Btk inhibitors

Abstract

Provide a compound of formula (I'): , or a pharmaceutically acceptable salt thereof, wherein the variables in the formula are as defined herein; and its use and methods of manufacture.

Description

technical field

[0001] Certain agents that inhibit Bruton's tyrosine kinase (Btk), and methods of making and using such agents are provided. prior art

[0002] Protein kinases are a large multigene family of more than 500 proteins that play key roles in the development and treatment of many human diseases in oncology, neurology and immunology. Tec kinase is a non-receptor tyrosine kinase composed of five members (Tec (tyrosine kinase expressed in hepatocellular carcinoma), Btk (Bruton's tyrosine kinase), Itk (interleukin 2 (IL-2) inducible T-cell kinase; also known as Emt or Tsk), Rlk (resting lymphocyte kinase; also known as Txk), and Bmx (myeloid tyrosine kinase gene on chromosome X; also known as Etk )) and is mainly expressed in hematopoietic cells, although expression of Bmx and Tec has been detected in endothelial cells and hepatocytes. Tec kinases (Itk, Rlk and Tec) are expressed in T cells and all are activated downstream of the T cell receptor (TCR). Btk is the downstream mediator of B cell receptor (BCR) signal transduction, which is involved in the regulation of B cell activation, proliferation and differentiation. More specifically, Btk contains a PH domain that binds phosphatidylinositol (3,4,5)-triphosphate (PIP3). PIP3 binding induces Btk to phosphorylate phospholipase C (PLCy), which in turn hydrolyzes PIP2 to generate two secondary messengers, inositol triphosphate (IP3) and diacylglycerol (DAG), both of which activate the protein kinase PKC, followed by Induces additional B cell signaling. Mutations that disable Btk's enzymatic activity lead to XLA syndrome (X-linked agammaglobulinemia), a primary immunodeficiency. Given their critical roles in both B-cell and T-cell signaling, Tec kinases are targets of interest in autoimmune disorders.

[0003] Therefore, there is a great need in the art for effective Btk inhibitors. Contents of the invention

[0004] []

[0005] One embodiment of the present invention is a compound represented by formula (I'): (I'), or a pharmaceutically acceptable salt thereof, wherein: Het is phenyl, 5-6 membered heteroaryl or N-(C 1-C 3 alkyl) pyridonyl; X 0 is N, X 1 is C, X 2 is N and X 4 is N; X 0 is CR 0, X 1 is C, X 2 is N and X 4 is N; X 0 is CR 0, X 1 is N, X2 is C and X4 is N; X0 is CR0, X1 is N, X2 is C and X4 is CH; or X0 is CR0, X1 is C, X2 is N and X4 is CH; R 0 is H, halo, methyl, halomethyl, cyclopropyl, CN or phenyl; R 1 is H or C 1-C 3 alkyl, C 1-C 3 alkoxy, C 1-C 3 haloalkyl or 4-7 membered monocyclic oxygen-containing heterocycle; R 3 is H or halo; X 3 is absent, CH 2, CH 2CH 2, O, O-CH 2*, O-CH 2CH 2*, NH, N(CH 3)-*, CH 2N(CH 3)-* or NH-CH 2*, where "*" indicates the connection point with R 2; When X3 is absent, CH2 or CH2CH2, R2 is a 4-12 membered monocyclic or bicyclic nitrogen-containing heterocyclic ring bonded to the bicyclic core or X3 via a ring nitrogen atom ("N-linked") ;When X 3 is CH 2, CH 2CH 2, O, O-CH 2*, NH, N(CH 3)-*, CH 2N(CH 3)-* or NH-CH 2*, R 2 is classic 4-12 membered monocyclic or bicyclic nitrogen-containing heterocycle, 4-7 membered monocyclic or bicyclic oxygen-containing heterocycle, 3-12 membered monocyclic or bicyclic ring carbon atom ("C-link") bonded to X3 Carbocyclyl or 5-6 membered heteroaryl; and when X 3 is O-CH 2-CH 2*, R 2 does not exist, is bonded to X 3 via a ring carbon atom ("C-link") 4-12 membered monocyclic or bicyclic nitrogen-containing heterocycle, or C 1-C 3 alkyl, provided that when R 2 does not exist, X 3 is directly connected to R 4; N-linked 4-12 membered monocyclic or bicyclic nitrogen-containing heterocycle, 4-7 membered oxygen-containing heterocycle, 3-12 membered monocyclic or bicyclic carbocycle, 5-6 membered heteroaryl and C 1-C 3 alkyl is substituted by a group represented by R 4 and optionally further substituted by one to three groups represented by R 10 , with the proviso that when the N-linked 4-12 membered monocyclic or bicyclic ring contains nitrogen When the heterocycle contains two ring nitrogen atoms, the N-linked 4-12 membered monocyclic or bicyclic nitrogen-containing heterocycle represented by R2 is optionally N-substituted by a group represented by R5 and optionally further modified by one or two A group represented by R 10 is substituted; The C-linked 4-12-membered monocyclic or bicyclic nitrogen-containing heterocyclic ring is N-substituted by a group represented by R 5 and optionally further substituted by one to three groups represented by R 10; R4 is , , , , , or ; R 5 is , , , , , or ; Each R 6 is independently H, CN, C 1-C 3 alkyl, C 1-C 3 haloalkyl, N(R a ) 2 or CH 2 N(R a ) 2, wherein each R a is independently H , C 1-C 3 alkyl or C 3-C 6 cycloalkyl; Each R 6' is independently H, C 1-C 3 alkyl, C 1-C 3 haloalkyl or C 3-C 6 cycloalkyl; Each R 7 is independently H, C 1-C 2 alkyl, C 1-C 2 fluoroalkyl or C 3-C 6 cycloalkyl; R 8 is H or C 1-C 3 alkyl; Each R 10 is halo, C 1-C 3 alkyl or C 3-C 6 cycloalkyl; R 11 is H or N(R 12) 2; each R 12 is independently H or C 1-C 3 alkyl; R 13 is CN or F; R 14 is halo; each n is independently 0 or 1; each p is independently 1 or 2; and q is 1 or 2.

[0006] Another embodiment of the present invention is a compound of formula (I): (I); or a pharmaceutically acceptable salt thereof, wherein: Het is phenyl, 5-6 member heteroaryl or N-(C 1-C 3 alkyl) pyridonyl; X 0 is N, X 1 is C, X 2 is N and X 4 is N; X 0 is CR 0, X 1 is C, X 2 is N and X 4 is N; X 0 is CR 0, X 1 is N, X2 is C and X4 is N; X0 is CR0, X1 is N, X2 is C and X4 is CH; or X0 is CR0, X1 is C, X2 is N and X4 is CH; R 0 is H, halo, methyl, halomethyl, cyclopropyl or CN; R 1 is H or C 1-C 3 alkyl, C 1-C 3 alkoxy, C 1-C 3 haloalkyl or 4-7 membered monocyclic oxygen-containing heterocycle; X3 does not exist, is CH2, CH2CH2, O, O-CH2*, NH or NH-CH2*, wherein "*" indicates the connection point with R2; When X3 is absent, CH2 or CH2CH2, R2 is a 4-12 membered monocyclic or bicyclic nitrogen-containing heterocyclic ring bonded to the bicyclic core or X3 via a ring nitrogen atom ("N-linked") and when X 3 is CH 2 , CH 2CH 2 , O, O-CH 2* or NH-CH 2* , R 2 is a 4- 12-membered monocyclic or bicyclic nitrogen-containing heterocycle, 4-7-membered monocyclic oxygen-containing heterocycle or 3-12-membered monocyclic or bicyclic carbocyclyl; The N-linked 4-12 membered monocyclic or bicyclic nitrogen-containing heterocyclic ring, 4-7 membered oxygen-containing heterocyclic ring and 3-12 membered monocyclic or bicyclic carbocycle represented by R2 are substituted by a group represented by R4, And as the case may be further substituted by one or two groups represented by R 10; The C-linked 4-12-membered monocyclic or bicyclic nitrogen-containing heterocyclic ring is N-substituted by a group represented by R 5 and optionally further substituted by one or two groups represented by R 10; R4 is , , or ; R 5 is , , or ; Each R 6 is independently H, C 1-C 3 alkyl, C 1-C 3 haloalkyl, N(R a ) 2 or CH 2N(R a ) 2, wherein each R a is independently H or methyl base; Each R 6' is independently H, C 1-C 3 alkyl or C 1-C 3 haloalkyl; Each R 7 is independently H, C 1-C 2 alkyl or C 1-C 2 fluoroalkyl; each R 10 is F or methyl; R 11 is H or N(R 12) 2 . Alternatively, R 11 is H or NH 2 ; Each R 12 is independently H or C 1-C 3 alkyl; or, R 12 is H or NH 2 ; R 13 is CN or F; each n is independently 0 or 1; each p is independently 1 or 2; and q is 1 or 2.

[0007] The present invention also provides a pharmaceutical composition comprising at least one compound described herein or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.

[0008] Another embodiment of the invention is a method of treating a condition responsive to Btk inhibition in a subject, the method comprising administering to the subject an effective amount of at least one compound described herein, or a pharmaceutically acceptable salt thereof .

[0009] The invention also encompasses the use of at least one compound described herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a condition responsive to Btk inhibition. Also provided is a compound described herein, or a pharmaceutically acceptable salt thereof, for use in the treatment of a condition responsive to Btk inhibition.

[0010] Other features or advantages will be apparent from the following detailed description of several embodiments and from the appended claims. Implementation

[0011] []

[0012] A compound as described herein, or a pharmaceutically acceptable salt thereof, may have activity as a Btk modulator. In particular, a compound as described herein, or a pharmaceutically acceptable salt thereof, may be a Btk inhibitor.

[0013] In a first embodiment, the compound of the present invention is represented by formula (I') or a pharmaceutically acceptable salt thereof, wherein the variables are as described above.

[0014] In a second embodiment, the compound of the present invention is represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein the variables are as described above.

[0015] In a third embodiment, for the compound of formula (I') or (I) or a pharmaceutically acceptable salt thereof, R 11 is H or NH 2 , and the remaining variables are as in the first or second embodiment mentioned.

[0016] In a fourth embodiment, the compound of the present invention is represented by formula (II): (II); or a pharmaceutically acceptable salt thereof. The variables in formula (II) are as described in formula (I') or (I) described in the first or second embodiment.

[0017] In a fifth embodiment, the compound of the present invention is represented by formula (I'), (I) or (II) or a pharmaceutically acceptable salt thereof, wherein formula (I'), (I) and (II ) in (R 1) q-Het- is selected from: ; ; ; ; ; ; and . The remaining variables in formulas (I), (I') and (II) are as described in any of the first to fourth embodiments.

[0018] In a sixth embodiment, the compound of the present invention is represented by formula (III): (III); or a pharmaceutically acceptable salt thereof. The variables in formula (III) are as described in formula (I') or (I) described in the first or second embodiment.

[0019] In the seventh embodiment, the compound of the present invention is represented by formula (I'), (I), (II) or (III) or a pharmaceutically acceptable salt thereof, wherein X 0 is N, X 1 is C, X2 is N and X4 is N; X0 is CH, X1 is C, X2 is N and X4 is N; X0 is CH, X1 is N, X2 is C and X4 is N; X 0 is CR 0, X 1 is N, X 2 is C and X 4 is CH; or X 0 is CH, X 1 is C, X 2 is N and X 4 is CH; X 3 is absent, is O, O-CH2*, NH or NH-CH2*, where "*" indicates the point of attachment to R2; when X3 is absent, R2 is bonded via a ring nitrogen atom ("N-attached") A 4-12-membered monocyclic or bicyclic nitrogen-containing heterocyclic ring bound to a bicyclic nucleus or X 3 ; and when X 3 is O, O-CH 2 * or NH-CH 2 *, R 2 is a ring carbon atom (" C-connection") is bonded to X 4-12 membered monocyclic or bicyclic nitrogen-containing heterocyclic ring, 4-7 membered monocyclic oxygen-containing heterocyclic ring or 3-12 membered monocyclic or bicyclic carbocyclyl; by R 2 The N-connected 4-12-membered monocyclic or bicyclic nitrogen-containing heterocyclic ring, 4-7 membered monocyclic oxygen-containing and 3-12 membered monocyclic or bicyclic carbocycles are substituted by the group represented by R 4 and further as the case may be Substituted by one or two groups represented by R 10; the C-linked 4-12 membered monocyclic or bicyclic nitrogen-containing heterocyclic ring is N-substituted by a group represented by R 5 and is further optionally replaced by one or two groups represented by The group represented by R 10 is substituted; and the remaining variables are as described in formulas (I'), (I), (II) and (III) described in any one of the first to sixth embodiments.

[0020] In an eighth embodiment, the compound of the present invention is represented by formula (IV), (V), (VI), (VII) or (VIII): (IV); (V); (VI); (VII); or (VIII); Or the pharmaceutically acceptable salt of any one of the foregoing, wherein the variables are as described in any one of the first to seventh embodiments.

[0021] In the ninth embodiment, the compound of the present invention is represented by formula (I'), (I), (II), (III), (IV), (V), (VI), (VII) and (VIII) Any one of them represents or a pharmaceutically acceptable salt thereof, wherein X 3 is a bond and R 2 is a 4-12 membered monocyclic or bicyclic nitrogen-containing heterocyclic ring bonded to a bicyclic nucleus through a ring nitrogen atom, and The monocyclic or bicyclic 4-12 membered nitrogen-containing heterocyclic ring represented by R 2 is substituted by a group represented by R 4 and optionally further substituted by a group represented by R 10 . Or, R 2 is a 4-7 membered monocyclic nitrogen-containing heterocyclic ring bonded to the bicyclic nucleus through a ring nitrogen atom, and the 4-7 membered monocyclic nitrogen-containing heterocyclic ring represented by R 2 is substituted by a group represented by R 4 and may be further substituted by a group represented by R 10 as appropriate. All the other variables are as in formula (I'), (I), (II), (III), (IV), (V), (VI), ( VII) or (VIII).

[0022] In the tenth embodiment, the compounds of the present invention are represented by formulas (I'), (I), (II), (III), (IV), (V), (VI), (VII) and (VIII) Any one of them represents or a pharmaceutically acceptable salt thereof, wherein X 3 is a bond and R 2 is a 7-10 membered bicyclic bicyclic nitrogen-containing heterocyclic ring bonded to the bicyclic nucleus through its ring nitrogen atom, and is represented by The 7-10 membered bicyclic nitrogen-containing heterocyclic ring represented by R 2 is substituted by a group represented by R 4 and optionally further substituted by one or two groups represented by R 10 ; and the remaining variables are as the first to ninth Any one of the examples.

[0023] In the eleventh embodiment, the compound of the present invention is represented by formula (I'), (I), (II), (III), (IV), (V), (VI), (VII) and (VIII ) or a pharmaceutically acceptable salt thereof, wherein the 7-10 membered bicyclic nitrogen-containing heterocyclic ring represented by R 2 is substituted by a group represented by R 4 and further represented by R 10 as the case may be Group substituted azaspiro[2.4]heptyl; and the remaining variables are as described in any one of the first to tenth embodiments.

[0024] In the twelfth embodiment, the compound of the present invention consists of (I'), (I), (II), (III), (IV), (V), (VI), (VII) and (VIII) Any one of them represents or a pharmaceutically acceptable salt thereof, wherein X 3 is a bond and R 2 is a 4-7 membered monocyclic nitrogen-containing heterocyclic ring bonded to a bicyclic nucleus through its ring nitrogen atom, and is represented by The 4-7 membered monocyclic nitrogen-containing heterocyclic ring represented by R 2 is substituted by the group represented by R 4 and further substituted by the group represented by R 10 as the case may be; and the remaining variables are as in the first to ninth embodiments either described.

[0025] In the thirteenth embodiment, the compound of the present invention consists of (I'), (I), (II), (III), (IV), (V), (VI), (VII) and (VIII) Any one of them represents or a pharmaceutically acceptable salt thereof, wherein the 4-7 membered monocyclic or bicyclic nitrogen-containing heterocyclic ring represented by R is azetidinyl, pyrrolidinyl, piperidine Pyridyl, azepanyl or oxazepanyl, each substituted by a group represented by R 4 and optionally further substituted by a group represented by R 10 ; and the remaining variables are as in the first to Any one of the ninth embodiments.

[0026] In a fourteenth embodiment, the compound of the present invention is represented by formula (IX), (X), (XI), (XII), (XIII) or (XIV): (IX); (X); (XI); (XII); i. (XIII); or (XIV); Or a pharmaceutically acceptable salt of any one of the foregoing, wherein the variables are as described in the thirteenth embodiment.

[0027] In the fifteenth embodiment, the compound of the present invention is represented by formula (I'), (I), (II), (III), (IV), (V), (VI), (VII), (VIII ), (IX), (X), (XI), (XII), (XIII) or (XIV), wherein R 6 and R 6' are independently H, CH 3 or CH 2 Cl, p is 2, and the remaining variables are as described in any one of the first to fourteenth embodiments.

[0028] In the sixteenth embodiment, the compound of the present invention is represented by formula (I'), (I), (II), (III), (IV), (V), (VI), (VII), (VIII ), (IX), (X), (XI), (XII), (XIII) or (XIV), wherein R 4 is CH 2 NHC (O) C ≡ CH, CH 2 NHC (O) CH=CH 2, N(CH 3)C(O)C≡CH, NHC(O)CH=CH 2, NHC(O)C≡CH or NHC(O)CH=CHCH 2Cl; and other variables are as in the first Any one of the first to fifteenth embodiments.

[0029] In the seventeenth embodiment, the compound of the present invention is represented by formula (I'), (I), (II), (III), (IV), (V), (VI), (VII), (VIII ), (IX), (X), (XI), (XII), (XIII) or (XIV), wherein R 4 is CH 2 NHC (O) C ≡ CH, CH 2 NHC (O) CH=CH2, N(CH3)C(O)C≡CH or CH2NR7C(O)CH=CHCH2Cl; and the rest of the variables are as described in any one of the first to fifteenth embodiments .

[0030] In the eighteenth embodiment, the compound of the present invention is represented by formula (I'), (I), (II), (III), (IV), (V), (VI), (VII) or (VIII ), wherein X3 is O, O-CH2*, O-CH2CH2*, NH, NH-CH2*, N(CH3) or CH2N(CH3)-*, R 2 is a 4-12 membered monocyclic or bicyclic nitrogen-containing heterocycle bonded to X 3 through a ring carbon atom ("C-linked"), and the C-linked 4-12 membered nitrogen-containing heterocycle is represented by R 5 The group N-substituted and optionally further substituted by one to three groups represented by R 10 ; and the remaining variables are as described in any one of the first to eighth embodiments.

[0031] In the nineteenth embodiment, the compound of the present invention is represented by formula (I'), (I), (II), (III), (IV), (V), (VI), (VII) or (VIII ) means that X3 is O, O-CH2*, NH or NH-CH2*, and R2 is a 4- 12-membered nitrogen-containing heterocyclic ring, and the C-linked 4-12-membered nitrogen-containing heterocyclic ring is N-substituted by a group represented by R 5 and optionally further substituted by a group represented by R 10 ; and the remaining variables are as in the first to any one of the eighth embodiment.

[0032] In the twentieth embodiment, the compound of the present invention is represented by formula (I'), (I), (II), (III), (IV), (V), (VI), (VII) or (VIII ) means that X 3 is O or O—CH 2 *, and the rest of the variables are as described in any one of the first to eighth, eighteenth and nineteenth embodiments.

[0033] In the twenty-first embodiment, the compound of the present invention consists of formula (I'), (I), (II), (III), (IV), (V), (VI), (VII) or ( Any one of VIII) represents, wherein the C-connected 4-12 membered nitrogen-containing heterocyclic ring represented by R is a 4-7 membered monocyclic heterocyclic ring containing an epoxy or a ring sulfur atom as the case may be, 6 -10-membered fused bicyclic ring, 8-12-membered spiro ring or 7-10 bridged bicyclic ring, and the C-linked 4-12-membered nitrogen-containing heterocyclic ring represented by R2 is N-substituted by a group represented by R5 and It may be further substituted by a group represented by R 10 as appropriate; and the remaining variables are as described in the first to eighth and eighteenth to twentieth embodiments.

[0034] In the twenty-second embodiment, the compound of the present invention consists of formula (I'), (I), (II), (III), (IV), (V), (VI), (VII) or ( Any one of VIII), wherein the C-linked 4-12 membered nitrogen-containing heterocyclic ring represented by R is azaspiro[3.3]heptyl, azaspiro[3.5]nonenyl, azaspiro[3.5]nonenyl, azaspiro[3.5]nonenyl, Spiro[4.4]nonylenyl, azaspiro[3.4]octyl, azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, diazepane base, morpholinyl, octahydrocyclopentadieno[c]pyrrolyl, oxazepanyl, azabicyclo[3.2.0]heptyl, azabicyclo[2.2.1] Heptyl, azabicyclo[3.1.1]heptyl, azabicyclo[3.2.1]octyl, azabicyclo[4.2.0]octyl, azatricyclo[4.1.1.03,7 ]octyl, azabicyclo[3.2.0]heptyl, azabicyclo[2.1.1]heptyl, azabicyclo[2.1.1]hexyl, azabicyclo[3.1.0]hexyl , 2λ 2-azaspiro[3.4]octyl or octahydrocyclopenta[c]pyrrolyl, and the C-linked 4-12 membered nitrogen-containing heterocyclic ring represented by R 2 is represented by R 5 The group N-substituted and optionally further substituted by one or two groups represented by R 10; and the remaining variables are as in the first to eighth and eighteenth to twenty-first embodiments either described. Exemplary 4-12 membered nitrogen-containing heterocycles represented by R include , , , , , , , , , , , , , , , , , , , , , , , , , , , and , wherein "**" indicates the connection point with X 3; and "***" indicates the connection point with R 5, wherein each group represented by R 2 is further optionally passed through one to three groups represented by R 10 group replaced.

[0035] In the twenty-third embodiment, the compound of the present invention is represented by formula (I'), (I), (II), (III), (IV), (V), (VI), (VII) or ( Any one of VIII), wherein the C-linked 4-12 membered nitrogen-containing heterocycle represented by R is azetidinyl, pyrrolidinyl, piperidinyl, azalidene heterocycle Heptyl, oxyazepanyl, azabicyclo[3.2.1]octyl, azatricyclo[4.1.1.0 3,7]octyl, azabicyclo[3.2.0]octyl Heptyl, azabicyclo[3.1.0]hexylene, 2λ 2-azaspiro[3.4]octyl or octahydrocyclopenta[c]pyrrolyl, and the C-link represented by R The 4-12 membered nitrogen-containing heterocyclic ring is N-substituted by a group represented by R 5 and optionally further substituted by one or two groups represented by R 10 , and the remaining variables are as the first to eighth and the first Any one of the eighteenth to twenty-first embodiments. Exemplary 4-12 membered nitrogen-containing heterocycles represented by R include , , , , , , or . The nitrogen-containing heterocycle represented by R 2 is optionally substituted by R 10; "**" indicates the connection point with X 3; and "***" indicates the connection point with R 5, wherein each group represented by R 2 The group is optionally further substituted by one or two groups represented by R 10 .

[0036] In the twenty-fourth embodiment, the compound of the present invention is represented by formula (I'), (I), (II), (III), (IV), (V), (VI), (VII) or ( Any one of VIII) represents that the stereochemical configuration of the ring carbon atom in the C-linked 4-12 membered nitrogen-containing heterocyclic ring represented by R 2 bonded to X 3 is R. Alternatively, the stereochemical configuration of the ring carbon atom in the C-linked 4-12 membered nitrogen-containing heterocyclic ring represented by R 2 bonded to X 3 is S. The remaining variables in formula (I'), (I), (II), (III), (IV), (V), (VI), (VII) or (VIII) are as the first to eighth and Any one of the eighteenth to twenty-third embodiments.

[0037] In the twenty-fifth embodiment, the compound of the present invention is represented by formula (I'), (I), (II), (III), (IV), (V), (VI), (VII) or ( Any one of VIII) represents, wherein R 6 and R 6' are independently H, CH 3 or CH 2 Cl and p is 2; and the remaining variables are as the first to the eighth and the eighteenth to the second Any one of the fourteen embodiments.

[0038] In the twenty-sixth embodiment, the compound of the present invention consists of formula (I'), (I), (II), (III), (IV), (V), (VI), (VII) or ( Any one of VIII) represents, wherein R 5 is SO 2CH=CH 2, SO 2CH=CHCH 3, SO 2CH=CHCH 2Cl, SO 2C≡CH, SO 2C≡CCH 3, SO 2C≡CCH 2Cl, COCH= CH 2, COCH=CHCH 3, COCH=CHCH 2Cl, CO-C≡CH, CO-C≡CCH 3, CO-C≡CCH 2Cl, COCF=CH 2, COCF=CHCH 3, COCF=CHCH 2Cl, or ; And the remaining variables are as described in the first to eighth and eighteenth to twenty-fifth embodiments.

[0039] In the twenty-seventh embodiment, the compound of the present invention consists of formula (I'), (I), (II), (III), (IV), (V), (VI), (VII) or ( Any one of VIII) represents, wherein R 5 is SO 2CH=CH 2, SO 2CH=CHCH 3, SO 2CH=CHCH 2Cl, SO 2C≡CH, SO 2C≡CCH 3, SO 2C≡CCH 2Cl, COCH= CH2, COCH=CHCH3, COCH=CHCH2Cl, CO-C≡CH, CO-C≡CCH3, or CO-C≡CCH2Cl. Alternatively, R5 is SO2CH=CH2, SO2CH=CHCH3, COCH=CH2, COCH=CHCH2Cl, CO-C≡CH or CO-C≡CCH3. The remaining variables in formula (I'), (I), (II), (III), (IV), (V), (VI), (VII) or (VIII) are as the first to eighth and Any one of the eighteenth to twenty-fifth embodiments.

[0040] In the twenty-eighth embodiment, the compound of the present invention consists of formula (I'), (I), (II), (III), (IV), (V), (VI), (VII) or ( Any one of VIII) represents, wherein X 3 is O, O-CH 2*, NH or NH-CH 2*, R 2 is 3-12 membered monocyclic or bicyclic carbocyclyl, 4-7 membered monocyclic Or bicyclic oxygen-containing heterocycle or 5-6 membered heteroaryl, and represented by R 2 3-12 membered monocyclic or bicyclic carbocycle, 4-7 membered monocyclic or bicyclic oxygen-containing heterocycle and 5-6 membered heterocycle The aryl group is substituted by a group represented by R 4 and optionally further substituted by one to three groups represented by R 10 ; and the remaining variables are as described in any one of the first to eighth embodiments.

[0041] In the twenty-ninth embodiment, the compound of the present invention consists of formula (I'), (I), (II), (III), (IV), (V), (VI), (VII) or ( Any one of VIII) represents, wherein X 3 is O, O-CH 2*, NH or NH-CH 2*, R 2 is a 4-7 membered monocyclic or bicyclic oxygen-containing heterocyclic ring or a 5-6 membered heterocyclic ring Aryl, and the 4-7 membered monocyclic or bicyclic oxygen-containing heterocyclic ring represented by R 2 and the 5-6 membered heteroaryl group are substituted by the group represented by R 4 and further optionally one to three represented by R 10 and the remaining variables are as described in any one of the first to eighth embodiments.

[0042] In the thirtieth embodiment, the compound of the present invention is represented by formula (I'), (I), (II), (III), (IV), (V), (VI), (VII) or (VIII ), wherein the 4-7 membered monocyclic or bicyclic oxygen-containing heterocyclic ring represented by R 2 is oxabicyclo[3.1.1]heptyl or tetrahydro-2H-pyranyl, each Substituted by a group represented by R 4 and optionally further substituted by one or two groups represented by R 10 ; and the 5-6 membered heteroaryl is substituted by a group represented by R 4 and optionally further substituted by one to three a pyridyl group substituted by a group represented by R 10; and the remaining variables are as described in any one of the first to eighth and twenty-ninth embodiments.

[0043] In the thirty-first embodiment, the compound of the present invention is represented by formula (I'), (I), (II), (III), (IV), (V), (VI), (VII) or ( Any one of VIII) represents, wherein R is selected from: , and , Each is substituted by a group represented by R 4 and optionally further substituted by one or two groups represented by R 10 ; and the remaining variables are as in any of the first to eighth and twenty-ninth embodiments described by the author.

[0044] In the thirty-second embodiment, the compound of the present invention is represented by formula (I'), (I), (II), (III), (IV), (V), (VI), (VII) or ( Any one of VIII) represents, wherein X 3 is O, O-CH 2*, NH or NH-CH 2*, R 2 is a 3-12-membered monocyclic or bicyclic carbocyclyl, and is represented by R 2 A 3-12 membered monocyclic or bicyclic carbocycle is substituted by a group represented by R 4 and optionally further substituted by one or two groups represented by R 10 , and the rest of the variables are as in the first to eighth embodiments either of the above. Alternatively, X 3 is O or O—CH 2 *. In another alternative, X3 is O. The rest of the variables in formula (I'), (I), (II), (III), (IV), (V), (VI), (VII) or (VIII) are implemented as the first to eighth described in any of the examples.

[0045] In the thirty-third embodiment, the compound of the present invention consists of formula (I'), (I), (II), (III), (IV), (V), (VI), (VII) or ( Any one of VIII) represents, wherein R 2 is a phenylene group, a C 3-C 7 cycloalkylene group or a C 6-C 9 bicyclic saturated carbocycle, and the phenylene group represented by R 2 , the C 3- C 7 cycloalkylene and C 6-C 9 bicyclic saturated carbocycles are substituted by a group represented by R 4 and optionally further substituted by one or two groups represented by R 10 ; and the remaining variables are as the first to Any one of the eighth and twenty-eighth to thirty-second embodiments.

[0046] In the thirty-fourth embodiment, the compound of the present invention is represented by formula (I'), (I), (II), (III), (IV), (V), (VI), (VII) or ( Any one of VIII), wherein R 2 is a phenylene group substituted by a group represented by R 4 and optionally further substituted by one or two groups represented by R 10 or a C 4-C 7 ring extension and the remaining variables are as described in any one of the first to eighth, thirty-second and thirty-third embodiments.

[0047] In the thirty-fifth embodiment, the compound of the present invention is represented by formula (I'), (I), (II), (III), (IV), (V), (VI), (VII) or ( Any one of VIII) represents, wherein X 3 is O; and the remaining variables are as described in any one of the first to eighth and twenty-eighth to thirty-fourth embodiments.

[0048] In the thirty-sixth embodiment, the compound of the present invention is represented by formula (I'), (I), (II), (III), (IV), (V), (VI), (VII) or ( Any one of VIII), wherein R is phenylene, cyclobutylene, cyclohexylene, cyclopentyl, cyclopropyl, bicyclo[3.3.1]heptyl, bicyclo[2.2. 1] Heptyl, bicyclo[4.1.0]heptyl or bicyclo[2.1.1]hexyl, each of which is substituted by a group represented by R and optionally further represented by one or two groups represented by R Group substitution; and all the other variables are as described in any one of the first to eighth and thirty-second to thirty-fifth embodiments.

[0049] In the thirty-seventh embodiment, the compound of the present invention is represented by formula (I'), (I), (II), (III), (IV), (V), (VI), (VII) or ( Any one of VIII), wherein R 2 is phenylene, cyclobutylene, ringylene substituted by a group represented by R 4 and optionally further substituted by one or two groups represented by R 10 Hexyl or bicyclo[3.3.1]heptyl; and the remaining variables are as described in the first to eighth and thirty-second to thirty-fifth embodiments.

[0050] In the thirty-eighth embodiment, the compound of the present invention is represented by formula (I'), (I), (II), (III), (IV), (V), (VI), (VII) or ( Any one of VIII) represents, wherein R 2 is , , , , , , , , , or , wherein "**" indicates the point of connection with X3; and "***" indicates the point of connection with R4, wherein the group represented by R2 is optionally replaced by one or two groups represented by R10 replace. The remaining variables in formula (I'), (I), (II), (III), (IV), (V), (VI), (VII) or (VIII) are as the first to eighth and The thirty-second to thirty-fifth embodiments described.

[0051] In the thirty-ninth embodiment, the compound of the present invention is represented by formula (I'), (I), (II), (III), (IV), (V), (VI), (VII) or ( Any one of VIII) represents, wherein R 2 is , , or , wherein the group represented by R2 is optionally substituted by one or two groups represented by R10; and the remaining variables are as in the first to eighth or thirty-second to thirty-fifth embodiments any of them.

[0052] In the fortieth embodiment, the compound of the present invention is represented by formula (I'), (I), (II), (III), (IV), (V), (VI), (VII) or (VIII ) means that wherein R 6 and R 6' are independently H, CN, CH 3 , CH 2 Cl, CF 3 , cyclopropyl, or CH 2N(R a); and the remaining variables are as in the first to Any one of the eighth and thirty-second to thirty-ninth embodiments.

[0053] In the forty-first embodiment, the compound of the present invention consists of formula (I'), (I), (II), (III), (IV), (V), (VI), (VII) or ( Any one of VIII) represents, wherein R a is each independently selected from -CH 3 and cyclopropyl; and the remaining variables are as in the first to eighth and thirty-second to fortieth embodiments either of the above.

[0054] In the forty-second embodiment, the compound of the present invention is represented by formula (I'), (I), (II), (III), (IV), (V), (VI), (VII) or ( Any one of VIII) represents, wherein R 6 and R 6' are each independently H, CH 3 or CH 2 Cl; and the remaining variables are as the first to eighth and the thirty-second to thirty-ninth any one of the examples.

[0055] In the forty-third embodiment, the compound of the present invention consists of formula (I'), (I), (II), (III), (IV), (V), (VI), (VII) or ( Any one of VIII) represents, wherein R 4 is NHC(O)CH=CH 2, N(CH 3)C(O)CH=CH 2, NHC(O)CH=CHCH 3, N(CH 3) C(O)CH=CHCH3, N(CH3)C(O)CH=CHCN, NHC(O)C≡CH, N(CH3)C(O)C≡CH, N(H)C(O )C≡CCH 3, N(CH 3)C(O)C≡CCH 3, N(CH 2CH 2F)C(O)CH=CH 2, N(CH 2CH 2F)C(O)CH=CHCH 3, N(CH 2CH 2F)C(O)C≡CH, N(CH 2CH 2F)C(O)C≡CCH 3, CH 2N(CH 3)C(O)CH=CH 2, N(CH 2CHF 2) C(O)CH=CH 2, N(CH 3)C(O)CH=CHCH 2Cl, NHC(O)CH=CHCF 3, N(CH 3)C(O)CH=CHCF 3, NHC(O) C≡C-cyclopropyl, NHC(O)CH=CHCH 2N(CH 3)-cyclobutyl, N(CH 2CHF 2)C(O)CH=CHCH 2N(CH 3) 2, N(cyclopropyl )C(O)CH=CH 2, N(CH 3)C(O)CH 2Cl, N(CH 3)CH 2CN, , , CH 2NHC(O)CH=CH 2 or CH(CH 3)NHC(O)CH=CH 2. The remaining variables in formula (I'), (I), (II), (III), (IV), (V), (VI), (VII) or (VIII) are as the first to eighth and Any one of the thirty-second to forty-first embodiments.

[0056] In the forty-fourth embodiment, the compound of the present invention is represented by formula (I'), (I), (II), (III), (IV), (V), (VI), (VII) or ( Any one of VIII) means that R 4 is NHCOCH=CH 2 , N(CH 3 )COCH=CH 2 , NHCOCH=CHCH 3 , N(CH 3 )COCH=CHCH 3 , N(H)COC≡CH, N(CH3)COC≡CH, N(H)COC≡CCH3, N(CH3)COC≡CCH3, N(CH2CH2F)COCH=CH2, N(CH2CH2F)COCH=CHCH3, N(CH2CH2F)COC≡CH or N(CH2CH2F)COC≡CCH3. Alternatively, R 4 is NHC(O)C≡CH, NHC(O)C≡CCH 3 , NHC(O)CH=CH 2 , N(CH 3 )COCH=CH 2 , N(CH 3 )COC≡CCH 3 Or N(CH2CH2F)COCH=CH2. The remaining variables in formula (I'), (I), (II), (III), (IV), (V), (VI), (VII) or (VIII) are as the first to eighth and Any one of the thirty-second to forty-second embodiments.

[0057] In the forty-fifth embodiment, the compound of the present invention is represented by formula (I'), (I), (II), (III), (IV), (V), (VI), (VII) or ( Any one of VIII) represents, wherein the stereochemical configuration of the ring carbon atom in the C-linked 3-12 membered carbocycle represented by R that is bonded to X is R. Alternatively, the stereochemical configuration of the ring carbon atom in the C-linked 3-12 membered carbon ring represented by R that is bonded to X is S. The remaining variables in formula (I'), (I), (II), (III), (IV), (V), (VI), (VII) or (VIII) are as the first to eighth and Any one of the thirty-second to forty-fourth embodiments.

[0058] In the forty-sixth embodiment, the compound of the present invention is represented by formula (I'), (I), (II), (III), (IV), (V), (VI), (VII) or ( Any one of VIII) represents, wherein X 3 and R 4 Orientation is trans. Alternatively, X and R are oriented in cis. The remaining variables in formula (I'), (I), (II), (III), (IV), (V), (VI), (VII) or (VIII) are as the first to eighth and Any one of the thirty-second to forty-fourth embodiments.

[0059] In the forty-seventh embodiment, the compound of the present invention is represented by formula (I'), (I), (II), (III), (IV), (V), (VI), (VII) or ( Any one of VIII) represents, wherein X 3 is O-CH 2CH 2*, and R 2 is substituted by a group represented by R 4 and optionally further substituted by one or two groups represented by R 10 C 1-C 3 alkyl, or R 2 is absent and X 3 is directly attached to R 4 . The rest of the variables in formula (I'), (I), (II), (III), (IV), (V), (VI), (VII) or (VIII) are implemented as the first to eighth example described.

[0060] In the forty-eighth embodiment, the compound of the present invention is represented by formula (I'), (I), (II), (III), (IV), (V), (VI), (VII) or ( Any one of VIII), wherein R2 is selected from ⁎⁎-CH2-⁎⁎⁎, ⁎⁎-CH2CH(CH3)-⁎⁎⁎, wherein "⁎⁎" represents the connection with X3 point, and "⁎⁎⁎" indicates the connection point with R 4. The remaining variables in formula (I'), (I), (II), (III), (IV), (V), (VI), (VII) or (VIII) are as the first to eighth and Any one of the forty-seventh embodiment.

[0061] In the forty-ninth embodiment, the compound of the present invention is represented by formula (I'), (I), (II), (III), (IV), (V), (VI), (VII) or ( Any one of VIII) represents, wherein R 4 is N(CH 3 )C(O)CH=CH 2 ; and the remaining variables are as the first to eighth, forty-seventh and forty-eighth Any one of the examples.

[0062] In the fiftieth embodiment, the compound of the present invention is represented by formula (I'), (I), (II), (III), (IV), (V), (VI), (VII), (VIII ), (IX), (X), (XI), (XII), (XIII) or (XIV), wherein R 1 is H or C 1-C 3 alkyl, C 1-C 3 fluoroalkyl or 4-7 membered monocyclic oxygen-containing heterocycle. Alternatively, R 1 is H, CH 3 , CH(CH 3 ) 2 , CHF 2 , oxetanyl or tetrahydrofuranyl. Formula (I'), (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), The remaining variables in (XII), (XIII) or (XIV) are as described in any one of the first to forty-ninth embodiments.

[0063] In the fifty-first embodiment, the compound of the present invention is represented by formula (I'), (I), (II), (III), (IV), (V), (VI), (VII), ( Any one of VIII), (IX), (X), (XI), (XII), (XIII) or (XIV) represents, wherein R 1 is H, CH 3 , CH(CH 3 ) 2 , CHF 2. CF 3 , oxetanyl or tetrahydrofuranyl; and the rest of the variables are as described in any one of the first to forty-ninth embodiments.

[0064] In the fifty-second embodiment, the compound of the present invention is represented by formula (I'), (I), (II), (III), (IV), (V), (VI), (VII), ( Any one of VIII), (IX), (X), (XI), (XII), (XIII) or (XIV) represents, wherein R 0 is H, F, CN, CH 3 , CF 3 , ring Propyl or phenyl; and the remaining variables are as described in any one of the first to fifty-first embodiments.

[0065] In the fifty-third embodiment, the compound of the present invention is represented by formula (I'), (I), (II), (III), (IV), (V), (VI), (VII), ( Any one of VIII), (IX), (X), (XI), (XII), (XIII) or (XIV), wherein R is H, F, CN, CH or CF ; and The remaining variables are as described in any one of the first to fifty-first embodiments.

[0066] In the fifty-fourth embodiment, the compound of the present invention is represented by formula (I'), (I), (II), (III), (IV), (V), (VI), (VII), ( Any one of VIII), (IX), (X), (XI), (XII), (XIII) or (XIV) represents, wherein R 7 is selected from H, CH 3 , CH 2 CH 3 , CH 2 CHF 2 and cyclopropyl; and the rest of the variables are as described in any one of the first to fifty-third embodiments.

[0067] In the fifty-fifth embodiment, the compound of the present invention is represented by formula (I'), (I), (II), (III), (IV), (V), (VI), (VII), ( Any one of VIII), (IX), (X), (XI), (XII), (XIII) or (XIV) represents, wherein R 8 is H or CH 3 ; and the remaining variables are as in the first to Any one of the fifty-fourth embodiment.

[0068] In the fifty-sixth embodiment, the compound of the present invention is represented by formula (I'), (I), (II), (III), (IV), (V), (VI), (VII), ( Any one of VIII), (IX), (X), (XI), (XII), (XIII) or (XIV) represents, wherein R 10 is F, Cl, CH 3 or cyclopropyl; and the formula (I'), (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), ( The remaining variables in XII), (XIII) or (XIV) are as described in any one of the first to fifty-fifth embodiments.

[0069] In the fifty-seventh embodiment, the compound of the present invention is represented by formula (I'), (I), (II), (III), (IV), (V), (VI), (VII), ( Any one of VIII), (IX), (X), (XI), (XII), (XIII) or (XIV) represents, wherein R 14 is Cl; And the remaining variables are as the first to fiftieth Any one of the six embodiments.

[0070] In a fifty-eighth embodiment, the compound is represented by the following formula: (XV), Or a pharmaceutically acceptable salt thereof, wherein: R 0 is H, halogen or cyclopropyl; X 3 is O or O-CH 2*; R 2 is 4-7 membered monocyclic or bicyclic saturated carbocyclyl , and the 4-7 membered monocyclic or bicyclic saturated carbocyclic group represented by R 2 is substituted by a group represented by R 4 and further substituted by one or two R 10 as the case may be, or R 2 is a ring carbon atom (" C-connected") bonded to X 7-9 membered bicyclic nitrogen-containing heterocyclic ring and the C-connected 7-9 membered bicyclic nitrogen-containing heterocyclic ring is substituted by a group represented by R 5 and optionally further replaced by one or two R 10 substitution; R 4 is N(R 7)C(O)C≡CCH 3, N(R 7)C(O)CH=CH 2, R 5 is C(O)CH=CH 2, R 7 is H, C 1-C 2 alkyl or C 1-C 2 haloalkyl; and R 10 is C 1-C 3 alkyl.

[0071] In the fifty-ninth embodiment, the compound of the present invention is represented by formula (XV), wherein X 3 is O; and the remaining variables in formula (XV) are as described in the fifty-eighth embodiment.

[0072] In a sixtieth embodiment, the compound of the present invention is represented by formula (XV), wherein R 2 is cyclobutylene, cyclohexylene, cyclopentylene or bicyclo[2.1.1]hexylene, each of which is represented by The group represented by R 4 is substituted and optionally further substituted by one or two R 10 . The remaining variables in formula (XV) are as described in the fifty-eighth or fifty-ninth embodiment.

[0073] In the sixty first embodiment, the compound of the present invention is represented by formula (XV), wherein R 2 is , , or , wherein the group represented by R 2 is further substituted by one or two groups represented by R 10 as appropriate. The remaining variables in formula (XV) are as described in the fifty-eighth or fifty-ninth embodiment.

[0074] In the sixty-second embodiment, the compound of the present invention is represented by formula (XV), wherein R 2 is azabicyclo[3.2.1]octyl, azabicyclo[3.1.1]heptyl or nitrogen Heterobicyclo[3.2.0]heptyl, each of which is substituted by a group represented by R 5 and further substituted by one or two R 10 as appropriate. The remaining variables in formula (XV) are as described in the fifty-eighth or fifty-ninth embodiment.

[0075] In a sixty-third embodiment, the compound of the present invention is represented by formula (XV), where R2 is , or , wherein "**" indicates the point of connection with X 3; and "***" indicates the point of connection with R 5, wherein each group represented by R 2 is further modified by one or two groups represented by R 10 as the case may be group substitution. The remaining variables in formula (XV) are as described in any of the fifty-eighth to sixty-second embodiments.

[0076] In a sixty-fourth embodiment, the compound of the present invention is represented by formula (XV), wherein R 7 is H, CH 3 or CH 2 CHF 2 . The remaining variables in formula (XV) are as described in any of the fifty-eighth to sixty-third embodiments.

[0077] In a sixty-fifth embodiment, the compound of the invention is represented by formula (XV), wherein R 10 is CH 3 . The remaining variables in formula (XV) are as described in any of the fifty-eighth to sixty-fourth embodiments.

[0078] The invention also includes both neutral forms and pharmaceutically acceptable salts of the compounds disclosed in the Examples.

[0079] As used herein, the term "alkyl" refers to a fully saturated branched or unbranched hydrocarbon moiety. Unless otherwise specified, alkyl groups contain 1 to 6 carbon atoms or 1 to 3 carbon atoms. Representative examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, second-butyl, isobutyl, tertiary-butyl, n-pentyl, isopentyl, Neopentyl or n-hexyl.

[0080] As used herein, the term "alkoxy" refers to a fully saturated branched or unbranched alkyl moiety attached through an oxygen bridge (i.e., --O--C 1-4 alkyl, where C 1-4 alk basis as defined herein). Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, and the like. In some embodiments, alkoxy groups have about 1-4 carbons, more preferably about 1-2 carbons.

[0081] The number of carbon atoms in a group is designated herein by the prefix "C x-xx", where x and xx are integers. For example, "C 1-3 alkyl" is an alkyl group having 1 to 3 carbon atoms.

[0082] "Halogen" or "halo" can be fluorine, chlorine, bromine or iodine.

[0083] The term "haloalkyl" or "halo-substituted alkyl" refers to an alkyl group having at least one halogen substitution. The term "fluoroalkyl" or "fluoro-substituted alkyl" refers to an alkyl group having at least one fluorine substitution.

[0084] "Heterocyclyl" or "heterocycle" means a saturated or partially unsaturated monocyclic or bicyclic (e.g., fused, bridged, or spiro ring system) ring system having 4 to 12 ring members, at least one of which is are heteroatoms, and up to four of them (e.g., 1, 2, 3, or 4) can be heteroatoms, wherein the heteroatoms are independently selected from O, S, and N, and wherein C can be oxidized (e.g., C( O)), N can be oxidized (e.g., N(O)) or quaternized, and S can be oxidized to sulfoxides and sulfones as appropriate. In some embodiments, if a "heterocyclyl" or "heterocycle" described herein contains both N and O, then the "heterocyclyl" or "heterocycle" is considered to be an N-containing heterocycle.

[0085] The 4-12 membered heterocyclic group may be a monocyclic 4 to 7 membered heterocyclic group or a fused, bridged or spiro bicyclic 7 to 12 membered heterocyclic group. Examples of 4 to 7 membered monocyclic heterocyclyl groups include, but are not limited to, oxetanyl, thietanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, thietanyl, Imidazolidinyl, pyrazolidine, oxazolidine, isoxazolidine, thiazolidinyl, isothiazolidine, dioxolane, dithiolanyl, oxathiolane Alkyl, piperidinyl, tetrahydropyranyl, thianyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxanyl, dithianyl, trioxanyl, trithianyl , azepanyl, oxepanyl, thiepanyl, dihydrofuryl, imidazolinyl and dihydropyranyl.

[0086] A "fused ring system" has 8 to 12 members (ring atoms) and two rings that share two adjacent ring atoms. A fused bicyclic heterocyclic group has a 4 to 7 membered heterocyclic group fused to a 4 to 7 membered heterocyclic group or a 3 to 7 membered non-aromatic carbocyclic ring. Examples include cyclopentadienopyrrolidinyl, cyclopentadienopiperidinyl, cyclopentadienazepanyl, cyclohexadienopyrrolidinyl, cyclohexadienopiperidinyl, Cycloheptadienoazepanyl, Cycloheptadienopyrrolidinyl, Cycloheptadienopiperidinyl, Cycloheptadienoazepanyl, Pyrrolopyrrolidinyl, Pyrrolo Piperidinyl, pyrroloazepanyl, furopyrrolidinyl, furopiperidinyl, furanoazepanyl, pyranopyrrolidinyl, pyranopiperidinyl, pyran Azepanyl and similar groups.

[0087] A "bridged bicyclic ring system" (also referred to herein as a "bridged bicyclic ring") has 7 to 10 members (ring atoms) and two rings that share three adjacent ring atoms. Bridged bicyclic heterocyclyls include 5 to 7 membered heterocyclyls that share three ring atoms with 5 to 7 membered heterocyclyls or 5 to 7 membered non-aromatic carbocyclyls. Examples of nitrogen-containing bridged bicyclic rings include azabicyclo[2.2.1]heptyl, azabicyclo[3.2.1]octyl, azabicyclo[3.3.1]nonyl, diazabicyclo[2.2.1] Heptyl, diazabicyclo[3.2.1]octyl and diazabicyclo[3.3.1]nonyl. Examples of oxygen-containing bridged bicyclic rings include oxobicyclo[2.2.1]heptyl, oxobicyclo[3.2.1]octyl, oxobicyclo[3.3.1]nonyl, oxa-azabicyclo [2.2.1] Heptyl, oxa-azabicyclo[3.2.1]octyl and oxa-azabicyclo[3.3.1]nonyl.

[0088] A "spiro ring system" (also referred to herein as a "spiro ring") has 8 to 12 members (ring atoms) and two rings that share one ring atom. Spirobicyclic heterocyclyls include 4 to 7 membered heterocyclyls that share one atom with 4 to 7 membered heterocyclyls or 4 to 7 membered non-aromatic carbocyclyls. Examples of 8 to 12 nitrogen-containing spiro ring systems include 3,4-azabicyclooctyl, 4,4-azabicyclononyl, 3,5-azabicyclononyl, 3,6-azabicyclodecanyl , 4,5-azabicyclodecanyl, 3,7-azabicycloundecyl, 4,6-azabicycloundecyl and 5,5-azabicycloundecyl. Examples of 8-12 oxygen-containing spiro ring systems include 3,4-oxobicyclooctyl, 4,4-oxobicyclononyl, 3,5-oxobicyclononyl, 3,6-oxo 4,5-oxobicyclodecanyl, 3,7-oxobicycloundecyl, 4,6-oxobicycloundecyl and 5,5-oxobicyclo Undecyl.

[0089] Examples of 4- to 12-membered nitrogen-containing heterocyclic rings include pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, piperidinyl, piperazine morpholinyl, thiomorpholinyl, azepanyl, oxepanyl, imidazolinyl, cyclopentadienopyrrolidinyl, cyclopentadienopiperidinyl, cyclopentadienyl Dienoazepanyl, cyclohexadienopyrrolidinyl, cyclohexadienopyrrolidinyl, cyclohexadienazepanyl, cycloheptadienopyrrolidinyl, cycloheptadienopyrrolidinyl, cyclohexadienopyrrolidinyl Heptadienopyrrolidinyl, cycloheptadienoazepanyl, pyrrolopyrrolidinyl, pyrrolopiperidinyl, pyrroloazepanyl, furopiperidinyl, furonitrogen Hepanyl, piperanopyrrolidinyl, piperanopyridinyl, pyranoazepanyl, azabicyclo[2.2.1]heptyl, azabicyclo[3.2.1]octyl Base, azabicyclo[3.3.1]nonyl, diazabicyclo[2.2.1]heptyl, diazabicyclo[3.2.1]octyl, diazabicyclo[3.3.1]nonyl, 3 ,4-Azabicyclooctyl, 4,4-Azabicyclononyl, 3,5-Azabicyclononyl, 3,6-Azabicyclodecanyl, 4,5-Azabicyclodecanyl, 3 , 7-azabicycloundecyl, 4,6-azabicycloundecyl and 5,5-azabicycloundecyl. Examples of 4- to 7-membered nitrogen-containing heterocycles (containing an epoxy or a ring sulfur atom as appropriate) include pyrrolidinyl, imidazolidinyl, pyrazolidine, oxazolidine, isoxazolidine, thiazolidinyl, group, isothiazolidine group, piperidinyl group, piperazinyl group, morpholinyl group, thiomorpholinyl group, azepanyl group, oxepanyl group and imidazolinyl group.

[0090] Examples of 4- to 7-membered oxygen-containing heterocycles include oxetanyl, tetrahydrofuranyl, oxazolidinyl, isoxazolidinyl, dioxolyl, oxathiolanyl, tetrahydro pyranyl, morpholinyl, dioxanyl, oxepanyl, dihydrofuranyl and dihydropyranyl.

[0091] "Heteroaryl" means an aromatic 5 to 6 membered monocyclic ring system having 1 to 4 heteroatoms independently selected from O, N and S, and wherein N may be oxidized (e.g., N(O)) Or quaternization, and S can be oxidized to sulfoxide and sulfone depending on the situation. Examples of 5 to 6 membered monocyclic heteroaryl groups include, but are not limited to, pyrrolyl, furyl, thiophenyl / thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazole Base, furanyl, oxadiazolyl, thiadiazolyl, bithiazolyl, triazolyl, tetrazolyl, pyridyl, pyryl, thiopyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, Oxazinyl, thiazinyl, dioxinyl, dithianyl, oxathianyl, triazinyl, tetrazinyl and the like. In one embodiment, the heteroaryl is a 5 membered heteroaryl. Examples of 5-membered heteroaryl include, but are not limited to, pyrazolyl, oxazolyl, isoxazolyl, 1,2,3-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2, 4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl and tetrazolyl.

[0092] "Carbocyclyl" refers to a saturated or partially unsaturated monocyclic or bicyclic (eg, fused, bridged, or spiro ring system) ring system having 4 to 12 ring members, all of which are carbon. The term "carbocyclyl" encompasses cycloalkyl, cycloalkenyl and aromatic groups (ie, aryl). "Cycloalkyl" refers to a fully saturated monocyclic hydrocarbon group of 3-7 carbon atoms, including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cyclopentyl; and "cycloalkenyl" refers to 3- Unsaturated non-aromatic monocyclic hydrocarbon groups of 7 carbon atoms, including cyclopentenyl, cyclohexenyl and cyclopentenyl. Exemplary aromatic carbocyclic groups include phenyl.

[0093] A fused bicyclic carbocyclyl has a 4 to 7 membered carbocyclyl fused to a 3 to 7 membered non-aromatic carbocyclyl. Examples include decahydronaphthalene, octahydro-1H-indene, octahydropentalene, decahydroazulene, decahydro-1H-annulene, bis[4.2.0]octane, bicyclo[3.2.0]heptane, and the like group.

[0094] A bridged bicyclic carbocyclyl comprises a non-aromatic 5 to 7 membered carbocyclyl which shares three ring atoms with a 5 to 7 membered nonaromatic carbocyclyl. Examples of bridged bicyclic carbocycles include bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl, bicyclo[3.3.1]nonyl.

[0095] The suffix "radical" added to the end of a chemical name indicates that the named moiety is bonded to the molecule at some point. The suffix "extension" added to the end of a chemical name indicates that the named moiety is bonded to the molecule at two points. Examples include azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, or oxazepanyl, which indicates that azetidine, pyrrolidinyl, piperidine , azepane or oxazepane are bonded to the rest of the compound at two points.

[0096] In the case of a nitrogen-containing heterocycle, "N-attached to the bicyclic core" means that the nitrogen-containing heterocycle is bonded to the core via its ring nitrogen atom. In the case of a nitrogen-containing heterocycle or carbocycle, "C-attached to the bicyclic core" means that the nitrogen-containing heterocycle or carbocycle is bonded to the core via a ring carbon atom.

[0097] A nitrogen-containing heterocycle is "N-substituted" when the ring nitrogen atoms are substituted.

[0098] In cases where the compounds provided herein are sufficiently basic or acidic to form stable non-toxic acid or base salts, it may be appropriate to prepare and administer the compounds as pharmaceutically acceptable salts. Examples of pharmaceutically acceptable salts are organic acid addition salts with acids forming physiologically acceptable anions, for example, tosylate, methanesulfonate, acetate, citrate, propanedisulfonate, salt, tartrate, succinate, benzoate, ascorbate, alpha-ketoglutarate, or alpha-glycerophosphate. Inorganic salts may also be formed, including hydrochlorides, sulfates, nitrates, bicarbonates, and carbonates.

[0099] Pharmaceutically acceptable salts can be obtained using standard procedures well known in the art, for example, by reacting a sufficiently basic compound, such as an amine, with a suitable acid to give a physiologically acceptable anion. Alkali metal (eg, sodium, potassium, or lithium) or alkaline earth metal (eg, calcium) salts of carboxylic acids can also be prepared.

[0100] Pharmaceutically acceptable base addition salts can be formed from inorganic and organic bases. Salts from inorganic bases may include, but are not limited to, sodium, potassium, lithium, ammonium, calcium or magnesium salts. Salts derived from organic bases may include, but are not limited to, salts of primary, secondary, or tertiary amines such as alkylamines, dialkylamines, trialkylamines, substituted alkylamines, di(substituted Alkyl) amines, tri(substituted alkyl) amines, alkenyl amines, dienyl amines, trienyl amines, substituted alkenyl amines, di(substituted alkenyl) amines, tri(substituted alkenyl) amines, Substituted alkenyl)amines, cycloalkylamines, di(cycloalkyl)amines, tri(cycloalkyl)amines, substituted cycloalkylamines, disubstituted cycloalkylamines, trisubstituted cycloalkylamines Alkylamine, Cycloalkenylamine, Di(cycloalkenyl)amine, Tri(cycloalkenyl)amine, Substituted Cycloalkenylamine, Disubstituted Cycloalkenylamine, Trisubstituted Cycloalkenylamine , arylamine, diarylamine, triarylamine, heteroarylamine, diheteroarylamine, triheteroarylamine, heterocycloalkylamine, diheterocycloalkylamine, triheterocycloalkylamine , or mixed diamines and triamines, wherein at least two substituents on the amine can be different and can be alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted ring Alkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl or heterocycloalkyl and the like. Also included are amines in which two or three substituents, taken together with the amine nitrogen, form a heterocycloalkyl or heteroaryl. Non-limiting examples of amines may include isopropylamine, trimethylamine, diethylamine, tri(isopropyl)amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, trimethylamine, lysoamine Acid, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, N-alkylglucosamine, theobromine , purine, piperazine, piperidine, morpholine or N-ethylpiperidine and the like. Other carboxylic acid derivatives may be suitable, for example, carboxylic acid amides, including carboxamides, lower alkyl carboxamides or dialkyl carboxamides and the like.

[0101] A compound as described herein, or a pharmaceutically acceptable salt thereof, may contain one or more asymmetric centers in the molecule. In accordance with the present disclosure, any structure for which no stereochemistry is specified is understood to include all of the various stereoisomers (e.g., diastereomers and enantiomers) in pure or substantially pure form, as well as mixtures thereof (such as a racemic mixture, or an enantiomerically enriched mixture). It is well known in the art how to prepare such optically active forms (e.g., resolution of racemic forms by recrystallization techniques, synthesis from optically active starting materials, by chiral synthesis or chromatography using chiral stationary phases) separation).

[0102] When a specific stereoisomer of a compound is depicted by name or structure, the stereochemical purity of the compound is at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 97% %, 99%, 99.5%, or 99.9%. "Stereochemical purity" means the weight percent of the desired stereoisomer relative to the combined weight of all stereoisomers.

[0103] When a specific enantiomer of a compound is depicted by name or structure, the stereochemical purity of the compound is at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 97%, 99%, 99.5%, or 99.9%. "Stereochemical purity" means the weight percent of the desired enantiomer relative to the combined weight of all stereoisomers.

[0104] When the stereochemistry of a disclosed compound is named or depicted by a structure, and the named or depicted structure encompasses more than one stereoisomer (for example, as in a diastereomeric pair), it is to be understood that the contemplated One of the stereoisomers or any mixture of the contemplated stereoisomers. It is further understood that the stereoisomeric purity of the named or depicted stereoisomer is at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 97%, 99% %, 99.5% or 99.9%. Stereomeric purity is the weight percent of the desired stereoisomer encompassed by name or structure relative to the combined weight of all stereoisomers.

[0105] When a disclosed compound is named or depicted by a structure without indicating stereochemistry, and the compound has one chiral center, it is understood that the name or structure encompasses one enantiomer of the compound in pure or substantially pure form, and Mixtures thereof (such as racemic mixtures of compounds and mixtures enriched in one enantiomer relative to the corresponding optical isomer).

[0106] When a disclosed compound is named or depicted by a structure without indication of stereochemistry, and, for example, the compound has at least two chiral centers, it is understood that the name or structure encompasses one stereoisomer in pure or substantially pure form, and Mixtures thereof (such as mixtures of stereoisomers, and mixtures of stereoisomers enriched in one or more stereoisomers relative to other stereoisomers).

[0107] The disclosed compounds can exist in tautomeric forms and mixtures, and the individual tautomers are contemplated individually. Additionally, some compounds may exhibit polymorphism.

[0108] In one embodiment, the present invention provides deuterated compounds disclosed herein, wherein any or more of the positions occupied by hydrogen can include a deuterium enrichment above the natural abundance of deuterium. For example, one or more hydrogen atoms are replaced with deuterium at least 3340 times the natural abundance of deuterium (0.015%) (i.e., at least 50.1% deuterium incorporation), at least 3500 times (at 52.5% deuterium incorporation at each specified deuterium atom), at least 4000 times (60% deuterium incorporation), at least 4500 times (67.5% deuterium incorporation), at least 5000 times (75% deuterium incorporation), at least 5500 times (82.5% deuterium incorporation) Incorporation), at least 6000-fold (90% deuterium incorporation), at least 6333.3-fold (95% deuterium incorporation), at least 6466.7-fold (97% deuterium incorporation), at least 6600-fold (99% deuterium incorporation) or at least 6633.3 times (99.5% deuterium incorporation). In one embodiment, hydrogen is present at all positions in its natural abundance. Compounds as described herein, or pharmaceutically acceptable salts thereof, may exist in tautomeric forms and mixtures, and the individual tautomers are contemplated individually.

[0109] Another embodiment is a pharmaceutical composition comprising at least one compound described herein, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

[0110] The compounds described herein, or pharmaceutically acceptable salts thereof, can be used to reduce the activity of Btk, or otherwise affect the properties and / or behavior of Btk, e.g., stability, phosphorylation, kinase activity, interaction with other proteins function etc.

[0111] In some embodiments, the present invention provides methods of reducing the enzymatic activity of Btk. In some embodiments, such methods comprise contacting Btk with an effective amount of a Btk inhibitor. Accordingly, the present invention further provides a method of inhibiting the enzymatic activity of Btk by contacting Btk with a Btk inhibitor of the present invention.

[0112] One embodiment of the invention includes a method of treating a condition responsive to Btk inhibition in a subject, the method comprising administering to the subject an effective amount of at least one compound described herein, or a pharmaceutically acceptable salt thereof.

[0113] In one embodiment, the present invention provides a method of treating autoimmune disorders, inflammatory disorders, and cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of at least one compound described herein, or its pharmaceutical acceptable salt.

[0114] The term "autoimmune disorder" includes diseases or disorders involving an inappropriate immune response against native antigens, such as acute disseminated encephalomyelitis (ADEM), Addison's disease, alopecia areata, antiphospholipid antibody syndrome (APS ), autoimmune hemolytic anemia, autoimmune hepatitis, bullous pemphigoid (BP), celiac disease, dermatomyositis, type 1 diabetes, Goodpasture's syndrome, Graves' disease ( Graves' disease), Guillain-Barre syndrome (Guillain-Barre syndrome, GBS), Hashimoto's disease, idiopathic thrombocytopenic purpura, lupus erythematosus, mixed connective tissue disease, multiple sclerosis, Myasthenia gravis, pemphigus vulgaris, pernicious anemia, polymyositis, primary biliary cirrhosis, Sjogren's syndrome, temporal arteritis, and Wegener's granulomatosis . The term "inflammatory disorder" includes diseases or disorders involving acute or chronic inflammation, such as allergies, asthma, prostatitis, glomerulonephritis, pelvic inflammatory disease (PID), inflammatory bowel disease (IBD, e.g. Crohn's disease ( Crohn's disease), ulcerative colitis), reperfusion injury, rheumatoid arthritis, transplant rejection, and vasculitis. In some embodiments, the present invention provides a method of treating rheumatoid arthritis or lupus. In some embodiments, the invention provides a method of treating multiple sclerosis.

[0115] The term "cancer" includes diseases or conditions involving abnormal cell growth and / or proliferation, such as glioma, thyroid cancer, breast cancer, lung cancer (e.g., small cell lung cancer, non-small cell lung cancer), gastric cancer, gastrointestinal interstitial glioma, pancreatic cancer, cholangiocarcinoma, ovarian cancer, endometrial cancer, prostate cancer, renal cell carcinoma, lymphoma (e.g., anaplastic large cell lymphoma), leukemia (e.g., acute myelogenous leukemia, T-cell leukemia , chronic lymphocytic leukemia), multiple myeloma, malignant mesothelioma, malignant melanoma, and colon cancer (eg, microsatellite instability-high colorectal cancer). In some embodiments, the present invention provides a method of treating leukemia or lymphoma.

[0116] As used herein, the terms "individual" and "patient" are used interchangeably and mean a mammal in need of treatment, for example, companion animals (e.g., dogs, cats, and similar animals), farm animals (e.g., cows, pigs, etc.) , horses, sheep, goats and similar animals) and laboratory animals (for example, rats, mice, guinea pigs and similar animals). Typically, an individual is a human in need of treatment.

[0117] As used herein, the term "treatment" or "therapy" refers to obtaining a desired pharmacological and / or physiological effect. The effect may be therapeutic, including partially or substantially achieving one or more of the following results: partial or complete alleviation of the degree of disease, disorder or syndrome; improvement or improvement of clinical symptoms or indicators associated with the disorder; or delay, inhibition or reduction Likelihood of disease, disease or syndrome progression.

[0118] The effective dose of a compound provided herein or a pharmaceutically acceptable salt thereof administered to a subject may range from 10 μg to 500 mg.

[0119] Administration of a compound described herein, or a pharmaceutically acceptable salt thereof, to a mammal includes any suitable method of delivery. Administration of a compound described herein, or a pharmaceutically acceptable salt thereof, to a mammal includes topical, enteral, parenteral, transdermal, transmucosal, inhalation, intracisternal, epidural, intravaginal, A compound described herein, or a pharmaceutically acceptable salt thereof, is administered intravenously, intramuscularly, subcutaneously, intradermally, or intravitreously. Administration of a compound described herein, or a pharmaceutically acceptable salt thereof, to a mammal also includes topical, enteral, parenteral, transdermal, transmucosal, inhalation, intracisternal, epidural, intravaginal administration to a mammal. , intravenous, intramuscular, subcutaneous, intradermal or intravitreal administration of a compound that is metabolized in or on a mammal to a compound described herein or a pharmaceutically acceptable salt thereof.

[0120] Thus, a compound as described herein, or a pharmaceutically acceptable salt thereof, may be administered systemically, eg orally, in combination with a pharmaceutically acceptable vehicle, such as an inert diluent or an assimilable edible carrier. It can be enclosed in hard- or soft-shell gelatin capsules, compressed into lozenges, or mixed directly with food in the patient's diet. For oral therapeutic administration, a compound as described herein, or a pharmaceutically acceptable salt thereof, may be combined with one or more excipients and presented as an ingestible lozenge, buccal lozenge, buccal lozenge, capsule, Elixirs, suspensions, syrups or wafers, and the like are used. Such compositions and preparations should contain at least about 0.1% of active compound. The percentages of compositions and formulations may of course vary and may suitably be between about 2 and about 60% by weight of a given unit dosage form. The amount of active compound in such therapeutically useful compositions is such that an effective dosage level will be obtained.

[0121] Tablets, lozenges, pills, capsules, and the like may include the following materials: binders, such as tragacanth, acacia, corn starch, or gelatin; excipients, such as dicalcium phosphate; disintegrants, such as corn starch , potato starch, alginic acid and the like; lubricants such as magnesium stearate; or sweeteners such as sucrose, fructose, lactose or aspartame or flavoring agents.

[0122] The active compounds can also be administered intravenously or intraperitoneally by infusion or injection. Solutions of the active compounds or their salts can be prepared in water, optionally mixed with a nontoxic surfactant.

[0123] Exemplary pharmaceutical dosage forms for injection or infusion may include sterile aqueous solutions or dispersions or sterile powders containing the active ingredient suitable for the extemporaneous preparation of sterile injectable or infusible solutions or dispersion. In all cases, the ultimate dosage form should be sterile, fluid and stable under the conditions of manufacture and storage.

[0124] Sterile injectable solutions can be prepared by incorporating the active compounds in the required amount in an appropriate solvent with various other ingredients enumerated above, as required, followed by filtered sterilization. In the case of sterile powders for the preparation of sterile injectable solutions, preferred methods of preparation are vacuum drying and freeze-drying techniques, which yield the active ingredient plus any additional requisites present in a previously sterile-filtered solution. Ingredient powder.

[0125] Exemplary solid carriers can include finely divided solids such as talc, clay, microcrystalline cellulose, silicon dioxide, aluminum oxide, and the like. Suitable liquid carriers include water, alcohols or glycols, or water-alcohol / glycol blends, in which a compound as described herein, or a pharmaceutically acceptable salt thereof, can be dissolved or dispersed at effective levels, as the case may be. With the help of non-toxic surfactants.

[0126] Useful dosages of compounds as described herein, or pharmaceutically acceptable salts thereof, can be determined by comparing their in vitro activity with in vivo activity in animal models. Methods for extrapolating effective doses in mice and other animals to humans are known in the art; see, for example, US Patent No. 4,938,949, which is incorporated by reference in its entirety.

[0127] The amount of a compound as described herein, or a pharmaceutically acceptable salt thereof, required for treatment will vary not only with the particular salt selected, but also with the route of administration, the nature of the condition being treated, and the age and condition of the patient. Varies and may ultimately be at the discretion of the attending physician or clinician. In general, however, dosages may range from about 0.1 to about 10 mg / kg body weight / day.

[0128] A compound as described herein, or a pharmaceutically acceptable salt thereof, may conveniently be administered in unit dosage form; for example, containing 0.01 to 10 mg or 0.05 to 1 mg of active ingredient per unit dosage form. In some embodiments, doses of 5 mg / kg or less may be suitable.

[0129] The required dose may conveniently be presented in a single dose or in divided doses administered at appropriate intervals.

[0130] The disclosed methods can include a kit comprising a compound as described herein, or a pharmaceutically acceptable salt thereof, and instructional material describing the administration of a compound as described herein, or a pharmaceutically acceptable salt thereof, to a cell or individual. Acceptable salts or compositions comprising a compound as described herein, or a pharmaceutically acceptable salt thereof. This should be construed to include other embodiments of kits known to those skilled in the art, such as comprising a compound for dissolving or a pharmaceutically acceptable salt or composition thereof as described herein prior to administration to a cell or individual. A set of solvents, such as sterile, in which to suspend a compound as described herein, or a pharmaceutically acceptable salt or composition thereof. In some embodiments, an individual can be a human.

[0131] The invention is illustrated by the following examples, which are not intended to be limiting. [example] []

[0132] Abbreviations and acronyms used herein include the following: ABPR means Automatic Back Pressure Regulator; Ac 2 O means acetic anhydride; ACN means acetonitrile; Aq. means water; Ar means argon; Bn means benzyl; Boc means tertiary butoxycarbonyl; Boc 2O means two-tertiary butyl dicarbonate; BPin means boron pinacol; B 2pin 2 means double pinacol diboron; br means wide; t-BuOH means tertiary butanol; n-BuLi means n-butyllithium; ℃ means Celsius; CHCl3 means chloroform; CDCl means deuterated chloroform; CO2 means carbon dioxide; Cs 2 CO 3 means cesium carbonate; CsF means cesium fluoride; CuI means copper iodide; δ means chemical shift; d means doublet; dd means double doublet; ddd means double double doublet; DCM means dichloromethane; DIEA or DIPEA means N-ethyldiisopropylamine or N,N-diisopropylethylamine; DEA means diethylamine; deg means degree; DIAD means diisopropyl azodicarboxylate; DME means 1,2-dimethoxyethane; DMF means N,N-dimethylformamide; DMSO means dimethylsulfoxide; DMSO-d 6 means hexadeuteriodimethylsulfoxide; DPPA means diphenylphosphoryl azide; Et means ethyl; Et2O means ether; EtOH means ethanol; EtOAc means ethyl acetate; Eq. means equivalent; g means grams; h means hour; HATU means O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate; HBr means hydrogen bromide; HCl means hydrochloric acid; HCO 2H means formic acid; Hept means heptane; HFIP means hexafluoroisopropanol; 1H NMR means proton nuclear magnetic resonance; H2O means water; H2SO4 means sulfuric acid; HMPA means hexamethylphosphoramide; HPLC means High Pressure Liquid Chromatography; Hz means Hertz; IPA or iPrOH means isopropanol; J means the coupling constant; K 2CO 3 means potassium carbonate; kg means kilogram; KHMDS means potassium hexamethyldisilazide; KOAc means potassium acetate; KOH means potassium hydroxide; KOt-Bu means potassium tertiary butoxide K 3PO 4 means tripotassium phosphate; K 4Fe(CN) 6 3H 2O means potassium hexacyanoferrate(II) trihydrate; L means liter; LCMS means Liquid Chromatography Mass Spectrometry; m means multiplet; M means molar concentration; MBPR means Manual Back Pressure Regulator; Me means methyl; MeB(OH) 2 means methylboronic acid; MeCN means acetonitrile; MeOH means methanol; MeOH-d 4 means deuterated methanol; mg means milligrams; MgSO4 means magnesium sulfate; MHz means megahertz; mins means minutes; mL means milliliter; mmol means millimoles; MMPNO means methylmorpholine N-oxide; mol means Mole; MS m / z means mass spectrum peak; N2 means nitrogen gas; NaOt-Bu means sodium tertiary butoxide; NaH means sodium hydride; NaHCO 3 means sodium bicarbonate; NaHMDS means sodium hexamethyldisilazide; NaIO 4 means sodium periodate; NaOH means sodium hydroxide; Na 2 S 2 O 3 means sodium thiosulfate; Na 2 SO 4 means sodium sulfate; NEt 3 means triethylamine; NFSI means N-fluorobenzenesulfonimide; NH3 means ammonia; NH4Cl means ammonium chloride; NH 4OH is ammonium hydroxide; NH4OAc is ammonium acetate; NIS means N-iodosuccinimide; OsO4 means osmium tetroxide; P(cy) 3 means tricyclohexylphosphine; Pd 2 (dba) 3 means ginseng (dibenzylidene acetone) dipalladium (0); Pd(dppf)Cl 2 means [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); Pd(dtbpf)Cl 2 means [1,1'-bis(di-tertiary butylphosphino)ferrocene]dichloropalladium(II); PEPPSI-IPr or Pd-PEPPSI-IPr means [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II) dichloride Ph means phenyl; POCl 3 means phosphoryl chloride; Pyr means pyridine; q means quartet; Rf means retardation factor; Rt means residence time; RT means room temperature; RuPhos means 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl; s means single peak; sat. means saturation; SCX means strong cation exchange; SFC means supercritical fluid chromatography; SiO2 means silicon dioxide; Si-SPE means silica solid phase extraction; t means triplet; td means triple doublet; t-BuONa means three levels of sodium butoxide; TEA means triethylamine; TFA means trifluoroacetic acid; THF means tetrahydrofuran; TLC means thin layer chromatography; T 3P means propane phosphonic anhydride; µL means microliter; µmol means micromole; µW means microwave; v / v means volume / volume; Xphos means 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl; Xphos G3 means methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1, 1'-biphenyl)] palladium (II). [plan] [1] Synthesis of 1-(1-methyl-1H-pyrazol-4-yl)ethan-1-one (2).

[0133] To a mixture of 1-methyl-1H-pyrazole (50.0 g, 1 equiv, 609 mmol) and acetic anhydride (112 g, 104 mL, 1.8 equiv, 1.10 mol) was added sulfuric acid (4.78 g, 2.61 mL) at room temperature , 0.08 equiv, 48.7 mmol). The mixture was heated at 150 °C for 7 hours, after which it was allowed to cool to room temperature overnight. The reaction mixture was poured into ice, the pH of the resulting solution was adjusted to 10 with 20% aqueous NaOH, then extracted with DCM, the organic phase was dried over sodium sulfate and concentrated. This gave 1-(1-methyl-1H-pyrazol-4-yl)ethan-1-one (36.8 g, 49% yield). 1H NMR (300 MHz, CDCl3) d 7.80-7.96 (m, 2H), 3.91 (s, 3H), 2.39 (s, 3H). Synthesis of 2-bromo-1-(1-methyl-1H-pyrazol-4-yl)ethan-1-one (3).

[0134] In a round bottom flask, 1-(1-methyl-1H-pyrazol-4-yl)ethan-1-one (36.8 g, 1 equiv, 296 mmol) was dissolved in dichloromethane (700 mL). Ethanol (175 mL) and pyridinium tribromide (94.7 g, 1 equiv, 296 mmol) were added portionwise at 15 °C. The mixture was stirred from 0 °C to room temperature overnight. The mixture was checked by TLC (heptane:EtOAc 4:6) and HPLC. After the addition was complete, the reaction was quenched with water. The layers were separated, and the organic phase was dried over sodium sulfate and concentrated to give the product as a brown solid. The solid was suspended in a mixture of DCM and heptane, warmed to 50 °C and cooled to room temperature again. The product precipitated and was isolated by filtration (28.8 g). More solid (7.43 g) precipitated from the mother liquor. In total 36.2 g (60% yield) of the title product were isolated as a brown solid. ESI-MS (M+H)+: 205.1. Synthesis of 1-(2-(1-methyl-1H-pyrazol-4-yl)-2-oxoethyl)-1H-pyrazole-3,5-dicarboxylic acid diethyl ester (5).

[0135] In a round bottom flask, dissolve 2-bromo-1-(1-methyl-1H-pyrazol-4-yl)ethan-1-one (60.6 g, 1 equiv, 298 mmol) in DMF (900 mL) , diethyl 1H-pyrazole-3,5-dicarboxylate (69.6 g, 1.1 equiv, 328 mmol) and cesium carbonate (126 g, 1.30 equiv, 388 mmol) were added. The reaction was stirred overnight at room temperature. The reaction mixture was diluted with water and extracted with DCM. The organic layer was dried over sodium sulfate and concentrated. The crude product was suspended in heptane:EtOAc 1:1 (50-100 mL) and filtered. The solid was washed once with EtOAc and once with heptane to give the product (68.5 g) as a white solid. The mother liquor was concentrated and purified by column chromatography (120 g silica, heptane:EtOAc gradient 0 to 100%) to give another portion of product (9.7 g). A total of 78.2 g (78% yield) of product was isolated as a white solid. ESI-MS (M+H)+: 335.2. Synthesis of ethyl 4-hydroxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-2-carboxylate (6).

[0136] Charge 1-(2-(1-methyl-1H-pyrazol-4-yl)-2-oxoethyl)-1H-pyrazole-3 in Berghoff reactor (Berghoff reactor), Diethyl 5-dicarboxylate (15.0 g, 1 equiv, 44.9 mmol), ethanol (150 mL) and ammonium acetate (10.4 g, 3.0 equiv, 135 mmol). The mixture was heated at 130 °C for 24 hours, after which time HPLC revealed complete conversion (sample was taken after cooling the reactor to room temperature again). The reaction mixture was filtered off, washed with water and dried in air to give the product (11.8 g, 92%) as a white solid. This reaction was performed in batches on a total of 78.2 g of starting material to give a total of 66.6 g of product (92% yield). ESI-MS (M+H)+: 288.3. Synthesis of 4-hydroxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-2-carboxylic acid (7).

[0137] In a round bottom flask, ethyl 4-hydroxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-2-carboxylate (66.6 g, 1.0 equiv, 232 mmol) was suspended in methanol (1.2 L), and 1M sodium hydroxide (27.9 g, 696 mL, 3.0 equiv, 696 mmol) was added at room temperature. The mixture was stirred overnight at room temperature. The mixture was acidified to pH 2 with concentrated HCl, then filtered (very slowly and with difficulty). The solid was washed with MeOH, transferred to a round bottom flask and stripped with acetonitrile. The resulting product became a mixture of methyl ester and salt (92.8 g, max. 232 mmol). The solid was divided into two portions and the hydrolysis repeated. In a round bottom flask, methyl 4-hydroxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-2-carboxylate (46.0 g, 1.0 equiv, 116 mmol) was suspended in methanol (1.2 L), and 1 M sodium hydroxide (13.9 g, 348 mL, 3.0 equiv, 348 mmol) and 10 ml of water were added at room temperature. The mixture was stirred overnight at room temperature. The mixture was neutralized to pH 7 with conc. HCl, then filtered (filtering was still difficult). The solid was washed with acetonitrile, dioxane, transferred to a round bottom flask and stripped with acetonitrile to give the first batch of 4-hydroxy-6-(1-methyl-1H-pyrazol-4-yl) containing a lot of salt Pyrazolo[1,5-a]pyrazine-2-carboxylic acid Batch 1 (71.0 g, max. 116 mmol, Batch 1). The same operation was repeated for the second batch of methyl ester. In this case, the reaction mixture was acidified to pH 5 when the conversion was complete. This gave 4-hydroxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-2-carboxylic acid (60.0 g, max. 116 mmol, batch 1 ) and a large amount of salt. ESI-MS (M-H)+: 258.0. Synthesis of 6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-ol (8).

[0138] Charge preheated sulfolane (0.24 kg, 0.19 L, 30 eq, 2.0 mol) into the three-necked flask, and heat it to 50°C. Then 4-hydroxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-2-carboxylic acid (41.8 g, 1.0 equiv, 68 mmol ) and a few drops of concentrated sulfuric acid. The reaction mixture was heated at 350°C (slow reflux external sulfolane) and the conversion was checked hourly. After 4 hours, the reaction mixture was cooled to room temperature, diluted with DCM, and filtered through a short plug of silica with 3L heptane (fr1), 6L heptane:EtOAc 1:1 (fr2-3), 6L EtOAc (fr4-5), 4 L DCM (fr6), 6 L DCM:MeOH 9:1 (fr7-8) were eluted for purification. The product (containing by-product 8a) was isolated from fr7 as a brown solid (2.88 g, 20%). ESI-MS (M-H) +: 214.1. Synthesis of 4-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine. [intermediate] [A]

[0139] In a round bottom flask, 6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-ol (2.88 g, 1.0 equiv, 13.4 mmol) Suspend in POCl 3 (32.8 g, 19.9 mL, 16 equiv, 214 mmol), and heat the reaction at 80 °C overnight. The mixture was diluted with acetonitrile and concentrated, the residue was suspended in DCM and the mixture was washed with saturated NaHCO 3 and brine, dried over sodium sulfate and concentrated. The crude product was purified by column chromatography (DCM:EtOAc / NEt 35% gradient 0 to 25%) to afford the product (1.35 g, 43%) as a yellow solid. ESI-MS (M+H)+: 234.0. [plan] [2] Synthesis of 7-chloro-5-(methylthio)imidazo[1,2-c]pyrimidine hydrochloride (11).

[0140] In a round bottom flask, 6-chloro-2-(methylthio)pyrimidin-4-amine (150 g, 1 equiv, 854 mmol) was dissolved in 1,4-dioxane (300 mL), and added 2-Chloroacetaldehyde (220 g, 0.18 L, 1.5 equiv, 1.28 mol). The mixture was stirred at 100°C. After 2 hours, a solid precipitated out of the reaction mixture, and after 3 hours the reaction was checked by HPLC to reveal complete conversion. The reaction mixture was cooled to room temperature overnight. The suspension was cooled to 0 °C and the solid was filtered off to give the product as a yellow solid (151 g, 75%). ESI-MS (M+H)+: 200.1. Synthesis of 7-chloroimidazo[1,2-c]pyrimidin-5(6H)-one (12).

[0141] In a three-necked flask, 7-chloro-5-(methylthio)imidazo[1,2-c]pyrimidine hydrochloride (52.2 g, 1 equiv, 221 mmol) was suspended in MeOH (200 mL). A solution of potassium hydroxide (55.9 g, 4.5 equiv, 996 mmol) in water (520 mL) was added slowly. The reaction was heated at reflux for 3 hours, then checked by HPLC-MS. The starting material disappeared. The reaction was cooled to room temperature overnight. The mixture was acidified to pH 6 with 1M HCl and the resulting suspension was filtered. The solid was washed with MeOH, then transferred to a round bottom flask and suspended in ACN, then concentrated. The pure product 7-chloroimidazo[1,2-c]pyrimidin-5(6H)-one (28.55 g, 76%) was obtained as a white solid. ESI-MS (M+H)+: 170.1. Synthesis of 7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5(6H)-one (13).

[0142] In a three-necked flask, 7-chloroimidazo[1,2-c]pyrimidin-5(6H)-one (40.0 g, 1 equivalent, 236 mmol), 1-methyl-4-(4,4, 5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (73.6 g, 1.5 equivalents, 354 mmol) and X-phos (11.2 g, 0.10 equiv, 23.6 mmol) was dissolved in 2-propanol (1.8 L), and a 2 M solution of potassium phosphate (150 g, 0.35 L, 3.0 equiv, 708 mmol) in water was added. The mixture was purged with N 2 for 15 minutes, then Pd 2 (dba) 3 (10.8 g, 0.05 equiv, 11.8 mmol) was added and the mixture was refluxed overnight. The reaction was checked by HPLC-MS and analysis showed almost complete conversion. Add Pd 2(dba) 3 (5.0 g) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl )-1H-pyrazole (25.0 g) and the mixture was refluxed for another night. HPLC-MS showed complete conversion. The reaction mixture was filtered to remove palladium residues. The organic solvent was evaporated and the residue was partitioned between water and a 1:1 mixture of heptane:EtOAc. A white solid precipitated in both the organic and aqueous layers: the mixture was filtered off. The solid was washed with water, ethyl acetate and acetonitrile and dried in vacuo to give the product (32.8 g). The filtrate layers were separated. Discard the organic phase and cool the aqueous layer on an ice bath. The solution was treated with concentrated HCl to pH 6 with stirring and the resulting fine precipitate was collected, washed with H 2 O and Et 2 O and dried under vacuum to give another crop of product (9.0 g). A total of 41.8 g (82%) of product were obtained as a yellowish solid. ESI-MS (M+H)+: 215.0. Synthesis of 5-chloro-7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidine. [intermediate] [B]

[0143] Charge 7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5(6H)-one (41.8 g, 1 equiv, 194 mmol ), anhydrous DCM (300 mL) and DIPEA (126 g, 0.17 L, 5 equiv, 971 mmol). After 5 minutes, the mixture was cooled to 0 °C and POCl 3 (89.3 g, 54.1 mL, 3 equiv, 583 mmol) was added dropwise over 5 minutes. The mixture was allowed to reach room temperature and diluted with DCM (150 mL), then stirred at room temperature for 24 hours. The suspension was diluted with hexanes and the solid (66.0 g) was collected by filtration. The collected solid was suspended in DCM:DIPEA (5:1,500 mL). The mixture was stirred for 30 min, then saturated aqueous NaHCO 3 was added and the mixture was stirred for 1 h. The mixture was filtered through celite, then the layers were separated, and the aqueous layer was extracted 3 times with DCM. The organic layer was dried over sodium sulfate and concentrated. The product 5-chloro-7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidine (22.5 g, 50%) was obtained as a yellow solid. ESI-MS (M+H)+: 234.0. [plan] [3] Synthesis of 4-methoxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine

[0144] To 6-bromo-4-methoxypyrazolo[1,5-a]pyridine (8.0 g, 35 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1 , 3,2-dioxaborolan-2-yl)-1H-pyrazole (8.8 g, 42 mmol) in water (30 mL) and dioxane (150 mL) was added K 2CO3 (9.74 g, 70.5 mmol) and Pd(dppf)Cl2 (1.29 g, 1.76 mmol), and the reaction mixture was stirred at 90 °C for 2 h under N2. The reaction mixture was diluted with H 2 O (80 mL) and extracted with EtOAc (100 mL x 2). The combined organic phases were dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE / EtOAc = 1 / 1-0 / 1) to give 4-methoxy-6-(1-methyl- 1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine (8.0 g). 1HNMR (400 MHz, CDCl 3 ) δ: 8.27 (s, 1H), 7.86 (d, J=1.6 Hz, 1H), 7.74 (s, 1H), 7.61 (s, 1H), 6.62 (s, 1H), 6.47 (s, 1H), 4.00 (s, 3H), 3.97 (s, 3H) 1. Synthesis of 6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-ol

[0145] 4-Methoxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine (15 g, 65.7 mmol) in HBr aqueous solution (100 mL, 48 %)) was stirred at 120°C for 48 hours. The reaction mixture was concentrated in vacuo, the residue was quenched with saturated NaHCO 3 until pH reached 8 and extracted with EtOAc (3 x 80 mL). The combined organic layers were dried over Na2SO4 and filtered. The filtrate was concentrated to give the crude product, which was purified by silica gel column chromatography (DCM / MeOH=20 / 1-10 / 1) to give 6-(1-methyl-1H-pyrazol-4-yl as a gray solid. ) pyrazolo[1,5-a]pyridin-4-ol (13.0 g, 92% yield). LCMS m / z = 215.0 (M+H)+ 2. Synthesis of 6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl trifluoromethanesulfonate [intermediate] [C]

[0146] To a solution of 6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-ol (40 g, 136 mmol) in THF (600 mL) DIPEA (87.58 g, 678 mmol) and N-phenyl-bis(trifluoromethanesulfonimide) (72.63 g, 203 mmol) were added, and the reaction was stirred at 20°C for 20 hours. The reaction mixture was diluted with H 2 O (500 mL) and extracted with EtOAc (3 x 350 mL). The combined organic layers were dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the crude material was purified by silica gel column chromatography (PE / EtOAc = 20 / 1-1 / 1) to give trifluoromethanesulfonic acid 6-(1-methyl-1H as a yellow solid -pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl ester (32.0 g, 68% yield) and another 10 g of crude material. LCMS m / z = 347.1 (M+H)+ [C.] [Synthesis example] [1-236] [example] [1]:1-[4-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]oxy-1-piperidinyl] Prop-2-yn-1-one. Synthesis of tertiary-butyl 4-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]oxypiperidine-1-carboxylate

[0147] A solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (664 mg, 3.30 mmol) in anhydrous DMF (10 mL) was cooled in an ice bath. Next, sodium hydride (396 mg, 9.90 mmol, 60% purity) was added in 4 portions with stirring. Stirring was continued for 45 min in the ice bath, during which time a pale yellow suspension formed. To this mixture was added a batch of 4-chloro-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazine (701 mg, 3.00 mmol), and the mixture immediately became Brown-orange. Stirring was continued overnight at room temperature. The mixture was diluted with EtOAc, followed by careful addition of water. The mixture was transferred to a separatory funnel and the phases were separated. The aqueous phase was extracted again with EtOAc, and the combined organic phases were washed with brine, dried over Na 2 SO 4 , filtered and evaporated in vacuo. The residue was purified on a 10 g Si-SPE column: Rt = 0.18 in heptane / EtOAc = 1 / 1 to give 4-[6-(1-methylpyrazole-4- yl)pyrazolo[1,5-a]pyrazin-4-yl]oxypiperidine-1-carboxylic acid tert-butyl ester (1.30 g, 98% yield, 90% purity). LCMS: m / z = 399.0 (M+H+). Synthesis of 6-(1-methylpyrazol-4-yl)-4-(4-piperidinyloxy)pyrazolo[1,5-a]pyrazine

[0148] 4-[6-(1-Methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]oxypiperidine-1-carboxylic acid tris To a solution of butyl ester (1.17 g, 2.94 mmol) in DCM (5 mL) was added TFA (6.70 g, 58.8 mmol, 4.5 mL). Stirring was continued overnight. The mixture was diluted with MeOH and purified on a 10 g SCX column, where the product was eluted with 2 M NH3-MeOH to give 6-(1-methylpyrazol-4-yl)-4-( 4-piperidinyloxy)pyrazolo[1,5-a]pyrazine (890 mg, 96% yield, 95% purity). LCMS: m / z = 299.0 (M+H+). Synthesis of 1-[4-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]oxy-1-piperidinyl]propan-2 - Alkyn-1-one

[0149] Add 6-(1-methylpyrazol-4-yl)-4-(4-piperidinyloxy)pyrazolo[1,5-a]pyrazine (30 mg, 101 µmol ) in DMF (1 mL) and propiolic acid (7.0 mg, 101 µmol, 6 µL) was added DIPEA (26 mg, 201 µmol, 35 µL). Next, T3P (128 mg, 201 µmol, 50% purity) was added with stirring. Stirring was continued overnight. The mixture was diluted with EtOAc and washed with water. The organic phase was dried over Na2SO4, filtered and the filtrate was evaporated to dryness. This material was dissolved in DMSO, filtered through a syringe filter and analyzed by preparative HPLC (Waters XSelect CSH C18, 5 μm, 19 mm × 100 mm column, mobile phase H2O (A) and MeCN (B) and gradient 5 - 50% B (0.2% NH4OH final v / v% modifier), flow rate 30 mL / min) to give 1-[4-[6-(1-methylpyrazole) as a white solid -4-yl)pyrazolo[1,5-a]pyrazin-4-yl]oxy-1-piperidinyl]prop-2-yn-1-one (12.6 mg, 95% purity, 34% Yield). LCMS: m / z = 351.0 (M+H+). 1H NMR (500 MHz, DMSO-d6) δ 8.76 (s, 1H), 8.20 (s, 1H), 7.98-8.04 (m, 2H), 6.83-6.92 (m, 1H), 5.55-5.69 (m, 1H ), 4.57 (s, 1H), 3.95-4.06 (m, 1H), 3.88 (s, 3H), 3.72-3.86 (m, 2H), 3.50-3.61 (m, 1H), 2.12-2.20 (m, 1H ), 2.02-2.11 (m, 1H), 1.82-1.91 (m, 1H), 1.73-1.81 (m, 1H). [example] [2]: 1-(4-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)piperidine -1-yl)prop-2-en-1-one

[0150] Put 6-(1-methylpyrazol-4-yl)-4-(4-piperidinyloxy)pyrazolo[1,5-a]pyrazine (30 mg, 101 µmol) and THF (1 mL). Acryloyl chloride (12 µL, 151 µmol) was then added with stirring, immediately forming a milky suspension. Next, triethylamine (28 µL, 201 µmol) was added with stirring. After stirring at room temperature for 5 minutes, the volatiles were evaporated and a white solid was left. This material was dissolved in DMSO, filtered through a syringe filter and analyzed by preparative HPLC (Waters XSelect CSH C18, 5 μm, 19 mm × 100 mm column, mobile phase H2O (A) and MeCN (B) and gradient 5 - 50% B (0.2% NH4OH final v / v% modifier), flow rate 30 mL / min) to give 1-(4-((6-(1-methyl- 1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)piperidin-1-yl)prop-2-en-1-one (24.9 mg, 95 % purity, 67% yield). LCMS: m / z = 353.0 (M+H+). 1H NMR (500 MHz, DMSO-d 6) δ 8.75 (d, J =1.22 Hz, 1H), 8.21 (s, 1H), 8.01-8.03 (m, 2H), 6.86-6.88 (m, 1H), 6.83 -6.90 (m, 1H), 6.12 (br dd, J =2.44, 16.48 Hz, 1H), 5.67-5.73 (m, 1H), 5.60 (ddd, J =3.97, 7.63, 11.60 Hz, 1H), 3.85- 3.97 (m, 2H), 3.89 (s, 3H), 3.39-3.69 (m, 2H), 1.98-2.21 (m, 2H), 1.59-1.91 (m, 2H). [example] [3]: 6-(1-methyl-1H-pyrazol-4-yl)-4-((1-(vinylsulfonyl)piperidin-4-yl)oxy)pyrazolo[1 ,5-a]pyrazine

[0151] 6-(1-methyl-1H-pyrazol-4-yl)-4-((1- (vinylsulfonyl)piperidin-4-yl)oxy)pyrazolo[1,5-a]pyrazine. Preparative HPLC (Waters XSelect CSH C18, 5 μm, 19 mm × 100 mm column, mobile phase H 2O (A) and MeCN (B) and gradient 5-55% B (0.2% NH 4OH final v / v % modifier), flow rate 30 mL / min) to obtain 6-(1-methyl-1H-pyrazol-4-yl)-4-((1-(vinylsulfonyl) as a white solid yl)piperidin-4-yl)oxy)pyrazolo[1,5-a]pyrazine (4.9 mg, 95% purity, 12% yield). LCMS: m / z = 389.0 (M+H+). 1H NMR (500 MHz, DMSO-d 6 ) δ 8.75 (d, J =1.22 Hz, 1H), 8.20 (s, 1H), 8.02 (d, J =2.44 Hz, 1H), 8.01 (s, 1H), 6.89 (dd, J =10.38, 16.48 Hz, 1H), 6.85 (d, J =3.05 Hz, 1H), 6.20 (d, J =9.77 Hz, 1H), 6.16 (d, J =17.09 Hz, 1H), 5.49 (ddd, J =3.66, 7.63, 11.29 Hz, 1H), 3.88 (s, 3H), 3.37-3.54 (m, 2H), 3.18 (m, 2H), 2.10-2.24 (m, 2H), 1.79- 1.96 (m, 2H). [example] [4]: (R)-1-(3-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy Base) piperidin-1-yl) prop-2-en-1-one

[0152] (R)-1-(3-((6-(1-methyl- 1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)piperidin-1-yl)prop-2-en-1-one. Preparative HPLC (Waters XSelect CSH C18, 5 μm, 19 mm × 100 mm column, mobile phase H 2O (A) and MeCN (B) and gradient 5-50% B (0.2% NH 4OH final v / v % modifier), the flow rate was 30 mL / min) to obtain (R)-1-(3-((6-(1-methyl-1H-pyrazol-4-yl)pyridine Azolo[1,5-a]pyrazin-4-yl)oxy)piperidin-1-yl)prop-2-en-1-one (23.1 mg, 95% purity, 67% yield). LCMS: m / z = 353.0 (M+H+). 1H NMR (500 MHz, DMSO-d 6) δ 8.76 (s, 1H), 8.28-8.33 (m, 1H), 8.14-8.22 (m, 1H), 7.97-8.03 (m, 1H), 6.67-6.77 ( m, 1H), 6.52-6.97 (m, 1H), 5.92-6.15 (m, 1H), 5.42-5.74 (m, 1H), 5.19-5.40 (m, 1H), 3.88 (s, 3H), 3.59- 4.27 (m, 4H), 1.47-2.22 (m, 4H). [example] [5]: (R)-6-(1-methyl-1H-pyrazol-4-yl)-4-((1-(vinylsulfonyl)piperidin-3-yl)oxy)pyridine Azolo[1,5-a]pyrazine

[0153] (R)-6-(1-methyl-1H-pyrazole-4- yl)-4-((1-(vinylsulfonyl)piperidin-3-yl)oxy)pyrazolo[1,5-a]pyrazine. Preparative HPLC (Waters XSelect CSH C18, 5 μm, 19 mm × 100 mm column, mobile phase H 2O (A) and MeCN (B) and gradient 5-55% B (0.2% NH 4OH final v / v % modifier), the flow rate was 30 mL / min) to purify the material to obtain (R)-6-(1-methyl-1H-pyrazol-4-yl)-4-((1-( Vinylsulfonyl)piperidin-3-yl)oxy)pyrazolo[1,5-a]pyrazine (8.9 mg, 95% purity, 22% yield). LCMS: m / z = 389.0 (M+H+). 1H NMR (500 MHz, DMSO-d 6) δ 8.78 (s, 1H), 8.21 (s, 1H), 8.03 (d, J =1.83 Hz, 1H), 8.02 (s, 1H), 6.84 (d, J =2.44 Hz, 1H), 6.78-6.88 (m, 1H), 6.11 (s, 1H), 6.08 (d, J =6.10 Hz, 1H), 5.38 (ddd, J =3.66, 7.17, 10.53 Hz, 1H) , 3.88 (s, 3H), 3.74 (br dd, J =3.66, 12.21 Hz, 1H), 3.46 (br d, J =18.31 Hz, 1H), 3.21-3.29 (m, 1H), 3.11 (ddd, J =3.36, 8.09, 11.75 Hz, 1H), 2.05 (ddd, J =3.66, 8.39, 12.36 Hz, 1H), 1.89-1.98 (m, 1H), 1.79-1.88 (m, 1H), 1.71 (tdd, J =4.04, 8.47, 17.01 Hz, 1H). [example] [6]: (S)-6-(1-methyl-1H-pyrazol-4-yl)-4-((1-(vinylsulfonyl)piperidin-3-yl)oxy)pyridine Azolo[1,5-a]pyrazine

[0154] (S)-6-(1-methyl-1H-pyrazole-4- yl)-4-((1-(vinylsulfonyl)piperidin-3-yl)oxy)pyrazolo[1,5-a]pyrazine. Preparative HPLC (Waters XSelect CSH C18, 5 μm, 19 mm × 100 mm column, mobile phase H 2O (A) and MeCN (B) and gradient 5-55% B (0.2% NH 4OH final v / v % modifier), flow rate 30 mL / min) to purify the material to obtain (S)-6-(1-methyl-1H-pyrazol-4-yl)-4-((1-(vinylsulfonyl )piperidin-3-yl)oxy)pyrazolo[1,5-a]pyrazine (8.0 mg, 95% purity, 18% yield). LCMS: m / z = 389.0 (M+H+). 1H NMR (500 MHz, DMSO-d 6) δ 8.78 (s, 1H), 8.21 (s, 1H), 8.03 (d, J =1.83 Hz, 1H), 8.02 (s, 1H), 6.84 (d, J =2.44 Hz, 1H), 6.79-6.86 (m, 1H), 6.11 (s, 1H), 6.08 (d, J =6.10 Hz, 1H), 5.38 (tt, J =3.59, 7.10 Hz, 1H), 3.88 (s, 3H), 3.74 (dd, J =3.36, 11.90 Hz, 1H), 3.48 (br s, 1H), 3.21-3.29 (m, 1H), 3.11 (ddd, J =3.36, 8.09, 11.75 Hz, 1H), 2.05 (ddd, J =3.97, 8.24, 12.21 Hz, 1H), 1.89-1.98 (m, 1H), 1.80-1.89 (m, 1H), 1.65-1.76 (m, 1H). [example] [7]: (R)-1-(3-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy Base) piperidin-1-yl) prop-2-yn-1-one Synthesis of (R)-3-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]oxypiperidine-1-carboxylic acid tertiary butyl ester

[0155] A solution of (R)-tert-butyl 3-hydroxypiperidine-1-carboxylate (221 mg, 1.10 mmol) in anhydrous DMF (3 mL) was cooled in an ice bath. Next, sodium hydride (132 mg, 3.30 mmol, 60% purity) was added in 2 portions with stirring. Stirring was continued for 45 min in the ice bath, during which time a pale yellow suspension formed. To this mixture was added a batch of 4-chloro-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazine (234 mg, 1.00 mmol), and the mixture immediately became Orange brown. Stirring was continued overnight at room temperature. The mixture was diluted with EtOAc, followed by careful addition of water. The mixture was transferred to a separatory funnel and the phases were separated. The aqueous phase was extracted again with EtOAc, and the combined organic phases were washed with brine, dried over Na 2 SO 4 , filtered and evaporated in vacuo. The residue was purified on a 10 g Si-SPE column: Rt = 0.22 in heptane / EtOAc = 1 / 1 to give (R)-3-[6-(1-methyl) as a colorless viscous gum Pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]oxypiperidine-1-carboxylic acid tert-butyl ester (390 mg, 88% yield, 90% purity). LCMS: m / z = 399.0 (M+H+). Synthesis of (R)-6-(1-methylpyrazol-4-yl)-4-(3-piperidinyloxy)pyrazolo[1,5-a]pyrazine

[0156] Under stirring at room temperature to (R)-3-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]oxypiperidine- To a solution of tert-butyl 1-carboxylate (390 mg, 979 µmol) in anhydrous DCM (3 mL) was added TFA (2.23 g, 19.58 mmol, 1.50 mL). After stirring overnight at room temperature, the mixture was diluted with MeOH and purified on a 5 g SCX column, where the product was eluted with 2M NH3-MeOH to give (R)-6-(1-methylpyridine as a colorless gum. Azol-4-yl)-4-(3-piperidinyloxy)pyrazolo[1,5-a]pyrazine (270 mg, 88% yield, 95% purity). LCMS: m / z = 299.0 (M+H+). Synthesis of (R)-1-(3-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)piper Pyridin-1-yl) prop-2-yn-1-one

[0157] (R)-6-(1-methylpyrazol-4-yl)-4-(3-piperidinyloxy)pyrazolo[1,5-a]pyrazine (30 mg, 101 µmol) in DMF (1 mL) was added propiolic acid (7.0 mg, 101 µmol, 6 µL), followed by DIPEA (26 mg, 201 µmol, 35 µL). Next, T3P (128 mg, 201 µmol, 50% purity) was added with stirring. Stirring was continued overnight at room temperature. The mixture was diluted with EtOAc and washed with water. The organic phase was dried over Na2SO4 and filtered. The filtrate was evaporated in vacuo and the residue was redissolved in DMSO. Preparative HPLC (Waters XSelect CSH C18, 5 μm, 19 mm × 100 mm column, mobile phase H 2O (A) and MeCN (B) and gradient 5-50% B (0.2% NH 4OH final v / v % modifier), the flow rate was 30 mL / min) to obtain (R)-1-(3-((6-(1-methyl-1H-pyrazol-4-yl)pyridine Azolo[1,5-a]pyrazin-4-yl)oxy)piperidin-1-yl)prop-2-yn-1-one (20.6 mg, 95% purity, 55% yield). LCMS: m / z = 350.1 (M+H+). 1H NMR (500 MHz, DMSO-d6) δ 8.75-8.77 (m, 1H), 8.02 (d, J =1.83 Hz, 1H), 8.00-8.27 (m, 2H), 6.76-6.77 (m, 1H) , 5.26-5.49 (m, 1H), 4.13-4.61 (m, 1H), 3.90-4.33 (m, 1H), 3.88 (s, 3H), 3.70-3.84 (m, 1H), 3.44-3.62 (m, 1H), 3.15-3.30 (m, 1H), 1.53-2.18 (m, 4H). [example] [8]: (Z)-4-chloro-1-(4-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-4 -yl)oxy)piperidin-1-yl)but-2-en-1-one Synthesis of (Z)-4-chloro-1-(4-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl) Oxy)piperidin-1-yl)but-2-en-1-one

[0158] Put 6-(1-methylpyrazol-4-yl)-4-(4-piperidinyloxy)pyrazolo[1,5-a]pyrazine (30 mg, 100 µmol) and DMF (1 mL). (Z)-4-Chlorobut-2-enoic acid (15.5 mg, 120 μmol) was then added with stirring, immediately forming a milky suspension. Next, HATU (57.7 mg, 150 μmol) was added and the mixture was stirred at room temperature for 5 minutes. Next, DIPEA (35 µL, 201 µmol) was added with stirring. Stirring was continued overnight at room temperature. The mixture was diluted with EtOAc and washed with water. The organic phase was dried over Na2SO4 and filtered. The filtrate was evaporated in vacuo and the residue was dissolved in DMSO and analyzed by preparative HPLC (Waters XSelect CSH C18, 5 μm, 19 mm × 100 mm column, mobile phase H2O (A) and MeCN (B) and gradient 5 - 55% B (0.2% NH4OH final v / v % modifier), flow rate 30 mL / min) to give (Z)-4-chloro-1-(4-(( 6-(1-Methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)piperidin-1-yl)but-2-ene- 1-Keto (17.8 mg, 95% purity, 42% yield). LCMS: m / z = 400.1. 1H NMR (500 MHz, DMSO-d 6) δ 8.76 (s, 1H), 8.21 (s, 1H), 8.00-8.03 (m, 2H), 6.88 (d, J =1.22 Hz, 1H), 6.84-6.87 (m, 1H), 6.65-6.72 (m, 1H), 5.61 (ddd, J =3.66, 7.48, 11.44 Hz, 1H), 4.38 (dd, J =1.22, 6.71 Hz, 2H), 3.89 (s, 3H ), 3.44-3.69 (m, 4H), 2.00-2.17 (m, 2H), 1.67-1.86 (m, 2H). [example] [9]: 1-(3-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)azepine Cyclobutan-1-yl)prop-2-en-1-one Synthesis of tertiary butyl 3-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]oxyazetidine-1-carboxylate

[0159] A solution of tert-butyl 3-hydroxyazetidine-1-carboxylate (191 mg, 1.10 mmol) in anhydrous DMF (3 mL) was cooled in an ice bath. Next, sodium hydride (132 mg, 3.30 mmol, 60% purity) was added in 2 portions with stirring. Stirring was continued for 45 min in the ice bath, during which time a light yellow suspension formed. To this mixture was added a batch of 4-chloro-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazine (234 mg, 1.00 mmol), and the mixture immediately became Orange brown. Stirring was continued overnight at room temperature. The mixture was diluted with EtOAc, followed by careful addition of water. The mixture was transferred to a separatory funnel and the phases were separated. The aqueous phase was extracted again with EtOAc, and the combined organic phases were washed with brine, dried over Na 2 SO 4 , filtered and evaporated in vacuo. The residue was purified on a 10 g Si-SPE column: Rt = 0.0.18 in heptane / EtOAc = 1 / 1 to give 3-[6-(1-methylpyrazole as a colorless viscous gum -4-yl)pyrazolo[1,5-a]pyrazin-4-yl]oxyazetidine-1-carboxylic acid tert-butyl ester (380 mg, 97% yield, 95% purity) . ESI-MS (M+H)+: 371.0. Synthesis of 4-(azetidin-3-yloxy)-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazine

[0160] 3-[6-(1-Methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]oxyazetidine-1 - To a solution of tert-butyl formate (380 mg, 1.03 mmol) in DCM (5 mL) was added TFA (2.34 g, 20.5 mmol, 1.57 mL). Stirring was continued overnight. The mixture was diluted with MeOH and purified on a 10 g SCX column, where the product was eluted with 2 M NH 3-MeOH to give 4-(azetidin-3-yloxy)-6-( 1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazine (250 mg, 85% yield, 95% purity). ESI-MS (M+H)+: 271.0. Synthesis of 1-(3-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)azetidine -1-yl) prop-2-en-1-one

[0161] In the same manner as Example 2, 1-(3-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy base) azetidin-1-yl) prop-2-en-1-one. Preparative HPLC (Waters XSelect CSH C18, 5 μm, 19 mm × 100 mm column, mobile phase H 2O (A) and MeCN (B) and gradient 5-45% B (0.2% NH 4OH final v / v % modifier), the flow rate was 30 mL / min) to purify the material to obtain 1-(3-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1 ,5-a]pyrazin-4-yl)oxy)azetidin-1-yl)prop-2-en-1-one (20 mg, 95% purity, 64% yield). LCMS: m / z = 325.0. 1H NMR (500 MHz, DMSO-d 6) δ 8.82 (s, 1H), 8.24 (s, 1H), 8.06 (d, J =2.44 Hz, 1H), 8.03 (s, 1H), 6.90-6.92 (m , 1H), 6.38 (dd, J =10.38, 17.09 Hz, 1H), 6.11-6.17 (m, 1H), 5.70 (dd, J =2.44, 10.38 Hz, 1H), 5.62 (tt, J =4.27, 6.71 Hz, 1H), 4.83 (br dd, J =6.71, 9.16 Hz, 1H), 4.52 (br dd, J =7.02, 11.29 Hz, 1H), 4.37 (br dd, J =3.66, 9.77 Hz, 1H), 4.08 (br dd, J =3.66, 11.60 Hz, 1H), 3.89 (s, 3H). [example]

[10] : (Z)-6-(1-methyl-1H-pyrazol-4-yl)-4-((1-(prop-1-en-1-ylsulfonyl)azetidine Alk-3-yl)oxy)pyrazolo[1,5-a]pyrazine

[0162] (Z)-6-(1-methyl-1H-pyrazole-4- yl)-4-((1-(prop-1-en-1-ylsulfonyl)azetidin-3-yl)oxy)pyrazolo[1,5-a]pyrazine. Preparative HPLC (Waters XSelect CSH C18, 5 μm, 19 mm × 100 mm column, mobile phase H 2O (A) and MeCN (B) and gradient 5-55% B (0.2% NH 4OH final v / v % modifier), flow rate 30 mL / min) to obtain (Z)-6-(1-methyl-1H-pyrazol-4-yl)-4-((1-( Prop-1-en-1-ylsulfonyl)azetidin-3-yl)oxy)pyrazolo[1,5-a]pyrazine (10 mg, 95% purity, 28% yield ). LCMS: m / z = 374.0. 1H NMR (500 MHz, DMSO-d 6) δ 8.82 (s, 1H), 8.23-8.27 (s, 1H), 8.06 (d, J =2.44 Hz, 1H), 7.98-8.04 (s, 1H), 6.87 -6.92 (m, 1H), 6.72-6.84 (m, 2H), 5.42-5.56 (m, 1H), 4.31-4.45 (m, 2H), 3.92-4.04 (m, 2H), 3.88 (s, 3H) , 1.95 (d, J =4.88 Hz, 3H). [example]

[11] : (R)-1-(3-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy Base) pyrrolidin-1-yl) prop-2-en-1-one Synthesis of (3R)-3-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]oxypyrrolidine-1-carboxylic acid tertiary butyl ester

[0163] A solution of (3R)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate (193 mg, 1.03 mmol) in anhydrous DMF (3 mL) was cooled in an ice bath. Next, sodium hydride (136 mg, 3.40 mmol, 60% purity) was added in 4 portions with stirring. Stirring was continued for 45 min in the ice bath, during which time a pale yellow suspension formed. To this mixture was added a batch of 4-chloro-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazine (240 mg, 1.03 mmol), and the mixture immediately became Orange brown. Stirring was continued overnight at room temperature. The mixture was diluted with EtOAc, followed by careful addition of water. The mixture was transferred to a separatory funnel and the phases were separated. The aqueous phase was extracted again with EtOAc, and the combined organic phases were washed with brine, dried over Na 2 SO 4 , filtered and evaporated in vacuo. The residue was purified on a 10 g Si-SPE column in heptane / EtOAc = 1 / 1 to give (3R)-3-[6-(1-methylpyrazole-4- yl)pyrazolo[1,5-a]pyrazin-4-yl]oxypyrrolidine-1-carboxylic acid tert-butyl ester (345 mg, 83% yield, 95% purity), which after further drying Turned into a sticky white foam. ESI-MS (M+H)+: 395.0. Synthesis of 6-(1-methylpyrazol-4-yl)-4-[(3R)-pyrrolidin-3-yl]oxy-pyrazolo[1,5-a]pyrazine

[0164] Under stirring at room temperature to (3R)-3-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]oxypyrrolidine- To a solution of tert-butyl 1-carboxylate (326 mg, 849 µmol) in DCM (5 mL) was added TFA (1.93 g, 17 mmol, 1.30 mL). Stirring was continued overnight. The mixture was diluted with MeOH and purified on a 10 g SCX column, where the product was eluted with 2 M NH3-MeOH to give 6-(1-methylpyrazol-4-yl)-4 as a viscous pale yellow gum. - [(3R)-Pyrrolidin-3-yl]oxy-pyrazolo[1,5-a]pyrazine (230 mg, 91% yield, 95% purity). ESI-MS (M+H)+: 285.0. Synthesis of (R)-1-(3-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)pyrrole Pyridin-1-yl) prop-2-en-1-one

[0165] Prepare (R)-1-(3-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-4 in the same manner as Example 2 -yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one. Preparative HPLC (Waters XSelect CSH C18, 5 μm, 19 mm × 100 mm column, mobile phase H 2O (A) and MeCN (B) and gradient 5-45% B (0.2% NH 4OH final v / v % modifier), flow rate 30 mL / min) to obtain (R)-1-(3-((6-(1-methyl-1H-pyrazol-4-yl)pyridine) as a white solid Azolo[1,5-a]pyrazin-4-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one (27.9 mg, 95% purity, 74% yield). ESI-MS (M+H)+: 339.0. 1H NMR (500 MHz, DMSO-d 6) δ 8.78 (s, 1H), 8.21-8.26 (m, 1H), 8.03 (d, J =1.83 Hz, 1H), 8.00-8.02 (m, 1H), 6.84 (br d, J =1.22 Hz, 1H), 6.54-6.69 (m, 1H), 6.12-6.20 (m, 1H), 5.81-5.94 (m, 1H), 5.64-5.73 (m, 1H), 3.89 ( s, 3H), 3.82-4.11 (m, 1H), 3.65-3.78 (m, 1H), 3.43-3.59 (m, 2H), 2.19-2.47 (m, 2H). [example]

[12] : (R)-6-(1-methyl-1H-pyrazol-4-yl)-4-((1-(vinylsulfonyl)pyrrolidin-3-yl)oxy)pyridine Azolo[1,5-a]pyrazine

[0166] (R)-6-(1-methyl-1H-pyrazol-4-yl)-4- ((1-(vinylsulfonyl)pyrrolidin-3-yl)oxy)pyrazolo[1,5-a]pyrazine. Preparative HPLC (Waters XSelect CSH C18, 5 μm, 19 mm × 100 mm column, mobile phase H 2O (A) and MeCN (B) and gradient 5-50% B (0.2% NH 4OH final v / v % modifier), flow rate 30 mL / min) to obtain (R)-6-(1-methyl-1H-pyrazol-4-yl)-4-((1-( Vinylsulfonyl)pyrrolidin-3-yl)oxy)pyrazolo[1,5-a]pyrazine (6.6 mg, 95% purity, 16% yield). ESI-MS (M+H)+: 375.0. 1H NMR (500 MHz, DMSO-d 6) δ 8.78 (s, 1H), 8.22 (s, 1H), 8.03 (d, J =2.44 Hz, 1H), 8.00-8.02 (m, 1H), 6.92 (dd , J =10.38, 16.48 Hz, 1H), 6.85-6.86 (m, 1H), 6.07-6.12 (m, 1H), 6.05 (d, J =9.77 Hz, 1H), 5.78-5.84 (m, 1H), 3.88 (s, 3H), 3.39-3.75 (m, 4H), 2.20-2.39 (m, 2H). [example]

[13] : (R)-1-(3-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy Base) pyrrolidin-1-yl) prop-2-yn-1-one

[0167] (R)-1-(3-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-4 was prepared in a manner similar to Example 1 -yl)oxy)pyrrolidin-1-yl)prop-2-yn-1-one. Preparative HPLC (Waters XSelect CSH C18, 5 μm, 19 mm × 100 mm column, mobile phase H 2O (A) and MeCN (B) and gradient 5-45% B (0.2% NH 4OH final v / v % modifier), flow rate 30 mL / min) to obtain (R)-1-(3-((6-(1-methyl-1H-pyrazol-4-yl)pyridine) as a white solid Azolo[1,5-a]pyrazin-4-yl)oxy)pyrrolidin-1-yl)prop-2-yn-1-one (18.2 mg, 95% purity, 51% yield). ESI-MS (M+H)+: 337.0. 1H NMR (500 MHz, DMSO-d 6) δ 8.77-8.81 (m, 1H), 8.21-8.26 (m, 1H), 8.00-8.06 (m, 2H), 6.86 (d, J =2.44 Hz, 1H) , 5.81-5.91 (m, 1H), 4.43-4.58 (m, 1H), 3.86-3.91 (m, 1H), 3.86 (s, 3H), 3.40-3.71 (m, 3H), 2.20-2.47 (m, 2H). [example]

[14] : (S)-1-(3-(((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl) Oxy)methyl)piperidin-1-yl)prop-2-en-1-one Synthesis of (3S)-3-[[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]oxymethyl]piperidine-1- Tertiary butyl formate

[0168] A solution of (3S)-tert-butyl 3-(hydroxymethyl)piperidine-1-carboxylate (222 mg, 1.03 mmol) in anhydrous DMF (3 mL) was cooled in an ice bath. Next, sodium hydride (136 mg, 3.40 mmol, 60% purity) was added in 4 portions with stirring. Stirring was continued for 45 min in the ice bath, during which time a pale yellow suspension formed. To this mixture was added a batch of 4-chloro-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazine (240 mg, 1.03 mmol), and the mixture immediately became Orange brown. Stirring was continued overnight at room temperature. The mixture was diluted with EtOAc, followed by careful addition of water. The mixture was transferred to a separatory funnel and the phases were separated. The aqueous phase was extracted again with EtOAc, and the combined organic phases were washed with brine, dried over Na 2 SO 4 , filtered and evaporated in vacuo. The residue was purified on a 10 g Si-SPE column: Rt = 0.1 in heptane / EtOAc = 2 / 1 to give (3S)-3-[[6-(1-methylpyrazole as an off-white solid -4-yl)pyrazolo[1,5-a]pyrazin-4-yl]oxymethyl]piperidine-1-carboxylic acid tert-butyl ester (386 mg, 86% yield, 95% purity) ; ESI-MS (M+H)+: 413.0. Synthesis of 6-(1-methylpyrazol-4-yl)-4-[[(3S)-3-piperidinyl]methoxy]pyrazolo[1,5-a]pyrazine

[0169] Under stirring at room temperature to (3S)-3-[[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]oxymethyl ] To a solution of tert-butyl piperidine-1-carboxylate (404 mg, 978 µmol) in DCM (5 mL) was added TFA (2.23 g, 19.6 mmol, 1.50 mL). Stirring was continued overnight. The mixture was diluted with MeOH and purified on a 10 g SCX column, where the product was eluted with 2 M NH3-MeOH to give 6-(1-methylpyrazol-4-yl)-4 as a pale yellow sticky gum. - [[(3S)-3-piperidinyl]methoxy]pyrazolo[1,5-a]pyrazine (240 mg, 75% yield, 95% purity), which formed a white color after further drying Foam. ESI-MS (M+H)+: 313.0. Synthesis of (S)-1-(3-(((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy) Methyl)piperidin-1-yl)prop-2-en-1-one

[0170] Prepare (S)-1-(3-(((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine- 4-yl)oxy)methyl)piperidin-1-yl)prop-2-en-1-one. Preparative HPLC (Waters XSelect CSH C18, 5 μm, 19 mm × 100 mm column, mobile phase H 2O (A) and MeCN (B) and gradient 5-50% B (0.2% NH 4OH final v / v % modifier), the flow rate was 30 mL / min) to purify the material to obtain (S)-1-(3-(((6-(1-methyl-1H-pyrazol-4-yl) Pyrazolo[1,5-a]pyrazin-4-yl)oxy)methyl)piperidin-1-yl)prop-2-en-1-one (10.6 mg, 95% purity, 28% yield Rate). ESI-MS (M+H)+: 367.0. 1H NMR (500 MHz, DMSO-d 6) δ 8.76 (s, 1H), 8.21 (br s, 1H), 8.03 (d, J =2.44 Hz, 1H), 8.01 (s, 1H), 6.85-6.92 ( m, 1H), 6.77-6.84 (m, 1H), 5.96-6.10 (m, 1H), 5.54-5.67 (m, 1H), 4.41-4.50 (m, 2H), 3.90-4.13 (m, 1H), 3.89 (s, 3H), 2.89-3.29 (m, 3H), 1.88-2.07 (m, 2H), 1.73 (s, 1H), 1.35-1.57 (m, 2H). [example]

[15] : (S)-6-(1-methyl-1H-pyrazol-4-yl)-4-((1-(vinylsulfonyl)piperidin-3-yl)methoxy) Pyrazolo[1,5-a]pyrazine

[0171] (S)-6-(1-methyl-1H-pyrazol-4-yl)-4- ((1-(vinylsulfonyl)piperidin-3-yl)methoxy)pyrazolo[1,5-a]pyrazine. Preparative HPLC (Waters SunFire Prep C18, 5 μm, OBD 19 mm × 100 mm column, mobile phase H 2 O (A) and MeCN (B) and gradient 5 - 55% B (0.1% TFA final v / v % modifier), flow rate 30 mL / min) to obtain (S)-6-(1-methyl-1H-pyrazol-4-yl)-4-((1-( Vinylsulfonyl)piperidin-3-yl)methoxy)pyrazolo[1,5-a]pyrazine (8.0 mg, 95% purity, 19% yield). ESI-MS (M+H)+: 403.0. 1H NMR (500 MHz, DMSO-d 6) δ 8.77 (s, 1H), 8.21 (s, 1H), 8.03 (d, J =2.44 Hz, 1H), 8.01 (s, 1H), 6.84 (d, J =3.05 Hz, 1H), 6.76-6.84 (m, 1H), 6.13 (d, J =9.77 Hz, 1H), 6.09 (d, J =16.48 Hz, 1H), 4.42-4.52 (m, 2H), 3.89 (s, 3H), 3.63 (br dd, J =3.66, 11.60 Hz, 1H), 3.38-3.55 (m, 2H), 2.59-2.74 (m, 1H), 2.12-2.28 (m, 1H), 1.84- 1.95 (m, 1H), 1.79 (td, J =3.66, 13.43 Hz, 1H), 1.50-1.64 (m, 1H), 1.18-1.38 (m, 1H).

[0172] [example]

[16] : (S)-1-(3-(((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl) Oxy)methyl)piperidin-1-yl)prop-2-yn-1-one

[0173] Prepare (S)-1-(3-(((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine- 4-yl)oxy)methyl)piperidin-1-yl)prop-2-yn-1-one. Preparative HPLC (Waters XSelect CSH C18, 5 μm, 19 mm × 100 mm column, mobile phase H 2O (A) and MeCN (B) and gradient 5-55% B (0.2% NH 4OH final v / v % modifier), flow rate 30 mL / min) to obtain (S)-1-(3-(((6-(1-methyl-1H-pyrazol-4-yl) Pyrazolo[1,5-a]pyrazin-4-yl)oxy)methyl)piperidin-1-yl)prop-2-yn-1-one (24.8 mg, 95% purity, 68% yield Rate). ESI-MS (M+H)+: 365.0. 1H NMR (500 MHz, DMSO-d 6) δ 8.74-8.78 (m, 1H), 8.21 (s, 1H), 7.96-8.07 (m, 2H), 6.78-6.90 (m, 1H), 4.52-4.55 ( m, 1H), 4.27-4.51 (m, 2H), 4.01-4.17 (m, 1H), 3.89 (s, 3H), 3.22-3.32 (m, 1H), 2.78-2.98 (m, 2H), 1.98- 2.21 (m, 1H), 1.88-1.95 (m, 1H), 1.67-1.83 (m, 1H), 1.28-1.55 (m, 2H). [example]

[17] : (R,E)-6-(1-methyl-1H-pyrazol-4-yl)-4-((1-(prop-1-en-1-ylsulfonyl)piperidine -3-yl)oxy)pyrazolo[1,5-a]pyrazine 1. Synthesis of (R,E)-6-(1-methyl-1H-pyrazol-4-yl)-4-((1-(prop-1-en-1-ylsulfonyl)piperidine- 3-yl)oxy)pyrazolo[1,5-a]pyrazine

[0174] Add 6-(1-methylpyrazol-4-yl)-4-[[(3R)-3-piperidinyl]oxy]pyrazolo[1,5-a]pyrazine sequentially to the vial (125 mg, 419 μmol), DCM (2.1 mL), N-ethyl-N-isopropyl-propan-2-amine (162 mg, 1.26 mmol, 220 μL) and (E)-prop-1-ene -1-sulfonyl chloride (88 mg, 628 µmol, 66 µL). The vial was stirred overnight at room temperature. The reaction was diluted with water, passed through a phase separator, and concentrated. The material was dissolved in 2.5 mL DMSO and passed through a syringe filter. After reverse phase HPLC (Waters XSelect CSH C18, 5 μm, 19 mm × 100 mm column, mobile phase H 2O (A) and MeCN (B) and gradient 5 - 60% B (0.2% NH 4OH final v / v % modifier), flow rate 30 mL / min) to obtain 6-(1-methylpyrazol-4-yl)-4-[[(3R)-1-[(E) -prop-1-enyl]sulfonyl-3-piperidinyl]oxy]pyrazolo[1,5-a]pyrazine (55 mg, yield: 30%). ESI-MS (M+H)+: 403.1. 1H NMR (500 MHz, DMSO-d 6) δ 8.78 (s, 1H), 8.21 (s, 1H), 7.99-8.06 (m, 1H), 6.84 (dd, J =1.22, 2.44 Hz, 1H), 6.61 (br d, J =6.71 Hz, 1H), 6.46-6.54 (m, 1H), 5.38 (td, J =3.89, 7.48 Hz, 1H), 3.88 (s, 3H), 3.72 (br dd, J =3.36 , 11.90 Hz, 1H), 3.12-3.28 (m, 2H), 3.05 (ddd, J =3.36, 8.09, 11.75 Hz, 1H), 2.02-2.08 (m, 1H), 1.90-1.98 (m, 2H), 1.85 (dd, J =1.83, 6.71 Hz, 3H), 1.71 (ddd, J =4.58, 8.55, 13.12 Hz, 2H). [ , example , ] [ , 18 , ]: 1-(4-(((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)amino)methyl )piperidin-1-yl)prop-2-en-1-one 1. Synthesis of 4-(((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)amino)methyl)piperidine -1- Tertiary butyl formate

[0175] To 4-chloro-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazine (500 mg, 2.14 mmol) and 4-(aminomethyl)piperidine- To a suspension of tert-butyl-1-carboxylate (504 mg, 2.35 mmol, 500 µL) in DMF (7.13 mL) was added Hunig's base (553 mg, 4.28 mmol, 750 µL). The reaction was warmed to 70 °C and stirred overnight. The reaction was concentrated and purified by column chromatography (40 g silica column, gradient elution 0-100% EtOAc:heptane) to give 4-[[[6-(1-methylpyridine) as a brown solid Azol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]amino]methyl]piperidine-1-carboxylic acid tert-butyl ester (398 mg, yield: 45%). ESI-MS (M+H)+: 412.2. 2. Synthesis of 6-(1-methyl-1H-pyrazol-4-yl)-N-(piperidin-4-ylmethyl)pyrazolo[1,5-a]pyrazin-4-amine

[0176] 4-[[[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]amino]methyl]piperidine-1-carboxylic acid tris Butyl ester (397 mg, 965 µmol) was dissolved in DCM (4.8 mL). TFA (1.10 g, 9.65 mmol, 738 µL) was added and the reaction was stirred overnight at room temperature. The reaction was concentrated, diluted with DCM and carefully quenched with saturated sodium bicarbonate solution. The aqueous layer was washed twice with DCM, then diluted with saturated ammonium hydroxide solution and extracted twice with ethyl acetate. The combined ethyl acetate layers were washed with brine, dried over magnesium sulfate, filtered and concentrated to give 6-(1-methylpyrazol-4-yl)-N-(4-piperidinyl) as a pale yellow oily solid. Methyl)pyrazolo[1,5-a]pyrazin-4-amine (300 mg, yield: 100%). ESI-MS (M+H)+: 312.1. 3. Synthesis of 1-(4-(((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)amino)methyl ) piperidin-1-yl) prop-2-en-1-one

[0177] To accommodate 6-(1-methylpyrazol-4-yl)-N-(4-piperidinylmethyl)pyrazolo[1,5-a]pyrazin-4-amine (75 mg, 241 μmol ) was added DCM (2.4 mL) and TEA (73 mg, 725 µmol, 100 µL), which were then placed on a dry ice / acetone bath for 10 minutes. To this solution was added acryloyl chloride (28 mg, 313 µmol, 26 µL) dropwise. The reaction was stirred for 10 minutes. The reaction was diluted with water and passed through a phase separator. The aqueous layer was extracted with DCM and the combined organic layers were concentrated, dissolved in DMSO, and subjected to reverse phase HPLC (Waters XSelect CSH C18, 5 μm, 19 mm × 100 mm column, mobile phase H2O (A) and MeCN (B ) and gradient 5 - 35% B (0.2% NH4OH final v / v % modifier), flow rate 30 mL / min) to give 1-[4-[[[6-(1 -Methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]amino]methyl]-1-piperidinyl]prop-2-en-1-one ( 35 mg, yield: 39%). ESI-MS (M+H)+: 366.2. 1H NMR (500 MHz, DMSO-d 6) δ 8.27 (s, 1H), 8.09 (s, 1H), 7.92 (s, 1H), 7.84 (d, J =2.44 Hz, 1H), 7.64 (br t, J =5.49 Hz, 1H), 6.93-6.97 (m, 1H), 6.80 (br dd, J =10.68, 16.79 Hz, 1H), 6.07 (br dd, J =2.44, 17.09 Hz, 1H), 5.61-5.68 (m, 1H), 4.42 (br d, J =12.21 Hz, 1H), 4.06 (br d, J =12.82 Hz, 1H), 3.87 (s, 3H), 3.40-3.50 (m, 1H), 2.97- 3.10 (m, 1H), 2.59-2.67 (m, 1H), 1.99 (ddd, J =3.97, 7.17, 10.83 Hz, 2H), 1.81 (br d, J =13.43 Hz, 2H), 1.06-1.22 (m , 2H). [example]

[19] : 6-(1-methyl-1H-pyrazol-4-yl)-N-((1-(vinylsulfonyl)piperidin-4-yl)methyl)pyrazolo[1 ,5-a]pyrazin-4-amine 1. Synthesis of 6-(1-methyl-1H-pyrazol-4-yl)-N-((1-(vinylsulfonyl)piperidin-4-yl)methyl)pyrazolo[1, 5-a] pyrazin-4-amine

[0178] To accommodate 6-(1-methylpyrazol-4-yl)-N-(4-piperidinylmethyl)pyrazolo[1,5-a]pyrazin-4-amine (75 mg, 241 μmol ) was added DCM (2.4 mL), DMF (200 µL) and TEA (73 mg, 725 µmol, 100 µL), which were then placed in a dry ice / acetone bath for 10 minutes. To this solution was added ethylenesulfonyl chloride (40 mg, 313 µmol, 28 µL) dropwise. The reaction was warmed to room temperature and stirred overnight. The reaction was diluted with water and passed through a phase separator. The aqueous layer was extracted with DCM and the combined organic layers were concentrated, dissolved in DMSO, and subjected to reverse phase HPLC (Waters XSelect CSH C18, 5 μm, 19 mm × 100 mm column, mobile phase H2O (A) and MeCN (B ) and gradient 5 - 40% B (0.2% NH 4OH final v / v % modifier), flow rate 30 mL / min) to give 6-(1-methylpyrazole-4- Base)-N-[(1-vinylsulfonyl-4-piperidinyl)methyl]pyrazolo-[1,5-a]pyrazin-4-amine (19 mg, yield: 20% ). ESI-MS (M+H)+: 402.2. 1H NMR (500 MHz, DMSO-d 6) δ 8.27 (s, 1H), 8.09 (s, 1H), 7.92 (s, 1H), 7.82-7.86 (m, 1H), 7.66 (br t, J =5.80 Hz, 1H), 6.93-6.96 (m, 1H), 6.78 (dd, J =9.77, 16.48 Hz, 1H), 6.06-6.15 (m, 2H), 3.87 (s, 3H), 3.55 (br d, J =11.60 Hz, 2H), 2.57-2.65 (m, 4H), 1.85 (br d, J =11.60 Hz, 3H), 1.25-1.35 (m, 2H). [example]

[20] : N-[1-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]-3-piperidinyl]propane- 2-enamide Synthesis of N-[1-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]-3-piperidinyl]carbamic acid tertiary Butyl ester

[0179] To a solution of 4-chloro-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazine (300 mg, 1.28 mmol) in t-BuOH (5.1 mL) Add N-ethyl-N-isopropyl-propan-2-amine (249 mg, 1.93 mmol, 336 µL) and tertiary butyl N-(3-piperidinyl)carbamate (264 mg, 1.32 mmol). The reaction mixture was stirred overnight at 80 °C. Assuming 100% yield, the material was concentrated and carried forward as crude material. LCMS m / z = 398.0. (M+H)+. Synthesis of 1-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]piperidin-3-amine hydrochloride

[0180] To N-[1-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]-3-piperidinyl]carbamic acid tertiary To a solution of the butyl ester (509 mg, 1.28 mmol) in dioxane (6.4 mL) was added HCl (4 M, 1.92 mL). The mixture was stirred overnight at room temperature. A solid separated out and was filtered off and washed with EtOAc. The solid was air dried to give 1-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]piperidine-3-yl as a brown solid. Amine hydrochloride (500 mg, 94% yield). The solid is assumed to be 80% pure. Synthesis of N-[1-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]-3-piperidinyl]prop-2-ene Amide

[0181] To 1-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]piperidin-3-amine hydrochloride (75 mg, 180 µmol ) in DCM (1.8 mL) were sequentially added N-ethyl-N-isopropyl-propan-2-amine (93 mg, 719 µmol, 126 µL) and prop-2-enyl chloride (18 mg, 198 µmol, 16 µL). The reaction mixture was stirred overnight at room temperature. The material was concentrated and purified via reverse phase purification (column: Waters XSelect CSH Prep C18 5um OBD 19x100mm; conditions: 5-45% acetonitrile in 0.1% v / v ammonium carbonate / water; flow rate: 30 mL / min) to give 30.5 mg (49% yield). LCMS m / z = 352.2 (M+H)+. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.19 - 1.30 (m, 1 H) 1.53 - 1.69 (m, 2 H) 1.81 - 2.01 (m, 2 H) 3.06 (dd, J =12.82, 9.77 Hz , 1 H) 3.23 - 3.27 (m, 1 H) 3.87 (s, 3 H) 3.91 - 3.97 (m, 1 H) 4.22 - 4.47 (m, 2 H) 5.57 - 5.66 (m, 1 H) 6.18 (s , 1 H) 6.23 - 6.34 (m, 1 H) 7.06 (d, J =2.44 Hz, 1 H) 7.89 - 8.03 (m, 1 H) 8.19 - 8.27 (m, 2 H) 8.40 - 8.53 (m, 1 h). [example]

[21] : N-[1-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]-3-piperidinyl]propane- 2-Alkynamide Synthesis of N-[1-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]-3-piperidinyl]prop-2-yne Amide

[0182] To 1-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]piperidin-3-amine hydrochloride (75 mg, 180 μmol ) in DCM (1.5 mL) were added sequentially N-ethyl-N-isopropyl-propan-2-amine (86 mg, 669 µmol, 117 µL) and HATU (68 mg, 178 µmol). The reaction mixture was stirred for 15 minutes, then prop-2-ynoic acid (15 mg, 216 μmol, 13 μL) was added thereto and the resulting mixture was stirred at room temperature overnight. The material was concentrated and purified via reverse phase purification (column: Waters XSelect CSH Prep C18 5um OBD 19x100mm; conditions: 5-45% acetonitrile in 0.1% v / v ammonium carbonate / water; flow rate: 30 mL / min) to give 14.8 mg (24% yield). LCMS m / z = 350.1 (M+H)+. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.22 - 1.43 (m, 1 H) 1.51 - 1.68 (m, 2 H) 1.78 - 1.99 (m, 2 H) 3.04 (dd, J =12.82, 9.16 Hz , 1H) 3.18 - 3.26 (m, 1H) 3.87 (s, 3H) 3.90 - 3.99 (m, 1H) 4.22 - 4.41 (m, 2H) 6.96 (d, J =1.83 Hz, 1H) 7.90 - 8.07 (m, 1 H) 8.20 (s, 1 H) 8.44 - 8.56 (m, 1 H) 8.92 (d, J =7.32 Hz, 1 H). One proton signal was masked by residual water in the deuterated solvent. [example]

[22] : 4-Chloro-N-[1-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]-3-piperidine Base]but-2-enamide Synthesis of 4-chloro-N-[1-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]-3-piperidinyl]butyl -2-enamide

[0183] To 1-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]piperidin-3-amine hydrochloride (75 mg, 180 μmol ) in DCM (1.5 mL) were added sequentially N-ethyl-N-isopropyl-propan-2-amine (86 mg, 669 µmol, 117 µL) and HATU (68 mg, 178 µmol). The reaction mixture was stirred for 15 minutes, then 4-chlorobut-2-enoic acid (26 mg, 216 μmol) was added thereto and the resulting mixture was stirred at room temperature overnight. The material was concentrated and purified via reverse phase purification (column: Waters XSelect CSH Prep C18 5um OBD 19x100mm; conditions: 5-55% acetonitrile in 0.1% v / v ammonium carbonate / water; flow rate: 30 mL / min) to give 5.7 mg (8% yield). LCMS m / z = 400.2 (M+H)+. 1H NMR (500MHz, DMSO-d 6) δ: 8.51 - 8.43 (m, 1H), 8.30 (d, J= 7.3 Hz, 1H), 8.25 - 8.17 (m, 1H), 8.02 - 7.89 (m, 1H) , 7.09 - 6.98 (m, 1H), 6.75 (td, J= 6.1, 14.6 Hz, 1H), 6.31 - 6.19 (m, 1H), 4.37 (dd, J= 1.2, 6.1 Hz, 3H), 4.32 - 4.19 (m, 1H), 4.02 - 3.91 (m, 1H), 3.87 (s, 3H), 3.31 - 3.22 (m, 1H), 3.15 - 3.00 (m, 1H), 2.03 - 1.90 (m, 1H), 1.86 (br d, J= 3.1 Hz, 1H), 1.70 - 1.54 (m, 2H), 1.33 - 1.17 (m, 1H). [example]

[23] : N-methyl-N-[1-[7-(1-methylpyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl]-3-piperidinyl ] prop-2-amide Synthesis of N-methyl-N-[1-[7-(1-methylpyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl]-3-piperidinyl]amino Tertiary butyl formate

[0184] To a solution of 5-chloro-7-(1-methylpyrazol-4-yl)imidazo[1,2-c]pyrimidine (1.00 g, 4.28 mmol) in t-BuOH (8.6 mL) sequentially Add N-ethyl-N-isopropyl-propan-2-amine (830 mg, 6.42 mmol, 1.1 mL) and tertiary butyl N-methyl-N-(3-piperidinyl)carbamate ( 945 mg, 4.41 mmol). The reaction mixture was stirred overnight at 80 °C. Assuming 100% yield, the material was concentrated and carried forward as crude material. LCMS m / z = 412.0 (M+H)+. Synthesis of N-methyl-1-[7-(1-methylpyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl]piperidin-3-amine hydrochloride

[0185] To N-methyl-N-[1-[7-(1-methylpyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl]-3-piperidinyl]amino To a solution of tert-butyl formate (1.76 g, 4.28 mmol) in dioxane (8.56 mL) was added HCl (4 M, 6.42 mL). The mixture was stirred overnight at room temperature. A solid precipitated out overnight and was filtered off and washed with EtOAc. The solid was air dried to afford N-methyl-1-[7-(1-methylpyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl]piperidine as an off-white solid -3-Amine hydrochloride (1.94 g, 3.90 mmol, 91% yield). The solid is assumed to be 70% pure. LCMS m / z = 312.1 (M+H)+. Synthesis of N-methyl-N-[1-[7-(1-methylpyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl]-3-piperidinyl]propane- 2-Alkynamide

[0186] To N-methyl-1-[7-(1-methylpyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl]piperidin-3-amine hydrochloride (100 mg , 201 µmol) in DCM (1 mL) were sequentially added N-ethyl-N-isopropyl-propan-2-amine (130 mg, 1.01 mmol, 176 µL), prop-2-ynoic acid (18 mg, 262 µmol, 16 µL). HATU (100 mg, 262 μmol) was then added to the vial and the resulting mixture was stirred at room temperature overnight. The material was concentrated and purified via reverse phase purification (column: Waters XSelect CSH Prep C18 5um OBD 19x100mm; conditions: 5-45% acetonitrile in 0.1% v / v ammonium carbonate / water; flow rate: 30 mL / min) to give 33.4 mg (46% yield). LCMS m / z = 364.3 (M+H)+. [example]

[24] : N-methyl-N-[1-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]-3-piper Pyridyl]prop-2-ynamide Synthesis of N-methyl-N-[1-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]-3-piperidinyl] Tertiary butyl carbamate

[0187] To a solution of 4-chloro-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazine (400 mg, 1.71 mmol) in t-BuOH (3.42 mL) Add N-ethyl-N-isopropyl-propan-2-amine (332 mg, 2.57 mmol, 448 µL) and tertiary butyl N-methyl-N-(3-piperidinyl)carbamate in sequence Esters (378 mg, 1.76 mmol). The vial was stirred overnight at 80°C. Assuming 100% yield, the material was concentrated and carried forward as crude material. LCMS m / z = 412.1 (M+H)+. Synthesis of N-methyl-1-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]piperidin-3-amine hydrochloride

[0188] To N-methyl-N-[1-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]-3-piperidinyl] To a solution of tert-butyl carbamate (704 mg, 1.71 mmol) in dioxane (8.6 mL) was added HCl (4 M, 2.57 mL). The mixture was stirred overnight at room temperature. A solid precipitated out overnight and was filtered off and washed with EtOAc. The solid was air dried to afford N-methyl-1-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl] as an off-white solid Piperidin-3-amine hydrochloride (651 mg, 88% yield). The solid is assumed to be 80% pure. LCMS m / z = 312.1 (M+H)+. Synthesis of N-methyl-N-[1-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]-3-piperidinyl] prop-2-acylamide

[0189] To 1 N-methyl-1-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]piperidin-3-amine hydrochloride (100 mg, 230 µmol) in DCM (1 mL) were added sequentially prop-2-ynoic acid (21 mg, 299 µmol, 18 µL), N-ethyl-N-isopropyl-prop- 2-Amine (86 mg, 669 µmol, 117 µL) and HATU (114 mg, 299 µmol). The reaction mixture was stirred overnight at room temperature. The material was concentrated and purified via reverse phase purification (column: Waters XSelect CSH Prep C18 5um OBD 19x100mm; conditions: 5-50% acetonitrile in 0.1% v / v ammonium carbonate / water; flow rate: 30 mL / min) to give 1.9 mg (2% yield). LCMS m / z = 364.2 (M+H)+. 1H NMR (500 MHz, DMSO- d 6 ) δ ppm 1.59 - 1.75 (m, 1 H) 1.78 - 2.05 (m, 4 H) 2.90 (s, 2 H), 2.99 - 3.11 (m, 1 H) 3.14 - 3.18 (m, 1 H) 3.87 (d, J =1.83 Hz, 3 H) 4.29 - 4.56 (m, 4 H) 6.95 (d, J =2.44 Hz, 1 H) 7.90 - 8.04 (m, 2 H) 8.17 (d, J =17.70 Hz, 1 H) 8.46 - 8.59 (m, 1 H). [example]

[25] : N-((1-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)piperidine-3- base) methyl) acrylamide Synthesis of N-[[1-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]-3-piperidinyl]methyl]amine tertiary butyl carbamate

[0190] Tri-butyl N-(3-piperidinylmethyl)carbamate (229 mg, 1.07 mmol), 4-chloro-6-(1-methylpyrazol-4-yl)pyrazolo[1 ,5-a] A suspension of pyrazine (250 mg, 1.07 mmol) and DIPEA (277 mg, 2.14 mmol, 374 µL) in isopropanol (4 mL) was heated to reflux for 17 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was dissolved in EtOAc and washed with water and brine. The organic layer was dried (MgSO 4 ), filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (0-100% EtOAc / heptane). N-[[1-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]-3-piperidine was obtained as a light yellow solid tert-butyl]methyl]carbamate (379 mg, 86% yield). LCMS: m / z = 412.3 (M+H)+. 1H NMR (500 MHz, chloroform-d) δ ppm 8.09 (s, 1 H), 7.82 - 7.96 (m, 3 H), 6.69 (br s, 1 H), 4.81 (br s, 1 H), 4.38 ( br d, J =13.4 Hz, 2 H), 3.98 (s, 3 H), 3.29 (br t, J =11.0 Hz, 1 H), 3.15 (br s, 2 H), 3.09 (br dd, J = 12.8, 9.8 Hz, 1 H), 1.95 (br d, J =12.2 Hz, 2 H), 1.87 (dt, J =13.4, 3.7 Hz, 1 H), 1.68 - 1.78 (m, 1 H), 1.45 - 1.53 (m, 9H), 1.33 - 1.42 (m, 1H). Synthesis of [1-[6-(1-methylpyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl]-3-piperidinyl]methanol Amine (hydrochloride)

[0191] Treat N-[[1-[6-(1-methylpyrazol-4-yl)pyrrolo[2,1-f][1, 2,4]Triazin-4-yl]-3-piperidinyl]methyl]carbamate (150 mg, 365 µmol) in anhydrous methanol (1 mL). The resulting mixture was stirred at room temperature for 1 hour and concentrated in vacuo. [1-[6-(1-Methylpyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl]-3- Piperidinyl]methylamine hydrochloride. LCMS: m / z = 312.3 (M+H)+. Synthesis of N-[[1-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]-3-piperidinyl]methyl]propane -2-Alkynamide

[0192] To the crude [1-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]-3-piperidine at 0°C under a nitrogen atmosphere To a suspension of methylamine hydrochloride (50 mg, 161 μmol) in anhydrous DMF (1 mL) was added DIPEA (62 mg, 482 μmol, 84 μL), followed by prop-2-ynoic acid (17 mg , 241 µmol, 15 µL) and T3P (204 mg, 321 µmol, 217 µL, 50%, in DMF). The resulting solution was stirred at room temperature for 1 h, quenched with saturated sodium bicarbonate solution and extracted with EtOAc. The organic layer was washed with water and brine, dried (MgSO 4 ), filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (0-10% MeOH / DCM). N-[[1-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]-3-piperidinyl] was obtained as an orange oil Methyl]prop-2-ynamide (42.8 mg, 66% yield, 90% purity). LCMS: m / z = 364.2 (M+H)+. 1H NMR (500 MHz, chloroform-d) δ ppm 8.07 (s, 1 H), 7.83 - 7.88 (m, 2 H), 7.79 - 7.83 (m, 1 H), 6.65 (d, J =2.4 Hz, 1 H), 6.45 (br s, 1 H), 4.16 - 4.25 (m, 2 H), 3.94 - 3.98 (m, 3 H), 3.44 - 3.52 (m, 1 H), 3.35 - 3.44 (m, 1 H ), 3.28 - 3.35 (m, 1 H), 3.20 - 3.27 (m, 1 H), 2.80 - 2.84 (m, 1 H), 2.08 (quintuplet doublet, J =9.0, 9.0, 9.0, 9.0, 3.7 Hz, 1H), 1.91 - 2.00 (m, 1H), 1.78 - 1.86 (m, 1H), 1.61 - 1.78 (m, 1H), 1.38 - 1.50 (m, 1H). [example]

[26] : (S)-N-((1-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)piper Pyridin-2-yl)methyl)propionamide and (R)-N-((1-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a ]pyrazin-4-yl)piperidin-2-yl)methyl)acrylamide Synthesis of N-[[1-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]-2-piperidinyl]methyl]amine tertiary butyl carbamate

[0193] N-(2-piperidinylmethyl)carbamate tertiary butyl ester (302 mg, 1.41 mmol), 4-chloro-6-(1-methylpyrazol-4-yl)pyrazolo[1 ,5-a] A suspension of pyrazine (300 mg, 1.28 mmol) and cesium carbonate (1.25 g, 3.84 mmol) in dioxane (5 mL) was bubbled with nitrogen for 5 min. RuPhos (119 mg, 256 μmol) and Pd2(dba)3 (117 mg, 128 μmol) were added, and the resulting mixture was heated to reflux overnight. Add tert-butyl N-(2-piperidinylmethyl)carbamate (302 mg, 1.41 mmol), RuPhos (119 mg, 256 µmol) and Pd 2(dba) 3 (117 mg, 128 µmol) And continue heating for another 24 hours. The reaction mixture was then cooled to room temperature, filtered through celite with a rinse of EtOAc, and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (0-100% EtOAc / heptane). N-[[1-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]-2-piperidinyl was obtained as a yellow foam ]methyl]carbamate (267 mg, 51% yield). LCMS: m / z = 412.3 (M+H)+. 1H NMR (400 MHz, chloroform-d) δ ppm 8.09 (s, 1 H), 7.82 - 7.95 (m, 3 H), 6.69 (br s, 1 H), 5.96 (br s, 1 H), 4.90 ( br s, 1 H), 4.29 - 4.42 (m, 1 H), 3.99 (s, 3 H), 3.85 (br t, J =11.8 Hz, 1 H), 3.35 (br d, J =13.6 Hz, 2 H), 1.71 - 1.92 (m, 6 H), 1.35 (s, 9 H). Synthesis of 1-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]-2-piperidinyl]methylamine (hydrochloride salt)

[0194] Treat N-[[1-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazine with hydrochloric acid (4 M in dioxane, 1 mL) -4-yl]-2-piperidinyl]methyl]carbamate tertiary butyl ester (150 mg, 365 µmol) in anhydrous methanol (1 mL) suspension, and the resulting solution was stirred at room temperature 2 Hour. A solid formed and the reaction mixture was concentrated in vacuo, and the residue was used directly. [1-[6-(1-Methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]-2-piperidinyl]methanol was obtained as a pale yellow solid Amine hydrochloride. Quantitative yield is assumed. LCMS: m / z = 312.2 (M+H)+. Synthesis of N-[[1-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]-2-piperidinyl]methyl]propane -2-Alkynamide

[0195] The crude [1-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]-2-piperidinyl ]Methylamine hydrochloride (50 mg, 161 μmol) in anhydrous DMF (1 mL) was added DIPEA (62 mg, 482 μmol, 84 μL), followed by prop-2-ynoic acid (17 mg , 241 µmol, 15 µL) and T3P (204 mg, 321 µmol, 217 µL, 50%, in DMF). The resulting solution was stirred at room temperature for 1 h, quenched with saturated sodium bicarbonate solution and extracted with EtOAc. The organic layer was washed with water and brine, dried (MgSO 4 ), filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (0-10% MeOH / DCM) and the product was further purified by prep-TLC (7% MeOH in DCM). N-[[1-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]-2-piperidinyl was obtained as a brown solid ]methyl]prop-2-ynamide (20 mg, 33% yield, 95% purity). LCMS: m / z = 364.2 (M+H)+. 1H NMR (400 MHz, chloroform-d) δ ppm 8.56 (br s, 1 H), 8.07 - 8.14 (m, 1 H), 7.89 (d, J =2.3 Hz, 1 H), 7.84 (s, 2 H ), 6.67 (d, J =2.0 Hz, 1 H), 4.90 - 5.02 (m, 1 H), 4.31 (br d, J =13.8 Hz, 1 H), 4.05 - 4.19 (m, 1 H), 3.92 - 4.00 (m, 3 H), 3.42 - 3.52 (m, 1 H), 3.36 (br s, 1 H), 2.54 (s, 1 H), 1.73 - 1.96 (m, 6 H).

[0196] Chiral SFC purification (using CHIRALPAK AD-H 30x250mm, 5um column; method: 30% MeOH, without modifier, in CO2 (flow rate: 100mL / min, ABPR 120 bar, MBPR 40psi, column temperature 40 °C)) to obtain enantiomer E1 (as the first eluting peak, 7.9 mg, 100% ee). Rf = 3.76 min, and enantiomer E2 (as the second eluting peak, 7.8 mg, 95.90% ee). Rf = 4.43 min. [example]

[27] : N-[[1-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]-2-piperidinyl]methyl yl]prop-2-enamide

[0197] Under nitrogen and 0°C, the crude [1-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]-2-piperidinyl ] Methylamine hydrochloride (60 mg, 193 μmol) in anhydrous THF (1 mL) was added DIPEA (75 mg, 578 μmol, 101 μL), followed by addition of prop-2-enyl chloride (26 mg , 289 µmol, 24 µL). The resulting suspension was stirred at 0 °C for 10 min, quenched with saturated sodium bicarbonate solution and extracted with EtOAc. The organic layer was washed with brine, dried (MgSO 4 ), filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (0-10% MeOH / DCM) and further purified by prep-TLC (93:7 DCM / MeOH). N-[[1-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]-2-piperidine was obtained as a brownish foam Methyl]methyl]prop-2-enamide (13.2 mg, 18% yield, 95% purity). LCMS: m / z = 366.1 (M+H)+. 1H NMR (400 MHz, chloroform-d) δ ppm 8.09 (s, 1 H), 7.86 - 7.90 (m, 1 H), 7.83 - 7.86 (m, 1 H), 7.78 (s, 1 H), 7.70- 7.90 (br s, 1H), 6.67 (d, J =2.0 Hz, 1 H), 6.08 (dd, J =17.1, 1.3 Hz, 1 H), 5.79 (dd, J =17.1, 10.3 Hz, 1 H) , 5.43 (dd, J =10.4, 1.4 Hz, 1 H), 4.98 - 5.08 (m, 1 H), 4.27 - 4.40 (m, 1 H), 4.08 - 4.22 (m, 1 H), 3.93 - 4.00 ( m, 3H), 3.44 - 3.53 (m, 1H), 3.28 - 3.44 (m, 1H), 1.72 - 1.96 (m, 6H). [example]

[28] : (R)-6-(1-methyl-1 H-pyrazol-4-yl)-4-((1-(vinylsulfonyl)azepan-4-yl) Oxy)pyrazolo[1,5-a]pyrazine 1. Synthesis of (R)-4-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)azepine Cycloheptane-1-carboxylate tertiary butyl ester

[0198] A solution of tert-butyl 4-hydroxyazepane-1-carboxylate (710 mg, 3.30 mmol) in anhydrous DMF (10 mL) was cooled in an ice bath. Next, sodium hydride (396 mg, 9.90 mmol, 60% purity) was added in 4 portions with stirring. Stirring was continued for 45 min in the ice bath, during which time a pale yellow suspension formed. To this mixture was added a portion of 4-chloro-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazine (700 mg, 3.00 mmol). Stirring was continued overnight at room temperature. The mixture was diluted with ethyl acetate, followed by careful addition of water. The mixture was transferred to a separatory funnel and the phases were separated. The aqueous phase was extracted again with ethyl acetate, and the combined organic phases were washed with brine, dried over Na 2 SO 4 , filtered and concentrated. The residue was purified on a 10 g silica column in 50% heptane / ethyl acetate to give 4-[6-(1-methylpyrazol-4-yl)pyridine as a viscous pale yellow gum Azolo[1,5-a]pyrazin-4-yl]oxyazepane-1-carboxylic acid tert-butyl ester (1.30 g, yield: 95%). Purified by chiral SFC (CHIRALPAK AD-H 30x250mm, 5um, 25% IPA and 0.1% DEA, in CO 2 , flow rate: 100mL / min, ABPR 120 bar, MBPR 60psi, column temperature 40°C) resolution The racemic material afforded (S)-4-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]oxo as an off-white solid. Tertiary butyl azepane-1-carboxylate (first elution peak) (389 mg, yield: 63%) and ( R )-4-[6-(1-methylpyrazole-4 -yl)pyrazolo[1,5-a]pyrazin-4-yl]oxyazepane-1-carboxylic acid tertiary butyl ester (second elution peak) (407 mg, yield: 66 %). The absolute stereochemistry of the product in these two peaks was later confirmed using commercially available chiral (4S)-hydroxyazepane-1-carboxylate tertiary butyl ester to synthesize a compound whose analytical data was consistent with the first eluting peak . ESI-MS (M+H)+: 413.2. 2. Synthesis of (R)-4-(azepan-4-yloxy)-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazine

[0199] To (4R)-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]oxyazepane under stirring at room temperature - To a solution of tert-butyl 1-carboxylate (407 mg, 987 µmol) in DCM (3 mL) was added TFA (2.25 g, 19.7 mmol, 1.51 mL). After stirring overnight, the mixture was dissolved in MeOH and purified on a 5 g SCX column, where the desired product was eluted with 2 M NH 3-MeOH to give 4-(azepane-4- oxy)-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazine (250 mg, yield: 77% yield). ESI-MS (M+H)+: 313.2. 3. Synthesis of (R)-6-(1-methyl-1H-pyrazol-4-yl)-N-((1-(vinylsulfonyl)piperidin-4-yl)methyl)pyrazole And[1,5-a]pyrazin-4-amine

[0200] To (4R)-(azepan-4-yloxy)-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazine (30 mg, 96 µmol) in THF (1 mL) was added 2-chloroethanesulfonyl chloride (31 mg, 192 µmol, 20 µL), and an immediate precipitation occurred. Next, TEA (39 mg, 384 µmol, 53 µL) was added with stirring at room temperature. After stirring overnight, volatiles were removed and the residue was redissolved in DMSO and analyzed by reverse phase HPLC (Waters XSelect CSH C18, 5 μm, 19 mm × 100 mm column, mobile phase H2O (A) and MeCN (B ) and gradient 5 - 60% B (0.2% NH 4OH final v / v % modifier), flow rate 30 mL / min) to obtain (R)-6-(1-methylpyrazole -4-yl)-4-(1-vinylsulfonylazepan-4-yl)oxy-pyrazolo[1,5-a]pyrazine (11mg, yield: 26%) . ESI-MS (M+H)+: 403.2. 1H NMR (500 MHz, DMSO-d 6) δ 8.74 (s, 1H), 8.19 (s, 1H), 7.98-8.03 (m, 1H), 6.79-6.94 (m, 2H), 6.05-6.11 (m, 2H), 5.57 (tt, J =3.66, 7.63 Hz, 1H), 3.88 (s, 3H), 3.40-3.67 (m, 2H), 3.33-3.38 (m, 2H), 3.21-3.31 (m, 1H) , 2.17-2.27 (m, 1H), 1.99-2.10 (m, 3H), 1.89-1.99 (m, 1H), 1.68-1.83 (m, 1H). [example]

[29] : (R)-1-(4-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy Base) azepan-1-yl) prop-2-en-1-one 1. Synthesis of (R)-1-(4-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy ) azepan-1-yl) prop-2-en-1-one

[0201] To (4R)-(azepan-4-yloxy)-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazine (30 mg, 96 µmol) in THF (1 mL) was added to prop-2-enyl chloride (17 mg, 192 µmol, 16 µL), and an immediate precipitation occurred. Next, TEA (19 mg, 192 µmol, 27 µL) was added with stirring at room temperature. After stirring overnight, volatiles were removed and the residue was redissolved in DMSO and analyzed by reverse phase HPLC (Waters XSelect CSH C18, 5 μm, 19 mm × 100 mm column, mobile phase H2O (A) and MeCN (B ) and gradient 5 - 50% B (0.2% NH 4OH final v / v % modifier), flow rate 30 mL / min) to obtain (R)-1-(4-((6- (1-Methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)azepan-1-yl)prop-2-ene -1-one (9 mg, yield: 23%). ESI-MS (M+H)+: 367.2. 1H NMR (500 MHz, DMSO-d 6) δ 8.73 (s, 1H), 8.18 (d, J =18.92 Hz, 1H), 7.98-8.03 (m, 1H), 6.76-6.87 (m, 2H), 6.18 (ddd, J =2.44, 3.66, 16.48 Hz, 1H), 5.65-5.75 (m, 1H), 5.45-5.58 (m, 1H), 3.88 (d, J =1.83 Hz, 3H), 3.56-3.79 (m , 4H), 2.71-2.92 (m, 1H), 2.17-2.26 (m, 1H), 1.99-2.10 (m, 2H), 1.84-1.98 (m, 2H), 1.63-1.82 (m, 1H). [example]

[30] : (R)-1-(4-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy Base) azepan-1-yl) prop-2-yn-1-one 1. Synthesis of (R)-1-(4-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy ) azepan-1-yl) prop-2-yn-1-one

[0202] To (4R)-(azepan-4-yloxy)-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyridine under stirring at room temperature To a solution of oxazine (30 mg, 96 µmol) in DMF (1 mL) was added propiolic acid (13 mg, 192 µmol, 12 µL), followed by DIPEA (25 mg, 192 µmol, 34 µL). After stirring at room temperature for 5 min, T3P (122 mg, 192 μmol, 50% purity) was added dropwise with stirring. After stirring for another 3 hours at room temperature, the mixture was diluted with ethyl acetate and washed with water. The organic phase was dried over sodium sulfate, filtered and evaporated. The residual white solid was redissolved in DMSO and subjected to reverse phase HPLC (Waters XSelect CSH C18, 5 μm, 19 mm × 100 mm column, mobile phase H2O (A) and MeCN (B) and a gradient of 5-55% B (0.2% NH4OH final v / v % modifier), flow rate 30 mL / min) was purified to obtain (R)-1-(4-((6-(1-methyl- 1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)azepan-1-yl)prop-2-yn-1-one (24 mg, yield: 48%). ESI-MS (M+H)+: 365.2. 1H NMR (500 MHz, DMSO-d 6) δ 8.70-8.81 (m, 1H), 8.19 (d, J =3.66 Hz, 1H), 7.95-8.08 (m, 2H), 6.74-6.88 (m, 1H) , 5.45-5.63 (m, 1H), 3.88 (s, 3H), 3.75-3.84 (m, 2H), 3.48-3.66 (m, 2H), 2.19-2.29 (m, 1H), 2.10-2.20 (m, 1H), 1.85-2.09 (m, 4H), 1.67-1.84 (m, 1H). [example]

[31] : (S)-1-(4-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy Base) azepan-1-yl) prop-2-yn-1-one 1. Synthesis of (S)-4-(azepan-4-yloxy)-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazine

[0203] To (4S)-4-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]oxyazepine under stirring at room temperature To a solution of tert-butyl cycloheptane-1-carboxylate (389 mg, 944 µmol) in DCM (3 mL) was added TFA (2.15 g, 18.9 mmol, 1.44 mL). After stirring overnight, the mixture was dissolved in MeOH and purified on a 5 g SCX column, where the desired product was eluted with 2 M NH3-MeOH to give the 4-[(4S)-azacycle as a white solid Heptan-4-yl]oxy-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazine (170 mg, yield: 55%). ESI-MS (M+H)+: 313.2. 2. Synthesis of (S)-1-(4-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy ) azepan-1-yl) prop-2-yn-1-one

[0204] (4S)-(azepan-4-yloxy)-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyridine under stirring at room temperature To a solution of oxazine (30 mg, 96 µmol) in DMF (1 mL) was added propiolic acid (13 mg, 192 µmol, 12 µL), followed by DIPEA (25 mg, 192 µmol, 34 µL). After stirring at room temperature for 5 min, T3P (122 mg, 192 μmol, 50% purity) was added dropwise with stirring. After stirring for another 3 hours at room temperature, the mixture was diluted with ethyl acetate and washed with water. The organic phase was dried over sodium sulfate, filtered and evaporated. The residual white solid was redissolved in DMSO and subjected to reverse phase HPLC (Waters XSelect CSH C18, 5 μm, 19 mm × 100 mm column, mobile phase H2O (A) and MeCN (B) and a gradient of 5-55% B (0.2% NH4OH final v / v % modifier), flow rate 30 mL / min) to obtain (S)-1-(4-((6-(1-methyl- 1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)azepan-1-yl)prop-2-yn-1-one (18 mg, yield: 48%). ESI-MS (M+H)+: 365.2. 1H NMR (500 MHz, DMSO-d 6) δ 8.74 (d, J =3.05 Hz, 1H), 8.19 (d, J =3.66 Hz, 1H), 7.98-8.05 (m, 2H), 6.79-6.87 (m , 1H), 5.46-5.64 (m, 1H), 3.88 (s, 3H), 3.75-3.84 (m, 2H), 3.50-3.67 (m, 2H), 2.12-2.29 (m, 2H), 1.87-2.11 (m, 4H), 1.67-1.84 (m, 1H). [example]

[32] : (S)-1-(4-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy Base) azepan-1-yl) prop-2-en-1-one 1. Synthesis of (S)-1-(4-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy ) azepan-1-yl) prop-2-en-1-one

[0205] To (S)-4-(azepan-4-yloxy)-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazine (30 mg , 96 µmol) in THF (1 mL) was added to a solution of prop-2-enyl chloride (17 mg, 192 µmol, 16 µL), and an immediate precipitation occurred. Next, TEA (19 mg, 192 µmol, 27 µL) was added with stirring at room temperature. After stirring overnight, volatiles were removed and the residue was redissolved in DMSO and analyzed by reverse phase HPLC (Waters XSelect CSH C18, 5 μm, 19 mm × 100 mm column, mobile phase H2O (A) and MeCN (B ) and gradient 5 - 50% B (0.2% NH 4OH final v / v % modifier), flow rate 30 mL / min) to obtain (S)-1-(4-((6 - (1-Methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)azepan-1-yl)prop-2-ene -1-one (25 mg, yield: 67%). ESI-MS (M+H)+: 367.2. 1H NMR (500 MHz, DMSO-d 6) δ 8.73 (d, J =1.22 Hz, 1H), 8.18 (d, J =18.92 Hz, 1H), 7.96-8.02 (m, 2H), 6.76-6.87 (m , 2H), 6.18 (ddd, J =2.44, 3.66, 16.48 Hz, 1H), 5.66-5.72 (m, 1H), 5.45-5.58 (m, 1H), 3.88 (d, J =1.83 Hz, 3H), 3.55-3.79 (m, 4H), 2.18-2.25 (m, 1H), 1.99-2.07 (m, 2H), 1.85-1.98 (m, 2H), 1.69-1.79 (m, 1H). [example]

[33] : (S)-6-(1-methyl-1 H-pyrazol-4-yl)-4-((1-(vinylsulfonyl)azepan-4-yl) Oxy)pyrazolo[1,5-a]pyrazine Synthesis of (S)-6-(1-methyl-1H-pyrazol-4-yl)-N-((1-(vinylsulfonyl)piperidin-4-yl)methyl)pyrazolo[ 1,5-a] pyrazin-4-amine

[0206] To 4-(azepan-4-yloxy)-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazine (30 mg, 96 µmol) 2-Chloroethanesulfonyl chloride (31 mg, 192 µmol, 20 µL) was added to a solution in THF (1 mL), and an immediate precipitation occurred. Next, TEA (39 mg, 384 µmol, 53 µL) was added with stirring at room temperature. After stirring overnight, volatiles were removed and the residue was redissolved in DMSO and analyzed by reverse phase HPLC (Waters XSelect CSH C18, 5 μm, 19 mm × 100 mm column, mobile phase H2O (A) and MeCN (B ) and gradient 5 - 60% B (0.2% NH 4OH final v / v % modifier), flow rate 30 mL / min) to obtain (S)-6-(1-methylpyrazole -4-yl)-4-(1-vinylsulfonylazepan-4-yl)oxy-pyrazolo[1,5-a]pyrazine (7 mg, yield: 16%) . ESI-MS (M+H)+: 403.2. 1H NMR (500 MHz, DMSO-d 6) δ 8.74 (s, 1H), 8.19 (s, 1H), 7.98-8.04 (m, 2H), 6.82-6.91 (m, 2H), 6.09 (d, J = 16.48 Hz, 1H), 6.06 (d, J =10.38 Hz, 1H), 5.57 (tt, J =3.66, 7.63 Hz, 1H), 3.88 (s, 3H), 3.43-3.52 (m, 1H), 2.17- 2.25 (m, 1H), 2.00-2.09 (m, 4H), 1.88-1.98 (m, 2H), 1.69-1.82 (m, 2H). [example]

[34] : (S) or (R)-1-(4-((7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl )Oxy)azepan-1-yl)prop-2-en-1-one or 1. Synthesis of (R) and (S)-4-((7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)oxy) Tertiary butyl azepane-1-carboxylate

[0207] A solution of tert-butyl 4-hydroxyazepane-1-carboxylate (355 mg, 1.65 mmol) in anhydrous DMF (5 mL) was cooled in an ice bath. Next, sodium hydride (198 mg, 4.95 mmol, 60% purity) was added in 4 portions with stirring. Stirring was continued for 45 min in the ice bath, during which time a pale yellow suspension formed. To this mixture was added a portion of 5-chloro-7-(1-methylpyrazol-4-yl)imidazo[1,2-c]pyrimidine (350 mg, 1.50 mmol). Stirring was continued overnight at room temperature. The mixture was diluted with ethyl acetate, followed by careful addition of water. The mixture was transferred to a separatory funnel and the phases were separated. The aqueous phase was extracted again with ethyl acetate, and the combined organic phases were washed with brine, dried over Na 2 SO 4 , filtered and concentrated. The residue was purified on a 10 g silica column in 50% heptane / ethyl acetate to give 4-[7-(1-methylpyrazol-4-yl)imidazolo as a viscous pale yellow gum [1,2-c]pyrimidin-5-yl]oxyazepane-1-carboxylic acid tert-butyl ester (520 mg, yield: 84%). Purified by chiral SFC (CHIRALPAK AD-H 30x250mm, 5um, 30% IPA and 0.1% DEA, in CO 2 , flow rate: 100mL / min, ABPR 120 bar, MBPR 60psi, column temperature 40°C) resolution 450 mg of racemic material, two products were obtained as an off-white solid, showing the first elution peak (E1) peak 1 (172 mg, yield: 76%) and the second elution peak (E2) peak 2 ( 171 mg, yield: 76%). ESI-MS (M+H)+: 413.3. The absolute stereochemistry of the product in each peak is not assigned. 2. Synthesis of (R) or (S)-5-(azepan-4-yloxy)-7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2 -c] pyrimidine

[0208] To E2 (4R) or (4S)-4-[7-(1-methylpyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl]oxyl group under stirring at room temperature To a solution of tert-butyl azepane-1-carboxylate (172 mg, 416 µmol) in DCM (3 mL) was added TFA (949 mg, 8.33 mmol, 637 µL). After stirring overnight, the reaction was dissolved in MeOH and purified on a 10 g SCX column, where the desired product was eluted with 2 M NH3-MeOH to give E3,5-[(4R) or ( 4S )-azepan-4-yl]oxy-7-(1-methylpyrazol-4-yl)imidazo[1,2-c]pyrimidine (95 mg, yield: 69%) . ESI-MS (M+H)+: 313.2. 3. Synthesis of (R) or (S)-1-(4-((7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl) Oxy) azepan-1-yl) prop-2-en-1-one

[0209] To E3 5-(4R) or (4S)-(azepan-4-yloxy)-7-(1-methylpyrazol-4-yl) imidazo[1,2-c]pyrimidine (30 mg, 96 µmol) (single enantiomer; chirality arbitrarily assigned) in THF (1 mL) was added prop-2-enyl chloride (17 mg, 192 µmol, 16 µL), immediately Precipitation occurs. Next, TEA (19 mg, 192 µmol, 27 µL) was added with stirring at room temperature. After stirring overnight, volatiles were removed and the residue was redissolved in DMSO and analyzed by reverse phase HPLC (Waters XSelect CSH C18, 5 μm, 19 mm × 100 mm column, mobile phase H2O (A) and MeCN (B ) and gradient 5 - 35% B (0.2% NH 4OH final v / v % modifier), flow rate 30 mL / min) to obtain (R)- or (S)-1-(4 -((7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)oxy)azepan-1-yl)propane- 2-en-1-one (17 mg, yield: 45%). ESI-MS (M+H)+: 367.2. 1H NMR (500 MHz, DMSO-d 6) δ 8.25 (d, J =12.82 Hz, 1H), 8.04 (d, J =3.66 Hz, 1H), 7.70 (s, 1H), 7.50 (t, J =1.53 Hz, 1H), 7.44 (s, 1H), 6.82 (ddd, J =8.55, 10.38, 16.48 Hz, 1H), 6.17 (dd, J =2.44, 16.48 Hz, 1H), 5.69 (dt, J =2.44, 10.38 Hz, 1H), 5.50-5.64 (m, 1H), 3.89 (d, J =1.22 Hz, 3H), 3.75-3.84 (m, 1H), 3.59-3.72 (m, 3H), 2.21 (dq, J =3.05, 7.32 Hz, 1H), 2.06-2.17 (m, 2H), 1.87-2.01 (m, 2H), 1.70-1.82 (m, 1H). [example]

[35] : (S) or (R)-1-(4-((7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl )Oxy)azepan-1-yl)prop-2-yn-1-one or Synthesis of (R) or (S) 1-(4-((7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)oxy) Azepan-1-yl) prop-2-yn-1-one

[0210] E3 5-(4R)-or (4S)-(azepan-4-yloxy)-7-(1-methylpyrazol-4-yl)imidazo[ To a solution of 1,2-c]pyrimidine (30 mg, 96 µmol) in DMF (1 mL) was added propiolic acid (13 mg, 192 µmol, 12 µL), followed by DIPEA (25 mg, 192 µmol, 34 µL). After stirring at room temperature for 5 min, T3P (122 mg, 192 μmol, 50% purity) was added dropwise with stirring. After stirring for another 3 hours at room temperature, the mixture was diluted with ethyl acetate and washed with water. The organic phase was dried over Na2SO4, filtered and concentrated. The residual white solid was redissolved in DMSO and subjected to reverse phase HPLC (Waters XSelect CSH C18, 5 μm, 19 mm × 100 mm column, mobile phase H2O (A) and MeCN (B) and gradient 5-40% B (0.2% NH4OH final v / v % modifier), flow rate 30 mL / min) was purified to obtain (R) or (S)-1-(4-((7-(1- Methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)oxy)azepan-1-yl)prop-2-yn-1-one ( 2 mg, yield: 5%). ESI-MS (M+H)+: 365.2. 1H NMR (500 MHz, DMSO-d 6) δ 8.26 (d, J =2.44 Hz, 1H), 8.05 (d, J =4.27 Hz, 1H), 7.73 (d, J =11.60 Hz, 1H), 7.52 ( t, J =1.53 Hz, 1H), 7.46 (d, J =2.44 Hz, 1H), 5.55-5.67 (m, 1H), 4.53 (d, J =17.70 Hz, 1H), 3.89 (s, 3H), 3.78-3.82 (m, 1H), 3.53-3.72 (m, 2H), 3.40-3.52 (m, 1H), 2.21-2.28 (m, 1H), 2.07-2.19 (m, 2H), 1.91-2.06 (m , 2H), 1.72-1.89 (m, 1H). [example]

[36] : (R)- or (S)-7-(1-methyl-1H-pyrazol-4-yl)-5-((1-(vinylsulfonyl)azepane- 4-yl)oxy)imidazo[1,2-c]pyrimidine or Synthesis of (R)- or (S)-7-(1-methyl-1H-pyrazol-4-yl)-5-((1-(vinylsulfonyl)azepan-4-yl ) oxy) imidazo[1,2-c]pyrimidine

[0211] To E3 5-(4R)-or (4S)-(azepan-4-yloxy)-7-(1-methylpyrazol-4-yl)imidazo[1,2-c] To a solution of pyrimidine (30 mg, 96 µmol) in THF (1 mL) was added 2-chloroethanesulfonyl chloride (31 mg, 192 µmol, 20 µL), and an immediate precipitation occurred. Next, TEA (39 mg, 384 µmol, 53 µL) was added with stirring at room temperature. After stirring overnight, volatiles were removed and the residue was redissolved in DMSO and analyzed by reverse phase HPLC (Waters XSelect CSH C18, 5 μm, 19 mm × 100 mm column, mobile phase H2O (A) and MeCN (B ) and gradient 5 - 40% B (0.2% NH 4OH final v / v % modifier), flow rate 30 mL / min) to obtain (R)- or (S)-7-( 1-methyl-1H-pyrazol-4-yl)-5-((1-(vinylsulfonyl)azepan-4-yl)oxy)imidazo[1,2-c] Pyrimidine (2 mg, yield: 4%). ESI-MS (M+H)+: 403.2. [example]

[37] : (R)- or (S)-1-(4-((7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidine-5- Base) oxy) azepan-1-yl) prop-2-yn-1-one or 1. Synthesis of (R) or (S)-5-(azepan-4-yloxy)-7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2 -c] pyrimidine

[0212] To E1 (4R) or (4S)-4-[7-(1-methylpyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl]oxyl under stirring at room temperature To a solution of tert-butyl azepane-1-carboxylate (172 mg, 416 µmol) in DCM (3 mL) was added TFA (949 mg, 8.33 mmol, 637 µL). After stirring overnight, the reaction was dissolved in MeOH and purified on a 10 g SCX column, where the desired product was eluted with 2 M NH3-MeOH to afford E4,5-[(4R) or ( 4S )-azepan-4-yl]oxy-7-(1-methylpyrazol-4-yl)imidazo[1,2-c]pyrimidine (95 mg, yield: 69%) . ESI-MS (M+H)+: 313.2. 2. Synthesis of (R) or (S)-1-(4-((7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl) Oxy) azepan-1-yl) prop-2-yn-1-one

[0213] E4 5-[(4R)-or (4S)-azepan-4-yl]oxy-7-(1-methylpyrazol-4-yl)imidazo[ To a solution of 1,2-c]pyrimidine (30 mg, 96 µmol) in DMF (1 mL) was added propiolic acid (13 mg, 192 µmol, 12 µL), followed by DIPEA (25 mg, 192 µmol, 34 µL). After stirring at room temperature for 5 min, T3P (122 mg, 192 μmol, 50% purity) was added dropwise with stirring. After stirring for another 3 hours at room temperature, the mixture was diluted with ethyl acetate and washed with water. The organic phase was dried over Na2SO4, filtered and concentrated. The residual white solid was redissolved in DMSO and subjected to reverse phase HPLC (Waters XSelect CSH C18, 5 μm, 19 mm × 100 mm column, mobile phase H2O (A) and MeCN (B) and a gradient of 5-40% B (0.2% NH4OH final v / v % modifier), flow rate 30 mL / min) was purified to obtain (R)- or (S)-1-(4-((7-(1 -Methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)oxy)azepan-1-yl)prop-2-yn-1-one (1 mg, yield: 3%). ESI-MS (M+H)+: 365.2. [example]

[38] : (R)- or (S)-1-(4-((7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidine-5- Base) oxy) azepan-1-yl) prop-2-en-1-one or 1. Synthesis of (R)- or (S)-1-(4-((7-(1-methyl-1H-pyrazol-4-yl) imidazo[1,2-c]pyrimidin-5-yl ) oxy) azepan-1-yl) prop-2-en-1-one

[0214] To E4 5-[(4R)-or (4S)-azepan-4-yl]oxyl-7-(1-methylpyrazol-4-yl)imidazo[1,2-c] To a solution of pyrimidine (32 mg, 104 µmol) in THF (1 mL) was added prop-2-enyl chloride (19 mg, 207 µmol, 17 µL), and an immediate precipitation occurred. Next, TEA (21 mg, 207 µmol, 29 µL) was added with stirring at room temperature. After stirring overnight, volatiles were removed and the residue was redissolved in DMSO and analyzed by reverse phase HPLC (Waters XSelect CSH C18, 5 μm, 19 mm × 100 mm column, mobile phase H2O (A) and MeCN (B ) and gradient 5 - 35% B (0.2% NH 4OH final v / v % modifier), flow rate 30 mL / min) to obtain (R)- or (S)-1-(4 -((7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)oxy)azepan-1-yl)propane- 2-en-1-one (11 mg, yield: 27%). ESI-MS (M+H)+: 367.2. 1H NMR (500 MHz, DMSO-d 6) δ 8.26 (d, J =12.82 Hz, 1H), 8.04 (d, J =3.05 Hz, 1H), 7.70 (s, 1H), 7.51 (t, J =1.53 Hz, 1H), 7.44 (s, 1H), 6.82 (ddd, J =8.55, 10.38, 16.48 Hz, 1H), 6.17 (dd, J =2.14, 16.18 Hz, 1H), 5.69 (dt, J =2.44, 10.38 Hz, 1H), 5.53-5.64 (m, 1H), 3.89 (s, 3H), 3.75-3.83 (m, 1H), 3.50-3.71 (m, 3H), 2.18-2.26 (m, 1H), 2.06 -2.17 (m, 2H), 1.91-2.02 (m, 2H), 1.69-1.82 (m, 1H). [example]

[39] : (R)-1-(3-((7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)oxy) Pyrrolidin-1-yl)prop-2-yn-1-one Synthesis of (R)-3-((7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)oxy)pyrrolidine-1-carboxylic acid tertiary butyl ester

[0215] To the vial was added 5-chloro-7-(1-methylpyrazol-4-yl)imidazo[1,2-c]pyrimidine (250 mg, 1.07 mmol), DMF (5.4 mL), sodium hydride (64 mg, 1.61 mmol, 60% suspension in mineral oil) and (3R)-3-hydroxypyrrolidine-1-carboxylic acid tertiary butyl ester (200 mg, 1.07 mmol). The vial was stirred overnight at 80°C. The mixture was then diluted with MeOH and concentrated, followed by purification of the residue by silica gel column chromatography (10-100% [3:1 EtOAc:EtOH] / heptane) to afford (3R)-3-[7-(1- Methylpyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl]oxypyrrolidine-1-carboxylic acid tert-butyl ester (310 mg, 75% yield) with the starting aryl A mixture of chlorides was used without further purification. LCMS m / z = 385.1 (M+H)+. Synthesis of (R)-7-(1-methyl-1H-pyrazol-4-yl)-5-(pyrrolidin-3-yloxy)imidazo[1,2-c]pyrimidine hydrochloride

[0216] (3R)-3-[7-(1-methylpyrazol-4-yl)imidazo[1,2-c]pyrimidine-5- A solution of tert-butyl]oxypyrrolidine-1-carboxylate (310 mg, 806 µmol) in methanol (4 mL), and the resulting mixture was stirred at room temperature for 1 h. The mixture was then concentrated in vacuo and the solid residue was used without further purification. LCMS m / z = 285.0 (M+H)+. Synthesis of (R)-1-(3-((7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)oxy)pyrrolidine- 1-yl) prop-2-yn-1-one

[0217] To the vial was added 7-(1-methylpyrazol-4-yl)-5-[(3R)-pyrrolidin-3-yl]oxy-imidazo[1,2-c]pyrimidine hydrochloride ( 114 mg, 355 μmol), DCM (3.6 mL), N-ethyl-N-isopropyl-propan-2-amine (310 μL, 1.78 mmol), then added prop-2-ynoic acid (33 μL, 533 µmol). The vial was stirred at room temperature for 16 hours. The mixture was then concentrated and the residue was purified by silica gel column chromatography (10-100% [3:1 EtOAc:EtOH] / heptane). Fractions were pooled and concentrated, then purified by preparative HPLC (Waters SunFire Prep, C18 5 µm, OBD 30 x 50 mm, eluting with 10-70% MeCN:HO [with 0.1% TFA modifier]) , to give 1-[(3R)-3-[7-(1-methylpyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl]oxypyrrolidine- 1-yl]prop-2-yn-1-one (27.3 mg, 23% yield). LCMS m / z = 337.0 (M+H)+. 1H NMR (500 MHz, MeOD-d 4) δ: 8.46 (d, J =4.3 Hz, 1H), 8.23 ​​(d, J =2.4 Hz, 1H), 8.12-8.07 (m, 1H), 7.92 (d, J =2.4 Hz, 1H), 7.65 (d, J =4.9 Hz, 1H), 6.21-6.09 (m, 1H), 4.33-4.22 (m, 1H), 4.16-4.07 (m, 1H), 4.01 (d , J =1.2 Hz, 5H), 3.92-3.68 (m, 1H), 2.66-2.47 (m, 2H). [example]

[40] [to]

[53] . The compounds in the table below were prepared following the procedure described in Example 39 from 5-chloro-7-(1-methylpyrazol-4-yl)imidazo[1,2-c]pyrimidine and the appropriate alcohol and carboxylic acid: instance number structure, starting material, name yield, data 40 SM: Acryloyl chloride and (3S)-3-(hydroxymethyl)piperidine-1-carboxylic acid tertiary butyl ester 34.3 mg, 29% yield LCMS m / z = 367.2 (M+H)+ 41 SM: Acryloyl chloride and (3R)-3-(hydroxymethyl)piperidine-1-carboxylic acid tertiary butyl ester 23.0 mg, 22% yield LCMS m / z = 367.2 (M+H)+ 42 SM: Acryloyl chloride and tertiary butyl 3-(hydroxymethyl)pyrrolidine-1-carboxylate 13.2 mg, 11% yield LCMS m / z = 353.2 (M+H)+ 43 SM: Acryloyl chloride and tertiary butyl (3-hydroxyphenyl) carbamate 30.1 mg, 26% yield LCMS m / z = 361.2 (M+H)+ 44 SM: Acryloyl chloride and tertiary butyl 4-(hydroxymethyl)piperidine-1-carboxylate 5.5 mg, 6% yield LCMS m / z = 367.2 (M+H)+ 45 SM: Acryloyl chloride and (R)-3-hydroxypiperidine-1-carboxylic acid tertiary butyl ester 50.9 mg, 43% yield LCMS m / z = 353.2 (M+H)+ 46 SM: propiolic acid and (S)-3-(hydroxymethyl)piperidine-1-carboxylic acid tertiary butyl ester 9.2 mg, 9% yield LCMS m / z = 365.2 (M+H)+ 47 SM: Acryloylchlorobut-2-ynoic acid and tertiary butyl (S)-3-(hydroxymethyl)piperidine-1-carboxylate 7.3 mg, 10% yield LCMS m / z = 379.2 (M+H)+ 48 SM: Acryloyl chloride and tertiary butyl (3-hydroxycyclohexyl) carbamate 21.1 mg, 15% yield LCMS m / z = 367.2 (M+H)+ 49 SM: propiolic acid and tertiary butyl 4-hydroxypiperidine-1-carboxylate 12.9 mg, 12% yield LCMS m / z = 351.2 (M+H)+ 50 SM: propiolic acid and tertiary butyl (3-hydroxycyclohexyl) carbamate 7.1 mg, 6% yield LCMS m / z = 364.2 (M+H)+ 51 SM: But-2-ynoic acid and (R)-3-(hydroxymethyl)piperidine-1-carboxylic acid tertiary butyl ester 24.2 mg, 34% yield LCMS m / z = 379.0 (M+H)+ 52 SM: But-2-ynoic acid and tertiary butyl (3-hydroxycyclohexyl) carbamate 10.4 mg, 28% yield LCMS m / z = 379.2 (M+H)+ 53 SM: propiolic acid and (R)-3-hydroxypiperidine-1-carboxylic acid tertiary butyl ester 8.9 mg, 8% yield LCMS m / z = 351.4 (M+H)+ [example]

[54] : (S)-1-(6-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy Base)-1,4-oxazepan-4-yl)prop-2-en-1-one Synthesis of (6S)-6-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]oxy-1,4-oxazacycle Heptane-4-carboxylate tertiary butyl ester

[0218] Cool a flask containing tert-butyl (6S)-6-hydroxy-1,4-oxazepane-4-carboxylate (247 mg, 1.14 mmol) in anhydrous THF (2 mL) in an ice-water bath , then sodium tert-butoxide (168 mg, 1.74 mmol) was carefully added portionwise to the cold mixture. After 10 min, 4-chloro-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazine (235 mg, 1.01 mmol) was carefully added in portions to a cold in a homogeneous mixture. After the addition of 4-chloro-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazine was complete, the mixture was allowed to warm to 23 °C and monitored by LCMS. After 18 hours, the reaction was carefully quenched by the slow addition of water, followed by extraction of the biphasic mixture three times with ethyl acetate. The organics were pooled and then dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was loaded onto a silica gel column and purified (30-100% ethyl acetate / heptane). Pooling of the desired fractions followed by concentration under reduced pressure afforded (6S)-6-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a] as a white solid Pyrazin-4-yl]oxy-1,4-oxazepane-4-carboxylic acid tert-butyl ester (319 mg, 76% yield) was used without further purification. LCMS m / z = 415.1 (M+H)+. 1H NMR (500MHz, DMSO-d 6) d = 8.77 (s, 1H), 8.29 - 8.17 (m, 1H), 8.11 - 7.91 (m, 2H), 6.85 - 6.75 (m, 1H), 5.62 - 5.53 ( m, 1H), 4.28 - 3.94 (m, 3H), 3.93 - 3.74 (m, 4H), 3.47 - 3.36 (m, 1H), 3.73 - 3.32 (m, 3H), 1.76 - 0.98 (m, 9H). Synthesis of (6S)-6-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]oxy-1,4-oxazacycle Heptane

[0219] Cool in an ice-water bath containing (6S)-6-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]oxyl-1, 4-Oxazepane-4-carboxylic acid tert-butyl ester (319 mg, 769 µmol) in a vial of anhydrous dichloromethane (2 mL), followed by trifluoroacetic acid (1 mL, 13 mmol) carefully Add dropwise to the cold mixture. After the TFA addition was complete, the mixture was allowed to warm to 23 °C and monitored with LCMS. After 1 hour, the reaction was carefully concentrated under reduced pressure to afford (6S)-6-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5- a] Pyrazin-4-yl]oxy-1,4-oxazepane (345 mg, trifluoroacetate salt), which was used without further purification. LCMS m / z = 315.0 (M+H)+. Synthesis of 1-[(6S)-6-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]oxy-1,4-oxo Azepan-4-yl]prop-2-en-1-one

[0220] At -25°C, it accommodates (6S)-6-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]oxyl-1 , 4-Oxazepane (329 mg, 769 µmol, trifluoroacetate) in a vial of anhydrous dichloromethane (3 mL) was carefully added dropwise with Junine's base (0.7 mL, 4.02 mmol) . After 5 min, acryloyl chloride (0.2 mL, 2.46 mmol) was carefully added dropwise to the cold homogeneous solution. After the acryloyl chloride addition was complete, the reaction was allowed to warm to 23 °C and monitored by LCMS and TLC. After 3 min, the reaction was carefully quenched by the slow addition of saturated aqueous sodium bicarbonate. The biphasic mixture was loaded onto a silica gel column and purified (15-75% [3:1 ethyl acetate:ethanol] / heptane). Pooling of the desired fractions followed by concentration under reduced pressure afforded 1-[(6S)-6-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5 -a]pyrazin-4-yl]oxy-1,4-oxazepan-4-yl]prop-2-en-1-one (226 mg, 76% yield). 1H NMR (500MHz, DMSO-d 6) d = 8.82 - 8.74 (m, 1H), 8.27 - 8.19 (m, 1H), 8.13 - 7.96 (m, 2H), 6.92 - 6.73 (m, 2H), 6.19 ( dd, J= 2.4, 16.5 Hz, 1H), 5.76 - 5.60 (m, 2H), 4.53 - 4.05 (m, 3H), 4.03 - 3.84 (m, 5H), 3.76 - 3.50 (m, 3H). LCMS m / z = 369.1 (M+H)+. [example]

[55] : (S)-1-(3-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy Base) azepan-1-yl) prop-2-en-1-one Synthesis of (3S)-3-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]oxyazepane-1-carboxylic acid tertiary butyl ester

[0221] Cool a vial containing tert-butyl (3S)-3-hydroxyazepane-1-carboxylate (464 mg, 2.16 mmol) in anhydrous THF (8 mL) in an ice-water bath, then dissolve tert-butyl Sodium alkoxide (314 mg, 3.27 mmol) was carefully added portionwise to the cold mixture. After 15 minutes, 4-chloro-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazine (495 mg, 2.12 mmol) was carefully added in portions to a cold in a homogeneous mixture. After the addition of 4-chloro-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazine was complete, the mixture was allowed to warm to 23 °C and monitored by LCMS. After 2.5 h, the reaction was carefully quenched by the slow addition of water. The biphasic mixture was extracted three times with ethyl acetate, followed by drying over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was loaded onto a silica gel column and purified (0-30% [3:1 ethyl acetate:ethanol] / heptane). Pooling of the desired fractions followed by concentration under reduced pressure afforded (3S)-3-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a] as a yellow film Pyrazin-4-yl]oxyxazepane-1-carboxylic acid tert-butyl ester was used without further purification. LCMS m / z = 413.2 (M+H)+. Synthesis of 4-[(3S)-azepan-3-yl]oxy-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazine

[0222] Cool in an ice-water bath to accommodate (3S)-3-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]oxynitroheterocycle A vial of tert-butyl heptane-1-carboxylate (787 mg, 1.91 mmol) in anhydrous methanol (2 mL) was followed by careful dropwise addition of HCl (1.25 M in methanol, 4 mL) to the cold mixture in. After the addition of 1.25 M HCl in methanol was complete, the mixture was allowed to warm to 23 °C and monitored by LCMS. After 6 days, the reaction was carefully concentrated under reduced pressure to afford 4-[(3S)-azepan-3-yl]oxy-6-(1-methylpyrazole- 4-yl)pyrazolo[1,5-a]pyrazine hydrochloride (672 mg, crude) was used without further purification. LCMS: m / z = 313.2 (M+H)+. Synthesis of 1-[(3S)-3-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]oxyazepane- 1-yl] prop-2-en-1-one

[0223] 4-[(3S)-azepan-3-yl]oxy-6-(1-methylpyrazol-4-yl)pyrazolo[1,5- a] To a vial of pyrazine hydrochloride (288 mg, 824 µmol) in anhydrous dichloromethane (2 mL) was carefully added Junine's base (0.7 mL, 4.02 mmol) dropwise. After 5 min, acryloyl chloride (0.15 mL, 1.85 mmol) was carefully added dropwise to the cold homogeneous solution. After the acryloyl chloride addition was complete, the reaction was allowed to warm to 23 °C and monitored by LCMS and TLC. After 3 min, the reaction was carefully quenched by the slow addition of saturated aqueous sodium bicarbonate. The biphasic mixture was loaded onto a silica gel column and purified (15-75% [3:1 ethyl acetate:ethanol] / heptane). Pooling of the desired fractions followed by concentration under reduced pressure afforded 1-[(3S)-3-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5 -a]pyrazin-4-yl]oxyazepan-1-yl]prop-2-en-1-one (73 mg, 23% yield). 1H NMR (500MHz, DMSO-d 6) d = 8.76 (d, J= 6.1 Hz, 1H), 8.29 - 8.18 (m, 1H), 8.06 - 7.99 (m, 1H), 6.88 - 6.68 (m, 2H) , 6.16 (dt, J= 2.4, 16.8 Hz, 1H), 5.74 - 5.51 (m, 2H), 4.33 (br dt, J= 5.5, 13.4 Hz, 1H), 4.01 - 3.91 (m, 1H), 3.90 - 3.64 (m, 3H), 3.64 - 3.43 (m, 2H), 2.13 - 2.00 (m, 1H), 2.00 - 1.62 (m, 4H), 1.62 - 1.37 (m, 2H). LCMS m / z = 367.1 (M+H)+. [example]

[56] : (R)-1-(3-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy Base) azepan-1-yl) prop-2-en-1-one [] Synthesis of (3R)-3-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]oxyazepane-1-carboxylic acid tertiary butyl ester

[0224] Cool a vial containing tert-butyl (3R)-3-hydroxyazepane-1-carboxylate (550 mg, 2.56 mmol) in anhydrous THF (9 mL) in an ice-water bath, then dissolve tert-butyl Sodium alkoxide (338 mg, 3.52 mmol) was carefully added to the cold mixture in portions. After 15 minutes, 4-chloro-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazine (537 mg, 2.30 mmol) was carefully added in portions to a cold in a homogeneous mixture. After the addition of 4-chloro-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazine was complete, the mixture was allowed to warm to 23 °C and monitored by LCMS. After 2 h, the reaction was carefully quenched by the slow addition of water. The biphasic mixture was extracted three times with ethyl acetate, followed by drying over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was loaded onto a silica gel column and purified (20-65% ethyl acetate / heptane). Pooling of the desired fractions followed by concentration under reduced pressure afforded (3R)-3-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a] as a yellow film Pyrazin-4-yl]oxyazepane-1-carboxylic acid tert-butyl ester (905.5 mg, 96% yield) was used without further purification. LCMS: m / z = 413.2 (M+H)+. 1H NMR (500MHz, DMSO-d 6) d = 8.79 - 8.72 (m, 1H), 8.28 - 8.18 (m, 1H), 8.11 - 7.97 (m, 2H), 6.78 (dd, J= 1.2, 18.3 Hz, 1H), 5.58 - 5.47 (m, 1H), 4.09 - 4.02 (m, 1H), 4.01 - 3.87 (m, 3H), 3.61 - 3.19 (m, 4H), 1.97 - 1.78 (m, 3H), 1.78 - 1.62 (m, 2H), 1.41 (s, 3H), 1.46 - 1.05 (m, 6H). Synthesis of 4-[(3R)-azepan-3-yl]oxy-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazine

[0225] Cool in an ice-water bath to accommodate (3R)-3-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]oxyxazepine A vial of tertiary-butyl cycloheptane-1-carboxylate (905.5 mg, 2.20 mmol) in anhydrous dichloromethane (2 mL) was then carefully added dropwise to a cold in the mixture. After the TFA addition was complete, the mixture was allowed to warm to 23 °C and monitored with LCMS. After 1 hour, the reaction was carefully concentrated under reduced pressure to afford 4-[(3R)-azepan-3-yl]oxy-6-(1-methylpyrazole as a pale yellow film -4-yl)pyrazolo[1,5-a]pyrazine (941.1 mg, 100% yield, trifluoroacetate salt), which was used without further purification. LCMS m / z = 313.1 (M+H)+. Synthesis of 1-[(3R)-3-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]oxyazepane- 1-yl] prop-2-en-1-one

[0226] At -25°C, to accommodate 4-[(3R)-azepan-3-yl]oxy-6-(1-methylpyrazol-4-yl)pyrazolo[1,5- a] To a vial of pyrazine (191 mg, 612 mmol, trifluoroacetate) in anhydrous dichloromethane (2 mL) was carefully added Junine's base (0.5 mL, 2.87 mmol) dropwise. After 5 min, acryloyl chloride (0.1 mL, 1.23 mmol) was carefully added dropwise to the cold homogeneous solution. After the acryloyl chloride addition was complete, the reaction was allowed to warm to 23 °C and monitored by LCMS and TLC. After 3 min, the reaction was carefully quenched by the slow addition of saturated aqueous sodium bicarbonate. The biphasic mixture was loaded onto a silica gel column and purified (15-75% [3:1 ethyl acetate:ethanol] / heptane). Pooling of the desired fractions followed by concentration under reduced pressure afforded 1-[(3R)-3-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5 -a]pyrazin-4-yl]oxyazepan-1-yl]prop-2-en-1-one. 1H NMR (500MHz, DMSO-d 6) d = 8.76 (d, J= 5.5 Hz, 1H), 8.29 - 8.18 (m, 1H), 8.06 - 8.01 (m, 1H), 6.88 - 6.71 (m, 2H) , 6.16 (dt, J= 2.1, 16.9 Hz, 1H), 5.74 - 5.51 (m, 2H), 4.33 (br dt, J= 5.5, 14.0 Hz, 1H), 3.99 - 3.91 (m, 1H), 3.90 - 3.68 (m, 3H), 3.59 - 3.43 (m, 2H), 2.06 (ddd, J= 4.3, 8.9, 13.7 Hz, 1H), 1.98 - 1.66 (m, 4H), 1.65 - 1.42 (m, 2H). LCMS m / z = 367.1 (M+H)+. [example]

[57] : 1-(4-((6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazine-8 -yl)oxy)azepan-1-yl)prop-2-en-1-one Synthesis of tertiary butyl 4-((6-bromo-[1,2,4]triazolo[1,5-a]pyrazin-8-yl)oxy)azepane-1-carboxylate

[0227] A vial containing tert-butyl 4-hydroxyazepane-1-carboxylate (659 mg, 3.06 mmol) in anhydrous THF (10 mL) was cooled in an ice-water bath, followed by sodium tert-butoxide (454 mg, 4.72 mmol) was carefully added to the cold mixture in portions. After 15 minutes, 6,8-dibromo-[1,2,4]triazolo[1,5-a]pyrazine (850 mg, 3.06 mmol) was carefully added portionwise to the cold heterogeneous mixture . After the addition of 6,8-dibromo-[1,2,4]triazolo[1,5-a]pyrazine was complete, the mixture was allowed to warm to 23 °C and monitored by LCMS. After 2.5 h, the reaction was carefully quenched by the slow addition of water. The biphasic mixture was extracted three times with ethyl acetate, followed by drying over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was loaded onto a silica gel column and purified (20-45% ethyl acetate / heptane). The desired fractions were pooled and then concentrated under reduced pressure to give 4-((6-bromo-[1,2,4]triazolo[1,5-a]pyrazine-8- yl)oxy)azepane-1-carboxylic acid tert-butyl ester (952.3 mg, 76% yield), which was used without further purification. LCMS: m / z = 412.0 (M+H)+. 1H NMR (500MHz, DMSO-d 6) d = 9.03 (s, 1H), 8.60 (s, 1H), 5.35 - 5.29 (m, 1H), 3.48 - 3.39 (m, 3H), 3.34 - 3.25 (m, 1H), 2.24 - 2.10 (m, 1H), 1.98 - 1.83 (m, 4H), 1.68 (br dd, J= 4.9, 9.2 Hz, 1H), 1.42 (s, 9H). Synthesis of 4-((6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-yl)oxy) Tertiary butyl azepane-1-carboxylate

[0228] Will accommodate tertiary butyl 4-((6-bromo-[1,2,4]triazolo[1,5-a]pyrazin-8-yl)oxy)azepane-1-carboxylate (952 mg, 2.31 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole ( 971 mg, 4.67 mmol), Pd(dppf)Cl 2 dichloromethane adduct (300 mg, 367 μmol) and potassium carbonate (961 mg, 6.95 mmol) were degassed and then backfilled with nitrogen. Dioxane (6 mL) and water (0.6 mL) were added to the mixture. After the water addition was complete, the reaction was heated to 90 °C and monitored with LCMS. After 2.5 h, the reaction was carefully quenched by the slow addition of water. The biphasic mixture was extracted three times with ethyl acetate, followed by drying over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was loaded onto a silica gel column and purified (25-100% ethyl acetate / heptane). Pooling of the desired fractions followed by concentration under reduced pressure gave 4-((6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4] as a viscous yellow foam Triazolo[1,5-a]pyrazin-8-yl)oxy)azepane-1-carboxylic acid tert-butyl ester (707.6 mg, 74% yield), which was used without further purification . 1H NMR (500MHz, DMSO-d 6) d = 8.97 (s, 1H), 8.55 (s, 1H), 8.25 (br d, J= 15.3 Hz, 1H), 8.04 (d, J= 9.8 Hz, 1H) , 5.52 - 5.45 (m, 1H), 3.59 - 3.42 (m, 3H), 3.41 - 3.35 (m, 1H), 3.35 - 3.25 (m, 4H), 2.26 - 2.19 (m, 1H), 2.05 - 1.85 ( m, 4H), 1.73 (br dd, J= 4.6, 8.9 Hz, 2H), 1.43 (d, J= 6.7 Hz, 7H). LCMS m / z = 414.2 (M+H)+. Synthesis of 8-(azepan-4-yloxy)-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5- a] pyrazine

[0229] Cool in an ice-water bath containing 4-((6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazine-8 -yl)oxy)azepane-1-carboxylic acid tert-butyl ester (708 mg, 1.71 mmol) in a vial of anhydrous dichloromethane (1 mL), followed by trifluoroacetic acid (1 mL, 13.1 mmol ) was carefully added dropwise to the cold mixture. After the TFA addition was complete, the mixture was allowed to warm to 23 °C and monitored with LCMS. After 1 hour, the reaction was carefully concentrated under reduced pressure to afford 8-(azepan-4-yloxy)-6-(1-methyl-1H-pyrazole- 4-yl)-[1,2,4]triazolo[1,5-a]pyrazine (301 mg, trifluoroacetate salt) was used without further purification. LCMS m / z = 314.1 (M+H)+. Synthesis of 1-(4-((6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-yl) Oxy) azepan-1-yl) prop-2-en-1-one

[0230] 8-(azepan-4-yloxy)-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]tri Azolo[1,5-a]pyrazine (301 mg, 704.5 µmol, trifluoroacetate) in anhydrous dichloromethane (2 mL) was carefully added dropwise with Junine's base (0.5 mL, 2.87 mmol). After 5 min, acryloyl chloride (0.1 mL, 1.23 mmol) was carefully added dropwise to the cold homogeneous solution. After the acryloyl chloride addition was complete, the reaction was allowed to warm to 23 °C and monitored by LCMS and TLC. After 3 min, the reaction was carefully quenched by the slow addition of saturated aqueous sodium bicarbonate. The biphasic mixture was loaded onto a silica gel column and purified (20-85% [3:1 ethyl acetate:ethanol] / heptane). Pooling of the desired fractions followed by concentration under reduced pressure afforded 1-(4-((6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4 ]triazolo[1,5-a]pyrazin-8-yl)oxy)azepan-1-yl)prop-2-en-1-one (96 mg, 35% yield). 1H NMR (500MHz, DMSO-d 6) d = 8.97 (s, 1H), 8.55 (d, J= 1.2 Hz, 1H), 8.28 - 8.21 (m, 1H), 8.04 (d, J= 7.3 Hz, 1H ), 6.82 (ddd, J= 10.4, 12.2, 16.5 Hz, 1H), 6.18 (td, J= 2.2, 16.9 Hz, 1H), 5.70 (dd, J= 2.4, 10.4 Hz, 1H), 5.53 - 5.44 ( m, 1H), 3.90 (d, J= 1.8 Hz, 3H), 3.88 - 3.61 (m, 3H), 3.59 - 3.49 (m, 2H), 2.31 - 2.21 (m, 1H), 2.06 - 1.97 (m, 3H), 1.83 - 1.71 (m, 1H). LCMS m / z = 368.1 (M+H)+. [example]

[58] : (R)-1-(6-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy Base)-1,4-oxazepan-4-yl)prop-2-en-1-one Synthesis of (6R)-6-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]oxy-1,4-oxazacycle Heptane-4-carboxylate tertiary butyl ester

[0231] Cool a flask containing tert-butyl (6R)-6-hydroxy-1,4-oxazepane-4-carboxylate (496 mg, 2.28 mmol) in anhydrous THF (4 mL) in an ice-water bath , then sodium tert-butoxide (308 mg, 3.20 mmol) was carefully added portionwise to the cold mixture. After 10 min, 4-chloro-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazine (465 mg, 1.99 mmol) was carefully added in portions to a cold in a homogeneous mixture. After the addition of 4-chloro-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazine was complete, the mixture was allowed to warm to 23 °C and monitored by LCMS. After 2 h, the reaction was carefully quenched by the slow addition of water, followed by extraction of the biphasic mixture three times with ethyl acetate. The organics were pooled and then dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was loaded onto a silica gel column and purified (30-100% ethyl acetate / heptane). Pooling of the desired fractions followed by concentration under reduced pressure afforded (6R)-6-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a] as a white solid Pyrazin-4-yl]oxy-1,4-oxazepane-4-carboxylic acid tert-butyl ester (757.9 mg, 92% yield) was used without further purification. 1H NMR (500MHz, DMSO-d 6) d = 8.77 (s, 1H), 8.27 - 8.19 (m, 1H), 8.08 - 7.95 (m, 2H), 6.82 - 6.76 (m, 1H), 5.58 (br d , J= 3.7 Hz, 1H), 4.14 - 3.92 (m, 3H), 3.88 (s, 3H), 3.85 - 3.80 (m, 1H), 3.79 - 3.57 (m, 3H), 3.45 - 3.37 (m, 1H ), 1.46 - 1.04 (m, 9H). LCMS m / z = 415.1 (M+H)+. Synthesis of (6R)-6-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]oxy-1,4-oxazacycle Heptane

[0232] Cool in an ice-water bath containing (6R)-6-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]oxyl-1, 4-Oxazepane-4-carboxylic acid tert-butyl ester (758 mg, 1.83 mmol) in a vial of anhydrous dichloromethane (2 mL), followed by trifluoroacetic acid (2 mL, 26.1 mmol) carefully Add dropwise to the cold mixture. After the TFA addition was complete, the mixture was allowed to warm to 23 °C and monitored with LCMS. After 18 hours, the reaction was carefully concentrated under reduced pressure to afford (6R)-6-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5- a] Pyrazin-4-yl]oxy-1,4-oxazepane (783.3 mg, crude, trifluoroacetate salt), which was used without further purification. LCMS m / z = 315.0 (M+H)+. Synthesis of 1-[(6R)-6-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]oxy-1,4-oxo Azepan-4-yl]prop-2-en-1-one

[0233] At -25°C, to accommodate (6R)-6-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]oxyl-1 , 4-Oxazepane (253 mg, 591 µmol, trifluoroacetate) in a vial of anhydrous dichloromethane (2 mL) was carefully added dropwise with Junine's base (0.5 mL, 2.87 mmol) . After 5 min, acryloyl chloride (0.1 mL, 1.23 mmol) was carefully added dropwise to the cold homogeneous solution. After the acryloyl chloride addition was complete, the reaction was allowed to warm to 23 °C and monitored by LCMS and TLC. After 3 min, the reaction was carefully quenched by the slow addition of saturated aqueous sodium bicarbonate. The biphasic mixture was loaded onto a silica gel column and purified (15-100% [3:1 ethyl acetate:ethanol] / heptane). Pooling of the desired fractions followed by concentration under reduced pressure afforded 1-[(6R)-6-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5 -a]pyrazin-4-yl]oxy-1,4-oxazepan-4-yl]prop-2-en-1-one. LCMS: m / z = 369.1 (M+H)+. 1H NMR (500MHz, DMSO-d 6) d = 8.80 - 8.73 (m, 1H), 8.28 - 8.19 (m, 1H), 8.13 - 7.99 (m, 2H), 6.92 - 6.73 (m, 2H), 6.19 ( dd, J= 2.1, 16.8 Hz, 1H), 5.90 - 5.59 (m, 3H), 4.56 - 4.42 (m, 1H), 4.18 - 4.09 (m, 1H), 4.03 - 3.92 (m, 2H), 3.90 - 3.84 (m, 3H), 3.78 - 3.54 (m, 3H). [example]

[59] : (R)-4-((1-acrylazepan-4-yl)oxy)-6-(1-methyl-1H-pyrazol-4-yl)pyrazole And[1,5-a]pyrazine-3-carbonitrile Synthesis of 4-chloro-3-iodo-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazine

[0234] Cool anhydrous DMF (5 mL ), then N-iodobutimide (1.23 g, 5.48 mmol) was carefully added portionwise to the cold mixture. After 15 minutes, the cloudy yellow mixture was carefully heated to 50 °C and monitored by LCMS. After 2 hours, the reaction was cooled to 23 °C and stirred overnight. After 19 hours, the heterogeneous mixture was filtered. The off-white solid was identified as 4-chloro-3-iodo-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazine and used without purification. 1H NMR (500MHz, DMSO-d 6) δ = 9.29 (s, 1H), 8.31 (s, 1H), 8.27 (s, 1H), 8.06 - 8.00 (m, 1H), 3.95 - 3.84 (m, 3H) . LCMS m / z = 359.9 (M+H)+. Synthesis of (4R)-4-[3-iodo-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]oxyazepane -1- Tertiary butyl formate

[0235] Cool a vial containing tert-butyl (4R)-4-hydroxyazepane-1-carboxylate (113 mg, 525 μmol) in anhydrous THF (2 mL) in an ice-water bath, then dissolve tert-butyl Sodium alkoxide (79.5 mg, 827 μmol) was carefully added portionwise to the cold mixture. After 10 min, 4-chloro-3-iodo-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazine (181 mg, 504 μmol) was carefully portioned Add to cold heterogeneous mixture. After the addition of 4-chloro-3-iodo-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazine was complete, the mixture was allowed to warm to 23 °C and monitored by LCMS. After 18 h, the heterogeneous reaction was carefully concentrated under reduced pressure. The residue was diluted with ethyl acetate, followed by washing with saturated aqueous sodium chloride. The organic layer was dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was loaded onto a silica gel column and purified (20-65% ethyl acetate / heptane). Pooling of the desired fractions followed by concentration under reduced pressure afforded (4R)-4-[3-iodo-6-(1-methylpyrazol-4-yl)pyrazolo as a colorless viscous film. [1,5-a]pyrazin-4-yl]oxyazepane-1-carboxylic acid tert-butyl ester (99.3 mg, 36% yield) was used without further purification. 1H NMR (400MHz, DMSO-d 6) δ = 8.78 (s, 1H), 8.19 (d, J= 6.0 Hz, 1H), 8.09 (s, 1H), 7.99 (d, J= 2.5 Hz, 1H), 5.59 (br s, 1H), 3.88 (s, 3H), 3.72 - 3.38 (m, 4H), 2.09 - 1.97 (m, 3H), 1.83 - 1.71 (m, 2H), 1.55 - 1.46 (m, 1H) , 1.42 (d, J= 5.0 Hz, 9H). LCMS m / z = 539.0 (M+H)+. Synthesis of (4R)-4-[3-cyano-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]oxyazepane tertiary butyl alkane-1-carboxylate

[0236] Will accommodate (4R)-4-[3-iodo-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]oxy nitrogen heterocycle Heptane-1-carboxylic acid tertiary butyl ester (106 mg , 196 μmol), potassium hexacyanoferrate (II) trihydrate (44 mg, 104 μmol), dicyclohexyl-[2-(2,4, 6-triisopropylphenyl)phenyl]phosphine (Xphos) (10 mg, 21 μmol), [2-(2-aminophenyl)phenyl]-methylsulfonyloxy-palladium; bicyclic Dioxane (1 mL) and water (1 mL) were degassed and backfilled with nitrogen. (Evacuation and nitrogen backfill were repeated three times.) The heterogeneous white reaction mixture was carefully heated to 90 °C and monitored by LCMS. After 18 hours, the heterogeneous reaction was cooled to room temperature, then carefully partitioned between water and ethyl acetate. The aqueous layer was extracted two more times with ethyl acetate. The organic extracts were pooled, washed once with saturated aqueous sodium chloride, and the organic layer was dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was loaded onto a silica gel column and purified (25-80% ethyl acetate / heptane). Pooling of the desired fractions followed by concentration under reduced pressure afforded (4R)-4-[3-cyano-6-(1-methylpyrazol-4-yl)pyrazole as a colorless viscous film Tert-butyl[1,5-a]pyrazin-4-yl]oxyazepane-1-carboxylate (10.2 mg, 12% yield) was used without further purification. LCMS m / z = 460.1 (M+Na)+. Synthesis of 4-[(4R)-azepan-4-yl]oxy-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazine-3- Formaldehyde

[0237] Cool in an ice-water bath to contain (4R)-4-[3-cyano-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl] A vial of tert-butyl oxyazepane-1-carboxylate (10 mg, 23 μmol) in anhydrous dichloromethane (0.5 mL) was followed by careful dropwise addition of TFA (0.05 mL, 653 μmol) into the cold mixture. After the TFA addition was complete, the mixture was allowed to warm to 23 °C and monitored with LCMS. After 15 minutes, the reaction was carefully concentrated under reduced pressure to afford 4-[(4R)-azepan-4-yl]oxy-6-(1-methylpyrazole) as a pale yellow film -4-yl)pyrazolo[1,5-a]pyrazine-3-carbonitrile (11 mg, trifluoroacetate salt), which was used without purification. LCMS m / z = 338.1 (M+H)+. Synthesis of 6-(1-methylpyrazol-4-yl)-4-[(4R)-1-prop-2-enylazepan-4-yl]oxy-pyrazolo[1 ,5-a]pyrazine-3-carbonitrile

[0238] At -25°C, to accommodate 4-[(4R)-azepan-4-yl]oxy-6-(1-methylpyrazol-4-yl)pyrazolo[1,5- a] To a vial of pyrazine-3-carbonitrile (11 mg, 24.4 μmol, trifluoroacetate salt) in anhydrous THF (0.5 mL) was carefully added Junine's base (0.1 mL, 574 μmol) dropwise. After 5 min, acryloyl chloride (0.01 mL, 123 μmol) was carefully added dropwise to the cold homogeneous solution. After the acryloyl chloride addition was complete, the reaction was allowed to warm to 23 °C and monitored by LCMS and TLC. After 3 min, the reaction was carefully quenched by the slow addition of saturated aqueous sodium bicarbonate. The biphasic mixture was loaded onto a silica gel column and purified (25-85% [3:1 ethyl acetate:ethanol] / heptane). Pooling of the desired fractions followed by concentration under reduced pressure afforded 6-(1-methylpyrazol-4-yl)-4-[(4R)-1-prop-2-enyl as a colorless film ylazepan-4-yl]oxy-pyrazolo[1,5-a]pyrazine-3-carbonitrile. 1H NMR (400MHz, dichloromethane-d 2 ) δ = 8.30 - 8.16 (m, 2H), 7.96 - 7.89 (m, 1H), 7.88 - 7.87 (m, 1H), 6.75 - 6.61 (m, 1H), 6.33 - 6.25 (m, 1H), 5.71 - 5.64 (m, 2H), 4.16 - 3.95 (m, 4H), 3.86 - 3.54 (m, 3H), 3.49 - 3.34 (m, 1H), 2.35 - 2.13 (m , 4H), 1.96 (br d, J= 11.5 Hz, 1H). LCMS m / z = 392.1 (M+H)+. [example]

[60] : N-methyl-N-((trans)-3-((3-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5- a] pyrazin-4-yl) oxy) cyclobutyl) acrylamide Synthesis of ((trans)-3-((3-iodo-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy ) cyclobutyl) (methyl) tertiary butyl carbamate

[0239] Cool anhydrous THF (6 mL) containing racemic trans-N-(3-hydroxycyclobutyl)-N-methyl-carbamic acid tertiary-butyl ester (406 mg, 2.0 mmol) in an ice-water bath Then sodium tert-butoxide (333 mg, 3.47 mmol) was carefully added to the cold mixture in portions. After 10 minutes, 4-chloro-3-iodo-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazine (593 mg, 1.65 mmol) was carefully added to in cold mixture. After the addition of 4-chloro-3-iodo-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazine was complete, the mixture was allowed to warm to 23 °C. After 1 h, the reaction was carefully quenched by the slow addition of saturated aqueous sodium bicarbonate, and the biphasic mixture was extracted three times with ethyl acetate. The organics were pooled and then dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was loaded onto a silica gel column and purified (15-70% ethyl acetate / heptane). Pooling of the desired fractions followed by concentration under reduced pressure afforded ((trans)-3-((3-iodo-6-(1-methyl-1H-pyrazol-4-yl)pyridine as a white solid Azolo[1,5-a]pyrazin-4-yl)oxy)cyclobutyl)(methyl)carbamate (698.5 mg, crude) was used without further purification. 1H NMR (500MHz, DMSO-d 6) δ= 8.79 (s, 1H), 8.16 (s, 1H), 8.11 (s, 1H), 7.98 (s, 1H), 5.45 (br t, J= 6.7 Hz, 1H), 4.89 (br s, 1H), 3.88 (s, 3H), 2.89 - 2.84 (m, 3H), 2.79 - 2.72 (m, 2H), 2.48 - 2.42 (m, 2H), 1.41 (s, 9H ). LCMS: m / z = 525.0 (M+H)+. Synthesis of methyl((trans)-3-((3-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl ) oxy) cyclobutyl) tertiary butyl carbamate

[0240] Will contain ((trans)-3-((3-iodo-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl) Oxy)cyclobutyl)(methyl)carbamate tert-butyl ester (204 mg, 389 μmol), methylboronic acid (81 mg, 1.35 mmol), tricyclohexylphosphine (29 mg, 105 μmol), Pd 2(dba) 3 (36 mg, 39 μmol), Pd(dppf)Cl 2 CH 2Cl 2 (68 mg, 84 μmol) and tripotassium phosphate (1.0 M solution, 1.2 mL) in dioxane (4 mL) The vial was degassed and backfilled with nitrogen. Repeat vacuuming and nitrogen backfilling three times. The heterogeneous reaction mixture was carefully heated to 90 °C. After 18 hours, the heterogeneous reaction was cooled to room temperature, then carefully partitioned between water and ethyl acetate. The aqueous layer was extracted two more times with ethyl acetate. The organic extracts were pooled, washed once with saturated aqueous sodium chloride, and the organic layer was dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was loaded onto a silica gel column and purified (30-90% ethyl acetate / heptane). Pooling of the desired fractions followed by concentration under reduced pressure afforded methyl((trans)-3-((3-methyl-6-(1-methyl-1H-pyrazole-4) as a dark yellow film -yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)cyclobutyl)carbamate (125.7 mg, 78% yield), which was obtained without further purification use. LCMS m / z = 413.2 (M+H)+. Synthesis of (trans)-N-methyl-3-((3-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-4 - yl) oxy) cyclobutan-1-amine

[0241] Cool in an ice-water bath to contain methyl ((trans)-3-((3-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a] Pyrazin-4-yl)oxy)cyclobutyl)carbamate (125.7 mg, 305 μmol) in a vial of anhydrous dichloromethane (2 mL), followed by trifluoroacetic acid (0.23 mL, 3 mmol) was carefully added dropwise to the cold mixture. After the TFA addition was complete, the mixture was allowed to warm to 23 °C. After 1.5 hours, the reaction was carefully concentrated under reduced pressure to afford (trans)-N-methyl-3-((3-methyl-6-(1-methyl-1H-pyridine) as a light yellow film. Azol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)cyclobutan-1-amine trifluoroacetate (133.9 mg, crude) was used without purification . LCMS m / z = 313.1 (M+H)+. Synthesis of N-methyl-N-((trans)-3-((3-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine (oxazin-4-yl)oxy)cyclobutyl)acrylamide

[0242] At -25°C, the solution containing (trans)-N-methyl-3-((3-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5 -a] To a vial of anhydrous THF (3 mL) of pyrazin-4-yl)oxy)cyclobutan-1-amine trifluoroacetate (133.9 mg, 314 μmol) was carefully added Junine's base dropwise (1 mL, 5.74 mmol). After 5 min, acryloyl chloride (0.05 mL, 615 μmol) was carefully added dropwise to the cold homogeneous solution. After the acryloyl chloride addition was complete, the reaction was allowed to warm to 23 °C and monitored by LCMS and TLC. After 3 min, the reaction was carefully quenched by the slow addition of saturated aqueous sodium bicarbonate. The mixture was stirred at 23 °C for 1 h, then the biphasic mixture was extracted three times with ethyl acetate. The organics were pooled and washed once with saturated aqueous sodium bicarbonate. The organic layer was separated, followed by drying over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was loaded onto a silica gel column and purified (15-65% [3:1 ethyl acetate:ethanol] / heptane). The desired fractions were pooled and concentrated under reduced pressure to give a white foam which was diluted with DMSO and filtered. The homogeneous mixture was purified by reverse phase mass directional HPLC purification. (Using Waters XSelect CSH C18, 5 μm, 19 mm × 100 mm column, mobile phase H 2O (A) and MeCN (B) and gradient 5 - 60% B (0.2% NH 4OH final v / v % modifier ) at a flow rate of 30 mL / min for liquid chromatography.) Fractions containing the desired product were pooled and then concentrated to obtain N-methyl-N-((trans)-3-(( 3-Methyl-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)cyclobutyl)-acrylamide . 1H NMR (500MHz, DMSO-d 6) δ = 8.62 (s, 1H), 8.14 (s, 1H), 7.97 (s, 1H), 7.84 (s, 1H), 6.76 (br dd, J= 11.0, 16.5 Hz, 1H), 6.09 (br s, 1H), 5.68 (br s, 1H), 5.49 (br s, 1H), 5.35 - 4.90 (m, 1H), 3.88 (s, 3H), 3.15 - 2.77 (m , 5H), 2.67 - 2.52 (m, 2H), 2.47 (s, 3H). LCMS m / z = 367.2 (M+H)+. [example]

[61] : 1-[(4R)-4-[3-fluoro-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]oxy ylazepan-1-yl]prop-2-en-1-one Synthesis of (4R)-4-[3-fluoro-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]oxyazepane -1- Tertiary butyl formate

[0243] (4R)-4-[3-iodo-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]oxyazepane - A solution of tert-butyl 1 -carboxylate (224 mg, 416 μmol) in THF (3 mL) was cooled to -78°C, and butyllithium (2.5 M, 200 μL) was added and stirred for 20 minutes. Then N-fluorobenzenesulfonimide (157 mg, 499 μmol) in THF was added and the reaction mixture was stirred for 1 hour. Aqueous NH 4 Cl solution was added to quench the reaction. The reaction was diluted with EtOAc, the layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na 2 SO 4 and the concentrated residue was purified (SiO 2 , 0-70% EtOAc / DCM) to give (4R)-4-[3-fluoro-6-(1 -Methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]oxyazepane-1-carboxylic acid tert-butyl ester (25.3 mg, 14% yield ). LCMS: Rt = 0.93 min, m / z 431.2. 1H NMR (400 MHz, chloroform-d) δ 7.99 (d, J= 1.51 Hz, 1H), 7.83 (s, 1H), 7.74-7.83 (m, 1H), 7.70 (d, J= 3.76 Hz, 1H) , 5.52-5.61 (m, 1H), 3.97 (s, 3H), 3.51-3.82 (m, 2H), 3.25-3.48 (m, 2H), 2.07-2.17 (m, 3H), 1.98 (br d, J = 12.05 Hz, 2H), 1.78 (br d, J= 5.02 Hz, 1H), 1.49 (s, 9H). 19F NMR (376 MHz, chloroform-d) δ -174.27 (s, 1F). Synthesis of 4-[(4R)-azepan-4-yl]oxy-3-fluoro-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyridine Zinc

[0244] To (4R)-4-[3-fluoro-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]oxyazepane - To a solution of tert-butyl 1-carboxylate (25 mg, 59 μmol) in DCM (1 mL) was added TFA (1.49 g, 13.1 mmol, 1 mL) and stirred at room temperature for 1 hour. After concentration, the crude residue 4-[(4R)-azepan-4-yl]oxy-3-fluoro-6-(1-methylpyrazol-4-yl)pyrazolo[1 ,5-a]pyrazine was used as such in the next step. LCMS: Rt = 0.63 min, m / z 183.2. Synthesis of 1-[(4R)-4-[3-fluoro-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]oxyazepine Cycloheptan-1-yl]prop-2-en-1-one

[0245] To 4-[(4R)-azepan-4-yl]oxy-3-fluoro-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyridine To a solution of oxazine (48 mg, 146 μmol) in DCM (4 mL) was added TEA (30 mg, 292 μmol, 41 μL) and the reaction was stirred for 5 minutes. After cooling to 0 °C, acryloyl chloride (16 mg, 175 μmol, 14 μL) was added and stirred for 3 minutes. The reaction was quenched with saturated aqueous NaHCO 3 and extracted with DCM. The organic layer was dried over Na2SO4 and the concentrated residue was chromatographed on silica gel (EtOAc / MeOH 0-30%) to give 1-[(4R)-4-[3-fluoro-6-(1- Methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]oxyazepan-1-yl]prop-2-en-1-one (12.6 mg , 21% yield, 95% purity). LCMS: Rt = 0.70 min, m / z 385.0. 1H NMR (400 MHz, chloroform-d) δ 8.01 (d, J= 1.51 Hz, 1H), 7.85 (br s, 1H), 7.76 (s, 1H), 7.71 (d, J= 3.76 Hz, 1H), 6.58-6.68 (m, 1H), 6.35-6.44 (m, 1H), 5.73 (br d, J= 10.54 Hz, 1H), 5.62 (br s, 1H), 3.99 (br d, J= 2.51 Hz, 3H ), 3.79 (br dd, J= 6.78, 13.55 Hz, 1H), 3.62-3.73 (m, 1H), 3.52-3.61 (m, 1H), 3.41-3.51 (m, 1H), 2.16-2.29 (m, 4H), 1.74-2.00 (m, 2H). 19F NMR (376 MHz, chloroform-d) δ -174.12 (br d, J= 58.58 Hz, 1F). [example]

[62] : 1-[(4R)-4-[6-(1-methylpyrazol-4-yl)-3-(trifluoromethyl)pyrazolo[1,5-a]pyrazine- 4-yl]oxyazepan-1-yl]prop-2-en-1-one Synthesis of (4R)-4-[6-(1-methylpyrazol-4-yl)-3-(trifluoromethyl)pyrazolo[1,5-a]pyrazin-4-yl]oxy Tertiary butyl azepane-1-carboxylate

[0246] To (4R)-4-[3-iodo-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]oxyazepane - Add fluorosulfonyl difluoroacetic acid to a solution of tertiary butyl 1-carboxylate (125 mg, 232 μmol) in DMF (1 mL) and hexamethylphosphoramide (42 mg, 232 μmol, 40 μL) Methyl ester (223 mg, 1.16 mmol, 148 μL) and copper(I) iodide (66 mg, 348 μmol) were degassed. The mixture was heated at 80 °C overnight. The cooled mixture was diluted with EtOAc, washed with aqueous NH 4 Cl and filtered through celite and dried over Na 2 SO 4 . Chromatography of the concentrated residue on silica gel (heptane / EtOAc 0-70%) afforded (4R)-4-[6-(1-methylpyrazol-4-yl)-3-(tri Fluoromethyl)pyrazolo[1,5-a]pyrazin-4-yl]oxyazepane-1-carboxylic acid tert-butyl ester (18 mg, 15% yield, 95% purity). LCMS: Rt = 1.03 min, m / z 481.2.381.2. Synthesis of 4-[(4R)-azepan-4-yl]oxy-6-(1-methylpyrazol-4-yl)-3-(trifluoromethyl)pyrazolo[1, 5-a] pyrazine

[0247] To (4R)-4-[6-(1-methylpyrazol-4-yl)-3-(trifluoromethyl)pyrazolo[1,5-a]pyrazin-4-yl]oxy To a solution of tert-butyl azepane-1-carboxylate (18 mg, 37 μmol) in DCM (1 mL) was added TFA (1.49 g, 13.1 mmol, 1 mL) and the reaction mixture was stirred at room temperature 1 Hour. Concentration of the crude material afforded 4-[(4R)-azepan-4-yl]oxy-6-(1-methylpyrazol-4-yl)-3-(trifluoro Methyl)pyrazolo[1,5-a]pyrazine (19.0 mg, crude, trifluoroacetic acid) and used as such in the next step. LCMS: Rt = 0.64 min, m / z 381.2. Synthesis of 1-[(4R)-4-[6-(1-methylpyrazol-4-yl)-3-(trifluoromethyl)pyrazolo[1,5-a]pyrazin-4-yl ] oxyazepan-1-yl] prop-2-en-1-one

[0248] To 4-[(4R)-azepan-4-yl]oxy-6-(1-methylpyrazol-4-yl)-3-(trifluoromethyl)-pyrazolo[1 ,5-a] To a solution of pyrazine (19 mg, 38 μmol, trifluoroacetic acid) in DCM (2 mL) was added TEA (7.8 mg, 77 μmol, 11 μL) and the reaction mixture was stirred for 5 min. After cooling to 0 °C, acryloyl chloride (4.2 mg, 46 μmol, 3.8 μL) was added and the reaction mixture was stirred for 3 minutes. The reaction was quenched with saturated aqueous NaHCO 3 and extracted with DCM. The organic layer was dried over Na2SO4 and the concentrated residue was chromatographed on silica gel (EtOAc / MeOH 0-30%) to give 1-[(4R)-4-[6-(1-methylpyrazole -4-yl)-3-(trifluoromethyl)pyrazolo[1,5-a]pyrazin-4-yl]oxyazepan-1-yl]prop-2-ene-1 - Ketone (9 mg, 51% yield, 95% purity). LCMS: Rt = 0.80 min, m / z 457.1 [M+Na]+. 1H NMR (400 MHz, chloroform-d) δ 8.24 (s, 1H), 8.11 (s, 1H), 7.88 (s, 1H), 7.78-7.87 (m, 1H), 6.58-6.70 (m, 1H), 6.39 (br t, J= 15.18 Hz, 1H), 5.73 (br d, J= 10.54 Hz, 1H), 5.67 (br s, 1H), 4.11-4.22 (m, 1H), 4.00 (s, 3H), 3.73-3.83 (m, 1H), 3.52-3.70 (m, 1H), 3.37 (br dd, J= 5.52, 14.31 Hz, 1H), 2.18-2.38 (m, 4H), 1.86-1.95 (m, 2H) . 19F NMR (376 MHz, chloroform-d) d -54.80 (d, J= 5.45 Hz, 3F). [example]

[63] : N-((cis)-3-((3-fluoro-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-4 -yl)oxy)cyclobutyl)-N-methacrylamide Synthesis of ((cis)-3-((3-iodo-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy ) cyclobutyl) (methyl) tertiary butyl carbamate

[0249] A vial containing tert-butyl ((cis)-3-hydroxycyclobutyl)(methyl)carbamate (175 mg, 868 μmol) in anhydrous THF (10 mL) was cooled in an ice-water bath, followed by Sodium tert-butoxide (132 mg, 1.37 mmol) was carefully added to the cold mixture in portions. After 10 min, 4-chloro-3-iodo-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazine (300 mg, 834 μmol) was carefully portioned Add to cold heterogeneous mixture. After the addition of 4-chloro-3-iodo-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazine was complete, the mixture was allowed to warm to 23 °C and monitored by LCMS. After 18 hours, the residue was diluted with ethyl acetate and filtered through celite. The concentrated residue was loaded onto a silica gel column and purified (20-65% ethyl acetate / heptane) to give ((cis)-3-((3-iodo-6-(1-methyl-1H- Pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)cyclobutyl)(methyl)carbamate (252 mg, 58% yield ). LCMS: Rt = 1.00 min, m / z 525.2. Synthesis of ((cis)-3-((3-fluoro-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy ) cyclobutyl) (methyl) tertiary butyl carbamate

[0250] ((cis)-3-((3-iodo-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy A solution of tert-butyl (cyclobutyl)(methyl)carbamate (292 mg, 557 μmol) in THF (3 mL) was cooled to −78° C., and butyllithium (2.5 M, 267.30 μL) was added And the reaction mixture was stirred for 20 minutes. Then N-fluorobenzenesulfonimide (211 mg, 668 μmol) in THF (1 mL) was added and the reaction mixture was continued to stir for 1 h. Aqueous NH 4 Cl solution was added to quench the reaction. The reaction was diluted with EtOAc, the layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over NaSO and the concentrated residue was purified (FCC, SiO, 0-70% EtOAc / DCM) to afford ((cis)-3-((3-fluoro- 6-(1-Methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)cyclobutyl)(methyl)-carbamic acid tris Butyl ester (75.5 mg, 33% yield). LCMS, Rt = 0.92 min, m / z 439.2, 317.1. 19F NMR (376 MHz, chloroform-d) δ -174.02 (br s, 1F). Synthesis of (cis)-3-((3-fluoro-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy) -N-Methylcyclobutan-1-amine

[0251] To ((cis)-3-((3-fluoro-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy To a solution of tert-butyl (cyclobutyl)(methyl)carbamate (76 mg, 181 μmol) in DCM (1 mL) was added TFA (1.49 g, 13.1 mmol, 1 mL) and stirred at room temperature The reaction mixture was allowed to react for 1 hour. Concentration of the crude material afforded (cis)-3-((3-fluoro-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine as a residue Oxyzin-4-yl)oxy)-N-methylcyclobutan-1-amine (166 mg, crude, trifluoroacetic acid) and used as such in the next step. LCMS: Rt = 0.57 min, m / z 317.1. Synthesis of N-((cis)-3-((3-fluoro-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl) Oxy)cyclobutyl)-N-methacrylamide

[0252] To (cis)-3-((3-fluoro-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy) - To a solution of N-methylcyclobutan-1-amine (166 mg, 386 μmol, trifluoroacetic acid) in DCM (5 mL) was added TEA (78 mg, 771 μmol, 108 μL) and the reaction mixture was stirred for 5 min . After cooling to 0 °C, acryloyl chloride (42 mg, 463 μmol, 38 μL) was added and stirring was continued for 3 minutes. The reaction was quenched with saturated aqueous NaHCO 3 and extracted with DCM. The organic layer was dried over Na2SO4 and the concentrated residue was chromatographed on silica gel (EtOAc / MeOH 0-30%) to give a residue which was further purified by preparative HPLC (10-90% H2O / ACN) , to give N-((cis)-3-((3-fluoro-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl )oxy)cyclobutyl)-N-methacrylamide (30.1 mg, 15% yield, 95% purity, trifluoroacetic acid). LCMS: Rt = 0.70 min, m / z 371.2 [M+H]+, 393.2 [M+Na]+. 1H NMR (400 MHz, chloroform-d) δ 8.06 (d, J= 1.76 Hz, 1H), 7.91 (br s, 1H), 7.84 (br s, 1H), 7.75 (br d, J= 3.51 Hz, 1H ), 6.58 (br d, J= 10.92, 16.69 Hz, 1H), 6.35 (br d, J= 19.07 Hz, 1H), 5.79 (br d, J= 10.79 Hz, 1H), 5.17-5.25 (m, 1H ), 4.82 (br s, 1H), 4.03 (s, 3H), 3.11 (br s, 3H), 3.00 (br s, 2H), 2.59 (br s, 1H), 2.43 (br s, 1H). 19F NMR (376 MHz, chloroform-d) δ -75.97 (s, 3F), -173.35 (br s, 1F). [example]

[64] : N-((trans)-3-((3-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,4-a ]pyrazin-4-yl)oxy)cyclobutyl-N-methacrylamide Synthesis of methyl((trans)-3-((6-(1-methyl-1H-pyrazol-4-yl)-3-vinylpyrazolo[1,5-a]pyrazin-4-yl ) oxy) cyclobutyl) tertiary butyl carbamate

[0253] Charge a microwave vial with ((trans)-3-((3-iodo-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-4 -yl)oxy)cyclobutyl)(methyl)carbamate tertiary butyl ester (135 mg, 257 μmol), 4,4,5,5-tetramethyl-2-vinyl-1,3, 2-dioxaborolane (79 mg, 515 μmol, 87 μL), di-tertiary butyl (cyclopentyl) phosphine; dichloropalladium; iron (34 mg, 51 μmol) and potassium carbonate ( 100 mg, 721 μmol) and placed under N 2 . The vial was capped and dioxane (1.2 mL) and water (0.3 mL) were added via syringe, and the red mixture was again placed under N 2 (2 cycles). After stirring at room temperature for 5 minutes, the mixture was heated to 90 °C and stirred at that temperature for 5 hours. After cooling to room temperature, the mixture was diluted with EtOAc and filtered. The filtrate was evaporated in vacuo and the residue was purified on 10 g Si-SPE: Rf = 0.27 in heptane / EtOAc = 5 / 1 to give methyl ((trans)-3-((6- (1-Methyl-1H-pyrazol-4-yl)-3-vinylpyrazolo[1,5-a]pyrazin-4-yl)oxy)cyclobutyl)carbamate Ester (110 mg, 91% yield, 90% purity). Synthesis of ((trans)-3-((3-formyl-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl) Oxy)cyclobutyl)(methyl)carbamate tertiary butyl ester

[0254] Charge the vial with methyl((trans)-3-((6-(1-methyl-1H-pyrazol-4-yl)-3-vinylpyrazolo[1,5-a]pyrazine -4-yl)oxy)cyclobutyl)carbamate (110 mg, 259 μmol) and water (0.5 mL) and THF (1.5 mL) and cooled in an ice bath. Next, osmium tetroxide (132 mg, 26 μmol, 5% purity; resin-bound) and 4-methyl-4-oxionyl-morpholin-4-ium (30 mg, 259 μmol) were added and the Stirring was continued for 1 hour. Next, sodium (meta)periodate (111 mg, 518 μmol) was added and stirring was continued in a water bath while the reaction mixture was warmed to room temperature overnight. Then saturated Na2S2O3 was added, followed by DCM. The mixture was filtered and the organic phase was separated, dried and evaporated in vacuo to give a dark green sticky gum. This material was carried forward without further purification. ESI-MS (M+Na)+: 449.4. Synthesis of ((trans)-3-((3-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-4 - yl) oxy) cyclobutyl) (methyl) tertiary butyl carbamate

[0255] Fill the vial with ((trans)-3-((3-formyl-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine- 4-yl)oxy)cyclobutyl)(methyl)carbamate (90 mg, 211 μmol) and DCM (2 mL) were placed under N2 and cooled in an ice bath. Next, N-ethyl-N-(trifluoro-sulfanyl)ethylamine (68 mg, 422 μmol, 56 μL) was added dropwise with stirring. Stirring was continued overnight, during which time the mixture was gradually warmed to room temperature. The mixture was diluted with DCM and silica gel was added. The volatiles were evaporated in vacuo and the residue was purified on 5 g Si-SPE: Rf = 0.5 in EtOAc to give ((trans)-3-((3-(difluoromethyl) as a light yellow viscous gum )-6-(1-Methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)cyclobutyl)(methyl)carbamate Tertiary butyl ester (45 mg, 43% yield, 90% purity). ESI-MS (M+H)+: 449.5. Synthesis of (trans)-3-((3-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-4- base) oxy)-N-methylcyclobutan-1-amine

[0256] To ((trans)-3-((3-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5- a] A solution of pyrazin-4-yl)oxy)cyclobutyl)(methyl)carbamate (40 mg, 89 μmol) in DCM (2 mL) was added with TFA (102 mg, 892 μmol, 68 μL). After stirring overnight, the mixture was diluted with MeOH and purified on a 2 g SCX column, where the product was eluted with 2 M NH 3-MeOH to give (trans)-3-((3- (Difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)-N-methylcyclo Butan-1-amine (28 mg, 81% yield, 90% purity). Synthesis of N-((trans)-3-((3-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine -4-yl)oxy)cyclobutyl)-N-methacrylamide

[0257] Charge the vial with (trans)-3-((3-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine (oxazin-4-yl)oxy)-N-methylcyclobutan-1-amine (28 mg, 80 μmol) and THF (1 mL). Next, acryloyl chloride (7.2 mg, 80 μmol) was added and precipitation occurred immediately. Next, TEA (12 mg, 121 μmol, 17 μL) was added and stirring was continued for 1 hour at room temperature. Volatiles were evaporated under vacuum and run on basic preparative HPLC (Waters XSelect CSH C18, 5 μm, 30 mm × 50 mm column, mobile phase H 2 O (A) and MeCN (B) and gradient 5 - 60% B ( 0.2% NH 4OH final v / v % modifier), flow rate 60 mL / min) to obtain N-((trans)-3-(( 3-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)cyclobutyl) -N-Methacrylamide (6.8 mg, 19% yield, 90% purity). ESI-MS (M+H)+: 403.4. 1H NMR (chloroform-d, 400MHz): δ = 10.39-10.44 (m, 1H), 8.45-8.47 (m, 1H), 8.30 (s, 1H), 7.9 (m, 1H), 7.82 (m, 1H) , 6.50-6.66 (m, 1H), 6.31 (br d, J= 15.8 Hz, 1H), 5.72 (br d, J= 10.3 Hz, 1H), 5.63 (br s, 1H), 5.07 (br s, 1H ), 4.01 (s, 3H), 3.12 (s, 3H), 2.80-2.90 (m, 2H), 2.70-2.78 (m, 1H), 2.64-2.84 (m, 2H). [example]

[65] : 1-[(4R)-4-[7-(1-methylpyrazol-4-yl)imidazo[1,2-a]pyridin-5-yl]oxyazepane -1-yl]prop-2-en-1-one Synthesis of tertiary-butyl (4R)-4-(7-iodoimidazo[1,2-a]pyridin-5-yl)oxyazepane-1-carboxylate

[0258] Cool a vial containing 5-chloro-7-iodo-imidazo[1,2-a]pyridine (155 mg, 557 µmol) in anhydrous THF (2 mL) in an ice-water bath, followed by sodium tert-butoxide (93 mg, 970 µmol) was carefully added to the cold mixture in portions. After 15 minutes, (4R)-4-hydroxyazepane-1-carboxylic acid tert-butyl ester (142 mg, 661 µmol) was carefully added portion-wise to the cold heterogeneous mixture. After the addition of 5-chloro-7-iodo-imidazo[1,2-a]pyridine was complete, the mixture was allowed to warm to 23 °C and monitored by LCMS. After 19 h, the reaction was carefully quenched by the slow addition of water, followed by extraction of the biphasic mixture three times with ethyl acetate. The organics were pooled and then dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was loaded onto a silica gel column and purified (20-65% ethyl acetate / heptane). Pooling of the desired fractions followed by concentration under reduced pressure gave (4R)-4-(7-iodoimidazo[1,2-a]pyridin-5-yl)oxyazepane as a pale yellow oil Alkane-1-carboxylic acid tert-butyl ester (119 mg, 47% yield) was used without further purification. LCMS m / z = 458.0 (M+H)+. Synthesis of (4R)-4-[7-(1-methylpyrazol-4-yl)imidazo[1,2-a]pyridin-5-yl]oxyazepane-1-carboxylic acid tertiary Butyl ester

[0259] Will contain (4R)-4-(7-iodoimidazo[1,2-a]pyridin-5-yl)oxyazepane-1-carboxylic acid tertiary butyl ester (119 mg, 260 µmol) , 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (111 mg, 534 µmol), Tricyclohexylphosphine (19.4 mg, 69 µmol), tris(dibenzylideneacetone) dipalladium (25.4 mg, 28 µmol) and tripotassium phosphate (1 M, 0.8 mL) in dioxane (1 mL) The vial was degassed and then backfilled with nitrogen. After evacuation and backfilling with nitrogen (x3), the reaction was heated to 90 °C and monitored by LCMS. After 2 h, the reaction was carefully quenched by the slow addition of water. The biphasic mixture was extracted three times with ethyl acetate, followed by drying over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was loaded onto a silica gel column and purified (20-100% [3:1 ethyl acetate:ethanol] / heptane). Pooling of the desired fractions followed by concentration under reduced pressure afforded (4R)-4-[7-(1-methylpyrazol-4-yl)imidazo[1,2-a]pyridine as a yellow film -5-yl]oxyazepane-1-carboxylic acid tert-butyl ester (75.9 mg, 71% yield), which was used without further purification. LCMS m / z = 412.1 (M+H)+. Synthesis of 5-[(4R)-azepan-4-yl]oxy-7-(1-methylpyrazol-4-yl)imidazo[1,2-a]pyridine

[0260] Cool in an ice-water bath to contain (4R)-4-[7-(1-methylpyrazol-4-yl)imidazo[1,2-a]pyridin-5-yl]oxyazepane - A vial of tertiary-butyl 1-carboxylate (76 mg, 184 µmol) in anhydrous dichloromethane (0.5 mL), then trifluoroacetic acid (149 mg, 1.31 mmol, 0.1 mL) was carefully added dropwise to the cold in the mixture. After the TFA addition was complete, the mixture was allowed to warm to 23 °C and monitored with LCMS. After 19 hours, the reaction was carefully concentrated under reduced pressure to afford 5-[(4R)-azepan-4-yl]oxy-7-(1-methylpyrazole) as a pale yellow film -4-yl)imidazo[1,2-a]pyridine (crude, trifluoroacetic acid), which was used without purification. LCMS m / z = 312.0 (M+H)+. Synthesis of 1-[(4R)-4-[7-(1-methylpyrazol-4-yl)imidazo[1,2-a]pyridin-5-yl]oxyazepane-1- base] prop-2-en-1-one

[0261] At -25°C, it accommodates 5-[(4R)-azepan-4-yl]oxy-7-(1-methylpyrazol-4-yl)imidazo[1,2-a ]Pyridine (79 mg, 254 µmol, trifluoroacetic acid) in anhydrous THF (1 mL) was carefully added Junine's base (445 mg, 3.44 mmol, 0.6 mL). After 4 min, acryloyl chloride (45 mg, 492 µmol, 0.04 mL) was carefully added dropwise to the cold homogeneous solution. After the acryloyl chloride addition was complete, the reaction was allowed to warm to 23 °C and monitored by LCMS and TLC. After 3 min, the reaction was carefully quenched by the slow addition of saturated aqueous sodium bicarbonate. The biphasic mixture was loaded onto a silica gel column and purified (40-100% [3:1 ethyl acetate:ethanol] / heptane; then rinsed with 20% methanol in dichloromethane). The desired fractions were pooled, then concentrated under reduced pressure to obtain 67 mg of a colorless thin film, which was analyzed by mass-directed reverse-phase HPLC (Waters XSelect CSH C18, 5 μm, 19 mm × 100 mm column, mobile Phase H2O (A) and MeCN (B) and a gradient of 5 - 50% B (0.2% NH4OH final v / v % modifier), flow rate 30 mL / min) were further purified. Fractions containing the desired product were concentrated to give 1-[(4R)-4-[7-(1-methylpyrazol-4-yl)imidazo[1,2-a]pyridine as a colorless film -5-yl]oxyazepan-1-yl]prop-2-en-1-one (1.6 mg, 2% yield). 1H NMR (500MHz, DMSO-d6) δ = 8.52 - 8.12 (m, 2H), 8.02 - 7.64 (m, 2H), 7.47 (s, 1H), 6.96 - 6.77 (m, 2H), 6.23 - 6.13 (m , 1H), 5.75 - 5.65 (m, 1H), 5.28 - 5.16 (m, 1H), 3.96 - 3.85 (m, 3H), 3.84 - 3.46 (m, 6H), 2.12 - 2.07 (m, 1H), 1.99 - 1.91 (m, 2H), 1.83 - 1.72 (m, 1H). LCMS: m / z = 366.1 (M+H)+. [example]

[66] : 1-[(4R)-4-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl]oxyazepane Alk-1-yl]prop-2-en-1-one Synthesis of tertiary-butyl (4R)-4-(6-bromopyrazolo[1,5-a]pyridin-4-yl)oxyazepane-1-carboxylate

[0262] (4S)-4-Hydroxyazepane-1-carboxylic acid tertiary butyl ester (303 mg, 1.41 mmol), 6-bromopyrazolo[1,5-a]pyridin-4-ol (300 mg , 1.41 mmol) and triphenylphosphine (554 mg, 2.11 mmol) in THF (5 mL) were added DIAD (342 mg, 1.69 mmol, 333 µL) and stirred at room temperature for 16 hours. Chromatography of the concentrated crude material on silica gel (heptane / EtOAc 0-60%) afforded (4R)-4-(6-bromopyrazolo[1,5-a]pyridine as a colorless oil -4-yl)oxyazepane-1-carboxylic acid tert-butyl ester (255 mg, 42% yield, 95% purity). LCMS: Rt = 1.00 min, m / z 356.1, 412.1 (M+H)+. Synthesis of (4R)-4-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl]oxyazepane-1-carboxylic acid tris grade butyl ester

[0263] 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (194 mg, 932 µmol), A solution of Pd(dppf)Cl 2DCM (51 mg, 62 µmol) and K 2CO 3 (258 mg, 1.86 mmol) in dioxane (3 mL) and water (0.5 mL) was degassed and heated to 95°C for 16 Hour. After cooling to room temperature, the mixture was filtered through celite and concentrated. Chromatography of the residue on silica gel (heptane / EtOAc 0-100%) afforded (4R)-4-[6-(1-methylpyrazol-4-yl)pyridine as a yellow gel. Azolo[1,5-a]pyridin-4-yl]oxyazepane-1-carboxylic acid tert-butyl ester (192 mg, 71% yield, 95% purity). LCMS: Rt = 0.87 min, m / z 412.3 (M+H)+. Synthesis of 4-[(4R)-azepan-4-yl]oxy-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyridine

[0264] To (4R)-4-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl]oxyazepane-1-carboxylic acid tri To a solution of butyl ester (192 mg, 467 µmol) in DCM (1 mL) was added TFA (1.49 g, 13.1 mmol, 1 mL) and the reaction mixture was stirred at room temperature for 1 hour. Concentration of the crude material afforded 4-[(4R)-azepan-4-yl]oxy-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyridine (345 mg, crude, trifluoroacetic acid), which was used as such in the next step. LCMS: Rt = 0.50 min, m / z 312.1 (M+H)+. Synthesis of 1-[(4R)-4-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl]oxyazepane-1 -yl] prop-2-en-1-one

[0265] To 4-[(4R)-azepan-4-yl]oxy-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyridine (345 mg, 811 µmol, trifluoroacetic acid) in DCM (10 mL) was added TEA (164 mg, 1.62 mmol, 226 µL) and the reaction mixture was stirred for 5 minutes. After cooling to 0 °C, acryloyl chloride (88 mg, 973 µmol, 79 µL) was added and the reaction mixture was stirred for 3 minutes. The reaction was quenched with saturated aqueous NaHCO 3 and extracted with DCM. The organic layer was dried over Na2SO4 and the concentrated residue was chromatographed on silica gel (EtOAc / MeOH 0-30%) to give 1-[(4R)-4-[6-(1-methylpyrazole -4-yl)pyrazolo[1,5-a]pyridin-4-yl]oxyazepan-1-yl]prop-2-en-1-one (112.1 mg, 36% yield , 95% purity). LCMS: Rt = 0.62 min, m / z 366.2 (M+H)+. 1H NMR (400 MHz, chloroform-d) δ 8.25 (s, 1H), 7.84 (t, J= 1.76 Hz, 1H), 7.70 (d, J= 3.26 Hz, 1H), 7.59 (d, J= 6.02 Hz , 1H), 6.55-6.66 (m,2H), 6.44 (d, J= 8.28 Hz, 1H), 6.31-6.41 (m, 1H), 5.68-5.75 (m, 1H), 4.72 (br s, 1H) , 3.95 (s, 3H), 3.63-3.80 (m, 2H), 3.45-3.61 (m, 2H), 2.07-2.25 (m, 4H), 1.88-1.99 (m, 1H), 1.69-1.86 (m, 1H). [example]

[67] :1-[(4R)-4-[2-amino-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl] Oxyazepan-1-yl]prop-2-en-1-one Synthesis of ethyl 4-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-2-carboxylate

[0266] Add ethyl 4-hydroxy-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazine-2-carboxylate (130 mg, 454 μmol) to anhydrous Phosphoryl chloride (1.11 g, 7.27 mmol, 677 µL) was added dropwise to the suspension in acetonitrile (2 mL). The resulting mixture was heated at 80°C for 17 hours. After cooling to room temperature, the reaction mixture was diluted with EtOAc and carefully quenched with saturated aqueous sodium bicarbonate. The layers were separated, and the organic layer was washed sequentially with saturated bicarbonate solution (2x) and brine. The organic phase was dried (MgSO 4 ), filtered and concentrated in vacuo. Ethyl 4-chloro-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazine-2-carboxylate was obtained as a white solid which was used directly. Quantitative yield is assumed. 1H NMR (500 MHz, Chloroform-d) δ ppm 8.50 (d, J= 1.2 Hz, 1 H), 7.94 (s, 1 H), 7.90 (s, 1 H), 7.37 - 7.42 (m, 1 H) , 4.50 (q, J= 6.9 Hz, 2 H), 3.97 - 4.01 (m, 3 H), 1.46 (t, J= 7.0 Hz, 3 H). LCMS: m / z = 306.3 [M+H]+. Synthesis of 4-(((R)-1-(tertiary butoxycarbonyl)azepan-4-yl)oxy)-6-(1-methyl-1H-pyrazol-4-yl) Pyrazolo[1,5-a]pyrazine-2-carboxylic acid (R)-1-(tertiary butoxycarbonyl)azepan-4-yl ester

[0267] To a solution of (4R)-tert-butyl 4-hydroxyazepane-1-carboxylate (232 mg, 1.08 mmol) in anhydrous DMF (2 mL) was added NaHMDS ( 1 M, 1.08 mL). The mixture was stirred at 20°C for 15 minutes. Add ethyl 4-chloro-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazine-2-carboxylate (150 mg, 491 µmol) in anhydrous DMF (2 mL), and the resulting mixture was stirred at room temperature for 2 h, quenched with H 2 O (1 mL) and diluted with EtOAc. The organic layer was washed with brine (3x), dried over MgSO 4 , filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (0-100% EtOAc / heptane) to afford 4-[(4R)-1-tert-butoxycarbonylazepane-4- Base]oxy-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazine-2-carboxylic acid[(4R)-1-tertiary butoxycarbonylazepine Cycloheptan-4-yl] ester (136 mg, 42% yield). 1H NMR (500 MHz, chloroform-d) δ ppm 8.23 ​​(s, 1 H), 7.76 - 7.90 (m, 2 H), 5.55 (br s, 1 H), 5.22 - 5.32 (m, 1 H), 3.98 (s, 3H), 3.58 - 3.72 (m, 2H), 3.30 - 3.58 (m, 6H), 2.06 - 2.25 (m, 4H), 1.89 - 2.06 (m, 6H), 1.69 - 1.84 (m, 2H), 1.51 (s, 9H), 1.49 (s, 9H). LCMS: m / z = 654.7 [M+H]+. Synthesis of (R)-4-((1-(tertiary butoxycarbonyl)azepan-4-yl)oxy)-6-(1-methyl-1H-pyrazol-4-yl) Pyrazolo[1,5-a]pyrazine-2-carboxylic acid

[0268] To 4-[(4R)-1-tertiary butoxycarbonylazepan-4-yl]oxyl-6-(1-methylpyrazol-4-yl)pyrazolo[1,5 -a] pyrazine-2-carboxylic acid [(4R)-1-tertiary butoxycarbonylazepan-4-yl] ester (41 mg, 63 µmol) in methanol (400 µL) Sodium hydroxide solution (2 M, 94 µL) was added, and the resulting mixture was stirred at room temperature for 30 min. The reaction mixture was quenched with HCl solution (1 M, 188 μL) and diluted with EtOAc and water. The layers were separated, the organic layer was washed with water and brine, dried (MgSO 4 ), filtered and concentrated in vacuo. 4-[(4R)-1-tert-butoxycarbonylazepan-4-yl]oxy-6-(1-methylpyrazol-4-yl)pyrazole was obtained as a white solid and[1,5-a]pyrazine-2-carboxylic acid and used directly. Quantitative yield is assumed. LCMS: m / z = 457.4 [M+H]+. Synthesis of (R)-4-((2-((tertiary butoxycarbonyl)amino)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a ] pyrazin-4-yl)oxy)azepane-1-carboxylic acid tertiary butyl ester

[0269] To 4-[(4R)-1-tertiary butoxycarbonylazepan-4-yl]oxyl-6-(1-methylpyrazol-4-yl)pyrazolo[1,5 -a] To a solution of pyrazine-2-carboxylic acid (110 mg, 241 µmol) in anhydrous DMF (1 mL) and tertiary butanol (0.5 mL) was added triethylamine (37 mg, 361 µmol, 50 µL ), followed by the dropwise addition of DPPA (99 mg, 361 µmol, 78 µL) at room temperature. The resulting mixture was stirred at 80 °C for 17 h, cooled to room temperature, diluted with EtOAc, and washed with water and brine (3x). The organic layer was dried (MgSO 4 ), filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (0-5% MeOH / DCM). (4R)-4-[2-(tertiary butoxycarbonylamino)-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazine was obtained as an oil -4-yl]oxyazepane-1-carboxylic acid tert-butyl ester (38 mg, 30% yield). 1H NMR (500 MHz, chloroform-d) δ ppm 7.99 (s, 1 H), 7.72 - 7.84 (m, 2 H), 7.33 (br s, 1 H), 6.82 - 7.05 (bs, 1 H), 5.47 - 5.55 (m, 1 H), 3.96 (s, 3 H), 3.58 - 3.76 (m, 2 H), 3.45 - 3.56 (m, 2 H), 1.88 - 2.03 (m, 6 H), 1.50 (s , 9 H), 1.46 (s, 9 H). LCMS: m / z = 528.3 [M+H]+. Synthesis of (R)-4-(azepan-4-yloxy)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine -2-Amine dihydrochloride

[0270] To (4R)-4-[2-(tertiary butoxycarbonylamino)-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazine-4- To a solution of tert-butyl]oxyazepane-1-carboxylate (38 mg, 72 µmol) in methanol (0.6 mL) was added HCl (4 M in dioxane, 360 µL). The resulting solution was stirred at room temperature for 2 hours and concentrated in vacuo. 4-[(4R)-azepan-4-yl]oxy-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a] was obtained as an off-white solid Pyrazin-2-amine (dihydrochloride), which was used directly. Quantitative yield is assumed. LCMS: m / z = 328.1 [M+H]+. Synthesis of 1-[(4R)-4-[2-amino-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]oxynitrogen Heteroheptan-1-yl]prop-2-en-1-one

[0271] The crude 4-[(4R)-azepan-4-yl]oxy-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyridine Triethylamine (21 mg, 210 µmol, 29 µL), and the resulting suspension was cooled to 0 °C. Acryloyl chloride (6 mg, 70 µmol, 6 µL) was added dropwise and the resulting mixture was stirred at 0 °C for 30 min. After quenching with saturated sodium bicarbonate solution and diluting with EtOAc, the layers were separated. The organic layer was washed with brine (3x), dried (MgSO 4 ), filtered and concentrated in vacuo. The residue was purified by silica gel chromatography and the desired product was further purified by preparative TLC (96:4 DCM / MeOH). 1-[(4R)-4-[2-Amino-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazine-4-yl was obtained as an off-white solid yl]oxyazepan-1-yl]prop-2-en-1-one (4.2 mg, 15% yield, 95% purity). 1H NMR (500 MHz, chloroform-d) δ ppm 7.93 (s, 1 H), 7.79 (s, 1 H), 7.68 - 7.76 (m, 1 H), 6.58 - 6.67 (m, 1 H), 6.36 - 6.43 (m, 1 H), 5.94 (d, J= 4.3 Hz, 1 H), 5.72 (dd, J= 10.4, 2.4 Hz, 1 H), 5.49 - 5.60 (m, 1 H), 4.02 (br s , 2 H), 3.96 (s, 3 H), 3.80 - 3.94 (m, 1 H), 3.55 - 3.77 (m, 3 H), 2.11 - 2.32 (m, 3 H), 1.93 - 2.11 (m, 2 H), 1.77 - 1.90 (m, 1 H). LCMS: m / z = 382.1 [M+H]+. [example]

[68] : N-((cis)-3-((2-amino-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine- 4-yl)oxy)cyclobutyl)-N-methacrylamide Synthesis of 4-((cis)-3-((tertiary butoxycarbonyl)(methyl)amino)cyclobutoxy)-6-(1-methyl-1H-pyrazol-4-yl)pyridine Azolo[1,5-a]pyrazine-2-carboxylic acid (cis)-3-((tertiary butoxycarbonyl)(methyl)amino)cyclobutyl ester

[0272] 4-Chloro-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazine-2-carboxylic acid ethyl ester (300 mg, 981 µmol ) and ((cis)-3-hydroxycyclobutyl)(methyl)-tert-butyl carbamate (494 mg, 2.45 mmol) in anhydrous THF (4 mL) and anhydrous DMSO (1 mL) A solution of potassium tert-butoxide (1 M in THF, 2.45 mL) was added to the solution. The mixture was allowed to warm to room temperature and stirred at room temperature for 2 hours, quenched with H 2 O (1 mL) and diluted with EtOAc. The organic layer was washed with brine (2x), dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (0-100% EtOAc / heptane) to afford 4-((cis)-3-((tertiary butoxycarbonyl)(methyl)amine as a light yellow foam Base) cyclobutoxy)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-2-carboxylic acid (cis)-3-((three (butoxycarbonyl)(methyl)amino)cyclobutyl ester (250 mg, 41% yield). 1H NMR (500 MHz, chloroform-d) δ ppm 8.23 ​​(s, 1 H), 7.74 - 7.92 (m, 2 H), 5.55 (br s, 1 H), 5.28 (br s, 1 H), 3.98 ( s, 3 H), 3.59 - 3.74 (m, 2 H), 3.39 - 3.59 (m, 5 H), 3.29 - 3.39 (m, 1 H), 1.89 - 2.32 (m, 10 H), 1.69 - 1.84 ( m, 2H), 1.48 - 1.53 (m, 18H). LCMS: m / z = 471.2 [M+H]+. Synthesis of 4-((cis)-3-((tertiary butoxycarbonyl)(methyl)amino)cyclobutoxy)-6-(1-methyl-1H-pyrazol-4-yl)pyridine Azolo[1,5-a]pyrazine-2-carboxylic acid

[0273] To 4-((cis)-3-((tertiary butoxycarbonyl)(methyl)amino)cyclobutoxy)-6-(1-methyl-1H-pyrazol-4-yl)pyridine Azolo[1,5-a]pyrazine-2-carboxylic acid (cis)-3-((tertiary butoxycarbonyl)(methyl)amino)cyclobutyl ester (332 mg, 531 µmol) in methanol ( 1 mL) was added sodium hydroxide solution (2 M, 266 µL), and the resulting mixture was stirred at room temperature for 30 min. After quenching with HCl (1 M, 531 µL) and diluting with EtOAc and water, the layers were separated. The organic layer was washed with water and brine, dried (MgSO 4 ), filtered and concentrated in vacuo. 4-((cis)-3-((tertiary butoxycarbonyl)(methyl)amino)cyclobutoxy)-6-(1-methyl-1H-pyrazole- 4-yl)pyrazolo[1,5-a]pyrazine-2-carboxylic acid and used directly. Quantitative yield is assumed. 1H NMR (500 MHz, DMSO-d6) δ ppm 13.26 (br s, 1 H), 8.81 (s, 1 H), 8.27 (s, 1 H), 8.05 (s, 1 H), 7.20 (s, 1 H), 5.05 - 5.16 (m, 1 H), 3.91 (s, 3 H), 2.84 (m, 2 H), 2.80 (s, 3 H), 2.32 - 2.42 (m, 2 H), 1.42 (s , 9H). LCMS: m / z = 443.1 [M+H]+. Synthesis of ((cis)-3-((2-((tertiary butoxycarbonyl)amino)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5- a] pyrazin-4-yl)oxy)cyclobutyl)(methyl)carbamate tertiary butyl

[0274] To 4-((cis)-3-((tertiary butoxycarbonyl)(methyl)amino)cyclobutoxy)-6-(1-methyl-1H-pyrazol-4-yl)pyridine Add triethylamine (39 mg , 390 µmol, 54 µL), then DPPA (107 mg, 390 µmol, 84 µL) was added dropwise at room temperature. The resulting mixture was stirred at 80 °C for 17 h, cooled to room temperature, diluted with EtOAc, and washed with water and brine (3x). The organic layer was dried (MgSO 4 ), filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (heptane / EtOAc 0-100%). ((cis)-3-((2-((tertiary butoxycarbonyl)amino)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo was obtained as white foam [1,5-a]pyrazin-4-yl)oxy)cyclobutyl)(methyl)carbamate (26 mg, 20% yield). 1H NMR (500 MHz, Chloroform-d) δ ppm 8.30-8.00 (br s, 1H), 8.10 (s, 1H), 7.81 (s, 1 H), 7.76 (s, 1 H), 6.82 - 7.09 (b s , 1 H), 5.10 (q, J= 7.2 Hz, 1 H), 3.94 - 3.99 (m, 3 H), 2.80 - 2.92 (m, 2 H), 2.86 (s, 3H), 2.33 (m, 2 H), 1.55 (s, 9 H), 1.49 (s, 9 H). LCMS: m / z = 514.2 [M+H]+.

[0275] ((cis)-3-((2-amino-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine- 4-yl)oxy)cyclobutyl)(methyl)carbamate (16 mg, 15% yield). 1H NMR (500 MHz, chloroform-d) δ ppm 7.94 (s, 1 H), 7.79 (s, 1 H), 7.72 (s, 1 H), 5.95 (s, 1 H), 5.01 - 5.10 (quintuplet Peak, J= 7.2 Hz, 1 H), 4.01 - 4.09 (b s, 2 H), 3.95 (s, 3 H), 2.83 - 2.93 (m, 2 H), 2.86 (s, 3 H), 2.28 - 2.42 (m, 2H), 1.48 (s, 9H). LCMS: m / z = 414.2 [M+H]+. Synthesis of 6-(1-methyl-1H-pyrazol-4-yl)-4-((cis)-3-(methylamino)cyclobutoxy)pyrazolo[1,5-a]pyridine Azin-2-amine

[0276] ((cis)-3-((2-((tertiary butoxycarbonyl)amino)-6-(1-methyl-1H- Pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)cyclobutyl)(methyl)carbamic acid tertiary butyl ester (26 mg, 51 µmol) in Solution in dry methanol (0.5 mL). The resulting mixture was stirred at room temperature for 1 hour. A solid was formed. The mixture was concentrated in vacuo. 6-(1-Methyl-1H-pyrazol-4-yl)-4-((cis)-3-(methylamino)cyclobutoxy)pyrazolo[1, 5-a] Pyrazin-2-amine (bishydrochloride), which was used directly. Quantitative yield is assumed. LCMS: m / z = 314.5 [M+H]+. Synthesis of N-((cis)-3-((2-amino-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl )oxy)cyclobutyl)-N-methacrylamide

[0277] The crude 6-(1-methyl-1H-pyrazol-4-yl)-4-((cis)-3-(methylamino)cyclobutoxy)pyrazolo[1,5 -a] To a suspension of pyrazin-2-amine dihydrochloride (14 mg, 36 µmol) in anhydrous THF (0.5 mL) and anhydrous DMF (0.5 mL) was added triethylamine (11 mg, 109 µmol, 15 µL) and the resulting suspension was cooled to 0°C. Acryloyl chloride (3.3 mg, 36 µmol, 3 µL) was added dropwise and the resulting mixture was stirred at 0°C for 30 minutes. The reaction mixture was quenched with saturated sodium bicarbonate solution and diluted with EtOAc. The layers were separated, and the organic layer was washed with brine (3x), dried (MgSO 4 ), filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (0-10% MeOH / DCM). N-((cis)-3-((2-amino-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine was obtained as white foam Oxyzin-4-yl)oxy)cyclobutyl)-N-methacrylamide (4.4 mg, 32% yield, 95% purity). 1H NMR (500 MHz, chloroform-d) δ ppm 7.94 (s, 1 H), 7.78 (br s, 1 H), 7.73 (br s, 1 H), 6.58 (dd, J= 16.8, 10.7 Hz, 1 H), 6.24 - 6.40 (m, 1 H), 5.95 (s, 1 H), 5.71 (dd, J= 10.4, 1.8 Hz, 1 H), 5.13 (quintet, J= 7.2 Hz, 1 H) , 4.83 and 4.30 (2 br s, 1 H), 4.02 (b s, 2 H), 3.96 (s, 3 H), 3.06 (br s, 3 H), 2.90 - 2.98 (m, 2 H), 2.51 and 2.36 (2br s, 2H). LCMS: m / z = 368.1 [M+H]+. [example]

[69] : (S)-1-(4-((6-(1,3-dimethyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-4- Base) oxy) azepan-1-yl) prop-2-en-1-one and (R)-1-(4-((6-(1,3-dimethyl-1H-pyr Azol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)azepan-1-yl)prop-2-en-1-one Synthesis of tertiary-butyl 4-(6-chloropyrazolo[1,5-a]pyrazin-4-yl)oxyazepane-1-carboxylate

[0278] To tertiary butyl 4-hydroxyazepane-1-carboxylate (4.0 g, 18.6 mmol) and 4,6-dichloropyrazolo[1,5-a]pyrazine (3.5 g, 18.6 mmol) To a solution in THF (100 mL) was slowly added a solution of potassium tert-butoxide (1 M in THF, 18.6 mL, 18.6 mmol). The flask was stirred at room temperature for 2 hours. Material was concentrated to half volume and dissolved in EtOAc and water. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified via an 80 g silica gel column using a gradient of 0-60% EtOAc / heptane. The relevant fractions were combined to obtain tertiary butyl 4-(6-chloropyrazolo[1,5-a]pyrazin-4-yl)oxyazepane-1-carboxylate (4.32 g, 63% yield). LCMS m / z = 367.1 (M+H)+. 1H NMR (400 MHz, DMSO-d 6) δ ppm 1.36 - 1.47 (m, 9 H) 1.68 (br dd, J= 11.7, 5.4 Hz, 1 H) 1.83 (br s, 1 H) 1.90 - 1.98 (m , 3H) 2.03 - 2.24 (m, 1H) 3.34 - 3.53 (m, 4H) 5.22 - 5.44 (m, 1H) 6.88 - 6.98 (m, 1H) 8.01 - 8.14 (m, 1H) 8.65 - 8.76 (m, 1H) Synthesis of 4-[6-(1,3-dimethylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]oxyazepane-1-carboxylic acid tris grade butyl ester

[0279] To a microwave vial was added tert-butyl 4-(6-chloropyrazolo[1,5-a]pyrazin-4-yl)oxyazepane-1-carboxylate (1 M, 0.55 mL, 0.55 mmol), 1,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (145 mg, 0.65 mmol), K 3PO 4 (1 M in water, 1.09 mL), Pd-PEPPSI™-IPr (37 mg, 55 µmol) and dioxane (5 mL). The vial was capped and stirred overnight at 60°C. The reaction mixture was concentrated and purified through a 12 g silica gel column using a gradient of 40-70% EtOAc / heptane. The relevant fractions were combined to give 4-[6-(1,3-dimethylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]oxyl as a pale yellow oil Azepane-1-carboxylic acid tert-butyl ester (136 mg, 58% yield). LCMS m / z = 427.2 (M+H)+. Synthesis of 4-[azepan-4-yl]oxy-6-(1,3-dimethylpyrazol-4-yl)pyrazolo[1,5-a]pyrazine hydrochloride

[0280] To 4-[6-(1,3-dimethylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]oxyazepane-1-carboxylic acid tri To a solution of butyl ester (136 mg, 0.32 mmol) in dioxane (2 mL) was added HCl (4 M in dioxane, 0.8 mL). The mixture was stirred overnight at room temperature. The material was concentrated to give 4-[azepan-4-yl]oxy-6-(1,3-dimethylpyrazol-4-yl)pyrazolo[1,5-yl) as an off-white solid. a] Pyrazine hydrochloride (115 mg, crude). LCMS m / z = 327.1 (M+H)+. Synthesis of (S)-1-(4-((6-(1,3-dimethyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy base) azepan-1-yl) prop-2-en-1-one and (R)-1-(4-((6-(1,3-dimethyl-1H-pyrazole-4 -yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)azepan-1-yl)prop-2-en-1-one

[0281] Add 4-[monoheptan-4-yl]oxy-6-(1,3-dimethylpyrazol-4-yl)pyrazolo[1,5-a] in sequence to the vial Pyrazine hydrochloride (115 mg, 0.32 mmol) in DCM (4 mL), triethylamine (193 mg, 1.9 mmol, 266 µL) and prop-2-enyl chloride (35 mg, 0.38 mmol, 31 µL) . The vial was stirred overnight at room temperature. The reaction mixture was concentrated, dissolved in DMSO and passed through a plug. The material was purified via reverse phase purification (column: Waters XSelect CSH Prep C18 5um OBD 19x100mm; conditions: 5-50% acetonitrile in 0.1% v / v ammonium carbonate / water; flow rate: 30 mL / min) to afford 60.6 mg ( 50% yield) of the desired product. LCMS m / z = 381.2 (M+H)+. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.67 - 1.80 (m, 1 H) 1.86 - 2.10 (m, 4 H) 2.16 - 2.26 (m, 1 H) 2.42 (s, 3 H) 3.56 - 3.78 (m, 4H) 3.81 (d, J=1.22 Hz, 3H) 5.42 - 5.56 (m, 1H) 5.65 - 5.74 (m, 1H) 6.13 - 6.21 (m, 1H) 6.75 - 6.87 (m , 2H) 7.98 - 8.04 (m, 1H) 8.08 - 8.15 (m, 1H) 8.42 - 8.49 (m, 1H).

[0282] Use the following conditions (column: CHIRALPAK AD-H 30x250mm, 5um; method: 30% MeOH, without modifier, in CO; flow rate: 100 mL / min; ABPR: 120 bar; MBPR: 40 PSI; Column temperature: 40°C) for chiral purification of the substance. Concentration of the first eluting peak E1 yielded 11.3 mg of 1-[-4-[6-(1,3-dimethylpyrazol-4-yl)pyrazolo[1,5-a] as a white solid One enantiomer of pyrazin-4-yl]oxyazepan-1-yl]prop-2-en-1-one. LCMS m / z = 381.2 (M+H)+. Concentration of the second eluting peak E2 afforded 5.4 mg of 1-[4-[6-(1,3-dimethylpyrazol-4-yl)pyrazolo[1,5-a]pyridine as a white solid. The second enantiomer of azin-4-yl]oxyazepan-1-yl]prop-2-en-1-one. LCMS m / z = 381.2 (M+H)+. The stereochemistry of the two isomers was not assigned. [example]

[70] :1-[(4R)-4-[[6-(1,3-dimethylpyrazol-4-yl)-[1,2,4]triazolo[1,5-a] Pyrazin-8-yl]oxy]azepan-1-yl]prop-2-en-1-one Synthesis of (4R) 4-((6-bromo-[1,2,4]triazolo[1,5-a]pyrazin-8-yl)oxy)azepane-1-carboxylic acid tertiary Butyl ester

[0283] (4R)-4-Hydroxyazepane-1-carboxylic acid tertiary butyl ester (775 mg, 3.60 mmol) and 6,8-dibromo-[1,2,4]triazolo[1,5 -a] To a solution of pyrazine (1 g, 3.60 mmol) in THF (36 mL) was slowly added a solution of potassium tert-butoxide (1 M in THF, 3.6 mL, 3.6 mmol). The flask was stirred at room temperature for 1 hour. Material was concentrated to half volume and dissolved in EtOAc and water. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified via a 40 g silica gel column using a gradient of 10-70% EtOAc / heptane. Relevant fractions were combined to give (4R)-4-[(6-bromo-[1,2,4]triazolo[1,5-a]pyrazin-8-yl)oxy] as a white foam Azepane-1-carboxylic acid tert-butyl ester (1.48 g, 2.79 mmol, 77.5% yield). LCMS m / z = 414.0 (M+H)+. 1H NMR (500 MHz, DMSO-d 6) δ ppm 1.43 (s, 9 H) 1.69 (br dd, J=8.85, 4.58 Hz, 1 H) 1.81 - 2.04 (m, 4 H) 2.10 - 2.31 (m, 1H) 3.37 - 3.53 (m, 4H) 5.27 - 5.39 (m, 1H) 8.52 - 8.66 (m, 1H) 8.97 - 9.15 (m, 1H) Synthesis of (4R)-4-[[6-(1,3-dimethylpyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-yl ]oxy]azepane-1-carboxylate tertiary butyl ester

[0284] To a microwave vial add (4R)-4-[(6-bromo-[1,2,4]triazolo[1,5-a]pyrazin-8-yl)oxy]azepane- tertiary-butyl 1-carboxylate (230 mg, 0.56 mmol), 1,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborine Pentan-2-yl)pyrazole (149 mg, 0.67 mmol), K 3PO 4 (1 M, in water, 1.12 mL), Pd-PEPPSI™-IPr (38 mg, 55.8 µmol) and dioxane (5.00 mL). The vial was capped and stirred overnight at 70°C. The reaction mixture was concentrated and purified through a 12 g silica gel column using a gradient of 30-100% EtOAc / heptane. The relevant fractions were combined to obtain (4R)-4-[[6-(1,3-dimethylpyrazol-4-yl)-[1,2,4]triazolo[1, 5-a]pyrazin-8-yl]oxy]azepane-1-carboxylic acid tert-butyl ester (65 mg, 27% yield). LCMS m / z = 428.2 (M+H)+ Synthesis of 8-[(4R)-azepan-4-yl]oxy-6-(1,3-dimethylpyrazol-4-yl)-[1,2,4]triazolo[ 1,5-a] pyrazine hydrochloride

[0285] To (4R)-4-[[6-(1,3-dimethylpyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-yl To a solution of tert-butyl ]oxy]azepane-1-carboxylate (65 mg, 0.15 mmol) in dioxane (5 mL) was added HCl (4 M in dioxane, 0.38 mL ). The mixture was stirred overnight at room temperature. The material was concentrated to afford 8-[(4R)-azepan-4-yl]oxy-6-(1,3-dimethylpyrazol-4-yl)-[1, 2,4] Triazolo[1,5-a]pyrazine hydrochloride (55.3 mg, 100% yield). LCMS m / z = 328.1 (M+H)+. Synthesis of 1-[(4R)-4-[[6-(1,3-dimethylpyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazine- 8-yl]oxy]azepan-1-yl]prop-2-en-1-one

[0286] Add 8-[(4R)-azepan-4-yl]oxy-6-(1,3-dimethylpyrazol-4-yl)-[1,2, 4] Triazolo[1,5-a]pyrazine hydrochloride (55.3 mg, 0.15 mmol) in DCM (4 mL), triethylamine (93 mg, 0.92 mmol, 128 µL) and prop-2-ene Acyl chloride (17 mg, 0.18 mmol, 15 µL). The vial was stirred overnight at room temperature. The reaction mixture was concentrated, dissolved in DMSO and passed through a plug. The material was purified via reverse phase purification (column: Waters XSelect CSH Prep C18 5um OBD 19x100mm; conditions: 5-40% acetonitrile in 0.1% v / v ammonium carbonate / water; flow rate: 30 mL / min) to afford 26.4 mg ( 45% yield) desired product. LCMS m / z = 382.3 (M+H)+. 1H NMR (500 MHz, DMSO- d 6 ) δ ppm 1.69 - 1.81 (m, 1 H) 1.91 - 2.07 (m, 4 H) 2.21 - 2.31 (m, 1 H) 2.44 (d, J=1.22 Hz, 3 H) 3.49 - 3.59 (m, 2H) 3.66 - 3.76 (m, 2H) 3.82 (d, J=1.83Hz, 3H) 5.41 - 5.54 (m, 1H) 5.65 - 5.77 (m, 1H) 6.11 - 6.22 (m, 1H) 6.75 - 6.88 (m, 1H) 8.11 - 8.23 ​​(m, 1H) 8.52 - 8.61 (m, 1H) 8.69 - 8.78 (m, 1H). [example]

[71] : (S)-5-(4-((1-acryloylazepan-4-yl)oxy)pyrazolo[1,5-a]pyrazin-6-yl) -1-methylpyridin-2(1H)-one and (R)-5-(4-((1-acryloylazepan-4-yl)oxy)pyrazolo[1,5 -a]pyrazin-6-yl)-1-methylpyridin-2(1H)-one Synthesis of 4-((6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy ) Tertiary butyl azepane-1-carboxylate

[0287] To a solution containing tertiary butyl 4-((6-chloropyrazolo[1,5-a]pyrazin-4-yl)oxy)azepane-1-carboxylate (200 mg, 0.55 mmol) To a 20-mL scintillation vial of dioxane (5.0 mL) was added 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane -2-yl)pyridin-2(1H)-one (154 mg, 0.64 mmol). Next, aqueous K 3PO 4 (1 M, 1.09 mmol, 1.1 mL) was added to the reaction mixture, followed by Pd-PEPPSI™-IPr (37 mg, 55 µmol). The vial was purged with N2 and heated at 100 °C overnight. After this time, the reaction mixture was filtered through a pad of Celite® and concentrated under reduced pressure to give an amber oil. The crude material was purified by silica gel chromatography (0 to 25% EtOAc / heptane, followed by 100% [3:1 EtOAc:EtOH]) to afford 4-((6-(1-methyl- 6-oxo-1,6-dihydropyridin-3-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)azepane-1-carboxylic acid tertiary butyl Ester (155 mg, 65% yield). LC-MS: m / z = 440.0 (M+H)+. Synthesis of 5-(4-(azepan-4-yloxy)pyrazolo[1,5-a]pyrazin-6-yl)-1-methylpyridin-2(1H)-one

[0288] To 4-((6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy ) To a solution of tert-butyl azepane-1-carboxylate (155 mg, 0.35 mmol) in dioxane (1.4 mL) was added HCl (4 M in dioxane, 883 µL, 3.5 mmol ). Immediately after the addition of HCl solution, the reaction mixture became heterogeneous and was stirred at room temperature for 1.5 hours. The reaction mixture was directly concentrated under reduced pressure to afford the title compound as an orange solid, which was used without further purification assuming 100% yield. LC-MS: m / z = 361.9 (M+Na)+. Synthesis of (S)-5-(4-((1-acryloylazepan-4-yl)oxy)pyrazolo[1,5-a]pyrazin-6-yl)-1- Pyridin-2(1H)-one and (R)-5-(4-((1-acryloylazepan-4-yl)oxy)pyrazolo[1,5-a] Pyrazin-6-yl)-1-methylpyridin-2(1H)-one

[0289] To 5-(4-(azepan-4-yloxy)pyrazolo[1,5-a]pyrazin-6-yl)-1-methylpyridin-2(1 H)-one (120 mg, 0.35 mmol) in DCM (1.4 mL) was added triethylamine (99 µL, 0.71 mmol), followed by acryloyl chloride (57 µL, 0.71 mmol). After the addition of acryloyl chloride, the solution turned red and homogeneous, and was stirred at room temperature for 20 minutes. The reaction mixture was then concentrated in vacuo and loaded onto a silica gel cartridge. The crude material was purified by silica gel chromatography (0 to 100% EtOAc / heptane, followed by 0 to 15% MeOH / heptane) to afford 5-(4-((1-acryloylazepine) as a white solid Cycloheptan-4-yl)oxy)pyrazolo[1,5-a]pyrazin-6-yl)-1-methylpyridin-2(1H)-one (52.1 mg, 38%, via 2 steps). LC-MS: m / z = 393.9 (M+H)+. 1H NMR (400 MHz, CDCl 3 ) δ ppm 1.72 (br s, 1 H) 1.74 - 1.91 (m, 2 H) 1.95 - 2.49 (m, 6 H) 3.46 - 3.64 (m, 2 H) 3.65 - 3.73 ( m, 4H) 3.77 - 4.12 (m, 2H) 5.46 - 5.65 (m, 1H) 5.69 - 5.75 (m, 1H) 6.35 - 6.43 (m, 1H) 6.58 - 6.70 (m, 2H) 6.73 - 6.78 (m, 1 H) 7.74 - 7.79 (m, 1 H) 7.91 (dd, J=4.39, 2.38 Hz, 1 H) 7.95 - 8.11 (m, 1 H) 8.23 ​​(d, J=0.75 Hz, 1H).

[0290] By chiral SFC (Chiralpak AD-H 30x250 mm, 5 µm column; 25% MeOH, in CO2, without modifier; flow rate = 100 mL / min, ABPR 120 bar, MBPR 40 psi, tube (column temperature 40°C) to separate the racemates to give the enantiomers, the first eluting enantiomer E1 (7.0 mg, 100% ee, Rf = 4.36 min) and the second eluting enantiomer Body E2 (arbitrarily designated as R7.6 mg, 90% ee, Rf = 4.77 min). [example]

[72] : 1-(4-((6-(2-methoxypyridin-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)azepane -1-yl)prop-2-en-1-one (chiral, but absolute chemistry unknown) Synthesis of 4-((6-(2-methoxypyridin-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)azepane-1-carboxylic acid tertiary Butyl ester

[0291] To a solution containing tertiary butyl 4-((6-chloropyrazolo[1,5-a]pyrazin-4-yl)oxy)azepane-1-carboxylate (200 mg, 0.55 mmol) Add 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane to a 20-mL scintillation vial in dioxane (5.0 mL) alk-2-yl)pyridine (100 mg, 0.65 mmol). Aqueous K 3PO 4 (1 M, 1.09 mmol, 1.09 mL) was then added to the reaction mixture, followed by Pd-PEPPSI™-IPr (37 mg, 55 µmol). The vial was purged with N2 and heated at 100 °C overnight. The reaction mixture was returned to room temperature, then filtered through a pad of Celite®. Concentration under reduced pressure afforded the crude product as an amber oil. The crude material was purified by silica gel chromatography (0 to 25% EtOAc / heptane) to afford 4-((6-(2-methoxypyridin-4-yl)pyrazolo[1, 5-a]pyrazin-4-yl)oxy)azepane-1-carboxylic acid tert-butyl ester (184 mg, 77% yield). LC-MS: m / z = 440.0 (M+H)+. Synthesis of 4-(azepan-4-yloxy)-6-(2-methoxypyridin-4-yl)pyrazolo[1,5-a]pyrazine

[0292] To 4-((6-(2-methoxypyridin-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)azepane-1-carboxylic acid tertiary To a solution of the butyl ester (184 mg, 0.42 mmol) in dioxane (1.7 mL) was added a solution of HCl (4 M in dioxane, 1.05 mL, 4.2 mmol). The reaction mixture was stirred at room temperature for 3 hours, then concentrated in vacuo to afford crude 4-(azepan-4-yloxy)-6-(2-methoxypyridine-4 as a bright yellow solid. -yl)pyrazolo[1,5-a]pyrazine. Assuming 100% yield, the crude product was used without further purification. LC-MS: m / z = 340.0 (M+H)+. Synthesis of chiral 1-(4-((6-(2-methoxypyridin-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)azepane- 1-yl) prop-2-en-1-one

[0293] To crude 4-(azepan-4-yloxy)-6-(2-methoxypyridin-4-yl)pyrazolo[1,5-a]pyrazine (142 mg , 0.42 mmol) in DCM (1.7 mL) was added triethylamine (0.29 mL, 2.09 mmol), followed immediately by acryloyl chloride (68 µL, 0.84 mmol). The reaction mixture turned dark red and homogeneous and was stirred at room temperature for 20 minutes. After this time, the reaction mixture was quenched by adding saturated aqueous NaHCO 3 and diluted with EtOAc. The resulting layers were separated, and the aqueous layer was further extracted with EtOAc (3x). The combined organics were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude material was purified by silica gel chromatography (0 to 100% EtOAc / heptane) to afford 1-(4-((6-(2-methoxypyridin-4-yl)pyrazolo) as a colorless oil [1,5-a]pyrazin-4-yl)oxy)azepan-1-yl)prop-2-en-1-one (64.5 mg, 39%, over 2 steps). LC-MS: m / z = 393.9 (M+H)+. 1H NMR (400 MHz, CDCl 3 ) δ ppm 1.81 - 1.92 (m, 1 H) 1.97 - 2.13 (m, 2 H) 2.16 - 2.31 (m, 3 H) 3.62 - 3.85 (m, 4 H) 4.01 - 4.04 (m, 3H) 5.64 - 5.70 (m, 1H) 5.72 (dd, J=10.29, 2.01Hz, 1H) 6.39 (ddd, J=16.75, 7.72, 2.13Hz, 1H) 6.57 - 6.68 (m , 1 H) 6.80 (dd, J=4.02, 2.01 Hz, 1 H) 7.31 - 7.39 (m, 2 H) 7.98 (t, J=2.01 Hz, 1 H) 8.24 (d, J=5.27 Hz, 1 H ) 8.56 (s, 1H).

[0294] By chiral SFC (Chiralpak IB 30x250 mm, 5 µm column; 15% MeOH, in CO 2 without modifier; flow rate = 100 mL / min, ABPR 120 bar, MBPR 40 psi, column temperature 40 ℃) to separate the racemic material to obtain the first eluting enantiomer E1 (12.2 mg, 100% ee, Rf = 6.91 min) and the second eluting enantiomer E2 (3.6 mg, 96% ee , Rf = 7.45 min). The second enantiomer contained inseparable impurities and was not further purified. [example]

[73] : (R)-1-(4-((6-phenylpyrazolo[1,5-a]pyrazin-4-yl)oxy)azepan-1-yl)propane -2-en-1-one Synthesis of (R)-4-((6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5 -a]pyrazin-4-yl)oxy)azepane-1-carboxylic acid tertiary butyl ester

[0295] (R)-4-((6-chloropyrazolo[1,5-a]pyrazin-4-yl)oxy)azepane- To a 20-mL scintillation vial of tert-butyl-1-carboxylate (734 mg, 2.0 mmol) was added bis(pinacol)diboron (610 mg, 2.4 mmol). Next, KOAc (589 mg, 6.0 mmol) was added to the reaction mixture followed by [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (293 mg, 0.40 mmol ). The vial was purged with N 2 followed by stirring overnight at 95 °C. After this time, the reaction mixture was cooled to room temperature and filtered through a pad of Celite® with the help of EtOAc. The crude material was dry loaded onto silica gel and purified by silica gel chromatography (0 to 40% EtOAc / heptane) to afford (R)-4-((6-(4,4, 5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)azepine Heptane-tert-butyl 1-carboxylate (744 mg, 81% yield). LC-MS: m / z=399.2 (M-86+Na)+. Synthesis of (R)-4-((6-phenylpyrazolo[1,5-a]pyrazin-4-yl)oxy)azepane-1-carboxylic acid tertiary butyl ester

[0296] To accommodate (R)-4-((6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1 ,5-a]pyrazin-4-yl)oxy)azepane-1-carboxylic acid tert-butyl ester (248 mg, 0.54 mmol) in dioxane (1.8 mL) in a 20-mL scintillation vial Bromobenzene (38 µL, 0.36 mmol) was added to the solution, followed by aqueous K 3PO 4 (0.5 M, 1.44 mL, 0.72 mmol) and Pd-PEPPSI™-IPr (49 mg, 72 µmol). The reaction mixture was heated at 95 °C overnight, after which it was cooled to room temperature and directly concentrated under reduced pressure. The crude material was purified by silica gel chromatography (0 to 100% EtOAc / heptane) to afford (R)-4-((6-phenylpyrazolo[1,5-a]pyrazine- 4-yl)oxy)azepane-1-carboxylic acid tert-butyl ester (47.6 mg, 32% yield). LC-MS: m / z = 409.2 (M+H)+. Synthesis of (R)-4-(azepan-4-yloxy)-6-phenylpyrazolo[1,5-a]pyrazine

[0297] To (R)-4-((6-phenylpyrazolo[1,5-a]pyrazin-4-yl)oxy)azepane-1-carboxylic acid tertiary butyl ester (48 mg, 0.12 mmol) in dioxane (1.2 mL) was added HCl (4 M in dioxane, 1.2 mmol, 291 µL). Immediately after the addition of HCl solution, the reaction mixture turned into a white slurry and was stirred at room temperature for 4 hours. Concentration of the reaction mixture directly under reduced pressure afforded crude (R)-4-(azepan-4-yloxy)-6-phenylpyrazolo[1,5-a]pyrazine, presumed to produce The yield was 100%, which was used without further purification. LC-MS: m / z = 332.2 (M+Na)+. Synthesis of (R)-1-(4-((6-phenylpyrazolo[1,5-a]pyrazin-4-yl)oxy)azepan-1-yl)propan-2- en-1-one

[0298] Crude (R)-4-(azepan-4-yloxy)-6-phenylpyrazolo[1,5-a]pyrazine (36 mg, 0.12 mmol) was dissolved in THF (1.2 mL ) in a dry ice / acetone bath cooled to -78°C. Triethylamine (81 µL, 0.58 mmol) was added via a micro-syringe with stirring, followed immediately by acryloyl chloride (19 µL, 0.23 mmol). The reaction mixture was removed from the ice bath and allowed to warm slowly to room temperature, turning red in the process. After stirring at room temperature for 2 h, the reaction mixture was diluted with EtOAc and quenched by adding saturated aqueous NaHCO 3 . The resulting layers were separated, and the aqueous layer was further extracted with EtOAc (2x). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product as a pale yellow oil. The crude material was purified by reverse phase HPLC (column: Waters XSelect CSH Prep C18 5µm OBD 19x100mm; conditions: 5-70% acetonitrile in 0.1% v / v ammonium carbonate / water) to afford (R) as a yellow film. -1-(4-((6-Phenylpyrazolo[1,5-a]pyrazin-4-yl)oxy)azepan-1-yl)prop-2-en-1- Ketone (16.7 mg, 40% yield over 2 steps). LC-MS: m / z = 363.3 (M+H)+. 1H NMR (500 MHz, DMSO-d 6) δ ppm 1.71 - 1.80 (m, 1 H) 1.87 - 2.13 (m, 5 H) 2.18 - 2.30 (m, 1 H) 3.52 - 3.78 (m, 4 H) 5.54 - 5.62 (m, 1H) 5.70 (dt, J=10.38, 2.14 Hz, 1H) 6.15 - 6.21 (m, 1H) 6.77 - 6.88 (m, 2H) 7.37 - 7.42 (m, 1H) 7.45 - 7.50 (m, 2H) 8.07 - 8.11 (m, 3H) 9.03 (s, 1H). [example]

[74] : (R)-1-(4-((6-(6-methoxypyrimidin-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)nitrogen Heteroheptan-1-yl)prop-2-en-1-one Synthesis of (R)-4-((6-(6-methoxypyrimidin-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)azepane-1 - Tertiary butyl formate

[0299] To accommodate (R)-4-((6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1 ,5-a]pyrazin-4-yl)oxy)azepane-1-carboxylic acid tert-butyl ester (138 mg, 0.30 mmol) in dioxane (3.0 mL) in a 2-dram scintillation vial 4-Bromo-6-methoxypyrimidine (38 mg, 0.20 mmol) was added. Then aqueous K 3PO 4 (0.5 M, 0.80 mL, 0.40 mmol) was added, followed by Pd-PEPPSI™-IPr (41 mg, 40 μmol). The reaction mixture was heated at 95 °C overnight, after which it was cooled to room temperature and directly concentrated under reduced pressure. The crude material was purified by silica gel chromatography (0 to 50% [3:1 EtOAc:EtOH] / heptane) to afford (R)-4-((6-(6-methoxypyrimidin-4-yl) Pyrazolo[1,5-a]pyrazin-4-yl)oxy)azepane-1-carboxylic acid tert-butyl ester (98.6 mg, 75% yield). LC-MS: m / z = 441.2 (M+H)+. Synthesis of (R)-4-(azepan-4-yloxy)-6-(6-methoxypyrimidin-4-yl)pyrazolo[1,5-a]pyrazine

[0300] To (R)-4-((6-(6-methoxypyrimidin-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)azepane-1 - To a solution of tert-butyl formate (99 mg, 0.22 mmol) in dioxane (2.2 mL) was added HCl (4 M in dioxane, 2.2 mmol, 0.56 mL), forming a milky white slurry. After stirring at room temperature for 4 hours, the reaction mixture was directly concentrated under reduced pressure to afford crude (R)-4-(azepan-4-yloxy)-6-(6-methoxypyrimidine-4 -yl)pyrazolo[1,5-a]pyrazine, assumed 100% yield, which was used without further purification. LC-MS: m / z = 363.3 (M+Na)+. Synthesis of (R)-1-(4-((6-(6-methoxypyrimidin-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)azepane Alk-1-yl) prop-2-en-1-one

[0301] Crude (R)-4-(azepan-4-yloxy)-6-(6-methoxypyrimidin-4-yl)pyrazolo[1,5-a]pyrazine (76 mg, 0.22 mmol) in THF (2.2 mL) was cooled to -78 °C in a dry ice / acetone bath. Triethylamine (156 µL, 1.1 mmol) was added with stirring, followed immediately by acryloyl chloride (36 µL, 0.45 mmol). The reaction mixture was removed from the ice bath and allowed to warm slowly to room temperature, turning red in the process. After stirring at room temperature for 2 h, the reaction mixture was diluted with EtOAc and quenched by adding saturated aqueous NaHCO 3 . The resulting layers were separated, and the aqueous layer was further extracted with EtOAc (2x). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product as a yellow oil. The crude material was purified via reverse phase HPLC (column: Waters XSelect CSH Prep C18 5 μm OBD 19x100 mm; conditions: 5-65% acetonitrile in 0.1% v / v ammonium carbonate / water) to afford (R)- 1-(4-((6-(6-methoxypyrimidin-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)azepan-1-yl ) prop-2-en-1-one (22.7 mg, 26% yield over 2 steps). LC-MS: m / z = 395.3 (M+H)+. 1H NMR (500 MHz, DMSO- d 6 ) δ ppm 1.71 - 1.81 (m, 1 H) 1.87 - 1.95 (m, 1 H) 1.97 (br s, 1 H) 1.98 - 2.11 (m, 2 H) 2.20 - 2.30 (m, 1H) 3.53 - 3.81 (m, 4H) 3.99 - 4.02 (m, 1H) 4.00 (s, 1H) 5.57 - 5.64 (m, 1H) 5.68 - 5.72 (m, 1H) 6.18 (dt, J=16.79, 2.59 Hz, 1 H) 6.82 (dt, J=16.48, 10.07 Hz, 1 H) 6.95 - 6.98 (m, 1 H) 7.53 (dd, J=10.99, 1.22 Hz, 1 H ) 8.17 - 8.22 (m, 1 H) 8.19 - 8.19 (m, 1 H) 8.19 - 8.20 (m, 1 H) 8.82 - 8.87 (m, 1 H) 8.83 - 9.11 (m, 1 H) 9.09 (s, 1H). [example]

[75] : (R)-1-(4-((6-(4-methyloxazol-2-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)nitrogen Heteroheptan-1-yl)prop-2-en-1-one Synthesis of (R)-4-((6-(4-methyloxazol-2-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)azepane-1 - Tertiary butyl formate

[0302] To accommodate (R)-4-((6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1 ,5-a]pyrazin-4-yl)oxy)azepane-1-carboxylic acid tert-butyl ester (138 mg, 0.30 mmol) in dioxane (3.0 mL) in a 2-dram scintillation vial 2-Bromo-4-methyloxazole (32 mg, 0.20 mmol) was added. Next, aqueous K 3PO 4 (0.5 M, 0.80 mL, 0.40 mmol) was added, followed by Pd-PEPPSI™-IPr (41 mg, 40 μmol). The reaction mixture was heated at 95 °C overnight, after which it was cooled to room temperature and directly concentrated under reduced pressure. The crude material was purified by silica gel chromatography (0 to 50% [3:1 EtOAc:EtOH] / heptane) to afford (R)-4-((6-(4-methyloxazol-2-yl) Pyrazolo[1,5-a]pyrazin-4-yl)oxy)azepane-1-carboxylic acid tert-butyl ester (95.4 mg, 77% yield). LC-MS: m / z = 441.2 (M+H)+. Synthesis of (R)-2-(4-(azepan-4-yloxy)pyrazolo[1,5-a]pyrazin-6-yl)-4-methyloxazole

[0303] To (R)-4-((6-(4-methyloxazol-2-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)azepane-1 - To a solution of tert-butyl formate (95 mg, 0.23 mmol) in dioxane (2.3 mL) was added HCl (4 M in dioxane, 2.3 mmol, 0.58 mL), forming a bright yellow slurry. After stirring at room temperature for 4 h, the reaction mixture was directly concentrated under reduced pressure to afford crude (R)-2-(4-(azepan-4-yloxy)pyrazolo[1,5-a ]pyrazin-6-yl)-4-methyloxazole, assumed 100% yield, which was used without further purification. LC-MS: m / z = 314.1 (M+Na)+. Synthesis of (R)-1-(4-((6-(4-methyloxazol-2-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)azepane Alk-1-yl) prop-2-en-1-one

[0304] Crude (R)-2-(4-(azepan-4-yloxy)pyrazolo[1,5-a]pyrazin-6-yl)-4-methyloxazole (72 mg, 0.23 mmol) in THF (2.3 mL) was cooled to -78 °C in a dry ice / acetone bath. Triethylamine (161 µL, 1.2 mmol) was added with stirring, followed immediately by acryloyl chloride (38 µL, 0.46 mmol). The reaction mixture was removed from the ice bath and allowed to warm slowly to room temperature, turning red in the process. After stirring at room temperature for 2 h, the reaction mixture was diluted with EtOAc and quenched by adding saturated aqueous NaHCO 3 . The resulting layers were separated, and the aqueous layer was further extracted with EtOAc (2x). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product as a yellow solid. The crude material was purified via reverse phase HPLC (column: Waters XSelect CSH Prep C18 5 µm OBD 19x100 mm; conditions: 5-55% acetonitrile in 0.1% v / v ammonium carbonate / water) to afford (R)- 1-(4-((6-(4-methyloxazol-2-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)azepan-1-yl ) prop-2-en-1-one (28.2 mg, 22% yield over 2 steps). LC-MS: m / z = 368.3 (M+H)+. 1H NMR (500 MHz, DMSO- d 6 ) δ ppm 1.67 - 1.79 (m, 1 H) 1.83 - 1.96 (m, 2 H) 2.02 - 2.13 (m, 3 H) 2.18 (d, J=1.22 Hz, 4 H) 3.54 - 3.77 (m, 3 H) 5.53 - 5.60 (m, 1 H) 5.69 (ddd, J=10.38, 3.66, 2.44 Hz, 1 H) 6.13 - 6.20 (m, 1 H) 6.80 (ddd, J =16.48, 14.04, 10.38 Hz, 1 H) 6.95 - 6.98 (m, 1 H) 7.97 (s, 1 H) 8.18 (d, J=1.22 Hz, 1 H) 8.90 (s, 1 H). [example]

[76] : (R)-1-(4-((6-(2-methylthiazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)azepine Cycloheptan-1-yl)prop-2-en-1-one Synthesis of (R)-4-((6-(2-methylthiazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)azepane-1- Tertiary butyl formate

[0305] (R)-4-((6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5 - a]pyrazin-4-yl)oxy)azepane-1-carboxylic acid tert-butyl ester (193 mg, 0.42 mmol), 4-bromo-2-methyl-thiazole (50 mg, 0.28 mmol ), dihydrodichlorobis(di-tertiary butylphosphinoyl)palladium(2-) (7 mg, 14 µmol) and cesium fluoride (128 mg, 0.84 mmol) in isopropanol (1.4 mL) The solution was stirred in the microwave at 90°C for 3 hours. The reaction was quenched with water and brine. The biphasic mixture was extracted three times with ethyl acetate, followed by drying over anhydrous MgSO 4 . After filtration and concentration under reduced pressure, the crude (R)-4-((6-(2-methylthiazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy ) azepane-1-carboxylic acid tert-butyl ester (110 mg, 91% yield) was used without further purification. LCMS: m / z = 430.0 (M+H)+. Synthesis of (R)-1-(4-((6-(2-methylthiazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)azepane -1-yl) prop-2-en-1-one

[0306] Step 1. The crude (R)-4-((6-(2-methylthiazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)azepane Tert-butyl alkane-1-carboxylate (110 mg, 0.26 mmol) was dissolved in HCl solution (1.25 M in MeOH, 1.5 mL). The reaction solution was stirred at 40°C. After 16 h, the reaction was carefully quenched by the slow addition of saturated aqueous NaHCO3. The biphasic mixture was extracted three times with a mixture of chloroform and isopropanol (5:1), then dried over anhydrous MgSO4. After filtration and concentration under reduced pressure, the crude (R)-4-(4-(azepan-4-yloxy)pyrazolo[1,5-a]pyrazin-6-yl) -2-Methylthiazole (84 mg, assuming 100% yield) was concentrated to dryness and used without purification. LCMS: m / z = 330.0 (M+H)+.

[0307] Step 2. To accommodate crude (R)-4-(4-(azepan-4-yloxy)pyrazolo[1,5-a]pyrazin-6-yl)-2-methyl To a 20 mL vial of thiazole (84 mg, 0.25 mmol) was added DCM (1.0 mL) followed by TEA (129 mg, 1.27 mmol, 178 µL). The reaction mixture was stirred at room temperature for 5 minutes, then cooled to 0 °C. Acryloyl chloride (35 mg, 0.38 mmol, 31 µL) was added dropwise. The solution was stirred at 0 °C. After 1 h, the reaction mixture was carefully quenched by the slow addition of saturated aqueous NH4Cl. The biphasic mixture was extracted three times with ethyl acetate, followed by drying over anhydrous MgSO 4 . After filtration and concentration under reduced pressure, the residue was loaded onto a silica gel column and purified (25-100% ethyl acetate / heptane). Pooling of the desired fractions followed by concentration under reduced pressure afforded (R)-1-(4-((6-(2-methylthiazol-4-yl)pyrazolo[1,5-a]pyrazine -4-yl)oxy)azepan-1-yl)prop-2-en-1-one (31.2 mg, 32% yield). 1H NMR (500 MHz, DMSO- d 6) δ ppm 8.67 (s, 1 H) 8.08 (s, 1 H) 7.96 (s, 1 H) 7.92 (rotamer, s, 1 H) 6.77 - 6.89 ( ( d, J= 1.22 Hz, 3 H) 2.23 (ddt, J= 10.91, 7.25, 3.43, 3.43 Hz, 1 H) 1.87 - 2.09 (m, 4 H) 1.71 - 1.82 (m, 1 H). LCMS m / z = 384.0 (M+H)+. [example]

[77] : (R)-1-(4-((6-(2-methylthiazol-5-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)azepine Cycloheptan-1-yl)prop-2-en-1-one Synthesis of (R)-4-((6-(2-methylthiazol-5-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)azepane-1- Tertiary butyl formate

[0308] (R)-4-((6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo [1,5-a]pyrazin-4-yl)oxy)azepane-1-carboxylic acid tert-butyl ester (200 mg, 0.44 mmol), 5-bromo-2-methyl-thiazole (156 mg, 0.87 mmol), dihydrodichlorobis(di-tertiary butylphosphinoyl) palladium (2-) (22 mg, 44 µmol) and cesium fluoride (199 mg, 1.3 mmol) in isopropanol (1.0 mL). After 16 hours, the reaction was quenched with water and brine. The biphasic mixture was extracted three times with ethyl acetate, followed by drying over anhydrous MgSO 4 . After filtration and concentration under reduced pressure, the crude (R)-4-((6-(2-methylthiazol-5-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy ) azepane-1-carboxylic acid tert-butyl ester (187 mg, assuming 100% yield) was used without further purification. LCMS: m / z = 430.0 (M+H)+. Synthesis of (R)-1-(4-((6-(2-methylthiazol-5-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)azepane -1-yl) prop-2-en-1-one

[0309] Step 1. The crude (R)-4-((6-(2-methylthiazol-5-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)azepane Tert-butyl alkane-1-carboxylate (187 mg, 0.44 mmol) was dissolved in HCl solution (1.25 M in MeOH, 1.7 mL). The reaction solution was stirred at 40°C. After 16 h, the reaction was carefully quenched by the slow addition of saturated aqueous NaHCO3. The biphasic mixture was extracted three times with a mixture of chloroform and isopropanol (5:1), then dried over anhydrous MgSO4. After filtration and concentration under reduced pressure, the crude (R)-5-(4-(azepan-4-yloxy)pyrazolo[1,5-a]pyrazin-6-yl) -2-Methylthiazole (143 mg, assuming 100% yield) was concentrated to dryness and used without purification. LCMS: m / z = 330.0 (M+H)+.

[0310] Step 2. To accommodate crude (R)-5-(4-(azepan-4-yloxy)pyrazolo[1,5-a]pyrazin-6-yl)-2-methyl To a 20 mL vial of thiazole (143 mg, 0.44 mmol) was added DCM (2 mL) followed by TEA (439 mg, 4.34 mmol, 605 µL). The reaction mixture was stirred at room temperature for 5 minutes, then cooled to 0 °C. Acryloyl chloride (79 mg, 0.87 mmol, 71 µL) was added dropwise. The solution was stirred at 0 °C. After 1 h, the reaction mixture was carefully quenched by the slow addition of saturated aqueous NH4Cl. The biphasic mixture was extracted three times with ethyl acetate, followed by drying over anhydrous MgSO 4 . After filtration and concentration under reduced pressure, the residue was loaded onto a silica gel column and purified (25-100% ethyl acetate / heptane). Pooling of the desired fractions followed by concentration under reduced pressure afforded (R)-1-(4-((6-(2-methylthiazol-5-yl)pyrazolo[1,5-a]pyrazine -4-yl)oxy)azepan-1-yl)prop-2-en-1-one (29.8 mg, 18% yield). 1H NMR (500 MHz, DMSO-d 6) δ ppm 9.02 - 9.04 (m, 1 H) 8.25 (d, J= 2.44 Hz, 1 H) 8.09 (dd, J= 2.44, 1.22 Hz, 1 H) 6.89 ( d, J= 3.05 Hz, 1 H) 6.81 (ddd, J= 16.48, 12.82, 10.38 Hz, 1 H) 6.17 (ddd, J= 16.63, 7.48, 2.75 Hz, 1 H) 5.70 (dt, J= 10.38, 2.44 Hz, 1H) 5.38 - 5.44 (m, 1H) 3.55 - 3.75 (m, 4H) 2.68 (s, 3H) 2.15 - 2.26 (m, 1H) 1.87 - 2.10 (m, 4H) 1.68 - 1.80 (m, 1H). LCMS m / z = 384.0 (M+H)+. [example]

[78] : (R)-1-(4-((6-(3-methylisothiazol-5-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)nitrogen Heteroheptan-1-yl)prop-2-en-1-one Synthesis of (R)-4-((6-(3-methylthiazol-5-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)azepane-1- Tertiary butyl formate

[0311] (R)-4-((6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo [1,5-a]pyrazin-4-yl)oxy)azepane-1-carboxylic acid tert-butyl ester (80 mg, 175 µmol), 5-bromo-3-methyl-isothiazole ( 47 mg, 262 µmol), dihydrodichlorobis(di-tertiary butylphosphinoyl) palladium (2-) (4.4 mg, 8.7 µmol) and cesium fluoride (80 mg, 524 µmol) in isopropyl solution in alcohol (1.0 mL). After 16 hours, the reaction was quenched with water and brine. The biphasic mixture was extracted three times with ethyl acetate, followed by drying over anhydrous MgSO 4 . After filtration and concentration under reduced pressure, the crude (R)-4-((6-(3-methylisothiazol-5-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy yl) azepane-1-carboxylic acid tert-butyl ester (75 mg, assuming 100% yield) was used without further purification. LCMS: m / z = 430.0 (M+H)+. Synthesis of (R)-1-(4-((6-(3-methylisothiazol-5-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)azepane Alk-1-yl) prop-2-en-1-one

[0312] Step 1. The crude (R)-4-((6-(3-methylisothiazol-5-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)azheterocyclic Heptane-1-carboxylic acid tert-butyl ester (75 mg, 175 µmol) was dissolved in HCl solution (1.25 M in MeOH, 1.4 mL). The reaction solution was stirred at 40°C. After 16 h, the reaction was carefully quenched by the slow addition of saturated aqueous NaHCO3. The biphasic mixture was extracted three times with a mixture of chloroform and isopropanol (5:1), then dried over anhydrous MgSO4. After filtration and concentration under reduced pressure, the crude (R)-5-(4-(azepan-4-yloxy)pyrazolo[1,5-a]pyrazin-6-yl) -3-Methylisothiazole (58 mg, assumed 100% yield) was concentrated to dryness and used without purification. LCMS: m / z = 330.0 (M+H)+.

[0313] Step 2. To accommodate crude (R)-5-(4-(azepan-4-yloxy)pyrazolo[1,5-a]pyrazin-6-yl)-3-methyl To a 20 mL vial of isothiazole (58 mg, 175 µmol) was added DCM (1.0 mL) followed by TEA (88 mg, 0.87 mmol, 122 µL). The reaction mixture was stirred at room temperature for 5 minutes, then cooled to 0 °C. Acryloyl chloride (24 mg, 262 µmol, 21 µL) was added dropwise. The solution was stirred at 0 °C. After 1 h, the reaction mixture was carefully quenched by the slow addition of saturated aqueous NH4Cl. The biphasic mixture was extracted three times with ethyl acetate, followed by drying over anhydrous MgSO 4 . After filtration and concentration under reduced pressure, the residue was loaded onto a silica gel column and purified (25-100% ethyl acetate / heptane). Pooling of the desired fractions followed by concentration under reduced pressure afforded (R)-1-(4-((6-(3-methylisothiazol-5-yl)pyrazolo[1,5-a]pyridine azin-4-yl)oxy)azepan-1-yl)prop-2-en-1-one (21.3 mg, 32% yield). 1H NMR (500 MHz, DMSO-d6) δ ppm 9.21 (d, J= 1.22 Hz, 1 H) 8.15 (dd, J= 2.44, 1.22 Hz, 1 H) 7.80 (d, J= 2.44 Hz, 1 H ) 6.94 (d, J= 3.05 Hz, 1 H) 6.81 (dt, J= 16.63, 10.30 Hz, 1 H) 6.14 - 6.21 (m, 1 H) 5.69 (ddd, J= 10.38, 5.49, 2.44 Hz, 1 H) 5.34 - 5.43 (m, 1 H) 3.65 - 3.76 (m, 2 H) 3.53 - 3.64 (m, 2 H) 2.45 (s, 3 H) 2.17 - 2.29 (m, 1 H) 1.95 - 2.12 (m , 3 H) 1.86 - 1.93 (m, 1 H) 1.63 - 1.83 (m, 1 H). LCMS m / z = 384.0 (M+H)+. [example]

[79] : N-methyl-N-((1s,3s)-3-methyl-3-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1, 5-a]pyrazin-4-yl)oxy)cyclobutyl)acrylamide Synthesis of methyl((1s,3s)-3-methyl-3-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-4 - yl) oxy) cyclobutyl) tertiary butyl carbamate

[0314] In a 100-mL single-necked round-bottom flask equipped with a condenser, potassium hexamethyldisilazide (1 M in THF, 2.2 mL) was added to ((1 s, 3 s) A solution of tertiary-butyl 3-hydroxy-3-methylcyclobutyl)carbamate (150 mg, 0.75 mmol) in dioxane (7.5 mL). After 5 min, a solution of 4,6-dichloropyrazolo[1,5-a]pyrazine (128 mg, 0.68 mmol) in dioxane (2.5 mL) was added dropwise to the thick white suspension middle. Iodomethane (240 mg, 1.70 mmol, 105 µL) was added to the resulting orange suspension at room temperature and stirring was continued for another 30 minutes. The resulting reaction mixture was degassed by purging with nitrogen for 30 minutes, after which a degassed solution of tripotassium phosphate (531 mg, 2.50 mmol) in water (2.5 mL) was added at room temperature. After purging the clear orange reaction mixture with nitrogen for another 10 min, 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2 A previously degassed solution of pyrazole (212 mg, 1.02 mmol) in dioxane (2.0 mL) was followed by the addition of solid Pd-PEPPSI™-IPr catalyst (93 mg, 0.14 mmol). After purging the reaction mixture with nitrogen for an additional 15 minutes, the reaction mixture was heated at reflux for 3 hours. To the vigorously stirred reaction mixture was added ethyl acetate (20 mL) followed by water (20 mL). After 30 minutes, the organic phase was separated and the volatiles were removed under reduced pressure. The resulting residue was purified by column chromatography (40 g silica gel, 0-80% [3:1 EtOAc:EtOH] with 2% NH4OH modifier in heptane) to give The title compound (130 mg, 47% yield). LCMS m / z = 413.1 (M+H)+. 1H NMR (500 MHz, methanol-d 4) δ ppm 8.42 (s, 1H), 8.05 (s, 1H), 7.93 (s, 1H), 7.91 (d, J=2.44 Hz, 1H), 6.77 (d, J=1.22 Hz, 1H), 4.10-4.45 (m, 1H), 3.95 (s, 3H), 2.82 (s, 3H), 2.74-2.81 (m, 2H), 2.67 (brs, 2H), 1.81 ( s, 3H), 1.46 (s, 9H). Synthesis of (1s,3s)-N,3-dimethyl-3-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-4 - yl) oxy) cyclobutan-1-amine

[0315] Methyl((1 s,3 s)-3-methyl-3-((6-(1-methyl-1 H-pyrazol-4-yl)pyrazolo[1,5 - a] To a solution of tert-butyl pyrazin-4-yl)oxy)cyclobutyl)carbamate (4.05 g, 9.82 mmol) in HFIP (45 mL) was added TFA (2.24 g, 19.6 mmol, 1.5 mL). The resulting reaction mixture was stirred overnight. Ethyl acetate (50 mL) was added followed by saturated aqueous NaHCO 3 (25 mL) and brine (10 mL). After vigorous stirring for 30 min, the organic phase was separated, dried over sodium sulfate, filtered and concentrated. The resulting residue was purified by column chromatography (24 g silica gel, 80-100% [3:1 EtOAc:EtOH] with 2% NH4OH modifier in heptane) to give a pale yellow gum The title compound (2.53 g, 82% yield). LCMS m / z = 313.1 (M+H)+. 1H NMR (500 MHz, methanol-d 4 ) δ ppm 8.41 (d, J=1.22 Hz, 1H), 8.05 (s, 1H), 7.86-7.97 (m, 2H), 6.72-6.81 (m, 1H), 3.95 (s, 3H), 2.96-3.11 (m, 1H), 2.76-2.90 (m, 2H), 2.31 (s, 3H), 2.25-2.31 (m, 2H), 2.25-2.31 (m, 2H), 1.80 (s, 3H). Synthesis of N-methyl-N-((1s,3s)-3-methyl-3-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a ]pyrazin-4-yl)oxy)cyclobutyl)acrylamide

[0316] N-methyl-N-((1 s,3 s)-3-methyl-3-((6-(1-methyl-1 H-pyrazol-4-yl)pyrazole [1,5-a]pyrazin-4-yl)oxy)cyclobutyl)acrylamide (4.05 g, 9.82 mmol) and DIPEA (2.81 g, 21.7 mmol, 3.8 mL) in THF (50 mL) Acryloyl chloride (819 mg, 9.04 mmol, 740 µL) was added to the solution in . After 30 minutes, the reaction mixture was diluted with EtOAc (50 mL) and saturated aqueous NaHCO 3 (50 mL) was added. The vigorously stirred biphasic mixture was allowed to reach room temperature and stirring was continued for another 30 minutes. The organic phase was separated, washed with water (25 mL) and brine (25 mL), dried over Na2SO4, filtered and concentrated. The resulting residue was purified by column chromatography (80 g silica gel, 0-100% [3:1 EtOAc:EtOH] with 2% NH4OH modifier in heptane). The colorless solid was recrystallized from EtOAc / heptane (1 / 3, 45 mL) to afford the title compound (1.8 g, 68% yield) as a free-flowing crystalline solid. Melting point = 137.5°C. LCMS m / z = 389.1.1 (M+Na)+. 1H NMR (500 MHz, methanol-d 4) δ ppm 8.44 (s, 1H), 8.06 (s, 1H), 7.85-7.98 (m, 2H), 6.67-6.85 (m, 2H), 6.12-6.26 (m , 1H), 5.74 (br d, J=9.16 Hz, 1H), 4.45-4.77 (m, 1H), 3.95 (s, 3H), 2.94-3.12 (m, 3H), 2.62-2.94 (m, 4H) , 1.86 (s, 3H). [example]

[80] : N-((1s,3s)-3-((6-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)- 3-Methylcyclobutyl)-N-methacrylamide Synthesis of ((1s,3s)-3-((6-chloropyrazolo[1,5-a]pyrazin-4-yl)oxy)-3-methylcyclobutyl)(methyl)amino Tertiary butyl formate

[0317] In a 100-mL single-necked round-bottom flask equipped with a condenser, potassium hexamethyldisilazide (1 M in THF, 6.8 mL) was added to ((1 s, 3 s) A solution of tertiary-butyl 3-hydroxy-3-methylcyclobutyl)carbamate (500 mg, 2.48 mmol) in dioxane (25 mL). After another 15 minutes, a solution of 4,6-dichloropyrazolo[1,5-a]pyrazine (425 mg, 2.26 mmol) in dioxane (7.5 mL) was added dropwise to the thick white in suspension. After a further 30 minutes, iodomethane (240 mg, 1.70 mmol, 105 µL) was added dropwise to the resulting orange suspension at room temperature and stirring was continued for 30 minutes. The reaction mixture was diluted with EtOAc (40 mL) and washed with water (30 mL). The organic phase was separated, concentrated under reduced pressure, and purified by column chromatography (40 g silica gel, 0-80% [3:1 EtOAc:EtOH] with 2% NH4OH modifier in heptane) Purification afforded the title compound (555 mg, 67% yield) as a beige solid. LCMS m / z = 367.1 (M+H)+. Synthesis of 4-(4-((1s,3s)-3-((tertiary butoxycarbonyl)(methyl)amino)-1-methylcyclobutoxy)pyrazolo[1,5-a ] Pyrazin-6-yl)-1H-pyrazole-1-carboxylic acid tertiary butyl ester

[0318] To ((1s,3s)-3-((6-chloropyrazolo[1,5-a]pyrazin-4-yl)oxy)-3-methylcyclobutyl)(methyl)amino Tertiary butyl formate (500 mg, 1.36 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole- To a solution of tertiary-butyl 1-formate (802 mg, 2.73 mmol) in dioxane (15 mL) was added sequentially Pd-PEPPSI™-IPr catalyst (186 mg, 0.27 mmol), tripotassium phosphate (579 mg , 2.73 mmol) and water (3 mL). The resulting mixture was degassed by purging with nitrogen for 30 minutes. After heating at reflux for 1 h, the reaction mixture was cooled to room temperature and EtOAc (20 mL) and water (20 mL) were added. After vigorous stirring for 30 min, the organic phase was separated, washed with brine (20 mL), dried over Na 2 SO 4 , and concentrated under reduced pressure. The crude residue was purified by column chromatography (40 g silica gel, 0-60% [3:1 EtOAc:EtOH] with 2% NH4OH modifier in heptane) to give the product as an orange gum The title compound (640 mg, 94% yield). LCMS m / z = 499.2 (M+H)+. Synthesis of (1s,3s)-3-((6-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)-N,3-dimethyl Cyclobutan-1-amine

[0319] To 4-(4-((1 s,3 s)-3-((tertiary butoxycarbonyl)(methyl)amino)-1-methylcyclobutoxy)pyrazolo[ To a solution of 1,5-a]pyrazin-6-yl)-1H-pyrazole-1-carboxylic acid tert-butyl ester (360 mg, 0.72 mmol) in HFIP (5 mL) was added TFA (374 mg, 3.3 mmol, 250 μL). The resulting reaction mixture was stirred for 2 hours. Ethyl acetate (20 mL) was added at room temperature, followed by saturated aqueous NaHCO 3 (10 mL) and brine (10 mL). After vigorous stirring for 30 min, the organic phase was separated, dried over sodium sulfate, filtered and concentrated. The resulting residue was purified by column chromatography (12 g silica gel, 80-100% [3:1 EtOAc:EtOH] with 2% NH4OH modifier in heptane) to give The title compound (162 mg, 75% yield). LCMS m / z = 299.0 (M+H)+. Synthesis of N-((1s,3s)-3-((6-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)-3-methyl Cyclobutyl)-N-methacrylamide

[0320] To (1 s,3 s)-3-((6-(1 H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy) at 0°C - To a solution of N,3-dimethylcyclobutan-1-amine (162 mg, 0.54 mmol) and DIPEA (211 mg, 1.63 mmol, 290 µL) in THF (5 mL) was added acryloyl chloride (54 mg , 0.60 mmol, 50 µL). After 30 minutes, the reaction mixture was diluted with EtOAc (20 mL) and saturated aqueous NaHCO 3 (20 mL) was added. The biphasic mixture was allowed to reach room temperature and vigorous stirring was continued for another 30 minutes. The organic phase was separated, washed sequentially with water (10 mL) and brine (10 mL), dried over Na2SO4, filtered and concentrated. The resulting residue was purified by column chromatography (12 g silica gel, 0-100% [3:1 EtOAc:EtOH] with 2% NH4OH modifier in heptane) to give The title compound (65 mg, 34% yield). LCMS m / z = 375.1 (M+Na)+. 1H NMR (500 MHz, methanol- d 4 ) δ ppm 8.39-8.48 (m, 1H), 8.07 (br s, 2H), 7.83-7.95 (m, 1H), 6.62-6.86 (m, 2H), 6.08- 6.27 (m, 1H), 5.56-5.83 (m, 1H), 4.03-4.75 (m, 1H), 2.88-3.09 (m, 3H), 2.44-2.88 (m, 4H), 1.83 (m, 3H). [example]

[81] . 1-(3-(2-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy) Ethyl) N-morpholino) prop-2-en-1-one [] 1. Synthesis of tertiary-butyl 3-(2-((methylsulfonyl)oxy)ethyl)morpholine-4-carboxylate

[0321] TEA (1.1 equiv) was added to 6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-ol (1.0 equiv) in anhydrous DCM (10 mL ), methanesulfonyl chloride (1.05 equiv) was then added, and the reaction mixture was stirred for 14 hours. The mixture was washed with H2O (10 mL), dried over Na2SO4, filtered and concentrated in vacuo to give the crude product which was used directly in the next step 2. Synthesis of 3-(2-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)ethyl)methanol tertiary butyl phenoline-4-carboxylate

[0322] 6-(1-Methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-ol (Intermediate C, step 2, 1.0 eq.) under Ar (g) , Cs 2CO 3 (1.1 equivalents), 3-(2-((methylsulfonyl)oxy)ethyl)morpholine-4-carboxylic acid tertiary butyl ester (1.0 equivalents) in anhydrous DMF (1 mL) The mixture was heated at 100°C for 16 hours. The reaction mixture was diluted with H 2 O (10 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (10 mL), dried over Na 2 SO 4 , filtered and concentrated in vacuo to give the crude product which was used directly in the next step. 3. Synthesis of 3-(2-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)ethyl)methanol Phenyl hydrochloride

[0323] To 3-(2-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)ethyl)morpholine- To a solution of tert-butyl 4-carboxylate (1 eq) in DCM (10 mL) was added 4M HCl in dioxane (10 eq) and the resulting solution was stirred at 25 °C for 14 h. The reaction mixture was concentrated under reduced pressure. The product was collected by filtration, washed with IPA (3×10 mL), and then dried under vacuum at 40 °C to give 3-(2-((6-(1-methyl-1H-pyrazol-4-yl)pyridine Azolo[1,5-a]pyridin-4-yl)oxy)ethyl)morpholine hydrochloride. 4. Synthesis of 1-(3-(2-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)ethyl Base) N-morpholinyl) prop-2-en-1-one

[0324] To 3-(2-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)ethyl)morpholine salt To a solution of acid salt (1 equiv) in DCM (10 mL) was added DIPEA (1.1 equiv), the mixture was cooled to -10 °C, acryloyl chloride (1.05 equiv) was added and the reaction was stirred at room temperature for 3 hours. The reaction mixture was washed with water (10 mL), dried over Na 2 SO 4 , filtered and concentrated in vacuo. The crude product was dissolved in DMSO (0.5 mL) and purified by preparative HPLC (Waters SunFire C18 19*100 5 mkm column) to give 1-(3-(2-((6-(1-methyl- 1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)ethyl)N-morpholinyl)prop-2-en-1-one, 10.2 mg. LCMS m / z = 382.2 (M+H)+. 1H NMR (400 MHz, CDCl 3 ) δ ppm: 8.43 - 8.25 (m, 1H), 7.86 (s, 1H), 7.70 (s, 1H), 7.64 - 7.55 (m, 1H), 6.65 - 6.39 (m, 3H), 6.21 (dd, J=16.7, 1.8 Hz, 1H), 5.68 - 4.43 (m, 2H), 4.30 - 4.03 (m, 2H), 4.01 - 3.83 (m, 5H), 3.72 - 3.01 (m, 3H), 2.55 - 2.45 (m, 1H), 2.32 - 2.25 (m, 2H) [example]

[82] . N-(5-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)bicyclo[2.2 .1] hept-2-yl)acrylamide

[0325] Following the procedure described in Example 81, from 6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-ol (Intermediate C, step 2) And (5-hydroxy bicyclo [2.2.1] hept-2-yl) tertiary butyl carbamate obtains N-(5-((6-(1-methyl-1H-pyrazol-4-yl) pyrazole Azolo[1,5-a]pyridin-4-yl)oxy)bicyclo[2.2.1]hept-2-yl)acrylamide. LCMS m / z = 378.2 (M+H)+. 1H NMR(400 MHz, CDCl 3 ) δ ppm: 8.27 (s, 1H), 7.89 (d, J=2.4 Hz, 1H), 7.72 (s, 1H), 7.59 (s, 1H), 6.58 (d, J =2.5 Hz, 1H), 6.43 (s, 1H), 6.25 (d, J=16.8 Hz, 1H), 6.07 (dd, J=17.0, 10.2 Hz, 1H), 5.83 (d, J=7.3 Hz, 1H ), 5.61 (d, J=10.3 Hz, 1H), 4.91 - 4.83 (m, 1H), 4.47 - 4.38 (m, 1H), 3.98 (s, 3H), 2.78 - 2.72 (m, 1H), 2.72 - 2.65 (m, 1H), 2.07 (t, J=13.3, 13.3 Hz, 2H), 1.73 - 1.59 (m, 4H) [example]

[83] . (R)-1-(2,2-Dimethyl-6-(((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a ]pyridin-4-yl)oxy)methyl)N-morpholinyl)prop-2-en-1-one

[0326] Following a method similar to that described in Example 81, from (R)-tert-butyl 6-(hydroxymethyl)-2,2-dimethylmorpholine-4-carboxylate and 6-(1-methyl- 1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-ol (intermediate C, step 2) to obtain (R)-1-(2,2-dimethyl-6- (((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)methyl)N-morpholinyl)propane- 2-en-1-one. LCMS m / z = 396.2 (M+H)+. 1H NMR (400 MHz, MeOH-d 4) δ ppm: 8.36 (s, 1H), 8.01 (s, 1H), 7.88 (s, 1H), 7.86 (d, J=2.4 Hz, 1H), 6.91 - 6.72 (m, 2H), 6.66 (s, 1H), 6.29 (dd, J=16.9, 8.1 Hz, 1H), 5.81 (dd, J=11.0, 5.6 Hz, 1H), 4.54 (dd, J=142.3, 13.0 Hz, 1H), 4.29 - 4.17 (m, 3.5H), 3.97 - 3.90 (m, 3.5H), 3.28 - 3.08 (m, 1H), 2.86 - 2.69 (m, 1H), 1.32 - 1.23 (m, 6H ) [example]

[84] [and]

[85] . 1-((1R,5S,6s)-6-(((3-fluoro-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a ]pyridin-4-yl)oxy)methyl)-3-azabicyclo[3.1.1]hept-3-yl)prop-2-en-1-one and 1-((1R,5S,6r) -6-(((3-fluoro-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)methyl)- 3-Azabicyclo[3.1.1]hept-3-yl)prop-2-en-1-one [] 1. Synthesis of tertiary butyl 6-(((methylsulfonyl)oxy)methyl)-3-azabicyclo[3.1.1]heptane-3-carboxylate

[0327] Add tertiary-butyl 6-(hydroxymethyl)-3-azabicyclo[3.1.1]heptane-3-carboxylate (1 g, 4.40 mmol) and TEA (1.34 g, 13.2 mmol) in DCM (20 mL ) was added methanesulfonyl chloride (0.72 g, 6.29 mmol) and the reaction was stirred at 0 °C for 1 hour. Water (10 mL) was added and the mixture was extracted with DCM (20 mL x 3). The combined organics were washed with brine (20 mL), dried over NaSO, filtered and concentrated in vacuo to give 6-(((methylsulfonyl)oxy)methyl)-3-nitrogen as a yellow oil Heterobicyclo[3.1.1]heptane-3-carboxylic acid tert-butyl ester (1.7 g, crude). 1H NMR: (500MHz, DMSO-d 6) δ: 4.45 (d, J = 8.0 Hz, 1H), 4.16 (d, J = 7.5 Hz, 1H), 3.57-3.31 (m, 5H), 3.18 (d, J = 14.5 Hz, 3H), 2.50-2.35 (m, 2H), 2.31-2.22 (m, 1H), 2.04-1.95 (m, 1H), 1.41 (s, 9H). 2. Synthesis of 6-(((6-bromo-3-fluoropyrazolo[1,5-a]pyridin-4-yl)oxy)methyl)-3-azabicyclo[3.1.1]heptane -3- Tertiary butyl formate

[0328] To a solution of 6-bromo-3-fluoropyrazolo[1,5-a]pyridin-4-ol (80 mg, 346 µmol) in DMF (4 mL) was added Cs 2CO 3 (200 mg, 614 µmol ) and tertiary butyl 6-(((methylsulfonyl)oxy)methyl)-3-azabicyclo[3.1.1]heptane-3-carboxylate (212 mg, 693 μmol) and in 100 The reaction was stirred at °C for 1 hour. The reaction mixture was concentrated in vacuo and the crude product was purified by prep-TLC (PE:EtOAc=3:1) to give 6-(((6-bromo-3-fluoropyrazolo[1,5- a] Pyridin-4-yl)oxy)methyl)-3-azabicyclo[3.1.1]heptane-3-carboxylic acid tert-butyl ester (100 mg, 56% yield). LCMS m / z = 384.2 (M+H)+ 3. Synthesis of 6-(((3-fluoro-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)methyl )-3-Azabicyclo[3.1.1]heptane-3-carboxylate tertiary butyl ester

[0329] 6-(((6-bromo-3-fluoropyrazolo[1,5-a]pyridin-4-yl)oxy)methyl)-3-azabicyclo[3.1.1]heptane-3 - Tertiary butyl formate (90 mg, 204 µmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2 -yl)-1H-pyrazole (60 mg, 288 µmol), K 2CO 3 (85 mg, 613 µmol) and Pd(dtbpf)Cl 2 (13 mg, 20 µmol) in dioxane (5 mL) and water (1 mL) was purged with N for 1 min, and the reaction was stirred at 90 °C for 2 h. The reaction mixture was concentrated in vacuo and purified by Combiflash® eluting with 0% to 100% EtOAc / PE to give 6-(((3-fluoro-6-(1-methyl-1H- Pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)methyl)-3-azabicyclo[3.1.1]heptane-3-carboxylic acid tertiary butyl ester (90 mg, 90% yield). LCMS m / z = 442.3 (M+H)+ 4. Synthesis of (1R,5S,6s)-6-(((3-fluoro-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-4 -yl)oxy)methyl)-3-azabicyclo[3.1.1]heptane and (1R,5S,6r)-6-(((3-fluoro-6-(1-methyl-1H- Pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)methyl)-3-azabicyclo[3.1.1]heptane

[0330] To 6-(((3-fluoro-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)methyl)- To a solution of tert-butyl 3-azabicyclo[3.1.1]heptane-3-carboxylate (85 mg, 193 µmol) in DCM (2 mL) was added HCl / EtOAc (4 M, 2 mL), and The reaction was stirred at 20°C for 30 minutes. DIPEA (0.5 mL) was added dropwise and the reaction mixture was concentrated in vacuo. By preparative HPLC (column: Welch Xtimate C18 150 x 25mm x 5 µm; conditions: water (10 mM NH 4HCO 3 )-MeCN, 13-33% B, gradient time (min) 15, flow rate (mL / min) 25) Purification of the crude material yielded: the first eluting peak (E1), peak 1 (10 mg, 15% yield), in the form of a yellow oil. LCMS m / z = 342.1 (M+H)+; and the second elution peak (E2), peak 2, (30 mg, 47% yield), in the form of a yellow oil. LCMS m / z = 342.1 (M+H)+ 5 [example]

[84] : Synthesis of 1-((1R,5S,6s) or (1R,5S,6r)-6-(((3-fluoro-6-(1-methyl-1H-pyrazol-4-yl) Pyrazolo[1,5-a]pyridin-4-yl)oxy)methyl)-3-azabicyclo[3.1.1]hept-3-yl)prop-2-en-1-one

[0331] E1 (1R,5S,6s) or (1R,5R,6r)-6-(((3-fluoro-6-(1-methyl-1H-pyrazol-4-yl)pyrazole And[1,5-a]pyridin-4-yl)oxy)methyl)-3-azabicyclo[3.1.1]heptane (10 mg, 29 µmol) and DIPEA (7.6 mg, 59 µmol) in To the mixture in DCM (2 mL) was added acryloyl chloride (5.3 mg, 59 μmol) and the reaction was stirred for 10 min. MeOH (0.5 mL) was added dropwise and the reaction mixture was concentrated in vacuo. By preparative HPLC (column: Welch Xtimate C18 150 x 25 mm x 5 µm; conditions: water (10 mM NH 4HCO 3 )-MeCN, 21-41% B, gradient time (min) 10, flow rate (mL / min) 25) Purify the crude product to give 1-((1R,5S,6s) or (1R,5S,6r)-6-(((3-fluoro-6-(1-methyl- 1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)methyl)-3-azabicyclo[3.1.1]hept-3-yl)propane- 2-en-1-one (3.0 mg, 26% yield). LCMS m / z = 396.1 (M+H)+. 1H NMR (500MHz, MeOH-d 4) δ = 8.23 ​​(s, 1H), 8.06 (s, 1H), 7.90 (s, 1H), 7.76 (d, J = 3.5 Hz, 1H), 6.81-6.74 (m , 2H), 6.33-6.28 (m, 1H), 5.76 (dd, J1 = 2.0 Hz, J2 = 10.5 Hz, 1H), 4.28-4.16 (m, 2H), 4.01-3.91 (m, 5H), 3.81- 3.73 (m, 2H), 2.97-2.85 (m, 1H), 2.72 (t, J = 6.0 Hz, 2H), 2.30-2.23 (m, 1H), 1.50 (d, J = 9.5 Hz, 1H). 6. [example]

[85] : Synthesis of 1-((1R,5S,6r) or (1R,5S,6s)-6-(((3-fluoro-6-(1-methyl-1H-pyrazol-4-yl) Pyrazolo...

Claims

1. A compound represented by formula (I') or a pharmaceutically acceptable salt thereof, (I'), wherein: Het is phenyl, 5-6 member heteroaryl, or N-(C1-C3 alkyl)pyridinone; X0 is N, X1 is C, X2 is N, and X4 is N; X0 is CR0, X1 is C, X2 is N, and X4 is N; X0 is CR0, X1 is N, X2 is C, and X4 is N; X0 is CR0, X1 is N, X2 is C, and X4 is CH; or X0 is CR0, X1 is C, X2 is N, and X4 is CH; R0 is H, halogen, methyl, halomethyl, cyclopropyl, CN, or phenyl; R1 is H or C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, or 4-7 member monocyclic oxygen-containing heterocycle; R3 is H or halogen; X3 is absent, or is CH2, CH2CH2, O, O-CH2*, O-CH2CH2*, NH, N(CH3)-, CH2N(CH3)-*, or NH-CH2*, where "*" indicates the connection point with R2; when X3 is absent, or is CH2 or CH2CH2, R2 is a 4-12 member monocyclic or bicyclic nitrogen-containing heterocycle of X3 bonded to the bicyclic nucleus via a cyclic nitrogen atom ("N-link"); when X3 is CH2, CH2CH2, O, O-CH2*, NH, N(CH3)-*, CH2N(CH3)-*, or NH-CH2*, R2 is a cyclic carbon atom bonded to X3 via a cyclic carbon atom ("C-link"). 4-12 member monocyclic or bicyclic nitrogen-containing heterocycles, 4-7 member monocyclic or bicyclic oxygen-containing heterocycles, 3-12 member monocyclic or bicyclic carbocyclic groups, or 5-6 member heteroaryl groups; and when X3 is O-CH2-CH2*, R2 is absent, or is a 4-12 member monocyclic or bicyclic nitrogen-containing heterocycle or C1-C3 alkyl group bonded to X3 via a cyclic carbon atom ("C-linked"); provided that when R2 is absent, X3 is directly connected to R4. The N-linked 4-12 member monocyclic or bicyclic nitrogen-containing heterocycle, the 4-7 member oxygen-containing heterocycle, the 3-12 member monocyclic or bicyclic carbocyclic ring, the 5-6 member heteroaryl group, and the C1-C3 alkyl group represented by R2 are substituted by a group represented by R4 and further substituted by zero or one to three groups represented by R10, provided that the N-linked 4-12 member monocyclic or bicyclic nitrogen-containing heterocycle contains two cyclic nitrogen atoms. The N-linked 4-12 member monocyclic or bicyclic nitrogen-containing heterocycle represented by R2 is substituted by zero or one group represented by R5 and further substituted by zero, one, or two groups represented by R10; the C-linked 4-12 member monocyclic or bicyclic nitrogen-containing heterocycle is N-substituted by a group represented by R5 and further substituted by zero or one to three groups represented by R10; R4 is , , , , , or; R5 is , , , , , , or; Each R6 is independently H, CN, C1-C3 alkyl, C1-C3 haloalkyl, N(Ra)2 or CH2N(Ra)2, wherein each Ra is independently H, C1-C3 alkyl or C3-C6 cycloalkyl; each R6' is independently H, C1-C3 alkyl, C1-C3 haloalkyl or C3-C6 cycloalkyl;Each R7 is independently H, C1-C2 alkyl, C1-C2 fluoroalkyl, or C3-C6 cycloalkyl; R8 is H or C1-C3 alkyl; each R10 is a halogroup, C1-C3 alkyl, or C3-C6 cycloalkyl; R11 is H or N(R12)2; each R12 is independently H or C1-C3 alkyl; R13 is CN or F; R14 is a halogroup; each n is independently 0 or 1; each p is independently 1 or 2; and q is 1 or 2.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is represented by formula (I), (I), wherein: R0 is H, a halogen, a methyl group, a halomethyl group, a cyclopropyl group, or CN; X3 is absent, or is CH2, CH2CH2, O, O-CH2*, NH, or NH-CH2*, where "*" indicates the connection point with R2; when X3 is absent, or is CH2 or CH2CH2, R2 is a 4-12 member monocyclic or bicyclic nitrogen-containing heterocycle of X3 bonded to a cyclic nitrogen atom ("N-linked"); and when X3 is CH2, CH2CH2, O, O-CH2*, NH, or NH-CH2, R2 is a 4-12 member monocyclic or bicyclic nitrogen-containing heterocycle, a 4-7 member monocyclic oxygen-containing heterocycle, or a 3-12 member monocyclic or bicyclic carbocyclic group of X3 bonded to a cyclic carbon atom ("C-linked"); The N-linked 4-12 member monocyclic or bicyclic nitrogen-containing heterocycle, the 4-7 member oxygen-containing heterocycle, and the 3-12 member monocyclic or bicyclic carbocyclic ring represented by R2 are substituted by the group represented by R4, and further substituted by zero, one, or two groups represented by R10; the C-linked 4-12 member monocyclic or bicyclic nitrogen-containing heterocycle is N-substituted by the group represented by R5, and further substituted by zero, one, or two groups represented by R10; R4 is , , or ; R5 is , , or ; each R6 is independently H, C1-C3 alkyl, C1-C3 haloalkyl, N(Ra)2, or CH2N(Ra)2, wherein each Ra is independently H or methyl; each R6' is independently H, C1-C3 alkyl, or C1-C3 haloalkyl; each R7 is independently H, C1-C2 alkyl, or C1-C2 fluoroalkyl; and each R10 is F or methyl.

3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R11 is H or NH2, and (R1)q-Het- is selected from: ; ; ; ; ; and.

4. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is represented by one of the following formulas: (IV); (V); (VI); (VII); and (VIII).

5. The compound of claim 1 or its pharmaceutically acceptable salt, wherein X3 is a single bond and R2 is a 4-12 member monocyclic or bicyclic nitrogen-containing heterocycle bonded to a bicyclic core via its cyclic nitrogen atom, and the 4-12 member monocyclic or bicyclic nitrogen-containing heterocycle represented by R2 is substituted by a group represented by R4 and further substituted by zero, one or two groups represented by R10.

6. The compound of claim 5 or its pharmaceutically acceptable salt, wherein X3 is a single bond and (i) R2 is a 7-10 member bicyclic nitrogen-containing heterocycle bonded to a bicyclic nucleus via its cyclic nitrogen atom, and the 7-10 member bicyclic nitrogen-containing heterocycle represented by R2 is substituted by a group represented by R4 and further substituted by zero, one or two groups represented by R10; or (ii) R2 is a 4-7 member monocyclic nitrogen-containing heterocycle bonded to a bicyclic nucleus via its cyclic nitrogen atom, and the 4-7 member monocyclic nitrogen-containing heterocycle represented by R2 is substituted by a group represented by R4 and further substituted by zero or one group represented by R10.

7. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is represented by a structural formula selected from the following: (XI), (XII), and.

8. The compound of claim 1 or its pharmaceutically acceptable salt, wherein R6 is H, CH3 or CH2Cl, p is 2, and R4 is CH2NHC(O)C≡CH, CH2NHC(O)CH=CH2, N(CH3)C(O)C≡CH, NHC(O)CH=CH2, NHC(O)C≡CH or NHC(O)CH=CHCH2Cl.

9. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein X3 is O, O-CH2*, O-CH2CH2*, NH, NH-CH2*, N(CH3) or CH2N(CH3)-*, R2 is a 4-12 member monocyclic or bicyclic nitrogen-containing heterocycle of X3 bonded to a cyclic carbon atom ("C-linked"), and the C-linked 4-12 member nitrogen-containing heterocycle is N-substituted by a group represented by R5 and further substituted by zero or one to three groups represented by R10.

10. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the C-linked 4-12-membered nitrogen-containing heterocycle represented by R2 is a 4-7-membered monocyclic ring, a 6-10-membered fused bicyclic ring, an 8-12-membered spirocyclic ring, or a 7-10-membered bridged bicyclic ring containing zero or one epoxide or cyclic sulfur atom, and the C-linked 4-12-membered nitrogen-containing heterocycle represented by R2 is N-substituted by a group represented by R5 and further substituted by zero, one, or two groups represented by R10.

11. The compound of claim 10 or a pharmaceutically acceptable salt thereof, wherein the 4-12 nitrogen-containing heterocycles represented by R2 at the C-link are azaspiro[3.3]heptyl, azaspiro[3.5]nonyl, azaspiro[4.4]nonyl, azaspiro[3.4]octyl, azaspirocyclic butyl, pyrrolidyl, piperidinyl, azaspirocyclic heptyl, diazaspirocyclic heptyl, morpholinyl, octahydrocyclopentadien[c]pyrrolidyl, oxazolidinyl heptyl, azabicyclo[3.2.0]heptyl, azabicyclo[2.2.1]heptyl, azabicyclo[3.1.1] Heptyl, azirbicyclo[3.2.1] octyl, azirbicyclo[4.2.0] octyl, azirtricyclo[4.1.1.03,7] octyl, azirbicyclo[3.2.0] heptyl, azirbicyclo[2.1.1] heptyl, azirbicyclo[2.1.1] hexyl, azirbicyclo[3.1.0] hexyl, 2λ2-azirspiro[3.4] octyl or octahydrocyclopentadienyl[c] pyrroleyl, and the 4-12 nitrogen-containing heterocycles linked by the C-represented by R2 are N-substituted by the group represented by R5 and further substituted by zero, one or two groups represented by R10.

12. The compound of claim 11 or a pharmaceutically acceptable salt thereof, wherein the 4-12 member monocyclic or bicyclic nitrogen-containing heterocycle represented by R2 is selected from: , ...

13. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the stereochemical configuration of the ring carbon atom in the 4-12 nitrogen-containing heterocycle bonded to X3 by R2 is R or S.

14. A compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R6 and R6' are independently H, CH3 or CH2Cl, p is 2, and R5 is SO2CH=CH2, SO2CH=CHCH3, SO2CH=CHCH2Cl, SO2C≡CH, SO2C≡CCH3, SO2C≡CCH2Cl, COCH=CH2, COCH=CHCH3, COCH=CHCH2Cl, CO-C≡CH, CO-C≡CCH3, CO-C≡CCH2Cl, COCF=CH2, COCF=CHCH3, COCF=CHCH2Cl, or.

15. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein X3 is O, O-CH2*, NH or NH-CH2*, R2 is a 3-12 member monocyclic or bicyclic carbocyclic group, a 4-7 member monocyclic or bicyclic oxygen-containing heterocycle or a 5-6 member heteroaryl group, and the 3-12 member monocyclic or bicyclic carbocyclic group, the 4-7 member monocyclic or bicyclic oxygen-containing heterocycle and the 5-6 member heteroaryl group represented by R2 are substituted by a group represented by R4 and further substituted by zero or one to three groups represented by R10.

16. The compound of claim 15 or a pharmaceutically acceptable salt thereof, wherein the 4-7 member monocyclic or bicyclic oxygen-containing heterocycle is an oxabicyclo[3.1.1] pentenyl or tetrahydro-2H-pentenyl, each substituted with a group represented by R4 and further substituted with zero, one or two groups represented by R10; and the 5-6 member heteroaryl is a pentenylpyridyl substituted with a group represented by R4 and further substituted with zero or one to three groups represented by R10.

17. The compound of claim 15 or its pharmaceutically acceptable salt, wherein R2 is selected from: , and , each substituted with a group represented by R4 and further substituted with zero, one or two groups represented by R10.

18. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein X3 is O, O-CH2*, NH or NH-CH2*, R2 is a 3-12 member monocyclic or bicyclic carbocyclic group, and the 3-12 member monocyclic or bicyclic carbocyclic group represented by R2 is substituted by a group represented by R4 and further substituted by zero, one or two groups represented by R10.

19. The compound of claim 18 or a pharmaceutically acceptable salt thereof, wherein R2 is an phenyl group, a C3-C7 cycloalkyl group, or a C6-C9 bicyclic saturated carbide ring, and the phenyl group, the C3-C7 cycloalkyl group, and the C6-C9 bicyclic saturated carbide ring represented by R2 are substituted by a group represented by R4 and further substituted by zero, one, or two groups represented by R10.

20. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein X3 is O, and R2 is phenyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclopropyl, bicyclo[3.3.1]heptyl, bicyclo[2.2.1]heptyl, bicyclo[4.1.0]heptyl or bicyclo[2.1.1]hexyl, each substituted by a group represented by R4 and further substituted by zero, one or two groups represented by R10.

21. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein X3 is O, R2 is , , , , , , , , , , , or, wherein "**" indicates the connection point with X3; and "***" indicates the connection point with R4, wherein the group represented by R2 is substituted by zero, one or two groups represented by R10.

22. A compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R6 is H, CN, CH3, CH2Cl, CF3 or CH2N(Ra)2, wherein Ra is independently selected from -CH3 and cyclopropyl, and R6' is H, CN, CH3, CH2Cl, CF3 or cyclopropyl; or R4 is NHC(O)CH=CH2, N(CH3)C(O)CH=CH2, NHC(O)CH=CHCH3, N(CH3)C(O)CH=CHCH3, N(CH3)C(O)CH=CHCN, NHC(O)C≡CH, N(CH3)C(O)C≡CH, N(H)C(O)C≡CCH3, N(CH3)C(O)C≡CCH3, N(CH2CH2F)C(O)CH=CH2, N(CH2CH2F)C(O)CH=CHC H3, N(CH2CH2F)C(O)C≡CH, N(CH2CH2F)C(O)C≡CCH3, CH2N(CH3)C(O)CH=CH2, N(CH2CHF2)C(O)CH=CH2, N(CH3)C(O)CH=CHCH2Cl, NHC(O)CH=CHCF3, N(CH3)C(O)CH=CHCF3, NHC(O)C≡C-cyclopropyl, NHC(O)CH=CHCH2N(CH3)-cyclobutyl, N(CH2CHF2)C(O)CH=CHCH2N(CH3)2, N(cyclopropyl)C(O)CH=CH2, N(CH3)C(O)CH2Cl, N(CH3)CH2CN, ..., CH2NHC(O)CH=CH2 or CH(CH3)NHC(O)CH=CH2.

23. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the stereochemical configuration of the ring carbon atom in the C-linked 3-12 member carbon ring, represented by R2, bonded to X3 is R or S.

24. The compound of claim 15 or its pharmaceutically acceptable salt, wherein X3 and R4 are oriented in the trans or cis configuration.

25. The compound of claim 1 or its pharmaceutically acceptable salt, wherein X3 is O-CH2CH2*, and R2 is a C1-C3 alkyl group substituted by a group represented by R4 and further substituted by zero, one or two groups represented by R10, or R2 is absent and X3 is directly connected to R4.

26. The compound of claim 25 or a pharmaceutically acceptable salt thereof, wherein R2 is selected from ⁎⁎-CH2-⁎⁎⁎, ⁎⁎-CH2CH(CH3)-⁎⁎⁎, wherein "⁎⁎" indicates the connection point with X3 and "⁎⁎⁎" indicates the connection point with R4; and wherein R4 is N(CH3)C(O)CH=CH2.

27. The compound of claim 26 or its pharmaceutically acceptable salt thereof, wherein one or more of the following statements apply: (i) R1 is H or C1-C3 alkyl, C1-C3 fluoroalkyl or 4-7 member monocyclic oxygen-containing heterocycle; (ii) R0 is H, F, CN, CH3, CF3, cyclopropyl or phenyl; (iii) R7 is selected from H, CH3, CH2CH3, CH2CHF2 and cyclopropyl; (iv) R8 is H or CH3; (v) R10 is F, Cl, CH3 or cyclopropyl; and (vi) R14 is Cl.

28. A compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is represented by formula (XV), (XV), wherein: R0 is H, a halogroup, or a cyclopropyl group; X3 is O or O-CH2*; R2 is a 4-7 member monocyclic or bicyclic saturated carbocyclic group, and the 4-7 member monocyclic or bicyclic saturated carbocyclic group represented by R2 is substituted by the group represented by R4 and further substituted by zero, one, or two R10 groups; or R2 is a 7-9 member bicyclic nitrogen-containing heterocycle bonded to X3 via a cyclic carbon atom ("C-linked"), and the C-linked 7-9 member bicyclic nitrogen-containing heterocycle is substituted by the group represented by R5 and further substituted by zero, one, or two R10 groups; R4 is N(R7)C(O)C≡CCH3 or N(R7)C(O)CH=CH2, R5 is C(O)CH=CH2, R7 is H, C1-C2 alkyl, or C1-C2 haloalkyl; and R10 is C1-C3 alkyl.

29. The compound of claim 28 or a pharmaceutically acceptable salt thereof, wherein X3 is O; R2 is cyclobutyl, cyclohexyl, cyclopentyl or bicyclo[2.1.1]cyclohexyl, each substituted by the group represented by R4 and further substituted by zero, one or two R10s; R7 is H, CH3 or CH2CHF2; and R10 is CH3.

30. A pharmaceutical composition comprising a compound of any one of claims 1-29 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

31. Use of a compound of any one of claims 1-29 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of claim 30 for the preparation of a medicament for treating a condition responsive to inhibition of Bruton's tyrosine kinase.

32. As requested in claim 31, wherein the condition is an autoimmune disease, atopic dermatitis, leukemia, or lymphoma.

33. As claimed in claim 32, wherein the autoimmune disease is rheumatoid arthritis or systemic lupus erythematosus.