PYRAZOLE COMPOUNDS AND METHODS OF MAKING AND USING SAME

CROSS-REFERENCE

[0001] This application claims benefit of U.S. Provisional Application No. 62/258,371, filed on November 20, 2015, which is herein incorporated by reference in its entirety.

BACKGROUND

[0002] Monoacylglycerol lipase (MAGL) is an enzyme responsible for hydrolyzing endocannabinoids such as 2-AG (2-arachidonoylglycerol), an arachidonate based lipid, in the nervous system. The serine hydrolase α-β-hydrolase domain 6 (ABHD6) is another lipid mediator.

BRIEF SUMMARY OF THE INVENTION

[0003] This disclosure provides, for example, compounds and compositions which are modulators of MAGL and/or ABHD6, and their use as medicinal agents, processes for their preparation, and pharmaceutical compositions that include disclosed compounds as at least one active ingredient. The disclosure also provides for the use of disclosed compounds as medicaments and/or in the manufacture of medicaments for the inhibition of MAGL and/or ABHD6 activity in warm-blooded animals such as humans.

[0004] In one aspect is a compound of Formula (I):

Formula (I);

wherein:

R ¹ is -N(R ² )C(0)R ¹⁵ or -N(H)S0 ₂ R ¹⁵ ;

R ² is H or C _h alky.;

R ³ is H or optionally substituted phenyl;

R ⁴ is H, halogen, -OR ⁷ , Ci-ehaloalkyl, optionally substituted heterocycloalkyl, optionally substituted Ci- ₆ alkyl-heterocycloalkyl, optionally substituted phenyl, optionally substituted heteroaryl, -C0 ₂ H, or -C(0)NR ⁸ R ⁹ ;

R ⁵ is H, halogen, Ci _-6 alkyl, Ci _-6 haloalkyl, or phenyl; or

R ⁴ and R ⁵ are combined to form a heterocycloalkyl ring;

R ⁶ is H, halogen or Ci _-6 alkyl; R ⁷ is H, Ci- ₆ alkyl, optionally substituted phenyl, optionally substituted

optionally substituted heteroaryl, optionally substituted heterocycloalkyl, or -Ci.

₆ alkylC(O) R ¹⁰ R ^u ;

R ⁸ and R ⁹ are each independently H, or Ci _-6 alkyl; or R ⁸ and R ⁹ together with the nitrogen to which they are attached are combined to form an optionally substituted heterocycloalkyl ring;

R ¹⁰ and R ¹¹ are each independently H, or Ci _-6 alkyl; or R ¹⁰ and R ¹¹ together with the nitrogen to which they are attached are combined to form a heterocycloalkyl ring; and

R ¹⁵ is optionally substituted

or a solvate, hydrate, tautomer, N-oxide, or pharmaceutically acceptable salt thereof.

[0005] In another aspect is a com ound of Formula (II):

Formula (II);

wherein:

R ¹ is -N(R ² )C(0)R ¹⁵ or -N(H)S0 ₂ R ¹⁵ ;

R ² is H or Ci _-6 alkyl;

R ³ is H or optionally substituted phenyl;

R ⁴ is H, halogen, -OR ⁷ , Ci _-6 alkyl, Ci _-6 haloalkyl, optionally substituted heterocycloalkyl, optionally substituted Ci _-6 alkyl-heterocycloalkyl, optionally substituted phenyl, optionally substituted heteroaryl, -C0 ₂ H, or -C(0) R ⁸ R ⁹ ;

R ⁵ is H, halogen, Ci- ₆ alkyl, Ci-ehaloalkyl, or phenyl; or

R ⁴ and R ⁵ are combined to form a heterocycloalkyl ring;

R ⁶ is H, halogen or Ci _-6 alkyl;

R ⁷ is H, Ci _-6 alkyl, optionally substituted phenyl, optionally substituted Ci _-6 alkyl -phenyl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, or -Ci.

6alkylC(O) R ¹⁰ R ^u ;

R ⁸ and R ⁹ are each independently H, or Ci _-6 alkyl; or R ⁸ and R ⁹ together with the nitrogen to which they are attached are combined to form an optionally substituted heterocycloalkyl ring; R ¹⁰ and R ¹¹ are each independently H, or or R ¹⁰ and R ¹¹ together with the nitrogen to which they are attached are combined to form a heterocycloalkyl ring;

R ¹² is H or C _h alky.;

R ¹³ is H or Ci _-6 alkyl; and

R ¹⁵ is optionally substituted

or a solvate, hydrate, tautomer, N-oxide, or pharmaceutically acceptable salt thereof.

[0006] In one embodiment is a compound of Formula (II), or a solvate, hydrate, tautomer, N- oxide, or pharmaceutically acceptable salt thereof, wherein R ¹² and R ¹³ are H.

[0007] In another aspect is a compound of Formula (III):

Formula (III);

wherein:

R ¹ is -N(R ² )C(0)R ¹⁵ or -N(H)S0 ₂ R ¹⁵ ;

R ² is H or Ci _-6 alkyl;

R ³ is H or optionally substituted phenyl;

R ⁴ is H, halogen, -OR ⁷ , C _2-6 alkynyl, Ci-ehaloalkyl, C3- ₆ cycloalkyl, optionally

substituted heterocycloalkyl, optionally substituted Ci _-6 alkyl -heterocycloalkyl, optionally substituted phenyl, optionally substituted heteroaryl, -C0 ₂ H, or -C(0) R ⁸ R ⁹ ;

R ⁵ is H, halogen, -CN, Ci _-6 alkyl, Ci _-6 haloalkyl, or phenyl; or

R ⁴ and R ⁵ are combined to form an optionally substituted heterocycloalkyl ring or an

optionally substituted heteroaryl ring;

R ⁶ is H, halogen or Ci _-6 alkyl;

R ⁷ is H, Ci _-6 alkyl, optionally substituted phenyl, optionally substituted Ci _-6 alkyl -phenyl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, or -Ci.

6alkylC(O) R ¹⁰ R ^u ;

R ⁸ and R ⁹ are each independently H, or Ci _-6 alkyl; or R ⁸ and R ⁹ together with the nitrogen to which they are attached are combined to form an optionally substituted heterocycloalkyl ring;

R ¹⁰ and R ¹¹ are each independently H, or or R ¹⁰ and R ¹¹ together with the nitrogen to which they are attached are combined to form a heterocycloalkyl ring; and

R ¹⁵ is optionally substituted

or a solvate, hydrate, tautomer, N-oxide, or pharmaceutically acceptable salt thereof. [0008] In another aspect is a compound of Formula (IV):

Formula (IV);

wherein:

R ¹ is -N(R ² )C(0)R ¹⁵ or -N(H)S0 ₂ R ¹⁵ ;

R ² is H or C _h alky.;

R ³ is H or optionally substituted phenyl;

R ⁴ is H, halogen, -OR ⁷ , C _2-6 alkynyl, Ci-ehaloalkyl, C3- ₆ cycloalkyl, optionally

substituted heterocycloalkyl, optionally substituted optionally substituted phenyl, optionally substituted heteroaryl, -C0 ₂ H, or -C(0) R ⁸ R ⁹ ;

R ⁵ is H, halogen, -CN, Ci _-6 alkyl, Ci _-6 haloalkyl, or phenyl; or

R ⁴ and R ⁵ are combined to form an optionally substituted heterocycloalkyl ring or an

optionally substituted heteroaryl ring;

R ⁶ is H, halogen or Ci _-6 alkyl;

R ⁷ is H, Ci _-6 alkyl, optionally substituted phenyl, optionally substituted Ci _-6 alkyl -phenyl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, or -Ci.

6alkylC(O) R ¹⁰ R ^u ;

R ⁸ and R ⁹ are each independently H, or Ci _-6 alkyl; or R ⁸ and R ⁹ together with the nitrogen to which they are attached are combined to form an optionally substituted heterocycloalkyl ring;

R ¹⁰ and R ¹¹ are each independently H, or or R ¹⁰ and R ¹¹ together with the nitrogen to which they are attached are combined to form a heterocycloalkyl ring;

R ¹² is H or C _h alky.;

R ¹³ is H or Ci _-6 alkyl; and

R ¹⁵ is optionally substituted

or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof.

[0009] In another embodiment is a compound of Formula (IV), or a solvate, hydrate, tautomer, N-oxide, or pharmaceutically acceptable salt thereof, wherein R ¹² and R ¹³ are H. [0010] In another embodiment is a compound of Formula (I), (II), (III), or (IV), or a solvate, hydrate, tautomer, N-oxide, or pharmaceutically acceptable salt thereof, wherein R ⁴ is optionally substituted heterocycloalkyl. In another embodiment is a compound of Formula (I), (II), (III), or (IV), or a solvate, hydrate, tautomer, N-oxide, or pharmaceutically acceptable salt thereof, wherein R ⁴ is heterocycloalkyl optionally substituted with one or more groups selected from halogen, hydroxy, -Ci- ₆ alkyl-OH, Ci-efluoroalkyl, C3- ₆ cycloalkyl, heteroaryl, -CO ₂ H, - Ci _-6 alkyl-C0 ₂ H, -C(0)Ci _-6 alkyl, -C(0)Ci _-6 alkyl-OH, -N(H)C(0)Ci _-6 alkyl, -C(0) H ₂ , - C(0)N(H)(Ci _-6 alkyl), -C(0)N(Ci _-6 alkyl) ₂ , -C(0)C _2-7 heterocycloalkyl, and -S(0) ₂ Ci _-6 alkyl. In another embodiment is a compound of Formula (I), (II), (III), or (IV), or a solvate, hydrate, tautomer, N-oxide, or pharmaceutically acceptable salt thereof, wherein R ⁴ is heterocycloalkyl optionally substituted with one or two groups selected from halogen, hydroxy, Ci _-6 alkyl, -Ci. ₆ alkyl-OH, Ci _-6 fluoroalkyl, C _3-6 cycloalkyl, heteroaryl, -C0 ₂ H, -Ci _-6 alkyl-C0 ₂ H, -C(0)Ci _-6 alkyl, -C(0)Ci _-6 alkyl-OH, -N(H)C(0)Ci _-6 alkyl, -C(0) H ₂ , -C(0)N(H)(Ci _-6 alkyl), -C(0)N(Ci _-6 alkyl) ₂ , -C(0)C _2-7 heterocycloalkyl, and -S(0) ₂ Ci- ₆ alkyl. In another embodiment is a compound of Formula (I), (II), (III), or (IV), or a solvate, hydrate, tautomer, N-oxide, or pharmaceutically acceptable salt thereof, wherein R ⁴ is optionally substituted heterocycloalkyl and the

heterocycloalkyl is a 4-6 membered monocyclic heterocycloalkyl, a 8-9 membered bicyclic heterocycloalkyl, a 7-8 membered bridged heterocycloalkyl, a 5,5 fused heterocycloalkyl, or an 8-11 membered spirocyclic heterocycloalkyl. In another embodiment is a compound of Formula (I), (II), (III), or (IV), or a solvate, hydrate, tautomer, N-oxide, or pharmaceutically acceptable

4

salt thereof wherein R is o tionall substituted heteroc cloalk l selected from Ή

another embodiment is a compound of Formula (I), (II), (III), or (IV), or a solvate, hydrate, tautomer, N-oxide, or pharmaceutically ac

substituted heterocycloalkyl selected from

(I) , (II), (III), or (IV), or a solvate, hydrate, tautomer, N-oxide, or pharmaceutically acceptable salt thereof, wherein R ⁴ is optionally substituted heteroaryl. In another embodiment is a compound of Formula (I), (II), (III), or (IV), or a solvate, hydrate, tautomer, N-oxide, or pharmaceutically acceptable salt thereof, wherein R ⁴ is heteroaryl optionally substituted with one or two groups selected from halogen, hydroxy, Ci- ₆ alkyl, Ci-efluoroalkyl, C3- ₆ cycloalkyl, - C0 ₂ H, -Ci _-6 alkyl-C0 ₂ H, and -C(0)NH ₂ . In another embodiment is a compound of Formula (I),

(II) , (III), or (IV), or a solvate, hydrate, tautomer, N-oxide, or pharmaceutically acceptable salt thereof, wherein R ⁴ is optionally substituted heteroaryl and the heteroaryl is a 5-6 membered heteroaryl ring. In another embodiment is a compound of Formula (I), (II), (III), or (IV), or a

or (IV), or a solvate, hydrate, tautomer, N-oxide, or pharmaceutically acceptable salt thereof, wherein R ⁴ is -OR ⁷ . In a further embodiment is a compound of Formula (I), (II), (III), or (IV), or a solvate, hydrate, tautomer, N-oxide, or pharmaceutically acceptable salt thereof, wherein R ⁴ is -OR and R is H, a phenyl optionally substituted with halogen,

6fluoroalkyl, or optionally substituted with ha Ci. ₆ fluoroalkyl, or Ci _-6 alkoxy, a heteroaryl optionally substituted with halogen, Ci _-6 alkyl, or Ci. ₆ fluoroalkyl, a 5-6 membered monocyclic heterocycloalkyl optionally substituted with halogen, Ci _-6 alkyl, Ci _-6 fluoroalkyl, or C _3-6 cycloalkyl, or a -Ci _-6 alkylC(O) R ¹⁰ R ^u . In a further embodiment is a compound of Formula (I), (II), (III), or (IV), or a solvate, hydrate, tautomer, TV- oxide, or pharmaceutically acceptable salt thereof, wherein R ⁴ is -OR ⁷ and R ⁷ is Ci _-6 alkyl,

. In a further embodiment is a compound of Formula (I), (II), (III), or (IV), or a solvate, hydrate, tautomer, N-oxide, or pharmaceutically acceptable salt thereof, wherein R ⁴ is -

OR I aanndd RR iiss \—_/ ' ₀ orr \— ' . In another embodiment is a compound of Formula (I),

(II) , (III), or (IV), or a solvate, hydrate, tautomer, N-oxide, or pharmaceutically acceptable salt thereof, wherein R ⁴ is halogen. In a further embodiment is a compound of Formula (I), (II),

(III) , or (IV), or a solvate, hydrate, tautomer, N-oxide, or pharmaceutically acceptable salt thereof, wherein R ⁴ is -CI. In another embodiment is a compound of Formula (I), (II), (III), or

(IV) , or a solvate, hydrate, tautomer, N-oxide, or pharmaceutically acceptable salt thereof, wherein R ⁴ is Ci- ₆ haloalkyl. In a further embodiment is a compound of Formula (I), (II), (III), or (IV), or a solvate, hydrate, tautomer, N-oxide, or pharmaceutically acceptable salt thereof, wherein R ⁴ is -CF ₃ . In a further embodiment is a compound of Formula (I), (II), (III), or (IV), or a solvate, hydrate, tautomer, N-oxide, or pharmaceutically acceptable salt thereof, wherein R ⁵ is H. In another embodiment is a compound of Formula (I), (II), (III), or (IV), or a solvate, hydrate, tautomer, N-oxide, or pharmaceutically acceptable salt thereof, wherein R ⁵ is halogen. In a further embodiment is a compound of Formula (I), (II), (III), or (IV), or a solvate, hydrate, tautomer, N-oxide, or pharmaceutically acceptable salt thereof, wherein R ⁵ is -CI. In another embodiment is a compound of Formula (I), (II), (III), or (IV), or a solvate, hydrate, tautomer, N- oxide, or pharmaceutically acceptable salt thereof, wherein R ⁵ is Ci-6haloalkyl. In a further embodiment is a compound of Formula (I), (II), (III), or (IV), or a solvate, hydrate, tautomer, N- oxide, or pharmaceutically acceptable salt thereof, wherein R ⁵ is -CF ₃ . In another embodiment is a compound of Formula (I), (II), (III), or (IV), or a solvate, hydrate, tautomer, N-oxide, or pharmaceutically acceptable salt thereof, wherein R ⁵ is phenyl. In another embodiment is a compound of Formula (I), (II), (III), or (IV), or a solvate, hydrate, tautomer, N-oxide, or pharmaceutically acceptable salt thereof, wherein R ⁶ is H. In another embodiment is a compound of Formula (I), (II), (III), or (IV), or a solvate, hydrate, tautomer, N-oxide, or pharmaceutically acceptable salt thereof, wherein R ³ is H. In another embodiment is a compound of Formula (I), (II), (III), or (IV), or a solvate, hydrate, tautomer, N-oxide, or pharmaceutically acceptable salt thereof, wherein R ³ is optionally substituted phenyl. In another embodiment is a compound of Formula (I), (II), (III), or (IV), or a solvate, hydrate, tautomer, N- oxide, or pharmaceutically acceptable salt thereof, wherein R ¹ is -N(R ² )C(0)R ¹⁵ . In another embodiment is a compound of Formula (I), (II), (III), or (IV), or a solvate, hydrate, tautomer, N- oxide, or pharmaceutically acceptable salt thereof, wherein R ¹ is -N(R ² )C(0)R ¹⁵ and R ² is H. In another embodiment is a compound of Formula (I), (II), (III), or (IV), or a solvate, hydrate, tautomer, N-oxide, or pharmaceutically acceptable salt thereof, wherein R ¹ is -N(R ² )C(0)R ¹⁵ and R ² is optionally substituted Ci _-6 alkyl. In another embodiment is a compound of Formula (I),

(II) , (III), or (IV), or a solvate, hydrate, tautomer, N-oxide, or pharmaceutically acceptable salt thereof, wherein R ¹ is -N(R ² )C(0)R ¹⁵ and R ² is -CH ₃ . In another embodiment is a compound of Formula (I), (II), (III), or (IV), or a solvate, hydrate, tautomer, N-oxide, or pharmaceutically acceptable salt thereof, wherein R ¹ is -N(H)S0 ₂ R ¹⁵ . In a further embodiment is a compound of Formula (I), (II), (III), or (IV), or a solvate, hydrate, tautomer, N-oxide, or pharmaceutically acceptable salt thereof, wherein R ¹⁵ is -CH ₂ OH. In a further embodiment is a compound of Formula (I), (II), (III), or (IV), or a solvate, hydrate, tautomer, N-oxide, or pharmaceutically acceptable salt thereof, wherein R ¹⁵ is -CF ₃ . In a further embodiment is a compound of Formula (I), (II), (III), or (IV), or a solvate, hydrate, tautomer, N-oxide, or pharmaceutically acceptable salt thereof, wherein R ¹⁵ is -CHF ₂ . In another embodiment is a compound of Formula (I), (II),

(III) , or (IV), or a solvate, hydrate, tautomer, N-oxide, or pharmaceutically acceptable salt thereof, wherein R ¹⁵ is unsubstituted Ci _-6 alkyl. In another embodiment is a compound of Formula (I), (II), (III), or (IV), or a solvate, hydrate, tautomer, N-oxide, or pharmaceutically acceptable salt thereof, wherein R ¹⁵ is -CH ₃ .

[0011] In another embodiment is a pharmaceutical composition comprising a compound of Formula (I), (II), (III), or (IV) described herein, or a solvate, hydrate, tautomer, N-oxide, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

[0012] In another embodiment is a method of treating a disease or disorder selected from the group consisting of multiple sclerosis, Alzheimer's disease, and inflammatory bowel disease in a patient in need thereof, comprising administering a therapeutically effective amount of a compound of Formula (I), (II), (III), or (IV) described herein, or a solvate, hydrate, tautomer, N- oxide, or a pharmaceutically acceptable salt thereof, to the patient in need thereof. In some embodiments, the disease is multiple sclerosis. In some embodiments, the disease is

Alzheimer's disease. In some embodiments, the disease is inflammatory bowel disease.

[0013] In another embodiment is a method of treating pain in a patient, comprising

administering a therapeutically effective amount of a compound of Formula (I), (II), (III), or (IV) described herein, or a solvate, hydrate, tautomer, N-oxide, or a pharmaceutically acceptable salt thereof, to the patient in need thereof to treat said pain. In another embodiment is a method of treating neuropathic pain in a patient, comprising administering a therapeutically effective amount of a compound of Formula (I), (II), (III), or (IV) described herein, or a solvate, hydrate, tautomer, N-oxide, or a pharmaceutically acceptable salt thereof, to the patient in need thereof to treat said neuropathic pain. In another embodiment is a method of treating inflammatory pain in a patient, comprising administering a therapeutically effective amount of a compound of Formula (I), (II), (III), or (IV) described herein, or a solvate, hydrate, tautomer, N-oxide, or a pharmaceutically acceptable salt thereof, to the patient in need thereof to treat said inflammatory pain.

[0014] In another embodiment is a method of treating a disease or disorder in a patient comprising administering to the patient in need thereof a therapeutically effective amount of a compound of Formula (I), (II), (III), or (IV) described herein, or a solvate, hydrate, tautomer, N- oxide, or a pharmaceutically acceptable salt thereof, wherein the disease is selected from epilepsy/seizure disorder, neuromyelitis optica (NMO), Tourette syndrome, persistent motor tic disorder, persistent vocal tic disorder, and abdominal pain associated with irritable bowel syndrome. In another embodiment is a method of treating epilepsy/seizure disorder in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), (II), (III), or (IV) described herein, or a solvate, hydrate, tautomer, N- oxide, or a pharmaceutically acceptable salt thereof. In another embodiment is a method of treating neuromyelitis optica (NMO) in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), (II), (III), or (IV) described herein, or a solvate, hydrate, tautomer, N-oxide, or a pharmaceutically acceptable salt thereof. In another embodiment is a method of treating Tourette syndrome in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), (II), (III), or (IV) described herein, or a solvate, hydrate, tautomer, N- oxide, or a pharmaceutically acceptable salt thereof. In another embodiment is a method of treating persistent motor tic disorder in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), (II), (III), or (IV) described herein, or a solvate, hydrate, tautomer, N-oxide, or a pharmaceutically acceptable salt thereof. In another embodiment is a method of treating persistent vocal tic disorder in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), (II), (III), or (IV) described herein, or a solvate, hydrate, tautomer, N- oxide, or a pharmaceutically acceptable salt thereof. In another embodiment is a method of treating abdominal pain associated with irritable bowel syndrome in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), (II), (III), or (IV) described herein, or a solvate, hydrate, tautomer, N-oxide, or a pharmaceutically acceptable salt thereof.

DETAILED DESCRIPTION OF THE INVENTION

[0015] This disclosure is directed, at least in part, to MAGL and/or ABHD6 modulators or inhibitors. In some embodiments, provided herein are compounds capable of inhibiting MAGL. In some embodiments, provided herein are compounds capable of inhibiting ABHD6. For example, provided herein are compounds capable of inhibiting MAGL. In some embodiments, the compounds described herein are dual inhibitors capable of inhibiting MAGL and ABHD6.

[0016] As used herein and in the appended claims, the singular forms "a," "and," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "an agent" includes a plurality of such agents, and reference to "the cell" includes reference to one or more cells (or to a plurality of cells) and equivalents thereof. When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulae, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included. The term "about" when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range varies between 1% and 15% of the stated number or numerical range. The term "comprising" (and related terms such as "comprise" or "comprises" or "having" or "including") is not intended to exclude that in other certain embodiments, for example, an embodiment of any composition of matter, composition, method, or process, or the like, described herein, may "consist of or "consist essentially of the described features.

Definitions

[0017] As used in the specification and appended claims, unless specified to the contrary, the following terms have the meaning indicated below.

[0018] "Amino" refers to the -NH ₂ radical.

[0019] "Cyano" refers to the -CN radical. [0020] "Nitro" refers to the -N0 ₂ radical.

[0021] "Oxa" refers to the -O- radical.

[0022] "Oxo" refers to the =0 radical.

[0023] "Thioxo" refers to the =S radical.

[0024] "Imino" refers to the =N-H radical.

[0025] "Oximo" refers to the =N-OH radical.

[0026] "Alkyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to fifteen carbon atoms (e.g. , C ₁ -C ₁₅ alkyl). In certain embodiments, an alkyl comprises one to thirteen carbon atoms (e.g. , C ₁ -C ₁₃ alkyl). In certain embodiments, an alkyl comprises one to eight carbon atoms (e.g., Ci-C ₈ alkyl). In other embodiments, an alkyl comprises one to five carbon atoms (e.g., C ₁ -C5 alkyl). In other embodiments, an alkyl comprises one to four carbon atoms (e.g., Ci- C ₄ alkyl). In other embodiments, an alkyl comprises one to three carbon atoms (e.g., C ₁ -C ₃ alkyl). In other embodiments, an alkyl comprises one to two carbon atoms (e.g., C ₁ -C ₂ alkyl). In other embodiments, an alkyl comprises one carbon atom (e.g., Ci alkyl). In other embodiments, an alkyl comprises five to fifteen carbon atoms (e.g., C5-C ₁₅ alkyl). In other embodiments, an alkyl comprises five to eight carbon atoms (e.g., C ₅ -C ₈ alkyl). In other embodiments, an alkyl comprises two to five carbon atoms (e.g., C ₂ -C ₅ alkyl). In other embodiments, an alkyl comprises three to five carbon atoms (e.g., C ₃ -C5 alkyl). In other embodiments, the alkyl group is selected from methyl, ethyl, 1 -propyl (^-propyl), 1 -methyl ethyl (z ^' so-propyl), 1 -butyl («-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (iso-buty\), 1,1 -dimethyl ethyl (tert-butyl), 1-pentyl («-pentyl). The alkyl is attached to the rest of the molecule by a single bond. Unless stated otherwise specifically in the specification, an alkyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo,

trimethylsilanyl, -OR ^a , -SR ^a , -OC(0)-R ^f , -N(R ^a ) ₂ , -C(0)R ^a , -C(0)OR ^a , -C(0)N(R ^a ) ₂ , - N(R ^a )C(0)OR ^f , -OC(0)- R ^a R ^f , -N(R ^a )C(0)R ^f , -N(R ^a )S(0) _t R ^f (where t is 1 or 2), -S(0) _t OR ^a (where t is 1 or 2), -S(0) _t R ^f (where t is 1 or 2) and -S(0) _t N(R ^a ) ₂ (where t is 1 or 2) where each R ^a is independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or heteroaryl alkyl, and each R is independently alkyl, fluoroalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or heteroaryl alkyl.

[0027] "Alkoxy" refers to a radical bonded through an oxygen atom of the formula -O-alkyl, where alkyl is an alkyl chain as defined above.

[0028] "Alkenyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon double bond, and having from two to twelve carbon atoms. In certain embodiments, an alkenyl comprises two to eight carbon atoms. In other embodiments, an alkenyl comprises two to four carbon atoms. The alkenyl is attached to the rest of the molecule by a single bond, for example, ethenyl (i.e., vinyl), prop-l-enyl (i. e., allyl), but-l-enyl, pent-l-enyl, penta-l,4-dienyl, and the like. Unless stated otherwise specifically in the specification, an alkenyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo,

trimethylsilanyl, -OR ^a , -SR ^a , -OC(0)-R ^f , -N(R ^a ) ₂ , -C(0)R ^a , -C(0)OR ^a , -C(0)N(R ^a ) ₂ , - N(R ^a )C(0)OR ^f , -OC(0)- R ^a R ^f , -N(R ^a )C(0)R ^f , -N(R ^a )S(0) _t R ^f (where t is 1 or 2), -S(0) _t OR ^a (where t is 1 or 2), -S(0) _t R ^f (where t is 1 or 2) and -S(0) _t N(R ^a ) ₂ (where t is 1 or 2) where each R ^a is independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or heteroaryl alkyl, and each R is independently alkyl, fluoroalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or heteroaryl alkyl.

[0029] "Alkynyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, having from two to twelve carbon atoms. In certain embodiments, an alkynyl comprises two to eight carbon atoms. In other embodiments, an alkynyl has two to four carbon atoms. The alkynyl is attached to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Unless stated otherwise specifically in the specification, an alkynyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR ^a , -SR ^a , -OC(0)-R ^f , -N(R ^a ) ₂ , -C(0)R ^a , - C(0)OR ^a , -C(0)N(R ^a ) ₂ , -N(R ^a )C(0)OR ^f , -OC(0)- R ^a R ^f , -N(R ^a )C(0)R ^f , -N(R ^a )S(0) _t R ^f (where t is 1 or 2), -S(0) _t OR ^a (where t is 1 or 2), -S(0) _t R ^f (where t is 1 or 2) and -S(0) _t N(R ^a ) ₂ (where t is 1 or 2) where each R ^a is independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl, and each R is independently alkyl, fluoroalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl.

[0030] "Alkylene" or "alkylene chain" refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing no unsaturation and having from one to twelve carbon atoms, for example, methylene, ethylene, propylene, «-butylene, and the like. The alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. In some embodiments, the points of attachment of the alkylene chain to the rest of the molecule and to the radical group are through one carbon in the alkylene chain or through any two carbons within the chain. In certain embodiments, an alkylene comprises one to eight carbon atoms (e.g., Ci-C ₈ alkylene). In other embodiments, an alkylene comprises one to five carbon atoms (e.g., C ₁ -C5 alkylene). In other embodiments, an alkylene comprises one to four carbon atoms (e.g., C ₁ -C4 alkylene). In other embodiments, an alkylene comprises one to three carbon atoms (e.g., C ₁ -C ₃ alkylene). In other embodiments, an alkylene comprises one to two carbon atoms (e.g., C ₁ -C ₂ alkylene). In other embodiments, an alkylene comprises one carbon atom (e.g., Ci alkylene). In other embodiments, an alkylene comprises five to eight carbon atoms (e.g., C ₅ -C ₈ alkylene). In other embodiments, an alkylene comprises two to five carbon atoms (e.g., C ₂ -C ₅ alkylene). In other embodiments, an alkylene comprises three to five carbon atoms (e.g., C ₃ -C5 alkylene). Unless stated otherwise specifically in the specification, an alkylene chain is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR ^a , -SR ^a , -OC(0)-R ^f , -N(R ^a ) ₂ , -C(0)R ^a , -C(0)OR ^a , - C(0)N(R ^a ) ₂ , -N(R ^a )C(0)OR ^f , -OC(0)- R ^a R ^f , -N(R ^a )C(0)R ^f , -N(R ^a )S(0) _t R ^f (where t is 1 or 2), - S(0) _t OR ^a (where t is 1 or 2), -S(0) _t R ^f (where t is 1 or 2) and -S(0) _t N(R ^a ) ₂ (where t is 1 or 2) where each R ^a is independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl, and each R is independently alkyl, fluoroalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl.

[0031] "Aryl" refers to a radical derived from an aromatic monocyclic or multicyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom. The aromatic monocyclic or multicyclic hydrocarbon ring system contains only hydrogen and carbon from five to eighteen carbon atoms, where at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) π-electron system in accordance with the Hiickel theory. The ring system from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin and naphthalene. Unless stated otherwise specifically in the specification, the term "aryl" or the prefix "ar-" (such as in "aralkyl") is meant to include aryl radicals optionally substituted by one or more substituents selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, cyano, nitro, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl, -R -OR ^a , -R -OC(0)-R ^a , - R -OC(0)-OR ^a , -R -OC(0)-N(R ^a ) ₂ , -R -N(R ^a ) ₂ , -R -C(0)R ^a , -R -C(0)OR ^a , -R -C(0)N(R ^a ) ₂ , - R -0-R ^c -C(0)N(R ^a ) ₂ , -R -N(R ^a )C(0)OR ^a , -R -N(R ^a )C(0)R ^a , -R -N(R ^a )S(0) _t R ^a (where t is 1 or 2), -R -S(0) _t OR ^a (where t is 1 or 2), -R -S(0) _t R ^a (where t is 1 or 2) and -R -S(0) _t N(R ^a ) ₂ (where t is 1 or 2), where each R ^a is independently hydrogen, alkyl, fluoroalkyl, cycloalkyl,

cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl, each R is independently a direct bond or a straight or branched alkylene or alkenylene chain, and R ^c is a straight or branched alkylene or alkenylene chain.

[0032] "Aryloxy" refers to a radical bonded through an oxygen atom of the formula -O-aiyl, where aryl is as defined above.

[0033] "Aralkyl" refers to a radical of the formula -R ^c -aryl where R ^c is an alkylene chain as defined above, for example, methylene, ethylene, and the like. The alkylene chain part of the aralkyl radical is optionally substituted as described above for an alkylene chain. The aryl part of the aralkyl radical is optionally substituted as described above for an aryl group.

[0034] "Aralkyloxy" refers to a radical bonded through an oxygen atom of the formula -O- aralkyl, where aralkyl is as defined above.

[0035] "Aralkenyl" refers to a radical of the formula -R ^d -aryl where R ^d is an alkenylene chain as defined above. The aryl part of the aralkenyl radical is optionally substituted as described above for an aryl group. The alkenylene chain part of the aralkenyl radical is optionally substituted as defined above for an alkenylene group.

[0036] "Aralkynyl" refers to a radical of the formula -R ^e -aryl, where R ^e is an alkynyl ene chain as defined above. The aryl part of the aralkynyl radical is optionally substituted as described above for an aryl group. The alkynyl ene chain part of the aralkynyl radical is optionally substituted as defined above for an alkynyl ene chain.

[0037] "Cycloalkyl " refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which includes fused or bridged ring systems, having from three to fifteen carbon atoms. In certain embodiments, a cycloalkyl comprises three to ten carbon atoms. In other embodiments, a cycloalkyl comprises five to seven carbon atoms. The cycloalkyl is attached to the rest of the molecule by a single bond. Cycloalkyls are saturated, (i.e., containing single C-C bonds only) or partially unsaturated (i.e., containing one or more double bonds or triple bonds.) Examples of monocyclic cycloalkyls include, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In certain embodiments, a cycloalkyl comprises three to eight carbon atoms (e.g., C ₃ -C ₈ cycloalkyl). In other embodiments, a cycloalkyl comprises three to seven carbon atoms (e.g., C ₃ -C ₇ cycloalkyl). In other embodiments, a cycloalkyl comprises three to six carbon atoms (e.g., C ₃ -C ₆ cycloalkyl). In other embodiments, a cycloalkyl comprises three to five carbon atoms (e.g., C ₃ -C ₅ cycloalkyl). In other embodiments, a cycloalkyl comprises three to four carbon atoms (e.g., C ₃ -C ₄ cycloalkyl). A partially unsaturated cycloalkyl is also referred to as "cycloalkenyl." Examples of monocyclic cycloalkenyls include, e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Polycyclic cycloalkyl radicals include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl,

7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unless stated otherwise specifically in the specification, the term "cycloalkyl" is meant to include cycloalkyl radicals that are optionally substituted by one or more substituents selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl, -R -OR ^a , -R -OC(0)-R ^a , -R -OC(0)-OR ^a , -R -OC(0)-N(R ^a ) ₂ , -R - N(R ^a ) ₂ , -R -C(0)R ^a , -R -C(0)OR ^a , -R -C(0)N(R ^a ) ₂ , -R -0-R ^c -C(0)N(R ^a ) ₂ , -R -N(R ^a )C(0)OR ^a , -R -N(R ^a )C(0)R ^a , -R -N(R ^a )S(0) _t R ^a (where t is 1 or 2), -R -S(0) _t OR ^a (where t is 1 or 2), -R - S(0) _t R ^a (where t is 1 or 2) and -R -S(0) _t N(R ^a ) ₂ (where t is 1 or 2), where each R ^a is

independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl, each R is independently a direct bond or a straight or branched alkylene or alkenylene chain, and R ^c is a straight or branched alkylene or alkenylene chain.

[0038] "Halo" or "halogen" refers to bromo, chloro, fluoro or iodo substituents.

[0039] "Haloalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above.

[0040] "Fluoroalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more fluoro radicals, as defined above, for example, trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, l-fluoromethyl-2-fluoroethyl, and the like. The alkyl part of the fluoroalkyl radical are optionally substituted as defined above for an alkyl group.

[0041] "Heterocycloalkyl" refers to a stable 3- to 18-membered non-aromatic ring radical that comprises two to twelve carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur. Unless stated otherwise specifically in the specification, the heterocycloalkyl radical is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which include fused, spiro, or bridged ring systems. The heteroatoms in the heterocycloalkyl radical are optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The

heterocycloalkyl radical is partially or fully saturated. In some embodiments, the

heterocycloalkyl is attached to the rest of the molecule through any atom of the ring(s).

Examples of such heterocycloalkyl radicals include, but are not limited to, dioxolanyl, thienyl[l,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl,

2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl,

tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and

1, 1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in the specification, the term "heterocycloalkyl" is meant to include heterocycloalkyl radicals as defined above that are optionally substituted by one or more substituents selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl,

heterocycloalkyl, heteroaryl, heteroarylalkyl, -R -OR ^a , -R -OC(0)-R ^a , -R -OC(0)-OR ^a , -R - OC(0)-N(R ^a ) ₂ , -R -N(R ^a ) ₂ , -R -C(0)R ^a , -R -C(0)OR ^a , -R -C(0)N(R ^a ) ₂ , -R -0-R ^c -C(0)N(R ^a ) ₂ , - R -N(R ^a )C(0)OR ^a , -R -N(R ^a )C(0)R ^a , -R -N(R ^a )S(0) _t R ^a (where t is 1 or 2), -R -S(0) _t OR ^a (where t is 1 or 2), -R -S(0) _t R ^a (where t is 1 or 2) and -R -S(0) _t N(R ^a ) ₂ (where t is 1 or 2), where each R ^a is independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl, each R is independently a direct bond or a straight or branched alkylene or alkenylene chain, and R ^c is a straight or branched alkylene or alkenylene chain.

[0042] "Heteroaryl" refers to a radical derived from a 3 - to 18-membered aromatic ring radical that comprises one to seventeen carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur. As used herein, the heteroaryl radical is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, wherein at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) π-electron system in accordance with the Hiickel theory. Heteroaryl includes fused or bridged ring systems. The heteroatom(s) in the heteroaryl radical is optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heteroaryl is attached to the rest of the molecule through any atom of the ring(s). Examples of heteroaryls include, but are not limited to, azepinyl, acridinyl,

benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzooxazolyl,

benzo[d]thiazolyl, benzothiadiazolyl, benzo[£][l,4]dioxepinyl, benzo[b][l,4]oxazinyl,

1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[l,2-a]pyridinyl, carbazolyl, cinnolinyl, cyclopenta[d]pyrimidinyl, 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl, 5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl, 6,7-dihydro-5H- benzo[6,7]cyclohepta[l,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, furo[3,2-c]pyridinyl, 5,6,7,8,9, 10-hexahydrocycloocta[d]pyrimidinyl,

5,6,7,8,9, 10-hexahydrocycloocta[d]pyridazinyl, 5,6,7,8,9, 10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, 5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl, 1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl,

5,6,6a,7,8,9,10, 10a-octahydrobenzo[h]quinazolinyl, 1 -phenyl- lH-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl,

pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl,

isoquinolinyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl,

5.6.7.8- tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl,

6.7.8.9- tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl,

5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pridinyl, and thiophenyl {i.e. thienyl). Unless stated otherwise specifically in the specification, the term "heteroaryl" is meant to include heteroaryl radicals as defined above which are optionally substituted by one or more substituents selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl, -R - OR ^a , -R -OC(0)-R ^a , -R -OC(0)-OR ^a , -R -OC(0)-N(R ^a ) ₂ , -R -N(R ^a ) ₂ , -R -C(0)R ^a , -R - C(0)OR ^a , -R -C(0)N(R ^a ) ₂ , -R -0-R ^c -C(0)N(R ^a ) ₂ , -R -N(R ^a )C(0)OR ^a , -R -N(R ^a )C(0)R ^a , -R - N(R ^a )S(0) _t R ^a (where t is 1 or 2), -R -S(0) _t OR ^a (where t is 1 or 2), -R -S(0) _t R ^a (where t is 1 or 2) and -R -S(0) _t N(R ^a ) ₂ (where t is 1 or 2), where each R ^a is independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl, each R is independently a direct bond or a straight or branched alkylene or alkenylene chain, and R ^c is a straight or branched alkylene or alkenylene chain.

[0043] "N-heteroaryl" refers to a heteroaryl radical as defined above containing at least one nitrogen and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a nitrogen atom in the heteroaryl radical. An N-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.

[0044] "C-heteroaryl" refers to a heteroaryl radical as defined above and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a carbon atom in the heteroaryl radical. A C-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.

[0045] "Heteroaryloxy" refers to radical bonded through an oxygen atom of the formula -O- heteroaryl, where heteroaryl is as defined above.

[0046] "Heteroarylalkyl" refers to a radical of the formula -R ^c -heteroaryl, where R ^c is an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heteroarylalkyl radical is optionally substituted as defined above for an alkylene chain. The heteroaryl part of the heteroarylalkyl radical is optionally substituted as defined above for a heteroaryl group.

[0047] "Heteroarylalkoxy" refers to a radical bonded through an oxygen atom of the formula - 0-R ^c -heteroaryl, where R ^c is an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heteroarylalkoxy radical is optionally substituted as defined above for an alkylene chain. The heteroaryl part of the heteroarylalkoxy radical is optionally substituted as defined above for a heteroaryl group.

[0048] In some embodiments, the compounds disclosed herein contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that are defined, in terms of absolute stereochemistry, as (R)- or (S)-. Unless stated otherwise, it is intended that all stereoisomeric forms of the compounds disclosed herein are contemplated by this disclosure. When the compounds described herein contain alkene double bonds, and unless specified otherwise, it is intended that this disclosure includes both E and Z geometric isomers (e.g., cis or trans?) Likewise, all possible isomers, as well as their racemic and optically pure forms, and all tautomeric forms are also intended to be included. The term "geometric isomer" refers to E or Z geometric isomers (e.g., cis or trans) of an alkene double bond. The term "positional isomer" refers to structural isomers around a central ring, such as ortho-, meta-, and para- isomers around a benzene ring.

[0049] A "tautomer" refers to a molecule wherein a proton shift from one atom of a molecule to another atom of the same molecule is possible. In certain embodiments, the compounds presented herein exist as tautomers. In circumstances where tautomerization is possible, a chemical equilibrium of the tautomers will exist. The exact ratio of the tautomers depends on several factors, including physical state, temperature, solvent, and pH. Some examples of tautomeric e uilibrium include:

[0050] "Optional" or "optionally" means that a subsequently described event or circumstance may or may not occur and that the description includes instances when the event or circumstance occurs and instances in which it does not. For example, "optionally substituted aryl" means that the aryl radical are or are not substituted and that the description includes both substituted aryl radicals and aryl radicals having no substitution.

[0051] "Pharmaceutically acceptable salt" includes both acid and base addition salts. A pharmaceutically acceptable salt of any one of the pyrazole compounds described herein is intended to encompass any and all pharmaceutically suitable salt forms. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0052] "Pharmaceutically acceptable acid addition salt" refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like. Also included are salts that are formed with organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and. aromatic sulfonic acids, etc. and include, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid,/?-toluenesulfonic acid, salicylic acid, and the like. Exemplary salts thus include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinate suberates, sebacates, fumarates, maleates, mandelates, benzoates,

chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates,

toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, and the like. Also contemplated are salts of amino acids, such as arginates, gluconates, and galacturonates (see, for example, Berge S.M. et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 66: 1-19 (1997). Acid addition salts of basic compounds are prepared by contacting the free base forms with a sufficient amount of the desired acid to produce the salt.

[0053] "Pharmaceutically acceptable base addition salt" refers to those salts that retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. In some embodiments, pharmaceutically acceptable base addition salts are formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, for example, isopropyl amine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol,

dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, N,N-dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, N- methylglucamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. See Berge et al., supra.

[0054] As used herein, "treatment" or "treating " or "palliating" or "ameliorating" are used interchangeably herein. These terms refers to an approach for obtaining beneficial or desired results including but not limited to therapeutic benefit and/or a prophylactic benefit. By

"therapeutic benefit" is meant eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient is still afflicted with the underlying disorder. For prophylactic benefit, the compositions are administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease has not been made.

[0055] "Prodrug" is meant to indicate a compound that is converted under physiological conditions or by solvolysis to a biologically active compound described herein. Thus, the term "prodrug" refers to a precursor of a biologically active compound that is pharmaceutically acceptable. In some embodiments, the prodrug is inactive when administered to a subject, but is converted in vivo to an active compound, for example, by hydrolysis. The prodrug compound often offers advantages of solubility, tissue compatibility or delayed release in a mammalian organism {see, e.g., Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier,

Amsterdam).

[0056] A discussion of prodrugs is provided in Higuchi, T., et al., "Pro-drugs as Novel Delivery Systems," A.C.S. Symposium Series, Vol. 14, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.

[0057] The term "prodrug" is also meant to include any covalently bonded carriers, which release the active compound in vivo when such prodrug is administered to a mammalian subject. In some embodiments, prodrugs of an active compound, as described herein, are prepared by modifying functional groups present in the active compound in such a way that the

modifications are cleaved, either in routine manipulation or in vivo, to the parent active compound. Prodrugs include compounds wherein a hydroxy, amino or mercapto group is bonded to any group that, when the prodrug of the active compound is administered to a mammalian subject, cleaves to form a free hydroxy, free amino or free mercapto group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol or amine functional groups in the active compounds and the like. Compounds

[0058] The compounds of Formula (I), (la), (II), (Ha), (III), or (IV) described herein which are be modulators of MAGL and/or ABHD6. In some embodiments, the compounds are inhibitors of MAGL. In some embodiments, the compounds are inhibitors of ABHD6. The compounds of Formula (I), (la), (II), (Ila), (III), or (IV) described herein, and compositions comprising these compounds, are useful for the treatment of pain, mutiple sclerosis, Alzheimer's disease, and/or inflammatory bowel disease.

[0059] In one embodiment is a

Formula (I);

wherein:

R ¹ is -N(R ² )C(0)R ¹⁵ or -N(H)S0 ₂ R ¹⁵ ;

R ² is H or C _h alky.;

R ³ is H or optionally substituted phenyl;

R ⁴ is H, halogen, -OR ⁷ , Ci-ehaloalkyl, optionally substituted heterocycloalkyl, optionally substituted Ci- ₆ alkyl-heterocycloalkyl, optionally substituted phenyl, optionally substituted heteroaryl, -C0 ₂ H, or -C(0) R ⁸ R ⁹ ;

R ⁵ is H, halogen, Ci _-6 alkyl, Ci _-6 haloalkyl, or phenyl; or

R ⁴ and R ⁵ are combined to form a heterocycloalkyl ring;

R ⁶ is H, halogen or

R ⁷ is H, Ci- ₆ alkyl, optionally substituted phenyl, optionally substituted

optionally substituted heteroaryl, optionally substituted heterocycloalkyl, or -Ci.

₆ alkylC(O) R ¹⁰ R ^u ;

R' 8 and R ⁹ are each independently H, or Ci- ₆ alkyl; or R ⁸ and R ⁹ together with the nitrogen to which they are attached are combined to form an optionally substituted heterocycloalkyl ring;

R ¹⁰ and R ¹¹ are each independently H, or Ci _-6 alkyl; or R ¹⁰ and R ¹¹ together with the nitrogen to which they are attached are combined to form a heterocycloalkyl ring; and

R ¹⁵ is optionally substituted

or a solvate, hydrate, tautomer, N-oxide, or pharmaceutically acceptable salt thereof.

[0060] In another embodiment is a compound of Formula (I), wherein R ¹ is -N(R ² )C(0)R ¹⁵ . In another embodiment is a compound of Formula (I), wherein R ¹ is -N(R ² )C(0)R ¹⁵ and R ² is H. In another embodiment is a compound of Formula (I), wherein R ¹ is -N(R ² )C(0)R ¹⁵ and R ² is Ci- ₆ alkyl. In another embodiment is a compound of Formula (I), wherein R ¹ is -N(R ² )C(0)R ¹⁵ and R ² is -CH ₃ . In another embodiment is a compound of Formula (I), wherein R ¹ is - N(R ² )C(0)R ¹⁵ , R ² is H, and R ¹⁵ is -CH ₂ OH. In another embodiment is a compound of Formula (I), wherein R ¹ is -N(R ² )C(0)R ¹⁵ , R ² is H, and R ¹⁵ is -CF ₃ . In another embodiment is a compound of Formula (I), wherein R ¹ is -N(R ² )C(0)R ¹⁵ , R ² is H, and R ¹⁵ is -CHF ₂ . In another embodiment is a compound of Formula (I), wherein R ¹ is -N(R ² )C(0)R ¹⁵ , R ² is H, and R ¹⁵ is unsubstituted Ci _-6 alkyl. In another embodiment is a compound of Formula (I), wherein R ¹ is - N(R ² )C(0)R ¹⁵ , R ² is H, R ¹⁵ is -CH ₃ . In another embodiment is a compound of Formula (I), wherein R ¹ is -N(R ² )C(0)R ¹⁵ , R ² is Ci _-6 alkyl, and R ¹⁵ is -CH ₂ OH. In another embodiment is a compound of Formula (I), wherein R ¹ is -N(R ² )C(0)R ¹⁵ , R ² is Ci _-6 alkyl, and R ¹⁵ is -CF ₃ . In another embodiment is a compound of Formula (I), wherein R ¹ is -N(R ² )C(0)R ¹⁵ , R ² is Ci. ₆ alkyl, and R ¹⁵ is -CHF ₂ . In another embodiment is a compound of Formula (I), wherein R ¹ is - N(R ² )C(0)R ¹⁵ , R ² is Ci- ₆ alkyl, and R ¹⁵ is unsubstituted In another embodiment is a compound of Formula (I), wherein R ¹ is -N(R ² )C(0)R ¹⁵ , R ² is Ci _-6 alkyl, R ¹⁵ is -CH ₃ . In another embodiment is a compound of Formula (I), wherein R ¹ is -N(R ² )C(0)R ¹⁵ , R ² is -CH ₃ , and R ¹⁵ is -CH ₂ OH. In another embodiment is a compound of Formula (I), wherein R ¹ is -N(R ² )C(0)R ¹⁵ , R ² is -CH ₃ , and R ¹⁵ is -CF ₃ . In another embodiment is a compound of Formula (I), wherein R ¹ is -N(R ² )C(0)R ¹⁵ , R ² is -CH ₃ , and R ¹⁵ is -CHF ₂ . In another embodiment is a compound of Formula (I), wherein R ¹ is -N(R ² )C(0)R ¹⁵ , R ² is -CH ₃ , and R ¹⁵ is unsubstituted Ci _-6 alkyl. In another embodiment is a compound of Formula (I), wherein R ¹ is -N(R ² )C(0)R ¹⁵ , R ² is -CH ₃ , R ¹⁵ is -CH ₃ . In another embodiment is a compound of Formula (I), wherein R ¹ -N(H)S0 ₂ R ¹⁵ . In another embodiment is a compound of Formula (I), wherein R ¹ is-N(H)S0 ₂ R ¹⁵ and R ¹⁵ is - CH ₂ OH. In another embodiment is a compound of Formula (I), wherein R ¹ is-N(H)S0 ₂ R ¹⁵ and R ¹⁵ is -CF ₃ . In another embodiment is a compound of Formula (I), wherein R ¹ is -N(H)S0 ₂ R ¹⁵ and R ¹⁵ is -CHF ₂ . In another embodiment is a compound of Formula (I), wherein R ¹ is - N(H)S0 ₂ R ¹⁵ and R ¹⁵ is unsubstituted Ci _-6 alkyl. In another embodiment is a compound of Formula (I), wherein R ¹ is -N(H)S0 ₂ R ¹⁵ and R ¹⁵ is -CH ₃ . In another embodiment is a compound of Formula (I), wherein R ³ is H. In another embodiment is a compound of Formula (I), wherein R ³ is optionally substituted phenyl.

[0061] In another embodiment is a compound of Formula (I), wherein R ⁴ is H. In another embodiment is a compound of Formula (I), wherein R ⁴ is halogen. In another embodiment is a compound of Formula (I), wherein R ⁴ is -CI. In another embodiment is a compound of Formula (I), wherein R ⁴ is -F. In another embodiment is a compound of Formula (I), wherein R ⁴ is Ci. ₆ alkyl. In another embodiment is a compound of Formula (I), wherein R ⁴ is Ci- ₆ haloalkyl. In another embodiment is a compound of Formula (I), wherein R ⁴ is -CF ₃ . In another embodiment is a compound of Formula (I), wherein R ⁴ is optionally substituted phenyl. In another embodiment is a compound of Formula (I), wherein R ⁴ is optionally substituted heteroaryl. In another embodiment is a compound of Formula (I), wherein R ⁴ is heteroaryl optionally substituted with one or two groups selected from halogen, hydroxy, Ci- ₆ alkyl, -Ci- ₆ alkyl-OH, Ci. efluoroalkyl, C ₃ - ₆ cycloalkyl, -C0 ₂ H, -Ci _-6 alkyl-C0 ₂ H, -C(0)Ci _-6 alkyl, -C(0)Ci _-6 alkyl-OH, - N(H)C(0)C _1-6 alkyl, -C(0) H ₂ , -C(0)N(H)(C _1-6 alkyl), -C(0)N(C _1-6 alkyl) ₂ , -C(0)C _{2- 7} heterocycloalkyl, and -S(0) ₂ Ci _-6 alkyl. In another embodiment is a compound of Formula (I), wherein R ⁴ is heteroaryl optionally substituted with one or two groups selected from halogen, hydroxy, Ci _-6 alkyl, Ci _-6 fluoroalkyl, C _3-6 cycloalkyl, -C0 ₂ H, -Ci _-6 alkyl-C0 ₂ H, and -C(0) H ₂ . In another embodiment is a compound of Formula (I), wherein R ⁴ is optionally substituted heteroaryl and the heteroaryl is a 5-6 membered heteroaryl ring. In another embodiment is a compound of Formula (I), wherein R ⁴ is a 5-6 membered heteroaryl ring optionally substituted with one or two groups selected from halogen, hydroxy, -Ci- ₆ alkyl-OH, Ci.

efluoroalkyl, C _3-6 cycloalkyl, -C0 ₂ H, -Ci _-6 alkyl-C0 ₂ H, -C(0)Ci _-6 alkyl, -C(0)Ci _-6 alkyl-OH, - N(H)C(0)C _1-6 alkyl, -C(0) H ₂ , -C(0)N(H)(C _1-6 alkyl), -C(0)N(C _1-6 alkyl) ₂ , -C(0)C _{2- 7} heterocycloalkyl, and -S(0) ₂ Ci- ₆ alkyl. In another embodiment is a compound of Formula (I), wherein R ⁴ is a 5-6 membered heteroaryl ring optionally substituted with one or two groups selected from halogen, Ci _-6 alkyl, -Ci _-6 alkyl-OH, Ci _-6 fluoroalkyl, -C0 ₂ H, -Ci _-6 alkyl-C0 ₂ H. In another embodiment is a compound of Formula (I), wherein R ⁴ is a 5-membered heteroaryl ring optionally substituted with one or two groups selected from halogen, hydroxy, -Ci. ₆ alkyl-OH, Ci _-6 fluoroalkyl, C _3-6 cycloalkyl, -C0 ₂ H, -Ci _-6 alkyl-C0 ₂ H, -C(0)Ci _-6 alkyl, -C(0)Ci. ₆ alkyl-OH, -N(H)C(0)C _1-6 alkyl, -C(0) H ₂ , -C(0)N(H)(C _1-6 alkyl), -C(0)N(C _1-6 alkyl) ₂ , - C(0)C _2-7 heterocycloalkyl, and -S(0) ₂ Ci _-6 alkyl. In another embodiment is a compound of Formula (I), wherein R ⁴ is a 5-membered heteroaryl ring optionally substituted with one or two groups selected from halogen, -Ci- ₆ alkyl-OH, Ci-efiuoroalkyl, -C0 ₂ H, -Ci- ₆ alkyl- C0 ₂ H. In another embodiment is a compound of Formula (I), wherein R ⁴ is a 6-membered heteroaryl ring optionally substituted with one or two groups selected from halogen, hydroxy, Ci _-6 alkyl, -Ci _-6 alkyl-OH, Ci _-6 fluoroalkyl, C _3-6 cycloalkyl, -C0 ₂ H, -Ci _-6 alkyl-C0 ₂ H, -C(0)Ci. ₆ alkyl, -C(0)Ci _-6 alkyl-OH, -N(H)C(0)Ci _-6 alkyl, -C(0) H ₂ , -C(0)N(H)(Ci _-6 alkyl), -C(0)N(Ci. ₆ alkyl) ₂ , -C(0)C _2-7 heterocycloalkyl, and -S(0) ₂ Ci _-6 alkyl. In another embodiment is a compound of Formula (I), wherein R ⁴ is a 6-membered heteroaryl ring optionally substituted with one or two groups selected from halogen, -Ci- ₆ alkyl-OH, Ci-efluoroalkyl, -C0 ₂ H, -Ci- ₆ alkyl-

C0 ₂ H. In another embodiment is a compound of Formula (I), wherein R N In another embodiment is a compound of Formula (I), wherein

embodiment is a compound of Formula (I), wherein R is N N _? N-N , N _? or N . In another embodiment is a compound of Formula (I), wherein R ⁴ is optionally substituted Ci _-6 alkyl -heterocycloalkyl. In another embodiment is a compound of Formula (I), wherein R ⁴ is optionally substituted heterocycloalkyl. In another embodiment is a compound of Formula (I), wherein R ⁴ is heterocycloalkyl optionally substituted with one or more groups selected from halogen, hydroxy, Ci _-6 alkyl, -Ci _-6 alkyl-OH, Ci.

efluoroalkyl, C _3-6 cycloalkyl, heteroaryl, -C0 ₂ H, -Ci _-6 alkyl-C0 ₂ H, -C(0)Ci _-6 alkyl, -C(0)d. 6alkyl-OH, -N(H)C(0)Ci _-6 alkyl, -C(0) H ₂ , -C(0)N(H)(Ci _-6 alkyl), -C(0)N(Ci _-6 alkyl) ₂ , - C(0)C _2-7 heterocycloalkyl, and -S(0) ₂ Ci- ₆ alkyl. In another embodiment is a compound of Formula (I), wherein R ⁴ is heterocycloalkyl optionally substituted with one or two groups selected from halogen, hydroxy, Ci _-6 alkyl, -Ci _-6 alkyl-OH, Ci _-6 fluoroalkyl, C _3-6 cycloalkyl, heteroaryl, -C0 ₂ H, -Ci _-6 alkyl-C0 ₂ H, -C(0)Ci _-6 alkyl, -C(0)Ci _-6 alkyl-OH, -N(H)C(0)Ci _-6 alkyl, - C(0) H ₂ , -C(0)N(H)(Ci _-6 alkyl), -C(0)N(Ci _-6 alkyl) ₂ , -C(0)C _2-7 heterocycloalkyl, and -S(0) ₂ Ci. 6alkyl. In another embodiment is a compound of Formula (I), wherein R ⁴ is optionally substituted heterocycloalkyl and the heterocycloalkyl is a 4-6 membered monocyclic heterocycloalkyl, a 8-9 membered bicyclic heterocycloalkyl, a 7-8 membered bridged heterocycloalkyl, a 5,5 fused heterocycloalkyl, or an 8-11 membered spirocyclic

heterocycloalkyl. In another embodiment is a compound of Formula (I), wherein R ⁴ is an optionally substituted 4-6 membered monocyclic heterocycloalkyl. In another embodiment is a compound of Formula (I), wherein R ⁴ is an optionally substituted 8-9 membered bicyclic heterocycloalkyl. In another embodiment is a compound of Formula (I), wherein R ⁴ is an optionally substituted 7-8 membered bridged heterocycloalkyl. In another embodiment is a compound of Formula (I), wherein R ⁴ is an optionally substituted 5,5 fused heterocycloalkyl. In another embodiment is a compound of Formula (I), wherein R ⁴ is an optionally substituted 8-11 membered spirocyclic heterocycloalkyl. In another embodiment is a compound of Formula (I), 4 ^" ^~N J ^' \ ^~Ν /

wherein R is optionally substituted heterocycloalkyl selected from \— / ,

/— v /— \ /— \ /— \ O /— \ O nother embodiment is a compound of Formula (I), wherein R ⁴ is optionally substituted heterocycloalkyl

embodiment is a compound of Formula (I), wherein R ⁴ is -OR ⁷ . In another embodiment is a compound of Formula (I), wherein R ⁴ is -OR ⁷ , and R ⁷ is H, Ci _-6 alkyl, a phenyl optionally substituted with halogen, Ci _-6 alkyl, Ci _-6 fluoroalkyl, or Ci _-6 alkoxy, a Ci _-6 alkyl-phenyl optionally substituted with halogen, Ci-efluoroalkyl, or Ci _-6 alkoxy, a heteroaryl optionally substituted with halogen, or Ci-efluoroalkyl, a 5-6 membered monocyclic

heterocycloalkyl optionally substituted with halogen, Ci-efluoroalkyl, or C _{3- 6} cycloalkyl, or a In another embodiment is a compound of Formula (I), wherein R ⁴ is -OR ⁷ , and R ⁷ is Ci- ₆ alkyl. In another embodiment is a compound of Formula (I), wherein R ⁴ is -OR ⁷ , and R ⁷ is optionally substituted phenyl. In another embodiment is a compound of Formula (I), wherein R ⁴ is -OR ⁷ , and R ⁷ is phenyl optionally substituted with halogen, Ci _-6 alkyl, Ci _-6 fluoroalkyl, or Ci _-6 alkoxy. In another embodiment is a compound of Formula (I), wherein R ⁴ is -OR ⁷ , and R ⁷ is optionally substituted Ci- ₆ alkyl-phenyl. In another embodiment is a compound of Formula (I), wherein R ⁴ is -OR ⁷ , and R ⁷ is

optionally substituted with halogen, Ci _-6 alkyl, Ci _-6 fluoroalkyl, or Ci _-6 alkoxy. In another embodiment is a compound of Formula (I), wherein R ⁴ is -OR ⁷ , and R ⁷ is optionally substituted heteroaryl. In another embodiment is a compound of Formula (I), wherein R ⁴ is -OR ⁷ , and R ⁷ is heteroaryl optionally substituted with halogen, or Ci-efluoroalkyl. In another embodiment is a compound of Formula (I), wherein R ⁴ is -OR ⁷ , and R ⁷ is optionally substituted heterocycloalkyl. In another embodiment is a compound of Formula (I), wherein R ⁴ is -OR ⁷ , and R ⁷ is a 5-6 membered monocyclic heterocycloalkyl optionally substituted with halogen, Ci. ₆ alkyl, Ci-efiuoroalkyl, or C3- ₆ cycloalkyl. In another embodiment is a compound of Formula (I), wherein R ⁴ is -OR ⁷ , and R ⁷ is In another embodiment is a compound of Formula (I), wherein R ⁴ is -OR ⁷ , and R ⁷ is -Ci _-6 alkylC(O) R ¹⁰ R ¹¹ , and R ¹⁰ and R ¹² are each independently H, or Ci- ₆ alkyl. In another embodiment is a compound of Formula (I), wherein R ⁴ is -OR ⁷ , and R ⁷ is -Ci _-6 alkylC(O) R ¹⁰ R ^u , and R ¹⁰ and R ¹¹ together with the nitrogen to which the are attached are combined to form a heteroc cloalk l rin . In another embodiment

r

another embodiment is a compound of Formula (I), wherein R ⁴ is -C(0)NR ⁸ R ⁹ . In another

4 8 9 8 9 embodiment is a compound of Formula (I), wherein R is -C(0) R R , and R and R are each independently H, or Ci _-6 alkyl. In another embodiment is a compound of Formula (I), wherein 4 8 9 8 9

R is -C(0) R°R ^: ', and R° and R ^* are H. In another embodiment is a compound of Formula (I), wherein R 4" is -C(0) R 8°R 9 ^: ', and R 8° is H and R 9 ^* are Ci- ₆ alkyl. In another embodiment is a compound of Formula (I), wherein R 4 is -C(0) R 8 R 9 , and R 8 and R 9 are Ci _-6 alkyl. In another embodiment is a compound of Formula (I), wherein R 4 is -C(0) R 8 R 9 , and R 8 and R 9 together with the nitrogen to which they are attached are combined to form an optionally substituted heterocycloalkyl ring. In another embodiment is a compound of Formula (I), wherein R ⁴ is - C(0) R ⁸ R ⁹ , and R ⁸ and R ⁹ together with the nitrogen to which they are attached are combined to form an unsubstituted heterocycloalkyl ring.

[0062] In another embodiment is a compound of Formula (I), wherein R ⁵ is H. In another embodiment is a compound of Formula (I), wherein R ⁵ is halogen. In another embodiment is a compound of Formula (I), wherein R ⁵ is -CI. In another embodiment is a compound of Formula (I), wherein R ⁵ is -F. In another embodiment is a compound of Formula (I), wherein R ⁵ is Ci. ₆ alkyl. In another embodiment is a compound of Formula (I), wherein R ⁵ is Ci- ₆ haloalkyl. In another embodiment is a compound of Formula (I), wherein R ⁵ is -CF ₃ . In another embodiment is a compound of Formula (I), wherein R ⁵ is phenyl.

[0063] In another embodiment is a compound of Formula (I), wherein R ⁶ is H. In another embodiment is a compound of Formula (I), wherein R ⁶ is halogen. In another embodiment is a compound of Formula (I), wherein R ⁶ is -CI. In another embodiment is a compound of Formula (I), wherein R ⁶ is -F. In another embodiment is a compound of Formula (I), wherein R ⁶ is Ci.

₆ alkyl.

[0064] In another embodiment is a compound of Formula (I) having the structure of Formula

(Ia):

Formula (Ia);

wherein:

R ¹ is -N(R ² )C(0)R ¹⁵ or -N(H)S0 ₂ R ¹⁵ ;

R ² is H or C _h alky.;

R ⁴ is H, halogen, -OR ⁷ , Ci _-6 alkyl, Ci _-6 haloalkyl, optionally substituted heterocycloalkyl, optionally substituted Ci- ₆ alkyl-heterocycloalkyl, optionally substituted phenyl, optionally substituted heteroaryl, -C0 ₂ H, or -C(0) R ⁸ R ⁹ ;

R ⁵ is H, halogen, Ci _-6 alkyl, Ci _-6 haloalkyl, or phenyl; or

R ⁴ and R ⁵ are combined to form a heterocycloalkyl ring; R ⁷ is H, Ci- ₆ alkyl, optionally substituted phenyl, optionally substituted

optionally substituted heteroaryl, optionally substituted heterocycloalkyl, or -Ci.

₆ alkylC(O) R ¹⁰ R ^u ;

R ⁸ and R ⁹ are each independently H, or Ci _-6 alkyl; or R ⁸ and R ⁹ together with the nitrogen to which they are attached are combined to form an optionally substituted heterocycloalkyl ring;

R ¹⁰ and R ¹¹ are each independently H, or Ci _-6 alkyl; or R ¹⁰ and R ¹¹ together with the nitrogen to which they are attached are combined to form a heterocycloalkyl ring; and

R ¹⁵ is optionally substituted

or a solvate, hydrate, tautomer, N-oxide, or pharmaceutically acceptable salt thereof.

[0065] In another embodiment is a compound of Formula (la), wherein R ¹ is -N(R ² )C(0)R ¹⁵ . In another embodiment is a compound of Formula (la), wherein R ¹ is -N(R ² )C(0)R ¹⁵ and R ² is H. In another embodiment is a compound of Formula (la), wherein R ¹ is -N(R ² )C(0)R ¹⁵ and R ² is Ci- ₆ alkyl. In another embodiment is a compound of Formula (la), wherein R ¹ is - N(R ² )C(0)R ¹⁵ and R ² is -CH ₃ . In another embodiment is a compound of Formula (la), wherein R ¹ is -N(R ² )C(0)R ¹⁵ , R ² is H, and R ¹⁵ is -CH ₂ OH. In another embodiment is a compound of Formula (la), wherein R ¹ is -N(R ² )C(0)R ¹⁵ , R ² is H, and R ¹⁵ is -CF ₃ . In another embodiment is a compound of Formula (la), wherein R ¹ is -N(R ² )C(0)R ¹⁵ , R ² is H, and R ¹⁵ is -CHF ₂ . In another embodiment is a compound of Formula (la), wherein R ¹ is -N(R ² )C(0)R ¹⁵ , R ² is H, and R ¹⁵ is unsubstituted Ci _-6 alkyl. In another embodiment is a compound of Formula (la), wherein R ¹ is -N(R ² )C(0)R ¹⁵ , R ² is H, R ¹⁵ is -CH ₃ . In another embodiment is a compound of Formula (la), wherein R ¹ is -N(R ² )C(0)R ¹⁵ , R ² is Ci _-6 alkyl, and R ¹⁵ is -CH ₂ OH. In another embodiment is a compound of Formula (la), wherein R ¹ is -N(R ² )C(0)R ¹⁵ , R ² is Ci _-6 alkyl, and R ¹⁵ is -CF ₃ . In another embodiment is a compound of Formula (la), wherein R ¹ is -N(R ² )C(0)R ¹⁵ , R ² is Ci. ₆ alkyl, and R ¹⁵ is -CHF ₂ . In another embodiment is a compound of Formula (la), wherein R ¹ is - N(R ² )C(0)R ¹⁵ , R ² is Ci- ₆ alkyl, and R ¹⁵ is unsubstituted In another embodiment is a compound of Formula (la), wherein R ¹ is -N(R ² )C(0)R ¹⁵ , R ² is Ci _-6 alkyl, R ¹⁵ is -CH ₃ . In another embodiment is a compound of Formula (la), wherein R ¹ is -N(R ² )C(0)R ¹⁵ , R ² is -CH ₃ , and R ¹⁵ is -CH ₂ OH. In another embodiment is a compound of Formula (la), wherein R ¹ is - N(R ² )C(0)R ¹⁵ , R ² is -CH ₃ , and R ¹⁵ is -CF ₃ . In another embodiment is a compound of Formula (la), wherein R ¹ is -N(R ² )C(0)R ¹⁵ , R ² is -CH ₃ , and R ¹⁵ is -CHF ₂ . In another embodiment is a compound of Formula (la), wherein R ¹ is -N(R ² )C(0)R ¹⁵ , R ² is -CH ₃ , and R ¹⁵ is unsubstituted Ci- ₆ alkyl. In another embodiment is a compound of Formula (la), wherein R ¹ is -N(R ² )C(0)R ¹⁵ , R ² is -CH ₃ , R ¹⁵ is -CH ₃ . In another embodiment is a compound of Formula (la), wherein R ¹ - N(H)S0 ₂ R ¹⁵ . In another embodiment is a compound of Formula (la), wherein R ¹ is- N(H)S0 ₂ R ¹⁵ and R ¹⁵ is -CH ₂ OH. In another embodiment is a compound of Formula (la), wherein R ¹ is-N(H)S0 ₂ R ¹⁵ and R ¹⁵ is -CF ₃ . In another embodiment is a compound of Formula (la), wherein R ¹ is-N(H)S0 ₂ R ¹⁵ and R ¹⁵ is -CHF ₂ . In another embodiment is a compound of Formula (la), wherein R ¹ is -N(H)S0 ₂ R ¹⁵ and R ¹⁵ is unsubstituted Ci _-6 alkyl. In another embodiment is a compound of Formula (la), wherein R ¹ is -N(H)S0 ₂ R ¹⁵ and R ¹⁵ is -CH ₃ .

[0066] In another embodiment is a compound of Formula (la), wherein R ⁴ is H. In another embodiment is a compound of Formula (la), wherein R ⁴ is halogen. In another embodiment is a compound of Formula (la), wherein R ⁴ is -CI. In another embodiment is a compound of

Formula (la), wherein R ⁴ is -F. In another embodiment is a compound of Formula (la), wherein R ⁴ is Ci- ₆ alkyl. In another embodiment is a compound of Formula (la), wherein R ⁴ is Ci.

6haloalkyl. In another embodiment is a compound of Formula (la), wherein R ⁴ is -CF ₃ . In another embodiment is a compound of Formula (la), wherein R ⁴ is optionally substituted phenyl. In another embodiment is a compound of Formula (la), wherein R ⁴ is optionally substituted heteroaryl. In another embodiment is a compound of Formula (la), wherein R ⁴ is heteroaryl optionally substituted with one or two groups selected from halogen, hydroxy, Ci _-6 alkyl, -Ci. ₆ alkyl-OH, Ci _-6 fluoroalkyl, C _3-6 cycloalkyl, -C0 ₂ H, -C _1-6 alkyl-C0 ₂ H, -C(0)Ci _-6 alkyl, -C(0)d. ₆ alkyl-OH, -N(H)C(0)Ci _-6 alkyl, -C(0) H ₂ , -C(0)N(H)(Ci _-6 alkyl), -C(0)N(Ci _-6 alkyl) ₂ , - C(0)C _2-7 heterocycloalkyl, and -S(0) ₂ Ci- ₆ alkyl. In another embodiment is a compound of Formula (la), wherein R ⁴ is heteroaryl optionally substituted with one or two groups selected from halogen, hydroxy, Ci _-6 alkyl, Ci _-6 fluoroalkyl, C _3-6 cycloalkyl, -C0 ₂ H, -Ci _-6 alkyl-C0 ₂ H, and -C(0) H ₂ . In another embodiment is a compound of Formula (la), wherein R ⁴ is optionally substituted heteroaryl and the heteroaryl is a 5-6 membered heteroaryl ring. In another embodiment is a compound of Formula (la), wherein R ⁴ is a 5-6 membered heteroaryl ring optionally substituted with one or two groups selected from halogen, hydroxy, Ci _-6 alkyl, -Ci. ₆ alkyl-OH, Ci _-6 fluoroalkyl, C _3-6 cycloalkyl, -C0 ₂ H, -Ci _-6 alkyl-C0 ₂ H, -C(0)Ci _-6 alkyl, -C(0)Ci. ₆ alkyl-OH, -N(H)C(0)Ci _-6 alkyl, -C(0) H ₂ , -C(0)N(H)(Ci _-6 alkyl), -C(0)N(Ci _-6 alkyl) ₂ , - C(0)C _2-7 heterocycloalkyl, and -S(0) ₂ Ci _-6 alkyl. In another embodiment is a compound of Formula (la), wherein R ⁴ is a 5-6 membered heteroaryl ring optionally substituted with one or two groups selected from halogen, -Ci- ₆ alkyl-OH, Ci-efluoroalkyl, -C0 ₂ H, -Ci- ₆ alkyl- C0 ₂ H. In another embodiment is a compound of Formula (la), wherein R ⁴ is a 5-membered heteroaryl ring optionally substituted with one or two groups selected from halogen, hydroxy, Ci _-6 alkyl, -Ci _-6 alkyl-OH, Ci _-6 fluoroalkyl, C _3-6 cycloalkyl, -C0 ₂ H, -Ci _-6 alkyl-C0 ₂ H, -C(0)d. ₆ alkyl, -C(0)Ci _-6 alkyl-OH, -N(H)C(0)Ci _-6 alkyl, -C(0) H ₂ , -C(0)N(H)(Ci _-6 alkyl), -C(0)N(Ci. ₆ alkyl) ₂ , -C(0)C _2-7 heterocycloalkyl, and -S(0) ₂ Ci _-6 alkyl. In another embodiment is a compound of Formula (la), wherein R ⁴ is a 5-membered heteroaryl ring optionally substituted with one or two groups selected from halogen, -Ci- ₆ alkyl-OH, Ci-efluoroalkyl, -C0 ₂ H, -Ci- ₆ alkyl- C0 ₂ H. In another embodiment is a compound of Formula (la), wherein R ⁴ is a 6-membered heteroaryl ring optionally substituted with one or two groups selected from halogen, hydroxy, Ci _-6 alkyl, -Ci _-6 alkyl-OH, Ci _-6 fluoroalkyl, C _3-6 cycloalkyl, -C0 ₂ H, -Ci _-6 alkyl-C0 ₂ H, -C(0)d. ₆ alkyl, -C(0)Ci _-6 alkyl-OH, -N(H)C(0)Ci _-6 alkyl, -C(0) H ₂ , -C(0)N(H)(Ci _-6 alkyl), -C(0)N(Ci. ₆ alkyl) ₂ , -C(0)C _2-7 heterocycloalkyl, and -S(0) ₂ Ci- ₆ alkyl. In another embodiment is a compound of Formula (la), wherein R ⁴ is a 6-membered heteroaryl ring optionally substituted with one or two groups selected from halogen, Ci _-6 alkyl, -Ci _-6 alkyl-OH, Ci _-6 fluoroalkyl, -C0 ₂ H, -Ci _-6 alkyl- -

la), wherein In another embodiment is a compound of Formula (la), wherein R ₄ is H NJ I-L N _? N-N N _? or N . In another embodiment is a compound of Formula (la), wherein R ⁴ is optionally substituted Ci _-6 alkyl -heterocycloalkyl. In another embodiment is a compound of Formula (la), wherein R ⁴ is optionally substituted heterocycloalkyl. In another embodiment is a compound of Formula (la), wherein R ⁴ is heterocycloalkyl optionally substituted with one or more groups selected from halogen, hydroxy, Ci _-6 alkyl, -Ci _-6 alkyl-OH, Ci _-6 fluoroalkyl, C _3-6 cycloalkyl, heteroaryl, -C0 ₂ H, -Ci _-6 alkyl-C0 ₂ H, -C(0)Ci _-6 alkyl, -C(0)d. ₆ alkyl-OH, -N(H)C(0)Ci _-6 alkyl, -C(0) H ₂ , -C(0)N(H)(Ci _-6 alkyl), -C(0)N(Ci _-6 alkyl) ₂ , - C(0)C _2-7 heterocycloalkyl, and -S(0) ₂ Ci- ₆ alkyl. In another embodiment is a compound of Formula (la), wherein R ⁴ is heterocycloalkyl optionally substituted with one or two groups selected from halogen, hydroxy, Ci _-6 alkyl, -Ci _-6 alkyl-OH, Ci _-6 fluoroalkyl, C _3-6 cycloalkyl, heteroaryl, -C0 ₂ H, -Ci _-6 alkyl-C0 ₂ H, -C(0)Ci _-6 alkyl, -C(0)Ci _-6 alkyl-OH, -N(H)C(0)Ci _-6 alkyl, - C(0) H ₂ , -C(0)N(H)(Ci _-6 alkyl), -C(0)N(Ci _-6 alkyl) ₂ , -C(0)C _2-7 heterocycloalkyl, and -S(0) ₂ Ci. ₆ alkyl. In another embodiment is a compound of Formula (la), wherein R ⁴ is optionally substituted heterocycloalkyl and the heterocycloalkyl is a 4-6 membered monocyclic heterocycloalkyl, a 8-9 membered bicyclic heterocycloalkyl, a 7-8 membered bridged heterocycloalkyl, a 5,5 fused heterocycloalkyl, or an 8-11 membered spirocyclic

heterocycloalkyl. In another embodiment is a compound of Formula (la), wherein R ⁴ is an optionally substituted 4-6 membered monocyclic heterocycloalkyl. In another embodiment is a compound of Formula (la), wherein R ⁴ is an optionally substituted 8-9 membered bicyclic heterocycloalkyl. In another embodiment is a compound of Formula (la), wherein R ⁴ is an optionally substituted 7-8 membered bridged heterocycloalkyl. In another embodiment is a compound of Formula (la), wherein R ⁴ is an optionally substituted 5,5 fused heterocycloalkyl. In another embodiment is a compound of Formula (la), wherein R ⁴ is an optionally substituted -11 membered spirocyclic heterocycloalkyl. In another embodiment is a com ou Formula

In another

In another embodiment is a compound of Formula (la), wherein R ⁴ is -OR ⁷ .

In another embodiment is a compound of Formula (la), wherein R ⁴ is -OR ⁷ , and R ⁷ is H, Ci. ₆ alkyl, a phenyl optionally substituted with halogen, Ci _-6 alkyl, Ci _-6 fluoroalkyl, or Ci _-6 alkoxy, a Ci _-6 alkyl -phenyl optionally substituted with halogen, Ci _-6 alkyl, Ci _-6 fluoroalkyl, or Ci _-6 alkoxy, a heteroaryl optionally substituted with halogen, or Ci-efluoroalkyl, a 5-6 membered monocyclic heterocycloalkyl optionally substituted with halogen, Ci-efluoroalkyl, or C _3-6 cycloalkyl, or a In another embodiment is a compound of Formula (la), wherein R ⁴ is -OR ⁷ , and R ⁷ is Ci _-6 alkyl. In another embodiment is a compound of Formula (la), wherein R ⁴ is -OR ⁷ , and R ⁷ is optionally substituted phenyl. In another embodiment is a compound of Formula (la), wherein R ⁴ is -OR ⁷ , and R ⁷ is phenyl optionally substituted with halogen, Ci _-6 alkyl, Ci _-6 fluoroalkyl, or Ci _-6 alkoxy. In another embodiment is a compound of Formula (la), wherein R ⁴ is -OR ⁷ , and R ⁷ is optionally substituted Ci _-6 alkyl-phenyl. In another embodiment is a compound of Formula (la), wherein R ⁴ is -OR ⁷ , and R ⁷ is

optionally substituted with halogen, Ci-efluoroalkyl, or Ci _-6 alkoxy. In another embodiment is a compound of Formula (la), wherein R ⁴ is -OR ⁷ , and R ⁷ is optionally substituted heteroaryl. In another embodiment is a compound of Formula (la), wherein R ⁴ is -OR ⁷ , and R ⁷ is heteroaryl optionally substituted with halogen, or Ci-efluoroalkyl. In another embodiment is a compound of Formula (la), wherein R ⁴ is -OR ⁷ , and R ⁷ is optionally substituted heterocycloalkyl. In another embodiment is a compound of Formula (la), wherein R ⁴ is -OR ⁷ , and R ⁷ is a 5-6 membered monocyclic heterocycloalkyl optionally substituted with halogen, Ci. ₆ alkyl, Ci _-6 fluoroalkyl, or C _3-6 cycloalkyl. In another embodiment is a compound of Formula (la), wherein R ⁴ is -OR ⁷ , and R ⁷ is -Ci _-6 alkylC(O)NR ¹⁰ R ¹¹ . In another embodiment is a compound of Formula (la), wherein R ⁴ is -OR ⁷ , and R ⁷ is -Ci _-6 alkylC(O)NR ¹⁰ R ^u , and R ¹⁰ and R ¹² are each independently H, or Ci _-6 alkyl. In another embodiment is a compound of Formula (la), wherein R ⁴ is -OR ⁷ , and R ⁷ is -Ci _-6 alkylC(O)NR ¹⁰ R ¹¹ , and R ¹⁰ and R ¹¹ together with the nitrogen to which they are attached are combined to form a heterocycloalkyl ring. In another embodiment is a compound of Formula (la), wherein R ⁴ is -OR ⁷ , and R ⁷ is another embodiment is a compound of Formula (la), wherein R ⁴ is -OR ⁷ , and R ⁷ is In another embodiment is a compound of Formula (la), wherein R ⁴ is -C0 ₂ H.

In another embodiment is a compound of Formula (la), wherein R ⁴ is -C(0) R ⁸ R ⁹ . In another embodiment is a compound of Formula (la), wherein R 4 is -C(0) R 8 R 9 , and R 8 and R 9 are each independently H, or Ci _-6 alkyl. In another embodiment is a compound of Formula (la), wherein

4 8 9 8 9

* is -QC TR', and R° and R ^* are H. In another embodiment is a compound of Formula (la), wherein R 4" is -C(0) R 8°R 9 ^: ', and R 8° is H and R 9 ^* are Ci- ₆ alkyl. In another embodiment is a

4 8 9 8 9

compound of Formula (la), wherein R is -C(0)NR R , and R and R are Ci _-6 alkyl. In another

4 8 9 8 9 embodiment is a compound of Formula (la), wherein R is -C(0) R R , and R and R together with the nitrogen to which they are attached are combined to form an optionally substituted heterocycloalkyl ring. In another embodiment is a compound of Formula (la), wherein R ⁴ is - C(0) R ⁸ R ⁹ , and R ⁸ and R ⁹ together with the nitrogen to which they are attached are combined to form an unsubstituted heterocycloalkyl ring.

[0067] In another embodiment is a compound of Formula (la), wherein R ⁵ is H. In another embodiment is a compound of Formula (la), wherein R ⁵ is halogen. In another embodiment is a compound of Formula (la), wherein R ⁵ is -CI. In another embodiment is a compound of Formula (la), wherein R ⁵ is -F. In another embodiment is a compound of Formula (la), wherein R ⁵ is Ci- ₆ alkyl. In another embodiment is a compound of Formula (la), wherein R ⁵ is Ci.

6haloalkyl. In another embodiment is a compound of Formula (la), wherein R ⁵ is -CF ₃ . In another embodiment is a compound of Formula (la), wherein R ⁵ is phenyl.

[0068] In another embodiment is a com ound of Formula (II):

Formula (II);

wherein:

R ¹ is -N(R ² )C(0)R ¹⁵ or -N(H)S0 ₂ R ¹⁵ ;

R ² is H or C _h alky.;

R ³ is H or optionally substituted phenyl;

R ⁴ is H, halogen, -OR ⁷ , Ci- ₆ haloalkyl, optionally substituted heterocycloalkyl, optionally substituted Ci _-6 alkyl-heterocycloalkyl, optionally substituted phenyl, optionally substituted heteroaryl, -C0 ₂ H, or -C(0) R ⁸ R ⁹ ;

R ⁵ is H, halogen, Ci- ₆ alkyl, Ci-ehaloalkyl, or phenyl; or

R ⁴ and R ⁵ are combined to form a heterocycloalkyl ring;

R ⁶ is H, halogen or Ci _-6 alkyl;

R ⁷ is H, Ci _-6 alkyl, optionally substituted phenyl, optionally substituted Ci _-6 alkyl -phenyl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, or -Ci.

6alkylC(O) R ¹⁰ R ^u ;

R ⁸ and R ⁹ are each independently H, or Ci _-6 alkyl; or R ⁸ and R ⁹ together with the nitrogen to which they are attached are combined to form an optionally substituted heterocycloalkyl ring;

R ¹⁰ and R ¹¹ are each independently H, or or R ¹⁰ and R ¹¹ together with the nitrogen to which they are attached are combined to form a heterocycloalkyl ring;

R ¹² is H or Ci _-6 alkyl;

R ¹³ is H or Ci- ₆ alkyl; and

R ¹⁵ is optionally substituted

or a solvate, hydrate, tautomer, N-oxide, or pharmaceutically acceptable salt thereof.

[0069] In another embodiment is a compound of Formula (II), wherein R ¹² and R ¹³ are H. In another embodiment is a compound of Formula (II), wherein R ¹² and R ¹³ are Ci- ₆ alkyl. In another embodiment is a compound of Formula (II), wherein R ¹² and R ¹³ are -CH ₃ . In another embodiment is a compound of Formula (II), wherein R ¹² is H and R ¹³ are -CH ₃ .

[0070] In another embodiment is a compound of Formula (II), wherein R ¹ is -N(R ² )C(0)R ¹⁵ . In another embodiment is a compound of Formula (II), wherein R ¹ is -N(R ² )C(0)R ¹⁵ and R ² is H. In another embodiment is a compound of Formula (II), wherein R ¹ is -N(R ² )C(0)R ¹⁵ and R ² is Ci _-6 alkyl. In another embodiment is a compound of Formula (II), wherein R ¹ is - N(R ² )C(0)R ¹⁵ and R ² is -CH ₃ . In another embodiment is a compound of Formula (II), wherein R ¹ is -N(R ² )C(0)R ¹⁵ , R ² is H, and R ¹⁵ is -CH ₂ OH. In another embodiment is a compound of Formula (II), wherein R ¹ is -N(R ² )C(0)R ¹⁵ , R ² is H, and R ¹⁵ is -CF ₃ . In another embodiment is a compound of Formula (II), wherein R ¹ is -N(R ² )C(0)R ¹⁵ , R ² is H, and R ¹⁵ is -CHF ₂ . In another embodiment is a compound of Formula (II), wherein R ¹ is -N(R ² )C(0)R ¹⁵ , R ² is H, and R ¹⁵ is unsubstituted Ci- ₆ alkyl. In another embodiment is a compound of Formula (II), wherein R ¹ is -N(R ² )C(0)R ¹⁵ , R ² is H, R ¹⁵ is -CH ₃ . In another embodiment is a compound of Formula (II), wherein R ¹ is -N(R ² )C(0)R ¹⁵ , R ² is Ci _-6 alkyl, and R ¹⁵ is -CH ₂ OH. In another embodiment is a compound of Formula (II), wherein R ¹ is -N(R ² )C(0)R ¹⁵ , R ² is Ci _-6 alkyl, and R ¹⁵ is -CF ₃ . In another embodiment is a compound of Formula (II), wherein R ¹ is -N(R ² )C(0)R ¹⁵ , R ² is Ci. ₆ alkyl, and R ¹⁵ is -CHF ₂ . In another embodiment is a compound of Formula (II), wherein R ¹ is - N(R ² )C(0)R ¹⁵ , R ² is Ci _-6 alkyl, and R ¹⁵ is unsubstituted Ci _-6 alkyl. In another embodiment is a compound of Formula (II), wherein R ¹ is -N(R ² )C(0)R ¹⁵ , R ² is Ci _-6 alkyl, R ¹⁵ is -CH ₃ . In another embodiment is a compound of Formula (II), wherein R ¹ is -N(R ² )C(0)R ¹⁵ , R ² is -CH ₃ , and R ¹⁵ is -CH ₂ OH. In another embodiment is a compound of Formula (II), wherein R ¹ is - N(R ² )C(0)R ¹⁵ , R ² is -CH ₃ , and R ¹⁵ is -CF ₃ . In another embodiment is a compound of Formula (II), wherein R ¹ is -N(R ² )C(0)R ¹⁵ , R ² is -CH ₃ , and R ¹⁵ is -CHF ₂ . In another embodiment is a compound of Formula (II), wherein R ¹ is -N(R ² )C(0)R ¹⁵ , R ² is -CH ₃ , and R ¹⁵ is unsubstituted Ci _-6 alkyl. In another embodiment is a compound of Formula (II), wherein R ¹ is -N(R ² )C(0)R ¹⁵ , R ² is -CH ₃ , R ¹⁵ is -CH ₃ . In another embodiment is a compound of Formula (II), wherein R ¹ - N(H)S0 ₂ R ¹⁵ . In another embodiment is a compound of Formula (II), wherein R ¹ is-N(H)S0 ₂ R ¹⁵ and R ¹⁵ is -CH ₂ OH. In another embodiment is a compound of Formula (II), wherein R ¹ is- N(H)S0 ₂ R ¹⁵ and R ¹⁵ is -CF ₃ . In another embodiment is a compound of Formula (II), wherein R ¹ is-N(H)S0 ₂ R ¹⁵ and R ¹⁵ is -CHF ₂ . In another embodiment is a compound of Formula (II), wherein R ¹ is -N(H)S0 ₂ R ¹⁵ and R ¹⁵ is unsubstituted In another embodiment is a compound of Formula (II), wherein R ¹ is -N(H)S0 ₂ R ¹⁵ and R ¹⁵ is -CH ₃ . In another embodiment is a compound of Formula (II), wherein R ³ is H. In another embodiment is a compound of Formula (II), wherein R ³ is optionally substituted phenyl.

[0071] In another embodiment is a compound of Formula (II), wherein R ³ is H. In another embodiment is a compound of Formula (II), wherein R ³ is optionally substituted phenyl.

[0072] In another embodiment is a compound of Formula (II), wherein R ⁴ is H. In another embodiment is a compound of Formula (II), wherein R ⁴ is halogen. In another embodiment is a compound of Formula (II), wherein R ⁴ is -CI. In another embodiment is a compound of

Formula (II), wherein R ⁴ is -F. In another embodiment is a compound of Formula (II), wherein R ⁴ is Ci _-6 alkyl. In another embodiment is a compound of Formula (II), wherein R ⁴ is Ci.

6haloalkyl. In another embodiment is a compound of Formula (II), wherein R ⁴ is -CF ₃ . In another embodiment is a compound of Formula (II), wherein R ⁴ is optionally substituted phenyl. In another embodiment is a compound of Formula (II), wherein R ⁴ is optionally substituted heteroaryl. In another embodiment is a compound of Formula (II), wherein R ⁴ is heteroaryl optionally substituted with one or two groups selected from halogen, hydroxy, -Ci. ₆ alkyl-OH, Ci _-6 fluoroalkyl, C ₃ - ₆ cycloalkyl, -C0 ₂ H, -Ci _-6 alkyl-C0 ₂ H, -C(0)Ci _-6 alkyl, -C(0)Ci. ₆ alkyl-OH, -N(H)C(0)C _1-6 alkyl, -C(0) H ₂ , -C(0)N(H)(C _1-6 alkyl), -C(0)N(C _1-6 alkyl) ₂ , - C(0)C _2-7 heterocycloalkyl, and -S(0) ₂ Ci _-6 alkyl. In another embodiment is a compound of Formula (II), wherein R ⁴ is heteroaryl optionally substituted with one or two groups selected from halogen, hydroxy, Ci-efiuoroalkyl, C _3-6 Cycloalkyl, -C0 ₂ H, -Ci- ₆ alkyl-C0 ₂ H, and -C(0) H ₂ . In another embodiment is a compound of Formula (II), wherein R ⁴ is optionally substituted heteroaryl and the heteroaryl is a 5-6 membered heteroaryl ring. In another embodiment is a compound of Formula (II), wherein R ⁴ is a 5-6 membered heteroaryl ring optionally substituted with one or two groups selected from halogen, hydroxy, -Ci. ₆ alkyl-OH, Ci _-6 fluoroalkyl, C _3-6 cycloalkyl, -C0 ₂ H, -Ci _-6 alkyl-C0 ₂ H, -C(0)Ci _-6 alkyl, -C(0)d. ₆ alkyl-OH, -N(H)C(0)C _1-6 alkyl, -C(0) H ₂ , -C(0)N(H)(C _1-6 alkyl), -C(0)N(C _1-6 alkyl) ₂ , - C(0)C _2-7 heterocycloalkyl, and -S(0) ₂ Ci- ₆ alkyl. In another embodiment is a compound of Formula (II), wherein R ⁴ is a 5-6 membered heteroaryl ring optionally substituted with one or two groups selected from halogen, Ci _-6 alkyl, -Ci _-6 alkyl-OH, Ci _-6 fluoroalkyl, -C0 ₂ H, -Ci _-6 alkyl- C0 ₂ H. In another embodiment is a compound of Formula (II), wherein R ⁴ is a 5-membered heteroaryl ring optionally substituted with one or two groups selected from halogen, hydroxy, Ci _-6 alkyl, -Ci _-6 alkyl-OH, Ci _-6 fluoroalkyl, C _3-6 cycloalkyl, -C0 ₂ H, -Ci _-6 alkyl-C0 ₂ H, -C(0)Ci. ₆ alkyl, -C(0)Ci _-6 alkyl-OH, -N(H)C(0)Ci _-6 alkyl, -C(0) H ₂ , -C(0)N(H)(Ci _-6 alkyl), -C(0)N(d. ₆ alkyl) ₂ , -C(0)C _2-7 heterocycloalkyl, and -S(0) ₂ Ci _-6 alkyl. In another embodiment is a compound of Formula (II), wherein R ⁴ is a 5-membered heteroaryl ring optionally substituted with one or two groups selected from halogen, -Ci- ₆ alkyl-OH, Ci-efluoroalkyl, -C0 ₂ H, -Ci- ₆ alkyl- C0 ₂ H. In another embodiment is a compound of Formula (II), wherein R ⁴ is a 6-membered heteroaryl ring optionally substituted with one or two groups selected from halogen, hydroxy, Ci _-6 alkyl, -Ci _-6 alkyl-OH, Ci _-6 fluoroalkyl, C _3-6 cycloalkyl, -C0 ₂ H, -Ci _-6 alkyl-C0 ₂ H, -C(0)Ci. ₆ alkyl, -C(0)Ci _-6 alkyl-OH, -N(H)C(0)Ci _-6 alkyl, -C(0) H ₂ , -C(0)N(H)(Ci _-6 alkyl), -C(0)N(Ci. ₆ alkyl) ₂ , -C(0)C _2-7 heterocycloalkyl, and -S(0) ₂ Ci _-6 alkyl. In another embodiment is a compound of Formula (II), wherein R ⁴ is a 6-membered heteroaryl ring optionally substituted with one or two groups selected from halogen, -Ci- ₆ alkyl-OH, Ci-efluoroalkyl, -C0 ₂ H, -Ci- ₆ alkyl- (II), wherein In another embodiment is a compound of Formula (II), wherein R is N-N , N _? or N . In another embodiment is a compound of Formula (II), wherein R ⁴ is optionally substituted In another embodiment is a compound of Formula (II), wherein R ⁴ is optionally substituted heterocycloalkyl. In another embodiment is a compound of Formula (II), wherein R ⁴ is heterocycloalkyl optionally substituted with one or more groups selected from halogen, hydroxy,

Ci _-6 fluoroalkyl, C ₃ - ₆ cycloalkyl, heteroaryl, -C0 ₂ H, -Ci _-6 alkyl-C0 ₂ H, -C(0)Ci _-6 alkyl, -C(0)Ci. ₆ alkyl-OH, -N(H)C(0)C _1-6 alkyl, -C(0) H ₂ , -C(0)N(H)(C _1-6 alkyl), -C(0)N(C _1-6 alkyl) ₂ , - C(0)C _2-7 heterocycloalkyl, and -S(0) ₂ Ci _-6 alkyl. In another embodiment is a compound of Formula (II), wherein R ⁴ is heterocycloalkyl optionally substituted with one or two groups selected from halogen, hydroxy, -Ci- ₆ alkyl-OH, Ci-efiuoroalkyl, C _3-6 Cycloalkyl, heteroaryl, -C0 ₂ H, -Ci _-6 alkyl-C0 ₂ H, -C(0)Ci _-6 alkyl, -C(0)Ci _-6 alkyl-OH, -N(H)C(0)Ci _-6 alkyl, - C(0) H ₂ , -C(0)N(H)(Ci _-6 alkyl), -C(0)N(Ci _-6 alkyl) ₂ , -C(0)C _2-7 heterocycloalkyl, and -S(0) ₂ Ci. ₆ alkyl. In another embodiment is a compound of Formula (II), wherein R ⁴ is optionally substituted heterocycloalkyl and the heterocycloalkyl is a 4-6 membered monocyclic

heterocycloalkyl, a 8-9 membered bicyclic heterocycloalkyl, a 7-8 membered bridged heterocycloalkyl, a 5,5 fused heterocycloalkyl, or an 8-11 membered spirocyclic

heterocycloalkyl. In another embodiment is a compound of Formula (II), wherein R ⁴ is an optionally substituted 4-6 membered monocyclic heterocycloalkyl. In another embodiment is a compound of Formula (II), wherein R ⁴ is an optionally substituted 8-9 membered bicyclic heterocycloalkyl. In another embodiment is a compound of Formula (II), wherein R ⁴ is an optionally substituted 7-8 membered bridged heterocycloalkyl. In another embodiment is a compound of Formula (II), wherein R ⁴ is an optionally substituted 5,5 fused heterocycloalkyl. In another embodiment is a compound of Formula (II), wherein R ⁴ is an optionally substituted 8- 11 membered spirocyclic heterocycloalkyl. In another embodiment is a compound of Formula

(II), wherein R is optionally substituted heterocycloalkyl selected from , and In another embodiment is a compound of Formula (II), wherein R is optionally substituted

. In another embodiment is a compound of Formula (II), wherein R 4 is -OR 7. In another embodiment is a compound of Formula (II), wherein R ⁴ is -OR ⁷ , and R ⁷ is H, Ci. 6alkyl, a phenyl optionally substituted with hal i-efluoroalkyl, or

Ci- ₆ alkyl -phenyl optionally substituted with ha Ci-efluoroalkyl, o a heteroaryl optionally substituted with halogen, efluoroalkyl, a 5-6 membered monocyclic heterocycloalkyl optionally substituted with halogen, Ci-efluoroalkyl, or C3- ₆ cycloalkyl, or a In another embodiment is a compound of Formula (II), wherein R ⁴ is - In another embodiment is a compound of Formula (II), wherein R ⁴ is -OR ⁷ , and R ⁷ is optionally substituted phenyl. In another embodiment is a compound of Formula (II), wherein R ⁴ is -OR ⁷ , and R ⁷ is phenyl optionally substituted with halogen, Ci-efluoroalkyl, or Ci _-6 alkoxy. In another embodiment is a compound of Formula (II), wherein R ⁴ is -OR ⁷ , and R ⁷ is optionally substituted Ci- ₆ alkyl-phenyl. In another embodiment is a compound of Formula (II), wherein R ⁴ is -OR ⁷ , and R ⁷ is Ci _-6 alkyl -phenyl optionally substituted with halogen, Ci _-6 alkyl, Ci _-6 fluoroalkyl, or Ci _-6 alkoxy. In another embodiment is a compound of Formula (II), wherein R ⁴ is -OR ⁷ , and R ⁷ is optionally substituted heteroaryl. In another embodiment is a compound of Formula (II), wherein R ⁴ is -OR ⁷ , and R ⁷ is heteroaryl optionally substituted with halogen, Ci _-6 alkyl, or Ci _-6 fluoroalkyl. In another embodiment is a compound of Formula (II), wherein R ⁴ is -OR ⁷ , and R ⁷ is optionally substituted heterocycloalkyl. In another embodiment is a compound of Formula (II), wherein R ⁴ is -OR ⁷ , and R ⁷ is a 5-6 membered monocyclic heterocycloalkyl optionally substituted with halogen, Ci. ₆ alkyl, Ci _-6 fluoroalkyl, or C _3-6 cycloalkyl. In another embodiment is a compound of Formula (II), wherein R ⁴ is -OR ⁷ , and R ⁷ is -Ci _-6 alkylC(O) R ¹⁰ R ^u . In another embodiment is a compound of Formula (II), wherein R ⁴ is -OR ⁷ , and R ⁷ is -Ci _-6 alkylC(O) R ¹⁰ R ¹¹ , and R ¹⁰ and R ¹² are each independently H, or Ci- ₆ alkyl. In another embodiment is a compound of Formula (II), wherein R ⁴ is -OR ⁷ , and R ⁷ is -Ci _-6 alkylC(O) R ¹⁰ R ¹¹ , and R ¹⁰ and R ¹¹ together with the nitrogen to which they are attached are combined to form a heterocycloalkyl ring. In another embodiment is a compound of Formula (II), wherein R ⁴ is -OR ⁷ , and R ⁷ is Ci _-6 alkyl,

In another embodiment is a compound of Formula (II), wherein R ⁴ is -OR ⁷ , and R ⁷ is \— / or \— f . In another embodiment is a compound of Formula (II), wherein R is -C0 ₂ H. In another embodiment is a compound of Formula (II), wherein R ⁴ is -C(0)NR ⁸ R ⁹ . In another

4 8 9 8 9 embodiment is a compound of Formula (II), wherein R is -C(0) R R , and R and R are each independently H, or Ci _-6 alkyl. In another embodiment is a compound of Formula (II), wherein 4 8 9 8 9

R is -C(0) R°R ^: ', and R° and R ^* are H. In another embodiment is a compound of Formula (II), wherein R 4" is -C(0) R 8°R 9 ^: ', and R 8° is H and R 9 ^* are Ci- ₆ alkyl. In another embodiment is a compound of Formula (II), wherein R 4 is -C(0) R 8 R 9 , and R 8 and R 9 are Ci _-6 alkyl. In another

4 8 9 8 9 embodiment is a compound of Formula (II), wherein R is -C(0) R R , and R and R together with the nitrogen to which they are attached are combined to form an optionally substituted heterocycloalkyl ring. In another embodiment is a compound of Formula (II), wherein R ⁴ is - C(0) R ⁸ R ⁹ , and R ⁸ and R ⁹ together with the nitrogen to which they are attached are combined to form an unsubstituted heterocycloalkyl ring.

[0073] In another embodiment is a compound of Formula (II), wherein R ⁵ is H. In another embodiment is a compound of Formula (II), wherein R ⁵ is halogen. In another embodiment is a compound of Formula (II), wherein R ⁵ is -CI. In another embodiment is a compound of Formula (II), wherein R ⁵ is -F. In another embodiment is a compound of Formula (II), wherein R ⁵ is Ci- ₆ alkyl. In another embodiment is a compound of Formula (II), wherein R ⁵ is Ci.

6haloalkyl. In another embodiment is a compound of Formula (II), wherein R ⁵ is -CF ₃ . In another embodiment is a compound of Formula (II), wherein R ⁵ is phenyl.

[0074] In another embodiment is a compound of Formula (II), wherein R ⁶ is H. In another embodiment is a compound of Formula (II), wherein R ⁶ is halogen. In another embodiment is a compound of Formula (II), wherein R ⁶ is -CI. In another embodiment is a compound of

Formula (II), wherein R ⁶ is -F. In another embodiment is a compound of Formula (II), wherein R ⁶ is C _h alky..

[0075] In another embodiment is a compound of Formula (II) having the structure of Formula (Da):

Formula (Ha);

wherein:

R ¹ is -N(R ² )C(0)R ¹⁵ or -N(H)S0 ₂ R ¹⁵ ;

R ² is H or Ci-ealkyl;

R ⁴ is H, halogen, -OR ⁷ , optionally substituted heterocycloalkyl, optionally substituted Ci- ₆ alkyl-heterocycloalkyl, optionally substituted phenyl, optionally substituted heteroaryl, -C0 ₂ H, or -C(0) R ⁸ R ⁹ ; R ⁵ is H, halogen, Ci-ehaloalkyl, or phenyl; or

R ⁴ and R ⁵ are combined to form a heterocycloalkyl ring;

R ⁷ is H, Ci _-6 alkyl, optionally substituted phenyl, optionally substituted Ci _-6 alkyl -phenyl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, or -Ci.

6alkylC(O) R ¹⁰ R ^u ;

R ⁸ and R ⁹ are each independently H, or Ci- ₆ alkyl; or R ⁸ and R ⁹ together with the nitrogen to which they are attached are combined to form an optionally substituted heterocycloalkyl ring;

R ¹⁰ and R ¹¹ are each independently H, or or R ¹⁰ and R ¹¹ together with the nitrogen to which they are attached are combined to form a heterocycloalkyl ring; and

R ¹⁵ is optionally substituted Ci _-6 alkyl;

or a solvate, hydrate, tautomer, N-oxide, or pharmaceutically acceptable salt thereof.

[0076] In another embodiment is a compound of Formula (Ila), wherein R ¹ is -N(R ² )C(0)R ¹⁵ . In another embodiment is a compound of Formula (Ila), wherein R ¹ is -N(R ² )C(0)R ¹⁵ and R ² is H. In another embodiment is a compound of Formula (Ila), wherein R ¹ is -N(R ² )C(0)R ¹⁵ and R ² is Ci _-6 alkyl. In another embodiment is a compound of Formula (Ila), wherein R ¹ is - N(R ² )C(0)R ¹⁵ and R ² is -CH ₃ . In another embodiment is a compound of Formula (Ila), wherein R ¹ is -N(R ² )C(0)R ¹⁵ , R ² is H, and R ¹⁵ is -CH ₂ OH. In another embodiment is a compound of Formula (Ila), wherein R ¹ is -N(R ² )C(0)R ¹⁵ , R ² is H, and R ¹⁵ is unsubstituted Ci _-6 alkyl. In another embodiment is a compound of Formula (Ila), wherein R ¹ is -N(R ² )C(0)R ¹⁵ , R ² is H, R ¹⁵ is -CH ₃ . In another embodiment is a compound of Formula (Ila), wherein R ¹ is -N(R ² )C(0)R ¹⁵ , R ² is Ci- ₆ alkyl, and R ¹⁵ is -CH ₂ OH. In another embodiment is a compound of Formula (Ila), wherein R ¹ is -N(R ² )C(0)R ¹⁵ , R ² is Ci _-6 alkyl, and R ¹⁵ is unsubstituted Ci _-6 alkyl. In another embodiment is a compound of Formula (Ila), wherein R ¹ is -N(R ² )C(0)R ¹⁵ , R ² is Ci _-6 alkyl, R ¹⁵ is -CH ₃ . In another embodiment is a compound of Formula (Ila), wherein R ¹ is -N(R ² )C(0)R ¹⁵ , R ² is -CH ₃ , and R ¹⁵ is -CH ₂ OH. In another embodiment is a compound of Formula (Ila), wherein R ¹ is -N(R ² )C(0)R ¹⁵ , R ² is -CH ₃ , and R ¹⁵ is unsubstituted Ci _-6 alkyl. In another embodiment is a compound of Formula (Ila), wherein R ¹ is -N(R ² )C(0)R ¹⁵ , R ² is -CH ₃ , R ¹⁵ is - CH ₃ . In another embodiment is a compound of Formula (Ila), wherein R ¹ -N(H)S0 ₂ R ¹⁵ . In another embodiment is a compound of Formula (Ila), wherein R ¹ is-N(H)S0 ₂ R ¹⁵ and R ¹⁵ is - CH ₂ OH. In another embodiment is a compound of Formula (Ila), wherein R ¹ is -N(H)S0 ₂ R ¹⁵ and R ¹⁵ is unsubstituted Ci _-6 alkyl. In another embodiment is a compound of Formula (Ila), wherein R ¹ is -N(H)S0 ₂ R ¹⁵ and R ¹⁵ is -CH ₃ .

[0077] In another embodiment is a compound of Formula (Ila), wherein R ⁴ is H. In another embodiment is a compound of Formula (Ila), wherein R ⁴ is halogen. In another embodiment is a compound of Formula (Ila), wherein R ⁴ is -CI. In another embodiment is a compound of Formula (Ila), wherein R ⁴ is -F. In another embodiment is a compound of Formula (Ila), wherein R ⁴ is Ci _-6 alkyl. In another embodiment is a compound of Formula (Ila), wherein R ⁴ is Ci _-6 haloalkyl. In another embodiment is a compound of Formula (Ila), wherein R ⁴ is -CF ₃ . In another embodiment is a compound of Formula (Ila), wherein R ⁴ is optionally substituted phenyl. In another embodiment is a compound of Formula (Ila), wherein R ⁴ is optionally substituted heteroaryl. In another embodiment is a compound of Formula (Ila), wherein R ⁴ is heteroaryl optionally substituted with one or two groups selected from halogen, hydroxy, C _\ . ealkyl, -Ci _-6 alkyl-OH, Ci _-6 fluoroalkyl, C ₃ - ₆ cycloalkyl, -C0 ₂ H, -Ci _-6 alkyl-C0 ₂ H, -C(0)Ci _-6 alkyl, -C(0)Ci _-6 alkyl-OH, -N(H)C(0)Ci _-6 alkyl, -C(0) H ₂ , -C(0)N(H)(Ci _-6 alkyl), -C(0)N(Ci _-6 alkyl) ₂ , -C(0)C _2-7 heterocycloalkyl, and -S(0) ₂ Ci _-6 alkyl. In another embodiment is a compound of Formula (Ila), wherein R ⁴ is heteroaryl optionally substituted with one or two groups selected from halogen, hydroxy, Ci-efiuoroalkyl, C _3-6 Cycloalkyl, -C0 ₂ H, -Ci- ₆ alkyl-C0 ₂ H, and -C(0) H ₂ . In another embodiment is a compound of Formula (Ila), wherein R ⁴ is optionally substituted heteroaryl and the heteroaryl is a 5-6 membered heteroaryl ring. In another embodiment is a compound of Formula (Ila), wherein R ⁴ is a 5-6 membered heteroaryl ring optionally substituted with one or two groups selected from halogen, hydroxy, -Ci. ₆ alkyl-OH, Ci _-6 fluoroalkyl, C _3-6 cycloalkyl, -C0 ₂ H, -Ci _-6 alkyl-C0 ₂ H, -C(0)Ci _-6 alkyl, -C(0)Ci. ₆ alkyl-OH, -N(H)C(0)C _1-6 alkyl, -C(0) H ₂ , -C(0)N(H)(C _1-6 alkyl), -C(0)N(C _1-6 alkyl) ₂ , - C(0)C _2-7 heterocycloalkyl, and -S(0) ₂ Ci _-6 alkyl. In another embodiment is a compound of Formula (Ila), wherein R ⁴ is a 5-6 membered heteroaryl ring optionally substituted with one or two groups selected from halogen, -Ci- ₆ alkyl-OH, Ci-efluoroalkyl, -C0 ₂ H, -Ci- ₆ alkyl- C0 ₂ H. In another embodiment is a compound of Formula (Ila), wherein R ⁴ is a 5-membered heteroaryl ring optionally substituted with one or two groups selected from halogen, hydroxy, Ci _-6 alkyl, -Ci _-6 alkyl-OH, Ci _-6 fluoroalkyl, C _3-6 cycloalkyl, -C0 ₂ H, -Ci _-6 alkyl-C0 ₂ H, -C(0)Ci. ₆ alkyl, -C(0)Ci _-6 alkyl-OH, -N(H)C(0)Ci _-6 alkyl, -C(0) H ₂ , -C(0)N(H)(Ci _-6 alkyl), -C(0)N(Ci. ₆ alkyl) ₂ , -C(0)C _2-7 heterocycloalkyl, and -S(0) ₂ Ci _-6 alkyl. In another embodiment is a compound of Formula (Ila), wherein R ⁴ is a 5-membered heteroaryl ring optionally substituted with one or two groups selected from halogen, -Ci- ₆ alkyl-OH, Ci-efluoroalkyl, -C0 ₂ H, -Ci- ₆ alkyl- C0 ₂ H. In another embodiment is a compound of Formula (Ila), wherein R ⁴ is a 6-membered heteroaryl ring optionally substituted with one or two groups selected from halogen, hydroxy, Ci _-6 alkyl, -Ci _-6 alkyl-OH, Ci _-6 fluoroalkyl, C _3-6 cycloalkyl, -C0 ₂ H, -Ci _-6 alkyl-C0 ₂ H, -C(0)d. ₆ alkyl, -C(0)Ci _-6 alkyl-OH, -N(H)C(0)Ci _-6 alkyl, -C(0) H ₂ , -C(0)N(H)(Ci _-6 alkyl), -C(0)N(Ci. ₆ alkyl) ₂ , -C(0)C _2-7 heterocycloalkyl, and -S(0) ₂ Ci _-6 alkyl. In another embodiment is a compound of Formula (Ila), wherein R ⁴ is a 6-membered heteroaryl ring optionally substituted with one or two groups selected from halogen, -Ci- ₆ alkyl-OH, Ci-efluoroalkyl, -C0 ₂ H, -Ci- ₆ alkyl-

nother embodiment is a compound of Formula (Ila), wherein R is N N _? . In another embodiment is a compound of Formula (Ila), wherein R ⁴ is optionally substituted Ci-ealkyl -heterocycloalkyl. In another embodiment is a compound of Formula (Ila), wherein R ⁴ is optionally substituted heterocycloalkyl. In another embodiment is a compound of Formula (Ila), wherein R ⁴ is heterocycloalkyl optionally substituted with one or more groups selected from halogen, hydroxy, Ci _-6 alkyl, -Ci _-6 alkyl-OH, Ci _-6 fluoroalkyl, C ₃ - ₆ cycloalkyl, heteroaryl, -C0 ₂ H, -Ci _-6 alkyl-C0 ₂ H, -C(0)Ci _-6 alkyl, -C(0)Ci. ₆ alkyl-OH, -N(H)C(0)Ci _-6 alkyl, -C(0) H ₂ , -C(0)N(H)(Ci _-6 alkyl), -C(0)N(Ci _-6 alkyl) ₂ , - C(0)C _2-7 heterocycloalkyl, and -S(0) ₂ Ci _-6 alkyl. In another embodiment is a compound of Formula (Ila), wherein R ⁴ is heterocycloalkyl optionally substituted with one or two groups selected from halogen, hydroxy, -Ci- ₆ alkyl-OH, Ci-efiuoroalkyl, C _3-6 Cycloalkyl, heteroaryl, -C0 ₂ H, -Ci _-6 alkyl-C0 ₂ H, -C(0)Ci _-6 alkyl, -C(0)Ci _-6 alkyl-OH, -N(H)C(0)Ci _-6 alkyl, - C(0) H ₂ , -C(0)N(H)(Ci _-6 alkyl), -C(0)N(Ci _-6 alkyl) ₂ , -C(0)C _2-7 heterocycloalkyl, and -S(0) ₂ Ci. ₆ alkyl. In another embodiment is a compound of Formula (Ila), wherein R ⁴ is optionally substituted heterocycloalkyl and the heterocycloalkyl is a 4-6 membered monocyclic

heterocycloalkyl, a 8-9 membered bicyclic heterocycloalkyl, a 7-8 membered bridged heterocycloalkyl, a 5,5 fused heterocycloalkyl, or an 8-11 membered spirocyclic

heterocycloalkyl. In another embodiment is a compound of Formula (Ila), wherein R ⁴ is an optionally substituted 4-6 membered monocyclic heterocycloalkyl. In another embodiment is a compound of Formula (Ila), wherein R ⁴ is an optionally substituted 8-9 membered bicyclic heterocycloalkyl. In another embodiment is a compound of Formula (Ila), wherein R ⁴ is an optionally substituted 7-8 membered bridged heterocycloalkyl. In another embodiment is a compound of Formula (Ila), wherein R ⁴ is an optionally substituted 5,5 fused heterocycloalkyl. In another embodiment is a compound of Formula (Ila), wherein R ⁴ is an optionally substituted -11 membered spirocyclic heterocycloalkyl. In another embodiment is a compou Formula

In another embodiment is a compound of Formula (Ila), wherein R is optionally substituted

heterocycloalkyl selected from

In another embodiment is a compound of Formula (Ila), wherein R is - OR ⁷ . In another embodiment is a compound of Formula (Ila), wherein R ⁴ is -OR ⁷ , and R ⁷ is H, Ci- ₆ alkyl, a phenyl optionally substituted with halogen, Ci- ₆ alkyl, Ci-efluoroalkyl, or Ci _-6 alkoxy, a Ci _-6 alkyl-phenyl optionally substituted with halogen, Ci _-6 alkyl, Ci _-6 fluoroalkyl, or Ci _-6 alkoxy, a heteroaryl optionally substituted with halogen, Ci _-6 alkyl, or Ci _-6 fluoroalkyl, a 5-6 membered monocyclic heterocycloalkyl optionally substituted with halogen, Ci-efluoroalkyl, or C3- ₆ cycloalkyl, or a In another embodiment is a compound of Formula (Ila), wherein R ⁴ is -OR ⁷ , and R ⁷ is Ci _-6 alkyl. In another embodiment is a compound of Formula (Ila), wherein R ⁴ is -OR ⁷ , and R ⁷ is optionally substituted phenyl. In another embodiment is a compound of Formula (Ila), wherein R ⁴ is -OR ⁷ , and R ⁷ is phenyl optionally substituted with halogen, Ci-efluoroalkyl, or Ci _-6 alkoxy. In another embodiment is a compound of Formula (Ila), wherein R ⁴ is -OR ⁷ , and R ⁷ is optionally substituted Ci _-6 alkyl-phenyl. In another embodiment is a compound of Formula (Ila), wherein R ⁴ is -OR ⁷ , and R ⁷ is Ci _-6 alkyl-phenyl optionally substituted with halogen, Ci-efluoroalkyl, or Ci _-6 alkoxy. In another embodiment is a compound of Formula (Ila), wherein R ⁴ is -OR ⁷ , and R ⁷ is optionally substituted heteroaryl. In another embodiment is a compound of Formula (Ila), wherein R ⁴ is - OR ⁷ , and R ⁷ is heteroaryl optionally substituted with halogen, Ci _-6 alkyl, or Ci _-6 fluoroalkyl. In another embodiment is a compound of Formula (Ila), wherein R ⁴ is -OR ⁷ , and R ⁷ is optionally substituted heterocycloalkyl. In another embodiment is a compound of Formula (Ila), wherein R ⁴ is -OR ⁷ , and R ⁷ is a 5-6 membered monocyclic heterocycloalkyl optionally substituted with halogen, Ci _-6 alkyl, Ci _-6 fluoroalkyl, or C _3-6 cycloalkyl. In another embodiment is a compound of Formula (Ila), wherein R ⁴ is -OR ⁷ , and R ⁷ is -Ci _-6 alkylC(O) R ¹⁰ R ¹¹ . In another embodiment is a compound of Formula (Ila), wherein R ⁴ is -OR ⁷ , and R ⁷ is -Ci _-6 alkylC(O) R ¹⁰ R ^u , and R ¹⁰ and R ¹² are each independently H, or Ci _-6 alkyl. In another embodiment is a compound of Formula (Ila), wherein R ⁴ is -OR ⁷ , and R ⁷ is -Ci _-6 alkylC(O) R ¹⁰ R ¹¹ , and R ¹⁰ and R ¹¹ together with the nitrogen to which they are attached are combined to form a heterocycloalkyl ring. In another embodiment is a compound of Formula (Ila), wherein R ⁴ is -OR ⁷ , and R ⁷ is Ci _-6 alkyl,

In another embodiment is a compound of Formula (Ila), wherein R ⁴ is -OR ⁷ , and R ⁷ is or \— ' . In another embodiment is a compound of Formula (Ila), wherein R is -C0 ₂ H. In another embodiment is a compound of Formula (Ila), wherein R ⁴ is -C(0)NR ⁸ R ⁹ . In another embodiment is a compound of Formula (Ila), wherein R ⁴ is -C(0)NR ⁸ R ⁹ , and R ⁸ and R ⁹ are each independently H, or Ci- ₆ alkyl. In another embodiment is a compound of Formula

4 8 9 8 9

(Ila), wherein R" is -C(0) R°R ^: ', and R° and R ^* are H. In another embodiment is a compound

4 8 9 8 9

of Formula (Ila), wherein R" is -0(0)Μ Γ, and R° is H and R ^* are Ci _-6 alkyl. In another

4 8 9 8 9 embodiment is a compound of Formula (Ila), wherein R is -C(0) R R , and R and R are Ci. ₆ alkyl. In another embodiment is a compound of Formula (Ila), wherein R ⁴ is -C(0) R ⁸ R ⁹ , and R ⁸ and R ⁹ together with the nitrogen to which they are attached are combined to form an optionally substituted heterocycloalkyl ring. In another embodiment is a compound of Formula

(Ila), wherein R 4 is -C(0) R 8 R 9 , and R 8 and R 9 together with the nitrogen to which they are attached are combined to form an unsubstituted heterocycloalkyl ring.

[0078] In another embodiment is a compound of Formula (Ila), wherein R ⁵ is H. In another embodiment is a compound of Formula (Ila), wherein R ⁵ is halogen. In another embodiment is a compound of Formula (Ila), wherein R ⁵ is -CI. In another embodiment is a compound of Formula (Ila), wherein R ⁵ is -F. In another embodiment is a compound of Formula (Ila), wherein R ⁵ is Ci- ₆ alkyl. In another embodiment is a compound of Formula (Ila), wherein R ⁵ is Ci _-6 haloalkyl. In another embodiment is a compound of Formula (Ila), wherein R ⁵ is -CF ₃ . In another embodiment is a compound of Formula (Ila), wherein R ⁵ is phenyl.

[0079] In one embodiment is a compound of Formula (III):

Formula (III);

wherein:

R ¹ is -N(R ² )C(0)R ¹⁵ or -N(H)S0 ₂ R ¹⁵ ;

R ² is H or C _h alky.;

R ³ is H or optionally substituted phenyl;

R ⁴ is H, halogen, -OR ⁷ , C _2-6 alkynyl, Ci-ehaloalkyl, C3- ₆ cycloalkyl, optionally

substituted heterocycloalkyl, optionally substituted optionally substituted phenyl, optionally substituted heteroaryl, -C0 ₂ H, or -C(0) R ⁸ R ⁹ ;

R ⁵ is H, halogen, -CN, Ci-ehaloalkyl, or phenyl; or R ⁴ and R ⁵ are combined to form an optionally substituted heterocycloalkyl ring or an optionally substituted heteroaryl ring;

R ⁶ is H, halogen or Ci _-6 alkyl;

R ⁷ is H, Ci _-6 alkyl, optionally substituted phenyl, optionally substituted Ci _-6 alkyl -phenyl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, or -Ci.

6alkylC(O) R ¹⁰ R ^u ;

R ⁸ and R ⁹ are each independently H, or Ci _-6 alkyl; or R ⁸ and R ⁹ together with the nitrogen to which they are attached are combined to form an optionally substituted heterocycloalkyl ring;

R ¹⁰ and R ¹¹ are each independently H, or or R ¹⁰ and R ¹¹ together with the nitrogen to which they are attached are combined to form a heterocycloalkyl ring; and

R ¹⁵ is optionally substituted Ci _-6 alkyl;

or a solvate, hydrate, tautomer, N-oxide, or pharmaceutically acceptable salt thereof.

[0080] In another embodiment is a compound of Formula (III), wherein R ¹ is -N(R ² )C(0)R ¹⁵ . In another embodiment is a compound of Formula (III), wherein R ¹ is -N(R ² )C(0)R ¹⁵ and R ² is H. In another embodiment is a compound of Formula (III), wherein R ¹ is -N(R ² )C(0)R ¹⁵ and R ² is Ci- ₆ alkyl. In another embodiment is a compound of Formula (III), wherein R ¹ is - N(R ² )C(0)R ¹⁵ and R ² is -CH ₃ . In another embodiment is a compound of Formula (III), wherein R ¹ is -N(R ² )C(0)R ¹⁵ , R ² is H, and R ¹⁵ is -CH ₂ OH. In another embodiment is a compound of Formula (III), wherein R ¹ is -N(R ² )C(0)R ¹⁵ , R ² is H, and R ¹⁵ is -CF ₃ . In another embodiment is a compound of Formula (III), wherein R ¹ is -N(R ² )C(0)R ¹⁵ , R ² is H, and R ¹⁵ is -CHF ₂ . In another embodiment is a compound of Formula (III), wherein R ¹ is -N(R ² )C(0)R ¹⁵ , R ² is H, and R ¹⁵ is unsubstituted Ci _-6 alkyl. In another embodiment is a compound of Formula (III), wherein R ¹ is -N(R ² )C(0)R ¹⁵ , R ² is H, R ¹⁵ is -CH ₃ . In another embodiment is a compound of Formula (III), wherein R ¹ is -N(R ² )C(0)R ¹⁵ , R ² is Ci _-6 alkyl, and R ¹⁵ is -CH ₂ OH. In another embodiment is a compound of Formula (III), wherein R ¹ is -N(R ² )C(0)R ¹⁵ , R ² is Ci _-6 alkyl, and R ¹⁵ is -CF ₃ . In another embodiment is a compound of Formula (III), wherein R ¹ is -N(R ² )C(0)R ¹⁵ , R ² is d. ₆ alkyl, and R ¹⁵ is -CHF ₂ . In another embodiment is a compound of Formula (III), wherein R ¹ is -N(R ² )C(0)R ¹⁵ , R ² is Ci- ₆ alkyl, and R ¹⁵ is unsubstituted In another embodiment is a compound of Formula (III), wherein R ¹ is -N(R ² )C(0)R ¹⁵ , R ² is Ci _-6 alkyl, R ¹⁵ is -CH ₃ . In another embodiment is a compound of Formula (III), wherein R ¹ is -N(R ² )C(0)R ¹⁵ , R ² is -CH ₃ , and R ¹⁵ is -CH ₂ OH. In another embodiment is a compound of Formula (III), wherein R ¹ is - N(R ² )C(0)R ¹⁵ , R ² is -CH ₃ , and R ¹⁵ is -CF ₃ . In another embodiment is a compound of Formula (III), wherein R ¹ is -N(R ² )C(0)R ¹⁵ , R ² is -CH ₃ , and R ¹⁵ is -CHF ₂ . In another embodiment is a compound of Formula (III), wherein R ¹ is -N(R ² )C(0)R ¹⁵ , R ² is -CH ₃ , and R ¹⁵ is unsubstituted Ci- ₆ alkyl. In another embodiment is a compound of Formula (III), wherein R ¹ is - N(R ² )C(0)R ¹⁵ , R ² is -CH ₃ , R ¹⁵ is -CH ₃ . In another embodiment is a compound of Formula (III), wherein R ¹ -N(H)S0 ₂ R ¹⁵ . In another embodiment is a compound of Formula (III), wherein R ¹ is-N(H)S0 ₂ R ¹⁵ and R ¹⁵ is -CH ₂ OH. In another embodiment is a compound of Formula (III), wherein R ¹ is-N(H)S0 ₂ R ¹⁵ and R ¹⁵ is -CF ₃ . In another embodiment is a compound of Formula (III), wherein R ¹ is-N(H)S0 ₂ R ¹⁵ and R ¹⁵ is -CHF ₂ . In another embodiment is a compound of Formula (III), wherein R ¹ is -N(H)S0 ₂ R ¹⁵ and R ¹⁵ is unsubstituted Ci _-6 alkyl. In another embodiment is a compound of Formula (III), wherein R ¹ is -N(H)S0 ₂ R ¹⁵ and R ¹⁵ is -CH ₃ . In another embodiment is a compound of Formula (III), wherein R ³ is H. In another embodiment is a compound of Formula (III), wherein R ³ is optionally substituted phenyl.

[0081] In another embodiment is a compound of Formula (III), wherein R ⁴ is H. In another embodiment is a compound of Formula (III), wherein R ⁴ is halogen. In another embodiment is a compound of Formula (III), wherein R ⁴ is -CI. In another embodiment is a compound of Formula (III), wherein R ⁴ is -F. In another embodiment is a compound of Formula (III), wherein R ⁴ is Ci _-6 alkyl. In another embodiment is a compound of Formula (III), wherein R ⁴ is Ci _-6 haloalkyl. In another embodiment is a compound of Formula (III), wherein R ⁴ is -CF ₃ . In another embodiment is a compound of Formula (III), wherein R ⁴ is optionally substituted phenyl. In another embodiment is a compound of Formula (III), wherein R ⁴ is optionally substituted heteroaryl. In another embodiment is a compound of Formula (III), wherein R ⁴ is heteroaryl optionally substituted with one or two groups selected from halogen, hydroxy, C _\ . ealkyl, -Ci _-6 alkyl-OH, Ci _-6 fluoroalkyl, C _3-6 cycloalkyl, -C0 ₂ H, -Ci _-6 alkyl-C0 ₂ H, -C(0)Ci _-6 alkyl, -C(0)Ci _-6 alkyl-OH, -N(H)C(0)Ci _-6 alkyl, -C(0) H ₂ , -C(0)N(H)(Ci _-6 alkyl), -C(0)N(Ci _-6 alkyl) ₂ , -C(0)C _2-7 heterocycloalkyl, and -S(0) ₂ Ci _-6 alkyl. In another embodiment is a compound of Formula (III), wherein R ⁴ is heteroaryl optionally substituted with one or two groups selected from halogen, hydroxy, Ci-efiuoroalkyl, C _3-6 Cycloalkyl, -C0 ₂ H, -Ci- ₆ alkyl-C0 ₂ H, and -C(0) H ₂ . In another embodiment is a compound of Formula (III), wherein R ⁴ is optionally substituted heteroaryl and the heteroaryl is a 5-6 membered heteroaryl ring. In another embodiment is a compound of Formula (III), wherein R ⁴ is a 5-6 membered heteroaryl ring optionally substituted with one or two groups selected from halogen, hydroxy, -Ci. ₆ alkyl-OH, Ci _-6 fluoroalkyl, C _3-6 cycloalkyl, -C0 ₂ H, -Ci _-6 alkyl-C0 ₂ H, -C(0)Ci _-6 alkyl, -C(0)Ci. ₆ alkyl-OH, -N(H)C(0)C _1-6 alkyl, -C(0) H ₂ , -C(0)N(H)(C _1-6 alkyl), -C(0)N(C _1-6 alkyl) ₂ , - C(0)C _2-7 heterocycloalkyl, and -S(0) ₂ Ci _-6 alkyl. In another embodiment is a compound of Formula (III), wherein R ⁴ is a 5-6 membered heteroaryl ring optionally substituted with one or two groups selected from halogen, Ci _-6 alkyl, -Ci _-6 alkyl-OH, Ci _-6 fluoroalkyl, -C0 ₂ H, -Ci _-6 alkyl- C0 ₂ H. In another embodiment is a compound of Formula (III), wherein R ⁴ is a 5-membered heteroaryl ring optionally substituted with one or two groups selected from halogen, hydroxy, Ci-ealkyl, -Ci _-6 alkyl-OH, Ci _-6 fluoroalkyl, C ₃ - ₆ cycloalkyl, -C0 ₂ H, -Ci _-6 alkyl-C0 ₂ H, -C(0)Ci. ealkyl, -C(0)Ci _-6 alkyl-OH, -N(H)C(0)Ci _-6 alkyl, -C(0) H ₂ , -C(0)N(H)(Ci _-6 alkyl), -C(0)N(d. ₆ alkyl) ₂ , -C(0)C _2-7 heterocycloalkyl, and -S(0) ₂ Ci _-6 alkyl. In another embodiment is a compound of Formula (III), wherein R ⁴ is a 5-membered heteroaryl ring optionally substituted with one or two groups selected from halogen, -Ci- ₆ alkyl-OH, Ci-efluoroalkyl, -C0 ₂ H, -Ci- ₆ alkyl- C0 ₂ H. In another embodiment is a compound of Formula (III), wherein R ⁴ is a 6-membered heteroaryl ring optionally substituted with one or two groups selected from halogen, hydroxy, Ci _-6 alkyl, -Ci _-6 alkyl-OH, Ci _-6 fluoroalkyl, C _3-6 cycloalkyl, -C0 ₂ H, -Ci _-6 alkyl-C0 ₂ H, -C(0)Ci. ₆ alkyl, -C(0)Ci _-6 alkyl-OH, -N(H)C(0)Ci _-6 alkyl, -C(0) H ₂ , -C(0)N(H)(Ci _-6 alkyl), -C(0)N(Ci. ₆ alkyl) ₂ , -C(0)C _2-7 heterocycloalkyl, and -S(0) ₂ Ci _-6 alkyl. In another embodiment is a compound of Formula (III), wherein R ⁴ is a 6-membered heteroaryl ring optionally substituted with one or two groups selected from halogen, -Ci- ₆ alkyl-OH, Ci-efluoroalkyl, -C0 H, -Ci- ₆ alkyl- wherein R ⁴ is optionally substituted Ci- ₆ alkyl-heterocycloalkyl. In another embodiment is a compound of Formula (III), wherein R ⁴ is optionally substituted heterocycloalkyl. In another embodiment is a compound of Formula (III), wherein R ⁴ is heterocycloalkyl optionally substituted with one or more groups selected from halogen, hydroxy, Ci _-6 alkyl, -Ci _-6 alkyl-OH, Ci _-6 fluoroalkyl, C _3-6 cycloalkyl, -C0 ₂ H, -Ci _-6 alkyl-C0 ₂ H, -C(0)Ci _-6 alkyl, -C(0)Ci _-6 alkyl-OH, - N(H)C(0)Ci _-6 alkyl, -C(0) H ₂ , -C(0)N(H)(Ci _-6 alkyl), -C(0)N(Ci _-6 alkyl) ₂ , -C(0)C _{2- 7} heterocycloalkyl, and -S(0) ₂ Ci- ₆ alkyl. In another embodiment is a compound of Formula (III), wherein R ⁴ is heterocycloalkyl optionally substituted with one or two groups selected from halogen, hydroxy, -Ci- ₆ alkyl-OH, Ci-efluoroalkyl, C3- ₆ cycloalkyl, -C0 ₂ H, -Ci- ₆ alkyl- C0 ₂ H, -C(0)Ci _-6 alkyl, -C(0)Ci _-6 alkyl-OH, -N(H)C(0)Ci _-6 alkyl, -C(0) H ₂ , -C(0)N(H)(Ci. 6alkyl), -C(0)N(Ci _-6 alkyl) ₂ , -C(0)C _2-7 heterocycloalkyl, and -S(0) ₂ Ci _-6 alkyl. In another embodiment is a compound of Formula (III), wherein R ⁴ is optionally substituted

heterocycloalkyl and the heterocycloalkyl is a 4-6 membered monocyclic heterocycloalkyl, a 8-9 membered bicyclic heterocycloalkyl, a 7-8 membered bridged heterocycloalkyl, a 5,5 fused heterocycloalkyl, or an 8-11 membered spirocyclic heterocycloalkyl. In another embodiment is a compound of Formula (III), wherein R ⁴ is an optionally substituted 4-6 membered monocyclic heterocycloalkyl. In another embodiment is a compound of Formula (III), wherein R ⁴ is an optionally substituted 8-9 membered bicyclic heterocycloalkyl. In another embodiment is a compound of Formula (III), wherein R ⁴ is an optionally substituted 7-8 membered bridged heterocycloalkyl. In another embodiment is a compound of Formula (III), wherein R ⁴ is an optionally substituted 5,5 fused heterocycloalkyl. In another embodiment is a compound of Formula (III), wherein R ⁴ is an optionally substituted 8-11 membered spirocyclic

heterocycloalkyl. In another embodiment is a compound of Formula (III), wherein R ⁴ is optionally substituted heterocycloalkyl selected from ^■ o o X

. In another embodiment is d o f Formula (III), wherein R ⁴ is optionally substituted heterocycloalkyl selected from

In another embodiment is a compound of Formula (III), wherein R ⁴ is -OR ⁷ . In another embodiment is a compound of Formula (III), wherein R ⁴ is -OR ⁷ , and R ⁷ is H, Ci _-6 alkyl, a phenyl optionally substituted with halogen, Ci-efluoroalkyl, or Ci _-6 alkoxy, a optionally substituted with halogen, Ci-efluoroalkyl, or Ci _-6 alkoxy, a heteroaryl optionally substituted with halogen, Ci _-6 alkyl, or Ci _-6 fluoroalkyl, a 5-6 membered monocyclic heterocycloalkyl optionally substituted with halogen, Ci _-6 alkyl, Ci _-6 fluoroalkyl, or C _3-6 cycloalkyl, or a -Ci.

6alkylC(O) R ¹⁰ R ^u . In another embodiment is a compound of Formula (III), wherein R ⁴ is - OR ⁷ , and R ⁷ is In another embodiment is a compound of Formula (III), wherein R ⁴ is -OR ⁷ , and R ⁷ is optionally substituted phenyl. In another embodiment is a compound of Formula (III), wherein R ⁴ is -OR ⁷ , and R ⁷ is phenyl optionally substituted with halogen, Ci. 6alkyl, Ci-efiuoroalkyl, or Ci _-6 alkoxy. In another embodiment is a compound of Formula (III), wherein R ⁴ is -OR ⁷ , and R ⁷ is optionally substituted In another embodiment is a compound of Formula (III), wherein R ⁴ is -OR ⁷ , and R ⁷ is Ci _-6 alkyl-phenyl optionally substituted with halogen, Ci _-6 alkyl, Ci _-6 fluoroalkyl, or Ci _-6 alkoxy. In another embodiment is a compound of Formula (III), wherein R ⁴ is -OR ⁷ , and R ⁷ is optionally substituted heteroaryl. In another embodiment is a compound of Formula (III), wherein R ⁴ is -OR ⁷ , and R ⁷ is heteroaryl optionally substituted with halogen, Ci _-6 alkyl, or Ci _-6 fluoroalkyl. In another embodiment is a compound of Formula (III), wherein R ⁴ is -OR ⁷ , and R ⁷ is optionally substituted

heterocycloalkyl. In another embodiment is a compound of Formula (III), wherein R ⁴ is -OR ⁷ , and R ⁷ is a 5-6 membered monocyclic heterocycloalkyl optionally substituted with halogen, Ci. 6alkyl, Ci _-6 fluoroalkyl, or C _3-6 cycloalkyl. In another embodiment is a compound of Formula (III), wherein R ⁴ is -OR ⁷ , and R ⁷ is -Ci _-6 alkylC(O)NR ¹⁰ R ^u . In another embodiment is a compound of Formula (III), wherein R ⁴ is -OR ⁷ , and R ⁷ is -Ci _-6 alkylC(O)NR ¹⁰ R ¹¹ , and R ¹⁰ and R ¹² are each independently H, or Ci- ₆ alkyl. In another embodiment is a compound of Formula (III), wherein R ⁴ is -OR ⁷ , and R ⁷ is -Ci _-6 alkylC(O)NR ¹⁰ R ¹¹ , and R ¹⁰ and R ¹¹ together with the nitrogen to which they are attached are combined to form a heterocycloalkyl ring. In another

another embodiment is a compound of Formula (III), wherein R 4 i:s_ -ORV , a -nd _{J R i s} or In another embodiment is a compound of Formula (III), wherein R ⁴ is -C0 ₂ H

In another embodiment is a compound of Formula (III), wherein R ⁴ is -C(0) R ⁸ R ⁹ . In another

4 8 9 8 9 embodiment is a compound of Formula (III), wherein R is -C(0) R R , and R and R are each independently H, or Ci- ₆ alkyl. In another embodiment is a compound of Formula (III), wherein

4 8 9 8 9

is -C(0) R°R ^: ', and R° and R ^* are H. In another embodiment is a compound of Formula

(III), wherein R 4 is -C(0) R 8°R 9 ^: ', and R 8° is H and R 9 ^* are Ci _-6 alkyl. In another embodiment is a

4 8 9 8 9

compound of Formula (III), wherein R is -C(0)NR R , and R and R are Ci _-6 alkyl. In another

4 8 9 8 9 embodiment is a compound of Formula (III), wherein R is -C(0) R R , and R and R together with the nitrogen to which they are attached are combined to form an optionally substituted heterocycloalkyl ring. In another embodiment is a compound of Formula (III), wherein R ⁴ is - CC((00)) RR ⁸⁸ RR ⁹⁹ ,, aanndd RR ⁸⁸ aanndd RR ⁹⁹ ttooggeetthheerr wwiitthh tthhee nniitrogen to which they are attached are combined to form an unsubstituted heterocycloalkyl ring.

[0082] In another embodiment is a compound of Formula (III), wherein R ⁵ is H. In another embodiment is a compound of Formula (III), wherein R ⁵ is halogen. In another embodiment is a compound of Formula (III), wherein R ⁵ is -CI. In another embodiment is a compound of Formula (III), wherein R ⁵ is -F. In another embodiment is a compound of Formula (III), wherein R ⁵ is Ci- ₆ alkyl. In another embodiment is a compound of Formula (III), wherein R ⁵ is Ci _-6 haloalkyl. In another embodiment is a compound of Formula (III), wherein R ⁵ is -CF ₃ . In another embodiment is a compound of Formula (III), wherein R ⁵ is phenyl

[0083] In another embodiment is a compound of Formula (III), wherein R ⁶ is H. In another embodiment is a compound of Formula (III), wherein R ⁶ is halogen. In another embodiment is a compound of Formula (III), wherein R ⁶ is -CI. In another embodiment is a compound of Formula (III), wherein R ⁶ is -F. In another embodiment is a compound of Formula (III), wherein R ⁶ is Ci _-6 alkyl.

[0084] In another embodiment is a compound of Formula (IV):

Formula (IV);

wherein:

R ¹ is -N(R ² )C(0)R ¹⁵ or -N(H)S0 ₂ R ¹⁵ ;

R ² is H or Ci-ealkyl;

R ³ is H or optionally substituted phenyl;

R ⁴ is H, halogen, -OR ⁷ , Ci _-6 alkyl, C _2-6 alkynyl, Ci _-6 haloalkyl, C _3-6 cycloalkyl, optionally

substituted heterocycloalkyl, optionally substituted optionally substituted phenyl, optionally substituted heteroaryl, -C0 ₂ H, or -C(0) R ⁸ R ⁹ ;

R ⁵ is H, halogen, -CN, Ci _-6 alkyl, Ci _-6 haloalkyl, or phenyl; or

R ⁴ and R ⁵ are combined to form an optionally substituted heterocycloalkyl ring or an

optionally substituted heteroaryl ring;

R ⁶ is H, halogen or

R ⁷ is H, Ci _-6 alkyl, optionally substituted phenyl, optionally substituted Ci _-6 alkyl -phenyl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, or -Ci.

6alkylC(O) R ¹⁰ R ^u ;

R ⁸ and R ⁹ are each independently H, or Ci- ₆ alkyl; or R ⁸ and R ⁹ together with the nitrogen to which they are attached are combined to form an optionally substituted heterocycloalkyl ring;

R ¹⁰ and R ¹¹ are each independently H, or Ci _-6 alkyl; or R ¹⁰ and R ¹¹ together with the nitrogen to which they are attached are combined to form a heterocycloalkyl ring;

R ¹² is H or Ci-ealkyl;

R ¹³ is H or Ci _-6 alkyl; and

R ¹⁵ is optionally substituted Ci _-6 alkyl;

or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof. [0085] In another embodiment is a compound of Formula (IV), wherein R ¹² and R ¹³ are H. In another embodiment is a compound of Formula (IV), wherein R ¹² and R ¹³ are In another embodiment is a compound of Formula (IV), wherein R ¹² and R ¹³ are -CH ₃ . In another embodiment is a compound of Formula (IV), wherein R ¹² is H and R ¹³ are -CH ₃ .

[0086] In another embodiment is a compound of Formula (IV), wherein R ¹ is -N(R ² )C(0)R ¹⁵ . In another embodiment is a compound of Formula (IV), wherein R ¹ is -N(R ² )C(0)R ¹⁵ and R ² is H. In another embodiment is a compound of Formula (IV), wherein R ¹ is -N(R ² )C(0)R ¹⁵ and R ² is Ci _-6 alkyl. In another embodiment is a compound of Formula (IV), wherein R ¹ is - N(R ² )C(0)R ¹⁵ and R ² is -CH ₃ . In another embodiment is a compound of Formula (IV), wherein R ¹ is -N(R ² )C(0)R ¹⁵ , R ² is H, and R ¹⁵ is -CH ₂ OH. In another embodiment is a compound of Formula (IV), wherein R ¹ is -N(R ² )C(0)R ¹⁵ , R ² is H, and R ¹⁵ is -CF ₃ . In another embodiment is a compound of Formula (IV), wherein R ¹ is -N(R ² )C(0)R ¹⁵ , R ² is H, and R ¹⁵ is -CHF ₂ . In another embodiment is a compound of Formula (IV), wherein R ¹ is -N(R ² )C(0)R ¹⁵ , R ² is H, and R ¹⁵ is unsubstituted Ci- ₆ alkyl. In another embodiment is a compound of Formula (IV), wherein R ¹ is -N(R ² )C(0)R ¹⁵ , R ² is H, R ¹⁵ is -CH ₃ . In another embodiment is a compound of Formula (IV), wherein R ¹ is -N(R ² )C(0)R ¹⁵ , R ² is Ci _-6 alkyl, and R ¹⁵ is -CH ₂ OH. In another embodiment is a compound of Formula (IV), wherein R ¹ is -N(R ² )C(0)R ¹⁵ , R ² is Ci _-6 alkyl, and R ¹⁵ is -CF ₃ . In another embodiment is a compound of Formula (IV), wherein R ¹ is -N(R ² )C(0)R ¹⁵ , R ² is Ci. ₆ alkyl, and R ¹⁵ is -CHF ₂ . In another embodiment is a compound of Formula (IV), wherein R ¹ is -N(R ² )C(0)R ¹⁵ , R ² is Ci _-6 alkyl, and R ¹⁵ is unsubstituted Ci _-6 alkyl. In another embodiment is a compound of Formula (IV), wherein R ¹ is -N(R ² )C(0)R ¹⁵ , R ² is Ci _-6 alkyl, R ¹⁵ is -CH ₃ . In another embodiment is a compound of Formula (IV), wherein R ¹ is -N(R ² )C(0)R ¹⁵ , R ² is -CH ₃ , and R ¹⁵ is -CH ₂ OH. In another embodiment is a compound of Formula (IV), wherein R ¹ is - N(R ² )C(0)R ¹⁵ , R ² is -CH ₃ , and R ¹⁵ is -CF ₃ . In another embodiment is a compound of Formula (IV), wherein R ¹ is -N(R ² )C(0)R ¹⁵ , R ² is -CH ₃ , and R ¹⁵ is -CHF ₂ . In another embodiment is a compound of Formula (IV), wherein R ¹ is -N(R ² )C(0)R ¹⁵ , R ² is -CH ₃ , and R ¹⁵ is unsubstituted Ci _-6 alkyl. In another embodiment is a compound of Formula (IV), wherein R ¹ is - N(R ² )C(0)R ¹⁵ , R ² is -CH ₃ , R ¹⁵ is -CH ₃ . In another embodiment is a compound of Formula (IV), wherein R ¹ -N(H)S0 ₂ R ¹⁵ . In another embodiment is a compound of Formula (IV), wherein R ¹ is-N(H)S0 ₂ R ¹⁵ and R ¹⁵ is -CH ₂ OH. In another embodiment is a compound of Formula (IV), wherein R ¹ is-N(H)S0 ₂ R ¹⁵ and R ¹⁵ is -CF ₃ . In another embodiment is a compound of Formula (IV), wherein R ¹ is-N(H)S0 ₂ R ¹⁵ and R ¹⁵ is -CHF ₂ . In another embodiment is a compound of Formula (IV), wherein R ¹ is -N(H)S0 ₂ R ¹⁵ and R ¹⁵ is unsubstituted In another embodiment is a compound of Formula (IV), wherein R ¹ is -N(H)S0 ₂ R ¹⁵ and R ¹⁵ is -CH ₃ . In another embodiment is a compound of Formula (IV), wherein R ³ is H. In another embodiment is a compound of Formula (IV), wherein R ³ is optionally substituted phenyl.

[0087] In another embodiment is a compound of Formula (IV), wherein R ³ is H. In another embodiment is a compound of Formula (IV), wherein R ³ is optionally substituted phenyl.

[0088] In another embodiment is a compound of Formula (IV), wherein R ⁴ is H. In another embodiment is a compound of Formula (IV), wherein R ⁴ is halogen. In another embodiment is a compound of Formula (IV), wherein R ⁴ is -CI. In another embodiment is a compound of Formula (IV), wherein R ⁴ is -F. In another embodiment is a compound of Formula (IV), wherein R ⁴ is Ci- ₆ alkyl. In another embodiment is a compound of Formula (IV), wherein R ⁴ is Ci- ₆ haloalkyl. In another embodiment is a compound of Formula (IV), wherein R ⁴ is -CF ₃ . In another embodiment is a compound of Formula (IV), wherein R ⁴ is optionally substituted phenyl. In another embodiment is a compound of Formula (IV), wherein R ⁴ is optionally substituted heteroaryl. In another embodiment is a compound of Formula (IV), wherein R ⁴ is heteroaryl optionally substituted with one or two groups selected from halogen, hydroxy, Ci. ₆ alkyl, -Ci _-6 alkyl-OH, Ci _-6 fluoroalkyl, C _3-6 cycloalkyl, -C0 ₂ H, -Ci _-6 alkyl-C0 ₂ H, -C(0)Ci _-6 alkyl, -C(0)Ci _-6 alkyl-OH, -N(H)C(0)Ci _-6 alkyl, -C(0) H ₂ , -C(0)N(H)(Ci _-6 alkyl), -C(0)N(Ci _-6 alkyl) ₂ , -C(0)C _2-7 heterocycloalkyl, and -S(0) ₂ Ci- ₆ alkyl. In another embodiment is a compound of Formula (IV), wherein R ⁴ is heteroaryl optionally substituted with one or two groups selected from halogen, hydroxy, Ci _-6 alkyl, Ci _-6 fluoroalkyl, C _3-6 cycloalkyl, -C0 ₂ H, -Ci _-6 alkyl-C0 ₂ H, and -C(0) H ₂ . In another embodiment is a compound of Formula (IV), wherein R ⁴ is optionally substituted heteroaryl and the heteroaryl is a 5-6 membered heteroaryl ring. In another embodiment is a compound of Formula (IV), wherein R ⁴ is a 5-6 membered heteroaryl ring optionally substituted with one or two groups selected from halogen, hydroxy, Ci _-6 alkyl, -Ci. ₆ alkyl-OH, Ci _-6 fluoroalkyl, C _3-6 cycloalkyl, -C0 ₂ H, -Ci _-6 alkyl-C0 ₂ H, -C(0)Ci _-6 alkyl, -C(0)d. ₆ alkyl-OH, -N(H)C(0)Ci _-6 alkyl, -C(0) H ₂ , -C(0)N(H)(Ci _-6 alkyl), -C(0)N(Ci _-6 alkyl) ₂ , - C(0)C _2-7 heterocycloalkyl, and -S(0) ₂ Ci- ₆ alkyl. In another embodiment is a compound of Formula (IV), wherein R ⁴ is a 5-6 membered heteroaryl ring optionally substituted with one or two groups selected from halogen, Ci _-6 alkyl, -Ci _-6 alkyl-OH, Ci _-6 fluoroalkyl, -C0 ₂ H, -Ci _-6 alkyl- C0 ₂ H. In another embodiment is a compound of Formula (IV), wherein R ⁴ is a 5-membered heteroaryl ring optionally substituted with one or two groups selected from halogen, hydroxy, Ci _-6 alkyl, -Ci _-6 alkyl-OH, Ci _-6 fluoroalkyl, C _3-6 cycloalkyl, -C0 ₂ H, -Ci _-6 alkyl-C0 ₂ H, -C(0)d. ₆ alkyl, -C(0)Ci _-6 alkyl-OH, -N(H)C(0)Ci _-6 alkyl, -C(0) H ₂ , -C(0)N(H)(Ci _-6 alkyl), -C(0)N(d. ₆ alkyl) ₂ , -C(0)C _2-7 heterocycloalkyl, and -S(0) ₂ Ci- ₆ alkyl. In another embodiment is a compound of Formula (IV), wherein R ⁴ is a 5-membered heteroaryl ring optionally substituted with one or two groups selected from halogen, -Ci- ₆ alkyl-OH, Ci-efluoroalkyl, -C0 ₂ H, -Ci- ₆ alkyl- C0 ₂ H. In another embodiment is a compound of Formula (IV), wherein R ⁴ is a 6-membered heteroaryl ring optionally substituted with one or two groups selected from halogen, hydroxy, Ci _-6 alkyl, -Ci _-6 alkyl-OH, Ci _-6 fluoroalkyl, C _3-6 cycloalkyl, -C0 ₂ H, -Ci _-6 alkyl-C0 ₂ H, -C(0)d. ₆ alkyl, -C(0)Ci _-6 alkyl-OH, -N(H)C(0)Ci _-6 alkyl, -C(0) H ₂ , -C(0)N(H)(Ci _-6 alkyl), -C(0)N(d. ₆ alkyl) ₂ , -C(0)C _2-7 heterocycloalkyl, and -S(0) ₂ Ci- ₆ alkyl. In another embodiment is a compound of Formula (IV), wherein R ⁴ is a 6-membered heteroaryl ring optionally substituted with one or two groups selected from halogen, Ci _-6 alkyl, -Ci _-6 alkyl-OH, Ci _-6 fluoroalkyl, -C0 H, -Ci _-6 alkyl-

(IV), wherein R ⁴ is optionally substituted Ci _-6 alkyl-heterocycloalkyl. In another embodiment is a compound of Formula (IV), wherein R ⁴ is optionally substituted heterocycloalkyl. In another embodiment is a compound of Formula (IV), wherein R ⁴ is heterocycloalkyl optionally substituted with one or more groups selected from halogen, hydroxy, -Ci- ₆ alkyl-OH, Ci _-6 fluoroalkyl, C _3-6 cycloalkyl, heteroaryl, -C0 ₂ H, -Ci _-6 alkyl-C0 ₂ H, -C(0)Ci _-6 alkyl, -C(0)d. ₆ alkyl-OH, -N(H)C(0)C _1-6 alkyl, -C(0) H ₂ , -C(0)N(H)(C _1-6 alkyl), -C(0)N(C _1-6 alkyl) ₂ , - C(0)C _2-7 heterocycloalkyl, and -S(0) ₂ Ci- ₆ alkyl. In another embodiment is a compound of Formula (IV), wherein R ⁴ is heterocycloalkyl optionally substituted with one or two groups selected from halogen, hydroxy, Ci _-6 alkyl, -Ci _-6 alkyl-OH, Ci _-6 fluoroalkyl, C _3-6 cycloalkyl, heteroaryl, -C0 ₂ H, -Ci _-6 alkyl-C0 ₂ H, -C(0)Ci _-6 alkyl, -C(0)Ci _-6 alkyl-OH, -N(H)C(0)Ci _-6 alkyl, - C(0) H ₂ , -C(0)N(H)(Ci _-6 alkyl), -C(0)N(Ci _-6 alkyl) ₂ , -C(0)C _2-7 heterocycloalkyl, and -S(0) ₂ Ci. ₆ alkyl. In another embodiment is a compound of Formula (IV), wherein R ⁴ is optionally substituted heterocycloalkyl and the heterocycloalkyl is a 4-6 membered monocyclic heterocycloalkyl, a 8-9 membered bicyclic heterocycloalkyl, a 7-8 membered bridged heterocycloalkyl, a 5,5 fused heterocycloalkyl, or an 8-11 membered spirocyclic heterocycloalkyl. In another embodiment is a compound of Formula (IV), wherein R ⁴ is an optionally substituted 4-6 membered monocyclic heterocycloalkyl. In another embodiment is a compound of Formula (IV), wherein R ⁴ is an optionally substituted 8-9 membered bicyclic heterocycloalkyl. In another embodiment is a compound of Formula (IV), wherein R ⁴ is an optionally substituted 7-8 membered bridged heterocycloalkyl. In another embodiment is a compound of Formula (IV), wherein R ⁴ is an optionally substituted 5,5 fused heterocycloalkyl. In another embodiment is a compound of Formula (IV), wherein R ⁴ is an optionally substituted 8-11 membered spirocyclic heterocycloalkyl. In another embodiment is a compound of Formula

4 ~\~ ⁿ /

(IV), wherein R is optionally substituted heterocycloalkyl selected from \— / ,

/— \ F /— /— \ /— \ /— \ O /— \ O

In another embodiment is a compound of Formula (IV), wherein R ⁴ is -

OR ⁷ . In another embodiment is a compound of Formula (IV), wherein R ⁴ is -OR ⁷ , and R ⁷ is H, Ci _-6 alkyl, a phenyl optionally substituted with halogen, Ci _-6 alkyl, Ci _-6 fluoroalkyl, or Ci _-6 alkoxy, a Ci _-6 alkyl-phenyl optionally substituted with halogen, Ci _-6 alkyl, Ci _-6 fluoroalkyl, or Ci _-6 alkoxy, a heteroaryl optionally substituted with halogen, or Ci-efluoroalkyl, a 5-6 membered monocyclic heterocycloalkyl optionally substituted with halogen, Ci-efluoroalkyl, or C _3-6 cycloalkyl, or a In another embodiment is a compound of Formula (IV), wherein R ⁴ is -OR ⁷ , and R ⁷ is Ci _-6 alkyl. In another embodiment is a compound of Formula (IV), wherein R ⁴ is -OR ⁷ , and R ⁷ is optionally substituted phenyl. In another embodiment is a compound of Formula (IV), wherein R ⁴ is -OR ⁷ , and R ⁷ is phenyl optionally substituted with halogen, Ci _-6 alkyl, Ci _-6 fluoroalkyl, or Ci _-6 alkoxy. In another embodiment is a compound of Formula (IV), wherein R ⁴ is -OR ⁷ , and R ⁷ is optionally substituted Ci _-6 alkyl-phenyl. In another embodiment is a compound of Formula (IV), wherein R ⁴ is -OR ⁷ , and R ⁷ is

optionally substituted with halogen, Ci-efluoroalkyl, or Ci _-6 alkoxy. In another embodiment is a compound of Formula (IV), wherein R ⁴ is -OR ⁷ , and R ⁷ is optionally substituted heteroaryl. In another embodiment is a compound of Formula (IV), wherein R ⁴ is - OR ⁷ , and R ⁷ is heteroaryl optionally substituted with halogen, or Ci-efluoroalkyl. In another embodiment is a compound of Formula (IV), wherein R ⁴ is -OR ⁷ , and R ⁷ is optionally substituted heterocycloalkyl. In another embodiment is a compound of Formula (IV), wherein R ⁴ is -OR ⁷ , and R ⁷ is a 5-6 membered monocyclic heterocycloalkyl optionally substituted with halogen, Ci _-6 alkyl, Ci _-6 fluoroalkyl, or C _3-6 cycloalkyl. In another embodiment is a compound of Formula (IV), wherein R ⁴ is -OR ⁷ , and R ⁷ is -Ci _-6 alkylC(O) R ¹⁰ R ^u . In another embodiment is a compound of Formula (IV), wherein R ⁴ is -OR ⁷ , and R ⁷ is -Ci _-6 alkylC(O) R ¹⁰ R ¹¹ , and R ¹⁰ and R ¹² are each independently H, or Ci _-6 alkyl. In another embodiment is a compound of Formula (IV), wherein R ⁴ is -OR ⁷ , and R ⁷ is -Ci _-6 alkylC(O)NR ¹⁰ R ¹¹ , and R ¹⁰ and R ¹¹ together with the nitrogen to which they are attached are combined to form a heterocycloalkyl ring. In another embodiment is a compound of Formula (IV), wherein R ⁴ is -OR ⁷ , and R ⁷ is

In another embodiment is a compound of Formula (IV), wherein R ⁴ is -OR ⁷ , and R ⁷ is or \— / . In another embodiment is a compound of Formula (IV), wherein R ⁴ is -CO ₂ H. In another embodiment is a compound of Formula (IV), wherein R ⁴ is -C(0)NR ⁸ R ⁹ . In another embodiment is a compound of Formula (IV), wherein R ⁴ is -C(0) R ⁸ R ⁹ , and R ⁸ and R ⁹ are each independently H, or Ci _-6 alkyl. In another embodiment is a compound of Formula

4 9 8 9

(IV), wherein R" -C(0 8

is ) R°R ^: ', and R° and R ^* are H. In another embodiment is a compound of Formula (IV), wherein R ⁴ is -C(0) R ⁸ R ⁹ , and R ⁸ is H and R ⁹ are Ci _-6 alkyl. In another embodiment is a compound of Formula (IV), wherein R 4 is -C(0) R 8 R 9 , and R 8 and R 9 are Ci. ₆ alkyl. In another embodiment is a compound of Formula (IV), wherein R ⁴ is -C(0)NR ⁸ R ⁹ , and R ⁸ and R ⁹ together with the nitrogen to which they are attached are combined to form an optionally substituted heterocycloalkyl ring. In another embodiment is a compound of Formula

(IV), wherein R 4 is -C(0) R 8 R 9 , and R 8 and R 9 together with the nitrogen to which they are attached are combined to form an unsubstituted heterocycloalkyl ring.

[0089] In another embodiment is a compound of Formula (IV), wherein R ⁵ is H. In another embodiment is a compound of Formula (IV), wherein R ⁵ is halogen. In another embodiment is a compound of Formula (IV), wherein R ⁵ is -CI. In another embodiment is a compound of

Formula (IV), wherein R ⁵ is -F. In another embodiment is a compound of Formula (IV), wherein R ⁵ is Ci _-6 alkyl. In another embodiment is a compound of Formula (IV), wherein R ⁵ is Ci- ₆ haloalkyl. In another embodiment is a compound of Formula (IV), wherein R ⁵ is -CF ₃ . In another embodiment is a compound of Formula (IV), wherein R ⁵ is phenyl

[0090] In another embodiment is a compound of Formula (IV), wherein R ⁶ is H. In another embodiment is a compound of Formula (IV), wherein R ⁶ is halogen. In another embodiment is a compound of Formula (IV), wherein R ⁶ is -CI. In another embodiment is a compound of

Formula (IV), wherein R ⁶ is -F. In another embodiment is a compound of Formula (IV), wherein R ⁶ is Ci _-6 alkyl.

[0091] Further embodiments provided herein include combinations of one or more of the particular embodiments set forth above.

[0092] In some embodiments, the compound disclosed herein is selected from:

-62-

-63 -

-64-

-65 -

-67-

-68 -

-69-

-70-

-71 -

N-oxide, or pharmaceutically acceptable salt thereof.

Preparation of Compounds

[0093] The compounds used in the reactions described herein are made according to organic synthesis techniques, starting from commercially available chemicals and/or from compounds described in the chemical literature. "Commercially available chemicals" are obtained from standard commercial sources including Acros Organics (Geel, Belgium), Aldrich Chemical (Milwaukee, WI, including Sigma Chemical and Fluka), Apin Chemicals Ltd. (Milton Park, UK), Ark Pharm, Inc. (Libertyville, IL), Avocado Research (Lancashire, U.K.), BDH Inc. (Toronto, Canada), Bionet (Cornwall, U.K.), Chemservice Inc. (West Chester, PA), Combi-blocks (San Diego, CA), Crescent Chemical Co. (Hauppauge, NY), eMolecules (San Diego, CA), Fisher Scientific Co. (Pittsburgh, PA), Fisons Chemicals (Leicestershire, UK), Frontier Scientific (Logan, UT), ICN Biomedicals, Inc. (Costa Mesa, CA), Key Organics (Cornwall, U.K.), Lancaster Synthesis (Windham, NH), Matrix Scientific, (Columbia, SC), Maybridge Chemical Co. Ltd. (Cornwall, U.K.), Parish Chemical Co. (Orem, UT), Pfaltz & Bauer, Inc. (Waterbury, CN), Polyorganix (Houston, TX), Pierce Chemical Co. (Rockford, IL), Riedel de Haen AG (Hanover, Germany), Ryan Scientific, Inc. (Mount Pleasant, SC), Spectrum Chemicals (Gardena, CA), Sundia Meditech, (Shanghai, China), TCI America (Portland, OR), Trans World Chemicals, Inc. (Rockville, MD), and WuXi (Shanghai, China).

[0094] Suitable reference books and treatise that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation, include for example, "Synthetic Organic Chemistry", John Wiley & Sons, Inc., New York; S. R. Sandler et al., "Organic Functional Group Preparations," 2nd Ed., Academic Press, New York, 1983; H. O. House, "Modern Synthetic Reactions", 2nd Ed., W. A. Benjamin, Inc. Menlo Park, Calif. 1972; T. L. Gilchrist, "Heterocyclic Chemistry", 2nd Ed., John Wiley & Sons, New York, 1992; J. March, "Advanced Organic Chemistry: Reactions, Mechanisms and Structure", 4th Ed., Wiley-Interscience, New York, 1992. Additional suitable reference books and treatise that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation, include for example, Fuhrhop, J. and Penzlin G. "Organic Synthesis: Concepts, Methods, Starting Materials", Second, Revised and Enlarged Edition (1994) John Wiley & Sons ISBN: 3-527-29074-5; Hoffman, R.V. "Organic Chemistry, An Intermediate Text" (1996) Oxford University Press, ISBN 0-19-509618-5;

Larock, R. C. "Comprehensive Organic Transformations: A Guide to Functional Group

Preparations" 2nd Edition (1999) Wiley- VCH, ISBN: 0-471-19031-4; March, J. "Advanced Organic Chemistry: Reactions, Mechanisms, and Structure" 4th Edition (1992) John Wiley & Sons, ISBN: 0-471-60180-2; Otera, J. (editor) "Modern Carbonyl Chemistry" (2000) Wiley- VCH, ISBN: 3-527-29871-1; Patai, S. "Patai's 1992 Guide to the Chemistry of Functional Groups" (1992) Interscience ISBN: 0-471-93022-9; Solomons, T. W. G. "Organic Chemistry" 7th Edition (2000) John Wiley & Sons, ISBN: 0-471-19095-0; Stowell, J.C., "Intermediate Organic Chemistry" 2nd Edition (1993) Wiley-Interscience, ISBN: 0-471-57456-2; "Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia" (1999) John Wiley & Sons, ISBN: 3-527-29645-X, in 8 volumes; "Organic Reactions" (1942-2000) John Wiley & Sons, in over 55 volumes; and "Chemistry of Functional Groups" John Wiley & Sons, in 73 volumes.

[0095] Specific and analogous reactants are also identified through the indices of known chemicals prepared by the Chemical Abstract Service of the American Chemical Society, which are available in most public and university libraries, as well as through on-line databases (the American Chemical Society, Washington, D.C.). Chemicals that are known but not commercially available in catalogs are prepared by custom chemical synthesis houses, where many of the standard chemical supply houses (e.g., those listed above) provide custom synthesis services. A reference for the preparation and selection of pharmaceutical salts of the pyrazole compounds described herein is P. H. Stahl & C. G. Wermuth "Handbook of Pharmaceutical Salts", Verlag Helvetica Chimica Acta, Zurich, 2002.

Further Forms of Pyrazole Compounds Disclosed Herein

Isomers

[0096] Furthermore, in some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein possess one or more double bonds. The compounds presented herein include all cis, trans, syn, anti, entgegen (£), and zusammen (Z) isomers as well as the corresponding mixtures thereof. In some situations, compounds exist as tautomers. The compounds described herein include all possible tautomers within the formulas described herein. In some situations, the compounds described herein possess one or more chiral centers and each center exists in the R configuration, or S

configuration. The compounds described herein include all diastereomeric, enantiomeric, and epimeric forms as well as the corresponding mixtures thereof. In additional embodiments of the compounds and methods provided herein, mixtures of enantiomers and/or diastereoisomers, resulting from a single preparative step, combination, or interconversion are useful for the applications described herein. In some embodiments, the compounds described herein are prepared as optically pure enantiomers by chiral chromatographic resolution of the racemic mixture. In some embodiments, the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers and recovering the optically pure enantiomers. In some embodiments, dissociable complexes are preferred (e.g., crystalline diastereomeric salts). In some embodiments, the diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and are separated by taking advantage of these dissimilarities. In some embodiments, the

diastereomers are separated by chiral chromatography, or preferably, by separation/resolution techniques based upon differences in solubility. In some embodiments, the optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that would not result in racemization. Labeled compounds

[0097] In some embodiments, the compounds described herein exist in their

isotopically-labeled forms. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds. In some

embodiments, the methods disclosed herein include methods of treating diseases by

administering such isotopically-labeled compounds as pharmaceutical compositions. Thus, in some embodiments, the compounds disclosed herein include isotopically-labeled compounds, which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that are incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine and chloride, such as ² H, ³ H, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ 0, ¹⁷ 0, ³¹ P, ³² P, ³⁵ S, ¹⁸ F, and ³⁶ C1, respectively. Compounds described herein, and the metabolites, pharmaceutically acceptable salts, esters, prodrugs, solvate, hydrates or derivatives thereof which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention. Certain isotopically-labeled compounds, for example those into which radioactive isotopes such as ³ H and ¹⁴ C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i. e., ³ H and carbon-14, i. e., ¹⁴ C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavy isotopes such as deuterium, i.e., ² H, produces certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements. In some embodiments, the isotopically labeled compounds, pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof is prepared by any suitable method.

[0098] In some embodiments, the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.

Pharmaceutically acceptable salts

[0099] In some embodiments, the compounds described herein exist as their pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts. In some

embodiments, the methods disclosed herein include methods of treating diseases by

administering such pharmaceutically acceptable salts as pharmaceutical compositions.

[00100] In some embodiments, the compounds described herein possess acidic or basic groups and therefore react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compounds of the invention, or by separately reacting a purified compound in its free form with a suitable acid or base, and isolating the salt thus formed.

Solvates

[00101] In some embodiments, the compounds described herein exist as solvates. The invention provides for methods of treating diseases by administering such solvates. The invention further provides for methods of treating diseases by administering such solvates as pharmaceutical compositions.

[00102] Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and, in some embodiments, are formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein are conveniently prepared or formed during the processes described herein. By way of example only, hydrates of the compounds described herein are conveniently prepared by recrystallization from an aqueous/organic solvent mixture, using organic solvents including, but not limited to, dioxane, tetrahydrofuran or MeOH. In addition, the compounds provided herein exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.

Prodrugs

[00103] In some embodiments, the compounds described herein exist in prodrug form. The invention provides for methods of treating diseases by administering such prodrugs. The invention further provides for methods of treating diseases by administering such prodrugs as pharmaceutical compositions.

[00104] In some embodiments, prodrugs include compounds wherein an amino acid residue, or a polypeptide chain of two or more {e.g., two, three or four) amino acid residues is covalently joined through an amide or ester bond to a free amino, hydroxy or carboxylic acid group of compounds of the present invention. The amino acid residues include but are not limited to the 20 naturally occurring amino acids and also includes 4-hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methylhistidine, norvaline, beta-alanine, gamma-aminobutyric acid, cirtulline, homocysteine, homoserine, ornithine and methionine sulfone. In other embodiments, prodrugs include compounds wherein a nucleic acid residue, or an oligonucleotide of two or more {e.g., two, three or four) nucleic acid residues is covalently joined to a compound of the present invention. [00105] Pharmaceutically acceptable prodrugs of the compounds described herein also include, but are not limited to, esters, carbonates, thiocarbonates, N-acyl derivatives, N-acyloxyalkyl derivatives, quaternary derivatives of tertiary amines, N-Mannich bases, Schiff bases, amino acid conjugates, phosphate esters, metal salts and sulfonate esters. In some embodiments, compounds having free amino, amido, hydroxy or carboxylic groups are converted into prodrugs. For instance, free carboxyl groups are derivatized as amides or alkyl esters. In certain instances, all of these prodrug moieties incorporate groups including but not limited to ether, amine and carboxylic acid functionalities.

[00106] Hydroxy prodrugs include esters, such as though not limited to, acyloxyalkyl (e.g. acyloxym ethyl, acyloxyethyl) esters, alkoxycarbonyloxyalkyl esters, alkyl esters, aryl esters, phosphate esters, sulfonate esters, sulfate esters and disulfide containing esters; ethers, amides, carbamates, hemi succinates, dimethylaminoacetates and phosphoryloxymethyloxycarbonyls, as outlined in Advanced Drug Delivery Reviews 1996, 19, 115.

[00107] Amine derived prodrugs include, but are not limited to the following groups and combinations of groups:

as well as sulfonamides and phosphonamides.

[00108] In certain instances, sites on any aromatic ring portions are susceptible to various metabolic reactions, therefore incorporation of appropriate substituents on the aromatic ring structures, reduce, minimize or eliminate this metabolic pathway.

Metabolites

[00109] In some embodiments, pyrazole compounds described herein are susceptible to various metabolic reactions. Therefore, in some embodiments, incorporation of appropriate substituents into the structure will reduce, minimize, or eliminate a metabolic pathway. In specific embodiments, the appropriate substituent to decrease or eliminate the susceptibility of an aromatic ring to metabolic reactions is, by way of example only, a halogen, or an alkyl group. [00110] In additional or further embodiments, pyrazole compounds described herein are metabolized upon administration to an organism in need to produce a metabolite that is then used to produce a desired effect, including a desired therapeutic effect.

Pharmaceutical Compositions

[00111] In certain embodiments, the compound of Formula (I), (la), (II), (Ila), (III), or (IV) as described herein is administered as a pure chemical. In some embodiments, the compound of Formula (I), (la), (II), (Ila), (III), or (IV) described herein is combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, physiologically suitable (or acceptable) excipient, or physiologically suitable (or acceptable) carrier) selected on the basis of a chosen route of administration and standard pharmaceutical practice as described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21 ^st Ed. Mack Pub. Co., Easton, PA (2005)).

[00112] Accordingly, provided herein is a pharmaceutical composition comprising at least one compound of Formula (I), (la), (II), (Ila), (III), or (IV) described herein, or a stereoisomer, pharmaceutically acceptable salt, hydrate, solvate, or N-oxide thereof, together with one or more pharmaceutically acceptable carriers. The carrier(s) (or excipient(s)) is acceptable or suitable if the carrier is compatible with the other ingredients of the composition and not deleterious to the recipient {i.e., the subject) of the composition.

[00113] One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula (I), or a pharmaceutically acceptable salt thereof. One embodiment provides a pharmaceutical composition comprising a

pharmaceutically acceptable excipient and a compound of Formula (la), or a pharmaceutically acceptable salt thereof.

[00114] One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula (II), or a pharmaceutically acceptable salt thereof. One embodiment provides a pharmaceutical composition comprising a

pharmaceutically acceptable excipient and a compound of Formula (Ila), or a pharmaceutically acceptable salt thereof.

[00115] Another embodiment provides a pharmaceutical composition consisting essentially of a pharmaceutically acceptable excipient and a compound of Formula (I), or a pharmaceutically acceptable salt thereof. Another embodiment provides a pharmaceutical composition consisting essentially of a pharmaceutically acceptable excipient and a compound of Formula (II), or a pharmaceutically acceptable salt thereof. Another embodiment provides a pharmaceutical composition consisting essentially of a pharmaceutically acceptable excipient and a compound of Formula (la), or a pharmaceutically acceptable salt thereof. Another embodiment provides a pharmaceutical composition consisting essentially of a pharmaceutically acceptable excipient and a compound of Formula (Ha), or a pharmaceutically acceptable salt thereof.

[00116] In certain embodiments, the compound of Formula (I), (la), (II), (Ha), (III), or (IV) as described herein is substantially pure, in that it contains less than about 5%, or less than about 1%, or less than about 0.1%, of other organic small molecules, such as contaminating

intermediates or by-products that are created, for example, in one or more of the steps of a synthesis method.

[00117] These formulations include those suitable for oral, rectal, topical, buccal, parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous), vaginal, or aerosol

administration, although the most suitable form of administration in any given case will depend on the degree and severity of the condition being treated and on the nature of the particular compound being used. For example, disclosed compositions are formulated as a unit dose, and/or are formulated for oral or subcutaneous administration.

[00118] Exemplary pharmaceutical compositions are used in the form of a pharmaceutical preparation, for example, in solid, semisolid or liquid form, which includes one or more of a disclosed compound, as an active ingredient, in admixture with an organic or inorganic carrier or excipient suitable for external, enteral or parenteral applications. In some embodiments, the active ingredient is compounded, for example, with the usual non-toxic, pharmaceutically acceptable carriers for tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, and any other form suitable for use. The active object compound is included in the

pharmaceutical composition in an amount sufficient to produce the desired effect upon the process or condition of the disease.

[00119] In some embodiments for preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical carrier, e.g., conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, di calcium phosphate or gums, and other pharmaceutical diluents, e.g., water, to form a solid

preformulation composition containing a homogeneous mixture of a disclosed compound or a non-toxic pharmaceutically acceptable salt thereof. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition is readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.

[00120] In solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules and the like), the subject composition is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, hypromellose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as crospovidone, croscarmellose sodium, sodium starch glycolate, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, docusate sodium, cetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such a talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and (10) coloring agents. In the case of capsules, tablets and pills, in some embodiments, the compositions comprise buffering agents. In some embodiments, solid compositions of a similar type are also employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.

[00121] In some embodiments, a tablet is made by compression or molding, optionally with one or more accessory ingredients. In some embodiments, compressed tablets are prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent. In some embodiments, molded tablets are made by molding in a suitable machine a mixture of the subject composition moistened with an inert liquid diluent. In some embodiments, tablets, and other solid dosage forms, such as dragees, capsules, pills and granules, are scored or prepared with coatings and shells, such as enteric coatings and other coatings.

[00122] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the subject composition, in some embodiments, the liquid dosage forms contain inert diluents, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, cyclodextrins and mixtures thereof.

[00123] In some embodiments, suspensions, in addition to the subject composition, contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

[00124] In some embodiments, formulations for rectal or vaginal administration are presented as a suppository, which are prepared by mixing a subject composition with one or more suitable non-irritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the body cavity and release the active agent.

[00125] Dosage forms for transdermal administration of a subject composition include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. In some embodiments, the active component is mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants as required.

[00126] In some embodiments, the ointments, pastes, creams and gels contain, in addition to a subject composition, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.

[00127] In some embodiments, powders and sprays contain, in addition to a subject composition, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. In some embodiments, sprays additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

[00128] In some embodiments, the compounds described herein are formulated as eye drops for ophthalmic administration.

[00129] Compositions and compounds disclosed herein alternatively are administered by aerosol. This is accomplished by preparing an aqueous aerosol, liposomal preparation or solid particles containing the compound. In some embodiments, a non-aqueous (e.g., fluorocarbon propellant) suspension is used. In some embodiments, sonic nebulizers are used because they minimize exposing the agent to shear, which results in degradation of the compounds contained in the subject compositions. Ordinarily, an aqueous aerosol is made by formulating an aqueous solution or suspension of a subject composition together with conventional pharmaceutically acceptable carriers and stabilizers. The carriers and stabilizers vary with the requirements of the particular subject composition, but typically include non-ionic surfactants (Tweens, Pluronics, or polyethylene glycol), innocuous proteins like serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars or sugar alcohols. Aerosols generally are prepared from isotonic solutions. [00130] Pharmaceutical compositions suitable for parenteral administration comprise a subject composition in combination with one or more pharmaceutically-acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders which are reconstituted into sterile injectable solutions or dispersions just prior to use, which, in some embodiments, contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.

[00131] Examples of suitable aqueous and non-aqueous carriers which are employed in the pharmaceutical compositions include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and inj ectable organic esters, such as ethyl oleate and cyclodextrins. Proper fluidity is maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants

[00132] Also contemplated are enteral pharmaceutical formulations including a disclosed compound and an enteric material; and a pharmaceutically acceptable carrier or excipient thereof. Enteric materials refer to polymers that are substantially insoluble in the acidic environment of the stomach, and that are predominantly soluble in intestinal fluids at specific pHs. The small intestine is the part of the gastrointestinal tract (gut) between the stomach and the large intestine, and includes the duodenum, jejunum, and ileum. The pH of the duodenum is about 5.5, the pH of the jejunum is about 6.5 and the pH of the distal ileum is about 7.5.

Accordingly, enteric materials are not soluble, for example, until a pH of about 5.0, of about 5.2, of about 5.4, of about 5.6, of about 5.8, of about 6.0, of about 6.2, of about 6.4, of about 6.6, of about 6.8, of about 7.0, of about 7.2, of about 7.4, of about 7.6, of about 7.8, of about 8.0, of about 8.2, of about 8.4, of about 8.6, of about 8.8, of about 9.0, of about 9.2, of about 9.4, of about 9.6, of about 9.8, or of about 10.0. Exemplary enteric materials include cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose phthalate (HPMCP), polyvinyl acetate phthalate (PVAP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), cellulose acetate trimellitate, hydroxypropyl methylcellulose succinate, cellulose acetate succinate, cellulose acetate hexahydrophthalate, cellulose propionate phthalate, cellulose acetate maleate, cellulose acetate butyrate, cellulose acetate propionate, copolymer of methylmethacrylic acid and methyl methacrylate, copolymer of methyl acrylate, methylmethacrylate and methacrylic acid, copolymer of methylvinyl ether and maleic anhydride (Gantrez ES series), ethyl methyacrylate-methylmethacrylate-chlorotrimethylammonium ethyl acrylate copolymer, natural resins such as zein, shellac and copal collophorium, and several commercially available enteric dispersion systems (e.g., Eudragit L30D55, Eudragit FS30D, Eudragit L100, Eudragit S 100, Kollicoat EMM30D, Estacryl 30D, Coateric, and Aquateric). The solubility of each of the above materials is either known or is readily determinable in vitro.

[00133] The dose of the composition comprising at least one compound of Formula (I), (la), (II), (Ila), (III), or (IV) as described herein differs, depending upon the patient's {e.g., human) condition, that is, stage of the disease, general health status, age, and other factors.

[00134] Pharmaceutical compositions are administered in a manner appropriate to the disease to be treated (or prevented). An appropriate dose and a suitable duration and frequency of administration will be determined by such factors as the condition of the patient, the type and severity of the patient's disease, the particular form of the active ingredient, and the method of administration. In general, an appropriate dose and treatment regimen provides the

composition(s) in an amount sufficient to provide therapeutic and/or prophylactic benefit {e.g., an improved clinical outcome, such as more frequent complete or partial remissions, or longer disease-free and/or overall survival, or a lessening of symptom severity. Optimal doses are generally determined using experimental models and/or clinical trials. In some embodiments, the optimal dose depends upon the body mass, weight, or blood volume of the patient.

[00135] Oral doses typically range from about 1.0 mg to about 1000 mg, one to four times, or more, per day.

Methods

[00136] Disclosed herein are methods of modulating the activity of MAGL and/or ABHD6. Contemplated methods, for example, comprise exposing said enzyme to a compound described herein. In some embodiments, the compound utilized by one or more of the foregoing methods is one of the generic, subgeneric, or specific compounds described herein, such as a compound of Formula (I), (la), (II), (Ila), (III), or (IV). In some embodiments, provided herein is a compound of Formula (I), (la), (II), (Ila), (III), or (IV) wherein the compound is a MAGL inhibitor. In some embodiments, provided herein is a compound of Formula (I), (la), (II), (Ila), (III), or (IV) wherein the compound is a selective MAGL inhibitor. In some embodiments, provided herein is a compound of Formula (I), (la), (II), (Ila), (III), or (IV) wherein the compound is a ABHD6 inhibitor. In some embodiments, provided herein is a compound of Formula (I), (la), (II), (Ila), (III), or (IV) wherein the compound is a selective ABHD6 inhibitor. The ability of compounds described herein to modulate or inhibit MAGL and/or ABHD6 is evaluated by procedures known in the art and/or described herein. Another aspect of this disclosure provides methods of treating a disease associated with expression or activity of MAGL and/or ABHD6 in a patient. In some embodiments, provided herein is a compound of Formula (I), (la), (II), (Ila), (III), or (IV) wherein the compound is selective in inhibiting MAGL or ABHD6, or both, as compared to inhibition of other serine hydrolases. In some embodiments, provided herein is a compound of Formula (I), (la), (II), (Ila), (III), or (IV) wherein the compound is 10, 100, or 1000 fold selective in inhibiting MAGL or ABHD6, or both, as compared to inhibition of other serine hydrolases. In some embodiments, provided herein is a compound of Formula (I), (la), (II), (Ila), (III), or (IV) wherein the compound is 10, 100, or 1000 fold selective in inhibiting MAGL or ABHD6, or both, as compared to inhibition of FAAH. In some embodiments, provided herein is a compound of Formula (I), (la), (II), (Ila), (III), or (IV) wherein the compound is selective in inhibition of MAGL as compared to ABHD6.

[00137] In another embodiment is a method of treating a disease or disorder selected from the group consisting of multiple sclerosis, Alzheimer's disease, and inflammatory bowel disease, comprising administering a therapeutically effective amount of a compound of Formula (I), (la),

(II) , (Ila), (III), or (IV) described herein, or a solvate, hydrate, tautomer, N-oxide, or a pharmaceutically acceptable salt thereof, to a patient in need thereof. In some embodiments, the disease is multiple sclerosis. In some embodiments, the disease is Alzheimer's disease. In some embodiments, the disease is inflammatory bowel disease.

[00138] In another embodiment is a method of treating pain in a patient, comprising

administering a therapeutically effective amount of a compound of Formula (I), (la), (II), (Ila),

(III) , or (IV) described herein, or a solvate, hydrate, tautomer, N-oxide, or a pharmaceutically acceptable salt thereof, to a patient in need thereof to treat said pain. In another embodiment is a method of treating neuropathic pain in a patient, comprising administering a therapeutically effective amount of a compound of Formula (I), (la), (II), (Ila), (III), or (IV) described herein, or a solvate, hydrate, tautomer, N-oxide, or a pharmaceutically acceptable salt thereof, to a patient in need thereof to treat said neuropathic pain. In another embodiment is a method of treating inflammatory pain in a patient, comprising administering a therapeutically effective amount of a compound of Formula (I), (la), (II), (Ila), (III), or (IV) described herein, or a solvate, hydrate, tautomer, N-oxide, or a pharmaceutically acceptable salt thereof, to a patient in need thereof to treat said inflammatory pain.

[00139] Also contemplated herein in some embodiments are methods of treating and/or preventing in a patient in need thereof a disorder such as one or more of acute or chronic pain, bone cancer pain, rheumatoid arthritis pain, pruritus, vomiting or nausea, Down's syndrome, Parkinson's disease, epilepsy, NSAID-induced ulcers, opioid withdrawal, cannabis withdrawal, nicotine withdrawal, traumatic brain injury, ischemia, renal ischemia, cancers (e.g., solid tumor cancers such as breast, lung, head and neck, ovarian, sarcoma, melanoma, and/or prostate cancer); cancers such as melanoma, metastatic tumors, kidney or bladder cancers, brain, gastrointestinal cancers (e.g., colon cancer), leukemia or blood cancers (e.g., myeloid, lymphoid or monocytic cancers), liver injury, lung injury, skeletal muscle contusions, inflammatory disorders, and/or anxiety disorders. Contemplated methods include administering a pharmaceutically effective amount of a disclosed compound.

[00140] In some embodiments, provided herein is a method for treating, ameliorating and/or preventing damage from ischemia, for example, hepatic ischemia or reperfusion in a patient in need thereof, comprising administering a disclosed compound. Methods of treating patients with liver conditions resulting from oxidative stress and/or inflammatory damage are contemplated herein, e.g., contemplated herein are methods of treating liver fibrosis, iron overload, and/or corticosteroid therapy that result in liver damage, in a patient in need thereof.

[00141] In some embodiments, provide herein is a method for treating chronic pain such as inflammatory pain, visceral pain, back pain, post operative pain, and pain related to migraine, osteoarthritis, or rheumatoid arthritis.

[00142] In some embodiments, provide herein are methods for ameliorating cognitive function in a patient suffering from Down's syndrome or Alzheimer's disease, comprising administering an effective amount of a disclosed compound. Exemplary patients suffering from Down's syndrome are a pediatric patient (e.g., a patient of age 0-11 years, 0-18 years, 0-6 years, or e.g., 12 to 18 years), an adult patient (e.g., 18 years or older), or e.g., an older patient e.g., 18-40 years, 20-50 years). In some embodiments, such patients also suffer from further cognitive impairment and/or dementia, and/or seizures which, in some embodiments are due to production of prostaglandins and/or amyloid beta. For example, such patients also are suffering from, or have one or more of the following symptoms associated with early- mid or late stage cognitive impairment: loss of language, impairment of social skills, progressive loss of activities of daily living, and include psychotic behavior. Provided herein, for example, is a method for treating a patient having Down's syndrome or Alzheimer's disease with cognitive impairment, comprising administering an effective amount of a disclosed compound. Such disclosed methods result in cognitive improvement, for example, measured by IQ or the Arizona Cognitive Test Battery (e.g., measured with a cognitive test battery designed for use in individuals with Down's syndrome). For example, a treated patient using a disclosed method has at least one of:

increased memory, improved memory or improved speech. In some embodiments, such disclosed methods result in a patient having an increased quality of life as measured by an adaptive behavior scale after said administration.

[00143] In other embodiments, a method for at least partially providing a Down's syndrome patient a neuroprotective (such as a disclosed compounds), that results in delayed onset of neurodegeneration or substantially prevents neurodegeneration, is provided. Administration to a patient is initiated before onset of neurodegeneration and/or onset of neurodegeneration symptoms. Contemplated herein are methods for treating and/or ameliorating cognitive decline, improving sleep duration and/or quality, and/or treating PANDAS (pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections) in a patient in need thereof, comprising administering a disclosed compound.

[00144] In another embodiment is a method of treating a disease or disorder in a patient in need thereof, comprising administering to the patient in need thereof a therapeutically effective amount of a compound of Formula (I), (la), (II), (Ha), (III), or (IV) described herein, or a pharmaceutically acceptable salt or solvate thereof, wherein the disease or disorder is selected from the group consisting of epilepsy/seizure disorder, neuromyelitis optica (NMO), Tourette syndrome, persistent motor tic disorder, persistent vocal tic disorder, and abdominal pain associated with irritable bowel syndrome. In another embodiment is a method of treating epilepsy/seizure disorder in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), (la), (II), (Ila), (III), or (IV) described herein, or a pharmaceutically acceptable salt or solvate thereof. In another embodiment is a method of treating neuromyelitis optica (NMO) in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), (la), (II), (Ila), (III), or (IV) described herein, or a pharmaceutically acceptable salt or solvate thereof. In another embodiment is a method of treating Tourette syndrome in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), (la), (II), (Ila), (III), or (IV) described herein, or a pharmaceutically acceptable salt or solvate thereof. In another embodiment is a method of treating persistent motor tic disorder in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), (la), (II), (Ila), (III), or (IV) described herein, or a pharmaceutically acceptable salt or solvate thereof. In another embodiment is a method of treating persistent vocal tic disorder in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), (la), (II), (Ila), (III), or (IV) described herein, or a pharmaceutically acceptable salt or solvate thereof. In another embodiment is a method of treating abdominal pain associated with irritable bowel syndrome in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), (la), (II), (Ila), (III), or (IV) described herein, or a pharmaceutically acceptable salt or solvate thereof.

[00145] In another embodiment is a method of treating cancer pain, pain caused by peripheral neuropathy, central pain, fibromyalgia, migraine, vasoocclussive painful crises in sickle cell disease, functional chest pain, rheumatoid arthritis, osteoarthritis, functional dyspepsia, or spasticity, pain, sleep disturbance, or bladder dysfunction associated with multiple sclerosis, in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), (la), (II), (Ila), (III), or (IV) described herein, or a pharmaceutically acceptable salt or solvate thereof. In another embodiment is a method of treating cancer pain in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), (la), (II), (Ila), (III), or (IV) described herein, or a pharmaceutically acceptable salt or solvate thereof. In another

embodiment is a method of treating pain caused by peripheral neuropathy in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), (la), (II), (Ila), (III), or (IV) described herein, or a pharmaceutically acceptable salt or solvate thereof. In another embodiment is a method of treating central pain in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), (la), (II), (Ila), (III), or (IV) described herein, or a pharmaceutically acceptable salt or solvate thereof. In another embodiment is a method of treating fibromyalgia in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), (la), (II), (Ila), (III), or (IV) described herein, or a pharmaceutically acceptable salt or solvate thereof. In another

embodiment is a method of treating migraine in a patient in need thereof, comprising

administering to the patient a therapeutically effective amount of a compound of Formula (I), (la), (II), (Ila), (III), or (IV) described herein, or a pharmaceutically acceptable salt or solvate thereof. In another embodiment is a method of treating vasoocclussive painful crises in sickle cell disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), (la), (II), (Ila), (III), or (IV) described herein, or a pharmaceutically acceptable salt or solvate thereof. In another embodiment is a method of treating spasticity, pain, sleep disturbance, or bladder dysfunction associated with multiple sclerosis in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), (la), (II), (Ila), (III), or (IV) described herein, or a pharmaceutically acceptable salt or solvate thereof. In another embodiment is a method of treating functional chest pain in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), (la), (II), (Ila), (III), or (IV) described herein, or a pharmaceutically acceptable salt or solvate thereof. In another

embodiment is a method of treating rheumatoid arthritis in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), (la), (II), (Ila), (III), or (IV) described herein, or a pharmaceutically acceptable salt or solvate thereof. In another embodiment is a method of treating osteoarthritis in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), (la), (II), (Ila), (III), or (IV) described herein, or a pharmaceutically acceptable salt or solvate thereof. In another embodiment is a method of treating functional dyspepsia in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), (la), (II), (Ha), (III), or (IV) described herein, or a pharmaceutically acceptable salt or solvate thereof.

[00146] In another embodiment is a method of lowering intraocular eye pressure (IOP) in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), (la), (II), (Ila), (III), or (IV) described herein, or a pharmaceutically acceptable salt or solvate thereof. In another embodiment is a method of treating glaucoma in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), (la), (II), (Ila), (III), or (IV) described herein, or a pharmaceutically acceptable salt or solvate thereof.

[00147] In another embodiment is a method of treating atopic dermatitis in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), (la), (II), (Ila), (III), or (IV) described herein, or a pharmaceutically acceptable salt or solvate thereof.

[00148] In another embodiment is a method of treating pruritis in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), (la), (II), (Ila), (III), or (IV) described herein, or a pharmaceutically acceptable salt or solvate thereof.

[00149] In some embodiments, disclosed herein is a method of synergistically potentiating the activity of an opioid analgesic in a patient being treated with an opioid analgesic, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), (la), (II), (Ila), (III), or (IV) described herein, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, disclosed herein is a method of reducing the acute side-effects associated with an opioid analgesic in a patient being treated with an opioid analgesic, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), (la), (II), (Ila), (III), or (IV) described herein, or a pharmaceutically acceptable salt or solvate thereof.

[00150] In certain embodiments, a disclosed compound utilized by one or more of the foregoing methods is one of the generic, subgeneric, or specific compounds described herein, such as a compound of Formula (I), (la), (II), (Ila), (III), or (IV).

[00151] Disclosed compounds are administered to patients (animals and humans) in need of such treatment in dosages that will provide optimal pharmaceutical efficacy. It will be appreciated that the dose required for use in any particular application will vary from patient to patient, not only with the particular compound or composition selected, but also with the route of administration, the nature of the condition being treated, the age and condition of the patient, concurrent medication or special diets then being followed by the patient, and other factors, with the appropriate dosage ultimately being at the discretion of the attendant physician. For treating clinical conditions and diseases noted above, a contemplated compound disclosed herein is administered orally, subcutaneously, topically, parenterally, by inhalation spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. Parenteral administration include subcutaneous injections, intravenous or intramuscular injections or infusion techniques.

[00152] Also contemplated herein are combination therapies, for example, co-administering a disclosed compound and an additional active agent, as part of a specific treatment regimen intended to provide the beneficial effect from the co-action of these therapeutic agents. The beneficial effect of the combination includes, but is not limited to, pharmacokinetic or pharmacodynamic co-action resulting from the combination of therapeutic agents.

Administration of these therapeutic agents in combination typically is carried out over a defined time period (usually weeks, months or years depending upon the combination selected).

Combination therapy is intended to embrace administration of multiple therapeutic agents in a sequential manner, that is, wherein each therapeutic agent is administered at a different time, as well as administration of these therapeutic agents, or at least two of the therapeutic agents, in a substantially simultaneous manner.

[00153] Substantially simultaneous administration is accomplished, for example, by

administering to the subj ect a single formulation or composition, (e.g., a tablet or capsule having a fixed ratio of each therapeutic agent or in multiple, single formulations (e.g., capsules) for each of the therapeutic agents. Sequential or substantially simultaneous administration of each therapeutic agent is effected by any appropriate route including, but not limited to, oral routes, intravenous routes, intramuscular routes, and direct absorption through mucous membrane tissues. The therapeutic agents are administered by the same route or by different routes. For example, a first therapeutic agent of the combination selected is administered by intravenous injection while the other therapeutic agents of the combination are administered orally.

Alternatively, for example, all therapeutic agents are administered orally or all therapeutic agents are administered by intravenous injection.

[00154] Combination therapy also embraces the administration of the therapeutic agents as described above in further combination with other biologically active ingredients and non-drug therapies. Where the combination therapy further comprises a non-drug treatment, the non-drug treatment is conducted at any suitable time so long as a beneficial effect from the co-action of the combination of the therapeutic agents and non-drug treatment is achieved. For example, in appropriate cases, the beneficial effect is still achieved when the non-drug treatment is temporally removed from the administration of the therapeutic agents, perhaps by days or even weeks.

[00155] The components of the combination are administered to a patient simultaneously or sequentially. It will be appreciated that the components are present in the same

pharmaceutically acceptable carrier and, therefore, are administered simultaneously.

Alternatively, the active ingredients are present in separate pharmaceutical carriers, such as, conventional oral dosage forms, that are administered either simultaneously or sequentially.

[00156] For example, e.g., for contemplated treatment of pain or other contemplated indications (e.g., Alzheimer's disease), a disclosed compound is co-administered with another therapeutic for pain such as an opioid, a cannabinoid receptor (CB-1 or CB-2) modulator, a COX-2 inhibitor, acetaminophen, and/or a non-steroidal anti-inflammatory agent. Additional therapeutics e.g., for the treatment of pain that are co-administered include morphine, codeine, hydromorphone, hydrocodone, oxymorphone, fentanyl, tramadol, and levorphanol.

[00157] Other contemplated therapeutics for co-administration include aspirin, naproxen, ibuprofen, salsalate, diflunisal, dexibuprofen, fenoprofen, ketoprofen, oxaprozin, loxoprofen, indomethacin, tolmetin, sulindac, etodolac, ketorolac, piroxicam, meloxicam, tenoxicam, droxicam, lornoxicam, celecoxib, parecoxib, rimonabant, and/or etoricoxib.

[00158] The following examples are provided merely as illustrative of various embodiments and shall not be construed to limit the invention in any way.

EXAMPLES

List of abbreviations

[00159] As used above, and throughout the description of the invention, the following abbreviations, unless otherwise indicated, shall be understood to have the following meanings:

ACN or MeCN acetonitrile

Bn benzyl

BOC or Boc tert-butyl carbamate

t-Bu tert-butyl

Cy cyclohexyl

DCE dichloroethane (C1CH ₂ CH ₂ C1)

DCM DCM (CH ₂ C1 ₂ )

DIPEA or DIEA diisopropylethylamine

DMAP 4-(N,N-dimethylamino)pyridine DMF dimethylformamide

DMA N,N-dimethylacetamide

DMSO dimethylsulfoxide

Dppf or dppf 1 , 1 '-bis(diphenylphosphino)ferrocene

equiv or eq equivalent(s)

Et ethyl

Et ₂ 0 diethyl ether

EtOH ethanol

EtOAc ethyl acetate

HPLC high performance liquid chromatography

LAH lithium aluminum anhydride

Me methyl

MeOH methanol

MS mass spectroscopy

NMM N-methyl-morpholine

MP N-methyl-pyrrolidin-2-one

MR nuclear magnetic resonance

RP-HPLC reverse phase-high pressure liquid chromatography

TFA trifluoroacetic acid

THF tetrahydrofuran

TLC thin layer chromatography

I. Chemical Synthesis

[00160] Unless otherwise noted, reagents and solvents were used as received from commercial suppliers. Anhydrous solvents and oven-dried glassware were used for synthetic transformations sensitive to moisture and/or oxygen. Yields were not optimized. Reaction times are approximate and were not optimized. Column chromatography and thin layer chromatography (TLC) were performed on silica gel unless otherwise noted. In some instances, compounds were purified using preparative HPLC on a Waters 2767-5 Chromatograph. Spectra are given in ppm (δ) and coupling constants (J) are reported in Hertz. For proton spectra the solvent peak was used as the reference peak. Example 1 : N-(l-(4-(2-(pyrrolidin-l-yl)-4-(trifluoromethyl)benzyl)piper azine-l-carbonyl)- lH-pyrazol-3-yl)acetamide

Step 1: Synthesis of 2-(pyrrolidin-l-yl)-4-(trifluoromethyl)benzaldehyde

[00161] A 250-mL round-bottom flask was charged with 2-fluoro-4-

(trifluoromethyl)benzaldehyde (10.0 g, 52.1 mmol, 1.00 equiv), DMSO (50 mL), pyrrolidine (5.55 g, 78.0 mmol, 1.50 equiv), and potassium carbonate (21.6 g, 156 mmol, 3.00 equiv) under nitrogen. The resulting solution was stirred overnight at 90 °C and quenched with water (150 mL). The resulting solution was extracted with EtOAc (2 x 250 mL) and the organic layers were combined, washed with brine (2 x 100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column to provide 4.70 g (37% yield) of 2-(pyrrolidin-l-yl)-4-(trifluoromethyl)benzaldehyde as a yellow solid. LCMS (ESI, m/z): 244 [M+H] ⁺ .

Step 2: Synthesis of tert-butyl 4-(2-(pyrrolidin-l-yl)-4-(trifluoromethyl)benzyl)piperazine- 1-carboxylate

[00162] A 250-mL round-bottom flask was charged with 2-(pyrrolidin-l-yl)-4- (trifluoromethyl)benzaldehyde (2.50 g, 10.3 mmol, 1.00 equiv), DCE (40 mL), and tert-butyl piperazine-l-carboxylate (2.30 g, 12.4 mmol, 1.10 equiv). The mixture was stirred for 1 h at room temperature. Sodium triacetoxyborohydride (6.55 g, 30.9 mmol, 3.00 equiv) was added. The resulting solution was stirred overnight at room temperature and quenched with water (100 mL). The resulting solution was extracted with DCM (2 x 150 mL) and the organic layers were combined, washed with brine (2 x 100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column to provide 2.50 g (59% yield) of tert-butyl 4-(2-(pyrrolidin-l-yl)-4- (trifluoromethyl)benzyl)piperazine-l-carboxylate as a yellow oil. LCMS (ESI, m/z): 414

[M+H] ⁺ . Step 3: Synthesis of l-(2-(pyrrolidin-l-yl)-4-(trifluoromethyl)benzyl)piperazine

[00163] A 100-mL round-bottom flask was charged with tert-butyl 4-(2-(pyrrolidin-l-yl)-4- (trifluoromethyl)benzyl)piperazine-l-carboxylate (2.50 g, 6.05 mmol, 1.00 equiv), DCM (20 mL), and TFA (10 mL). The resulting solution was stirred overnight at room temperature and concentrated under reduced pressure. The crude product was dissolved in 1M NaOH solution (10 mL) and extracted with DCM (3 x 20 mL). The organic layers were combined, washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to provide 1.80 g (95% yield) of l -(2-(pyrrolidin-l-yl)-4- (trifluoromethyl)benzyl)piperazine as a yellow oil. LCMS (ESI, m/z): 314 [M+H] ⁺ .

Step 4: Synthesis of 4-(2-(pyrrolidin-l-yl)-4-(trifluoromethyl)benzyl)piperazine- l-carbonyl chloride

[00164] A 100-mL round-bottom flask was charged with triphosgene (0.878 g, 2.96 mmol, 0.50 equiv) and DCM (15 mL). l-(2-(pyrrolidin-l-yl)-4-(trifluorom ethyl )benzyl)piperazine (1.85 g, 5.90 mmol, 1.00 equiv) was added at 0 °C. N,N-Diisopropylethylamine (2.29 g, 17.7 mmol, 3.00 equiv) was added dropwise at 0 °C. The resulting solution was stirred for 1 h at room

temperature and quenched with water (80 mL). The resulting solution was extracted with DCM (2 x 100 mL) and the organic layers were combined, washed with brine (2 x 100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to provide 3.00 g (crude) of 4-(2-(pyrrolidin-l-yl)-4-(trifluorom ethyl )benzyl)piperazine-l-carbonyl chloride as a yellow oil.

Step 5: Synthesis of (3-amino-lH-pyrazol-l-yl)(4-(2-(pyrrolidin-l-yl)-4- (trifluoromethyl)benzyl)piperazin-l-yl)methanone

, overn g

[00165] A 100-mL round-bottom flask was charged with 4-(2-(pyrrolidin-l-yl)-4- (trifluoromethyl)benzyl)piperazine-l-carbonyl chloride (3.50 g, 9.31 mmol, 1.00 equiv), THF (25 mL), lH-pyrazol-3-amine (0.927 g, 1 1.2 mmol, 1.20 equiv), N,N-diisopropylethylamine (3.60 g, 27.9 mmol, 3.00 equiv), and 4-dimethylaminopyridine (0.227 g, 1.86 mmol, 0.20 equiv). The resulting solution was stirred overnight at 60 °C and quenched with water (100 mL). The resulting solution was extracted with DCM (2 x 150 mL) and the organic layers were combined, dried over anhydrous sodium sulfate, washed with brine (2 x 100 mL), filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column to provide 1.70 g (43% yield) of (3-amino-lH-pyrazol-l-yl)(4-(2-(pyrrolidin-l-yl)-4- (trifluoromethyl)benzyl)piperazin-l-yl)methanone as a light yellow solid. LCMS (ESI, m/z): 423 [M+H] ⁺ .

Step 6: Synthesis of N-(l-(4-(2-(pyrrolidin-l-yl)-4-(trifluoromethyl)benzyl)piper azine-l- carbonyl)-lH-pyrazol-3-yl)acetamide

[00166] A 50-mL round-bottom flask was charged with (3-amino-lH-pyrazol-l-yl)(4-(2- (pyrrolidin-l-yl)-4-(trifluorom ethyl )benzyl)piperazin-l-yl)methanone (100 mg, 0.240 mmol, 1.00 equiv), DCM (10 mL), and triethylamine (48.0 mg, 0.470 mmol, 2.00 equiv). Acetyl chloride (28.0 mg, 0.360 mmol, 1.50 equiv) was added at 0 °C. The resulting solution was stirred overnight at room temperature and quenched with water (30 mL). The resulting solution was extracted with DCM (2 x 50 mL) and the organic layers were combined, dried over anhydrous sodium sulfate, washed with brine (2 x 30 mL), filtered and concentrated under reduced pressure. The crude product (300 mg) was purified by preparative HPLC. Purification resulted in 34.2 mg (31% yield) of N-(l -(4-(2-(pyrrolidin-l-yl)-4-(trifluorom ethyl )benzyl)piperazine-l- carbonyl)-lH-pyrazol-3-yl)acetamide as a light yellow solid. 1H MR (300 MHz, Chloroform- d) δ 8.01 (d, J= 2.7 Hz, 1H), 7.70 (br, 1H), 7.52 (br, 1H), 7.10 (br, 2H), 6.87 (d, J= 2.7 Hz, 1H), 3.84 (br, 4H), 3.59 (br, 2H), 3.24 (br, 4H), 2.53 (br, 4H), 2.17 (s, 3H), 1.93 - 2.01 (m, 4H). LCMS (ESI, m/z): 465 [M+H] ⁺ .

Example 2: N-methyl-N-(l-(4-(2-(pyrrolidin-l-yl)-4-(trifluoromethyl)ben zyl)piperazine-l- carbonyl)-lH-pyrazol-3-yl)acetamide

[00167] A 50-mL round-bottom flask was charged with N-(l-(4-(2-(pyrrolidin-l-yl)-4- (trifluoromethyl)benzyl)piperazine-l-carbonyl)-lH-pyrazol-3- yl)acetamide (Example 1, 100 mg, 0.220 mmol, 1.00 equiv), acetonitrile (10 mL), cesium carbonate (105 mg, 0.320 mmol, 1.50 equiv), and iodomethane (46.0 mg, 0.320 mmol, 1.50 equiv). The resulting solution was stirred overnight at room temperature and quenched with water (30 mL). The resulting solution was extracted with DCM (2 x 50 mL) and the organic layers were combined, dried over anhydrous sodium sulfate, washed with brine (2 x 30 mL), filtered and concentrated under reduced pressure. The crude product (300 mg) was purified by preparative HPLC. Purification resulted in 21.3 mg (21% yield) of N-methyl-N-(l-(4-(2-(pyrrolidin-l-yl)-4- (trifluoromethyl)benzyl)piperazine-l-carbonyl)-lH-pyrazol-3- yl)acetamide as a light yellow solid. 1H MR (300 MHz, OMSO-d ₆ ) δ 8.10 (d, J= 3.0 Hz, 1H), 7.53 - 7.56 (m, 1H), 7.06 - 7.10 (m, 2H), 6.60 (d, J= 3.0 Hz, 1H), 3.72 (t, J= 4.95 Hz, 4H), 3.61 (s, 2H), 3.24 - 3.28 (m, 7H), 2.47 - 2.51 (m, 4H), 2.10 (s, 3H), 1.85 - 1.95 (m, 4H). LCMS (ESI, m/z): 479 [M+H] ⁺ . Example 3: N-(l-(4-(2-morpholino-4-(trifluoromethyl)benzyl)piperazine-l -carbonyl)-lH- pyrazol-3-yl)acetamide

Step 1: Synthesis of -nitrophenyl 3-acetamido-lH-pyrazole-l-carboxylate

[00168] A 100-mL round-bottom flask was charged with 4-nitrophenyl carbonochloridate (3.54 g, 17.6 mmol, 1.10 equiv) in DCM (20 mL), N-(lH-pyrazol-3-yl)acetamide (2.00 g, 16.0 mmol, 1.00 equiv), and triethylamine (4.85 g, 48.0 mmol, 3.00 equiv) under nitrogen. The resulting solution was stirred for 3 h at room temperature and concentrated under reduced pressure to provide 5.60 g (crude) of 4-nitrophenyl 3-acetamido-lH-pyrazole-l-carboxylate as a yellow solid. LCMS (ESI, m/z): 291 [M+H] ⁺ .

Step 2: Synthesis of 2-mor holino-4-(trifluoromethyl)benzaldehyde

[00169] A 40-mL round-bottom flask was charged with 2-fluoro-4-

(trifluoromethyl)benzaldehyde (400 mg, 2.08 mmol, 1.00 equiv) in DMSO (10 mL), morpholine (272 mg, 3.12 mmol, 1.50 equiv), and potassium carbonate (862 mg, 6.24 mmol, 3.00 equiv) under nitrogen. The resulting solution was stirred overnight at 80 °C and quenched with water (10 mL). The resulting solution was extracted with EtOAc (3 x 10 mL) and the organic layers were combined, washed with brine (2 x 10 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column to provide 220 mg (41% yield) of 2-morpholino-4-(trifluorom ethyl )benzaldehyde as a yellow solid. LCMS (ESI, m/z): 260 [M+H] ⁺ .

Step 3: Synthesis of tert-butyl 4-(2-morpholino-4-(trifluoromethyl)benzyl)piperazine-l- carboxylate

[00170] A 40-mL round-bottom flask was charged with 2-(morpholin-4-yl)-4- (trifluoromethyl)benzaldehyde (1 10 mg, 0.420 mmol, 1.00 equiv) in dichloroethane (10 mL), tert-butyl piperazine-l-carboxylate (1 19 mg, 0.640 mmol, 1.50 equiv), and triethylamine (130 mg, 1.29 mmol, 3.00 equiv). The resulting solution was stirred for 30 min at room temperature. Sodium triacetoxyborohydride (274 mg, 1.29 mmol, 3.00 equiv) was added. The resulting solution was stirred overnight at room temperature and quenched with water (10 mL). The resulting solution was extracted with DCM (3 x 10 mL) and the organic layers were combined, washed with brine (2 x 10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column to yield 150 mg (82% yield) of tert-butyl 4-(2-morpholino-4-(trifluoromethyl)benzyl)piperazine-l - carboxylate as a yellow oil. LCMS (ESI, m/z): 430 [M+H] ⁺ .

Step 4: Synthesis of 4-(2-(piperazin-l-ylmethyl)-5-(trifluoromethyl)phenyl)morpho line

[00171] A 100-mL round-bottom flask was charged with tert-butyl 4-(2-morpholino-4- (trifluoromethyl)benzyl)piperazine-l-carboxylate (150 mg, 0.350 mmol, 1.00 equiv) in DCM (10 mL) and TFA (2.5 mL). The resulting solution was stirred overnight at room temperature and concentrated under reduced pressure to yield 190 mg (crude) of 4-(2-(piperazin-l-ylmethyl)- 5-(trifluoromethyl)phenyl)morpholine as a yellow oil. LCMS (ESI, m/z): 330 [M+H] ⁺ . Step 5: Synthesis of N-(l-(4-(2-morpholino-4-(trifluoromethyl)benzyl)piperazine-l - carbonyl)-lH-pyrazol-3-yl)acetamide

[00172] A 40-mL round-bottom flask was charged with 4-(2-(piperazin-l-ylmethyl)-5- (trifluoromethyl)phenyl)morpholine (110 mg, 0.330 mmol, 1.00 equiv) in DCM (10 mL), 4- nitrophenyl 3-acetamido-lH-pyrazole-l-carboxylate (145 mg, 0.500 mmol, 1.50 equiv), and triethylamine (101 mg, 1.00 mmol, 3.00 equiv) under nitrogen. The resulting solution was stirred for 3 h at room temperature and quenched with water (10 mL). The mixture was extracted with DCM (3 x 10 mL) and the organic layers were combined, washed with brine (2 x 10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product (200 mg) was purified by preparative HPLC. Purification resulted in 50.7 mg

pyrazol-3-yl)acetamide as a white solid. 1H MR (300 MHz, Chloroform- ) δ 8.02 (d, J= 2.1 Hz, 1H), 7.72 (br, 1H), 7.60 - 7.62 (m, 1H), 7.32 - 7.36 (m, 2H), 6.87 (s, 1H), 3.84 - 3.85 (m, 8H), 3.64 (br, 2H), 2.98 (br, 4H), 2.57 (br, 4H), 2.18 (s, 3H). LCMS (ESI, m/z): 481 [M+H] ⁺ . Example 4: N-(l-(4-(2-(4-fluoropiperidin-l-yl)-4-(trifluoromethyl)benzy l)piperazine-l- carbonyl)-lH-pyrazol-3-yl)acetamide

[00173] The title compound was synthesized as described in Example 3 using 4-fluoropiperidine in Step 2. Purification resulted in 101.0 mg of N-(l-(4-(2-(4-fluoropiperidin-l-yl)-4- (trifluoromethyl)benzyl)piperazine-l-carbonyl)-lH-pyrazol-3- yl)acetamide as a white solid. 1H MR (300 MHz, Chloroform-i ) δ 8.02 (d, J= 2.1 Hz, 1H), 7.71 (br, 1H), 7.60 - 7.62 (m, 1H), 7.32 (br, 2H), 6.88 (s, 1H), 4.72 - 4.90 (m, 1H), 3.83 (br, 4H), 3.62 (br, 2H), 3.11 - 3.15 (m, 2H), 2.84 - 2.88 (m, 2H), 2.56 (br, 4H), 2.18 (s, 3H), 1.98 - 2.12 (m, 4H). LCMS (ESI, m/z): 497 [M+H] ⁺ . Example 5: N-(l-(4-(4-chloro-2-(pyrrolidin-l-yl)benzyl)piperazine-l-car bonyl)-lH- pyrazol-3-yl)acetamide

[00174] The title compound was synthesized as described in Example 3 using pyrrolidine and 4- chloro-2-fluorobenzaldehyde in Step 2. Purification resulted in 73.8 mg of N-(l-(4-(4-chloro-2- (pyrrolidin-l-yl)benzyl)piperazine-l-carbonyl)-lH-pyrazol-3- yl)acetamide as a white solid. 1H NMR (300 MHz, Chloroform-i ) δ 7.89 - 8.01 (m, 2H), 7.26 - 7.30 (m, 1H), 6.80 - 6.88 (m, 3H), 3.81 (br, 4H), 3.51 (s, 2H), 3.19 - 3.23 (m, 4H), 2.49 - 2.52 (m, 4H), 2.16 (s, 3H), 1.88 - 1.94 (m, 4H). LCMS (ESI, m/z): 431 [M+H] ⁺ .

Example 6: N-(l-(4-(4-chloro-2-morpholinobenzyl)piperazine-l-carbonyl)- lH-pyrazol-3- yl)acetamide

[00175] The title compound was synthesized as described in Example 3 using morpholine and 4- chloro-2-fluorobenzaldehyde in Step 2. Purification resulted in 190.9 mg of N-(l-(4-(4-chloro-2- morpholinobenzyl)piperazine-l-carbonyl)-lH-pyrazol-3-yl)acet amide as a white solid. ¹ H MR (300 MHz, Chloroform-ύ δ 8.01 (d, J= 2.7 Hz, 1H), 7.90 (br, 1H), 7.36 (d, J= 9.0 Hz, 1H), 7.05 - 7.08 (m, 2H), 6.88 (d, J= 2.7 Hz, 1H), 3.81 - 3.84 (m, 8H), 3.55 (s, 2H), 2.94 - 2.97 (m, 4H), 2.52 - 2.55 (m, 4H), 2.17 (s, 3H). LCMS (ESI, m/z): 447 [M+H] ⁺ .

Example 7: N-(l-(4-(4-chloro-2-(4-fluoropiperidin-l-yl)benzyl)piperazin e-l-carbonyl)-lH- pyrazol-3-yl)acetamide

[00176] The title compound was synthesized as described in Example 3 using 4-fluoropiperidine and 4-chloro-2-fluorobenzaldehyde in Step 2. Purification resulted in 164.8 mg of N-(l-(4-(4- chloro-2-(4-fluoropiperidin-l-yl)benzyl)piperazine-l-carbony l)-lH-pyrazol-3-yl)acetamide as a white solid. 1H NMR (300 MHz, Chloroform-i ) δ 8.01 (d, J= 3.0 Hz, 1H), 7.83 (br, 1H), 7.37 (d, J= 7.8 Hz, 1H), 7.03 - 7.06 (m, 2H), 6.88 (d, J= 2.7 Hz, 1H), 4.68 - 4.91 (m, 1H), 3.81 (br, 4H), 3.54 (s, 2H), 3.06 - 3.13 (m, 2H), 2.79 - 2.87 (m, 2H), 2.52 - 2.55 (m, 4H), 2.17 (s, 3H), 1.94 - 2.10 (m, 4H). LCMS (ESI, m/z): 463 [M+H] ⁺ .

Example 8: N-(l-(l-(2-(pyrrolidin-l-yl)-4-(trifluoromethyl)benzyl)-l,8- diazaspiro[4.5]decane-8-carbony -lH-pyrazol-3-yl)acetamide

[00177] The title compound was synthesized as described in Example 3 using pyrrolidine and 2- fluoro-4-(trifluoromethyl)benzaldehyde in Step 2 and tert-butyl l,8-diazaspiro[4.5]decane-8- carboxylate in Step 3. Purification resulted in 75.5 mg of N-(l-(l-(2-(pyrrolidin-l-yl)-4- (trifluoromethyl)benzyl)-l,8-diazaspiro[4.5]decane-8-carbony l)-lH-pyrazol-3-yl)acetamide as a white solid. 1H NMR (300 MHz, Chloroform-i ) δ 8.01 (d, J= 2.7 Hz, 1H), 7.69 - 7.71 (m, 2H), 7.12 - 7.16 (m, 2H), 6.88 (d, J= 2.4 Hz, 1H), 4.59 - 4.63 (m, 2H), 3.66 (s, 2H), 3.02 - 3.17 (m, 6H), 2.59 - 2.70 (m, 2H), 2.18 (s, 3H), 1.82 - 1.97 (m, 10H), 1.50 - 1.58 (m, 2H). LCMS (ESI, m/z): 519 [M+H] ⁺ .

Example 9: N-(l-(l-(4-chloro-2-(8-oxa-2-azaspiro[4.5]decan-2-yl)benzyl) -l,8- diazaspiro[4.5]decane-8-carbonyl -lH-pyrazol-3-yl)acetamide

[00178] The title compound was synthesized as described in Example 3 using 8-oxa-2- azaspiro[4.5]decane and 4-chloro-2-fluorobenzaldehyde in Step 2 and tert-butyl 1,8- diazaspiro[4.5]decane-8-carboxylate in Step 3. Purification resulted in 38.1 mg of N-(l-(l-(4- chloro-2-(8-oxa-2-azaspiro[4.5]decan-2-yl)benzyl)-l,8-diazas piro[4.5]decane-8-carbonyl)-lH- pyrazol-3-yl)acetamide as an off-white solid. 1H NMR (300 MHz, Chloroform-i ) δ 8.36 (br, 1H), 7.98 (d, J= 2.4 Hz, 1H), 7.49 - 7.51 (m, 1H), 6.87 - 6.90 (m, 3H), 4.52 - 4.64 (m, 2H), 3.74 - 3.79 (m, 4H), 3.60 (s, 2H), 3.19 - 3.24 (m, 2H), 2.97 - 3.05 (m, 4H), 2.60 (br, 2H), 2.17 (s, 3H), 1.74 - 1.89 (m, 12H), 1.41 - 1.52 (m, 2H). LCMS (ESI, m/z): 555 [M+H] ⁺ . Example 10: N-(l-(l-(2-morpholino-4-(trifluoromethyl)benzyl)-l,8-diazasp iro[4.5]decane- 8-carbonyl)-lH-pyrazol-3-yl)acetamide

[00179] The title compound was synthesized as described in Example 3 using morpholine and 2- fluoro-4-(trifluoromethyl)benzaldehyde in Step 2 and tert-butyl l,8-diazaspiro[4.5]decane-8- carboxylate in Step 3. Purification resulted in 12.6 mg of N-(l-(l-(2-morpholino-4- (trifluoromethyl)benzyl)-l,8-diazaspiro[4.5]decane-8-carbony l)-lH-pyrazol-3-yl)acetamide as a white solid. 1H NMR (300 MHz, Chloroform-i ) δ 8.37 (s, 1H), 7.99 (d, J= 2.7 Hz, 1H), 7.51 - 7.54 (m, 1H), 7.33 - 7.41 (m, 2H), 6.91 - 6.92 (m, 1H), 4.56 - 4.82 (m, 2H), 3.99 - 4.14 (m, 4H), 3.73 (s, 2H), 2.97 - 3.11 (m, 6H), 2.69 - 2.86 (m, 2H), 2.26 (s, 3H), 2.01 - 2.17 (m, 2H), 1.83 (br, 4H), 1.46 - 1.56 (m, 2H). LCMS (ESI, m/z): 535 [M+H] ⁺ .

Example 11 : N-(l-(l-(4-chloro-2-(4,4-difluoropiperidin-l-yl)benzyl)-l,8- diazaspiro[4.5]decane-8-carbonyl)-lH-pyrazol-3-yl)acetamide

[00180] The title compound was synthesized as described in Example 3 using 4,4- difluoropiperidine and 4-chloro-2-fluorobenzaldehyde in Step 2 and tert-butyl 1,8- diazaspiro[4.5]decane-8-carboxylate in Step 3. Purification resulted in 70.4 mg of N-(l-(l-(4- chloro-2-(4,4-difluoropiperidin-l-yl)benzyl)-l,8-diazaspiro[ 4.5]decane-8-carbonyl)-lH-pyrazol- 3-yl)acetamide as a light yellow solid. 1H NMR (300 MHz, Chloroform- ) δ 8.01 (d, J= 2.7 Hz, 1H), 7.70 (br, 1H), 7.40 - 7.43 (m, 1H), 7.06 (br, 2H), 6.89 (s, 1H), 4.59 - 4.69 (m, 2H), 3.63 (s, 2H), 2.99 - 3.07 (m, 6H), 2.60 - 2.75 (m, 2H), 2.01 - 2.18 (m, 7H), 1.79 - 1.93 (m, 6H), 1.45 - 1.50 (m, 2H). LCMS (ESI, m/z): 535 [M+H] ⁺ .

Example 12: N-(l-(l-(2-(4-fluoropiperidin-l-yl)-4-(trifluoromethyl)benzy l)-l,8- diazaspiro[4.5]decane-8-carbonyl -lH-pyrazol-3-yl)acetamide

[00181] The title compound was synthesized as described in Example 3 using 4-fluoropiperidine and 2-fluoro-4-(trifluorom ethyl )benzaldehyde in Step 2 and tert-butyl 1,8- diazaspiro[4.5]decane-8-carboxylate in Step 3. Purification resulted in 102.7 mg of N-(l-(l-(2- (4-fluoropiperidin-l-yl)-4-(trifluoromethyl)benzyl)-l,8-diaz aspiro[4.5]decane-8-carbonyl)-lH- pyrazol-3-yl)acetamide as a white solid. 1H MR (400 MHz, Chloroform-i ) δ 8.01 (d, J= 2.8 Hz, 1H), 7.79 (br, 1H), 7.61 (d, J= 8.4 Hz, 1H), 7.30 (br, 2H), 6.89 (d, J= 2.8 Hz, 1H), 4.61 - 4.89 (m, 3H), 3.71 (br, 2H), 3.01 - 3.11 (m, 4H), 2.78 - 2.84 (m, 2H), 2.68 - 2.71 (m, 2H), 2.21 (s, 3H), 2.01 - 2.18 (m, 4H), 1.81 - 1.98 (m, 6H), 1.42 - 1.57 (m, 2H). LCMS (ESI, m/z): 551

[M+H] ⁺ .

Example 13: N-(l-(l-(4-chloro-2-(4-cyclopropylpiperazin-l-yl)b'

diazaspiro[4.5]decane-8-carbonyl -lH-pyrazol-3-yl)acetamide

[00182] The title compound was synthesized as described in Example 3 using 1- cyclopropylpiperazine and 4-chloro-2-fluorobenzaldehyde in Step 2 and tert-butyl 1,8- diazaspiro[4.5]decane-8-carboxylate in Step 3. Purification resulted in 57.6 mg of N-(l-(l-(4- chloro-2-(4-cyclopropylpiperazin-l-yl)benzyl)-l,8-diazaspiro [4.5]decane-8-carbonyl)-lH- pyrazol-3-yl)acetamide as a white solid. 1H MR (400 MHz, Chloroform-i ) δ 8.02 (d, J= 2.8 Hz, 1H), 7.82 (s, 1H), 7.48 - 7.54 (m, 1H), 7.03 - 7.05 (m, 2H), 6.89 (d, J= 2.8 Hz, 1H), 4.60 - 4.63 (m, 2H), 3.68 (br, 2H), 3.04 - 3.10 (m, 2H), 2.88 - 2.90 (m, 4H), 2.71 - 2.77 (m, 6H), 2.20 (s, 3H), 1.89 - 1.94 (m, 4H), 1.80 - 1.82 (m, 2H), 1.68 - 1.71 (m, 1H), 1.52 - 1.54 (m, 2H), 0.48 - 0.53 (m, 4H). LCMS (ESI, m/z): 540 [M+H] ⁺ .

Example 14: N-(l-(l-(4-chloro-2-(pyrrolidin-l-yl)benzyl)-l,8-diazaspiro[ 4.5]decane-8- carbonyl)-lH-pyrazol-3-yl)acetamide

[00183] The title compound was synthesized as described in Example 3 using pyrrolidine and 4- chloro-2-fluorobenzaldehyde in Step 2 and tert-butyl l,8-diazaspiro[4.5]decane-8-carboxylate in Step 3. Purification resulted in 50.0 mg of N-(l-(l-(4-chloro-2-(pyrrolidin-l-yl)benzyl)-l,8- diazaspiro[4.5]decane-8-carbonyl)-lH-pyrazol-3-yl)acetamide as a white solid. 1H NMR (300 MHz, Chloroform-i ) δ 8.00 (s, 1H), 7.71 (br, 1H), 7.48 - 7.51 (m, 1H), 6.88 (br, 3H), 4.57 - 4.62 (m, 2H), 3.60 (br, 2H), 3.01 - 3.13 (m, 6H), 2.64 (br, 2H), 2.18 (s, 3H), 1.80 - 2.01 (m, 10H), 1.48 - 1.57 (m, 2H). LCMS (ESI, m/z): 485 [M+H] ⁺ .

Example 15: N-(l-(l-(4-chloro-2-(4-ethylpiperazin-l-yl)benzyl)-l,8-diaza spiro[4.5]decane- 8-carbonyl)-lH-pyrazol-3-yl)acetamide

[00184] The title compound was synthesized as described in Example 3 using 1-ethylpiperazine and 4-chloro-2-fluorobenzaldehyde in Step 2 and tert-butyl l,8-diazaspiro[4.5]decane-8- carboxylate in Step 3. Purification resulted in 50.0 mg of N-(l-(l-(4-chloro-2-(4-ethylpiperazin- l-yl)benzyl)-l,8-diazaspiro[4.5]decane-8-carbonyl)-lH-pyrazo l-3-yl)acetamide as a white solid. 1H NMR (300 MHz, Chloroform-i ) δ 8.00 (d, J= 2.7 Hz, 1H), 7.82 (br, 1H), 7.44 - 7.47 (m, 1H), 7.02 - 7.05 (m, 2H), 6.88 (d, J= 2.7 Hz, 1H), 4.58 - 4.62 (m, 2H), 3.64 (s, 2H), 3.00 - 3.09 (m, 6H), 2.60 - 2.82 (m, 8H), 2.19 (s, 3H), 1.78 - 1.94 (m, 6H), 1.46 - 1.57 (m, 2H), 1.19 (t, J = 6.9 Hz, 3H). LCMS (ESI, m/z): 528 [M+H] ⁺ .

Example 16: N-(l-(l-(4-chloro-2-morpholinobenzyl)-l,8-diazaspiro[4.5]dec ane-8- carbonyl)-lH-pyrazol-3-yl)acetamide

[00185] The title compound was synthesized as described in Example 3 using morpholine and 4- chloro-2-fluorobenzaldehyde in Step 2 and tert-butyl l,8-diazaspiro[4.5]decane-8-carboxylate in Step 3. Purification resulted in 118.0 mg of N-(l-(l-(4-chloro-2-morpholinobenzyl)-l,8- diazaspiro[4.5]decane-8-carbonyl)-lH-pyrazol-3-yl)acetamide as a white solid. 1H NMR (300 MHz, Chloroform-i δ 8.47 (br, 1H), 7.99 (d, J= 2.7 Hz, 1H), 7.30 - 7.33 (m, 1H), 7.06 - 7.09 (m, 2H), 6.91 (d, J= 2.7 Hz, 1H), 4.54 - 4.59 (m, 2H), 3.96 - 3.99 (m, 4H), 3.64 (br, 2H), 2.92 - 3.03 (m, 6H), 2.77 (br, 2H), 2.17 (s, 3H), 2.00 - 2.10 (m, 2H), 1.69 - 1.82 (m, 4H), 1.43 - 1.48 (m, 2H). LCMS (ESI, m/z): 501 [M+H] ⁺ . Example 17: N-(l-(l-(4-chloro-2-(dihydro-lH-furo[3,4-c]pyrrol-5(3H,6H,6a H)-yl)b l,8-diazaspiro[4.5]decane-8-carbonyl)-lH-pyrazol-3-yl)acetam ide

[00186] The title compound was synthesized as described in Example 3 using hexahydro-lH- furo[3,4-c]pyrrole and 4-chloro-2-fluorobenzaldehyde in Step 2 and tert-butyl 1,8- diazaspiro[4.5]decane-8-carboxylate in Step 3. Purification resulted in 46.2 mg of N-(l-(l-(4- chloro-2-(dihydro-lH-furo[3,4-c]pyrrol-5(3H,6H,6aH)-yl)benzy l)-l,8-diazaspiro[4.5]decane-8- carbonyl)-lH-pyrazol-3-yl)acetamide as a white solid. 1H NMR (300 MHz, Chloroform-<f) δ 8.70 (br, 1H), 7.96 (d, J= 2.7 Hz, 1H), 7.41 - 7.44 (m, 1H), 7.04 (br, 2H), 6.90 (s, 1H), 4.48 - 4.52 (m, 2H), 4.13 - 4.18 (m, 2H), 3.68 (br, 4H), 2.94 - 2.99 (m, 8H), 2.71 - 2.79 (m, 2H), 2.16 (s, 3H), 1.84 - 2.01 (m, 6H), 1.44 - 1.47 (m, 2H). LCMS (ESI, m/z): 527 [M+H] ⁺ .

Example 18: N-(l-(l-(4-chloro-2-(4-fluoropiperidin-l-yl)benzyl)-l,8-diaz aspiro[4.5]decane- 8-carbonyl)-lH-pyrazol-3-yl)acetamide

[00187] The title compound was synthesized as described in Example 3 using 4-fluoropiperidine and 4-chloro-2-fluorobenzaldehyde in Step 2 and tert-butyl l,8-diazaspiro[4.5]decane-8- carboxylate in Step 3. Purification resulted in 159.8 mg of N-(l-(l-(4-chloro-2-(4- fluoropiperidin-l-yl)benzyl)-l,8-diazaspiro[4.5]decane-8-car bonyl)-lH-pyrazol-3-yl)acetamide as a light yellow solid. 1H MR (300 MHz, Chloroform-i ) δ 8.01 (d, J= 2.7 Hz, 1H), 7.78 (br, 1H), 7.38 - 7.41 (m, 1H), 7.02 - 7.04 (m, 2H), 6.90 (s, 1H), 4.59 - 4.88 (m, 3H), 3.63 (br, 2H), 2.98 - 3.07 (m, 4H), 2.69 - 2.81 (m, 4H), 2.18 (s, 3H), 1.70 - 2.07 (m, 10H), 1.39 - 1.58 (m, 2H). LCMS (ESI, m/z): 517 [M+H] ⁺ .

Example 19: N-(l-(l-(2-(piperidin-l-yl)-4-(trifluoromethyl)benzyl)-l,8- diazaspiro[4.5]decane-8-carbony -lH-pyrazol-3-yl)acetamide

[00188] The title compound was synthesized as described in Example 3 using piperidine and 2- fluoro-4-(trifluoromethyl)benzaldehyde in Step 2 and tert-butyl l,8-diazaspiro[4.5]decane-8- carboxylate in Step 3. Purification resulted in 56.3 mg of N-(l-(l-(2-(piperidin-l-yl)-4- (trifluoromethyl)benzyl)-l,8-diazaspiro[4.5]decane-8-carbony l)-lH-pyrazol-3-yl)acetamide as a white solid. 1H MR (300 MHz, Chloroform-i ) δ 8.01 (d, J= 2.7 Hz, 1H), 7.66 - 7.72 (m, 2H), 7.26 (br, 2H), 6.87 (d, J= 2.7 Hz, 1H), 4.58 - 4.62 (m, 2H), 3.71 (br, 2H), 3.06 (d, J= 12.3 Hz, 2H), 2.83 (d, J= 5.0 Hz, 4H), 2.68 (br, 2H), 2.18 (s, 3H), 1.59 - 1.88 (m, 10H), 1.50 - 1.58 (m, 4H). LCMS (ESI, m/z): 533 [M+H] ⁺

Example 20: N-(l-(l-(2-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-4-(trifluor omethyl)benzyl)- l,8-diazaspiro[4.5]decane-8-carbonyl)-lH-pyrazol-3-yl)acetam ide

[00189] The title compound was synthesized as described in Example 3 using 8-oxa-3- azabicyclo[3.2.1]octane and 2-fluoro-4-(trifluoromethyl)benzaldehyde in Step 2 and tert-butyl l,8-diazaspiro[4.5]decane-8-carboxylate in Step 3. Purification resulted in 56.1 mg of N-(l-(l- (2-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-4-(trifluoromethyl) benzyl)-l,8-diazaspiro[4.5]decane- 8-carbonyl)-lH-pyrazol-3-yl)acetamide as a white solid. 1H MR (300 MHz, Chloroform- ) δ 8.00 (d, J= 2.7 Hz, 1H), 7.71 (br, 2H), 7.31 (br, 2H), 6.88 (d, J= 2.7 Hz, 1H), 4.60 - 4.64 (m, 2H), 4.42 (br, 2H), 3.76 (br, 2H), 3.03 - 3.11 (m, 4H), 2.64 - 2.72 (m, 4H), 2.18 (s, 3H), 1.98 - 2.10 (m, 4H), 1.84 - 1.88 (m, 4H), 1.52 - 1.60 (m, 4H). LCMS (ESI, m/z): 561 [M+H] ⁺

Example 21: N-(l-(l-(2-(4-(methylsulfonyl)piperazin-l-yl)-4-(trifluorome thyl)benzyl)-l,8- diazaspiro[4.5]decane-8-carbony -lH-pyrazol-3-yl)acetamide

[00190] The title compound was synthesized as described in Example 3 using 1- (m ethyl sulfonyl)piperazine and 2-fluoro-4-(trifluoromethyl)benzaldehyde in Step 2 and tert- butyl l,8-diazaspiro[4.5]decane-8-carboxylate in Step 3. Purification resulted in 67.4 mg of N- ( 1 -( 1 -(2-(4-(methylsulfonyl)piperazin- 1 -yl)-4-(trifluorom ethyl )b enzyl)- 1 , 8- diazaspiro[4.5]decane-8-carbonyl)-lH-pyrazol-3-yl)acetamidea s an off-white semi-solid. H MR (300 MHz, Chloroform-i ) δ 8.00 (d, J 7.29 - 7.36 (m, 2H), 6.89 (d, J= 2.1 Hz, 1H), 4.62 - 4.66 (m, 2H), 3.72 (br, 2H), 3.40 - 3.42 (m, 4H), 3.00 - 3.08 (m, 6H), 2.90 (s, 3H), 2.70 (br, 2H), 2.19 (s, 3H), 1.86 - 1.87 (m, 6H), 1.47 - 1.51 (m, 2H). LCMS (ESI, m/z): 612 [M+H] ⁺ .

Example 22: N-(l-(l-(2-(4-acetylpiperazin-l-yl)-4-(trifluoromethyl)benzy l)-l,8- diazaspiro[4.5]decane-8-carbony -lH-pyrazol-3-yl)acetamide

[00191] The title compound was synthesized as described in Example 3 using l-(piperazin-l- yl)ethanone and 2-fluoro-4-(trifluoromethyl)benzaldehyde in Step 2 and tert-butyl 1,8- diazaspiro[4.5]decane-8-carboxylate in Step 3. Purification resulted in 84.2 mg of N-(l-(l-(2-(4- acetylpiperazin-l-yl)-4-(trifluoromethyl)benzyl)-l,8-diazasp iro[4.5]decane-8-carbonyl)-lH- pyrazol-3-yl)acetamide as a white solid. 1H MR (300 MHz, Chloroform- ) δ 8.00 (d, J= 3.0 Hz, 1H), 7.94 (br, 1H), 7.61 - 7.64 (m, 1H), 7.32 - 7.35 (m, 1H), 7.26 (br,lH), 6.88 (br, 1H), 4.60 - 4.64 (m, 2H), 3.74 - 3.79 (m, 4H), 3.62 (br, 2H), 2.94 - 3.08 (m, 6H), 2.71 (br, 2H), 2.21 (s, 3H), 2.15 (s, 3H), 1.82 - 1.93 (m, 6H), 1.47 - 1.51 (m, 2H). LCMS (ESI, m/z): 576 [M+H] ⁺ . Example 23: N-(l-(l-(4-methyl-3-(trifluoromethyl)benzyl)-l,8-diazaspiro[ 4.5]decane-8- carbonyl)-lH-pyrazol-3-yl)acetamide

Step 1: Synthesis of tert-butyl 8-(3-acetamido-lH-pyrazole-l-carbonyl)-l,8- diazaspiro[4.5]deca -l-carboxylate

[00192] A 100-mL round-bottom flask was charged with 4-nitrophenyl 3-acetamido-lH- pyrazole-l-carboxylate (2.32 g, 7.99 mmol, 1.50 equiv), DCM (20 mL), tert-butyl 1,8- diazaspiro[4.5]decane-l-carboxylate (1.28 g, 5.33 mmol, 1.00 equiv), and triethylamine (1.62 g, 16.0 mmol, 3.00 equiv). The resulting solution was stirred overnight at room temperature and quenched with water (50 mL). The resulting solution was extracted with DCM (2 x 80 mL) and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column to provide 1.90 g (61% yield) of tert-butyl 8-(3-acetamido-lH-pyrazole-l-carbonyl)-l,8- diazaspiro[4.5]decane-l-carboxylate as a yellow oil. LCMS (ESI, m/z): 392 [M+H] ⁺ .

Step 2: Synthesis of N-(l-(l,8-diazaspiro[4.5]decane-8-carbonyl)-lH-pyrazol-3- yl)acetamide

[00193] A 100-mL round-bottom flask was charged with tert-butyl 8-(3-acetamido-lH-pyrazole- l-carbonyl)-l,8-diazaspiro[4.5]decane-l-carboxylate (800 mg, 2.04 mmol, 1.00 equiv), DCM (20 mL), and TFA (4 mL). The resulting solution was stirred overnight at room temperature and concentrated under reduced pressure to provide 800 mg (crude) of N-(l-(l,8- diazaspiro[4.5]decane-8-carbonyl)-lH-pyrazol-3-yl)acetamide as a yellow oil. LCMS (ESI, m/z): 292 [M+H] ⁺ .

Step 3: Synthesis of N-(l-(l-(4-methyl-3-(trifluoromethyl)benzyl)-l,8- diazaspiro[4.5]decane-8-carbonyl)-lH-pyrazol-3-yl)acetamide

[00194] A 50-mL round-bottom flask was charged with N-(l-(l,8-diazaspiro[4.5]decane-8- carbonyl)-lH-pyrazol-3-yl)acetamide (147 mg, 0.500 mmol, 1.00 equiv), DCE (10 mL), triethylamine (154 mg, 1.52 mmol, 3.00 equiv), and 4-methyl-3-(trifluoromethyl)benzaldehyde (95.0 mg, 0.500 mmol, 1.00 equiv). The mixture was stirred for 1 h at room temperature.

Sodium triacetoxyborohydride (322 mg, 1.52 mmol, 3.00 equiv) was added. The resulting solution was stirred overnight at room temperature and quenched with water (30 mL). The resulting solution was extracted with DCM (2 x 50 mL) and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product (300 mg) was purified by preparative HPLC. Purification resulted in 103.1 mg (44% yield) of N-(l-(l-(4-methyl-3-(trifluoromethyl)benzyl)-l,8-diazaspiro[ 4.5]decane-8- carbonyl)-lH-pyrazol-3-yl)acetamide as a white solid. 1H MR (400 MHz, Chloroform-<f) δ

8.02 (d, J= 2.8 Hz, 1H), 7.84 (br, 1H), 7.55 (s, 1H), 7.36 - 7.38 (m, 1H), 7.21 - 7.23 (m, 1H), 6.90 (d, J= 2.8 Hz, 1H), 4.60 - 4.63 (m, 2H), 3.63 (s, 2H), 3.07 (t, J= 12.4 Hz, 2H), 2.66 - 2.69 (m, 2H), 2.48 (s, 3H), 2.20 (s, 3H), 1.81 - 1.90 (m, 6H), 1.51 - 1.54 (m, 2H). LCMS (ESI, m/z): 464 [M+H] ⁺ .

Example 24: N-(l-(l-(3-chloro-4-(trifluoromethyl)benzyl)-l,8-diazaspiro[ 4.5]decane-8- carbonyl)-lH-pyrazol-3-yl)acetamide

[00195] The title compound was synthesized as described in Example 23 using 3-chloro-4- (trifluoromethyl)benzaldehyde in Step 3. Purification resulted in 76.9 mg of N-(l-(l-(3-chloro- 4-(trifluoromethyl)benzyl)-l,8-diazaspiro[4.5]decane-8-carbo nyl)-lH-pyrazol-3-yl)acetamide as a white solid. 1H MR (300 MHz, Chloroform-i ) δ 8.00 (d, J= 2.7 Hz, 1H), 7.78 (br, 1H), 7.60 (d, J= 8.1 Hz, 1H), 7.48 (s, 1H), 7.26 - 7.30 (m, 1H), 6.88 (d, J= 2.7 Hz, 1H), 4.58 - 4.62 (m, 2H), 3.65 (s, 2H), 3.04 (t, J= 12.3 Hz, 2H), 2.65 - 2.69 (m, 2H), 2.18 (s, 3H), 1.78 - 1.86 (m, 6H), 1.48 - 1.53 (m, 2H). LCMS (ESI, m/z): 506 [M+Na] ⁺ .

Example 25: N-(l-(l-(4-chloro-3-(trifluoromethyl)benzyl)-l,8-diazaspiro[ 4.5]decane-8- carbonyl)-lH-pyrazol-3-yl)acetamide

[00196] The title compound was synthesized as described in Example 23 using 4-chloro-3- (trifluoromethyl)benzaldehyde in Step 3. Purification resulted in 91.6 mg of N-(l-(l-(4-chloro- 3-(trifluoromethyl)benzyl)-l,8-diazaspiro[4.5]decane-8-carbo nyl)-lH-pyrazol-3-yl)acetamide as a white solid. 1H MR (300 MHz, Chloroform-i ) δ 8.00 (d, J= 2.7 Hz, 1H), 7.74 (br, 1H), 7.63 (s, 1H), 7.42 (s, 2H), 6.88 (d, J= 2.7 Hz, 1H), 4.58 - 4.62 (m, 2H), 3.63 (s, 2H), 3.04 (t, J= 12.4 Hz, 2H), 2.63 - 2.67 (m, 2H), 2.19 (s, 3H), 1.79 - 1.86 (m, 6H), 1.48 - 1.52 (m, 2H). LCMS (ESI, m/z): 506 [M+Na] ⁺ .

Example 26: N-(l-(l-(2-(2-(methylsulfonyl)-2,8-diazaspiro[4.5]decan-8-yl )-4- (trifluoromethyl)benzyl)-l,8-di zaspiro[4.5]decane-8-carbonyl)-lH-pyrazol-3-yl)acetamide

Step 1: Synthesis of tert-butyl 8-(2-formyl-5-(trifluoromethyl)phi

diazaspiro[4.5]decane-2-carboxylate

[00197] A 100-mL round-bottom flask was charged with 2-fluoro-4-

(trifluoromethyl)benzaldehyde (2.00 g, 10.4 mmol, 1.00 equiv), DMSO (20 mL), tert-butyl 2,8- diazaspiro[4.5]decane-2-carboxylate (3.75 g, 15.6 mmol, 1.50 equiv), potassium carbonate (4.31 g, 31.2 mmol, 3.00 equiv) under nitrogen. The resulting solution was stirred overnight at 80 °C and quenched with water (20 mL). The resulting solution was extracted with EtOAc (3 x 20 mL) and the organic layers were combined, washed with brine (2 x 20 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column to provide 3.50 g (82% yield) of tert-butyl 8-(2-formyl-5- (trifluoromethyl)phenyl)-2,8-diazaspiro[4.5]decane-2-carboxy late as a yellow oil. LCMS (ESI, m/z): 413 [M+H] ⁺ .

Step 2: Synthesis of 2-( -diazaspiro[4.5]decan-8-yl)-4-(trifluoromethyl)benzaldehyde

[00198] A 100-mL round-bottom flask was charged with tert-butyl 8-(2-formyl-5- (trifluoromethyl)phenyl)-2,8-diazaspiro[4.5]decane-2-carboxy late (3.50 g, 9.20 mmol, 1.00 equiv) in DCM (30 mL) and TFA (6 mL). The resulting solution was stirred for 5 h at room temperature and concentrated under reduced pressure to provide 3.60 g (crude) of 2-(2,8- diazaspiro[4.5]decan-8-yl)-4-(trifluoromethyl)benzaldehyde as a yellow solid. LCMS (ESI, m/z): 313 [M+H] ⁺ .

Step 3: Synthesis of 2-(2-(methylsulfonyl)-2,8-diazaspiro[4.5]decan-8-yl)-4- (trifluoromethyl)benzaldehyde

[00199] A 100-mL round-bottom flask was charged with 2-(2,8-diazaspiro[4.5]decan-8-yl)-4- (trifluoromethyl)benzaldehyde (2.60 g, 8.32 mmol, 1.00 equiv) in DCM (20 mL) and triethylamine (2.52 g, 24.9 mmol, 3.00 equiv) under nitrogen. Methanesulfonyl chloride (1.42 g, 12.4 mmol, 1.50 equiv) was added dropwise with stirring. The resulting solution was stirred for 3 h at room temperature and quenched with water (20 mL). The resulting solution was extracted with DCM (3 x 20 mL) and the organic layers were combined, washed with brine (2 x 20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column to yield 2.20 g (68% yield) of 2-(2- (methylsulfonyl)-2,8-diazaspiro[4.5]decan-8-yl)-4-(trifluoro methyl)benzaldehyde as a yellow solid. LCMS (ESI, m/z): 391 [M+H] ⁺ .

Step 4: N-(l-(l-(2-(2-(methylsulfonyl)-2,8-diazaspiro[4.5]decan-8-yl )-4- (trifluoromethyl)benzyl)-l,8-diazaspiro[4.5]decane-8-carbony l)-lH-pyrazol-3-yl)acetamide

[00200] The title compound was synthesized as described in Example 3, Step 1, 3-5 using 2-(2- (methylsulfonyl)-2,8-diazaspiro[4.5]decan-8-yl)-4-(trifluoro methyl)benzaldehyde and tert-butyl l,8-diazaspiro[4.5]decane-8-carboxylate in Step 3. Purification resulted in 96.4 mg of N-(l-(l- (2-(2-(methylsulfonyl)-2,8-diazaspiro[4.5]decan-8-yl)-4-(tri fluoromethyl)benzyl)-l,8- diazaspiro[4.5]decane-8-carbonyl)-lH-pyrazol-3-yl)acetamide as a white solid. 1H NMR (300 MHz, Chloroform-i δ 8.00 (d, J= 2.7 Hz, 1H), 7.78 (br, 1H), 7.66 - 7.67 (m, 1H), 7.26 - 7.32 (m, 2H), 6.89 (d, J= 2.7 Hz, 1H), 4.60 - 4.64 (m, 2H), 3.69 (br, 2H), 3.45 (t, J= 7.0 Hz, 2H), 3.26 (s, 2H), 3.06 (t, J= 12.6 Hz, 2H), 2.80 - 2.94 (m, 7H), 2.68 (br, 2H), 2.18 (s, 3H), 1.81 - 1.93 (m, 7H), 1.69 - 1.76 (m, 5H), 1.48 - 1.52 (m, 2H). LCMS (ESI, m/z): 666 [M+H] ⁺ .

Example 27: N-(l-(l-(2-(2-(methylsulfonyl)-2,6-diazaspiro[3.4]octan-6-yl )-4- (trifluoromethyl)benzyl)-l,8-diazaspiro[4.5]decane-8-carbony l)-lH-pyrazol-3-yl)acetamide

Step 1: Synthesis of tert-butyl 6-(2-formyl-5-(trifluoromethyl)phi

diazaspiro[3.4]octane-2-carboxylate

[00201] A 100-mL round-bottom flask was charged with 2-fluoro-4-

(trifluoromethyl)benzaldehyde (1.00 g, 5.21 mmol, 1.00 equiv), DMSO (20 mL), tert-butyl 2,6- diazaspiro[3.4]octane-2-carboxylate (1.66 g, 7.82 mmol, 1.50 equiv), and potassium carbonate (2.16 g, 15.6 mmol, 3.00 equiv) under nitrogen. The resulting solution was stirred overnight at 80 °C and quenched with water (20 mL). The resulting solution was extracted with EtOAc (3 x 20 mL) and the organic layers were combined, washed with brine (2 x 20 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was

chromatographed on a silica gel column to provide 1.40 g (70% yield) of tert-butyl 6-(2-formyl- 5-(trifluoromethyl)phenyl)-2,6-diazaspiro[3.4]octane-2-carbo xylate as a yellow oil. LCMS (ESI, m/z): 385 [M+H] ⁺ .

Step 2: Synthesis of 2-(2 -diazaspiro[3.4]octan-6-yl)-4-(trifluoromethyl)benzaldehyde

[00202] A 100-mL round-bottom flask was charged with tert-butyl 6-[2-formyl-5- (trifluoromethyl)phenyl]-2,6-diazaspiro[3.4]octane-2-carboxy late (1.40 g, 3.64 mmol, 1.00 equiv) in DCM (20 mL) and TFA (5 mL). The resulting solution was stirred for 5 h at room temperature and concentrated under reduced pressure to provide 1.80 g (crude) of 2-(2,6- diazaspiro[3.4]octan-6-yl)-4-(trifluoromethyl)benzaldehyde as a yellow oil. LCMS (ESI, m/z): 285 [M+H] ⁺ .

Step 3: Synthesis of 2-(2-(methylsulfonyl)-2,6-diazaspiro[3.4]octan-6-yl)-4- (trifluoromethyl)benzal hyde

[00203] A 100-mL round-bottom flask was charged with 2-(2,6-diazaspiro[3.4]octan-6-yl)-4- (trifluoromethyl)benzaldehyde (1.00 g, 3.52 mmol, 1.00 equiv) in DCM (20 mL) and triethylamine (1.07 g, 10.6 mmol, 3.00 equiv) under nitrogen. Methanesulfonyl chloride (803 mg, 7.01 mmol, 1.50 equiv) was added dropwise with stirring. The resulting solution was stirred for 3 h at room temperature and quenched with water (20 mL). The resulting solution was extracted with DCM (3 x 20 mL) and the organic layers were combined, washed with brine (2 x 20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column to yield 300 mg (24% yield) of 2-(2- (methylsulfonyl)-2,6-diazaspiro[3.4]octan-6-yl)-4-(trifluoro methyl)benzaldehyde as a yellow oil. LCMS (ESI, m/z): 363 [M+H] ⁺ .

Step 4: N-(l-(l-(2-(2-(methylsulfonyl)-2,6-diazaspiro[3.4]octan-6-yl )-4- (trifluoromethyl)benzyl)-l,8-diazaspiro[4.5]decane-8-carbony l)-lH-pyrazol-3-yl)acetamide

[00204] The title compound was synthesized as described in Example 3, Step 1, 3-5 using 2-(2- (methylsulfonyl)-2,6-diazaspiro[3.4]octan-6-yl)-4-(trifluoro methyl)benzaldehyde and tert-butyl l,8-diazaspiro[4.5]decane-8-carboxylate in Step 3. Purification resulted in 21.7 mg of N-(l-(l- (2-(2-(methylsulfonyl)-2,6-diazaspiro[3.4]octan-6-yl)-4-(tri fluoromethyl)benzyl)-l,8- diazaspiro[4.5]decane-8-carbonyl)-lH-pyrazol-3-yl)acetamide as an off-white solid. 1H NMR (300 MHz, Chloroform-ύ δ 8.06 (br, 1H), 8.00 (d, J= 2.7 Hz, 1H), 7.68 (d, J= 8.1 Hz, 1H), 7.23 (d, J= 8.4 Hz, 1H), 7.13 (s, 1H), 6.89 (d, J= 2.7 Hz, 1H), 4.62 - 4.66 (m, 2H),3.93 - 3.99 (m, 4H), 3.66 (br, 2H), 3.35 (br, 2H),3.23 (t, J= 6.9 Hz, 2H), 3.04 (t, J= 12.4 Hz, 2H), 2.90 (s, 3H), 2.62 - 2.66 (m, 2H), 2.19 - 2.24 (m, 5H), 1.80 - 1.88 (m, 6H), 1.50 - 1.54 (m, 2H). LCMS (ESI, m/z): 638 [M+H] ⁺ .

Example 28: N-(l-(l-(2-(8-oxa-2-azaspiro[4.5]decan-2-yl)-4-(trifluoromet hyl)benzyl)-l,8- diazaspiro[4.5]decane-8-carbonyl -lH-pyrazol-3-yl)acetamide

- I l l - [00205] The title compound was synthesized as described in Example 3 using 8-oxa-2- azaspiro[4.5]decane and 2-fluoro-4-(trifluoromethyl)benzaldehyde in Step 2 and tert-butyl 1,8- diazaspiro[4.5]decane-8-carboxylate in Step 3. Purification resulted in 57.1 mg of N-(l-(l-(2-(8- oxa-2-azaspiro[4.5]decan-2-yl)-4-(trifluoromethyl)benzyl)-l, 8-diazaspiro[4.5]decane-8- carbonyl)-lH-pyrazol-3-yl)acetamide as a white solid. 1H NMR (300 MHz, Chloroform-<f) δ

8.40 (br, 1H), 7.99 (d, J= 2.7 Hz, 1H), 7.71 - 7.73 (m, 1H), 7.18 - 7.28 (m, 2H), 6.90 (d, J= 2.7 Hz, 1H), 4.55 - 4.59 (m, 2H), 3.68 - 3.86 (m, 6H), 3.27 (t, J= 7.2 Hz, 2H), 2.99 - 3.08 (m, 4H), 2.61 (br, 2H), 2.17 (s, 3H), 1.68 - 1.95 (m, 12H), 1.50 - 1.56 (m, 2H). LCMS (ESI, m/z): 589

[M+H] ⁺ .

Example 29: N-(l-(l-(2-(4,4-difluoropiperidin-l-yl)-4-(trifluoromethyl)b i

diazaspiro[4.5]decane-8-carbonyl)-lH-pyrazol-3-yl)acetami de

[00206] The title compound was synthesized as described in Example 3 using 4,4- difluoropiperidine and 2-fluoro-4-(trifluoromethyl)benzaldehyde in Step 2 and tert-butyl 1,8- diazaspiro[4.5]decane-8-carboxylate in Step 3. Purification resulted in 78.8 mg of N-(l-(l-(2- (4,4-difluoropiperidin-l-yl)-4-(trifluoromethyl)benzyl)-l,8- diazaspiro[4.5]decane-8-carbonyl)- lH-pyrazol-3-yl)acetamide as a white solid. 1H NMR (300 MHz, Chloroform-i ) δ 8.01 (d, J = 3.0 Hz, 1H), 7.58 - 7.72 (m, 2H), 7.28 - 7.34 (m, 2H), 6.89 (d, J= 2.4 Hz, 1H), 4.61 - 4.65 (m, 2H), 3.72 (br, 2H), 3.00 - 3.04 (m, 6H), 2.68 (br, 2H), 2.05 - 2.22 (m, 7H), 1.69 - 1.86 (br, 6H), 1.48 - 1.52 (m, 2H). LCMS (ESI, m/z): 569 [M+H] ⁺ .

Example 30: N-(l-(l-(2-(4-cyclopropylpiperazin-l-yl)-4-(trifluoromethyl) benzyl)-l,8- diazaspiro[4.5]decane-8-carbony -lH-pyrazol-3-yl)acetamide

[00207] The title compound was synthesized as described in Example 3 using 1- cyclopropylpiperazine and 2-fluoro-4-(trifluoromethyl)benzaldehyde in Step 2 and tert-butyl l,8-diazaspiro[4.5]decane-8-carboxylate in Step 3. Purification resulted in 68.2 mg of N-(l-(l- (2-(4-cyclopropylpiperazin-l-yl)-4-(trifluoromethyl)benzyl)- l,8-diazaspiro[4.5]decane-8- carbonyl)-lH-pyrazol-3-yl)acetamide as a white solid. 1H NMR (300 MHz, Chloroform-<f) δ 8.02 (d, J= 2.7 Hz, 1H), 7.78 (br, 1H), 7.62 - 7.69 (m, 1H), 7.27 - 7.31 (m, 2H), 6.89 (d, J= 2.7 Hz, 1H), 4.60 - 4.64 (m, 2H), 3.74 (br, 2H), 3.08 (t, J= 12.4 Hz, 2H), 2.90 - 2.93 (m, 4H), 2.79 (br, 4H), 2.67 - 2.71 (m, 2H), 2.19 (s, 3H), 1.71 - 1.95 (m, 8H), 1.51 - 1.55 (m, 1H), 0.49 - 0.51 (m, 4H). LCMS (ESI, m/z): 574 [M+H] ⁺ .

Example 31: N-(l-(l-(2-(4-ethylpiperazin-l-yl)-4-(trifluoromethyl)benzyl )-l,8- diazaspiro[4.5]decane-8-carbony -lH-pyrazol-3-yl)acetamide

[00208] The title compound was synthesized as described in Example 3 using 1-ethylpiperazine and 2-fluoro-4-(trifluorom ethyl )benzaldehyde in Step 2 and tert-butyl 1,8- diazaspiro[4.5]decane-8-carboxylate in Step 3. Purification resulted in 120.5 mg of N-(l-(l-(2- (4-ethylpiperazin-l-yl)-4-(trifluoromethyl)benzyl)-l,8-diaza spiro[4.5]decane-8-carbonyl)-lH- pyrazol-3-yl)acetamide as an off-white solid. 1H NMR (300 MHz, Chloroform-i ) δ 8.01 (d, J = 2.7 Hz, 1H), 7.78 (br, 1H), 7.66 (d, J= 8.4 Hz, 1H), 7.27 - 7.30 (m, 2H), 6.88 (d, J= 2.7 Hz, 1H), 4.59 - 4.64 (m, 2H), 3.71 (s, 2H), 2.92 - 3.10 (m, 6H), 2.46 - 2.69 (m, 8H), 2.18 (s, 3H), 1.71 - 1.96 (m, 6H), 1.48 - 1.53 (m, 2H), 1.17 (t, J= 7.0 Hz, 3H). LCMS (ESI, m/z): 562

[M+H] ⁺ .

Example 32: N-(l-(l-(2-(dihydro-lH-furo[3,4-c]pyrrol-5(3H,6H,6aH)-yl)-4- (trifluoromethyl)benzyl)-l,8-diazaspiro[4.5]decane-8-carbony l)-lH-pyrazol-3-yl)acetamide

[00209] The title compound was synthesized as described in Example 3 using hexahydro-lH- furo[3,4-c]pyrrole and 2-fluoro-4-(trifluorom ethyl )benzaldehyde in Step 2 and tert-butyl 1,8- diazaspiro[4.5]decane-8-carboxylate in Step 3. Purification resulted in 81.4 mg of N-(l-(l-(2- (dihydro-lH-furo[3,4-c]pyrrol-5(3H,6H,6aH)-yl)-4-(trifluorom ethyl)benzyl)-l,8- diazaspiro[4.5]decane-8-carbonyl)-lH-pyrazol-3-yl)acetamide as a white solid. 1H NMR (300 MHz, Chloroform-i δ 8.66 (br, 1H), 8.01 (d, J= 2.4 Hz, 1H), 7.64 (d, J= 7.8 Hz, 1H), 7.27 - 7.31 (m, 2H), 6.90 (d, J= 2.1 Hz, 1H), 4.48 - 4.52 (m, 2H), 4.41 - 4.19 (m, 2H), 3.76 (s, 2H), 3.66 - 3.70 (m, 2H), 2.94 - 3.03 (m, 8H), 2.72 (br, 2H), 2.16 (s, 3H), 1.73 - 1.96 (m, 6H), 1.45 - 1.53 (m, 2H). LCMS (ESI, m/z): 561 [M+H] ⁺ . Example 33: N-(l-(l-(4-chloro-2-(piperidin-l-yl)benzyl)-l,8-diazaspiro[4 .5]decane-8- carbonyl)-lH-pyrazol-3-yl)acetamide

[00210] The title compound was synthesized as described in Example 3 using piperidine and 4- chloro-2-fluorobenzaldehyde in Step 2 and tert-butyl l,8-diazaspiro[4.5]decane-8-carboxylate in Step 3. Purification resulted in 73.5 mg of N-[l-[(l-[[4-chloro-2-(piperidin-l-yl)phenyl]methyl]- l,8-diazaspiro[4.5]decan-8-yl)carbonyl]-lH-pyrazol-3-yl]acet amide as a light yellow solid. 1H MR (300 MHz, Chloroform-i ) δ 8.00 (d, J= 2.7 Hz, 1H), 7.71 (br, 1H), 7.38 - 7.44 (m, 1H), 6.91 - 7.07 (m, 2H), 6.85 - 6.88 (m, 1H), 4.57 - 4.61 (m, 2H), 3.70 (br, 2H), 3.00 - 3.08 (m, 2H), 2.67 - 2.80 (m, 6H), 2.19 (s, 3H), 1.66 - 2.10 (m, 12H), 1.40 - 1.57 (m, 2H). LCMS (ESI, m/z): 499 [M+H] ⁺ .

Example 34: N-(l-(l-(2-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-4-chloroben zyl)-l,8- diazaspiro[4.5]decane-8-carbonyl -lH-pyrazol-3-yl)acetamide

[00211] The title compound was synthesized as described in Example 3 using 8-oxa-3- azabicyclo[3.2.1]octane and 4-chloro-2-fluorobenzaldehyde in Step 2 and tert-butyl 1,8- diazaspiro[4.5]decane-8-carboxylate in Step 3. Purification resulted in 24.8 mg of N-(l-(l-(2-(8- oxa-3-azabicyclo[3.2.1]octan-3-yl)-4-chlorobenzyl)-l,8-diaza spiro[4.5]decane-8-carbonyl)-lH- pyrazol-3-yl)acetamide as a white solid. 1H MR (400 MHz, Chloroform-i ) δ 8.02 (d, J= 2.8 Hz, 1H), 7.70 (br, 1H), 7.51 - 7.54 (m, 1H), 7.05 (br, 2H), 6.90 (s, 1H), 4.61 - 4.63 (m, 2H), 4.42 (br, 2H), 3.70 (s, 2H), 3.04 - 3.11 (m, 4H), 2.65 - 2.77 (m, 4H), 2.21 (s, 3H), 2.00 - 2.15 (m, 4H), 1.70 - 1.88 (m, 6H), 1.45 - 1.55 (m, 2H). LCMS (ESI, m/z): 527 [M+H] ⁺ .

Example 35: N-(l-(l-(4-chloro-2-(4-(methylsulfonyl)piperazin-l-yl)benzyl )-l,8- diazaspiro[4.5]decane-8-carbonyl -lH-pyrazol-3-yl)acetamide

[00212] The title compound was synthesized as described in Example 3 using 1- (m ethyl sulfonyl)piperazine and 4-chloro-2-fluorobenzaldehyde in Step 2 and tert-butyl 1,8- diazaspiro[4.5]decane-8-carboxylate in Step 3. Purification resulted in 74.8 mg of N-(l-(l-(4- chloro-2-(4-(methylsulfonyl)piperazin-l-yl)benzyl)-l,8-diaza spiro[4.5]decane-8-carbonyl)-lH- pyrazol-3-yl)acetamide as a light yellow solid. 1H MR (300 MHz, Chloroform- ) δ 7.95 - 8.00 (m, 2H), 7.40 - 7.43 (m, 1H), 7.03 - 7.09 (m, 2H), 6.89 (d, J= 2.4 Hz, 1H), 4.61 - 4.65 (m, 2H), 3.64 (s, 2H), 3.39 (br, 4H), 2.98 - 3.12 (m, 6H), 2.89 (s, 3H), 2.69 (br, 2H), 2.20 (s, 3H), 1.80 - 2.01 (m, 6H), 1.45 - 1.49 (m, 2H). LCMS (ESI, m/z): 578 [M+H] ⁺ .

Example 36: N-(l-(l-(2-(4-acetylpiperazin-l-yl)-4-chlorobenzyl)-l,8-diaz aspiro[4.5]decane- 8-carbonyl)-lH-pyrazol-3-yl)acetamide

[00213] The title compound was synthesized as described in Example 3 using l-(piperazin-l- yl)ethanone and 4-chloro-2-fluorobenzaldehyde in Step 2 and tert-butyl 1,8- diazaspiro[4.5]decane-8-carboxylate in Step 3. Purification resulted in 99.2 mg of N-(l-(l-(2-(4- acetylpiperazin-l-yl)-4-chlorobenzyl)-l,8-diazaspiro[4.5]dec ane-8-carbonyl)-lH-pyrazol-3- yl)acetamide as a white solid. 1H MR (300 MHz, Chloroform- ) δ 8.00 (d, J= 2.7 Hz, 2H), 7.40 - 7.42 (m, 1H), 6.99 - 7.07 (m, 2H), 6.89 (s, 1H), 4.59 - 4.63 (m, 2H), 3.77 (br, 2H), 3.60 - 3.66 (m, 4H), 2.92 - 3.07 (m, 6H), 2.65 - 2.77 (m, 2H), 2.22 (s, 3H), 2.14 (s, 3H), 1.80 - 1.93 (m, 6H), 1.45 - 1.49 (m, 2H). LCMS (ESI, m/z): 542 [M+H] ⁺ .

Example 37: N-(l-(l-(4-chloro-2-(2-(methylsulfonyl)-2,8-diazaspiro[4.5]d ecan-8-yl)benzyl)- l,8-diazaspiro[4.5]decane-8-carbonyl)-lH-pyrazol-3-yl)acetam ide

[00214] The title compound was synthesized as described in Example 26 using 4-chloro-2- fluorobenzaldehyde in Step 1. Purification resulted in 43.1 mg of N-(l-(l-(4-chloro-2-(2- (methylsulfonyl)-2,8-diazaspiro[4.5]decan-8-yl)benzyl)-l,8-d iazaspiro[4.5]decane-8-carbonyl)- lH-pyrazol-3-yl)acetamide as a white solid. 1H NMR (400 MHz, Chloroform-i ) δ 8.01 (d, J = 2.4 Hz, 1H), 7.79 (br, 1H), 7.47 (br, 1H), 7.04 (br, 2H), 6.90 (d, J= 2.4 Hz, 1H), 4.61 - 4.63 (m, 2H), 3.63 (br, 2H), 3.46 (t, J= 7.2 Hz, 2H), 3.26 (s, 2H), 3.03 - 3.10 (m, 2H), 2.81 - 2.88 (m, 7H), 2.69 (br, 2H), 2.21 (s, 3H), 1.70 - 1.92 (m, 12H), 1.51 - 1.61 (m, 2H). LCMS (ESI, m/z): 632 [M+H] ⁺ .

Example 38: N-(l-(l-(4-chloro-2-(2-(methylsulfonyl)-2,6-diazaspiro[3.4]o ctan-6-yl)benzyl)- l,8-diazaspiro[4.5]decane-8-carbonyl)-lH-pyrazol-3-yl)acetam ide

[00215] The title compound was synthesized as described in Example 27 using 4-chloro-2- fluorobenzaldehyde in Step 1. Purification resulted in 57.3 mg of N-(l-(l-(4-chloro-2-(2- (methylsulfonyl)-2,6-diazaspiro[3.4]octan-6-yl)benzyl)-l,8-d iazaspiro[4.5]decane-8-carbonyl)- lH-pyrazol-3-yl)acetamide as a white solid. 1H MR (400 MHz, Chloroform- ) δ 8.02 - 8.08 (m, 2H), 7.47 - 7.49 (m, 1H), 6.91 - 6.98 (m, 3H), 4.64 - 4.73 (m, 2H), 3.96 (s, 4H), 3.60 (s, 2H), 3.33 (s, 2H), 3.19 - 3.22 (m, 2H), 3.01 - 3.08 (m, 2H), 2.91 (s, 3H), 2.63 - 2.66 (m, 2H), 2.19 - 2.21 (m, 5H), 1.78 - 1.88 (m, 6H), 1.49 - 1.52 (m, 2H). LCMS (ESI, m/z): 604 [M+H] ⁺ .

Example 39: N-(l-(4-(2-(piperidin-l-yl)-4-(trifluoromethyl)benzyl)pipera zine-l-carbonyl)- lH-pyrazol-3-yl)acetamide

Step 1: Synthesis of 2-(piperidin-l-yl)-4-(trifluoromethyl)benzaldehyde

[00216] A 50-mL round-bottom flask was charged with 2-fluoro-4-

(trifluoromethyl)benzaldehyde (0.500 g, 2.60 mmol, 1.00 equiv), DMSO (15 mL), piperidine (0.332 g, 3.90 mmol, 1.50 equiv), and potassium carbonate (1.08 g, 7.81 mmol, 3.00 equiv) under nitrogen. The resulting solution was stirred overnight at 100 °C and diluted with water (30 mL). The resulting solution was extracted with EtOAc (2 x 50 mL) and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column to provide 260 mg (39% yield) of 2-(piperidin-l -yl)-4-(trifluorom ethyl )benzaldehyde as a yellow oil. LCMS (ESI, m/z): 258 [M+H] ⁺ .

Step 2: Synthesis of -nitrophenyl 3-acetamido-lH-pyrazole-l-carboxylate

[00217] A 250-mL round-bottom flask was charged with N-(lH-pyrazol-3-yl)acetamide (6.00 g, 48.0 mmol, 1.00 equiv), DCM (120 mL), triethylamine (14.5 g, 143 mmol, 3.00 equiv), 4- nitrophenyl chloroformate (10.7 g, 53.1 mmol, 1.10 equiv). The resulting solution was stirred for 2 h at room temperature and concentrated under reduced pressure to provide 13.9 g (crude) of 4- nitrophenyl 3-acetamido-lH-pyrazole-l-carboxylate as a yellow semi-solid. LCMS (ESI, m/z): 291 [M+H] ⁺ .

Step 3: Synthesis of tert-butyl 4-(3-acetamido-lH-pyrazole-l-carbonyl)piperazine-l- carboxylate

[00218] A 500-mL round-bottom flask was charged with tert-butyl piperazine-l-carboxylate (7.44 g, 40.0 mmol, 1.00 equiv), DCM (120 mL), 4-nitrophenyl 3-acetamido-lH-pyrazole-l- carboxylate (13.9 g, 47.9 mmol, 1.20 equiv), triethylamine (12.1 g, 120 mmol, 3.00 equiv). The resulting solution was stirred overnight at room temperature and quenched with water (180 mL). The resulting solution was extracted with DCM (2 x 250 mL) and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column to provide 4.10 g (30% yield) of tert-butyl 4-(3-acetamido-lH-pyrazole-l-carbonyl)piperazine-l-carboxyla te as a white solid. LCMS (ESI, m/z): 338 [M+H] ⁺ .

Step 4: Synthesis of N-(l-(piperazine-l-carbonyl)-lH-pyrazol-3-yl)acetamide

[00219] A 100-mL round-bottom flask was charged with tert-butyl 4-(3-acetamido-lH-pyrazole- l-carbonyl)piperazine-l-carboxylate (600 mg, 1.78 mmol, 1.00 equiv), DCM (15 mL), TFA (4 mL). The resulting solution was stirred for 4 h at room temperature and concentrated under reduced pressure to provide 423 mg (crude) of N-(l-(piperazine-l-carbonyl)-lH-pyrazol-3- yl)acetamide as a light yellow oil. LCMS (ESI, m/z): 238 [M+H] ⁺ . Step 5: Synthesis of N-(l-(4-(2-(piperidin-l-yl)-4-(trifluoromethyl)benzyl)pipera zine-l- carbonyl)-lH-pyrazol-3-yl)acetamide

[00220] A 50-mL round-bottom flask was charged with 2-(piperidin-l-yl)-4- (trifluoromethyl)benzaldehyde (100 mg, 0.390 mmol, 1.00 equiv), DCE (10 mL), N-Q- (piperazine-l-carbonyl)-lH-pyrazol-3-yl)acetamide (93.0 mg, 0.390 mmol, 1.00 equiv), and triethylamine (118 mg, 1.17 mmol, 3.00 equiv). The mixture was stirred for 1 h at room temperature. Sodium triacetoxyborohydride (247 mg, 1.17 mmol, 3.00 equiv) was added. The resulting solution was stirred overnight at room temperature and quenched with water (30 mL). The resulting solution was extracted with DCM (2 x 50 mL) and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product (300 mg) was purified by preparative HPLC. Purification resulted in 90.0 mg (48% yield) of N-(l -(4-(2-(piperi din- l-yl)-4-(trifiuorom ethyl )benzyl)piperazine-l- carbonyl)-lH-pyrazol-3-yl)acetamide as a white solid. 1H NMR (300 MHz, Chloroform-<f) δ 8.01 (d, J= 2.7 Hz, 1H), 7.61 - 7.73 (m, 2H), 7.29 (br, 2H), 6.88 (d, J= 2.7 Hz, 1H), 3.84 (br, 4H), 3.63 (br, 2H), 2.86 (t, J= 5.1 Hz, 4H), 2.57 (br, 4H), 2.18 (s, 3H), 1.68 - 1.72 (m, 4H), 1.58 - 1.60 (m, 2H). LCMS (ESI, m/z): 479 [M+H] ⁺ .

Example 40: N-(l-(4-(2-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-4- (trifluoromethyl)benzyl)piperazine-l-carbonyl)-lH-pyrazol-3- yl)acetamide

[00221] The title compound was synthesized as described in Example 39 using 8-oxa-3- azabicyclo[3.2.1]octane in Step 1. Purification resulted in 135.4 mg of N-(l-(4-(2-(8-oxa-3- azabicyclo[3.2.1]octan-3-yl)-4-(trifluoromethyl)benzyl)piper azine-l-carbonyl)-lH-pyrazol-3- yl)acetamide as a white solid. 1H MR (300 MHz, Chloroform-i ) δ 8.02 (d, J= 2.7 Hz, 1H), 7.74 (br, 1H), 7.61 - 7.63 (m, 1H), 7.33 - 7.36 (m, 2H), 6.88 (d, J= 2.7 Hz, 1H), 4.41 (br, 2H), 3.84 (br, 4H), 3.66 (br, 2H), 3.10 (d, J = 10.2 Hz, 2H), 2.81 (d, J= 11.1 Hz, 2H), 2.54 (br, 4H), 2.18 (s, 3H), 2.08 - 2.12 (m, 2H), 1.99 - 2.02 (m, 2H). LCMS (ESI, m/z): 507 [M+H] ⁺ . Example 41: N-(l-(4-(2-(4-(methylsulfonyl)piperazin-l-yl)-4-

(trifluoromethyl)benzyl)piperazine-l-carbonyl)-lH-pyrazol -3-yl)acetamide

[00222] The title compound was synthesized as described in Example 39 using 1-

(m ethyl sulfonyl)piperazine in Step 1. Purification resulted in 65.0 mg of N-(l-(4-(2-(4-

(methylsulfonyl)piperazin-l-yl)-4-(trifluoromethyl)benzyl )piperazine-l-carbonyl)-lH-pyrazol-

3-yl)acetamide as a white solid. 1H NMR (300 MHz, Chloroform-i ) δ 8.02 (d, J= 2.7 Hz, 1H),

7.61 - 7.72 (m, 2H), 7.33 - 7.40 (m, 2H), 6.88 (d, J= 2.7 Hz, 1H), 3.84 (br, 4H), 3.62 (br, 2H),

3.41 (br, 4H), 3.10 (t, J = 4.5 Hz, 4H), 2.88 (s, 3H), 2.57 (br, 4H), 2.18 (s, 3H). LCMS (ESI, m/z): 558 [M+H] ⁺ .

Example 42: N-(l-(4-(2-(4-acetylpiperazin-l-yl)-4-(trifluoromethyl)benzy l)piperazine-l- carbonyl)-lH-pyrazol-3-yl)acetamide

[00223] The title compound was synthesized as described in Example 39 using l-(piperazin-l- yl)ethanone in Step 1. Purification resulted in 76.8 mg of N-(l-(4-(2-(4-acetylpiperazin-l-yl)-4- (trifluoromethyl)benzyl)piperazine-l-carbonyl)-lH-pyrazol-3- yl)acetamide as a white solid. 1H NMR (300 MHz, Chloroform-i ) δ 8.02 (d, J= 2.7 Hz, 1H), 7.61 - 7.78 (m, 2H), 7.36 - 7.39 (m, 1H), 7.30 (s, 1H), 6.88 (d, J= 2.7 Hz, 1H), 3.76 - 3.84 (m, 6H), 3.60 - 3.64 (m, 4H), 2.94 - 3.02 (m, 4H), 2.58 (br, 4H), 2.15 (s, 3H), 2.18 (s, 3H). LCMS (ESI, m/z): 522 [M+H] ⁺ .

Example 43: N-(l-(4-(2-(2-(methylsulfonyl)-2,8-diazaspiro[4.5]decan-8-yl )-4- (trifluoromethyl)benzyl)piperazi -l-carbonyl)-lH-pyrazol-3-yl)acetamide

[00224] The title compound was synthesized as described in Example 39, Steps 2-5 using 2-(2- (methylsulfonyl)-2,8-diazaspiro[4.5]decan-8-yl)-4-(trifluoro methyl)benzaldehyde (Example 26, Step 3) in Step 5. Purification resulted in 182.8 mg of N-(l-(4-(2-(2-(methylsulfonyl)-2,8- diazaspiro[4.5]decan-8-yl)-4-(trifluoromethyl)benzyl)piperaz ine-l-carbonyl)-lH-pyrazol-3- yl)acetamide as a white solid. 1H MR (300 MHz, Chloroform-i ) δ 8.06 (br, 1H), 7.64 - 7.72 (m, 2H), 7.34 (br, 2H), 6.91 (br, 1H), 3.87 (br, 4H), 3.64 (br, 2H), 3.49 (t, J= 7.0 Hz, 2H), 3.30 (s, 2H), 2.90 - 2.96 (m, 7H), 2.59 (br, 4H), 2.21 (s, 3H), 1.95 (t, J= 7.0 Hz, 2H), 1.80 (br, 4H). LCMS (ESI, m/z): 612 [M+H] ⁺ .

Example 44: N-(l-(4-(2-(2-(methylsulfonyl)-2,6-diazaspiro[3.4]octan-6-yl )-4- (trifluoromethyl)benzyl)piperazine-l-carbonyl)-lH-pyrazol-3- yl)acetamide

[00225] The title compound was synthesized as described in Example 39, Steps 2-5 using 2-(2- (methylsulfonyl)-2,6-diazaspiro[3.4]octan-6-yl)-4-(trifluoro methyl)benzaldehyde (Example 27, Step 3) in Step 5. Purification resulted in 51.4 mg of N-(l-(4-(2-(2-(methylsulfonyl)-2,6- diazaspiro[3.4]octan-6-yl)-4-(trifluoromethyl)benzyl)piperaz ine-l-carbonyl)-lH-pyrazol-3- yl)acetamide as a white solid. 1H MR (300 MHz, Chloroform-i ) δ 8.01 (d, J= 2.7 Hz, 1H), 7.83 (br, 1H), 7.54 (br, 1H), 7.19 (d, J= 8.1 Hz, 1H), 7.10 (s, 1H), 6.88 (d, J= 2.7 Hz, 1H), 3.91 - 3.97 (m, 4H), 3.84 (br, 4H), 3.58 (br, 2H), 3.47 (s, 2H), 3.30 (t, J= 7.0 Hz, 2H), 2.89 (s, 3H), 2.53 (br, 4H), 2.18 - 2.24 (m, 5H). LCMS (ESI, m/z): 584 [M+H] ⁺ .

Example 45: N-(l-(4-(2-(8-oxa-2-azaspiro[4.5]decan-2-yl)-4- (trifluoromethyl)benzyl)piperazine-l-carbonyl)-lH-pyrazol-3- yl)acetamide

[00226] The title compound was synthesized as described in Example 39 using 8-oxa-2- azaspiro[4.5]decane in Step 1. Purification resulted in 120 mg of N-(l-(4-(2-(8-oxa-2- azaspiro[4.5]decan-2-yl)-4-(trifluoromethyl)benzyl)piperazin e-l-carbonyl)-lH-pyrazol-3- yl)acetamide as a white solid. 1H MR (300 MHz, Chloroform-i ) δ 8.01 (d, J= 2.7 Hz, 1H), 7.77 (br, 1H), 7.48 - 7.50 (m, 1H), 7.07 - 7.12 (m, 2H), 6.87 (d, J= 2.7 Hz, 1H), 3.83 (br, 4H), 3.64 - 3.78 (m, 4H), 3.58 (br, 2H), 3.34 (t, J= 6.9 Hz, 2H), 3.20 (s, 2H), 2.53 (br, 4H), 2.17 (s, 3H), 1.86 (t, J= 7.0 Hz, 2H), 1.68 (t, J= 5.2 Hz, 4H). LCMS (ESI, m/z): 535 [M+H] ⁺ .

Example 46: N-(l-(4-(2-(4,4-difluoropiperidin-l-yl)-4-(trifluoromethyl)b enzyl)piperazine- l-carbonyl)-lH-pyrazol-3-yl)acetamide

[00227] The title compound was synthesized as described in Example 39 using 4,4- difluoropiperidine in Step 1. Purification resulted in 37.5 mg of N-(l-(4-(2-(4,4- difluoropiperi din- l-yl)-4-(trifluorom ethyl )benzyl)piperazine-l-carbonyl)-lH-pyrazol-3- yl)acetamide as a white solid. 1H MR (300 MHz, Chloroform-i ) δ 8.02 (d, J= 2.7 Hz, 1H), 7.61 - 7.69 (m, 2H), 7.35 - 7.38 (m, 2H), 6.88 (d, J= 2.7 Hz, 1H), 3.84 (br, 4H), 3.62 (m, 2H), 3.06 - 3.10 (m, 4H), 2.57 (br, 4H), 2.08 - 2.18 (m, 7H). LCMS (ESI, m/z): 515 [M+H] ⁺ .

Example 47: N-(l-(4-(2-(4-cyclopropylpiperazin-l-yl)-4- (trifluoromethyl)benzyl)piperazine-l-carbonyl)-lH-pyrazol-3- yl)acetamide

[00228] The title compound was synthesized as described in Example 39 using 1- cyclopropylpiperazine in Step 1. Purification resulted in 110 mg of N-(l-(4-(2-(4- cyclopropylpiperazin-l-yl)-4-(trifluoromethyl)benzyl)piperaz ine-l-carbonyl)-lH-pyrazol-3- yl)acetamide as a white solid. 1H MR (300 MHz, Chloroform-i ) δ 8.02 (d, J= 2.7 Hz, 1H), 7.68 (br, 1H), 7.59 (d, J= 8.4 Hz, 1H), 7.30 - 7.32 (m, 2H), 6.88 (d, J= 2.7 Hz, 1H), 3.83 (br, 4H), 3.63 (s, 2H), 2.96 (br, 4H), 2.78 (br, 4H), 2.57 (t, J= 5.0 Hz, 4H), 2.18 (s, 3H), 1.17 (br, 1H), 0.49 - 0.51 (m, 4H). LCMS (ESI, m/z): 520 [M+H] ⁺ .

Example 48: N-(l-(4-(2-(4-ethylpiperazin-l-yl)-4-(trifluoromethyl)benzyl )piperazine-l- carbonyl)-lH-pyrazol-3-yl)acetamide

[00229] The title compound was synthesized as described in Example 39 using 1 -ethylpiperazine in Step 1. Purification resulted in 58.0 mg of N-(l-(4-(2-(4-ethylpiperazin-l-yl)-4- (trifluoromethyl)benzyl)piperazine-l-carbonyl)-lH-pyrazol-3- yl)acetamide as a white solid. 1H NMR (300 MHz, Chloroform-i ) δ 8.02 (d, J= 2.7 Hz, 1H), 7.68 (br, 1H), 7.59 (d, J= 8.4 Hz, 1H), 7.31 - 7.33 (m, 2H), 6.87 (d, J= 2.7 Hz, 1H), 3.89 (br, 4H), 3.61 (s, 2H), 3.07 (br, 4H), 2.67 (br, 4H), 2.54 - 2.57 (m, 6H), 2.18 (s, 3H), 1.19 (t, J= 7.0 Hz, 3H). LCMS (ESI, m/z): 508 [M+H] ⁺

Example 49: N-(l-(4-(2-(dihydro-lH-furo[3,4-c]pyrrol-5(3H,6H,6aH)-yl)-4- (trifluoromethyl)benzyl)piperazine-l-carbonyl)-lH-pyrazol-3- yl)acetamide

^FJC O I LO¼ NHcocH _j

[00230] The title compound was synthesized as described in Example 39 using hexahydro-lH- furo[3,4-c]pyrrole in Step 1. Purification resulted in 91.7 mg of N-(l-(4-(2-(dihydro-lH- furo[3,4-c]pyrrol-5(3H,6H,6aH)-yl)-4-(trifluoromethyl)benzyl )piperazine-l-carbonyl)-lH- pyrazol-3-yl)acetamide as a white solid. 1H MR (300 MHz, Chloroform- ) δ 8.01 (d, J= 2.7 Hz, 1H), 7.85 (br, 1H), 7.59 - 7.61 (m, 1H), 7.26 - 7.30 (m, 2H), 6.88 (d, J= 2.7 Hz, 1H), 4.03 (t, J= 7.8 Hz, 2H), 3.83 (br, 4H), 3.61 - 3.65 (m, 4H), 3.09 - 3.17 (m, 2H), 3.03 (d, J= 4.8 Hz, 2H), 2.90 (br, 2H), 2.56 (br, 4H), 2.18 (s, 3H). LCMS (ESI, m/z): 507 [M+H] ⁺ .

Example 50: N-(l-(4-(4-chloro-2-(piperidin-l-yl)benzyl)piperazine-l-carb onyl)-lH- pyrazol-3-yl)acetamide

[00231] The title compound was synthesized as described in Example 39 using piperidine and 4- chloro-2-fluorobenzaldehyde in Step 1. Purification resulted in 118.7 mg of N-(l-(4-(4-chloro-2- (piperidin-l-yl)benzyl)piperazine-l-carbonyl)-lH-pyrazol-3-y l)acetamide as a white solid. 1H NMR (300 MHz, Chloroform-i ) δ 8.01 (d, J= 2.7 Hz, 1H), 7.75 (br, 1H), 7.37 - 7.39 (m, 1H), 7.00 - 7.03 (m, 2H), 6.87 (d, J= 2.7 Hz, 1H), 3.81 (br, 4H), 3.54 (br, 2H), 2.83 (t, J= 5.0 Hz, 4H), 2.54 (br, 4H), 2.18 (s, 3H), 1.67 - 1.72 (m, 4H), 1.56 - 1.58 (m, 2H). LCMS (ESI, m/z): 445 [M+H] ⁺ . Example 51: N-(l-(4-(2-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-4-chloroben zyl)piperazine-l- carbonyl)-lH-pyrazol-3-yl)acetamide

[00232] The title compound was synthesized as described in Example 39 using 8-oxa-3- azabicyclo[3.2.1]octane and 4-chloro-2-fluorobenzaldehyde in Step 1. Purification resulted in 37.2 mg of N-(l-(4-(2-(8-oxa-3-azabicyclo[3.2. l]octan-3-yl)-4-chlorobenzyl)piperazine-l- carbonyl)-lH-pyrazol-3-yl)acetamide as a light yellow oil. 1H NMR (300 MHz, Chloroform-<f) δ 8.02 (d, J= 2.7 Hz, 1H), 7.82 (br, 1H), 7.39 (d, J= 8.1 Hz, 1H), 7.05 - 7.10 (m, 2H), 6.88 (d, J = 2.7 Hz, 1H), 4.39 (br, 2H), 3.83 (br, 4H), 3.60 (s, 2H), 3.02 - 3.06 (m, 2H), 2.80 (d, J= 11.1 Hz, 2H), 2.53 (br, 4H), 2.18 (s, 3H), 2.02 - 2.13 (m, 2H), 1.93 - 2.00 (m, 2H). LCMS (ESI, m/z): 473 [M+H] ⁺ .

Example 52: N-(l-(4-(4-chloro-2-(4-(methylsulfonyl)piperazin-l-yl)benzyl )piperazine-l- carbonyl)-lH-pyrazol-3-yl)acetamide

[00233] The title compound was synthesized as described in Example 39 using 1- (m ethyl sulfonyl)piperazine and 4-chloro-2-fluorobenzaldehyde in Step 1. Purification resulted in 73.0 mg of N-( 1 -(4-(4-chloro-2-(4-(m ethyl sulfonyl)piperazin- 1 -yl)benzyl)piperazine- 1 - carbonyl)-lH-pyrazol-3-yl)acetamide as a white solid. 1H NMR (300 MHz, Chloroform-<f) δ 8.01 (d, J= 2.7 Hz, 1H), 7.74 (br, 1H), 7.38 (d, J= 8.1 Hz, 1H), 7.06 - 7.12 (m, 2H), 6.87 (d, J = 2.7 Hz, 1H), 3.83 (br, 4H), 3.55 (br, 2H), 3.36 - 3.39 (m, 4H), 3.06 - 3.09 (m, 4H), 2.87 (s, 3H), 2.55 (br, 4H), 2.18 (s, 3H). LCMS (ESI, m/z): 524 [M+H] ⁺ .

Example 53: N-(l-(4-(2-(4-acetylpiperazin-l-yl)-4-chlorobenzyl)piperazin e-l-carbonyl)- lH-pyrazol-3-yl)acetamide

[00234] The title compound was synthesized as described in Example 39 using l-(piperazin-l- yl)ethanone and 4-chloro-2-fluorobenzaldehyde in Step 1. Purification resulted in 44.0 mg of N- ( 1 -(4-(2-(4-acetylpiperazin- 1 -yl)-4-chlorobenzyl)piperazine- 1 -carbonyl)- lH-pyrazol-3 - yl)acetamide as a white solid. 1H MR (300 MHz, Chloroform-i ) δ 8.01 (d, J= 2.7 Hz, 1H), 7.72 (br, 1H), 7.36 (br, 1H), 7.04 - 7.11 (m, 2H), 6.88 (d, J= 2.7 Hz, 1H), 3.74 - 3.82 (m, 6H), 3.58 - 3.61 (m, 4H), 2.93 - 2.98 (m, 4H), 2.55 (br, 4H), 2.18 (s, 3H), 2.15 (s, 3H). LCMS (ESI, m/z): 488 [M+H] ⁺ .

Example 54: N-(l-(4-(4-chloro-2-(2-(methylsulfonyl)-2,8-diazaspiro[4.5]d ecan-8- yl)benzyl)piperazine-l-carbonyl)-lH-pyrazol-3-yl)acetamide

[00235] The title compound was synthesized as described in Example 39, Step 5 using 4-chloro- 2-(2-(methylsulfonyl)-2,8-diazaspiro[4.5]decan-8-yl)benzalde hyde (synthesized as described in Example 26 using 4-chloro-2-fluorobenzaldehyde in Step 1). Purification resulted in 282.6 mg of N-(l-(4-(4-chloro-2-(2-(methylsulfonyl)-2,8-diazaspiro[4.5]d ecan-8-yl)benzyl)piperazine-l- carbonyl)-lH-pyrazol-3-yl)acetamide as a white solid. 1H NMR (300 MHz, Chloroform-<f) δ 8.01 (d, J= 2.7 Hz, 1H), 7.80 (br, 1H), 7.39 (br, 1H), 7.05 - 7.07 (m, 2H), 6.88 (d, J= 2.7 Hz, 1H), 3.84 (br, 4H), 3.56 (br, 2H), 3.44 (t, J= 7.0 Hz, 2H), 3.25 (s, 2H), 2.81 - 2.97 (m, 7H), 2.56 (br, 4H), 2.18 (s, 3H), 1.90 (t, J= 7.2 Hz, 2H), 1.69 - 1.79 (m, 4H). LCMS (ESI, m/z): 578

[M+H] ⁺ .

Example 55: N-(l-(4-(4-chloro-2-(2-(methylsulfonyl)-2,6-diazaspiro[3.4]o ctan-6- yl)benzyl)piperazine-l-carbonyl)- -pyrazol-3-yl)acetamide

[00236] The title compound was synthesized as described in Example 39, Step 5 using 4-chloro- 2-(2-(methylsulfonyl)-2,6-diazaspiro[3.4]octan-6-yl)benzalde hyde (synthesized as described in Example 27 using 4-chloro-2-fluorobenzaldehyde in Step 1). Purification resulted in 125.3 mg of N-(l-(4-(4-chloro-2-(2-(methylsulfonyl)-2,6-diazaspiro[3.4]o ctan-6-yl)benzyl)piperazine-l- carbonyl)-lH-pyrazol-3-yl)acetamide as a white solid. 1H NMR (300 MHz, Chloroform-<f) δ 8.00 (d, J= 2.7 Hz, 1H), 7.89 (br, 1H), 7.29 (d, J= 8.1 Hz, 1H), 6.85 - 6.92 (m, 3H), 3.89 - 3. (br, 4H), 3.81 (br, 4H), 3.46 (d, J= 14.1 Hz, 4H), 3.27 (t, J= 6.9 Hz, 2H), 2.89 (s, 3H), 2.48 - 2.52 (m, 4H), 2.16 - 2.21 (m, 5H). LCMS (ESI, m/z): 550 [M+H] ⁺ .

Example 56: N-(l-(4-(4-chloro-2-(8-oxa-2-azaspiro[4.5]decan-2-yl)benzyl) piperazine-l- carbonyl)-lH-pyrazol-3-yl)acetamide

[00237] The title compound was synthesized as described in Example 39 using 8-oxa-2- azaspiro[4.5]decane and 4-chloro-2-fluorobenzaldehyde in Step 1. Purification resulted in 107.4 mg of N-(l-(4-(4-chloro-2-(8-oxa-2-azaspiro[4.5]decan-2-yl)benzyl) piperazine-l-carbonyl)-lH- pyrazol-3-yl)acetamide as a white solid. 1H MR (300 MHz, Chloroform-i ) δ 8.00 (d, J= 2.7 Hz, 1H), 7.72 (br, 1H), 7.26 (br, 1H), 6.84 - 6.91 (m, 3H), 3.81 (br, 4H), 3.62 - 3.77 (m, 4H), 3.51 (br, 2H), 3.31 (t, J= 6.9 Hz, 2H), 3.18 (br, 2H), 2.51 (br, 4H), 2.18 (s, 3H), 1.84 (t, J= 6.9 Hz, 2H), 1.66 (t, J= 5.4 Hz, 4H). LCMS (ESI, m/z): 501 [M+H] ⁺ .

Example 57: N-(l-(4-(4-chloro-2-(4,4-difluoropiperidin-l-yl)benzyl)piper azine-l- carbonyl)-lH-pyrazol-3-yl)acetamide

[00238] The title compound was synthesized as described in Example 39 using 4,4- difluoropiperidine and 4-chloro-2-fluorobenzaldehyde in Step 1. Purification resulted in 30.8 mg of N-(l-(4-(4-chloro-2-(4,4-difluoropiperidin-l-yl)benzyl)piper azine-l-carbonyl)-lH-pyrazol-3- yl)acetamide as a white solid. 1H MR (300 MHz, Chloroform-i ) δ 8.01 (d, J= 2.7 Hz, 1H), 7.70 (br, 1H), 7.38 (d, J= 8.4 Hz, 1H), 7.04 - 7.09 (m, 2H), 6.88 (d, J= 2.7 Hz, 1H), 3.82 (br, 4H), 3.56 (br, 2H), 3.05 (t, J= 5.4 Hz, 4H), 2.56 (br, 4H), 2.18 (s, 3H), 2.05 - 2.14 (m, 4H). LCMS (ESI, m/z): 481 [M+H] ⁺ . Example 58: N-(l-(4-(4-chloro-2-(4-cyclopropylpiperazin-l-yl)benzyl)pipe razine-l- carbonyl)-lH-pyrazol-3-yl)acetamide

[00239] The title compound was synthesized as described in Example 39 using 1- cyclopropylpiperazine and 4-chloro-2-fluorobenzaldehyde in Step 1. Purification resulted in 98.3 mg of N-(l-(4-(4-chloro-2-(4-cyclopropylpiperazin-l-yl)benzyl)pipe razine-l-carbonyl)- lH-pyrazol-3-yl)acetamide as a white solid. 1H NMR (300 MHz, Chloroform-i ) δ 8.01 (d, J = 2.7 Hz, 1H), 7.74 (br, 1H), 7.34 - 7.37 (m, 1H), 7.01 - 7.05 (m, 2H), 6.87 (d, J= 2.7 Hz, 1H), 3.81 (br, 4H), 3.55 (br, 2H), 2.92 - 2.93 (m, 4H), 2.76 (br, 4H), 2.55 (t, J= 5.0 Hz, 4H), 2.18 (s, 3H), 1.66 - 1.70 (m, 1H), 0.46 - 0.53 (m, 4H). LCMS (ESI, m/z): 486 [M+H] ⁺ .

Example 59: N-(l-(4-(4-chloro-2-(4-ethylpiperazin-l-yl)benzyl)piperazine -l-carbonyl)-lH- pyrazol-3-yl)acetamide

[00240] The title compound was synthesized as described in Example 39 using 1 -ethylpiperazine and 4-chloro-2-fluorobenzaldehyde in Step 1. Purification resulted in 94.9 mg of N-(l-(4-(4- chloro-2-(4-ethylpiperazin-l-yl)benzyl)piperazine-l-carbonyl )-lH-pyrazol-3-yl)acetamide as an off-white solid. 1H MR (300 MHz, Chloroform-i ) δ 8.01 (d, J= 2.7 Hz, 1H), 7.72 (br, 1H), 7.36 (d, J= 8.1 Hz, 1H), 7.03 - 7.06 (m, 2H), 6.87 (d, J= 2.7 Hz, 1H), 3.80 (br, 4H), 3.53 (s, 2H), 3.01 - 3.03 (m, 4H), 2.64 (br, 4H), 2.52 - 2.57 (m, 6H), 2.18 (s, 3H), 1.16 (d, J= 7.2 Hz, 3H). LCMS (ESI, m/z): 474 [M+H] ⁺ .

Example 60: N-(l-(4-(4-chloro-2-(dihydro-lH-furo[3,4-c]pyrrol-5(3H,6H,6a H)- yl)benzyl)piperazine-l-carbonyl)-lH-pyrazol-3-yl)acetamide

[00241] The title compound was synthesized as described in Example 39 using hexahydro-lH- furo[3,4-c]pyrrole and 4-chloro-2-fluorobenzaldehyde in Step 1. Purification resulted in 101 mg ofN-(l-(4-(4-chloro-2-(dihydro-lH-furo[3,4-c]pyrrol-5(3H,6H, 6aH)-yl)benzyl)piperazine-l- carbonyl)-lH-pyrazol-3-yl)acetamide as a white solid. 1H NMR (300 MHz, Chloroform-<f) δ 8.00 (d, J= 2.7 Hz, 1H), 7.81 (br, 1H), 7.32 - 7.38 (m, 1H), 7.00 - 7.01 (m, 2H), 6.87 (d, J= 2.7 Hz, 1H), 4.01 - 4.09 (m, 2H), 3.81 (br, 4H), 3.53 - 3.63 (m, 4H), 2.98 - 3.11 (m, 4H), 2.93 (br, 2H), 2.54 (br, 4H), 2.18 (s, 3H). LCMS (ESI, m/z): 473 [M+H] ⁺ .

Example 61: N-(l-(l-(3-(pyrrolidin-l-yl)-5-(trifluoromethyl)benzyl)-l,8- diazaspiro[4.5]decane-8-carbonyl)-lH-pyrazol-3-yl)acetamide

Step 1: Synthesis of 3-(pyrrolidin-l-yl)-5-(trifluoromethyl)benzaldehyde

[00242] A 100-mL round-bottom flask was charged with 3-bromo-5-

(trifluoromethyl)benzaldehyde (2.00 g, 7.90 mmol, 1.00 equiv), toluene (50 mL), pyrrolidine (0.840 g, 11.8 mmol, 1.50 equiv), cesium carbonate (5.15 g, 15.8 mmol, 2.00 equiv), 2,2'- bis(diphenylphosphino)-l,l'-binaphthyl (0.492 g, 0.790 mmol, 0.10 equiv), and

tris(dibenzylideneacetone)dipalladium (0.361 g, 0.390 mmol, 0.05 equiv) under nitrogen. The resulting solution was stirred overnight at 80 °C and quenched by water (50 mL). The mixture was extracted with EtOAc (3 x 50 mL) and the organic layers were combined, washed with water (3 x 50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column to provide 1.25 g (65% yield) of 3- (pyrrolidin-l-yl)-5-(trifluoromethyl)benzaldehyde as a yellow solid. LCMS (ESI, m/z): 244 [M+H] ⁺ .

Step 2: Synthesis of tert-butyl l-(3-(pyrrolidin-l-yl)-5-(trifluoromethyl)benzyl)-l,8- diazaspiro [4.5] decane- -carboxylate

[00243] A 40-mL vial was charged with 3-(pyrrolidin-l-yl)-5-(trifluoromethyl)benzaldehyde (243 mg, 1.00 mmol, 1.00 equiv), DCE (10 mL), and tert-butyl l,8-diazaspiro[4.5]decane-8- carboxylate (288 mg, 1.20 mmol, 1.20 equiv). The mixture was stirred for 2 h at room temperature. Then sodium triacetoxyborohydride (530 mg, 2.50 mmol, 2.50 equiv) was added. The resulting solution was stirred overnight at room temperature and quenched by water (10 mL). The mixture was extracted with DCM (3 x 10 mL) and the organic layers were combined, washed with water (3 x 10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column to provide 344 mg (74% yield) of tert-butyl l-(3-(pyrrolidin-l-yl)-5-(trifluoromethyl)benzyl)-l,8- diazaspiro[4.5]decane-8-carboxylate as a yellow oil. LCMS (ESI, m/z): 468 [M+H] ⁺ .

Step 3: Synthesis of l-(3-(pyrrolidin-l-yl)-5-(trifluoromethyl)benzyl)-l,8- diazaspiro [4.5] decan

[00244] A 40-mL vial was charged with tert-butyl l-(3-(pyrrolidin-l-yl)-5- (trifluoromethyl)benzyl)-l,8-diazaspiro[4.5]decane-8-carboxy late (344 mg, 0.740 mmol, 1.00 equiv), MeOH (5 mL), and hydrogen chloride (1 mL). The resulting solution was stirred overnight at room temperature and concentrated under reduced pressure to provide 210 mg (crude) of l-(3-(pyrrolidin-l-yl)-5-(trifluoromethyl)benzyl)-l,8-diazas piro[4.5]decane as a white solid. LCMS (ESI, m/z): 368 [M+H] ⁺ .

Step 4: Synthesis of N-(l-(l-(3-(pyrrolidin-l-yl)-5-(trifluoromethyl)benzyl)-l,8- diazaspiro[4.5]decane-8-carbonyl)-lH-pyrazol-3-yl)acetamide

[00245] A 40-mL vial was charged with N-(lH-pyrazol-3-yl)acetamide (71.5 mg, 0.570 mmol, 1.00 equiv), DCM (10 mL), and N,N-diisopropylethylamine (148 mg, 1.15 mmol, 2.00 equiv). 4-Nitrophenyl chloroformate (127 mg, 0.630 mmol, 1.10 equiv) in DCM (2 mL) was added dropwise at 0 °C. The resulting solution was stirred for 2 h at room temperature. Then l -(3- (pyrrolidin-l-yl)-5-(trifluoromethyl)benzyl)-l,8-diazaspiro[ 4.5]decane (210 mg, 0.570 mmol, 1.00 equiv) was added. The resulting solution was stirred overnight at room temperature and quenched by water (10 mL). The mixture was extracted with DCM (3 x 10 mL) and the organic layers were combined, washed with water (3 x 10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC. Purification resulted in 79.7 mg (27% yield) of N-(l-(l-(3-(pyrrolidin-l-yl)-5- (trifluoromethyl)benzyl)-l,8-diazaspiro[4.5]decane-8-carbony l)-lH-pyrazol-3-yl)acetamide as an off-white solid. 1H MR (400 MHz, Chloroform-i ) δ 8.10 (d, J= 2.6 Hz, 1H), 7.81 (s, 1H), 6.75 - 7.00 (m, 2H), 6.45 - 6.72 (m, 2H), 4.50 - 4.71 (m, 2H), 3.55 - 3.85 (m, 2H), 3.20 - 3.40 (m, 4H), 3.28 (t, J= 3.0 Hz, 2H), 2.60 - 2.85 (m, 2H), 2.22 (s, 3H), 2.00 - 2.10 (m, 4H), 1.70 - 2.00 (m, 6H), 1.45 - 1.60 (m, 2H). LCMS (ESI, m/z): 519 [M+H] ⁺ .

Example 62: N-(l-(l-(3-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-5-(trifluor omethyl)benzyl)- l,8-diazaspiro[4.5]decane-8-carb nyl)-lH-pyrazol-3-yl)acetamide

[00246] The title compound was synthesized as described in Example 61 using 3-oxa-8- azabicyclo[3.2.1]octane in Step 1. Purification resulted in 133.3 mg of N-(l-(l-(3-(3-oxa-8- azabicyclo[3.2.1]octan-8-yl)-5-(trifluoromethyl)benzyl)-l,8- diazaspiro[4.5]decane-8-carbonyl)- lH-pyrazol-3-yl)acetamide as an off-white solid. 1H NMR (300 MHz, Chloroform- ) δ 7.50 - 8.10 (m, 2H), 6.65 - 7.05 (m, 4H), 4.40 - 4.80 (m, 2H), 4.00 - 4.20 (m, 2H), 3.81 - 4.00 (m, 2H), 3.30 - 3.80 (m, 4H), 3.00 (t, J= 12.8 Hz, 2H), 2.55 - 2.85 (m, 2H), 2.20 (s, 3H), 1.96 - 2.15 (m, 4H), 1.68 - 1.96 (m, 6H), 1.37 - 1.60 (m, 2H). LCMS (ESI, m/z): 561 [M+H] ⁺ .

Example 63: N-(l-(l-(3-chloro-5-(pyrrolidin-l-yl)benzyl)-l,8-diazaspiro[ 4.5]decane-8- carbonyl)-lH-pyrazol-3-yl)acetamide

COCH _j

[00247] The title compound was synthesized as described in Example 61 using pyrrolidine and 3-bromo-5-chlorobenzaldehyde in Step 1. Purification resulted in 41.3 mg of N-(l-(l-(3-chloro- 5-(pyrrolidin-l-yl)benzyl)-l,8-diazaspiro[4.5]decane-8-carbo nyl)-lH-pyrazol-3-yl)acetamide as an off-white solid. 1H NMR (300 MHz, Chloroform-i ) δ 8.02 (d, J= 2.7 Hz, 1H), 7.88 (s, 1H), 7.89 (d, J= 2.7 Hz, 1H), 6.60 (s, 1H), 6.38 - 6.56 (m, 2H), 4.45 - 4.70 (m, 2H), 3.40 - 3.68 (s, 2H), 3.25 (m, 4H), 2.95 - 3.15 (m, 2H), 2.69 - 2.80 (m, 2H), 2.20 (s, 3H), 1.73 - 2.10 (m, 10H), 1.38 - 1.58 (m, 2H). LCMS (ESI, m/z): 485 [M+H] ⁺ .

Example 64: N-(l-(l-(3-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-5-chloroben zyl)-l,8- diazaspiro[4.5]decane-8-carbonyl -lH-pyrazol-3-yl)acetamide

[00248] The title compound was synthesized as described in Example 61 using 3-oxa-8- azabicyclo[3.2.1]octane and 3-bromo-5-chlorobenzaldehyde in Step 1. Purification resulted in 13.2 mg ofN-(l-(l-(3-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-5-chlorob enzyl)-l,8- diazaspiro[4.5]decane-8-carbonyl)-lH-pyrazol-3-yl)acetamide as a yellow oil. 1H NMR (300 MHz, Chloroform-ύ δ 8.05 (s, 1H), 7.90 (br, 1H), 6.78 - 6.98 (m, 1H), 6.72 (s, 1H), 6.46 - 6.65 (m, 2H), 4.45 - 4.60 (m, 2H), 4.00 - 4.20 (m, 2H), 3.78 - 3.98 (m, 2H), 3.48 - 3.65 (m, 4H), 2.95 - 3.20 (m, 2H), 2.60 - 2.80 (m, 2H), 2.20 (s, 3H), 1.98 - 2.15 (m, 4H), 1.72 - 1.96 (m, 6H), 1.39 - 1.60 (m, 2H). LCMS (ESI, m/z): 527 [M+H] ⁺ .

Example 65: N-(l-(l-(3-(5-acetylhexahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)- 5-chlorobenzyl)- l,8-diazaspiro[4.5]decane-8-carbonyl)-lH-pyrazol-3-yl)acetam ide

Step 1: Synthesis of tert-butyl 5-(3-chloro-5-formylphenyl)hexahydropyrrolo[3,4-c]pyrrole- 2(lH)-carboxylate

[00249] A 40-mL vial was charged with 3-bromo-5-chlorobenzaldehyde (219 mg, 1.00 mmol, 1.00 equiv), toluene (10 mL), tert-butyl octahydropyrrolo[3,4-c]pyrrole-2-carboxylate (254 mg, 1.20 mmol, 1.20 equiv), cesium carbonate (652 mg, 2.00 mmol, 2.01 equiv), 2,2'- bis(diphenylphosphino)-l, l'-binaphthyl (62.3 mg, 0.10 mmol, 0.10 equiv), and tris(dibenzylideneacetone)dipalladium (45.8 mg, 0.050 mmol, 0.05 equiv) under nitrogen. The resulting solution was stirred overnight at 80 °C and quenched by water (20 mL). The mixture was extracted with EtOAc (3 x 20 mL) and the organic layers were combined, washed with water (3 x 20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column to give 1 13 mg (32% yield) of tert-butyl 5-(3-chloro-5-formylphenyl)hexahydropyrrolo[3,4-c]pyrrole-2( lH)-carboxylate as a yellow oil. LCMS (ESI, m/z): 351 [M+H] ⁺ .

Step 2: Synthesis of 3-chloro-5-(hexahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)benzaldeh yde

[00250] A 40-mL vial was charged with tert-butyl 5-(3-chloro-5- formylphenyl)hexahydropyrrolo[3,4-c]pyrrole-2(lH)-carboxylat e (113 mg, 0.32 mmol, 1.00 equiv), DCM (10 mL) and TFA (5 mL). The resulting solution was stirred overnight at room temperature and concentrated under reduced pressure to provide 81.0 mg (crude) of 3-chloro-5- (hexahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)benzaldehyde as a brown oil. LCMS (ESI, m/z): 251 [M+H] ⁺ .

Step 3: Synthesis of 3-(5-acetylhexahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)-5- chlorobenzaldehyde

[00251] A 40-mL vial was charged with 3-chloro-5-(hexahydropyrrolo[3,4-c]pyrrol-2(lH)- yl)benzaldehyde (81.0 mg, 0.323 mmol, 1.00 equiv), DCM (10 mL), acetyl acetate (36.2 mg, 0.355 mmol, 1.10 equiv), and triethylamine (65.2 mg, 0.646 mmol, 2.00 equiv). The resulting solution was stirred overnight at room temperature and quenched by water (10 mL). The mixture was extracted with DCM (3 x 10 mL) and the organic layers were combined, washed with water (3 x 10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column to provide 72.9 mg (77% yield) of 3-(5-acetylhexahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)-5-chlorob enzaldehyde as a yellow oil. LCMS (ESI, m/z): 293 [M+H] ⁺ . Step 4: N-(l-(l-(3-(5-acetylhexahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)- 5-chlorobenzyl)-l,8- diazaspiro[4.5]decane-8-carbonyl)-lH-pyrazol-3-yl)acetamide

[00252] The title compound was synthesized as described in Example 61, Steps 2-4, using 3-(5- acetylhexahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)-5-chlorobenzal dehyde in Step 2. Purification resulted in 10.5 mg of N-(l-(l-(3-(5-acetylhexahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)- 5- chlorobenzyl)-l,8-diazaspiro[4.5]decane-8-carbonyl)-lH-pyraz ol-3-yl)acetamide as a yellow semi-solid. 1H MR (400 MHz, Chloroform-i ) δ 8.05 (s, 1H), 7.70 - 7.95 (m, 1H), 6.89 (s, 1H), 6.70 (s, 1H), 6.22 - 6.52 (m, 2H), 4.40 - 4.75 (m, 2H), 3.71 - 3.89 (m, 2H), 3.50 - 3.65 (m, 5H), 3.32 - 3.43 (m, 1H), 3.15- 3.28 (m, 2H), 3.00 - 3.15 (m, 4H), 2.55 - 2.82 (m, 2H), 2.19 (s, 3H), 2.05 (s, 3H), 1.75 - 1.90 (m, 6H), 1.43 - 1.56 (m, 2H). LCMS (ESI, m/z): 568 [M+H] ⁺ .

Example 66: N-methyl-N-(l-(l-(3-(pyrrolidin-l-yl)-5-(trifluoromethyl)ben zyl)-l,8- diazaspiro[4.5]decane-8-carbonyl)- -pyrazol-3-yl)acetamide

[00253] The title compound was synthesized as described in Example 2 using N-(l-(l -(3- (pyrrolidin-l-yl)-5-(trifluoromethyl)benzyl)-l,8-diazaspiro[ 4.5]decane-8-carbonyl)-lH-pyrazol- 3-yl)acetamide (Example 61) as the starting material (DMF used instead of ACN). Purification resulted in 18.2 mg of N-methyl-N-(l-(l-(3-(pyrrolidin-l-yl)-5-(trifluoromethyl)ben zyl)-l,8- diazaspiro[4.5]decane-8-carbonyl)-lH-pyrazol-3-yl)acetamide as a yellow oil. 1H NMR (300 MHz, DMSO-i¾) δ 8.10 (d, J= 2.7 Hz, 1H), 6.78 - 6.86 (s, 1H), 6.65 - 6.76 (s, 1H), 6.50 - 6.65 (m, 2H), 4.25 - 4.50 (m, 2H), 3.64 (s, 2H), 3.20 - 3.35 (m, 7H), 3.05 - 3.20 (m, 2H), 2.58 - 2.72 (m, 2H), 2.10 (s, 3H), 1.90 - 2.05 (m, 4H), 1.65 - 1.90 (m, 6H), 1.40 - 1.55 (m, 2H). LCMS (ESI, m/z): 533 [M+H] ⁺ . Example 67: N-(l-(l-(3-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-5-(trifluor omethyl)b l,8-diazaspiro[4.5]decane-8-carbon -lH-pyrazol-3-yl)-N-methylacetamide

[00254] The title compound was synthesized as described in Example 2 using N-(l-(l -(3-(3-oxa- 8-azabicyclo[3.2.1]octan-8-yl)-5-(trifluoromethyl)benzyl)-l, 8-diazaspiro[4.5]decane-8- carbonyl)-lH-pyrazol-3-yl)acetamide (Example 62) as the starting material (DMF used instead of ACN). Purification resulted in 61.6 mg of N-(l-(l-(3-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)- 5-(trifluoromethyl)benzyl)-l,8-diazaspiro[4.5]decane-8-carbo nyl)-lH-pyrazol-3-yl)-N- methylacetamide as a yellow oil. 1H NMR (300 MHz, DMSO-i¾) δ 8.15 (br, 1H), 7.05 (s, 1H), 6.85 - 6.98 (m, 2H), 6.50 - 6.85 (m, 1H), 4.30 - 4.50 (m, 2H), 4.30 (s, 2H), 3.64 - 3.78 (m, 4H), 3.32 - 3.52 (m, 3H), 3.20 - 3.32 (m, 2H), 3.02 - 3.18 (m, 2H), 2.55 - 2.68 (m, 2H), 2.00 - 2.32 (m, 3H), 1.65 - 2.00 (m, 10H), 1.38 - 1.50 (m, 2H). LCMS (ESI, m/z): 575 [M+H] ⁺ .

Example 68: N-methyl-N-(l-(l-(2-(pyrrolidin-l-yl)-4-(trifluoromethyl)ben zyl)-l,8- diazaspiro[4.5]decane-8-carbonyl)- -pyrazol-3-yl)acetamide

[00255] The title compound was synthesized as described in Example 2 using N-(l-(l -(2- (pyrrolidin-l-yl)-4-(trifluoromethyl)benzyl)-l,8-diazaspiro[ 4.5]decane-8-carbonyl)-lH-pyrazol-

3-yl)acetamide (Example 8) as the starting material (DMF used instead of ACN). Purification resulted in 96.4 mg of N-methyl-N-(l-(l-(2-(pyrrolidin-l-yl)-4-(trifluoromethyl)ben zyl)-l,8- diazaspiro[4.5]decane-8-carbonyl)-lH-pyrazol-3-yl)acetamide as a yellow oil. 1H NMR (300 MHz, DMSO-i¾, 353K) δ 8.10 (d, J = 2.7 Hz, 1H), 6.65 - 6.80 (m, 2H), 6.35 - 6.60 (m, 2H), 4.05 - 4.60 (m, 2H), 3.62 (s, 2H), 3.02 - 3.35 (m, 9H), 2.56 - 2.79 (m, 2H), 2.10 (s, 3H), 1.91 - 2.03 (m, 4H), 1.70 - 1.92 (m, 6H), 1.35 - 1.65 (m, 2H). LCMS (ESI, m/z): 533 [M+H] ⁺ . Example 69: N-(l-(l-(3-(5-acetylhexahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)- 5- (trifluoromethyl)benzyl)-l,8-diazaspiro[4.5]decane-8-carbony l)-lH-pyrazol-3-yl)acetamide

Step 1: Synthesis of tert-butyl 8-(3-acetamido-lH-pyrazole-l-carbonyl)-l,8- diazaspiro[4.5]decane-l-carboxylate

[00256] A 40-mL vial was charged with N-(lH-pyrazol-3-yl)acetamide (125 mg, 1.00 mmol, 1.00 equiv), DCM (10 mL), and N,N-diisopropylethylamine (258 mg, 2.00 mmol, 2.00 equiv). 4-Nitrophenyl chloroformate (222 mg, 1.10 mmol, 1.10 equiv) in DCM (2 mL) was

addeddropwise at 0 °C. The resulting solution was stirred for 2 h at room temperature. Then tert- butyl l,8-diazaspiro[4.5]decane-l-carboxylate (240 mg, 1.00 mmol, 1.00 equiv) was added. The resulting solution was stirred overnight at room temperature and quenched by water (10 mL). The mixture was extracted with DCM (3 x 10 mL) and the organic layers were combined, washed with water (3 x 10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column to provide 295 mg (75% yield) of tert-butyl 8-(3-acetamido-lH-pyrazole-l-carbonyl)-l,8- diazaspiro[4.5]decane-l-carboxylate as a light yellow oil. LCMS (ESI, m/z): 392 [M+H] ⁺ .

Step 2: Synthesis of N-(l-(l,8-diazaspiro[4.5]decane-8-carbonyl)-lH-pyrazol-3- yl)acetamide

[00257] A 40-mL vial was charged with tert-butyl 8-(3-acetamido-lH-pyrazole-l-carbonyl)-l,8- diazaspiro[4.5]decane-l-carboxylate (295 mg, 0.75 mmol, 1.00 equiv), 1,4-dioxane (5 mL), and hydrogen chloride (1 mL). The resulting solution was stirred overnight at room temperature and concentrated under reduced pressure to provide 219 mg (crude) of N-(l-(l,8- diazaspiro[4.5]decane-8-carbonyl)-lH-pyrazol-3-yl)acetamide as a brown oil. LCMS (ESI, m/z): 292 [M+H] ⁺ .

Step 3: Synthesis of N-(l-(l-(3-(5-acetylhexahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)- 5- (trifluoromethyl)benzyl)-l,8-diazaspiro[4.5]decane- -carbonyl)-lH-pyrazol-3-yl)acetamide

[00258] A 40-mL vial was charged with 3-(5-acetylhexahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)-5- (trifluoromethyl)benzaldehyde (synthesized as described in Example 65, Steps 1-3 using 3- bromo-5-(trifluoromethyl)benzaldehyde in Step 1, 228 mg, 0.70 mmol, 1.00 equiv), DCE (10 mL), and N-(l-(l,8-diazaspiro[4.5]decane-8-carbonyl)-lH-pyrazol-3-yl) acetamide (204 mg, 0.70 mmol, 1.00 equiv). The mixture was stirred for 2 h at room temperature. Then sodium triacetoxyborohydride (371 mg, 1.75 mmol, 2.50 equiv) was added. The resulting solution was stirred overnight at room temperature and quenched by water (10 mL). The mixture was extracted with DCM (3 x 10 mL) and the organic layers were combined, washed with water (3 x 10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC. Purification resulted in 37.0 mg (9% yield) of N-(l-(l-(3-(5-acetylhexahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)- 5- (trifluoromethyl)benzyl)-l,8-diazaspiro[4.5]decane-8-carbony l)-lH-pyrazol-3-yl)acetamide as a yellow oil. 1H MR (400 MHz, Chloroform-i ) δ 8.12 (d, J= 2.7 Hz, 1H), 7.96 (s, 1H), 6.80 - 7.00 (m, 2H), 6.50 - 6.75 (m, 2H), 4.46 - 4.75 (m, 2H), 3.72 - 3.88 (m, 2H), 3.55 - 3.65 (m, 5H), 3.35 - 3.46 (m, 1H), 3.18- 3.31 (m, 2H), 3.00 - 3.18 (m, 4H), 2.62 - 2.80 (m, 2H), 2.18 (s, 3H), 2.05 (s, 3H), 1.75 - 1.88 (m, 6H), 1.42 - 1.57 (m, 2H). LCMS (ESI, m/z): 602 [M+H] ⁺ .

Example 70: N-methyl-N-(l-(4-(3-(pyrrolidin-l-yl)-5-(trifluoromethyl)ben zyl)piperazine-l- carbonyl)-lH-pyrazol-3-yl)acetamide

Step 1: Synthesis of 3-(pyrrolidin-l-yl)-5-(trifluoromethyl)benzaldehyde

80 °C, overnight

[00259] A 100-mL round-bottom flask was charged with 3-bromo-5-

(trifluoromethyl)benzaldehyde (2.00 g, 7.90 mmol, 1.00 equiv), toluene (50 mL), pyrrolidine (0.840 g, 11.8 mmol, 1.50 equiv), cesium carbonate (5.15 g, 15.8 mmol, 2.00 equiv), 2,2'- bis(diphenylphosphino)-l,l'-binaphthyl (0.492 g, 0.790 mmol, 0.10 equiv), and

tris(dibenzylideneacetone)dipalladium (0.361 g, 0.390 mmol, 0.05 equiv) under nitrogen. The resulting solution was stirred overnight at 80 °C and quenched by water (50 mL). The mixture was extracted with EtOAc (3 x 50 mL) and the organic layers were combined, washed with water (3 x 50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column to provide 1.25 g (65% yield) of 3- (pyrrolidin-l-yl)-5-(trifluoromethyl)benzaldehyde as a yellow solid. LCMS (ESI, m/z): 244 [M+H] ⁺ .

Step 2: Synthesis of tert-butyl 4-(3-(pyrrolidin-l-yl)-5-(trifluoromethyl)benzyl)piperazine- 1-carboxylate

[00260] A 40-mL vial was charged with 3-(pyrrolidin-l-yl)-5-(trifluoromethyl)benzaldehyde (243 mg, 1.00 mmol, 1.00 equiv), DCE (10 mL), and tert-butyl piperazine-l-carboxylate (223 mg, 1.20 mmol, 1.20 equiv). The mixture was stirred for 2 h at room temperature. Then sodium triacetoxyborohydride (530 mg, 2.50 mmol, 2.50 equiv) was added. The resulting solution was stirred overnight at room temperature and quenched by water (10 mL). The mixture was extracted with DCM (3 x 10 mL) and the organic layers were combined, washed with water (3 x 10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column to provide 324 mg (78% yield) of tert- butyl 4-(3-(pyrrolidin-l-yl)-5-(trifluoromethyl)benzyl)piperazine- l-carboxylate as a yellow oil. LCMS (ESI, m/z): 414 [M+H] ⁺ .

Step 3: Synthesis of l-(3-(pyrrolidin-l-yl)-5-(trifluoromethyl)benzyl)piperazine [00261] A 40-mL vial was charged with tert-butyl 4-(3-(pyrrolidin-l-yl)-5- (trifluoromethyl)benzyl)piperazine-l-carboxylate (324 mg, 0.78 mmol, 1.00 equiv), MeOH (5 mL), and hydrogen chloride (1 mL). The resulting solution was stirred overnight at room temperature and concentrated under reduced pressure to provide 202 mg (crude) of l -(3- (pyrrolidin-l-yl)-5-(trifluoromethyl)benzyl)piperazine as a yellow solid. LCMS (ESI, m/z): 314 [M+H] ⁺ .

Step 4: Synthesis of N-(l-(4-(3-(pyrrolidin-l-yl)-5-(trifluoromethyl)benzyl)piper azine-l- carbonyl)-lH-pyrazol-3-yl)acetamide

[00262] A 40-mL vial was charged with N-(lH-pyrazol-3-yl)acetamide (105 mg, 0.84 mmol, 1.00 equiv), DCM (8 mL), and N,N-diisopropylethylamine (217 mg, 1.68 mmol, 1.99 equiv). 4- Nitrophenyl chloroformate (187 mg, 0.93 mmol, 1.10 equiv) in DCM (2 mL) was added dropwise at O °C. Then the resulting solution was stirred for 2 h at room temperature. Then l -(3- (pyrrolidin-l-yl)-5-(trifluoromethyl)benzyl)piperazine (264 mg, 0.843 mmol, 1.00 equiv) was added. The resulting solution was stirred overnight at room temperature and quenched by water (10 mL). The mixture was extracted with DCM (3 x 10 mL) and the organic layers were combined, washed with water (3 x 10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to provide 143 mg (37% yield) of N-(l-(4-(3-(pyrrolidin-l- yl)-5-(trifluoromethyl)benzyl)piperazine-l -carbonyl)-lH-pyrazol-3-yl)acetamide as a light yellow solid. LCMS (ESI, m/z): 465 [M+H] ⁺ .

Step 5: Synthesis of N-methyl-N-(l-(4-(3-(pyrrolidin-l-yl)-5- (trifluoromethyl)benzyl)piperazine-l-carbonyl)-lH-pyrazol-3- yl)acetamide

[00263] A 40-mL vial was charged with N-(l-(4-(3-(pyrrolidin-l-yl)-5- (trifluoromethyl)benzyl)piperazine-l-carbonyl)-lH-pyrazol-3- yl)acetamide (97.0 mg, 0.21 mmol, 1.00 equiv), N,N-dimethylformamide (4 mL), cesium carbonate (136 mg, 0.42 mmol, 2.00 equiv), and methyl iodide (29.7 mg, 0.21 mmol, 1.00 equiv). The resulting solution was stirred overnight at room temperature and the solids were filtered out. Then the filtrate was purified by preparative HPLC. Purification resulted in 84.1 mg (84% yield) of N-methyl-N-(l- (4-(3-(pyrrolidin-l-yl)-5-(trifluoromethyl)benzyl)piperazine -l-carbonyl)-lH-pyrazol-3- yl)acetamide as a yellow semi-solid. ¹ H MR (300 MHz, Chloroform- ) δ 8.10 (br, 1H), 7.45 - 7.62 (m, 1H), 6.85 - 7.25 (m, 2H), 6.10 - 6.35 (br, 1H), 3.75 - 4.02 (m, 4H), 3.62 (s, 2H), 3.15 - 3.50 (m, 7H), 2.45 - 2.70 (m, 4H), 2.05 - 2.42 (m, 3H), 1.88 - 2.05 (m, 4H). LCMS (ESI, m/z): 479 [M+H] ⁺ .

Example 71: N-(l-(4-(2-(l-cyclopropylpiperidin-4-yloxy)-4- (trifluoromethyl)benzyl)piperazine-l-carbonyl)-lH-pyrazol-3- yl)acetamide

Step 1: Synthesis of 2-hydroxy-4-(trifluoromethyl)benzaldehyde

[00264] A 100-mL round-bottom flask was charged with 2-fluoro-4-

(trifluoromethyl)benzaldehyde (3.00 g, 15.6 mmol, 1.00 equiv), potassium carbonate (4.30 g, 31.1 mmol, 2.00 equiv), water (2 mL), and DMSO (20 mL). The resulting solution was stirred overnight at 100°C and then quenched with water (20 mL). The resulting solution was extracted with EtOAc (3 x 20 mL) and the organic layers were combined, washed with brine (1 x 100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column to provide 1.10 g (37% yield) of 2- hydroxy-4-(trifluorom ethyl )benzaldehyde as a yellow oil.

Step 2: Synthesis of tert-butyl 4-(2-hydroxy-4-(trifluoromethyl)benzyl)piperazine-l- carboxylate

[00265] A 100-mL round-bottom flask was charged with 2-hydroxy-4- (trifluoromethyl)benzaldehyde (0.650 g, 3.42 mmol, 1.00 equiv), tert-butyl piperazine-1- carboxylate (1.30 g, 6.98 mmol, 2.00 equiv), glacial acetic acid (0.616 g, 10.3 mmol, 3.00 equiv), and MeOH (10 mL). The mixture was stirred for 1 h at room temperature. Sodium cyanoborohydride (0.646 g, 10.3 mmol, 3.00 equiv) was added. The resulting solution was stirred overnight at room temperature and then quenched with water (10 mL). The resulting mixture was extracted with DCM (3 x 10 mL) and the organic layers were combined, washed with brine (1 x 50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column to provide 1.00 g (81% yield) oftert-butyl 4-(2-hydroxy-4-(trifluoromethyl)benzyl)piperazine-l-carboxyl ate as a yellow solid. LCMS (ESI, m/z): 361 [M+H] ⁺ .

Step 3: Synthesis of l-cyclopropylpiperidin-4-yl methanesulfonate

[00266] A 100-mL round-bottom flask was charged with l-cyclopropylpiperidin-4-ol (1.50 g, 10.6 mmol, 1.00 equiv), triethylamine (3.22 g, 31.8 mmol, 3.00 equiv), and DCM (20 mL). Methanesulfonyl chloride (1.82 g, 16.0 mmol, 1.50 equiv) was added at 0 °C. The resulting solution was stirred overnight at room temperature and then quenched with water (30 mL). The resulting solution was extracted with DCM (3 x 30 mL) and the organic layers were combined, washed with brine (1 x 100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to provide 2.20 g (94% yield) of l-cyclopropylpiperidin-4-yl methanesulfonate as a yellow solid. LCMS (ESI, m/z): 220 [M+H] ⁺ .

Step 4: Synthesis of tert-butyl 4-(2-(l-cyclopropylpiperidin-4-yloxy)-4- (trifluoromethyl)benzyl)piperazine-l-carboxylate

[00267] A 50-mL round-bottom flask was charged with tert-butyl 4-(2-hydroxy-4- (trifluoromethyl)benzyl)piperazine-l-carboxylate (150 mg, 0.42 mmol, 1.00 equiv), 1- cyclopropylpiperidin-4-yl methanesulfonate (548 mg, 2.50 mmol, 6.00 equiv), cesium carbonate (408 mg, 1.25 mmol, 3.00 equiv), and N,N-dimethylformamide (5 mL). The resulting solution was stirred overnight at 80 °C and then quenched with water (5 mL). The resulting solution was extracted with DCM (3 x 5 mL) and the organic layers were combined, washed with brine (1 x 30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column to provide 200 mg (99% yield) of tert- butyl 4-(2-(l-cyclopropylpiperidin-4-yloxy)-4-(trifluoromethyl)ben zyl)piperazine-l-carboxylate as a yellow oil. LCMS (ESI, m/z): 484 [M+H] ⁺ . Step 5: Synthesis of l-(2-(l-cyclopropylpiperidin-4-yloxy)-4- (trifluoromethyl)benzyl)piperazine

[00268] A 100-mL round-bottom flask was charged with tert-butyl 4-(2-(l-cyclopropylpiperidin- 4-yloxy)-4-(trifluoromethyl)benzyl)piperazine-l-carboxylate (200 mg, 0.41 mmol, 1.00 equiv), TFA (3 mL), and DCM (10 mL). The resulting solution was stirred overnight at room

temperature and concentrated under reduced pressure to provide 250 mg (crude) of l-(2-(l- cyclopropylpiperidin-4-yloxy)-4-(trifluorom ethyl )benzyl)piperazine as a yellow oil. LCMS (ESI, m/z): 384 [M+H] ⁺ .

Step 6: Synthesis of N-(l-(4-(2-(l-cyclopropylpiperidin-4-yloxy)-4- (trifluoromethyl)benzyl)piperazine-l-carbonyl)-lH-pyrazol-3- l)acetamide

[00269] A 50-mL round-bottom flask was charged with l-(2-(l-cyclopropylpiperidin-4-yloxy)- 4-(trifluoromethyl)benzyl)piperazine (100 mg, 0.26 mmol, 1.00 equiv), 4-nitrophenyl 3- acetamido-lH-pyrazole-l-carboxylate (83.0 mg, 0.290 mmol, 1.10 equiv), triethylamine (53.0 mg, 0.52 mmol, 2.00 equiv), and DCM (5 mL). The resulting solution was stirred overnight at room temperature and then quenched with water (5 mL). The resulting mixture was extracted with DCM (3 x 5 mL) and the organic layers were combined, washed with brine (1 x 30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product (220 mg) was purified by preparative HPLC. Purification resulted in 20.9 mg (15% yield) of N-(l-(4-(2-(l-cyclopropylpiperidin-4-yloxy)-4-

(trifluoromethyl)benzyl)piperazine-l-carbonyl)-lH-pyrazol -3-yl)acetamide as a white solid. 1H MR (400 MHz, Chloroform-i ) δ 8.02 - 8.03 (m, 1H), 7.89 (br, 1H), 7.51 (d, J= 8.0 Hz, 1H), 7.22 (d, J= 8.0 Hz, 1H), 7.08 (s, 1H), 6.89 - 6.90 (m, 1H), 4.52 (br, 1H), 3.86 (br, 4H), 3.65 (s, 2H), 3.01 (br, 2H), 2.75 (br, 2H), 2.58 - 2.64 (m, 4H), 2.20 (s, 3H), 2.04 - 2.09 (m, 2H), 1.81 - 1.91 (m, 3H), 0.60 (br, 4H). LCMS (ESI, m/z): 535 [M+H] ⁺ . Example 72: N-(l-(4-(3-(l-cyclopropylpiperidin-4-yloxy)-5- (trifluoromethyl)benzyl)piperazi -l-carbonyl)-lH-pyrazol-3-yl)acetamide

[00270] The title compound was synthesized as described in Example 71, Steps 2-6 using 3- hydroxy-5-(trifluoromethyl)benzaldehyde in Step 2. Purification resulted in 32.6 mg of N-(l-(4- (3-(l-cyclopropylpiperidin-4-yloxy)-5-(trifluoromethyl)benzy l)piperazine-l-carbonyl)-lH- pyrazol-3-yl)acetamide as a yellow oil. 1H MR (300 MHz, Chloroform- ) δ 8.01 (d, J= 3.0 Hz, 1H), 7.70 (br, 1H), 7.16 (s, 1H), 7.03 - 7.06 (m, 2H), 6.87 (d, J= 2.7 Hz, 1H), 4.39 (br, 1H), 3.85 (br, 4H), 3.54 (s, 2H), 2.91 (br, 2H), 2.51 - 2.54 (m, 6H), 2.18 (s, 3H), 1.98 (br, 2H), 1.81 (br, 2H), 1.66 (br, 1H), 0.48 - 0.50 (m, 4H). LCMS (ESI, m/z): 535 [M+H] ⁺ .

Example 73: N-(l-(4-(2-(pyrimidin-5-yloxy)-4-(trifluoromethyl)benzyl)pip erazine-l- carbonyl)-lH-pyrazol-3-yl)acetamide

Step 1: Synthesis of tert-butyl 4-(2-(pyrimidin-5-yloxy)-4- (trifluoromethyl)benzyl)piperazine-l-carboxylate

[00271] A 100-mL round-bottom flask was charged with tert-butyl 4-[[2-hydroxy-4- (trifluoromethyl)phenyl]methyl]piperazine-l-carboxylate (300 mg, 0.830 mmol, 1.00 equiv), 5- bromopyrimidine (395 mg, 2.48 mmol, 3.00 equiv), copper(I) iodide (32.0 mg, 0.170 mmol, 0.20 equiv), L-proline (39.0 mg, 0.340 mmol, 0.40 equiv), cesium carbonate (815 mg, 2.50 mmol, 3.00 equiv), and N,N-dimethylformamide (10 mL) under nitrogen. The resulting solution was stirred overnight at 140 °C and then quenched with water (10 mL). The resulting mixture was extracted with DCM (3 x 15 mL) and the organic layers were combined, washed with brine (1 x 50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column to provide 300 mg (82% yield) of tert-butyl 4-(2-(pyrimidin-5-yloxy)-4-(trifluoromethyl)benzyl)piperazin e-l-carboxylate as a yellow oil. LCMS (ESI, m/z): 439 [M+H] ⁺ . Step 2: Synthesis of -(2-(piperazin-l-ylmethyl)-5-(trifluoromethyl)phenoxy)pyrimi dine

[00272] A 100-mL round-bottom flask was charged with tert-butyl 4-(2-(pyrimidin-5-yloxy)-4-

(trifluoromethyl)benzyl)piperazine-l-carboxylate (300 mg, 0.68 mmol, 1.00 equiv), TFA (3 mL), and DCM (10 mL). The resulting solution was stirred overnight at room temperature and concentrated under reduced pressure to yield 350 mg (crude) of 5-(2-(piperazin-l-ylmethyl)-5-

(trifluoromethyl)phenoxy)pyrimidine as a yellow oil. LCMS (ESI, m/z): 339 [M+H] ⁺ .

Step 3: Synthesis of N-(l-(4-(2-(pyrimidin-5-yloxy)-4-(trifluoromethyl)benzyl)pip erazine-l- carbonyl)-lH-pyrazol-3-yl)acetamide

[00273] A 50-mL round-bottom flask was charged with 5-(2-(piperazin-l-ylmethyl)-5- (trifluoromethyl)phenoxy)pyrimidine (200 mg, 0.59 mmol, 1.00 equiv), 4-nitrophenyl 3- acetamido-lH-pyrazole-l-carboxylate (189 mg, 0.65 mmol, 1.10 equiv), triethylamine (120 mg, 1.19 mmol, 2.00 equiv), and DCM (5 mL). The resulting solution was stirred overnight at room temperature and then quenched with water (5 mL). The resulting mixture was extracted with DCM (3 x 5 mL) and the organic layers were combined, washed with brine (1 x 30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product (450 mg) was purified by preparative HPLC. Purification resulted in 59.7 mg (21% yield) of N-(l-(4-(2-(pyrimidin-5-yloxy)-4-(trifluoromethyl)benzyl)pip erazine-l-carbonyl)-lH- pyrazol-3-yl)acetamide as a white solid. 1H MR (300 MHz, Chloroform- ) δ 9.01 (s, 1H), 8.45 (s, 2H), 8.15 - 8.23 (m, 1H), 7.98 - 7.99 (m, 1H), 7.65 (d, J= 7.8 Hz, 1H), 7.53 (d, J= 8.1 Hz, 1H), 7.25 (s, 1H), 6.87 - 6.88 (m, 1H), 3.66 - 3.69 (m, 6H), 2.51 (br, 4H), 2.20 (s, 3H). LCMS (ESI, m/z): 490 [M+H] ⁺ .

Example 74: N-(l-(4-(3-(pyrimidin-5-yloxy)-5-(trifluoromethyl)benzyl)pip erazine-l- carbonyl)-lH-pyrazol-3-yl)acetamide [00274] The title compound was synthesized as described in Example 73 using tert-butyl 4-(3- hydroxy-5-(trifluoromethyl)benzyl)piperazine-l-carboxylate in Step 1. Purification resulted in 72.9 mg of N-(l-(4-(3-(pyrimidin-5-yloxy)-5-(trifluoromethyl)benzyl)pip erazine-l-carbonyl)- lH-pyrazol-3-yl)acetamide as a yellow solid. 1H MR (400 MHz, Chloroform-i ) δ 9.08 (s, 1H), 8.58 (s, 2H), 8.17 (br, 1H), 8.02 (d, J= 2.8 Hz, 1H), 7.45 (s, 1H), 7.24 - 7.26 (m, 2H), 6.90 (d, J = 2.8 Hz, 1H), 3.85 (br, 4H), 3.62 (s, 2H), 2.52 - 2.55 (m, 4H), 2.20 (s, 3H). LCMS (ESI, m/z): 490 [M+H] ⁺ .

Example 75: N-(l-(4-(2-(benzo[d]thiazol-2-yloxy)-4-(trifluoromethyl)benz yl)piperazine-l- carbonyl)-lH-pyrazol-3-yl)acetamide

Step 1: Synthesis of tert-butyl 4-(2-(benzo[d]thiazol-2-yloxy)-4- (trifluoromethyl)benzyl)piperazine-l-carboxylate

[00275] A 50-mL round-bottom flask was charged with tert-butyl 4-[[2-hydroxy-4- (trifluoromethyl)phenyl]methyl]piperazine-l-carboxylate (200 mg, 0.55 mmol, 1.00 equiv), 2- chloro-l,3-benzothiazole (189 mg, 1.11 mmol, 2.00 equiv), potassium carbonate (230 mg, 1.66 mmol, 3.00 equiv), and N,N-dimethylformamide (5 mL). The resulting solution was stirred overnight at 60°C and then quenched with water (5 mL). The resulting mixture was extracted with DCM (3 x 5 mL) and the organic layers were combined, washed with brine (1 x 30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column to provide 220 mg (80% yield) of tert-butyl 4-(2-(benzo[d]thiazol-2-yloxy)-4-(trifluoromethyl)benzyl)pip erazine-l-carboxylate as a yellow oil. LCMS (ESI, m/z): 494 [M+H] ⁺ .

Step 2: Synthesis of 2-(2-(piperazin-l-ylmethyl)-5- (trifluoromethyl)ph noxy)benzo[d]thiazole

[00276] A 100-mL round-bottom flask was charged with tert-butyl 4-(2-(benzo[d]thiazol-2- yloxy)-4-(trifluoromethyl)benzyl)piperazine-l-carboxylate (300 mg, 0.61 mmol, 1.00 equiv), TFA (3 mL), and DCM (10 mL). The resulting solution was stirred overnight at room temperature and concentrated under reduced pressure to provide 350 mg (crude) of 2-(2- (piperazin-l-ylmethyl)-5-(trifluoromethyl)phenoxy)benzo[d]th iazole as a yellow oil. LCMS (ESI, m/z): 394 [M+H] ⁺ .

Step 3: Synthesis of N-(l-(4-(2-(benzo[d]thiazol-2-yloxy)-4- (trifluoromethyl)benzyl)piperazine-l-carbonyl)-lH-pyrazol-3- yl)acetamide

[00277] A 100-mL round-bottom flask was charged with 2-(2-(piperazin-l-ylmethyl)-5- (trifluoromethyl)phenoxy)benzo[d]thiazole (100 mg, 0.25 mmol, 1.00 equiv), 4-nitrophenyl 3- acetamido-lH-pyrazole-l-carboxylate (81.0 mg, 0.28 mmol, 1.10 equiv), triethylamine (51.0 mg, 0.50 mmol, 2.00 equiv), and DCM (5 mL). The resulting solution was stirred overnight at room temperature and then quenched with water (5 mL). The resulting mixture was extracted with DCM (3 x 5 mL) and the organic layers were combined, washed with brine (1 x 30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product (230 mg) was purified by preparative HPLC. Purification resulted in 73.5 mg (53% yield) of N-(l-(4-(2-(benzo[d]thiazol-2-yloxy)-4-(trifluoromethyl)benz yl)piperazine-l- carbonyl)-lH-pyrazol-3-yl)acetamide as a white solid. 1H MR (400 MHz, Chloroform-<f) δ 7.96 - 7.98 (m, 2H), 7.67 - 7.72 (m, 4H), 7.59 - 7.61 (m, 1H), 7.40 - 7.44 (m, 1H), 7.29 - 7.33 (m, 1H), 6.86 - 6.87 (m, 1H), 3.65 (br, 6H), 2.50 (br, 4H), 2.18 (s, 3H). LCMS (ESI, m/z): 545 [M+H] ⁺ .

Example 76: N-(l-(4-(3-(benzo[d]thiazol-2-yloxy)-5-(trifluoromethyl)benz yl)piperazine-l- carbonyl)-lH-pyrazol-3-yl)acetamide

[00278] The title compound was synthesized as described in Example 75 using tert-butyl 4-(3- hydroxy-5-(trifluoromethyl)benzyl)piperazine-l-carboxylate in Step 1. Purification resulted in 55.8 mg of N-(l-(4-(3-(benzo[d]thiazol-2-yloxy)-5-(trifluoromethyl)benz yl)piperazine-l- carbonyl)-lH-pyrazol-3-yl)acetamide as a white solid. 1H NMR (300 MHz, Chloroform-<f) δ 8.00 - 8.01 (m, 1H), 7.69 - 7.92 (m, 5H), 7.39 - 7.44 (m, 1H), 7.30 - 7.35 (m, 1H), 6.89 (d, J- 2.7 Hz, 1H), 3.92 (br, 6H), 2.54 - 3.03 (m, 4H), 2.17 (s, 3H). LCMS (ESI, m/z): 545 [M+H] ⁺ . Example 77: N-(l-(4-(2-((l,l-dioxidotetrahydro-2H-thiopyran-4-yl)oxy)-4- (trifluoromethyl)benzyl)piperazine-l-carbon l -lH- razol-3-yl)acetamide

Step 1: Synthesis of l,l-dioxo-thian-4-yl methanesulfonate

[00279] A 250-mL round-bottom flask was charged with 4-hydroxy-thiane-l, l-dione (3.50 g, 23.3 mmol, 1.00 equiv), methanesulfonyl chloride (5.30 g, 46.5 mmol, 2.00 equiv),

triethylamine (7.10 g, 70.2 mmol, 3.00 equiv), and DCM (40 mL). The resulting solution was stirred overnight at room temperature and then quenched with water (40 mL). The resulting mixture was extracted with DCM (3 x 30 mL) and the organic layers were combined, washed with brine (1 x 200 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column to provide 4.00 g (75% yield) of l, l-dioxo-thian-4-yl methanesulfonate as a white solid.

Step 2: Synthesis of tert-butyl 4-([2-[(l,l-dioxo-thian-4-yl)oxy]-4- (trifluoromethyl)phenyl]methyl)piperazine-l-carboxylate

[00280] A 50-mL round-bottom flask was charged with tert-butyl 4-[[2-hydroxy-4- (trifluoromethyl)phenyl]methyl]piperazine-l-carboxylate (200 mg, 0.55 mmol, 1.00 equiv), 1,1- dioxo-thian-4-yl methanesulfonate (253 mg, 1.11 mmol, 2.00 equiv), cesium carbonate (543 mg, 1.67 mmol, 3.00 equiv), and N,N-dimethylformamide (5 mL). The resulting solution was stirred overnight at 80°C and then quenched with water (5 mL). The resulting mixture was extracted with DCM (3 x 5 mL) and the organic layers were combined, washed with brine (1 x 30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column to provide 220 mg (80% yield) of tert-butyl 4-([2-[(l, l-dioxo-thian-4-yl)oxy]-4-(trifluoromethyl)phenyl]methyl)pip erazine-l-carboxylate as a white solid. LCMS (ESI, m/z): 493 [M+H] ⁺ . Step 3: Synthesis of 4-[2-(piperazin-l-ylmethyl)-5-(trifluoromethyl)phenoxy]-thia ne-l,l- dione

[00281] A 100-mL round-bottom flask was charged with tert-butyl 4-([2-[(l, l-dioxo-thian-4- yl)oxy]-4-(trifluoromethyl)phenyl]methyl)piperazine-l-carbox ylate (150 mg, 0.30 mmol, 1.00 equiv), TFA (3 mL), and DCM (10 mL). The resulting solution was stirred overnight at room temperature and concentrated under reduced pressure to provide 200 mg (crude) of 4-[2- (piperazin-l-ylmethyl)-5-(trifluoromethyl)phenoxy]-thiane-l, l-dione as a yellow oil. LCMS (ESI, m/z): 393 [M+H] ⁺ .

Step 4: Synthesis of N-(l-(4-(2-((l,l-dioxidotetrahydro-2H-thiopyran-4-yl)oxy)-4- (trifluoromethyl)benzyl)piperazine-l-carbonyl)-lH-pyrazol-3- yl)acetamide

[00282] A 1001-mL round-bottom flask was charged with 4-[2-(piperazin-l-ylmethyl)-5- (trifluoromethyl)phenoxy]-thiane-l, l-dione (80.0 mg, 0.20 mmol, 1.00 equiv), 4-nitrophenyl 3- acetamido-lH-pyrazole-l-carboxylate (65.0 mg, 0.22 mmol, 1.10 equiv), triethylamine (41.0 mg, 0.41 mmol, 2.00 equiv), and DCM (5 mL). The resulting solution was stirred overnight at room temperature and then quenched with water (5 mL). The resulting mixture was extracted with DCM (3 x 5 mL) and the organic layers were combined, washed with brine (1 x 30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product (180 mg) was purified by preparative HPLC. Purification resulted in 12 mg (1 1% yield) of N-(l -(4-(2-((l, l-dioxidotetrahydro-2H-thiopyran-4-yl)oxy)-4-

(trifluoromethyl)benzyl)piperazine-l-carbonyl)-lH-pyrazol -3-yl)acetamide as a white solid. 1H MR (300 MHz, DMSO-i¾) δ 10.68 (s, 1H), 8.08 - 8.09 (m, 1H), 7.50 (d, J= 7.8 Hz, 1H), 7.41 (s, 1H), 7.31 (d, J = 7.8 Hz, 1H), 6.72 - 6.73 (m, 1H), 5.04 (br, 1H), 3.74 - 3.83 (m, 4H), 3.56 (s, 2H), 3.40 - 3.47 (m, 2H), 3.08 - 3.18 (m, 2H), 2.50 - 2.51 (m, 3H), 2.12 - 2.36 (m, 4H), 2.03 - 2.08 (m, 4H). LCMS (ESI, m/z): 544 [M+H] ⁺ . Example 78: N-(l-(4-(3-((l,l-dioxidotetrahydro-2H-thiopyran-4-yl)oxy)-5- (trifluoromethyl)benzyl)piperazine-l-carbonyl)-lH-pyrazol-3- yl)acetamide

[00283] The title compound was synthesized as described in Example 77 using tert-butyl 4-(3- hydroxy-5-(trifluoromethyl)benzyl)piperazine-l-carboxylate in Step 2. Purification resulted in 71.7 mg ofN-(l-(4-(3-((l, l-dioxidotetrahydro-2H-thiopyran-4-yl)oxy)-5- (trifluoromethyl)benzyl)piperazine-l-carbonyl)-lH-pyrazol-3- yl)acetamide as a yellow oil. 1H MR (400 MHz, Chloroform-i ) δ 8.20 (d, J = 2.7 Hz, 1H), 7.96 (br, 1H), 7.26 (s, 1H), 7.15 (s, 1H), 7.08 (s, 1H), 6.89 (d, J= 2.8 Hz, 1H), 4.74 (br, 1H), 3.87 (br, 4H), 3.58 (s, 2H), 3.38 - 3.45 (m, 2H), 2.97 - 3.02 (m, 2H), 2.40 - 2.56 (m, 8H), 2.19 (s, 3H). LCMS (ESI, m/z): 544 [M+H] ⁺ . Example 79: N-(l-(4-(2-(2-oxo-2-(pyrrolidin-l-yl)ethoxy)-4- (trifluoromethyl)benzyl)piperazine-l-carbonyl)-lH-pyrazol-3- yl)acetamide

Step 1: Synthesis of 2-chloro-l-(pyrrolidin-l-yl)ethanone

o

Et ₃ N, CH ₂ CI ₂ \ l

rt, 1

[00284] A 100-mL round-bottom flask was charged with pyrrolidine (0.500 g, 7.03 mmol, 1.00 equiv), triethylamine (2.13 g, 21.1 mmol, 3.00 equiv), and DCM (20 mL). 2-Chloroacetyl chloride (1.18 g, 10.4 mmol, 1.50 equiv) was added at 0 °C. The resulting solution was stirred for 1 h at room temperature and concentrated under reduced pressure. The residue was chromatographed on a silica gel column to provide 0.902 g (87% yield) of 2-chloro-l- (pyrrolidin-l-yl)ethanone as a yellow solid. LCMS (ESI, m/z): 148 [M+H] ⁺ .

Step 2: Synthesis of tert-butyl 4-(2-(2-oxo-2-(pyrrolidin-l-yl)ethoxy)-4- (trifluoromethyl)benzyl)piperazine-l-carboxylate

[00285] A 100-mL round-bottom flask was charged with tert-butyl 4-[[2-hydroxy-4- (trifluoromethyl)phenyl]methyl]piperazine-l-carboxylate (130 mg, 0.36 mmol, 1.00 equiv), 2- chloro-l-(pyrrolidin-l-yl)ethanone (159 mg, 1.08 mmol, 3.00 equiv), potassium carbonate (150 mg, 1.09 mmol, 3.00 equiv), and acetonitrile (10 mL). The resulting solution was stirred overnight at 80°C and concentrated under reduced pressure. The residue was chromatographed on a silica gel column to provide 150 mg (88% yield) of tert-butyl 4-(2-(2-oxo-2-(pyrrolidin-l- yl)ethoxy)-4-(trifluoromethyl)benzyl)piperazine-l-carboxylat e as a yellow oil. LCMS (ESI, m/z): 472 [M+H] ⁺ .

Step 3: Synthesis of 2-(2-(piperazin-l-ylmethyl)-5-(trifluoromethyl)phenoxy)-l-(p yrrolidin- l-yl)ethanone

C o rt, overnight _Λ n

[00286] A 100-mL round-bottom flask was charged with tert-butyl 4-([2-[2-oxo-2-(pyrrolidin-l- yl)ethoxy]-4-(trifluoromethyl)phenyl]methyl)piperazine-l-car boxylate (200 mg, 0.42 mmol, 1.00 equiv), TFA (3 mL), and DCM (5 mL). The resulting solution was stirred overnight at room temperature and concentrated under reduced pressure to yield 260 mg (crude) of 2-(2- (piperazin-l-ylmethyl)-5-(trifluoromethyl)phenoxy)-l-(pyrrol idin-l-yl)ethanone as a yellow oil. LCMS (ESI, m/z): 372 [M+H] ⁺ .

Step 4: Synthesis of N-(l-(4-(2-(2-oxo-2-(pyrrolidin-l-yl)ethoxy)-4- (trifluoromethyl)benzyl)piperazine-l-carbonyl)-lH-pyrazol-3- yl)acetamide

[00287] A 100-mL round-bottom flask was charged with 2-(2-(piperazin-l-ylmethyl)-5- (trifluoromethyl)phenoxy)-l-(pyrrolidin-l-yl)ethanone (100 mg, 0.27 mmol, 1.00 equiv), 4- nitrophenyl 3-acetamido-lH-pyrazole-l-carboxylate (86.0 mg, 0.30 mmol, 1.10 equiv), triethylamine (54.0 mg, 0.53 mmol, 2.00 equiv), and DCM (5 mL). The resulting solution was stirred overnight at room temperature and then quenched with water (5 mL). The resulting mixture was extracted with DCM (3 x 5 mL) and the organic layers were combined, washed with brine (1 x 30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product (230 mg) was purified by preparative HPLC. Purification resulted in 52.2 mg (37% yield) of N-(l-(4-(2-(2-oxo-2-(pyrrolidin-l-yl)ethoxy)-4- (trifluoromethyl)benzyl)piperazine-l-carbonyl)-lH-pyrazol-3- yl)acetamide as an off-white solid. 1H MR (400 MHz, Chloroform-i ) δ 8.72 (br, 1H), 7.99 - 8.00 (m, 1H), 7.58 - 7.60 (m, 1H), 7.30 (s, 1H), 7.07 (s, 1H), 6.90 - 6.91 (m, 1H), 4.74 (s, 2H), 3.89 (br, 6H), 3.50 - 3.57 (m, 4H), 2.77 (br, 4H), 2.21 (s, 3H), 2.02 - 2.08 (m, 2H), 1.89 - 1.98 (m, 2H). LCMS (ESI, m/z): 523 [M+H] ⁺ .

Example 80: N-(l-(4-(3-(2-oxo-2-(pyrrolidin-l-yl)ethoxy)-5- (trifluoromethyl)benzyl)piperazine-l-carbonyl)-lH-pyrazol-3- yl)acetamide

[00288] The title compound was synthesized as described in Example 79 using tert-butyl 4-(3- hydroxy-5-(trifluoromethyl)benzyl)piperazine-l-carboxylate in Step 2. Purification resulted in 23.1 mg of N-(l-(4-(3 -(2-oxo-2-(pyrrolidin-l-yl)ethoxy)-5-(trifluorom ethyl )benzyl)piperazine- l-carbonyl)-lH-pyrazol-3-yl)acetamide as a white solid. ¹ H MR (400 MHz, Chloroform-<f) 6 8.12 (s, 1H), 8.02 (d, J= 2.8 Hz, 1H), 7.23 (s, 1H), 7.17 (s, 1H), 7.08 (s, 1H), 6.89 (d, J= 2.8 Hz, 1H), 4.69 (s, 2H), 3.85 (br, 4H), 3.50 - 3.57 (m, 6H), 2.52 - 2.54 (m, 4H), 2.19 (s, 3H), 1.98 - 2.06 (m, 2H), 1.86 - 1.93 (m, 2H). LCMS (ESI, m/z): 523 [M+H] ⁺ .

Example 81: N-(l-(l-(2-(l-cyclopropylpiperidin-4-yloxy)-4-(trifluorometh yl)benzyl)-l,8- diazaspiro[4.5]decane-8-carbonyl)- -pyrazol-3-yl)acetamide

Step 1: Synthesis of tert-butyl l-(2-hydroxy-4-(trifluoromethyl)b'

diazaspiro [4.5] decane- -carboxylate

[00289] A 100-mL round-bottom flask was charged with 2-hydroxy-4- (trifluoromethyl)benzaldehyde (1.00 g, 5.26 mmol, 1.00 equiv), tert-butyl 1,8- diazaspiro[4.5]decane-8-carboxylate (1.89 g, 7.86 mmol, 1.50 equiv), acetic acid (0.948 g, 15.8 mmol, 3.00 equiv), and MeOH (30 mL). The mixture was stirred for 1 h at room temperature. Sodium cyanoborohydride (0.995 g, 15.8 mmol, 3.00 equiv) was added. The resulting solution was stirred overnight at room temperature and quenched with water (50 mL). The mixture was extracted with DCM (3 x 70 mL) and the organic layers were combined, washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column to provide 1.60 g (73% yield) of tert- butyl l-(2 -hydroxy -4-(trifluoromethyl)benzyl)-l,8-diazaspiro[4.5]decane-8-carb oxylate as a yellow solid. LCMS (ESI, m/z): 415 [M+H] ⁺ .

Step 2: N-(l-(l-(2-(l-cyclopropylpiperidin-4-yloxy)-4-(trifluorometh yl)benzyl)-l,8- diazaspiro[4.5]decane-8-carbonyl)- -pyrazol-3-yl)acetamide

[00290] The title compound was synthesized as described for Example 71 using tert-butyl l-(2- hydroxy-4-(trifluoromethyl)benzyl)-l,8-diazaspiro[4.5]decane -8-carboxylate in Step 4.

Purification resulted in 40.1 mg of N-(l-(l-(2-(l-cyclopropylpiperidin-4-yloxy)-4- (trifluoromethyl)benzyl)-l,8-diazaspiro[4.5]decane-8-carbony l)-lH-pyrazol-3-yl)acetamide as a yellow oil. 1H MR (300 MHz, Chloroform-i ) δ 8.00 (d, J= 3.0 Hz, 1H), 7.56 (br, 1H), 7.20 (d, J= 7.5 Hz, 1H), 7.05 (s, 1H), 6.90 (d, J= 4.8 Hz, 1H), 4.62 (br, 2H), 4.49 (br, 1H), 3.73 (br, 2H), 2.99 - 3.08 (m, 4H), 2.70 - 2.79 (m, 4H), 2.21 (s, 4H), 1.90 - 2.13 (m, 12H), 0.60 (br, 4H). LCMS (ESI, m/z): 589 [M+H] ⁺ .

Example 82: N-(l-(l-(3-(l-cyclopropylpiperidin-4-yloxy)-5-(trifluorometh yl)benzyl)-l,8- diazaspiro[4.5]decane-8-carbon -lH-pyrazol-3-yl)acetamide

[00291] The title compound was synthesized as described in Example 81 using 3-hydroxy-5- (trifluoromethyl)benzaldehyde in Step 1. Purification resulted in 27.8 mg of N-(l-(l-(3-(l- cyclopropylpiperidin-4-yloxy)-5-(trifluoromethyl)benzyl)-l,8 -diazaspiro[4.5]decane-8- carbonyl)-lH-pyrazol-3-yl)acetamide as a yellow oil. 1H MR (300 MHz, Chloroform-i ) δ 7.99 - 8.03 (m, 2H), 7.20 (s, 1H), 7.07 (br, 1H), 6.88 (d, J= 2.7 Hz, 1H), 4.68 - 4.73 (m, 3H), 3.13 - 3.88 (m, 5H), 1.45 - 3.10 (m, 23H), 0.82 - 0.84 (m, 2H). LCMS (ESI, m/z): 589 [M+H] ⁺ .

Example 83: N-(l-(l-(2-(pyrimidin-5-yloxy)-4-(trifluoromethyl)benzyl)-l, 8- diazaspiro[4.5]decane-8-carbonyl)- -pyrazol-3-yl)acetamide

[00292] The title compound was synthesized as described in Example 73 using tert-butyl l-(2- hydroxy-4-(trifluoromethyl)benzyl)-l,8-diazaspiro[4.5]decane -8-carboxylate in Step 1.

Purification resulted in 50.6 mg of N-(l-(l-(2-(pyrimidin-5-yloxy)-4-(trifluoromethyl)benzyl)- l,8-diazaspiro[4.5]decane-8-carbonyl)-lH-pyrazol-3-yl)acetam ide as a white solid. 1H MR (300 MHz, Chloroform-ύ δ 9.48 (br, 1H), 8.98 (br, 1H), 8.48 (br, 2H), 7.96 (d, J= 2.7 Hz, 1H), 7.52 - 7.54 (m, 2H), 7.33 (br, 1H), 6.92 (d, J= 2.7 Hz, 1H), 4.50 - 4.53 (m, 2H), 3.62 (br, 2H), 2.86 - 2.94 (m, 2H), 2.76 (br, 2H), 2.28 (s, 3H), 1.60 - 1.79 (m, 6H), 1.25 - 1.36 (m, 2H). LCMS (ESI, m/z): 544 [M+H] ⁺ .

Example 84: N-(l-(l-(3-(pyrimidin-5-yloxy)-5-(trifluoromethyl)benzyl)-l, 8- diazaspiro[4.5]decane-8-carbonyl)- -pyrazol-3-yl)acetamide

[00293] The title compound was synthesized as described in Example 73 using tert-butyl l-(3- hydroxy-5-(trifluoromethyl)benzyl)-l,8-diazaspiro[4.5]decane -8-carboxylate in Step 1.

Purification resulted in 51.4 mg of N-(l-(l-(3-(pyrimidin-5-yloxy)-5-(trifluoromethyl)benzyl)- l,8-diazaspiro[4.5]decane-8-carbonyl)-lH-pyrazol-3-yl)acetam ide as a yellow solid. 1H MR (400 MHz, Chloroform-ύ δ 9.06 (s, 1H), 8.54 (br, 2H), 8.15 (br, 1H), 8.01 (d, J= 2.8 Hz, 1H), 7.44 (br, 1H), 7.25 (br, 1H), 7.19 (br, 1H), 6.90 (d, J= 2.8 Hz, 1H), 4.59 - 4.62 (m, 2H), 3.70 (s, 2H), 3.00 - 3.06 (m, 2H), 2.71 (t, J= 6.6 Hz, 2H), 2.20 (s, 3H), 1.75 - 1.90 (m, 6H), 1.47 - 1.52 (m, 2H). LCMS (ESI, m/z): 544 [M+H] ⁺ .

Example 85: N-(l-(l-(2-(benzo[d]thiazol-2-yloxy)-4-(trifluoromethyl)benz yl)-l,8- diazaspiro[4.5]decane-8-carbonyl)- -pyrazol-3-yl)acetamide

[00294] The title compound was synthesized as described in Example 75 using tert-butyl l-(2- hydroxy-4-(trifluoromethyl)benzyl)-l,8-diazaspiro[4.5]decane -8-carboxylate in Step 1.

Purification resulted in 58.8 mg of N-(l-(l-(2-(benzo[d]thiazol-2-yloxy)-4- (trifluoromethyl)benzyl)-l,8-diazaspiro[4.5]decane-8-carbony l)-lH-pyrazol-3-yl)acetamide as an off-white solid. 1H MR (300 MHz, Chloroform-i ) δ 8.61 (br, 1H), 7.95 (d, J= 2.7 Hz, 2H), 7.72 (d, J= 8.4 Hz, 2H), 7.58 - 7.64 (m, 2H), 7.40 - 7.45 (m, 1H), 7.30 - 7.35 (m, 1H), 6.88 (d, J = 2.7 Hz, 1H), 4.58 - 4.62 (m, 3H), 4.01 (br, 2H), 2.92 - 3.00 (m, 4H), 2.20 (s, 3H), 1.94 - 2.01 (m, 7H). LCMS (ESI, m/z): 599 [M+H] ⁺ .

Example 86: N-(l-(l-(3-(benzo[d]thiazol-2-yloxy)-5-(trifluoromethyl)benz yl)-l,8- diazaspiro[4.5]decane-8-carbony -lH-pyrazol-3-yl)acetamide

[00295] The title compound was synthesized as described in Example 75 using tert-butyl l-(3- hydroxy-5-(trifluoromethyl)benzyl)-l,8-diazaspiro[4.5]decane -8-carboxylate in Step 1.

Purification resulted in 47.0 mg of N-(l-(l-(3-(benzo[d]thiazol-2-yloxy)-5- (trifluoromethyl)benzyl)-l,8-diazaspiro[4.5]decane-8-carbony l)-lH-pyrazol-3-yl)acetamide as a white solid. 1H MR (300 MHz, Chloroform-i ) δ 8.31 - 8.40 (m, 1H), 8.00 (d, J= 3.6 Hz, 1H), 7.69 - 7.74 (m, 2H), 7.53 - 7.58 (m, 3H), 7.38 - 7.46 (m, 1H), 7.30 - 7.33 (m, 1H), 6.88 (d, J = 3.6 Hz, 1H), 4.55 - 4.60 (m, 3H), 3.69 (br, 2H), 2.96 - 3.04 (m, 2H), 2.72 (br, 2H), 2.13 (s, 3H), 1.86 (br, 7H). LCMS (ESI, m/z): 599 [M+H] ⁺ .

Example 87: N-(l-(l-(2-((l,l-dioxidotetrahydro-2H-thiopyran-4-yl)oxy)-4- (trifluoromethyl)benzyl)-l,8-diazaspiro[4.5]decane-8-carbony l)-lH-pyrazol-3-yl)acetamide

[00296] The title compound was synthesized as described in Example 77 using tert-butyl l-(2- hydroxy-4-(trifluoromethyl)benzyl)-l,8-diazaspiro[4.5]decane -8-carboxylate in Step 2.

Purification resulted in 52.4 mg of N-(l-(l-(2-((l, l-dioxidotetrahydro-2H-thiopyran-4-yl)oxy)- 4-(trifluoromethyl)benzyl)-l,8-diazaspiro[4.5]decane-8-carbo nyl)-lH-pyrazol-3-yl)acetamide as a white solid. 1H MR (400 MHz, Chloroform-i ) δ 8.73 (br, 1H), 8.00 (d, J= 2.4 Hz, 1H), 7.52 (d, J= 7.6 Hz, 1H), 7.25 - 7.29 (m, 1H), 7.09 (s, 1H), 6.93 (d, J= 2.8 Hz, 1H), 4.84 (br, 1H), 4.60 - 4.63 (m, 2H), 3.75 (br, 2H), 3.47 - 3.54 (m, 2H), 2.98 - 3.09 (m, 4H), 2.74 (t, J= 6.6 Hz, 2H), 2.44 - 2.57 (m, 4H), 2.22 (s, 3H), 1.97 - 2.03 (m, 2H), 1.84 - 1.90 (m, 4H), 1.61 - 1.65 (m, 2H). LCMS (ESI, m/z): 598 [M+H] ⁺ . Example 88: N-(l-(l-(3-((l,l-dioxidotetrahydro-2H-thiopyran-4-yl)oxy)-5- (trifluoromethyl)benzyl)-l,8-diazaspiro[4.5]decane-8-carbony l)-lH-pyrazol-3-yl)acetamide

[00297] The title compound was synthesized as described in Example 77 using tert-butyl l-(3- hydroxy-5-(trifluoromethyl)benzyl)-l,8-diazaspiro[4.5]decane -8-carboxylate in Step 2.

Purification resulted in 31.5 mg of N-(l-(l-(3-((l, l-dioxidotetrahydro-2H-thiopyran-4-yl)oxy)- 5-(trifluoromethyl)benzyl)-l,8-diazaspiro[4.5]decane-8-carbo nyl)-lH-pyrazol-3-yl)acetamide as a white solid. 1H MR (400 MHz, Chloroform-i ) δ 8.01 (d, J= 2.8 Hz, 1H), 7.94 (br, 1H), 7.23 (s, 1H), 7.11 (br, 1H), 7.02 (br, 1H), 6.90 (d, J= 2.8 Hz, 1H), 4.72 (br, 1H), 4.60 - 4.63 (m, 2H), 3.66 (br, 2H), 3.38 - 3.46 (m, 2H), 2.96 - 3.10 (m, 4H), 2.70 (br, 2H), 2.35 - 2.51 (m, 4H), 2.20 (s, 3H), 1.86 - 2.04 (m, 6H), 1.60 - 1.68 (m, 2H). LCMS (ESI, m/z): 598 [M+H] ⁺ .

Example 89: N-(l-(l-(2-(2-oxo-2-(pyrrolidin-l-yl)ethoxy)-4-(trifluoromet hyl)benzyl)-l,8- diazaspiro[4.5]decane-8-carbonyl)- -pyrazol-3-yl)acetamide

[00298] The title compound was synthesized as described in Example 79 using tert-butyl l-(2- hydroxy-4-(trifluoromethyl)benzyl)-l,8-diazaspiro[4.5]decane -8-carboxylate in Step 2.

Purification resulted in 20.4 mg of N-(l-(l-(2-(2-oxo-2-(pyrrolidin-l-yl)ethoxy)-4- (trifluoromethyl)benzyl)-l,8-diazaspiro[4.5]decane-8-carbony l)-lH-pyrazol-3-yl)acetamide as a white solid. 1H MR (400 MHz, Chloroform-i ) δ 9.67 (br, 1H), 8.00 (d, J= 2.8 Hz, 1H), 7.39 - 7.41 (m, 1H), 7.24 - 7.26 (m, 1H), 7.05 (s, 1H), 6.94 (d, J= 2.8 Hz, 1H), 4.66 - 4.69 (m, 2H), 4.53 - 4.56 (m, 2H), 3.71 - 3.79 (m, 2H), 3.51 - 3.59 (m, 4H), 2.93 - 2.99 (m, 2H), 2.78 (br, 2H), 2.23 (s, 3H), 1.98 - 2.07 (m, 4H), 1.83 - 1.94 (m, 6H), 1.38 - 1.43 (m, 2H). LCMS (ESI, m/z): 577 [M+H] ⁺ .

Example 90: N-(l-(l-(3-(2-oxo-2-(pyrrolidin-l-yl)ethoxy)-5-(trifluoromet hyl)benzyl)-l,8- diazaspiro[4.5]decane-8-carbonyl -lH-pyrazol-3-yl)acetamide

[00299] The title compound was synthesized as described in Example 79 using tert-butyl l-(3- hydroxy-5-(trifluoromethyl)benzyl)-l,8-diazaspiro[4.5]decane -8-carboxylate in Step 2.

Purification resulted in 17.2 mg of N-(l-(l-(3-(2-oxo-2-(pyrrolidin-l-yl)ethoxy)-5- (trifluoromethyl)benzyl)-l,8-diazaspiro[4.5]decane-8-carbony l)-lH-pyrazol-3-yl)acetamide as a colorless oil. 1H MR (400 MHz, Chloroform-i ) δ 8.23 - 8.28 (m, 1H), 8.00 (d, J= 2.4 Hz, 1H), 7.17 - 7.20 (m, 2H), 7.03 (br, 1H), 6.90 (d, J= 2.8 Hz, 1H), 4.68 (br, 2H), 4.58 - 4.60 (m, 2H), 3.65 (br, 2H), 3.50 - 3.56 (m, 4H), 2.99 - 3.07 (m, 2H), 2.71 (br, 2H), 2.20 (s, 3H), 1.98 - 2.05 (m, 2H), 1.84 - 1.92 (m, 8H), 1.48 - 1.51 (m, 2H). LCMS (ESI, m/z): 577 [M+H] ⁺ .

Example 91: N-(l-(4-(4-chlorobenzyl)piperazine-l-carbonyl)-lH-pyrazol-3- yl)-2- hydroxyacetamide

Step 1: Synthesis of tert-butyl 3-nitro-lH-pyrazole-l-carboxylate

[00300] A 500-mL round-bottom flask was charged with 3-nitro-lH-pyrazole (17.8 g, 157 mmol, 1.00 equiv), DCM (200 mL), triethylamine (31.9 g, 315 mmol, 2.00 equiv), and di -tert- butyl dicarbonate (37.8 g, 173 mmol, 1.10 equiv). The resulting solution was stirred overnight at room temperature and concentrated under reduced pressure to provide 31.0 g (crude) of tert- butyl 3-nitro-lH-pyrazole-l-carboxylate as a white solid. LCMS (ESI, m/z): 214 [M+H] ⁺ .

Step 2: Synthesis of tert-butyl 3-amino-lH-pyrazole-l-carboxylate

[00301] A 500-mL 3-necked round-bottom flask was charged with tert-butyl 3-nitro-lH- pyrazole-l-carboxylate (20.0 g, 93.8 mmol, 1.00 equiv), EtOAc (100 mL), and 10% palladium carbon (5.00 g). The resulting solution was stirred overnight at room temperature under hydrogen atmosphere. The solids were filtered and washed with EtOAc (2 x 20 mL). The filtrate was concentrated under reduced pressure to provide 17.6 g (crude) of tert-butyl 3-amino-lH- pyrazole-l-carboxylate as a brown solid. LCMS (ESI, m/z): 184 [M+H] ⁺ .

Step 3: Synthesis of 2-hydroxy-N-(lH-pyrazol-3-yl)acetamide

^BOt

, overn g [00302] A 100-mL round-bottom flask was charged with tert-butyl 3-amino-lH-pyrazole-l- carboxylate (2.00 g, 10.9 mmol, 1.00 equiv), DCM (20 mL), and triethylamine (2.75 g, 27.2 mmol, 2.50 equiv). 2-Chloro-2-oxoethyl acetate (1.93 g, 14.1 mmol, 1.30 equiv) was added dropwise at 0 °C. The resulting solution was stirred 4 h at room temperature and concentrated under reduce pressure. Then the resulting solid was dissolved in MeOH (20 mL). Potassium carbonate (3.03 g, 21.8 mmol, 2.00 equiv) and water (5 mL) was added. The mixture was stirred for overnight at room temperature and concentrated under reduced pressure. The residue was triturated in acetonitrile (50 mL). The solids were filtered and washed with acetonitrile (3 x 20 mL). The filtrate was concentrated under reduced pressure to provide 1.38 g (crude) of 2- hydroxy-N-(lH-pyrazol-3-yl)acetamide as a brown solid. LCMS (ESI, m/z): 142 [M+H] ⁺ . Step 4: Synthesis of 4-(4-chlorobenzyl)piperazine-l-carbonyl chloride

[00303] A 50-mL round-bottom flask was charged with l-[(4-chlorophenyl)methyl]piperazine (210 mg, 1.00 mmol, 1.00 equiv), DCM (10 mL), and triphosgene (206 mg, 0.699 mmol, 0.70 equiv). N,N-Diisopropylethylamine (516 mg, 3.99 mmol, 4.00 equiv) was added dropwise at 0 °C. The resulting solution was stirred for 5 h at 0 °C and quenched by water (20 mL). The mixture was extracted with DCM (3 x 30 mL) and the organic layers were combined, washed with water (3 x 10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to provide 232 mg (crude) of 4-(4-chlorobenzyl)piperazine-l-carbonyl chloride as a yellow oil.

Step 5: Synthesis of N-(l-(4-(4-chlorobenzyl)piperazine-l-carbonyl)-lH-pyrazol-3- yl)-2- hydroxyacetamide

[00304] A 50-mL round-bottom flask was charged with 4-(4-chlorobenzyl)piperazine-l- carbonyl chloride (232 mg, 0.85 mmol, 1.00 equiv), THF (10 mL), 2-hydroxy-N-(lH-pyrazol-3- yl)acetamide (120 mg, 0.85 mmol, 1.00 equiv), 4-dimethylaminopyridine (20.9 mg, 0.18 mmol, 0.20 equiv), and N,N-diisopropylethylamine (221 mg, 1.72 mmol, 2.00 equiv). The resulting solution was stirred overnight at 60 °C and diluted with water (20 mL). The mixture was extracted with EtOAc (3 x 30 mL) and the organic layers were combined, washed with water (3 x 10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC. Purification resulted in 83.7 mg (26% yield) of N-(l-(4-(4-chlorobenzyl)piperazine-l-carbonyl)-lH-pyrazol-3- yl)-2- hydroxyacetamide as a yellow oil. 1H MR: (400 MHz, Chloroform- ) δ 8.85 (s, 1H), 8.04 (d, J = 2.7 Hz, 1H), 7.25 - 7.34 (m, 4H), 6.94 (d, J= 2.7 Hz, 1H), 4.29 (s, 2H), 3.85 (s, 4H), 3.53 (s, 2H), 2.90 (br, 1H), 2.54 (m, 4H). LCMS (ESI, m/z): 378 [M+H] ⁺ .

Example 92: 2-hydroxy-N-(l-(4-(3-phenoxybenzyl)piperazine-l-carbonyl)-lH -pyrazol-3- yl)acetamide

Step 1: Synthesis of tert-butyl 4-(3-phenoxybenzyl)piperazine-l-carboxylate

a ^. HN N-Boc ,,Boc

NNaaBBHH((OOAAcc)), ₃ ,, CCIICCHH, ₂ CCHH, ₂ CCII ^^-"^r ₀ ,-^^^- ¹ ^ _^ ^

rt, overnight

[00305] A 250-mL round-bottom flask was charged with 3-phenoxybenzaldehyde (5.00 g, 25.2 mmol, 1.00 equiv), tert-butyl piperazine-l-carboxylate (4.25 g, 22.8 mmol, 0.90 equiv), DCE (100 mL), and sodium triacetoxyborohydride (10.6 g, 50.0 mmol, 1.98 equiv). The resulting solution was stirred overnight at room temperature and quenched by water (50 mL). The mixture was extracted with DCM (3 x 30 mL) and the organic layers were combined, washed with water (3 x 30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel to provide 8.80 g (95% yield) of tert- butyl 4-(3-phenoxybenzyl)piperazine-l-carboxylate as a yellow oil. LCMS (ESI, m/z): 369

[M+H] ⁺ .

Step 2: Synthesis -(3-phenoxybenzyl)piperazine

[00306] A 250-mL round-bottom flask was charged with tert-butyl 4-(3- phenoxybenzyl)piperazine-l-carboxylate (8.80 g, 23.9 mmol, 1.00 equiv), DCM (100 mL), and TFA (20 mL). The resulting solution was stirred for 2 h at room temperature and concentrated under reduced pressure to provide 6.03 g (crude) of l-(3-phenoxybenzyl)piperazine as a white solid. LCMS (ESI, m/z): 269 [M+H] ⁺ .

Step 3: 2-hydroxy-N-(l-(4-(3-phenoxybenzyl)piperazine-l-carbonyl)-lH -pyrazol-3- yl)acetamide

[00307] The title compound was synthesized as described in Example 91 using l-(3- phenoxybenzyl)piperazine in Step 4. Purification resulted in 24.1 mg of 2-hydroxy-N-(l-(4-(3- phenoxybenzyl)piperazine-l-carbonyl)-lH-pyrazol-3-yl)acetami de as a white solid. ¹ H MR: (400 MHz, Chloroform-i δ 8.85 (s, 1H), 7.86 - 8.15 (d, J= 2.8 Hz, 1H), 7.28 - 7.39 (m, 3H), 7.04 - 7.15 (m, 2H), 6.97 - 7.04 (m, 3H), 6.87 - 6.94 (m, 2H), 4.26 (s, 2H), 3.83 (s, 4H), 3.53 (s, 2H), 2.73 - 3.30 (br, 1H), 2.46 - 2.64 (t, J= 9.3 Hz, 4H). LCMS (ESI, m/z): 435 [M+H] ⁺ .

Example 93: N-(l-(l-(3-methyl-4-(trifluoromethyl)benzyl)-l,8-diazaspiro[ 4.5]decane-8- carbonyl)-lH-pyrazol-3-yl)acetamide

Step 1: Synthesis of tert-butyl 8-(3-acetamido-lH-pyrazole-l-carbonyl)-l,8- diazaspiro [4.5] deca -l-carboxylate

[00308] A 100-mL round-bottom flask was charged with 4-nitrophenyl 3-acetamido-lH- pyrazole-l-carboxylate (2.32 g, 7.99 mmol, 1.50 equiv), DCM (20 mL), tert-butyl 1,8- diazaspiro[4.5]decane-l-carboxylate (1.28 g, 5.33 mmol, 1.00 equiv), and triethylamine (1.62 g, 16.0 mmol, 3.00 equiv). The resulting solution was stirred overnight at room temperature and quenched with water (50 mL). The resulting solution was extracted with DCM (2 x 80 mL) and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and

concentrated under reduced pressure. The residue was chromatographed on a silica gel column to provide 1.90 g (61% yield) of tert-butyl 8-(3-acetamido-lH-pyrazole-l-carbonyl)-l,8- diazaspiro[4.5]decane-l-carboxylate as a yellow oil. LCMS (ESI, m/z): 392 [M+H] ⁺ .

Step 2: Synthesis of N-(l-(l,8-diazaspiro[4.5]decane-8-carbonyl)-lH-pyrazol-3- yl)acetamide

[00309] A 100-mL round-bottom flask was charged with tert-butyl 8-(3-acetamido-lH-pyrazole- l-carbonyl)-l,8-diazaspiro[4.5]decane-l-carboxylate (800 mg, 2.04 mmol, 1.00 equiv), DCM (20 mL), and TFA (4 mL). The resulting solution was stirred overnight at room temperature and concentrated under reduced pressure to provide 800 mg (crude) of N-(l-(l,8- diazaspiro[4.5]decane-8-carbonyl)-lH-pyrazol-3-yl)acetamide as a yellow oil. LCMS (ESI, m/z): 292 [M+H] ⁺ . Step 3: Synthesis of N-(l-(l-(3-methyl-4-(trifluoromethyl)benzyl)-l,8- diazaspiro[4.5]decane-8-carbonyl)-lH-pyrazol-3-yl)acetamide

[00310] A 50-mL round-bottom flask was charged with N-(l-(l,8-diazaspiro[4.5]decane-8- carbonyl)-lH-pyrazol-3-yl)acetamide (147 mg, 0.50 mmol, 1.00 equiv), DCE (10 mL), triethylamine (154 mg, 1.52 mmol, 3.00 equiv), and 3-methyl-4-(trifluoromethyl)benzaldehyde (95.0 mg, 0.50 mmol, 1.00 equiv). The mixture was stirred for 1 h at room temperature. Sodium triacetoxyborohydride (322 mg, 1.52 mmol, 3.00 equiv) was added. The resulting solution was stirred overnight at room temperature and quenched with water (30 mL). The resulting solution was extracted with DCM (2 x 50 mL) and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product (300 mg) was purified by preparative HPLC. Purification resulted in 97.5 mg (42% yield) of N- (l-(l-(3-methyl-4-(trifluoromethyl)benzyl)-l,8-diazaspiro[4. 5]decane-8-carbonyl)-lH-pyrazol- 3-yl)acetamide as a white solid. 1H NMR (400 MHz, Chloroform-i ) δ 8.02 (d, J= 2.8 Hz, 1H), 7.79 (br, 1H), 7.54 (d, J= 8.0 Hz, 1H), 7.22 - 7.24 (m, 2H), 6.90 (d, J= 2.8 Hz, 1H), 4.60 - 4.63 (m, 2H), 3.64 (s, 2H), 3.07 (t, J= 12.2 Hz, 2H), 2.68 - 2.71 (m, 2H), 2.49 (s, 3H), 2.21 (s, 3H), 1.84 - 1.90 (m, 6H), 1.51 - 1.54 (m, 2H). LCMS (ESI, m/z): 486 [M+Na] ⁺ .

Example 94: N-(l-(l-(4-chloro-3-methylbenzyl)-l,8-diazaspiro[4.5]decane- 8-carbonyl)-lH- pyrazol-3-yl)acetamide

[00311] The title compound was synthesized as described in Example 93 using 4-chloro-3- methylbenzaldehyde in Step 3. Purification resulted in 66.3 mg of N-[l-([l-[(4-chloro-3- methylphenyl)methyl]-l,8-diazaspiro[4.5]decan-8-yl]carbonyl) -lH-pyrazol-3-yl]acetamide as a white solid. 1H NMR (300 MHz, Chloroform-i ) δ 8.00 (d, J= 2.7 Hz, 1H), 7.79 (br, 1H), 7.24 (s, 1H), 7.06 - 7.16 (m, 2H), 6.88 (d, J= 2.7 Hz, 1H), 4.57 - 4.61 (m, 2H), 3.55 (s, 2H), 3.05 (t, J = 12.0 Hz, 2H), 2.66 (br, 2H), 2.35 (s, 3H), 2.19 (s, 3H), 1.82 - 1.85 (m, 6H), 1.48 - 1.52 (m, 2H). LCMS (ESI, m/z): 430 [M+H] ⁺ . Example 95: N-(l-(l-(3-ethyl-4-fluorobenzyl)-l,8-diazaspiro[4.5]decane-8 -carbonyl)-lH- pyrazol-3-yl)acetamide

Step 1: Synthesis of 3-ethyl- -fluorobenzaldehyde

[00312] A 100-mL round-bottom flask was charged with 4-bromo-2-ethyl-l-fluorobenzene (2.00 g, 9.85 mmol, 1.00 equiv), and THF (25 mL) under nitrogen. The mixture was cooled to -78 °C. n-Butyllithium (2.5 M in hexane, 4.80 mL, 11.8 mmol, 1.20 equiv) was added dropwise at -78 °C. The mixture was stirred for 1 h at -78 °C and N,N-dimethylformamide (2.17 g, 29.6 mmol, 3.00 equiv) was added. The resulting solution was stirred for 1 h at -78 °C and quenched with saturated H ₄ C1 solution (30 mL). The resulting solution was extracted with EtOAc (2 x 100 mL), the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column to provide 1.20 g (80% yield) of 3-ethyl-4-fluorobenzaldehyde as a light yellow oil. 1H MR (300 MHz, Chloroform-ύ δ 9.94 (s, 1H), 7.71 - 7.82 (m, 2H), 7.16 (t, J= 8.8 Hz, 1H), 2.68 - 2.78 (m, 2H), 1.28 (t, J= 6.4 Hz, 3H).

Step 2: Synthesis of N-(l-(l-(3-ethyl-4-fluorobenzyl)-l,8-diazaspiro[4.5]decane-8 - carbonyl)-lH-pyrazol-3-yl)acetami

[00313] The title compound was synthesized as described in Example 93 using 3-ethyl-4- fluorobenzaldehyde in Step 3. Purification resulted in 67.9 mg of N-(l-(l-(3-ethyl-4- fluorobenzyl)-l,8-diazaspiro[4.5]decane-8-carbonyl)-lH-pyraz ol-3-yl)acetamide as a white solid. 1H MR (400 MHz, MeOH-i¾) δ 8.05 (d, J= 2.8 Hz, 1H), 7.20 - 7.26 (m, 2H), 6.98 - 7.03 (m, 1H), 6.81 (d, J= 2.8 Hz, 1H), 4.62 - 4.65 (m, 2H), 3.73 (br, 2H), 3.16 (t, J= 13.0 Hz, 2H), 2.86 (br, 2H), 2.65 - 2.71 (m, 2H), 2.15 (s, 3H), 2.02 (br, 4H), 1.88 (br, 2H), 1.60 - 1.63 (m, 6H), 1.24 (t, J= 7.6 Hz, 3H). LCMS (ESI, m/z): 428 [M+H] ⁺ . Example 96: N-(l-(l-(3-chloro-4-methylbenzyl)-l,8-diazaspiro[4.5]decane- 8-carbonyl)-lH- pyrazol-3-yl)acetamide

[00314] The title compound was synthesized as described in Example 93 using 3-chloro-4- methylbenzaldehyde in Step 3. Purification resulted in 98.6 mg of N-(l-(l-(3-chloro-4- methylbenzyl)-l,8-diazaspiro[4.5]decane-8-carbonyl)-lH-pyraz ol-3-yl)acetamide as a white solid. 1H MR (300 MHz, Chloroform-i ) δ 8.00 (d, J= 2.7 Hz, 1H), 7.80 (br, 1H), 7.31 (br, 1H), 7.14 - 7.16 (m, 2H), 6.88 (d, J= 2.7 Hz, 1H), 4.57 - 4.61(m, 2H), 3.57 (br, 2H), 2.99 - 3.09 (m, 2H), 2.68 ( br, 2H), 2.34 (s, 3H), 2.19 (s, 3H), 1.82 - 1.97 (m, 6H), 1.52 (br, 2H). LCMS (ESI, m/z): 430 [M+H] ⁺ .

Example 97: N-(l-(l-((l,3-dihydroisobenzofuran-5-yl)methyl)-l,8-diazaspi ro[4.5]decane-8- carbonyl)-lH-pyrazol-3-yl)acetamide

Step 1: Synthesis of (4-brom -l,2-phenylene)dimethanol

[00315] A 250-mL round-bottom flask was charged with 5-bromo-l,3-dihydro-2-benzofuran- 1,3-dione (8.00 g, 35.2 mmol, 1.00 equiv) and THF (100 mL). Lithium aluminium hydride (2.69 g, 70.9 mmol, 2.00 equiv) was added at 0 °C. The resulting solution was stirred for 2 h at 10 °C and quenched by EtOAc (50 mL). The resulting solution was diluted with water (100 mL). The pH value of the solution was adjusted to 3 with hydrochloric acid (1 mol/L). The resulting solution was extracted with EtOAc (2 x 100 mL) and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column to provide 4.00 g (52% yield) of (4-bromo-l,2- phenylene)dimethanol as a white solid. 1H MR (300 MHz, Chloroform-i ) δ 7.66 - 7.70 (m, 1H), 7.43 - 7.47 (m, 1H), 7.23 (d, J= 7.8 Hz, 1H), 4.71 (s, 4H), 2.62 (br, 2H). Step 2: Synthesis of (5-bromo-2-(chloromethyl)phenyl)methanol

[00316] A 100-mL round-bottom flask was charged with (4-bromo-l,2-phenylene)dimethanol (4.00 g, 18.4 mmol, 1.00 equiv) and hydrochloric acid (25 mL). The resulting solution was stirred for 15 min at 70 °C and quenched with water (50 mL). The resulting solution was extracted with EtOAc (2 x 80 mL) and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was

chromatographed on a silica gel column to provide 2.70 g (62% yield) of (5-bromo-2- (chloromethyl)phenyl)methanol as an off-white solid. 1H NMR (300 MHz, DMSO-<f ₆ ) δ 7.64 - 7.66 (m, 1H), 7.45 - 7.49 (m, 1H), 7.36 (d, J= 8.1 Hz, 1H), 5.40 - 5.45 (m, 1H), 4.78 (s, 2H), 4.66 (d, J= 4.5 Hz, 2H).

Step 3: Synthesis of 5-bromo-l,3-dihydroisobenzofuran

[00317] A 250-mL round-bottom flask was charged with (5-bromo-2- (chloromethyl)phenyl)methanol (2.50 g, 10.7 mmol, 1.00 equiv) and THF (40 mL). Sodium hydride (60% in mineral oil, 856 mg, 21.4 mmol, 2.00 equiv) was added at 0 °C. The resulting solution was stirred for 2 h at 45 °C and quenched with water (80 mL). The resulting solution was extracted with EtOAc (2 x 100 mL) and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column to provide 1.90 g (90% yield) of 5-bromo-l,3- dihydroisobenzofuran as an off-white solid. 1H NMR (300 MHz, DMSO-i¾) δ 7.54 (s, 1H), 7.45 (d, J= 8.1 Hz, 1H), 7.28 (d, J= 8.1 Hz, 1H), 4.95 - 4.98 (m, 1H).

Step 4: Synthesis of l,3-dihydroisobenzofuran-5-carbaldehyde

[00318] A 100-mL round-bottom flask was charged with 5-bromo-l,3-dihydroisobenzofuran (1.60 g, 8.08 mmol, 1.00 equiv) and THF (25 mL) under nitrogen. Butyllithium (2.5 M in hexane, 3.90 mL, 9.70 mmol, 1.20 equiv) was added dropwise at -78 °C. The mixture was stirred at -78 °C for 1 h and N,N-dimethylformamide (1.77 g, 24.2 mmol, 3.00 equiv) was added. The resulting solution was stirred for 1 h at -78 °C and quenched with saturated NH ₄ C1 solution (50 mL). The resulting solution was extracted with EtOAc (2 x 80 mL) and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column to provide 900 mg (76% yield) of l,3-dihydroisobenzofuran-5-carbaldehyde as a white solid. 1H NMR (300 MHz, Chloroform-ύ δ 10.0 (s, 1H), 7.77 - 7.82 (m, 2H), 7.40 (d, J= 7.5 Hz, 1H), 5.16 (s, 4H).

Step 5: Synthesis of N-(l-(l-((l,3-dihydroisobenzofuran-5-yl)methyl)-l,8- diazaspiro[4.5]decane-8-carbonyl)-lH- razol-3-yl)acetamide

[00319] The title compound was synthesized as described in Example 93 using 1,3- dihydroisobenzofuran-5-carbaldehyde in Step 3. Purification resulted in 107.7 mg of N-(l-(l- ((l,3-dihydroisobenzofuran-5-yl)methyl)-l,8-diazaspiro[4.5]d ecane-8-carbonyl)-lH-pyrazol-3- yl)acetamide as a white solid. 1H MR (400 MHz, DMSO-i¾) δ 10.63 (s, 1H), 8.07 (d, J= 2.4 Hz, 1H), 7.22 (br, 3H), 6.72 (d, J= 2.4 Hz, 1H), 4.98 (s, 4H), 4.42 - 4.44 (m, 2H), 3.59 (s, 2H), 3.07 (t, J= 12.4 Hz, 2H), 2.58 (br, 2H), 2.04 (s, 3H), 1.70 - 1.83 (m, 6H), 1.43 - 1.46 (m, 2H). LCMS (ESI, m/z): 446 [M+Na] ⁺

Example 98: N-(l-(l-((2,3-dihydrobenzo[b] [l,4]dioxin-6-yl)methyl)-l,8- diazaspiro[4.5]decane-8-carbonyl)- -pyrazol-3-yl)acetamide

[00320] The title compound was synthesized as described in Example 93 using 2,3- dihydrobenzo[b][l,4]dioxine-6-carbaldehyde in Step 3. Purification resulted in 72.9 mg of N-(l- (l-((2,3-dihydrobenzo[b][l,4]dioxin-6-yl)methyl)-l,8-diazasp iro[4.5]decane-8-carbonyl)-lH- pyrazol-3-yl)acetamide as a light yellow solid. ¹ H MR (300 MHz, Chloroform- ) δ 8.00 (d, J = 3.0 Hz, 1H), 7.78 (br, 1H), 6.87 - 6.91 (m, 2H), 6.78 (br, 2H), 4.56 - 4.60 (m, 2H), 4.24 (s, 4H), 3.53 (br, 2H), 3.03 (t, J= 12.3 Hz, 2H), 2.71 ( br, 2H), 2.19 (s, 3H), 1.83 - 1.87 (m, 6H), 1.50 - 1.52 (m, 2H). LCMS (ESI, m/z): 440 [M+H] ⁺ .

Example 99: N-(l-(l-(3-chloro-4-morpholinobenzyl)-l,8-diazaspiro[4.5]dec ane-8- carbonyl)-lH-pyrazol-3-yl)acetamide

Step 1: Synthesis of 3-chloro-4-morpholinobenzaldehyde

[00321] A 50-mL round-bottom flask was charged with 3-chloro-4-fluorobenzaldehyde (1.00 g, 6.31 mmol, 1.00 equiv), DMSO (10 mL), morpholine (0.827 g, 9.49 mmol, 1.50 equiv), and potassium carbonate (2.62 g, 19.0 mmol, 3.00 equiv) under nitrogen. The resulting solution was stirred overnight at 90 °C and quenched with water (50 mL). The resulting solution was extracted with EtOAc (2 x 80 mL) and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was

chromatographed on a silica gel column to provide 1.04 g (73% yield) of 3-chloro-4- morpholinobenzaldehyde as a light yellow solid. LCMS (ESI, m/z): 260 [M+H] ⁺ .

Step 2: Synthesis of N-(l-(l-(3-chloro-4-morpholinobenzyl)-l,8-diazaspiro[4.5]dec ane-8- carbonyl)-lH-pyrazol-3-yl)acetamide

[00322] The title compound was synthesized as described in Example 93 using 3-chloro-4- morpholinobenzaldehyde in Step 3. Purification resulted in 180.0 mg of N-(l-(l-(3-chloro-4- morpholinobenzyl)-l,8-diazaspiro[4.5]decane-8-carbonyl)-lH-p yrazol-3-yl)acetamide as a light yellow solid. 1H MR (300 MHz, Chloroform-i ) δ 8.00 (d, J= 2.7 Hz, 1H), 7.87 (br, 1H), 7.34 (s, 1H), 7.16 (br, 1H), 6.97 (d, J= 8.1 Hz, 1H), 6.88 (d, J= 2.7 Hz, 1H), 4.57 - 4.61 (m, 2H), 3.87 (t, J= 4.5 Hz, 4H), 3.55 (br, 2H), 3.00 - 3.08 (m, 6H), 2.68 (br, 2H), 2.19 (s, 3H), 1.71 - 1.97 (m, 6H), 1.52 - 1.59 (m, 2H). LCMS (ESI, m/z): 501 [M+H] ⁺ .

Example 100: N-(l-(l-(3-chloro-4-(pyrrolidin-l-yl)benzyl)-l,8-diazaspiro[ 4.5]decane-8- carbonyl)-lH-pyrazol-3-yl)acetamide

[00323] The title compound was synthesized as described in Example 93 using 3-chloro-4- (pyrrolidin-l-yl)benzaldehyde (synthesized as described in Example 103, Step 1 using pyrrolidine) in Step 3. Purification resulted in 112.2 mg of N-(l-(l-(3-chloro-4-(pyrrolidin-l- yl)benzyl)-l,8-diazaspiro[4.5]decane-8-carbonyl)-lH-pyrazol- 3-yl)acetamide as a white solid. 1H NMR (300 MHz, Chloroform-i ) δ 8.00 (d, J= 2.7 Hz, 1H), 7.81 (br, 1H), 7.07 (br, 1H), 6.88 (d, J= 2.7 Hz, 1H), 6.83 (d, J= 8.4 Hz, 1H), 4.56 - 4.60 (m, 2H), 3.52 (br, 2H), 3.34 (t, J= 6.4 Hz, 4H), 3.03 (t, J= 12.2 Hz, 2H), 2.69 (br, 2H), 2.19 (s, 3H), 1.71 - 1.99 (m, 10H), 1.45 - 1.51 (m, 2H). LCMS (ESI, m/z): 485 [M+H] ⁺ .

Example 101: N-(l-(l-(4-morpholino-3-(trifluoromethyl)benzyl)-l,8-diazasp iro[4.5]decane- 8-carbonyl)-lH-pyrazol-3-yl)acetamide

[00324] The title compound was synthesized as described in Example 93 using 4-morpholino-3- (trifluoromethyl)benzaldehyde (synthesized as described in Example 99, Step 1 using morpholine and 4-fluoro-3-(trifluorom ethyl )benzaldehyde) in Step 3. Purification resulted in 113.0 mg of N-(l-(l-(4-morpholino-3-(trifluoromethyl)benzyl)-l,8-diazasp iro[4.5]decane-8- carbonyl)-lH-pyrazol-3-yl)acetamide as an off-white solid. 1H NMR (300 MHz, Chloroform-i ) δ 8.00 (d, J= 2.7 Hz, 1H), 7.85 (br, 1H), 7.56 (s, 1H), 7.46 (br, 1H), 7.30 (d, J= 8.4 Hz, 1H), 6.88 (d, J= 2.7 Hz, 1H), 4.58 - 4.62 (m, 2H), 3.82 (t, J= 4.4 Hz, 4H), 3.62 (s, 2H), 3.05 (t, J = 12.3 Hz, 2H), 2.90 (t, J= 4.5 Hz, 4H), 2.68 (br, 2H), 2.18 (s, 3H), 1.67 - 1.97 (m, 6H), 1.49 - 1.53 (m, 2H). LCMS (ESI, m/z): 535 [M+H] ⁺ .

Example 102: N-(l-(l-(4-(pyrrolidin-l-yl)-3-(trifluoromethyl)benzyl)-l,8- diazaspiro[4.5]decane-8-carbonyl -lH-pyrazol-3-yl)acetamide

[00325] The title compound was synthesized as described in Example 93 using 4-(pyrrolidin-l- yl)-3-(trifluoromethyl)benzaldehyde (synthesized as described in Example 99, Step 1 using pyrrolidine and 4-fluoro-3-(trifluoromethyl)benzaldehyde) in Step 3. Purification resulted in 129.0 mg of N-(l-(l-(4-(pyrrolidin-l-yl)-3-(trifluoromethyl)benzyl)-l,8- diazaspiro[4.5]decane- 8-carbonyl)-lH-pyrazol-3-yl)acetamide as an off-white solid. 1H NMR (300 MHz, Chloroform- d) δ 8.00 (d, J= 2.7 Hz, 1H), 7.78 (br, 1H), 7.48 (s, 1H), 7.33 (br, 1H), 6.94 (d, J= 8.4 Hz, 1H), 6.88 (d, J= 2.7 Hz, 1H), 4.57 - 4.61 (m, 2H), 3.56 (s, 2H), 3.30 (br, 4H), 3.04 (t, J= 12.3 Hz, 2H), 2.68 (br, 2H), 2.19 (s, 3H), 1.84 - 1.95 (m, 10H), 1.39 - 1.52 (m, 2H). LCMS (ESI, m/z): 519 [M+H] ⁺ . Example 103: N-(l-(l-(4-chloro-3-morpholinobenzyl)-l,8-diazaspiro[4.5]dec ane-8- carbonyl)-lH-pyrazol-3-yl)acetami

Step 1: Synthesis of 4-chloro-3-mor holinobenzaldehyde

[00326] A 250-mL round-bottom flask was charged with 3-bromo-4-chlorobenzaldehyde (2.00 g, 9.11 mmol, 1.00 equiv), tris(dibenzylideneacetone)dipalladium (0.420 g, 0.460 mmol, 0.05 equiv), cesium carbonate (8.97 g, 27.5 mmol, 3.00 equiv), 2,2'-bis(diphenylphosphino)-l, l'- binaphthyl (0.856 g, 1.37 mmol, 0.15 equiv), morpholine (1.20 g, 13.8 mmol, 1.50 equiv), and toluene (40 mL) under nitrogen. The resulting solution was stirred overnight at 85 °C and quenched with water (100 mL). The resulting solution was extracted with EtOAc (2 x 150 mL) and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column to provide 1.60 g (78% yield) of 4-chloro-3-morpholinobenzaldehyde as a yellow oil. LCMS (ESI, m/z): 226 [M+H] ⁺

Step 2: Synthesis of N-(l-(l-(4-chloro-3-morpholinobenzyl)-l,8-diazaspiro[4.5]dec ane-8- carbonyl)-lH-pyrazol-3-yl)acetami

[00327] The title compound was synthesized as described in Example 93 using 4-chloro-3- morpholinobenzaldehyde in Step 3. Purification resulted in 86.2 mg of N-(l-(l-(4-chloro-3- morpholinobenzyl)-l,8-diazaspiro[4.5]decane-8-carbonyl)-lH-p yrazol-3-yl)acetamide as a white solid. 1H MR (300 MHz, Chloroform-i ) δ 8.02 (s, 1H), 7.77 (br, 1H), 7.31 (br, 1H), 6.97 - 7.04 (m, 2H), 6.90 (s, 1H), 4.59 - 4.62 (m, 2H), 3.90 (t, J= 4.2 Hz, 4H), 3.60 (s, 2H), 3.04 - 3.07 (m, 6H), 2.70 (t, J= 6.6 Hz, 2H), 2.21 (s, 3H), 1.83 - 1.90 (m, 6H), 1.51 (d, J= 6.6 Hz, 2H). LCMS (ESI, m/z): 523 [M+Na] ⁺ .

Example 104: N-(l-(l-(4-chloro-3-(pyrrolidin-l-yl)benzyl)-l,8-diazaspiro[ 4.5]decane-8- carbonyl)-lH-pyrazol-3-yl)acetamide

[00328] The title compound was synthesized as described in Example 93 using 4-chloro-3- (pyrrolidin-l-yl)benzaldehyde (synthesized as described in Example 103, Step 1 using pyrrolidine) in Step 3. Purification resulted in 61.5 mg of N-(l-(l-(4-chloro-3-(pyrrolidin-l- yl)benzyl)-l,8-diazaspiro[4.5]decane-8-carbonyl)-lH-pyrazol- 3-yl)acetamide as a white solid. 1H NMR (300 MHz, Chloroform-i ) δ 7.99 (d, J= 2.7 Hz, 1H), 7.72 (br, 1H), 7.24 (d, J= 8.1 Hz, 1H), 6.87 (d, J= 2.7 Hz, 1H), 6.83 (s, 1H), 4.54 - 4.59 (m, 2H), 3.56 (s, 2H), 3.37 (t, J= 6.4 Hz, 4H), 3.04 (t, J= 12.2 Hz, 2H), 2.71 (t, J= 6.4 Hz, 2H), 2.19 (s, 3H), 1.92 - 1.96 (m, 4H), 1.81 - 1.88 (m, 6H), 1.46 - 1.50 (m, 2H). LCMS (ESI, m/z): 507 [M+Na] ⁺ .

Example 105: N-(l-(l-(3-morpholino-4-(trifluoromethyl)benzyl)-l,8-diazasp iro[4.5]decane- 8-carbonyl)-lH-pyrazol-3-yl)acetamide

[00329] The title compound was synthesized as described in Example 93 using 3-morpholino-4- (trifluoromethyl)benzaldehyde (synthesized as described in Example 103, Step 1 using morpholine and 3-bromo-4-(trifluoromethyl)benzaldehyde) in Step 3. Purification resulted in 74.4 mg of N-(l-(l-(3-morpholino-4-(trifluoromethyl)benzyl)-l,8-diazasp iro[4.5]decane-8- carbonyl)-lH-pyrazol-3-yl)acetamide as a white solid. 1H NMR (300 MHz, Chloroform-<f)

6 8.00 (d, J= 2.7 Hz, 1H), 7.74 (br, 1H), 7.55 (d, J= 7.8 Hz, 1H), 7.31 (br, 1H), 7.19 (d, J= 7.8 Hz, 1H), 6.88 (d, J= 2.7 Hz, 1H), 4.58 - 4.62 (m, 2H), 3.83 (t, J= 4.5 Hz, 4H), 3.66 (s, 2H), 3.05 (t, J= 12.6 Hz, 2H), 2.92 (br, 4H), 2.68 (t, J= 6.2 Hz, 2H), 2.19 (s, 3H), 1.71 - 1.87 (m, 6H), 1.48 - 1.50 (m, 2H). LCMS (ESI, m/z): 557 [M+Na] ⁺ . Example 106: N-(l-(l-(3-(pyrrolidin-l-yl)-4-(trifluoromethyl)b

diazaspiro[4.5]decane-8-carbonyl -lH-pyrazol-3-yl)acetamide

[00330] The title compound was synthesized as described in Example 93 using 3-(pyrrolidin-l- yl)-4-(trifluoromethyl)benzaldehyde (synthesized as described in Example 103, Step 1 using pyrrolidine and 3-bromo-4-(trifluoromethyl)benzaldehyde) in Step 3. Purification resulted in 69.3 mg of N-(l-(l-(3-(pyrrolidin-l-yl)-4-(trifluoromethyl)benzyl)-l,8- diazaspiro[4.5]decane-8- carbonyl)-lH-pyrazol-3-yl)acetamide as an off-white solid. 1H NMR (300 MHz, Chloroform-i ) δ 8.00 (d, J= 2.7 Hz, 1H), 7.72 (br, 1H), 7.49 (d, J= 8.1 Hz, 1H), 6.92 (br, 1H), 6.87 (d, J= 2.7 Hz, 1H), 6.81 (d, J= 7.8 Hz, 1H), 4.56 - 4.60 (m, 2H), 3.60 (s, 2H), 3.33 (br, 4H), 3.04 (t, J = 12.3 Hz, 2H), 2.71 - 2.73 (m, 2H), 2.19 (s, 3H), 1.92 - 1.96 (m, 4H), 1.80 - 1.85 (m, 6H), 1.51 - 1.58 (m, 2H). LCMS (ESI, m/z): 541 [M+Na] ⁺ .

Example 107: 5-((8-(3-acetamido-lH-pyrazole-l-carbonyl)-l,8-diazaspiro[4. 5]decan-l- yl)methyl)-2-(trifluoromethyl)benzamide

Step 1: Synthesis of meth -formyl-2-(trifluoromethyl)benzoate

[00331] A 250-mL round-bottom flask was charged with 3-bromo-4- (trifluoromethyl)benzaldehyde (3.00 g, 11.9 mmol, 1.00 equiv), MeOH (50 mL), 1,1'- bis(diphenylphosphino)ferrocenepalladiumdichloride (870 mg, 1.19 mmol, 0.10 equiv), and triethylamine (3.61 g, 35.7 mmol, 3.00 equiv). Carbon monoxide (10 atm) was introduced. The resulting solution was stirred overnight at 100 °C and quenched with water (50 mL). The resulting solution was extracted with EtOAc (2 x 80 mL) and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column to provide 2.20 g (80% yield) of methyl 5- formyl-2-(trifluoromethyl)benzoate as an off-white semi- solid. 1H NMR (400 MHz, Chloroform-^ 10.1 (s, 1H), 8.31 (s, 1H), 8.12 - 8.15 (m, 1H), 7.97 (d, J= 8.0 Hz, 1H), 4.00 (s, 3H).

Step 2: Synthesis of tert-butyl l-(3-(methoxycarbonyl)-4-(trifluoromethyl)benzyl)-l,8- diazaspiro[4.5]deca -8-carboxylate

[00332] A 250-mL round-bottom flask was charged with methyl 5-formyl-2- (trifluoromethyl)benzoate (2.20 g, 9.48 mmol, 1.00 equiv), DCE (50 mL), and tert-butyl 1,8- diazaspiro[4.5]decane-8-carboxylate (2.27 g, 9.44 mmol, 1.00 equiv). The mixture was stirred for lh at room temperature. Sodium triacetoxyborohydride (6.02 g, 28.4 mmol, 3.00 equiv) was added. The resulting solution was stirred overnight at room temperature and quenched with water (80 mL). The resulting solution was extracted with DCM (2 x 150 mL) and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column to provide 3.10 g (72% yield) of tert-butyl l-(3-(methoxycarbonyl)-4-(trifluoromethyl)benzyl)-l,8- diazaspiro[4.5]decane-8-carboxylate as a white solid. LCMS (ESI, m/z): 457 [M+H] ⁺ .

Step 3: Synthesis of 5-((8-(tert-butoxycarbonyl)-l,8-diazaspiro[4.5]decan-l-yl)me thyl)-2- (trifluoromethyl)benzoic acid

[00333] A 100-mL round-bottom flask was charged with tert-butyl l-(3-(methoxycarbonyl)-4- (trifluoromethyl)benzyl)-l,8-diazaspiro[4.5]decane-8-carboxy late (1.50 g, 3.29 mmol, 1.00 equiv), THF (10 mL), MeOH (10 mL), water (20 mL), and lithium hydroxide (1.38 g, 32.9 mmol, 10.0 equiv). The resulting solution was stirred overnight at room temperature. The pH value of the solution was adjusted to 5 with hydrochloric acid (1 mol/L). The resulting solution was extracted with DCM (2 x 80 mL) and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to 800 mg (55% yield) of 5-((8-(tert-butoxycarbonyl)-l,8-diazaspiro[4.5]decan-l-yl)me thyl)-2- (trifluoromethyl)benzoic acid as a light yellow solid. LCMS (ESI, m/z): 443 [M+H] ⁺ . Step 4: Synthesis of tert-butyl l-(3-carbamoyl-4-(trifluoromethyl)b'

diazaspiro[4.5]deca -8-carboxylate

[00334] A 100-mL round-bottom flask was charged with 5-((8-(tert-butoxycarbonyl)-l,8- diazaspiro[4.5]decan-l-yl)methyl)-2-(trifluoromethyl)benzoic acid (600 mg, 1.36 mmol, 1.00 equiv), N,N-dimethylformamide (15 mL), 1-hydroxybenzotrizole (275 mg, 2.04 mmol, 1.50 equiv), and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (392 mg, 2.04 mmol, 1.50 equiv). The resulting solution was stirred for lh at room temperature. A saturated solution of ¾ in dioxane (2 mL) was added. The resulting solution was stirred overnight at room temperature and quenched with water (30 mL). The resulting solution was extracted with EtOAc (2 x 50 mL) and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column to 120 mg (20% yield) of tert-butyl l-(3-carbamoyl-4-(trifluoromethyl)benzyl)-l,8- diazaspiro[4.5]decane-8-carboxylate as a light yellow solid. LCMS (ESI, m/z): 442 [M+H] ⁺ . Step 5: Synthesis of -(l,8-diazaspiro[4.5]decan-l-ylmethyl)-2-(trifluoromethyl)be nzamide

[00335] A 50-mL round-bottom flask was charged with tert-butyl 1 -(3 -carbarn oyl-4- (trifluoromethyl)benzyl)-l,8-diazaspiro[4.5]decane-8-carboxy late (120 mg, 0.27 mmol, 1.00 equiv), 1,4-dioxane (10 mL), and hydrochloric acid (2 mL). The resulting solution was stirred overnight at room temperature and concentrated under reduced pressure to provide 150 mg (crude) of 5-(l,8-diazaspiro[4.5]decan-l-ylmethyl)-2-(trifluoromethyl)b enzamide as a yellow oil. LCMS (ESI, m/z): 342 [M+H] ⁺ .

Step 6: Synthesis of 5-((8-(3-acetamido-lH-pyrazole-l-carbonyl)-l,8-diazaspiro[4. 5]decan- l-yl)methyl)-2-(trifluoromethyl)benzamide

[00336] A 50-mL round-bottom flask was charged with 5-(l,8-diazaspiro[4.5]decan-l- ylmethyl)-2-(trifluoromethyl)benzamide (45.0 mg, 0.13 mmol, 1.00 equiv), DCM (10 mL), 4- nitrophenyl 3-acetamido-lH-pyrazole-l-carboxylate (50.0 mg, 0.17 mmol, 1.30 equiv), and triethylamine (40.0 mg, 0.40 mmol, 3.00 equiv). The resulting solution was stirred overnight at room temperature and quenched with water (30 mL). The resulting solution was extracted with DCM (2 x 50 mL) and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product (300 mg) was purified by preparative HPLC. Purification resulted in 12.0 mg (18% yield) of 5-((8-(3-acetamido-lH- pyrazole- 1 -carbonyl)- 1 , 8-diazaspiro[4.5]decan- 1 -yl)methyl)-2-(trifluorom ethyl )benzamide as a light yellow solid. 1H NMR (300 MHz, MeOH-i¾) δ 8.02 (d, J= 2.7 Hz, 1H), 7.67 - 7.70 (m, 1H), 7.54 - 7.60 (m, 2H), 6.80 (d, J= 2.7 Hz, 1H), 4.56 - 4.61 (m, 2H), 3.76 (s, 2H), 3.13 (t, J = 12. 3 Hz, 2H), 2.72 (t, J= 6.9 Hz, 2H), 2.13 (s, 3H), 1.78 - 1.96 (m, 6H), 1.54 - 1.58 (m, 2H). LCMS (ESI, m/z): 515 [M+Na] ⁺ .

Example 108: 5-((8-(3-acetamido-lH-pyrazole-l-carbonyl)-l,8-diazaspiro[4. 5]decan-l- yl)methyl)-2-(trifluoromethyl)benzoic acid

Step 1: Synthesis of 5-(l,8-diazaspiro[4.5]decan-l-ylmethyl)-2-(trifluoromethyl)b enzoic acid

[00337] A 50-mL round-bottom flask was charged with 5-((8-(tert-butoxycarbonyl)-l,8- diazaspiro[4.5]decan-l-yl)methyl)-2-(trifluoromethyl)benzoic acid (Example 107, Step 3, 400 mg, 0.90 mmol, 1.00 equiv), 1,4-dioxane (20 mL), and hydrochloric acid (5 mL). The resulting solution was stirred overnight at room temperature and concentrated under reduced pressure to provide 400 mg (crude) of 5-(l,8-diazaspiro[4.5]decan-l-ylmethyl)-2-(trifluoromethyl)b enzoic acid as a light yellow solid. LCMS (ESI, m/z): 343 [M+H] ⁺ .

Step 2: Synthesis of 5-((8-(3-acetamido-lH-pyrazole-l-carbonyl)-l,8-diazaspiro[4. 5]decan- l-yl)methyl)-2-(trifluoromethyl)benzoic acid

[00338] The title compound was synthesized as described in Example 107, Step 6 using 5-(l,8- diazaspiro[4.5]decan-l-ylmethyl)-2-(trifluoromethyl)benzoic acid. Purification resulted in 21.8 mg of 5-((8-(3-acetamido-lH-pyrazole-l-carbonyl)-l,8-diazaspiro[4. 5]decan-l-yl)methyl)-2- (trifluoromethyl)benzoic acid as a white solid. 1H NMR (300 MHz, MeOH-<f ₄ ) δ 8.02 (d, J= 2.7 Hz, 1H), 7.74 (br, 1H), 7.62 - 7.65 (m, 1H), 7.50 - 7.52 (m, 1H), 6.77 (d, J= 2.7 Hz, 1H), 4.66 - 4.71 (m, 2H), 4.21 (s, 2H), 3.13 - 3.21 (m, 4H), 2.16 - 2.31 (m, 2H), 2.10 (s, 3H), 2.01 - 2.06 (m, 2H), 1.86 - 1.90 (m, 2H). LCMS (ESI, m/z): 516 [M+Na] ⁺ .

Example 109: 4-((8-(3-acetamido-lH-pyrazole-l-carbonyl)-l,8-diazaspiro[4. 5]decan-l- yl)methyl)-2-(trifluoromethyl)benzamide

[00339] The title compound was synthesized as described in Example 107 using 4-bromo-3- (trifluoromethyl)benzaldehyde in Step 1. Purification resulted in 67.1 mg of 4-((8-(3-acetamido- lH-pyrazole-l-carbonyl)-l,8-diazaspiro[4.5]decan-l-yl)methyl )-2-(trifluoromethyl)benzamide as a white solid. 1H MR (300 MHz, Chloroform-i ) δ 7.96 - 7.99 (m, 2H), 7.67 (s, 1H), 7.54 (s, 1H), 6.88 (d, J= 2.7 Hz, 1H), 5.84 - 5.95 (m, 2H), 4.57 - 4.61 (m, 2H), 3.70 (br, 2H), 3.04 (t, J = 12.3 Hz, 2H), 2.66 (m, 2H), 2.18 (s, 3H), 1.83 - 1.87 (m, 6H), 1.49 - 1.59 (m, 2H). LCMS (ESI, m/z): 464 [M+H] ⁺ .

Example 110: 4-((8-(3-acetamido-lH-pyrazole-l-carbonyl)-l,8-diazaspiro[4. 5]decan-l- yl)methyl)-2-(trifluoromethyl)b nzoic acid

Step 1: Synthesis of 4-(l,8-diazaspiro[4.5]decan-l-ylmethyl)-2-(trifluoromethyl)b enzoic acid

[00340] A 100-mL round-bottom flask was charged with 4-((8-(tert-butoxycarbonyl)-l,8- diazaspiro[4.5]decan-l-yl)methyl)-2-(trifluoromethyl)benzoic acid (synthesized as described in Example 107, Steps 1-2 using 4-bromo-3-(trifluorom ethyl )benzaldehyde in Step 1, 400 mg, 0.900 mmol, 1.00 equiv), 1,4-dioxane (20 mL), and hydrochloric acid (5 mL). The resulting solution was stirred overnight at room temperature and concentrated under reduced pressure to provide 400 mg (crude) of 4-(l,8-diazaspiro[4.5]decan-l-ylmethyl)-2-(trifluoromethyl)b enzoic acid as a light yellow solid. LCMS (ESI, m/z): 343 [M+H] ⁺ . Step 2: Synthesis of 4-((8-(3-acetamido-lH-pyrazole-l-carbonyl)-l,8-diazaspiro l-yl)methyl)-2-(trifluoromethyl)b nzoic acid

[00341] The title compound was synthesized as described in Example 107, Step 6 using 4-(l,8- diazaspiro[4.5]decan-l-ylmethyl)-2-(trifluoromethyl)benzoic acid. Purification resulted in 15.2 mg of 4-((8-(3 -acetamido- lH-pyrazole- 1 -carbonyl)- 1 , 8-diazaspiro[4.5]decan- 1 -yl)methyl)-2- (trifluoromethyl)benzoic acid as a white solid. 1H MR (300 MHz, Chloroform-i ) δ 8.02 (d, J = 2.7 Hz, 1H), 7.76 (s, 1H), 7.64 - 7.67 (m, 1H), 7.53 - 7.56 (m, 1H), 6.76 (d, J= 2.7 Hz, 1H), 4.66 - 4.70 (m, 2H), 4.17 (s, 2H), 3.12 - 3.20 (m, 4H), 2.14 - 2.18 (m, 4H), 2.10 (s, 3H), 1.98 - 2.05 (m, 2H), 1.78 - 1.81 (m, 2H). LCMS (ESI, m/z): 516 [M+Na] ⁺ .

Example 111: N-(l-(l-(4-chloro-3-cyclopropylbenzyl)-l,8-diazaspiro[4.5]de cane-8- carbonyl)-lH-pyrazol-3-yl)acetamide

Step 1: Preparation of tert-butyl l-(3-bromo-4-chlorobenzyl)-l,8-diazaspiro[4.5]decane-8- carboxylate

[00342] A 50-mL round-bottom flask was charged with tert-butyl l-(3-bromo-4-chlorobenzyl)- l,8-diazaspiro[4.5]decane-8-carboxylate (1.15 g, 4.78 mmol, 1.20 equiv), 1,2-dichloroethane (20 mL), and 3-bromo-4-chlorobenzaldehyde (0.876 g, 3.99 mmol, 1.00 equiv). The mixture was stirred for 1 h at room temperature. Sodium triacetoxyborohydride (2.54 g, 12.0 mmol, 3.00 equiv) was added, and the resulting solution was stirred overnight at room temperature and quenched with water (30 mL). The mixture was extracted with dichloromethane (2 x 50 mL) and the organic layers were combined, washed with brine (2 x 30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with methanol/dichloromethane (3/97) to provide 1.30 g (73% yield) of tert- butyl l-(3-bromo-4-chlorobenzyl)-l,8-diazaspiro[4.5]decane-8-carbo xylate as a white solid. LCMS (ESI, m/z): 443 [M+H] ⁺ . Step 2: Preparation of tert-butyl l-(4-chloro-3-cyclopropylb'

diazaspiro [4.5] decane-8-carboxylate

[00343] A 50-mL round-bottom flask was charged with tert-butyl l-(3-bromo-4-chlorobenzyl)- l,8-diazaspiro[4.5]decane-8-carboxylate (444 mg, 1.00 mmol, 1.00 equiv), cyclopropylboronic acid (129 mg, 1.50 mmol, 1.50 equiv), tetrakis(triphenylphosphine)palladium (58.0 mg, 0.0500 mmol, 0.05 equiv), potassium carbonate (414 mg, 3.00 mmol, 3.00 equiv), 1,4-dioxane (10 mL), and water (2 mL) under nitrogen. The resulting solution was stirred overnight at 90 °C and quenched with water (30 mL). The mixture was extracted with dichloromethane (2 x 50 mL) and the organic layers were combined, washed with brine (2 x 30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (4/1) to provide 110 mg (27% yield) of tert-butyl l-(4-chloro-3-cyclopropylbenzyl)-l,8-diazaspiro[4.5]decane-8 -carboxylate as a white solid. LCMS (ESI, m/z): 405 [M+H] ⁺ .

Step 3: Synthesis of l-(4-chloro-3-cyclopropylbenzyl)-l,8-diazaspiro[4.5]decane

[00344] A 50-mL round-bottom flask was charged with tert-butyl l-(4-chloro-3- cyclopropylbenzyl)-l,8-diazaspiro[4.5]decane-8-carboxylate (110 mg, 0.270 mmol, 1.00 equiv), trifluoroacetic acid (2 mL), and dichloromethane (10 mL). The resulting solution was stirred overnight at room temperature and concentrated under reduced pressure to provide 120 mg (crude) of l-[(4-chloro-3-cyclopropylphenyl)methyl]-l,8-diazaspiro[4.5] decane TFA as a light yellow oil. LCMS (ESI, m/z): 305 [M+H] ⁺ .

Step 4: Synthesis of l-(4-chloro-3-cyclopropylbenzyl)-l,8-diazaspiro[4.5]decane-8 -carbonyl chloride

[00345] A 50-mL round-bottom flask was charged with triphosgene (40.0 mg, 0.135 mmol, 0.50 equiv), dichloromethane (10 mL), and l-[(4-chloro-3-cyclopropylphenyl)methyl]-l,8- diazaspiro[4.5]decane (83.0 mg, 0.270 mmol, 1.00 equiv) was added at 0 °C, followed by N,N- Diisopropylethylamine (105 mg, 0.810 mmol, 3.00 equiv). The resulting solution was stirred for 3 h at room temperature and quenched with water (30 mL). The mixture was extracted with dichloromethane (2 x 50 mL) and the organic layers were combined, washed with brine (2 x 30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to provide 150 mg (crude) of l-(4-chloro-3-cyclopropylbenzyl)-l,8-diazaspiro[4.5]decane-8 - carbonyl chloride as light yellow oil. LCMS (ESI, m/z): 367 [M+H] ⁺ .

Step 5: Synthesis of N-(l-(l-(4-chloro-3-cyclopropylbenzyl)-l,8-diazaspiro[4.5]de cane-8- carbonyl)-lH-pyrazol-3-yl)acetamide

[00346] A 50-mL round-bottom flask was charged with l-(4-chloro-3-cyclopropylbenzyl)-l,8- diazaspiro[4.5]decane-8-carbonyl chloride (99.0 mg, 0.270 mmol, 1.00 equiv), tetrahydrofuran (10 mL), N-(lH-pyrazol-3-yl)acetamide (41.0 mg, 0.324 mmol, 1.20 equiv), N,N- diisopropylethylamine (105 mg, 0.810 mmol, 3.00 equiv), and N,N-dimethylpyridin-4-amine (7.00 mg, 0.054 mmol, 0.20 equiv). The resulting solution was stirred overnight at 60 °C and quenched with water (30 mL). The mixture was extracted with dichloromethane (2 x 50 mL) and the organic layers were combined, washed with brine (2 x 30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product (250 mg) was purified by preparative HPLC using the following gradient conditions: 20% CH ₃ CN/80% Phase A increasing to 80% CH ₃ CN over 10 min, then to 100% CH ₃ CN over 0.1 min, holding at 100% CH ₃ CN for 1.9 min, then reducing to 20% CH ₃ CN over 0.1 min, and holding at 20% for 1.9 min, on a Waters 2767-5 Chromatograph. Column: Xbridge Prep C18, 19* 150mm 5um; Mobile phase: Phase A: aqueous NH ₄ HC0 ₃ (0.05%); Phase B: CH ₃ CN; Detector, UV220 & 254nm. Purification resulted in 19.0 mg (15% yield) of N-(l-(l-(4-chloro-3-cyclopropylbenzyl)-l,8- diazaspiro[4.5]decane-8-carbonyl)-lH-pyrazol-3-yl)acetamide as a white solid. ¹ H NMR (300MHz, Chloroform-ύ 7.99 (d, J= 2.7 Hz, 1H), 7.86 - 7.88 (m, 1H), 7.25 - 7.28 (m, 1H), 7.04 - 7.08 (m, 1H), 6.87 - 6.88 (m, 2H), 4.56 - 4.60 (m, 2H), 3.54 (s, 2H), 2.99 - 307 (m, 2H), 2.62 - 2.68 (m, 2H), 2.12 - 2.19 (m, 4H), 1.79 - 1.88 (m, 6H), 1.48 - 1.52 ( m, 2H), 1.00 - 1.03 (m, 2H), 0.65 - 0.72 (m, 2H). LCMS (ESI, m/z): 456 [M+H] ⁺ . Example 112: N-(l-(4-(2-(l,2,4-oxadiazol-3-yl)-4-(trifluoromethyl)benzyl) piperazine-l- carbonyl)-lH-pyrazol-3-yl)methanesulfonamide

Step 1: Synthesis of 4-nitrophenyl 3-(methylsulfonamido)-lH-pyrazole-l-carboxylate

[00347] A 50-mL round-bottom flask was charged with N-(lH-pyrazol-3- yl)methanesulfonamide (4.12 g, 25.6 mmol, 1.00 equiv) in dichloromethane (10 mL), 4- nitrophenyl chloroformate (5.42 g, 26.8 mmol, 1.05 equiv), and triethylamine (7.76 g, 76.6 mmol, 3.00 equiv). The resulting solution was stirred for 2 h at room temperature and concentrated under reduced pressure to provide 10.0 g (crude) of 4-nitrophenyl 3- (methylsulfonamido)-lH-pyrazole-l-carboxylate as yellow oil. LCMS (ESI, m/z): 327 [M+H] ⁺ . Step 2: Synthesis of tert-butyl 4-(2-bromo-4-(trifluoromethyl)benzyl)piperazine-l- carboxylate

[00348] A 500-mL round-bottom flask was charged with 2-bromo-4-

(trifluoromethyl)benzaldehyde (10.0 g, 39.5 mmol, 1.00 equiv) in 1,2-dichloroethane (150 mL), tert-butyl piperazine-l-carboxylate (8.82 g, 47.4 mmol, 1.20 equiv), and triethylamine (12.0 g, 1 18 mmol, 3.00 equiv). The resulting solution was stirred for 2 h at room temperature. Sodium triacetoxyborohydride (25.1 g, 1 18 mmol, 3.00 equiv) was added and the mixture was stirred overnight at room temperature before quenching with water (100 mL). The resulting solution was extracted with dichloromethane (3 x 100 mL) and the organic layers were combined, washed with brine (2 x 100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with methanol/dichloromethane (1/15) to provide 10.0 g (60% yield) of tert-butyl 4-(2-bromo-4- (trifluoromethyl)benzyl)piperazine-l-carboxylate as an off-white solid. LCMS (ESI, m/z): 423 [M+H] ⁺ . Step 3: tert-butyl 4-(2-cyano-4-(trifluoromethyl)benzyl)piperazine-l-carboxylat e

[00349] A 50-mL round-bottom flask was charged with tert-butyl 4-(2-bromo-4- (trifluoromethyl)benzyl)piperazine-l-carboxylate (2.00 g, 4.73 mmol, 1.00 equiv) ίη Ν,Ν- dimethylformamide (20 mL), zinc cyanide (0.830 g, 7.09 mmol, 1.50 equiv), and

tetrakis(triphenylphosphine)palladium (0.547 g, 0.470 mmol, 0.10 equiv) under nitrogen. The resulting solution was stirred overnight at 80 °C and quenched with water (20 mL). The mixture was extracted with ethyl acetate (3 x 20 mL) and the organic layers were combined, washed with brine (2 x 20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (1/3) to provide 1.50 g (86% yield) of tert-butyl tert-butyl 4-(2-cyano-4- (trifluoromethyl)benzyl)piperazine-l-carboxylate as a yellow solid. LCMS (ESI, m/z): 370 [M+H] ⁺ .

Step 4: Synthesis of tert-butyl (Z)-4-(2-(N'-hydroxycarbamimidoyl)-4- (trifluoromethyl)benzyl)piperazine-l-carboxylate

[00350] A 50-mL round-bottom flask was charged with tert-butyl 4-(2-cyano-4- (trifluoromethyl)benzyl)piperazine-l-carboxylate (600 mg, 1.62 mmol, 1.00 equiv) in dimethyl sulfoxide (10 mL), hydroxylamine hydrochloride (561 mg, 8.13 mmol, 5.00 equiv), and triethylamine (821 mg, 8.11 mmol, 5.00 equiv). The resulting solution was stirred overnight at 75 °C and quenched with water (20 mL). The pH of the solution was adjusted to 10 with sodium hydroxide (1 M). The resulting solution was extracted with ethyl acetate (3 x 20 mL) and the organic layers were combined, washed with brine (2 x 20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (1/3) to provide 400 mg (61% yield) of tert-butyl (Z)-4-(2-(TSr'-hydroxycarbamimidoyl)-4-(trifluoromethyl)benz yl)piperazine- 1 - carboxylate as an off-white solid. LCMS (ESI, m/z): 403 [M+H] ⁺ . Step 5: Synthesis of tert-butyl 4-(2-(l,2,4-oxadiazol-3-yl)-4- (trifluoromethyl)benzyl)piperazine-l-carboxylate

[00351] A 50-mL round-bottom flask was charged with tert-butyl (Z)-4-(2-(N - hydroxycarbamimidoyl)-4-(trifluoromethyl)benzyl)piperazine-l -carboxylate (600 mg, 1.49 mmol, 1.00 equiv) in dimethyl sulfoxide (10 mL), and (diethoxymethoxy)ethane (884 mg, 5.96 mmol, 4.00 equiv). The resulting solution was stirred for 1 h at room temperature. Boron fluoride ethyl ether (254 mg, 1.79 mmol, 1.20 equiv) was added dropwise at 0 °C. The reaction mixture was stirred overnight at 80 °C and quenched with water (20 mL). The resulting solution was extracted with ethyl acetate (3 x 20 mL) and the organic layers were combined, washed with brine (2 x 20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (1/3) to provide 280 mg (46% yield) of tert-butyl 4-(2-(l,2,4-oxadiazol-3-yl)-4- (trifluoromethyl)benzyl)piperazine-l-carboxylate as an off-white solid. LCMS (ESI, m/z): 413 [M+H] ⁺ .

Step 6: Synthesis of 3-(2-(piperazin-l-ylmethyl)-5-(trifluoromethyl)phenyl)-l,2,4 - oxadiazole

[00352] A 50-mL round-bottom flask was charged with tert-butyl 4-(2-(l,2,4-oxadiazol-3-yl)-4- (trifluoromethyl)benzyl)piperazine-l-carboxylate (350 mg, 0.850 mmol, 1.00 equiv) in dichloromethane (10 mL), and trifluoroacetic acid (2 mL). The resulting solution was stirred for 3 h at room temperature and concentrated under reduce pressure to provide 450 mg (crude) of 1 - [[2-(l,2,4-oxadiazol-3-yl)-4-(trifluoromethyl)phenyl]methyl] piperazine TFA as yellow oil. LCMS (ESI, m/z): 313 [M+H] ⁺ . Step 7: N-(l-(4-(2-(l,2,4-oxadiazol-3-yl)-4-(trifluoromethyl)benzyl) piperazine-l-carbonyl)- lH-pyrazol-3-yl)methanesulfonamide

rt, overnight

[00353] A 50-mL round-bottom flask was charged with 4-nitrophenyl 3-(methylsulfonamido)- lH-pyrazole-l-carboxylate (418 mg, 1.28 mmol, 2.00 equiv), 3-(2-(piperazin-l-ylmethyl)-5- (trifluoromethyl)phenyl)-l,2,4-oxadiazole (200 mg, 0.640 mmol, 1.00 equiv), and triethylamine (194 mg, 1.92 mmol, 3.00 equiv). The resulting solution was stirred overnight at room temperature and quenched with water (20 mL). The mixture was extracted with dichloromethane (3 x 20 mL) and the organic layers were combined, washed with brine (2 x 20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product (400 mg) was purified by preparative HPLC using the following gradient conditions: 20% CH ₃ CN/80% Phase A increasing to 80% CH ₃ CN over 10 min, then to 100% CH ₃ CN over 0.1 min, holding at 100% CH ₃ CN for 1.9 min, then reducing to 20% CH ₃ CN over 0.1 min, and holding at 20% for 1.9 min, on a Waters 2767-5 Chromatograph. Column: Xbridge Prep C I 8, 19* 150mm 5um; Mobile phase: Phase A: aqueous H ₄ HC0 ₃ (0.05%); Phase B: CH ₃ CN;

Detector, UV220 & 254nm. Purification resulted in 108.9 mg (34% yield) of N-(l-(4-(2-(l,2,4- oxadiazol-3-yl)-4-(trifluoromethyl)benzyl)piperazine-l-carbo nyl)-lH-pyrazol-3- yl)methanesulfonamide as a yellow solid. ¹ H MR (300MHz, Methanol -<¾) δ 9.36 (s, 1H), 8.19 - 8.20 (m, 1H), 8.00 - 8.03 (m, 1H), 7.82 - 7.87 (m, 2H), 6.21 - 6.23 (m, 1H), 4.00 (s, 2H), 3.73 (br, 4H), 3.10 (s, 3H), 2.51 - 2.61 (m, 4H). LCMS (ESI, m/z): 500 [M+H] ⁺ .

Example 113: N-(l-(4-(2-(l,3,4-oxadiazol-2-yl)-4-(trifluoromethyl)benzyl) piperazine-l- carbonyl)-lH-pyrazol-3-yl)methanesulfonamide

Step 1: Synthesis of tert-butyl 4-(2-(methoxycarbonyl)-4- (trifluoromethyl) nzyl)piperazine-l-carboxylate [00354] A 50-mL round-bottom flask was charged with tert-butyl 4-(2-bromo-4- (trifluoromethyl)benzyl)piperazine-l-carboxylate (Example 113, Step 2, 1.50 g, 3.54 mmol, 1.00 equiv) in methanol (15 mL), l, l'-bis(diphenylphosphino)ferrocenepalladiumdi chloride (0.260 g, 0.360 mmol, 0.10 equiv), and triethylamine (1.07 g, 10.6 mmol, 3.00 equiv). Carbon monoxide was introduced. The resulting solution was stirred overnight at 70 °C and quenched with water (20 mL). The mixture was extracted with ethyl acetate (3 x 20 mL) and the organic layers were combined, washed with brine (2 x 20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (1/3) to provide 1.50 g (84% yield) tert-butyl 4-(2- (methoxycarbonyl)-4-(trifluoromethyl)benzyl)piperazine-l-car boxylate as yellow oil. LCMS (ESI, m/z): 403 [M+H] ⁺ .

Step 2: Synthesis of tert-butyl 4-(2-(hydrazinecarbonyl)-4- (trifluoromethyl)benzyl)piperazine-l-carboxylate

[00355] A 50-mL round-bottom flask was charged with tert-butyl 4-(2-(methoxycarbonyl)-4- (trifluoromethyl)benzyl)piperazine-l-carboxylate (2.50 g, 6.21 mmol, 1.00 equiv) in methanol (25 mL), and hydrazine hydrate (1.55 g, 31.0 mmol, 5.00 equiv). The resulting solution was stirred overnight at 80 °C and quenched with water (20 mL). The mixture was extracted with ethyl acetate (3 x 20 mL) and the organic layers were combined, washed with brine (2 x 20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (1/1) to provide 1.70 g (68% yield) of tert-butyl 4-(2-(hydrazinecarbonyl)-4-

(trifluoromethyl)benzyl)piperazine-l-carboxylate as an off-white solid. LCMS (ESI, m/z): 403 [M+H] ⁺ .

Step 3: Synthesis of terf-butyl 4-(2-(l,3,4-oxadiazol-2-yl)-4- (trifluoromethyl)benzyl)piperazine-l-carboxylate

[00356] A 50-mL round-bottom flask was charged with tert-butyl 4-(2-(hydrazinecarbonyl)-4- (trifluoromethyl)benzyl)piperazine-l-carboxylate (0.800 g, 1.99 mmol, 1.00 equiv) in dimethyl sulfoxide(5 mL), (diethoxymethoxy)ethane (1.18 g, 7.96 mmol, 4.00 equiv), and boron fluoride ethyl ether (0.339 g, 2.39 mmol, 1.20 equiv). The resulting solution was stirred for 3 h at 80 °C and quenched with water (20 mL). The mixture was extracted with ethyl acetate (3 x 20 mL) and the organic layers were combined, washed with brine (2 x 20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (1/3) to provide 0.500 g (61% yield) of tert-butyl 4-(2-(l,3,4-oxadiazol-2-yl)-4-(trifluoromethyl)benzyl)pipera zine-l-carboxylate as yellow oil. LCMS (ESI, m/z): 413 [M+H] ⁺ .

Step 4: Synthesis of 2-(2-(piperazin-l-ylmethyl)-5-(trifluoromethyl)phenyl)-l,3,4 - oxadiazole

[00357] A 50-mL round-bottom flask was charged with tert-butyl 4-(2-(l,3,4-oxadiazol-2-yl)-4- (trifluoromethyl)benzyl)piperazine-l-carboxylate (500 mg, 1.21 mmol, 1.00 equiv) in dichloromethane (10 mL), trifluoroacetic acid (2 mL). The resulting solution was stirred for 3 h at room temperature and concentrated under reduced pressure to provide 600 mg (crude) of 2-(2- (piperazin-l-ylmethyl)-5-(trifluoromethyl)phenyl)-l,3,4-oxad iazole TFA as yellow oil. LCMS (ESI, m/z): 313 [M+H] ⁺ .

Step 5: Synthesis of N-(l-(4-(2-(l,3,4-oxadiazol-2-yl)-4-(trifluoromethyl)benzyl) piperazine- l-carbonyl)- -pyrazol-3-yl)methanesulfonamide

[00358] A 50-mL round-bottom flask was charged with 4-nitrophenyl 3-methanesulfonamido- lH-pyrazole-l-carboxylate (Example 113, Step 1, 313 mg, 0.960 mmol, 2.00 equiv) in dichloromethane (10 mL), 2-(2-(piperazin-l-ylmethyl)-5-(trifluoromethyl)phenyl)-l,3,4 - oxadiazole (150 mg, 0.480 mmol, 1.00 equiv), and triethylamine (146 mg, 1.44 mmol, 3.00 equiv). The resulting solution was stirred overnight at room temperature and quenched with water (20 mL). The mixture was extracted with dichloromethane (3 x 20 mL) and the organic layers were combined, washed with brine (2 x 20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product (200 mg) was purified by preparative HPLC using the following gradient conditions: 20% CH ₃ CN/80% Phase A increasing to 80% CH ₃ CN over 10 min, then to 100% CH ₃ CN over 0.1 min, holding at 100% CH ₃ CN for 1.9 min, then reducing to 20% CH ₃ CN over 0.1 min, and holding at 20% for 1.9 min, on a Waters 2767-5 Chromatograph. Column: Xbridge Prep C18, 19* 150mm 5um; Mobile phase: Phase A: aqueous NH ₄ HC0 ₃ (0.05%); Phase B: CH ₃ CN; Detector, UV220 & 254nm. Purification resulted in 79.2 mg (33% yield) of N-(l-(4-(2-(l,2,4-oxadiazol-3-yl)-4- (trifluoromethyl)benzyl)piperazine-l-carbonyl)-lH-pyrazol-3- yl)methanesulfonamide as a white solid. 1H MR (300MHz, Methanol-^) δ 9.12 - 9.15 (m, 1H), 8.16 - 8.17 (m, 1H), 8.02 (s, 1H), 7.84 - 7.93 (m, 2H), 6.21 - 6.22 (m, 1H), 4.02 (s, 2H), 3.68 (br, 4H), 3.10 (s, 3H), 2.49 - 2.52 (m, 4H). LCMS (ESI, m/z): 500 [M+H] ⁺ .

Example 114: N-(l-(4-(2-(l,3,4-thiadiazol-2-yl)-4-(trifluoromethyl)benzyl )piperazine-l- carbonyl)-lH-pyrazol-3-yl)methanesulfonamide

Step 1: Synthesis of tert-b tyl 4-(2-(2-formylhydrazine

(trifluoromethyl)benzyl)piperazine-l-carboxylate

[00359] A 50-mL round-bottom flask was charged with tert-butyl 4-(2-(hydrazinecarbonyl)-4- (trifluoromethyl)benzyl)piperazine-l-carboxylate (Example 114, Step 2, 100 mg, 0.250 mmol, 1.00 equiv), formic acid (34.3 mg, 0.750 mmol, 3.00 equiv), and formyl acetate (32.8 mg, 0.375 mmol, 1.50 equiv). The resulting solution was stirred overnight at room temperature and concentrated under reduced pressure to provide 200 mg (crude) of tert-butyl 4-(2-(2- formylhydrazine-l-carbonyl)-4-(trifluorom ethyl )benzyl)piperazine-l-carboxylate as yellow oil. LCMS (ESI, m/z): 431 [M+H] ⁺ .

Step 2: Synthesis of tert-butyl 4-(2-(l,3,4-thiadiazol-2-yl)-4- (trifluoromethyl)benzyl)piperazine-l-carboxylate

[00360] A 50-mL round-bottom flask was charged with tert-butyl 4-(2-(2-formylhydrazine-l- carbonyl)-4-(trifluoromethyl)benzyl)piperazine-l-carboxylate (50.0 mg, 0.120 mmol, 1.00 equiv) in 1,4-dioxane (5 mL), and phosphorus pentasulfide (28.4 mg, 0.130 mmol, 1.10 equiv). The resulting solution was stirred for 3 h at room temperature and quenched with water (10 mL). The mixture was extracted with ethyl acetate (3 x 10 mL) and the organic layers were combined, washed with brine (2 x 10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (1/1) to provide 40.0 mg (80% yield) of tert-butyl 4-(2-(l,3,4-thiadiazol- 2-yl)-4-(trifluoromethyl)benzyl)piperazine-l-carboxylate as yellow oil. LCMS (ESI, m/z): 429 [M+H] ⁺ .

Step 3: Synthesis of 2-(2-(piperazin-l-ylmethyl)-5-(trifluoromethyl)phenyl)-l,3,4 - thiadiazole

[00361] A 40-mL round-bottom flask was charged with fert-butyl 4-(2-(l,3,4-thiadiazol-2-yl)-4- (trifluoromethyl)benzyl)piperazine-l-carboxylate (40.0 mg, 0.0900 mmol, 1.00 equiv), dichloromethane (5 mL), and trifluoroacetic acid (1 mL). The resulting solution was stirred for 3 h at room temperature and concentrated under reduced pressure to provide 35.0 mg (crude) of 2- (2-(piperazin-l-ylmethyl)-5-(trifluoromethyl)phenyl)-l,3,4-t hiadiazole TFA as orange oil.

LCMS (ESI, m/z): 329 [M+H] ⁺ .

Step 4: Synthesis of N-(l-(4-(2-(l,3,4-thiadiazol-2-yl)-4-(trifluoromethyl)benzyl )piperazine- l-carbonyl)-lH-pyrazol-3-yl)methanesulfonamide

[00362] A 40-mL round-bottom flask was charged with 2-(2-(piperazin-l-ylmethyl)-5- (trifluoromethyl)phenyl)-l,3,4-thiadiazole (29.5 mg, 0.0900 mmol, 1.00 equiv),

dichloromethane (5 mL), triethylamine (27.3 mg, 0.270 mmol, 3.00 equiv), and 4-nitrophenyl 3- (methylsulfonamido)-lH-pyrazole-l-carboxylate (Example 113, Step 1, 44.0 mg, 0.160 mmol, 1.50 equiv). The resulting solution was stirred for 5 h at room temperature and quenched with water (10 mL). The mixture was extracted with dichloromethane (3 x 10 mL) and the organic layers were combined, washed with brine (2 x 10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product (100 mg) was purified by preparative HPLC using the following gradient conditions: 20% CH ₃ CN/80% Phase A increasing to 80% CH ₃ CN over 10 min, then to 100% CH ₃ CN over 0.1 min, holding at 100% CH ₃ CN for 1.9 min, then reducing to 20% CH ₃ CN over 0.1 min, and holding at 20% for 1.9 min, on a Waters 2767-5 Chromatograph. Column: Xbridge Prep C ₁₈ , 19* 150mm 5um; Mobile phase: Phase A: aqueous NH ₄ HC0 ₃ (0.05%); Phase B: CH ₃ CN; Detector, UV220 & 254nm. This resulted in 15.0 mg (32% yield) of N-(l-(4-(2-(l,2,4-oxadiazol-3-yl)-4- (trifluoromethyl)benzyl)piperazine-l-carbonyl)-lH-pyrazol-3- yl)methanesulfonamide as a white solid. 1H MR (300MHz, Chloroform-i ) δ 9.29 (s, 1H), 7.98 - 8.02 (m, 2H), 7.67 - 7.77 (m, 2H), 6.30 (d, J= 2.4 Hz, 1H), 3.94 (s, 2H), 3.71 (br, 4H), 3.14 (s, 3H), 5.48 (br, 4H). LCMS (ESI, m/z): 516 [M+H] ⁺ .

Example 115: N-(l-(4-(4-cyano-2-(lH-tetrazol-5-yl)benzyl)piperazine-l-car bonyl)-lH- pyrazol-3-yl)acetamide

Step 1: Synthesis of tert-butyl 4-(4-bromo-2-cyanobenzyl)piperazine-l-carboxylate

[00363] A 50-mL round-bottom flask was charged with 5-bromo-2-formylbenzonitrile (0.840 g, 4.00 mmol, 1.00 equiv), tert-butyl piperazine-l-carboxylate (0.893 g, 4.79 mmol, 1.20 equiv) and 1,2-dichloroethane (20 mL). The resulting solution was stirred for 1 h at room temperature and sodium triacetoxyborohydride (1.70 g, 8.02 mmol, 2.00 equiv) was added. The resulting solution was stirred overnight at room temperature and quenched by water (40 mL). The mixture was extracted with dichloromethane (3 x 50 mL) and the organic layers were combined, washed with water (3 x 20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (1/1) to provide 1.43 g (94% yield) of tert-butyl 4-(4-bromo-2- cyanobenzyl)piperazine-l-carboxylate as yellow oil. LCMS (ESI, m/z): 380 [M+H] ⁺ . Step 2: Synthesis of tert-butyl 4-(4-bromo-2-(lH-tetrazol-5-yl)benzyl)piperazine-l- carboxylate

[00364] A 50-mL round-bottom flask was charged with tert-butyl 4-(4-bromo-2- cyanobenzyl)piperazine-l-carboxylate (1.43 g, 3.76 mmol, 1.00 equiv), sodium azide (0.489 g, 7.52 mmol, 2.00 equiv), ammonium chloride (0.399 g, 7.46 mmol, 2.00 equiv) and N,N- dimethylformamide (20 mL). The resulting solution was stirred overnight at 100 °C and quenched by water (40 mL). The mixture was extracted with ethyl acetate (3 x 50 mL) and the organic layers were combined, washed with water (3 x 20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (2/1) to provide 1.03 g (65% yield) of tert- butyl 4-(4-bromo-2-(lH-tetrazol-5-yl)benzyl)piperazine-l-carboxyla te as yellow oil. LCMS (ESI, m/z): 423 [M+H] ⁺ .

Step 3: Synthesis of tert-butyl 4-(4-cyano-2-(lH-tetrazol-5-yl)benzyl)piperazine-l- carboxylate

[00365] A 50-mL round-bottom flask was charged with tert-butyl 4-(4-bromo-2-(lH-tetrazol-5- yl)benzyl)piperazine-l-carboxylate (1.00 g, 2.36 mmol, 1.00 equiv), zinc cyanide (0.166 g, 1.42 mmol, 0.60 equiv), tris(dibenylideneacetone)dipalladium-chloroform (0.122 g, 0.131 mmol, 0.05 equiv), l,l'-bis(diphenylphosphino)ferrocene (0.157 g, 0.281 mmol, 0.12 equiv) and N,N- dimethylformamide (20 mL). The resulting solution was stirred overnight at 120 °C under nitrogen atmosphere and quenched by water (40 mL). The mixture was extracted with ethyl acetate (3 x 50 mL) and the organic layers were combined, washed with water (3 x 20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (2/1) to provide 0.662 g (76% yield) of tert-butyl 4-(4-cyano-2-(lH-tetrazol-5-yl)benzyl)piperazine-l- carboxylate as yellow oil. LCMS (ESI, m/z): 370 [M+H] ⁺ . Step 4: Synthesis of 4-(piperazin-l-ylmethyl)-3-(lH-tetrazol-5-yl)benzonitrile

[00366] A 50-mL round-bottom flask was charged with tert-butyl 4-(4-cyano-2-(lH-tetrazol-5- yl)benzyl)piperazine-l-carboxylate (662 mg, 1.79 mmol, 1.00 equiv), trifluoroacetic acid (2 mL) and dichloromethane (10 mL). The resulting solution was stirred for 3 h at room temperature and concentrated under reduced pressure to provide 448 mg (crude) of 4-(piperazin-l- ylmethyl)-3-(lH-tetrazol-5-yl)benzonitrile TFA as yellow oil. LCMS (ESI, m/z): 270 [M+H] ⁺ . Step 5: Synthesis of 3-acetamido-lH- razole-l-carbonyl chloride

[00367] A 50-mL round-bottom flask was charged with N-(lH-pyrazol-3-yl)acetamide (125 mg, 1.00 mmol, 1.00 equiv), triphosgene (149 mg, 0.500 mmol, 0.50 equiv) and dichloromethane (10 mL). Then N,N-diisopropylethylamine (258 mg, 2.00 mmol, 2.00 equiv) was added dropwise at 0 °C. The resulting solution was stirred for 5 h at room temperature and concentrated under reduced pressure to provide 188 mg (crude) of 3-acetamido-lH-pyrazole-l-carbonyl chloride as yellow oil.

Step 6: Synthesis of N-(l-(4-(4-cyano-2-(lH-tetrazol-5-yl)benzyl)piperazine-l-car bonyl)- lH-pyrazol-3-yl)acetamide

[00368] A 50-mL round-bottom flask was charged with 4-(piperazin-l-ylmethyl)-3-(lH-tetrazol- 5-yl)benzonitrile (269 mg, 1.00 mmol, 1.00 equiv), 3-acetamido-lH-pyrazole-l-carbonyl chloride (188 mg, 1.00 mmol, 1.00 equiv), N,N-diisopropylethylamine (258 mg, 2.00 mmol, 2.00 equiv) and dichloromethane (10 mL). The resulting solution was stirred for 3 h at room temperature and concentrated under reduced pressure. The crude product was purified by preparative HPLC using the following gradient conditions: 10% CH ₃ CN/90% Phase A increasing to 25% CH ₃ CN over 10 min, then to 100% CH ₃ CN over 0.1 min, holding at 100% CH ₃ CN for 1.9 min, then reducing to 10% CH ₃ CN over 0.1 min, and holding at 10% for 1.9 min, on a Waters 2767-5 Chromatograph. Column: X bridge Prep Ci ₈ , 19* 150mm 5um; Mobile phase: Phase A: aqueous NH ₄ HC0 ₃ (0.05%); Phase B: CH ₃ CN; Detector, UV220 & 254nm. Purification resulted in 35.9 mg (9% yield) of N-(l-(4-(4-cyano-2-(lH-tetrazol-5- yl)benzyl)piperazine-l-carbonyl)-lH-pyrazol-3-yl)acetamide as a white solid. 1H NMR: (300 MHz, Dimethyl sulfoxide-^) δ 10.7 (s, 1H), 8.35 (d, J= 1.7 Hz, 1H), 8.10 (d, J= 2.8 Hz, 1H), 7.96 (m, 1H), 7.80 (d, J= 8.0 Hz, 1H), 6.84 (d, J= 2.8 Hz, 1H), 4.24 (s, 2H), 3.82 (s, 4H), 2.86 (s, 4H), 2.03 (s, 3H). LCMS (ESI, m/z): 421 [M+H] ⁺ .

Example 116: N-(l-(4-(2-(4-(2-hydroxyacetyl)piperazin-l-yl)-4-

(trifluoromethyl)benzyl)piperazine-l-carbonyl)-lH-pyrazol -3-yl)methanesulfonamide

Step 1: Synthesis of terf-butyl 4-(2-formyl-5-(trifluoromethyl)phenyl)piperazine-l- carboxylate

[00369] A 250-mL round-bottom flask was charged with 2-fluoro-4- (trifluoromethyl)benzaldehyde (5.00 g, 26.0 mmol, 1.00 equiv), tert-butyl piperazine-1- carboxylate (10.0 g, 53.7 mmol, 2.00 equiv), potassium carbonate (11.2 g, 81.0 mmol, 3.00 equiv), and dimethyl sulfoxide (50 mL). The resulting solution was stirred overnight at 100 °C and quenched with water (100 mL). The mixture was extracted with ethyl acetate (3 x 100 mL) and the organic layers were combined, washed with brine (2 x 100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was

chromatographed on a silica gel column with ethyl acetate/petroleum ether (1/4) to provide 9.00 g (96% yield) of tert-butyl 4-(2-formyl-5-(trifluoromethyl)phenyl)piperazine-l-carboxyla te as a yellow solid. LCMS (ESI, m/z): 359 [M+H] ⁺ .

Step 2: Synthesis of 2-(piperazin-l-yl)-4-(trifluorometh l)benzaldehyde

[00370] A 50-mL round-bottom flask was charged with tert-butyl 4-(2-formyl-5- (trifluoromethyl)phenyl)piperazine-l-carboxylate (500 mg, 1.40 mmol, 1.00 equiv), 1,4-dioxane (10 mL), and concentrated hydrochloric acid (2 mL). The resulting solution was stirred for 2 h at room temperature and concentrated under pressure to provide 600 mg (crude) of 2-(piperazin-l- yl)-4-(trifluoromethyl)benzaldehyde-HCl as a white solid. LCMS (ESI, m/z): 259 [M+H] ⁺ .

Step 3: Synthesis of 2-(4-(2-formyl-5-(trifluoromethyl)phenyl)piperazin-l-yl)-2-o xoethyl acetate

[00371] A 100-mL round-bottom flask was charged wtih 2-(piperazin-l-yl)-4- (trifluoromethyl)benzaldehyde (593 mg, 2.30 mmol, 1.00 equiv), dichloromethane (20 mL), triethylamine (697 mg, 6.89 mmol, 3.00 equiv), and 2-chloro-2-oxoethyl acetate (344 mg, 2.52 mmol, 1.10 equiv). The resulting solution was stirred for 1 h at 0 °C and quenched with water (20 mL). The mixture was extracted with dichloromethane (3 x 20 mL) and the organic layers were combined, washed with brine (2 x 20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (1/4) to provide 770 mg (94% yield) of 2-[4-[2- formyl-5-(trifluoromethyl)phenyl]piperazin-l-yl]-2-oxoethyl acetate as yellow oil. LCMS (ESI, m/z): 359 [M+H] ⁺ .

Step 4: Synthesis of 2-(4-(2-hydroxyacetyl)piperazin-l-yl)-4-(trifluoromethyl)ben zaldehyde

[00372] A 50-mL round-bottom flask was charged with 2-[4-[2-formyl-5- (trifluoromethyl)phenyl]piperazin-l-yl]-2-oxoethyl acetate (700 mg, 1.95 mmol, 1.00 equiv), methanol (15 mL), and potassium carbonate (539 mg, 3.90 mmol, 2.00 equiv). The resulting solution was stirred for 2 h at room temperature and quenched with water (10 mL). The mixture was extracted with dichloromethane (3 x 10 mL) and the organic layers were combined, washed with brine (2 x 10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (1/1) to provide 500 mg (81% yield) of 2-(4-(2-hydroxyacetyl)piperazin- l-yl)-4-(trifluoromethyl)benzaldehyde as a yellow solid. LCMS (ESI, m/z): 317 [M+H] ⁺ .

Step 5: Synthesis of terf-butyl 4-(3-(methylsulfonamido)-lH-pyrazole-l- carbonyl)piperazine-l-carboxylate

[00373] A 250-mL round-bottom flask was charged with 4-nitrophenyl 3-(methylsulfonamido)- lH-pyrazole-l-carboxylate (Exampe 113, Step 1; 9.07 g, 27.8 mmol, 1.00 equiv), tert-butyl piperazine-l-carboxylate (5.18 g, 27.8 mmol, 1.00 equiv), dichloromethane (50 mL), and triethylamine (8.50 g, 84.0 mmol, 3.00 equiv). The resulting solution was stirred for 3 h at room temperature and quenched with water (50 mL). The mixture was extracted with dichloromethane (3 x 50 mL) and the organic layers were combined, washed with brine (2 x 50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (6/4) to provide 4.20 g (40% yield) of tert-butyl 4-(3-(methylsulfonamido)-lH-pyrazole-l-carbonyl)piperazine-l - carboxylate as a yellow oil. LCMS (ESI, m/z): 374 [M+H] ⁺ .

Step 6: Synthesis of N-(l-(piperazine-l-carbonyl)-lH-pyrazol-3-yl)methanesulfonam ide

[00374] A 40-mL round-bottom flask was charged with tert-butyl 4-(3-(methylsulfonamido)-lH- pyrazole-l-carbonyl)piperazine-l-carboxylate (375 mg, 1.00 mmol, 1.00 equiv),

dichloromethane (5 mL), and trifluoroacetic acid (1 mL). The resulting solution was stirred for 2 h at room temperature and concentrated under reduced pressure to provide 400 mg (crude) of /V- (l-(piperazine-l-carbonyl)-lH-pyrazol-3-yl)methanesulfonamid e TFA as a white solid. LCMS (ESI, m/z): 274 [M+H] ⁺ . Step 7: Synthesis of N-(l-(4-(2-(4-(2-hydroxyacetyl)piperazin-l-yl)-4- (trifluoromethyl)benzyl)piperazine-l-carbonyl)-lH-pyrazol-3- yl)methanesulfonamide

[00375] A 40-mL round-bottom flask was charged with 2-[4-(2-hydroxyacetyl)piperazin-l-yl]- 4-(trifluoromethyl)benzaldehyde (158 mg, 0.500 mmol, 1.00 equiv), N-(l-(piperazine-l- carbonyl)-lH-pyrazol-3-yl)methanesulfonamide (177 mg, 0.650 mmol, 1.30 equiv),

triethylamine (152 mg, 1.50 mmol, 3.00 equiv), and 1,2-dichloroethane (10 mL). The resulting solution was stirred for 1 h at room temperature before sodium triacetoxyborohydride (318 mg, 1.50 mmol, 3.00 equiv) was added. The resulting solution was stirred overnight at room temperature and quenched with water (10 mL). The mixture was extracted with dichloromethane (3 x 10 mL) and the organic layers were combined, washed with brine (2 x 10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product (200 mg) was purified by preparative HPLC using the following gradient conditions: 30% CH ₃ CN/70% Phase A increasing to 70% CH ₃ CN over 10 min, then to 100% CH ₃ CN over 0.1 min, holding at 100% CH ₃ CN for 1.9 min, then reducing to 30% CH ₃ CN over 0.1 min, and holding at 30% for 1.9 min, on a Waters 2767-5 Chromatograph. Column: Xbridge Prep CI 8, 19* 150mm 5um; Mobile phase: Phase A: aqueous H ₄ HC0 ₃ (0.05%); Phase B: CH ₃ CN;

Detector, UV220 & 254nm. Purification resulted in 71.5 mg (25% yield) of N-(l-(4-(2-(4-(2- hydroxyacetyl)piperazin-l-yl)-4-(trifluorom ethyl )benzyl)piperazine-l-carbonyl)-lH-pyrazol-3- yl)methanesulfonamide as a white solid. ¹ H MR (300MHz, Chloroform- ) δ 8.04 (d, J= 2.7 Hz, 1H), 7.58 - 7.61 (m, 1H), 7.37 - 7.39 (m, 1H), 7.29 (s, 1H), 7.14 (br, 1H), 6.31 (d, 7= 2.7 Hz, 1H), 4.23 - 4.24 (m, 2H), 3.83 (br, 6H), 3.64 (s, 3H), 3.24 - 3.46 (m, 2H), 3.14 (s, 3H), 3.01 - 3.04 (m, 4H), 2.56 - 2.59 (m, 4H). LCMS (ESI, m/z): 574 [M+H] ⁺ .

Example 117: N-(l-(l-(4-chloro-3-methylbenzyl)-l,8-diazaspiro[4.5]decane- 8-carbonyl)- lH-pyrazol-3-yl)-2,2,2-trifluoroacetamide

Step 1: Synthesis of tert-butyl l-(4-chloro-3-methylbenzyl)-l,8-diazaspiro[4.5]decane-8- carboxylate

[00376] A 50-mL round-bottom flask was charged with 4-chloro-3-methylbenzaldehyde (0.930 g, 6.02 mmol, 1.00 equiv), 1,2-dichloroethane (30 mL), and tert-butyl 1,8- diazaspiro[4.5]decane-8-carboxylate (1.73 g, 7.22 mmol, 1.20 equiv). The mixture was stirred for 1 h at room temperature before sodium triacetoxyborohydride (3.82 g, 18.1 mmol, 3.00 equiv) was added. The resulting solution was stirred overnight at room temperature and quenched with water (30 mL). The mixture was extracted with dichloromethane (2 x 50 mL) and the organic layers were combined, washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/hexane (3/7) to provide 1.20 g (53% yield) of tert-butyl 1- (4-chloro-3-methylbenzyl)-l,8-diazaspiro[4.5]decane-8-carbox ylate as colorless oil. LCMS (ESI, m/z): 379 [M+H] ⁺ .

Step 2: Synthesis of l-(4-chloro-3-methylbenzyl)-l,8-diazaspiro[4.5]decane

[00377] A 50-mL round-bottom flask was charged with tert-butyl l-(4-chloro-3-methylbenzyl)- l,8-diazaspiro[4.5]decane-8-carboxylate (1.00 g, 2.64 mmol, 1.00 equiv), dichloromethane (10 mL), and trifluoroacetic acid (2 mL). The resulting solution was stirred for 3 h at room temperature and concentrated under reduced pressure. The crude product was dissolved in 1M NaOH solution (30 mL) and extracted with dichloromethane (3 x 50 mL). The organic layers were combined, washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to provide 0.900 g (crude) of l-(4-chloro-3-methylbenzyl)- l,8-diazaspiro[4.5]decane as light yellow oil. LCMS (ESI, m/z): 279 [M+H] ⁺ . Step 3: Synthesis of l-(4-chloro-3-methylbenzyl)-l,8-diazaspiro[4.5]decane-8-carb onyl chloride

[00378] A 50-mL round-bottom flask was charged with triphosgene (0.532 g, 1.79 mmol, 0.50 equiv), dichloromethane (10 mL), and l-[(4-chloro-3-methylphenyl)methyl]-l,8- diazaspiro[4.5]decane (1.00 g, 3.58 mmol, 1.00 equiv). N,N-Diisopropylethylamine (1.39 g, 10.7 mmol, 3.00 equiv) was added at 0 °C. The resulting solution was stirred for 3 h at room temperature and quenched with water (30 mL). The resulting solution was extracted with dichloromethane (2 x 50 mL) and the organic layers were combined, washed with brine (2 x 30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to provide 1.40 g (crude) of l-(4-chloro-3-methylbenzyl)-l,8-diazaspiro[4.5]decane-8-carb onyl chloride as light yellow oil. LCMS (ESI, m/z): 341 [M+H] ⁺ .

Step 4: Synthesis of (l-(4-chloro-3-methylbenzyl)-l,8-diazaspiro[4.5]decan-8-yl)( 3-nitro- lH-pyrazol-l-yl)methanone

[00379] A 50-mL round-bottom flask was charged with l-[(4-chloro-3-methylphenyl)methyl]- l,8-diazaspiro[4.5]decane-8-carbonyl chloride (1.22 g, 3.57 mmol, 1.00 equiv), tetrahydrofuran (15 mL), 3-nitro-lH-pyrazole (0.485 g, 4.29 mmol, 1.20 equiv), N,N-diisopropylethylamine (1.39 g, 10.7 mmol, 3.00 equiv), and 4-dimethylaminopyridine (0.0870 g, 0.714 mmol, 0.20 equiv). The resulting solution was stirred overnight at 60 °C and quenched with water (30 mL). The mixture was extracted with dichloromethane (2 x 50 mL) and the organic layers were combined, washed with brine (2 x 30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with dichloromethane/methanol (97/3) to provide 1.24 g (83% yield) of l-[(4-chloro-3- methylphenyl)methyl]-8-[(3-nitro-lH-pyrazol-l-yl)carbonyl]-l ,8-diazaspiro[4.5]decane as a light yellow solid. LCMS (ESI, m/z): 418 [M+H] ⁺ . Step 5: Synthesis of (3-amino-lH-pyrazol-l-yl)(l-(4-chloro-3-methylb'

diazaspiro [4.5] decan-8-yl)methanone

[00380] A 50-mL round-bottom flask was charged with l-[(4-chloro-3-methylphenyl)methyl]-8- [(3-nitro-lH-pyrazol-l-yl)carbonyl]-l,8-diazaspiro[4.5]decan e (300 mg, 0.720 mmol, 1.00 equiv), ethyl acetate (10 mL), and 10% palladium on carbon (100 mg)l; hydrogen was introduced in. The resulting solution was stirred for 1 h at room temperature and the solids were removed by filtration. The filtrate was concentrated under reduced pressure to provide 330 mg (crude) of (3-amino-lH-pyrazol-l-yl)(l-(4-chloro-3-methylbenzyl)-l,8-di azaspiro[4.5]decan-8- yl)methanone as a light yellow solid. LCMS (ESI, m/z): 388 [M+H] ⁺ .

Step 6: Synthesis of N-(l-(l-(4-chloro-3-methylbenzyl)-l,8-diazaspiro[4.5]decane- 8- carbonyl)-lH-pyrazol-3-yl)-2,2,2-trifluoroacetamide

[00381] A 50-mL round-bottom flask was charged with (3-amino-lH-pyrazol-l-yl)(l-(4-chloro- 3-methylbenzyl)-l,8-diazaspiro[4.5]decan-8-yl)methanone (160 mg, 0.410 mmol, 1.00 equiv), dichloromethane (10 mL), N,N-diisopropylethylamine (106 mg, 0.820 mmol, 2.00 equiv), and trifluoroacetic anhydride (129 mg, 0.615 mmol, 1.50 equiv). The resulting solution was stirred for 2 h at room temperature and quenched with water (30 mL). The mixture was extracted with dichloromethane (2 x 50 mL) and the organic layers were combined, washed with brine (2 x 30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product (300 mg) was purified by preparative HPLC using the following gradient conditions: 20% CH ₃ CN/80% Phase A increasing to 80% CH ₃ CN over 10 min, then to 100% CH ₃ CN over 0.1 min, holding at 100% CH ₃ CN for 1.9 min, then reducing to 20% CH ₃ CN over 0.1 min, and holding at 20% for 1.9 min, on a Waters 2767-5 Chromatograph. Column: Xbridge Prep C18, 19* 150mm 5um; Mobile phase: Phase A: aqueous H ₄ HC0 ₃ (0.05%); Phase B: CH ₃ CN; Detector, UV220 & 254nm. Purification resulted in 60.5 mg (30% yield) of N-(l-(l-(4- chloro-3-methylbenzyl)-l,8-diazaspiro[4.5]decane-8-carbonyl) -lH-pyrazol-3-yl)-2,2,2- trifluoroacetamide as a white solid. ¹ H MR (300MHz, Chloroform- ) δ 8.70 (br, 1H), 8.08 (d, J= 2.7 Hz, 1H), 7.24 (s, 1H), 7.16 (s, 1H), 7.05 - 7.08 (m, 1H), 6.91 (d, J= 3.0 Hz, 1H), 4.55 - 4.59 (m, 2H), 3.55 (s, 2H), 3.03 - 3.11 (m, 2H), 2.67 (t, J= 6.9 Hz, 2H), 2.35 (s, 3H), 1.77 - 1.91 (m, 6H), 1.50 - 1.69 ( m, 2H). LCMS (ESI, m/z): 484 [M+H] ⁺ .

Example 118: 2-(4-(2-((4-(3-(methylsulfonamido)-lH-pyrazole-l-carbonyl)pi perazin-l- yl)methyl)-5-(trifluoromethyl)phenyl)piperidin-l-yl)acetic acid

Step 1: Synthesis of tert-butyl 4-(2-formyl-5-(trifluoromethyl)phenyl)piperidine-l- carboxylate

[00382] A 100-mL 3-necked round-bottom flask was charged with zinc powder (546 mg, 8.40 mmol, 2.00 equiv) and N, N-dimethylacetamide (40 mL) under nitrogen. 1,2-Dibrom ethane (158 mg, 0.840 mmol, 0.20 equiv) and chlorotrimethylsilane (91.6 mg, 0.840 mmol, 0.20 equiv) were added in sequence. The resulting solution was stirred for 15 min at room temperature and then tert-butyl 4-iodopiperidine-l-carboxylate (1.96 g, 6.30 mmol, 1.50 equiv) was added. The resulting solution was stirred for 1 h at room temperature before the addition of 2-iodo-4- (trifluoromethyl)benzaldehyde (1260 mg, 4.20 mmol, 1.00 equiv), 1, 1'- bis(diphenylphosphino)ferrocenepalladium (294 mg, 0.400 mmol, 0.10 equiv) and cuprous iodide (80.0 mg, 0.400 mmol, 0.10 equiv). The reaction mixture was stirred overnight at 80 °C and quenched with water (20 mL). The mixture was extracted with dichloromethane (3 x 40 mL) and the organic layers were combined, washed with brine (3 x 10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was

chromatographed on a silica gel column with ethyl acetate/petroleum ether (1/4) to provide 640 mg (43% yield) of tert-butyl 4-(2-formyl-5-(trifluoromethyl)phenyl)piperidine-l-carboxyla te as yellow oil. LCMS (ESI, m/z): 358 [M+H] ⁺ . Step 2: Synthesis of 2-(piperidin-4-yl)-4-(trifluoromethyl)benzaldehyde

[00383] A 50-mL round-bottom flask was charged with tert-butyl 4-(2-formyl-5- (trifluoromethyl)phenyl)piperidine-l-carboxylate (640 mg, 1.79 mmol, 1.00 equiv),

trifluoroacetic acid (2 mL) and dichloromethane (15 mL). The resulting solution was stirred for 2 h at room temperature and concentrated under reduced pressure to provide 460 mg (crude) of 2-(piperidin-4-yl)-4-(trifluoromethyl)benzaldehyde TFA as yellow oil. LCMS (ESI, m/z): 258 [M+H] ⁺ .

Step 3: Synthesis of terf-butyl 2-(4-(2-formyl-5-(trifluoromethyl)phenyl)piperidin-l- yl)acetate

[00384] A 50-mL round-bottom flask was charged with 2-(piperidin-4-yl)-4- (trifluoromethyl)benzaldehyde (460 mg, 1.79 mmol, 1.00 equiv), tert-butyl 2-bromoacetate (525 mg, 2.69 mmol, 1.50 equiv), potassium carbonate (746 mg, 5.40 mmol, 3.00 equiv) and acetonitrile (20 mL). The resulting solution was stirred for 2 h at room temperature and quenched with water (20 mL). The mixture was extracted with dichloromethane (3 x 30 mL) and the organic layers were combined, washed with brine (3 x 10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (1/3) to provide 501 mg (75% yield) of tert-butyl tert-butyl 2-(4-(2-foimyl-5-(trifluoromethyl)phenyl)piperidin-l-yl)acet ate as a white solid. LCMS (ESI, m/z): 372 [M+H] ⁺ . Step 4: Synthesis of tert-butyl 4-(2-(l-(2-(terf-butoxy)-2-oxoethyl)piperidin

(trifluoromethyl)benzyl)piperazine-l-carboxylate

[00385] A 50-mL round-bottom flask was charged with tert-butyl 2-(4-(2-formyl-5- (trifluoromethyl)phenyl)piperidin-l-yl)acetate (100 mg, 0.270 mmol, 1.00 equiv), tert-butyl piperazine-l-carboxylate (75.3 mg, 0.405 mmol, 1.50 equiv), 1,2-dichloroethane (5 mL), and triethylamine (81.8 mg, 0.810 mmol, 3.00 equiv). The resulting solution was stirred for 1 h at room temperature before the addition of sodium triacetoxyborohydride (172 mg, 0.810 mmol, 3.00 equiv). The resulting solution was stirred overnight at room temperature and quenched with water (10 mL). The mixture was extracted with dichloromethane (3 x 10 mL) and the organic layers were combined, washed with brine (2 x 10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with dichloromethane/methanol (97/3) to provide 120 mg (82% yield) of tert-butyl 4-(2-(l-(2-(tert-butoxy)-2-oxoethyl)piperidin-4-yl)-4-(trifl uoromethyl)benzyl)piperazine-l- carboxylate as yellow oil. LCMS (ESI, m/z): 542 [M+H] ⁺ .

Step 5: Synthesis of 2-(4-(2-(piperazin-l-ylmethyl)-5-(trifluoromethyl)phenyl)pip eridin-l- yl)acetic acid

[00386] A 50-mL round-bottom flask was charged with tert-butyl 4-[(2-[l-[2-(tert-butoxy)-2- oxoethyl]piperidin-4-yl]-4-(trifluoromethyl)phenyl)methyl]pi perazine- 1 -carboxylate (196 mg, 0.360 mmol, 1.00 equiv), 1,4-dioxane (5 mL), concentrated hydrochloric acid (1 mL). The resulting solution was stirred for 2 h at room temperature and concentrated under reduced pressure to provide 200 mg (crude) of 2-(4-(2-(piperazin-l-ylmethyl)-5- (trifluoromethyl)phenyl)piperidin-l-yl)acetic acid HCI as yellow oil. LCMS (ESI, m/z): 386 [M+H] ⁺ . Step 6: Synthesis of 2-(4-(2-((4-(3-(methylsulfonamido)-lH-pyrazole-l-carbonyl)pi perazin- l-yl)methyl)-5-(trifluoromethyl)phenyl)piperidin-l-yl)acetic acid

[00387] A 50-mL round-bottom flask was charged with 2-(4-(2-(piperazin-l-ylmethyl)-5- (trifluoromethyl)phenyl)piperidin-l-yl)acetic acid HCl (139 mg, 0.360 mmol, 1.00 equiv), dichloromethane (5 mL), 4-nitrophenyl 3-(methylsulfonamido)-lH-pyrazole-l-carboxylate (Example 113, Step 1; 236 mg, 0.720 mmol, 2.00 equiv), and triethylamine (110 mg, 1.09 mmol, 3.00 equiv). The resulting solution was stirred for 2 h at room temperature and quenched with water (10 mL). The mixture was extracted with dichloromethane (3 x 10 mL) and the organic layers were combined, washed with brine (2 x 10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product (200 mg) was purified by preparative HPLC using the following gradient conditions: 15% CH ₃ CN/85% Phase A increasing to 35% CH ₃ CN over 7 min, then to 100% CH ₃ CN over 0.1 min, holding at 100% CH ₃ CN for 1.9 min, then reducing to 15% CH ₃ CN over 0.1 min, and holding at 15% for 1.9 min, on a Waters 2767-5 Chromatograph. Column: Xbridge Prep C18, 19* 150mm 5um; Mobile phase: Phase A: aqueous NH ₄ HC0 ₃ (0.05%); Phase B: CH ₃ CN; Detector, UV220 & 254nm. Purification resulted in 62.3 mg (30% yield) of 2-(4-(2-((4-(3-(methylsulfonamido)-lH- pyrazole- 1 -carbonyl)piperazin- 1 -yl)methyl)-5-(trifluorom ethyl )phenyl)piperi din- 1 -yl)acetic acid as a white solid. 1H MR (300MHz, Methanol-^) δ 8.04 (d, J=2.7 Hz, 1H), 7.64 (br, 1H), 7.46 - 7.52 (m, 2H), 6.23 (d, J= 2.7 Hz, 1H), 3.81 (br, 4H), 3.69 - 3.73 (m, 4H), 3.62 (br, 2H), 3.40 (br, 1H), 3.08 - 3.13 (m, 5H), 2.55 - 2.58 (m, 4H), 2.07 - 2.09 (m, 4H). LCMS (ESI, m/z): 573 [M+H] ⁺ .

Example 119: 2-(4-(5-((4-(3-(methylsulfonamido)-lH-pyrazole-l-carbonyl)pi perazin-l- yl)methyl)-2-(trifluoromethyl)phenyl)piperidin-l-yl)acetic acid

Step 1: Synthesis of tert-butyl 4-(5-formyl-2-(trifluoromethyl)phenyl)-3,6-dihydropyridine- 1 (2H)-carboxylate

80 °C, overnight

[00388] A 50-mL round-bottom flask was charged with 3-bromo-4-

(trifluoromethyl)benzaldehyde (1.00 g, 3.95 mmol, 1.00 equiv), tert-butyl 4-(tetramethyl-l,3,2- dioxaborolan-2-yl)-l,2,3,6-tetrahydropyridine-l-carboxylate (1.84 g, 5.95 mmol, 1.50 equiv), tetrakis(triphenylphosphine)palladium (230 mg, 0.198 mmol, 0.05 equiv), potassium carbonate (1.64 g, 11.9 mmol, 3.00 equiv), 1,4-dioxane (10 mL), and water (2 mL) under nitrogen. The resulting solution was stirred overnight at 80 °C and quenched with water (10 mL). The mixture was extracted with dichloromethane (3 x 10 mL) and the organic layers were combined, washed with brine (2 x 10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (1/4) to provide 1.00 g (71% yield) of tert-butyl 4-(5-formyl-2- (trifluoromethyl)phenyl)-3,6-dihydropyridine-l(2H)-carboxyla te as yellow oil. LCMS (ESI, m/z): 356 [M+H] ⁺ .

Step 2: Synthesis of tert-butyl 4-(5-((4-(3-(methylsulfonamido)-lH-pyrazole-l- carbonyl)piperazin-l-yl)methyl)-2-(trifluoromethyl)phenyl)-3 ,6-dihydropyridine-l(2H)- carboxylate

, overn g

[00389] A 100-mL round-bottom flask was charged with tert-butyl 4-(5-formyl-2- (trifluoromethyl)phenyl)-3,6-dihydropyridine-l(2H)-carboxyla te (500 mg, 1.41 mmol, 1.00 equiv), N-[l-[(piperazin-l-yl)carbonyl]-lH-pyrazol-3-yl]methanesulfo namide (500 mg, 1.83 mmol, 1.30 equiv), 1,2-dichloroethane (10 mL), and triethylamine (427 mg, 4.23 mmol, 3.00 equiv). The resulting solution was stirred for 1 h at room temperature before addition of sodium triacetoxyborohydride (897 mg, 4.23 mmol, 3.00 equiv). The reaction mixture was stirred overnight at room temperature and quenched with water (10 mL). The resulting solution was extracted with dichloromethane (3 x 10 mL) and the organic layers were combined, washed with brine (2 x 10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with

dichloromethane/methanol (96/4) to provide 835 mg (97% yield) of tert-butyl 4-(5-((4-(3- (methylsulfonamido)-lH-pyrazole-l-carbonyl)piperazin-l-yl)me thyl)-2- (trifluoromethyl)phenyl)-3,6-dihydropyridine-l(2H)-carboxyla te as yellow oil. LCMS (ESI, m/z): 613 [M+H] ⁺ .

Step 3: Synthesis of tert-butyl 4-(5-((4-(3-(methylsulfonamido)-lH-pyrazole-l- carbonyl)piperazin-l-yl)methyl)-2-(trifluoromethyl)phenyl)pi peridine-l-carboxylate

[00390] A 100-mL round-bottom flask was charged with tert-butyl 4-(5-((4-(3- (methylsulfonamido)-lH-pyrazole-l-carbonyl)piperazin-l-yl)me thyl)-2- (trifluoromethyl)phenyl)-3,6-dihydropyridine-l(2H)-carboxyla te (400 mg, 0.650 mmol, 1.00 equiv), methanol (10 mL), and platinum(IV) oxide hydrate (200 mg). Hydrogen was introduced. The reaction mixture was stirred overnight at room temperature. The solids were removed by filtration and the filtrate was concentrated under reduced pressure to provide 50.0 mg (12% yield) of tert-butyl 4-(5-((4-(3-(methylsulfonamido)-lH-pyrazole-l-carbonyl)piper azin-l- yl)methyl)-2-(trifluoromethyl)phenyl)piperidine-l-carboxylat e as yellow oil. LCMS (ESI, m/z): 615 [M+H] ⁺ .

Step 3: Synthesis of N-(l-(4-(3-(piperidin-4-yl)-4-(trifluoromethyl)benzyl)pipera zine-l- carbonyl)-lH-pyrazol-3-yl)methanesulfonamide

[00391] A 50-mL round-bottom flask was charged with tert-butyl 4-(5-((4-(3- (methylsulfonamido)-lH-pyrazole-l-carbonyl)piperazin-l-yl)me thyl)-2- (trifluoromethyl)phenyl)piperidine-l-carboxylate (50.0 mg, 0.0814 mmol, 1.00 equiv), dichloromethane (5 mL), and trifluoroacetic acid (1 mL). The resulting solution was stirred for 2 h at room temperature and concentrated under reduced pressure to provide 55.0 mg (crude) of N-(l-(4-(3-(piperidin-4-yl)-4-(trifluoromethyl)benzyl)pipera zine-l-carbonyl)-lH-pyrazol-3- yl)methanesulfonamide TFA as yellow oil. LCMS (ESI, m/z): 515 [M+H] ⁺ . Step 4: Synthesis of tert-butyl 2-(4-(5-((4-(3-(methylsulfonamido)-lH-pyrazole-l- carbonyl)piperazin-l-yl)methyl)-2-(trifluoromethyl)phenyl)pi peridin-l-yl)acetate

[00392] A 50-mL round-bottom flask was charged with N-(l-(4-(3-(piperidin-4-yl)-4- (trifluoromethyl)benzyl)piperazine-l-carbonyl)-lH-pyrazol-3- yl)methanesulfonamide TFA (41.9 mg, 0.0814 mmol, 1.00 equiv), acetonitrile (5 mL), potassium carbonate (22.5 mg, 0.163 mmol, 2.00 equiv), and tert-butyl 2-bromoacetate (17.4 mg, 0.0897 mmol, 1.10 equiv). The resulting solution was stirred for 2 h at room temperature and quenched with water (10 mL). The resulting mixture was extracted with dichloromethane (3 x 10 mL) and the organic layers were combined, washed with brine (2 x 10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with dichloromethane/methanol (12/1) to provide 30.0 mg (59% yield) of tert-butyl 2-(4-(5-((4- (3 -(methylsulfonamido)- lH-pyrazole- 1 -carbonyl)piperazin- 1 -yl)methyl)-2- (trifluoromethyl)phenyl)piperidin-l-yl)acetate as yellow oil. LCMS (ESI, m/z): 629 [M+H] ⁺ .

Step 5: Synthesis of 2-(4-(5-((4-(3-(methylsulfonamido)-lH-pyrazole-l-carbonyl)pi perazin- l-yl)methyl)-2-(trifluoromethyl)phenyl)piperidin-l-yl)acetic acid

[00393] A 50-mL round-bottom flask was charged with tert-butyl 2-(4-(5-((4-(3- (methylsulfonamido)-lH-pyrazole-l-carbonyl)piperazin-l-yl)me thyl)-2- (trifluoromethyl)phenyl)piperidin-l-yl)acetate (30.0 mg, 0.0478 mmol, 1.00 equiv),

dichloromethane (5 mL), and trifluoroacetic acid (1 mL). The resulting solution was stirred overnight at room temperature and concentrated under reduced pressure. The residue was dissolved in saturated NaHC0 ₃ solution (10 mL), extracted with dichloromethane (3 x 10 mL) and the organic layers were combined, washed with brine (2 x 10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product (200 mg) was purified by preparative HPLC using the following gradient conditions: 15% CH ₃ CN/85% Phase A increasing to 40% CH ₃ CN over 7 min, then to 100% CH ₃ CN over 0.1 min, holding at 100% CH ₃ CN for 1.9 min, then reducing to 15% CH ₃ CN over 0.1 min, and holding at 15% for 1.9 min, on a Waters 2767-5 Chromatograph. Column: Xbridge Prep C18, 19* 150mm 5um; Mobile phase: Phase A: aqueous H ₄ HCO ₃ (0.05%); Phase B: CH ₃ CN; Detector, UV220 & 254nm. Purification resulted in 7.60 mg (28% yield) of 2-(4-(5-((4-(3-(methylsulfonamido)-lH- pyrazole- 1 -carbonyl)piperazin- 1 -yl)methyl)-2-(trifluorom ethyl )phenyl)piperi din- 1 -yl)acetic acid as colorless oil. 1H MR (300MHz, Methanol-^) δ 7.97 (d, J= 2.7 Hz, 1H), 7.62 - 7.63 (m, 2H), 7.39 - 7.41 (m, 1H), 6.16 (d, J = 2.7 Hz, 1H), 3.88 (br, 4H), 3.65 (s, 2H), 3.50 - 3.53 (m, 2H), 3.42 (s, 2H), 3.05 - 3.12 (m, 4H), 2.79 - 2.81 (m, 2H), 2.56 - 2.59 (m, 4H), 2.03 - 2.05 (m, 2H), 1.87 - 1.90 (m, 2H). LCMS (ESI, m/z): 573 [M+H] ⁺ .

[00394] Examples 120-296 (Table 1) were synthesized using similar procedures as described in previous Examples, using the appropriate starting materials.

TABLE 1

(m, 2H), 3.38 (s, 2H), 3.16 - 3.35

(m, 2H), 3.13 (s, 3H), 2.54 (br, 4H), 2.16 - 2.24 (m, 2H), 1.91 (s, 3H).

N-(l-(4-(5-chloro-2- ¾ NMR (300 MHz,

morpholinobenzyl)pipe Chloroform-d) δ 8.05 (d, J = 3.0 razine-l-carbonyl)-lH- Hz, IH), 7.46 (s, IH), 7.21 - pyrazol-3- 7.24 (m, IH), 7.04 (d, J = 8.7

123 0 ₂ CH ₃ 483 yl)methanesulfonamide _J NHS

Hz, 2H), 6.32 (d, J = 3.0 Hz, y IH), 3.81 - 3.84 (m, 8H), 3.58 (s,

2H), 3.14 (s, 3H), 2.89 - 2.92 (m, 4H), 2.57 (br, 4H).

N-( 1 -(4-(2-morpholino- ¾ NMR (300 MHz,

5- CF ₃ 0 Chloroform-d) δ 8.05 (d, J = 2.7

(trifluoromethyl)benzyl Hz, IH), 7.75 (s, IH), 7.52 (d, J )piperazine-l- = 7.8 Hz, IH), 7.13 - 7.16 (m,

124 517 carbonyl)- lH-pyrazol- _J NHS0 ₂ CH ₃

2H), 6.32 (d, J = 2.7 Hz, IH),

3- 3.84 - 3.87 (m, 8H), 3.61 (s, 2H), yl)methanesulfonamide 3.14 (s, 3H), 2.98 - 3.01 (m, 4H),

2.57 (br, 4H).

N-(l-(l-(2-(pyrrolidin- I I NMR (300 MHz,

l-yl)-4- Chloroform-d) δ 8.03 (d, J = 2.7

(trifluoromethyl)benzyl Hz, IH), 7.69 (d, J = 7.5 Hz,

)-l,8- IH), 7.12 - 7.15 (m, 2H), 6.32

125 diazaspiro [4.5 ] decane - (d, J = 2.7 Hz, IH), 4.59 (d, J = 555

8-carbonyl)-lH- 12.3 Hz, 2H), 3.66 (s, 2H), 3.05

pyrazol-3- - 3.19 (m, 9H), 2.64 (t, J = 6.6 yl)methanesulfonamide Hz, 2H), 1.82 - 2.03 (m, 10H),

1.52 - 1.56 (m, 2H).

N-( 1 -( 1 -(2-morpholino - l NMR (300 MHz,

4- Chloroform-d) δ 8.03 (d, J = 2.7

(trifluoromethyl)benzyl Hz, IH), 7.58 8.03 (d, J = 8.1

)-l,8- Hz, 2H), 7.32 - 7.34 (m, 2H), diazaspiro[4.5]decane- 6.36 (d, J = 2.7 Hz, IH), 4.58 (d,

126 8-carbonyl)-lH- J = 12.9 Hz, 2H), 3.93 (t, J = 8.7 571 pyrazol-3- Hz, 4H), 3.72 (s, 2H), 2.94 -

yl)methanesulfonamide 3.12 (m, 9H), 2.73 (t, J = 6.2 Hz,

2H), 1.97 - 2.04 (m, 2H), 1.80 - 1.84 (m, 4H), 1.48 - 1.53 (m,

2H). N-(l-(4-(4-chloro-2- ¾ NMR (300 MHz, (pyrrolidin-1- Chloroform-d) δ 8.03 (d, J = 2.7 yl)benzyl)piperazine- 1 - Hz, IH), 7.28 - 7.30 (m, IH), carbonyl)- lH-pyrazol- 6.81 - 6.84 (m, 2H), 6.30 (d, J =

127 466 3- T NHso ₂ CH ₃ 2.7 Hz, IH), 3.82 (br, 4H), 3.52 yl)methanesulfonamide 0 (s, 2H), 3.22 (t, J = 6.2 Hz, 4H),

3.13 (s, 3H), 2.52 (br, 4H), 1.92 (t, J = 6.3 Hz, 4H).

N-(l-(4-(4-chloro-2- ¾ NMR (300 MHz,

(piperidin-1- Chloroform-d) δ 8.04 (d, J = 2.7 yl)benzyl)piperazine- 1 - Hz, IH), 7.37 (d, J = 8.1 Hz, carbonyl)- lH-pyrazol-

128 3- ^C' IH), 7.00 - 7.06 (m, 2H), 6.31

T LO¾ NHSo ₂ CH ₃ (d, J = 2.7 Hz, IH), 3.81 (br, 481 yl)methanesulfonamide O 4H), 3.55 (s, 2H), 3.13 (s, 3H),

2.81 - 2.90 (m, 4H), 2.55 (br,

4H), 1.67 - 1.68 (m, 4H), 1.56 - 1.57 (m, 2H).

N-(l-(4-(2-(piperidin- ¾ NMR (300 MHz,

l-yl)-4- Chloroform-d) δ 8.04 (d, J = 2.7

(trifluoromethyl)benzyl Hz, IH), 7.60 (d, J = 7.8 Hz,

)piperazine-l- IH), 7.28 - 7.30 (m, 2H), 7.05

129 carbonyl)- lH-pyrazol- 1 NHSO2CH3 (br, IH), 6.31 (d, J = 2.7 Hz, 515 3- IH), 3.83 (br, 4H), 3.62 (s, 2H), yl)methanesulfonamide O 3.13 (s, 3H), 2.84 - 2.93 (m, 4H),

2.56 (br, 4H), 1.69 - 1.70 (m,

4H), 1.58 - 1.60 (m, 2H).

N-(l-(4-(2-(8-oxa-3- I I NMR (300 MHz,

azabicyclo [3.2.1] octan- Chloroform-d) δ 8.05 (d, J = 2.7 3-yl)-4- Hz, IH), 7.61 (d, J = 7.8 Hz,

(trifluoromethyl)benzyl IH), 7.33 - 7.36 (m, 2H), 6.94

130 )piperazine-l- ^F,C OLC ^N ¼ (br, IH), 6.32 (d, J = 2.7 Hz, 543

NHSO2CH3

carbonyl)- lH-pyrazol- IH), 4.42 (br, 2H), 3.84 (br, 4H), 3- Θ 3.66 (s, 2H), 3.08 - 3.14 (m, 5H), yl)methanesulfonamide 2.79 - 2.83 (m, 2H), 2.55 - 2.56

(m, 4H), 1.99 - 2.13 (m, 4H).

N-(l-(l-(4-chloro-2- ΪΙ NMR (300 MHz,

(pyrrolidin-1- Chloroform-d) δ 8.03 (d, J = 2.7 yl)benzyl)-l,8- Hz, IH), 7.49 (d, J = 8.7 Hz,

131 521 diazaspiro[4.5]decane- IH), 6.86 - 6.88 (m, 2H), 6.32

NHSO2CH3

8-carbonyl)-lH- (d, J = 2.7 Hz, IH), 4.55 - 4.59 pyrazol-3- (m, 2H), 3.60 (s, 2H), 3.04 - 3.15 yl)methanesulfonamide (m, 9H), 2.64 (t, J = 6.6 Hz, 2H),

1.78 - 1.94 (m, 10H), 1.50 - 1.54 (m, 2H).

N-(l-(l-(4-chloro-2- ¾ NMR (300 MHz,

(piperidin- 1 -yl)benzy 1) - Chloroform-d) δ 8.02 (d, J = 2.7 1,8- Hz, 1H), 7.43 (d, J = 8.7 Hz, diazaspiro [4.5 ] decane - 1H), 6.96 - 6.99 (m, 2H), 6.31

8-carbonyl)-lH- (d, J = 2.7 Hz, 1H), 5.79 (br,

132 pyrazol-3- 1H), 4.54 - 4.58 (m, 2H), 3.62 - 535 yl)methanesulfonamide 3.64 (m, 2H), 3.03 - 3.13 (m,

NHS0 ₂ CH ₃

5H), 2.79 (t, J = 4.8 Hz, 4H),

2.66 (t, J = 6.6 Hz, 2H), 1.76 - 1.93 (m, 6H), 1.66 - 1.74 (m,

4H), 1.52 - 1.56 (m, 4H).

N-(l-(l-(2-(piperidin- ¾ NMR (300 MHz,

l-yl)-4- Chloroform-d) δ 8.03 (d, J = 2.7

(trifluoromethyl)benzyl Hz, 1H), 7.64 (d, J = 8.1 Hz,

)-l,8- 1H), 7.25 - 7.36 (m, 2H), 6.32 diazaspiro[4.5]decane- (d, J = 2.7 Hz, 1H), 5.43 - 6.22

133 8-carbonyl)-lH- (m, 1H), 4.56 - 4.60 (m, 2H), 569 pyrazol-3- NHS0 ₂ CH ₃ 3.70 (s, 2H), 3.05 - 3.15 (m, 5H), yl)methanesulfonamide 2.81 - 2.90 (m, 4H), 2.66 (t, J =

6.8 Hz, 2H), 1.76 - 1.93 (m, 6H), 1.70 (br, 4H), 1.51 - 1.59 (m,

4H).

N-( 1 -(4-(2-(pyrrolidin- ¾ NMR (300 MHz,

l-yl)-4- Chloroform-d) δ 8.00 (d, J = 2.7

(trifluoromethyl)benzyl O Hz, 1H), 7.51 - 7.54 (m, 1H),

)piperazine-l- 7.09 - 7.11 (m, 2H), 6.66 (br,

134 carbonyl)- lH-pyrazol- 1H), 6.34 (d, J = 2.7 Hz, 1H), 529 3-yl)propane-2- 3.82 (br, 4H), 3.58 (s, 2H), 3.35 sulfonamide - 3.44 (m, 1H), 3.24 (br, 4H),

2.53 (br, 4H), 1.95 (br, 4H), 1.42 (d, J = 6.9 Hz, 6H).

N-(l-(4-(4-chloro-2- ¾ NMR (300 MHz,

moφholinoberlzyl)pipe Chloroform-d) δ 8.04 (d, J = 3.0 razine-l-carbonyl)-lH- Hz, 1H), 7.38 (d, J = 8.7 Hz,

135 pyrazol-3- 1H), 7.06 - 7.08 (m, 2H), 6.31 483 yl)methanesulfonamide (d, J = 2.7 Hz, 1H), 3.82 - 3.85

(m, 8H), 3.56 (s, 2H), 3.14 (s, 3H), 2.94 - 2.96 (m, 4H), 2.55 - N-( 1 -(4-(2-morpholino- ¾ NMR (300 MHz, 4- Chloroform-d) δ 8.04 (d, J = 3.0

(trifluoromethyl)benzyl Hz, 1H), 7.61 (d, J = 7.5 Hz,

)piperazine-l- (m, 2H), 7.23

140 517 carbonyl)- lH-pyrazol- ^F,C OLC ^N ¼ 1H), 7.32 - 7.36

NHS0 ₂ CH ₃ (br, 1H), 6.31 (d, J = 2.7 Hz,

3- 1H), 3.84 - 3.87 (m, 8H), 3.64 (s, yl)methanesulfonamide 2H), 3.14 (s, 3H), 2.98 (t, J = 4.4

Hz, 4H), 2.57 (br, 4H).

N-(l-(l-(2-chloro-3- ¾ NMR (300MHz, Chloroform-

(pyrrolidin-1- d) δ 8.04 (d, J = 2.7 Hz, 1H), yl)benzyl)-l,8- 7.04 - 7.14 (m, 2H), 6.85 - 6.87 diazaspiro [4.5 ] decane - (m, 1H), 6.32 (d, J = 2.4 Hz,

141 8-carbonyl)-lH- 1H), 4.54 - 4.58 (m, 2H), 3.74 (s, 521 pyrazol-3- NHS0 ₂ CH ₃ 2H), 3.30 - 3.32 (m, 4H), 3.13 (s, yl)methanesulfonamide 3H), 3.02 - 3.06 (m, 2H), 2.75 - 2.79 (m, 2H), 1.85 - 2.01 (m,

10H), 1.51 - 1.69 (m, 2H).

N-(l-(l-(2-methyl-3- ¾ NMR (300MHz, Chloroform- (piperidin- 1 -yl)benzy 1) - d) 5 8.04 (d, J = 3.0 Hz, 1H),

1,8- 7.01 - 7.12 (m, 2H), 6.93 - 6.95 diazaspiro [4.5 ] decane - (m, 1H), 6.33 (d, J = 2.7 Hz,

142 8-carbonyl)-lH- 1H), 4.55 - 4.60 (m, 2H), 3.59 (s, 515

NHso ₂ cH ₃

pyrazol-3- 2H), 3.14 (s, 3H), 3.03 - 3.12 (m, yl)methanesulfonamide 2H), 2.80 (br, 4H), 2.67 (br, 2H),

2.29 (s, 3H), 1.67 - 1.97 (m,

10H), 1.50 - 1.54 (m, 4H).

N-(l-(l-(2-chloro-3- ¾ NMR (300MHz, Chloroform- morpholinobenzy 1) - d) 5 8.04 (d, J = 3.0 Hz, 1H),

1,8- 7.17 - 7.22 (m, 2H), 6.94 - 6.97 diazaspiro[4.5]decane- (m, 1H), 6.32 (d, J = 2.7 Hz,

143 8-carbonyl)-lH- 1H), 4.55 - 4.60 (m, 2H), 3.87 - 537 pyrazol-3- 3.90 (m, 4H), 3.74 (s, 2H), 3.02 - yl)methanesulfonamide 3.26 (m, 9H), 2.73 - 2.78 (m,

2H), 1.82 - 1.94 (m, 6H), 1.51 - 1.55 (m, 2H).

N-(l-(l-(2-chloro-3- ¾ NMR (300MHz, Chloroform- (piperidin- 1 -yl)benzy 1) - d) 5 8.04 (d, J = 2.7 Hz, 1H),

1,8- 7.16 - 7.17 (m, 2H), 6.93 - 6.96

144 535 diazaspiro[4.5]decane- NHS0 ₂ CH ₃ (m, 1H), 6.33 (d, J = 2.7 Hz,

8-carbonyl)-lH- 1H), 4.54 - 4.59 (m, 2H), 3.74 (s, pyrazol-3- 2H), 3.02 - 3.14 (m, 5H), 2.94

yl)methanesulfonamide (s, 3H), 2.69 (br, 4H).

(trifluoromethyl)benzyl 7.57 - 7.60 (m, IH), 7.33 (s, IH), )piperazine-l- 7.19 - 7.22 (m, IH), 6.91 (br, carbonyl)- lH-pyrazol- IH), 6.31 (d, J = 3.0 Hz, IH), 3- 3.83 - 3.86 (m, 8H), 3.57 (s, 2H), yl)methanesulfonamide 3.14 (s, 3H), 2.92 - 2.95 (m, 4H),

2.54 - 2.55 (m, 4H).

l-(4-((4-(3- ¾ NMR (300MHz, Methanol-

(methy lsulfonamido) - d4) δ 8.03 (d, J = 2.7 Hz, IH), lH-pyrazole-1- 7.62 - 7.63 (m, IH), 7.54 - 7.57 carbonyl)piperazin- 1 - (m, IH), 7.42 - 7.45 (m, IH), yl)methyl)-2- 6.17 (d, J = 3.0 Hz, IH), 3.87

169 559

(trifluoromethyl)phenyl HN-S— (br, 4H), 3.57 (s, 2H), 3.02 -

O

)piperidine-4- 3.06 (m, 5H), 2.72 - 2.80 (m, carboxylic acid 2H), 2.54 - 2.57 (m, 4H), 2.18 - 2.30 (m, IH), 1.80 - 2.01 (m,

4H).

N-(l-(4-(3-chloro-4- ¾ NMR (300MHz, Chloroform- moφholinoberlzyl)pipe d) δ 8.03 (d, J = 2.7 Hz, IH),

o

razine-l-carbonyl)-lH- 7.37 (s, IH), 7.18 - 7.20 (m, 2H),

170 pyrazol-3- 6.99 - 7.08 (m, 1H), 6.31 (d, J = 483 yl)methanesulfonamide NH-S— 3.0 Hz, IH), 3.88 - 3.91 (m, 8H),

O

3.49 (br, 2H), 3.14 (s, 3H), 3.05 - 3.08 (m, 4H), 2.54 (br, 4H).

4-(2-((4-(3- ¾ NMR (300MHz, Chloroform-

O

(methy lsulfonamido) - d) δ 8.03 - 8.04 (m, IH), 7.59 - lH-pyrazole-1- 7.60 (m, IH), 7.34 - 7.37 (m, carbonyl)piperazin- 1 - IH), 7.29 (s, IH), 6.30 (d, J =

171 559 yl)methyl)-5- 3.0 Hz, IH), 4.74 (s, 2H), 3.83

N

(trifluoromethyl)phenyl (br, 4H), 3.64 (s, 2H), 3.54 -

O^NH ₂

)piperazine-l- 3.57 (m, 4H), 3.14 (s, 3H), 2.91 - carboxamide 3.01 (m, 4H), 2.58 (br, 4H).

N-(l-(4-(2-(4- ¾ NMR (300MHz, Chloroform- cyclopropylpiperazin- d) δ 8.03 (d, J = 2.7 Hz, IH), l-yl)-4- 7.56 - 7.59 (m, 1H), 7.31 - 7.33

(trifluoromethyl)benzyl (m, 2H), 7.05 (br, IH), 6.31 (d, J

172 )piperazine-l- = 3.0 Hz, IH), 3.83 (br, 4H), 556 carbonyl)- lH-pyrazol- 3.64 (s, 2H), 3.14 (s, 3H), 2.99

N

3- (br, 4H), 2.82 (br, 4H), 2.52 - yl)methanesulfonamide A 2.60 (m, 4H), 1.75 (br, IH), 0.53

(br, 4H).

yl)methanesulfonamide (m, 4H).

)piperazine-l- 4.02 -4.07 (m, 4H), 3.83 (br,

yl)methanesulfonamide (m, 4H), 2.00 - 2.15 (m, 3H),

yl)methanesulfonamide 3.10-3.15 (m, 5H), 2.84-2.91

carbonyl)- lH-pyrazol- IH), 6.92 - 6.95 (m, IH), 6.32

yl)methanesulfonamide (m, 2H), 2.50 - 2.53 (m, 4H),

2.08 (s, 3H).

N-(l-(4-(3-(8-acetyl- ¾ NMR (300MHz, Chloroform- 2,8- d) δ 8.03 (d, J = 2.7 Hz, 1H), diazaspiro [4.5 ] decan-2 - 7.22 - 7.28 (m, 1H), 6.74 - 6.83 yl)-4- o (m, 2H), 6.30 (d, J = 2.7 Hz, chlorobenzyl)piperazin 1H), 3.85 (br, 4H), 3.43 - 3.69

216 578 e-l-carbonyl)-lH- K r°— ^N ¾ o- (m, 8H), 3.20 - 3.31 (m, 2H), pyrazol-3- 3.12 (s, 3H), 2.54 (br, 4H), 2.11 yl)methanesulfonamide (s, 3H), 1.82 - 1.86 (m, 2H), 1.60

- 1.76 (m, 4H). LCMS (ESI, m/z): 578 [M+H]+.

N-(l-(4-(4-chloro-3-(5- ¾ NMR (300MHz, Chloroform-

(methylsulfonyl)hexah d) δ 8.03 (d, J = 2.7 Hz, 1H), ydropyrrolo[3,4- 7.26 - 7.29 (m, 1H), 6.88 - 6.95 c]pyrrol-2(lH)- o (m, 2H), 6.31 (d, J = 2.7 Hz, yl)benzyl)piperazine- 1 - 1H), 3.84 (br, 4H), 3.60 - 3.66

217 586 carbonyl)- lH-pyrazol- ι—Λ J ^c ' ^Λ Ό

HN-S— (m, 2H), 3.49 (s, 2H), 3.19 - 3.32

3- Λ (m, 6H), 3.06 - 3.12 (m, 5H), yl)methanesulfonamide 2.87 - 2.89 (m, 3H), 2.55 - 2.54

(m, 4H). LCMS (ESI, m/z): 586

[M+H]+.

N-(l-(4-(3-(3-oxa-8- ¾ NMR (300MHz, Chloroform- azabicyclo [3.2.1] octan- d) δ 8.04 (d, J = 2.7 Hz, 1H),

8-yl)-4- o 7.54 - 7.57 (m, 1H), 6.98 - 7.00

(trifluoromethyl)benzyl (m, 2H), 6.31 (d, J = 2.7 Hz,

218 543 )piperazine-l- 1H), 3.85 - 3.94 (m, 6H), 3.54 -

^HN - - carbonyl)- lH-pyrazol- 3.72 (m, 6H), 3.13 (s, 3H), 2.54 3- (br, 4H), 1.93 - 2.11 (m, 4H).

yl)methanesulfonamide LCMS (ESI, m/z): 543 [M+H]+.

N-(l-(4-(4-chloro-3- ¾ NMR (300MHz, Chloroform- ((tetrahydro -2H-pyran- d) 5 8.03 (d, J = 3.0 Hz, 1H),

4- 7.26 - 7.32 (m, 1H), 6.96 - 6.97 yl)oxy)benzyl)piperazi (m, 1H), 6.85 - 6.88 (m, 1H), ne-l-carbonyl)-lH- 6.30 (d, J = 3.0 Hz, 1H), 4.54 -

219 pyrazol-3- 4.60 (m, 1H), 3.98 - 4.06 (m, 498 yl)methanesulfonamide 2H), 3.83 (br, 4H), 3.58 - 3.65

(m, 2H), 3.49 (s, 2H), 3.13 (s,

3H), 2.50 - 2.53 (m, 4H), 1.97 - 2.06 (m, 2H), 1.80 - 1.90 (m,

2H).

yl)methanesulfonarnide 1.88- 1.79 (m, 7H).

l-carbonyl)-lH- 7.27 (s, IH), 7.17- 7.14 (m, pyrazol-3- 1H), 7.09 - 7.05 (m, 1H), 6.07 yl)methanesulfonamide (s, 1H), 4.50 - 4.36 (m, 1H),

3.75 - 3.58 (m, 4H), 3.29 (s,

2H), 2.95 (s, 3H), 2.40 (d, J =

5.0 Hz, 4H), 1.90 (s, 1H), 1.44 (dd, J = 6.7, 0.9 Hz, 6H).

N-(l-(l-(2-(4- ¾ NMR (300MHz, Chloroform- ethy lpiperazin- 1 -y 1) -4 - d) 5 8.01 (d, J = 2.7 Hz, 1H),

(trifluoromethyl)benzyl

)-l,8- rf 7.55 - 7.57 (m, 1H), 7.31 - 7.34

(m, 2H), 6.35 (d, J = 2.7 Hz, diazaspiro[4.5]decane- 1H), 4.56 - 4.61 (m, 2H), 3.70

238 599

8-carbonyl)-lH- (br, 2H), 3.03 - 3.08 (m, 9H), pyrazol-3- J HN-S— 2.88 - 3.00 (m, 4H), 2.69 - 2.76 yl)methanesulfonamide o (m, 4H), 1.98 - 2.05 (m, 2H),

1.78 - 1.84 (m, 4H), 1.48 - 1.52 (m, 2H), 1.17 - 1.22 (m, 3H).

N-(l-(l-(2-(4- ¾ NMR (300MHz, Chloroform- cyclopropylpiperazin- d) δ 8.04 (d, J = 2.7 Hz, 1H), l-yl)-4- 7.62 - 7.64 (m, 1H), 7.29 (br,

(trifluoromethyl)benzyl 2H), 6.33 (d, J = 2.7 Hz, 1H),

)-l,8- 4.58 - 4.63 (m, 2H), 3.72 (br,

239 611 diazaspiro[4.5]decane- ^FsC t rf J 2H), 3.05 - 3.72 (m, 5H), 2.90 -

8-carbonyl)-lH- 2.93 (m, 4H), 2.82 (br, 4H), pyrazol-3- o 2.67 - 2.69 (m, 2H), 1.82 - 1.94 yl)methanesulfonamide (m, 7H), 1.52 - 1.56 (m, 2H),

0.59 - 0.60 (m, 4H).

N-(l-(4-(2-(4-(lH- ¾ NMR (400MHz, Methanol- tetrazol-5 -y l)piperidin- d4) δ 8.04 (d, J = 2.8 Hz, 1H), l-yl)-4- 7.68 - 7.70 (m, 1H), 7.42 (s,

(trifluoromethyl)benzyl 1H),7.37 - 7.43 (m, 1H), 6.24 (d,

240 )piperazine-l- J = 2.8 Hz, 1H), 3.85 (br, 4H), 583 carbonyl)- lH-pyrazol- 3.76 (s, 2H), 3.29 - 3.31 (m, 2H), 3- 3.15 - 3.19 (m, 1H), 3.11 (s, 3H),

yl)methanesulfonamide 2.88 - 2.94 (m, 2H), 2.63 - 2.65

(m, 4H) , 2.02 - 2.18 (m, 4H).

2-(4-(2-((4-(3- ¾ NMR (400MHz, Dimethyl (methy lsulfonamido) - sulfoxide-d6) δ 8.10 (d, J = 2.7 lH-pyrazole-1- Hz, 1H), 7.66 - 7.68 (m, 1H),

241 carbonyl)piperazin- 1 - 7.41 - 7.43 (m, 1H), 7.35 (s, 1H), 574 yl)methyl)-5- 6.17(d, J = 2.7 Hz, 1H), 3.61 - (trifluoromethyl)phenyl 3.72 (m, 6H), 3.23 (s, 2H), 3.14

l-(2-((4-(3- ¾ NMR (400MHz, Chloroform-

(methy lsulfonamido) - d) δ 8.03 (d, J = 2.7 Hz, 1H), lH-pyrazole-1- 7.52 - 7.67 (m, 2H), 7.26 - 7.28 carbonyl)piperazin- 1 - (m, 1H), 6.33 (d, J = 2.7 Hz,

250 yl)methyl)-5- 1H), 5.61 (br, 2H), 3.81 (br, 4H), 580

(trifluoromethyl)phenyl 3.61 (br, 2H), 3.22 - 3.24 (m,

)piperidine-4- 2H), 3.14 (s, 3H), 2.70 - 2.80 (m,

carboxamide 2H), 2.62 ( br, 4H), 2.29 - 2.36

(m, 1H), 1.97 - 2.03 (m, 4H).

N-(l-(4-(3-(4- ¾ NMR (300MHz, Chloroform- acetylpiperazin- 1 -yl)-5 - d) δ 8.04 (d, J = 2.7 Hz, 1H),

(trifluoromethyl)benzyl CF ₃ 0 7.27 (s, 1H), 7.03 - 7.09 (m, 3H), )piperazine-l- 6.31 (d, J = 2.7 Hz, 1H), 3.78 -

251 558 carbonyl)- lH-pyrazol- n J HN-s— 3.86 (m, 6H), 3.63 - 3.66 (m,

3- 2H), 3.55 (br, 2H), 3.23 - 3.24 yl)methanesulfonamide (m, 4H), 3.14 (s, 3H), 2.54 (br,

4H), 2.16 (s, 3H).

N-(l-(4-(2-(4- ¾ NMR (400MHz, Chloroform- hydroxypiperidin-1 -yl)- d) δ 8.04 (d, J = 2.7 Hz, 1H),

4- 7.58 - 7.60 (m, 1H), 7.31 - 7.32

(trifluoromethyl)benzyl (m, 2H), 6.99 - 7.25 (m, 1H),

252 )piperazine-l- 6.63 (d, J = 2.7 Hz, 1H), 3.83 - 531 carbonyl)- lH-pyrazol- 3.67 (m, 5H), 3.62 (s, 2H), 3.14 3- - 3.16 (m, 5H), 2.76 - 2.80 (m, yl)methanesulfonamide 2H), 2.57 (br, 4H), 2.01 - 2.05

(m, 2H), 1.66 - 1.78 (m, 2H).

N-(1-(1-((1H- ¾ NMR (300MHz, DMSO-d6) benzo [d] imidazol-5 - δ 12.3 (br, 1H), 10.6 (br, 1H), yl)methyl)-l,8- 8.14 (s, 1H), 8.07 (d, J = 2.7 Hz, diazaspiro[4.5]decane- 1H), 7.47 (br, 2H), 7.13 (d, J = 8-carbonyl)-lH- 8.1 Hz, 1H), 6.72 (d, J = 2.7 Hz,

253 422 pyrazol-3 -yl)acetamide 1H), 4.41 - 4.45 (m, 2H), 3.68 (s,

2H), 3.07 (t, J = 12.3 Hz, 2H), 2.59 (t, J = 6.8 Hz, 2H), 2.04 (s, 3H), 1.67 - 1.87 (m, 6H), 1.47

(d, J = 12.3 Hz, 2H).

N-(l-(4-(3-(4- ¾ NMR (300MHz, Chloroform-

(methylsulfonyl)pipera d) δ 8.04 (d, J = 2.7 Hz, 1H),

254 zin-l-yl)-5- 7.27 (s, 1H), 7.03 - 7.09 (m, 3H), 594

(trifluoromethyl)benzyl 6.31 (d, J = 2.7 Hz, 1H), 3.78 -

)piperazine-l- 3.86 (m, 6H), 3.63 - 3.66 (m,

8-carbonyl)-lH- HN-s— (d, J = 2.7 Hz, 1H), 4.54-4.58

carbonyl)- lH-pyrazol- (br, 4H), 3.61 (s, 2H), 3.27 - 3-yl)acetamide 3.30 (m, IH), 3.05 - 3.14 (m,

3H), 2.97 (br, IH), 2.66 (br, IH), 2.54 - 2.57 (m, 4H), 2.45 (br,

IH), 2.18 - 2.39 (m, 5H), 1.67 - 1.96 (m, 4H).

N-(l-(2-((4-(3- ¾ NMR (300MHz, Chloroform- (methy lsulfonamido) - d) δ 8.02 (d, J = 2.7 Hz, IH), lH-pyrazole-1- 7.57 - 7.60 (m, IH), 7.29 - 7.33 carbonyl)piperazin- 1 - (m, 2H), 6.30 (d, J = 2.7 Hz,

269 yl)methyl)-5- IH), 5.60 - 5.62 (m, IH), 3.83 - 573 (trifluoromethyl)phenyl 3.99 (m, 5H), 3.60 (s, 2H), 3.10 )piperidin-4- - 3.17 (m, 5H), 2.78 - 2.85 (m,

yl)acetamide 2H), 2.57 (br, 4H), 1.99 - 2.10

(m, 5H) , 1.54 - 1.67 (m, 2H).

N-(l-(4-(2-(4-(2- ¾ NMR (300MHz, Chloroform- hydroxypropan-2- O d) 5 8.05 (d, J = 2.7 Hz, IH), yl)piperidin- 1 -yl)-4- 7.61 - 7.64 (m, IH), 7.28 - 7.35

(trifluoromethyl)benzyl ^F3C ? ^A O (m, 2H), 6.33 (d, J = 2.7 Hz,

270 )piperazine-l- IH), 3.85 (br, 4H), 3.64 (s, 2H), 573 carbonyl)- lH-pyrazol- 3.15 - 3.24 (m, 5H), 2.60 - 2.72

3- (m, 6H), 1.86 - 1.90 (m, 2H), yl)methanesulfonamide 1.54 - 1.62 (m, 2H), 1.43 - 1.53

(m, IH), 1.21 - 1.27 (m, 6H).

N-(l-(4-(3-(4- ¾ NMR (300MHz, Chloroform- fluoropiperidin- 1 -yl)-4- d) δ 8.04 (d, J = 2.7 Hz, IH),

(trifluoromethyl)benzyl 7.57 (d, J = 8.1 Hz, IH), 7.33 (s, )piperazine-l- IH), 7.18 (d, J = 8.1 Hz, IH),

271 carbonyl)- lH-pyrazol- 6.31 (d, J = 2.7 Hz, IH), 4.74 - 533 3- 4.92 (m, IH), 3.85 (br, 4H), 3.56

yl)methanesulfonamide (br, 2H), 3.05 - 3.14 (m, 5H),

2.80 - 2.87 (m, 2H), 2.52 - 2.55 (m, 4H), 1.95 - 2.12 (m, 4H).

N-(l-(4-(4-chloro-3- ¾ NMR (300MHz, Chloroform- cyclopentylbenzyl)pipe d) δ 8.02 (d, J = 2.7 Hz, IH), razine-l-carbonyl)-lH- 7.30 (s, 1H), 7.28 (d, J = 1.8 Hz,

O

pyrazol-3- IH), 7.05 - 7.09 (m, IH), 6.31

272 yl)methanesulfonamide (d, J = 2.7 Hz, IH), 3.83 (br, 488

4H), 3.36 - 3.45 (m, 3H), 3.13 (s,

0

3H), 2.50 - 2.54 (m, 4H), 2.04 - 2.13 (m, 2H), 1.52 - 1.84 (m,

6H). N-(l-(4-(2-(4- ¾ NMR (300MHz, Chloroform- fluoropiperidin- 1 -yl)-3 - d) 5 8.05 (d, J = 3.0 Hz, 1H),

(trifluoromethyl)benzyl 7.75 - 7.79 (m, 1H), 7.57 (d, J =

o

)piperazine-l- 7.8 Hz, 1H), 7.24 (s, 1H), 6.98 carbonyl)- lH-pyrazol- (br, 1H), 6.32 (d, J = 3.0 Hz,

273 3- A O ^A,

X ^m~ $~ 1H), 4.49 - 5.02 (m, 1H), 3.85 534 yl)methanesulfonamide φ (br, 4H), 3.57 - 3.64 (m, 2H),

3.41 - 3.49 (m, 1H), 3.09 - 3.14

F

(m, 5H), 2.79 - 2.83 (m, 1H),

2.54 - 2.59 (m, 4H), 1.89 - 2.09 (m, 4H).

l-(2-((4-(3-acetamido- ¾ NMR: (300 MHz, Methanol- lH-pyrazole-1- d) δ 8.05 (s, 1H), 7.60 - 7.65 (m, carbonyl)piperazin- 1 - 1H), 7.30 - 7.35 (m, 2H), 6.80 (s,

274 yl)methyl)-5- 1H), 3.85 (br, 4H), 3.68 (s, 2H), 544

(trifluoromethyl)phenyl 3.18 - 3.23 (m, 2H), 2.50 - 2.80

)piperidine-4- (m, 6H), 2.30 - 2.45 (m, 1H),

carboxamide 2.10 (s, 3H), 1.81 -1.92 (m, 4H).

N-(l-(2-((4-(3- ¾ NMR: (300 MHz, Methanol- o

acetamido-lH- d) δ 8.05 (s, 1H), 7.55 - 7.60 (m, pyrazole-1- 1H), 7.30 - 7.35 (m, 2H), 6.80 (s, carbonyl)piperazin- 1 - 1H), 3.85 (br, 5H), 3.68 (s, 2H),

275 536 yl)methyl)-5- 3.15 - 3.23 (m, 2H), 2.71 - 2.85

(trifluoromethyl)phenyl HN^O (m, 2H), 2.55 - 2.61 (br, 4H),

)piperidin-4- 2.10 (s, 3H), 1.90 - 2.05 (m, 5H), yl)acetamide 1.55 -1.75 (m, 2H).

N-(l-(4-(2-(4- ¾ NMR: (300 MHz, Methanol- hydroxypiperidin-1 -yl)- 0 d) δ 8.05 (s, 1H), 7.55 - 7.60 (m, 4- 1H), 7.30 - 7.35 (m, 2H), 6.80 (s,

(trifluoromethyl)benzyl 1H), 3.85 (br, 5H), 3.68 (s, 2H),

276 495 )piperazine-l- 3.10 - 3.20 (m, 2H), 2.70 - 2.85 carbonyl)- lH-pyrazol- (m, 2H), 2.55 - 2.61 (m, 4H),

3-yl)acetamide OH 2.10 (s, 3H), 1.910 - 2.05 (m,

2H), 1.63 - 1.78 (m, 2H).

2-(4-(2-((4-(3- ¾ NMR: (300 MHz, Methanol- acetamido-lH- d) δ 8.02 (s, 1H), 7.65 - 7.70 (m, pyrazole-1- 1H), 7.28 - 7.39 (m, 2H), 6.79 (s,

277 carbonyl)piperazin- 1 - 1H), 3.85 - 3.95 (m, 8H), 3.50 - 438 yl)methyl)-5- 3.60 (m, 4H), 3.30 - 3.40 (m,

(trifluoromethyl)phenyl 4H), 2.70 - 2.85 (m, 4H), 2.10 (s,

)piperazin- 1 -y l)acetic V OH 3H).

II. Biological Evaluation

[00395] Compounds are tested to assess their MAGL and other serine hydrolase activity using the following in vitro and in vivo assays. In vitro competitive activity-based protein profiling (mouse).

[00396] Proteomes (mouse brain membrane fraction or cell lysates) (50 μΐ., 1.0 mg/mL total protein concentration) were preincubated with varying concentrations of inhibitors at 37 °C. After 30 min, FP-Rh or HT-01 (Ι .Ομί, 50 μΜ in DMSO) was added and the mixture was incubated for another 30 min at 37 °C. Reactions were quenched with SDS loading buffer (15 μΐ. - 4X) and run on SDS-PAGE. Following gel imaging, serine hydrolase activity was determined by measuring fluorescent intensity of gel bands corresponding to MAGL, ABFID6, and FAAH, using ImageJ 1.43u software.

In vitro competitive activity-based protein profiling (human).

[00397] Proteomes (human prefrontal cortex or cell membrane fractions) (50 μΐ _^ , 1.0-2.0 mg/mL total protein concentration) were preincubated with varying concentrations of inhibitors at 37 °C. After 30 min, FP-Rh or JW912 (1.0 μί, 50 μΜ in DMSO) was added and the mixture was incubated for another 30 min at room temperature. Reactions were quenched with SDS loading buffer (15 μΐ. - 4X) and run on SDS-PAGE. Following gel imaging, serine hydrolase activity was determined by measuring fluorescent intensity of gel bands corresponding to MAGL using ImageJ 1.49k software. IC ₅₀ data from this assay is shown in Table 2.

Preparation of Mouse Brain Proteomes from inhibitor treated mice.

[00398] Inhibitors were administered to wild-type C57B1/6J by oral gavage in a vehicle of polyethylene glycol. Each animal was sacrificed 4 h following administration and brain proteomes were prepared and analyzed according to previously established methods {See Niphakis, M. J., et al. (2011) ACS Chem. Neurosci. and Long, J. Z., et al. Nat. Chem. Biol. 5:37-44)

[00399] Compounds demonstrated activity in the assays described herein as indicated in Table 2.

TABLE 2

* * * IC ₅₀ is less than or equal to 100 nM; * * IC ₅₀ is greater than 100 nM and less than 1 μΜ; * IC ₅₀ is greater than or equal to 1 μΜ and less or equal to 10 μΜ.

A = % inhibition is greater than or equal to 75%; B = % inhibition is greater than or equal to 50% and less than 75 %; C— % inhibition is greater than or equal to 25% and less than 50%; D = % inhibition is greater than or equal to 0% and less than 25%.