Claims for Patent: 10,730,880

Summary for Patent: 10,730,880

Title:	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.
Inventor(s):	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)
Assignee:	Array BioPharma Inc. (Boulder, CO) Celgene Corporation (Summit, NJ)
Application Number:	16/212,493
Patent Claims:	1. A method for treating an autoimmune disease or inflammatory disease associated with a JAK kinase in a subject in need thereof, which comprises administering to said subject a therapeutically effective amount of a compound of Formula I ##STR00354## 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--, hetCyl.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).sub.1NH(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-6-1H-p- yrazol-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-pyrazolo-4-yl)py- razolo[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,3S)-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,3S)-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,3S)-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-((1S,2R)-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-(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-(dimethyl amino)-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; (1S,2S)-2-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6- -yl)-1H-pyrazol-1-yl)cyclopentanol; (2S,3S)-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,3S)-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; (3S,4R)-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; (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; (1r,3r)-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; (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)-1-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-(methyl amino)-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; (1S,2R)-2-(4-(4-(1-(pentan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6- -yl)-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-11,2-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)pyrazolo[1,5- -a]pyrazin-6-yl)-1H-pyrazol-1-yl)propane-1,2-diol; (R)-3-(4-(4-(1-((1S,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)-24(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[1,5-a]pyraz- in-6-yl)-1H-pyrazol-1-yl)propane-1,3-diol; (R)-3-(4-(4-(1-(dicyclopropylmethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyraz- in-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 11, wherein the compuund of Formula I or the pharmaceuitcally acceptable salt thereof is selected from: ##STR00355## ##STR00356## ##STR00357## and pharmaceutically acceptable salts thereof. 14. The method according to claim 11, wherein the compund of Formula I or the pharmaceutically acceptable salt thereof is selected from: ##STR00358## ##STR00359## ##STR00360## ##STR00361## ##STR00362## ##STR00363## ##STR00364## ##STR00365## ##STR00366## ##STR00367## ##STR00368## ##STR00369## ##STR00370## ##STR00371## ##STR00372## ##STR00373## ##STR00374## ##STR00375## ##STR00376## ##STR00377## and pharmaceutically acceptable salts thereof. 15. The method according to claim 11, wherein the compound of Formula I or the pharmaceutically acceptable salt thereof is selected from: ##STR00378## ##STR00379## ##STR00380## ##STR00381## and pharmaceutically acceptable salts thereof. 16. The method according to claim 11, wherein the compound of Formula I or the pharmaceutically acceptable salt thereof is selected from: ##STR00382## ##STR00383## ##STR00384## ##STR00385## ##STR00386## ##STR00387## and pharmaceutically acceptable salts thereof. 17. The method according to claim 11, wherein the compound of Formula I or the pharmaceutically acceptable salt thereof is selected from: ##STR00388## ##STR00389## ##STR00390## ##STR00391## ##STR00392## ##STR00393## ##STR00394## ##STR00395## ##STR00396## ##STR00397## ##STR00398## ##STR00399## ##STR00400## ##STR00401## ##STR00402## ##STR00403## ##STR00404## ##STR00405## and pharmaceutically acceptable salts thereof. 18. The method according to claim 11, wherein the compound of Formula I or the pharmaceutically acceptable salt thereof is selected from: ##STR00406## ##STR00407## ##STR00408## and pharmaceutically acceptable salts thereof. 19. The method according to claim 11, wherein the compound of Formula I or the pharmaceutically acceptable salt thereof is selected from: ##STR00409## ##STR00410## ##STR00411## ##STR00412## ##STR00413## ##STR00414## ##STR00415## and pharmaceutically acceptable salts thereof. 20. The method according to claim 1, wherein the disease or disorder is selected from: (i) arthritis; (ii) intestinal inflammations; (iii) airways diseases; (iv) allergic reactions; (v) eye diseases, disorders or conditions; (vi) skin diseases, conditions or disorders; (vii) sepsis, systemic inflammatory response syndrome, and neutropenic fever; (viii) fibrosis; (ix) gout; (x) lupus and manifestations of lupus; (xi) neurodegenerative diseases; (xii) diabetes and complications from diabetes; metabolic syndrome and obesity; (xii) axial spondyloarthorpathy (axial SpA); and (xiv) interferon type 1 activation disorders. 21. The method of claim 20, wherein the disease or disorder is selected from: (i) arthritis; (ii) intestinal inflammations; (vi) skin diseases; and (x) lupus and manifestations or lupus. 22. The method according to claim 1, wherein said compound of Formula I is formulated for oral administration. 23. The method according to claim 22, wherein said compound of Formula I is formulated as a tablet or capsule. 24. The method according to claim 1, further comprising administering an additional therapy or therapeutic agent. 25. The method according to claim 24, wherein the additional therapeutic agent is selected from the group consisting of cyclosporin A, rapamycin, tacrolimus, leflunomide, deoxyspergualin, mycophenolate, daclizumab, OKT3, AtGam, aspirin, acetaminophen, ibuprofen, naproxen, piroxicam, antiinflammatory steroids, methotrexate, statins, anti-TNF agents, abatacept, cyclophosphamide, mycophenolic acid, hydroxychloroquine, and metformin.

Details for Patent 10,730,880

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Pharmacia & Upjohn Company Llc	ATGAM	lymphocyte immune globulin, anti-thymocyte globulin (equine)	Injection	103676	December 04, 1996	10,730,880	2034-12-05
Hoffmann-la Roche Inc.	ZENAPAX	daclizumab	Injection	103749	December 10, 1997	10,730,880	2034-12-05
Bristol-myers Squibb Company	ORENCIA	abatacept	For Injection	125118	December 23, 2005	10,730,880	2034-12-05
Bristol-myers Squibb Company	ORENCIA	abatacept	Injection	125118	July 29, 2011	10,730,880	2034-12-05
Bristol-myers Squibb Company	ORENCIA	abatacept	Injection	125118	June 07, 2016	10,730,880	2034-12-05