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Msg  4161 of 4337  at  9/17/2020 1:21:05 AM  by

JBWIN


Building IP: CELG/ARRY Patent Application re "4,6-SUBSTITUTED-PYRAZOLO[1,5-a]PYRAZINES AS JANUS KINASE INHIBITORS"

 
United States Patent Application20200291039
Kind CodeA1
Allen; Shelley ; et al.September 17, 2020

4,6-SUBSTITUTED-PYRAZOLO[1,5-a]PYRAZINES AS JANUS KINASE INHIBITORS

Abstract

Compounds of Formula I: ##STR00001## and stereoisomers and pharmaceutically acceptable salts and solvates thereof in which R.sup.1, R.sup.2, R.sup.3 and R.sup.4 have the meanings given in the specification, are inhibitors of one or more JAK kinases and are useful in the treatment of JAK kinase-associated diseases and disorders, such as autoimmune diseases, inflammatory diseases, rejection of transplanted organs, tissues and cells, as well as hematologic disorders and malignancies and their co-morbidities.


Inventors:Allen; Shelley; (Boulder, CO) ; Boys; Mark Laurence; (Boulder, CO) ; Chicarelli; Mark J.; (Boulder, CO) ; Fell; Jay Bradford; (Boulder, CO) ; Fischer; John P.; (Boulder, CO) ; Gaudino; John; (Boulder, CO) ; Hicken; Erik James; (Boulder, CO) ; Hinklin; Ronald Jay; (Boulder, CO) ; Kraser; Christopher F.; (Boulder, CO) ; Laird; Ellen; (Boulder, CO) ; Robinson; John E.; (Boulder, CO) ; Tang; Tony P.; (Boulder, CO) ; Burgess; Laurence E.; (Boulder, CO) ; Rieger; Robert Andrew; (Boulder, CO) ; Pheneger; Jed; (Boulder, CO) ; Satoh; Yoshitaka; (Poway, CA) ; Leftheris; Katerina; (San Diego, CA) ; Raheja; Raj K.; (Poway, CA) ; Bennett; Brydon L.; (San Diego, CA)
Applicant:
NameCityStateCountryType

Array BioPharma Inc.
Celgene Corporation

Boulder
Summit

CO
NJ

US
US
Assignee:Array BioPharma Inc.
Boulder
CO

Celgene Corporation
Summit
NJ

Family ID:1000004870056
Appl. No.:16/890663
Filed:June 2, 2020

Related U.S. Patent Documents

Application NumberFiling DatePatent Number
16212493Dec 6, 201810730880
16890663
15532937Jun 2, 201710189845
PCT/US2015/064062Dec 4, 2015
16212493
62088068Dec 5, 2014

Current U.S. Class:1/1
Current CPC Class:C07D 487/04 20130101; A61K 31/4985 20130101; A61K 31/5377 20130101; A61K 45/06 20130101
International Class:C07D 487/04 20060101 C07D487/04; A61K 31/4985 20060101 A61K031/4985; A61K 31/5377 20060101 A61K031/5377; A61K 45/06 20060101 A61K045/06

Claims



1. A method for inhibiting JAK kinase activity in a cell comprising, contacting the cell with a compound of Formula I ##STR00351## or a stereoisomer or pharmaceutically acceptable salt or solvate thereof, wherein: R.sup.1 is hydroxy(1-6C)alkyl, HOCH.sub.2(cyclopropylidine)CH.sub.2--, (1-4C alkoxy)(1-6C)hydroxyalkyl, (hydroxy)trifluoro(1-6C)alkyl, dihydroxy(2-6C)alkyl, H.sub.2N(3-6C)hydroxyalkyl, (1-3C alkyl)NH(3-6C)hydroxyalkyl, (1-3C alkyl).sub.2N(3-6C)hydroxyalkyl, H.sub.2N(1-4C alkoxy)(3-6C)alkyl, Cyc.sup.1(CH.sub.2).sub.m--, hetCyc.sup.1, hetCyc.sup.2CH.sub.2--, R.sup.aR.sup.bNC(.dbd.O)CH.sub.2--, hetCyc.sup.3a(1-3C)alkyl, hetCyc.sup.3b(2-3C)hydroxyalkyl, R.sup.cR.sup.dN(2-3C)alkyl, (1-3C alkyl).sub.2NSO.sub.2(2-3C)alkyl, hetCyc.sup.4, (1-6C)alkyl or CH.sub.3SO.sub.2(1-6C)alkyl; Cyc.sup.1 is a 4-6 membered cycloalkyl substituted with 1-2 substituents independently selected from the group consisting of HO, HOCH.sub.2--, (1-3C)alkyl, H.sub.2NHC(.dbd.O)--, (1-3C alkyl).sub.2NC(.dbd.O)--, and HOCH.sub.2CH.sub.2NHC(.dbd.O)--; m is 0 or 1; hetCyc.sup.1 is a 4-6 membered heterocyclic ring having a ring heteroatom selected from N, O and S wherein the S is optionally oxidized to SO.sub.2, wherein said heterocyclic ring is optionally substituted with a substituent selected from the group consisting of OH, (1-3C alkyl)C(.dbd.O)--, (1-3C alkyl)SO.sub.2--, (1-3C alkyl)NHC(.dbd.O)-- and NH.sub.2CH.sub.2C(.dbd.O)--; hetCyc.sup.2 is a 4-6 membered heterocyclic ring having a ring S atom, wherein the S is oxidized to SO.sub.2; R.sup.a and R.sup.b are independently H or (1-3C)alkyl, or R.sup.a and R.sup.b together with the nitrogen atom to which they are attached form a 4-6 membered ring optionally having a ring oxygen atom; hetCyc.sup.3a and hetCyc.sup.3b are independently a 4-6 membered heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O, wherein said heterocyclic ring is optionally substituted with 1-2 substituents independently selected from the group consisting of halogen, OH, (1-4C)alkoxy, HOCH.sub.2--, (1-3C alkyl)C(.dbd.O)-- and oxo; R.sup.c is H or (1-3C)alkyl; R.sup.d is (1-3C)alkyl, (1-3C alkyl)SO.sub.2--, hetCyc.sup.a, or (3-6C)cycloalkyl optionally substituted with HOCH.sub.2--; hetCyc.sup.a is a 5-6 membered azacyclic ring optionally substituted with 1-2 substituents independently selected from oxo and (1-3C)alkyl; hetCyc.sup.4 is azetidinyl substituted with ((CH.sub.3).sub.2N).sub.2P(.dbd.O)-- or Y--C(.dbd.O)--; Y is R.sup.eR.sup.fN(CH.sub.2).sub.n--, hetCyc.sup.bCH.sub.2--, Cyc.sup.2, hydroxy(1-3C)alkyl, (1-3C alkyl).sub.2NC(.dbd.O)--, (1-3C)alkylSO.sub.2- or (1-3C)alkyl; n is 0 or 1; R.sup.e and R.sup.f are independently H or (1-3C)alkyl; hetCyc.sup.b is a 4-5 membered azacyclic ring optionally substituted with OH; Cyc.sup.2 is a (3-6C)cycloalkyl optionally substituted with OH; R.sup.2 is (1-6C)alkyl, trifluoro(1-6C)alkyl, difluoro(1-6C)alkyl, fluoro(1-6C)alkyl, hydroxy(1-6C)alkyl, (1-6C)alkoxy, (3-6C)cycloalkyl (optionally substituted with one or two halogens), (3-6C)cycloalkylCH.sub.2-, HOC(.dbd.O)-- or phenyl, and R.sup.3 is (1-6C)alkyl or (3-6C)cycloalkyl, or R.sup.2 and R.sup.3 together with the carbon atom to which they are attached form a 3-7 membered cycloalkyl ring optionally substituted with one or two substituents independently selected from OH, (1-6C)alkyl and hydroxy(1-6C)alkyl, or R.sup.2 and R.sup.3 together with the carbon atom to which they are attached form a 4-membered saturated azacyclic ring substituted with SO.sub.2CF.sub.3; and R.sup.4 is hydrogen or (1-6C)alkyl.

2. The method according to claim 1, wherein R.sup.1 is hydroxy(1-6C)alkyl, HOCH.sub.2(cyclopropylidine)CH.sub.2--, (1-4C alkoxy)(1-6C)hydroxyalkyl, (hydroxy)trifluoro(1-6C)alkyl, dihydroxy(2-6C)alkyl, H.sub.2N(3-6C)hydroxyalkyl, (1-3C alkyl)NH(3-6C)hydroxyalkyl, (1-3C alkyl).sub.2N(3-6C)hydroxyalkyl, H.sub.2N(1-4C alkoxy)(3-6C)alkyl, Cyc.sup.1(CH.sub.2).sub.m--, hetCyc.sup.1, hetCyc.sup.2CH.sub.2--, R.sup.aR.sup.bNC(.dbd.O)CH.sub.2-, hetCyc.sup.3a(1-3C)alkyl, hetCyc.sup.3b(2-3C)hydroxyalkyl, R.sup.cR.sup.dN(2-3C alkyl)-, (1-3C alkyl).sub.2NSO.sub.2(2-3C alkyl)- or hetCyc.sup.4.

3. The method according to claim 1, wherein R.sup.1 is hydroxy(1-6C)alkyl, HOCH.sub.2(cyclopropylidine)CH.sub.2--, (1-4C alkoxy)(1-6C)hydroxyalkyl, (hydroxy)trifluoro(1-6C)alkyl, dihydroxy(2-6C)alkyl, H.sub.2N(3-6C)hydroxyalkyl, (1-3C alkyl)NH(3-6C)hydroxyalkyl, (1-3C alkyl).sub.2N(3-6C)hydroxyalkyl or H.sub.2N(1-4C alkoxy)(3-6C)alkyl.

4. The method according to claim 1, wherein R.sup.1 is dihydroxy(2-6C)alkyl, H.sub.2N(3-6C)hydroxyalkyl, (1-3C alkyl)NH(3-6C)hydroxyalkyl or (1-3C alkyl).sub.2N(3-6C)hydroxyalkyl.

5. The method according to claim 1, wherein R.sup.1 is dihydroxy(2-6C)alkyl.

6. The method according to claim 1, wherein R.sup.1 is H.sub.2N(3-6C)hydroxyalkyl, (1-3C alkyl)NH(3-6C)hydroxyalkyl or (1-3C alkyl).sub.2N(3-6C)hydroxyalkyl.

7. The method according to claim 1, wherein R.sup.2 is (1-6C)alkyl, trifluoro(1-6C)alkyl, difluoro(1-6C)alkyl, fluoro(1-6C)alkyl, hydroxy(1-6C)alkyl, (1-6C)alkoxy, (3-6C)cycloalkyl (optionally substituted with one or two halogens), (3-6C)cycloalkylCH.sub.2-, HOC(.dbd.O)-- or phenyl; R.sup.3 is (1-6C)alkyl or (3-6C)cycloalkyl; and R.sup.4 is hydrogen or (1-6C)alkyl.

8. The method according to claim 7, wherein: R.sup.2 is (1-6C)alkyl; R.sup.3 is (1-6C)alkyl; and R.sup.4 is hydrogen.

9. The method according to claim 1, wherein: R.sup.2 and R.sup.3 together with the carbon atom to which they are attached form a 3-7 membered cycloalkyl ring optionally substituted by one or two groups independently selected from OH, (1-6C)alkyl and hydroxy(1-6C)alkyl; and R.sup.4 is hydrogen or (1-6C)alkyl.

10. The method according to claim 1, wherein: R.sup.2 and R.sup.3 together with the carbon atom to which they are attached form a 4-membered saturated azacyclic ring substituted with SO.sub.2CF.sub.3; and R.sup.4 is hydrogen or (1-6C)alkyl.

11. The method according to claim 1, wherein the compound of Formula I or the pharmaceutically acceptable salt thereof is selected from 4-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazol- o[1,5-a]pyrazine; 4-(1-cycloheptyl-1H-pyrazol-4-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,- 5-a]pyrazine; 4-(2-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-- 1H-pyrazol-1-yl)ethyl)morpholine; 4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)-6-(1-((tetrahydro-2H-pyran-4-yl)methy- l)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine; N,N-dimethyl-2-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyra- zin-6-yl)-1H-pyrazol-1-yl)acetamide; 1-morpholino-2-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyra- zin-6-yl)-1H-pyrazol-1-yl)ethanone; 6-(1-(3-(methylsulfonyl)propyl)-1H-pyrazol-4-yl)-4-(1-(pentan-3-yl)-1H-py- razol-4-yl)pyrazolo[1,5-a]pyrazine; 5-((4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H- -pyrazol-1-yl)methyl)oxazolidin-2-one; N-methyl-N-(2-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyraz- in-6-yl)-1H-pyrazol-1-yl)ethyl)methanesulfonamide; N,N-dimethyl-2-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyra- zin-6-yl)-1H-pyrazol-1-yl)ethanamine; 4-((4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H- -pyrazol-1-yl)methyl)tetrahydro-2H-thiopyran 1,1-dioxide; N,N-dimethyl-3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyra- zin-6-yl)-1H-pyrazol-1-yl)propan-1-amine; 3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-- pyrazol-1-yl)thietane 1,1-dioxide; (R)-2-methyl-3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyra- zin-6-yl)-1H-pyrazol-1-yl)propan-1-ol; (S)-2-methyl-3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyra- zin-6-yl)-1H-pyrazol-1-yl)propan-1-ol; (3-((4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1- H-pyrazol-1-yl)methyl)oxetan-3-yl)methanol; (S)-5-((4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl- )-1H-pyrazol-1-yl)methyl)pyrrolidin-2-one; (R)-5-((4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl- )-1H-pyrazol-1-yl)methyl)pyrrolidin-2-one; 3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-- pyrazol-1-yl)propan-1-ol; 2-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-- pyrazol-1-yl)ethanol; (R)-4-(4-(4-(1-(sec-butyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1- H-pyrazol-1-yl)tetrahydro-2H-thiopyran 1,1-dioxide; 6-(1-(2-(methylsulfonyl)ethyl)-1H-pyrazol-4-yl)-4-(1-(pentan-3-yl)-1H-pyr- azol-4-yl)pyrazolo[1,5-a]pyrazine; N,N-dimethyl-2-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyra- zin-6-yl)-1H-pyrazol-1-yl)ethanesulfonamide; 4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl- )pyrazolo[1,5-a]pyrazine; 4-(1-isopropyl-1H-pyrazol-4-yl)-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyr- azolo[1,5-a]pyrazine; (R)-4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)-6-(1-(pyrrolidin-2-ylmethyl)-1H-p- yrazol-4-yl)pyrazolo[1,5-a]pyrazine; (S)-4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)-6-(1-(pyrrolidin-2-ylmethyl)-1H-p- yrazol-4-yl)pyrazolo[1,5-a]pyrazine; (R)-4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)-6-(1-(piperidin-3-yl)-1H-pyrazol-- 4-yl)pyrazolo[1,5-a]pyrazine; (S)-3-((4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl- )-1H-pyrazol-1-yl)methyl)morpholine; 1-(4-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-- 1H-pyrazol-1-yl)piperidin-1-yl)ethanone; 6-(1-(1-(methylsulfonyl)piperidin-4-yl)-1H-pyrazol-4-yl)-4-(1-(pentan-3-y- l)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine; N-methyl-4-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-- 6-yl)-1H-pyrazol-1-yl)piperidine-1-carboxamide; 2-amino-1-(4-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazi- ne-6-yl)-1H-pyrazol-1-yl)piperidin-1-yl)ethanone; 6-(1-(1-(methylsulfonyl)azetidin-3-yl)-1H-pyrazol-4-yl)-4-(1-(pentan-3-yl- )-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine; 1-(3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-- 1H-pyrazol-1-yl)azetidin-1-yl)ethanone; N-methyl-3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-- 6-yl)-1H-pyrazol-1-yl)azetidine-1-carboxamide; N,N-dimethyl-3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyra- zin-6-yl)-1H-pyrazol-1-yl)azetidine-1-carboxamide; Bis-N,N-dimethyl-P-(3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5- -a]pyrazin-6-yl)-1H-pyrazol-1-yl)azetidin-1-yl)phosphonic amide; 2-methyl-1-(3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyraz- in-6-yl)-1H-pyrazol-1-yl)azetidin-1-yl)propan-1-one; cyclopropyl(3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyraz- in-6-yl)-1H-pyrazol-1-yl)azetidin-1-yl)methanone; 2-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)-1H-pyrazo- l-1-yl)butanoic acid; 2-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol- -1-yl)butan-1-ol; 2-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol- -1-yl)propan-1-ol; 3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol- -1-yl)pentan-1-ol; 4-(1-(3-ethyl-1-((trifluoromethyl)sulfonyl)azetidin-3-yl)-1H-pyrazol-4-yl- )-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine; 6-(1-methyl-1H-pyrazol-4-yl)-4-(1-(1-methylcyclopentyl)-1H-pyrazol-4-yl)p- yrazolo[1,5-a]pyrazine; 6-(1-methyl-1H-pyrazol-4-yl)-4-(1-(3-methylpentan-3-yl)-1H-pyrazol-4-yl)p- yrazolo[1,5-a]pyrazine; (2-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazo- l-1-yl)cyclopentyl)methanol; 6-(1-methyl-1H-pyrazol-4-yl)-4-(1-(2-methylcycloheptyl)-1H-pyrazol-4-yl)p- yrazolo[1,5-a]pyrazine; 2-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol- -1-yl)cyclopentanol; (R)-3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)- -1H-pyrazol-1-yl)propane-1,2-diol; (S)-3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)- -1H-pyrazol-1-yl)propane-1,2-diol; (S)-3-methyl-1-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyra- zin-6-yl)-1H-pyrazol-1-yl)butane-2,3-diol; (R)-3-methyl-1-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyra- zin-6-yl)-1H-pyrazol-1-yl)butane-2,3-diol; 3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-- pyrazol-1-yl)propane-1,2-diol; (2R,3R)-1-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6- -yl)-1H-pyrazol-1-yl)butane-2,3-diol; 2-methyl-3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-- 6-yl)-1H-pyrazol-1-yl)propane-1,2-diol; 2-((4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H- -pyrazol-1-yl)methyl)propane-1,3-diol; (S)-4-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)- -1H-pyrazol-1-yl)butane-1,2-diol; 4-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-- pyrazol-1-yl)butane-1,3-diol; (R)-4-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)- -1H-pyrazol-1-yl)butane-1,2-diol; (2S,3 S)-1-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-- 1H-pyrazol-1-yl)butane-2,3-diol; (2R)-3-(4-(4-(1-(1-phenylpropyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6- -yl)-1H-pyrazol-1-yl)propane-1,2-diol; (2R)-3-(4-(4-(1-(sec-butyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-- 1H-pyrazol-1-yl)propane-1,2-diol; (R)-3-(4-(4-(1-((S)-sec-butyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-y- l)-1H-pyrazol-1-yl)propane-1,2-diol; (R)-3-(4-(4-(1-((R)-sec-butyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-y- l)-1H-pyrazol-1-yl)propane-1,2-diol; (S)-3-(4-(4-(1-((S)-sec-butyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-y- l)-1H-pyrazol-1-yl)propane-1,2-diol; (S)-3-(4-(4-(1-((R)-sec-butyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-y- l)-1H-pyrazol-1-yl)propane-1,2-diol; (R)-3-(4-(4-(1-((S)-pentan-2-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6- -yl)-1H-pyrazol-1-yl)propane-1,2-diol; (R)-3-(4-(4-(1-((R)-pentan-2-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6- -yl)-1H-pyrazol-1-yl)propane-1,2-diol; (S)-3-(4-(4-(1-((R)-pentan-2-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6- -yl)-1H-pyrazol-1-yl)propane-1,2-diol; (R)-3-(4-(4-(1-((S)-4-methylpentan-2-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]p- yrazin-6-yl)-1H-pyrazol-1-yl)propane-1,2-diol; (S)-3-(4-(4-(1-((S)-4-methylpentan-2-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]p- yrazin-6-yl)-1H-pyrazol-1-yl)propane-1,2-diol; (R)-3-(4-(4-(1-((R)-4-methylpentan-2-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]p- yrazin-6-yl)-1H-pyrazol-1-yl)propane-1,2-diol; (S)-3-(4-(4-(1-((R)-4-methylpentan-2-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]p- yrazin-6-yl)-1H-pyrazol-1-yl)propane-1,2-diol; (2R)-3-(4-(4-(1-(1-(3,3-difluorocyclobutyl)propyl)-1H-pyrazol-4-yl)pyrazo- lo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propane-1,2-diol; (R)-3-(4-(4-(1-((S)-3-methylbutan-2-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]py- razin-6-yl)-1H-pyrazol-1-yl)propane-1,2-diol; 2-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-- pyrazol-1-yl)propane-1,3-diol; (S)-2-(4-(4-(1-(pentan-2-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)- -1H-pyrazol-1-yl)propane-1,3-diol; (R)-2-(4-(4-(1-(pentan-2-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)- -1H-pyrazol-1-yl)propane-1,3-diol; (S)-2-(4-(4-(1-(sec-butyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1- H-pyrazol-1-yl)propane-1,3-diol; (R)-2-(4-(4-(1-(sec-butyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1- H-pyrazol-1-yl)propane-1,3-diol; (S)-3-(4-(4-(1-((S)-pentan-2-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6- -yl)-1H-pyrazol-1-yl)propane-1,2-diol; (S)-2-(4-(4-(1-(4-methylpentan-2-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyraz- in-6-yl)-1H-pyrazol-1-yl)propane-1,3-diol; (R)-2-(4-(4-(1-(4-methylpentan-2-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyraz- in-6-yl)-1H-pyrazol-1-yl)propane-1,3-diol; (2S,3 S)-3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-- 1H-pyrazol-1-yl)butane-1,2-diol; (2S,3R)-3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6- -yl)-1H-pyrazol-1-yl)butane-1,2-diol; (2R,3 S)-3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-- 1H-pyrazol-1-yl)butane-1,2-diol; (2R,3R)-3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6- -yl)-1H-pyrazol-1-yl)butane-1,2-diol; (R)-3-(4-(4-(1-((1R,2S)-2-methylcyclopentyl)-1H-pyrazol-4-yl)pyrazolo[1,5- -a]pyrazin-6-yl)-1H-pyrazol-1-yl)propane-1,2-diol; (R)-3-(4-(4-(1-((1 S,2R)-2-methylcyclopentyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1- H-pyrazol-1-yl)propane-1,2-diol; (R)-3-(4-(4-(1-((S)-2,2-dimethylcyclopentyl)-1H-pyrazol-4-yl)pyrazolo[1,5- -a]pyrazin-6-yl)-1H-pyrazol-1-yl)propane-1,2-diol; (R)-3-(4-(4-(1-((R)-2,2-dimethylcyclopentyl)-1H-pyrazol-4-yl)pyrazolo[1,5- -a]pyrazin-6-yl)-1H-pyrazol-1-yl)propane-1,2-diol; N-isopropyl-2-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyraz- in-6-yl)-1H-pyrazol-1-yl)acetamide; 1-amino-3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6- -yl)-1H-pyrazol-1-yl)propan-2-ol; (R)-1-(dimethylamino)-3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1- ,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propan-2-ol; (R)-1-(methylamino)-3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5- -a]pyrazin-6-yl)-1H-pyrazol-1-yl)propan-2-ol; (S)-1-(dimethylamino)-3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1- ,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propan-2-ol; (S)-1-(methylamino)-3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5- -a]pyrazin-6-yl)-1H-pyrazol-1-yl)propan-2-ol; (R)-1-(3-methoxyazetidin-1-yl)-3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)p- yrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propan-2-ol; (S)-1-(3-methoxyazetidin-1-yl)-3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)p- yrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propan-2-ol; (R)-1-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)- -1H-pyrazol-1-yl)-3-(pyrrolidin-1-yl)propan-2-ol; (S)-1-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)- -1H-pyrazol-1-yl)-3-(pyrrolidin-1-yl)propan-2-ol; (R)-1-methoxy-3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyr- azin-6-yl)-1H-pyrazol-1-yl)propan-2-ol; (S)-1-methoxy-3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyr- azin-6-yl)-1H-pyrazol-1-yl)propan-2-ol; (R)-1-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)- -1H-pyrazol-1-yl)propan-2-ol; (S)-1-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)- -1H-pyrazol-1-yl)propan-2-ol; 4,4,4-trifluoro-1-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]p- yrazin-6-yl)-1H-pyrazol-1-yl)butan-2-ol; 3,3-dimethyl-1-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyra- zin-6-yl)-1H-pyrazol-1-yl)butan-2-ol; 3-methyl-1-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-- 6-yl)-1H-pyrazol-1-yl)butan-2-ol; (S)-1-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)- -1H-pyrazol-1-yl)butan-2-ol; (R)-1-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)- -1H-pyrazol-1-yl)butan-2-ol; 4-((4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H- -pyrazol-1-yl)methyl)tetrahydro-2H-pyran-4-ol; 2-methyl-1-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-- 6-yl)-1H-pyrazol-1-yl)propan-2-ol; trans-4-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-y- l)-1H-pyrazol-1-yl)cyclohexanol; cis-3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)- -1H-pyrazol-1-yl)cyclobutanol; (1s,3s)-3-((4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-- 6-yl)-1H-pyrazol-1-yl)methyl)cyclobutanol; cis-4-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)- -1H-pyrazol-1-yl)cyclohexanol; ((1s,3s)-3-((4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin- -6-yl)-1H-pyrazol-1-yl)methyl)cyclobutyl)methanol; ((1r,3r)-3-((4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin- -6-yl)-1H-pyrazol-1-yl)methyl)cyclobutyl)methanol; 2-methyl-2-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-- 6-yl)-1H-pyrazol-1-yl)propan-1-ol; (S)-2-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)- -1H-pyrazol-1-yl)propan-1-ol; (S)-2-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)- -1H-pyrazol-1-yl)propan-1-ol; (S)-2-((4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl- )-1H-pyrazol-1-yl)methyl)morpholine; (R)-2-((4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl-

)-1H-pyrazol-1-yl)methyl)morpholine; (S)-2-(dimethylamino)-3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1- ,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propan-1-ol; (R)-2-amino-3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyraz- in-6-yl)-1H-pyrazol-1-yl)propan-1-ol; (R)-2-(dimethylamino)-3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1- ,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propan-1-ol; (1R,2S,4s)-4-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazi- n-6-yl)-1H-pyrazol-1-yl)cyclopentane-1,2-diol; (1R,2S,4r)-4-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazi- n-6-yl)-1H-pyrazol-1-yl)cyclopentane-1,2-diol; N-(2-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-- 1H-pyrazol-1-yl)ethyl)cyclopropanamine; 4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)-6-(1-(2-(pyrrolidin-1-yl)ethyl)-1H-py- razol-4-yl)pyrazolo[1,5-a]pyrazine; (R)-6-(1-(2-(3-methoxypyrrolidin-1-yl)ethyl)-1H-pyrazol-4-yl)-4-(1-(penta- n-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine; (S)-6-(1-(2-(3-methoxypyrrolidin-1-yl)ethyl)-1H-pyrazol-4-yl)-4-(1-(penta- n-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine; 6-(1-(2-(3-fluoroazetidin-1-yl)ethyl)-1H-pyrazol-4-yl)-4-(1-(pentan-3-yl)- -1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine; 1-(2-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-- 1H-pyrazol-1-yl)ethyl)piperidin-4-ol; (R)-1-(2-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-- yl)-1H-pyrazol-1-yl)ethyl)pyrrolidin-3-ol; (S)-1-(2-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-- yl)-1H-pyrazol-1-yl)ethyl)pyrrolidin-3-ol; (S)-1-methyl-3-((2-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]- pyrazin-6-yl)-1H-pyrazol-1-yl)ethyl)amino)pyrrolidin-2-one; (R)-1-methyl-3-((2-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]- pyrazin-6-yl)-1H-pyrazol-1-yl)ethyl)amino)pyrrolidin-2-one; 4-(2-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-- 1H-pyrazol-1-yl)ethyl)piperazin-2-one; (3-((2-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl- )-1H-pyrazol-1-yl)ethyl)amino)cyclobutyl)methanol; (1-(2-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)- -1H-pyrazol-1-yl)ethyl)piperidin-4-yl)methanol; 1-(2-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-- 1H-pyrazol-1-yl)ethyl)piperazin-2-one; (R)-2-methoxy-3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyr- azin-6-yl)-1H-pyrazol-1-yl)propan-1-amine; (S)-2-methoxy-3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyr- azin-6-yl)-1H-pyrazol-1-yl)propan-1-amine; 2-(4-(4-(1-((1R,2R)-2-methylcyclohexyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]py- razin-6-yl)-1H-pyrazol-1-yl)propane-1,3-diol; (R)-3-(4-(4-(1-((1R,2R)-2-methylcyclohexyl)-1H-pyrazol-4-yl)pyrazolo[1,5-- a]pyrazin-6-yl)-1H-pyrazol-1-yl)propane-1,2-diol; (S)-3-(4-(4-(1-((1R,2R)-2-methylcyclohexyl)-1H-pyrazol-4-yl)pyrazolo[1,5-- a]pyrazin-6-yl)-1H-pyrazol-1-yl)propane-1,2-diol; (1R,2R)-2-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6- -yl)-1H-pyrazol-1-yl)cyclopentanol; (1 S,2S)-2-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-y- l)-1H-pyrazol-1-yl)cyclopentanol; (2S,3 S)-3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-- 1H-pyrazol-1-yl)butan-2-ol; (2R,3R)-3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6- -yl)-1H-pyrazol-1-yl)butan-2-ol; (2R,3 S)-3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-- 1H-pyrazol-1-yl)butan-2-ol; (2S,3R)-3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6- -yl)-1H-pyrazol-1-yl)butan-2-ol; (3 S,4R)-4-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-y- l)-1H-pyrazol-1-yl)tetrahydrofuran-3-ol; (3R,4S)-4-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6- -yl)-1H-pyrazol-1-yl)tetrahydrofuran-3-ol; trans-3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-y- l)-1H-pyrazol-1-yl)cyclobutanol; (1s,3s)-1-methyl-3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]- pyrazin-6-yl)-1H-pyrazol-1-yl)cyclobutanol; (1s,3s)-1-(hydroxymethyl)-3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazo- lo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)cyclobutanol; (1 r,3r)-1-(hydroxymethyl)-3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo- [1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)cyclobutanol; (trans-3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-- yl)-1H-pyrazol-1-yl)cyclobutyl)methanol; (cis-3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl- )-1H-pyrazol-1-yl)cyclobutyl)methanol; (1r,3r)-3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6- -yl)-1H-pyrazol-1-yl)cyclobutanecarboxamide; (1s,3s)-3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6- -yl)-1H-pyrazol-1-yl)cyclobutanecarboxamide; (1r,3r)-N,N-dimethyl-3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,- 5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)cyclobutanecarboxamide; (1s,3s)-N,N-dimethyl-3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,- 5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)cyclobutanecarboxamide; (1r,3r)-N-(2-hydroxyethyl)-3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyraz- olo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)cyclobutanecarboxamide; (1s,3s)-N-(2-hydroxyethyl)-3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyraz- olo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)cyclobutanecarboxamide; (S)-2-hydroxy-1-(3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]- pyrazin-6-yl)-1H-pyrazol-1-yl)azetidin-1-yl)propan-1-one; 2-hydroxy-1-(3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyra- zin-6-yl)-1H-pyrazol-1-yl)azetidin-1-yl)ethanone; (R)-2-hydroxy-1-(3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]- pyrazin-6-yl)-1H-pyrazol-1-yl)azetidin-1-yl)propan-1-one; 2-hydroxy-2-methyl-1-(3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1- ,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)azetidin-1-yl)propan-1-one; (1-hydroxycyclopropyl)(3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[- 1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)azetidin-1-yl)methanone; (cis-3-hydroxycyclobutyl)(3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazo- lo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)azetidin-1-yl)methanone; (trans-3-hydroxycyclobutyl)(3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyra- zolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)azetidin-1-yl)methanone; 2-(3-hydroxyazetidin-1-yl)-1-(3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)py- razolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)azetidin-1-yl)ethanone; 1-(3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-- 1H-pyrazol-1-yl)azetidin-1-yl)-2-(pyrrolidin-1-yl)ethanone; N,N-dimethyl-2-oxo-2-(3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1- ,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)azetidin-1-yl)acetamide; (S)-3-amino-2-methyl-4-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,- 5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)butan-2-ol; 4-((4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H- -pyrazol-1-yl)methyl)piperidin-4-ol; 1-(4-hydroxy-4-((4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyr- azin-6-yl)-1H-pyrazol-1-yl)methyl)piperidin-1-yl)ethanone; 2-amino-1-(3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazi- n-6-yl)-1H-pyrazol-1-yl)azetidin-1-yl)ethanone; 2-(methylamino)-1-(3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-- a]pyrazin-6-yl)-1H-pyrazol-1-yl)azetidin-1-yl)ethanone; (3R,4R)-4-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6- -yl)-1H-pyrazol-1-yl)piperidin-3-ol; (1 S,2R)-2-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-y- l)-1H-pyrazol-1-yl)cyclopentanol; (1R,2S)-2-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6- -yl)-1H-pyrazol-1-yl)cyclopentanol; 2,2-dimethyl-3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyra- zin-6-yl)-1H-pyrazol-1-yl)propan-1-ol; (1-((4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1- H-pyrazol-1-yl)methyl)cyclopropyl)methanol; (2R)-3-(4-(4-(1-(1,1,1-trifluorobutan-2-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-- a]pyrazin-6-yl)-1H-pyrazol-1-yl)propane-1,2-diol; (R)-3-(4-(4-(1-((R)-4,4,4-trifluorobutan-2-yl)-1H-pyrazol-4-yl)pyrazolo[1- ,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propane-1,2-diol; (R)-3-(4-(4-(1-((S)-4,4,4-trifluorobutan-2-yl)-1H-pyrazol-4-yl)pyrazolo[1- ,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propane-1,2-diol; (R)-3-(4-(4-(1-((R)-1-cyclobutylpropyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]py- razin-6-yl)-1H-pyrazol-1-yl)propane-1,2-diol; (R)-3-(4-(4-(1-((S)-1-cyclobutylpropyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]py- razin-6-yl)-1H-pyrazol-1-yl)propane-1,2-diol; (R)-3-(4-(4-(1-((S)-2,2-difluoropentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5- -a]pyrazin-6-yl)-1H-pyrazol-1-yl)propane-1,2-diol; (R)-3-(4-(4-(1-((R)-2,2-difluoropentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5- -a]pyrazin-6-yl)-1H-pyrazol-1-yl)propane-1,2-diol; (S)-4-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)- -1H-pyrazol-1-yl)butane-1,3-diol; (R)-4-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)- -1H-pyrazol-1-yl)butane-1,3-diol; (R)-2-methyl-3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyra- zin-6-yl)-1H-pyrazol-1-yl)propane-1,2-diol; (S)-2-methyl-3-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyra- zin-6-yl)-1H-pyrazol-1-yl)propane-1,2-diol; (R)-3-(4-(4-(1-((R)-1-((S)-2,2-difluorocyclopropyl)propyl)-1H-pyrazol-4-y- l)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propane-1,2-diol; (R)-3-(4-(4-(1-((S)-1-cyclopropylbutan-2-yl)-1H-pyrazol-4-yl)pyrazolo[1,5- -a]pyrazin-6-yl)-1H-pyrazol-1-yl)propane-1,2-diol; (R)-3-(4-(4-(1-((R)-1-cyclopropylbutan-2-yl)-1H-pyrazol-4-yl)pyrarazolo[1- ,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propane-1,2-diol; (R)-3-(4-(4-(1-((1 S,2R)-2-ethylcyclopentyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H- -pyrazol-1-yl)propane-1,2-diol; (R)-3-(4-(4-(1-((1R,2S)-2-ethylcyclopentyl)-1H-pyrazol-4-yl)pyrazolo[1,5-- a]pyrazin-6-yl)-1H-pyrazol-1-yl)propane-1,2-diol; (R)-3-(4-(4-(1-((R)-1,1,1-trifluoropentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[- 1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propane-1,2-diol; (R)-3-(4-(4-(1-((S)-1,1,1-trifluoropentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[- 1,5-a]pyrazin-6-yl)-1H-pyrazol-1-yl)propane-1,2-diol; (R)-2-(4-(4-(1-(1,1,1-trifluoropentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-- a]pyrazin-6-yl)-1H-pyrazol-1-yl)propane-1,3-diol; (S)-2-(4-(4-(1-(1,1,1-trifluoropentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-- a]pyrazin-6-yl)-1H-pyrazol-1-yl)propane-1,3-diol; (R)-3-(4-(4-(1-((R)-1-cyclopropylpropyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]p- yrazin-6-yl)-1H-pyrazol-1-yl)propane-1,2-diol; (R)-3-(4-(4-(1-((S)-1-cyclopropylpropyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]p- yrazin-6-yl)-1H-pyrazol-1-yl)propane-1,2-diol; (R)-2-(4-(4-(1-(1-cyclopropylpropyl)-1H-pyrazol-4-yl)pyrazolo[5-a]pyrazin- -6-yl)-1H-pyrazol-1-yl)propane-1,3-diol; (R)-3-(4-(4-(1-(dicyclopropylmethyl)-1H-pyrazol-4-yl)pyrarazolo[1,5-a]pyr- azin-6-yl)-1H-pyrazol-1-yl)propane-1,2-diol; (R)-3-(4-(4-(1-(cis-2-methylcyclobutyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]py- razin-6-yl)-1H-pyrazol-1-yl)propane-1,2-diol; and (S)-1-(4-(4-(1-((R)-1-cyclopropylpropyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]p- yrazin-6-yl)-1H-pyrazol-1-yl)propan-2-ol; and pharmaceutically acceptable salts thereof.

12. The method according to claim 11, wherein the pharmaceutically acceptable salt is a trifluoroacetic acid salt or a hydrochloric acid salt.

13. The method according to claim 1, wherein the compound of Formula I or the pharmaceutically acceptable salt thereof is selected from: ##STR00352## ##STR00353## and pharmaceutically acceptable salts thereof.

14. The method according to claim 1, wherein the compound of Formula I or the pharmaceutically acceptable salt thereof is selected from: ##STR00354## ##STR00355## ##STR00356## ##STR00357## ##STR00358## ##STR00359## ##STR00360## ##STR00361## ##STR00362## ##STR00363## ##STR00364## ##STR00365## ##STR00366## ##STR00367## ##STR00368## ##STR00369## ##STR00370## ##STR00371## ##STR00372## and pharmaceutically acceptable salts thereof.

15. The method according to claim 1, wherein the compound of Formula I or the pharmaceutically acceptable salt thereof is_selected from: ##STR00373## ##STR00374## ##STR00375## and pharmaceutically acceptable salts thereof.

16. The method according to claim 1, wherein the compound of Formula I or the pharmaceutically acceptable salt thereof is selected from: ##STR00376## ##STR00377## ##STR00378## ##STR00379## ##STR00380## ##STR00381## and pharmaceutically acceptable salts thereof.

17. The method according to claim 1, wherein the compound of Formula I or the pharmaceutically acceptable salt thereof is selected from: ##STR00382## ##STR00383## ##STR00384## ##STR00385## ##STR00386## ##STR00387## ##STR00388## ##STR00389## ##STR00390## ##STR00391## ##STR00392## ##STR00393## ##STR00394## ##STR00395## ##STR00396## ##STR00397## ##STR00398## ##STR00399## ##STR00400## and pharmaceutically acceptable salts thereof.

18. The method according to claim 1, wherein the compound of Formula I or the pharmaceutically acceptable salt thereof is selected from: ##STR00401## ##STR00402## ##STR00403## ##STR00404## and pharmaceutically acceptable salts thereof.

19. The method according to claim 1, wherein the compound of Formula I or the pharmaceutically acceptable salt thereof is selected from: ##STR00405## ##STR00406## ##STR00407## ##STR00408## ##STR00409## ##STR00410## ##STR00411## and pharmaceutically acceptable salts thereof.
Description



CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application is a Division of U.S. patent application Ser. No. 16/212,493, filed Dec. 6, 2018, which is a Division of U.S. patent application Ser. No. 15/532,937, now U.S. Pat. No. 10,189,845, which issued Jan. 29, 2019, which is a 35 U.S.C .sctn. 371 application of International Patent Application No. PCT/US2015/064062, filed Dec. 4, 2015, which claims the benefit of Provisional Patent Application No. 62/088,068 filed Dec. 5, 2014. The entire content of the applications referenced above are hereby incorporated by reference herein.

[0002] The present invention relates to novel compounds, to pharmaceutical compositions comprising the compounds, to processes for making the compounds, and to the use of the compounds in therapy. More particularly, it relates to 4,6-substituted-pyrazolo[1,5-a]pyrazine compounds which are inhibitors of JAK kinases. In particular, the compounds are inhibitors of Tyk2, JAK1, JAK2, and/or JAK3, and are useful in the treatment of JAK kinase-associated diseases such as autoimmune diseases, inflammatory diseases, organ, tissue and cell transplant rejection, and hematological disorders and malignancies.

[0003] The members of the Janus kinase (JAK) family of non-receptor, intracellular tyrosine kinases are components of cytokine signal transduction. Four family members have been identified: JAK1, JAK2, JAK3 and Tyk2. The JAKs play a key role in the intracellular signaling mediated through Type I and Type II cytokine receptors. Specific cytokine receptor chains are associated with particular JAK kinases (reviewed in O'Sullivan et al., Mol. Immunol., 2007, 44:2497; Murray J., Immunol., 2007, 178:2623). Upon binding of cytokines to their receptors, JAKs are activated and phosphorylate the receptors, creating docking sites for other signaling molecules, in particular members of the signal transducer and activator of transcription (STAT) family. Upon phosphorylation, STATs dimerize, translocate to the nucleus and activate expression of genes involved in development, growth, differentiation, and maintenance of a variety of cell types. The cytokine-induced responses mediated by JAK kinases are important in host defense and, when dysregulated, play a role in pathogenesis of immune or inflammatory diseases, immune deficiencies, and malignancy (O'Sullivan et al., Mol. Immunol., 2007, 44:2497). Elevated or decreased levels of JAK/STAT-utilizing cytokines have been implicated in a number of disease states. In addition, mutations or polymorphisms in Type 1 and II cytokine receptors, JAK kinases, STAT proteins, and JAK/STAT regulatory proteins such as phosphotyrosine phosphatases, SOCS proteins, PIAS proteins have been reported in a variety of diseases. When dysregulated, JAK-mediated responses can positively or negatively affect cells leading to over-activation and malignancy or immune and hematopoietic deficiencies, respectively, and suggests the utility for use of inhibitors of JAK kinases. The JAK/STAT signaling pathway is involved in a variety of hyperproliferative and cancer-related processes including cell-cycle progression, apoptosis, angiogenesis, invasion, metastasis and evasion of the immune system (Haura et al., Nature Clinical Practice Oncology, 2005, 2(6), 315-324; Verna et al., Cancer and Metastasis Reviews, 2003, 22, 423-434). In addition, the JAK/STAT signaling pathway is important in the genesis and differentiation of hematopoietic cells and regulating both pro- and anti-inflammatory and immune responses (O'Sullivan et al., Molecular Immunology 2007, 44:2497). Because cytokines utilize different patterns of JAK kinases (O'Sullivan et al., Mol. Immunol., 2007, 44:2497; Murray J., Immunol., 2007, 178:2623), there may be utility for antagonists of JAK kinases with differing intra-family selectivity profiles in diseases associated with particular cytokines or in diseases associated with mutations or polymorphisms in the JAK/STAT pathways.

[0004] JAK3 deficient mice exhibit a severe combined immunodeficiency syndrome (scid). The failure of lymphocyte development in an otherwise healthy animal supports the utility of targeting JAK3 for diseases associated with lymphocyte activation.

[0005] In addition to the scid phenotype of the JAK3-deficient mice, the elevated expression of cytokines which signal through the JAK3-associated gamma common chain in inflammatory and immune responses suggests that inhibitors of JAK3 could impede T-cell activation and prevent rejection of grafts following transplant surgery, or to provide therapeutic benefit to patients suffering autoimmune or inflammatory disorders (reviewed in O'Sullivan et al., Mol. Immunol., 2007, 44:2497; Murray J., Immunol., 2007, 178:2623).

[0006] Inhibitors of the tyrosine kinase JAK3 have been described to be useful as immunosuppressants (see, for example, U.S. Pat. No. 6,313,129; Borie et al., Curr. Opin. Investigational Drugs, 2003, 4:1297). JAK3 has also been shown to play a role in mast-cell mediated allergic reactions and inflammatory diseases.

[0007] JAK1-deficient and/or JAK2-deficient animals are not viable. Studies have identified a high prevalence of an acquired activating JAK2 mutation (JAK2V617F) in myleoproliferative disorders such as polycythemia vera, essential thrombocythemia and idiopathic myelofibrosis and to a lesser extent in several other diseases. The mutant JAK2 protein is able to activate downstream signaling in the absence of cytokine stimulation, resulting in autonomous growth and/or hypersensitivity to cytokines and is believed to play a role in driving these diseases (Percy, M. J. and McMullin, M. F., Hematological Oncology, 2005, 23(3-4), 91-93). Additional mutations or translocations resulting dysregulated JAK2 function have been described in other malignancies (Ihle J. N. and Gilliland D. G., Curr. Opin. Genet. Dev., 2007, 17:8; Sayyah J. and Sayeski P. P., Curr. Oncol. Rep., 2009, 11:117). Inhibitors of JAK2 have been described to be useful in myeloproliferative diseases (Santos et al., Blood, 2010, 115:1131; Barosi G. and Rosti V., Curr. Opin. Hematol., 2009, 16:129, Atallah E. and Versotvsek S., 2009 Exp. Rev. Anticancer Ther. 9:663). More rarely, mutations in JAK1 and JAK3 have been reported in hematologic malignancies (Vainchecker et al., Semin. Cell Dev. Biol., 2008, Aug. 1; 9(4):385-93). JAK family kinase inhibitors may be useful in these settings (Sayyah J. and Sayeski P. P., Curr. Oncol. Rep., 2009, 11:117). In addition, over expression of cytokines which utilize JAK2 for signaling have been implicated in disease states (JAK2 utilizing cytokines are reviewed in O'Sullivan et al., Mol. Immunol., 2007, 44:2497; Murray J., Immunol., 2007, 178:2623).

[0008] JAK1 has been reported to signal with other JAK1 molecules or in collaboration with JAK2 or JAK3 depending on the cytokine input (JAK1 utilizing cytokines reviewed in O'Sullivan 2007, Murray 2007). Elevated levels of cytokines which signal through JAK1 have been implicated in a number of immune and inflammatory diseases. JAK1 or JAK family kinase antagonists may be useful for modulating or treating in such diseases.

[0009] Tyk2-deficient animals exhibit blunted immune responses to several types of pathogens and are less susceptible to some autoimmune diseases. This phenotype supports the utility of inhibiting Tyk2 in particular disease settings. Particularly, targeting Tyk2 appears to be a promising strategy for the treatment of IL-12-, IL-23- or Type 1 IFN-mediated diseases or diseases. These include but are not limited to rheumatoid arthritis, multiple sclerosis, lupus, psoriasis, psoriatic arthritis, inflammatory bowel disease, uveitis, and sarcoidosis (Shaw, M. et al., Proc. Natl. Acad. Sci. USA, 2003, 100, 11594-11599; Ortmann, R. A., and Shevach, E. M., Clin. Immunol., 2001, 98, 109-118; Watford et al., Immunol. Rev., 2004, 202:139).

[0010] International Publication Nos. WO 2011/130146 (Array BioPharma Inc.) and WO 2013/055645 (Array BioPharma Inc.) disclose 5,7-substituted imidazo[1,2-c]pyrimidines as inhibitors of one or more JAK kinases useful in the treatment of autoimmune diseases, inflammatory diseases, rejection of transplanted organs, tissues and cells, as well as hematologic disorders and malignancies and their co-morbidities.

[0011] There remains a need for compounds and methods for the treatment of autoimmune diseases, inflammatory diseases, organ, tissue and cell transplant rejection, and hematologic disorders and malignancies.

SUMMARY OF THE INVENTION

[0012] It has now been found that 4,6-substituted-pyrazolo[1,5-a]pyrazine compounds are inhibitors of one or more JAK kinases and are useful for treating JAK kinase-associated diseases and disorders, including autoimmune diseases, inflammatory diseases, rejection of transplanted organs, tissues and cells, as well as hematologic disorders and malignancies and their co-morbidities.

[0013] More specifically, provided herein are compounds of General Formula I:

##STR00002##

[0014] and stereoisomers and pharmaceutically acceptable salts and solvates thereof, wherein R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are as defined herein.

[0015] Also provided herein are pharmaceutical compositions comprising a compound of the present invention or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

[0016] Also provided herein are methods of treating a disease or disorder modulated by (i.e., associated with) one or more JAK kinases, comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of General Formula I or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof as defined herein.

[0017] In one embodiment, provided herein is a method of treating an autoimmune disease or inflammatory disease, comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of General Formula I or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof as defined herein.

[0018] In one embodiment, provided herein is a method of preventing an autoimmune disease or inflammatory disease, comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of General Formula I or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof as defined herein.

[0019] In one embodiment, provided herein is a method of treating organ, tissue or cell transplant rejection, comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of General Formula I or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof as defined herein.

[0020] In one embodiment, provided herein is a method of preventing organ, tissue and cell transplant rejection, comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of General Formula I or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof as defined herein.

[0021] In another embodiment, provided herein is a method of treating hematological disorders and malignancies, comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of General Formula I or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof as defined herein.

[0022] Also provided herein are compounds of General Formula I, or pharmaceutically acceptable salts or solvates thereof, or pharmaceutical compositions thereof, as defined herein, for use in therapy, e.g., for use in the treatment of a JAK kinase-associated disease or disorder.

[0023] Also provided herein are compounds of General Formula I, or pharmaceutically acceptable salts or solvates thereof, or pharmaceutical compositions thereof, as defined herein, for use in the treatment of autoimmune diseases and inflammatory diseases.

[0024] Also provided herein are compounds of General Formula I, or pharmaceutically acceptable salts or solvates thereof, or pharmaceutical compositions thereof, as defined herein, for use in the treatment of organ, tissue and cell transplant rejection.

[0025] Also provided herein are compounds of General Formula I, or pharmaceutically acceptable salts or solvates thereof, or pharmaceutical compositions thereof, as defined herein, for use in the treatment of hematological disorders and malignancies.

[0026] Also provided herein is the use of a compound of General Formula I or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for the treatment of a JAK kinase-associated disease or disorder, such as autoimmune diseases, inflammatory diseases, and organ, tissue and cell transplant rejection, and hematological disorders and malignancies.

[0027] Also provided herein is the use of a compound of General Formula I or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for the treatment of hematological disorders and malignancies.

[0028] Also provided herein is a method for inhibiting JAK kinase activity in a cell, the method comprising contacting the cell with a compound of Formula I or pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof, wherein said contacting is in vitro or in vivo. In one embodiment, the cell is a mammalian cell.

[0029] Also provided herein is a pharmaceutical combination for treating a JAK kinase-associated disease or disorder in a subject in need thereof, which comprises (a) a compound of General Formula I or a pharmaceutically acceptable salt or solvate thereof, (b) an additional therapeutic agent, and (c) optionally at least one pharmaceutically acceptable carrier, for simultaneous, separate or sequential use for the treatment of a JAK kinase-associated disorder, wherein the amounts of the compound of General Formula I or pharmaceutically acceptable salt or solvate thereof and the additional therapeutic agent are together effective in treating the JAK kinase-associated disease or disorder. Also provided herein is a pharmaceutical composition comprising such a combination. Also provided herein is the use of such a combination for the preparation of a medicament for the treatment of a JAK kinase-associated disorder. Also provided herein is a commercial package or product comprising such a combination for simultaneous, separate or sequential use.

[0030] Also provided herein are intermediates for preparing compounds of General Formula I.

[0031] Also provided herein are methods of preparing, methods of separation, and methods of purification of the compounds of this invention.


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