3-substituted pyrazoles and uses thereof
First Claim
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1. A method for inhibiting degeneration of a central nervous system (CNS) neuron in a patient having a neurodegenerative disease or condition;
- or for decreasing one or more symptoms of a neurodegenerative disease or condition in a patient suffering therefrom;
or for decreasing the progression of a neurodegenerative disease or condition in a patient suffering therefrom;
wherein said neurodegenerative disease or condition is selected from the group consisting of;
Alzheimer'"'"'s disease, Huntington'"'"'s disease, Parkinson'"'"'s disease, amyotrophic lateral sclerosis (ALS), and glaucoma;
comprising administering to said patient a therapeutically effective amount of a compound of Formula (I)
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Abstract
The present invention provides for compounds of Formula (I) and various embodiments thereof, and compositions comprising compounds of Formula (I) and various embodiments thereof.
In compounds of Formula I, the groups R1, R2, R3, R4, R5, R6 and R7 have the meaning as described herein. The present invention also provides for methods of using compounds of Formula I and compositions comprising compounds of Formula (I) as DLK inhibitors and for treating neurodegeneration diseases and disorders.
16 Citations
69 Claims
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1. A method for inhibiting degeneration of a central nervous system (CNS) neuron in a patient having a neurodegenerative disease or condition;
- or for decreasing one or more symptoms of a neurodegenerative disease or condition in a patient suffering therefrom;
or for decreasing the progression of a neurodegenerative disease or condition in a patient suffering therefrom;
wherein said neurodegenerative disease or condition is selected from the group consisting of;
Alzheimer'"'"'s disease, Huntington'"'"'s disease, Parkinson'"'"'s disease, amyotrophic lateral sclerosis (ALS), and glaucoma;
comprising administering to said patient a therapeutically effective amount of a compound of Formula (I) - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31)
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2. The method of claim 1, wherein R5 and R6 are each H.
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3. The method of claim 1, wherein R4 is selected from the group consisting of C1-12 alkyl, C1-12 haloalkyl, —
- F, —
Cl, —
(X4)0-1—
CN, —
(X4)0-1—
OR4A, —
(X4)0-1—
SR4A, 3 to 7 membered cycloalkyl-(X4)0-1—
, —
(X4)0-1—
S(═
O)1-2—
R4A and is further optionally substituted.
- F, —
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4. The method of claim 1, wherein R4 is selected from the group consisting of —
- F, —
Cl, C1-4 alkyl, C1-4 haloalkyl, —
(C1-4 alkylene)0-1-CN, C1-4 alkyloxy, C1-4 haloalkyloxy, C1-4 alkylthio, C1-4 haloalkylthio, 3 to 5 membered cycloalkyl-(C1-4 alkyloxy)-, 3 to 6 membered cycloalkyl, and (C1-4 alkyl)-S(O)2—
, wherein R4 is further optionally substituted.
- F, —
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5. The method of claim 1, wherein R4 is selected from the group consisting of —
- F, Cl, —
CN, methyl, monofluoromethyl, difluoromethyl, trifluoromethyl, ethyl, 2-fluoroeth-1-yl, 1-fluoroeth-1-yl, 2,2-difluoroeth-1-yl, 1,2-difluoroeth-1-yl, 1,1-difluoroeth-1-yl, 2,2,2-trifluoroeth-1-yl, 1,2,2-trifluoroeth-1-yl, 1,1,2-trifluoroeth-1-yl, methoxy, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-fluoroethan-1-oxy, 2,2-difluoroethan-1oxy, 1,2-difluoroethan-1-oxy, 1,1-difluoroethan-1-oxy, 2,2,2-trifluoroethan-1-oxy, 1,2,2-trifluoroethan-1-oxy, 1,1,2-trifluoroethan-1-oxy, isopropoxy, 1-fluoro-propan-2-oxy, 1,1-difluoro-propan-2-oxy, 1,3-difluoro-propan-2-oxy, 1,1,1-trifluoro-propan-2-oxy, 1,1,3-trifluoro-propan-2-oxy, 1,1,1,3,3,3-hexafluoro-propan-2-oxy, monofluoromethylthio, difluoromethylthio, trifluroromethylthio, cyclopropylmethoxy and cyclopropyl.
- F, Cl, —
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6. The method of claim 1, wherein R6 is H;
- and R4 and R5 are combined to form a 5 to 7 membered ring selected from the group consisting of pyrrole, imidazole, pyrazole, pyrrolidone, pyrrolidine, morpholine, piperdine and piperazine, wherein R4 and R5 combined are optionally substituted with 1 to 3 R4/5cy substituents.
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7. The method of claim 1, wherein R4/5cy is selected from the group consisting of C1-12 alkyl, C1-12 haloalkyl, —
- F, —
Cl, —
(X4/5)0-1—
CN, —
(X4/5)0-1—
OR45A, 3 to 7 membered cycloalkyl-(X4/5)0-1—
, —
(X4/5)0-1—
S(═
O)1-2—
R45A, wherein R4/5cy is optionally substituted with 1 to 3 R4/5cy-1 substituents.
- F, —
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8. The method of claim 1, wherein R4/5cy is selected from the group consisting of —
- F, —
Cl, C1-4 alkyl, C1-4 haloalkyl, —
(C1-4 alkylene)0-1-CN, C1-4 alkyloxy, C1-4 haloalkyloxy, C1-4 alkylthio, C1-4 haloalkylthio, 3-6 membered cycloalkyl-(C1-4 alkyloxy)-, 3 to 6 membered cycloalkyl, and (C1-4 alkyl)-S(O)2—
, wherein R4/5cy is optionally substituted with 1 to 5 R4/5cy-1 substituents.
- F, —
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9. The method of claim 1, wherein R4/5cy is selected from the group consisting of —
- F, Cl, —
CN, methyl, monofluoromethyl, difluoromethyl, trifluoromethyl, ethyl, 2-fluoroeth-1-yl, 1-fluoroeth-1-yl, 2,2-difluoroeth-1-yl, 1,2-difluoroeth-1-yl, 1,1-difluoroeth-1-yl, 2,2,2-trifluoroeth-1-yl, 1,2,2-trifluoroeth-1-yl, 1,1,2-trifluoroeth-1-yl, methoxy, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-fluoroethan-1-oxy, 2,2-difluoroethan-1oxy, 1,2-difluoroethan-1-oxy, 1,1-difluoroethan-1-oxy, 2,2,2-trifluoroethan-1-oxy, 1,2,2-trifluoroethan-1-oxy, 1,1,2-trifluoroethan-1-oxy, isopropoxy, 1-fluoro-propan-2-oxy, 1,1-difluoro-propan-2-oxy, 1,3-difluoro-propan-2-oxy, 1,1,1-trifluoro-propan-2-oxy, 1,1,3-trifluoro-propan-2-oxy, 1,1,1,3,3,3-hexafluoro-propan-2-oxy, monofluoromethylthio, difluoromethylthio, trifluroromethylthio, cyclopropylmethoxy and cyclopropyl.
- F, Cl, —
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10. The method of claim 1, wherein R1 is selected from the group consisting of hydrogen, C1-4 alkyl and C1-4 haloalkyl.
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11. The method of claim 1, wherein R1 is hydrogen, monofluoromethyl, difluoromethyl, trifluormethyl and methyl.
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12. The method of claim 1, wherein R1 is hydrogen.
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13. The method of claim 1, wherein R2 is a fused or bridged 3 to 12 membered cycloalkyl or a fused or bridged bicyclic or tricyclic C-linked 3 to 12 membered heterocycloalkyl ring, wherein R2 is optionally substituted with 1-5 R2-A substituents.
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14. The method of claim 1, wherein R2 is selected from the group consisting of 3-azabicyclo[3.1.0]hexane, 3-azabicyclo[3.2.1]octane, 3-azabicyclo[3.1.1]heptane, 1,1a,5,5a-tetrahydro-4a-aza-cyclopropa[a]pentalene, 1,1a,5,5a-tetrahydro-2,4a-diaza-cyclopropa[a]pentalene, 1,1a,5,5a-tetrahydro-3,4a-diaza-cyclopropa[a]pentalene, 1,1a,5,5a-tetrahydro-2,3,4a-triaza-cyclopropa[a]pentalene, 1,1a,5,5a-tetrahydro-4,4a-diaza-cyclopropa[a]pentalene, octahydro-4a-aza-cyclopropa[a]pentalene, 3-oxabicyclo[3.2.1]octane, 3-oxabicyclo[3.1.1]heptane and 3-oxabicyclo[3.1.0]hexane, and wherein R2 is optionally substituted with 1 to 5 R2-A substituents.
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15. The method of claim 1, wherein R2 is selected from the group consisting of
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16. The method of claim 1, wherein R2 is selected from the group consisting of
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17. The method of claim 1, wherein R2 is a monocyclic ring, wherein R2 is optionally substituted with 1 to 5 R2-A substituents.
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18. The method of claim 1, wherein R2 is a monocyclic ring selected from the group consisting of azetidine, pyrrolidine, pyrrolidone, piperidine, piperidone, azepane, azepanone, tetrahydrofuran, tetrahydrofuranone, tetrahydropyan, tetrahydropyanone, oxetane, oxetanone, oxepane and oxepanone, wherein R2 is optionally substituted with 1 to 5 R2-A substituents and wherein R2-A is further optionally substituted.
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19. The method of claim 1, wherein R2 is selected from the group consisting of
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20. The method of claim 1, wherein R2-A is selected from the group consisting of C1-12 alkyl, C1-12 haloalkyl, C1-12 heteroalkyl, —
- (X2)0-1—
CN, —
(X2)0-1—
OR2A, 3 to 12 membered cycloalkyl-(X2)0-1—
, 3 to 12 membered heterocycloalkyl-(X2)0-1—
, —
(X2)0-1—
S(═
O)1-2—
R2A and —
(X2)0-1—
C(═
O)R2A, wherein R2-A is optionally substituted.
- (X2)0-1—
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21. The method of claim 1, wherein R2-A is selected from the group consisting of OH, (C1-6 alkyl)-C(═
- O)—
, (C1-6 alkyl)-S(═
O)2—
, oxepane, azetidine, C1-6 alkyl, C1-6 haloalkyl, C1-6 heteroalkyl and —
(C1-6 alkyl)-CN, wherein R2-A is optionally substituted.
- O)—
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22. The method of claim 1, wherein R2-A is selected from the group consisting of CH3—
- C(═
O)—
, oxetanyl, methyl, monofluoromethyl, difluoromethyl, trifluoromethyl, ethyl, 2-fluoroeth-1-yl, 1-fluoroeth-1-yl, 1,2-difluoroeth-1-yl, 2,2-difluoroeth-1-yl, 1,1,2-trifluoroeth-1-yl 2,2,2-trifluoroeth-1-yl, 1,2,2-trifluoroeth-1-yl, cyanomethyl, cyanoethyl, methoxyethyl, hydroxy, (CH3)2(OH)CC(H)2—
, CH3OCH2C(H)(CH3)—
, CH3OC(CH3)2CH2—
, NCC(H)(CH3)CH2—
, NCC(H)(CH3)2CH2—
, CH3OC(H)(CH3)CH2—
, NCCH2C(H)(CH3)—
, NCCCH2C(CH3)2—
, CH3—
S(O)2— and
isopropyl-OC(═
O)—
.
- C(═
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23. The method of claim 1, wherein R2 is —
- C(RA2)(C1-6 alkyl)2, wherein RA2 is hydrogen, —
F, —
Cl, —
Br, —
I, —
CN, —
OH, —
NH2, —
SF5, —
OSF5, C1-4 alkylthio, C1-4 alkoxy, C1-4 alkylamino and C1-4 dialkylamino and wherein R2 is optionally substituted with 1 to 5 R2-A substituents.
- C(RA2)(C1-6 alkyl)2, wherein RA2 is hydrogen, —
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24. The method of claim 1, wherein R3 is selected from the group consisting of C1-6 alkyl, 3 to 6 membered cycloalkyl-C1-4 alkyl, 3 to 6 membered cycloalkyl, 3 to 6 membered heterocycloalkyl-C1-4 alkyl, and 3-6 membered heterocycloalkyl, wherein R3 is optionally substituted with R3A.
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25. The method of claim 1, wherein R3 is selected from the group consisting of methyl, monofluoromethyl, difluoromethyl, ethyl, 1,1,1-trifluoroeth-2-yl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclobutylmethyl, cyclopentyl, cyclopentylmethyl, cyclohexyl, cyclohexylmethyl, 1,1-difluorocyclobut-3-yl, 1,1-difluorocyclopent-3-yl, oxetan-2-yl, oxetan-2-yl-methyl, oxetan-3-yl, oxetan-3-yl-methyl, tetrahydrofuran-3-yl, tetrahydrofuran-3-yl-methyl, tetrahydropyran-3-yl, tetrahydropyran-3-yl-methyl, tetrahydropyran-4-yl, tetrahydropyran-4-yl-methyl, azetindin-3-yl, azetindin-3-yl-methyl, pyrrolidin-3-yl, pyrrolidin-3-yl-methyl, piperidin-4yl, piperidin-4-yl-methyl, piperidin-3-yl and piperidin-3-yl-methyl.
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26. The method of claim 1, wherein said compound has a formula selected from the group consisting of:
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27. The method of claim 1, wherein said compound has the formula selected from the group consisting of
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28. The method of claim 27, wherein XH1 and XH2 are independently CH or C(R4/5cy).
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29. The method of claim 1, wherein said compound of Formula (I) is selected from the group consisting of
5-(5-isopropyl-1-(1-(oxetan-3-yl)azetidin-3-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine, 2-(3-(6-amino-5-(trifluoromethyl)pyridin-3-yl)-1-isopropyl-1H-pyrazol-5-yl)propan-2-ol, 2-(3-(6-amino-5-(difluoromethoxy)pyridin-3-yl)-1-isopropyl-1H-pyrazol-5-yl)propan-2-ol, 2-(3-(6-amino-5-(trifluoromethyl)pyridin-3-yl)-1-isopropyl-1H-pyrazol-5-yl)-2-methylpropanenitrile, 2-(3-(6-amino-5-(difluoromethyl)pyridin-3-yl)-1-isopropyl-1H-pyrazol-5-yl)-2-methylpropanenitrile, 2-(3-(6-amino-5-(trifluoromethoxy)pyridin-3-yl)-1-isopropyl-1H-pyrazol-5-yl)-2-methylpropanenitrile, 5-(1-isopropyl-5-(1-methylazetidin-3-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)pyridin-2-amine, 1-(3-(1-(cyclopropylmethyl)-3-(3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazol-5-yl)azetidin-1-yl)ethanone, 1-(3-(1-(cyclopropylmethyl)-3-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazol-5-yl)azetidin-1-yl)ethanone, 1-(3-(1-isopropyl-3-(3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazol-5-yl)azetidin-1-yl)ethanone, 1-(3-(1-methyl-3-(3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazol-5-yl)azetidin-1-yl)ethanone, 1-(3-(1-isopropyl-3-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-H-pyrazol-5-yl)azetidin-1-yl)ethanone, racemic-5-(1-(cyclopropylmethyl)-5-(tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)-3-methyl-1H-pyrrolo[2,3-b]pyridine, 5-(1-(3,3-difluorocyclopentyl)-5-(tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)-3-methyl-1H-pyrrolo[2,3-b]pyridine, 5-(1,5-bis(tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine 5-(1-(3,3-difluorocyclopentyl)-5-(tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine, (R)-5-(1-(cyclopropylmethyl)-5-(tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)-3-methyl-1H-pyrrolo[2,3-b]pyridine, (S)-5-(1-(cyclopropylmethyl)-5-(tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)-3-methyl-1H-pyrrolo[2,3-b]pyridine, 5-(1-(3,3-difluorocyclobutyl)-5-(tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)-3-methyl-1H-pyrrolo[2,3-b]pyridine, 5-(1-(3,3-difluorocyclobutyl)-5-(tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)-3-ethyl-1H-pyrrolo[2,3-b]pyridine, 5-(1,5-bis(tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)-3-chloropyridin-2-amine, 5-(1,5-bis(tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)-3-fluoropyridin-2-amine, 3-chloro-5-(1-(3,3-difluorocyclopentyl)-5-(tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)pyridin-2-amine, 5-(1-(3,3-difluorocyclopentyl)-5-(tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)-3-fluoropyridin-2-amine, 3-chloro-5-(1-(3,3-difluorocyclobutyl)-5-(tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)pyridin-2-amine, 5-(1-((R)-tetrahydrofuran-3-yl)-5-((S)-tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine, 5-(1-((R)-3,3-difluorocyclopentyl)-5-((R)-tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)-3-methyl-1H-pyrrolo[2,3-b]pyridine, 5-(5-((R)-tetrahydrofuran-3-yl)-1-((S)-tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine, 5-(1,5-bis((S)-tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine, 5-(1,5-bis((R)-tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine, 5-(1-((S)-3,3-difluorocyclopentyl)-5-((S)-tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)-3-methyl-1H-pyrrolo[2,3-b]pyridine, 5-(1-((R)-3,3-difluorocyclopentyl)-5-((S)-tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)-3-methyl-1H-pyrrolo[2,3-b]pyridine, 5-(1-((S)-3,3-difluorocyclopentyl)-5-((R)-tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)-3-methyl-1H-pyrrolo[2,3-b]pyridine, 1-(3-(6-amino-5-(trifluoromethyl)pyridin-3-yl)-1-isopropyl-1H-pyrazol-5-yl)cyclopentanol, 5-(1-(3,3-difluorocyclobutyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-3-yl)-3-methyl-1H-pyrrolo[2,3-b]pyridine, 5-(1-(3,3-difluorocyclobutyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-3-yl)-3-ethyl-1H-pyrazolo[3,4-b]pyridine, 5-(1-(3,3-difluorocyclobutyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-3-yl)-3-fluoropyridin-2-amine, 5-(1-(3,3-difluorocyclobutyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine, 3-chloro-5-(1-(3,3-difluorocyclobutyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-3-yl)pyridin-2-amine, 5-(1-isopropyl-5-(1-methylpiperidin-4-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine, 5-(1-isopropyl-5-(1-methylpiperidin-4-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)pyridin-2-amine, 4-(1-(3,3-difluorocyclobutyl)-3-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazol-5-yl)-1-methylpiperidin-2-one, 4-(3-(6-amino-5-chloropyridin-3-yl)-11-(3,3-difluorocyclobutyl)-1H-pyrazol-5-yl)-1-methylpiperidin-2-one, 4-(3-(6-amino-5-fluoropyridin-3-yl)-1-(3,3-difluorocyclobutyl)-1H-pyrazol-5-yl)-1-methylpiperidin-2-one, 4-(1-(3,3-difluorocyclobutyl)-3-(3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazol-5-yl)-1-methylpiperidin-2-one, 5-(1-isopropyl-5-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)-1H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile, 1-(4-(1-methyl-3-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazol-5-yl)piperidin-1-yl)ethanone, 1-(4-(1-methyl-3-(3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazol-5-yl)piperidin-1-yl)ethanone, 1-(4-(1-isopropyl-3-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazol-5-yl)piperidin-1-yl)ethanone, 1-(4-(1-isopropyl-3-(3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazol-5-yl)piperidin-1-yl)ethanone, 2-(4-(1-isopropyl-3-(3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazol-5-yl)piperidin-1-yl)acetonitrile, 2-(4-(3-(6-amino-5-(trifluoromethyl)pyridin-3-yl)-1-isopropyl-1H-pyrazol-5-yl)piperidin-1-yl)acetonitrile, 5-(1-isopropyl-5-(1-(2-methoxyethyl)piperidin-4-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)pyridin-2-amine, 5-(1-isopropyl-5-(1-(oxetan-3-yl)azetidin-3-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine, 5-(5-(1-(oxetan-3-yl)azetidin-3-yl)-1-(tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine, 5-(1-(3,3-difluorocyclopentyl)-5-(1-(oxetan-3-yl)azetidin-3-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine, 3-chloro-5-(1-isopropyl-5-(1-(oxetan-3-yl)azetidin-3-yl)-1H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridine, 3-fluoro-5-(1-isopropyl-5-(1-(oxetan-3-yl)azetidin-3-yl)-1H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridine, 5-(1-isopropyl-5-(1-(oxetan-3-yl)azetidin-3-yl)-1H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile, 5-(1-isopropyl-5-(1-(oxetan-3-yl)azetidin-3-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)pyridin-2-amine, 5-(1-isopropyl-5-(1-(oxetan-3-yl)azetidin-3-yl)-H-pyrazol-3-yl)-3, 3-dimethyl-1H-pyrrolo[2,3-b]pyridin-2(3H)-one, 6-(1-isopropyl-5-(1-(oxetan-3-yl)azetidin-3-yl)-1H-pyrazol-3-yl)-3H-imidazo[4,5-b]pyridine, 3-methyl-5-(1-methyl-5-(1-(oxetan-3-yl)pyrrolidin-3-yl)-1H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridine, 5-(1-isopropyl-5-(1-(oxetan-3-yl)pyrrolidin-3-yl)-1H-pyrazol-3-yl)-3-methyl-1H-pyrrolo[2,3-b]pyridine, 3-chloro-5-(1-isopropyl-5-(1-(oxetan-3-yl)pyrrolidin-3-yl)-1H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridine, 3-fluoro-5-(1-isopropyl-5-(1-(oxetan-3-yl)pyrrolidin-3-yl)-1H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridine, 5-(1-isopropyl-5-(1-(oxetan-3-yl)pyrrolidin-3-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)pyridin-2-amine, 5-(1-methyl-5-(1-(oxetan-3-yl)piperidin-4-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine, 5-(1-isopropyl-5-(1-(oxetan-3-yl)piperidin-4-yl)-1H-pyrazol-3-yl)-3-methyl-1H-pyrrolo[2,3-b]pyridine, 5-(1-isopropyl-5-(1-(oxetan-3-yl)piperidin-4-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine, 3-chloro-5-(1-cyclopentyl-5-(1-(oxetan-3-yl)piperidin-4-yl)-1H-pyrazol-3-yl)pyridin-2-amine, 3-chloro-5-(1-isopropyl-5-(1-(oxetan-3-yl)piperidin-4-yl)-1H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridine, 5-(1-isopropyl-5-(1-(oxetan-3-yl)piperidin-4-yl)-1H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-2(3H)-one, 3-chloro-5-(5-(1-(oxetan-3-yl)piperidin-4-yl)-1-(tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)pyridin-2-amine, 3-fluoro-5-(1-isopropyl-5-(1-(oxetan-3-yl)piperidin-4-yl)-1H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridine, 5-(1-isopropyl-5-(1-(oxetan-3-yl)piperidin-4-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)pyridin-2-amine, 5-(1-isopropyl-5-(1-(oxetan-3-yl)piperidin-4-yl)-1H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile, 3-chloro-5-(1-isopropyl-5-(1-(oxetan-3-yl)piperidin-4-yl)-1H-pyrazol-3-yl)pyridin-2-amine, 6-(1-isopropyl-5-(1-(oxetan-3-yl)piperidin-4-yl)-1H-pyrazol-3-yl)-3H-imidazo[4,5-b]pyridine, 5-(1-isopropyl-5-(1-(oxetan-3-yl)piperidin-4-yl)-1H-pyrazol-3-yl)-3,3-dimethyl-1H-pyrrolo[2,3-b]pyridin-2(3H)-one, 5-(1-cyclopentyl-5-(1-(oxetan-3-yl)piperidin-4-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)pyridin-2-amine, 5-(1-isopropyl-5-(1-(oxetan-3-yl)piperidin-4-yl)-1H-pyrazol-3-yl)-3-methylpyridin-2-amine, 3-ethoxy-5-(1-isopropyl-5-(1-(oxetan-3-yl)piperidin-4-yl)-1H-pyrazol-3-yl)pyridin-2-amine, 3-isopropoxy-5-(1-isopropyl-5-(1-(oxetan-3-yl)piperidin-4-yl)-1H-pyrazol-3-yl)pyridin-2-amine, 5-(1-(3,3-difluorocyclopentyl)-5-(1-(oxetan-3-yl)piperidin-4-yl)-1H-pyrazol-3-yl)-3-ethoxypyridin-2-amine, 5-(1-(3,3-difluorocyclopentyl)-5-(1-(oxetan-3-yl)piperidin-4-yl)-1H-pyrazol-3-yl)-3-isopropoxypyridin-2-amine, 3-(cyclopropylmethoxy)-5-(1-(3,3-difluorocyclopentyl)-5-(1-(oxetan-3-yl)piperidin-4-yl)-1H-pyrazol-3-yl)pyridin-2-amine, 5-(1-cyclopentyl-5-(1-(oxetan-3-yl)piperidin-4-yl)-1H-pyrazol-3-yl)-3-methoxypyridin-2-amine, 5-(1-isopropyl-5-(1-(oxetan-3-yl)piperidin-4-yl)-1H-pyrazol-3-yl)-3-methoxypyridin-2-amine, 5-(1-cyclopentyl-5-(1-(oxetan-3-yl)piperidin-4-yl)-1H-pyrazol-3-yl)-3-isopropoxypyridin-2-amine, 3-chloro-5-(1-(3,3-difluorocyclopentyl)-5-(1-(oxetan-3-yl)piperidin-4-yl)-1H-pyrazol-3-yl)pyridin-2-amine, 2-amino-5-(1-isopropyl-5-(1-(oxetan-3-yl)piperidin-4-yl)-1H-pyrazol-3-yl)nicotinonitrile, 2-amino-5-(1-cyclopentyl-5-(1-(oxetan-3-yl)piperidin-4-yl)-1H-pyrazol-3-yl)nicotinonitrile, 7-(1-isopropyl-5-(1-(oxetan-3-yl)piperidin-4-yl)-1H-pyrazol-3-yl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine, 5-(1-isopropyl-5-(1-(oxetan-3-yl)piperidin-4-yl)-1H-pyrazol-3-yl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine, 6-(1-isopropyl-5-(1-(oxetan-3-yl)piperidin-4-yl)-1H-pyrazol-3-yl)-1,2,3,4-tetrahydro-1,8-naphthyridine, 5-(5-(1-(oxetan-3-yl)piperidin-4-yl)-1-(tetrahydrofuran-3-yl)-H-pyrazol-3-yl)-3-(trifluoromethyl)pyridin-2-amine, 3-cyclopropyl-5-(1-isopropyl-5-(1-(oxetan-3-yl)piperidin-4-yl)-1H-pyrazol-3-yl)pyridin-2-amine, 3-(difluoromethoxy)-5-(1-isopropyl-5-(1-(oxetan-3-yl)piperidin-4-yl)-1H-pyrazol-3-yl)pyridin-2-amine, 5-(1-(3,3-difluorocyclopentyl)-5-(1-(oxetan-3-yl)piperidin-4-yl)-1H-pyrazol-3-yl)-3-methoxypyridin-2-amine, 5-(5-(1-cyclobutylpiperidin-4-yl)-1-isopropyl-1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine, 5-(5-(1-cyclobutylpiperidin-4-yl)-1-isopropyl-1H-pyrazol-3-yl)-3-(trifluoromethyl)pyridin-2-amine, 5-(1-isopropyl-5-(4-methoxy-1-(oxetan-3-yl)piperidin-4-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)pyridin-2-amine, 5-(5-((1R,5S,6s)-3-oxabicyclo[3.1.0]hexan-6-yl)-1-isopropyl-1H-pyrazol-3-yl)-3-(trifluoromethyl)pyridin-2-amine, 5-(5-((1R,5S,6s)-3-oxabicyclo[3.1.0]hexan-6-yl)-1-cyclopentyl-1H-pyrazol-3-yl)-3-chloropyridin-2-amine, 5-(5-((1R,5S,6s)-3-oxabicyclo[3.1.0]hexan-6-yl)-1-isopropyl-1H-pyrazol-3-yl)-3-fluoro-1H-pyrrolo[2,3-b]pyridine, 5-(5-((1R,5S,6r)-3-azabicyclo[3.1.0]hexan-6-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)pyridin-2-amine, 5-(1-isopropyl-5-((1R,5S,6r)-3-(methylsulfonyl)-3-azabicyclo[3.1.0]hexan-6-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)pyridin-2-amine 5-(5-((1R,5S,6r)-3-(2,2-difluoroethyl)-3-azabicyclo[3.1.0]hexan-6-yl)-1-isopropyl-1H-pyrazol-3-yl)-3-(trifluoromethyl)pyridin-2-amine, 3-(difluoromethoxy)-5-(1-isopropyl-5-((1R,5S,6r)-3-(2,2,2-trifluoroethyl)-3-azabicyclo[3.1.0]hexan-6-yl)-1H-pyrazol-3-yl)pyridin-2-amine, 3-chloro-5-(1-(oxetan-3-yl)-5-((1R,5S,6r)-3-(2,2,2-trifluoroethyl)-3-azabicyclo[3.1.0]hexan-6-yl)-1H-pyrazol-3-yl)pyridin-2-amine, 3-chloro-5-(1-((3-methyloxetan-3-yl)methyl)-5-((1R,5S,6r)-3-(2,2,2-trifluoroethyl)-3-azabicyclo[3.1.0]hexan-6-yl)-1H-pyrazol-3-yl)pyridin-2-amine, 2-amino-5-(1-(cyclopropylmethyl)-5-((1R,5S,6r)-3-(2,2,2-trifluoroethyl)-3-azabicyclo[3.1.0]hexan-6-yl)-1H-pyrazol-3-yl)nicotinonitrile, 7-(1-isopropyl-5-((1R,5S,6r)-3-(2,2,2-trifluoroethyl)-3-azabicyclo[3.1.0]hexan-6-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[4,3-c]pyridin-4-amine, 1-((1R,5S,6r)-6-(3-(6-amino-5-(trifluoromethyl)pyridin-3-yl)-1-isopropyl-1H-pyrazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)ethanone, 3-chloro-5-(5-((1R,5S,6r)-3-(2-methoxyethyl)-3-azabicyclo[3.1.0]hexan-6-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)pyridin-2-amine, 5-(1-isopropyl-5-((1R,5S,6r)-3-(2-methoxyethyl)-3-azabicyclo[3.1.0]hexan-6-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)pyridin-2-amine, 3-chloro-5-(1-isopropyl-5-((1R,5S,6r)-3-(2-methoxyethyl)-3-azabicyclo[3.1.0]hexan-6-yl)-1H-pyrazol-3-yl)pyridin-2-amine, 3-(difluoromethoxy)-5-(1-isopropyl-5-((1R,5S,6r)-3-(2-methoxyethyl)-3-azabicyclo[3.1.0]hexan-6-yl)-1H-pyrazol-3-yl)pyridin-2-amine, 3-chloro-5-(1-isobutyl-5-((1R,5S,6r)-3-(2-methoxyethyl)-3-azabicyclo[3.1.0]hexan-6-yl)-1H-pyrazol-3-yl)pyridin-2-amine, 3-chloro-5-(1-((2,2-difluorocyclopropyl)methyl)-5-((1R,5S,6r)-3-(2-methoxyethyl)-3-azabicyclo[3.1.0]hexan-6-yl)-1H-pyrazol-3-yl)pyridin-2-amine, 5-(1-(cyclopropylmethyl)-5-((1R,5S,6r)-3-(2-methoxyethyl)-3-azabicyclo[3.1.0]hexan-6-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)pyridin-2-amine, 3-chloro-5-(1-(cyclopropylmethyl)-5-((1R,5S,6r)-3-(2-methoxyethyl)-3-azabicyclo[3.1.0]hexan-6-yl)-1H-pyrazol-3-yl)pyridin-2-amine, 5-(1-(cyclobutylmethyl)-5-((1R,5S,6r)-3-(2-methoxyethyl)-3-azabicyclo[3.1.0]hexan-6-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)pyridin-2-amine, 5-(1-isopropyl-5-((1R,5S,6r)-3-(2-methoxyethyl)-3-azabicyclo[3.1.0]hexan-6-yl)-1H-pyrazol-3-yl)-3-(trifluoromethoxy)pyridin-2-amine, 5-(5-((1R,5S,6r)-3-(2-methoxyethyl)-3-azabicyclo[3.1.0]hexan-6-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)pyridin-2-amine, 3-((1R,5S,6r)-6-(3-(6-amino-5-(trifluoromethyl)pyridin-3-yl)-1-isopropyl-1H-pyrazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)propanenitrile, 1-((1R,5S,6r)-6-(3-(6-amino-5-(trifluoromethyl)pyridin-3-yl)-1-isopropyl-1H-pyrazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-2-methylpropan-2-ol, 5-(1-isopropyl-5-((1R,5S,6r)-3-(1-methoxypropan-2-yl)-3-azabicyclo[3.1.0]hexan-6-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)pyridin-2-amine, (1R,5S,6r)-isopropyl 6-(3-(6-amino-5-(trifluoromethyl)pyridin-3-yl)-1-isopropyl-1H-pyrazol-5-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate, 3-((1R,5S,6r)-6-(3-(6-amino-5-(trifluoromethyl)pyridin-3-yl)-1-isopropyl-1H-pyrazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)butanenitrile, 5-(1-isopropyl-5-((1R,5S,6r)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl)-1H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile, 5-(1-isopropyl-5-((1R,5S,6r)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine, 5-(1-isopropyl-5-((1R,5S,6r)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)pyridin-2-amine, 5-(1-cyclopentyl-5-((1R,5S,6r)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)pyridin-2-amine, 3-chloro-5-(1-cyclopentyl-5-((1R,5S,6r)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl)-1H-pyrazol-3-yl)pyridin-2-amine, 5-(1-cyclopentyl-5-((1R,5S,6r)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl)-1H-pyrazol-3-yl)-3-(difluoromethoxy)pyridin-2-amine, 2-amino-5-(1-cyclopentyl-5-((1R,5S,6r)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl)-1H-pyrazol-3-yl)nicotinonitrile, 5-(1-cyclopentyl-5-((1R,5S,6r)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl)-1H-pyrazol-3-yl)-3-cyclopropylpyridin-2-amine, 3-chloro-5-(1-isopropyl-5-((1R,5S,6r)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl)-1H-pyrazol-3-yl)pyridin-2-amine, 3-(difluoromethoxy)-5-(1-isopropyl-5-((1R,5S,6r)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl)-1H-pyrazol-3-yl)pyridin-2-amine, 3-cyclopropyl-5-(1-isopropyl-5-((1R,5S,6r)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl)-1H-pyrazol-3-yl)pyridin-2-amine, 5-(1-isopropyl-5-((1R,5S,6r)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl)-1H-pyrazol-3-yl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine, 2-amino-5-(1-isopropyl-5-((1R,5S,6r)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl)-1H-pyrazol-3-yl)nicotinonitrile, 5-(1-isopropyl-5-((1R,5S,6r)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl)-1H-pyrazol-3-yl)-3-methoxypyridin-2-amine, 3-isopropoxy-5-(1-isopropyl-5-((1R,5S,6r)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl)-1H-pyrazol-3-yl)pyridin-2-amine, 3-chloro-5-(1-cyclobutyl-5-((1R,5S,6r)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl)-1H-pyrazol-3-yl)pyridin-2-amine, 5-(1-cyclobutyl-5-((1R,5S,6r)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)pyridin-2-amine, 5-(1-cyclobutyl-5-((1R,5S,6r)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl)-1H-pyrazol-3-yl)-3-isopropoxypyridin-2-amine, 3-chloro-5-(5-((1R,5S,6r)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)pyridin-2-amine, 5-(1-cyclobutyl-5-((1R,5S,6r)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl)-1H-pyrazol-3-yl)-3-(difluoromethoxy)pyridin-2-amine, 5-(1-(cyclopropylmethyl)-5-((1R,5S,6r)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)pyridin-2-amine, 5-(1-cyclobutyl-5-((1R,5S,6r)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl)-1H-pyrazol-3-yl)-3-cyclopropylpyridin-2-amine, 3-chloro-5-(1-(cyclopropylmethyl)-5-((1R,5S,6r)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl)-1H-pyrazol-3-yl)pyridin-2-amine, 5-(1-cyclopentyl-5-((1R,5S,6r)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl)-1H-pyrazol-3-yl)-3-(methylsulfonyl)pyridin-2-amine, 5-(1-cyclopentyl-5-((1R,5S,6r)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl)-1H-pyrazol-3-yl)-3-isopropoxypyridin-2-amine, 5-(1-cyclopentyl-5-((1R,5S,6r)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl)-1H-pyrazol-3-yl)-3-methoxypyridin-2-amine, 3-(difluoromethyl)-5-(1-isopropyl-5-((1R,5S,6r)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl)-1H-pyrazol-3-yl)pyridin-2-amine, 5-(1-cyclobutyl-5-((1R,5S,6r)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl)-1H-pyrazol-3-yl)-3-methoxypyridin-2-amine, 5-(1-(cyclobutylmethyl)-5-((1R,5S,6r)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)pyridin-2-amine, 3-cyclopropyl-5-(1-(cyclopropylmethyl)-5-((1R,5S,6r)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl)-1H-pyrazol-3-yl)pyridin-2-amine, 5-(1-(cyclobutylmethyl)-5-((1R,5S,6r)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl)-1H-pyrazol-3-yl)-3-cyclopropylpyridin-2-amine, 5-(1-cyclobutyl-5-((1R,5S,6r)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl)-1H-pyrazol-3-yl)-3-(trifluoromethoxy)pyridin-2-amine, 5-(1-(cyclobutylmethyl)-5-((1R,5S,6r)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl)-1H-pyrazol-3-yl)-3-(difluoromethoxy)pyridin-2-amine, 5-(1-isopropyl-5-((1R,5S,6r)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl)-1H-pyrazol-3-yl)-3-(trifluoromethoxy)pyridin-2-amine, 5-(1-cyclopentyl-5-((1R,5S,6r)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl)-1H-pyrazol-3-yl)-3-(trifluoromethoxy)pyridin-2-amine, 5-(1-(tert-butyl)-5-((1R,5S,6r)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)pyridin-2-amine, 5-(1-cyclopropyl-5-((1R,5S,6r)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)pyridin-2-amine, 5-(1-(cyclopropylmethyl)-5-((1R,5S,6r)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl)-1H-pyrazol-3-yl)-3-(difluoromethyl)pyridin-2-amine, 5-(1-cyclopropyl-5-((1R,5S,6r)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl)-1H-pyrazol-3-yl)-3-(difluoromethyl)pyridin-2-amine, 5-(1-cyclopentyl-5-((1R,5S,6r)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl)-1H-pyrazol-3-yl)-3-(difluoromethyl)pyridin-2-amine, 7-(1-isopropyl-5-((1R,5S,6r)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[4,3-c]pyridin-4-amine, 5-(1-(cyclopropylmethyl)-5-((1R,5S,6r)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl)-1H-pyrazol-3-yl)-3-(difluoromethoxy)pyridin-2-amine, 5-(5-((1R,5S,6r)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)pyridin-2-amine, 3-(1,1-difluoroethyl)-5-(1-isopropyl-5-((1R,5S,6r)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl)-1H-pyrazol-3-yl)pyridin-2-amine, 3-(1,1-difluoroethoxy)-5-(1-isopropyl-5-((1R,5S,6r)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl)-1H-pyrazol-3-yl)pyridin-2-amine, 5-(1-((1-methylcyclopropyl)methyl)-5-((1R,5S,6r)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)pyridin-2-amine, 5-(5-((1R,5S,6r)-3-cyclobutyl-3-azabicyclo[3.1.0]hexan-6-yl)-1-cyclopentyl-1H-pyrazol-3-yl)-3-(methylsulfonyl)pyridin-2-amine, 5-(1-isopropyl-5-(3-(oxetan-3-yl)-3-azabicyclo[3.1.1]heptan-6-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)pyridin-2-amine, 3-chloro-5-(1-isopropyl-5-(3-(oxetan-3-yl)-3-azabicyclo[3.1.1]heptan-6-yl)-1H-pyrazol-3-yl)pyridin-2-amine, 3-(difluoromethoxy)-5-(1-isopropyl-5-(3-(oxetan-3-yl)-3-azabicyclo[3.1.1]heptan-6-yl)-1H-pyrazol-3-yl)pyridin-2-amine, and 5-(1-isopropyl-5-(3-(oxetan-3-yl)-3-azabicyclo[3.1.1]heptan-6-yl)-1H-pyrazol-3-yl)-3-(trifluoromethoxy)pyridin-2-amine, and pharmaceutically acceptable salts thereof. -
30. The method of claim 1, wherein said neurodegenerative disease or condition is selected from the group consisting of:
- Alzheimer'"'"'s disease, Parkinson'"'"'s disease, and amyotrophic lateral sclerosis (ALS).
-
31. The method of claim 1, wherein the compound of Formula (I) is administered in combination with one or more additional pharmaceutical agents.
-
2. The method of claim 1, wherein R5 and R6 are each H.
- or for decreasing one or more symptoms of a neurodegenerative disease or condition in a patient suffering therefrom;
-
32. A method for inhibiting degeneration of a central nervous system (CNS) neuron or a portion thereof, the method comprising administering to the CNS neuron a compound of Formula (I)
- View Dependent Claims (33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69)
-
33. The method of claim 32, wherein R5 and R6 are each H.
-
34. The method of claim 32, wherein R4 is selected from the group consisting of C1-12 alkyl, C1-12 haloalkyl, —
- F, —
Cl, —
(X4)0-1—
CN, —
(X4)0-1—
OR4A, —
(X4)0-1—
SR4A, 3 to 7 membered cycloalkyl-(X4)0-1—
, —
(X4)0-1—
S(═
O)1-2—
R4A and is further optionally substituted.
- F, —
-
35. The method of claim 32, wherein R4 is selected from the group consisting of —
- F, —
Cl, C1-4 alkyl, C1-4 haloalkyl, —
(C1-4 alkylene)0-1-CN, C1-4 alkyloxy, C1-4 haloalkyloxy, C1-4 alkylthio, C1-4 haloalkylthio, 3 to 5 membered cycloalkyl-(C1-4 alkyloxy)-, 3 to 6 membered cycloalkyl, and (C1-4 alkyl)-S(O)2—
, wherein R4 is further optionally substituted.
- F, —
-
36. The method of claim 32, wherein R4 is selected from the group consisting of —
- F, Cl, —
CN, methyl, monofluoromethyl, difluoromethyl, trifluoromethyl, ethyl, 2-fluoroeth-1-yl, 1-fluoroeth-1-yl, 2,2-difluoroeth-1-yl, 1,2-difluoroeth-1-yl, 1,1-difluoroeth-1-yl, 2,2,2-trifluoroeth-1-yl, 1,2,2-trifluoroeth-1-yl, 1,1,2-trifluoroeth-1-yl, methoxy, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-fluoroethan-1-oxy, 2,2-difluoroethan-1oxy, 1,2-difluoroethan-1-oxy, 1,1-difluoroethan-1-oxy, 2,2,2-trifluoroethan-1-oxy, 1,2,2-trifluoroethan-1-oxy, 1,1,2-trifluoroethan-1-oxy, isopropoxy, 1-fluoro-propan-2-oxy, 1,1-difluoro-propan-2-oxy, 1,3-difluoro-propan-2-oxy, 1,1,1-trifluoro-propan-2-oxy, 1,1,3-trifluoro-propan-2-oxy, 1,1,1,3,3,3-hexafluoro-propan-2-oxy, monofluoromethylthio, difluoromethylthio, trifluroromethylthio, cyclopropylmethoxy and cyclopropyl.
- F, Cl, —
-
37. The method of claim 32, wherein R6 is H;
- and R4 and R5 are combined to form a 5 to 7 membered ring selected from the group consisting of pyrrole, imidazole, pyrazole, pyrrolidone, pyrrolidine, morpholine, piperdine and piperazine, wherein R4 and R5 combined are optionally substituted with 1 to 3 R4/5cy substituents.
-
38. The method of claim 32, wherein R4/5cy is selected from the group consisting of C1-12 alkyl, C1-12 haloalkyl, —
- F, —
Cl, —
(X4/5)0-1—
CN, —
(X4/5)0-1—
OR45A, 3 to 7 membered cycloalkyl-(X4/5)0-1—
, —
(X4/5)0-1—
S(═
O)1-2—
R45A, wherein R4/5cy is optionally substituted with 1 to 3 R4/5cy-1 substituents.
- F, —
-
39. The method of claim 32, wherein R4/5cy is selected from the group consisting of —
- F, —
Cl, C1-4 alkyl, C1-4 haloalkyl, —
(C1-4 alkylene)0-1-CN, C1-4 alkyloxy, C1-4 haloalkyloxy, C1-4 alkylthio, C1-4 haloalkylthio, 3-6 membered cycloalkyl-(C1-4 alkyloxy)-, 3 to 6 membered cycloalkyl, and (C1-4 alkyl)-S(O)2—
, wherein R4/5cy is optionally substituted with 1 to 5 R4/5cy-1 substituents.
- F, —
-
40. The method of claim 32, wherein R4/5cy is selected from the group consisting of —
- F, Cl, —
CN, methyl, monofluoromethyl, difluoromethyl, trifluoromethyl, ethyl, 2-fluoroeth-1-yl, 1-fluoroeth-1-yl, 2,2-difluoroeth-1-yl, 1,2-difluoroeth-1-yl, 1,1-difluoroeth-1-yl, 2,2,2-trifluoroeth-1-yl, 1,2,2-trifluoroeth-1-yl, 1,1,2-trifluoroeth-1-yl, methoxy, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-fluoroethan-1-oxy, 2,2-difluoroethan-1oxy, 1,2-difluoroethan-1-oxy, 1,1-difluoroethan-1-oxy, 2,2,2-trifluoroethan-1-oxy, 1,2,2-trifluoroethan-1-oxy, 1,1,2-trifluoroethan-1-oxy, isopropoxy, 1-fluoro-propan-2-oxy, 1,1-difluoro-propan-2-oxy, 1,3-difluoro-propan-2-oxy, 1,1,1-trifluoro-propan-2-oxy, 1,1,3-trifluoro-propan-2-oxy, 1,1,1,3,3,3-hexafluoro-propan-2-oxy, monofluoromethylthio, difluoromethylthio, trifluroromethylthio, cyclopropylmethoxy and cyclopropyl.
- F, Cl, —
-
41. The method of claim 32, wherein R1 is selected from the group consisting of hydrogen, C1-4 alkyl and C1-4 haloalkyl.
-
42. The method of claim 32, wherein R1 is hydrogen, monofluoromethyl, difluoromethyl, trifluormethyl and methyl.
-
43. The method of claim 32, wherein R1 is hydrogen.
-
44. The method of claim 32, wherein R2 is a fused or bridged 3 to 12 membered cycloalkyl or a fused or bridged bicyclic or tricyclic C-linked 3 to 12 membered heterocycloalkyl ring, wherein R2 is optionally substituted with 1-5 R2-A substituents.
-
45. The method of claim 32, wherein R2 is selected from the group consisting of 3-azabicyclo[3.1.0]hexane, 3-azabicyclo[3.2.1]octane, 3-azabicyclo[3.1.1]heptane, 1,1a,5,5a-tetrahydro-4a-aza-cyclopropa[a]pentalene, 1,1a,5,5a-tetrahydro-2,4a-diaza-cyclopropa[a]pentalene, 1,1a,5,5a-tetrahydro-3,4a-diaza-cyclopropa[a]pentalene, 1,1a,5,5a-tetrahydro-2,3,4a-triaza-cyclopropa[a]pentalene, 1,1a,5,5a-tetrahydro-4,4a-diaza-cyclopropa[a]pentalene, octahydro-4a-aza-cyclopropa[a]pentalene, 3-oxabicyclo[3.2.1]octane, 3-oxabicyclo[3.1.1]heptane and 3-oxabicyclo[3.1.0]hexane, and wherein R2 is optionally substituted with 1 to 5 R2-A substituents.
-
46. The method of claim 32, wherein R2 is selected from the group consisting of
-
47. The method of claim 32, wherein R2 is selected from the group consisting of
-
48. The method of claim 32, wherein R2 is a monocyclic ring, wherein R2 is optionally substituted with 1 to 5 R2-A substituents.
-
49. The method of claim 32, wherein R2 is a monocyclic ring selected from the group consisting of azetidine, pyrrolidine, pyrrolidone, piperidine, piperidone, azepane, azepanone, tetrahydrofuran, tetrahydrofuranone, tetrahydropyan, tetrahydropyanone, oxetane, oxetanone, oxepane and oxepanone, wherein R2 is optionally substituted with 1 to 5 R2-A substituents and wherein R2-A is further optionally substituted.
-
50. The method of claim 32, wherein R2 is selected from the group consisting of
-
51. The method of claim 32, wherein R2-A is selected from the group consisting of C1-12 alkyl, C1-12 haloalkyl, C1-12 heteroalkyl, —
- (X2)0-1—
CN, —
(X2)0-1—
OR2A, 3 to 12 membered cycloalkyl-(X2)0-1—
, 3 to 12 membered heterocycloalkyl-(X2)0-1—
, —
(X2)0-1—
S(═
O)1-2—
R2A and —
(X2)0-1—
C(═
O)R2A, wherein R2-A is optionally substituted.
- (X2)0-1—
-
52. The method of claim 32, wherein R2-A is selected from the group consisting of OH, (C1-6 alkyl)-C(═
- O)—
, (C1-6 alkyl)-S(═
O)2—
, oxepane, azetidine, C1-6 alkyl, C1-6 haloalkyl, C1-6 heteroalkyl and —
(C1-6 alkyl)-CN, wherein R2-A is optionally substituted.
- O)—
-
53. The method of claim 32, wherein R2-A is selected from the group consisting of CH3—
- C(═
O)—
, oxetanyl, methyl, monofluoromethyl, difluoromethyl, trifluoromethyl, ethyl, 2-fluoroeth-1-yl, 1-fluoroeth-1-yl, 1,2-difluoroeth-1-yl, 2,2-difluoroeth-1-yl, 1,1,2-trifluoroeth-1-yl 2,2,2-trifluoroeth-1-yl, 1,2,2-trifluoroeth-1-yl, cyanomethyl, cyanoethyl, methoxyethyl, hydroxy, (CH3)2(OH)CC(H)2—
, CH3OCH2C(H)(CH3)—
, CH3OC(CH3)2CH2—
, NCC(H)(CH3)CH2—
, NCC(H)(CH3)2CH2—
, CH3OC(H)(CH3)CH2—
, NCCH2C(H)(CH3)—
, NCCCH2C(CH3)2—
, CH3—
S(O)2— and
isopropyl-OC(═
O)—
.
- C(═
-
54. The method of claim 32, wherein R2 is —
- C(RA2)(C1-6 alkyl)2, wherein RA2 is hydrogen, —
F, —
Cl, —
Br, —
I, —
CN, —
OH, —
NH2, —
SF5, —
OSF5, C1-4 alkylthio, C1-4 alkoxy, C1-4 alkylamino and C1-4 dialkylamino and wherein R2 is optionally substituted with 1 to 5 R2-A substituents.
- C(RA2)(C1-6 alkyl)2, wherein RA2 is hydrogen, —
-
55. The method of claim 32, wherein R3 is selected from the group consisting of C1-6 alkyl, 3 to 6 membered cycloalkyl-C1-4 alkyl, 3 to 6 membered cycloalkyl, 3 to 6 membered heterocycloalkyl-C1-4 alkyl, and 3-6 membered heterocycloalkyl, wherein R3 is optionally substituted with R3A.
-
56. The method of claim 32, wherein R3 is selected from the group consisting of methyl, monofluoromethyl, difluoromethyl, ethyl, 1,1,1-trifluoroeth-2-yl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclobutylmethyl, cyclopentyl, cyclopentylmethyl, cyclohexyl, cyclohexylmethyl, 1,1-difluorocyclobut-3-yl, 1,1-difluorocyclopent-3-yl, oxetan-2-yl, oxetan-2-yl-methyl, oxetan-3-yl, oxetan-3-yl-methyl, tetrahydrofuran-3-yl, tetrahydrofuran-3-yl-methyl, tetrahydropyran-3-yl, tetrahydropyran-3-yl-methyl, tetrahydropyran-4-yl, tetrahydropyran-4-yl-methyl, azetindin-3-yl, azetindin-3-yl-methyl, pyrrolidin-3-yl, pyrrolidin-3-yl-methyl, piperidin-4yl, piperidin-4-yl-methyl, piperidin-3-yl and piperidin-3-yl-methyl.
-
57. The method of claim 32, wherein said compound has a formula selected from the group consisting of:
-
58. The method of claim 32, wherein said compound has the formula selected from the group consisting of
-
59. The method of claim 58, wherein XH1 and XH2 are independently CH or C(R4/5cy).
-
60. The method of claim 32, wherein said compound of Formula (I) is selected from the group consisting of
5-(5-isopropyl-1-(1-(oxetan-3-yl)azetidin-3-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine, 2-(3-(6-amino-5-(trifluoromethyl)pyridin-3-yl)-1-isopropyl-1H-pyrazol-5-yl)propan-2-ol, 2-(3-(6-amino-5-(difluoromethoxy)pyridin-3-yl)-1-isopropyl-1H-pyrazol-5-yl)propan-2-ol, 2-(3-(6-amino-5-(trifluoromethyl)pyridin-3-yl)-1-isopropyl-1H-pyrazol-5-yl)-2-methylpropanenitrile, 2-(3-(6-amino-5-(difluoromethyl)pyridin-3-yl)-1-isopropyl-1H-pyrazol-5-yl)-2-methylpropanenitrile, 2-(3-(6-amino-5-(trifluoromethoxy)pyridin-3-yl)-1-isopropyl-1H-pyrazol-5-yl)-2-methylpropanenitrile, 5-(1-isopropyl-5-(1-methylazetidin-3-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)pyridin-2-amine, 1-(3-(1-(cyclopropylmethyl)-3-(3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazol-5-yl)azetidin-1-yl)ethanone, 1-(3-(1-(cyclopropylmethyl)-3-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazol-5-yl)azetidin-1-yl)ethanone, 1-(3-(1-isopropyl-3-(3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazol-5-yl)azetidin-1-yl)ethanone, 1-(3-(1-methyl-3-(3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazol-5-yl)azetidin-1-yl)ethanone, 1-(3-(1-isopropyl-3-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-H-pyrazol-5-yl)azetidin-1-yl)ethanone, racemic-5-(1-(cyclopropylmethyl)-5-(tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)-3-methyl-1H-pyrrolo[2,3-b]pyridine, 5-(1-(3,3-difluorocyclopentyl)-5-(tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)-3-methyl-1H-pyrrolo[2,3-b]pyridine, 5-(1,5-bis(tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine 5-(1-(3,3-difluorocyclopentyl)-5-(tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine, (R)-5-(1-(cyclopropylmethyl)-5-(tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)-3-methyl-1H-pyrrolo[2,3-b]pyridine, (S)-5-(1-(cyclopropylmethyl)-5-(tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)-3-methyl-1H-pyrrolo[2,3-b]pyridine, 5-(1-(3,3-difluorocyclobutyl)-5-(tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)-3-methyl-1H-pyrrolo[2,3-b]pyridine, 5-(1-(3,3-difluorocyclobutyl)-5-(tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)-3-ethyl-1H-pyrrolo[2,3-b]pyridine, 5-(1,5-bis(tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)-3-chloropyridin-2-amine, 5-(1,5-bis(tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)-3-fluoropyridin-2-amine, 3-chloro-5-(1-(3,3-difluorocyclopentyl)-5-(tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)pyridin-2-amine, 5-(1-(3,3-difluorocyclopentyl)-5-(tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)-3-fluoropyridin-2-amine, 3-chloro-5-(1-(3,3-difluorocyclobutyl)-5-(tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)pyridin-2-amine, 5-(1-((R)-tetrahydrofuran-3-yl)-5-((S)-tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine, 5-(1-((R)-3,3-difluorocyclopentyl)-5-((R)-tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)-3-methyl-1H-pyrrolo[2,3-b]pyridine, 5-(5-((R)-tetrahydrofuran-3-yl)-1-((S)-tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine, 5-(1,5-bis((S)-tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine, 5-(1,5-bis((R)-tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine, 5-(1-((S)-3,3-difluorocyclopentyl)-5-((S)-tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)-3-methyl-1H-pyrrolo[2,3-b]pyridine, 5-(1-((R)-3,3-difluorocyclopentyl)-5-((S)-tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)-3-methyl-1H-pyrrolo[2,3-b]pyridine, 5-(1-((S)-3,3-difluorocyclopentyl)-5-((R)-tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)-3-methyl-1H-pyrrolo[2,3-b]pyridine, 1-(3-(6-amino-5-(trifluoromethyl)pyridin-3-yl)-1-isopropyl-1H-pyrazol-5-yl)cyclopentanol, 5-(1-(3,3-difluorocyclobutyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-3-yl)-3-methyl-1H-pyrrolo[2,3-b]pyridine, 5-(1-(3,3-difluorocyclobutyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-3-yl)-3-ethyl-1H-pyrazolo[3,4-b]pyridine, 5-(1-(3,3-difluorocyclobutyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-3-yl)-3-fluoropyridin-2-amine, 5-(1-(3,3-difluorocyclobutyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine, 3-chloro-5-(1-(3,3-difluorocyclobutyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-3-yl)pyridin-2-amine, 5-(1-isopropyl-5-(1-methylpiperidin-4-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine, 5-(1-isopropyl-5-(1-methylpiperidin-4-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)pyridin-2-amine, 4-(1-(3,3-difluorocyclobutyl)-3-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazol-5-yl)-1-methylpiperidin-2-one, 4-(3-(6-amino-5-chloropyridin-3-yl)-1-(3,3-difluorocyclobutyl)-1H-pyrazol-5-yl)-1-methylpiperidin-2-one, 4-(3-(6-amino-5-fluoropyridin-3-yl)-1-(3,3-difluorocyclobutyl)-1H-pyrazol-5-yl)-1-methylpiperidin-2-one, 4-(1-(3,3-difluorocyclobutyl)-3-(3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazol-5-yl)-1-methylpiperidin-2-one, 5-(1-isopropyl-5-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)-1H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile, 1-(4-(1-methyl-3-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazol-5-yl)piperidin-1-yl)ethanone, 1-(4-(1-methyl-3-(3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazol-5-yl)piperidin-1-yl)ethanone, 1-(4-(1-isopropyl-3-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazol-5-yl)piperidin-1-yl)ethanone, 1-(4-(1-isopropyl-3-(3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazol-5-yl)piperidin-1-yl)ethanone, 2-(4-(1-isopropyl-3-(3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazol-5-yl)piperidin-1-yl)acetonitrile, 2-(4-(3-(6-amino-5-(trifluoromethyl)pyridin-3-yl)-1-isopropyl-1H-pyrazol-5-yl)piperidin-1-yl)acetonitrile, 5-(1-isopropyl-5-(1-(2-methoxyethyl)piperidin-4-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)pyridin-2-amine, 5-(1-isopropyl-5-(1-(oxetan-3-yl)azetidin-3-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine, 5-(5-(1-(oxetan-3-yl)azetidin-3-yl)-1-(tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine, 5-(1-(3,3-difluorocyclopentyl)-5-(1-(oxetan-3-yl)azetidin-3-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine, 3-chloro-5-(1-isopropyl-5-(1-(oxetan-3-yl)azetidin-3-yl)-1H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridine, 3-fluoro-5-(1-isopropyl-5-(1-(oxetan-3-yl)azetidin-3-yl)-1H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridine, 5-(1-isopropyl-5-(1-(oxetan-3-yl)azetidin-3-yl)-1H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile, 5-(1-isopropyl-5-(1-(oxetan-3-yl)azetidin-3-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)pyridin-2-amine, 5-(1-isopropyl-5-(1-(oxetan-3-yl)azetidin-3-yl)-H-pyrazol-3-yl)-3, 3-dimethyl-1H-pyrrolo[2,3-b]pyridin-2(3H)-one, 6-(1-isopropyl-5-(1-(oxetan-3-yl)azetidin-3-yl)-1H-pyrazol-3-yl)-3H-imidazo[4,5-b]pyridine, 3-methyl-5-(1-methyl-5-(1-(oxetan-3-yl)pyrrolidin-3-yl)-1H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridine, 5-(1-isopropyl-5-(1-(oxetan-3-yl)pyrrolidin-3-yl)-1H-pyrazol-3-yl)-3-methyl-1H-pyrrolo[2,3-b]pyridine, 3-chloro-5-(1-isopropyl-5-(1-(oxetan-3-yl)pyrrolidin-3-yl)-1H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridine, 3-fluoro-5-(1-isopropyl-5-(1-(oxetan-3-yl)pyrrolidin-3-yl)-1H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridine, 5-(1-isopropyl-5-(1-(oxetan-3-yl)pyrrolidin-3-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)pyridin-2-amine, 5-(1-methyl-5-(1-(oxetan-3-yl)piperidin-4-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine, 5-(1-isopropyl-5-(1-(oxetan-3-yl)piperidin-4-yl)-1H-pyrazol-3-yl)-3-methyl-1H-pyrrolo[2,3-b]pyridine, 5-(1-isopropyl-5-(1-(oxetan-3-yl)piperidin-4-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine, 3-chloro-5-(1-cyclopentyl-5-(1-(oxetan-3-yl)piperidin-4-yl)-1H-pyrazol-3-yl)pyridin-2-amine, 3-chloro-5-(1-isopropyl-5-(1-(oxetan-3-yl)piperidin-4-yl)-1H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridine, 5-(1-isopropyl-5-(1-(oxetan-3-yl)piperidin-4-yl)-1H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-2(3H)-one, 3-chloro-5-(5-(1-(oxetan-3-yl)piperidin-4-yl)-1-(tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)pyridin-2-amine, 3-fluoro-5-(1-isopropyl-5-(1-(oxetan-3-yl)piperidin-4-yl)-1H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridine, 5-(1-isopropyl-5-(1-(oxetan-3-yl)piperidin-4-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)pyridin-2-amine, 5-(1-isopropyl-5-(1-(oxetan-3-yl)piperidin-4-yl)-1H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile, 3-chloro-5-(1-isopropyl-5-(1-(oxetan-3-yl)piperidin-4-yl)-1H-pyrazol-3-yl)pyridin-2-amine, 6-(1-isopropyl-5-(1-(oxetan-3-yl)piperidin-4-yl)-1H-pyrazol-3-yl)-3H-imidazo[4,5-b]pyridine, 5-(1-isopropyl-5-(1-(oxetan-3-yl)piperidin-4-yl)-1H-pyrazol-3-yl)-3,3-dimethyl-1H-pyrrolo[2,3-b]pyridin-2(3H)-one, 5-(1-cyclopentyl-5-(1-(oxetan-3-yl)piperidin-4-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)pyridin-2-amine, 5-(1-isopropyl-5-(1-(oxetan-3-yl)piperidin-4-yl)-1H-pyrazol-3-yl)-3-methylpyridin-2-amine, 3-ethoxy-5-(1-isopropyl-5-(1-(oxetan-3-yl)piperidin-4-yl)-1H-pyrazol-3-yl)pyridin-2-amine, 3-isopropoxy-5-(1-isopropyl-5-(1-(oxetan-3-yl)piperidin-4-yl)-1H-pyrazol-3-yl)pyridin-2-amine, 5-(1-(3,3-difluorocyclopentyl)-5-(1-(oxetan-3-yl)piperidin-4-yl)-1H-pyrazol-3-yl)-3-ethoxypyridin-2-amine, 5-(1-(3,3-difluorocyclopentyl)-5-(1-(oxetan-3-yl)piperidin-4-yl)-1H-pyrazol-3-yl)-3-isopropoxypyridin-2-amine, 3-(cyclopropylmethoxy)-5-(1-(3,3-difluorocyclopentyl)-5-(1-(oxetan-3-yl)piperidin-4-yl)-1H-pyrazol-3-yl)pyridin-2-amine, 5-(1-cyclopentyl-5-(1-(oxetan-3-yl)piperidin-4-yl)-1H-pyrazol-3-yl)-3-methoxypyridin-2-amine, 5-(1-isopropyl-5-(1-(oxetan-3-yl)piperidin-4-yl)-1H-pyrazol-3-yl)-3-methoxypyridin-2-amine, 5-(1-cyclopentyl-5-(1-(oxetan-3-yl)piperidin-4-yl)-1H-pyrazol-3-yl)-3-isopropoxypyridin-2-amine, 3-chloro-5-(1-(3,3-difluorocyclopentyl)-5-(1-(oxetan-3-yl)piperidin-4-yl)-1H-pyrazol-3-yl)pyridin-2-amine, 2-amino-5-(1-isopropyl-5-(1-(oxetan-3-yl)piperidin-4-yl)-1H-pyrazol-3-yl)nicotinonitrile, 2-amino-5-(1-cyclopentyl-5-(1-(oxetan-3-yl)piperidin-4-yl)-1H-pyrazol-3-yl)nicotinonitrile, 7-(1-isopropyl-5-(1-(oxetan-3-yl)piperidin-4-yl)-1H-pyrazol-3-yl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine, 5-(1-isopropyl-5-(1-(oxetan-3-yl)piperidin-4-yl)-1H-pyrazol-3-yl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine, 6-(1-isopropyl-5-(1-(oxetan-3-yl)piperidin-4-yl)-1H-pyrazol-3-yl)-1,2,3,4-tetrahydro-1,8-naphthyridine, 5-(5-(1-(oxetan-3-yl)piperidin-4-yl)-1-(tetrahydrofuran-3-yl)-H-pyrazol-3-yl)-3-(trifluoromethyl)pyridin-2-amine, 3-cyclopropyl-5-(1-isopropyl-5-(1-(oxetan-3-yl)piperidin-4-yl)-1H-pyrazol-3-yl)pyridin-2-amine, 3-(difluoromethoxy)-5-(1-isopropyl-5-(1-(oxetan-3-yl)piperidin-4-yl)-1H-pyrazol-3-yl)pyridin-2-amine, 5-(1-(3,3-difluorocyclopentyl)-5-(1-(oxetan-3-yl)piperidin-4-yl)-1H-pyrazol-3-yl)-3-methoxypyridin-2-amine, 5-(5-(1-cyclobutylpiperidin-4-yl)-1-isopropyl-1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine, 5-(5-(1-cyclobutylpiperidin-4-yl)-1-isopropyl-1H-pyrazol-3-yl)-3-(trifluoromethyl)pyridin-2-amine, 5-(1-isopropyl-5-(4-methoxy-1-(oxetan-3-yl)piperidin-4-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)pyridin-2-amine, 5-(5-((1R,5S,6s)-3-oxabicyclo[3.1.0]hexan-6-yl)-1-isopropyl-1H-pyrazol-3-yl)-3-(trifluoromethyl)pyridin-2-amine, 5-(5-((1R,5S,6s)-3-oxabicyclo[3.1.0]hexan-6-yl)-1-cyclopentyl-1H-pyrazol-3-yl)-3-chloropyridin-2-amine, 5-(5-((1R,5S,6s)-3-oxabicyclo[3.1.0]hexan-6-yl)-1-isopropyl-1H-pyrazol-3-yl)-3-fluoro-1H-pyrrolo[2,3-b]pyridine, 5-(5-((1R,5S,6r)-3-azabicyclo[3.1.0]hexan-6-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)pyridin-2-amine, 5-(1-isopropyl-5-((1R,5S,6r)-3-(methylsulfonyl)-3-azabicyclo[3.1.0]hexan-6-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)pyridin-2-amine 5-(5-((1R,5S,6r)-3-(2,2-difluoroethyl)-3-azabicyclo[3.1.0]hexan-6-yl)-1-isopropyl-1H-pyrazol-3-yl)-3-(trifluoromethyl)pyridin-2-amine, 3-(difluoromethoxy)-5-(1-isopropyl-5-((1R,5S,6r)-3-(2,2,2-trifluoroethyl)-3-azabicyclo[3.1.0]hexan-6-yl)-1H-pyrazol-3-yl)pyridin-2-amine, 3-chloro-5-(1-(oxetan-3-yl)-5-((1R,5S,6r)-3-(2,2,2-trifluoroethyl)-3-azabicyclo[3.1.0]hexan-6-yl)-1H-pyrazol-3-yl)pyridin-2-amine, 3-chloro-5-(1-((3-methyloxetan-3-yl)methyl)-5-((1R,5S,6r)-3-(2,2,2-trifluoroethyl)-3-azabicyclo[3.1.0]hexan-6-yl)-1H-pyrazol-3-yl)pyridin-2-amine, 2-amino-5-(1-(cyclopropylmethyl)-5-((1R,5S,6r)-3-(2,2,2-trifluoroethyl)-3-azabicyclo[3.1.0]hexan-6-yl)-1H-pyrazol-3-yl)nicotinonitrile, 7-(1-isopropyl-5-((1R,5S,6r)-3-(2,2,2-trifluoroethyl)-3-azabicyclo[3.1.0]hexan-6-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[4,3-c]pyridin-4-amine, 1-((1R,5S,6r)-6-(3-(6-amino-5-(trifluoromethyl)pyridin-3-yl)-1-isopropyl-1H-pyrazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)ethanone, 3-chloro-5-(5-((1R,5S,6r)-3-(2-methoxyethyl)-3-azabicyclo[3.1.0]hexan-6-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)pyridin-2-amine, 5-(1-isopropyl-5-((1R,5S,6r)-3-(2-methoxyethyl)-3-azabicyclo[3.1.0]hexan-6-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)pyridin-2-amine, 3-chloro-5-(1-isopropyl-5-((1R,5S,6r)-3-(2-methoxyethyl)-3-azabicyclo[3.1.0]hexan-6-yl)-1H-pyrazol-3-yl)pyridin-2-amine, 3-(difluoromethoxy)-5-(1-isopropyl-5-((1R,5S,6r)-3-(2-methoxyethyl)-3-azabicyclo[3.1.0]hexan-6-yl)-1H-pyrazol-3-yl)pyridin-2-amine, 3-chloro-5-(1-isobutyl-5-((1R,5S,6r)-3-(2-methoxyethyl)-3-azabicyclo[3.1.0]hexan-6-yl)-1H-pyrazol-3-yl)pyridin-2-amine, 3-chloro-5-(1-((2, 2-difluorocyclopropyl)methyl)-5-((1R,5S,6r)-3-(2-methoxyethyl)-3-azabicyclo[3.1.0]hexan-6-yl)-1H-pyrazol-3-yl)pyridin-2-amine, 5-(1-(cyclopropylmethyl)-5-((1R,5S,6r)-3-(2-methoxyethyl)-3-azabicyclo[3.1.0]hexan-6-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)pyridin-2-amine, 3-chloro-5-(1-(cyclopropylmethyl)-5-((1R,5S,6r)-3-(2-methoxyethyl)-3-azabicyclo[3.1.0]hexan-6-yl)-1H-pyrazol-3-yl)pyridin-2-amine, 5-(1-(cyclobutylmethyl)-5-((1R,5S,6r)-3-(2-methoxyethyl)-3-azabicyclo[3.1.0]hexan-6-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)pyridin-2-amine, 5-(1-isopropyl-5-((1R,5S,6r)-3-(2-methoxyethyl)-3-azabicyclo[3.1.0]hexan-6-yl)-1H-pyrazol-3-yl)-3-(trifluoromethoxy)pyridin-2-amine, 5-(5-((1R,5S,6r)-3-(2-methoxyethyl)-3-azabicyclo[3.1.0]hexan-6-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)pyridin-2-amine, 3-((1R,5S,6r)-6-(3-(6-amino-5-(trifluoromethyl)pyridin-3-yl)-1-isopropyl-1H-pyrazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)propanenitrile, 1-((1R,5S,6r)-6-(3-(6-amino-5-(trifluoromethyl)pyridin-3-yl)-1-isopropyl-1H-pyrazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-2-methylpropan-2-ol, 5-(1-isopropyl-5-((1R,5S,6r)-3-(1-methoxypropan-2-yl)-3-azabicyclo[3.1.0]hexan-6-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)pyridin-2-amine, (1R,5S,6r)-isopropyl 6-(3-(6-amino-5-(trifluoromethyl)pyridin-3-yl)-1-isopropyl-1H-pyrazol-5-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate, 3-((1R,5S,6r)-6-(3-(6-amino-5-(trifluoromethyl)pyridin-3-yl)-1-isopropyl-1H-pyrazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)butanenitrile, 5-(1-isopropyl-5-((1R,5S,6r)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl)-1H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile, 5-(1-isopropyl-5-((1R,5S,6r)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine, 5-(1-isopropyl-5-((1R,5S,6r)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)pyridin-2-amine, 5-(1-cyclopentyl-5-((1R,5S,6r)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)pyridin-2-amine, 3-chloro-5-(1-cyclopentyl-5-((1R,5S,6r)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl)-1H-pyrazol-3-yl)pyridin-2-amine, 5-(1-cyclopentyl-5-((1R,5S,6r)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl)-1H-pyrazol-3-yl)-3-(difluoromethoxy)pyridin-2-amine, 2-amino-5-(1-cyclopentyl-5-((1R,5S,6r)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl)-1H-pyrazol-3-yl)nicotinonitrile, 5-(1-cyclopentyl-5-((1R,5S,6r)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl)-1H-pyrazol-3-yl)-3-cyclopropylpyridin-2-amine, 3-chloro-5-(1-isopropyl-5-((1R,5S,6r)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl)-1H-pyrazol-3-yl)pyridin-2-amine, 3-(difluoromethoxy)-5-(1-isopropyl-5-((1R,5S,6r)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl)-1H-pyrazol-3-yl)pyridin-2-amine, 3-cyclopropyl-5-(1-isopropyl-5-((1R,5S,6r)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl)-1H-pyrazol-3-yl)pyridin-2-amine, 5-(1-isopropyl-5-((1R,5S,6r)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl)-1H-pyrazol-3-yl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine, 2-amino-5-(1-isopropyl-5-((1R,5S,6r)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl)-1H-pyrazol-3-yl)nicotinonitrile, 5-(1-isopropyl-5-((1R,5S,6r)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl)-1H-pyrazol-3-yl)-3-methoxypyridin-2-amine, 3-isopropoxy-5-(1-isopropyl-5-((1R,5S,6r)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl)-1H-pyrazol-3-yl)pyridin-2-amine, 3-chloro-5-(1-cyclobutyl-5-((1R,5S,6r)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl)-1H-pyrazol-3-yl)pyridin-2-amine, 5-(1-cyclobutyl-5-((1R,5S,6r)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)pyridin-2-amine, 5-(1-cyclobutyl-5-((1R,5S,6r)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl)-1H-pyrazol-3-yl)-3-isopropoxypyridin-2-amine, 3-chloro-5-(5-((1R,5S,6r)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)pyridin-2-amine, 5-(1-cyclobutyl-5-((1R,5S,6r)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl)-1H-pyrazol-3-yl)-3-(difluoromethoxy)pyridin-2-amine, 5-(1-(cyclopropylmethyl)-5-((1R,5S,6r)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)pyridin-2-amine, 5-(1-cyclobutyl-5-((1R,5S,6r)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl)-1H-pyrazol-3-yl)-3-cyclopropylpyridin-2-amine, 3-chloro-5-(1-(cyclopropylmethyl)-5-((1R,5S,6r)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl)-1H-pyrazol-3-yl)pyridin-2-amine, 5-(1-cyclopentyl-5-((1R,5S,6r)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl)-1H-pyrazol-3-yl)-3-(methylsulfonyl)pyridin-2-amine, 5-(1-cyclopentyl-5-((1R,5S,6r)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl)-1H-pyrazol-3-yl)-3-isopropoxypyridin-2-amine, 5-(1-cyclopentyl-5-((1R,5S,6r)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl)-1H-pyrazol-3-yl)-3-methoxypyridin-2-amine, 3-(difluoromethyl)-5-(1-isopropyl-5-((1R,5S,6r)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl)-1H-pyrazol-3-yl)pyridin-2-amine, 5-(1-cyclobutyl-5-((1R,5S,6r)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl)-1H-pyrazol-3-yl)-3-methoxypyridin-2-amine, 5-(1-(cyclobutylmethyl)-5-((1R,5S,6r)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)pyridin-2-amine, 3-cyclopropyl-5-(1-(cyclopropylmethyl)-5-((1R,5S,6r)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl)-1H-pyrazol-3-yl)pyridin-2-amine, 5-(1-(cyclobutylmethyl)-5-((1R,5S,6r)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl)-1H-pyrazol-3-yl)-3-cyclopropylpyridin-2-amine, 5-(1-cyclobutyl-5-((1R,5S,6r)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl)-1H-pyrazol-3-yl)-3-(trifluoromethoxy)pyridin-2-amine, 5-(1-(cyclobutylmethyl)-5-((1R,5S,6r)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl)-1H-pyrazol-3-yl)-3-(difluoromethoxy)pyridin-2-amine, 5-(1-isopropyl-5-((1R,5S,6r)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl)-1H-pyrazol-3-yl)-3-(trifluoromethoxy)pyridin-2-amine, 5-(1-cyclopentyl-5-((1R,5S,6r)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl)-1H-pyrazol-3-yl)-3-(trifluoromethoxy)pyridin-2-amine, 5-(1-(tert-butyl)-5-((1R,5S,6r)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)pyridin-2-amine, 5-(1-cyclopropyl-5-((1R,5S,6r)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)pyridin-2-amine, 5-(1-(cyclopropylmethyl)-5-((1R,5S,6r)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl)-1H-pyrazol-3-yl)-3-(difluoromethyl)pyridin-2-amine, 5-(1-cyclopropyl-5-((1R,5S,6r)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl)-1H-pyrazol-3-yl)-3-(difluoromethyl)pyridin-2-amine, 5-(1-cyclopentyl-5-((1R,5S,6r)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl)-1H-pyrazol-3-yl)-3-(difluoromethyl)pyridin-2-amine, 7-(1-isopropyl-5-((1R,5S,6r)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[4,3-c]pyridin-4-amine, 5-(1-(cyclopropylmethyl)-5-((1R,5S,6r)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl)-1H-pyrazol-3-yl)-3-(difluoromethoxy)pyridin-2-amine, 5-(5-((1R,5S,6r)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)pyridin-2-amine, 3-(1,1-difluoroethyl)-5-(1-isopropyl-5-((1R,5S,6r)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl)-1H-pyrazol-3-yl)pyridin-2-amine, 3-(1,1-difluoroethoxy)-5-(1-isopropyl-5-((1R,5S,6r)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl)-1H-pyrazol-3-yl)pyridin-2-amine, 5-(1-((1-methylcyclopropyl)methyl)-5-((1R,5S,6r)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)pyridin-2-amine, 5-(5-((1R,5S,6r)-3-cyclobutyl-3-azabicyclo[3.1.0]hexan-6-yl)-1-cyclopentyl-1H-pyrazol-3-yl)-3-(methylsulfonyl)pyridin-2-amine, 5-(1-isopropyl-5-(3-(oxetan-3-yl)-3-azabicyclo[3.1.1]heptan-6-yl)-1H-pyrazol-3-yl)-3-(trifluoromethyl)pyridin-2-amine, 3-chloro-5-(1-isopropyl-5-(3-(oxetan-3-yl)-3-azabicyclo[3.1.1]heptan-6-yl)-1H-pyrazol-3-yl)pyridin-2-amine, 3-(difluoromethoxy)-5-(1-isopropyl-5-(3-(oxetan-3-yl)-3-azabicyclo[3.1.1]heptan-6-yl)-1H-pyrazol-3-yl)pyridin-2-amine, and 5-(1-isopropyl-5-(3-(oxetan-3-yl)-3-azabicyclo[3.1.1]heptan-6-yl)-1H-pyrazol-3-yl)-3-(trifluoromethoxy)pyridin-2-amine, and salts thereof. -
61. The method of claim 32, wherein said administering to the CNS neuron is performed in vitro.
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62. The method of claim 61, wherein the method further comprises grafting or implanting the CNS neuron into a human patient after administration of the agent.
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63. The method of claim 32, wherein the CNS neuron is present in a human patient.
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64. The method of claim 32, wherein administering to the CNS neuron comprises administration of said compound of formula I in a pharmaceutically acceptable carrier, diluent or excipient.
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65. The method of claim 32, wherein administering to the CNS neuron is carried out by an administration route selected from the group consisting of parenteral, subcutaneous, intravenous, intraperitoneal, intracerebral, intralesional, intramuscular, intraocular, intraarterial interstitial infusion and implanted delivery device.
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66. The method of claim 32 further comprising administering one or more additional pharmaceutical agents.
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67. The method of claim 32, wherein the administering of a compound of Formula (I) results in a decrease in JNK phosphorylation, JNK activity and/or JNK expression.
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68. The method of claim 32, wherein the administering of a compound of Formula (I) results in a decrease of cJun phosphorylation, cJun activity, and/or cJun expression.
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69. The method of claim 32, wherein the administering of a compound of Formula (I) results in a decrease in p38 phosphorylation, p38 activity, and/or p38 expression.
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33. The method of claim 32, wherein R5 and R6 are each H.
Specification
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Current AssigneeGenentech, Inc. (Roche Holding AG)
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Original AssigneeGenentech, Inc. (Roche Holding AG)
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InventorsEstrada, Anthony, Liu, Wen, Patel, Snahel, Siu, Michael
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Primary Examiner(s)Carcanague, Daniel R
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Application NumberUS15/374,047Publication NumberTime in Patent Office592 DaysField of Search546112US Class CurrentCPC Class CodesA61K 31/437 the heterocyclic ring syste...A61K 31/4439 containing a five-membered ...A61K 31/4545 containing a six-membered r...A61P 19/00 Drugs for skeletal disordersA61P 21/00 Drugs for disorders of the ...A61P 21/04 for myasthenia gravisA61P 25/00 Drugs for disorders of the ...A61P 25/02 for peripheral neuropathiesA61P 25/04 Centrally acting analgesics...A61P 25/08 Antiepileptics; Anticonvuls...A61P 25/14 for treating abnormal movem...A61P 25/16 Anti-Parkinson drugsA61P 25/28 for treating neurodegenerat...A61P 27/02 Ophthalmic agentsA61P 27/06 Antiglaucoma agents or mioticsA61P 29/00 Non-central analgesic, anti...A61P 43/00 Drugs for specific purposes...A61P 9/10 for treating ischaemic or a...C07D 401/04 directly linked by a ring-m...C07D 401/14 containing three or more he...C07D 405/14 : containing three or more he...C07D 471/04 : Ortho-condensed systems