BR112018014705B1 - Bruton's tyrosine kinase inhibitor compounds and pharmaceutical composition - Google Patents

Abstract

Bruton's tyrosine kinase (Btk) inhibitors have the following formula (I):

Description

[001] The present application claims priority to U.S. Provisional Application No. 62/281,252, filed on January 21, 2016, which is incorporated by reference for all purposes as if fully set forth herein.

FIELD OF INVENTION

[002] Described herein are Bruton's tyrosine kinase inhibitors, methods of preparing such inhibitors, and pharmaceutical compositions containing such inhibitors.

BACKGROUND OF THE INVENTION

[003] Bruton's tyrosine kinase (Btk) plays an important role in signal transduction in B cells and is a factor that contributes to the survival, differentiation, proliferation and activation of B cells. There is currently a need for treatment of diseases in which B cells or mast cells participate. Btk is also known to participate in the activation of mast cells and the physiological functions of platelets. Therefore, Btk inhibitors are effective for the treatment of diseases in which B cells or mast cells participate, for example, allergic diseases, autoimmune diseases, inflammatory diseases, thromboembolic diseases and cancers.

SUMMARY OF THE INVENTION

[004] The Btk inhibitors described here have the following formula (I): . In Formula (I), A is N or CR1; B, C, and D are each N or CH, with the proviso that only one or two of A, B, C, and D can be N. R1 is hydrogen, amino, OH, CN, -NHOH, or CONH2; R2 is

[005] -X-E is one of the following: (1) X is O, OCRaRb, S(O), S(O)2, CRaRb, CRaRbO, NRc(C = O), C=ONRc or a bond; and E is a hydrogen, an aryl or a heteroaryl substituted with one to three substituents R5; or a saturated or partially unsaturated 3-7 membered carbocyclic ring, a saturated, partially unsaturated 8-10 membered bicyclic ring, or aryl ring, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, a saturated or partially unsaturated 4-7 membered heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur, a saturated or partially unsaturated bicyclic 7-10 membered heterocyclic ring having 1- 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen or sulfur; or (2)-X-E is hydrogen, halogen, -ORa, -O(CH2)1-4Ra, -CN, -NO2. R4 and R5 are each independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, OCF3, OCF2H, C1-6 alkyl, optionally substituted with one to five fluorine atoms, C3-6 cycloalkyl, optionally substituted with one to five fluorine atoms, C1-4 alkoxy, optionally substituted with one to five fluorine atoms, C1-4 alkyl thio, optionally substituted with one to five fluorine atoms, C1-4 alkylsulfonyl, optionally substituted with one to five fluorine, carboxy, C1-4 alkyloxycarbonyl and C1-4 alkylcarbonyl atoms. Ra and Rb are each independently hydrogen, fluorine or C1-3 alkyl, optionally substituted with one to five fluorine atoms. Rc is hydrogen or C1-3 alkyl, optionally substituted with one to five fluorine atoms. R3 is a group with a double bond.

[006] An isomer or tautomer thereof, a pharmaceutically acceptable solvate thereof, or a pharmaceutically acceptable prodrug thereof is further described.

[007] In one aspect, in Formula (I), E is selected from aryl, heteroaryl, carbocyclyl, heterocyclyl, any of which is optionally substituted with one to three R5 substituents.

[008] In another aspect, in Formula (I), R3 is selected from the group consisting of:

[009] Y is C(=O); OC(=O), NHC(=O), S=O, S(=O)2, or NHS(=O)2; R6, R7, R8 are each independently hydrogen, halogen, CN, C1-4 alkyl, C1-6 alkoxyalkyl, C1-8 alkyl aminoalkyl, or C1-4 alkylphenyl; or R7 and R8 together form a bond.

[010] In another aspect, in Formula (I), R3 is selected from the group consisting of:

[011] Y is C(=O); OC(=O), NHC(=O), S=O, S(=O)2, or NHS(=O)2; R6, R7, R8 are each independently hydrogen, halogen, CN, C1-4 alkyl, C1-6 alkoxyalkyl, C1-8 alkyl aminoalkyl, or C1-4 alkylphenyl; and R7 and R8 together optionally form a bond.

[012] In another aspect, in Formula (I), R3 is selected from the group consisting of:

[013] In another aspect, in Formula (I), A is CR1 and one of B, C and D is N.

[014] In another aspect, in Formula (I), A is CR1, B is N, and C and D are C-H.

[015] In another aspect, described herein is a pharmaceutical composition including a therapeutically effective amount of the compound of Formula (I), and a pharmaceutically acceptable excipient.

[016] In another aspect, described herein is a method for treating an autoimmune disease comprising administering to an individual in need thereof a composition containing a therapeutically effective amount of the compound of Formula (I) and other therapeutic agents.

[017] In another aspect, the Btk inhibitors described here are selected from the group consisting of (R)-1-(3-(3-(4-phenoxyphenyl)-1H-pyrazolo[4,3-c] pyridin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one; (R)-1-(3-(3-(4-(2-chloro-3-methoxyphenoxy)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)prop -2-en-1- one; (R)-1-(3-(3-(4-(2-fluoro-3-methoxyphenoxy)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidin-1-yl)prop -2-en-1-one; (R)-1-(3-(3-(4-(2-fluoro-3-methoxyphenoxy)phenyl)- 1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidin-1-yl)prop -2-en-1-one; (R)-1-(3-(3-(4-(2-fluoro-3-methoxy-phenoxy)phenyl)-7-methyl-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidin -1- il)prop-2-en-1-one; (R)-1-(3-(3-(4-(2-fluoro-3-methoxyphenoxy)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)prop -2-en-1-one; (R)-1-(3-(3-(4-(naphthalen-1-yloxy)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidin-1-yl)prop-2 -en-1- one; (R)-1-(3-(3-(4-(benzo[d][1,3]dioxol-4-yloxy)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl) piperidin-1-yl)prop-2-en-1-one; (R)-1-(3-(3-(4-(3-chlorophenoxy)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)prop-2-en -1-one; (R)-1-(3-(3-(4-(m-tolyloxy)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidin-1-yl)prop-2-en -1-one; (R)-1- (3-(3-(3-chloro-4-phenoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidin-1-yl)prop-2- en- 1-one; (R)-1-(3-(3-(4-(2,3-difluorophenoxy)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)prop-2 -en-1-one; (R)-1-(3-(3-(4-(2,3-dimethylphenoxy)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidin-1-yl)prop-2 -en-1-one; (R)-1-(3-(3-(4-(2,3-difluorophenoxy)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidin-1-yl)prop-2 -en-1- one; (R)-1-(3-(3-(4-(3-chloro-2-fluorophenoxy)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidin-1-yl)prop -2-en-1-one; R)-1-(3-(3-(4-(3-chloro-2-fluorophenoxy)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)prop- 2-en-1-one; 1-(3-((3-(4-phenoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)pyrrolidin-1-yl)prop-2-en-1-one; (R)-1-(3-(3-(4-(2-chloro-3-methoxyphenoxy)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidin-1-yl)prop -2-en-1-one; (R)-1-(3-(3-(4-(3-fluoro-2-methylphenoxy)phenyl)- 1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)prop -2-en-1-one; 1-(4-(3-(4-phenoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)prop-2-on-1-one; (R)-1-(3-(3-(4-(3-fluoro-2-methylphenoxy)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)prop -2-en-1-one; N-(3-(3-(4-phenoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)phenyl) acrylamide; (R)-1-(3-(3-(4-(3-isopropoxyphenoxy)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)prop-2-en -1-one; (R)-1-(3-(3-(4-(2,3-dimethylphenoxy)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)prop-2 -en-1-one; (R)-1-(3-(3-(4-(2-chloro-3-methoxyphenoxy)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl) but -2- en-1-one; 1-(6-(3-(4-(2-fluoro-3-methoxyphenoxy)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)-2-azaspiro [3.3] heptan-2- il)prop-2-en-1-one; (R)-1-(3-(7-chloro-3-(4-(2-fluoro-3-methoxyphenoxy)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidin-1 -il)prop-2-en-1-one; (R)-1-(1-acryloylpyrrolidin-3-yl)-3-(4-(2-fluoro-3-methoxyphenoxyphenyl)-1H-pyrazolo[4,3-c]pyridine-7-carbonitrile; (R) -1-(3-(3-(4-(cyclohexyloxy)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)prop-2-en-1-one; 1-(6-(3-(4-(2-chloro-3-methoxyphenoxy)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)-2-azaspiro [3.3] heptan -2- il)prop-2-en-1-one; (R)-1-(3-(3-(4-((2,3-dihydro-1H-inden-4-yl)oxyphenyl)-1H-pyrazolo[ 4,3-c]pyridin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one; methoxyphenoxy)phenyl)-1H-pyrazolo[3,4-c]pyridin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one (R)-1-(3-(3-(); 4-phenoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)prop-2-en-1-one (S)-1-(3-(3-(); 4-((3-chlorophenyl)thio)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one (S)-1; -(3-(3-(3-chloro-4-phenoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)prop-2-en-1-one; S)-1-(3-(3-(4-(3-chlorophenoxy)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidin-1-yl)prop-2-en- 1-one; (S)-1-(3-(3-(4-(m-tolyloxy)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)prop - 2-en-1-one; (R)-1-(3-(3-(4-(2-chloro-3-fluorophenoxy)phenyl)-2H-pyrazolo[4,3- c]pyridin-2-yl)pyrrolidin-1-yl)prop -2-en-1-one; (R)-1-(3-(3-(4-(2-chloro-3-fluorophenoxy)phenyl)-2H-pyrazolo[4,3-c]pyridin-2-yl)piperidin-1-yl)prop -2-en-1-one; (S)-1-(3-(3-(4-(2-chloro-3-fluorophenoxy)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1yl)prop-2 -en-1-one; (R)-1-(3-(3-(4-(2,3-dichlorophenoxy)phenyl)-2H-pyrazolo[4,3-c]pyridin-2-yl)pyrrolidin-1-yl)prop-2 -en-1-one; (R)-1-(3-(3-(4-(2,3-dichlorophenoxy)phenyl)-2H-pyrazolo[4,3-c]pyridin-2-yl)pyrrolidin-1-yl)prop-2 -en-1- one; (S)-1-(3-(3-(4-(2,3-dichlorophenoxy)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidin-1-yl)prop-2 -en-1-one; (R)-1-(3-(3-(4-(2,3-dichlorophenoxy)phenyl)-2H-pyrazolo[4,3-c]pyridin-2-yl)piperidin-1-yl)prop-2 -en-1-one; (S)-1-(3-(3-(4-(2,3-dichlorophenoxy)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)prop-2 -en-1-one; (R)-1-(3-(3-(4-((2-fluorobenzyl)oxy)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidin-1-yl)prop- 2-en-1-one; (R)-1-(3-(3-(4-((2-fluorobenzyl)oxy)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)prop- 2-en-1-one; (R)-4-(1-(1-acryloylpyrrolidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)-N-(3-methoxybenzyl) benzamide; (R)-4-(1-(1-acryloylpiperidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)-N-(3-methoxybenzyl) benzamide; (R)-1-(3-(3-(3'-methyl [1,1'-biphenyl]-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1 -yl)prop-2-en-1-one: (R)-1-(3-(3-(3'-methyl [1,1'-biphenyl]-4-yl)-2H-pyrazole [ 4, 3-c]pyridin-2-yl)pyrrolidin-1-yl)prop-2-en-1-one; (R)-1-(3-(3-(3'-methyl [1,1'-biphenyl]-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidin- 1 -yl)prop-2-en-1-one; N-{4-[1-(1-acryloyl-pyrrolidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-phenyl}-3-trifluoromethyl-benzamide (R)-N -(4-(1-(1-acryloylpiperidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)phenyl)-3-(trifluoromethyl) benzamide; (R)-1-(3-(5-acetyl-3-(4-(2-fluoro-3-methoxyphenoxy)phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c ]pyridin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one; (R)-1-(3-(5-acryloyl-3-(4-(2-fluoro-3-methoxyphenoxy)phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c ]pyridin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one; (R)-1-(3-(3-(4-(2-fluoro-3-methylphenoxy)phenyl)-1H-pyrazolo[4,3- c]pyridin-1-yl)pyrrolidin-1-yl)prop -2-en-1-one; (R)-1-(3-(3-(4-(2-fluoro-3-methylphenoxy)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)prop -2-en-1-one; (R)-1-(3-(3-(4-(3-fluoro-2-methoxyphenoxy)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidin-1-yl)prop -2-en-1-one; (R)-1-(3-(3-(4-(3-fluoro-2-methoxyphenoxy)phenyl)- 1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)prop -2-en-1-one; (R)-1-(3-(3-(3-fluoro-4-phenoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)prop-2-en- 1- one; 1-(3-(3-(4-phenoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)azetidin-1-yl)prop-2-en-1-one; 1-(3-((3-(4-phenoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)piperidin-1-yl)prop-2-en-1-one; (R)-1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-indazol-1-yl)pyrrolidin-1-yl)prop-2-en-1-one; (R)-1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-indazol-1-yl)piperidin-1-yl)prop-2-en-1-one; (R)-1-(3-(3-(4-(3-chloro-2-methylphenoxy)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)prop -2-en-1-one; (R)-1-(3- 3-(4-(3-methoxy-2-methylphenoxy)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)prop- 2-en-1-one; (R)-1-(3-(3-(4-((3-fluorophenyl)thio)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidin-1-yl)prop- 2-en-1-one; (R)-1-(3-(3-(4-(3-methoxy-2-methylphenoxy)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidin-1-yl)prop -2- en-1-one; (R)-1-(3-(3-(4-(3-chloro-2-methylphenoxy)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidin-1-yl)prop -2-en-1-one; (R)-1-(3-(3-(3-fluoro-4-phenoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidin-1-yl)prop-2-en- 1-one; (R)-1-(3-(3-(4-(3-fluorophenoxy)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)prop-2-en -1-one; (R)-1-(3-(3-(4-(3-fluorophenoxy)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidin-1-yl)prop-2-en -1-one; (R)-1-(3-(3-(4-(3-methoxyphenoxy)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidin-1-yl)prop-2-en -1-one; (R)-1-(3-(3-(4-(3-methoxyphenoxy)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)prop-2-en -1-one; ((R)-1-(3-(7-fluoro-3-(4-phenoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidin-1-yl)prop-2-en -1-one; (R)-1-(3-(7-(difluoromethyl)-3-(4-(2-fluoro-3-methoxyphenoxy)phenyl)-1H-pyrazolo[4,3-c]pyridin- 1-yl)pyrrolidin-1-yl)prop-2-en-1-one; 1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one; (R)-1-(3-(3-(4-(2-chloro-3-methoxyphenoxy)phenyl)-7-methoxy-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidin-1 -yl)prop- 2-en-1-one; (R)-1-(3-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidin-1-yl)prop -2-en-1-one; (R)-1-(3-(7-fluoro-3-(4-(2-fluoro-3-methoxyphenoxy)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1 -il)prop-2-en-1-one; (R)-1-(3-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)prop -2-en-1-one; (R)-1-(3-(3-(4-([1,4'-bipiperidin]-1'-yl)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin -1-yl)prop-2-en-1-one; (R)-1-(3-(3-(3-fluoro-4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1 -yl)prop-2-en-1-one; 1-(3-(3-(4-(2-fluoro-3-methoxyphenoxy)phenyl)-7-methoxy-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)prop -2-en-1-one; (R)-1-(3-(3-(4-(4-(methylsulfonyl)piperazin-1-yl)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1- il)prop-2-en-1-one; (R)-1-(3-(3-(2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1 -yl)prop-2-en-1-one; (R)-4-(1-(1-(but-2-inoyl)piperidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)-N-(pyridin-2- il) benzamide; (R)- 1-(3-(7-(difluoromethyl)-3-(4-(2-fluoro-3-methoxyphenoxy)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin -1-yl)prop-2-en-1-one; (R)-1-(3-(3-(4-(2-fluoro-3-methoxyphenoxy)phenyl)-7-isopropoxy-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1 - il)prop-2-en-1-one; (R)-1-(3-(7-ethoxy-3-(4-(2-fluoro-3-methoxyphenoxy)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1 -yl)prop-2-en-1-one; (R)-(3-(3-(4-(2-fluoro-3-methoxyphenoxy)phenyl)-7-methoxy-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl ) (2-tosyl-2-azaspiro [3.3] heptan-6-yl) methanone; (R)-1-(3-(3-((4-(4-methylpiperazin-1-yl)phenyl)amino)-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1- il)prop-2-en-1-one; (R)- 1-(3-(3-(4-(2-chloro-3-methoxyphenoxy)phenyl)-7-methoxy-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1 -yl)prop-2-en-1-one; (R)-1-(3-(7-butoxy-3-(4-(2-fluoro-3-methoxyphenoxy)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1 -il)prop-2-en-1-one; (R)-1-(3-(3-(4-(2-fluoro-3-methoxyphenoxy)phenyl)-7-propoxy-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1 -yl)prop-2-en-1-one; (R)-1-(3-(3-(4-(2-fluoro-3-methoxyphenoxy)phenyl)-4-methyl-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1 -yl)prop-2-en-1-one; (R)-1-(3-(3-(4-(2-fluoro-3-methoxyphenoxy)phenyl)-7-methoxy-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidin-1 -yl)prop-2-en-1-one; (R)-1-(3-(7-ethoxy-3-(4-(2-fluoro-3-methoxyphenoxy)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidin-1 - il)prop-2-en-1-one; (R)-1-(3-(3-(4-(2-chloro-3-methoxyphenoxy)phenyl)-7-ethoxy-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidin-1 -yl)prop-2-en-1-one; (R)-1-(3-(3-(4-(2-chloro-3-methoxyphenoxy)phenyl)-7-ethoxy-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1 - il)prop-2-en-1-one; (R)-1-(3-(3-(4-(2-fluoro-3-methoxyphenoxy)phenyl)-7-hydroxy-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1 -yl)prop-2-en-1-one; (R)-1-(3-(3-(4-(2-chloro-3-methoxyphenoxy)phenyl)-7-propoxy-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1 - il)prop-2-en-1-one; (R)-1-(3-(7-butoxy-3-(4-(2-chloro-3-methoxyphenoxy)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1 -yl)prop-2-en-1-one; (R)-1-(3-(3-(4-(2-chloro-3-methoxyphenoxy)phenyl)-7-isopropoxy-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin- 1 -yl)prop-2-en-1-one; (R)-1-(3-(3-(4-(2-fluoro-3-methoxyphenoxy)phenyl)-7-(2-hydroxyethoxy)-1H-pyrazolo[4,3-c]pyridin-1-yl )piperidin-1-yl)prop-2-en-1-one; 1-((3R)-3-(3-(4-(2-fluoro-3-methoxyphenoxy)phenyl)-7-((tetrahydrofuran-3-yl)oxy)-1H-pyrazolo[4,3-c] pyridin-1-yl)piperidin-1-yl)prop-2-en-1-one; 1-((3R)-3-(3-(4-(2-chloro-3-methoxyphenoxy)phenyl)-7-((tetrahydrofuran-3-yl)oxy)-1H-pyrazolo[4,3- c] pyridin-1-yl)piperidin-1-yl)prop-2-en-1-one; (R)-1-(3-(7-(2-aminoethoxy)-3-(4-(2-fluoro-3-methoxyphenoxy)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl )piperidin-1-yl)prop-2-en-1-one; (R)-1-(3-(3-(4-(3-methoxy-2-propoxyphenoxy)phenyl)-7-propoxy-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1 -yl)prop-2-en-1-one; (R)-1-(3-(3-(4-(2-fluoro-3-methoxyphenoxy)phenyl)-7-methoxy-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1 - il)propan-1-one; 1-(3-(3-(4-(2-fluoro-3-methoxyphenoxy)phenyl)-7-methoxy-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)- 2-hydroxypropan-1-one; 2-(3-(3-(4-(2-fluoro-3-methoxyphenoxy)phenyl)-7-methoxy-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl acid) -2-oxoacetic acid; 2-(3-(3-(4-(2-fluoro-3-methoxyphenoxy)phenyl)-7-methoxy-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl acid) - 2-oxoacetamide3-(3-(4-(2-fluoro-3-methoxyphenoxy)phenyl)-7-methoxy-1H-pyrazolo[4,3-c]pyridin-1-yl) cyclohexanecarboxylic acid; 4-(3-(4-(2-fluoro-3-methoxyphenoxy)phenyl)-7-methoxy-1H-pyrazolo[4,3-c]pyridin-1-yl)cyclohexanecarboxylic acid; (E)-2-(3-(3-(4-(2-fluoro-3-methoxyphenoxy)phenyl)-7-methoxy-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1 - carbonyl)-4,4-dimethylpent-2-enonitrile; 1-(2-((3-(4-(2-fluoro-3-methoxyphenoxy)phenyl)-7-methoxy-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)pyrrolidin-1- il)prop-2-en-1-one; (E)-2-(2-((3-(4-(2-fluoro-3-methoxyphenoxy)phenyl)-7-methoxy-1H-pyrazolo[4,3-c]pyridin-1-yl) methyl) pyrrolidine-1-carbonyl)-4,4-dimethylpent-2-enonitrile; (R)-1-(3-(7-(2-(dimethylamino)ethoxy)-3-(4-(2-fluoro-3-methoxyphenoxy)phenyl)-1H-pyrazolo[4,3-c]pyridin- 1-yl)piperidin-1-yl)prop-2-en-1-one; (R)-1-(3-(7-(2-(dimethylamino)ethoxy)-3-(4-(2-fluoro-3-methoxyphenoxy)phenyl)- 1H-pyrazolo[4,3-c]pyridin- 1-yl)piperidin-1-yl)but-2-yn-1-one; 4-(3-(4-benzamidophenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl) cyclohexanecarboxylic acid; 4-(3-([1,1'-biphenyl]-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl) cyclohexanecarboxylic acid; (S)- 1-(3-(3-(4-(1-phenylvinyl)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)prop-2- en -1-one; 3-(3-(4-phenoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl) cyclohexanecarboxylic acid; 4-(3-(4-(benzyloxy)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl) cyclohexanecarboxylic acid.

DETAILED DESCRIPTION OF THE INVENTION

[018] The methods described herein include administering to an individual in need of a composition containing a therapeutically effective amount of one or more Btk inhibitor compounds described herein.

[019] Prodrugs means any compound that releases a drug of active origin, according to Formula I in vivo, when that prodrug is administered to a mammalian individual. Prodrugs of a compound of Formula I are prepared by modifying functional groups present in the compound of Formula I in such a way that the modifications can be cleaved in vivo to release the parent compound. Prodrugs can be prepared by modifying the functional groups present in the compounds, in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compounds.

[020] Tautomers mean compounds produced by the phenomenon, in which a proton from an atom of a molecule moves to another atom. Tautomers also refer to one of two or more structural isomers that exist in equilibrium and are easily converted from one isomeric form to another. One skilled in the art would recognize that other tautomeric ring atom arrangements are possible. All such isomeric forms of the same compounds are expressly included in the present invention.

[021] Isomers mean compounds with identical molecular formulas but differ in the nature or sequence of bonds of their atoms or in the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are called stereoisomers. Stereoisomers that are not mirror images of each other are called diastereoisomers, and those that are nonsuperimposable mirror images of each other are called enantiomers. When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. A chiral compound can exist as an individual enantiomer or as a mixture thereof. Unless otherwise indicated, the description is intended to include individual stereoisomers as well as mixtures.

[022] Certain compounds of the present invention can exist in unsolvated forms, as well as in solvated forms, including hydrated forms. Solvates refer to a complex formed by combining solvent molecules with the compound of Formula I. The solvent can be an organic compound, an inorganic compound or a mixture thereof.

[023] Pharmaceutically acceptable salts represent those salts that are, within the scope of medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurable with a reasonable benefit/risk ratio. They may be obtained during the isolation and final purification of the compounds of the invention, or separately by reacting the free base function with a suitable mineral acid, such as hydrochloric acid, phosphoric acid, or sulfuric acid, or with an organic acid, such as , for example, ascorbic acid, citric acid, tartaric acid, lactic acid, maleic acid, malonic acid, fumaric acid, glycolic acid, succinic acid, propionic acid, acetic acid, methanesulfonic acid, and the like. The acidic function can react with an organic or mineral base, such as sodium hydroxide, potassium hydroxide, or lithium hydroxide.

[024] Therapeutically effective amount means an amount of compound or composition of the present invention effective in inhibiting Bruton's tyrosine kinase and thus producing the desired therapeutic effect.

[025] As used herein, the term alkyl refers to a straight or branched chain saturated aliphatic monovalent hydrocarbon radical having a number of carbon atoms in the specified range. For example, C1-6 alkyl refers to any of the isomers of hexyl alkyl and pentyl alkyl, as well as, n-, iso-, sec- and t-butyl, n- and iso-propyl, ethyl and methyl. Alkyl also includes saturated aliphatic hydrocarbon radicals, in which one or more hydrogens are replaced by deuterium, for example, CD3.

[026] The term branched alkyl refers to an alkyl group as defined above, in which straight-chain alkyl groups in the specified range are excluded. As defined herein, branched alkyl includes alkyl groups, wherein the alkyl is attached to the remainder of the compound through a secondary or tertiary carbon. For example, isopropyl is a branched alkyl group.

[027] The term cycloalkyl refers to any monocyclic ring of an alkane having a number of carbon atoms in the specified range. For example, C3-6 cycloalkyl refers to cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

[028] The term halogen refers to fluorine, chlorine, bromine and iodine (alternatively referred to as fluoro, chlorine, bromine and iodine).

[029] The term haloalkyl refers to an alkyl group as defined above, in which one or more of the hydrogen atoms has been replaced with a halogen (i.e., F, Cl, Br and/or I). For example, C1-6 haloalkyl refers to a linear or branched C1 to C6 alkyl group as defined above with one or more halogen substituents. The term fluoroalkyl has an analogous meaning except that the halogen substituents are restricted to fluorine. Suitable fluoroalkyls include the (CH2)0-4CF3 series.

[030] The term C(O) or CO refers to carbonyl. The terms S(O)2 or SO2 refer to sulfonyl.

[031] The term aryl refers to phenyl, naphthyl, tetrahydronaphthyl, idenyl, dihydroindenyl and the like. An aryl of particular interest is phenyl.

[032] The term heteroaryl refers to (i) a 5- or 6-membered heteroaromatic ring containing 1 to 4 heteroatoms independently selected from N, O and S, or (ii) is a heterobicyclic ring selected from quinolinyl, isoquinolinyl, quinoxalinyl. Suitable 5- and 6-membered heteroaromatic rings include, for example, pyridyl (also referred to as pyridinyl), pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thienyl, furanyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isooxazolyl, oxadiazolyl, oxatriazolyl, thiazolyl, isothiazolyl and thiadiazolyl. One class of heteroaryls of interest consists of (i) 5- and 6-membered heteroaromatic rings containing 1 to 3 heteroatoms independently selected from N, O, and S, and (ii) heterobicyclic rings selected from quinolinyl, isoquinolinyl, and quinoxalinyl . Heteroaryls of particular interest are pyrrolyl, imidazolyl, pyridyl, pyrazinyl, quinolinyl (or quinolyl), isoquinolyl (or isoquinolyl), and quinoxalinyl.

[033] Examples of 4- to 7-membered saturated heterocyclic rings within the scope of this invention include, for example, azetidinyl, piperidinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, pyrrolidinyl, imidazolidinyl, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl , pyrazolidinyl, hexahydropyrimidinyl, thiazinanyl, thiazepanil, azepanil, diazepanil, tetrahydropyranyl, tetrahydrothiopyranyl and dioxanil. Examples of unsaturated 4- to 7-membered heterocyclic rings within the scope of this invention include monounsaturated heterocyclic rings corresponding to the saturated heterocyclic rings mentioned in the previous sentence, wherein a single bond is replaced with a double bond (e.g., a single bond carbon-carbon is replaced by a carbon-carbon double bond).

[034] It is understood that the specific rings listed above are not a limitation on the rings that can be used in the present invention. These rings are merely representative.

[035] The synthetic methods for preparing the compounds of the present invention are illustrated in the following schemes, methods and examples. The starting materials are commercially available or can be prepared according to procedures known in the art or as described herein. The compounds of the invention are illustrated by the specific examples presented below. However, these specific examples should not be interpreted as forming the only genre that is considered to be the invention. These examples further illustrate details for the preparation of the compounds of the present invention. Those skilled in the art will readily appreciate that known variations in conditions and processes can be used to prepare such compounds. Formula (I)

[036] Btk inhibitor compounds of Formula I can be prepared by methods well known in the art of organic chemistry. The starting material used for the synthesis of these compounds can be synthesized or obtained from commercial sources, such as, but not limited to, China Chemical companies or Sigma-Aldrich Chemical Co. (St. Louis, Mo.) in China. The compounds described herein, and other related compounds having different substituents are optionally synthesized using techniques and materials such as described, for example, in March, ADVANCED ORGANIC CHEMISTRY 4th Ed., (Wiley 1992); Carey and Sundberg, ADVANCED ORGANIC CHEMISTRY 4th Ed., Vols. A and B (Plenum 2000, 2001); Fieser and Fieser’s Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd’s Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991); and Larock’s Comprehensive Organic Transformations (VCH Publishers Inc., 1989). Other methods for the syntheses of compounds described herein can be found in United States Patent Application Publication No. US 2011/0130429 A1, Burgey et al. Bioorganic & Medicinal Chemistry Letters 10 (2006) 5052-5056. Definitions of chemical terms used in this application can be found in these references (if not otherwise defined herein). As a guide, the following synthetic methods can be used.

[037] During synthetic sequences, it may be necessary and/or desirable to protect reactive or sensitive groups in any of the molecules involved. This is achieved by means of conventional protecting groups, such as those described in T.W Greene and P.G.M. Wutts "Protective groups in Organic Synthesis" 3rd Edition, John Wiley and Sons, 1999. Protective groups are optionally removed in a convenient subsequent step using methods well known in the art. The reaction products are optionally isolated and purified. If desired, using conventional techniques, but not limited to filtration, distillation-assisted crystallization, chromatography and the like. Such materials are optionally characterized using conventional means, including physical constants and spectral data.

[038] The compounds described herein may have one or more stereocenters and each center may exist in the R or S configuration. The compounds presented herein include all diasterometric, enantiomeric, and epimeric forms, as well as appropriate mixtures thereof.

[039] Btk inhibitor compounds of Formula I can be, for example, 1H-pyrazolo[4,3-c]pyridine derivatives. Specifically, the Btk inhibitory compounds of Formula I can be, for example, compounds F, wherein R1-R2 have the previously defined meanings. A non-limiting example of a synthetic approach for preparing compounds F can be prepared by the general synthetic route shown in Scheme I and Scheme II. Scheme I

[040] Referring to Scheme I, different aldehydes (B), where FG is a functional group (e.g., ester, protected anilines, protected phenols, bromide), can be added to a range of substituted o-haloaromatics A to form an alcohol, followed by oxidation of product C with CrO3 in acetone to give benzoyl D. Ring closure of D with (NH2)2- H2O, under reflux, to obtain the key intermediates indazole E. Intermediate E is coupled with R2OH via the Mitsunobu reaction or with R2OTs via substitution to provide intermediate G, which are then derived by the metal catalyst coupling reaction using suitably substituted phenylboronic acid (corresponding boronic esters can also be used), provides directly the desired compounds F. In a typical procedure, a mixture of intermediates G, a copper catalyst (e.g. Cu(OAc)2), base (e.g. TEA, DIPEA or similar) and an aryl boronic acid or ester aryl boronic acid in a suitable solvent, such as DCM, or toluene, to form compounds F (FG is converted to defined groups for XAR). Scheme II

[041] Referring to Scheme II, compounds F can be obtained from another route, selective ortho-lithiation in dry THF with in situ LDA carried out and subsequent reaction with DMF to provide aldehyde H, which reacts with (NH2 )2- H2O under reflux to obtain the key intermediate indazole I, then a regioselective bromination or iodination with Br2/I2 or NBS/NIS to provide compound J. Coupling reaction of the 1-nitrogen in indazole with R2OH through the reaction of Mitsunobu or with R2OTs through substitution to obtain intermediate K, which is then derived by metal catalyst coupling reaction using suitably substituted phenylboronic acid (corresponding boronic esters can also be used) to provide a key intermediate G or directly, to provide the desired F compounds. The transformation from G to F is synthesized in a similar manner as previously shown in Scheme I.

[042] Alternatively, compound F can be obtained from compounds G, where FG is a functional group (e.g., ester, protected anilines, protected phenols, bromide) that can be easily converted into groups defined for XAr. Non-limiting examples of suitable functional groups in compounds G are a benzyl ether, dibenzyl amine, methyl ester, which can be treated with base or Pd/C/H2 to form the key intermediates G-1a, G-2a, G- 3a then form the corresponding compounds F-1, F-2, F-3, F-4 in Scheme III. Scheme III

[043] The deprotection reactions for the protecting groups of compounds F in Scheme IV are known and can be carried out by the methods described below. Examples here are (a) deprotection reaction under acidic conditions for the Boc protecting group and (b) hydrogenolysis-based deprotection reactions for the benzyl protecting group. After deprotection under these conditions, coupling with, but not limited to, an acid chloride, such as, but not limited to, arylyl chloride, completes the syntheses to provide the compound Fb. Scheme IV

[044] General experimental conditions: Preparative thin layer chromatography (PTLC) was carried out on 20 x 20 cm plates (500 micron thick silica gel). Silica gel chromatography was performed on a Biotage Horizon flash chromatography system. 1H NMR spectra were recorded on a Bruker Ascend TM 400 spectrometer at 400 MHz at 298 °K, and chemical shifts are given in parts per million (ppm) with reference to the residual proton signal of the deuterated solvents: CDCl3 at δ = 7.26 ppm and CH3OH or CH3OD at δ = 3.30 ppm. LCMS spectra were obtained on an Agilent Technologies 1260 Infinity or 6120 Quadrupole spectrometer. The mobile phase for LC was acetonitrile (A) and water (B) with 0.01% formic acid, and the eluent gradient was 5-95% A in 6.0 min, 60-95% A in 5.0 min, 80-100% A in 5.0 min, and 85-100% A in 10 min using a 50 mm x 4.6 mm x 2.7 μm SBC18 capillary column. Mass spectra (MS) were measured by electrospray ionization (ESI) mass spectroscopy. All temperatures are in degrees Celsius unless otherwise noted.

[045] HPLC analytical conditions with mass spectrometer: LC1: Column: 50 mm x 4.6 mm x 2.7 μm SB-C18 Temperature: 50 °C Eluent: 5:95 v/v acetonitrile/water + 0.01% formic acid in 6 min. Flow Rate: 1.5 mL/min, 5 μL Injection Detection: PDA, 200-600 nm MS: mass range 150-750 amu; positive ion electrospray ionization LC2: Column: 50 mm x 4.6 mm x 2.7 μm SB-C18 Temperature: 50 oC Eluent: 5:95 to 95: 5 v/v acetonitrile/water + 0.05 % TFA over 3.00 min. Flow rate: 1.5 mL/min, 5 μL injection Detection: PDA, 200-600 nm MS: mass range 150-750 amu; positive ion electrospray ionization LC3: Column: 50 mm x 4.6 mm x 2.7 μm SB-C18 Temperature: 50 oC Eluent: 10:90 to 98: 2 v/v acetonitrile/water + 0.05 % TFA over 3.75 min. Flow Rate: 1.0 mL/min, 10 μL Injection Detection: PDA, 200-600 nm MS: mass range 150-750 amu; positive ion electrospray ionization

[046] List of Abbreviations:

[047] AcOH = acetic acid; Alk = alkyl; Ar = aryl; Boc = tert-butyloxycarbonyl; bs = wide singlet; CH2Cl2 = dichloromethane; d = doublet; dd = double of doublet; DBU = 1,8-diazabicyclo[5,4,0] undec-7-ene; DCM = dichloromethane; DEAD = diethyl azodicarboxylate; DMF = N,N-dimethylformamide; DMSO = Dimethyl sulfoxide; EA = ethyl acetate; ESI = electrospray ionization; Et = ethyl; EtOAc = ethyl acetate; EtOH = ethyl alcohol; h = hours; HOAc = acetic acid; LiOH = lithium hydroxide; m = multiplet; Me = methyl; MeCN = acetonitrile; MeOH = methyl alcohol; MgSO4 = magnesium sulfate; min = minutes; MS = mass spectroscopy; NaCl = sodium chloride; NaOH = sodium hydroxide; Na2SO4 = sodium sulfate; NMR = nuclear magnetic resonance spectroscopy; PE = petroleum ether; PG = protecting group; Ph = phenyl; rt = ambient temperature; s = singlet; t = triplet; TFA = trifluoroacetic acid; THF = tetrahydrofuran; Ts = p-toluenesulfonyl (tosyl).

[048] The compounds of the present invention can be prepared following the general methods detailed below. In certain embodiments, methods of producing the tyrosine kinase inhibitor compounds described herein are provided herein. In certain embodiments, the compounds described herein are synthesized using the following synthetic schemes. In other embodiments, the compounds are synthesized using methodologies analogous to those described below by using appropriate alternative starting materials. All key intermediates were prepared according to the following methods.

[049] Intermediate 1: (4-(2-chloro-3-methoxyphenoxy)phenyl) boronic acid

[050] Step A: 2-chloro-3-hydroxybenzaldehyde (1)

[051] To a suspension of 3-hydroxybenzaldehyde (5 g, 40.98 mmol) in AcOH (10 mL) was carefully added t-BuOCl (5 mL, 45.08 mmol) with stirring. It was left to cool and stirred for 16 hours, resulting in a white precipitate. The solid was filtered, washed with H2O and dried to give the title product (3 g, 46.9%). 1H-NMR (400 MHz, CDCl3): δ 10.66 (br, 1H), 10.33 (s, 1H), 7.31-7.25 (m, 3H).

[052] Step B: 2-chloro-3-hydroxybenzaldehyde (2)

[053] To a solution of 2-chloro-3-hydroxybenzaldehyde 1 (3.4 g, 21.66 mmol) in DMF (22 mL) was added K2CO3 (3.59 g, 26 mmol) followed by MeI (2 mL , 32.5 mmol), and the mixture was stirred at room temperature for 18 hours. After concentration under vacuum, the residue was taken up in ethyl acetate, washed with H2O, brine, dried over Na2SO4 and concentrated. Purification by column chromatography on silica gel with 1/5 ethyl acetate/hexanes provided the title product (3.5 g, 95.1%). 1H-NMR (400 MHz, CDCl3): δ 10.53 (s, 1H), 7.53 (d, J = 7.6 Hz, 1H), 7.36-7.32 (m, 1H), 7 .01 (d, J = 8.8 Hz, 1H) 3.95 (s, 3H).

[054] Step C: 2-chloro-3-hydroxybenzaldehyde (3)

[055] To a solution of 2-chloro-3-methoxybenzaldehyde 2 (2 g, 11.7 mmol) in DCM (50 ml) was added 3-chloroperoxybenzoic acid (3 g, 17.5 mmol). The mixture was stirred for 12 hours at 40°C. Filtered, the residue was contracted into a sole. The sole was desalted in 18 mL of MeOH, then 5 mL of 10% NaOH was added with cooling. After stirring for 45 min at 10°C, the mixture was conditioned at 30°C on a rotary evaporator to remove MeOH, then 22 mL of 5% NaOH was added and the solution was added with concentrated HCl with cooling, at then extracted (3 x 20) with EA, desired with H2O, 5% NaHCOs, dried over Na2SO4 and concentrated in vacuo to give the title compound (1.2 g, 66.6%). 1H- NMR (400 MHz, CDCl3): δ 7.14-7.10 (m, 1H), 6.67 (d, J = 8.4 Hz, 1H), 6.51 (d, J = 8, 4Hz, 1H), 5.62 (s, 1H) 3.89 (s, 3H).

[056] Step D: 1-(4-bromophenoxy)-2-chloro-3-methoxybenzene (4)

[057] To a solution of 1-bromo-4-iodobenzene (2.68 g, 9.5 mmol) in dioxene (40 mL) was added 3 (1.5 g, 9.5 mmol), CuI (0.182 g , 0.95 mmol), N,N-dimethylglycine hydrochloride (0.396 g, 2.85 mmol), Cs2CO3 (6.2 g, 19 mmol). The mixture was stirred at 105°C in N2 for 18 h. The mixture was filtered, contracted and extracted with EA. The organic layer was washed with water and brine, dried with anhydrous Na2SO4, and purified by flash chromatography to provide the title product (1.2 g, 40.4%). 1H-NMR (400 MHz, CDCl3): δ 7,437.39 (m, 2H), 7.18-7.15 (m, 1H), 6.85-6.75 (m, 3H), 6.65- 6.15 (m, 1H), 3.93 (s 3H).

[058] Step E: 1-(4-bromophenoxy)-2-chloro-3-methoxybenzene (5)

[059] To a solution of 4 (1.2 g, 3.85 mmol) in THF (30 mL) was cooled to -78 C under N2, n-BuLi (1.82 mL, 4.61 mmol) was added drop by drop under the same temperature. The mixture was stirred for 30 min at the same temperature. Triisopropyl borate (0.868 g, 4.61 mmol) was added dropwise under the same temperature. After 15 min, the mixture was left at room temperature and stirred for 2 h, then 2N HCl was added to adjust to pH = 5 and stirred for 30 min, then the mixture was extracted with EA. The organic layer was washed with water and brine, dried with anhydrous Na2SO4, to give the crude title product (0.4 g crude).

[060] Example 1: (R)-1-(3-(3-(4-phenoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidin-1-yl)prop-2- en-1-one:

[061] Step A: (4-(benzyloxy)phenyl) (4-chloropyridin-3-yl) methanol (2)

[062] To a solution of diisopropylamine (4.1 mL, 29.8 mmol) in dry THF (64 mL) at -78 °C was added a solution of 2.5 M BuLi in hexane (15 mL, 29.8 mmol). The mixture was allowed to warm to 0 °C and stirred for about 1 h, then the solution was cooled to -78 °C and 4-chloropyridine (3.07 g, 27.1 mmol) in 10 mL of dry THF was added. The reaction mixture was stirred for a further 4 h, and then the corresponding 4-(benzyloxy)benzaldehyde (5.75 g, 27.1 mmol) was added and the mixture was stirred and allowed to warm to room temperature overnight. The reaction was stopped with H2O (25 mL), and the mixture was extracted with Et2O (3 x 50 mL). The organic phases were combined, dried over Na2SO4, the volatile components were removed under vacuum and the residue was purified by silica gel column chromatography (gradient: DCM/MeOH = 200:1 - 50/1) to give the title product (2.5 g, 28.46% yield). 1H-NMR (400 MHz, CDCl3): δ 8.86 (s, 1H), 8.36 (d, J = 4.0 Hz, 1H), 7.39-7.23 (m, 8H), 6 .94 (d, J = 8.0 Hz, 2H), 6.12 (s, 1H), 5.03 (s, 2H), 2.98 (s, 1H), 2.16 (s, 1H) . LCMS: m/z = 326, 328 [M+H]+.

[063] Step B: (4-(benzyloxy)phenyl) (4-chloropyridin-3-yl) methanone (3)

[064] A solution of (4-(benzyloxy)phenyl) (4-chloropyridin-3-yl) methanol (2) (1 g, 3.07 mmol) in dry acetone (10 mL) was cooled to 0 OC and CrOs (0.92 g, 9.23 mmol) was added carefully in small portions. The resulting solution was stirred at room temperature until complete consumption of the starting material (3 h), then the reaction was stopped with 2-propanol (6 mL), and the mixture was stirred for 30 min. A saturated NaHCO3 solution (50 ml) was finally added to precipitate the chromium salts which were filtered over celite and washed with CH2Cl2 (6 x 15 ml). The solvent was removed in vacuo and the residue was purified by silica gel column chromatography (gradient: DCM/MeOH = 200:1) to give the title product (0.7 g, 70.7% yield). 1H-NMR (400 MHz, CDCl3): δ 8.61 (d, J = 8.0 Hz, 1H), 8.58 (S, 1H), 7.79 (d, J = 8.0 Hz, 2H ), 7.44-7.35 (m, 6H) 7.04 (d, J = 8.0 Hz, 2H), 5.15 (s, 2H). LCMS: m/z = 324, 326 [M+H]+.

[065] Step C: 3-(4-(benzyloxy)phenyl)-1H-pyrazolo[4,3-c]pyridine (4)

[066] To a stirred solution of (4-(benzyloxy)phenyl) (4-chloropyridin-3-yl) methanone (3) (0.7 g, 2.16 mol) in absolute ethanol (5 ml) was added hydrazine (1.08 g, 17.3 mol). The solution was heated under reflux for 3 h then cooled and the product was separated by filtration and washed consecutively with water and methanol to give the title product (0.54 g, 83% yield). 1H-NMR (400 MHz, DMSO-d6): δ 13.48 (br, 1H), 9.39 (s, 1H), 8.37 (d, J = 8.0 Hz, 1H), 8.01 (d, J = 8.0 Hz, 2H), 7.56-7.35 (m, 6H), 7.18 (d, J = 8.0 Hz, 2H), 5.20 (S, 2H) . LCMS: m/z = 302 [M+H]+.

[067] Step D: (R) -tert-butyl-3-(3-(4-(benzyloxy)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidine-1-carboxylate ( 5)

[068] In a 100 mL 3-neck round bottom flask, a solution of 3-(4-(benzyloxy)phenyl)-1H-pyrazolo[4,3-c]pyridine (4) (0.5 g, 1.66 mmol) in N,N-dimethylformamide (41 mL), (S)-tert-butyl-3-(tosyloxy)pyrrolidine-1-carboxylate (0.68 g, 1.99 mmol), and Cs2CO3 (0.97 g, 2.98 mmol). The resulting solution was stirred for 12 h at 60 °C and then quenched by adding 100 mL of water. The resulting solution was extracted with EA and the organic layers combined. The organics were washed with brine, dried over anhydrous NaHCO3. The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel (gradient: DCM/MeOH = 200:1 - 100:1) to give the title product (0.7 g, yield 89.7 %). 1H-NMR (400 MHz, CDCl3): δ 9.32 (br, 1H), 8.45 (br, 1H), 7.85-7.83 (m, 2H), 7.37-7.36 ( m, 1H), 7.04-7.02 (m, 2H), 5.18-5.15 (m, 1H), 3.963.79 (m, 3H), 3.63-3.59 (m, 1H), 2.89 (br, 1H), 2.45 (br, 1H), 1.47 (s, 9H). LCMS: m/z = 471 [M+H]+.

[069] Step E: (R)-tert-butyl-3-(3-(4-hydroxyphenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidine-1-carboxylate (6)

[070] A suspension of (R)-tert-butyl-3-(3-(4-(benzyloxy)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidine-1-carboxylate ( 5) (0.7 g, 1.48 mmol) and 10% Pd/C (0.1 g) in MeOH (15 mL) was hydrogenated at 50 psi H2 for 3 h. The suspension was filtered through Celite and concentrated. The residue was dried in vacuo to give the title product (0.48 g, 85.7% yield). LCMS: m/z = 381 [M+H]+.

[071] Step F: (R)-tert-butyl 3-(3-(4-phenoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)-pyrrolidine-1-carboxylate (7)

[072] (R)-tert-butyl-3-(3-(4-hydroxyphenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidine-1-carboxylate (6) (50 mg, 0.1 mmol), phenylboronic acid (25.4 mg, 0.2 mmol), TEA (21 mg, 0.2 mmol) and 4A molecular sieves (0.1 g) were added to DCM (10 mL) in a bottle. Copper (II) acetate (18.8 mg, 0.1 mmol) added in one portion. The mixture was stirred for about 22 h at room temperature. The volatile components were removed under vacuum before being poured into H2O. The reaction mixture was extracted with EA, the organic phase was purified by column chromatography on silica gel (gradient: DCM/MeOH = 100/1-50/1) to give the title product (40 mg, yield 88.8 %). LCMS: m/z = 457 [M+H]+.

[073] Step G: (R)-1-(3-(3-(4-phenoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidin-1-yl)prop-2- en-1-one (8)

[074] (R)-tert-butyl 3-(3-(4-phenoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)-pyrrolidine-1-carboxylate (7) (40 mg, 0.087 mmol) was added to CF3COOH/DCM = 4/1 (5 mL) in one portion. The mixture was stirred for about 1 h at rt. The volatile components were removed under vacuum to provide the crude title product (30 mg), and used directly in the next step without further purification. LCMS: m/z = 357 [M+H]+.

[075] To a solution of acryloyl chloride (8.7 mg, 0.095 mmol) in DCM (1 mL) was added to a stirred solution of (R)-3-(4-phenoxyphenyl)-1- (pyrrolidin-3 -yl)-1H-pyrazolo[4,3-c]pyridine (8) (30 mg, 0.087 mmol) and TEA (44 mg, 0.43 mmol) in DCM (5 mL) at 0 °C. The reaction mixture was stirred for 1 h, poured into brine and extracted with DCM. The organic layer was dried, concentrated and recrystallized from DCM/MeOH = 100/1 to provide the title product (16 mg, 45.7% yield). 1H-NMR (400 MHz, CDCl3): δ 9.35 (br, 1H), 8.49 (br, 1H), 7.95-7.91 (m, 2H), 7.40-7.36 ( m, 3H), 7.15-7.08 (m, 5H), 6.53-6.42 (m, 2H), 5.76-5.71 (m, 1H), 5.27-5, 15 (m, 1H), 4.17-4.03 (m, 3H), 3.85-3.82 (m, 1H), 2.79-2.49 (m, 2H). LCMS: m/z = 411.2 [M+H]+.

[076] Example 2: (R)-1-(3-(3-(4-(2-chloro-3-methoxyphenoxy)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin -1-yl)prop-2-en-1-one:

[077] Step A: 1H-pyrazolo[4,3-c]pyridine (2)

[078] To a stirred solution of 1H-pyrazolo[4,3-c]pyridine (1) (17 g, 0.12 mol) in absolute ethanol (120 mL) was added hydrazine (80%) (75 g, 1 .2 mol). The solution was heated under reflux for 5 h, the EtOH was removed in vacuo and the mixture was extracted with EA (10 x 100 mL). The organic phases were combined, dried over Na2SO4. The volatile components were removed under vacuum and the residue was purified by column chromatography on silica gel (gradient: DCM/MeOH = 200: 1-50/1) to give the title product (8 g, 57.1% yield ). 1H-NMR (400 MHz, CDCl3): δ 13.48 (br, 1H), 9.18 (s, 1H), 8.44 (d, J = 6.0 Hz, 1H), 8.25 (s , 1H), 7.45 (d, J = 6.0 Hz, 1H). LCMS: m/z = 120 [M+H]+.

[079] Step B: 3-bromo-1H-pyrazolo[4,3-c]pyridine (3)

[080] To a solution of 1H-pyrazolo[4,3-c]pyridine (2) (8 g, 67.2 mmol) in AcOH (100.0 mL), bromine (5.1 mL, 0.0 mL) was added. 1 mol) at room temperature. The reaction was stirred at room temperature for 72 h and quenched with 10% NaOH (aq.) at pH 12. The organics were separated. The aqueous layer was extracted again with EA (10 x 100 mL). The organic phases were combined, dried over Na2SO4, the volatile components were removed under vacuum and the residue was purified by silica gel column chromatography (gradient: DCM/MeOH = 200: 1-50/1) to give the title product (4.5 g, 34.3% yield). 1H-NMR (400 MHz, CDCl3): δ 13.32 (br, 1H), 9.06 (s, 1H), 8.54 (d, J = 5.6 Hz, 1H), 7.43 (d , J = 5.6 Hz, 1H). LCMS: m/z = 198, 200 [M+H]+.

[081] Step D: (R)-tert-butyl-3-(3-bromo-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate (4)

[082] In a 100 mL round bottom flask, a solution of 3-bromo-1H-pyrazolo[4,3-c]pyridine (3) (2 g, 10 mmol) in DMF (20 mL) was placed, (S)-tert-butyl 3-(tosyloxy)piperidine-1-carboxylate (4.3 g, 12 mmol) and Cs2CO3 (5.9 g, 18 mmol). The resulting solution was stirred for 24 h at 65 °C and then quenched by the addition of 100 mL of water. The resulting solution was extracted with EA and the organic layers combined. The organics were washed with brine, dried over anhydrous NaHCO3. The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel (gradient: DCM/MeOH = 200:1 - 100:1) to give the title product (0.8 g, yield 21.0 %). 1H-NMR (400 MHz, CDCl3): δ 8.97 (s, 1H), 8.48 (d, J = 5.6 Hz, 1H), 7.36 (d, J = 5.6 Hz, 1H ), 4.43-4.38 (m, 3H), 3.2 (br, 1H), 2.88-2.81 (m, 1H), 2.30-2.17 (m, 2H), 1.95-1.91 (m, 1H), 1.72-1.62 (m, 1H), 1.46 (s, 9H). LCMS: m/z = 382 [M+H]+.

[083] Step E: (R)-tert-butyl-3-(3-(4-(2-chloro-3-methoxyphenoxy)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl) piperidine-1 -carboxylate (5)

[084] A solution of 4 (100 mg, 0.262 mmol) and (4-(2-chloro-3-methoxyphenoxy)phenyl) boronic acid (109.9 mg, 0.393 mmol) in toluene (5 mL) and water ( 1 mL) K2CO3 (72 mg, 0.524 mmol) was added followed by (Ph3P)4Pd (30 mg) under N2 with stirring. The mixture was refluxed for 8 h until the material disappeared. The reaction mixture was cooled to room temperature. Dioxane was removed by rotary evaporation. The residue was poured into water and extracted with EA. The organic layer was dried over Na2SO4, filtered and the solvent was removed in vacuo, the residue was purified by flash chromatography on silica gel using 100:1 - 50:1 DCM:MeOH, to give the title product (50 mg) . LCMS: m/z = 534.2 [M+H]+.

[085] Step F: (R)-1-(3-(3-(4-(2-chloro-3-methoxyphenoxy)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine -1-yl)prop-2-en-1-one (6)

[086] Intermediate 5 (50 mg, 0.093 mmol) was added to CF3COOH/DCM = 4/1 (5 mL) in one portion. The mixture was stirred for about 2 h at rt. The volatile components were removed under vacuum to provide the crude title product, and used directly in the next step without further purification. A solution of acryloyl chloride (8.5 mg, 0.095 mmol) in DCM (1 mL) was added to a stirred solution of crude residue, TEA (44 mg, 0.43 mmol) in DCM (5 mL) at 0 oC. . The reaction mixture was stirred for 1 h, poured into brine and extracted with DCM. The organic layer was dried, concentrated and recrystallized from DCM/MeOH = 100/1 to provide the title product (29 mg, 65% yield). 1H-NMR (400 MHz, CDCl3): δ 9.35 (s, 1H), 8.45 (d, J = 5.6 Hz, 1H), 7.93 (d, J = 8.4 Hz, 2H ), 7.45-7.34 (m, 1H) 7.24-7.20 (m, 2H), 7.11 (d, J = 8.4 Hz, 2H), 6.80 (d, J = 8.4 Hz, 1H), 6.73 (d, J = 8.4 Hz, 2H), 26.68-6.53 (m, 1H), 6.38-6.34 (m, 1H) , 5.77-5.69 (m, 1H), 4.94-4.91 (m, 0.5H), 4.72-4.48 (br, 1.4H), 4.25-4, 07 (m, 1H), 3.96 (s, 3H), 3.803,3.78 (m, 0.6H), 3.24-3.22 (m, 1H), 2.91 (br, 0, 4H), 2.50-2.47 (m, 1H), 2.30-2.28 (m, 1H), 2.06-2.02 (m, 1H), 1.73-1.71 ( m, 1H). LCMS: m/z = 489.2 [M+H]+.

[087] Example 3: (R)-1-(3-(3-(4-(2-fluoro-3-methoxyphenoxy)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidin -1-yl)prop-2-en-1-one:

[088] Step A: 1-(4-bromophenoxy)-2-fluoro-3-methoxybenzene (1)

[089] To a solution of 1-bromo-4-iodobenzene (20.7 g, 73 mmol, 1.0 eq) in dioxene (180 mL) was added 2-fluoro-3-methoxyphenol (10.4 g, 73 mmol, 1.0 eq), CuI (1.39 g, 7.3 mmol, 0.1 eq), N,N-dimethylglycine hydrochloride (2.03 g, 14.6 mmol, 0.2 eq), Cs2CO3 (35.9 g, 109.5 mmol, 1.5 eq). The mixture was stirred at 100 oC in N2 for 15 h, then the mixture was filtered, contracted and extracted with EA, the organic layer was washed with water and brine, dried with anhydrous Na2SO4, concentrated and the residue was purified by chromatography. of silica gel column to provide the product of title 1 (9.2 g, 42.4%). 1H-NMR (400 MHz, CDCl3): δ 7.59 (d, J = 7.6 Hz, 1H), 7.41 (d, J = 8.0 Hz, 1H), 7.00-7.04 (m, 1H), 6.87 (d, J = 8.0 Hz, 1H), 6.74-6.81 (m, 2H), 6.62-6.66 (m, 1H), 3, 92 (s, 3H).

[090] Step B: (4-(2-fluoro-3-methoxyphenoxy)phenyl)boronic acid

[091] To a solution of 1 (9.2 g, 30.96 mmol, 1.0 eq) in THF (100 mL) was cooled to -78 oC under N2, n-BuLi (16.1 mL, 40.25 mmol, 1.3 eq) dropwise under the same temperature. The mixture was stirred for 50 min at the same temperature. Triisopropyl borate (7.57 g, 40.25 mmol, 1.3 eq) was added dropwise under the same temperature. After 15 min, the mixture was left at room temperature and stirred for 2 h, then 1N HCl was added to adjust to pH = 5.0 and stirred for 30 min, then the mixture was extracted with EA. The organic layer was washed with water and brine, dried with anhydrous Na2SO4, filtered and concentrated to provide the crude title product 2 (7.8 g, 95.8%).

[092] Step C: (R)-tert-butyl 3-(3-Bromo-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidine-1-carboxylate (3)

[093] In a 100 mL round bottom flask, a solution of 3-bromo-1H-pyrazolo[4,3-c]pyridine (2.45 g, 23.34 mmol, 1.0 eq) was placed in DMF (40 mL), (S)-tert-butyl 3-(tosyloxy)piperidine-1-carboxylate (5.06 g, 14.48 mmol, 1.2 eq) and Cs2CO3 (6.1 g, 18.55 mmol, 1.5 eq). The resulting solution was stirred for 12 h at 65 °C and then quenched by the addition of 100 mL of water. The resulting solution was extracted with EA (80 mL * 3) and the organic layers were combined. The organics were washed with brine, dried over anhydrous Na2CO3. The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel (DCM/MeOH = 200:1 - 100:1) to give the title product (3.5 g, 76.9% yield). . 1H-NMR (400 MHz, CDCl3): δ 8.98 (s, 1H), 8.50 (d, J = 4.8 Hz, 1H), 7.32 (d, J = 5.6 Hz, 1H ), 3.91 (s, 1H), 3.76 -3.80 (m, 2H), 3.53-3.59 (m, 1H), 2.59 (s, 1H), 2.38- 2.44 (m, 1H), 1.48 (s, 9H). LCMS: m/z = 367 [M+H]+.

[094] Step D: (R)-tert-butyl 3-(3-(4-(2-fluoro-3-methoxyphenoxy)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidine -1-carboxylate (4)

[095] A solution of 3 (430 mg, 1.17 mmol, 1.0 eq) and 2 (460 mg, 1.76 mmol, 1.5 eq) in dioxane (20 mL) and water (3 mL) K2CO3 (324 mg, 2.34 mmol, 2.0 eq) and (Ph3P)4Pd (30 mg) were added under N2 with stirring. The mixture was refluxed for 6 h until the material disappeared. The reaction mixture was cooled to room temperature. Dioxane was removed by rotary evaporation. The residue was poured into water and extracted with EA. The organic layer was dried over Na2SO4, filtered and the solvent was removed by rotary evaporation. The residue was purified by flash chromatography on silica gel (DCM: MeOH = 100:1 - 50:1) to give the title product (0.5 g, 84.4% yield). 1H-NMR (400 MHz, CDCl3): δ 9.33 (s, 1H), 8.46 (d, J = 5.2 Hz, 1H), 7.94 (d, J = 8.4 Hz, 2H ), 7.34 (d, J = 5.6 Hz 1H, 7.14 (d, J = 8.8 Hz, 2H), 7.03-7.08 (m, 1H), 6.80-6 .84 (m, 1H), 6.71-6.75 (m, 1H), 5.18 (s, 1H), 3.94 (s, 6H), 3.59 (s, 1H), 2. 64 (s, 1H), 2.41-2.46 (m, 1H), 1.47 (s, 9H) LCMS: m/z = 505 [M+H]+.

[096] Step E: (R)-1-(3-(3-(4-(2-fluoro-3-methoxyphenoxy)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidin -1-yl)prop-2-en-1-one (5):

[097] Intermediate 4 (870 mg, 1.73 mmol, 1.0 eq) was dissolved in DCM (30 mL), added TFA (2.5 mL) in one portion. The mixture was stirred for about 1.5 h at rt. The volatile components were removed under vacuum to provide the crude title product and used directly in the next step without further purification. The crude product was dissolved in DCM (20 mL), added TEA to the solution until pH = 8.0, then added acryloyl chloride (187 mg, 2.07 mmol, 1.2 eq) in DCM (3.0 mL) dropwise to the solution. The reaction mixture was stirred for 0.5 h, poured into water and extracted with DCM. The organic layer was dried with anhydrous Na2SO4, filtered and concentrated, the residue was purified by silica gel column chromatography (DCM/MeOH = 200:1 - 50:1) to give the title product (400 mg, yield 50 .6%). 1H-NMR (400 MHz, CDCl3): δ 9.34 (d, J = 4.4 Hz, 1H), 8.47-8.49 (m, 1H), 7.90-7.94 (m, 2H), 7.34 (d, J = 4.8 Hz, 1H), 7.12-7.14 (m, 2H), 7.03-7.07 (m, 1H), 6.80-6 .84 (m, 1H), 6.71-6.75 (m, 1H), 6.40-6.52 (m, 2H), 5.695.75 (m, 1H), 5.20-5.23 (m, 1H), 4.06-4.17 (m, 3H), 3.94 (s, 3H), 3.81-3.85 (m, 1H), 2.47-2.78 (m , 2H). LCMS: m/z = 459.1 [M+H]+.

[098] Example 4: (R)-1-(3-(3-(4-(2-chloro-3-fluorophenoxy)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidin -1-yl)prop-2-en-1-one:

[099] Step A: tert-butyl (R)-3-(3-(4-(2-chloro-3-fluorophenoxy)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidine -1-carboxylate (2)

[0100] A solution of 1 (80 mg, 0.22 mmol, 1.0 eq) and corresponding boronic acid (88 mg, 0.33 mmol, 1.5 eq) in toluene (10 mL) and water (2 mL) K2CO3 (61 mg, 0.44 mmol, 2.0 eq) and (Ph3P)4Pd (25 mg, 0.1 eq) were added under N2 with stirring. The mixture was refluxed for 6 h until the material disappeared. The reaction mixture was cooled to room temperature. Toluene was removed by rotary evaporation. The residue was poured into water and extracted with EA. The organic layer was dried over Na2SO4, filtered and the solvent was removed by rotary evaporation. The product was purified with flash chromatography on silica gel (DCM: MeOH = 100:1 - 50:1), providing the title product (90 mg, 81% yield). LCMS: m/z = 509 [M+H]+.

[0101] Step B: (R)-1-(3-(3-(4-(2-chloro-3-fluorophenoxy)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidin -1-yl)prop-2-en-1-one:

[0102] Intermediate 2 (90 mg, 0.18 mmol, 1.0 eq) was dissolved in DCM (4 mL), added TFA (1 mL) in one portion. The mixture was stirred for about 1.5 h at rt. The volatile components were removed under vacuum to provide the crude title product which was used directly in the next step without further purification. The crude product was dissolved in DCM (4 mL), added TEA to the solution at pH = 8.0, then added acryloyl chloride (16 mg, 0.18 mmol, 1.0 eq) in DCM (1.0 mL) dropwise to the solution. The reaction mixture was stirred for 0.5 h, poured into water and extracted with DCM. The organic layer was dried with anhydrous Na2SO4, filtered and concentrated, the residue was purified by silica gel column chromatography (DCM/MeOH = 200:1 - 50 1) to give the title product (40 mg, 50% yield ). 1H-NMR (400 MHz, CDCl3): δ 9.35 (d, J = 4.1 Hz, 1H), 8.49 (t, J = 5.9 Hz, 1H), 7.96 (dd, J = 8.2, 6.0 Hz, 2H), 7.41 - 7.31 (m, 1H), 7.25 - 7.17 (m, 1H), 7.13 (dd, J = 8.6 , 2.5 Hz, 2H), 7.00 (t, J = 8.4 Hz, 1H), 6.87 (d, J = 8.3 Hz, 1H), 6.48 (ddd, J = 14 .5, 13.7, 7.2Hz, 2H), 5.83-5.65 (m, 1H), 5.38-5.15 (m, 1H), 4.26-3.94 (m , 3H), 3.95-3.69 (m, 1H), 2.85-2.42 (m, 2H). LCMS: m/z = 463.2 [M+H]+.

[0103] Example 5: (R)-1-(3-(3-(4-(2-fluoro-3-methoxy-phenoxy)-phenyl)-7-methyl-1H-pyrazolo[4,3-c] pyridin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one:

[0104] Step A: 4-(2-fluoro-3-methoxyphenoxy) benzaldehyde (1)

[0105] To a solution of 4-bromobenzaldehyde (6.99 g, 38 mmol, 1.2 eq) in dioxene (100 mL) was added 2-fluoro-3-methoxyphenol (4.5 g, 32 mmol, 1. 0 eq), CuI (0.60 g, 3.2 mmol, 0.1 eq), N,N-dimethylglycine hydrochloride (1.32 g, 9.5 mmol, 0.3 eq), Cs2CO3 (20. 59 g, 60 mmol, 2 eq). The mixture was stirred at 100°C in N2 for 15 h. The mixture was filtered, contracted and extracted with EtOAc. The organic layer was washed with water and brine, dried with anhydrous Na2SO4, and purified by silica gel column chromatography to provide the title product. (4.1 g, 52.6%). 1H-NMR (400 MHz, CDCl3): δ 9.9 (s, 1H), 7.85-7.83 (m, 2H), 7.26-7.04 (m, 3H), 6.89- 6.85 (m, 1H), 6.77-6.73 (m 1H) 3.92 (s, 3H).

[0106] Step B: 4,5-(dichloropyridin-3-yl)(4-(2-fluoro-3-methoxy-phenoxy)phenyl)-methanol (2)

[0107] To a solution of diisopropylamine (2.1 mL, 15.1 mmol, 1.1 eq) in dry THF (24 mL) at -78 oC was added a solution of 2.5 M BuLi in hexane (8 .2 mL, 20.0 mmol, 1.3 eq). The mixture was allowed to warm to 0°C and stirred for about 1 hour. After this time, the solution was cooled to -78 °C and 3,4-dichloropyridine (2.0 g, 13.7 mmol, 1 eq) in 5 mL of dry THF was added. The reaction mixture was stirred for a further 4 h and then the corresponding 4-(2-fluoro-3-methoxyphenoxy)benzaldehyde (3.36 g, 13.7 mmol, 1 eq) was added and the mixture was stirred and left warm to room temperature overnight. Excess LDA was destroyed with H2O (25 mL) and the mixture was extracted with Et2O (3x50 mL). The organic phases were combined, dried over Na2SO4, the volatile components were removed under vacuum and the residue was purified by silica gel column chromatography (gradient: DCM/MeOH = 200:1 - 50/1) to give the title product (4.5 g, 83.6% yield). 1H-NMR (400 MHz, CDCl3): δ 8.78 (s, 1H), 8.55 (s, 1H), 7.30 (d, J = 8.0 Hz, 2H), 7.02 (d , J = 8.0 Hz, 2H), 6.98 -66.66 (m, 3H), 6.12 (s, 1H), 3.93 (s, 3H). LCMS: m/z = 394.1 [M+H]+.

[0108] Step C: (4,5-dichloropyridin-3-yl)(4-(2-fluoro-3-methoxyphenoxy)phenyl)-methanone (3)

[0109] A solution of 4,5-(dichloropyridin-3-yl)(4-(2-fluoro-3-methoxyphenoxy)phenyl)methanol (2) (1 g, 2.5 mmol) in dry acetone (10 mL ) was cooled to 0°C and CrO3 (0.92 g, 9.23 mmol) was added carefully in small portions. The resulting solution was stirred at room temperature until complete consumption of the starting material (3 h), after this time the reaction was stopped with 2-propanol (6 mL) and the mixture was stirred for 30 min. A saturated NaHCO3 solution (50 mL) was finally added to precipitate the chromium salts which were filtered over celite and washed with CH2Cl2 (6 x 15 mL). The solvent was removed in vacuo and the residue was purified by silica gel column chromatography (gradient: DCM/MeOH = 200:1) to give the title product (0.69 g, 70.7% yield). LCMS: m/z = 392.1 [M+H]+.

[0110] Step D: 7-chloro-3-(4-(2-fluoro-3-methylphenoxy)phenyl)-1H-pyrazolo[4,3-c]pyridine (4)

[0111] To a stirred solution (4-(benzyloxy)phenyl)(4-chloropyridin-3-yl)methanone (3) (0.7 g, 1.77 mol) in absolute ethanol (5 mL) was added hydrazine ( 1.08 g, 17.3 mol). The solution was heated under reflux for 3 h, cooled, the product removed by filtration and washed consecutively with water and methanol to give the title product (0.54 g, 83% yield). 1H-NMR (400 MHz, CDCl3): δ 9.30 (s, 1H), 8.37 (s, 1H), 8.01 (d, J = 8 Hz, 2H), 7.13-7.3 .74 (m, 4H), 7.18 (d, J = 8 Hz, 2H), 3.92 (S, 3H). LCMS: mz = 370.1 [M+H]+.

[0112] Step E: (R) tert-butyl 3-(7-chloro-3-(4-(2-fluoro-3-methoxy-phenoxy)phenyl)-1H-pyrazolo[4,3-c]pyridin- 1-yl)pyrrolidine-1-carboxylate (5)

[0113] In a 100 mL 3-neck round bottom flask, a solution of 3-(4-(benzyloxy)phenyl)-1H-pyrazolo[4,3-c]pyridine (4) (0.52 g, 1.41 mmol) in N,N-dimethylformamide (41 mL), (S)-tert-butyl-3-(tosyloxy)pyrrolidine-1-carboxylate (0.68 g, 1.99 mmol), and Cs2CO3 (0.97 g, 2.98 mmol). The resulting solution was stirred for 12 h at 60 °C and then quenched by adding 100 mL of water. The resulting solution was extracted with EA and the organic layers combined. The organics were washed with brine, dried over anhydrous NaHCO3. The solvent was removed in vacuo and the residue was purified by silica gel column chromatography (gradient: DCM/MeOH = 200:1 - 100:1) to give the title product (0.68 g, 90% yield) . LCMS: m/z = 539.1 [M+H]+.

[0114] Step F: ((R)-tert-butyl3-(3-(4-(2-fluoro-3-methoxyphenoxy)phenyl)-7-methyl-1H-pyrazolo[4,3-c]pyridin-1 -yl)pyrrolidine-1-carboxylate (6)

[0115] To a solution of (R)-tert-butyl 3-(7-chloro-3-(4-(2-fluoro-3-methoxyphenoxy)phenyl)-1H-pyrazolo[4,3-c]pyridin- 1-yl)pyrrolidine-1-carboxylate (100 mg, 0.18 mmol), methylboronic acid (12.2 mg, 0.20 mmol), K3PO4. H2O (102 mg, 0.44 mmol) and tricyclohexylphosphine (10.09 mg, 0.036 mmol) in toluene (10.0 mL) and water (2 mL) under a nitrogen atmosphere were added to diacetoxypalladium (5 mg g, 0.018 mmol). The mixture was heated to 100 °C overnight and then cooled to room temperature. Water (100 mL) was added and the mixture was extracted with EtOAc, the combined organics were washed with brine, dried over MgSO4 and concentrated in vacuo to give the crude compound. The residue was purified by silica gel column chromatography (DCM/MeOH = 200:1 - 50:1) to give the title product (25 mg, 26% yield). LCMS: m/z = 519.1 [M+H]+.

[0116] Step G: (R)-1-(3-(3-(4-(2-fluoro-3-methoxy-phenoxy)-phenyl)-7-methyl- 1H-pyrazolo[4,3-c] pyridin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one (7)

[0117] ((R)-tert-butyl 3-(3-(4-(2-fluoro-3-methoxyphenoxy)phenyl)-7-methyl- 1H-pyrazolo[4,3-c]pyridin-1-yl )pyrrolidine-1-carboxylate (25 mg, 0.048 mmol) was added to CF3COOH/DCM = 4/1 (5 mL) in one portion. The mixture was stirred for about 1 h at rt. to provide the crude title product (20 mg), and used directly in the next step without further purification LCMS: m/z = 419 [M+H]+.

[0118] A solution of acryloyl chloride (4.3 mg, 0.048 mmol) in DCM (1 mL) was added to a stirred solution of (R)-3-(4-(2-fluoro-3-methoxyphenoxy)phenyl )-7-methyl-1-(pyrrolidin-3-yl)-1H-pyrazolo[4,3-c]pyridine (472-7) (20 mg, 0.048 mmol) and TEA (44 mg, 0.43 mmol) in DCM (5 mL) at 0 oC. The reaction mixture was stirred for 1 h, poured into brine and extracted with DCM. The organic layer was dried, concentrated and recrystallized from DCM/MeOH = 100/1 to give the title product (11 mg, 50% yield). 1H-NMR (400 MHz, CDCl3): δ 9.18 (br, 1H), 8.21 (br, 1H), 7.89-7.86 (m, 2H), 7.26-7.02 ( m, 3H), 6.83-6.49 (m, 2H), 6.43-6.41 (m, 2H), 5.74-5.71 (m, 1H), 5.34-5, 29 (m, 1H), 4.13-3.93 (m, 6H), 2.73-2.19 (m, 4H), 2.04-2.00 (m, 2H). LCMS: m/z = 473.2 [M+H]+.

[0119] Example 6: (R)-1-(3-(3-(4-(2-fluoro-3-methoxyphenoxyphenyl)-7-methoxy-1H-pyrazolo[4,3-c]pyridin-1-yl )piperidin-1-yl)prop-2-en-1-one:

[0120] Step A: (4-chloro-5-fluoropyridin-3-yl)(4-(2-fluoro-3-methoxyphenoxy)phenyl)methanol (1)

[0121] To a solution of 4-chloro-3-fluoropyridine (6.4.0 g, 49 mmol, 1.2 eq) in anhydrous THF (100 mL) was added LDA (2 N, 25.6 mL) dropwise Drop slowly at -65 degrees under nitrogen atmosphere. After the addition was complete, the resulting solution was stirred at that temperature for 4.0 h. Then, a solution of 4-(2-fluoro-3-methoxyphenoxy) benzaldehyde (10.0 g, 41 mmol, 1.0 eq) in anhydrous THF (20 mL) was added carefully at the same temperature. After addition, the reaction was stirred at room temperature (15 degrees) for 1.0 h, monitored by TLC and LCMS. The reaction mixture was quenched with water, then poured into water, extracted with ethyl acetate, washed with water and brine. The organic layer was dried over anhydrous Na2SO4, concentrated in vacuo to provide crude product 1 and used for the next step without further purification. LCMS: m/z = 378.1 [M+H]+.

[0122] Step B: (4-chloro-5-fluoropyridin-3-yl)(4-(2-fluoro-3-methoxyphenoxy)phenyl) methanone (2)

[0123] To a solution of 1 (10.0 g, (crude), 26.53 mmol, 1.0 eq) in DCM was added Dess-Martin (22.5 g, 53.05 mmol, 2.0 eq ) in portions slowly under an ice bath. The resulting solution was stirred at 15 degrees for 4.0 h, monitored by TLC and LCMS. The reaction mixture was added to saturated NaHCO3 solution, then filtered. The filtrate was poured into water, extracted with DCM, washed with saturated NaHCO3, Na2SO3 solution, water and brine. The organic solution was dried over anhydrous Na2SO4, concentrated in vacuo to give crude product 2 (10.0 g) and used for the next step without further purification. LCMS: m/z = 376.1 [M+H]+.

[0124] Step C: 7-fluoro-3-(4-(2-fluoro-3-methoxyphenoxy)phenyl)-1H-pyrazolo[4,3-c]pyridine (3)

[0125] To a solution of 2 (48 g, 128 mmol, 1.0 eq) in EtOH (300 mL) was added N2H4 • H2O (64 g, 1.28 mol, 10.0 eq). The resulting solution was stirred at 90 degrees for 2.5 h. The reaction was monitored by TLC and LCMS, and the reaction mixture was cooled to room temperature then filtered. The cake was washed with EtOH and EA, dried under vacuum to give pure product 3 (33.3 g). 1H-NMR (400 MHz, D6-DMSO): δ 9.24-9.23 (d, J = 2.0 Hz, 1H), 8.39-8.38 (d, J = 2.4 Hz, 1H), 8.08-8.06 (d, J = 8.8 Hz, 2H), 7.22-7.17 (m, 1H), 7.14-7.06 (m, 3H), 6 .86-6.82 (m, 1H), 3.90 (s, 3H). LCMS: m/z = 354.1 [M+H]+.

[0126] Step D: (R)-tert-butyl-3-(7-fluoro-3-(4-(2-fluoro-3-methoxyphenoxy)phenyl)-1H-pyrazolo[4,3-c]pyridin- 1-yl)piperidine-1-carboxylate (4)

[0127] A solution of 3 (20 g, 57 mmol, 1.0 eq), (S)-tert-butyl 3-(tosyloxy)piperidine-1-carboxylate (40 g, 113 mmol, 2.0 eq), cesium carbonate (37 g, 113 mmol, 2.0 eq) in DMF (20 mL) was stirred at 60 degrees for 60 h. The reaction was monitored by LC-MS. The reaction mixture was cooled to room temperature, poured into water. The mixture was extracted with ethyl acetate, washed with water and brine. The organic layer was dried over anhydrous Na2SO4, concentrated in vacuo. The product was purified by column chromatography on silica gel (DCM: MeOH = 200:1 to 150:1) to give 4 (17 g). 1H- NMR (400 MHz, CDCl3): δ 9.09 (s, 1H), 8.30-8.29 (d, J = 3.2 Hz, 1H), 7.91-7.89 (d, J = 8.4 Hz, 2H), 7.14-7.12 (d, J = 8.4 Hz, 2H), 7.08-7.03 (m, 1H), 6.84-6.80 (m, 1H), 6.74-6.71 (m, 1H), 4.75-4.73 (m, 1H), 4.13-4.11 (m, 3H), 3.93 (s , 3H), 3,413.38 (m, 1H), 2.92-2.86 (m, 1H), 2.44-2.29 (m, 2H), 1.95-1.86 (m, 1H ), 1.73-1.70 (m, 1H), 1.47-1.42 (m, 9H). LCMS: m/z = 537.2 [M+H]+.

[0128] Step E: (R)-tert-butyl-3-(3-(4-(2-fluoro-3-methoxyphenoxy)phenyl)-7-methoxy-1H-pyrazolo[4,3-c]pyridin- 1-yl)piperidine-1-carboxylate (5)

[0129] A solution of 4 (15 g, 28.0 mmol, 1.0 eq), MeONa (15 g, 280 mmol, 10.0 eq) in MeOH (120 mL) was added to a 250 ml sealing tube. mL, stirred at 100 degrees overnight. The reaction was monitored by TLC and LC-MS. The reaction mixture was cooled to room temperature, poured into water, extracted with ethyl acetate, washed with water and brine. The organic layer was dried over anhydrous Na2SO4, concentrated in vacuo to provide the crude product. The product was purified by column chromatography on silica gel (DCM: MeOH = 150:1 to 100:1) to give 5 (13.2 g). 1H-NMR (400 MHz, CDCl3): δ 8.94 (s, 1H), 7.99 (s, 1H), 7.91-7.89 (d, J = 8.8 Hz, 2H), 7 .13-7.11 (d, J = 8.8 Hz, 2H), 7.06-7.01 (m, 1H), 6.82-6.78 (m, 1H), 6.73-6 .69 (m, 1H), 5.06-5.04 (m, 1H), 4.14-4.11 (m, 1H), 4.08 (s, 3H), 3.93 (s, 3H ), 3.37 (s, 1H), 2.89-2.83 (m, 1H), 2.30-2.24 (m, 2H), 1.92 (s, 1H), 1.70- 1.67 (m, 1H), 1.48-1.44 (m, 11H). LCMS: m/z = 549.2 [M+H]+.

[0130] Step F: (R)-3-(4-(2-fluoro-3-methoxyphenoxy)phenyl)-7-methoxy-1-(piperidin-3-yl)-1H-pyrazolo[4,3-c ]pyridine (6)

[0131] To a solution of 5 (13 g, 23.7 mmol) in DCM (100 mL) TFA (14 mL) was added at 18 degrees for 4.0 h, the reaction was monitored by LC-MS and TLC. The reaction mixture was concentrated under vacuum to provide crude product 6 (5.5 g) and used for the next step without further purification. LCMS: m/z = 449.2 [M+H]+.

[0132] Step G: (R)-1-(3-(3-(4-(2-fluoro-3-methoxyphenoxy)phenyl)-7-methoxy-1H-pyrazolo[4,3-c]pyridin-1 -yl)piperidin-1-yl)prop-2-en-1-one (7)

[0133] To a solution of 6 (5.5 g, crude), TEA (2.2 g, 21.9 mmol, 2.0 eq) in anhydrous DCM (50 mL) was added acryloyl chloride (40 mg/ mL in anhydrous DCM) at -30 degrees. The resulting solution was stirred at 18 degrees for 30 min, monitored by LC-MS and TLC. The reaction mixture was quenched with water, and then poured into water, extracted with DCM, washed with water and brine. The organic solution was dried over anhydrous Na2SO4, concentrated in vacuo. The product was purified by column chromatography on silica gel (DCM: MeOH = 200:1 to 150:1 to 100:1) to give 7 (3.2 g). 1H-NMR (400 MHz, CDCl3): δ 8.95 (s, 1H), 8.00 (s, 1H), 7.91-7.89 (d, J = 8.8 Hz, 2H), 7 .14-7.11 (d, J = 8.4 Hz, 2H), 7.06-7.02 (m, 1H), 6.83-6.79 (m, 1H), 6.73-6 .70 (m, 1H), 6.64-6.61 (m, 1H), 6.346.30 (m, 1H), 5.73 5.67 (m, 1H), 5.07-4.66 ( m, 2H), 4.29-4.06 (m, 4H), 3.93 (m, 3H), 3.625-2.82 (m, 2H), 2.32-1.72 (m, 4H) . LCMS: m/z = 503.2 [M+H]+.

[0134] The following additional Examples 7-99 shown in the Table below were prepared following the procedures outlined in the general methods above and detailed in Examples 1-6.

[0135] Example 100: (R)-1-(3-(3-(4-((2-fluorobenzyl)oxy)phenyl)-1Hpyrazolo[4,3-c]pyridin-1-yl)pyrrolidin-1- il)prop-2-en-1-one:

[0136] Step A: (R)-tert-butyl-3-(3-(4-((2-fluorobenzyl)oxy)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidine -1- carboxylate (1)

[0137] In a 100 mL round bottom flask, a solution of (R)-tert-butyl-3-(3-(4-hydroxyphenyl)-1H-pyrazolo[4,3-c]pyridin-1- il)pyrrolidine-1-carboxylate (30 mg, 0.078 mmol) in DMF (3 mL), 1-(bromomethyl)-2-fluorobenzene (22 mg, 0.117 mmol) and Cs2CO3 (51.3 mg, 0.16 mmol) . The resulting solution was stirred for 3 h at rt, and then quenched by the addition of 100 mL of water. The resulting solution was extracted with EtOAc and the organic layers combined. The organics were washed with brine, dried over anhydrous Na2SO4. The solvent was removed under vacuum and the residue was purified by silica gel column chromatography (gradient: DCM/MeOH = 200:1 - 100:1) to give the title product (30 mg, 80% yield). LCMS: m/z = 489.2 [M+H]+.

[0138] Step B: (R)-1-(3-(3-(4-((2-fluorobenzyl)oxy)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidin- 1-yl)prop-2-en-1-one (2)

[0139] ((R)-tert-butyl 3-(3-(4-(2-fluoro-3-methoxyphenoxy)phenyl)-7-methyl- 1H-pyrazolo[4,3-c]pyridin-1-yl )pyrrolidine-1-carboxylate (30 mg, 0.061 mmol) was added to CF3COOH/DCM = 4/1 (5 mL) in one portion. The mixture was stirred for about 1 h at rt. to provide the crude title product (24 mg), and used directly in the next step without further purification LCMS: m/z = 389.2 [M+H]+.

[0140] A solution of acryloyl chloride (5.5 mg, 0.061 mmol) in DCM (1 mL) was added to a stirred solution of (R)-3-(4-((2-fluorobenzyl)oxy)phenyl) -1-(pyrrolidin-3-yl)-1H-pyrazolo[4,3-c]pyridine (24 mg, 0.061 mmol) and TEA (44 mg, 0.43 mmol) in DCM (5 mL) at 0°C . The reaction mixture was stirred for 1 h, poured into brine and extracted with DCM. The organic layer was dried, concentrated and recrystallized from DCM/MeOH = 100/1 to give the title product (13 mg, 50% yield). 1H-NMR (400 MHz, CDCl3): δ 9.18 (br, 1H), 8.48 (br, 1H), 7.93-7.89 (m, 2H), 7.55-7.52 ( m, 1H), 7.34-7.26 (m, 2H), 7.20-7.09 (m, 4H), 6.52-6.40 (m, 2H), 5.75-5, 70 (m, 1H), 5.27-5.23 (m, 1H), 5.22 (s, 1H), 4.16-4.07 (m, 3H), 3.82-3.80 ( m, 1H), 2.89-2.49 (m, 2H). LCMS: m/z = 443.2 [M+H]+.

[0141] The following additional Examples 101, 102 shown in the Table below were prepared following the procedures outlined in the general methods above and detailed in Example 100.

[0142] Example 103: (R)-4-(1-(1-acryloylpyrrolidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)-N-(3-methoxybenzyl) benzamide :

[0143] Step A: (R)-tert-butyl 3-(3-(4-(methoxycarbonyl)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidine-1-carboxylate (1 ):

[0144] To a solution of (R)-tert-butyl 3-(3-bromo-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidine-1-carboxylate (105 mg, 0.286 mmol, 1 .0 eq) and (4-(methoxycarbonyl)phenyl) boronic acid (77 mg, 0.429 mmol, 1.5 eq) in dioxane (8.0 mL) and water (1.0 mL), K2CO3 (79 mg , 0.572 mmol, 2.0 eq) and (Ph3P)4Pd (20 mg) under N2 with stirring. The mixture was refluxed for 5.5 hours until the material disappeared. The reaction mixture was cooled to room temperature. Dioxane was removed by rotary evaporation. The residue was poured into water and extracted with EA. The organic layer was dried over Na2SO4, filtered and the solvent was removed in vacuo and the residue was purified by flash chromatography on silica gel (DCM: MeOH = 100:1 - 50:1) to give the title product (90 mg, yield of 77.4%). 1H-NMR (400 MHz, CDCl3): δ 9.45 (s, 1H), 8.53 (s, 1H), 8.19 (d, J = 8.4 Hz, 2H), 8.04-8 .11 (m, 3H), 5.20 (s, 1H), 3.97 (s, 3H), 3.93 (s, 3H), 3.61 (s, 1H), 2.62-2, 66 (m, 1H), 2.46 (d, J = 6.0 Hz, 1H), 1.48 (s, 9H). LCMS: m/z = 423 [M+H]+.

[0145] Step B: (R)-4-(1-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl) benzoic acid (2 ):

[0146] To a solution of 1 (90 mg, 0.213 mmol, 1.0 eq) in THF (5.0 mL) and EtOH (5.0 mL), LiOH (45 mg, 1.067 mmol, 5.0 eq). The mixture was stirred at room temperature until the starting material disappeared, water was added, then 1N HCl was added to adjust to pH = 5.0, then the mixture was extracted with EA. The organic layer was washed with water and brine, dried with anhydrous Na2SO4, filtered and concentrated to provide the crude product of title 2 (75 mg, 86.2%) used in the next step without purification. LCMS: m/z = 409 [M+H]+.

[0147] Step C: (R)-tert-butyl 3-(3-(4-((3-methoxybenzyl) carbamoyl)phenyl)- 1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidine- 1-carboxylate (3)

[0148] In a 50 mL round bottom flask, a solution of 2 (75 mg, 0.184 mmol, 1.0 eq) in THF (5.0 mL), (3-methoxyphenyl) methylamine (38 mg, 0.276 mmol, 1.5 eq) and TEA (47 mg, 0.460 mmol, 2.5 eq), HATU (84 mg, 0.221 mmol, 1.2 eq). The resulting solution was stirred for 1.5 h at room temperature. The reaction mixture was stopped with 30 mL of water. The resulting solution was extracted with EA (20 mL * 3) and the organic layers were combined and washed with brine, dried over anhydrous Na2SO4. The solvent was removed in vacuo and the residue was purified by silica gel column chromatography (DCM/MeOH = 100:1 - 50:1) to give the title product (85 mg, 87.7% yield). 1H-NMR (400 MHz, CDCl3): δ 9.37 (s, 1H), 8.48 (s, 1H), 8.07 (d, J = 7.6 Hz, 1H), 7.94 (d , J = 7.6 Hz, 1H), 7.38 (s, 1H), 7.26-7.32 (m, 1H), 6.94-6.99 (m, 2H), 6.86 ( d, J = 8.4 Hz, 1H), 6.48 (s, 1H), 5.19 (s, 1H), 4.67 (d, J = 5.2 Hz, 2H), 3.78- 3.93 (m, 6H), 3.60 (s, 1H), 2.64 (d, J = 6.0 Hz, 1H), 2.46 (d, J = 7.6 Hz, 1H), 1.47 (s, 9H). LCMS: m/z = 528 [M+H]+.

[0149] Step D: (R)-4-(1-(1-acryloylpyrrolidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)-N-(3-methoxybenzyl) benzamide (4) :

[0150] Intermediate 3 (85 mg, 0.157 mmol, 1.0 eq) was dissolved in DCM (8.0 mL), added TFA (1.5 mL) in one portion. The mixture was stirred for about 1.5 h at rt. The volatile components were removed under vacuum to provide the title product of crude TFA salt, and used directly in the next step without further purification. The crude product was dissolved in DCM (7.0 mL), added TEA to the solution until pH = 8.0, then added acryloyl chloride (17 mg, 0.188 mmol, 1.2 eq) in DCM (1.0 mL) dropwise to the solution. The reaction mixture was stirred for 0.5 h, poured into water and extracted with DCM. The organic layer was dried with anhydrous Na2SO4, filtered and concentrated, the residue was purified with silica gel plate (DCM/MeOH = 50:1) to give the title product (20 mg, 25.8% yield). 1H-NMR (400 MHz, CDCl3): δ 9.82 (s, 1H), 8.62 (s, 1H), 8.35 (d, J = 6.0 Hz, 1H), 8.18 (d , J = 8.0 Hz, 2H), 8.08 (d, J = 8.0 Hz, 2H), 7.25-7.29 (m, 1H), 6.97 (d, J = 8, 0 Hz, 2H), 6.84 (d, J = 8.0 Hz, 1H), 6.61-6.79 (m, 1H), 6.32-6.38 (m, 1H), 5, 77-5.85 (m, 2H), 4.60 (s, 2H), 4.28 (d, J = 4.0 Hz, 1H), 4.00 (d, J = 6.8 Hz, 1H ), 3.80 (s, 3H), 2.62-2.75 (m, 2H). LCMS: m/z = 482.2 [M+H]+.

[0151] The following additional Examples 104-105 shown in the Table below were prepared following the procedures outlined in the general methods above and detailed in Example 103.

[0152] Example 106: (R)-1-(3-(3-(3'-methyl-[1,1'-biphenyl]-4-yl)-1H-pyrazolo[4,3-c]pyridin- 1-yl)piperidin-1-yl)prop-2-en-1-one:

[0153] Step A: (R)-tert-butyl 3-(3-(3'-methyl- [1,1'-biphenyl] -4-yl)-1H- pyrazolo[4,3-c]pyridin- 1-yl)piperidine-1-carboxylate (1):

[0154] To a solution of (R)-tert-butyl 3-(3-bromo-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate (66.5 mg, 0.175 mmol , 1.0 eq) and (3'-methyl-[1,1'-biphenyl]-4-yl) boronic acid (55.5 mg, 0.262 mmol, 1.5 eq) in dioxane (7.0 mL) and water (1.0 mL), K2CO3 (60.4 mg, 0.436 mmol, 2.0 eq) and Pd [Ph3P]4 (15 mg) were added under N2 with stirring. The mixture was refluxed for 6.0 hours and the reaction mixture was cooled to room temperature. Dioxane was removed by rotary evaporation. The residue was poured into water and extracted with EA. The organic layer was dried over Na2SO4, filtered and the solvent was removed by rotary evaporation. The product was purified by flash chromatography on silica gel (DCM: MeOH = 100:1 - 50:1), to provide the title product (70 mg, 85.7% yield). LCMS: mz = 469 [M+H]+.

[0155] Step B: (R)-1-(3-(3-(3'-methyl- [1,1'- biphenyl] -4-yl)-1H-pyrazolo[4,3- c]pyridin- 1-yl)piperidin-1-yl)prop-2-en-1-one (2):

[0156] Intermediate 1 (70 mg, 0.15 mmol, 1.0 eq) was dissolved in DCM (5.0 mL), added TFA (1.0 mL) in one portion. The mixture was stirred for about 1.5 h at rt. The volatile components were removed under vacuum to provide the crude product of the TFA salt title, and used directly in the next step without further purification. The crude product was dissolved in DCM (5.0 mL), added TEA until pH = 8.0, then added acryloyl chloride (20 mg, 0.224 mmol, 1.5 eq) in DCM (1.0 mL) drop by drop into the solution. The reaction mixture was stirred for 0.5 h, poured into water and extracted with DCM. The organic layer was dried with anhydrous Na2SO4, filtered and concentrated, the residue was purified with silica gel plate (DCM/MeOH = 50:1) to give the title product (20 mg, 31.7% yield). -NMR (400 MHz, CDCl3): δ 9.40 (s, 1H), 8.48 (s, 1H), 8.06 (d, J = 8.0 Hz, 2H), 7.76 (d, J = 8.4 Hz, 2H), 7.35 -7.48 (m, 4H), 7.20 (d, J = 7.6 Hz, 1H), 6,566.69 (m, 1H), 6, 34-6.39 (m, 1H), 5.70-5.78 (m, 1H), 4.95 (d, J = 11.2 Hz, 0.5H), 4.66 (d, J = 7.2 Hz, 0.5H), 4.50 (d, J = 10.4 Hz, 1H), 4.08-4.23 (m, 1H), 3.84 (s, 0.5H), 3.21-3.30 (m, 1H), 2.93 (s, 0.5), 2.30 (d, J = 11.2 Hz, 1H), 1.74 (s, 1H). LCMS: m/z = 423 [M+H]+.

[0157] The following additional Examples 107-115 shown in the Table below were prepared following the procedures outlined in the general methods above and detailed in Examples 106.

[0158] Example 116: N- {4- [1-(1-Acryloyl-pyrrolidin-3-yl)-1H-pyrazolo[4,3- c]pyridin-3-yl] -phenyl} -3-trifluoromethyl- benzamide:

[0159] Step A: (R)-tert-butyl 3-(3-(4-aminophenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidine-1-carboxylate (1):

[0160] To a solution of (R)-tert-butyl 3-(3-bromo-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidine-1-carboxylate (77 mg, 0.209 mmol, 1 .0 eq) and (4-aminophenyl)-boronic acid (57 mg, 0.418 mmol, 2.0 eq) in dioxane (8.0 mL) and water (1.0 mL), K2CO3 (87 mg, 0.628 mmol, 3.0 eq) and (Ph3P)4Pd (20 mg) under N2 with stirring. The mixture was refluxed for 5.5 hours until the material disappeared. The reaction mixture was cooled to room temperature. Dioxane was removed by rotary evaporation. The residue was poured into water and extracted with EA. The organic layer was dried over Na2SO4, filtered and the solvent was removed in vacuo and the residue was purified by flash chromatography on silica gel (DCM: MeOH = 100:1 - 50:1), to give the title product (77 mg , yield 96.8%). LCMS: m/z = 380 [M+H]+.

[0161] Step B: (R)-tert-butyl 3-(3-(4-((3-(trifluoromethyl)phenyl)amino)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl )pyrrolidine-1-carboxylate (2):

[0162] To a solution of 1 (77 mg, 0.203 mmol, 1.0 eq) in DCM (5.0 mL), 3-(trifluoromethyl) benzoyl chloride (51 mg, 0.243 mmol, 1.2 eq) which was dissolved in DCM (2.0 mL) added dropwise. The mixture was stirred at room temperature for 2.0 h, water added, then the mixture was extracted with DCM. The organic layer was washed with water and brine, dried with anhydrous Na2SO4, filtered and concentrated. The product was purified by flash chromatography on silica gel (DCM:MeOH = 100:1 - 50:1), to provide the title product (60 mg, 56.5%). LCMS: m/z = 524 [M+H]+.

[0163] Step C: (R)-1-(3-(3-(4-((3-(trifluoromethyl)phenyl)amino)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl )pyrrolidine-1-yl)prop-2-en-1-one (3)

[0164] Intermediate 2 (60 mg, 0.115 mmol, 1.0 eq) was dissolved in DCM (8.0 mL), added TFA (1.0 mL) in one portion. The mixture was stirred for about 1.5 h at rt. The volatile components were removed under vacuum to provide the crude product of the TFA salt title, and used directly in the next step without further purification. The crude product was dissolved in DCM (5.0 mL), added TEA until pH = 8.0, then added acryloyl chloride (12 mg, 0.133 mmol, 1.2 eq) in DCM (1.0 mL) drop by drop into the solution. The reaction mixture was stirred for 0.5 h, poured into water and extracted with DCM. The organic layer was dried with anhydrous Na2SO4, filtered and concentrated, the residue was purified with silica gel plate (DCM/MeOH = 50:1) to give the title product (19 mg, 34.7% yield). 1H-NMR (400 MHz, CDCl3): δ 9.34 (d, J = 14.0 Hz, 1H), 9.09 (d, J = 6.0 Hz, 1H), 8.15-8.47 (m, 3H), 7.77-7.95 (m, 5H), 7.58-7.62 (m, 1H), 7.35-7.39 (m, 1H), 6.37-6 .54 (m, 2H), 5.69-5.75 (m, 1H), 5.21-5.30 (m, 1H), 4.38 (d, J = 9.6 Hz, 1H), 4.01-4.18 (m, 3H), 3.80-3.85 (m, 1H), 2.47-2.75 (m, 2H). LCMS: m/z = 506.2 [M+H]+.

[0165] The following additional Example 117 shown in the Table below was prepared following the procedures outlined in the general methods above and detailed in Example 116.

[0166] The following other additional Examples 118-123 in the Table below were prepared following the procedures in the general methods above or described in the literature.

Btk kinase assay and other kinase assays

[0167] Btk kinase activity was determined using a time-resolved homogeneous fluorescence (HTRF) methodology. Measurements were performed in a 15 μL reaction volume using 384-well assay plates. Kinase enzyme, inhibitor, ATP and 1 μM peptide substrate were incubated in a reaction buffer consisting of Hepes50mM (pH 7.0), 0.02% NaN3, 0.01% BSA, Orthocanadate0.1mM. After one hour, the kinase reaction was stopped by adding Eμ-labeled antibody and XL-665 in 1x detection buffer containing 60 mM EDTA (Cisbio) and the mixture was allowed to incubate for one hour. The HTRF signal was measured on a multimode plate reader (EnVision® Multilabel Reader, Perkin Elmer) with an excitation wavelength (ÀEX) of 330 nm and detection wavelengths (ÀEm) of 615 and 665 nm. Activity was determined by the ratio of fluorescence at 665 nm and 615 nm. For each compound, enzyme activity as measured at various concentrations of the compound, negative control reactions were performed in the absence of inhibitor in two replicates, and eight without enzyme controls were used to determine standard fluorescence levels. IC50s were obtained according to the equation: Y = 100/(1+10A((LogIC50-X)*HillSlope)). For the BTK assay, [ATP] = 80 μM, BTK = 3.4 nM. For the LYN assay, [ATP] = 20 μM, LYN = 0.12 nM. For the LCK assay, [ATP] = 20 μM, LCK = 0.2 nM. For the BLK assay, [ATP] = 20 μM, BLK = 0.6 nM.

Example 127

[0168] The following Table shows the activity of selected compounds of this invention in the BTK inhibition assay. Compound numbers correspond to compound numbers in the previous Tables. Compounds with an activity designated as “A” provided an IC50 < 10 nM; Compounds with an activity designated as “B” provided an IC50 of 10-100 nM; Compounds with an activity designated as "C" provided an IC50 of 100-1000 nM; Compounds with an activity designated as "D" provided an IC50 of 1000-10000 nM; Compounds with an activity designated as “E” provided an IC50 > 10000 nM.

Example 128

[0169] The following Table shows the activity of selected compounds of this invention in the BTK, BLK, LYN, LCK inhibition assay. Compound numbers correspond to compound numbers in the previous Tables. Compounds with an activity designated as "A" provided an IC50 < 10 nM; Compounds with an activity designated as “B” provided an IC50 of 10-100 nM; Compounds with an activity designated as "C" provided an IC50 of 100-1000 nM; Compounds with an activity designated as "D" provided an IC50 of 1000-10000 nM; Compounds with an activity designated "E" provided an IC50 > 10000 nM; N/A is not available. Table 2

Calcium Flux Assay

[0170] Fluorescence-based calcium flux assays were performed on an FDSS7000EX fluorometric imaging plate reader (Hamamatsu Photonics) according to the manufacturer's instructions. Compounds to be tested were dissolved in DMSO, diluted to appropriate concentrations in Ca2+ buffer ranging from 0 to 10 μM (with a dilution factor of 0.1), 5 μl (6X) added to each well (the final concentration of DMSO was 0.1% in each well). Then, 12.5 μL of 2X dye solution (Fluo-4 NW Calcium Assay Kits, Invitrogen) was added per well of a 384-well plate. Subsequently, actively growing Ramos cells (ATCC) in RPM1640 medium supplemented with 10% FBS (Invitrogen) were washed and replated in assay buffer (from Fluo-4 NW Calcium Assay Kits, Invitrogen) for approximately 6.4 x 106/ml (80000 cells/12.5 μL in 384-well plates). Plates were incubated at 37°C for 30 minutes, then at room temperature for an additional 30 minutes. The plates were now ready to be used in an experiment. Immediately after transfer and a 10-s baseline fluorescence recording, compound-treated cells were stimulated with a goat anti-human IgM antibody (10 μg/mL/Jackson Immuno Research) and read on an FDSS for 240 seconds. The difference between the signal and that in the standard, designated the adjusted relative fluorescence unit, was calculated using a custom Excel model (Microsoft, Redmond, WA) to determine IgM-induced calcium influx and its inhibition by compounds. The table below shows the result. Compounds with an activity designated as “A” provided an IC50 < 10 nM; Compounds with an activity designated as “B” provided an IC50 10-100 nM; Compounds with an activity designated as "C" provided an IC50 100-1000 nM; Table 3

Btk occupancy in cellular assays

[0171] For PCI-33380 labeling of human B cells, 106 Jeko-1 cells were pre-incubated with the compound for 1.5 h before labeling. Then, cells were treated with 5 μM PCI-33380 for 1 h. Washed, lysed in Ripa buffer containing sample reducing agent, and analyzed by SDS/PAGE and in-gel fluorescence scanning using a Typhoon 9500 scanner (GE Healthcare) (Ex, 532 nm; Em, 555 nm). The gel was then transferred and total Btk levels detected by standard Western blot with Btk antibody (CST). Using the fluorescently labeled derivative PCI-33380, it was found that 25 nM of compound 77; 50 nM of Compounds 3, 78, 79, 80, 83, 100 nM of Compounds 2, 4, 17, 41, 43, 69, 71, 73, 98 and 99 were sufficient to fully occupy the active site of Btk in strains of Human mantle cell lymphoma from Jeko-1 cells in culture.

Btk occupation in vivo

[0172] For analysis of Btk occupancy in Babc/L mice after oral administration of compounds after 4 hours. Isolation of peripheral blood mononuclear cells (PBMCs) with a mouse peripheral blood separation kit (Hao Yang Biological Manufacture CO., LTD, Tianjin) was collected from Babc/L mice (1 ml blood from two mice). Spleens were processed to splenocytes, followed by 5 min incubation in red blood cell lysis buffer (from the mouse peripheral blood separation kit). PBMCs or splenocytes were then labeled with PCI-33380 and lysates were analyzed by in-gel fluorescence scanning as described in cellular assays. Compounds 2, 3, 4, 71 achieved full occupancy at 10 mg/kg single oral dose in all Babc/L mice. Compounds 73, 91 achieved full occupancy at 5 mg/kg single oral dose in all Babc/L mice.

Claims (4)

1. COMPOUND OF FORMULA (I), characterized by the fact that it has the following structure: Formula (I) where: A is CR1; A, C and D are CH and B is N; R1 is hydrogen; R2 is X is O; and E is an aryl or a heteroaryl substituted with one to three R5 substituents; R4 and R5 are each independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, OCF3, OCF2H, C1-6 alkyl, optionally substituted with one to five fluorine atoms, C3-6 cycloalkyl, optionally substituted with one to five fluorine atoms, C1-4 alkoxy, optionally substituted with one to five fluorine atoms, C1-4 alkylthio, optionally substituted with one to five fluorine atoms, C1-4 alkylsulfonyl, optionally substituted with one to five fluorine, carboxy, C1-4 alkyloxycarbonyl and C1-4 alkylcarbonyl atoms; Ra and Rb are each independently hydrogen, fluorine or C1-3 alkyl, optionally substituted with one to five fluorine atoms; Rc is hydrogen or C1-3 alkyl, optionally substituted with one to five fluorine atoms; R3 is a group with a double bond, Y is C(=O), OC(=O), NHC(=O), S=O, S(=O)2 or NHS(=O)2; and R6, R7, R8 are each independently hydrogen, halogen, CN, C1-4 alkyl, C1-6 alkoxyalkyl, C18 alkylaminoalkyl or C1-4 alkylphenyl; or R7 and R8 together form a bond. 2. COMPOUND, according to claim 1, characterized by the fact that it is selected from the group consisting of: 3. COMPOUND, characterized by the fact that it is selected from the group consisting of: 4. PHARMACEUTICAL COMPOSITION, characterized by the fact that it comprises a therapeutically effective amount of the compound defined in any one of claims 1 to 3 and a pharmaceutically acceptable excipient.