mL of acetic acid was heated at 50°C for 6 h. A 1.0 M aquesous solution of Na2S03 was added (10 mL). The mixture was stirred for 30 minutes, extrated with EtOAc ( 10 mL x 2). The combined orgnaic extracts were dired and

concentrated, purified by reversed phase preparative HPLC (MeCN / H ₂ 0 = 5 to 95%) to afford 35 mg of the titled sulfone product Ex. 129 (66%) as a colorless solid. HPLC: 100%. 1H NMR (400 MHz, CDC1 _3> ) δ: 8.96 (d, J = 2.4 Hz, IH), 8.58 (d, J = 2.4 Hz, IH), 7.88-7.84 (m, 2H), 7.66 (d, J = 8.4 Hz, IH), 7.45-7.39 (m, IH), 7.33 (d, J = 8.0 Hz, IH), 7.16 (t, J = 8.0 Hz, IH), 6.15 (br s, IH), 5.67 (br s, IH), 3.53-3.42 (m, 2H), 3.35 (s, 3H), 1.95- 1.87 (m, IH), 1.81- 1.72 (m, IH), 1.06 (t, J = 7.2 Hz, 3H). LC-MS: m/z = 524.0 [M+H] ⁺ .

[00404] Examples 130 to 136

[00405] The following compounds of the present invention listed in Table 12 were prepared following the procedures set forth in Example 82, steps 2 to 4, starting with intermediate 82- B by reacting with a variety of R ⁴ X. For compounds 130, 131 and 132, iodomethane in Example 82, step 3 was replaced with other R X reagents.

[00406] Table 12:

[00407] Examples 163, 165, 167, 168, and 171

[00408] The following compounds of the present invention listed in Table 12 were prepared following the procedures set forth in Example 89 (steps 1 to 7) using a variety of R ⁴ X. For compounds of example 163, 165, and 167, iodomethane was substituted with iodomethane-d ₃ in step 5 of the procedure described in example 89.

[00409] Table 12:

Ex # Structure Characterization Data

[00410] Preparative Example 148: N-(3-((lR,3r,5S)-bicyclo[3.1.0]hexan-3-yloxy)-5-(5- carbamoyl-2-chlorophenyl)pyridin-2-yl)-2-chloro-6-fluoro-N-m ethylbenzamide.

[00411] Step 1. To a solution of cis-bicyclo .l.OJhexan-S-ol (800 mg, 8.1 mmol, 1.5 eq) in THF (3 mL) was added NaH (324 mg, 8.1 mmol, 1.5 eq) at 0 °C. The mixture was stirred for 2 h at room temp., then 3-fluoro-2-nitropyridine (760 mg, 5.4 mmol, 1.0 eq) was added. The mixture was stirred for 16 h at 60 °C then allowed to cool to room temp, and diluted with ethyl acetate (20 mL). The mixture was washed with brine (2x20 mL) and concentrated. The residue was purified by flash chromatography on silica gel (EtOAc: petroleum ether = 1/5) to give 148b (420 mg, 35%) as a light yellow oil. ESI-MS (M+H) ⁺ : 221.1. 1H NMR (400 MHz, CDC1 ₃ ) δ: 8.03 (dd, J = 1.2 Hz, 4.4 Hz, IH), 7.46 (dd, J = 4.0 Hz, 8.0 Hz, IH), 7.38 (dd, J = 1.2 Hz, 8.0 Hz, IH), 4.93-4.90 (m, IH), 2.30-2.24 (m, 2H), 2.08-2.05 (m, 2H), 1.39-1.36 (m, 2H), 0.60-0.52 (m, 2H).

[00412] Step 2. A mixture of 148b (420 mg, 1.9 mmol, 1.0 eq), Fe powder (535 mg, 9.5 mmol, 5.0 eq) and HOAc (1 mL) in EtOH (10 mL) was stirred at 80 °C for 1 h. The mixture was then filtered and the filtrate was concentrated. The residue was dissolved in EtOAc (50 mL) and the mixture was washed with aq. NaHC0 ₃ (2x50 mL) and water (50 mL). The organic phase was concentrated to give 148c (360 mg) as yellow oil. The crude product was used for the next step without further purification. ESI-MS (M+H) ⁺ : 191.1.

[00413] Step 3. Into a stirred solution of 148c (360 mg, 1.9 mmol, 1.0 eq) in acetic acid (3 mL) was added bromine (0.1 mL, 1.9 mmol, 1.0 eq) at room temp. The resulting mixture was stirred for 12 h at room temp, and then concentrated in vacuo. The residue was dissolved in EtOAc (100 mL) and washed with sat. aq. NaHC0 ₃ (100 mLX 2), brine (60 mL) and concentrated to give 148d (330 mg, 64% for two steps) as yellow oil. ESI-MS (M+H) ⁺ : 269.1. ¹ H NMR (400 MHz, CDC1 ₃ ) δ: 7.67 (d, J = 2.4 Hz, 1H), 6.86 (d, J = 2.0 Hz, 1H), 4.76-4.73 (m, 1H), 4.63 (br s, 2H), 2.30-2.24 (m, 2H), 2.05-2.01 (m, 2H), 1.39-1.36 (m, 2H), 0.57-0.41 (m, 2H).

[00414] Step 4. To a mixture of 148d (330 mg, 1.2 mmol, 1.0 eq) in pyridine (5 mL) was added 2-chloro-6-fluorobenzoyl chloride (465 mg, 2.4 mmol, 2.0 eq) at room temp. The reaction was stirred at 60 °C for 12 h and then concentrated in vacuo. The residue was dissolved in EtOAc (20 mL), washed with brine (2x20 mL) and concentrated. The crude 148e was used for the next step without further purification. ESI-MS (M+H) ⁺ : 581.1.

[00415] Step 5. To a mixture of 148e (710 mg, 1.2 mmol, 1.0 eq) in MeOH (5 mL) was added K ₂ C0 ₃ (330 mg, 2.4 mmol, 2.0 eq). The reaction was stirred at 70 °C for 2 h and then concentrated in vacuo. The residue was dissolved in EtOAc (20 mL), washed with brine (2x20 mL) and concentrated. The residue was purified by reverse phase HPLC (MeCN/water = 5% - 95%) to give 148f (250 mg, 47% for two steps) as yellow oil. ESI-MS (M+H) ⁺ : 425.1. 1H NMR (400 MHz, CDC1 ₃ ) δ: 8.08-8.02 (m, 1H), 7.34-7.32 (m, 1H), 7.23-7.05 (m, 3H), 4.83-4.79 (m, 1H), 2.33-2.20 (m, 2H), 2.08-2.01 (m, 2H), 1.41-1.40 (m, 2H), 0.59-0.39 (m, 2H).

[00416] Step 6. To a solution of 148f (250 mg, 0.6 mmol, 1.0 eq) in DMF (3 mL) was added NaH (48 mg, 1.2 mmol, 2.0 eq), followed by Mel (90 mg, 0.7 mmol, 1.2 eq) at 0 °C. The mixture was stirred for 1 h at 0 °C and then quenched with MeOH (0.5 mL). The mixture was directly purified by reversed phase HPLC (MeCN/water = 5% - 95%) to give 148g (170 mg, 65%) as light yellow solid. ESI-MS (M+H) ⁺ : 439.1.

[00417] Step 7. A mixture of 148g (170 mg, 0.4 mmol, 1.0 eq), (5-carbamoyl-2- chlorophenyl)boronic acid (95 mg, 0.5 mmol, 1.2 eq), Na ₂ C0 ₃ (85 mg, 0.8 mmol, 2.0 eq) and Pd(dppf)Cl ₂ (32 mg, 0.04 mmol. 0.1 eq) in DMF/H ₂ 0 (2.0 mL, 3/1, v/v) was stirred at 100 °C for 16 h under N ₂ . The mixture was then diluted with MeOH (3.0 mL) and filtered. The filtrate was purified by reverse phase HPLC (MeCN/water = 5% - 95%) to give 148 (75 mg, 37%) as a white solid. ESI-MS (M+H) ⁺ : 514.1, HPLC: 93.27%. 1H NMR (400 MHz, CDC1 ₃ , a mixture of conformers) δ: 8.11-7.29 (m, 5H), 7.25-6.79 (m, 3H), 6.32 (br s, 1H), 5.70 (br s, 1H), 4.83-4.80 (m, 1H), 3.30 (s, 2H), 3.28 (s, 1H), 2.30-2.12 (m, 2H), 2.10-2.07 (m, 2H), 1.39-1.34 (m, 2H), 0.64-0.57 (m, 2H).

[00418] Examples 140, 141, 142, 149, 150, 151, 152, 158, 160, 162, 166, and 170.

[00419] The following compounds of the present invention listed in Table 13 were prepared following the procedures set forth in Example 148 (steps 1 to 7) using a variety of alcohols R ₄ OH in place of ds-bicyclo .l.OJhexan-S-ol. For compounds of example 140 and 142, iodomethane was substituted with iodomethane-d ₃ in step 6 of the procedure described in example 148.

[00420] Table 13:

[00421] Preparative Example 156: 2-chloro-N-(5-(2-chloro-5-((2- hydroxyethyl)carbamoyl)phenyl)-3-(2,2,2-trifluoroethoxy)pyri din-2-yl)-6-fluoro-N- methylbenzamide

From Example 90, Step 5 156a

Ex. 156

[00422] Step. 1. The preparation of 156a was done as set forth in Example 90, Steps 1 to 7 by substituting the intermediate boronic acid 8-D with 3-borono-4-chlorobenzoic acid. EST MS (M+H) ⁺ : 517.2.

[00423] Step 2. Into a vial was added 4-Chloro-3-[6-[(2-chloro-6-fluoro-benzoyl)-methyl- amino]-5-(2,2,2-trifluoro-ethoxy)-pyridin-3-yl]-benzoic acid (156a, 50.1 mg, 0.0968 mmol), Ethanolamine (16 mg, 0.26 mmol), N,N,N',N'-Tetramethyl-0-(7-azabenzotriazol-l- yl)uronium Hexafluorophosphate (54 mg,0.14 mmol), and N,N-Dimethylformamide (1.2 mL, 16 mmol). To this was added N,N-Diisopropylethylamine (83 uL, 0.48 mmol) and the reaction was stirred at room temperature for 2 hours. EtOAc was then added and the mixture washed with NaHC0 ₃ , water and Brine. The organic layer was dried over sodium sulfate and solvent removed in vacuo. The crude product was purified by reversed phase HPLC. A second purification was done by flash column chromatography using gradient elution of 0 tol00 ethyl acetate/heptanes to give 29.7 mg (55%) of 156 as an off white solid powder. 1H NMR (400 MHz, DICHLOROMETHANE-d ₂ ) δ 8.30 (br. s., 1H), 7.91 (s, 1H), 7.27 - 7.85 (m, 4H), 7.08 - 7.24 (m, 1H), 7.01 (d, J = 8.03 Hz, 1H), 6.85 (t, J = 8.53 Hz, 1H), 6.68 (br. s., 1H), 4.39 - 4.62 (m, 2H), 3.73 - 3.85 (m, 2H), 3.57 (d, J = 4.77 Hz, 2H), 3.24 - 3.52 (m, 3H). LCMS m/z = 559.9 [M+H].

[00424] Examples 155, 154, 146, 145, 144, and 143.

[00425] The following compounds of the present invention listed in Table 14 were prepared by coupling of the intermediate 156a with a variety of amines (R ^la NR ^lb ).

00426] Table 14:

[00427] Preparative Example 190: 6-chloro-4'-(2-chloro-6-fluoro-N-methylbenzamido)-3'-

(3-fluoroazetidin-l-yl)-[l,l'-biphenyl]-3-carboxamide.

Ex. 190

190e

[00428] Step 1. Into a solution of 190a (2.0 g, 9.0 mmol, 1.0 eq) and 3-fluoroazetidine hydrochloride (1.0 g, 9.0 mmol, 1.0 eq) in DMF (20 mL) was added K ₂ C0 ₃ (3.7 g, 27.0 mmol, 3.0 eq). The mixture was stirred at 50 °C for 20 h and poured into water (100 mL). The mixture was extracted with EtOAc (100 mL X 3). The combined organic layers were washed with brine (2x100 mL), dried over Na ₂ S0 ₄ and concentrated to give 190b (2.2 g, 85%) as yellow solid. ESI-MS (M+H) ⁺ : 275.0. 1H NMR (400 MHz, Acetone- ₆ ) δ: 7.76 (d, J = 9.2 Hz, 1H), 6.99-6.97 (m, 2H), 5.59-5.42 (m, 1H), 4.39-4.29 (m, 2H), 4.23-4.13 (m, 2H).

[00429] Step 2. Into a solution of 190b (2.2 g, 8.0 mmol, 1.0 eq) in AcOH (20 mL) was added Fe powder (2.2 g, 40.0 mmol, 5.0 eq) at room temp. The mixture was then stirred at 60 °C for 2 h. The mixture was filtered and the filtrate was concentrated. The residue was dissolved in EtOAc (150 mL) and washed with aq. NaHC0 ₃ (100 mLX 2). The organic layer was dried, filtered and concentrated. The residue was purified by column chromatography on silica gel (petroleum ether/EtOAc = 5: 1) to afford 190c (1.4 g, 72%) as yellow oil. ESI-MS (M+H) ⁺ : 245.0. 1H NMR (400 MHz, CDC1 ₃ ) δ: 7.92 (dd, J = 2.4 Hz, 8.4 Hz, 1H), 6.72 (d, J = 2.0 Hz, 1H), 6.54 (d, J = 8.4 Hz, 1H), 5.43-5.24 (m, 1H), 4.18-4.09 (m, 2H), 3.90-3.81 (m, 2H), 3.58 (br s, 2H). [00430] Step 3. A mixture of 190c (1.4 g, 5.7 mmol, 1.0 eq) and 2-chloro-6-fluorobenzoyl chloride (1.1 g, 5.7 mmol, 1.0 eq) in pyridine (10 mL) was stirred at rt for 20 h. The mixture was concentrated and the residue was purified by column chromatography on silica gel (petroleum ether/EtOAc = 4: 1) to afford 190d (1.9 g, 55%) as yellow solid. ESI-MS (M+H) ⁺ : 401.0. 1H NMR (400 MHz, DMSO- ₆ ) δ: 10.10 (s, IH), 7.55-7.50 (m, IH), 7.42 (d, J = 8.0 Hz, IH), 7.36 (t, J = 8.8 Hz, IH), 7.18 (d, J = 8.8 Hz, IH), 6.97 (dd, J = 1.6 Hz, 8.0 Hz, IH), 6.73 (d, J = 2.0 Hz, IH), 5.49-5.32 (m, IH), 4.30-4.21 (m, 2H), 4.05-3.97 (m, 2H).

[00431] Step 4. Into a stirred solution of 190d (1.9 g, 4.7 mmol, 1.0 eq) in DMF (20 mL) was added NaH (224 mg, 60% in mineral, 5.6 mmol, 1.2 eq) at room temp, followed by iodomethane (674 mg, 4.7 mmol, 1.0 eq). The resulting mixture was stirred for 2 h at rt. The mixture was then poured into H ₂ 0 (100 mL) and extracted with EtOAc (50 mLX 3). The combined organic layers were washed with brine (100 mL), dried over Na ₂ S0 ₄ , and concentrated to give 190e (2.0 g, 85%) as yellow oil, which was used for the next step without further purification. ESI-MS (M+H) ⁺ : 415.0.

[00432] Step 5. A mixture of 190e (100 mg, 0.24 mmol, 1.0 eq), 5-carbamoyl-2- chlorophenylboronic acid (48 mg, 0.24 mmol, 1.0 eq), Pd(dppf)Cl ₂ (39 mg, 0.04 mmol, 0.2 eq) and Na ₂ C0 ₃ (127 mg, 1.2 mmol, 5.0 eq) in DMF/H ₂ 0 (3 mL, 3: 1, v/v) was stirred at 80 °C under N ₂ for 20 h. The mixture was filtered and the filtrate was directly purified by reversed phase HPLC (MeCN/water = 5%~95%) to give 190 (70 mg, Y: 60%) as white solid. ESI-MS (M+H) ⁺ : 490.0. 1H NMR (400 MHz, CDC1 ₃ , a mixture of conformers) δ: 7.80-7.28 (m, 5H), 7.24-6.22 (m, 4H), 6.12 (br s, IH), 5.50 (br s, IH), 5.47-5.28 (m, IH), 4.56-3.77 (m, 4H), 3.50 (s, 0.5H), 3.46 (s, IH), 3.14 (s, 1.5H).

[00433] Preparative Example 188: 6-chloro-4'-(2-chloro-6-fluoro-N-methylbenzamido)-3'- (3-fluoroazetidin-l-yl)-N-(2-hydroxyethyl)-[l,l'-biphenyl]-3 -carboxamide.

Ex. 188

[00434] Step 1. The preparation of 188a was the same as reported for 190 to provide 188a (1.18 g, 50%) as a white solid. ESI-MS (M+H) ⁺ : 491.0.

[00435] Step 2. To a solution of 188a (100 mg, 0.2 mmol, 1.0 eq) in DCM (5 mL) was added HATU (114 mg, 0.3 mmol, 1.5 eq) and DIPEA (77 mg, 0.6 mmol, 3.0 eq). The mixture was stirred at room temperature for 30 minutes and 2-aminoethanol (18 mg, 0.3 mmol, 1.5 eq) was added. The mixture was stirred for another 1 h at room temp. Water (20 mL) was added and the mixture was extracted with CH ₂ CI ₂ (20 mL). The organic layer was dried and concentrated. The residue was purified by reversed phase HPLC (MeCN/water = 5%~95%) to give 188 (32 mg, 29%) as a white solid. ESI-MS (M+H) ⁺ : 534.1. 1H NMR (400 MHz, CDCI ₃ , a mixture of conformers) δ: 7.77-7.27 (m, 4H), 7.23-6.25 (m, 5H), 5.46-5.30 (m, 1H), 4.57-3.88 (m, 4H), 3.83-3.81 (m, 2H), 3.63-3.58 (m, 2H), 3.49 (s, 0.5H), 3.46 (s, 1H), 3.14 (s, 1.5H).

[00436] Examples 187, 186, 181, 177, 184, 180, 176, 185, 174, 178, 192, 182, 183, 175, 189, 173, 194, 172, 179, and 193.

[00437] The following compounds of the present invention listed in Table 15 were prepared following the procedures set forth in Examples 190 (steps 1 to 5) and 188 (steps 1 and 2) using a variety of R ₃ amines in step 1 of example 190. For compounds of example 181, 185, 178, 183, 175, 189, 173, 174, and 179 iodomethane was substituted with iodomethane-d ₃ in step 4 of the procedure described in example 190.

[00438] Table 15:

[00439] Preparative Example 200: N-(5-(5-carbamoyl-2-chlorophenyl)-3-(3-fluoroazetidin- l-yl)pyridin-2-yl)-2-chloro-6-fluoro-N-methylbenzamide.

Ex. 200

[00440] Step 1. Hydrogen peroxide (30% in water, 5 mL) was added to sulfuric acid (10 mL) at 0 °C. The mixture was stirred below 15 °C for 1.5 h and recooled to 0 °C. A solution of 5-bromo-3-fluoro-pyridin-2-ylamine (200a, 1.3 g, 6.8 mmol, 1.0 eq) in sulfuric acid (10 mL) was then added and the reaction mixture was stirred for 16 h at rt. The mixture was carefully poured into water (100 mL) and made basic (to pH=9) with sodium carbonate. The mixture was then extracted with EtOAc (100 mL X 3). The Organic layers were combined and solvent removed in vacuo to give 200b (430 mg, 30%) as a yellow solid. ESI-MS (M+H) ⁺ : 221.0. 1H NMR (400 MHz, CDC1 ₃ ) δ: 8.48 (d, J = 1.2 Hz, 1H), 7.99 (dd, J = 1.6 Hz, 8.8 Hz, 1H).

[00441] Step 2. To a solution of 200b (450 mg, 2.0 mmol, 1.0 eq) in DMF (5 mL) were added TEA (400 mg, 4.0 mmol, 2.0 eq) and 3-fluoroazetidine (300 mg, 4.0 mmol, 2.0 eq) at rt. The mixture was stirred for 2 h under N ₂ at 90 °C and then diluted with EtOAc (200 mL). The mixture was washed with brine (3x100 mL), dried over Na ₂ S0 ₄ and concentrated to give black oil, which was purified by reversed phase HPLC (MeCN/H ₂ 0 = 2: 1) to give 200c (300 mg, 53%) as yellow oil. ESI-MS (M+H) ⁺ : 276.0.

[00442] Step 3. The preparation of 200d was the same as for 190c (Example 190, Step 2).

ESI-MS (M+H) ⁺ : 246.0. 1H NMR (400 MHz, CDC1 ₃ ) δ: 7.55 (d, J = 2.0 Hz, 1H), 6.85 (d, J = 2.0 Hz, 1H), 5.56 (br s, 2H), 5.46-5.27 (m, 1H), 4.20-4.11 (m, 2H), 3.90-3.81 (m, 2H). [00443] Step 4. The preparation of 200e was the same as 190d (Example 190, Step 3). ESI- MS (M+H) ⁺ : 558.0.

[00444] Step 5. The preparation of 200f was the same as for 190e (Example 190, Step 4).

ESI-MS (M+H) ⁺ : 402.0.

[00445] Step 6. The preparation of 200g was the same as 190e (Example 190, Step 4). ESI- MS (M+H) ⁺ : 416.0.

[00446] Step 7. The preparation of 200 was the same as for 190 (Example 190, Step 5).

ESI-MS (M+H) ⁺ : 491.1. 1H NMR (400 MHz, CD ₃ OD, a mixture of conformers) δ: 8.09-6.87 (m, 8H), 5.50-5.33 (m, 1H), 4.41-3.86 (m, 4H), 3.53 (s, 2H), 3.25-3.22 (m, 1H).

[00447] Examples 195, 197, 198 and 199.

[00448] The following compounds of the present invention listed in Table 16 were prepared following the procedures described in Example 200.

[00449] Table 16:

[00450] Preparative Example 201: N-(5-(5-carbamoyl-2-chlorophenyl)-3-(pyrrolidin-d ₈ -l- yl)pyridin-2-yl)-2-chloro-6-fluoro-N-(methyl-d3)-benzamide.

[00451] Step 1. To a solution of 201a (1.0 g, 4.6 mmol, 1.0 eq) and TEA (926 mg, 9.2 mmol, 2.0 eq) in dichloromethane (50 mL) was added slowly triflic anhydride (2.6 g, 9.2 mmol, 2.0 eq) at -78 oC. The reaction was stirred for 2 h under N2 at -78 oC and then allowed to warm to room temp, and diluted with EtOAc (100 mL). The mixture was washed with brine (3x50 mL), dried over Na2S04 and concentrated to give 201b (1.6 g, 100%) as brown oil. ESI-MS (M+H) +: 350.9. 1H NMR (400 MHz, CDC13) δ: 8.67 (d, J = 1.6 Hz, 1H), 8.10 (d, J = 1.6 Hz, 1H).

[00452] Step 2. To a solution of 201b (350 mg, 1.0 mmol, 1.0 eq) in THF (5 mL) were added TEA (202 mg, 2.0 mmol, 2.0 eq) and 212625-79-1 (79 mg, 1.0 mmol, 1.0 eq) at room temp. The mixture was stirred for 1 h at 70 °C, allowed to cool to room temp, and then diluted with EtOAc (20 mL). The organic layer was washed with brine (2x20 mL) and concentrated to give 201c. The crude product was used to the next step without further purification. ESI-MS (M+H) ⁺ : 280.0.

[00453] Step 3. A mixture of 201c (530 mg, 1.9 mmol, 1.0 eq), Fe powder (535 mg, 9.5 mmol, 5.0 eq) and HOAc (1 mL) in EtOH (10 mL) was stirred at 100 °C for 1 h. The mixture was then filtered and the filtrate was concentrated to give a residue which was dissolved in EtOAc (50 mL). The mixture was washed with aq. NaHC0 ₃ (2x50 mL) and water (2x50 mL). The organic phase was concentrated to give 201d (498 mg, 50% for two steps) as a yellow solid. ESI-MS (M+H) ⁺ : 250.0. 1H NMR (400 MHz, CDC1 ₃ ) δ: 7.76 (d, J = 2.0 Hz, 1H), 7.15 (d, J = 2.0 Hz, 1H), 4.65 (br s, 2H).

[00454] Step 4. Into a mixture of 201d (299 mg, 1.2 mmol, 1.0 eq) in pyridine (5 mL) was added 79455-63-3 (465 mg, 2.4 mmol, 2.0 eq) at rt. The reaction was stirred at 70 °C for 12 h and concentrated. The residue was dissolved in EtOAc (20 mL), washed with brine (2x20 mL) and concentrated to provide 201e. The residue was used to the next step without further purification. ESI-MS (M+H) ⁺ : 562.1.

[00455] Step 5. Into a mixture of 201e (from previous step, 1.2 mmol, 1.0 eq) in MeOH (5 mL) was added K ₂ C0 ₃ (330 mg, 2.4 mmol, 2.0 eq). The reaction was stirred at 80 °C for 2 h and then concentrated. The residue was dissolved in EtOAc (20 mL), washed with brine (2x20 mL) and concentrated. The residue was purified by reversed phase HPLC

(MeCN/water = 5%~95%) to give 201f (405 mg, 40% for two steps) as a light yellow solid. ESI-MS (M+H) ⁺ : 406.0.

[00456] Step 6. To a solution of 201f (243 mg, 0.4 mmol, 1.0 eq) in DMF (3 mL) was added NaH (30 mg, 0.8 mmol, 2.0 eq), followed by Mel-d (116 mg, 0.8 mmol, 2.0 eq) at room temp. The mixture was stirred for 1 h at room temp, and then quenched with aq. NH ₄ C1 (50 mL). The mixture was extracted with EtOAc (50 mLX 2). The combined organic extracts were dried and concentrated to give crude 201g which was used to the next step without further purification. ESI-MS (M+H) ⁺ : 423.0.

[00457] Step 7. A mixture of 201g (from previous step, 0.4 mmol, 1.0 eq), 8D (1150114-35-

4) (95 mg, 0.5 mmol, 1.2 eq), Na ₂ C0 ₃ (85 mg, 0.8 mmol, 2.0 eq) and Pd(dppf)Cl ₂ (32 mg, 0.04 mmol. 0.1 eq) in DMF/H ₂ 0 (2.0 mL, 3/1, v/v) was stirred at 90 °C for 6 h under N ₂ atmosphere. The mixture was then diluted with MeOH (3 mL) and filtered. The filtrate was purified by reversed phase HPLC (MeCN/water = 5%~95%) to give 201 (84 mg, 34%) as a white solid. ESI-MS (M+H) ⁺ : 498.0. 1H NMR (400 MHz, DMSO-d ₆ , a mixture of conformers) δ: 8.12-8.08 (m, 1H), 8.02-6.88 (m, 9H).

[00458] Examples 203, 206, 207, 214, 216, 219, 229, 202, 211, 217, 215, 218, 220, 221, 223, 224, 225, 226, 222, 205, 209, 227, 228, 230, 231, 232. The following compounds of the present invention listed in Table 17 were prepared following the procedures described in Examples 201

[00459] Table 17:

[00460] Preparative Example 212: N-(5-(5-carbamoyl-2-chlorophenyl)-3-(4-chloro- lH- pyrazol-l-yl)pyridin-2-yl)-2-chloro-6-fluoro-N-methylbenzami de.

Ex. 212

[00461] Step 1. To a mixture of 212a (1 g, 3.4 mmol, 1.0 eq) in DMF (5 mL) were added 4- chloro-lH-pyrazole (340 mg, 3.4 mmol, 1.0 eq), Cul (32 mg, 0.17 mmol, 0.05 eq), K ₂ C0 ₃ (940 mg, 6.8 mmol, 2.0 eq) and cyclohexane-l,2-diamine (78 mg, 0.68 mmol, 0.2 eq) at rt. The mixture was stirred for 16 h under N ₂ at 130 °C and then allowed to cool to room temp, and then diluted with EtOAc (300 mL). The mixture was washed with brine (3x100 mL), dried over Na ₂ S0 ₄ and concentrated to give black oil, which was purified by reversed phase HPLC (MeCN/H ₂ 0 =1: 1) to give 212b (500 mg, 55%) as a yellow solid. ESI-MS (M+H) ⁺ : 273.0. ¹ H NMR (400 MHz, CDC1 ₃ ) 5: 8.11 (d, J = 2.0 Hz, 1H), 7.76 (s, 1H), 7.68 (s, 1H), 7.54 (d, J = 2.0 Hz, 1H), 5.78 (br s, 2H).

[00462] Step 2. The preparation of 212c was the same as for 200e (Example 200, Step 4).

ESI-MS (M+H) ⁺ : 584.9.

[00463] Step 3. The preparation of 212d was the same as for 200f (Example 200, Step 5).

ESI-MS (M+H) ⁺ : 428.9. [00464] Step 4. The preparation of 212e was the same as for 133-lg (Example 200, Step 6).

ESI-MS (M+H) ⁺ : 442.9.

[00465] Step 5. The preparation of 212 was the same as for 200 (Example 200, Step 7).

ESI-MS (M+H) ⁺ : 518.0. 1H NMR (400 MHz, CDC1 ₃ , a mixture of conformers) δ: 8.70-6.78 (m, 10H), 6.61 (br s, 1H), 5.93 (br s, 1H), 3.29 (s, 3H).

[00466] Example 210. The following compound of the present invention listed in Table 18 was prepared following the procedures set forth in Example 212 (steps 1 to 5) replacing 4- chloro-lH-pyrazole with 4-Methyl-lH-pyrazole.

[00467] Table 18:

[00468] Preparative Example 196: N-(5-(5-carbamoyl-2-chlorophenyl)-3-(3- oxomorpholino)pyridin-2-yl)-2-chloro-6-fluoro-N-methylbenzam ide.

Ex. 196

[00469] Step 1. The preparation of 196a was the same as for 200c using sodium hydride as base in place of TEA. ESI-MS (M+H) ⁺ : 302.1. 1H NMR (400 MHz, DMSO- ₆ ) δ: 8.76 (d, J = 2.0 Hz, 1H), 8.74 (d, J = 2.0 Hz, 1H), 4.21 (s, 2H), 4.03-4.00 (m, 2H), 3.92-3.90 (m, 2H).

[00470] Step 2. The preparation of 196b was the same as for 200d. ESI-MS (M+H) ⁺ :

272.0. 1H NMR (400 MHz, DMSO- ₆ ) δ: 7.98 (d, J = 2.8 Hz, 1H), 7.98 (d, J = 2.4 Hz, 1H), 6.25 (br s, 2H), 4.16 (s, 2H), 4.05-3.95 (m, 2H), 3.49-3.41 (m, 2H).

[00471] Step 3. The preparation of 196c was the same as for 190d (Example 132-1, Step 3).

ESI-MS (M+H) ⁺ : 428.0

[00472] Step 4. The preparation of 196d was the same as 190e (Example 132-1, Step 4).

ESI-MS (M+H) ⁺ : 442.3.

[00473] Step 5. The preparation of 196 was the same as 190 (Example 132-1, Step 5). ESI- MS (M+H) ⁺ : 517.1. 1H NMR (400 MHz, CD ₃ OD) δ: 8.70 (d, J = 2.4 Hz, 1H), 8.19 (d, J = 1.6 Hz, 1H), 8.04 (d, J = 1.6 Hz, 1H), 7.96 (dd, J = 2.0 Hz, 8.4 Hz, 1H), 7.71 (d, J = 8.4 Hz, 1H), 7.59-7.53 (m, 1H), 7.45 (d, J = 8.4 Hz, 1H), 7.33 (t, J = 8.8

[00474] Preparative Example 234: N-(5-(5-carbamoyl-2-chlorophenyl)-3-(tetrahydrofuran-2- yl)pyridin-2-yl)-2-chloro-6-fluoro-N-methylbenzamide.

Ex. 234

[00475] Step 1. To a solution of 3-bromo-2-nitropyridine (163a, 1.0 g, 5.0 mmol, 1.0 eq) in 1,4-dioxane (3 mL) were added [tBu ₃ PH]BF ₄ (145 mg, 0.5 mmol, 0.1 eq), N-methyl- dicyclhexylamine (1.95 g, 10 mmol, 2.0 eq), Pd ₂ (dba) ₃ (145 mg, 0.5 mmol, 0.1 eq) and 2,3- dihydrofuran (700 mg, 10 mmol, 2.0 eq). The mixture was stirred for 2 h at 80 °C and then allowed to cool to room temp. The catalyst was removed by filtration and the filtrate was diluted with EtOAc (50 mL) washed with brine (2x50 mL) and concentrated in vacuo to give 234b as yellow oil. This material was used to the next step without further purification. ESI- MS (M+H) ⁺ : 193.0, 1H NMR (400 MHz, CDC1 ₃ ) δ: 8.53 (dd, J = 2.0 Hz, 8.8 Hz, 1H), 8.19- 8.16 (m, 1H), 7.68-7.64 (m, 1H), 6.51-6.49 (m, 1H), 6.02-5.97 (m, 1H), 5.00-4.97 (m, 1H), 3.45-3.38 (m, 1H), 2.51-2.45 (m, 1H).

[00476] Step 2. To a solution of 234b (5.0 mmol, 1.0 eq) in MeOH (15 mL) was added Pd/C (100 mg, 10% wt). The mixture was hydrogenated under one atmosphere of pressure for 16 h at rt. The catalyst was then removed by filtration and the filtrate was concentrated to give 234c as yellow oil. This material was used to the next step without further purification. EST MS (M+H) ⁺ : 165.0, 1H NMR (400 MHz, CD ₃ OD) δ: 7.84 (dd, J = 1.2 Hz, 4.8 Hz, 1H), 7.50 (dd, J = 0.8 Hz, 7.6 Hz, 1H), 6.65 (dd, J = 0.8 Hz, 7.2 Hz, 1H), 4.80 (t, J = 1.2 Hz, 1H), 4.12- 4.07 (m, 1H), 3.92-3.86 (m, 1H), 2.34-2.29 (m, 1H), 2.08-2.01 (m, 2H), 1.92-1.90 (m, 1H).

[00477] Step 3. Into a stirred solution of 234c (from previous step, 5.0 mmol, 1.0 eq) in acetic acid (10 mL) was added bromine (0.4 mL, 7.5 mmol, 1.5 eq) at room temp. The resulting mixture was stirred for 2 h at room temp, and then concentrated in vacuo. The residue was neutralized to pH = 7 with sat. aq. NaHC0 ₃ solution. The mixture was then extracted with EtOAc (4x30 mL). The combined organic extracts were washed with brine (60 mL), dried over Na ₂ S0 ₄ , filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (petroleum ether/EtOAc = 3: 1) to give 234d (691 mg, 57%) as a yellow solid. ESI-MS (M+H) ⁺ : 243.0, 1H NMR (400 MHz, CD ₃ OD) δ: 7.89 (d, J = 2.4 Hz, 1H), 7.59 (d, J = 2.4 Hz, 1H), 4.78 (t, J = 7.2 Hz, 1H), 4.13-4.07 (m, 1H), 3.92-3.86 (m, 1H), 2.40-2.31 (m, 1H), 2.11-1.95 (m, 2H), 1.84-1.75 (m, 1H).

[00478] Step 4. To a mixture of 234d (360 mg, 1.5 mmol, 1.0 eq) in pyridine (2 mL) was added 2-chloro-6-fluorobenzoyl chloride (864 mg, 4.5 mmol, 3.0 eq). The mixture was stirred at 70 °C for 12 h and then concentrated in vacuo. The residue was dissolved in EtOAc (20 mL) and washed with brine (2x20 mL). The organic layer was concentrated in vacuo to give crude 234e as yellow oil. ESI-MS (M+H) ⁺ : 555.0.

[00479] Step 5. A mixture of 234e (from previous step, 1.5 mmol, 1.0 eq) and K ₂ C0 ₃ (621 mg, 4.5 mmol, 3.0 eq) in MeOH (20 mL) was heated at reflux for 2 h and then allowed to cool to room temp, and filtered. The filtrate was concentrated and the residue was directly purified by reverse phase HPLC (MeCN/water = 5%-95%) to give 234f (200 mg, 30%) as a yellow solid. ESI-MS (M+H) ⁺ : 399.0, 1H NMR (400 MHz, CD ₃ OD) δ: 8.48 (s, 1H), 8.15 (s, 1H), 7.54-7.18 (m, 3H), 5.17 (t, J = 7.2 Hz, 1H), 4.17-4.11 (m, 1H), 3.93-3.88 (m, 1H), 2.58- 2.53 (m, 1H), 2.04-2.02 (m, 2H), 1.78-1.73 (m, 1H).

[00480] Step 6. To a solution of 234f (200 mg, 0.5 mmol, 1.0 eq) in DMF (3 mL) at room temp, was added NaH (40 mg, 60% in oil, 1.0 mmol, 2.0 eq), followed by Mel (142 mg, 1.0 mmol, 2.0 eq). The mixture was allowed to stir for 1 h and then quenched with aq. NH ₄ C1 (20 mL). The aqueous was extracted with EtOAc (20 mLX 2) and the combined organics were dried, filtered and concentrated in vacuo to give 234g as yellow oil. This material was used for the next step without further purification. ESI-MS (M+H) ⁺ : 413.0. [00481] Step 7. A mixture of 234g (from previous step, 0.5 mmol, 1.0 eq), PdCl ₂ (dppf) (40 mg, 0.05 mmol, 0.1 eq), 5-carbamoyl-2-chlorophenylboronic acid (120 mg, 0.6 mmol, 1.2 eq) and Na ₂ C0 ₃ (106 mg, 1.0 mmol, 2.0 eq) in DMF/H ₂ 0 (2.0 mL, 3: 1) was stirred for 6 h at 90 °C under N ₂ . The mixture was allowed to cool to room temp., filtered and the filtrate was purified by reverse phase HPLC (MeCN : H ₂ 0 = 5% - 95%) to give 234 (77 mg, 32%) as a white solid. ESI-MS (M+H) ⁺ : 488.0. 1H NMR (400 MHz, CD ₃ OD, a mixture of conformers) δ: 8.62-6.91 (m, 8H), 5.37-5.07 (m, 1H), 4.19-4.08 (m, 1H), 3.96-3.88 (m, 1H), 3.52 (s, 0.7H), 3.31 (s, 2.1H), 2.59-2.47 (m, 1H), 2.15-1.72 (m, 3H).

[00482] Preparative Example 235: N-(5-(5-carbamoyl-2-chlorophenyl)-3-(tetrahydrofuran-3- yl)pyridin-2-yl)-2-chloro-6-fluoro-N-methylbenzamide.

Ex. 235

[00483] Step 1. A mixture of 3-bromo-2-nitropyridine (235a, 1.03 g, 5.08 mmol), 2-(2,5- dihydrofuran-3-yl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (996 mg, 5.08 mmol, 1.0 eq), S- phos (208 mg, 0.51 mmol, 0.1 eq), Pd(OAc) ₂ (56 mg, 0.25 mmol, 0.05 eq) and K ₃ P0 ₄ (3.23 g, 15.2 mmol, 3.0 eq) in THF/H ₂ 0 (20 mL, 9: 1) was stirred at 60 °C for 3 h under N ₂ . The mixture was then allowed to cool to room temp., diluted with EtOAc (150 mL) and washed with water (100 mLX 2). The organic layer was dried, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (petroleum ether/EtOAc = 4: 1) to give 235b (890 mg, 94%) as brown oil. ESI-MS (M+H) ⁺ : 193.1. 1H NMR (400 MHz, CDC1 ₃ ) δ: 8.46 (dd, J = 1.6 Hz, 4.8 Hz, 1H), 7.79 (dd, J = 1.6 Hz, 8.0 Hz, 1H), 7.57 (dd, J = 4.8 Hz, 8.0 Hz, 1H), 6.13-6.11 (m, 1H), 4.92-4.83 (m, 4H).

[00484] Steps 2 to 7. Intermediate 235b was converted to the final product of example 235 following the procedures set forth in steps 2 to 7 of example 234. ESI-MS (M+H) ⁺ : 399.1, 1H NMR (400 MHz, CDC1 ₃ , a mixture of conformers) δ: 8.52-7.31 (m, 7H), 7.15-7.11 (m, 1H), 6.21 (br s, 1H), 5.66 (br s, 1H), 4.14-3.75 (m, 5H), 3.52-3.35 (m, 3H), 2.59-2.45 (m, 1H), 2.15-1.90 (m, 1H).

[00485] Preparative Example 233. The following compound of the present invention listed in Table 19 was prepared following the procedures set forth in Example 235 (steps 1 to 7) replacing 2-(2,5-dihydrofuran-3-yl)-4,4,5,5-tetramethyl-l,3,2-dioxabor olane with 2-(3,6- dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-l,3,2-dioxaborola ne.

[00486] Table 19:

[00487] Preparative Example 239 and 238: N-(5-(5-carbamoyl-2-chlorophenyl)-3- ((cyclopropylmethyl)sulfonyl)pyridin-2-yl)-2-chloro-6-fluoro -N-methylbenzamide.

Ex. 238

[00488] Step 1. The preparation of 239a was the same as that for step 2 of Example 128 (128-B) substituting propanethiol with p-methoxybenzylthiol. ESI-MS (M+H) ⁺ : 277.0. 1H NMR (400 MHz, CD ₃ OD) δ: 8.34 (dd, J = 1.6 Hz, 4.4 Hz, 1H), 7.88 (dd, J = 1.6 Hz, 8.0 Hz, 1H), 7.49 (dd, J = 4.4 Hz, 8.0 Hz, 1H), 7.30 (d, J = 8.8 Hz, 2H), 6.87 (d, J = 8.8 Hz, 2H), 4.16 (s, 2H), 3.80 (s , 3H).

[00489] Step 2. A solution of 239a (3.0 g, 10.8 mmol, 1.0 eq) in TFA (15 mL) was stirred at 70 °C for 20 h. The mixture was concentrated and the residue was purified by column chromatography on silica gel (petroleum ether/EtOAc = 3: 1) to afford 1.35 g of 239b (81 ) as brown powder. ESI-MS (M+H) ⁺ : 157.1. 1H NMR (400 MHz, CDC1 ₃ ) δ: 8.53 (dd, J = 1.6 Hz, 4.8 Hz, 1H), 8.32 (dd, J = 1.6 Hz, 8.4 Hz, 1H), 7.62 (dd, J = 4.4 Hz, 8.4 Hz, 1H). [00490] Step 3. Into a stirred solution of compound 239b (1.35 g, 8.6 mmol, 1.0 eq) in DMF (15 mL) was added NaH (0.52 g, 12.9 mmol, 1.5 eq), followed by cyclopropylmethyl bromide (1.72 g, 12.9 mmol, 1.5 eq). The resulting reaction mixture was stirred for 4 h at rt. and then poured into H ₂ 0 (50 mL) and extracted with EtOAc (50 mL X 3). The combined organic layers were dried over Na ₂ S0 ₄ and concentrated. The residue was purified by column chromatography on silica gel (petroleum ether/EtOAc = 5: 1) to afford 1.36 g (75%) of 239c as yellow oil. ESI-MS (M+H) ⁺ : 211.0. ¹ H NMR (400 MHz, DMSO- ₆ ) δ: 8.37 (dd, J = 1.6 Hz, 4.4 Hz, 1H), 8.23 (dd, J = 1.6 Hz, 8.4 Hz, 1H), 7.76 (dd, J = 4.0 Hz, 8.0 Hz, 1H), 3.05 (d, J = 7.2 Hz, 2H), 1.03-0.96 (m, 1H), 0.58-0.54 (m, 2H), 0.31-0.21 (m , 2H).

[00491] Step 4. The preparation of 239d was the same as for 128-C (Example 128, Step 3). ESI-MS (M+H) ⁺ : 181.0. 1H NMR (400 MHz, CD ₃ OD) δ: 7.73 (dd, J = 1.6 Hz, 4.8 Hz, 1H), 7.56 (dd, J = 1.6 Hz, 7.6 Hz, 1H), 6.47 (dd, J = 4.8 Hz, 7.6 Hz, 1H), 2.56 (d, J = 1.6 Hz, 2H), 0.84-0.80 (m, 1H), 0.39-0.34 (m, 2H), 0.02-0.01 (m , 2H).

[00492] Step 5. The preparation of 239e was the same as for 128-D (Example 128, Step 4). ESI-MS (M+H) ⁺ : 259.0.

[00493] Step 6. The preparation of 239f was the same as for 128-E (Example 128, Step 5). ESI-MS (M+H) ⁺ : 571.0.

[00494] Step 7. The preparation of 239g was the same as for 128-F (Example 128, Step 6). ESI-MS (M+H) ⁺ : 415.0.

[00495] Step 8. The preparation of 239h was the same as for 128-G (Example 128, Step 7). ESI-MS (M+H) ⁺ : 429.1.

[00496] Step 9. The preparation of 239 was the same as for Example 128 (Step 8). ESI-MS (M+H) ⁺ : 504.0, HPLC: 100%. 1H NMR (400 MHz, CD ₃ OD _, a mixture of conformers) δ: 8.45 (d, J = 1.6 Hz, 0.5H), 8.08 (dd, J = 2.0 Hz, 10.4 Hz, 1H), 8.01-7.86 (m, 2H), 7.82 (d, J = 1.6 Hz, 0.5H), 7.70 (d, J = 8.4 Hz, 0.5H), 7.62 (d, J = 8.4 Hz, 0.5H), 7.51-7.53 (m , 0.5H), 7.44 (d, J = 8.8 Hz, 0.5H), 7.33-7.22 (m, 1H), 7.11 (d, J = 8.0 Hz, 0.5H), 6.94 (t, J = 8.8 Hz, 0.5H), 3.53 (s, 1.5H), 3.29 (s, 1.5H), 3.11-2.97 (m, 2H), 1.13-1.106 (m, 1H), 0.65-0.60 (m, 2H), 0.34-0.31 (m, 2H).

[00497] Step 10. The preparation of 238 was the same as for Example 129. ESI-MS (M+H) ⁺ : 536.0, HPLC: 100%. 1H NMR (400 MHz, CDC1 ₃ ) δ: 9.04 (d, J = 1.6 Hz, 1H), 8.69 (s, 1H), 8.06 (d, J = 1.6 Hz, 1H), 8.01 (d, J = 8.4 Hz, 1H), 7.75 (d, J = 8.4 Hz, 1H), 7.59-7.55 (m, 1H), 7.45 (d, J = 8.0 Hz, 1H), 7.33-7.30 (m, 1H), 3.53-3.38 (m, 2H), 3.31 (s, 3H), 1.15- 1.09 (m, 1H), 0.66-0.64 (m, 1H), 0.48-0.44 (m, 1H), 0.42-0.25 (m, 2H).

[00498] Examples 237 and 236. The following compounds of the present invention listed in Table 20 were prepared from intermediate 128-A following the procedures set forth in Example 239 and 238 (steps 1 to 10) substituting cyclopropylmethyl bromide with iodomethane and iodoethane.

[00499] Table 20:

[00500] Preparative Example 243: 6-chloro-4'-(2-chloro-6-fluoro-N-CD ₃ -benzamido)-N-(2- hydroxyethyl)-3'-(2,2,2-trifluoroethoxy)-[l, l'-biphenyl]-3-carboxamide.

Ex. 243

[00501] Step .1 : A mixture of 2-iiitraphenol ( 1 .39 g, 10 mmol), CF ₃ CH ₂ OTf (3.48 g, 15 mmol,, i .5 eq) and CS2CO3 (6.5 g. 20 mmol, 2.0 eq) in 10 mi, ofDMF was stirred at it for 16 h. The mixture was diluted with 150 niL of EtOAc and washed with water (100 niL*2) and brine (100 ml). The organic was dried and concenirated in vacuo to give 243a (2.2 g, 99%) as yellow solid, which was used to the next step without further purification. ESI- S

(M+H)+: 222.1 . ^} H NM (400 MHz, COC ) δ: 7.89 (d, J - 8.4 Hz, 1 H). 7.59-7.56 (ra, 1H), 7.23-7.18 (m, l H), 7.13 (d, J - 8.4 Hz, 1H), 4.49 (q, J ^' = 8.0 l¾, 2H).

[00502] Step 2: A mixture of 243 a (2,2 g, 10 mmol), Fe powder (2.8 g, 50 mmof 5.0 eq) and HO Ac (3.0 g, 50 mmol, 5.0 eq) in 30 ml, of EtOH was heated, at reflux for 2 h and cooled down. The mixture was filtered through a ("elite pad and the filtrate was concentrated to give 243b ( 1.9 g, 100%) as brown solid, which was used to the ne t step without further purification. ESI-MS (M+H) ⁺ : 192.1.

[00503] Step 3: To a solution of 243b (1.9 g, 10 mmol) in 20 mL of HOAc was added Br ₂ (2.4 g, 15 mmol, 1.5 eq). The mixture was stirred at rt for 1 h and concentrated. The residue was dissolved in 100 mL of EtOAc and washed with aq. NaHC0 ₃ (100 mL X 3). The organic was dried and concentrated in vacuo. The residue was purified by column chromatography on silica gel (petroleum ether/EtOAc = 4: 1) to give 243c (1.6 g, 60%) as light yellow solid. ESI- MS (M+H) ⁺ : 270.2. 1H NMR (400 MHz, CDC1 ₃ ) δ: 6.99 (dd, J = 1.6 Hz, 8.4 Hz, 1H), 6.89 (d, J = 1.6 Hz, 1H), 6.62 (d, J = 8.0 Hz, 1H), 4.34 (q, J = 8.0 Hz, 2H).

[00504] Step 4: To a solution of 243c (1.6 g, 5.92 mmol) in pyridine (10 mL) was added 1-B (1.4 g, 7.10 mmol, 1.2 eq). The mixture was stirred at rt for 16 h and then concentrated in vacuo. The residue was purified by column chromatography on silica gel (petroleum ether/EtOAc = 6: 1) to give 243d as yellow solid (1.8 g, 70%). ESI-MS (M+H) ⁺ : 426.1

[00505] Step 5: To a solution of 243d (500 mg, 1.17 mmol) in 5 mL of DMF was added NaH (94 mg, 60% in mineral oil, 2.34 mmol, 2.0 eq), followed by CD ₃ I (203 mg, 1.4 mmol, 1.2 eq). The reaction was stirred at rt for lh and quenched with water (50 mL). The mixture was extracted with EtOAc (50 mLX 2). The combined organics were washed with water (50 mL), brine (50 mL), dried over Na ₂ S0 ₄ and concentrated in vacuo to give 243e as yellow solid (470 mg, Y: 90%), which was used to the next step without further purification. ESI-MS (M+H) ⁺ : 443.1.

[00506] Step 6: A mixture of 243e (1.0 g, 2.3 mmol, 1.0 eq), 3-borono-4-chlorobenzoic acid 2-C (550 mg, 2.8 mmol, 1.2 eq), Na ₂ C0 ₃ (488 mg, 4.6 mmol, 2.0 eq) and Pd(dppf)Cl ₂ (150 mg, 0.2 mmol. 0.1 eq) in DMF/H ₂ 0 (12 mL, 3/1, v/v) was stirred at 90 °C for 16 h under N ₂ atmosphere. The mixture was diluted with MeOH (5 mL) and filtered. The filtrate was directly purified by reversed phase HPLC (MeCN/water = 5%~95%) to give 243f (1.1 g, 86%) as a yellow solid.

[00507] ESI-MS (M+H) ⁺ : 519.0. 1H NMR (400 MHz, CDC1 ₃ , a mixture of conformers) δ: 8.10-7.95 (m, 2H), 7.62-7.36 (m, 3H), 7.16-6.72 (m, 4H), 4.51-4.38 (m, 2H).

[00508] Step 7: A mixture of 243f (104 mg, 0.2 mmol, 1.0 eq), 2-aminoethanol (24 mg, 0.4 mmol, 2.0 eq), HATU (152 mg, 0.4 mmol, 2.0 eq) and TEA (40 mg, 0.4 mmol. 2.0 eq) in DMF (3 mL) was stirred at rt for 1 h. The mixture was then directly purified by reversed phase HPLC (MeCN/water = 5%~95%) to give 243 (35 mg, 31%) as a white solid. ESI-MS (M+H) ⁺ : 562.1. 1H NMR (400 MHz, CD ₃ OD, a mixture of conformers) δ: 7.84-6.77 (m, 9H), 4.67-4.43 (m, 2H), 3.63-3.57 (m, 2H), 3.42-3.36 (m, 2H).

[00509] Preparative Examples 244 to 270:

[00510] In some embodiments of the compounds of Formula II, the compound has the Formula Ilf:

Formula Ilf

[00511] The following compounds of the present invention listed in Table 21 were prepared following the procedures set forth in Example 243, Steps 1 to 7. The 2-aminoethanol in Step 7 was replaced with a variety of amines to give the final products. For Examples 245, 247, 253, ie/t-butyl piperidin-4-ylcarbamate, ie/t-butyl azetidin-3-ylcarbamate and iert-butyl piperazine-l-carboxylate were used (respectively) in Step 7 and the final products were obtained after removal of the BOC group using trifluoroacetic acid in methylene chloride at room temperature.

[00512] Table 21:

3.30-3.21 (m, 2H),

2.82 (s, 6H). ESI- MS (M+H) ⁺ : 589.1.

[00513] Preparative Examples 271 and 272: 3-(6-chloro-4'-(2-chloro-6-fluoro-N-CD ₃ - benzamido)-3'-(2,2,2-trifluoroethoxy)-[l, -biphenyl]-3-ylcarboxamido)propanoic acid and N-(3-amino-3-oxopropyl)-6-chloro-4'-(2-chloro-6-fluoro-N-CD ₃ -benzamido)-3'-(2,2,2- trifhioroethoxy) -[1,1 '-biphenyl] - 3 -c arboxamide .

Ex. 272

[00514] Step 1: A mixture of intermediate 243f (108 mg, 0.32 mmol, 1.0 eq), ethyl 3- aminopropanoate hydrochloride (100 mg, 0.65 mmol, 2.0 eq), HATU (246 mg, 0.65 mmol, 2.0 eq) and TEA (65 mg, 0.38 mmol. 2.0 eq) in DMF (3 mL) was stirred at rt for 1 h. The mixture was directly purified by reversed phase HPLC (MeCN/water~0.05% ammonia) to give 271a (200 mg, 76%) as a brown solid. ESI-MS (M+H) ⁺ : 618.2.

[00515] Step 2: Into a solution of 271a (200 mg, 0.32 mmol, 1.0 eq) in MeOH (3 mL) was added LiOH (39 mg, 0.97 mmol, 3.0 eq) and H ₂ 0 (0.5 mL). The reaction was stirred at 35 °C for 2 h. The mixture was acidified with IN HC1 to pH = 6 and concentrated in vacuo. The residue was purified by reverse phase HPLC (MeCN/water = 5%~95%) to give 271 (150 mg, 79%) as a white solid. ESI-MS (M+H) ⁺ : 590.1.

[00516] Step 3: A mixture of 271 (104 mg, 0.19 mmol, 1.0 eq), ammonium chloride (21 mg, 0.39 mmol, 2.0 eq), HATU (149 mg, 0.38 mmol, 2.0 eq) and TEA (38 mg, 0.39 mmol. 2.0 eq) in DMF (3 mL) was stirred at rt for 1 h. The mixture was directly purified by reversed phase HPLC (MeCN/water~0.05% ammonia) to give 272 (50 mg, 43%) as a white solid. ESI-MS (M+H) ⁺ : 589.1. 1H NMR (400 MHz, CDC1 ₃ , a mixture of conformers) δ: 7.76-6.72 (m, 10H), 5.95-5.46 (m, 2H), 4.52-4.38 (m, 2H), 3.73-3.69 (m, 2H), 2.57-2.54 (m, 2H).

[00517] Examples 273 to 277. The following compounds of the present invention listed in Table 22 were prepared following the procedures described in Example 271, steps 1 and 2.

[00518] Table 22:

[00519] Examples 278 to 281. The following compounds of the present invention listed in Table 23 were prepared following the procedures described in Example 148.

[00520] Table 23:

[00521] Preparative Examples 282-311

[00522] The following compounds of the present invention listed in Table 24 were prepared following the procedures set forth in Example 243, Steps 1 to 7. The 2-aminoethanol in Step 7 was replaced with a variety of amines to give the final products. For compounds 447, 449 and 450, tert-butyl azetidin-3-yl(methyl)carbamate, (S)-tert-butyl pyrrolidin-3- ylcarbamate and (R) -tert-butyl pyrrolidin-3-ylcarbamate were used respectively in Step 7 and the final products were isolated after removal of the BOC groups with trifluoroacetic acid in methylene chloride at room temperature.

[00523] Table 24:

337

SUBSTITUTE SHEET (RLILE 26)

[00524] Preparative Example 312. The following compound of the present invention listed in Table 25 was prepared following the procedures described in Example 271, steps 1 and 2.

[00525] Table 25:

[00526] In some embodiments of the compounds of Formula II, the compound has the Formula Ilg:

Formula Ilg

[00527] Examples 313 to 365.

[00528] The following compounds of the present invention listed in Table 26 were prepared following the procedures set forth in Examples 190 (steps 1 to 5) and 188 (steps 1 and 2) using a variety of R ₃ amines in step 1 of Example 190. For compounds of example, 314, 319, 333, 334, 335, 341, 351, 352, 353, 354, 357, 358, 359, 360, 362, 364, iodomethane was substituted with iodomethane-d ₃ in step 4 of the procedure described in Example 190.

[00529] Table 26:

[00530] Preparative Examples: 366 to 372.

[00531] Preparative Example 366: 4'-(2-chloro-6-fluoro-N-methylbenzamido)-3'-(3- fluoroazetidin-l-yl)-6-methyl-[l,l'-biphenyl]-3-carboxamide.

Ex. 366

[00532] Step 1: A mixture of Intermediate 190e (4.0 g, 9.6 mmol, 1.0 eq), Pin ₂ B ₂ (3.0 g, 11.5 mmol, 1.2 eq), Pd(dppf)Cl ₂ (816 mg, 1.0 mmol, 0.2 eq) and KOAc (2.8 g, 29 mmol, 3.0 eq) in 1,4-dioxane (30 mL) was stirred at 80 °C under N ₂ for 20 h. The mixture was then filtered and the filtrate was concentrated in vacuo. The residue was purified by reverse phase HPLC (MeCN/water = 5%~95%) to give 366a (2.6 g, 60%) as white solid. ESI-MS (M+H) ⁺ : 463.2.

[00533] Step 2: A mixture of 366a (150 mg, 0.3 mmol, 1.0 eq), 366b (463 mg, 0.3 mmol, 1.0 eq), Pd(dppf)Cl ₂ (24 mg, 0.03 mmol, 0.1 eq) and Na ₂ C0 ₃ (160 mg, 1.5 mmol, 5.0 eq) in DMF/H ₂ 0 (3 mL, 3: 1, v/v) was stirred at 80 °C under N ₂ for 20 h. The mixture was then filtered and the filtrate was directly purified by reversed phase HPLC (MeCN/water = 5%~95%) to give 366c (80 mg, 50%) as white solid. ESI-MS (M+H) ⁺ : 471.1.

[00534] Step 3: Into the stirred solution of 366c (80 mg, 0.17 mmol, 1.0 eq), HATU (95 mg, 0.25 mmol, 1.5 eq) and NH ₄ C1 (18 mg, 0.34 mmol, 2.0 eq) in DCM (5 mL) was added Et N (57 mg, 0.57 mmol, 3.0 eq). The mixture was stirred at rt for 3 h. The mixture was then filtered, and the filtrate was concentrated in vacuo to remove the solvent. The product was purified by reversed phase HPLC (MeCN/water = 5%~95%) to give 366 (70 mg, 87%) as white solid. ESI-MS (M+H) ⁺ : 470.2. 1H NMR (400 MHz, CD ₃ OD, a mixture of conformers) δ: 7.68-6.14 (m, 9H), 5.39-5.19 (m, 1H), 4.33-3.64 (m, 4H), 3.39-3.37 (m, 1.8H), 3.06-3.04 (m, 1.2H), 2.25 (s, 1.2H), 2.00 (s, 1.8H).

[00535] Preparative Example 367: 4'-(2-chloro-6-fluoro-N-methylbenzamido)-3'-(3- fluoroazetidin-l-yl)-6-isopropyl-[l,l'-biphenyl]-3-carboxami de

[00536] Compound 367 was prepared following the procedures set forth in Example 366 by coupling of the intermediate 366a with 3-bromo-4-isopropylbenzamide to provide 60 mg (80%) of 367 as a white solid. ESI-MS (M+H) ⁺ : 498.2. 1H NMR (400 MHz, CD ₃ OD, a mixture of conformers) δ: 7.87-6.19 (m, 9H), 5.51-5.31 (m, 1H), 4.48-4.01 (m, 4H), 3.51- 3.49 (m, 1.5H), 3.17-3.15 (m, 1.5H), 2.71-2.60 (m, 1H), 1.23-1.03 (m, 6H).

[00537] Preparative Example 368: 2-chloro-N-(2'-chloro-3-(3-fluoroazetidin-l-yl)-4'- sulfamoyl- [1,1 '-biphenyl] -4-yl)-6-fluoro-N-methylbenzamide.

[00538] Compound 368 was prepared following the procedures set forth in Example 366 by coupling of the intermediate 366a with 4-bromo-3-chlorobenzenesulfonamide to provide 80 mg (58%) of 368 as a white solid. ESI-MS (M+H) ⁺ : 526.1. 1H NMR (400 MHz, CD ₃ OD, a mixture of conformers) δ: 8.03-6.34 (m, 9H), 5.53-5.31 (m, 1H), 4.50-3.84 (m, 4H), 3.50- 3.48 (m, 1.6H), 3.17-3.15 (m, 1.4H).

[00539] Preparative Example 369: 2-chloro-N-(2'-chloro-3-(3-fluoroazetidin-l-yl)-5'- sulfamoyl- [1,1 '-biphenyl] -4-yl)-6-fluoro-N-methylbenzamide.

[00540] Compound 369 was prepared following the procedures set forth in Example 366 by coupling of the intermediate 366a with 3-bromo-4-chlorobenzenesulfonamide to provide 120 mg (50%) of 369 as a white solid. ESI-MS (M+H) ⁺ : 526.1. 1H NMR (400 MHz, CD ₃ OD, a mixture of conformers) δ: 7.92-6.34 (m, 9H), 5.54-5.30 (m, 1H), 4.50-3.79 (m, 4H), 3.50- 3.48 (m, 1.7H), 3.17-3.15 (m, 1.3H).

[00541] Preparative Example 370: 2-chloro-4'-(2-chloro-6-fluoro-N-methylbenzamido)-3'- (3-fluoroazetidin-l-yl)- [1,1 '-biphenyl] -3-carboxamide.

[00542] Compound 370 was prepared following the procedures set forth in Example 366 by coupling of the intermediate 366a with 3-bromo-2-chlorobenzamide to provide 100 mg (75%) of 370 as a white solid. ESI-MS (M+H) ⁺ : 490.1. 1H NMR (400 MHz, CD ₃ OD, a mixture of conformers) δ: 7.57-6.30 (m, 9H), 5.51-5.31 (m, 1H), 4.88-3.75 (m, 4H), 3.50- 3.47 (m, 1.6H), 3.17-3.15 (m, 1.4H).

[00543] Preparative Example 371: 4'-(2-chloro-6-fluoro-N-methylbenzamido)-3'-(3- fluoroazetidin-l-yl)-6-methoxy-[l,l'-biphenyl]-3-carboxamide .

[00544] Compound 371 was prepared following the procedures set forth in Example 366 by coupling of the intermediate 366a with 3-bromo-4-methoxybenzamide to provide 65 mg (73%) of 371 as a white solid. ESI-MS (M+H) ⁺ : 486.2. 1H NMR (400 MHz, CD ₃ OD, a mixture of conformers) δ: 7.93-6.47 (m, 9H), 5.51-5.30 (m, 1H), 4.47-3.95 (m, 4H), 3.89 (s, 1.5H), 3.82 (s, 1.5H), 3.48-3.14 (m, 3H).

[00545] Preparative Example 372: 4'-(2-chloro-6-fluoro-N-methylbenzamido)-3'-(3- fluoroazetidin- 1 -yl)-6-(trifluoromethyl)- [ 1 , 1 '-biphenyl] -3-carboxamide.

[00546] Compound 372 was prepared following the procedures set forth in Example 366 by coupling of the intermediate 366a with 3-bromo-4-(trifluoromethyl)benzamide to provide 70 mg (64%) of 372 as a white solid. ESI-MS (M+H) ⁺ : 516.1. 1H NMR (400 MHz, CD ₃ OD, a mixture of conformers) δ: 7.99-6.30 (m, 9H), 5.49-5.35 (m, 1H), 4.39-3.48 (m, 6H), 3.17- 3.16 (m, 1H).

[00547] Preparative Example 373: 4'-(2-chloro-6-fluoro-N-methylbenzamido)-6-fluoro-3'- (3-fluoroazetidin-l-yl)-[ 1,1 '-biphenyl] -3-carboxamide.

[00548] Compound 373 was prepared following the procedures set forth in Example 366 by coupling of the intermediate 366a with 3-bromo-4-fluorobenzamide to provide 80 mg (67%) of 373 as a white solid. ESI-MS (M+H) ⁺ : 574.1. 1H NMR (400 MHz, CD ₃ OD, a mixture of conformers) δ: 8.09-6.54 (m, 9H), 5.55-5.39 (m, 1H), 4.42-3.41 (m, 5.5H), 3.16-3.01 (m, 1.5H).

[00549] Preparative Examples 374-380:

Formula Ilh

[00550] The following compounds of the present invention listed in Table 27 were prepared following the procedures set forth in Examples 190 (steps 1 to 5) and 188 (steps 1 and 2) using a variety of R amines in step 1 of example 190. For compounds of Example 375, 376, 377, 378, 379, 380, iodomethane was substituted with iodomethane-d ₃ in Step 4 of the procedure described in example 190. [00551] Table 27:

[00552] Examples 382 to 399.

Ex. 382 to 399

[00553] Step 1: A mixture of 381a (3.2 g, 12.7 mmol, 1.0 eq), Boc ₂ 0 (5.5 g, 25.4 mmol, 2.0 eq) and K ₂ C0 ₃ (3.5 g, 25.4 mmol, 2.0 eq) in THF-H ₂ 0 (1: 1, 50 mL) was heated at 70 °C for 16 h. The reaction mixture was cooled to room temp and then diluted with EtOAc (100 mL). The mixture was washed with brine (3x50 mL), dried over Na ₂ S0 ₄ and concentrated to give 381b (3.8 g, 85%) as brown oil. ESI-MS (M+H) ⁺ : 352.9.

[00554] Step 2: Into a solution of 381b (3.6 g, 10.2 mmol, 1.0 eq) in anhydrous DMF (10 mL) was added K ₂ C0 ₃ (2.8 g, 20.8 mmol, 2.0 eq) at room temp, under N ₂ and then Mel (1.7 g, 12.2 mmol, 1.2 eq) was added. After stirring for 16 h at room temp., the mixture was diluted with aq. NH ₄ C1 (50 mL) and extracted with EtOAc (50 mLx3). The combined organic layers were washed with brine (100 mL), dried over Na ₂ S0 ₄ and concentrated to give 381c (3.7 g, 99%) as a yellow solid. ESI-MS (M+H) ⁺ : 367.1.

[00555] Step 3: A mixture of 381c (3.7 g, 10 mmol, 1.0 eq), Pd(dppf)Cl ₂ (40 mg, 0.5 mmol, 0.05 eq), 5-carbamoyl-2-chlorophenylboronic acid (4.0 g, 20 mmol, 2.0 eq) and Na ₂ C0 ₃ (2.1 g, 20 mmol, 2.0 eq) in DMF/H ₂ 0 (30 mL, 3: 1, v/v) was stirred for 16 h at 90 °C under N ₂ . The mixture was then allowed to cool to room temp, filtered and the filtrate was concentrated in vacuo. The residue was purified by reversed phase HPLC (MeCN/H ₂ 0 = 3:2) to give 381d (4.3 g, 96%) as a yellow solid, ESI-MS (M+H) ⁺ : 442.2.

[00556] Step 4: A solution of 381d (4.3 g, 9.8 mmol, 1.0 eq) in TFA (50 mL) was stirred at room temp, for 16 h and then concentrated. The residue was purified by reversed phase HPLC (MeCN/H ₂ 0 = 2: 1) to give 381e (3.3 g, 99%) as a yellow solid. ESI-MS (M+H) ⁺ : 342.1.

[00557] Step 5: This reaction step was done in parallel. To a mixture of 381e (100 mg, 0.29 mmol) and TEA (88 mg, 0.87 mmol, 3.0 eq) in 3 mL of DCM was added acid chloride (0.58 mmol, 2.0 eq). The mixture was stirred at room temp, for 16 h and then concentrated in vacuo. The residue was purified by reversed phase HPLC (MeCN and H ₂ 0 with 0.05% ammonia) to give the desired product.

[00558] Examples 382 to 399. The following compounds of the present invention listed in Table 28 were prepared following the procedures described in Steps 1 to 5.

[00559] Table 28:

[00560] Preparative Example 400: N-(3-(3-azabicyclo[3.1.0]hexan-3-yl)-5-(2-chloro-5-((2-

(dimethylamino)ethyl)carbamoyl)phenyl)pyridin-2-yl)-2-chl oro-6-fluoro-N- methylbenzamide.

Ex. 400

[00561] Intermediate 400 of the present invention was prepared following the procedures described in Steps 1 to 6 of Example 201. 3-azabicyclo[3.1.0]hexane hydrochloride was used in Step 1.

[00562] Step 1: A mixture of 400a (2.8 g, 6.6 mmol, 1.0 eq), 913835-75-3 (2.0 g, 9.9 mmol, 1.5 eq), Na ₂ C0 ₃ (1.4 g, 13.2 mmol, 2.0 eq) and Pd(dppf)Cl ₂ (0.5 g, 0.66 mmol. 0.1 eq) in DMF/H ₂ 0 (15.0 mL, 3/1, v/v) was stirred at 80 °C for 20 h under N ₂ atmosphere. The mixture was then allowed to cool to room temp., diluted with MeOH (30 mL) and then filtered. The filtrate was concentrated in vacuo and the residue was purified by reversed phase HPLC (MeCN/water = 5%~95%) to give 400b (1.3 g, 40%) as a brown solid. ESI-MS (M+H) ⁺ : 500.1. 1H NMR (400 MHz, CD ₃ OD, a mixture of conformers) δ: 8.05-6.93 (m, 8H), 3.78-3.32 (m, 5H), 3.31-2.87 (m, 2H), 1.68-1.66 (m, 2H), 0.72-0.44 (m, 2H).

[00563] Step 2: Into a stirred solution of 400b (100 mg, 0.2 mmol, 1.0 eq), HATU (115 mg, 0.3 mmol, 1.5 eq) and Nl,Nl-dimethylethane-l,2-diamine (35 mg, 0.4 mmol, 2.0 eq) in DMF (3 mL) was added Et N (60 mg, 0.6 mmol, 3.0 eq). The mixture was stirred at room temp, for 2 h. The mixture was directly purified by reverse phase HPLC (MeCN/water = 5%~95%) to give 400 (60 mg, 55%) as a yellow solid. ESI-MS (M+H) ⁺ : 570.2. 1H NMR (400 MHz, CD ₃ OD, a mixture of conformers) δ: 8.02-6.93 (m, 8H), 3.78-3.36 (m, 9H), 3.32-3.26 (m, 2H), 3.00-2.99 (m, 6H), 1.70-1.68 (m, 2H), 0.74-0.69 (m, IH), 0.52-0.41 (m, IH).

[00564] Examples 401 to 416. The following compounds of the present invention listed in Table 29 were prepared following the procedures described in Example 400.

[00565] Table 29:

[00566] Examples 417 to 422. The following compounds of the present invention listed in Table 30 were prepared following the procedures described in Example 201.

[00567] Table 30:

[00568] Examples 423 and 424. The following compounds of the present invention listed in Table 31 were prepared following the procedures described in Example 200.

[00569] Table 31:

[00570] Examples 425 and 426. The following compounds of the present invention listed in Table 32 were prepared following the procedures described in Example 212.

[00571] Table 32:

[00572] Examples 427 and 428. The following compounds of the present invention listed in Table 33 were prepared following the procedures described in Example 156 by coupling of the intermediate 156a with suitable amines (R ^la NR ^lb ).

[00573] Table 33:

[00574] Examples 429 to 434. Compounds of examples 429, 431, and 435 of the present invention listed in Table 34 were prepared by coupling of the intermediate 156a with a variety of amino esters as set forth in Example 271, Step 1. Compounds of Examples 430, 432, and 434 were prepared from 429, 431, and 455 respectively by hydrolysis of the methyl ester moiety using the procedure as set forth in Example 271, Step 2.

[00575] Table 34:

[00576] Examples 435 and 436. Compounds of examples 435 and 436 of the present invention listed in Table 35 were prepared by coupling of the intermediate 156a with a variety of amino esters followed by hydrolysis of the esters as set forth in Example 271, Steps 1 and 2.

[00577] Table 35:

[00578] Preparative Example 437:

[00579] Step 1: To a mixture of 691872-15-8 (800 mg, 3.7 mmol, 1.0 eq), bicyclic alcohol 109-0104 (490 mg, 3.9 mmol, 1.05 eq) and PPh ₃ (1.45 g, 5.5 mmol, 1.5 eq) in THF (10 mL) was added DIAD (1.11 g, 5.5 mmol, 1.5 eq) at 0 °C under N ₂ atmosphere. The mixture was stirred at rt for 16 h and then concentrated. The residue was dissolved in EtOAc (30 mL), washed with brine (2x20 mL) and concentrated in vacuo. The residue was purified byTLC on silica gel (EtOAc: petroleum ether = 1/10) to give 437a as light yellow oil (650 mg, 54%). ESI-MS (M+H) ⁺ : 327.1. 1H NMR (400 MHz, CDC1 ₃ ) δ: 8.08 (d, J = 2.0 Hz 1H), 7.53 (d, J = 2.0 Hz, 1H), 5.26-5.22 (m, 1H), 2.51-2.50 (m, 2H), 1.64-1.58 (m, 2H), 1.14-1.12 (m, 2H), 1.07 (s, 3H), 1.03 (s, 3H).

[00580] Step 2: A mixture of 437a (650 mg, 2.0 mmol, 1.0 eq), Fe powder (560 mg, 10.0 mmol, 5.0 eq) and HOAc (1 mL) in EtOH (10 mL) was stirred at 80 °C for 1 h. The mixture was filtered and the filtrate was concentrated in vacuo to give a residue which was dissolved in EtOAc (50 mL). The mixture was washed with aq. NaHC0 ₃ (2x50 mL) and water (50 mL). The organic phase was dried and concentrated to give 437b (540 mg) as yellow oil which was used for the next step without further purification. ESI-MS (M+H) ⁺ : 297.1. 1H NMR (400 MHz, CDC1 ₃ ) δ: 7.62 (s, 1H), 6.89 (s, 1H), 4.99-4.92 (m, 1H), 4.66 (br s, 2H), 2.53-2.45 (m, 2H), 1.55-1.50 (m, 2H), 1.12-1.10 (m, 2H), 1.08 (s, 3H), 1.03 (s, 3H).

[00581] Step 3: Into a mixture of 437b (540 mg, 1.8 mmol, 1.0 eq) in pyridine (5 mL) was added 79455-63-3 (695 mg, 3.6 mmol, 2.0 eq) at rt. The reaction was stirred at 60 °C for 2 h and concentrated in vacuo. The residue was dissolved in EtOAc (20 mL), washed with brine (2x20 mL) and concentrated. The crude 437c was used to the next step without further purification. ESI-MS (M+H) ⁺ : 609.1.

[00582] Step 4: Into a mixture of 437c (1.1 g, 1.8 mmol, 1.0 eq) in MeOH (10 mL) was added K ₂ C0 ₃ (495 mg, 3.6 mmol, 2.0 eq). The reaction was stirred at 70 °C for 2 h and concentrated. The residue was dissolved in EtOAc (20 mL), washed with brine (2x20 mL) and concentrated in vacuo. The residue was purified by reversed phase HPLC (MeCN/water = 5%~95%) to give 437d (420 mg, 51% for two steps) as yellow oil. ESI-MS (M+H) ⁺ : 453.1.

[00583] Step 5: To a solution of 437d (420 mg, 0.93 mmol, 1.0 eq) in DMF (3 mL) was added NaH (75 mg, 1.86 mmol, 2.0 eq), followed by CD ₃ I (160 mg, 1.12 mmol, 1.2 eq) at 0 °C. The mixture was stirred for 1 h at 0 °C and quenched with H ₂ 0 (5 mL). The residue was dissolved in EtOAc (20 mL), washed with brine (2x20 mL) and concentrated in vacuo. The crude 437e was used to the next step without further purification. ESI-MS (M+H) ⁺ : 470.1.

[00584] Step 6: A mixture of 437e (430 mg, 0.93 mmol, 1.0 eq), 1150114-35-4 (220 mg, 1.12 mmol, 1.2 eq), Na ₂ C0 ₃ (200 mg, 1.86 mmol, 2.0 eq) and Pd(dppf)Cl ₂ (73 mg, 0.09 mmol. 0.1 eq) in DMF/H ₂ 0 (2.0 mL, 3/1, v/v) was stirred at 100 °C for 16 h under N ₂ atmosphere. The mixture was diluted with MeOH (3.0 mL) and filtered. The filtrate was purified by reversed phase HPLC (MeCN/water = 5%~95%) to give 437 (120 mg, 24% for two steps) as a white solid. ESI-MS (M+H) ⁺ : 545.2. 1H NMR (400 MHz, CDC1 ₃ , a mixture ofconformers) S: 8.11-7.30 (m, 5H), 7.15-6.78 (rn, 3H), 6.34 (br s, 1H), 5,78 (br s, 1H), 4.96- 4.94 (m, 1H), 2.51-2.44 (m, 2H), 1.64-1.59 (m, 2H), 1.11-1.01 (m, 8H).

[00585] Preparative Sample 438: -(5-(5-carbamoyl-2-chIorop enyl 3-((( lR,3.r,5S)-6,6- dimethy]bieyclo[3.L0]hexan-3-y|)^^

[00586] Step 1: To a solution of 109-01 4 {850 mg, 6.7 mrnol.1.2 eq) in THF (8 raL) was added aH (336 mg, 8.4 mmol, 1.5 eq) at 0 "C. The mixture was stirred for 2 h at rt. then 3- fluoro-2-nilTopyridine (800 mg, 5.6 mraol, 1.0 eq) was added. The mixture was stirred at 60 °C for additional 1 h and diluted with EtOAc (20 mL). The mixture was washed with brine (2*20 mL) and concentrated in vacuo. The residue was purified by TLC on silica gel (EtOAc: petroleum ether - 1/10) to give 438a as yellow oil (820 mg, 59%). ESI- S (M+Hf : 249.1. 1HNM . (400MHz, CDClj) S 8.05 (dd.J- 1.2 Hz, 4.4 Hz, 1H), 7.47 (dd„/ = 4.8 Hz, 8.4 Hz, IH), 7.37 (dd, J - 0.8 Hz, 8.8 Hz, HI), 4.72-4.69 (m, 1.H), 2.08-2.07 (m, 4H), 1.33-1.32 (m ₅ 2H), 1.01 (s, 3H), 0.88 (s ₅ 3H), [00587] Step 2: The synthesis of 438b was the same as for Example 437b (crude product). ESI-MS (M+H) ⁺ : 219.1.

[00588] Step 3: Into a stirred solution of 438b (720 mg, 3.3 mmol, 1.0 eq) in acetic acid (5 mL) was added bromine (0.16 mL, 3.3 mmol, 1.0 eq) at rt. The resulting reaction mixture was stirred for 2 h at rt. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc (100 mL) and washed with sat. aq. NaHC0 ₃ (100 mLX 2), brine (60 mL) and concentrated. The residue was purified by TLC on silica gel (EtOAc: petroleum ether = 1/10) to give 438c as yellow oil (270 mg, 27% for two steps). ESI-MS (M+H) ⁺ : 297.1. 1H NMR (400 MHz, CDC1 ₃ ) δ: 7.66 (d, J = 1.6 Hz IH), 6.86 (d, J = 1.6 Hz, IH), 4.80 (br s, 2H), 4.58-4.55 (m, IH), 2.05-1.91 (m, 4H), 1.32-1.30 (m, 2H), 1.01 (s, 3H), 0.89 (s, 3H).

[00589] Step 4: The synthesis of 438d was the same as for Example 437c (crude product). ESI-MS (M+H) ⁺ : 609.1.

[00590] Step 5: The synthesis of 438e was the same as 437d (220 mg, 53% for two steps; yellow solid). ESI-MS (M+H) ⁺ : 453.0.

[00591] Step 6: The synthesis of 438f was the same as 437e (crude product, yellow solid). ESI-MS (M+H) ⁺ : 470.1.

[00592] Step 7: The synthesis of 438 was the same as 437 (80 mg, 30% for two steps, white solid). ESI-MS (M+H) ⁺ : 545.2. 1H NMR (400 MHz, CDC1 _3> a mixture of conformers) δ: 8.11-7.52 (m, 4.7H), 7.11-6.82 (m, 3.3H), 6.37 (br s, IH), 5.82 (br s, IH), 4.71-4.57 (m, IH), 2.13-2.03 (m, 4H), 1.33 (s, 2H), 1.01 (s, 3H), 0.85 (s, 3H).

[00593] Preparative Example 439: N-(5-(5-carbamoyl-2-trifluoromethylphenyl)-3- (((lR,3r,5S)-6,6-dimethylbicyclo[3.1.0]hexan-3-yl)oxy)pyridi n-2-yl)-2-chloro-6-fluoro-N- CD ₃ -benzamide

[00594] Compound of Example 439 was prepared using the procedures as set forth in

Example 438. In Step 7, the boronic acid 8-D was replaced with (5-carbamoyl-2- (trifluoromethyl)phenyl)boronic acid to provide 401. 1H NMR (400 MHz, CD ₃ OD, a mixture of conformers) δ: 8.07-6.95 (m, 8H), 4.71-4.70 (m, 1H), 2.08-2.00 (m, 4H), 1.36-1.33 (m, 2H), 1.02-1.00 (m, 3H), 0.90-0.87 (m, 3H). ESI-MS (M+H) ⁺ : 579.2.

[00595] Preparative Example 440: N-(5-(5-carbamoyl-2-trifluoromethylphenyl)-3-

(((lR,3r,5S)-6,6-dimethylbicyclo[3.1.0]hexan-3-yl)oxy)pyr idin-2-yl)-2-chloro-6-fluoro-N- methylbenzamide

[00596] Compound of Example 440 was prepared using the procedures as set forth in

Example 438. In Step 7, the boronic acid 8-D was replaced with (5-carbamoyl-2- (trifluoromethyl)phenyl)boronic acid to provide 440. 1H NMR (400 MHz, CD ₃ OD) δ: 8.07- 6.95 (m, 8H), 4.71-4.70 (m, 1H), 3.49 (s, 2.5H), 3.28 (s, 0.5H), 2.08-2.00 (m, 4H), 1.36-1.33 (m, 2H), 1.02-1.00 (m, 3H), 0.90-0.87 (m, 3H). ESI-MS (M+H) ⁺ : 579.2.

[00597] Preparative Example 441:4-(3-(3-azabicyclo[3.1.0]hexan-3-yl)-4-(2-chloro-6- fluoro-N-CD ₃ -benzamido)phenyl)-5-chloro-N,N-dimethylpicolinamide.

Ex. 441

[00598] Step 1: A mixture of 441a (5.0 g, 11.7 mmol, 1.0 eq), Pin ₂ B ₂ (5.9 g, 23.5 mmol, 2.0 eq), KOAc (2.3 g, 23.5 mmol, 2.0 eq) and Pd(dppf)Cl ₂ (979 mg, 1.2 mmol. 0.1 eq) in dioxane (50 mL) was stirred at 80 °C for 4 h under N ₂ atmosphere. The mixture was cooled to rt and concentrated in vacuo. The residue was purified by column chromatography on silica gel (petroleum ether/EtOAc = 10/1) to give the desired product 441b (5 g, 90%) as a white solid. ESI-MS (M+H) ⁺ : 474.2.

[00599] Step 2: A mixture of 441b (900 mg, 1.9 mmol, 1.0 eq), 1256822-21-5 (447 mg, 1.9 mmol, 1.0 eq), Na ₂ C0 ₃ (403 mg, 3.8 mmol, 2.0 eq) and Pd(dppf)Cl ₂ (163 mg, 0.2 mmol. 0.1 eq) in DMF/H ₂ 0 (40 mL, 3/1, v/v) was stirred at 90 °C for 16 h under N ₂ atmosphere. The solvent was concentrated. The residue was diluted with MeOH (20 mL) and filtered. The filtrate was purified by reversed phase HPLC (MeCN/water = 5%~95%) to give 441c (240 mg, 25%) as a brown solid. ESI-MS (M+H) ⁺ : 503.1. [00600] Step 3: A mixture of 441c (80 mg, 0.16 mmol, 1.0 eq), dimethylamine (11 mg, 0.24 mmol, 1.5 eq), HOBT (32 mg, 0.24 mmol, 1.5 eq), EDCI (46 mg, 0.24 mmol. 1.5 eq) and DIPEA (31 mg, 0.24 mmol. 1.5 eq) in DMF (3 mL) was stirred at 80 °C for 4 h. The mixture was directly purified by reverse phase HPLC (MeCN/water = 5 ~95 ) to give 441 (25 mg, 30%) as a white solid. ESI-MS (M+H) ⁺ : 530.1. ¹ H NMR (400 MHz, CDC1 ₃ , a mixture of conformers) δ: 8.62-6.58 (m, 8H), 3.87-3.22 (m, 4H), 3.16-3.10 (m, 6H), 1.60-1.58 (m, 2H), 0.65-0.45 (m, 2H).

[00601] Examples 442 to 445. Compounds of examples 428, of the present invention listed in Table 36 were prepared by coupling of the intermediate 441c with a variety of amines as set forth in Example 441, Step 3.

[00602] Table 36:

[00603] Preparative Example 446: 5-chloro-4-(4-(2-chloro-6-fluoro-N-CD ₃ -benzamido)-3- (2,2,2-trifluoroethoxy)phenyl)-N,N-dimethylpicolinamide.

[00604] Step 1: A mixture of 243e (1.8 g, 4.0 mmol, 1.0 eq), Pin ₂ B ₂ (2.0 g, 8.0 mmol, 2.0 eq), KOAc (785 mg, 8.0 mmol, 2.0 eq) and Pd(dppf)Cl ₂ (326 mg, 0.4 mmol. 0.1 eq) in dioxane (20 mL) was stirred at 90 °C for 4 h under N ₂ atmosphere. The mixture was cooled to room temp, and concentrated to give 446a. The crude product was used for the next step without further purification. ESI-MS (M+H) ⁺ : 491.1.

[00605] Step 2: A mixture of 446a (7.8 g, 16.0 mmol, 1.0 eq), 4-bromo-5-chloropicolinic acid (3.7 g, 19.2 mmol, 1.2 eq), Na ₂ C0 ₃ (3.4 g, 32.0 mmol, 2.0 eq) and Pd(dppf)Cl ₂ (1.3 g, 1.6 mmol. 0.1 eq) in DMF/H ₂ 0 (20 mL, 3/1, v/v) was stirred at 100 °C for 16 h under N ₂ atmosphere. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by reversed phase HPLC (MeCN/water = 5%~95%) to give 446b (1.8 g, 22%) as a yellow solid. ESI-MS (M+H) ⁺ : 520.0.

[00606] Step 3: A mixture of 446b (80 mg, 0.15 mmol, 1.0 eq), dimethylamine

hydrochloride (25 mg, 0.30 mmol, 2.0 eq), HATU (114 mg, 0.30 mmol, 2.0 eq) and TEA (30 mg, 0.30 mmol. 2.0 eq) in THF (2 mL) was stirred at 40 °C for 1 h. The mixture was then directly purified by reversed phase HPLC (MeCN/water = 5%~95%) to give 446 (18 mg, 21%) as a white solid. ESI-MS (M+H) ⁺ : 547.1. 1H NMR (400 MHz, CD ₃ OD, a mixture of conformers) δ: 8.73-8.66 (m, 1H), 7.74-6.85 (m, 7H), 4.79-4.58 (m, 2H), 3.16-3.08 (m, 6H).

[00607] Preparative Examples 447 to 456:

[00608] The following compounds of the present invention listed in Table 37 were prepared following the procedures set forth in Example 446 (Steps 1 to 3) and using a variety of R ^la R ^2a NH amines in Step 3. 00609] Table 37:

[00610] Preparative Example 466: N-(5-(4-Carbamoyl-2-chlorophenyl)-3-(piperidin-l- yl)pyridin-2-yl)-2-chloro-6-fluoro-N-methylbenzamide.

[00611] To a mixture of 3-chloro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-ben zamide (60 mg, 0.21 mmol) and N-(5'-bromo-3,4,5,6-tetrahydro-2H-[l,3']bipyridinyl-2'-yl)-2 -chloro- 6-fluoro-N-methyl-benzamide (91 mg, 0.21 mmol) in N,N-dimethylformamide (3.0 mL) and water (0.30 mL, 17 mmol) was added [l, l'bis(diphenylphosphino)ferrocene]

dichloropalladium(II), complex with dichloromethane (1 : 1) (14 mg, 0.017 mmol) and cesium carbonate (208.3 mg, 0.64 mmol). The reaction mixture was stirred at 95 °C in a microwave reactor for 40 minutes. EtOAc and water were added and two layers were separated. The organic layer was concentrated and flash chromatography on silica gel (0-20% MeOH in CH ₂ CI ₂ ) gave the title product. The sample was further purified with reverse phase HPLC (30x50 mm, 10 m, 10-90% CH ₃ CN in water, 10 mL/min flow rate) as TFA salt of N-(5-(4- carbamoyl-2-chlorophenyl)-3-(piperidin-l-yl)pyridin-2-yl)-2- chloro-6-fluoro-N- methylbenzamide (51 mg). 1HNMR (400 MHz, DMSO-d6): a mixture of conformers, δ 8.31 - 7.07 (m, 10H), 3.48 (m, 1.3H), 3.17 (m, 1.7H), 2.95 - 2.75 (m, 2.8H), 2.54 (m, 1.2H), 1.66 (m, 4H), 1.53 (m, 2H). ESI-MS (M+l) ⁺ : 501.1.

[00612] Preparative Example 467: 2-Chloro-4'-(2-chloro-6-fluoro-N-CD ₃ -benzamido)-3'- (2,2,2-trifluoroethoxy)- [ 1 , 1 '-biphenyl] -4-carboxamide.

[00613] A mixture of 2-chloro-4'-(2-chloro-6-fluoro-N-CD ₃ -benzamido)-3'-(2,2,2- trifluoroethoxy)-[l,l'-biphenyl]-4-carboxylic acid (Intermediate Yl, 0.5 mmol), NH ₄ C1 (56 mg, 1.0 mmol), HATU (380 mg, 1.0 mmol) and triethylamine (101 mg, 1.0 mmol) in DMF (3 mL) was stirred at room temperature for 1 hour. The mixture was directly purified by reversed phase HPLC (CH CN/water = 5% to 95%) to give the title compound (95 mg) as a white solid. ¹ H NMR (400 MHz, CD ₃ OD, a mixture of conformers) δ 8.07-6.87 (m, 9H), 4.79-4.53 (m, 2H). ESI-MS (M+H) ⁺ : 518.0.

[00614] Preparative Examples 468 to 476:

[00615] Following a procedure similar to that for Example 408, the following analogues were synthesized from a suitable carboxylic acid intermediate Y and an amine (or ammonium chloride) as shown in Table 38.

[00616] Table 38:

[00617] Preparation of Intermediate Yl: 2-Chloro-4 '-(2-chloro-6-fluoro-N-CD ₃ - benzamido)-3'-(2,2,2-trifluoroethoxy)-[l,l'-biphenyl]-4-carb oxylic acid

[00618] A mixture of N-(4-bromo-2-(2,2,2-trifluoroethoxy)phenyl)-2-chloro-6-fluor o-N- CD -benzamide (220 mg, 0.5 mmol), 4-borono-3-chlorobenzoic acid (120 mg, 0.6 mmol), Na ₂ C0 ₃ (106 mg, 1.0 mmol) and Pd(dppf)Cl ₂ (73 mg, 0.1 mmol) in DMF/H ₂ 0 (4.0 mL/1.3 mL) was stirred at 100 °C for 16 hours under N ₂ atmosphere. The mixture was diluted with MeOH (3 mL) and filtered. The filtrate was purified by reversed phase HPLC (MeCN/water = 5 ~95 ) to give the title compound as a yellow solid. ESI-MS (M+H) ⁺ : 519.1.

[00619] Preparation of Intermediates Y2-Y10:

[00620] Following a procedure similar to that for Intermediate Yl, the following intermediates were synthesized as shown in Table 39.

400

401

402 [00622] Preparative Examples 477 to 478:

[00623] Example 477 can be prepared following the procedures set forth in Example 190 (steps 1 to 5) by using piperidine-dlO in step 1 and (5-carbamoyl-2- (trifluoromethyl)phenyl)boronic acid in step 5.

[00624] Example 478 can be prepared following the procedures set forth in Example 190 (stepl 1 to 5) by using piperidine-dlO in step 1, iodomethane-d3 in step 4, and (5-carbamoyl- 2-(trifluoromethyl)phenyl)boronic acid in step 5.

[00625] All of the compounds described herein can also be isolated as pharmaceutically acceptable salts. In some embodiments, each of the compounds described herein may be isolated as a TFA salt. Assay Examples

[00626] Assay 1: Biochemical GST-RORy TR-FRET assay

[00627] Assay 1 is a method that measures the disruption or activation of co-activator peptide/RORy binding by quantifying the ability of molecules to inhibit or enhance the activity of RORy.

[00628] RORy TR-FRET Assay Reagents

[00629] RORy TR-FRET Assay Buffer Components

[00631] Final conditions for RORy FRET Assay: (20 μL· of compound + 5 μL· of detection mix = 25 total assay volume): 20 mM Tris-HCl pH 7.0, 60 mM NaCl, 5 mM MgCl ₂ , ImM DTT, 0.1%BSA; 10 nM GST-RORy (LBD); 40 nM Biotin-TRAP220; 50nM SA-APC; 1.5nM Eu-Anti GST IgG; 1.0% DMSO. As compounds exhibit more potent inhibitory activity, 2.5 nM of GST-RORy (LBD) was used instead of 10 nM in order to improve the assay sensitivity.

[00632] Assay Protocol:

[00633] Compound dilutions were prepared (125x final test concentrations) by making a 2.5 mM dilution from a 10 mM stock using 100% DMSO. Three-fold dilutions of the compounds were then prepared for nine points beyond the 2.5 mM starting concentration (2.5, 0.83, 0.28, 0.093, 0031, 0.0102, 0.0034, 0.0011, 0.00038 mM). For example, 6 μΐ, οΐ 10 mM of the compound was added into 18 μΐ _^ of DMSO, and 10 μΐ _^ of the resulting solution was titrated into 20 μΐ _^ of DMSO. Subsequently 1 μϊ _^ of 125x of the test compound in 100% DMSO was diluted into 99 μΐ _^ of assay buffer in the compound buffer dilution greiner plate to result in a final DMSO concentration of 1%.

[00634] A 8.3x solution containing Europium-labeled antibody and RORy LBD was prepared, then 3 uL of this solution was added to each well on a 384-well plate, followed by the addition of 20 uL of each concentration of a compound previously diluted in assay buffer (described above). Assay controls (0% inhibition and 100% inhibition controls) were added into columns 1,12, 13, and 24 of the 384 well dilution greiner plate. For the 0% inhibition control, 1 μL· of 100% DMSO was added into 99 μΐ _^ of assay buffer. For the 100% inhibition control, 1 of 3.125 mM T0901317 (125x, 25 μΜ final concentration) was added.

[00635] The plate was shaken for one minute, centrifuged at 1000 rpm for 10 seconds, then incubated at room temperature for 1 hr and followed by the addition of 2 uL of 12.5x TRAP220 peptide and Streptavidin-APC, and read on a plate reader.

[00636] For initial assay development, the LJL Analyst was used. The LJL Analyst settings were as follows: Ratio: acceptor/donor; Acceptor: HRTF(Packard); Excitation: Europium FRET 330nm; Emission: FRET acceptor 665nm; Donor: HRTF(Packard); Excitation:

Europium FRET 330nm; Emission: FRET chelate donor; Flashes/well: 100; Intergration time: 400 μ8; Interval between: 1x10 ms flashes; Delay after flash: 50 μ8.

[00637] For routine assay screening, Envision plate reader was used. The Envision settings were as follows: Excitation: 330 ± 75 nm, Emission 1: 665 ±7.5 nm, Emission 2: 615 ±8.5 nm; time delay: 90 μ8; window: 300 μ8; number of flashes: 100; time between flashes: 2000 [00638] Data analysis:

[00639] The RORy FRET assay is an end point assay with a readout (emission ratio) of acceptor/donor* 1000. The assay dose response testing is performed in duplicate points per concentration, with ten dilution concentrations per compound curve. The conversion of raw data to % Activity is performed using assay controls, where 100% Activity is represented by the average DMSO controls. Zero percent Activity is the average of the 25 μΜ, T0901317 compound controls. IC curve fitting is performed using graphpad prism, and fitting to the sigmoidal dose-response (variable slope) equation as follows:

Y=Bottom + (Top-Bottom)/(l+10 ^A ((Log _E c ₅ o-X)*HillSlope)); where X is the logarithm of concentration and Y is the response (Y begins at the Bottom and goes to Top with a sigmoid shape, which is identical to the "four parameter logistic equation")

[00640] In the final assay plate setup, there were sixteen compounds per 384 well plate. The DMSO controls (0% Inhibition) were in columns 1 and 13. The 25 μΜ T0901317 controls (100% Inhibition) were in columns 12 and 24. The compound titrations were in columns 2- 11, 14-23. Ten-point IC ₅₀ curves were generated with n=2 per concentration.

[00641] Assay 2: Protocol of the RORy Gal4 cellular reporter assay 293T cells

[00642] Cell Cultivation.

[00643] Cells were used for transactivation assays following 2 to 3 passages after thawing from liquid nitrogen. The freeze medium was culture medium supplemented with DMSO to 10%. The routine culture includes two weekly passages. The cells were discarded after 4-6 weeks in assay production. For transactivation assay purposes, the cells were grown to subconfluence (80-90%).

[00644] Subcultivation of 293T cells. Cells were seeded in a T75 cm ² flask in 20 mL of culture medium by adding 50 mL of FBS, 5 mL of Glutamax, 5 mL of NEAA, 5 mL of Sodium Pyruvate, and 5 mL of Pen/Strep to a 500 mL MEM bottle (with phenol red). The cells were grown at 37 °C in the presence of 5% C0 ₂ until they reached subconfluence (80-90%), at which point the culture medium was discarded. PBS (about 5 mL per flask) was added to the flask at room temperature, and the cells were detached by tapping the flask. The viable cells were counted, the desired number of cells was transferred into a new flask, and the volume of the new flask was completed with new culture medium (final volume: 20 mL in a T75 cm flask). The flasks were incubated at 37°C under 5% of C0 _2.

[00645] Performance of the RORy Gal4 cellular reporter assays. On Day 1, cells were seeded in 96 well plates in plating medium (MEM w/o phenol red, 10% CCDS). On Day 2, the plating medium was removed and the cells were transfected. About 4-6 hours after transfection, assay medium (MEM without phenol red and serum) was added, and then the compounds were added. On Day 3, the cells were lysed, lucif erase buffers were added, and luminescence was measured in a dual-flash procedure.

[00646] Seeding cells. For each assay point, 50,000 293T cells per well of a 96 well white walled, clear bottom assay plate were used. Cells were plated in plating medium by adding 50 mL of CCDS, 5 mL of Glutamax, 5 mL of NEAA, 5 mL of Sodium Pyruvate, and 5 mL Pen/Strep to a 500 mL MEM bottle (without phenol red). Trypsinate cells were used for plating to ensure reproducibility of the process. After one washing step with about 10 mL of PBS, 1.5 mL of Trypsin-EDTA solution (Sigma- Aldrich; T3924) was added. After 2 to 3 minutes, the flask was tapped and 8 mL of culture medium was added. The cells were spun down for 2 minutes at 200xg, the supernatant was discarded, and the cells were resuspended in a small volume by pipetting the suspension up and down more than 10 times. As cells tend to form clumps, special care must be taken to separate cells from each other. Cells were then counted and plated with 50,000 cells per well in 100 μΐ _^ plating medium. The 96 well assay plates were incubated overnight at 37 °C with 5% C0 ₂ in a humidified atmosphere. [00647] Transfection. The transfection was carried out using a PEI solution generated at Phenex, with 71 ng total DNA per well (50 ng of nuclear receptor expressing plasmid plus 20 ng of pFR-Luc reporter and 0.5 ng of pRL-CMV reporter for each well). The DNA:PEI- solution ratio is 1:5 ^g^L), with a PEI concentration of 0.45 μg/μL, and a DNA:PEI ratio of 1:2.25 (μ _§ /μ _§ ).

[00648] The DNA solution was prepared by diluting the DNA in OptiMEM and gently vortexing. Enough solution should be prepared for 15μί of DNA mix per well. For the experiments described herein, a 16% excess was used. For example, for one assay plate, 2.24 μg of Firefly Luciferase reporter plasmid (pFR-Luc), 5.6 μg of NR expression vector (pCMV-BD-nuclear receptor), and 56 ng of Renilla Luciferase reporter plasmid was used. These DNA amounts were diluted in 1680 μΐ, OptiMEM.

[00649] The PEI-solution was prepared by diluting the PEI in the same volume of

OptiMEM. The amount of PEI-solution was calculated using the following formula: μg of DNA x 5. For the experiments described herein, a 16% excess was used. For example, for one assay plate, 39.8 μΐ _^ of PEI-solution was diluted in 1640 μΐ _^ of OptiMEM.

[00650] The transfection mix was generated by immediately adding the PEI-solution to the plasmid solution (the plasmid solution was not added to the PEI-solution), vortexing gently, and incubating the resulting solution for a minimum of 20 minutes at room temperature.

[00651] The plating medium is removed from the cells by dumping the plate and tapping dry on paper towels.

[00652] The transfection mix (PEI + DNA) was added to the adherent cells. The 96 well assay plates were incubated for 4-6 hrs at 37 °C with 5% C0 ₂ in a humidified atmosphere.

[00653] Compound treatment and enzyme activity measurement. The master DMSO compound plate was made by diluting the compounds from the 10 mM stock in column 11, and then diluting in a ratio of 1:3 across the plate to column 4. Column 3 contained DMSO only (high control), and column 2 contained 2.5 mM Tularik control (low). The compounds were at 1000X.

[00654] To a new 96- well plate, 132 μL· of plating media (with CCDS) was added to every well. Then, 1 μL· was transferred from each well of the DMSO compound plate to the corresponding well of the new dilution plate. The DMSO concentration was 7.5% and the compounds were 7.5X. The plate was covered and mixed on a plate shaker. About 4-6 hours after adding the transfection solution, 100 μΐ _^ of assay medium was added to the cells. The assay medium was prepared by adding 5mL of Glutamax, 5 mL of NEAA, 5 mL Sodium Pyruvate, and 5 mL Pen/Strep to a 500ml MEM bottle (w/o phenol red). Exactly 20 μΐ _^ of the compounds from the new dilution plate were added to the cells in triplicate. Although all of the wells on the edge of plate were excluded from analysis due to edge effects, they should all contain the same final volume of media: 150μί (1.3% CCDS, 0.1% DMSO and IX compound). The cells were incubated at 37 °C with 5% C0 ₂ in a humidified atmosphere for 16 to 20 hours. After the incubation, the medium was completely removed by dumping and tapping the plate dry on paper towels. Exactly 20 μL· oΐ Ix Passive Lysis Buffer (Promega) was added and the plates were incubated at room temperature on a plate shaker for 10- 15 min.

[00655] The measurement was performed using a BMG LUMIstar OPTIMA luminescence plate reader. First, 75 μΐ _^ per well of Firefly luciferase buffer was injected. Exactly 1.1 seconds after the start of the Firefly buffer injection, 75 μΐ _^ per well of Renilla luciferase buffer was injected. The complete measurement time was 2 seconds per well. For the direct firefly measurements, the average of the values 7- 11 (0.6 to 1 sec) was used. For the direct renilla measurements, the average of the values 16-20 (1.5 to 1.9 sec) was used.

[00656] Materials and equipment used for ROR Gal4 cellular reporter assays. All plasmids used for the transfection of 293T cells were prepared with QIAGEN Maxi, Giga or Mega Kits and were eluted and diluted with MilliQ water.

[00657] Firefly Luciferase Buffer

[00658] Renilla Luciferase Buffer

BSA (fraction V) 0.44 mg/mL 10% (w/v)

NaN3 1.3 mM 1 M

Coelenterazine 2.5 μΜ 2.5 mM (in methanol)

[00659] Materials.

Name Company Cat.No

293T cells DSMZ ACC635

MEM (with Phenol Red) Sigma Aldrich M2279

MEM (without Phenol Red) Fisher Scientific (Ivtg) VX51200087

OptiMEM Fisher Scientific (Ivtg) VX31985054

FBS Sigma Aldrich F7542

CCDS Perbio (HyClone) SH30068.03

Glutamax In vitro gen 35050038

Pen/Strep Sigma Aldrich P4333

Sodium Pyruvate Sigma Aldrich S8636

Non Essential Amino Acids (NEAA) Sigma Aldrich M7145

PBS Sigma Aldrich D8537

PEI Sigma Aldrich 408727

DMSO Sigma Aldrich 41648

Passive Lysis Buffer (5x) Promega E1941

D-Luciferine PIK 260150

Coelentrazine PIK 260350

EGTA Sigma Aldrich E3889

ATP Sigma Aldrich A26209

AMP Sigma Aldrich 01930

BSA (fraction V) Serva 11930.04

T75 Flasks NUNC 353136

U-bottom 96 well plates Greiner 650101

96 well assay plates Corning 3903

[00660] Equipment.

Name Company Type

LUMIstar OPTIMA BMG (with two Reagent Injectors)

Pipetting Robot BioTek Precision XS. [00661] ROR-gamma has been implicated in the development and function of lymphoid tissue inducer cells, thymocytes, γδ T cells, natural killer cells, and both cytotoxic and helper β T cells. These cell types and soluble factors produced by these cells, including the cytokines IL-17, IL-17F and IL-26, have been demonstrated to contribute to autoimmune pathology in numerous animal models of disease and have been implicated in the pathogenesis of human immune-mediated diseases. Inverse agonists of ROR-gamma block the development of these pathogenic cell types and the proinflamatory cytokines they produce. Such action provides therapeutic benefit to the immune mediated diseases in which these cells act.

[00662] The compounds exhibit inverse agonist ROR-gamma activity against the nuclear receptor. Most of the compounds of the invention have IC ₅₀ values of less than 15 μΜ, and others have IC ₅₀ values as low as 0.010 μΜ, as determined by the Biochemical GST-RORy TR-FRET assay. In the RORy Gal4 cellular reporter assay, as described above, most of the compounds of the invention tested have EC ₅₀ values of less than 15 μΜ, and others have EC ₅₀ values as low 0.050 μΜ.

[00663] Assay 3: RORy Splenocyte IL-17

[00664] Reagents and buffer used in RORy Splenocyte IL-17 assay

Buffer Storage

Lysis buffer: Hemolytic Geys Solution (Media Prep) o

4 C

IL-17 ELISA Reagent Diluent: 1% BSA in PBS, pH7.2-7.4, o

4 C

0.2uM filtered.

Wash Buffer: 10 X PBS in 0.5% TWEEN 20 RT

[00665] Equipment and Materials.

[00666] Assay Protocol.

[00667] Day -1. The round-bottom 96 well plate (Corning, # 3799) was coated with 10 μg per mL of anti-mCD3e in PBS (50 per well) and stored at 4 °C overnight.

[00668] Day 0. The primary compound dilutions (lOOOx final test concentrations) were prepared in a 96 well polypropylene plate (Greiner Bio-one, # 651201) by making a 5 mM dilution from a 10 mM stock using 100% DMSO. Three-fold dilutions of the compounds were then prepared for seven points beyond the 5 mM starting concentration (5, 1.667, 0.556, 0.185, 0.062, 0.021, 0.007, and 0.002 mM). For example, 10 μΐ, of 10 mM compound was added into 10 of DMSO, of which 8 μΐ, was titrated into 16 μί of DMSO. The plate was covered and stored in a hood at room temperature.

[00669] The splenocytes were then prepared. Spleens from 3 wild type C57BL/6 mice were harvested, and then dissociated using a syringe plunger with a 70 μιη cell strainer (BD Falcon, # REF 352350) on a 50 mL tube. The cells were rinsed through the strainer using about 20 mL RPMI, and then centrifuged for 5 minutes at 0.3 rcf (1300 rpm, Eppendorf, # Centrifuge 5702R, # rotor A-4-38). The supernatant was discarded. The pellet was dispersed and properly resuspended by tapping the tube and adding to the pellet 1 mL of lysis buffer per spleen. After incubation at room temperature for 5 minutes, the cells were centrifuged for 5 min at 0.3 rcf and the supernatant was discarded. The cells were resuspended in 5 mL RPMI and counted. The cell concentration was then adjusted to 5xl0 ⁶ cells per mL. Anti- mCD3e were aspirated from the wells, and 100 per well of the cells were coated in a 96 well plate (Corning, #3799).

[00670] A mixture of cytokines and antibody in RPMI (5% excess) was prepared: 1 ng/mL TGF-b, 10 ng/mL IL-6, 0.625 ng/mL IL-23, 5 μg/ml anti-mCD28. To each well was added 90 μΐ of the cytokines antibody mixture, to result in a total volume of 190 μΐ per well.

[00671] Exactly 5 μΐ, of the diluted compound was added to the 245 μΐ, RPMI, the solution was mixed, and 10 μί was transferred to each well. The final volume for each well was 200LL, resulting in a final concentration of 5, 1.667, 0.556, 0.185, 0.062, 0.021, 0.007, 0.002 μΜ for each compound. Control wells were prepared by adding 7 μΐ 100% DMSO into 343 μΐ RPMI for the DMSO high controls, and 2.5 μΜ T0901317 for the low controls (prepared by adding 4 of 5 mM T0901317 stock to 4 μί DMSO, mixing the solution, and then add 7 μί into 343 μΐ RPMI). The cells were incubated at 37 °C in C0 ₂ incubator for 2 days.

[00672] Day 2. The supernatant was collected at stored at -20 °C. The IL- 17 cytokine level from the supernatant was then determined using the Mouse IL-17 DuoSet ELISA

Development kit. Assay dose response testing was performed in triplicate points per concentration using eight dilution concentrations per compound curve. The conversion of raw data to % Activity was performed using assay controls, where 100% Activity was represented by the average DMSO controls, and 0% Activity was the average of the 2.5 μΜ T0901317 compound controls. EC ₅₀ curve fitting was performed using graphpad prism and fitting to the sigmoidal dose-response (variable slope) equation as follows: Y = Bottom + (Top-Bottom)/(l+10 ^A ((LogEC50-X)*HillSlope)), with all of the variables as previously described.

[00673] In the RORy Splenocyte IL-17 assay, as described above, the compounds of the invention that were tested have EC ₅₀ values between 0.500 μΜ and 12.000 μΜ. Specific exemplary activities of tested compounds are shown below.

[00674] Table 40. Specific RORy Splenocyte EC ₅₀ activities of exemplary tested compounds

415

419

421

422

423

424

425

427

428

429

431

436

437

438

439

442

[00675] In the foregoing, EC ₅₀ data is represented as follows: greater than or equal to 10 microMolar is designated as A; less than 10 microMolar but greater than or equal to 1 microMolar is designated as B; less than 1 microMolar but greater than or equal to 500 nanoMolar is designated as C; less than 500 nanoMolar but greater or equal to 100 nanoMolar is designated as D; and less than 100 nanoMolar is designated as E.