Pyrazolo[1,5-A]pyrazine derivatives as BTK inhibitors

Abstract

Compounds of formula (I') or pharmaceutically acceptable salts thereof are provided, wherein the variables in the formula are as defined herein; and methods of their use and manufacture are also provided.

Description

[0001] Related applications

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 113,515, filed November 13, 2020, pursuant to 35 U.S. SC §119(e), the entire contents of which are incorporated herein by reference. Technical Field

[0003] Certain agents that inhibit Bruton's tyrosine kinase (Btk) are provided, as well as methods for manufacturing and using such agents. Background Technology

[0004] Protein kinases are a large, multi-gene family of over 500 proteins that play crucial roles in the development and treatment of many human diseases in oncology, neurology, and immunology. Tec kinases are non-receptor tyrosine kinases composed of five members: Tec (a tyrosine kinase expressed in hepatocellular carcinoma), Btk (Bruton's tyrosine kinase), Itk (interleukin-2 (IL-2)-induced T-cell kinase; also known as Emt or Tsk), Rlk (resting lymphocyte kinase; also known as Txk), and Bmx (the bone marrow tyrosine kinase gene on chromosome X; also known as Etk)). They are primarily 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 are all activated downstream of the T-cell receptor (TCR). Btk is a downstream mediator of B-cell receptor (BCR) signaling, involved in regulating B-cell activation, proliferation, and differentiation. More specifically, Btk contains a pH domain that binds to phosphatidylinositol (3,4,5)-triphosphate (PIP3). PIP3 binding induces Btk to phosphorylate phospholipase C (PLCy), which in turn hydrolyzes PIP2 to produce two secondary messengers, inositol triphosphate (IP3) and diacylglycerol (DAG), which activate protein kinase PKC, subsequently inducing additional B cell signaling. Mutations that disable the enzymatic activity of Btk result in XLA syndrome (X-linked agammaglobulinemia), a primary immunodeficiency. Given the crucial role of Tec kinases in both B cell and T cell signaling, Tec kinases are a target of interest in autoimmune diseases.

[0005] Therefore, there is a great need in this field for effective Btk inhibitors. Summary of the Invention

[0006] One embodiment of the present invention is a compound represented by formula (I'):

[0007]

[0008] Or its pharmaceutically acceptable salt, wherein:

[0009] Het is phenyl, 5-6-membered heteroaryl or N-(C1-C3 alkyl)pyridinone group;

[0010] X 0 Let N, X 1 Let C, X 2 For N and X 4 For N; X 0 For CR 0 X 1 Let C, X 2 For N and X 4 For N; X 0 For CR 0 X 1 Let N, X 2 For C and X 4 For N; X 0 For CR 0 X 1 Let N, X 2 For C and X 4 For CH; or X 0 For CR 0 X 1 Let C and X be the values ​​of C and X respectively. 2 For N and X 4 For CH;

[0011] R 0 It can be H, halogen, methyl, halomethyl, cyclopropyl, CN, or phenyl;

[0012] R 1 It is H or C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl or 4-7 membered monocyclic oxygen-containing heterocycle;

[0013] R 3 It is an H or a halogen group;

[0014] X 3 It does not exist, and is CH2, CH2CH2, O, O-CH2*, O-CH2CH2*, NH, N(CH3)-*, CH2N(CH3)-*, or NH-CH2*, where "*" indicates the presence of R. 2 The connection point;

[0015] When X 3 When R does not exist, is CH2 or CH2CH2, 2 To be bonded to the double-ring nucleus or X via cyclic nitrogen atoms (“N-link”). 3 4-12 membered monocyclic or bicyclic nitrogen-containing heterocycles; when X 3When R is CH2, CH2CH2, O, O-CH2*, NH, N(CH3)-*, CH2N(CH3)-*, or NH-CH2*, 2 To bond to X via a ring carbon atom (“C-link”) 3 4-12 membered monocyclic or bicyclic nitrogen-containing heterocycles, 4-7 membered monocyclic or bicyclic oxygen-containing heterocycles, 3-12 membered monocyclic or bicyclic carbocyclic groups, or 5-6 membered heteroaryl groups; and when X 3 When it is O-CH2-CH2*, R 2 It does not exist; it is bonded to X via a ring carbon atom (“C-link”). 3 4-12 membered monocyclic or bicyclic nitrogen-containing heterocycles, or C1-C3 alkyl groups, provided that R 2 When X does not exist, 3 Directly connected to R 4 ;

[0016] By R 2 The N-linked 4-12 membered monocyclic or bicyclic nitrogen-containing heterocycles, 4-7 membered oxygen-containing heterocycles, 3-12 membered monocyclic or bicyclic carbocyclic rings, 5-6 membered heteroaryl groups, and C1-C3 alkyl groups are represented by R. 4 The indicated group is substituted and optionally further replaced by one to three groups derived from R. 10 The group substitution is indicated by R when the N-linked 4-12 membered monocyclic or bicyclic nitrogen-containing heterocycle contains two cyclic nitrogen atoms. 2 The N-linked 4-12 member monocyclic or bicyclic nitrogen-containing heterocycles are optionally represented by R 5 The indicated group is N-substituted and optionally further substituted by one or two R groups. 10 The group to be represented is substituted;

[0017] C-linked 4-12 member monocyclic or bicyclic nitrogen-containing heterocycles are R 5 The indicated group is N-substituted and optionally further substituted by one to three R groups. 10 The group to be represented is substituted;

[0018] R 4 For

[0019] R 5 for

[0020] Each R 6 Independently H, CN, C1-C3 alkyl, C1-C3 haloalkyl, N(R) a )2 or CH2N(R a )2, where each R a Independently, it is H, C1-C3 alkyl, or C3-C6 cycloalkyl;

[0021] Each R 6 'Independently H, C1-C3 alkyl, C1-C3 haloalkyl or C3-C6 cycloalkyl;

[0022] Each R 7 It can be independently H, C1-C2 alkyl, C1-C2 fluoroalkyl, or C3-C6 cycloalkyl;

[0023] R 8 It is H or C1-C3 alkyl;

[0024] Each R 10 It is a halogenated group, a C1-C3 alkyl group, or a C3-C6 cycloalkyl group;

[0025] R 11 For H or N(R) 12 )2;

[0026] Each R 12 Independently, it is H or C1-C3 alkyl;

[0027] R 13 It can be CN or F;

[0028] R 14 It is a halogenated group;

[0029] Each n is independently 0 or 1;

[0030] Each p is independently 1 or 2; and

[0031] q is 1 or 2.

[0032] Another embodiment of the present invention is a compound of formula (I):

[0033]

[0034] Or its pharmaceutically acceptable salt, wherein:

[0035] Het is phenyl, 5-6-membered heteroaryl or N-(C1-C3 alkyl)pyridinone group;

[0036] X 0 Let N, X 1 Let C and X be the values ​​of C and X respectively. 2 For N and X 4 For N; X 0 For CR 0 X 1 Let C and X be the values ​​of C and X respectively. 2 For N and X 4 For N; X 0 For CR 0 X 1 Let N, X 2For C and X 4 For N; X 0 For CR 0 X 1 Let N, X 2 For C and X 4 For CH; or X 0 For CR 0 X 1 Let C and X be the values ​​of C and X respectively. 2 For N and X 4 For CH;

[0037] R 0 It can be H, halogen, methyl, halomethyl, cyclopropyl, or CN;

[0038] R 1 It is H or C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl or 4-7 membered monocyclic oxygen-containing heterocycle;

[0039] X 3 It does not exist; it is CH2, CH2CH2, O, O-CH2*, NH, or NH-CH2*, where "*" indicates the presence of R. 2 The connection point;

[0040] When X 3 When R does not exist, is CH2 or CH2CH2, 2 To be bonded to the double-ring nucleus or X via cyclic nitrogen atoms (“N-link”). 3 4-12 membered monocyclic or bicyclic nitrogen-containing heterocycles; and when X 3 When R is CH2, CH2CH2, O, O-CH2*, or NH-CH2*, 2 To bond to X via a ring carbon atom (“C-link”) 3 4-12 membered monocyclic or bicyclic nitrogen-containing heterocycles, 4-7 membered monocyclic or oxygen-containing heterocycles, or 3-12 membered monocyclic or bicyclic carbocyclic groups;

[0041] By R 2 The N-linked 4-12 member monocyclic or bicyclic nitrogen-containing heterocycles, 4-7 member oxygen-containing heterocycles, and 3-12 member monocyclic or bicyclic carbon rings are represented by R. 4 The indicated group is substituted and optionally further replaced by one or two groups derived from R. 10 The group to be represented is substituted;

[0042] C-linked 4-12 member monocyclic or bicyclic nitrogen-containing heterocycles are R 5 The indicated group is N-substituted and optionally further substituted by one or two R groups. 10 The group to be represented is substituted;

[0043] R 4 for

[0044] R 5 for

[0045] Each R 6 Independently H, C1-C3 alkyl, C1-C3 haloalkyl, N(R) a )2 or CH2N(R a )2, where each R a Independently, it is either H or methyl;

[0046] Each R 6' It is independently H, C1-C3 alkyl, or C1-C3 haloalkyl;

[0047] Each R 7 It is independently H, C1-C2 alkyl, or C1-C2 fluoroalkyl;

[0048] Each R 10 It is F or methyl;

[0049] R 11 For H or N(R) 12 )2. Or, R 11 It is H or NH2;

[0050] Each R 12 Independently H or C1-C3 alkyl; or, R 12 It is H or NH2;

[0051] R 13 It can be CN or F;

[0052] Each n is independently 0 or 1;

[0053] Each p is independently 1 or 2; and

[0054] q is 1 or 2.

[0055] 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.

[0056] Another embodiment of the present invention is a method for treating a condition in a subject that responds to Btk inhibition, the method comprising administering to the subject an effective amount of at least one compound described herein or a pharmaceutically acceptable salt thereof.

[0057] The present invention also includes the use of at least one of the compounds described herein or a pharmaceutically acceptable salt thereof for the manufacture of an agent for treating a condition responsive to Btk inhibition. A compound described herein or a pharmaceutically acceptable salt thereof is also provided for the treatment of a condition responsive to Btk inhibition.

[0058] Other features or advantages will be apparent from the following detailed description of several embodiments and from the appended claims. Detailed Implementation

[0059] Compounds described herein or pharmaceutically acceptable salts thereof may have activity as Btk modulators. In particular, compounds described herein or pharmaceutically acceptable salts thereof may be Btk inhibitors.

[0060] In the 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.

[0061] 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.

[0062] In the third embodiment, for compounds of formula (I') or (I) or their pharmaceutically acceptable salts, R 11 It is H or NH2, and the remaining variables are as described in the first or second implementation scheme.

[0063] In the fourth embodiment, the compound of the present invention is represented by formula (II):

[0064]

[0065] Or a pharmaceutically acceptable salt thereof. The variables in formula (II) are as described in formula (I') or (I) in the first or second embodiment.

[0066] In a fifth embodiment, the compounds of the present invention are represented by formula (I'), (I), or (II) or pharmaceutically acceptable salts thereof, wherein (R) in formulas (I'), (I), and (II) 1 ) q -Het- is selected from: The remaining variables in equations (I), (I'), and (II) are as described in any of the first to fourth embodiments.

[0067] In the sixth embodiment, the compound of the present invention is represented by formula (III):

[0068]

[0069] Or a pharmaceutically acceptable salt thereof. The variables in formula (III) are as described in formula (I') or (I) in the first or second embodiment.

[0070] In the seventh embodiment, the compounds of the present invention are represented by formula (I'), (I), (II) or (III) or pharmaceutically acceptable salts thereof, wherein X 0 Let N, X 1 Let C and X be the values ​​of C and X respectively. 2 For N and X 4 For N; X 0 For CH, X 1 Let C and X be the values ​​of C and X respectively. 2 For N and X 4 For N; X 0 For CH, X 1 Let N, X 2 For C and X 4 For N; X 0 For CR 0 X 1 Let N, X 2 For C and X 4 For CH; or X 0 For CH, X 1 Let C and X be the values ​​of C and X respectively. 2 For N and X 4 For CH; X 3 It does not exist, and is O, O-CH2*, NH, or NH-CH2*, where "*" indicates the relationship with R. 2 The connection point; when X 3 When it does not exist, R 2 To be bonded to the double-ring nucleus or X via cyclic nitrogen atoms (“N-link”). 3 4-12 membered monocyclic or bicyclic nitrogen-containing heterocycles; and when X 3 When R is O, O-CH2* or NH-CH2*, 2 To bond to X via a ring carbon atom (“C-link”) 3 4-12 membered monocyclic or bicyclic nitrogen-containing heterocycles, 4-7 membered monocyclic or oxygen-containing heterocycles, or 3-12 membered monocyclic or bicyclic carbocyclic groups; composed of R 2 The N-linked 4-12 member monocyclic or bicyclic nitrogen-containing heterocycles, 4-7 member monocyclic oxygen-containing heterocycles, and 3-12 member monocyclic or bicyclic carbon rings are represented by R. 4 The indicated group is substituted and optionally further replaced by one or two groups derived from R. 10 The indicated group is substituted; the C-linked 4-12 membered monocyclic or bicyclic nitrogen-containing heterocycle is replaced by R. 5 The indicated group is N-substituted and optionally further substituted by one or two R groups. 10The group substitutions are indicated; and the remaining variables are as described in formulas (I'), (I), (II) and (III) as in any of the first to sixth embodiments.

[0071] In the eighth embodiment, the compounds of the present invention are represented by formula (IV), (V), (VI), (VII), or (VIII):

[0072]

[0073] Or a pharmaceutically acceptable salt of any of the foregoing, wherein the variables are as described in any of the first to seventh embodiments.

[0074] In a ninth embodiment, the compound of the present invention is represented by any one of formulas (I'), (I), (II), (III), (IV), (V), (VI), (VII), and (VIII) or a pharmaceutically acceptable salt thereof, wherein X 3 For key and R 2 It is a 4-12 membered monocyclic or bicyclic nitrogen-containing heterocycle bonded to a bicyclic core via a cyclic nitrogen atom, and is composed of R 2 The monocyclic or bicyclic 4-12 member nitrogen-containing heterocycles represented by R 4 The indicated group is substituted and optionally further replaced by R. 10 The group substitution is indicated. Alternatively, R 2 It is a 4-7 membered monocyclic nitrogen-containing heterocycle bonded to a bicyclic core via a cyclic nitrogen atom, and is composed of R 2 The 4-7 member monocyclic nitrogen-containing heterocycles represented by R 4 The indicated group is substituted and optionally further replaced by R. 10 The group substitutions are indicated. The remaining variables are as described in formulas (I'), (I), (II), (III), (IV), (V), (VI), (VII), or (VIII) in any of the first to eighth embodiments.

[0075] In a tenth embodiment, the compound of the present invention is represented by any one of formulas (I'), (I), (II), (III), (IV), (V), (VI), (VII), and (VIII) or a pharmaceutically acceptable salt thereof, wherein X 3 For key and R 2 It is a 7-10 membered bicyclic nitrogen-containing heterocycle bonded to a bicyclic core via its cyclic nitrogen atom, and is composed of R 2 The 7-10 membered bicyclic nitrogen-containing heterocycles represented by R 4 The indicated group is substituted and optionally further replaced by one or two groups derived from R. 10 The group substitutions are indicated; and the remaining variables are as described in any of the first to ninth embodiments.

[0076] In the eleventh embodiment, the compound of the invention is represented by any one of formulas (I'), (I), (II), (III), (IV), (V), (VI), (VII), and (VIII) or a pharmaceutically acceptable salt thereof, wherein R 2 The 7-10 membered bicyclic nitrogen-containing heterocycles represented by R are... 4 The indicated group is substituted and optionally further replaced by R. 10 The group represented is substituted with azirospiro[2.4]heptenyl; and the remaining variables are as described in any of the first to tenth embodiments.

[0077] In the twelfth embodiment, the compound of the invention is represented by any one of (I'), (I), (II), (III), (IV), (V), (VI), (VII) and (VIII) or a pharmaceutically acceptable salt thereof, wherein X 3 For key and R 2 It is a 4-7 membered monocyclic nitrogen-containing heterocycle bonded to a bicyclic core via its cyclic nitrogen atom, and is composed of R 2 The 4-7 member monocyclic nitrogen-containing heterocycles represented by R 4 The indicated group is substituted and optionally further replaced by R. 10 The group substitutions are indicated; and the remaining variables are as described in any of the first to ninth embodiments.

[0078] In the thirteenth embodiment, the compound of the invention is represented by any one of (I'), (I), (II), (III), (IV), (V), (VI), (VII), and (VIII) or a pharmaceutically acceptable salt thereof, wherein R 2 The 4-7 membered monocyclic or bicyclic nitrogen-containing heterocycles are azapyridine, pyrrolidinyl, piperidinyl, azapyridine heptyl, or oxazolidinyl heptyl, each represented by R. 4 The indicated group is substituted and optionally further replaced by R. 10 The group substitutions are indicated; and the remaining variables are as described in any of the first to ninth embodiments.

[0079] In the fourteenth embodiment, the compounds of the present invention are represented by formula (IX), (X), (XI), (XII), (XIII), or (XIV):

[0080]

[0081] Or a pharmaceutically acceptable salt of any of the foregoing, wherein the variables are as described in the thirteenth embodiment.

[0082] In the fifteenth embodiment, the compound of the present invention is represented by any one of formulas (I'), (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII) or (XIV), wherein R 6 and R 6' Independently, it is H, CH3, or CH2Cl, p is 2, and the remaining variables are as described in any of the first to fourteenth embodiments.

[0083] In the sixteenth embodiment, the compound of the present invention is represented by any one of formulas (I'), (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII) or (XIV), wherein R 4 The variables are 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; and the remaining variables are as described in any of the first to fifteenth embodiments.

[0084] In the seventeenth embodiment, the compound of the present invention is represented by any one of formula (I'), (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII) or (XIV), wherein R 4 The possible values ​​are CH2NHC(O)C≡CH, CH2NHC(O)CH=CH2, N(CH3)C(O)C≡CH, or CH2NR. 7 C(O)CH=CHCH2Cl; and the remaining variables are as described in any of the first to fifteenth embodiments.

[0085] In the eighteenth embodiment, the compound of the present invention is represented by any one of formula (I'), (I), (II), (III), (IV), (V), (VI), (VII) or (VIII), wherein X 3 For O, O-CH2*, O-CH2CH2*, NH, NH-CH2*, N(CH3) or CH2N(CH3)-*, R 2 To bond to X via a ring carbon atom (“C-link”) 3 The 4-12 member monocyclic or bicyclic nitrogen-containing heterocycle, and the C-linked 4-12 member nitrogen-containing heterocycle is R 5 The indicated group is N-substituted and optionally further substituted by one to three R groups. 10The group substitutions are indicated; and the remaining variables are as described in any of the first to eighth embodiments.

[0086] In the nineteenth embodiment, the compound of the present invention is represented by any one of formula (I'), (I), (II), (III), (IV), (V), (VI), (VII) or (VIII), wherein X 3 For O, O-CH2*, NH or NH-CH2*, R 2 To bond to X via a ring carbon atom (“C-link”) 3 The 4-12 membered nitrogen-containing heterocycle, and the C-linked 4-12 membered nitrogen-containing heterocycle is R 5 The indicated group is N-substituted and optionally further modified by R. 10 The group substitutions are indicated; and the remaining variables are as described in any of the first to eighth embodiments.

[0087] In the twentieth embodiment, the compound of the present invention is represented by any one of formula (I'), (I), (II), (III), (IV), (V), (VI), (VII) or (VIII), X 3 It is O or O-CH2*, and the remaining variables are as described in any of the first through eighth, eighteenth and nineteenth embodiments.

[0088] In the twenty-first embodiment, the compound of the present invention is represented by any one of formula (I'), (I), (II), (III), (IV), (V), (VI), (VII) or (VIII), wherein R 2 The C-linked 4-12-membered nitrogen-containing heterocycle represented is optionally a 4-7-membered monocyclic heterocycle, a 6-10-membered fused bicyclic ring, an 8-12-membered spirocyclic ring, or a 7-10-membered bridged bicyclic ring containing one epoxide or one cyclic sulfur atom, and is composed of R 2 The C-linked 4-12-membered nitrogen-containing heterocycle represented by R 5 The indicated group is N-substituted and optionally further modified by R. 10 The group substitutions are indicated; and the remaining variables are as described in the first to eighth and eighteenth to twentieth embodiments.

[0089] In the twenty-second embodiment, the compound of the present invention is represented by any one of formula (I'), (I), (II), (III), (IV), (V), (VI), (VII) or (VIII), wherein R 2The C-linked 4-12 nitrogen-containing heterocycles represented are azaspiro[3.3]heptene, azaspiro[3.5]nonene, azaspiro[4.4]nonene, azaspiro[3.4]octene, azaspirocyclic butylene, pyridinealkylene, piperidinylene, azaspirocyclic heptylene, diazaspirocyclic heptylene, morpholinylene, octahydrocyclopentadien[c]pyridineylene, oxazolidinyl heptylene, and azabicyclo[3.2.0]heptene. 2λ, azidobicyclo[2.2.1]heptyle, azidobicyclo[3.1.1]heptyle, azidobicyclo[3.2.1]octyl, azidobicyclo[4.2.0]octyl, azidotricyclo[4.1.1.03,7]octyl, azidobicyclo[3.2.0]heptyle, azidobicyclo[2.1.1]heptyle, azidobicyclo[2.1.1]hexyl, azidobicyclo[3.1.0]hexyl, 2λ 2 -azaspiro[3.4]octylene or octahydrocyclopentadienyl[c]pyridine, and derived from R 2 The C-linked 4-12-membered nitrogen-containing heterocycle represented by R 5 The indicated group is N-substituted and optionally further substituted by one or two R groups. 10 The indicated group substitution; and the remaining variables are as described in any of the first to eighth and eighteenth to twenty-first embodiments. (By R) 2 The exemplary 4-12 member nitrogen-containing heterocycles represented include The "**" indicates X 3 The connection point; and "***" indicates the connection with R. 5 The connection point, where R is the connection point. 2 Each group represented may optionally be further divided by one to three R groups. 10 The group substitution is indicated.

[0090] In the twenty-third embodiment, the compound of the present invention is represented by any one of formula (I'), (I), (II), (III), (IV), (V), (VI), (VII) or (VIII), wherein R 2 The C-linked 4-12 membered nitrogen-containing heterocycles represented are azapyrocyclic butyl, pyridinealkyl, piperidinyl, azapyrocyclic heptyl, oxazolidinyl heptyl, azabicyclic [3.2.1] octyl, and azatricyclic [4.1.1.0]. 3,7 [Octenyl, azabicyclo[3.2.0]heptenyl, azabicyclo[3.1.0]hexyl, 2λ] 2 -azaspiro[3.4]octylene or octahydrocyclopentadienyl[c]pyridine, and derived from R 2 The C-linked 4-12-membered nitrogen-containing heterocycle represented by R 5The indicated group is N-substituted and optionally further substituted by one or two R groups. 10 The indicated group substitutions, and the remaining variables as described in any of the first to eighth and eighteenth to twenty-first embodiments. (By R) 2 The exemplary 4-12 member nitrogen-containing heterocycles represented include By R 2 The nitrogen-containing heterocycle represented may optionally be further modified by R 10 Replace; "**" indicates X 3 The connection point; and "***" indicates the connection with R. 5 The connection point, where R is the connection point. 2 Each group represented may optionally be further defined by one or two R groups. 10 The group substitution is indicated.

[0091] In the twenty-fourth embodiment, the compound of the present invention is represented by any one of formula (I'), (I), (II), (III), (IV), (V), (VI), (VII) or (VIII), wherein the bond to X 3 by R 2 The stereochemical configuration of the cyclic carbon atom in a C-linked 4-12 member nitrogen-containing heterocycle is represented by R. Alternatively, it can be bonded to X. 3 by R 2 The stereochemical configuration of the cyclic carbon atom in the C-linked 4-12 member nitrogen-containing heterocycle is S. The remaining variables in formulas (I'), (I), (II), (III), (IV), (V), (VI), (VII), or (VIII) are as described in any of the first to eighth and eighteenth to twenty-third embodiments.

[0092] In the twenty-fifth embodiment, the compound of the present invention is represented by any one of formula (I'), (I), (II), (III), (IV), (V), (VI), (VII) or (VIII), wherein R 6 and R 6' Independently, it is H, CH3, or CH2Cl and p is 2; and the remaining variables are as described in any of the first to eighth and eighteenth to twenty-fourth embodiments.

[0093] In the twenty-sixth embodiment, the compound of the present invention is represented by any one of formula (I'), (I), (II), (III), (IV), (V), (VI), (VII) or (VIII), wherein R 5For 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, And the remaining variables are as described in the first through eighth and the eighteenth through twenty-fifth implementation schemes.

[0094] In the twenty-seventh embodiment, the compound of the present invention is represented by any one of formula (I'), (I), (II), (III), (IV), (V), (VI), (VII) or (VIII), wherein R 5 For example, SO2CH=CH2, SO2CH=CHCH3, SO2CH=CHCH2Cl, SO2C≡CH, SO2C≡CCH3, SO2C≡CCH2Cl, COCH=CH2, COCH=CHCH3, COCH=CHCH2Cl, CO-C≡CH, CO-C≡CCH3, or CO-C≡CCH2Cl. Alternatively, R 5 The variables are SO2CH=CH2, SO2CH=CHCH3, COCH=CH2, COCH=CHCH2Cl, CO-C≡CH, or CO-C≡CCH3. The remaining variables in formulas (I'), (I), (II), (III), (IV), (V), (VI), (VII), or (VIII) are as described in any of the first to eighth and eighteenth to twenty-fifth embodiments.

[0095] In the twenty-eighth embodiment, the compound of the present invention is represented by any one of formula (I'), (I), (II), (III), (IV), (V), (VI), (VII) or (VIII), wherein X 3 For O, O-CH2*, NH or NH-CH2*, R 2 It is a 3-12 membered monocyclic or bicyclic carbocyclic group, a 4-7 membered monocyclic or bicyclic oxygen-containing heterocyclic group, or a 5-6 membered heteroaryl group, and is composed of R 2 The 3-12 membered monocyclic or bicyclic carbocyclic rings, 4-7 membered monocyclic or bicyclic oxygen-containing heterocycles, and 5-6 membered heteroaryl groups are represented by R. 4 The indicated group is substituted and optionally further replaced by one to three groups derived from R. 10 The group substitutions are indicated; and the remaining variables are as described in any of the first to eighth embodiments.

[0096] In the twenty-ninth embodiment, the compound of the present invention is represented by any one of formula (I'), (I), (II), (III), (IV), (V), (VI), (VII) or (VIII), wherein X 3 For O, O-CH2*, NH or NH-CH2*, R 2 It is a 4-7 membered monocyclic or bicyclic oxygen-containing heterocycle or a 5-6 membered heteroaryl group, and is composed of R 2 The 4-7 membered monocyclic or bicyclic oxygen-containing heterocycles and the 5-6 membered heteroaryl groups are represented by R. 4 The indicated group is substituted and optionally further replaced by one to three groups derived from R. 10 The group substitutions are indicated; and the remaining variables are as described in any of the first to eighth embodiments.

[0097] In the thirtieth embodiment, the compound of the present invention is represented by any one of formula (I'), (I), (II), (III), (IV), (V), (VI), (VII) or (VIII), wherein R 2 The 4-7 membered monocyclic or bicyclic oxygen-containing heterocycles are oxabicyclic [3.1.1]heptene or tetrahydro-2H-pyranene, each represented by R 4 The indicated group is substituted and optionally further replaced by one or two groups derived from R. 10 The indicated group is substituted; and the 5-6 membered heteroaryl group is replaced by R. 4 The indicated group is substituted and optionally further replaced by one to three groups derived from R. 10 The group represented is a pyridyl group substituted with the group; and the remaining variables are as described in any of the first to eighth and twenty-ninth embodiments.

[0098] In the thirty-first embodiment, the compound of the present invention is represented by any one of formula (I'), (I), (II), (III), (IV), (V), (VI), (VII) or (VIII), wherein R 2 Selected from:

[0099]

[0100] Each was R 4 The indicated group is substituted and optionally further replaced by one or two groups derived from R. 10 The group substitutions are indicated; and the remaining variables are as described in any of the first through eighth and twenty-ninth embodiments.

[0101] In the thirty-second embodiment, the compound of the present invention is represented by any one of formula (I'), (I), (II), (III), (IV), (V), (VI), (VII) or (VIII), wherein X 3For O, O-CH2*, NH or NH-CH2*, R 2 It is a 3-12 member monocyclic or bicyclic carbocyclic group, and is composed of R 2 The 3-12 cyclic monocyclic or bicyclic carbon rings represented by R 4 The indicated group is substituted and optionally further replaced by one or two groups derived from R. 10 The indicated group substitution, and the remaining variables as described in any of the first through eighth embodiments. Alternatively, X 3 For O or O-CH2*. In another alternative, X 3 The remaining variables in equations (I'), (I), (II), (III), (IV), (V), (VI), (VII), or (VIII) are as described in any of the first to eighth embodiments.

[0102] In the thirty-third embodiment, the compound of the present invention is represented by any one of formula (I'), (I), (II), (III), (IV), (V), (VI), (VII) or (VIII), wherein R 2 It is a phenylene, C3-C7 cycloalkylene, or C6-C9 bicyclic saturated carbon ring, and is composed of R 2 The phenylene, C3-C7 cycloalkylene, and C6-C9 bicyclic saturated carbocyclic rings represented by R are... 4 The indicated group is substituted and optionally further replaced by one or two groups derived from R. 10 The group substitutions are indicated; and the remaining variables are as described in any of the first to eighth and twenty-eighth to thirty-second embodiments.

[0103] In the thirty-fourth embodiment, the compound of the present invention is represented by any one of formula (I'), (I), (II), (III), (IV), (V), (VI), (VII) or (VIII), wherein R 2 For R 4 The indicated group is substituted and optionally further replaced by one or two groups derived from R. 10 The indicated group is a substituted phenylene or C4-C7 cycloalkylene group; and the remaining variables are as described in any of the first to eighth, thirty-second and thirty-third embodiments.

[0104] In the thirty-fifth embodiment, the compound of the present invention is represented by any one of formula (I'), (I), (II), (III), (IV), (V), (VI), (VII) or (VIII), wherein X 3 It is 0; and the remaining variables are as described in any of the first to eighth and twenty-eighth to thirty-fourth embodiments.

[0105] In the thirty-sixth embodiment, the compound of the present invention is represented by any one of formula (I'), (I), (II), (III), (IV), (V), (VI), (VII) or (VIII), wherein R 2 It is phenylene, cyclobutylene, cyclohexylene, cyclopentylene, cyclopropylene, bicyclo[3.3.1]heptylene, bicyclo[2.2.1]heptylene, bicyclo[4.1.0]heptylene, or bicyclo[2.1.1]hexylene, each of which is R 4 The indicated group is substituted and optionally further replaced by one or two groups derived from R. 10 The group substitutions are indicated; and the remaining variables are as described in any of the first to eighth and thirty-second to thirty-fifth embodiments.

[0106] In the thirty-seventh embodiment, the compound of the present invention is represented by any one of formula (I'), (I), (II), (III), (IV), (V), (VI), (VII) or (VIII), wherein R 2 For R 4 The indicated group is substituted and optionally further replaced by one or two groups derived from R. 10 The indicated group is substituted with phenylene, cyclobutylene, cyclohexylene, or bicyclic [3.3.1]heptenylene; and the remaining variables are as described in the first to eighth and thirty-second to thirty-fifth embodiments.

[0107] In the thirty-eighth embodiment, the compound of the present invention is represented by any one of formula (I'), (I), (II), (III), (IV), (V), (VI), (VII) or (VIII), wherein R 2 for The "**" indicates X 3 The connection point; and "***" indicates the connection with R. 4 The connection point, where R is the connection point. 2 The indicated group is optionally represented by one or two R groups. 10 The group substitutions are indicated. The remaining variables in formulas (I'), (I), (II), (III), (IV), (V), (VI), (VII) or (VIII) are as described in the first to eighth and thirty-second to thirty-fifth embodiments.

[0108] In the thirty-ninth embodiment, the compound of the present invention is represented by any one of formula (I'), (I), (II), (III), (IV), (V), (VI), (VII) or (VIII), wherein R 2 for Among them, R2 The indicated group is optionally represented by one or two R groups. 10 The group substitutions are indicated; and the remaining variables are as described in any of the first to eighth or thirty-second to thirty-fifth embodiments.

[0109] In the fortieth embodiment, the compound of the present invention is represented by any one of formula (I'), (I), (II), (III), (IV), (V), (VI), (VII) or (VIII), wherein R 6 and R 6 Independently, it can be H, CN, CH3, CH2Cl, CF3, cyclopropyl, or CH2N(R) a ); and the remaining variables are as described in any of the first to eighth and thirty-second to thirty-ninth embodiments.

[0110] In the forty-first embodiment, the compound of the present invention is represented by any one of formula (I'), (I), (II), (III), (IV), (V), (VI), (VII) or (VIII), wherein R a Each is independently selected from -CH3 and cyclopropyl; and the remaining variables are as described in any of the first to eighth and thirty-second to fortieth embodiments.

[0111] In the forty-second embodiment, the compound of the present invention is represented by any one of formulas (I'), (I), (II), (III), (IV), (V), (VI), (VII) or (VIII), wherein R 6 and R 6' Each is independently H, CH3, or CH2Cl; and the remaining variables are as described in any of the first to eighth and thirty-second to thirty-ninth embodiments.

[0112] In the forty-third embodiment, the compound of the present invention is represented by any one of formula (I'), (I), (II), (III), (IV), (V), (VI), (VII) or (VIII), wherein R 4For 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=CHCH3, 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. The remaining variables in formulas (I'), (I), (II), (III), (IV), (V), (VI), (VII) or (VIII) are as described in any of the first to eighth and thirty-second to forty-first embodiments.

[0113] In the forty-fourth embodiment, the compound of the present invention is represented by any one of formula (I'), (I), (II), (III), (IV), (V), (VI), (VII) or (VIII), R 4 For NHCOCH=CH2, N(CH3)COCH=CH2, NHCOCH=CHCH3, N(CH3)COCH=CHCH3, 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 4The variables are NHC(O)C≡CH, NHC(O)C≡CCH3, NHC(O)CH=CH2, N(CH3)COCH=CH2, N(CH3)COC≡CCH3, or N(CH2CH2F)COCH=CH2. The remaining variables in equations (I'), (I), (II), (III), (IV), (V), (VI), (VII), or (VIII) are as described in any of the first to eighth and thirty-second to forty-second embodiments.

[0114] In the forty-fifth embodiment, the compound of the present invention is represented by any one of formula (I'), (I), (II), (III), (IV), (V), (VI), (VII), or (VIII), wherein the bond to X 3 by R 2 The stereochemical configuration of the cyclic carbon atom in a C-linked 3-12 membered carbon ring is represented by R. Alternatively, it is bonded to X. 3 by R 2 The stereochemical configuration of the cyclic carbon atom in the C-linked 3-12 membered carbon ring is S. The remaining variables in formulas (I'), (I), (II), (III), (IV), (V), (VI), (VII), or (VIII) are as described in any of the first to eighth and thirty-second to forty-fourth embodiments.

[0115] In the forty-sixth embodiment, the compound of the present invention is represented by any one of formula (I'), (I), (II), (III), (IV), (V), (VI), (VII) or (VIII), wherein X 3 and R 4 The orientation is reversed. Or, X 3 and R 4 The orientation is cis. The remaining variables in formulas (I'), (I), (II), (III), (IV), (V), (VI), (VII), or (VIII) are as described in any of the first to eighth and thirty-second to forty-fourth embodiments.

[0116] In the forty-seventh embodiment, the compound of the present invention is represented by any one of formula (I'), (I), (II), (III), (IV), (V), (VI), (VII) or (VIII), wherein X 3 It is O-CH2CH2*, and R 2 For R 4 The indicated group is substituted and optionally further replaced by one or two groups derived from R. 10 The group represented is a C1-C3 alkyl group substituted with R. 2 It does not exist and X 3Directly connected to R 4 The remaining variables in equations (I'), (I), (II), (III), (IV), (V), (VI), (VII), or (VIII) are as described in the first through eighth embodiments.

[0117] In the forty-eighth embodiment, the compound of the present invention is represented by any one of formula (I'), (I), (II), (III), (IV), (V), (VI), (VII) or (VIII), wherein R 2 Selected from **-CH2-*** and **-CH2CH(CH3)-***, where "**" indicates a combination with X. 3 The connection point, and "***" indicates the connection with R. 4 The connection points. The remaining variables in equations (I'), (I), (II), (III), (IV), (V), (VI), (VII), or (VIII) are as described in any of the first through eighth and forty-seventh embodiments.

[0118] In the forty-ninth embodiment, the compound of the present invention is represented by any one of formula (I'), (I), (II), (III), (IV), (V), (VI), (VII) or (VIII), wherein R 4 It is N(CH3)C(O)CH=CH2; and the remaining variables are as described in any of the first to eighth, forty-seventh and forty-eighth embodiments.

[0119] In the fiftieth embodiment, the compound of the present invention is represented by any one of formula (I'), (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII) or (XIV), wherein R 1 It is H or C1-C3 alkyl, C1-C3 fluoroalkyl, or a 4-7 membered monocyclic oxygen-containing heterocycle. Alternatively, R... 1 It is H, CH3, CH(CH3)2, CHF2, oxetane, or tetrahydrofuranyl. The remaining variables in formulas (I'), (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), or (XIV) are as described in any of the first to forty-ninth embodiments.

[0120] In the fifty-first embodiment, the compound of the present invention is represented by any one of formula (I'), (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII) or (XIV), wherein R 1 The variable is H, CH3, CH(CH3)2, CHF2, CF3, oxecyclobutane, or tetrahydrofuranyl; and the remaining variables are as described in any of the first to forty-ninth embodiments.

[0121] In the fifty-second embodiment, the compound of the present invention is represented by any one of formulas (I'), (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII) or (XIV), wherein R 0 The variable is H, F, CN, CH3, CF3, cyclopropyl, or phenyl; and the remaining variables are as described in any of the first to fifty-first embodiments.

[0122] In the fifty-third embodiment, the compound of the present invention is represented by any one of formula (I'), (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII) or (XIV), wherein R 0 It is H, F, CN, CH3, or CF3; and the remaining variables are as described in any of the first to fifty-first embodiments.

[0123] In the fifty-fourth embodiment, the compound of the present invention is represented by any one of formula (I'), (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII) or (XIV), wherein R 7 The components are selected from H, CH3, CH2CH3, CH2CHF2, and cyclopropyl; and the remaining variables are as described in any of the first to fifty-third embodiments.

[0124] In the fifty-fifth embodiment, the compound of the present invention is represented by any one of formula (I'), (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII) or (XIV), wherein R 8 It is H or CH3; and the remaining variables are as described in any of the first to fifty-fourth embodiments.

[0125] In the fifty-sixth embodiment, the compound of the present invention is represented by any one of formula (I'), (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII) or (XIV), wherein R 10 It is F, Cl, CH3 or cyclopropyl; and the remaining variables in formula (I'), (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII) or (XIV) are as described in any of the first to fifty-fifth embodiments.

[0126] In the fifty-seventh embodiment, the compound of the present invention is represented by any one of formulas (I'), (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII) or (XIV), wherein R 14 Let Cl be the variable; and the remaining variables are as described in any of the first to fifty-sixth embodiments.

[0127] In the fifty-eighth embodiment, the compound is represented by the following formula:

[0128]

[0129] Or a pharmaceutically acceptable salt thereof, wherein: R 0 H, halogroup, or cyclopropyl group; X 3 For O or O-CH2*; R 2 It is a 4-7 member monocyclic or bicyclic saturated carbocyclic group, and is composed of R 2 The 4-7 member monocyclic or bicyclic saturated carbocyclic group represented by R 4 The indicated group is substituted and optionally further replaced by one or two R groups. 10 Replacement, or R 2 To bond to X via a ring carbon atom (“C-link”) 3 The 7-9 nucleotide bicyclic nitrogen-containing heterocycle and the C-linked 7-9 nucleotide bicyclic nitrogen-containing heterocycle are R 5 The indicated group is substituted and optionally further replaced by one or two R groups. 10 Replace; R 4 For N(R) 7 C(O)C≡CCH3、N(R) 7 C(O)CH=CH2, R 5 For C(O)CH=CH2, R 7 It is H, C1-C2 alkyl, or C1-C2 haloalkyl; and R 10It is a C1-C3 alkyl group.

[0130] In the fifty-ninth embodiment, the compound of the present invention is represented by formula (XV), wherein X 3 The value is O; and the remaining variables in equation (XV) are as described in the fifty-eighth embodiment.

[0131] In the sixtieth embodiment, the compound of the present invention is represented by formula (XV), wherein R 2 It is a cyclobutylene, cyclohexylene, cyclopentylene, or bicyclic [2.1.1]hexylene, each of which is R 4 The indicated group is substituted and optionally further replaced by one or two R groups. 10 Replace. The remaining variables in equation (XV) are as described in the fifty-eighth or fifty-ninth embodiment.

[0132] In the sixty-first embodiment, the compound of the present invention is represented by formula (XV), wherein R 2 for Among them, R 2 The indicated group is optionally further defined by one or two R groups. 10 The group substitutions are indicated. The remaining variables in formula (XV) are as described in the fifty-eighth or fifty-ninth embodiment.

[0133] In the sixty-second embodiment, the compound of the present invention is represented by formula (XV), wherein R 2 It is an azidobicyclo[3.2.1]octylene, an azidobicyclo[3.1.1]heptylene, or an azidobicyclo[3.2.0]heptylene, each of which is R 5 The indicated group is substituted and optionally further replaced by one or two R groups. 10 Replace. The remaining variables in equation (XV) are as described in the fifty-eighth or fifty-ninth embodiment.

[0134] In the sixty-third embodiment, the compound of the present invention is represented by formula (XV), wherein R 2 for The "**" indicates X 3 The connection point; and "***" indicates the connection with R. 5 The connection point, where R is the connection point. 2 Each group represented may optionally be further defined by one or two R groups. 10 The group substitutions are indicated. The remaining variables in formula (XV) are as described in any of the fifty-eighth to sixty-second embodiments.

[0135] In the sixty-fourth embodiment, the compound of the present invention is represented by formula (XV), wherein R 7It is H, CH3, or CH2CHF2. The remaining variables in equation (XV) are as described in any of the fifty-eighth to sixty-third embodiments.

[0136] In the sixty-fifth embodiment, the compound of the present invention is represented by formula (XV), wherein R 10 CH3. The remaining variables in equation (XV) are as described in any of the fifty-eighth to sixty-fourth embodiments.

[0137] The present invention also includes both the neutral form of the compounds disclosed in the examples and pharmaceutically acceptable salts.

[0138] As used herein, the term "alkyl" refers to a fully saturated branched or unbranched hydrocarbon moiety. Unless otherwise stated, an alkyl group comprises 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, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, or n-hexyl.

[0139] As used herein, the term "alkoxy" refers to a fully saturated branched or unbranched alkyl moiety connected via an oxygen bridge (i.e., --O--C). 1-4 Alkyl, wherein C 1-4 Alkyl groups are defined herein. Representative examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, etc. In some embodiments, the alkoxy group has about 1 to 4 carbons, more preferably about 1 to 2 carbons.

[0140] The number of carbon atoms in a group is determined by the prefix "C" in this paper. x-xx "Specifies that x and xx are integers. For example, "C 1-3 "Alkyl" refers to an alkyl group having 1 to 3 carbon atoms.

[0141] "Halogen" or "halogen group" can be fluorine, chlorine, bromine or iodine.

[0142] The term "haloalkyl" or "halogen-substituted alkyl" refers to an alkyl group having at least one halogen substitution. The term "fluoroalkyl" or "fluorine-substituted alkyl" refers to an alkyl group having at least one fluorine substitution.

[0143] "Heterocyclic group" or "heterocyclic ring" refers to a saturated or partially unsaturated monocyclic or bicyclic (e.g., fused, bridged, or spirocyclic) ring system having 4 to 12 ring members, of which at least one is a heteroatom, and of which up to 4 (e.g., 1, 2, 3, or 4) may be heteroatoms, wherein the heteroatoms are independently selected from O, S, and N, and wherein C may be oxidized (e.g., C(O)), N may be oxidized (e.g., N(O)) or quaternized, and S may optionally be oxidized to sulfoxides and sulfones. In some embodiments, if the "heterocyclic group" or "heterocyclic ring" described herein contains both N and O, then the "heterocyclic group" or "heterocyclic ring" is considered an N-containing heterocyclic ring.

[0144] The 4-12 membered heterocyclic group can be a monocyclic 4- to 7-membered heterocyclic group or a fused, bridged, or spirobicyclic 7- to 12-membered heterocyclic group. Examples of 4- to 7-membered monocyclic heterocyclic groups include, but are not limited to, oxacyclobutane, thioheterobutane, azacyclobutane, pyrrolidinyl, tetrahydrofuranyl, thioheteropentane, imidazoalkyl, pyrazolyl, oxazolyl, isoxazolyl, thiazoalkyl, isothiazolyl, dioxacyclopentane, dithioheteropentane, oxazolyl, tetrahydropyranyl, thiazoalkyl, piperidinyl, morpholinyl, thiomorpholinyl, dioxane, dithiazoalkyl, trioxane, trithiazoalkyl, azacycloheptane, oxacycloheptane, thioheteropentane, dihydrofuranyl, imidazolinyl, and dihydropyranyl.

[0145] A "fused-ring system" has 8 to 12 members (ring atoms) and two rings sharing two adjacent ring atoms. Fused bicyclic heterocyclic groups have 4 to 7-membered heterocyclic groups fused with 4 to 7-membered heterocyclic groups or 3 to 7-membered non-aromatic carbocyclic groups. Examples include cyclopentadienopyridine, cyclopentadienopiperidinyl, cyclopentadienoazonyl, cyclohexadienopyridine, cyclohexadienopiperidinyl, cyclohexadienoazonyl, cycloheptadienopyridine, cycloheptadienopyridine, cycloheptadienopiperidinyl, cycloheptadienoazonyl, pyrrolopyridine, pyrrolopiperidinyl, pyrrolopyridine, furanopyridine, furanopiperidinyl, furanoazonyl, pyrrolopyridine, pyrrolopiperidinyl, pyrrolopyridine, etc.

[0146] A “bridged bicyclic system” (also referred to herein as a “bridged bicyclic”) has 7 to 10 members (ring atoms) and two rings sharing three adjacent ring atoms. Bridged bicyclic heterocyclic groups comprise 5 to 7-membered heterocyclic groups that share three ring atoms with 5 to 7-membered heterocyclic groups or 5 to 7-membered non-aromatic carbocyclic groups. Examples of nitrogen-containing bridged bicyclics include azabicyclic [2.2.1]heptyl, azabicyclic [3.2.1]octyl, azabicyclic [3.3.1]nonyl, diazabicyclic [2.2.1]heptyl, diazabicyclic [3.2.1]octyl, and diazabicyclic [3.3.1]nonyl. Examples of oxygen-bridged bicyclic compounds include oxobicyclic [2.2.1]heptyl, oxobicyclic [3.2.1]octyl, oxobicyclic [3.3.1]nonyl, oxa-azabicyclic [2.2.1]heptyl, oxa-azabicyclic [3.2.1]octyl, and oxa-azabicyclic [3.3.1]nonyl.

[0147] A “spirocyclic system” (also referred to herein as a “spirocycle”) has 8 to 12 members (ring atoms) and two rings sharing one ring atom. Spirobicyclic heterocyclic groups comprise 4 to 7-membered heterocyclic groups that share one atom with 4 to 7-membered heterocyclic groups or 4 to 7-membered non-aromatic carbocyclic groups. Examples of 8 to 12-membered nitrogen-containing spirocyclic systems include 3,4-azabicyclooctyl, 4,4-azabicyclononyl, 3,5-azabicyclononyl, 3,6-azabicyclodecyl, 4,5-azabicyclodecyl, 3,7-azabicycloundecyl, 4,6-azabicycloundecyl, and 5,5-azabicycloundecyl. Examples of 8-12 oxo-bicyclo spirocyclic systems include 3,4-oxobicyclooctyl, 4,4-oxobicyclononyl, 3,5-oxobicyclononyl, 3,6-oxobicyclodecyl, 4,5-oxobicyclodecyl, 3,7-oxobicycloundecyl, 4,6-oxobicycloundecyl, and 5,5-oxobicycloundecyl.

[0148] Examples of 4- to 12-membered nitrogen-containing heterocycles include pyrrolidinyl, imidazoalkyl, pyrazolyl, oxazolyl, isoxazolyl, thiazoalkyl, isothiazolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, aziridine, oxazolidine, imidazolinyl, cyclopentadienylpyrrolidinyl, cyclopentadienylpiperidinyl, cyclopentadienylaziridine, cyclohexadienylpyrrolidinyl, cyclohexadienylpyrrolidinyl, cyclohexadienylaziridine, cyclohexadienylpyrrolidinyl, cyclohexadienylaziridine, cyclohexadienylpyrrolidinyl, cyclohexadienylpyrrolidinyl, cyclohexadienylaziridine, pyrrolopyrrolidinyl, pyrrolopiperidinyl, pyrroloaziridine, furanylpiperidinyl Furano-azirheptanyl, pyrano-pyrrolidinyl, pyrano-piperidinyl, pyrano-azirheptanyl, azirbicyclo[2.2.1]heptyl, azirbicyclo[3.2.1]octyl, azirbicyclo[3.3.1]nonyl, diazirbicyclo[2.2.1]heptyl, diazirbicyclo[3.2.1]octyl, diazirbicyclo[3.3.1]nonyl, 3,4-azirbicyclooctyl, 4,4-azirbicyclononyl, 3,5-azirbicyclononyl, 3,6-azirbicyclodecyl, 4,5-azirbicyclodecyl, 3,7-azirbicycloundecyl, 4,6-azirbicycloundecyl and 5,5-azirbicycloundecyl. Examples of 4- to 7-membered nitrogen-containing heterocycles (optionally containing an epoxy or a cyclic sulfur atom) include pyrrolidinyl, imidazoalkyl, pyrazolyl, oxazolyl, isoxazolyl, thiazoalkyl, isothiazolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, nitrogen-containing heptyl, oxonium-containing heptyl, and imidazolinyl.

[0149] Examples of 4- to 7-membered oxygen-containing heterocycles include oxacyclobutane, tetrahydrofuranyl, oxazolyl, isoxazolyl, dioxacyclopentane, oxothionyl, tetrahydropyranyl, morpholinyl, dioxane, oxacycloheptane, dihydrofuranyl, and dihydropyranyl.

[0150] "Heteroaryl" refers to an aromatic 5- to 6-membered monocyclic ring system having 1 to 4 heteroatoms independently selected from O, N, and S, wherein N may be oxidized (e.g., N(O)) or quaternized, and S may optionally be oxidized to sulfoxide and sulfone. Examples of 5- to 6-membered monocyclic heteroaryl groups include, but are not limited to, pyrroleyl, furanyl, thiophenyl / thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furazolyl, oxadiazolyl, thiazolyl, triazolyl, tetrazolyl, pyridyl, pyranyl, thiaranyl, pyrazinyl, pyrimidinyl, pyrazinyl, thiazolyl, dioxazinyl, dithiocyclohexadienyl, oxothiocyclohexadienyl, triazinyl, tetraazinyl, etc. In one embodiment, the heteroaryl group is a 5-membered heteroaryl group. Examples of 5-membered heteroaryl groups 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.

[0151] "Carbocyclic" refers to a saturated or partially unsaturated monocyclic or bicyclic (e.g., fused, bridged, or spirocyclic) ring system having 4 to 12 ring members, all of which are carbon. The term "carbocyclic" encompasses cycloalkyl, cycloalkenyl, and aromatic groups (i.e., aryl). "Cycloalkyl" refers to a fully saturated monocyclic hydrocarbon group with 3 to 7 carbon atoms, including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclopentyl; and "cycloalkenyl" refers to an unsaturated non-aromatic monocyclic hydrocarbon group with 3 to 7 carbon atoms, including cyclopentenyl, cyclohexenyl, and cyclopentenyl. Exemplary aromatic carbocyclic groups include phenyl.

[0152] Fused bicyclic carbocyclic groups have 4 to 7-membered carbocyclic groups fused with 3 to 7-membered non-aromatic carbocyclic groups. Examples include decahydronaphthalene, octahydro-1H-indene, octahydropentane, decahydroazine, decahydro-1H-annucleene, bis[4.2.0]octane, bicyclo[3.2.0]heptane, etc.

[0153] Bridged bicyclic carbocyclic groups comprise non-aromatic 5- to 7-membered carbocyclic groups, which share three ring atoms with the 5- to 7-membered non-aromatic carbocyclic groups. Examples of bridged bicyclic carbocyclic groups include bicyclic [2.2.1]heptyl, bicyclic [3.2.1]octyl, and bicyclic [3.3.1]nonyl.

[0154] The suffix "-" added to the end of a chemical name indicates that the named portion is bonded to the molecule at one point. The suffix "-" added to the end of a chemical name indicates that the named portion is bonded to the molecule at two points. Examples include aza-butane, pyrrolidine, piperidinyl, aza-heptane, or oxazolidinyl, which indicate that aza-butane, pyrrolidine, piperidine, aza-heptane, or oxazolidinyl are bonded to the rest of the compound at two points.

[0155] In the case of nitrogen-containing heterocycles, "N-linked to the bicyclic nucleus" means that the nitrogen-containing heterocycle is bonded to the nucleus via its cyclic nitrogen atoms. In the case of nitrogen-containing heterocycles or carbon rings, "C-linked to the bicyclic nucleus" means that the nitrogen-containing heterocycle or carbon ring is bonded to the nucleus via a cyclic carbon atom.

[0156] When a nitrogen atom in a ring is substituted, the nitrogen-containing heterocycle is called "N-substituted".

[0157] Where the compounds provided herein possess sufficient basicity or acidity to form stable, non-toxic acids or base salts, it is appropriate to prepare and administer the compounds in pharmaceutically acceptable salt form. Examples of pharmaceutically acceptable salts are addition salts of organic acids that form physiologically acceptable anions, such as toluenesulfonates, methanesulfonates, acetates, citrates, malonates, tartrates, succinates, benzoates, ascorbic acid salts, α-ketoglutarate, or α-glycerophosphates. Inorganic salts, including hydrochlorides, sulfates, nitrates, bicarbonates, and carbonates, may also be formed.

[0158] Pharmaceutically acceptable salts can be obtained using standard procedures well known in the art, for example, by reacting a sufficiently basic compound (e.g., an amine) with a suitable acid to give a physiologically acceptable anion. Alkali metal (e.g., sodium, potassium, or lithium) or alkaline earth metal (e.g., calcium) salts of carboxylic acids can also be prepared.

[0159] Pharmaceutically acceptable base addition salts can be formed from inorganic and organic bases. Salts derived 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 the following primary, secondary, or tertiary amines: for example, alkylamines, dialkylamines, trialkylamines, substituted alkylamines, di(substituted alkyl)amines, tri(substituted alkyl)amines, alkenylamines, dienylamines, trienylamines, substituted alkenylamines, di(substituted alkenyl)amines, tri(substituted alkenyl)amines, cycloalkylamines, di(cycloalkyl)amines, tri(cycloalkyl)amines, substituted cycloalkylamines, disubstituted cycloalkylamines, trisubstituted cycloalkylamines, cycloalkenylamines, di(cycloalkenyl)amines, trisubstituted cycloalkylamines, cycloalkenylamines, di(cycloalkenyl)amines, di(cycloalkenyl)amines, di(cycloalkyl ... Amines, tri(cycloalkenyl)amines, substituted cycloalkenylamines, disubstituted cycloalkenylamines, trisubstituted cycloalkenylamines, arylamines, diarylamines, triarylamines, heteroarylamines, diheteroarylamines, triheteroarylamines, heterocyclic alkylamines, diheterocyclic alkylamines, triheterocyclic alkylamines, or mixtures of diamines and triamines, wherein at least two substituents on the amine may be different and may be alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl, or heterocyclic alkyl, etc. Also includes amines in which two or three substituents together with an amino nitrogen form a heterocyclic alkyl or heteroaryl group. Non-limiting examples of amines may include isopropylamine, trimethylamine, diethylamine, tri(isopropyl)amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, trimethylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, N-alkylglucosamine, theobromine, purine, piperazine, piperidine, morpholine, or N-ethylpiperidine. Other carboxylic acid derivatives may be applicable, such as carboxylic amides, including carboxamides, lower alkyl carboxamides, or dialkyl carboxamides.

[0160] Compounds described herein, or pharmaceutically acceptable salts thereof, may contain one or more asymmetric centers in their molecules. According to this disclosure, any structure without specified stereochemistry should be understood to include all various stereoisomers (e.g., diastereomers and enantiomers) in pure or substantially pure forms, as well as mixtures thereof (e.g., racemic mixtures, or enantiomer-rich mixtures). How such optically active forms are prepared is well known in the art (e.g., by recrystallization to resolve racemic forms, synthesis from optically active starting materials, chiral synthesis, or chromatographic separation using a chiral stationary phase).

[0161] When a particular stereoisomer of a compound is described by its 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" refers to the weight percentage of the desired stereoisomer relative to the combined weight of all stereoisomers.

[0162] When a particular enantiomer of a compound is described by its 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" refers to the weight percentage of the desired enantiomer relative to the combined weight of all stereoisomers.

[0163] When the stereochemistry of the disclosed compound is named or described by a structure, and the named or described structure covers more than one stereoisomer (e.g., as in a diastereomer pair), it should be understood that this includes one of the covered stereoisomers or any mixture of the covered stereoisomers. It should be further understood that the stereoisomer purity of the named or described stereoisomer is at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 97%, 99%, 99.5%, or 99.9%. Stereoisomer purity is the weight percentage of the desired stereoisomer covered by the name or structure relative to the combined weight of all stereoisomers.

[0164] When a disclosed compound is named or described in terms of structure without indicating stereochemistry, and the compound has a chiral center, it should be understood that the name or structure covers an enantiomer of the compound in its pure or substantially pure form, as well as mixtures thereof (e.g., racemic mixtures of compounds and mixtures rich in an enantiomer relative to the corresponding optical isomers).

[0165] When a disclosed compound is named or described in terms of structure without indicating stereochemistry, and for example when the compound has at least two chiral centers, it should be understood that the name or structure covers a stereoisomer in pure or substantially pure form, as well as mixtures thereof (e.g., mixtures of stereoisomers, and mixtures of stereoisomers rich in one or more stereoisomers relative to other stereoisomers).

[0166] The disclosed compounds may exist in tautomer forms and mixtures, and include individual tautomers. In addition, some compounds may exhibit polymorphism.

[0167] In one embodiment, the present invention provides deuterated compounds disclosed herein, wherein any or more sites occupied by hydrogen may include deuterium enrichment at a level higher than the natural abundance of deuterium. For example, one or more hydrogen atoms are replaced by deuterium, the abundance of which is at least 3340 times (i.e., at least 50.1% deuterium inclusion), at least 3500 times (52.5% deuterium inclusion at each specified deuterium atom), at least 4000 times (60% deuterium inclusion), at least 4500 times (67.5% deuterium inclusion), at least 5000 times (75% deuterium), at least 5500 times (82.5% deuterium inclusion), at least 6000 times (90% deuterium inclusion), at least 6333.3 times (95% deuterium inclusion), at least 6466.7 times (97% deuterium inclusion), at least 6600 times (99% deuterium inclusion), or at least 6633.3 times (99.5% deuterium inclusion) of the natural abundance of deuterium (0.015%). In one embodiment, hydrogen is present in its natural abundance at all locations. Compounds as described herein, or their pharmaceutically acceptable salts, may exist in tautomer forms and mixtures, and encompass individual tautomers.

[0168] 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.

[0169] The compounds described herein, or their pharmaceutically acceptable salts, may be used to reduce the activity of Btk, or otherwise affect the properties and / or behavior of Btk, such as stability, phosphorylation, kinase activity, interactions with other proteins, etc.

[0170] In some embodiments, the present invention provides a method for reducing the enzymatic activity of Btk. In some embodiments, such a method includes contacting Btk with an effective amount of a Btk inhibitor. Therefore, the present invention further provides a method for inhibiting the enzymatic activity of Btk by contacting Btk with the Btk inhibitor of the present invention.

[0171] One embodiment of the present invention includes a method for treating a condition in a subject that responds to Btk inhibition, the method comprising administering to the subject an effective amount of at least one compound described herein or a pharmaceutically acceptable salt thereof.

[0172] In one embodiment, the present invention provides a method for treating autoimmune diseases, inflammatory diseases, and cancer in a subject in need, the method comprising administering to the subject an effective amount of at least one compound described herein or a pharmaceutically acceptable salt thereof.

[0173] The term "autoimmune disease" includes diseases or conditions involving inappropriate immune responses 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, Guillain-Barré 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. Granulomatosis). The term "inflammatory condition" includes diseases or conditions involving acute or chronic inflammation, such as allergies, asthma, prostatitis, glomerulonephritis, pelvic inflammatory disease (PID), inflammatory bowel disease (IBD, such as Crohn's disease, ulcerative colitis), reperfusion injury, rheumatoid arthritis, transplant rejection, and vasculitis. In some embodiments, the present invention provides a method for treating rheumatoid arthritis or lupus. In some embodiments, the present invention provides a method for treating multiple sclerosis.

[0174] 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 stromal tumor, pancreatic cancer, bile duct cancer, ovarian cancer, endometrial cancer, prostate cancer, renal cell carcinoma, lymphoma (e.g., anaplastic large cell lymphoma), leukemia (e.g., acute myeloid leukemia, T-cell leukemia, chronic lymphocytic leukemia), multiple myeloma, malignant mesothelioma, malignant melanoma, and colon cancer (e.g., high microsatellite instability colorectal cancer). In some embodiments, the present invention provides a method for treating leukemia or lymphoma.

[0175] As used herein, the terms “subject” and “patient” are used interchangeably and refer to mammals in need of treatment, such as companion animals (e.g., dogs, cats, etc.), farm animals (e.g., cattle, pigs, horses, sheep, goats, etc.), and laboratory animals (e.g., rats, mice, guinea pigs, etc.). Typically, a subject is a person in need of treatment.

[0176] As used herein, the term “treatment” or “therapeutic method” refers to achieving a desired pharmacological and / or physiological effect. The effect may be therapeutic and includes partially or substantially achieving one or more of the following results: partial or complete reduction of the severity of a disease, symptom, or syndrome; improvement or enhancement of clinical symptoms or indicators associated with the symptom; or delay, inhibit, or reduce the likelihood of progression of the disease, symptom, or syndrome.

[0177] The effective dose of the compounds or their pharmaceutically acceptable salts provided herein administered to subjects may be 10 μg to 500 mg.

[0178] Administration of the compounds described herein or their pharmaceutically acceptable salts to mammals includes any suitable method of delivery. Administration of the compounds described herein or their pharmaceutically acceptable salts to mammals includes topical, enteric, parenteral, transdermal, mucosal, inhalation, intracranial, epidural, vaginal, intravenous, intramuscular, subcutaneous, intradermal, or vitreous administration of the compounds described herein or their pharmaceutically acceptable salts to mammals. Administration of the compounds described herein or their pharmaceutically acceptable salts to mammals also includes topical, enteric, parenteral, transdermal, mucosal, inhalation, intracranial, epidural, vaginal, intravenous, intramuscular, subcutaneous, intradermal, or vitreous administration of compounds that metabolize the compounds described herein or their pharmaceutically acceptable salts within or on the surface of the mammal.

[0179] Therefore, compounds as described herein, or pharmaceutically acceptable salts thereof, may be combined with pharmaceutically acceptable media, such as inert diluents or assimilated food carriers, for systemic administration, e.g., orally. They may be encapsulated in hard or soft-shell gelatin capsules, compressed into tablets, or directly incorporated into the patient's diet. For oral therapeutic administration, compounds as described herein, or pharmaceutically acceptable salts thereof, may be combined with one or more excipients and used in the form of ingestible tablets, buccal tablets, lozenges, capsules, elixirs, suspensions, syrups, or rice paper capsules. Such compositions and formulations should contain at least about 0.1% of the active compound. Of course, the percentage of the composition and formulation may vary and may suitably range from about 2% to about 60% by weight for a given unit dosage form. The amount of the active compound in such therapeutically suitable compositions may be an amount that will achieve an effective dose level.

[0180] Tablets, lozenges, pills, capsules, etc. may include the following substances: binders such as gum arabic, gum arabic, corn starch or gelatin; excipients such as dicalcium phosphate; disintegrants such as corn starch, potato starch, alginic acid, etc.; lubricants such as magnesium stearate; or sweeteners such as sucrose, fructose, lactose or aspartame or flavoring agents.

[0181] The active compound can also be administered intravenously or intraperitoneally by infusion or injection. Solutions of the active compound or its salts can be prepared in water, optionally mixed with a non-toxic surfactant.

[0182] Exemplary drug dosage forms for injection or infusion may include sterile aqueous solutions or dispersions or sterile powders containing an active ingredient, said sterile powders being suitable for provisional preparation of sterile injectable or infusionable solutions or dispersions. In all cases, the final dosage form should be sterile, flowable, and stable under the conditions of manufacture and storage.

[0183] Sterile injectable solutions can be prepared by incorporating the desired amount of the active compound with various other ingredients listed above into a suitable solvent, followed by filtration and sterilization as needed. In the case of sterile powders used to prepare sterile injectable solutions, preferred preparation methods include vacuum drying and freeze-drying techniques, which produce powders of the active ingredient and any additional desired components present in the previously sterile filtered solution.

[0184] Exemplary solid carriers may include finely powdered solids such as talc, clay, microcrystalline cellulose, silica, alumina, etc. Suitable liquid carriers include water, alcohols or glycols or water-alcohol / glycol blends, wherein the compounds as described herein or their pharmaceutically acceptable salts can be dissolved or dispersed at effective levels, optionally with the aid of nontoxic surfactants.

[0185] The appropriate dose of the compounds described herein or their pharmaceutically acceptable salts can be determined by comparing their in vitro activity with their in vivo activity in animal models. Methods for extrapolating effective doses to humans from mice and other animals are known in the art; see, for example, U.S. Patent No. 4,938,949, which is incorporated herein by reference in its entirety.

[0186] The amount of the compound or its pharmaceutically acceptable salt described herein required for treatment may vary not only with the specific salt chosen, but also with the route of administration, the nature of the disease being treated, and the patient's age and condition, and may ultimately be determined by the attending physician or clinician. However, generally, the dosage can range from about 0.1 to about 10 mg / kg body weight per day.

[0187] The compounds described herein or their pharmaceutically acceptable salts may suitably be administered in unit dosage forms; for example, each unit dosage form may contain 0.01 to 10 mg or 0.05 to 1 mg of the active ingredient. In some embodiments, a dose of 5 mg / kg or less may be suitable.

[0188] The required dosage may be presented as a single dose or as multiple doses administered at appropriate time intervals.

[0189] The disclosed methods may include a kit containing a compound as described herein or a pharmaceutically acceptable salt thereof, and instruction material describing the administration of the compound as described herein or a pharmaceutically acceptable salt thereof, or a composition containing such a compound as described herein or a pharmaceutically acceptable salt thereof, to cells or a subject. This should be construed as including other embodiments of the kit known to those skilled in the art, such as kits containing a solvent (e.g., sterile) for dissolving or suspending the compound as described herein or a pharmaceutically acceptable salt thereof or a composition thereof prior to administration to cells or a subject. In some embodiments, the subject may be a human.

[0190] The present invention is illustrated by the following embodiments, which are not intended to be limiting.

[0191] example

[0192] The abbreviations and acronyms used in this article include the following:

[0193] ABPR stands for Automatic Back Pressure Regulator;

[0194] Ac2O refers to acetic anhydride;

[0195] ACN stands for acetonitrile;

[0196] Aq. refers to water-related qualities;

[0197] Ar refers to argon gas;

[0198] Bn refers to benzyl;

[0199] Boc stands for tert-butoxycarbonyl;

[0200] Boc2O refers to di-tert-butyl dicarbonate;

[0201] BPin refers to pinacol boron;

[0202] B2pin2 refers to dual-frequency diboron;

[0203] br means wide;

[0204] t-BuOH refers to tert-butanol;

[0205] n-BuLi refers to n-butyllithium;

[0206] ℃ means Celsius;

[0207] CHCl3 refers to chloroform;

[0208] CDCl3 refers to deuterated chloroform;

[0209] CO2 refers to carbon dioxide;

[0210] Cs2CO3 refers to cesium carbonate;

[0211] CsF stands for cesium fluoride;

[0212] CuI refers to copper iodide;

[0213] δ refers to chemical shift;

[0214] d means double peak;

[0215] dd means double double peak;

[0216] ddd means double double peak;

[0217] DCM stands for dichloromethane;

[0218] DIEA or DIPEA refers to N-ethyl diisopropylamine or N,N-diisopropylethylamine;

[0219] DEA stands for diethylamine;

[0220] deg indicates degree;

[0221] DIAD stands for diisopropyl azodicarbonate;

[0222] DME stands for 1,2-dimethoxyethane;

[0223] DMF stands for N,N-dimethylformamide;

[0224] DMSO stands for dimethyl sulfoxide;

[0225] DMSO-d6 refers to hexadeuterated dimethyl sulfoxide;

[0226] DPPA stands for diphenylphosphohydrin;

[0227] Et stands for ethyl;

[0228] Et2O refers to diethyl ether;

[0229] EtOH refers to ethanol;

[0230] EtOAc refers to ethyl acetate;

[0231] Eq. refers to equivalent quantity;

[0232] g means gram;

[0233] h means hour;

[0234] HATU refers to O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethylureonium hexafluorophosphate;

[0235] HBr stands for hydrogen bromide;

[0236] HCl refers to hydrochloric acid;

[0237] HCO2H is a nail acid;

[0238] Hept refers to heptane;

[0239] HFIP stands for hexafluoroisopropanol;

[0240] 1 H NMR stands for proton nuclear magnetic resonance;

[0241] H2O means water;

[0242] H2SO4 refers to sulfuric acid;

[0243] HMPA stands for hexamethylphosphamide;

[0244] HPLC stands for High Performance Liquid Chromatography.

[0245] Hz refers to Hertz;

[0246] IPA or iPrOH refers to isopropanol;

[0247] J refers to the coupling constant;

[0248] K2CO3 refers to potassium carbonate;

[0249] kg means kilogram;

[0250] KHMDS stands for potassium hexamethyldisilazide;

[0251] KOAc refers to potassium acetate;

[0252] KOH refers to potassium hydroxide.

[0253] KOt-Bu refers to potassium tert-butoxide

[0254] K3PO4 refers to tripotassium phosphate;

[0255] K4Fe(CN)6·3H2O refers to potassium hexacyanoferric(II) trihydrate;

[0256] L means rise;

[0257] LCMS stands for Liquid Chromatography-Mass Spectrometry.

[0258] m indicates multiple peaks;

[0259] M refers to molar concentration;

[0260] MBPR stands for Manual Back Pressure Regulator;

[0261] Me refers to methyl;

[0262] MeB(OH)2 refers to methylboronic acid;

[0263] MeCN stands for acetonitrile;

[0264] MeOH refers to methanol;

[0265] MeOH-d4 refers to deuterated methanol;

[0266] mg stands for milligram;

[0267] MgSO4 refers to magnesium sulfate;

[0268] MHz stands for megahertz;

[0269] mins means minutes;

[0270] mL means milliliters;

[0271] mmol stands for millimole;

[0272] MMPNO refers to methylmorpholine N-oxide;

[0273] mol means mole;

[0274] MS m / z refers to the mass spectrum peak;

[0275] N2 refers to nitrogen gas;

[0276] NaOt-Bu refers to sodium tert-butoxide;

[0277] NaH refers to sodium hydride;

[0278] NaHCO3 refers to sodium bicarbonate.

[0279] NaHMDS refers to sodium hexamethyldimethylsilyl azide.

[0280] NaIO4 refers to sodium periodate;

[0281] NaOH refers to sodium hydroxide.

[0282] Na2S2O3 refers to sodium thiosulfate;

[0283] Na2SO4 refers to sodium sulfate;

[0284] NEt3 refers to triethylamine;

[0285] NFSI stands for N-fluorobenzenesulfonamide;

[0286] NH3 refers to ammonia;

[0287] NH4Cl refers to ammonium chloride;

[0288] NH4OH is ammonium hydroxide;

[0289] NH4OAc is ammonium acetate;

[0290] NIS stands for N-iodosuccinimide;

[0291] OsO4 refers to osmium tetroxide;

[0292] P(cy)3 refers to tricyclohexylphosphine;

[0293] Pd2(dba)3 refers to tris(diphenylmethyleneacetone)dipalladium(0);

[0294] Pd(dppf)Cl2 refers to [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride;

[0295] Pd(dtbpf)Cl2 refers to [1,1'-bis(di-tert-butylphosphino)ferrocene]palladium(II) chloride;

[0296] PEPPSI-IPr or Pd-PEPPSI-IPr refers to [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II) dichloride.

[0297] Ph stands for phenyl;

[0298] POCl3 refers to phosphoric acid chloride;

[0299] Pyr refers to pyridine;

[0300] q means four peaks;

[0301] Rf refers to the blocking factor;

[0302] Rt refers to the retention period;

[0303] RT refers to room temperature;

[0304] RuPhos refers to 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl;

[0305] 's' indicates a single peak;

[0306] sat. means saturated;

[0307] SCX stands for Strong Cation Exchange;

[0308] SFC stands for Supercritical Fluid Chromatography.

[0309] SiO2 refers to silicon dioxide;

[0310] Si-SPE refers to silica solid-phase extraction;

[0311] 't' refers to a triple peak;

[0312] td means triple double peak;

[0313] t-BuONa refers to sodium tert-butoxide;

[0314] TEA stands for triethylamine;

[0315] TFA stands for trifluoroacetic acid;

[0316] THF stands for tetrahydrofuran;

[0317] TLC stands for Thin-Layer Chromatography.

[0318] T3P refers to propanephosphonic anhydride;

[0319] μL means a tiny liter;

[0320] μmol means micromolar;

[0321] μW stands for microwave.

[0322] v / v means volume / volume;

[0323] Xphos refers to 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl;

[0324] Xphos G3 refers to methyl sulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II).

[0325]

[0326] Option 1

[0327] Synthesize 1-(1-methyl-1H-pyrazol-4-yl)ethyl-1-one (2).

[0328]

[0329] Sulfuric acid (4.78 g, 2.61 mL, 0.08 equivalent, 48.7 mmol) was added to a mixture of 1-methyl-1H-pyrazole (50.0 g, 1 equivalent, 609 mmol) and acetic anhydride (112 g, 104 mL, 1.8 equivalent, 1.10 mol) at room temperature. The mixture was heated at 150 °C for 7 hours, and then cooled to room temperature overnight. The reaction mixture was poured into ice, and the pH of the resulting solution was adjusted to 10 with a 20% aqueous solution of NaOH. The solution was then extracted with DCM, and the organic phase was dried over sodium sulfate and concentrated. This gave 1-(1-methyl-1H-pyrazole-4-yl)ethyl-1-one (36.8 g, 49% yield). 1H NMR(300MHz, CDCl3)d 7.80-7.96(m,2H),3.91(s,3H),2.39(s,3H).

[0330] Synthesize 2-bromo-1-(1-methyl-1H-pyrazol-4-yl)ethyl-1-one (3).

[0331]

[0332] In a round-bottom flask, 36.8 g (1 equivalent, 296 mmol) of 1-(1-methyl-1H-pyrazol-4-yl)ethyl-1-one was dissolved in dichloromethane (700 mL). Ethanol (175 mL) and pyridinium tribromide (94.7 g, 1 equivalent, 296 mmol) were added fractionally at 15 °C. The mixture was stirred overnight from 0 °C to room temperature. The mixture was examined by TLC (heptane:EtOAc 4:6) and HPLC. After the addition was complete, the reaction mixture was quenched with water. The layers were separated, and the organic phase was dried over sodium sulfate and concentrated to give a product as a brown solid. The solid was suspended in a mixture of DCM and heptane, heated to 50 °C, and then cooled to room temperature. The product precipitated and was separated by filtration (28.8 g). More solid (7.43 g) precipitated from the mother liquor. A total of 36.2 g (60% yield) of the title product as a brown solid was separated. ESI-MS(M+H) + :205.1.

[0333] Synthesize 1-(2-(1-methyl-1H-pyrazol-4-yl)-2-oxoethyl)-1H-pyrazol-3,5-dicarboxylic acid diethyl ester (5).

[0334]

[0335] In a round-bottom flask, 60.6 g (1 methyl-1H-pyrazole-4-yl)ethyl-1-one (1 equivalence, 298 mmol) was dissolved in DMF (900 mL), and diethyl 1H-pyrazole-3,5-dicarboxylate (69.6 g, 1.1 equivalence, 328 mmol) and cesium carbonate (126 g, 1.30 equivalence, 388 mmol) were added. The reaction mixture 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 a white solid product (68.5 g). The concentrated mother liquor was purified by column chromatography (120 g silica, heptane:EtOAc gradient 0 to 100%) to obtain another portion of the product (9.7 g). A total of 78.2 g (78% yield) of the product was separated as a white solid. ESI-MS (M+H) + :335.2.

[0336] Synthesize ethyl 4-hydroxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-2-carboxylate (6).

[0337]

[0338] A Berghoff reactor was charged with diethyl 1-(2-(1-methyl-1H-pyrazol-4-yl)-2-oxoethyl)-1H-pyrazol-3,5-dicarboxylate (15.0 g, 1 equivalent, 44.9 mmol), ethanol (150 mL), and ammonium acetate (10.4 g, 3.0 equivalent, 135 mmol). The mixture was heated at 130 °C for 24 h, after which HPLC revealed complete conversion (the reactor was cooled to room temperature again before sampling). The reaction mixture was filtered, washed with water, and air-dried to give a product as a white solid (11.8 g, 92%). This reaction was carried out fractionally with a total of 78.2 g of starting material, yielding a total of 66.6 g of product (92% yield). ESI-MS (M+H) + :288.3.

[0339] Synthesize 4-hydroxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-2-carboxylic acid (7).

[0340]

[0341] In a round-bottom flask, ethyl 4-hydroxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-2-carboxylate (66.6 g, 1.0 equivalent, 232 mmol) was suspended in methanol (1.2 L), and 1M sodium hydroxide (27.9 g, 696 mL, 3.0 equivalent, 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, followed by filtration (filtration was extremely slow and difficult). The solid was washed with MeOH, transferred to a round-bottom flask, and stripped with acetonitrile. The resulting product was a mixture of methyl ester and salt (92.8 g, maximum 232 mmol). The solid was divided into two fractions and hydrolyzed repeatedly. In a round-bottom flask, methyl 4-hydroxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-2-carboxylic acid (46.0 g, 1.0 equivalent, 116 mmol) was suspended in methanol (1.2 L), and 1 M sodium hydroxide (13.9 g, 348 mL, 3.0 equivalent, 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 concentrated HCl, followed by filtration (filtration was still difficult). The solid was washed with acetonitrile and 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)pyrazolo[1,5-a]pyrazin-2-carboxylic acid, batch 1 (71.0 g, maximum 116 mmol, batch 1), containing a large amount of salt. The same procedure was repeated for the second batch of methyl ester. In this case, when the conversion is complete, the reaction mixture is acidified to pH 5. This yields 4-hydroxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-2-carboxylic acid (60.0 g, maximum 116 mmol, batch 1) containing a large amount of salt. ESI-MS (MH) + :258.0.

[0342] Synthesize 6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-ol (8).

[0343]

[0344] Preheated sulfolane (0.24 kg, 0.19 L, 30 equivalences, 2.0 mol) was added to a three-necked flask and heated to 50 °C. Then, 4-hydroxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-2-carboxylic acid (41.8 g, 1.0 equivalences, 68 mmol) and a few drops of concentrated sulfuric acid were added sequentially. The reaction mixture was heated at 350 °C (external, with sulfolane slowly refluxed) and the conversion was checked hourly. After 4 hours, the reaction mixture was cooled to room temperature, diluted with DCM, and purified by filtration through a short silica stopper eluted with 3 L heptane (fr1), 6 L heptane:EtOAc 1:1 (fr2-3), 6 L EtOAc (fr4-5), 4 L DCM (fr6), and 6 L DCM:MeOH 9:1 (fr7-8). A brown solid product (containing byproduct 8a) (2.88 g, 20%) was separated from fr7. ESI-MS (MH) + :214.1.

[0345] Synthesize 4-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine.

[0346]

[0347] In a round-bottom flask, 6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-ol (2.88 g, 1.0 equivalent, 13.4 mmol) was suspended in POCl3 (32.8 g, 19.9 mL, 16 equivalent, 214 mmol), and the reaction mixture was heated overnight at 80 °C. The mixture was diluted and concentrated with acetonitrile, the residue was suspended in DCM, and the mixture was washed with saturated NaHCO3 and brine, dried over sodium sulfate, and concentrated. The crude product was purified by column chromatography (DCM: EtOAc / NEt3 5% gradient 0 to 25%) to give a yellow solid (1.35 g, 43%). ESI-MS (M+H) + :234.0.

[0348]

[0349] Option 2

[0350] Synthesize 7-chloro-5-(methylthio)imidazo[1,2-c]pyrimidine hydrochloride (11).

[0351]

[0352] In a round-bottom flask, 150 g (1 equivalent, 854 mmol) of 6-chloro-2-(methylthio)pyrimidin-4-amine was dissolved in 300 mL of 1,4-dioxane, and 2-chloroacetaldehyde (220 g, 0.18 L, 1.5 equivalent, 1.28 mol) was added. The mixture was stirred at 100 °C. After 2 hours, a solid precipitated from the reaction mixture, and after 3 hours, the reaction mixture was examined by HPLC to confirm the completion of the 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 a product as a yellow solid (151 g, 75%). ESI-MS (M+H) + :200.1.

[0353] Synthesize 7-chloroimidazolo[1,2-c]pyrimidine-5(6H)-one(12).

[0354]

[0355] In a three-necked flask, 52.2 g (1 equivalent, 221 mmol) of 7-chloro-5-(methylthio)imidazo[1,2-c]pyrimidine hydrochloride was suspended in 200 mL of MeOH. A solution of 55.9 g (4.5 equivalent, 996 mmol) of potassium hydroxide in 520 mL of water was slowly added. The reaction mixture was heated under reflux for 3 hours, followed by examination by HPLC-MS. The starting material disappeared. The reaction mixture was cooled to room temperature overnight. The mixture was acidified to pH 6 with 1 M HCl and the resulting suspension was filtered. The solid was washed with MeOH, transferred to a round-bottom flask, suspended in ACN, and then concentrated. A pure product, 7-chloroimidazo[1,2-c]pyrimidine-5(6H)-one (28.55 g, 76%), was obtained as a white solid. ESI-MS (M+H) + :170.1.

[0356] Synthesize 7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidine-5(6H)-one (13).

[0357]

[0358] In a three-necked flask, 7-chloroimidazolo[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-dioxaborhecyclopentan-2-yl)-1H-pyrazole (73.6 g, 1.5 equivalent, 354 mmol), and X-phos (11.2 g, 0.10 equivalent, 23.6 mmol) were dissolved in 1.8 L of 2-propanol, and a 2 M solution of potassium phosphate (150 g, 0.35 L, 3.0 equivalent, 708 mmol) in water was added. The mixture was purged with nitrogen for 15 min, followed by the addition of Pd2(dba)3 (10.8 g, 0.05 equivalent, 11.8 mmol), and the mixture was refluxed overnight. The reactants were examined by HPLC-MS, and analysis showed almost complete conversion. Pd2(dba)3 (5.0 g) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-1H-pyrazole (25.0 g) were added, and the mixture was refluxed overnight. HPLC-MS showed complete conversion. The reaction mixture was filtered to remove palladium residues. The organic solvent was evaporated, and the residues were partitioned between a 1:1 mixture of water and heptane:EtOAc. A white solid precipitated in both the organic and aqueous layers: the mixture was filtered off. The solids were washed with water, ethyl acetate, and acetonitrile and dried under vacuum to give the product (32.8 g). The filtrate layer was separated. The organic phase was discarded, and the aqueous layer was cooled in an ice bath. The solution was treated with concentrated HCl to pH 6 with stirring, and the resulting fine precipitate was collected, washed with H2O and Et2O, and dried under vacuum to give another portion of the product (9.0 g). A total of 41.8 g (82%) of a pale yellow solid was obtained. ESI-MS(M+H) + :215.0.

[0359] Synthesize 5-chloro-7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidine.

[0360]

[0361] A round-bottom flask was filled with 41.8 g (1 equivalent, 194 mmol), anhydrous DCM (300 mL), and DIPEA (126 g, 0.17 L, 5 equivalent, 971 mmol). After 5 minutes, the mixture was cooled to 0 °C and POCl3 (89.3 g, 54.1 mL, 3 equivalent, 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 hexane 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 minutes, then a saturated aqueous solution of NaHCO3 was added and the mixture was stirred for 1 hour. The mixture was filtered through diatomaceous earth, and the layers were separated. The aqueous layer was extracted three 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.

[0362]

[0363] Option 3

[0364] Synthesis of 4-methoxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine

[0365]

[0366] A solution of 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-dioxaborhecyclopentan-2-yl)-1H-pyrazole (8.8 g, 42 mmol) in water (30 mL) and dioxane (150 mL) was mixed with K₂CO₃ (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 under N₂ for 2 hours. The reaction mixture was diluted with H₂O (80 mL) and extracted with EtOAc (100 mL x 2). The combined organic phases were dried over Na₂SO₄ and filtered. The filtrate was concentrated under vacuum and the residue was purified by silica gel column chromatography (PE / EtOAc = 1 / 1-0 / 1) to give 8.0 g of 4-methoxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine as a white solid. ¹H NMR (400 MHz, CDCl₃) 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)

[0367] 1. Synthesis of 6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-ol

[0368]

[0369] A solution of 4-methoxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine (15 g, 65.7 mmol) in 100 mL of 48% HBr aqueous solution was stirred at 120 °C for 48 h. The reaction mixture was concentrated under vacuum, the residue was quenched with saturated NaHCO3 until pH 8 was reached, and extracted with EtOAc (3 x 80 mL). The combined organic layers were dried over Na2SO4 and filtered. The filtrate was concentrated to give a crude product, which was purified by silica gel column chromatography (DCM / MeOH = 20 / 1-10 / 1) to give 13.0 g, 92% yield, as a gray solid of 6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-4-ol. LCMS m / z = 215.0 (M+H)+

[0370] 2. Synthesis of 6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl trifluoromethanesulfonic acid ester

[0371]

[0372] DIPEA (87.58 g, 678 mmol) and N-phenyl-bis(trifluoromethanesulfonylimide) (72.63 g, 203 mmol) were added 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), and the reaction mixture was stirred at 20 °C for 20 h. The reaction mixture was diluted with H2O (500 mL) and extracted with EtOAc (3 x 350 mL). The combined organic layers were dried over Na2SO4 and filtered. The filtrate was concentrated under vacuum and purified by silica gel column chromatography (PE / EtOAc = 20 / 1-1 / 1) to give 6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl ester of trifluoromethanesulfonic acid (32.0 g, 68% yield) as a yellow solid and another 10 g of crude product. LCMS m / z = 347.1 (M+H)+

[0373] C. Synthesis Examples 1-236

[0374] Example 1 : 1-[4-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]oxy-1-piperidinyl]prop-2-yn-1-one.

[0375]

[0376] Synthesis of tert-butyl 4-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]oxypiperidine-1-carboxylate

[0377]

[0378] The solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (664 mg, 3.30 mmol) in anhydrous DMF (10 mL) was cooled in an ice bath. Then, sodium hydride (396 mg, 9.90 mmol, 60% purity) was added in four portions with stirring. Stirring was continued in an ice bath for 45 minutes, during which time a pale yellow suspension formed. A batch of 4-chloro-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazine (701 mg, 3.00 mmol) was added to this mixture, and the mixture immediately turned brownish-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 Na₂SO₄, filtered, and evaporated under vacuum. The residue was purified on a 10 g Si-SPE column (Rt = 0.18) in heptane / EtOAc = 1 / 1 to give 1.30 g of tert-butyl 4-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]oxypiperidine-1-carboxylate (90% purity), which was a viscous yellow gel. LCMS: m / z = 399.0 (M+H) + ).

[0379] Synthesis of 6-(1-methylpyrazol-4-yl)-4-(4-piperidinoxy)pyrazolo[1,5-a]pyrazine

[0380]

[0381] TFA (6.70 g, 58.8 mmol, 4.5 mL) was added to a solution of 4-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]oxypiperidine-1-carboxylic acid tert-butyl ester (1.17 g, 2.94 mmol) in DCM (5 mL) at room temperature with stirring. Stirring was continued overnight. The mixture was diluted with MeOH and purified on a 10 g SCX column, wherein the product was eluted with 2 M NH3-MeOH to give 6-(1-methylpyrazol-4-yl)-4-(4-piperidineoxy)pyrazolo[1,5-a]pyrazine as a pale yellow solid (890 mg, 96% yield, 95% purity). LCMS: m / z = 299.0 (M+H) + ).

[0382] Synthesis of 1-[4-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]oxy-1-piperidinyl]prop-2-yn-1-one

[0383]

[0384] DIPEA (26 mg, 201 μmol, 35 μL) was added to a solution of 6-(1-methylpyrazol-4-yl)-4-(4-piperidinoxy)pyrazolo[1,5-a]pyrazine (30 mg, 101 μmol) in DMF (1 mL) and propionic acid (7.0 mg, 101 μmol, 6 μL) at room temperature with stirring. Then, T3P (128 mg, 201 μmol, 50% purity) was added with stirring. Stirring 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. The substance was dissolved in DMSO, filtered through a syringe filter, and purified by preparative HPLC (Waters XSelect CSH C18, 5 μm, 19 mm × 100 mm column, mobile phases H2O (A) and MeCN (B) with a gradient of 5–50% B (0.2% NH4OH final v / v% modifier), flow rate 30 mL / min) to obtain a white solid 1-[4-[6-(1-methylpyrazol-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) + ). 1 HNMR(500MHz,DMSO-d6)δ8.76(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).

[0385] Example 2 :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

[0386]

[0387] 6-(1-methylpyrazol-4-yl)-4-(4-piperidinoxy)pyrazolo[1,5-a]pyrazine (30 mg, 101 μmol) and THF (1 mL) were added to a 20 mL screw-top flask. Acryloyl chloride (12 μL, 151 μmol) was then added with stirring, immediately forming an emulsion suspension. Next, triethylamine (28 μL, 201 μmol) was added with stirring. After stirring for 5 minutes at room temperature, the evaporation was evaporated, leaving a white solid. The substance was dissolved in DMSO, filtered through a syringe filter, and purified by preparative HPLC (WatersXSelect CSH C18, 5μm, 19mm×100mm column, mobile phases H2O (A) and MeCN (B) with a gradient of 5-50% B (0.2% NH4OH final v / v% modifier), flow rate 30mL / min) to obtain a white solid 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 (24.9mg, 95% purity, 67% yield). LCMS: m / z = 353.0 (M+H) + ). 1 H NMR(500MHz,DMSO-d6)δ8.75(d,J=1.22Hz,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(brdd,J=2.44,16.48Hz,1H ),5.67-5.73(m,1H),5.60(ddd,J=3.97,7.63,11.60Hz,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).

[0388] Example 3 6-(1-Methyl-1H-pyrazol-4-yl)-4-((1-(vinylsulfonyl)piperidin-4-yl)oxy)pyrazolo[1,5-a]pyrazine

[0389]

[0390] 6-(1-methyl-1H-pyrazol-4-yl)-4-((1-(vinylsulfonyl)piperidin-4-yl)oxy)pyrazolo[1,5-a]pyrazine was prepared in a manner similar to that in Example 2, except that 2-chloro-ethane-sulfonyl chloride was used instead of acryloyl chloride. The substance was purified by preparative HPLC (Waters XSelect CSH C18, 5 μm, 19 mm × 100 mm column, mobile phase H2O (A) and MeCN (B) with a gradient of 5-55% B (0.2% NH4OH final v / v% modifier), flow rate 30 mL / min) to give 6-(1-methyl-1H-pyrazol-4-yl)-4-((1-(vinylsulfonyl)piperidin-4-yl)oxy)pyrazolo[1,5-a]pyrazine (4.9 mg, 95% purity, 12% yield) as a white solid. LCMS: m / z = 389.0(M+H) + ). 1 H NMR(500MHz,DMSO-d6)δ8.75(d,J=1.22Hz,1H),8.20(s,1H),8.02(d,J=2.44Hz,1 H),8.01(s,1H),6.89(dd,J=10.38,16.48Hz,1H),6.85(d,J=3.05Hz,1H),6.20(d, J=9.77Hz,1H),6.16(d,J=17.09Hz,1H),5.49(ddd,J=3.66,7.63,11.29Hz,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).

[0391] Example 4 :(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

[0392]

[0393] (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 was prepared in a manner similar to that of Example 2, except that it was started with (R)-3-hydroxypiperidin-1-yl)prop-2-en-1-one. The substance was purified using preparative HPLC (Waters XSelect CSH C18, 5 μm, 19 mm × 100 mm column, mobile phase H2O (A) and MeCN (B) with a gradient of 5–50% B (0.2% NH4OH final v / v% modifier), flow rate 30 mL / min) to obtain (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 (23.1 mg, 95% purity, 67% yield) as a white powder. LCMS: m / z = 353.0 (M+H) + ). 1 HNMR(500MHz,DMSO-d6)δ8.76(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).

[0394] Example 5 :(R)-6-(1-methyl-1H-pyrazol-4-yl)-4-((1-(vinylsulfonyl)piperidin-3-yl)oxy)pyrazolo[1,5-a]pyrazine

[0395]

[0396] (R)-6-(1-methyl-1H-pyrazole-4-yl)-4-((1-(vinylsulfonyl)piperidin-3-yl)oxy)pyrazolo[1,5-a]pyrazine was prepared in a manner similar to that in Example 3, except that it was started with (R)-3-hydroxypiperidin-1-carboxylate. The substance was purified by preparative HPLC (Waters XSelect CSH C18, 5 μm, 19 mm × 100 mm column, mobile phase H2O (A) and MeCN (B) with a gradient of 5-55% B (0.2% NH4OH final v / v% modifier), flow rate 30 mL / min) to give (R)-6-(1-methyl-1H-pyrazole-4-yl)-4-((1-(vinylsulfonyl)piperidin-3-yl)oxy)pyrazolo[1,5-a]pyrazine (8.9 mg, 95% purity, 22% yield) as a white powder. LCMS: m / z = 389.0(M+H) + ). 1 H NMR (500MHz, DMSO-d6) δ8.78(s,1H),8.21(s,1H),8.03(d,J=1.83Hz,1H),8.02(s,1H),6.84(d,J=2.44Hz,1H),6. 78-6.88(m,1H),6.11(s,1H),6.08(d,J=6.10Hz,1H),5.38(ddd,J=3.66,7.17,10.53Hz,1H),3.88(s,3H),3.74(br dd,J=3.66,12.21Hz,1H),3.46(br d,J=18.31Hz,1H),3.21-3.29(m,1H),3.11(ddd,J=3.36,8.09,11.75Hz,1H),2.05(ddd,J=3.66, 8.39, 12.36Hz, 1H), 1.89-1.98 (m, 1H), 1.79-1.88 (m, 1H), 1.71 (tdd, J = 4.04, 8.47, 17.01Hz, 1H).

[0397] Example 6 (S)-6-(1-Methyl-1H-pyrazol-4-yl)-4-((1-(vinylsulfonyl)piperidin-3-yl)oxy)pyrazolo[1,5-a]pyrazine

[0398]

[0399] (S)-6-(1-methyl-1H-pyrazole-4-yl)-4-((1-(vinylsulfonyl)piperidin-3-yl)oxy)pyrazolo[1,5-a]pyrazine was prepared in a manner similar to that in Example 3, except that it was started with (S)-3-hydroxypiperidin-1-carboxylate. The material was purified by preparative HPLC (Waters XSelect CSH C18, 5 μm, 19 mm × 100 mm column, mobile phases H2O (A) and MeCN (B) and gradient 5-55% B (0.2% NH4OH final v / v% modifier), flow rate 30 mL / min) to give (S)-6-(1-methyl-1H-pyrazole-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) + ). 1 H NMR (500MHz, DMSO-d6)δ

[0400] 8.78(s,1H),8.21(s,1H),8.03(d,J=1.83Hz,1H),8.02(s,1H),6.84(d,J=2.44Hz,1H),6.79-6.86(m,1H),6.11(s ,1H),6.08(d,J=6.10Hz,1H),5.38(tt,J=3.59,7.10Hz,1H),3.88(s,3H),3.74(dd,J=3.36,11.90Hz,1H),3.48(br s,1H),3.21-3.29(m,1H),3.11(ddd,J=3.36,8.09,11.75Hz,1H),2.05(ddd,J=3. 97,8.24,12.21Hz,1H),1.89-1.98(m,1H),1.80-1.89(m,1H),1.65-1.76(m,1H).

[0401] Example 7 :(R)-1-(3-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)piperidin-1-yl)prop-2-yn-1-one

[0402]

[0403] Synthesis of (R)-3-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]oxypiperidine-1-carboxylic acid tert-butyl ester

[0404]

[0405] The solution of (R)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (221 mg, 1.10 mmol) in anhydrous DMF (3 mL) was cooled in an ice bath. Then, sodium hydride (132 mg, 3.30 mmol, 60% purity) was added in two portions with stirring. Stirring was continued in the ice bath for 45 minutes, during which time a pale yellow suspension formed. A batch of 4-chloro-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazine (234 mg, 1.00 mmol) was added to this mixture, and the mixture immediately turned 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 Na₂SO₄, filtered, and evaporated under vacuum. 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-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]oxypiperidine-1-carboxylic acid tert-butyl ester (390 mg, 88% yield, 90% purity) as a colorless, viscous gel. LCMS: m / z = 399.0 (M+H) + ).

[0406] Synthesis of (R)-6-(1-methylpyrazol-4-yl)-4-(3-piperidinoxy)pyrazolo[1,5-a]pyrazine

[0407]

[0408] TFA (2.23 g, 19.58 mmol, 1.50 mL) was added to a solution of (R)-3-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]oxypiperidine-1-carboxylic acid tert-butyl ester (390 mg, 979 μmol) in anhydrous DCM (3 mL) at room temperature with stirring. After stirring overnight at room temperature, the mixture was diluted with MeOH and purified on a 5 g SCX column, wherein the product was eluted with 2 M NH3-MeOH to give (R)-6-(1-methylpyrazol-4-yl)-4-(3-piperidineoxy)pyrazolo[1,5-a]pyrazine as a colorless gel (270 mg, 88% yield, 95% purity). LCMS: m / z = 299.0 (M+H + ).

[0409] Synthesis of (R)-1-(3-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)piperidin-1-yl)prop-2-yn-1-one

[0410]

[0411] Propynic acid (7.0 mg, 101 μmol, 6 μL) was added to a solution of (R)-6-(1-methylpyrazol-4-yl)-4-(3-piperidinoxy)pyrazolo[1,5-a]pyrazine (30 mg, 101 μmol) in 1 mL of DMF under stirring at room temperature, followed by the addition of DIPEA (26 mg, 201 μmol, 35 μL). Then, T3P (128 mg, 201 μmol, 50% purity) was added under 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 under vacuum, and the residue was redissolved in DMSO. The substance was purified using preparative HPLC (Waters XSelect CSH C18, 5 μm, 19 mm × 100 mm column, mobile phase H2O (A) and MeCN (B) with a gradient of 5-50% B (0.2% NH4OH final v / v% modifier), flow rate 30 mL / min) to obtain (R)-1-(3-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)piperidin-1-yl)prop-2-yn-1-one (20.6 mg, 95% purity, 55% yield) as a white powder. LCMS: m / z = 350.1 (M+H + ). 1 H NMR(500MHz,DMSO-d6)δ8.75-8.77(m,1H),8.02(d,J=1.83Hz,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).

[0412] Example 8 :(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

[0413]

[0414] 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

[0415]

[0416] 6-(1-methylpyrazol-4-yl)-4-(4-piperidinoxy)pyrazolo[1,5-a]pyrazine (30 mg, 100 μmol) and DMF (1 mL) were added to a 20 mL screw-top flask. Then, (Z)-4-chlorobut-2-enoic acid (15.5 mg, 120 μmol) was added with stirring, immediately forming an emulsion suspension. Next, HATU (57.7 mg, 150 μmol) was added and the mixture was stirred at room temperature for 5 minutes. Then, 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 under vacuum and the residue was dissolved in DMSO and purified by preparative HPLC (Waters XSelect CSH C18, 5 μm, 19 mm × 100 mm column, mobile phases H2O (A) and MeCN (B) with a gradient of 5–55% B (0.2% NH4OH final v / v% modifier), flow rate 30 mL / min) to obtain (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 (17.8 mg, 95% purity, 42% yield) as a white powder. LCMS: m / z = 400.1. 1 H NMR(500MHz,DMSO-d6)δ8.76(s,1H),8.21(s,1H),8.00-8.03(m,2H),6.88(d,J=1.22Hz,1H),6.84-6.87(m,1H),6.65-6.72(m,1H),5.61 (ddd,J=3.66,7.48,11.44Hz,1H),4.38(dd,J=1.22,6.71Hz,2H),3.89(s,3H),3.44-3.69(m,4H),2.00-2.17(m,2H),1.67-1.86(m,2H).

[0417] Example 9 :1-(3-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)azacyclobutane-1-yl)prop-2-en-1-one

[0418]

[0419] Synthesis of tert-butyl 3-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]oxyazinon-1-carboxylate

[0420]

[0421] A solution of tert-butyl 3-hydroxyazacyclobutane-1-carboxylate (191 mg, 1.10 mmol) in anhydrous DMF (3 mL) was cooled in an ice bath. Then, sodium hydride (132 mg, 3.30 mmol, 60% purity) was added in two portions with stirring. Stirring was continued in an ice bath for 45 minutes, during which time a pale yellow suspension formed. A batch of 4-chloro-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazine (234 mg, 1.00 mmol) was added to this mixture, and the mixture immediately turned 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 Na₂SO₄, filtered, and evaporated under vacuum. The residue was purified on a 10 g Si-SPE column (Rt = 0.0.18) in heptane / EtOAc = 1 / 1 to give tert-butyl 3-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]oxyazacyclobutane-1-carboxylate (380 mg, 97% yield, 95% purity) as a colorless, viscous gel. ESI-MS (M+H) + :371.0.

[0422] Synthesis of 4-(azacyclobutane-3-yloxy)-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazine

[0423]

[0424] TFA (2.34 g, 20.5 mmol, 1.57 mL) was added to a solution of 3-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]oxyazinobutane-1-carboxylic acid tert-butyl ester (380 mg, 1.03 mmol) in DCM (5 mL) at room temperature with stirring. Stirring was continued overnight. The mixture was diluted with MeOH and purified on a 10 g SCX column, wherein the product was eluted with 2 M NH3-MeOH to give 4-(azinobutane-3-yloxy)-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazine as a white solid (250 mg, 85% yield, 95% purity). ESI-MS (M+H) + :271.0.

[0425] Synthesis of 1-(3-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)azacyclobutan-1-yl)prop-2-en-1-one

[0426]

[0427] 1-(3-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)azacyclobutan-1-yl)prop-2-en-1-one was prepared in the same manner as in Example 2. The substance was purified by preparative HPLC (Waters XSelect CSHC18, 5 μm, 19 mm × 100 mm column, mobile phase H2O (A) and MeCN (B) with a gradient of 5-45% B (0.2% NH4OH final v / v% modifier), flow rate 30 mL / min) to obtain 1-(3-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)azacyclobutan-1-yl)prop-2-en-1-one (20 mg, 95% purity, 64% yield) as a white powder. LCMS: m / z = 325.0. 1 H NMR(500MHz,DMSO-d6)δ8.82(s,1H),8.24(s,1H),8.06(d,J=2.44Hz,1H),8.03(s,1H),6.90-6.92(m,1H),6.38(dd ,J=10.38,17.09Hz,1H),6.11-6.17(m,1H),5.70(dd,J=2.44,10.38Hz,1H),5.62(tt,J=4.27,6.71Hz,1H),4.83(br dd,J=6.71,9.16Hz,1H),4.52(br dd,J=7.02,11.29Hz,1H),4.37(br dd,J=3.66,9.77Hz,1H), 4.08(br dd,J=3.66,11.60Hz,1H), 3.89(s,3H).

[0428] Example 10 :(Z)-6-(1-methyl-1H-pyrazol-4-yl)-4-((1-(prop-1-en-1-ylsulfonyl)azacyclobutane-3-yl)oxy)pyrazolo[1,5-a]pyrazine

[0429]

[0430] (Z)-6-(1-methyl-1H-pyrazol-4-yl)-4-((1-(prop-1-en-1-ylsulfonyl)azacyclobutane-3-yl)oxy)pyrazolo[1,5-a]pyrazine was prepared in a manner similar to that of Example 9, except that (Z)-prop-1-en-1-sulfonyl chloride was used instead of acryloyl chloride. The substance was purified by preparative HPLC (Waters XSelect CSH C18, 5 μm, 19 mm × 100 mm column, mobile phases H2O (A) and MeCN (B) with a gradient of 5–55% B (0.2% NH4OH 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)azacyclobutane-3-yl)oxy)pyrazolo[1,5-a]pyrazine (10 mg, 95% purity, 28% yield) as a beige solid. LCMS: m / z = 374.0. 1 H NMR(500MHz,DMSO-d6)δ8.82(s,1H),8.23-8.27(s,1H),8.06(d,J=2.44Hz,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=4.88Hz,3H).

[0431] Example 11 :(R)-1-(3-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)pyrrolidine-1-yl)prop-2-en-1-one

[0432]

[0433] Synthesis of (3R)-3-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]oxypyrrolidine-1-carboxylic acid tert-butyl ester

[0434]

[0435] The solution of (3R)-3-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (193 mg, 1.03 mmol) in anhydrous DMF (3 mL) was cooled in an ice bath. Then, sodium hydride (136 mg, 3.40 mmol, 60% purity) was added in four portions with stirring. Stirring was continued in an ice bath for 45 minutes, during which time a pale yellow suspension formed. A batch of 4-chloro-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazine (240 mg, 1.03 mmol) was added to this mixture, and the mixture immediately turned 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 Na₂SO₄, filtered, and evaporated under vacuum. The residue was purified on a 10 g Si-SPE column in heptane / EtOAc = 1 / 1 to give (3R)-3-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]oxypyrrolidine-1-carboxylic acid tert-butyl ester (345 mg, 83% yield, 95% purity) as a viscous, colorless gel, which turned into a viscous, white foam upon further drying. ESI-MS (M+H)+: 395.0.

[0436] Synthesis of 6-(1-methylpyrazol-4-yl)-4-[(3R)-pyrrolidine-3-yl]oxy-pyrazolo[1,5-a]pyrazine

[0437]

[0438] TFA (1.93 g, 17 mmol, 1.30 mL) was added to a solution of (3R)-3-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]oxypyrrolidine-1-carboxylic acid tert-butyl ester (326 mg, 849 μmol) in DCM (5 mL) at room temperature with stirring. Stirring was continued overnight. The mixture was diluted with MeOH and purified on a 10 g SCX column, with the product eluted with 2 MNH3-MeOH, to give a viscous, pale yellow gel of 6-(1-methylpyrazol-4-yl)-4-[(3R)-pyrrolidine-3-yl]oxy-pyrazol[1,5-a]pyrazine (230 mg, 91% yield, 95% purity). ESI-MS (M+H)+: 285.0.

[0439] Synthesis of (R)-1-(3-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)pyrrolidine-1-yl)prop-2-en-1-one

[0440]

[0441] (R)-1-(3-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)pyrrolidine-1-yl)prop-2-en-1-one was prepared in the same manner as in Example 2. The substance was purified by preparative HPLC (Waters XSelect CSHC18, 5 μm, 19 mm × 100 mm column, mobile phase H2O (A) and MeCN (B) with a gradient of 5-45% B (0.2% NH4OH final v / v% modifier), flow rate 30 mL / min) to give (R)-1-(3-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)pyrrolidine-1-yl)prop-2-en-1-one (27.9 mg, 95% purity, 74% yield) as a white solid. ESI-MS(M+H)+:339.0. 1 H NMR (500MHz, DMSO-d6) δ8.78(s,1H),8.21-8.26(m,1H),8.03(d,J=1.83Hz,1H),8.00-8.02(m,1H),6.84(br d,J=1.22Hz,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).

[0442] Example 12 :(R)-6-(1-methyl-1H-pyrazole-4-yl)-4-((1-(vinylsulfonyl)pyrrolidine-3-yl)oxy)pyrazole[1,5-a]pyrazine

[0443]

[0444] (R)-6-(1-methyl-1H-pyrazole-4-yl)-4-((1-(vinylsulfonyl)pyrrolidine-3-yl)oxy)pyrazolo[1,5-a]pyrazine was prepared in a manner similar to that in Example 11, except that 2-chloro-ethane-sulfonyl chloride was used instead of acryloyl chloride. The substance was purified by preparative HPLC (Waters XSelect CSH C18, 5 μm, 19 mm × 100 mm column, mobile phase H2O (A) and MeCN (B) with a gradient of 5-50% B (0.2% NH4OH final v / v% modifier), flow rate 30 mL / min) to give (R)-6-(1-methyl-1H-pyrazole-4-yl)-4-((1-(vinylsulfonyl)pyrrolidine-3-yl)oxy)pyrazolo[1,5-a]pyrazine (6.6 mg, 95% purity, 16% yield) as a white solid. ESI-MS(M+H)+: 375.0. 1 H NMR (500MHz, DMSO-d6) δ8.78(s,1H),8.22(s,1H),8.03(d,J=2.44Hz,1H),8.00-8.02(m,1H),6.92(dd,J=10.38,16.48Hz,1H),6. 85-6.86(m,1H),6.07-6.12(m,1H),6.05(d,J=9.77Hz,1H),5.78-5.84(m,1H),3.88(s,3H),3.39-3.75(m,4H),2.20-2.39(m,2H).

[0445] Example 13 :(R)-1-(3-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)pyrrolidine-1-yl)prop-2-yn-1-one

[0446]

[0447] (R)-1-(3-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)pyrrolidine-1-yl)prop-2-yn-1-one was prepared in a manner similar to that of Example 1. The substance was purified by preparative HPLC (Waters XSelect CSHC18, 5 μm, 19 mm × 100 mm column, mobile phase H2O (A) and MeCN (B) with a gradient of 5-45% B (0.2% NH4OH final v / v% modifier), flow rate 30 mL / min) to give (R)-1-(3-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)pyrrolidine-1-yl)prop-2-yn-1-one (18.2 mg, 95% purity, 51% yield) as a white solid. ESI-MS(M+H)+:337.0. 1 H NMR(500MHz,DMSO-d6)δ8.77-8.81(m,1H),8.21-8.26(m,1H),8.00-8.06(m,2H),6.86(d,J=2.44Hz,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).

[0448] 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

[0449]

[0450] Synthesis of (3S)-3-[[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]oxymethyl]piperidine-1-carboxylic acid tert-butyl ester

[0451]

[0452] The solution of (3S)-3-(hydroxymethyl)piperidine-1-carboxylic acid tert-butyl ester (222 mg, 1.03 mmol) in anhydrous DMF (3 mL) was cooled in an ice bath. Then, sodium hydride (136 mg, 3.40 mmol, 60% purity) was added in four portions with stirring. Stirring was continued in the ice bath for 45 minutes, during which time a pale yellow suspension formed. A batch of 4-chloro-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazine (240 mg, 1.03 mmol) was added to this mixture, and the mixture immediately turned 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 Na₂SO₄, filtered, and evaporated under vacuum. 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-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]oxymethyl]piperidine-1-carboxylic acid tert-butyl ester (386 mg, 86% yield, 95% purity) as a grayish-white solid; ESI-MS (M+H)+: 413.0.

[0453] Synthesis of 6-(1-methylpyrazol-4-yl)-4-[[(3S)-3-piperidinyl]methoxy]pyrazolo[1,5-a]pyrazine

[0454]

[0455] TFA (2.23 g, 19.6 mmol, 1.50 mL) was added to a solution of (3S)-3-[[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]oxymethyl]piperidine-1-carboxylic acid tert-butyl ester (404 mg, 978 μmol) in DCM (5 mL) at room temperature with stirring. Stirring was continued overnight. The mixture was diluted with MeOH and purified on a 10 g SCX column, wherein the product was eluted with 2 M NH3-MeOH to give 6-(1-methylpyrazol-4-yl)-4-[[(3S)-3-piperidinyl]methoxy]pyrazolo[1,5-a]pyrazine (240 mg, 75% yield, 95% purity) as a pale yellow, viscous gel, which formed a white foam upon further drying. ESI-MS (M+H)+: 313.0.

[0456] 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

[0457]

[0458] (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 was prepared in the same manner as in Example 2. The substance was purified by preparative HPLC (Waters X Select CSH C18, 5 μm, 19 mm × 100 mm column, mobile phase H2O (A) and MeCN (B) with a gradient of 5–50% B (0.2% NH4OH final v / v% modifier), flow rate 30 mL / min) to give (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) as a white powder. ESI-MS (M+H)+: 367.0. 1 H NMR(500MHz,DMSO-d6)δ8.76(s,1H),8.21(br s,1H),8.03(d,J=2.44Hz,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).

[0459] Example 15 (S)-6-(1-Methyl-1H-pyrazol-4-yl)-4-((1-(vinylsulfonyl)piperidin-3-yl)methoxy)pyrazolo[1,5-a]pyrazine

[0460]

[0461] (S)-6-(1-methyl-1H-pyrazol-4-yl)-4-((1-(vinylsulfonyl)piperidin-3-yl)methoxy)pyrazolo[1,5-a]pyrazine was prepared in a manner similar to that of Example 14, except that 2-chloro-ethane-sulfonyl chloride was used instead of acryloyl chloride. The substance was purified by preparative HPLC (Waters SunFire Prep C18, 5 μm, OBD 19 mm × 100 mm column, mobile phase H2O (A) and MeCN (B) with a gradient of 5–55% B (0.1% TFA final v / v% modifier), flow rate 30 mL / min) to give (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) as a beige solid. ESI-MS (M+H)+: 403.0. 1 H NMR (500MHz, DMSO-d6) δ8.77(s,1H),8.21(s,1H),8.03(d,J=2.44Hz,1H),8.01(s,1H),6.84(d,J=3.05Hz,1H) ,6.76-6.84(m,1H),6.13(d,J=9.77Hz,1H),6.09(d,J=16.48Hz,1H),4.42-4.52(m,2H),3.89(s,3H),3.63(br dd,J=3.66,11.60Hz,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=3.66,13.43Hz,1H),1.50-1.64(m,1H),1.18-1.38(m,1H).

[0462] 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

[0463]

[0464] (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 was prepared in a manner similar to that of Example 1. The substance was purified by preparative HPLC (Waters X Select CSH C18, 5 μm, 19 mm × 100 mm column, mobile phase H2O (A) and MeCN (B) with a gradient of 5-55% B (0.2% NH4OH final v / v% modifier), flow rate 30 mL / min) to give (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) as a white solid. ESI-MS(M+H)+:365.0. 1 H NMR(500MHz,DMSO-d6)δ8.74-8.78(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).

[0465] Example 17 :(R,E)-6-(1-methyl-1H-pyrazol-4-yl)-4-((1-(prop-1-en-1-ylsulfonyl)piperidin-3-yl)oxy)pyrazolo[1,5-a]pyrazine

[0466]

[0467] 1. Synthesis of (R,E)-6-(1-methyl-1H-pyrazol-4-yl)-4-((1-(prop-1-en-1-ylsulfonyl)piperidin-3-yl)oxy)pyrazolo[1,5-a]pyrazine

[0468]

[0469] Add 6-(1-methylpyrazol-4-yl)-4-[[(3R)-3-piperidinyl]oxy]pyrazolo[1,5-a]pyrazine (125 mg, 419 μmol), DCM (2.1 mL), N-ethyl-N-isopropyl-prop-2-amine (162 mg, 1.26 mmol, 220 μL), and (E)-prop-1-ene-1-sulfonyl chloride (88 mg, 628 μmol, 66 μL) to the vial in that order. Stir the vial overnight at room temperature. Dilute the reaction mixture with water, pass it through a phase separator, and concentrate it. Dissolve the substance in 2.5 mL of DMSO and pass it through a syringe filter. The substance was purified by reversed-phase HPLC (Waters XSelect CSH C18, 5 μm, 19 mm × 100 mm column, mobile phase H2O (A) and MeCN (B) with a gradient of 5-60% B (0.2% NH4OH final v / v% modifier), flow rate 30 mL / min) to obtain a grayish-white solid 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. 1 H NMR(500MHz,DMSO-d6)δ8.78(s,1H),8.21(s,1H),7.99-8.06(m,1H),6.84(dd,J=1.22,2.44Hz,1H),6.61(br d,J=6.71Hz,1H),6.46-6.54(m,1H),5.38(td,J=3.89,7.48Hz,1H),3.88(s,3H),3.72(br dd,J=3.36,11.90Hz,1H),3.12-3.28(m,2H),3.05(ddd,J=3.36,8.09,11.75Hz,1H),2.02-2.08( m,1H),1.90-1.98(m,2H),1.85(dd,J=1.83,6.71Hz,3H),1.71(ddd,J=4.58,8.55,13.12Hz,2H).

[0470] 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

[0471]

[0472] 1. Synthesis of tert-butyl 4-(((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)amino)methyl)piperidine-1-carboxylic acid

[0473]

[0474] Add Hunig's base (553 mg, 4.28 mmol, 750 μL) to a suspension of 4-chloro-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazine (500 mg, 2.14 mmol) and 4-(aminomethyl)piperidine-1-carboxylic acid tert-butyl ester (504 mg, 2.35 mmol, 500 μL) in DMF (7.13 mL). Heat the reaction mixture to 70 °C and stir overnight. Concentrate the mixture and purify by column chromatography (40 g silica column, gradient elution 0-100% EtOAc:heptane) to give 4-[[[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazine-4-yl]amino]methyl]piperidine-1-carboxylic acid tert-butyl ester (398 mg, yield: 45%) as a brown solid. ESI-MS(M+H) + :412.2.

[0475] 2. Synthesis of 6-(1-methyl-1H-pyrazol-4-yl)-N-(piperidin-4-ylmethyl)pyrazolo[1,5-a]pyrazin-4-amine

[0476]

[0477] 4-[[[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]amino]methyl]piperidine-1-carboxylic acid tert-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 mixture was stirred overnight at room temperature. The reaction mixture was concentrated, diluted with DCM, and carefully quenched with saturated sodium bicarbonate solution. The aqueous layer was washed twice with DCM, followed by dilution with saturated ammonium hydroxide solution and extraction 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-piperidinylmethyl)pyrazolo[1,5-a]pyrazin-4-amine (300 mg, yield: 100%) as a pale yellow oily solid. ESI-MS (M+H) + :312.1.

[0478] 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

[0479]

[0480] Add DCM (2.4 mL) and TEA (73 mg, 725 μmol, 100 μL) to a vial containing 6-(1-methylpyrazol-4-yl)-N-(4-piperidinylmethyl)pyrazolo[1,5-a]pyrazin-4-amine (75 mg, 241 μmol), then place the vial on dry ice / acetone for 10 minutes. Add acryloyl chloride (28 mg, 313 μmol, 26 μL) dropwise to this solution. Stir the reaction mixture for 10 minutes. Dilute the reaction mixture with water and pass it through a phase separator. The aqueous layer was extracted with DCM, and the combined organic layers were concentrated, dissolved in DMSO, and purified by reversed-phase HPLC (Waters XSelect CSH C18, 5 μm, 19 mm × 100 mm column, mobile phases H2O (A) and MeCN (B) with a gradient of 5–35% B (0.2% NH4OH final v / v% modifier), flow rate 30 mL / min) to obtain a yellow solid, 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. 1 H NMR (500MHz, DMSO-d6) δ8.27(s,1H),8.09(s,1H),7.92(s,1H),7.84(d,J=2.44Hz,1H),7.64(br t,J=5.49Hz,1H),6.93-6.97(m,1H),6.80(br dd,J=10.68,16.79Hz,1H),6.07(br dd,J=2.44,17.09Hz,1H),5.61-5.68(m,1H),4.42(br d,J=12.21Hz,1H),4.06(br d,J=12.82Hz,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=3.97,7.17,10.83Hz,2H),1.81(br d,J=13.43Hz,2H),1.06-1.22(m,2H).

[0481] Example 19 6-(1-methyl-1H-pyrazol-4-yl)-N-((1-(vinylsulfonyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyrazin-4-amine

[0482]

[0483] 1. Synthesis of 6-(1-methyl-1H-pyrazol-4-yl)-N-((1-(vinylsulfonyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyrazin-4-amine

[0484]

[0485] Add DCM (2.4 mL), DMF (200 μL), and TEA (73 mg, 725 μmol, 100 μL) to a vial containing 6-(1-methylpyrazol-4-yl)-N-(4-piperidinylmethyl)pyrazolo[1,5-a]pyrazin-4-amine (75 mg, 241 μmol), and then place it in a dry ice / acetone bath for 10 minutes. Add vinylsulfonyl chloride (40 mg, 313 μmol, 28 μL) dropwise to this solution. Heat the reaction mixture to room temperature and stir overnight. Dilute the reaction mixture with water and pass it through a phase separator. The aqueous layer was extracted with DCM, and the combined organic layer was concentrated, dissolved in DMSO, and purified by reversed-phase HPLC (Waters XSelect CSH C18, 5 μm, 19 mm × 100 mm column, mobile phases H2O (A) and MeCN (B) with a gradient of 5–40% B (0.2% NH4OH final v / v% modifier), flow rate 30 mL / min) to give 6-(1-methylpyrazol-4-yl)-N-[(1-vinylsulfonyl-4-piperidinyl)methyl]pyrazolo-[1,5-a]pyrazin-4-amine (19 mg, yield: 20%) as a yellow solid. ESI-MS (M+H) + :402.2. 1 H NMR(500MHz,DMSO-d6)δ8.27(s,1H),8.09(s,1H),7.92(s,1H),7.82-7.86(m,1H),7.66(br t,J=5.80Hz,1H),6.93-6.96(m,1H),6.78(dd,J=9.77,16.48Hz,1H),6.06-6.15(m,2H),3.87(s,3H),3.55(br d,J=11.60Hz,2H),2.57-2.65(m,4H),1.85(br d,J=11.60Hz,3H),1.25-1.35(m,2H).

[0486] Example 20 :N-[1-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]-3-piperidinyl]prop-2-enamide

[0487]

[0488] Synthesis of N-[1-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]-3-piperidinyl]tert-butyl carbamate

[0489]

[0490] N-ethyl-N-isopropyl-propane-2-amine (249 mg, 1.93 mmol, 336 μL) and N-(3-piperidinyl)carbamate tert-butyl ester (264 mg, 1.32 mmol) were added sequentially 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). The reaction mixture was stirred overnight at 80 °C. The concentrated material was used as crude material, assuming a yield of 100%. LCMS m / z = 398.0.(M+H)+.

[0491] Synthesis of 1-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]piperidine-3-amine hydrochloride

[0492]

[0493] HCl (4 M, 1.92 mL) was added to a solution of N-[1-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]-3-piperidinyl]carbamate tert-butyl (509 mg, 1.28 mmol) in dioxane (6.4 mL). The mixture was stirred overnight at room temperature. The solid precipitated 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]piperidin-3-amine hydrochloride (500 mg, 94% yield) as a brown solid. The solid is assumed to have a purity of 80%.

[0494] Synthesis of N-[1-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]-3-piperidinyl]prop-2-enamide

[0495]

[0496] N-ethyl-N-isopropyl-propane-2-amine (93 mg, 719 μmol, 126 μL) and acrylonitrile-2-yl chloride (18 mg, 198 μmol, 16 μL) were added sequentially to a solution of 1-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]piperidine-3-amine hydrochloride (75 mg, 180 μmol, 16 μL) in DCM (1.8 mL). The reaction mixture was stirred overnight at room temperature. The substance was concentrated and purified by reverse-phase purification (column: Waters XSelect CSH Prep C18 5 μm OBD 19 x 100 mm; 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)+. 1 H NMR(500MHz,DMSO-d6)δppm 1.19-1.30(m,1H)1.53-1.69(m,2H)1.81-2.01(m,2H)3.06(dd,J=12.82,9.77Hz,1H)3.23-3.27(m,1H)3.87(s,3H)3.91-3.97(m,1H)4.22 -4.47(m,2H)5.57-5.66(m,1H)6.18(s,1H)6.23-6.34(m,1H)7.06(d,J=2.44Hz,1H)7.89-8.03(m,1H)8.19-8.27(m,2H)8.40-8.53(m,1H).

[0497] Example 21 :N-[1-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]-3-piperidinyl]prop-2-yneamide

[0498]

[0499] Synthesis of N-[1-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]-3-piperidinyl]prop-2-yneamide

[0500]

[0501] N-ethyl-N-isopropyl-propane-2-amine (86 mg, 669 μmol, 117 μL) and HATU (68 mg, 178 μmol) were added sequentially to a solution of 1-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]piperidine-3-amine hydrochloride (75 mg, 180 μmol) in DCM (1.5 mL). The reaction mixture was stirred for 15 min, followed by the addition of propargyl-2-acetylic acid (15 mg, 216 μmol, 13 μL), and the mixture was stirred overnight at room temperature. The substance was concentrated and purified by reverse-phase purification (column: WatersXSelect CSH Prep C18 5 μm OBD 19 x 100 mm; 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)+. 1 ¹H NMR (500MHz, DMSO-d⁶) δppm 1.22-1.43 (m, 1H) 1.51-1.68 (m, 2H) 1.78-1.99 (m, 2H) 3.04 (dd, J = 12.82, 9.16Hz, 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 = 1.83Hz, 1H) 7.90-8.07 (m, 1H) 8.20 (s, 1H) 8.44-8.56 (m, 1H) 8.92 (d, J = 7.32Hz, 1H). A proton signal was masked by residual water in the deuterated solvent.

[0502] Example 22 :4-Chloro-N-[1-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]-3-piperidinyl]but-2-enamide

[0503]

[0504] Synthesis of 4-chloro-N-[1-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]-3-piperidinyl]but-2-enamide

[0505]

[0506] N-ethyl-N-isopropyl-propane-2-amine (86 mg, 669 μmol, 117 μL) and HATU (68 mg, 178 μmol) were added sequentially to a solution of 1-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]piperidine-3-amine hydrochloride (75 mg, 180 μmol) in DCM (1.5 mL). The reaction mixture was stirred for 15 min, followed by the addition of 4-chlorobutyric acid (26 mg, 216 μmol), and the mixture was stirred overnight at room temperature. The substance was concentrated and purified by reverse-phase chromatography (column: Waters XSelect CSH Prep C18 5 μm OBD 19 x 100 mm; 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)+. 1 H NMR(500MHz,DMSO-d6)δ:8.51-8.43(m,1H),8.30(d,J=7.3Hz,1H),8.25-8.17( m,1H),8.02-7.89(m,1H),7.09-6.98(m,1H),6.75(td,J=6.1,14.6Hz,1H),6.31 -6.19(m,1H),4.37(dd,J=1.2,6.1Hz,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=3.1Hz,1H),1.70-1.54(m,2H),1.33-1.17(m,1H).

[0507] Example 23 N-Methyl-N-[1-[7-(1-methylpyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl]-3-piperidinyl]prop-2-yneamide

[0508]

[0509] Synthesis of N-methyl-N-[1-[7-(1-methylpyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl]-3-piperidinyl]tert-butyl carbamate

[0510]

[0511] N-ethyl-N-isopropyl-propane-2-amine (830 mg, 6.42 mmol, 1.1 mL) and N-methyl-N-(3-piperidinyl)carbamate tert-butyl ester (945 mg, 4.41 mmol) were added sequentially 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). The reaction mixture was stirred overnight at 80 °C. The concentrated material was used as crude material, assuming a yield of 100%. LCMS m / z = 412.0(M+H)+.

[0512] Synthesis of N-methyl-1-[7-(1-methylpyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl]piperidine-3-amine hydrochloride

[0513]

[0514] HCl (4 M, 6.42 mL) was added to a solution of N-methyl-N-[1-[7-(1-methylpyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl]-3-piperidinyl]carbamate tert-butyl (1.76 g, 4.28 mmol) in dioxane (8.56 mL). The mixture was stirred overnight at room temperature. The solid precipitated overnight and was filtered off and washed with EtOAc. The solid was air-dried to give N-methyl-1-[7-(1-methylpyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl]piperidin-3-amine hydrochloride (1.94 g, 3.90 mmol, 91% yield) as a grayish-white solid. The solid is assumed to have a purity of 70%. LCMS m / z = 312.1(M+H)+.

[0515] Synthesis of N-methyl-N-[1-[7-(1-methylpyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl]-3-piperidinyl]prop-2-yneamide

[0516]

[0517] N-ethyl-N-isopropyl-propane-2-amine (130 mg, 1.01 mmol, 176 μL) and propanediol (18 mg, 262 μmol, 16 μL) were added sequentially to a solution of N-methyl-1-[7-(1-methylpyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl]piperidine-3-amine hydrochloride (100 mg, 201 μmol) in DCM (1 mL). Then, HATU (100 mg, 262 μmol) was added to the vial, and the mixture was stirred overnight at room temperature. The substance was concentrated and purified by reverse-phase chromatography (column: Waters XSelect CSH Prep C18 5 μm OBD 19 x 100 mm; 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)+.

[0518] Example 24 N-methyl-N-[1-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]-3-piperidinyl]prop-2-yneamide

[0519]

[0520] Synthesis of N-methyl-N-[1-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]-3-piperidinyl]tert-butyl carbamate

[0521]

[0522] N-ethyl-N-isopropyl-propane-2-amine (332 mg, 2.57 mmol, 448 μL) and N-methyl-N-(3-piperidinyl)carbamate tert-butyl carbamate (378 mg, 1.76 mmol) were added sequentially 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). The vial was stirred overnight at 80 °C. The concentrated material was used as crude material, assuming a yield of 100%. LCMS m / z = 412.1(M+H)+.

[0523] Synthesis of N-methyl-1-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]piperidine-3-amine hydrochloride

[0524]

[0525] HCl (4 M, 2.57 mL) was added to a solution of N-methyl-N-[1-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]-3-piperidinyl]carbamate tert-butyl (704 mg, 1.71 mmol) in dioxane (8.6 mL). The mixture was stirred overnight at room temperature. The solid precipitated overnight and was filtered off and washed with EtOAc. The solid was air-dried to give N-methyl-1-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]piperidin-3-amine hydrochloride (651 mg, 88% yield) as a grayish-white solid. The solid is assumed to have 80% purity. LCMS m / z = 312.1(M+H)+.

[0526] Synthesis of N-methyl-N-[1-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]-3-piperidinyl]prop-2-yneamide

[0527]

[0528] To a solution of 1N-methyl-1-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]piperidine-3-amine hydrochloride (100 mg, 230 μmol) in DCM (1 mL), propargyl acid (21 mg, 299 μmol, 18 μL), N-ethyl-N-isopropyl-propan-2-amine (86 mg, 669 μmol, 117 μL) and HATU (114 mg, 299 μmol) were added sequentially. The reaction mixture was stirred overnight at room temperature. The substance was concentrated and purified by reverse-phase purification (column: Waters XSelect CSH Prep C18 5um OBD 19x100 mm; 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)+. 1 H NMR(500MHz,DMSO-d6)δppm 1.59-1.75(m,1H)1.78-2.05(m,4H)2.90(s,2H),2.99-3.11(m,1H)3.14-3.18(m,1H)3.87(d,J=1.83Hz, 3H)4.29-4.56(m,4H)6.95(d,J=2.44Hz,1H)7.90-8.04(m,2H)8.17(d,J=17.70Hz,1H)8.46-8.59(m,1H).

[0529] Example 25:N-((1-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)piperidin-3-yl)methyl)propionamide

[0530]

[0531] Synthesis of N-[[1-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]-3-piperidinyl]methyl]tert-butyl carbamate

[0532]

[0533] A suspension of N-(3-piperidinylmethyl)carbamate tert-butyl ester (229 mg, 1.07 mmol), 4-chloro-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]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 under vacuum. The residue was dissolved in EtOAc and washed with water and brine. The organic layer was dried (MgSO4), filtered, and concentrated under vacuum. 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-piperidinyl]methyl]tert-butyl carbamate (379 mg, 86% yield) was obtained as a pale yellow solid. LCMS: m / z = 412.3(M+H)+. 1 H NMR (500MHz, chloroform-d) δppm 8.09 (s, 1H), 7.82-7.96 (m, 3H), 6.69 (br s, 1H), 4.81 (br s, 1H), 4.38 (br d, J = 13.4Hz, 2H), 3.98 (s, 3H), 3.29 (br t,J=11.0Hz,1H),3.15(br s,2H),3.09(br dd,J=12.8,9.8Hz,1H),1.95(br d,J=12.2Hz,2H),1.87(dt,J=13.4,3.7Hz,1H),1.68-1.78(m,1H),1.45-1.53(m,9H),1.33-1.42(m,1H).

[0534] Synthesis of [1-[6-(1-methylpyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl]-3-piperidinyl]methylamine (hydrochloride)

[0535]

[0536] A solution of N-[[1-[6-(1-methylpyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl]-3-piperidinyl]methyl]carbamate (1 mL) in anhydrous methanol (1 mL) was treated with hydrochloric acid (4 M solution in dioxane, 1 mL). The resulting mixture was stirred at room temperature for 1 hour and concentrated under vacuum. A grayish-white solid of [1-[6-(1-methylpyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl]-3-piperidinyl]methylamine hydrochloride was obtained. LCMS: m / z = 312.3(M+H)+.

[0537] Synthesis of N-[[1-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]-3-piperidinyl]methyl]prop-2-yneamide

[0538]

[0539] Under a nitrogen atmosphere at 0 °C, DIPEA (62 mg, 482 μmol, 84 μL) was added to a suspension of crude [1-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]-3-piperidinyl]methylamine hydrochloride (50 mg, 161 μmol) in anhydrous DMF (1 mL), followed by the addition of propargyl 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 hour, quenched with saturated sodium bicarbonate solution, and extracted with EtOAc. The organic layer was washed with water and brine, dried (MgSO4), filtered, and concentrated under vacuum. 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]methyl]prop-2-acetylamide (42.8 mg, 66% yield, 90% purity) was obtained as an orange oil. LCMS: m / z = 364.2(M+H)+. 1¹H NMR (500MHz, chloroform-d) δppm 8.07 (s, 1H), 7.83–7.88 (m, 2H), 7.79–7.83 (m, 1H), 6.65 (d, J = 2.4Hz, 1H), 6.45 (br) s, 1H), 4.16-4.25(m, 2H), 3.94-3.98(m, 3H), 3.44-3.52(m, 1H), 3.35-3.44(m, 1H), 3.28-3.35(m, 1H), 3.20-3.27(m, 1H), 2.80-2.84(m, 1H), 2.08 (pentaplex doublet, J = 9.0, 9.0, 9.0, 9.0, 3.7Hz, 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).

[0540] Example 26 (S)-N-((1-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)piperidin-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)propionamide

[0541]

[0542] Synthesis of N-[[1-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]-2-piperidinyl]methyl]tert-butyl carbamate

[0543]

[0544] A suspension of N-(2-piperidinylmethyl)carbamate tert-butyl ester (302 mg, 1.41 mmol), 4-chloro-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazine (300 mg, 1.28 mmol), and cesium carbonate (1.25 g, 3.84 mmol) in dioxane (5 mL) was bubbled under nitrogen for 5 minutes. RuPhos (119 mg, 256 μmol) and Pd2(dba)3 (117 mg, 128 μmol) were added, and the resulting mixture was heated to reflux overnight. Then, N-(2-piperidinylmethyl)carbamate tert-butyl ester (302 mg, 1.41 mmol), RuPhos (119 mg, 256 μmol), and Pd2(dba)3 (117 mg, 128 μmol) were added again, and heating was continued for another 24 hours. The reaction mixture was then cooled to room temperature, filtered through diatomaceous earth under EtOAc rinsing, and the filtrate was concentrated under vacuum. 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]methyl]tert-butyl carbamate (267 mg, 51% yield) was obtained as a yellow foam. LCMS: m / z = 412.3(M+H)+. 1 H NMR (400MHz, chloroform-d) δppm 8.09(s,1H),7.82-7.95(m,3H),6.69(br s,1H),5.96(br s,1H),4.90(br s,1H),4.29-4.42(m,1H),3.99(s,3H),3.85(brt,J=11.8Hz,1H),3.35(br d,J=13.6Hz,2H),1.71-1.92(m,6H),1.35(s,9H).

[0545] Synthesis of 1-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]-2-piperidinyl]methylamine (hydrochloride)

[0546]

[0547] A suspension of N-[[1-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]-2-piperidinyl]methyl]carbamate (150 mg, 365 μmol) in anhydrous methanol (1 mL) was treated with hydrochloric acid (4 M solution in dioxane, 1 mL), and the resulting solution was stirred at room temperature for 2 hours. A solid was formed, and the reaction mixture was concentrated under vacuum, and the residue was used directly. A pale yellow solid of [1-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]-2-piperidinyl]methylamine hydrochloride was obtained. Quantitative yield was assumed. LCMS: m / z = 312.2(M+H)+.

[0548] Synthesis of N-[[1-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]-2-piperidinyl]methyl]prop-2-yneamide

[0549]

[0550] DIPEA (62 mg, 482 μmol, 84 μL) was added to a suspension of 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) at 0 °C under nitrogen atmosphere, followed by the addition of propargyl 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 hour, quenched with saturated sodium bicarbonate solution, and extracted with EtOAc. The organic layer was washed with water and brine, dried (MgSO4), filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (0–10% MeOH / DCM), and the product was further purified by preparative TLC (7% MeOH, in DCM). N-[[1-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]-2-piperidinyl]methyl]prop-2-yneamide (20 mg, 33% yield, 95% purity) was obtained as a brown solid. LCMS: m / z = 364.2(M+H)+. 1H NMR (400MHz, chloroform-d) δppm 8.56 (br s, 1H), 8.07-8.14 (m, 1H), 7.89 (d, J = 2.3Hz, 1H), 7.84 (s, 2H), 6.67 (d, J = 2.0Hz, 1H), 4.90-5.02 (m, 1H), 4.31 (br d,J=13.8Hz,1H),4.05-4.19(m,1H),3.92-4.00(m,3H),3.42-3.52(m,1H),3.36(br s,1H),2.54(s,1H),1.73-1.96(m,6H).

[0551] Chiral SFC purification (using a CHIRALPAK AD-H 30x250mm, 5µm column; method: 30% MeOH, without modifier, in CO2 (flow rate: 100mL / min, ABPR 120 bar, MBPR 40psi, column temperature 40℃)) yielded enantiomer E1 (first elution peak, 7.9 mg, 100% ee) Rf = 3.76 min, and enantiomer E2 (second elution peak, 7.8 mg, 95.90% ee) Rf = 4.43 min.

[0552] Example 27 :N-[[1-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]-2-piperidinyl]methyl]prop-2-enamide

[0553]

[0554] DIPEA (75 mg, 578 μmol, 101 μL) was added to a suspension of 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) under nitrogen and at 0 °C, followed by the addition of acrylonitrile 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 (MgSO4), filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (0–10% MeOH / DCM) and further purified by preparative TLC (93:7DCM / MeOH). N-[[1-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]-2-piperidinyl]methyl]prop-2-enamide (13.2 mg, 18% yield, 95% purity) was obtained as a slightly brownish foam. LCMS: m / z = 366.1(M+H)+. 1¹H NMR (400MHz, chloroform-d) δppm 8.09 (s, ¹H), 7.86–7.90 (m, ¹H), 7.83–7.86 (m, ¹H), 7.78 (s, ¹H), 7.70–7.90 (br) s,1H),6.67(d,J=2.0Hz,1H),6.08(dd,J=17.1,1.3Hz,1H),5.79(dd,J=17.1,10.3Hz,1H),5.43(dd,J=10.4,1.4Hz,1H),4.98- 5.08(m,1H),4.27-4.40(m,1H),4.08-4.22(m,1H),3.93-4.00(m,3H),3.44-3.53(m,1H),3.28-3.44(m,1H),1.72-1.96(m,6H).

[0555] Example 28 :(R)-6-(1-methyl-1H-pyrazol-4-yl)-4-((1-(vinylsulfonyl)azacycloheptane-4-yl)oxy)pyrazolo[1,5-a]pyrazine

[0556]

[0557] 1. Synthesis of (R)-4-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)azacycloheptane-1-carboxylic acid tert-butyl ester

[0558]

[0559] A solution of tert-butyl 4-hydroxyazacycloheptan-1-carboxylate (710 mg, 3.30 mmol) in anhydrous DMF (10 mL) was cooled in an ice bath. Then, sodium hydride (396 mg, 9.90 mmol, 60% purity) was added in four portions with stirring. Stirring was continued in an ice bath for 45 minutes, during which time a pale yellow suspension formed. A batch of 4-chloro-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazine (700 mg, 3.00 mmol) was added to this mixture. 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 Na₂SO₄, filtered, and concentrated. The residue was purified on a 10 g silica column in 50% heptane / ethyl acetate to give 1.30 g of 4-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]oxyazinon-1-carboxylic acid tert-butyl ester (yield: 95%), which was a viscous, pale yellow gel. Racemic compounds were resolved by chiral SFC (CHIRALPAK AD-H 30x250mm, 5µm, 25% IPA and 0.1% DEA, in CO2, flow rate: 100mL / min, ABPR 120 bar, MBPR 60psi, column temperature 40℃) to yield (S)-4-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]oxyazinon-heptane-1-carboxylic acid tert-butyl ester (first elution peak) (389 mg, yield: 63%) and (R)-4-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]oxyazinon-heptane-1-carboxylic acid tert-butyl ester (second elution peak) (407 mg, yield: 66%) as grayish-white solids. The absolute stereochemistry of the products in these two peaks was later confirmed using commercially available chiral (4S)-hydroxyazacycloheptan-1-carboxylic acid tert-butyl ester to synthesize the compound whose analytical data were consistent with the first elution peak. ESI-MS (M+H) + :413.2.

[0560] 2. Synthesis of (R)-4-(azacycloheptane-4-yloxy)-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazine

[0561]

[0562] TFA (2.25 g, 19.7 mmol, 1.51 mL) was added to a solution of (4R)-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]oxyazinoheptan-1-carboxylic acid tert-butyl ester (407 mg, 987 μmol) in DCM (3 mL) at room temperature with stirring. After stirring overnight, the mixture was dissolved in MeOH and purified on a 5 g SCX column, wherein the desired product was eluted with 2 M NH3-MeOH to give 4-(azinoheptan-4-yloxy)-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazine (250 mg, yield: 77%) as a white solid. ESI-MS (M+H) + :313.2.

[0563] 3. Synthesis of (R)-6-(1-methyl-1H-pyrazol-4-yl)-N-((1-(vinylsulfonyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyrazin-4-amine

[0564]

[0565] When 2-chloroethanesulfonyl chloride (31 mg, 192 μmol, 20 μL) was added to a solution of (4R)-(azacycloheptane-4-yloxy)-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazine (30 mg, 96 μmol) in THF (1 mL), precipitation occurred immediately. Then, TEA (39 mg, 384 μmol, 53 μL) was added at room temperature with stirring. After stirring overnight, volatiles were removed and the residue was redissolved in DMSO. The solution was then purified by reversed-phase HPLC (Waters XSelect CSH C18, 5 μm, 19 mm × 100 mm column, mobile phases H₂O (A) and MeCN (B) with a gradient of 5–60% B (0.2% NH₄OH final v / v% modifier), flow rate 30 mL / min) to obtain a yellow oily (R)-6-(1-methylpyrazol-4-yl)-4-(1-vinylsulfonylazetane-4-yl)oxy-pyrazolo[1,5-a]pyrazine (11 mg, yield: 26%). ESI-MS (M+H) was also performed. + :403.2. 1H NMR(500MHz,DMSO-d6)δ8.74(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=3.66,7.63Hz,1H),3.8 8(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).

[0566] Example 29 :(R)-1-(4-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)azacycloheptane-1-yl)prop-2-en-1-one

[0567]

[0568] 1. Synthesis of (R)-1-(4-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)azacycloheptane-1-yl)prop-2-en-1-one

[0569]

[0570] When a solution of (4R)-(azacycloheptane-4-yloxy)-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazine (30 mg, 96 μmol) in THF (1 mL) was added, 17 mg, 192 μmol, 16 μL of acrylonitrile chloride was immediately precipitated. Then, TEA (19 mg, 192 μmol, 27 μL) was added at room temperature with stirring. After stirring overnight, volatiles were removed and the residue was redissolved in DMSO. The solution was then purified by reversed-phase HPLC (Waters XSelect CSH C18, 5 μm, 19 mm × 100 mm column, mobile phases H2O (A) and MeCN (B) with a gradient of 5–50% B (0.2% NH4OH final v / v% modifier), flow rate 30 mL / min) to obtain a transparent oily (R)-1-(4-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)azacycloheptane-1-yl)prop-2-en-1-one (9 mg, yield: 23%). ESI-MS (M+H) + 367.2. 1H NMR(500MHz,DMSO-d6)δ8.73(s,1H),8.18(d,J=18.92Hz,1H),7.98-8.03(m,1H ),6.76-6.87(m,2H),6.18(ddd,J=2.44,3.66,16.48Hz,1H),5.65-5.75(m,1H) ,5.45-5.58(m,1H),3.88(d,J=1.83Hz,3H),3.56-3.79(m,4H),2.71-2.92(m,1 H),2.17-2.26(m,1H),1.99-2.10(m,2H),1.84-1.98(m,2H),1.63-1.82(m,1H).

[0571] Example 30 :(R)-1-(4-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)azacycloheptane-1-yl)prop-2-yn-1-one

[0572]

[0573] 1. Synthesis of (R)-1-(4-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)azacycloheptane-1-yl)prop-2-yn-1-one

[0574]

[0575] Propynic acid (13 mg, 192 μmol, 12 μL) was added to a solution of (4R)-(azacycloheptane-4-yloxy)-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazine (30 mg, 96 μmol) in DMF (1 mL) at room temperature with stirring, followed by the addition of DIPEA (25 mg, 192 μmol, 34 μL). After stirring for 5 minutes at room temperature, 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 purified by reversed-phase HPLC (WatersXSelect CSH C18, 5 μm, 19 mm × 100 mm column, mobile phases H2O (A) and MeCN (B) with a gradient of 5–55% B (0.2% NH4OH 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)azacycloheptane-1-yl)prop-2-yn-1-one (24 mg, yield: 48%) as a white solid. ESI-MS (M+H) + 365.2. 1 H NMR(500MHz,DMSO-d6)δ8.70-8.81(m,1H),8.19(d,J=3.66Hz,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).

[0576] Example 31 :(S)-1-(4-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)azacycloheptane-1-yl)prop-2-yn-1-one

[0577]

[0578] 1. Synthesis of (S)-4-(azacycloheptane-4-yloxy)-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazine

[0579]

[0580] TFA (2.15 g, 18.9 mmol, 1.44 mL) was added to a solution of (4S)-4-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]oxyazinoheptan-1-carboxylic acid tert-butyl ester (389 mg, 944 μmol) in DCM (3 mL) at room temperature with stirring. After stirring overnight, the mixture was dissolved in MeOH and purified on a 5 g SCX column, wherein the desired product was eluted with 2 M NH3-MeOH to give 4-[(4S)-azinoheptan-4-yl]oxy-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazine (170 mg, yield: 55%) as a white solid. ESI-MS (M+H) + :313.2.

[0581] 2. Synthesis of (S)-1-(4-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)azacycloheptane-1-yl)prop-2-yn-1-one

[0582]

[0583] Propynic acid (13 mg, 192 μmol, 12 μL) was added to a solution of (4S)-(azacycloheptane-4-yloxy)-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazine (30 mg, 96 μmol) in DMF (1 mL) at room temperature with stirring, followed by the addition of DIPEA (25 mg, 192 μmol, 34 μL). After stirring for 5 minutes at room temperature, 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 purified by reversed-phase HPLC (WatersXSelect CSH C18, 5 μm, 19 mm × 100 mm column, mobile phases H2O (A) and MeCN (B) with a gradient of 5–55% B (0.2% NH4OH final v / v% modifier), flow rate 30 mL / min) to obtain a yellow solid (S)-1-(4-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)azacycloheptane-1-yl)prop-2-yn-1-one (18 mg, yield: 48%). ESI-MS (M+H) + 365.2. 1H NMR (500MHz, DMSO-d6) δ8.74(d,J=3.05Hz,1H),8.19(d,J=3.66Hz,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).

[0584] Example 32 :(S)-1-(4-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)azacycloheptane-1-yl)prop-2-en-1-one

[0585]

[0586] 1. Synthesis of (S)-1-(4-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)azacycloheptane-1-yl)prop-2-en-1-one

[0587]

[0588] When a solution of (S)-4-(azacycloheptane-4-yloxy)-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazine (30 mg, 96 μmol) in THF (1 mL) was added, acrylonitrile chloride (17 mg, 192 μmol, 16 μL) precipitated immediately. Then, TEA (19 mg, 192 μmol, 27 μL) was added at room temperature with stirring. After stirring overnight, volatiles were removed and the residue was redissolved in DMSO. The solution was then purified by reversed-phase HPLC (Waters XSelect CSH C18, 5 μm, 19 mm × 100 mm column, mobile phases H₂O (A) and MeCN (B) with a gradient of 5–50% B (0.2% NH₄OH final v / v% modifier), flow rate 30 mL / min) to obtain a transparent oily (S)-1-(4-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)azacycloheptane-1-yl)prop-2-en-1-one (25 mg, yield: 67%). ESI-MS (M+H) + 367.2. 1H NMR(500MHz,DMSO-d6)δ8.73(d,J=1.22Hz,1H),8.18(d,J=18.92Hz,1H),7.9 6-8.02(m,2H),6.76-6.87(m,2H),6.18(ddd,J=2.44,3.66,16.48Hz,1H),5.6 6-5.72(m,1H),5.45-5.58(m,1H),3.88(d,J=1.83Hz,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).

[0589] Example 33 (S)-6-(1-methyl-1H-pyrazol-4-yl)-4-((1-(vinylsulfonyl)azacycloheptane-4-yl)oxy)pyrazolo[1,5-a]pyrazine

[0590]

[0591] Synthesis of (S)-6-(1-methyl-1H-pyrazol-4-yl)-N-((1-(vinylsulfonyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyrazin-4-amine

[0592]

[0593] When 2-chloroethanesulfonyl chloride (31 mg, 192 μmol, 20 μL) was added to a solution of 4-(azacycloheptane-4-yloxy)-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazine (30 mg, 96 μmol) in THF (1 mL), precipitation occurred immediately. Then, TEA (39 mg, 384 μmol, 53 μL) was added at room temperature with stirring. After stirring overnight, volatiles were removed and the residue was redissolved in DMSO. The solution was then purified by reversed-phase HPLC (Waters XSelect CSH C18, 5 μm, 19 mm × 100 mm column, mobile phases H₂O (A) and MeCN (B) with a gradient of 5–60% B (0.2% NH₄OH final v / v% modifier), flow rate 30 mL / min) to obtain a yellow oily (S)-6-(1-methylpyrazol-4-yl)-4-(1-vinylsulfonylazine-heptane-4-yl)oxy-pyrazolo[1,5-a]pyrazine (7 mg, yield: 16%). ESI-MS (M+H) was also performed. + :403.2. 1H NMR (500MHz, DMSO-d6) δ8.74(s,1H),8.19(s,1H),7.98-8.04(m,2H),6.82-6.91(m,2H),6.09(d,J=16.48Hz,1H),6.06(d,J=10.38Hz,1H), 5.57(tt,J=3.66,7.63Hz,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).

[0594] Example 34 :(S) or (R)-1-(4-((7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)oxy)azacycloheptane-1-yl)prop-2-en-1-one

[0595]

[0596] 1. Synthesis of (R) and (S)-4-((7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)oxy)azacycloheptane-1-carboxylic acid tert-butyl ester

[0597]

[0598] A solution of tert-butyl 4-hydroxyazacycloheptan-1-carboxylate (355 mg, 1.65 mmol) in anhydrous DMF (5 mL) was cooled in an ice bath. Then, sodium hydride (198 mg, 4.95 mmol, 60% purity) was added in four portions with stirring. Stirring was continued in an ice bath for 45 minutes, during which time a pale yellow suspension formed. A batch of 5-chloro-7-(1-methylpyrazol-4-yl)imidazo[1,2-c]pyrimidine (350 mg, 1.50 mmol) was added to this mixture. 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 Na₂SO₄, filtered, and concentrated. The residue was purified on a 10 g silica column in 50% heptane / ethyl acetate to give a viscous, pale yellow gel-like tert-butyl 4-[7-(1-methylpyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl]oxyazacycloheptan-1-carboxylic acid (520 mg, yield: 84%). 450 mg of the racemic compound was resolved by chiral SFC (CHIRALPAK AD-H 30x250 mm, 5 μm, 30% IPA and 0.1% DEA, in CO2, flow rate: 100 mL / min, ABPR 120 bar, MBPR 60 psi, column temperature 40 °C) to give two products as grayish-white solids, exhibiting a first elution peak (E1) peak 1 (172 mg, yield: 76%) and a second elution peak (E2) peak 2 (171 mg, yield: 76%). ESI-MS (M+H) + :413.3. The absolute stereochemistry of the products in each peak is not specified.

[0599] 2. Synthesis of (R) or (S)-5-(azacycloheptane-4-yloxy)-7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidine

[0600]

[0601] TFA (949 mg, 8.33 mmol, 637 μL) was added to a solution of E2(4R) or (4S)-4-[7-(1-methylpyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl]oxyazinoheptan-1-carboxylic acid tert-butyl ester (172 mg, 416 μmol) in DCM (3 mL) at room temperature with stirring. After stirring overnight, the reactants were dissolved in MeOH and purified on a 10 g SCX column, with the desired product eluted with 2 M NH3-MeOH to give E3, 5-[(4R) or (4S)-azinoheptan-4-yl]oxy-7-(1-methylpyrazol-4-yl)imidazo[1,2-c]pyrimidinyl ester (95 mg, yield: 69%) as a white solid. ESI-MS (M+H) + :313.2.

[0602] 3. Synthesis of (R) or (S)-1-(4-((7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)oxy)azacycloheptane-1-yl)prop-2-en-1-one

[0603]

[0604] When a solution of E3 5-(4R) or (4S)-(azacycloheptane-4-yloxy)-7-(1-methylpyrazol-4-yl)imidazo[1,2-c]pyrimidine (30 mg, 96 μmol) (single enantiomer; chirality arbitrarily specified) in THF (1 mL) was added, acrylonitrile chloride (17 mg, 192 μmol, 16 μL) precipitated immediately. Then, TEA (19 mg, 192 μmol, 27 μL) was added at room temperature with stirring. After stirring overnight, volatiles were removed and the residue was redissolved in DMSO. The solution was then purified by reversed-phase HPLC (Waters XSelect CSH C18, 5 μm, 19 mm × 100 mm column, mobile phases H2O (A) and MeCN (B) with a gradient of 5–35% B (0.2% NH4OH final v / v% modifier), flow rate 30 mL / min) to obtain a transparent oily (R)- or (S)-1-(4-((7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)oxy)azacycloheptane-1-yl)prop-2-en-1-one (17 mg, yield: 45%). ESI-MS (M+H) + 367.2. 1H NMR (500MHz, DMSO-d6) δ8.25(d,J=12.82Hz,1H),8.04(d,J=3.66Hz,1H),7.70(s,1H),7.50(t,J=1. 53Hz,1H),7.44(s,1H),6.82(ddd,J=8.55,10.38,16.48Hz,1H),6.17(dd,J=2.44,16.48Hz,1H),5. 69(dt,J=2.44,10.38Hz,1H),5.50-5.64(m,1H),3.89(d,J=1.22Hz,3H),3.75-3.84(m,1H),3.59-3 .72(m,3H),2.21(dq,J=3.05,7.32Hz,1H),2.06-2.17(m,2H),1.87-2.01(m,2H),1.70-1.82(m,1H).

[0605] Example 35 :(S) or (R)-1-(4-((7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)oxy)azacycloheptane-1-yl)prop-2-yn-1-one

[0606]

[0607] Synthesize (R) or (S) 1-(4-((7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)oxy)azacycloheptane-1-yl)prop-2-yn-1-one

[0608]

[0609] Propynic acid (13 mg, 192 μmol, 12 μL) was added to a solution of E3 5-(4R)- or (4S)-(azacycloheptane-4-yloxy)-7-(1-methylpyrazol-4-yl)imidazo[1,2-c]pyrimidine (30 mg, 96 μmol) in DMF (1 mL) at room temperature with stirring, followed by the addition of DIPEA (25 mg, 192 μmol, 34 μL). After stirring for 5 minutes at room temperature, 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 purified by reversed-phase HPLC (Waters XSelect CSH C18, 5 μm, 19 mm × 100 mm column, mobile phases H2O (A) and MeCN (B) with a gradient of 5–40% B (0.2% NH4OH final v / v% modifier), flow rate 30 mL / min) to obtain a yellow oily (R) or (S)-1-(4-((7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)oxy)azacycloheptane-1-yl)prop-2-yn-1-one (2 mg, yield: 5%). ESI-MS (M+H) + 365.2. 1 H NMR(500MHz,DMSO-d6)δ8.26(d,J=2.44Hz,1H),8.05(d,J=4.27Hz,1H),7.73(d,J=1 1.60Hz,1H),7.52(t,J=1.53Hz,1H),7.46(d,J=2.44Hz,1H),5.55-5.67(m,1H),4.5 3(d,J=17.70Hz,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).

[0610] Example 36 :(R)- or (S)-7-(1-methyl-1H-pyrazol-4-yl)-5-((1-(vinylsulfonyl)azacycloheptane-4-yl)oxy)imidazo[1,2-c]pyrimidine

[0611]

[0612] Synthesis of (R)- or (S)-7-(1-methyl-1H-pyrazol-4-yl)-5-((1-(vinylsulfonyl)azacycloheptane-4-yl)oxy)imidazo[1,2-c]pyrimidine

[0613]

[0614] When 2-chloroethanesulfonyl chloride (31 mg, 192 μmol, 20 μL) was added to a solution of E3 5-(4R)- or (4S)-(azacycloheptane-4-yloxy)-7-(1-methylpyrazol-4-yl)imidazo[1,2-c]pyrimidine (30 mg, 96 μmol) in THF (1 mL), precipitation occurred immediately. Then, TEA (39 mg, 384 μmol, 53 μL) was added at room temperature with stirring. After stirring overnight, volatiles were removed and the residue was redissolved in DMSO. The solution was then purified by reversed-phase HPLC (Waters XSelect CSH C18, 5 μm, 19 mm × 100 mm column, mobile phases H₂O (A) and MeCN (B) with a gradient of 5–40% B (0.2% NH₄OH final v / v% modifier), flow rate 30 mL / min) to obtain a yellow solid (R)- or (S)-7-(1-methyl-1H-pyrazol-4-yl)-5-((1-(vinylsulfonyl)azacycloheptane-4-yl)oxy)imidazo[1,2-c]pyrimidine (2 mg, yield: 4%). ESI-MS (M+H) + :403.2.

[0615] Example 37 :(R)- or (S)-1-(4-((7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)oxy)azacycloheptane-1-yl)prop-2-yn-1-one

[0616]

[0617] 1. Synthesis of (R) or (S)-5-(azacycloheptane-4-yloxy)-7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidine

[0618]

[0619] TFA (949 mg, 8.33 mmol, 637 μL) was added to a solution of E1(4R) or (4S)-4-[7-(1-methylpyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl]oxyazinoheptan-1-carboxylic acid tert-butyl ester (172 mg, 416 μmol) in DCM (3 mL) at room temperature with stirring. After stirring overnight, the reactants were dissolved in MeOH and purified on a 10 g SCX column, with the desired product eluted with 2 M NH3-MeOH to give E4,5-[(4R) or (4S)-azinoheptan-4-yl]oxy-7-(1-methylpyrazol-4-yl)imidazo[1,2-c]pyrimidinyl ester (95 mg, yield: 69%) as a white solid. ESI-MS (M+H) + :313.2.

[0620] 2. Synthesis of (R) or (S)-1-(4-((7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)oxy)azacycloheptane-1-yl)prop-2-yn-1-one

[0621]

[0622] Propynic acid (13 mg, 192 μmol, 12 μL) was added to a solution of E4 5-[(4R)- or (4S)-azacycloheptane-4-yl]oxy-7-(1-methylpyrazol-4-yl)imidazo[1,2-c]pyrimidine (30 mg, 96 μmol) in DMF (1 mL) at room temperature with stirring, followed by the addition of DIPEA (25 mg, 192 μmol, 34 μL). After stirring for 5 minutes at room temperature, 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 purified by reversed-phase HPLC (Waters XSelect CSH C18, 5 μm, 19 mm × 100 mm column, mobile phases H2O (A) and MeCN (B) with a gradient of 5–40% B (0.2% NH4OH final v / v% modifier), flow rate 30 mL / min) to obtain a clear oily (R)- or (S)-1-(4-((7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)oxy)azacycloheptane-1-yl)prop-2-yn-1-one (1 mg, yield: 3%). ESI-MS (M+H) + 365.2.

[0623] Example 38:(R)- or (S)-1-(4-((7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)oxy)azacycloheptane-1-yl)prop-2-en-1-one

[0624]

[0625] 1. Synthesis of (R)- or (S)-1-(4-((7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)oxy)azacycloheptane-1-yl)prop-2-en-1-one

[0626]

[0627] When a solution of E4 5-[(4R)- or (4S)-azacycloheptane-4-yl]oxy-7-(1-methylpyrazol-4-yl)imidazo[1,2-c]pyrimidine (32 mg, 104 μmol) in THF (1 mL) was added, acrylonitrile chloride (19 mg, 207 μmol, 17 μL) precipitated immediately. Then, TEA (21 mg, 207 μmol, 29 μL) was added at room temperature with stirring. After stirring overnight, volatiles were removed and the residue was redissolved in DMSO. The solution was then purified by reversed-phase HPLC (Waters XSelect CSH C18, 5 μm, 19 mm × 100 mm column, mobile phases H2O (A) and MeCN (B) with a gradient of 5–35% B (0.2% NH4OH final v / v% modifier), flow rate 30 mL / min) to obtain a yellow oily (R)- or (S)-1-(4-((7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)oxy)azacycloheptane-1-yl)prop-2-en-1-one (11 mg, yield: 27%). ESI-MS (M+H) + 367.2. 1H NMR(500MHz,DMSO-d6)δ8.26(d,J=12.82Hz,1H),8.04(d,J=3.05Hz,1H),7.70(s,1H),7.51(t ,J=1.53Hz,1H),7.44(s,1H),6.82(ddd,J=8.55,10.38,16.48Hz,1H),6.17(dd,J=2.14,16.18 Hz,1H),5.69(dt,J=2.44,10.38Hz,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).

[0628] Example 39 :(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

[0629]

[0630] Synthesis of (R)-3-((7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester

[0631]

[0632] Add 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 tert-butyl ester (200 mg, 1.07 mmol) to a vial. Stir the vial 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% [3:1EtOAc:EtOH] / heptane) to give a mixture of (3R)-3-[7-(1-methylpyrazol-4-yl)imidazo[1,2-c]pyrimidine-5-yl]oxypyrrolidine-1-carboxylic acid tert-butyl ester (310 mg, 75% yield) and the starting aryl chloride, which was used without further purification. LCMS m / z = 385.1(M+H)+.

[0633] Synthesis of (R)-7-(1-methyl-1H-pyrazol-4-yl)-5-(pyrrolidine-3-yloxy)imidazo[1,2-c]pyrimidine hydrochloride

[0634]

[0635] A solution of (3R)-3-[7-(1-methylpyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl]oxypyrrolidine-1-carboxylic acid tert-butyl ester (310 mg, 806 μmol) in methanol (4 mL) was treated with HCl (4 M, in dioxane, 2.0 mL), and the resulting mixture was stirred at room temperature for 1 hour. The mixture was then concentrated under vacuum, and the solid residue was used without further purification. LCMS m / z = 285.0(M+H)+.

[0636] 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

[0637]

[0638] 7-(1-methylpyrazol-4-yl)-5-[(3R)-pyrrolidine-3-yl]oxy-imidazo[1,2-c]pyrimidine hydrochloride (114 mg, 355 μmol), DCM (3.6 mL), and N-ethyl-N-isopropyl-prop-2-amine (310 μL, 1.78 mmol) were added to the vial, followed by propargyl 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% [3:1EtOAc:EtOH] / heptane). The fractions were combined and concentrated, then purified by preparative HPLC (Waters SunFire Prep, C18 5 μm, OBD 30x50 mm, eluted with 10-70% MeCN:H2O [containing 0.1% TFA modifier]) to obtain 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) in solid form. LCMS m / z = 337.0(M+H)+. 1H NMR(500MHz,MeOD-d4)δ:8.46(d,J=4.3Hz,1H),8.23(d,J=2.4Hz,1H),8.12-8.07(m,1H),7.92(d,J=2.4Hz,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=1.2Hz,5H),3.92-3.68(m,1H),2.66-2.47(m,2H).

[0639] Examples 40 to 53 .

[0640] The compounds in the table below were prepared from 5-chloro-7-(1-methylpyrazol-4-yl)imidazo[1,2-c]pyrimidine and appropriate alcohols and carboxylic acids according to the steps described in Example 39:

[0641]

[0642]

[0643]

[0644] Example 54 :(S)-1-(6-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)-1,4-oxazetane-4-yl)prop-2-en-1-one

[0645]

[0646] Synthesis of (6S)-6-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]oxy-1,4-oxazetane-4-carboxylic acid tert-butyl ester

[0647]

[0648] A flask containing 2 mL of anhydrous THF containing (6S)-6-hydroxy-1,4-oxazacycloheptan-4-carboxylate (247 mg, 1.14 mmol) was cooled in an ice-water bath. Sodium tert-butoxide (168 mg, 1.74 mmol) was then carefully added in multiples to the cold mixture. After 10 minutes, 4-chloro-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazine (235 mg, 1.01 mmol) was carefully added in multiples to the cold heterogeneous mixture. After the addition of 4-chloro-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazine was complete, the mixture was heated to 23 °C and monitored by LC-MS. After 18 hours, water was slowly added to carefully quench the reaction mixture, followed by extraction of the two-phase mixture three times with ethyl acetate. The organic matter was collected and 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). The desired fraction was collected and then concentrated under reduced pressure to give (6S)-6-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]oxy-1,4-oxazetane-4-carboxylic acid tert-butyl ester (319 mg, 76% yield) as a white solid, which was used without further purification. LCMS m / z = 415.1 (M+H) + . 1 H NMR (500MHz, DMSO-d6)d=8.77(s,1H),8.29-8.17(m,1H),8.11-7.91(m,2H),6.85-6.75(m,1H),5.62-5.5 3(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).

[0649] Synthesis of (6S)-6-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]oxy-1,4-oxazacycloheptane

[0650]

[0651] A vial containing 2 mL of anhydrous dichloromethane containing (6S)-6-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]oxy-1,4-oxazacycloheptane-4-carboxylic acid tert-butyl ester (319 mg, 769 μmol) was cooled in an ice-water bath. Trifluoroacetic acid (1 mL, 13 mmol) was then carefully added dropwise to the cooled mixture. After the TFA addition was complete, the mixture was heated to 23 °C and monitored by LCMS. After 1 hour, the reactants were carefully concentrated under reduced pressure to give a pale yellow film of (6S)-6-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]oxy-1,4-oxazacycloheptane (345 mg, trifluoroacetate), which was used without further purification. LCMS m / z = 315.0 (M+H) + .

[0652] Synthesis of 1-[(6S)-6-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]oxy-1,4-oxazacycloheptane-4-yl]prop-2-en-1-one

[0653]

[0654] At -25°C, a Huenig base (0.7 mL, 4.02 mmol) was carefully added dropwise to a vial containing 3 mL of anhydrous dichloromethane containing (6S)-6-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]oxy-1,4-oxazacycloheptane (329 mg, 769 μmol, trifluoroacetate). After 5 minutes, acryloyl chloride (0.2 mL, 2.46 mmol) was carefully added dropwise to the cold homogeneous solution. After the addition of acryloyl chloride was complete, the reaction mixture was heated to 23°C and monitored by LCMS and TLC. After 3 minutes, the reaction mixture was carefully quenched by slowly adding saturated sodium bicarbonate aqueous solution. The two-phase mixture was loaded onto a silica gel column and purified (15–75% [3:1 ethyl acetate: ethanol] / heptane). The desired fractions were collected and then concentrated under reduced pressure to give 1-[(6S)-6-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]oxy-1,4-oxazacycloheptane-4-yl]prop-2-en-1-one (226 mg, 76% yield) as a white solid. 1H NMR (500MHz, DMSO-d6)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=2.4,16.5Hz,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) + .

[0655] Example 55 :(S)-1-(3-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)azacycloheptane-1-yl)prop-2-en-1-one

[0656]

[0657] Synthesis of (3S)-3-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]oxyazinon-1-carboxylic acid tert-butyl ester

[0658]

[0659] A vial containing 8 mL of anhydrous THF containing (3S)-3-hydroxyazine-1-heptane-1-carboxylic acid tert-butyl ester (464 mg, 2.16 mmol) was cooled in an ice-water bath. Sodium tert-butoxide (314 mg, 3.27 mmol) was then carefully added in multiples 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 multiples to the cold heterogeneous mixture. After the addition of 4-chloro-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazine was complete, the mixture was heated to 23 °C and monitored by LC-MS. After 2.5 hours, water was slowly added to carefully quench the reaction mixture. The two-phase mixture was extracted three times with ethyl acetate 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 (0-30% [3:1 ethyl acetate: ethanol] / heptane). The desired fractions were collected and then concentrated under reduced pressure to give (3S)-3-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]oxyoxazonylheptan-1-carboxylic acid tert-butyl ester, which appeared as a yellow film and was used without further purification. LCMS m / z = 413.2 (M+H) + .

[0660] Synthesis of 4-[(3S)-azacycloheptane-3-yl]oxy-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazine

[0661]

[0662] A vial containing 2 mL of anhydrous methanol (787 mg, 1.91 mmol) of (3S)-3-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]oxyazinoheptan-1-carboxylic acid tert-butyl ester was cooled in an ice-water bath. Then, 4 mL of 1.25 M methanol was carefully added dropwise to the cooled mixture. After the addition of the methanol containing 1.25 M HCl was complete, the mixture was heated to 23 °C and monitored by LC-MS. After 6 days, the reaction mixture was carefully concentrated under reduced pressure to give a pale yellow film of 4-[(3S)-azinoheptan-3-yl]oxy-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazine hydrochloride (672 mg, crude product), which was used without further purification. LC-MS: m / z = 313.2 (M+H) + .

[0663] Synthesis of 1-[(3S)-3-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]oxyazacycloheptane-1-yl]prop-2-en-1-one

[0664]

[0665] At -25°C, a shunig base (0.7 mL, 4.02 mmol) was carefully added dropwise to a vial containing 2 mL of anhydrous dichloromethane containing 288 mg (824 μmol) of 4-[(3S)-azacycloheptane-3-yl]oxy-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazine hydrochloride (0.15 mL, 1.85 mmol) was carefully added dropwise to the cold homogeneous solution. After the addition of acryloyl chloride was complete, the reaction mixture was heated to 23°C and monitored by LCMS and TLC. After 3 minutes, the reaction mixture was carefully quenched by slowly adding saturated sodium bicarbonate aqueous solution. The two-phase mixture was loaded onto a silica gel column and purified (15–75% [3:1 ethyl acetate: ethanol] / heptane). The desired fractions were collected and then concentrated under reduced pressure to give 1-[(3S)-3-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]oxyazacycloheptane-1-yl]prop-2-en-1-one (73 mg, 23% yield) as a white solid. 1H NMR (500MHz, DMSO-d6)d=8.76(d,J=6.1Hz,1H),8.29-8.18(m,1H),8.06-7.99(m, 1H),6.88-6.68(m,2H),6.16(dt,J=2.4,16.8Hz,1H),5.74-5.51(m,2H),4.33(br dd,J=5.5,13.4Hz,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) + .

[0666] Example 56 :(R)-1-(3-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)azacycloheptane-1-yl)prop-2-en-1-one

[0667]

[0668] Synthesis of (3R)-3-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]oxyazinon-1-carboxylic acid tert-butyl ester

[0669]

[0670] A vial containing 9 mL of anhydrous THF containing tert-butyl (3R)-3-hydroxyazine-1-heptane-1-carboxylate (550 mg, 2.56 mmol) was cooled in an ice-water bath. Sodium tert-butoxide (338 mg, 3.52 mmol) was then carefully added in multiples to the cold mixture. After 15 minutes, 4-chloro-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazine (537 mg, 2.30 mmol) was carefully added in multiples to the cold heterogeneous mixture. After the addition of 4-chloro-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazine was complete, the mixture was heated to 23 °C and monitored by LC-MS. After 2 hours, water was slowly added to carefully quench the reaction mixture. The two-phase mixture was extracted three times with ethyl acetate 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). The desired fraction was collected and then concentrated under reduced pressure to give (3R)-3-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]oxyazacycloheptan-1-carboxylic acid tert-butyl ester (905.5 mg, 96% yield) as a yellow film, which was used without further purification. LCMS: m / z = 413.2 (M+H) + . 1 H NMR (500MHz, DMSO-d6)d=8.79-8.72(m,1H),8.28-8.18(m,1H),8.11-7.97(m,2H),6.78(dd,J=1.2,18.3Hz,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).

[0671] Synthesis of 4-[(3R)-azacycloheptane-3-yl]oxy-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazine

[0672]

[0673] A vial containing 2 mL of anhydrous dichloromethane containing (3R)-3-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]oxyazinocycloheptan-1-carboxylic acid tert-butyl ester (905.5 mg, 2.20 mmol) was cooled in an ice-water bath. Trifluoroacetic acid (2 mL, 26.1 mmol) was then carefully added dropwise to the cooled mixture. After the TFA addition was complete, the mixture was heated to 23 °C and monitored by LCMS. After 1 hour, the reaction mixture was carefully concentrated under reduced pressure to give a pale yellow film of 4-[(3R)-azinocycloheptan-3-yl]oxy-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazine (941.1 mg, 100% yield, trifluoroacetate), which was used without further purification. LCMS m / z = 313.1 (M+H) + .

[0674] Synthesis of 1-[(3R)-3-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]oxyazacycloheptane-1-yl]prop-2-en-1-one

[0675]

[0676] At -25°C, a shunig base (0.5 mL, 2.87 mmol) was carefully added dropwise to a vial containing 2 mL of anhydrous dichloromethane containing 4-[(3R)-azacycloheptane-3-yl]oxy-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazine (191 mg, 612 mmol, trifluoroacetate). After 5 minutes, acryloyl chloride (0.1 mL, 1.23 mmol) was carefully added dropwise to the cold homogeneous solution. After the addition of acryloyl chloride was complete, the reaction mixture was heated to 23°C and monitored by LCMS and TLC. After 3 minutes, the reaction mixture was carefully quenched by slowly adding a saturated aqueous sodium bicarbonate solution. The two-phase mixture was loaded onto a silica gel column and purified (15–75% [3:1 ethyl acetate: ethanol] / heptane). The desired fractions were collected and then concentrated under reduced pressure to obtain 1-[(3R)-3-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]oxyazacycloheptane-1-yl]prop-2-en-1-one as a white solid. 1H NMR (500MHz, DMSO-d6)d=8.76(d,J=5.5Hz,1H),8.29-8.18(m,1H),8.06-8.01( m,1H),6.88-6.71(m,2H),6.16(dt,J=2.1,16.9Hz,1H),5.74-5.51(m,2H),4.33 (brdd,J=5.5,14.0Hz,1H),3.99-3.91(m,1H),3.90-3.68(m,3H),3.59-3.43(m ,2H),2.06(ddd,J=4.3,8.9,13.7Hz,1H),1.98-1.66(m,4H),1.65-1.42(m,2H). LCMS m / z = 367.1(M+H) + .

[0677] Example 57 :1-(4-((6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-yl)oxy)azacycloheptane-1-yl)prop-2-en-1-one

[0678]

[0679] Synthesis of tert-butyl 4-((6-bromo-[1,2,4]triazolo[1,5-a]pyrazin-8-yl)oxy)azacycloheptane-1-carboxylate

[0680]

[0681] A vial containing 10 mL of anhydrous THF containing tert-butyl 4-hydroxyazacycloheptan-1-carboxylate (659 mg, 3.06 mmol) was cooled in an ice-water bath. Sodium tert-butoxide (454 mg, 4.72 mmol) was then carefully added in multiples to the cold mixture. After 15 minutes, 6,8-dibromo-[1,2,4]triazolo[1,5-a]pyrazine (850 mg, 3.06 mmol) was carefully added in multiples 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 heated to 23 °C and monitored by LC-MS. After 2.5 hours, water was slowly added to carefully quench the reaction mixture. The two-phase mixture was extracted three times with ethyl acetate 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 (20–45% ethyl acetate / heptane). The desired fractions were collected and then concentrated under reduced pressure to give tert-butyl 4-((6-bromo-[1,2,4]triazolo[1,5-a]pyrazin-8-yl)oxy)azacycloheptan-1-carboxylate (952.3 mg, 76% yield), which was used directly without further purification. LCMS: m / z = 412.0 (M+H) + . 1 H NMR (500MHz, DMSO-d6)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=4.9,9.2Hz,1H),1.42(s,9H).

[0682] Synthesis of tert-butyl 4-((6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-yl)oxy)azacycloheptane-1-carboxylate

[0683]

[0684] A flask containing tert-butyl 4-((6-bromo-[1,2,4]triazolo[1,5-a]pyrazin-8-yl)oxy)azacycloheptan-1-carboxylate (952 mg, 2.31 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)pyrazole (971 mg, 4.67 mmol), Pd(dppf)Cl2 dichloromethane adduct (300 mg, 367 μmol), and potassium carbonate (961 mg, 6.95 mmol) was 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 mixture was heated to 90 °C and monitored by LCMS. After 2.5 hours, water was slowly added to carefully quench the reaction mixture. The two-phase mixture was extracted three times with ethyl acetate 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 (25-100% ethyl acetate / heptane). The desired fractions were collected and then concentrated under reduced pressure to give 4-((6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-yl)oxy)azacycloheptan-1-carboxylic acid tert-butyl ester (707.6 mg, 74% yield) as a viscous yellow foam, which was used without further purification. 1 H NMR (500MHz, DMSO-d6)d=8.97(s,1H),8.55(s,1H),8.25(br d,J=15.3Hz,1H),8.04(d,J=9.8Hz,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) + .

[0685] Synthesis of 8-(azacycloheptane-4-yloxy)-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazine

[0686]

[0687] A vial containing 1 mL of anhydrous dichloromethane containing 708 mg (1.71 mmol) of 4-((6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-yl)oxy)azacycloheptane-1-carboxylic acid tert-butyl ester (TFA) was cooled in an ice-water bath. Trifluoroacetic acid (1 mL, 13.1 mmol) was then carefully added dropwise to the cooled mixture. After the TFA addition was complete, the mixture was heated to 23 °C and monitored by LCMS. After 1 hour, the reactants were carefully concentrated under reduced pressure to give a pale yellow film of 8-(azacycloheptane-4-yloxy)-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazine (301 mg, trifluoroacetate), which was used without further purification. LCMS m / z = 314.1 (M+H) + .

[0688] Synthesis of 1-(4-((6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-yl)oxy)azacycloheptane-1-yl)prop-2-en-1-one

[0689]

[0690] At -25°C, a shunig base (0.5 mL, 2.87 mmol) was carefully added dropwise to a vial containing 2 mL of anhydrous dichloromethane containing 8-(azacycloheptane-4-yloxy)-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazine (301 mg, 704.5 μmol, trifluoroacetate). After 5 minutes, acryloyl chloride (0.1 mL, 1.23 mmol) was carefully added dropwise to the cold homogeneous solution. After the addition of acryloyl chloride was complete, the reaction mixture was heated to 23°C and monitored by LCMS and TLC. After 3 minutes, the reaction mixture was carefully quenched by slowly adding saturated sodium bicarbonate aqueous solution. The two-phase mixture was loaded onto a silica gel column and purified (20–85% [3:1 ethyl acetate: ethanol] / heptane). The desired fractions were collected and then concentrated under reduced pressure to give 1-(4-((6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-yl)oxy)azacycloheptane-1-yl)prop-2-en-1-one (96 mg, 35% yield) as a white solid. 1H NMR (500MHz, DMSO-d6)d=8.97(s,1H),8.55(d,J=1.2Hz,1H),8.28-8.21(m,1H),8.0 4(d,J=7.3Hz,1H),6.82(ddd,J=10.4,12.2,16.5Hz,1H),6.18(td,J=2.2,16.9Hz,1H ),5.70(dd,J=2.4,10.4Hz,1H),5.53-5.44(m,1H),3.90(d,J=1.8Hz,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) + .

[0691] Example 58 :(R)-1-(6-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)-1,4-oxazetane-4-yl)prop-2-en-1-one

[0692]

[0693] Synthesis of (6R)-6-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]oxy-1,4-oxazetane-4-carboxylic acid tert-butyl ester

[0694]

[0695] A flask containing 4 mL of anhydrous THF containing 496 mg (2.28 mmol) of (6R)-6-hydroxy-1,4-oxazacycloheptan-4-carboxylic acid tert-butyl ester was cooled in an ice-water bath. Sodium tert-butoxide (308 mg, 3.20 mmol) was then carefully added in multiples to the cold mixture. After 10 minutes, 4-chloro-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazine (465 mg, 1.99 mmol) was carefully added in multiples to the cold heterogeneous mixture. After the addition of 4-chloro-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazine was complete, the mixture was heated to 23 °C and monitored by LC-MS. After 2 hours, water was slowly added to carefully quench the reaction mixture, followed by extraction of the two-phase mixture three times with ethyl acetate. The organic matter was collected and 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). The desired fraction was collected and then concentrated under reduced pressure to give (6R)-6-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]oxy-1,4-oxazetane-4-carboxylic acid tert-butyl ester (757.9 mg, 92% yield) as a white solid, which was used without further purification. 1 H NMR (500MHz, DMSO-d6)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=3.7Hz,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) + .

[0696] Synthesis of (6R)-6-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]oxy-1,4-oxazacycloheptane

[0697]

[0698] A vial containing 2 mL of anhydrous dichloromethane containing (6R)-6-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]oxy-1,4-oxazacycloheptane-4-carboxylic acid tert-butyl ester (758 mg, 1.83 mmol) was cooled in an ice-water bath. Trifluoroacetic acid (2 mL, 26.1 mmol) was then carefully added dropwise to the cooled mixture. After the TFA addition was complete, the mixture was heated to 23 °C and monitored by LC-MS. After 18 hours, the reactants were carefully concentrated under reduced pressure to give a pale yellow film of (6R)-6-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]oxy-1,4-oxazacycloheptane (783.3 mg, crude material, trifluoroacetate), which was used without further purification. LCMS m / z = 315.0(M+H) + .

[0699] Synthesis of 1-[(6R)-6-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]oxy-1,4-oxazacycloheptane-4-yl]prop-2-en-1-one

[0700]

[0701] At -25°C, a shunig base (0.5 mL, 2.87 mmol) was carefully added dropwise to a vial containing 2 mL of anhydrous dichloromethane containing (6R)-6-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]oxy-1,4-oxazacycloheptane (253 mg, 591 μmol, trifluoroacetate). After 5 minutes, acryloyl chloride (0.1 mL, 1.23 mmol) was carefully added dropwise to the cold homogeneous solution. After the addition of acryloyl chloride was complete, the reaction mixture was heated to 23°C and monitored by LCMS and TLC. After 3 minutes, the reaction mixture was carefully quenched by slowly adding a saturated aqueous sodium bicarbonate solution. The two-phase mixture was loaded onto a silica gel column and purified (15–100% [3:1 ethyl acetate: ethanol] / heptane). The desired fractions were collected and then concentrated under reduced pressure to give 1-[(6R)-6-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]oxy-1,4-oxazacycloheptane-4-yl]prop-2-en-1-one as a white solid. LCMS: m / z = 369.1 (M+H) + . 1H NMR (500MHz, DMSO-d6)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).

[0702] Example 59 :(R)-4-((1-Acryloylazetane-4-yl)oxy)-6-(1-Methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-3-carboxynitrile

[0703]

[0704] Synthesis of 4-chloro-3-iodo-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazine

[0705]

[0706] A vial containing 5 mL of anhydrous DMF containing 4-chloro-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazine (477 mg, 2.04 mmol) was cooled in an ice-water bath. Then, N-iodosuccinimide (1.23 g, 5.48 mmol) was carefully added in multiple portions to the cold mixture. After 15 minutes, the turbid yellow mixture was carefully heated to 50 °C and monitored by LCMS. After 2 hours, the reaction mixture 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, which was used without purification. 1 H NMR (500MHz, DMSO-d6) 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) + .

[0707] Synthesis of (4R)-4-[3-iodo-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]oxyazinon-1-carboxylic acid tert-butyl ester

[0708]

[0709] A vial containing 2 mL of anhydrous THF containing 113 mg (525 μmol) of (4R)-4-hydroxyazine-1-heptane-1-carboxylic acid tert-butyl ester was cooled in an ice-water bath. Sodium tert-butoxide (79.5 mg, 827 μmol) was then carefully added in multiples to the cold mixture. After 10 minutes, 181 mg (504 μmol) of 4-chloro-3-iodo-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazine was carefully added in multiples to the 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 heated to 23 °C and monitored by LC-MS. After 18 hours, the heterogeneous reaction mixture was carefully concentrated under reduced pressure. The residue was diluted with ethyl acetate and then washed with a saturated aqueous sodium chloride solution. 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). The desired fractions were collected and then concentrated under reduced pressure to give (4R)-4-[3-iodo-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]oxyazacycloheptan-1-carboxylic acid tert-butyl ester (99.3 mg, 36% yield) as a colorless, viscous film, which was used without further purification. 1 H NMR (400MHz, DMSO-d6) δ = 8.78 (s, 1H), 8.19 (d, J = 6.0Hz, 1H), 8.09 (s, 1H), 7.99 (d, J = 2.5Hz, 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=5.0Hz,9H). LCMS m / z=539.0(M+H) + .

[0710] Synthesis of (4R)-4-[3-cyano-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]oxyaziridine-1-carboxylic acid tert-butyl ester

[0711]

[0712] The vial containing (4R)-4-[3-iodo-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]oxyazinon-1-carboxylic acid tert-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; dicyclohexyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphine (Xphos G3) (17 mg, 20 μmol) and potassium acetate (40 mg, 408 μmol) was degassed and backfilled with nitrogen. (The vacuum and nitrogen backfilling 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 mixture was cooled to room temperature and then carefully partitioned between water and ethyl acetate. The aqueous layer was extracted twice more with ethyl acetate. The organic extract was collected, washed once with a saturated aqueous sodium chloride solution, 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 (25–80% ethyl acetate / heptane). The desired fraction was collected and then concentrated under reduced pressure to give (4R)-4-[3-cyano-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]oxyazacycloheptan-1-carboxylic acid tert-butyl ester (10.2 mg, 12% yield) as a colorless, viscous film, which was used without further purification. LCMS m / z = 460.1 (M + Na) + .

[0713] Synthesis of 4-[(4R)-azacycloheptane-4-yl]oxy-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazine-3-carboxynitrile

[0714]

[0715] A vial containing 0.5 mL of anhydrous dichloromethane containing (4R)-4-[3-cyano-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]oxyazinoheptan-1-carboxylate (10 mg, 23 μmol) was cooled in an ice-water bath. TFA (0.05 mL, 653 μmol) was then carefully added dropwise to the cold mixture. After the TFA addition was complete, the mixture was heated to 23 °C and monitored by LCMS. After 15 minutes, the reactants were carefully concentrated under reduced pressure to give a pale yellow film of 4-[(4R)-azinoheptan-4-yl]oxy-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-3-carboxylonitrile (11 mg, trifluoroacetate), which was used directly without purification. LCMS m / z = 338.1 (M+H) + .

[0716] Synthesis of 6-(1-methylpyrazol-4-yl)-4-[(4R)-1-prop-2-enoylazonylheptan-4-yl]oxy-pyrazolo[1,5-a]pyrazine-3-carboxynitrile

[0717]

[0718] At -25°C, a shunig base (0.1 mL, 574 μmol) was carefully added dropwise to a vial containing 0.5 mL of anhydrous THF containing 11 mg (24.4 μmol, trifluoroacetate) of 4-[(4R)-azacycloheptane-4-yl]oxy-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-3-carboxynitrile (trifluoroacetate). After 5 minutes, acryloyl chloride (0.01 mL, 123 μmol) was carefully added dropwise to the cold homogeneous solution. After the addition of acryloyl chloride was complete, the reaction mixture was heated to 23°C and monitored by LCMS and TLC. After 3 minutes, the reaction mixture was carefully quenched by slowly adding a saturated aqueous sodium bicarbonate solution. The two-phase mixture was loaded onto a silica gel column and purified (25–85% [3:1 ethyl acetate: ethanol] / heptane). The desired fractions were collected and then concentrated under reduced pressure to obtain 6-(1-methylpyrazol-4-yl)-4-[(4R)-1-prop-2-enoylazonylheptan-4-yl]oxy-pyrazolo[1,5-a]pyrazine-3-carboxynitrile, which appears as a colorless thin film. 1¹H NMR (400 MHz, dichloromethane-d²) 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) + .

[0719] 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

[0720]

[0721] Synthesis of ((trans)-3-((3-iodo-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)cyclobutyl)(methyl)carbamate tert-butyl

[0722]

[0723] A vial containing 6 mL of anhydrous THF containing racemic trans-N-(3-hydroxycyclobutyl)-N-methylcarbamate (406 mg, 2.0 mmol) was cooled in an ice-water bath. Sodium tert-butoxide (333 mg, 3.47 mmol) was then carefully added in multiple portions to the cold mixture. 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 the 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 heated to 23 °C. After 1 hour, the reactants were carefully quenched by slowly adding a saturated aqueous solution of sodium bicarbonate, followed by extraction of the two-phase mixture three times with ethyl acetate. The organic matter was collected 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). The desired fractions were collected and then concentrated under reduced pressure to give ((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 (698.5 mg, crude) as a white solid, which was used without further purification.1 H NMR (500MHz, DMSO-d6) δ = 8.79 (s, 1H), 8.16 (s, 1H), 8.11 (s, 1H), 7.98 (s, 1H), 5.45 (br t, J = 6.7Hz, 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) + .

[0724] Synthesis of methyl((trans)-3-((3-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)cyclobutyl)carbamate tert-butyl

[0725]

[0726] A vial containing 4 mL of dioxane containing (trans)-3-((3-iodo-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)cyclobutyl)(methyl)carbamate (204 mg, 389 μmol), methylboronic acid (81 mg, 1.35 mmol), tricyclohexylphosphine (29 mg, 105 μmol), Pd2(dba)3 (36 mg, 39 μmol), Pd(dppf)Cl2·CH2Cl2 (68 mg, 84 μmol), and tripotassium phosphate (1.0 M solution, 1.2 mL) was degassed and backfilled with nitrogen. This vacuuming and nitrogen backfilling process was repeated three times. The heterogeneous reaction mixture was carefully heated to 90 °C. After 18 hours, the heterogeneous reaction mixture was cooled to room temperature and then carefully partitioned between water and ethyl acetate. The aqueous layer was extracted twice more with ethyl acetate. The organic extract was collected, washed once with a saturated aqueous sodium chloride solution, 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). The desired fraction was collected and concentrated under reduced pressure to give tert-butyl 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, 78% yield) as a dark yellow film, which was used without further purification. LCMS m / z = 413.2 (M+H) + .

[0727] Synthesis of (trans)-N-methyl-3-((3-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)cyclobut-1-amine

[0728]

[0729] A vial containing 2 mL of anhydrous dichloromethane containing 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) was cooled in an ice-water bath. Trifluoroacetic acid (0.23 mL, 3 mmol) was then carefully added dropwise to the cold mixture. After the TFA addition was complete, the mixture was heated to 23 °C. After 1.5 hours, the reactants were carefully concentrated under reduced pressure to give a pale yellow film of (trans)-N-methyl-3-((3-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)cyclobutyl-1-amine trifluoroacetate (133.9 mg, crude product), which was used without purification. LCMS m / z = 313.1(M+H) + .

[0730] Synthesis of N-methyl-N-((trans)-3-((3-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)cyclobutyl)acrylamide

[0731]

[0732] At -25°C, a 1 mL solution of Huenig base (5.74 mmol) was carefully added dropwise to a vial containing 3 mL of anhydrous THF containing (trans)-N-methyl-3-((3-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)cyclobut-1-amine trifluoroacetate (133.9 mg, 314 μmol). After 5 minutes, acryloyl chloride (0.05 mL, 615 μmol) was carefully added dropwise to the cold homogeneous solution. After the addition of acryloyl chloride was complete, the reaction mixture was heated to 23°C and monitored by LCMS and TLC. After 3 minutes, a saturated aqueous sodium bicarbonate solution was slowly added to carefully quench the reaction mixture. The mixture was stirred at 23°C for 1 hour, followed by extraction of the two-phase mixture three times with ethyl acetate. The organic matter was collected and washed once with a saturated aqueous sodium bicarbonate solution. The organic layer was separated and dried 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 fraction was collected and then concentrated under reduced pressure to give a white foamy substance, which was diluted with DMSO and then filtered. The homogeneous mixture was purified by reversed-phase mass-oriented HPLC. (HPLC was performed using a Waters XSelect CSH C18, 5 μm, 19 mm × 100 mm column, mobile phases H2O (A) and MeCN (B) with a gradient of 5-60% B (0.2% NH4OH final v / v% modifier), at a flow rate of 30 mL / min.) The fraction containing the desired product was collected and then concentrated to give N-methyl-N-((trans)-3-((3-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)cyclobutyl)-acrylamide as a colorless film. 1 H NMR (500MHz, DMSO-d6) δ=8.62(s,1H),8.14(s,1H),7.97(s,1H),7.84(s,1H),6.76(br dd,J=11.0,16.5Hz,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) + .

[0733] Example 61 1-[(4R)-4-[3-fluoro-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]oxyazacycloheptane-1-yl]prop-2-en-1-one

[0734]

[0735] Synthesis of (4R)-4-[3-fluoro-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]oxyazinon-1-carboxylic acid tert-butyl ester

[0736]

[0737] A solution of (4R)-4-[3-iodo-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]oxyazinoheptan-1-carboxylic acid tert-butyl ester (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 min. Then, THF containing N-fluorobenzenesulfonylimide (157 mg, 499 μmol) was added and the reaction mixture was stirred for 1 h. An aqueous solution of NH4Cl was added to quench the reaction mixture. The reaction mixture was diluted with EtOAc, the layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na2SO4 and purified (SiO2, 0-70% EtOAc / DCM). The concentrated residue yielded (4R)-4-[3-fluoro-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]oxyazinon-1-carboxylic acid tert-butyl ester (25.3 mg, 14% yield) as an amorphous solid. LCMS: Rt = 0.93 min, m / z 431.2. 1 HNMR (400MHz, chloroform-d) δ7.99(d,J=1.51Hz,1H),7.83(s,1H),7.74-7.83(m,1H),7.70(d,J=3.76Hz,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=12.05Hz,2H),1.78(br d,J=5.02Hz,1H),1.49(s,9H). 19 F NMR (376MHz, chloroform-d) δ -174.27 (s, 1F).

[0738] Synthesis of 4-[(4R)-azacycloheptane-4-yl]oxy-3-fluoro-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazine

[0739]

[0740] TFA (1.49 g, 13.1 mmol, 1 mL) was added to a solution of (4R)-4-[3-fluoro-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]oxyazinoheptan-1-carboxylic acid tert-butyl ester (25 mg, 59 μmol) in DCM (1 mL) and stirred at room temperature for 1 hour. After concentration, the crude residue 4-[(4R)-azinoheptan-4-yl]oxy-3-fluoro-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazine was used as is in the next step. LCMS: Rt = 0.63 min, m / z 183.2.

[0741] Synthesis of 1-[(4R)-4-[3-fluoro-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]oxyazacycloheptane-1-yl]prop-2-en-1-one

[0742]

[0743] TEA (30 mg, 292 μmol, 41 μL) was added to a solution of 4-[(4R)-azacycloheptane-4-yl]oxy-3-fluoro-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazine (48 mg, 146 μmol) in DCM (4 mL), and the reaction mixture was stirred for 5 min. After cooling to 0 °C, acryloyl chloride (16 mg, 175 μmol, 14 μL) was added, and the mixture was stirred for 3 min. The reaction mixture was quenched with saturated NaHCO3 aqueous solution and extracted with DCM. The organic layer was dried with Na2SO4, and the concentrated residue was analyzed by chromatography 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]oxyazacycloheptane-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 (400MHz, chloroform-d) δ8.01(d,J=1.51Hz,1H),7.85(br s,1H),7.76(s,1H),7.71(d,J=3.76Hz,1H),6.58-6.68(m,1H),6.35-6.44(m,1H),5.73(br d,J=10.54Hz,1H),5.62(br s,1H),3.99(br d,J=2.51Hz,3H),3.79(br dd,J=6.78,13.55Hz,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). 19 F NMR (376MHz, chloroform-d) δ-174.12 (br d, J=58.58Hz, 1F).

[0744] Example 62 1-[(4R)-4-[6-(1-methylpyrazol-4-yl)-3-(trifluoromethyl)pyrazolo[1,5-a]pyrazin-4-yl]oxyazacycloheptane-1-yl]prop-2-en-1-one

[0745]

[0746] Synthesis of (4R)-4-[6-(1-methylpyrazol-4-yl)-3-(trifluoromethyl)pyrazolo[1,5-a]pyrazin-4-yl]oxyaziridine-1-carboxylic acid tert-butyl ester

[0747]

[0748] A solution of (4R)-4-[3-iodo-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]oxyazinoheptan-1-carboxylic acid tert-butyl ester (125 mg, 232 μmol) in DMF (1 mL) and hexamethylphosphoramide (42 mg, 232 μmol, 40 μL) was added and degassed. The mixture was heated at 80 °C overnight. The cooled mixture was diluted with EtOAc, washed with aqueous NH4Cl solution, filtered through diatomaceous earth, and dried over Na2SO4. The concentrated residue was analyzed by chromatography on silica gel (heptane / EtOAc 0-70%) to give (4R)-4-[6-(1-methylpyrazol-4-yl)-3-(trifluoromethyl)pyrazolo[1,5-a]pyrazin-4-yl]oxyazacycloheptan-1-carboxylic acid tert-butyl ester (18 mg, 15% yield, 95% purity). LCMS: Rt = 1.03 min, m / z 481.2.381.2.

[0749] Synthesis of 4-[(4R)-azacycloheptane-4-yl]oxy-6-(1-methylpyrazol-4-yl)-3-(trifluoromethyl)pyrazolo[1,5-a]pyrazine

[0750]

[0751] TFA (1.49 g, 13.1 mmol, 1 mL) was added to a solution of (4R)-4-[6-(1-methylpyrazol-4-yl)-3-(trifluoromethyl)pyrazolo[1,5-a]pyrazin-4-yl]oxyazinoheptan-1-carboxylic acid tert-butyl ester (18 mg, 37 μmol) in DCM (1 mL), and the reaction mixture was stirred at room temperature for 1 hour. The crude product was concentrated to give 4-[(4R)-azinoheptan-4-yl]oxy-6-(1-methylpyrazol-4-yl)-3-(trifluoromethyl)pyrazololo[1,5-a]pyrazine (19.0 mg, crude product, trifluoroacetic acid) as residue, and used as is for the next step. LCMS: Rt = 0.64 min, m / z 381.2.

[0752] Synthesis of 1-[(4R)-4-[6-(1-methylpyrazol-4-yl)-3-(trifluoromethyl)pyrazolo[1,5-a]pyrazin-4-yl]oxyazacycloheptane-1-yl]prop-2-en-1-one

[0753]

[0754] TEA (7.8 mg, 77 μmol, 11 μL) was added to a solution of 4-[(4R)-azacycloheptane-4-yl]oxy-6-(1-methylpyrazol-4-yl)-3-(trifluoromethyl)-pyrazolo[1,5-a]pyrazine (19 mg, 38 μmol, trifluoroacetic acid) in DCM (2 mL), 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 min. The reaction mixture was quenched with saturated NaHCO3 aqueous solution and extracted with DCM. The organic layer was dried with Na₂SO₄, and the concentrated residue was analyzed by chromatography on silica gel (EtOAc / MeOH 0-30%) to give 1-[(4R)-4-[6-(1-methylpyrazol-4-yl)-3-(trifluoromethyl)pyrazolo[1,5-a]pyrazin-4-yl]oxyazacycloheptane-1-yl]prop-2-en-1-one (9 mg, 51% yield, 95% purity). LCMS: Rt = 0.80 min, m / z 457.1 [M+Na] + . 1 H NMR (400MHz, chloroform-d) δ8.24(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=15.18Hz,1H),5.73(br d,J=10.54Hz,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=5.52,14.31Hz,1H),2.18-2.38(m,4H),1.86-1.95(m,2H). 19 F NMR (376MHz, chloroform-d) d-54.80 (d, J = 5.45Hz, 3F).

[0755] Example 63 :N-((cis)-3-((3-fluoro-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)cyclobutyl)-N-methylacrylamide

[0756]

[0757] Synthesis of ((cis)-3-((3-iodo-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)cyclobutyl)(methyl)carbamate tert-butyl

[0758]

[0759] A vial containing 10 mL of anhydrous THF containing tert-butyl((cis)-3-hydroxycyclobutyl)(methyl)carbamate (175 mg, 868 μmol) was cooled in an ice-water bath. Sodium tert-butoxide (132 mg, 1.37 mmol) was then carefully added in multiples to the cold mixture. After 10 minutes, 4-chloro-3-iodo-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazine (300 mg, 834 μmol) was carefully added in multiples to the 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 heated to 23 °C and monitored by LC-MS. After 18 hours, the residue was diluted with ethyl acetate and filtered through diatomaceous earth. 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 tert-butyl ester (252 mg, 58% yield). LCMS: Rt = 1.00 min, m / z 525.2.

[0760] Synthesis of ((cis)-3-((3-fluoro-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)cyclobutyl)(methyl)carbamate tert-butyl

[0761]

[0762] A solution of ((cis)-3-((3-iodo-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)cyclobutyl)(methyl)carbamate tert-butyl ester (292 mg, 557 μmol) in THF (3 mL) was cooled to -78 °C, and butyllithium (2.5 M, 267.30 μL) was added, followed by stirring of the reaction mixture for 20 min. Then, THF (1 mL) containing N-fluorobenzenesulfonylimide (211 mg, 668 μmol) was added, and stirring of the reaction mixture continued for 1 h. An aqueous solution of NH4Cl was added to quench the reaction mixture. The reaction mixture was diluted with EtOAc, the layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na2SO4 and the purified and concentrated residue (FCC, SiO2, 0-70% EtOAc / DCM) was used to give ((cis)-3-((3-fluoro-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)cyclobutyl)(methyl)carbamate tert-butyl ester (75.5 mg, 33% yield) as an amorphous solid. LCMS, Rt = 0.92 min, m / z 439.2, 317.1.19 F NMR (376MHz, chloroform-d) δ -174.02 (br s, 1F).

[0763] Synthesis of (cis)-3-((3-fluoro-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)-N-methylcyclobut-1-amine

[0764]

[0765] TFA (1.49 g, 13.1 mmol, 1 mL) was added to a solution of ((cis)-3-((3-fluoro-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)cyclobutyl)(methyl)carbamate (76 mg, 181 μmol) in DCM (1 mL), and the reaction mixture was stirred at room temperature for 1 hour. The crude product was concentrated to give (cis)-3-((3-fluoro-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)-N-methylcyclobutyl-1-amine (166 mg, crude product, trifluoroacetic acid) as residue, and used as is for the next step. LCMS: Rt = 0.57 min, m / z 317.1.

[0766] Synthesis of N-((cis)-3-((3-fluoro-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)cyclobutyl)-N-methylacrylamide

[0767]

[0768] TEA (78 mg, 771 μmol, 108 μL) was added to a solution of (cis)-3-((3-fluoro-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)-N-methylcyclobut-1-amine (166 mg, 386 μmol, trifluoroacetic acid) in DCM (5 mL), 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 min. The reaction mixture was quenched with saturated NaHCO3 aqueous solution and extracted with DCM. The organic layer was dried with Na2SO4, and the concentrated residue was analyzed by chromatography on silica gel (EtOAc / MeOH 0-30%). The residue was further purified by preparative HPLC (10-90% H2O / ACN) to obtain N-((cis)-3-((3-fluoro-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)cyclobutyl)-N-methylacrylamide (30.1 mg, 15% yield, 95% purity, trifluoroacetic acid). LCMS: Rt = 0.70 min, m / z 371.2 [M+H] + 393.2 [M+Na] + . 1 H NMR (400MHz, chloroform-d) δ8.06(d,J=1.76Hz,1H),7.91(br s,1H),7.84(br s,1H),7.75(br d,J=3.51Hz,1H),6.58(br dd,J=10.92,16.69Hz,1H),6.35(br d,J=19.07Hz,1H),5.79(br d,J=10.79Hz,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). 19 F NMR (376MHz, chloroform-d) δ -75.97 (s, 3F), -173.35 (br s, 1F).

[0769] Example 64 :N-((trans)-3-((3-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,4-a]pyrazin-4-yl)oxy)cyclobutyl-N-methylacrylamide

[0770]

[0771] Synthesis of methyl((trans)-3-((6-(1-methyl-1H-pyrazol-4-yl)-3-vinylpyrazolo[1,5-a]pyrazin-4-yl)oxy)cyclobutyl)tert-butyl carbamate

[0772]

[0773] A microwave-safe vial was filled with ((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 (135 mg, 257 μmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborhecyclopentane (79 mg, 515 μmol, 87 μL), di-tert-butyl(cyclopentyl)phosphine; palladium dichlorophosphate; iron (34 mg, 51 μmol) and potassium carbonate (100 mg, 721 μmol) and placed under N2. The vial was capped and dioxane (1.2 mL) and water (0.3 mL) were added via syringe, and the red mixture was placed under N2 again (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 under vacuum and the residue was purified on 10 g Si-SPE: Rf = 0.27, in heptane / EtOAc = 5 / 1, to give tert-butyl methyl((trans)-3-((6-(1-methyl-1H-pyrazol-4-yl)-3-vinylpyrazolo[1,5-a]pyrazin-4-yl)oxy)cyclobutyl)carbamate (110 mg, 91% yield, 90% purity) as a yellow gel.

[0774] Synthesis of ((trans)-3-((3-formyl-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)cyclobutyl)(methyl)carbamate tert-butyl

[0775]

[0776] A vial was filled with methyl((trans)-3-((6-(1-methyl-1H-pyrazol-4-yl)-3-vinylpyrazolo[1,5-a]pyrazin-4-yl)oxy)cyclobutyl)carbamate tert-butyl ester (110 mg, 259 μmol), 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-oxo-morpholino-4-onium (30 mg, 259 μmol) were added and stirring continued in an ice bath for 1 hour. Then, sodium (meta)periodate (111 mg, 518 μmol) was added and stirring continued in a water bath while the reaction mixture was heated to room temperature overnight. Saturated Na₂S₂O₃ was then added, followed by DCM. The mixture was filtered, and the organic phase was separated. The solution was dried and evaporated under vacuum to give a dark green, viscous gel. This substance was used without further purification. ESI-MS (M+Na) + :449.4.

[0777] Synthesis of ((trans)-3-((3-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)cyclobutyl)(methyl)carbamate tert-butyl

[0778]

[0779] Add ((trans)-3-((3-formyl-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)cyclobutyl)(methyl)carbamate tert-butyl ester (90 mg, 211 μmol) and DCM (2 mL) to a vial, place under N2, and cool in an ice bath. Next, add N-ethyl-N-(trifluoro-thioalkyl)ethylamine (68 mg, 422 μmol, 56 μL) dropwise with stirring. Continue stirring overnight, gradually warming the mixture to room temperature during this period. Dilute the mixture with DCM and add silica gel. The evaporator was evaporated under vacuum and the residue was purified on 5 g Si-SPE (Rf = 0.5) in EtOAc to give ((trans)-3-((3-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)cyclobutyl)(methyl)carbamate tert-butyl ester (45 mg, 43% yield, 90% purity) as a pale yellow, viscous gel. ESI-MS (M+H) + :449.5.

[0780] Synthesis of (trans)-3-((3-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)-N-methylcyclobut-1-amine

[0781]

[0782] TFA (102 mg, 892 μmol, 68 μL) was added to a solution of ((trans)-3-((3-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)cyclobutyl)(methyl)carbamate (40 mg, 89 μmol) in DCM (2 mL) at room temperature with stirring. After stirring overnight, the mixture was diluted with MeOH and purified on a 2 g SCX column, wherein the product was eluted with 2 M NH3-MeOH, and after removal of volatiles, (trans)-3-((3-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)-N-methylcyclobutyl-1-amine (28 mg, 81% yield, 90% purity) was obtained as a yellow gel.

[0783] Synthesis of N-((trans)-3-((3-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)cyclobutyl)-N-methylacrylamide

[0784]

[0785] (trans)-3-((3-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)-N-methylcyclobut-1-amine (28 mg, 80 μmol) and THF (1 mL) were added to a vial. Acryloyl chloride (7.2 mg, 80 μmol) was then added, and precipitation occurred immediately. Next, TEA (12 mg, 121 μmol, 17 μL) was added, and stirring was continued at room temperature for 1 hour. The evaporator was evaporated under vacuum, and the residue was purified by alkaline preparative HPLC (Waters XSelect CSH C18, 5 μm, 30 mm × 50 mm column, mobile phases H2O (A) and MeCN (B) with a gradient of 5–60% B (0.2% NH4OH final v / v% modifier), flow rate 60 mL / min). After lyophilization by HPLC fractionation, N-((trans)-3-((3-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)cyclobutyl)-N-methylacrylamide (6.8 mg, 19% yield, 90% purity) was obtained as a white solid. 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=15.8Hz,1H),5.72(br d,J=10.3Hz,1H),5.63(brs,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).

[0786] Example 65 1-[(4R)-4-[7-(1-methylpyrazol-4-yl)imidazo[1,2-a]pyridin-5-yl]oxyazacycloheptane-1-yl]prop-2-en-1-one

[0787]

[0788] Synthesis of (4R)-4-(7-iodoimidazole[1,2-a]pyridin-5-yl)oxyaziridine-1-carboxylic acid tert-butyl ester

[0789]

[0790] A vial containing 2 mL of anhydrous THF containing 155 mg (557 μmol) of 5-chloro-7-iodo-imidazo[1,2-a]pyridine was cooled in an ice-water bath. Sodium tert-butoxide (93 mg, 970 μmol) was then carefully added in multiples to the cold mixture. After 15 minutes, tert-butyl (4R)-4-hydroxyazacycloheptan-1-carboxylate (142 mg, 661 μmol) was carefully added in multiples to the cold heterogeneous mixture. After the addition of 5-chloro-7-iodo-imidazo[1,2-a]pyridine was complete, the mixture was heated to 23 °C and monitored by LC-MS. After 19 hours, water was slowly added to carefully quench the reaction mixture, followed by extraction of the two-phase mixture three times with ethyl acetate. The organic matter was collected and 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). The desired fractions were collected and then concentrated under reduced pressure to give (4R)-4-(7-iodoimidazolo[1,2-a]pyridin-5-yl)oxyazacycloheptan-1-carboxylic acid tert-butyl ester (119 mg, 47% yield), a pale yellow oil, which was used without further purification. LCMS m / z = 458.0 (M+H) + .

[0791] Synthesis of (4R)-4-[7-(1-methylpyrazol-4-yl)imidazo[1,2-a]pyridin-5-yl]oxyaziridine-1-carboxylic acid tert-butyl ester

[0792]

[0793] A vial containing tert-butyl (4R)-4-(7-iodoimidazolo[1,2-a]pyridin-5-yl)oxyazacycloheptan-1-carboxylate (119 mg, 260 μmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)pyrazole (111 mg, 534 μmol), tricyclohexylphosphine (19.4 mg, 69 μmol), tris(diphenylmethyleneacetone)dipalladium (25.4 mg, 28 μmol), and tripotassium phosphate (1 M, 0.8 mL) in dioxane (1 mL) was degassed and then backfilled with nitrogen. After vacuuming and backfilling with nitrogen (x3), the reaction mixture was heated to 90 °C and monitored by LCMS. After 2 hours, water was slowly added to carefully quench the reaction mixture. The two-phase mixture was extracted three times with ethyl acetate 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 (20-100% [3:1 ethyl acetate: ethanol] / heptane). The desired fraction was collected and then concentrated under reduced pressure to give (4R)-4-[7-(1-methylpyrazol-4-yl)imidazo[1,2-a]pyridin-5-yl]oxyazacycloheptan-1-carboxylic acid tert-butyl ester (75.9 mg, 71% yield) as a yellow film, which was used without further purification. LCMS m / z = 412.1 (M+H) + .

[0794] Synthesis of 5-[(4R)-azacycloheptane-4-yl]oxy-7-(1-methylpyrazol-4-yl)imidazo[1,2-a]pyridine

[0795]

[0796] A vial containing 0.5 mL of anhydrous dichloromethane containing (4R)-4-[7-(1-methylpyrazol-4-yl)imidazo[1,2-a]pyridin-5-yl]oxyazinoheptan-1-carboxylic acid tert-butyl ester (76 mg, 184 μmol) was cooled in an ice-water bath. Trifluoroacetic acid (149 mg, 1.31 mmol, 0.1 mL) was then carefully added dropwise to the cold mixture. After the TFA addition was complete, the mixture was heated to 23 °C and monitored by LCMS. After 19 hours, the reactants were carefully concentrated under reduced pressure to give a pale yellow film of 5-[(4R)-azinoheptan-4-yl]oxy-7-(1-methylpyrazol-4-yl)imidazo[1,2-a]pyridine (crude substance, trifluoroacetic acid), which was used without purification. LCMS m / z = 312.0 (M+H) + .

[0797] Synthesis of 1-[(4R)-4-[7-(1-methylpyrazol-4-yl)imidazo[1,2-a]pyridin-5-yl]oxyazacycloheptane-1-yl]prop-2-en-1-one

[0798]

[0799] The Huenig base (445 mg, 3.44 mmol, 0.6 mL) was carefully added to a vial containing 1 mL of anhydrous THF containing 5-[(4R)-azacycloheptane-4-yl]oxy-7-(1-methylpyrazol-4-yl)imidazo[1,2-a]pyridine (79 mg, 254 μmol, trifluoroacetic acid) at -25 °C. After 4 minutes, acryloyl chloride (45 mg, 492 μmol, 0.04 mL) was carefully added dropwise to the cold homogeneous solution. After the addition of acryloyl chloride was complete, the reaction mixture was heated to 23 °C and monitored by LCMS and TLC. After 3 minutes, the reaction mixture was carefully quenched by slowly adding a saturated aqueous sodium bicarbonate solution. The two-phase mixture was loaded onto a silica gel column and purified (40–100% [3:1 ethyl acetate: ethanol] / heptane; followed by washing with dichloromethane containing 20% ​​methanol). The desired fraction was collected and then concentrated under reduced pressure to obtain 67 mg of a colorless thin film, which was further purified by mass-directed reversed-phase HPLC (WatersXSelect CSH C18, 5 μm, 19 mm × 100 mm column, mobile phases H2O (A) and MeCN (B) with a gradient of 5–50% B (0.2% NH4OH final v / v% modifier), flow rate 30 mL / min). The fraction containing the desired product was concentrated to obtain 1-[(4R)-4-[7-(1-methylpyrazol-4-yl)imidazo[1,2-a]pyridin-5-yl]oxyazacycloheptane-1-yl]prop-2-en-1-one (1.6 mg, 2% yield) as a colorless thin film. 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),5.75-5.6 5(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)+.

[0800] Example 66 1-[(4R)-4-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl]oxyazacycloheptane-1-yl]prop-2-en-1-one

[0801]

[0802] Synthesis of (4R)-4-(6-bromopyrazolo[1,5-a]pyridin-4-yl)oxyazine-1-heptane-1-carboxylic acid tert-butyl ester

[0803]

[0804] DIAD (342 mg, 1.69 mmol, 333 μL) was added to a solution of (4S)-4-hydroxyazazole[1,5-a]pyridin-4-ol (300 mg, 1.41 mmol) and triphenylphosphine (554 mg, 2.11 mmol) in THF (5 mL), and the mixture was stirred at room temperature for 16 hours. The concentrated crude product was analyzed by silica gel chromatography (heptane / EtOAc 0–60%) to give (4R)-4-(6-bromopyrazolo[1,5-a]pyridin-4-yl)oxyazazole-1-carboxylic acid tert-butyl ester (255 mg, 42% yield, 95% purity) as a colorless oil. LCMS: Rt = 1.00 min, m / z 356.1, 412.1 (M+H) + .

[0805] Synthesis of (4R)-4-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl]oxyaziridine-1-carboxylic acid tert-butyl ester

[0806]

[0807] A solution of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)pyrazole (194 mg, 932 μmol), Pd(dppf)Cl2 DCM (51 mg, 62 μmol), and K2CO3 (258 mg, 1.86 mmol) in dioxane (3 mL) and water (0.5 mL) was degassed and heated to 95 °C for 16 hours. After cooling to room temperature, the mixture was filtered through diatomaceous earth and concentrated. The residue was analyzed by silica gel chromatography (heptane / EtOAc 0-100%) to give a yellow gel-like (4R)-4-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl]oxyazacycloheptane-1-carboxylic acid tert-butyl ester (192 mg, 71% yield, 95% purity). LCMS: Rt=0.87min, m / z 412.3(M+H) + .

[0808] Synthesis of 4-[(4R)-azacycloheptane-4-yl]oxy-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyridine

[0809]

[0810] TFA (1.49 g, 13.1 mmol, 1 mL) was added to a solution of (4R)-4-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl]oxyazinoheptan-1-carboxylic acid tert-butyl ester (192 mg, 467 μmol) in DCM (1 mL), and the reaction mixture was stirred at room temperature for 1 hour. The crude product was concentrated to give 4-[(4R)-azinoheptan-4-yl]oxy-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyridine (345 mg, crude product, trifluoroacetic acid), which was used as is in the next step. LCMS: Rt = 0.50 min, m / z 312.1 (M+H) + .

[0811] Synthesis of 1-[(4R)-4-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl]oxyazacycloheptane-1-yl]prop-2-en-1-one

[0812]

[0813] TEA (164 mg, 1.62 mmol, 226 μL) was added to a solution of 4-[(4R)-azacycloheptane-4-yl]oxy-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyridine (345 mg, 811 μmol, trifluoroacetic acid) in DCM (10 mL), and the reaction mixture was stirred for 5 min. After cooling to 0 °C, acryloyl chloride (88 mg, 973 μmol, 79 μL) was added, and the reaction mixture was stirred for 3 min. The reaction mixture was quenched with saturated NaHCO3 aqueous solution and extracted with DCM. The organic layer was dried with Na₂SO₄, and the concentrated residue was analyzed by chromatography on silica gel (EtOAc / MeOH 0-30%) to give 1-[(4R)-4-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl]oxyazacycloheptane-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) + . 1 H NMR (400MHz, chloroform-d) δ8.25(s,1H),7.84(t,J=1.76Hz,1H),7.70(d,J=3.26Hz,1H),7.59(d,J=6.02 Hz,1H),6.55-6.66(m,2H),6.44(d,J=8.28Hz,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).

[0814] Example 67 1-[(4R)-4-[2-amino-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]oxyazacycloheptane-1-yl]prop-2-en-1-one

[0815]

[0816] Synthesis of ethyl 4-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-2-carboxylate

[0817]

[0818] Phosphoryl chloride (1.11 g, 7.27 mmol, 677 μL) was added dropwise to a suspension of ethyl 4-hydroxy-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazine-2-carboxylate (130 mg, 454 μmol) in anhydrous acetonitrile (2 mL) under nitrogen atmosphere. 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 a saturated aqueous sodium bicarbonate solution. The layers were separated, and the organic layer was washed sequentially with a saturated bicarbonate solution (2x) and brine. The organic phase was dried (MgSO4), filtered, and concentrated under vacuum. Ethyl 4-chloro-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazine-2-carboxylate was obtained as a white solid and used directly. Quantitative yield is assumed. 1 H NMR (500MHz, chloroform-d) δppm 8.50(d,J=1.2Hz,1H),7.94(s,1H),7.90(s,1H),7.37-7.42(m,1H),4.50(q,J=6.9Hz,2H),3.97-4.01(m,3H),1.46(t,J=7.0Hz,3H). LCMS: m / z=306.3[M+H]+.

[0819] Synthesis of 4-(((R)-1-(tert-butoxycarbonyl)azacycloheptane-4-yl)oxy)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-2-carboxylic acid(R)-1-(tert-butoxycarbonyl)azacycloheptane-4-yl ester

[0820]

[0821] NaHMDS (1M, 1.08mL) was added to a solution of (4R)-4-hydroxyazine-1-heptane-tert-butyl ester (232mg, 1.08mmol) in anhydrous DMF (2mL) at 20°C under nitrogen atmosphere. The mixture was stirred at 20°C for 15 minutes. Ethyl 4-chloro-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-2-carboxylate (150mg, 491μmol) was added to a solution of anhydrous DMF (2mL), and the resulting mixture was stirred at room temperature for 2 hours. The mixture was quenched with H₂O (1mL) and diluted with EtOAc. The organic layer was washed with brine (3x), dried over MgSO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (0-100% EtOAc / heptane) to give 4-[(4R)-1-tert-butoxycarbonylazine-4-yl]oxy-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazine-2-carboxylic acid [(4R)-1-tert-butoxycarbonylazine-4-yl] ester (136 mg, 42% yield), which was a pale yellow foam. 1 H NMR (500MHz, chloroform-d) δppm 8.23 ​​(s, 1H), 7.76-7.90 (m, 2H), 5.55 (br s,1H),5.22-5.32(m,1H),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]+.

[0822] Synthesis of (R)-4-((1-(tert-butoxycarbonyl)azacycloheptane-4-yl)oxy)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-2-carboxylic acid

[0823]

[0824] A solution of sodium hydroxide (2 M, 94 μL) was added to a solution of 4-[(4R)-1-tert-butoxycarbonylazetane-4-yl]oxy-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-2-carboxylic acid [(4R)-1-tert-butoxycarbonylazetane-4-yl] ester (41 mg, 63 μmol) in methanol (400 μL), 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 (MgSO4), filtered, and concentrated under vacuum. 4-[(4R)-1-tert-butoxycarbonylazetane-4-yl]oxy-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-2-carboxylic acid was obtained as a white solid and used directly. Assuming a quantitative yield. LCMS: m / z = 457.4[M+H]+.

[0825] Synthesis of (R)-4-((2-((tert-butoxycarbonyl)amino)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)azacycloheptan-1-carboxylic acid tert-butyl ester

[0826]

[0827] Triethylamine (37 mg, 361 μmol, 50 μL) was added to a solution of 4-[(4R)-1-tert-butoxycarbonylazyroheptan-4-yl]oxy-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-2-carboxylic acid (110 mg, 241 μmol) in anhydrous DMF (1 mL) and tert-butanol (0.5 mL), followed by dropwise addition of DPPA (99 mg, 361 μmol, 78 μL) at room temperature. The resulting mixture was stirred at 80 °C for 17 hours, cooled to room temperature, diluted with EtOAc, and washed with water and brine (3x). The organic layer was dried (MgSO4), filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (0–5% MeOH / DCM). (4R)-4-[2-(tert-butoxycarbonylamino)-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]oxyazinon-1-carboxylic acid tert-butyl ester (38 mg, 30% yield) was obtained in oil form. 1H NMR (500MHz, chloroform-d) δppm 7.99 (s, 1H), 7.72-7.84 (m, 2H), 7.33 (br s,1H),6.82-7.05(bs,1H),5.47-5.55(m,1H),3.96(s,3H),3.58-3.76( m,2H),3.45-3.56(m,2H),1.88-2.03(m,6H),1.50(s,9H),1.46(s,9H). LCMS: m / z=528.3[M+H]+.

[0828] Synthesis of (R)-4-(azacycloheptane-4-yloxy)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-2-amine dihydrochloride

[0829]

[0830] HCl (4M, in dioxane, 360 μL) was added to a solution of (4R)-4-[2-(tert-butoxycarbonylamino)-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]oxyazinoheptan-1-carboxylic acid tert-butyl ester (38 mg, 72 μmol) in methanol (0.6 mL). The resulting solution was stirred at room temperature for 2 hours and concentrated under vacuum. 4-[(4R)-azinoheptan-4-yl]oxy-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-2-amine (dihydrochloride) as a grayish-white solid was obtained and used directly. Quantitative yield is assumed. LCMS: m / z = 328.1 [M+H]+.

[0831] Synthesis of 1-[(4R)-4-[2-amino-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]oxyazacycloheptane-1-yl]prop-2-en-1-one

[0832]

[0833] Triethylamine (21 mg, 210 μmol, 29 μL) was added to a suspension of crude 4-[(4R)-azacycloheptane-4-yl]oxy-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-2-amine (28 mg, 70 μmol, dihydrochloride) in anhydrous THF (1 mL) and anhydrous DMF (0.5 mL) under nitrogen atmosphere, and the resulting suspension was cooled to 0 °C. Acryloyl chloride (6 mg, 70 μmol, 6 μL) was added dropwise, and the 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 (MgSO4), filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography, and the desired product was further purified by preparative TLC (96:4DCM / MeOH). 1-[(4R)-4-[2-amino-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]oxyazacycloheptane-1-yl]prop-2-en-1-one (4.2 mg, 15% yield, 95% purity) was obtained as a grayish-white solid. 1 H NMR (500MHz, chloroform-d) δppm 7.93(s,1H),7.79(s,1H),7.68-7.76(m,1H),6.58-6.67(m,1H),6.36-6.43(m,1H ),5.94(d,J=4.3Hz,1H),5.72(dd,J=10.4,2.4Hz,1H),5.49-5.60(m,1H),4.02(br s,2H),3.96(s,3H),3.80-3.94(m,1H),3.55-3.77(m,3H),2.11-2.32(m,3H),1.93-2.11(m,2H),1.77-1.90(m,1H). LCMS: m / z = 382.1[M+H]+.

[0834] Example 68 :N-((cis)-3-((2-amino-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)cyclobutyl)-N-methacrylamide

[0835]

[0836] Synthesis of 4-(cis)-3-((tert-butoxycarbonyl)(methyl)amino)cyclobutoxy)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-2-carboxylic acid (cis)-3-((tert-butoxycarbonyl)(methyl)amino)cyclobutyl ester

[0837]

[0838] Under nitrogen atmosphere and at 0°C, potassium tert-butoxide solution (1M, in THF, 2.45 mL) was added to a solution of ethyl 4-chloro-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-2-carboxylate (300 mg, 981 μmol) and ((cis)-3-hydroxycyclobutyl)(methyl)-carbamate (494 mg, 2.45 mmol) in anhydrous THF (4 mL) and anhydrous DMSO (1 mL). The mixture was heated to room temperature and stirred at room temperature for 2 hours, quenched with H2O (1 mL) and diluted with EtOAc. The organic layer was washed with brine (2x), dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (0-100% EtOAc / heptane) to give 4-((cis)-3-((tert-butoxycarbonyl)(methyl)amino)cyclobutoxy)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-2-carboxylic acid (cis)-3-((tert-butoxycarbonyl)(methyl)amino)cyclobutyl ester (250 mg, 41% yield), which was a pale yellow foam. 1 H NMR (500MHz, chloroform-d) δppm 8.23(s,1H),7.74-7.92(m,2H),5.55(br s,1H),5.28(br s,1H),3.98(s,3H),3.59-3.74(m,2H),3.39-3.59(m,5H),3.29-3.39(m,1H),1.89-2.32(m,10H),1.69-1.84(m,2H),1.48-1.53(m,18H). LCMS: m / z=471.2[M+H]+.

[0839] Synthesis of 4-(cis)-3-((tert-butoxycarbonyl)(methyl)amino)cyclobutoxy)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-2-carboxylic acid

[0840]

[0841] A solution of sodium hydroxide (2M, 266 μL) was added to a solution of 4-(cis)-3-((tert-butoxycarbonyl)(methyl)amino)cyclobutoxy)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-2-carboxylic acid (cis)-3-((tert-butoxycarbonyl)(methyl)amino)cyclobutyl ester (332 mg, 531 μmol) in methanol (1 mL), and the mixture was stirred at room temperature for 30 minutes. The layers were separated after quenching with HCl (1M, 531 μL) and diluting with EtOAc and water. The organic layer was washed with water and brine, dried (MgSO4), filtered, and concentrated under vacuum. 4-((cis)-3-((tert-butoxycarbonyl)(methyl)amino)cyclobutoxy)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-2-carboxylic acid was obtained as a white solid and used directly. A quantitative yield is assumed. 1 H NMR(500MHz,DMSO-d6)δppm 13.26(br s,1H),8.81(s,1H),8.27(s,1H),8.05(s,1H),7.20(s,1H),5.05-5.16(m,1 H),3.91(s,3H),2.84(m,2H),2.80(s,3H),2.32-2.42(m,2H),1.42(s,9H). LCMS: m / z=443.1[M+H]+.

[0842] Synthesis of ((cis)-3-((2-((tert-butoxycarbonyl)amino)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)cyclobutyl)(methyl)carbamate tert-butyl

[0843]

[0844] Triethylamine (39 mg, 390 μmol, 54 μL) was added to a solution of 4-(cis)-3-((tert-butoxycarbonyl)(methyl)amino)cyclobutoxy)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-2-carboxylic acid (115 mg, 260 μmol) in anhydrous DMF (1 mL) and tert-butanol (0.5 mL), followed by dropwise addition of DPPA (107 mg, 390 μmol, 84 μL) at room temperature. The resulting mixture was stirred at 80 °C for 17 hours, cooled to room temperature, diluted with EtOAc, and washed with water and brine (3x). The organic layer was dried (MgSO4), filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (heptane / EtOAc 0-100%). To obtain ((cis)-3-((2-((tert-butoxycarbonyl)amino)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)cyclobutyl)(methyl)carbamate tert-butyl ester (26 mg, 20% yield) in white foam form. 1 H NMR (500MHz, chloroform-d) δppm 8.30-8.00 (br s,1H),8.10(s,1H),7.81(s,1H),7.76(s,1H),6.82-7.09(bs,1H),5.10(q,J=7.2Hz,1H), 3.94-3.99(m,3H),2.80-2.92(m,2H),2.86(s,3H),2.33(m,2H),1.55(s,9H),1.49(s,9H). LCMS: m / z=514.2[M+H]+.

[0845] Also isolated was an oily ((cis)-3-((2-amino-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)cyclobutyl)(methyl)carbamate tert-butyl ester (16 mg, 15% yield). 1 ¹H NMR (500MHz, chloroform-d) δppm 7.94(s, 1H), 7.79(s, 1H), 7.72(s, 1H), 5.95(s, 1H), 5.01–5.10 (quintet, J = 7.2Hz, 1H), 4.01–4.09(bs, 2H), 3.95(s, 3H), 2.83–2.93(m, 2H), 2.86(s, 3H), 2.28–2.42(m, 2H), 1.48(s, 9H). LCMS: m / z = 414.2 [M+H]+.

[0846] Synthesis of 6-(1-methyl-1H-pyrazol-4-yl)-4-((cis)-3-(methylamino)cyclobutoxy)pyrazolo[1,5-a]pyrazin-2-amine

[0847]

[0848] A solution of ((cis)-3-((2-((tert-butoxycarbonyl)amino)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)cyclobutyl)(methyl)carbamate (26 mg, 51 μmol) in anhydrous methanol (0.5 mL) was treated with HCl (4 M, in dioxane, 506 μL). The resulting mixture was stirred at room temperature for 1 hour. A solid was formed. The mixture was concentrated under vacuum. A white solid, 6-(1-methyl-1H-pyrazol-4-yl)-4-((cis)-3-(methylamino)cyclobutoxy)pyrazolo[1,5-a]pyrazin-2-amine (bishydrochloride), was obtained and 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-methylacrylamide

[0849]

[0850] Triethylamine (11 mg, 109 μmol, 15 μL) was added to a suspension of crude 6-(1-methyl-1H-pyrazol-4-yl)-4-((cis)-3-(methylamino)cyclobutoxy)pyrazolo[1,5-a]pyrazin-2-amine dihydrochloride (14 mg, 36 μmol) in anhydrous THF (0.5 mL) and anhydrous DMF (0.5 mL) under nitrogen atmosphere, and the resulting suspension was cooled to 0 °C. Acryloyl chloride (3.3 mg, 36 μmol, 3 μL) was added dropwise, and the mixture was stirred at 0 °C for 30 min. 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 (MgSO4), filtered, and concentrated under vacuum. 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]pyrazin-4-yl)oxy)cyclobutyl)-N-methylacrylamide (4.4 mg, 32% yield, 95% purity) was obtained as a white foam. 1¹H NMR (500MHz, chloroform-d) δppm 7.94 (s, 1H), 7.78 (br s, 1H), 7.73 (br s, 1H), 6.58 (dd, J = 16.8, 10.7Hz, 1H), 6.24–6.40 (m, 1H), 5.95 (s, 1H), 5.71 (dd, J = 10.4, 1.8Hz, 1H), 5.13 (quintet, J = 7.2Hz, 1H), 4.83 and 4.30 (2br s, 1H), 4.02 (bs, 2H), 3.96 (s, 3H), 3.06 (br s, 3H), 2.90–2.98 (m, 2H), 2.51 and 2.36 (2br s, 2H). LCMS: m / z = 368.1 [M+H]+.

[0851] Example 69 (S)-1-(4-((6-(1,3-dimethyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)azacycloheptane-1-yl)prop-2-en-1-one and (R)-1-(4-((6-(1,3-dimethyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)azacycloheptane-1-yl)prop-2-en-1-one

[0852]

[0853] Synthesis of tert-butyl 4-(6-chloropyrazolo[1,5-a]pyrazin-4-yl)oxyaziridine-1-carboxylate

[0854]

[0855] To a solution of 4-hydroxyazyrazo[1,5-a]pyrazin-4-yl)oxyazyrazo[1,5-a]pyrazine (3.5 g, 18.6 mmol) in THF (100 mL), potassium tert-butoxide solution (1 M, in THF, 18.6 mL, 18.6 mmol) was slowly added. The flask was stirred at room temperature for 2 hours. The mixture was concentrated to half its 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 by a gradient of 0–60% EtOAc / heptane via an 80 g silica gel column. The fractions were combined to give 4-(6-chloropyrazo[1,5-a]pyrazin-4-yl)oxyazyrazo[1,5-a]pyrazin-4-yl)oxyazyrazo[1,5-a]pyrazin-4-yl)oxyazyrazo[1,5-a]pyrazin-4-yl)oxyazyrazin-1-yl) tert-butyl 4-(6-chloropy ... oxyazyrazin-1-yl) tert-butyl 4-(6-chloropyrazo[1,5-a]pyrazin-4-yl) oxyazyrazin-1-yl) tert-butyl 4-(6-chloropyrazo[1,5-a LCMS m / z=367.1(M+H)+. 1H NMR(400MHz,DMSO-d6)δppm 1.36-1.47(m,9H)1.68(br dd,J=11.7,5.4Hz,1H)1.83(brs,1H)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)

[0856] Synthesis of tert-butyl 4-[6-(1,3-dimethylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]oxyazinon-1-carboxylate

[0857]

[0858] Add tert-butyl 4-(6-chloropyrazolo[1,5-a]pyrazin-4-yl)oxyazacycloheptan-1-carboxylate (1M, 0.55mL, 0.55mmol), 1,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)pyrazole (145mg, 0.65mmol), K3PO4 (1M, in water, 1.09mL), and Pd-PEPPSI to a microwave-safe vial. TM -IPr (37 mg, 55 μmol) and dioxane (5 mL). The vials were capped and stirred overnight at 60 °C. The reaction mixture was concentrated and purified via a 12 g silica gel column using a gradient of 40–70% EtOAc / heptane. The relevant fractions were combined to give tert-butyl 4-[6-(1,3-dimethylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]oxyazacycloheptan-1-carboxylate (136 mg, 58% yield) as a pale yellow oil. LCMS m / z = 427.2 (M+H)+.

[0859] Synthesis of 4-[azacycloheptane-4-yl]oxy-6-(1,3-dimethylpyrazol-4-yl)pyrazolo[1,5-a]pyrazine hydrochloride

[0860]

[0861] HCl (4 M, in dioxane, 0.8 mL) was added to a solution of 4-[6-(1,3-dimethylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]oxyazinon-1-carboxylic acid tert-butyl ester (136 mg, 0.32 mmol) in dioxane (2 mL). The mixture was stirred overnight at room temperature. The substance was concentrated to give 4-[azinon-4-yl]oxy-6-(1,3-dimethylpyrazol-4-yl)pyrazolo[1,5-a]pyrazine hydrochloride (115 mg, crude substance) as a grayish-white solid. LCMS m / z = 327.1 (M+H)+.

[0862] Synthesize (S)-1-(4-((6-(1,3-dimethyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)azacycloheptane-1-yl)prop-2-en-1-one and (R)-1-(4-((6-(1,3-dimethyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)azacycloheptane-1-yl)prop-2-en-1-one

[0863]

[0864] Add DCM (4 mL) containing 4-[monohepane-4-yl]oxy-6-(1,3-dimethylpyrazol-4-yl)pyrazolo[1,5-a]pyrazine hydrochloride (115 mg, 0.32 mmol), triethylamine (193 mg, 1.9 mmol, 266 μL), and acrylonitrile-2-enoyl chloride (35 mg, 0.38 mmol, 31 μL) in sequence to a vial. Stir the vial overnight at room temperature. Concentrate the reaction mixture in DMSO and pass it through a stopper. Purify the material by reverse-phase purification (column: Waters XSelect CSH Prep C18 5 μm OBD 19 x 100 mm; conditions: 5-50% acetonitrile in 0.1% v / v ammonium carbonate / water; flow rate: 30 mL / min) to give 60.6 mg (50% yield) of the desired product. LCMS m / z = 381.2(M+H)+. 1 H NMR(500MHz,DMSO-d6)δppm 1.67-1.80(m,1H)1.86-2.10(m,4H)2.16-2.26(m,1H)2.42(s,3H)3.56-3.78(m,4H)3.81(d,J=1.22Hz,3H)5.42-5.5 6(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).

[0865] Chiral purification of the substance was performed under the following conditions (column: CHIRALPAK AD-H 30x250mm, 5µm; method: 30% MeOH, without modifier, in CO2; flow rate: 100mL / min; ABPR: 120 bar; MBPR: 40PSI; column temperature: 40℃). The first elution peak E1 was concentrated to give 11.3 mg of an enantiomer of 1-[-4-[6-(1,3-dimethylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]oxyazacycloheptane-1-yl]prop-2-en-1-one as a white solid. LCMS m / z = 381.2(M+H)+. Concentrating the second elution peak E2 yielded 5.4 mg of the second enantiomer of 1-[4-[6-(1,3-dimethylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]oxyazacycloheptane-1-yl]prop-2-en-1-one as a white solid. LCMS m / z = 381.2(M+H)+. The stereochemistry of the two isomers was not specified.

[0866] Example 70 :1-[(4R)-4-[[6-(1,3-dimethylpyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-yl]oxy]azacycloheptane-1-yl]prop-2-en-1-one

[0867]

[0868] Synthesis of (4R)4-((6-bromo-[1,2,4]triazolo[1,5-a]pyrazin-8-yl)oxy)azacycloheptane-1-carboxylic acid tert-butyl ester

[0869]

[0870] To a solution of (4R)-4-hydroxyazacycloheptan-1-carboxylic acid tert-butyl ester (775 mg, 3.60 mmol) and 6,8-dibromo-[1,2,4]triazolo[1,5-a]pyrazine (1 g, 3.60 mmol) in THF (36 mL), potassium tert-butoxide solution (1 M, in THF, 3.6 mL, 3.6 mmol) was slowly added. The flask was stirred at room temperature for 1 hour. The substance was concentrated to half its 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 by a gradient of 10–70% EtOAc / heptane through a 40 g silica gel column. The fractions were combined to give (4R)-4-[(6-bromo-[1,2,4]triazolo[1,5-a]pyrazin-8-yl)oxy]azacycloheptane-1-carboxylic acid tert-butyl ester (1.48 g, 2.79 mmol, 77.5% yield) as a white foam. LCMS m / z = 414.0(M+H)+. 1 H NMR(500MHz,DMSO-d6)δppm 1.43(s,9H)1.69(brdd,J=8.85,4.58Hz,1H)1.81-2.04(m,4H)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)

[0871] Synthesis of (4R)-4-[[6-(1,3-dimethylpyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-yl]oxy]azacycloheptane-1-carboxylic acid tert-butyl ester

[0872]

[0873] Add (4R)-4-[(6-bromo-[1,2,4]triazolo[1,5-a]pyrazin-8-yl)oxy]azacycloheptane-1-carboxylic acid tert-butyl ester (230 mg, 0.56 mmol), 1,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)pyrazole (149 mg, 0.67 mmol), K3PO4 (1 M, in water, 1.12 mL), and Pd-PEPPSI to a microwave-safe vial. TM-IPr (38 mg, 55.8 μmol) and dioxane (5.00 mL). The vials were capped and stirred overnight at 70 °C. The reaction mixture was concentrated and purified via a 12 g silica gel column using a gradient of 30–100% EtOAc / heptane. The relevant fractions were combined to give (4R)-4-[[6-(1,3-dimethylpyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-yl]oxy]azacycloheptan-1-carboxylic acid tert-butyl ester (65 mg, 27% yield) as a pale yellow oil. LCMS m / z = 428.2 (M+H)+

[0874] Synthesis of 8-[(4R)-azacycloheptane-4-yl]oxy-6-(1,3-dimethylpyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazine hydrochloride

[0875]

[0876] To a solution of (4R)-4-[[6-(1,3-dimethylpyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-yl]oxy]azacycloheptane-1-carboxylic acid tert-butyl ester (65 mg, 0.15 mmol) in dioxane (5 mL), HCl (4 M, in dioxane, 0.38 mL) was added. The mixture was stirred overnight at room temperature. The substance was concentrated to give 8-[(4R)-azacycloheptane-4-yl]oxy-6-(1,3-dimethylpyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazine hydrochloride (55.3 mg, 100% yield) as a grayish-white solid. LCMS m / z = 328.1(M+H)+.

[0877] Synthesis of 1-[(4R)-4-[[6-(1,3-dimethylpyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-yl]oxy]azacycloheptane-1-yl]prop-2-en-1-one

[0878]

[0879] Add DCM (4 mL) containing 8-[(4R)-azacycloheptane-4-yl]oxy-6-(1,3-dimethylpyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazine hydrochloride (55.3 mg, 0.15 mmol), triethylamine (93 mg, 0.92 mmol, 128 μL), and acrylonitrile-2-enoyl chloride (17 mg, 0.18 mmol, 15 μL) in sequence to a vial. Stir the vial overnight at room temperature. Concentrate the reaction mixture in DMSO and pass it through a stopper. Purify the material by reverse-phase purification (column: Waters XSelect CSH Prep C18 5 μm OBD 19 x 100 mm; conditions: 5-40% acetonitrile in 0.1% v / v ammonium carbonate / water; flow rate: 30 mL / min) to give 26.4 mg (45% yield) of the desired product. LCMS m / z = 382.3(M+H)+. 1 H NMR(500MHz,DMSO-d6)δppm 1.69-1.81(m,1H)1.91-2.07(m,4H)2.21-2.31(m,1H)2.44(d,J=1.22Hz,3H)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).

[0880] Example 71 (S)-5-(4-((1-acryloylazetane-4-yl)oxy)pyrazolo[1,5-a]pyrazin-6-yl)-1-methylpyridin-2(1H)-one and (R)-5-(4-((1-acryloylazetane-4-yl)oxy)pyrazolo[1,5-a]pyrazin-6-yl)-1-methylpyridin-2(1H)-one

[0881]

[0882] Synthesis of tert-butyl 4-((6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)azacycloheptane-1-carboxylate

[0883]

[0884] Add 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborheptan-1-carboxylic acid tert-butyl ester (200 mg, 0.55 mmol))pyridine-2(1H)-one (154 mg, 0.64 mmol) to a 20-mL scintillation vial containing 200 mg of ((6-chloropyrazolo[1,5-a]pyrazin-4-yl)oxy)zacycloheptan-1-carboxylic acid tert-butyl ester (200 mg, 0.55 mmol)). Immediately afterwards, add an aqueous solution of K3PO4 (1 M, 1.09 mmol, 1.1 mL) to the reaction mixture, followed by the addition of Pd-PEPPSITM-IPr (37 mg, 55 μmol). Purge the vial with N2 and heat overnight at 100 °C. Subsequently, the reaction mixture was subjected to… The mixture was filtered and concentrated under reduced pressure to give an amber oil. The crude product was purified by silica gel chromatography (0 to 25% EtOAc / heptane, followed by 100% [3:1 EtOAc:EtOH]) to give tert-butyl 4-((6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)azacycloheptan-1-carboxylate (155 mg, 65% yield) as a grayish-white solid. LC-MS: m / z = 440.0 (M+H) + .

[0885] Synthesis of 5-(4-(azacycloheptane-4-yloxy)pyrazolo[1,5-a]pyrazin-6-yl)-1-methylpyridin-2(1H)-one

[0886]

[0887] HCl (4 M, in dioxane, 883 μL, 3.5 mmol) was added to a solution of tert-butyl 4-((6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)azacycloheptan-1-carboxylate (155 mg, 0.35 mmol) in 1.4 mL of dioxane. Upon addition of the HCl solution, the reaction mixture immediately became heterogeneous and was stirred at room temperature for 1.5 h. The reaction mixture was concentrated directly under reduced pressure to give the title compound as an orange solid, which was used without further purification, assuming a 100% yield. LC-MS: m / z = 361.9 (M + Na) + .

[0888] Synthesize (S)-5-(4-((1-acryloylazacycloheptane-4-yl)oxy)pyrazolo[1,5-a]pyrazin-6-yl)-1-methylpyridin-2(1H)-one and (R)-5-(4-((1-acryloylazacycloheptane-4-yl)oxy)pyrazolo[1,5-a]pyrazin-6-yl)-1-methylpyridin-2(1H)-one

[0889]

[0890] Triethylamine (99 μL, 0.71 mmol) was added to a solution of 5-(4-(azacycloheptane-4-yloxy)pyrazolo[1,5-a]pyrazin-6-yl)-1-methylpyridin-2(1H)-one (120 mg, 0.35 mmol) in DCM (1.4 mL), followed by the addition of acryloyl chloride (57 μL, 0.71 mmol). After the addition of acryloyl chloride, the solution became red and homogeneous, and the mixture was stirred at room temperature for 20 minutes. The reaction mixture was then concentrated under vacuum and loaded onto a silica gel cartridge. The crude substance was purified by silica gel chromatography (0 to 100% EtOAc / heptane, followed by 0 to 15% MeOH / heptane) to give a white solid, 5-(4-((1-acryloylazetane-4-yl)oxy)pyrazolo[1,5-a]pyrazin-6-yl)-1-methylpyridin-2(1H)-one (52.1 mg, 38%, in two steps). LC-MS: m / z = 393.9 (M+H) + . 1 H NMR (400MHz, CDCl3) δppm 1.72 (br s,1H)1.74-1.91(m,2H)1.95-2.49(m,6H)3.46-3.64(m,2H)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,1H)7.74-7.79(m,1H)7.91(dd,J=4.39,2.38Hz,1H)7.95-8.11(m,1H)8.23(d,J=0.75Hz,1H).

[0891] Racemic substances were separated using a chiral SFC (Chiralpak AD-H 30x250 mm, 5 μm column; 25% MeOH in CO2, without modifiers; flow rate = 100 mL / min, ABPR 120 bar, MBPR 40 psi, column temperature 40 °C) to obtain enantiomers. The first eluted enantiomer E1 (7.0 mg, 100% ee, Rf = 4.36 min) and the second eluted enantiomer E2 (arbitrarily designated as R 7.6 mg, 90% ee, Rf = 4.77 min) were obtained.

[0892] Example 72 : 1-(4-((6-(2-methoxypyridin-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)azacycloheptane-1-yl)prop-2-en-1-one (chiral, but absolutely chemically unknown)

[0893]

[0894] Synthesis of tert-butyl 4-((6-(2-methoxypyridin-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)azacycloheptan-1-carboxylate

[0895]

[0896] Add 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborheptan-1-carboxylic acid tert-butyl ester (200 mg, 0.55 mmol))pyridine (100 mg, 0.65 mmol) to a 20-mL scintillation vial containing 5.0 mL of dioxane containing 200 mg (200 mg, 0.55 mmol) of dioxane. Then, add an aqueous solution of K3PO4 (1 M, 1.09 mmol, 1.09 mL) to the reaction mixture, followed by the addition of Pd-PEPPSI. TM -IPr (37 mg, 55 μmol). The vial was purged with N2 and heated overnight at 100 °C. The reaction mixture was then brought to room temperature and then... The mixture was filtered through a pad. Concentration under reduced pressure yielded a crude product as an amber oil. Purification of the crude product by silica gel chromatography (0 to 25% EtOAc / heptane) gave tert-butyl 4-((6-(2-methoxypyridin-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)azacycloheptan-1-carboxylate (184 mg, 77% yield) as a grayish-white solid. LC-MS: m / z = 440.0 (M+H) + .

[0897] Synthesis of 4-(azacycloheptane-4-yloxy)-6-(2-methoxypyridin-4-yl)pyrazolo[1,5-a]pyrazine

[0898]

[0899] A solution of 4-((6-(2-methoxypyridin-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)azacycloheptane-1-carboxylic acid tert-butyl ester (184 mg, 0.42 mmol) in dioxane (1.7 mL) was added to HCl solution (4 M, in dioxane, 1.05 mL, 4.2 mmol). The reaction mixture was stirred at room temperature for 3 hours, followed by concentration under vacuum to give crude 4-(azacycloheptane-4-yloxy)-6-(2-methoxypyridin-4-yl)pyrazolo[1,5-a]pyrazine as a bright yellow solid. The crude product was used without further purification, assuming a yield of 100%. LC-MS: m / z = 340.0 (M+H) + .

[0900] Synthesis of chiral 1-(4-((6-(2-methoxypyridin-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)azacycloheptane-1-yl)prop-2-en-1-one

[0901]

[0902] Triethylamine (0.29 mL, 2.09 mmol) was added to a solution of crude 4-(azacycloheptan-4-yloxy)-6-(2-methoxypyridin-4-yl)pyrazolo[1,5-a]pyrazine (142 mg, 0.42 mmol) in DCM (1.7 mL) at room temperature, followed immediately by the addition of acryloyl chloride (68 μL, 0.84 mmol). The reaction mixture became deep red and homogeneous, and was stirred at room temperature for 20 min. The reaction mixture was then quenched by adding saturated aqueous NaHCO3 solution and diluted with EtOAc. The resulting layer was separated, and the aqueous layer was further extracted with EtOAc (3x). The combined organic matter was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude substance was purified by silica gel chromatography (0 to 100% EtOAc / heptane) to obtain a colorless oil, 1-(4-((6-(2-methoxypyridin-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)azacycloheptane-1-yl)prop-2-en-1-one (64.5 mg, 39%, in two steps). LC-MS: m / z = 393.9 (M+H) + . 1¹H NMR (400MHz, CDCl₃) δppm 1.81-1.92(m,1H)1.97-2.13(m,2H)2.16-2.31(m,3H)3.62-3.85(m,4H)4.0 1-4.04(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,1H)6.80(dd,J=4.02,2.01Hz,1H)7 .31-7.39(m,2H)7.98(t,J=2.01Hz,1H)8.24(d,J=5.27Hz,1H)8.56(s,1H).

[0903] Racemic substances were separated using a chiral SFC (Chiralpak IB 30x250 mm, 5 μm column; 15% MeOH in CO2, without modifiers; flow rate = 100 mL / min, ABPR 120 bar, MBPR 40 psi, column temperature 40 °C) to obtain the first eluted enantiomer E1 (12.2 mg, 100% ee, Rf = 6.91 min) and the second eluted enantiomer E2 (3.6 mg, 96% ee, Rf = 7.45 min). The second enantiomer contained inseparable impurities and was not further purified.

[0904] Example 73 :(R)-1-(4-((6-phenylpyrazolo[1,5-a]pyrazin-4-yl)oxy)azacycloheptane-1-yl)prop-2-en-1-one

[0905]

[0906] Synthesis of (R)-4-((6-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)azacycloheptane-1-carboxylic acid tert-butyl ester

[0907]

[0908] To a 20-mL scintillation vial containing (R)-4-((6-chloropyrazolo[1,5-a]pyrazin-4-yl)oxy)azacycloheptan-1-carboxylic acid tert-butyl ester (734 mg, 2.0 mmol) dissolved in dioxane (10 mL), bis(pinacol)diboron (610 mg, 2.4 mmol) was added. Immediately thereafter, 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 N2, and then stirred overnight at 95 °C. The reaction mixture was then cooled to room temperature and subjected to EtOAc-assisted... The crude material was filtered through a filter pad. It was then dry-loaded onto silica gel and purified by silica gel chromatography (0 to 40% EtOAc / heptane) to give (R)-4-((6-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)azacycloheptane-1-carboxylic acid tert-butyl ester (744 mg, 81% yield) as a colorless oil. LC-MS: m / z = 399.2 (M - 86 + Na). + .

[0909] Synthesis of (R)-4-((6-phenylpyrazolo[1,5-a]pyrazin-4-yl)oxy)azacycloheptan-1-carboxylic acid tert-butyl ester

[0910]

[0911] Add bromobenzene (38 μL, 0.36 mmol) to a 20-mL scintillation vial containing (R)-4-((6-(4,4,5,5-tetramethyl-1,3,2-dioxaborphane-2-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)azacycloheptan-1-carboxylic acid tert-butyl ester (248 mg, 0.54 mmol) in dioxane (1.8 mL), followed by the sequential addition of K3PO4 aqueous solution (0.5 M, 1.44 mL, 0.72 mmol) and Pd-PEPPSI. TM -IPr (49 mg, 72 μmol). The reaction mixture was heated at 95 °C overnight, then cooled to room temperature and concentrated directly under reduced pressure. The crude product was purified by silica gel chromatography (0 to 100% EtOAc / heptane) to give (R)-4-((6-phenylpyrazolo[1,5-a]pyrazin-4-yl)oxy)azacycloheptan-1-carboxylic acid tert-butyl ester (47.6 mg, 32% yield) as a yellow oil. LC-MS: m / z = 409.2 (M+H) + .

[0912] Synthesis of (R)-4-(azacycloheptane-4-yloxy)-6-phenylpyrazolo[1,5-a]pyrazine

[0913]

[0914] HCl (4 M, 1.2 mmol, 291 μL in dioxane) was added to a solution of (R)-4-((6-phenylpyrazolo[1,5-a]pyrazin-4-yl)oxy)azacycloheptane-1-carboxylic acid tert-butyl ester (48 mg, 0.12 mmol) in dioxane (1.2 mL). Upon addition of HCl, the reaction mixture immediately turned into a white slurry and was stirred at room temperature for 4 hours. The reaction mixture was concentrated directly under reduced pressure to give crude (R)-4-(azacycloheptane-4-yloxy)-6-phenylpyrazolo[1,5-a]pyrazine, which was used without further purification, assuming a 100% yield. LC-MS: m / z = 332.2 (M + Na) + .

[0915] Synthesis of (R)-1-(4-((6-phenylpyrazolo[1,5-a]pyrazin-4-yl)oxy)azacycloheptane-1-yl)prop-2-en-1-one

[0916]

[0917] A solution of crude (R)-4-(azacycloheptane-4-yloxy)-6-phenylpyrazolo[1,5-a]pyrazine (36 mg, 0.12 mmol) in THF (1.2 mL) was cooled to -78 °C in a dry ice / acetone bath. Triethylamine (81 μL, 0.58 mmol) was added via a microsyringe with stirring, followed immediately by acryloyl chloride (19 μL, 0.23 mmol). The reaction mixture was removed from the ice bath and allowed to slowly warm to room temperature, turning red in the process. After stirring at room temperature for 2 hours, the reaction mixture was diluted with EtOAc and quenched by adding a saturated aqueous solution of NaHCO3. 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 a crude product as a pale yellow oil. The crude substance was purified by reversed-phase HPLC (column: Waters XSelect CSH Prep C18 5μm OBD 19x100mm; conditions: 5-70% acetonitrile in 0.1% v / v ammonium carbonate / water) to obtain a yellow film-like (R)-1-(4-((6-phenylpyrazolo[1,5-a]pyrazin-4-yl)oxy)azacycloheptane-1-yl)prop-2-en-1-one (16.7 mg, 40% yield, in 2 steps). LC-MS: m / z = 363.3 (M+H) + . 1H NMR(500MHz,DMSO-d6)δppm 1.71-1.80(m,1H)1.87-2.13(m,5H)2.18-2.30(m,1H)3.52-3.78(m,4H)5.54-5.62(m,1H)5.70(dt,J=10.38,2. 14Hz,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).

[0918] Example 74 :(R)-1-(4-((6-(6-methoxypyrimidin-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)azacycloheptane-1-yl)prop-2-en-1-one

[0919]

[0920] Synthesis of (R)-4-((6-(6-methoxypyrimidin-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)azacycloheptan-1-carboxylic acid tert-butyl ester

[0921]

[0922] Add 4-bromo-6-methoxypyrimidine (38 mg, 0.20 mmol) to a 2-daramid scintillation vial containing dioxane (3.0 mL) of (R)-4-((6-(4,4,5,5-tetramethyl-1,3,2-dioxaborphane-2-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)azacycloheptan-1-carboxylic acid tert-butyl ester (138 mg, 0.30 mmol). Then add K3PO4 aqueous solution (0.5 M, 0.80 mL, 0.40 mmol), followed by Pd-PEPPSI. TM -IPr (41 mg, 40 μmol). The reaction mixture was heated overnight at 95 °C, then cooled to room temperature and concentrated directly under reduced pressure. The crude product was purified by silica gel chromatography (0 to 50% [3:1EtOAc:EtOH] / heptane) to give (R)-4-((6-(6-methoxypyrimidin-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)azacycloheptan-1-carboxylic acid tert-butyl ester (98.6 mg, 75% yield). LC-MS: m / z = 441.2 (M+H) + .

[0923] Synthesis of (R)-4-(azacycloheptane-4-yloxy)-6-(6-methoxypyrimidin-4-yl)pyrazolo[1,5-a]pyrazine

[0924]

[0925] HCl (4 M, 2.2 mmol, 0.56 mL in dioxane) was added to a solution of (R)-4-((6-(6-methoxypyrimidin-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)azacycloheptane-1-carboxylic acid tert-butyl ester (99 mg, 0.22 mmol) in dioxane (2.2 mL), forming a milky white slurry. After stirring at room temperature for 4 hours, the reaction mixture was concentrated directly under reduced pressure to give crude (R)-4-(azacycloheptane-4-yloxy)-6-(6-methoxypyrimidin-4-yl)pyrazolo[1,5-a]pyrazine, which was used without further purification, assuming a 100% yield. LC-MS: m / z = 363.3 (M + Na) + .

[0926] Synthesis of (R)-1-(4-((6-(6-methoxypyrimidin-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)azacycloheptane-1-yl)prop-2-en-1-one

[0927]

[0928] A solution of crude (R)-4-(azacycloheptane-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 slowly warm to room temperature, turning red in the process. After stirring at room temperature for 2 hours, the reaction mixture was diluted with EtOAc and quenched by adding a saturated aqueous solution of NaHCO3. 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 a crude product as a yellow oil. The crude substance was purified by reversed-phase HPLC (column: Waters XSelect CSH Prep C18 5μm OBD 19x100mm; conditions: 5-65% acetonitrile, in 0.1% v / v ammonium carbonate / water) to give (R)-1-(4-((6-(6-methoxypyrimidin-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)azacycloheptane-1-yl)prop-2-en-1-one (22.7 mg, 26% yield, in 2 steps) as a white solid. LC-MS: m / z = 395.3 (M+H) + . 1H NMR(500MHz,DMSO-d6)δppm 1.71-1.81(m,1H)1.87-1.95(m,1H)1.97(br s,1H)1.98-2.11(m,2H)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=16.79,2.59Hz,1H)6.82(dt,J=1 6.48,10.07Hz,1H)6.95-6.98(m,1H)7.53(dd,J=10.99,1.22Hz,1H)8.17-8.22(m,1H )8.19-8.19(m,1H)8.19-8.20(m,1H)8.82-8.87(m,1H)8.83-9.11(m,1H)9.09(s,1H).

[0929] Example 75 :(R)-1-(4-((6-(4-methyloxazol-2-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)azacycloheptane-1-yl)prop-2-en-1-one

[0930]

[0931] Synthesis of (R)-4-((6-(4-methyloxazol-2-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)azacycloheptane-1-carboxylic acid tert-butyl ester

[0932]

[0933] Add 2-bromo-4-methyloxazole (32 mg, 0.20 mmol) to a 2-duralumin scintillation vial containing (R)-4-((6-(4,4,5,5-tetramethyl-1,3,2-dioxaborphane-2-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)azacycloheptane-1-carboxylic acid tert-butyl ester (138 mg, 0.30 mmol) and 0.5 M K3PO4 aqueous solution (0.80 mL, 0.40 mmol), followed by the addition of Pd-PEPPSI. TM-IPr (41 mg, 40 μmol). The reaction mixture was heated overnight at 95 °C, then cooled to room temperature and concentrated directly under reduced pressure. The crude product was purified by silica gel chromatography (0 to 50% [3:1EtOAc:EtOH] / heptane) to give (R)-4-((6-(4-methyloxazol-2-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)azacycloheptan-1-carboxylic acid tert-butyl ester (95.4 mg, 77% yield). LC-MS: m / z = 441.2 (M+H) + .

[0934] Synthesis of (R)-2-(4-(azacycloheptane-4-yloxy)pyrazolo[1,5-a]pyrazin-6-yl)-4-methyloxazole

[0935]

[0936] HCl (4 M, 2.3 mmol, 0.58 mL, in dioxane) was added to a solution of (R)-4-((6-(4-methyloxazol-2-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)azacycloheptane-1-carboxylic acid tert-butyl ester (95 mg, 0.23 mmol) in dioxane (2.3 mL), forming a bright yellow slurry. After stirring at room temperature for 4 hours, the reaction mixture was concentrated directly under reduced pressure to give crude (R)-2-(4-(azacycloheptane-4-yloxy)pyrazolo[1,5-a]pyrazin-6-yl)-4-methyloxazole, which was used without further purification, assuming a 100% yield. LC-MS: m / z = 314.1 (M + Na) + .

[0937] Synthesis of (R)-1-(4-((6-(4-methyloxazol-2-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)azacycloheptane-1-yl)prop-2-en-1-one

[0938]

[0939] A solution of crude (R)-2-(4-(azacycloheptane-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 slowly warm to room temperature, turning red in the process. After stirring at room temperature for 2 hours, the reaction mixture was diluted with EtOAc and quenched by adding a saturated aqueous solution of NaHCO3. 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 a crude product as a yellow solid. The crude substance was purified by reversed-phase HPLC (column: Waters XSelect CSH Prep C18 5μm OBD 19x100mm; conditions: 5-55% acetonitrile, in 0.1% v / v ammonium carbonate / water) to obtain a grayish-white solid (R)-1-(4-((6-(4-methyloxazol-2-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)azacycloheptane-1-yl)prop-2-en-1-one (28.2 mg, 22% yield, in 2 steps). LC-MS: m / z = 368.3 (M+H) + . 1 H NMR(500MHz,DMSO-d6)δppm 1.67-1.79(m,1H)1.83-1.96(m,2H)2.02-2.13(m,3H)2.18(d,J=1.22Hz,4H)3.54-3.77(m,3H)5.53-5.60(m,1H)5.69(ddd,J=10.38,3.66 ,2.44Hz,1H)6.13-6.20(m,1H)6.80(ddd,J=16.48,14.04,10.38Hz,1H)6.95-6.98(m,1H)7.97(s,1H)8.18(d,J=1.22Hz,1H)8.90(s,1H).

[0940] Example 76 :(R)-1-(4-((6-(2-methylthiazolyl-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)azacycloheptane-1-yl)prop-2-en-1-one

[0941]

[0942] Synthesis of (R)-4-((6-(2-methylthiazolyl-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)azacycloheptan-1-carboxylic acid tert-butyl ester

[0943]

[0944] A solution of (R)-4-((6-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)azacycloheptane-1-carboxylic acid tert-butyl ester (193 mg, 0.42 mmol), 4-bromo-2-methyl-thiazole (50 mg, 0.28 mmol), dihydrodichlorobis(di-tert-butylphosphine)palladium (2-) (7 mg, 14 μmol), and cesium fluoride (128 mg, 0.84 mmol) in isopropanol (1.4 mL) was stirred in a microwave at 90 °C for 3 hours. The reaction mixture was quenched with water and brine. The two-phase mixture was extracted three times with ethyl acetate and then dried over anhydrous MgSO4. After filtration and concentration under reduced pressure, crude (R)-4-((6-(2-methylthiazo-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)azacycloheptan-1-carboxylic acid tert-butyl ester (110 mg, 91% yield) was used without further purification. LCMS: m / z = 430.0 (M+H) + .

[0945] Synthesis of (R)-1-(4-((6-(2-methylthiazo-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)azacycloheptane-1-yl)prop-2-en-1-one

[0946]

[0947] Step 1. Crude (R)-4-((6-(2-methylthiazolyl-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)azacycloheptane-1-carboxylic acid tert-butyl ester (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 hours, the reactants were carefully quenched by slowly adding saturated NaHCO3 aqueous solution. The two-phase mixture was extracted three times with a mixture of chloroform and isopropanol (5:1), followed by drying over anhydrous MgSO4. After filtration and concentration under reduced pressure, crude (R)-4-(4-(azacycloheptane-4-yloxy)pyrazolo[1,5-a]pyrazin-6-yl)-2-methylthiazolium (84 mg, assuming 100% yield) was concentrated to dryness and used unpurified. LCMS: m / z = 330.0(M+H) + .

[0948] Step 2. Add DCM (1.0 mL) to a 20 mL vial containing crude (R)-4-(4-(azacycloheptane-4-yloxy)pyrazolo[1,5-a]pyrazin-6-yl)-2-methylthiazole (84 mg, 0.25 mmol), followed by TEA (129 mg, 1.27 mmol, 178 μL). Stir the reaction mixture at room temperature for 5 minutes, then cool to 0 °C. Add acryloyl chloride (35 mg, 0.38 mmol, 31 μL) dropwise. Stir the solution at 0 °C. After 1 hour, carefully quench the reaction mixture by slowly adding saturated NH4Cl aqueous solution. Extract the two-phase mixture three times with ethyl acetate, then dry over anhydrous MgSO4. After filtration and concentration under reduced pressure, load the residue onto a silica gel column and purify (25–100% ethyl acetate / heptane). The desired fractions were collected and then concentrated under reduced pressure to give (R)-1-(4-((6-(2-methylthiazo-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)azacycloheptane-1-yl)prop-2-en-1-one (31.2 mg, 32% yield). 1 ¹H NMR (500MHz, DMSO-d⁶) δppm 8.67(s, 1H) 8.08(s, 1H) 7.96(s, 1H) 7.92(rotational isomer, s, 1H) 6.77-6.89(m, 2H) 6.14-6.20(m, 1H) 5.69(ddd, J = 10.22, 7.48, 2.44Hz, 1H) 5.52-5.62(m, 1H) 3.58-3.78(m, 4H) 2.74(d, J = 1.22Hz, 3H) 2.23(ddt, J = 10.91, 7.25, 3.43, 3.43Hz, 1H) 1.87-2.09(m, 4H) 1.71-1.82(m, 1H). LCMSm / z = 384.0(M+H) + .

[0949] Example 77 :(R)-1-(4-((6-(2-methylthiazolyl-5-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)azacycloheptane-1-yl)prop-2-en-1-one

[0950]

[0951] Synthesis of (R)-4-((6-(2-methylthiazolyl-5-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)azacycloheptane-1-carboxylic acid tert-butyl ester

[0952]

[0953] A solution of (R)-4-((6-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)azacycloheptane-1-carboxylic acid tert-butyl ester (200 mg, 0.44 mmol), 5-bromo-2-methyl-thiazole (156 mg, 0.87 mmol), dihydrodichlorobis(di-tert-butylphosphine)palladium (2-) (22 mg, 44 μmol), and cesium fluoride (199 mg, 1.3 mmol) in isopropanol (1.0 mL) was stirred at 90 °C. After 16 hours, the reaction mixture was quenched with water and brine. The two-phase mixture was extracted three times with ethyl acetate and then dried over anhydrous MgSO4. After filtration and concentration under reduced pressure, crude (R)-4-((6-(2-methylthiazo-5-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)azacycloheptan-1-carboxylic acid tert-butyl ester (187 mg, assuming 100% yield) was used without further purification. LCMS: m / z = 430.0 (M+H) + .

[0954] Synthesis of (R)-1-(4-((6-(2-methylthiazo-5-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)azacycloheptane-1-yl)prop-2-en-1-one

[0955]

[0956] Step 1. Crude (R)-4-((6-(2-methylthiazolyl-5-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)azacycloheptane-1-carboxylic acid tert-butyl ester (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 hours, the reactants were carefully quenched by slowly adding saturated NaHCO3 aqueous solution. The two-phase mixture was extracted three times with a mixture of chloroform and isopropanol (5:1), followed by drying over anhydrous MgSO4. After filtration and concentration under reduced pressure, crude (R)-5-(4-(azacycloheptane-4-yloxy)pyrazolo[1,5-a]pyrazin-6-yl)-2-methylthiazolyl (143 mg, assuming 100% yield) was concentrated to dryness and used unpurified. LCMS: m / z = 330.0(M+H) + .

[0957] Step 2. Add 2 mL of DCM to a 20 mL vial containing crude (R)-5-(4-(azacycloheptane-4-yloxy)pyrazolo[1,5-a]pyrazin-6-yl)-2-methylthiazole (143 mg, 0.44 mmol), followed by TEA (439 mg, 4.34 mmol, 605 μL). Stir the reaction mixture at room temperature for 5 minutes, then cool to 0 °C. Add acryloyl chloride (79 mg, 0.87 mmol, 71 μL) dropwise. Stir the solution at 0 °C. After 1 hour, carefully quench the reaction mixture by slowly adding saturated aqueous NH4Cl solution. Extract the two-phase mixture three times with ethyl acetate, then dry over anhydrous MgSO4. After filtration and concentration under reduced pressure, load the residue onto a silica gel column and purify (25–100% ethyl acetate / heptane). The desired fractions were collected and then concentrated under reduced pressure to give (R)-1-(4-((6-(2-methylthiazo-5-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)azacycloheptane-1-yl)prop-2-en-1-one (29.8 mg, 18% yield). 1 H NMR(500MHz,DMSO-d6)δppm 9.02-9.04(m,1H)8.25(d,J=2.44Hz,1H)8.09(dd,J=2.44,1.22Hz,1H)6.89( d,J=3.05Hz,1H)6.81(ddd,J=16.48,12.82,10.38Hz,1H)6.17(ddd,J=16.63 ,7.48,2.75Hz,1H)5.70(dt,J=10.38,2.44Hz,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) + .

[0958] Example 78 :(R)-1-(4-((6-(3-methylisothiazo-5-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)azacycloheptane-1-yl)prop-2-en-1-one

[0959]

[0960] Synthesis of (R)-4-((6-(3-methylthiazolyl-5-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)azacycloheptane-1-carboxylic acid tert-butyl ester

[0961]

[0962] A solution of (R)-4-((6-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)azacycloheptane-1-carboxylic acid tert-butyl ester (80 mg, 175 μmol), 5-bromo-3-methylisothiazolium (47 mg, 262 μmol), dihydrodichlorobis(di-tert-butylphosphine)palladium (2-) (4.4 mg, 8.7 μmol), and cesium fluoride (80 mg, 524 μmol) in isopropanol (1.0 mL) was stirred at 90 °C. After 16 hours, the reaction mixture was quenched with water and brine. The two-phase mixture was extracted three times with ethyl acetate and then dried over anhydrous MgSO4. After filtration and concentration under reduced pressure, crude (R)-4-((6-(3-methylisothiazo-5-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)azacycloheptan-1-carboxylic acid tert-butyl ester (75 mg, assuming 100% yield) was used without further purification. LCMS: m / z = 430.0 (M+H) + .

[0963] Synthesis of (R)-1-(4-((6-(3-methylisothiazo-5-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)azacycloheptane-1-yl)prop-2-en-1-one

[0964]

[0965] Step 1. Crude (R)-4-((6-(3-methylisothiazo-5-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)azacycloheptane-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 hours, the reactants were carefully quenched by slowly adding saturated NaHCO3 aqueous solution. The two-phase mixture was extracted three times with a mixture of chloroform and isopropanol (5:1), followed by drying over anhydrous MgSO4. After filtration and concentration under reduced pressure, crude (R)-5-(4-(azacycloheptane-4-yloxy)pyrazolo[1,5-a]pyrazin-6-yl)-3-methylisothiazolyl (58 mg, assuming 100% yield) was concentrated to dryness and used unpurified. LCMS: m / z = 330.0(M+H) + .

[0966] Step 2. Add DCM (1.0 mL) to a 20 mL vial containing crude (R)-5-(4-(azacycloheptane-4-yloxy)pyrazolo[1,5-a]pyrazin-6-yl)-3-methylisothiazolium (58 mg, 175 μmol), followed by TEA (88 mg, 0.87 mmol, 122 μL). Stir the reaction mixture at room temperature for 5 minutes, then cool to 0 °C. Add acryloyl chloride (24 mg, 262 μmol, 21 μL) dropwise. Stir the solution at 0 °C. After 1 hour, carefully quench the reaction mixture by slowly adding saturated NH4Cl aqueous solution. Extract the two-phase mixture three times with ethyl acetate, then dry over anhydrous MgSO4. After filtration and concentration under reduced pressure, load the residue onto a silica gel column and purify (25–100% ethyl acetate / heptane). The desired fractions were collected and then concentrated under reduced pressure to give (R)-1-(4-((6-(3-methylisothiazo-5-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)azacycloheptane-1-yl)prop-2-en-1-one (21.3 mg, 32% yield). 1 H NMR(500MHz,DMSO-d6)δppm 9.21(d,J=1.22Hz,1H)8.15(dd,J=2.44,1.22Hz,1H)7.80(d,J=2.44Hz,1H)6.94( d,J=3.05Hz,1H)6.81(dt,J=16.63,10.30Hz,1H)6.14-6.21(m,1H)5.69(ddd,J=1 0.38,5.49,2.44Hz,1H)5.34-5.43(m,1H)3.65-3.76(m,2H)3.53-3.64(m,2H)2.4 5(s,3H)2.17-2.29(m,1H)1.95-2.12(m,3H)1.86-1.93(m,1H)1.63-1.83(m,1H). LCMS m / z=384.0(M+H) + .

[0967] 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

[0968]

[0969] Synthesis of tert-butyl methyl((1s,3s)-3-methyl-3-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)cyclobutyl)carbamate

[0970]

[0971] In a 100-mL single-necked round-bottom flask equipped with a condenser under a nitrogen atmosphere, 2.2 mL of 1 M potassium disilicide in THF was added to a solution of ((1s,3s)-3-hydroxy-3-methylcyclobutyl)carbamate tert-butyl ester (150 mg, 0.75 mmol) in dioxane (7.5 mL) at room temperature. After 5 minutes, 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. Iodimethane (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 10 minutes, 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborphanecyclopentan-2-yl)pyrazole (212 mg, 1.02 mmol) was added to the previously degassed solution in dioxane (2.0 mL), followed by the addition of solid Pd-PEPPSI. TM -IPr catalyst (93 mg, 0.14 mmol). The reaction mixture was purged with nitrogen for 15 minutes, then heated under reflux for 3 hours. Ethyl acetate (20 mL) was added to the vigorously stirred reaction mixture, followed by water (20 mL). After 30 minutes, the organic phase was separated, and volatiles were removed under reduced pressure. The residue was purified by column chromatography (40 g silica gel, 0-80% [3:1 EtOAc:EtOH], containing 2% NH4OH modifier, in heptane) to give the title compound (130 mg, 47% yield) as a pale yellow oil. LCMS m / z = 413.1 (M+H)+. 1 ¹H NMR (500MHz, methanol-d⁴) δppm 8.42(s, 1H), 8.05(s, 1H), 7.93(s, 1H), 7.91(d, J = 2.44Hz, 1H), 6.77(d, J = 1.22Hz, 1H), 4.10–4.45(m, 1H), 3.95(s, 3H), 2.82(s, 3H), 2.74–2.81(m, 2H), 2.67(br s, 2H), 1.81(s, 3H), 1.46(s, 9H).

[0972] Synthesis of (1s,3s)-N,3-dimethyl-3-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)cyclobut-1-amine

[0973]

[0974] TFA (2.24 g, 19.6 mmol, 1.5 mL) was added to a solution of methyl ((1S,3S)-3-methyl-3-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)cyclobutyl)carbamate (4.05 g, 9.82 mmol) in HFIP (45 mL). The resulting reaction mixture was stirred overnight. Ethyl acetate (50 mL) was added, followed by saturated aqueous solution of NaHCO3 (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 residue was purified by column chromatography (24 g silica gel, 80-100% [3:1 EtOAc:EtOH], with 2% NH4OH modifier, in heptane) to give the title compound (2.53 g, 82% yield) as a pale yellow gel. LCMS m / z=313.1(M+H)+. 1 ¹H NMR (500MHz, methanol-d⁴) δppm 8.41 (d, J = 1.22Hz, 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).

[0975] 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

[0976]

[0977] Acryloyl chloride (819 mg, 9.04 mmol, 740 μL) was added to a solution 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 (4.05 g, 9.82 mmol) and DIPEA (2.81 g, 21.7 mmol, 3.8 mL) in THF (50 mL) at 0 °C. After 30 minutes, the reaction mixture was diluted with EtOAc (50 mL) and a saturated aqueous solution of NaHCO3 (50 mL) was added. The two-phase mixture was allowed to reach room temperature with vigorous stirring and stirred 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 residue was purified by column chromatography (80 g silica gel, 0-100% [3:1 EtOAc:EtOH], containing 2% NH4OH modifier, in heptane). The colorless solid was recrystallized from EtOAc / heptane (1 / 3, 45 mL) to give 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)+. 1 H NMR (500MHz, methanol-d4) δppm 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=9.16Hz,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).

[0978] Example 80 :N-((1s,3s)-3-((6-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)-3-methylcyclobutyl)-N-methacrylamide

[0979]

[0980] Synthesis of ((1s,3s)-3-((6-chloropyrazolo[1,5-a]pyrazin-4-yl)oxy)-3-methylcyclobutyl)(methyl)carbamate tert-butyl

[0981]

[0982] In a 100-mL single-necked round-bottom flask equipped with a condenser under a nitrogen atmosphere, 6.8 mL of 1 M potassium disilicide in THF was added to a solution of ((1s,3s)-3-hydroxy-3-methylcyclobutyl)carbamate tert-butyl ester (500 mg, 2.48 mmol) in dioxane (25 mL) at room temperature. After 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 suspension. After 30 minutes, 105 μL of iodomethane (240 mg, 1.70 mmol) 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], containing 2% NH4OH modifier, in heptane) to give the title compound (555 mg, 67% yield) as a beige solid. LCMS m / z = 367.1(M+H)+.

[0983] Synthesis of tert-butyl 4-(4-((1s,3s)-3-((tert-butoxycarbonyl)(methyl)amino)-1-methylcyclobutoxy)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-carboxylic acid

[0984]

[0985] Pd-PEPPSI was sequentially added to a solution of ((1s,3s)-3-((6-chloropyrazolo[1,5-a]pyrazin-4-yl)oxy)-3-methylcyclobutyl)(methyl)carbamate tert-butyl ester (500 mg, 1.36 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)pyrazol-1-carbamate tert-butyl ester (802 mg, 2.73 mmol) in dioxane (15 mL). TM-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 min. After heating under reflux for 1 hour, 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 Na2SO4, and concentrated under reduced pressure. The crude residue was purified by column chromatography (40 g silica gel, 0-60% [3:1 EtOAc:EtOH], containing 2% NH4OH modifier, in heptane) to give the title compound (640 mg, 94% yield) as an orange gel. LCMS m / z = 499.2(M+H)+.

[0986] Synthesis of (1s,3s)-3-((6-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)-N,3-dimethylcyclobut-1-amine

[0987]

[0988] TFA (374 mg, 3.3 mmol, 250 μL) was added to a solution of tert-butyl 4-(4-((1s,3s)-3-((tert-butoxycarbonyl)(methyl)amino)-1-methylcyclobutoxy)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-1-carboxylate (360 mg, 0.72 mmol) in HFIP (5 mL) at room temperature. The resulting reaction mixture was stirred for 2 hours. Ethyl acetate (20 mL) was added at room temperature, followed by saturated aqueous solution of NaHCO3 (10 mL) and brine (10 mL). After vigorous stirring for 30 minutes, the organic phase was separated, dried over sodium sulfate, filtered, and concentrated. The 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) as a colorless gel. LCMS m / z=299.0(M+H)+.

[0989] Synthesis of N-((1s,3s)-3-((6-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)-3-methylcyclobutyl)-N-methylacrylamide

[0990]

[0991] Acryloyl chloride (54 mg, 0.60 mmol, 50 μL) was added to a solution of (1s,3s)-3-((6-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)-N,3-dimethylcyclobut-1-amine (162 mg, 0.54 mmol) and DIPEA (211 mg, 1.63 mmol, 290 μL) in THF (5 mL) at 0 °C. After 30 minutes, the reaction mixture was diluted with EtOAc (20 mL) and a saturated aqueous solution of NaHCO3 (20 mL) was added. The two-phase mixture was allowed to reach room temperature and stirred vigorously 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 residue was purified by column chromatography (12 g silica gel, 0-100% [3:1 EtOAc:EtOH], containing 2% NH4OH modifier, in heptane) to give the title compound (65 mg, 34% yield) as a colorless solid. LCMS m / z = 375.1 (M+Na)+. 1 H NMR (500MHz, methanol-d4) δppm 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).

[0992] Example 81 .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

[0993]

[0994] 1. Synthesis of tert-butyl 3-(2-((methanesulfonyl)oxy)ethyl)morpholine-4-carboxylate

[0995]

[0996] TEA (1.1 equivalents) was added to a solution of 6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-ol (1.0 equivalents) in anhydrous DCM (10 mL), followed by the addition of methanesulfonyl chloride (1.05 equivalents), and the reaction mixture was stirred for 14 hours. The mixture was washed with H2O (10 mL), dried over Na2SO4, filtered, and concentrated under vacuum to obtain a crude product, which was used directly in the next step.

[0997] 2. Synthesis of tert-butyl 3-(2-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)ethyl)morpholine-4-carboxylic acid

[0998]

[0999] A mixture of 6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-ol (intermediate C, step 2, 1.0 equivalent), Cs₂CO₃ (1.1 equivalent), and 3-(2-(((methanesulfonyl)oxy)ethyl)morpholino-4-carboxylic acid tert-butyl ester (1.0 equivalent) in anhydrous DMF (1 mL) was heated at 100 °C for 16 hours. The reaction mixture was diluted with H₂O (10 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over Na₂SO₄, filtered, and concentrated under vacuum to give a crude product, which was used directly in the next step.

[1000] 3. Synthesis of 3-(2-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)ethyl)morpholine hydrochloride

[1001]

[1002] A solution of tert-butyl morpholine-4-carboxylate (1 equivalent) in DCM (10 mL) was added to a solution containing 4 M HCl and stirred at 25 °C for 14 hours. 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)pyrazol[1,5-a]pyridin-4-yl)oxy)morpholine hydrochloride.

[1003] 4. Synthesis of 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

[1004]

[1005] DIPEA (1.1 equivalents) was added to a solution of 3-(2-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)ethyl)morpholine hydrochloride (1 equivalent) in DCM (10 mL). The mixture was cooled to -10 °C, acryloyl chloride (1.05 equivalents) was added, and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was washed with water (10 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was dissolved in DMSO (0.5 mL) and purified by preparative HPLC (Waters SunFire C1819*100 5 mkm column) to give 10.2 mg of 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. LCMS m / z=382.2(M+H)+. 1H NMR(400MHz, CDCl3)δppm: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 ,1.8Hz,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)

[1006] 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

[1007]

[1008] Following the steps described in Example 81, N-(5-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-ol, intermediate C, step 2) and (5-hydroxybicyclo[2.2.1]hept-2-yl)carbamate tert-butyl ester were obtained. LCMS m / z = 378.2(M+H)+. 1H NMR (400MHz, CDCl3) δppm: 8.27 (s, 1H), 7.89 (d, J = 2.4Hz, 1H), 7.72 (s, 1H), 7.59 (s, 1H), 6. 58(d,J=2.5Hz,1H),6.43(s,1H),6.25(d,J=16.8Hz,1H),6.07(dd,J=17.0,10.2Hz,1H),5. 83(d,J=7.3Hz,1H),5.61(d,J=10.3Hz,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=13.3,13.3Hz,2H),1.73-1.59(m,4H)

[1009] 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

[1010]

[1011] Following a method similar to that described in Example 81, (R)-1-(2,2-dimethyl-6-(((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)methyl)N-morpholino)prop-2-en-1-one was obtained from (R)-6-(hydroxymethyl)-2,2-dimethyl-6-(((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)methyl)N-morpholino)prop-2-en-1-one. LCMS m / z = 396.2(M+H)+. 1H NMR(400MHz,MeOH-d4)δppm:8.36(s,1H),8.01(s,1H),7.88(s,1H),7.86(d,J =2.4Hz,1H),6.91-6.72(m,2H),6.66(s,1H),6.29(dd,J=16.9,8.1Hz,1H),5.8 1(dd,J=11.0,5.6Hz,1H),4.54(dd,J=142.3,13.0Hz,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)

[1012] Examples 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

[1013]

[1014] 1. Synthesis of tert-butyl 6-(((methanesulfonyl)oxy)methyl)-3-azabicyclo[3.1.1]heptane-3-carboxylate

[1015]

[1016] Methanesulfonyl chloride (0.72 g, 6.29 mmol) was added to a solution of 6-(hydroxymethyl)-3-azabicyclo[3.1.1]heptane-3-carboxylic acid tert-butyl ester (1 g, 4.40 mmol) and TEA (1.34 g, 13.2 mmol) in DCM (20 mL), and the r...

Claims

1. A compound represented by formula (I'), (I')， Or its pharmaceutically acceptable salt, wherein: Het is phenyl, 5-6-membered heteroaryl or N-(C1-C3 alkyl)pyridinone group; X 0 For CR 0 X 1 Let C and X be the values ​​of C and X respectively. 2 For N and X 4 Let N be the number of people in the group. R 0 It can be H, halogen, methyl, halomethyl, cyclopropyl, CN, or phenyl; R 1 It is H or C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl or 4-7 membered monocyclic oxygen-containing heterocycle; R 3 It is an H or a halogen group; X 3 It does not exist, and is CH2, CH2CH2, O, O-CH2*, O-CH2CH2*, NH, N(CH3), CH2N(CH3)-*, or NH-CH2*, where "*" indicates the presence of R. 2 The connection point; When X 3 When R does not exist, is CH2 or CH2CH2, 2 It is bonded to the double-ring nucleus or X-linked ring via nitrogen atom ("N-link") 3 4-12 membered monocyclic or bicyclic nitrogen-containing heterocycles; when X 3 When R is CH2, CH2CH2, O, O-CH2*, NH, N(CH3), CH2N(CH3)-* or NH-CH2*, 2 To bond to X via a ring carbon atom ("C-link") 3 4-12 membered monocyclic or bicyclic nitrogen-containing heterocycles, 4-7 membered monocyclic or bicyclic oxygen-containing heterocycles, 3-12 membered monocyclic or bicyclic carbocyclic groups, or 5-6 membered heteroaryl groups; and when X 3 When it is O-CH2-CH2*, R 2 It does not exist; it is bonded to X via a ring carbon atom ("C-link"). 3 4-12 membered monocyclic or bicyclic nitrogen-containing heterocycles, or C1-C3 alkyl groups, provided that R 2 When X does not exist, 3 Directly connected to R 4 ; By R 2 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 R 4 The indicated group is substituted and optionally further replaced by one to three groups derived from R. 10 The group substitution is indicated when the N-linked 4-12 membered monocyclic or bicyclic nitrogen-containing heterocycle contains two cyclic nitrogen atoms, as determined by R. 2 The N-linked 4-12-membered monocyclic or bicyclic nitrogen-containing heterocycles represented are optionally replaced by R 5 The indicated group is substituted and optionally further replaced by one or two groups derived from R. 10 The group to be represented is substituted; The C-linked 4-12 member monocyclic or bicyclic nitrogen-containing heterocycle is R 5 The indicated group is N-substituted and optionally further substituted by one to three R groups. 10 The group to be represented is substituted; R 4 for , , , , , or ; R 5 for , , , , , or ; Each R 6 Independently H, CN, C1-C3 alkyl, C1-C3 haloalkyl, N(R) a )2 or CH2N(R a )2, where each R a Independently, it is H, C1-C3 alkyl, or C3-C6 cycloalkyl; Each R 6 'Independently H, C1-C3 alkyl, C1-C3 haloalkyl or C3-C6 cycloalkyl; Each R 7 It can be independently H, C1-C2 alkyl, C1-C2 fluoroalkyl, or C3-C6 cycloalkyl; R 8 It is H or C1-C3 alkyl; Each R 10 It is a halogenated group, a C1-C3 alkyl group, or a C3-C6 cycloalkyl group; R 11 For H or N(R) 12 )2; Each R 12 Independently, it is H or C1-C3 alkyl; R 13 It can be CN or F; R 14 It is a halogenated group; 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, wherein the compound is represented by formula (I): (I)， Or its pharmaceutically acceptable salt, wherein: R 0 It can be H, halogen, methyl, halomethyl, cyclopropyl, or CN; X 3 It does not exist; it is CH2, CH2CH2, O, O-CH2*, NH, or NH-CH2*, where "*" indicates the presence of R. 2 The connection point; When X 3 When R does not exist, is CH2 or CH2CH2, 2 It is bonded to the double-ring nucleus or X-linked ring via nitrogen atom ("N-link") 3 4-12 membered monocyclic or bicyclic nitrogen-containing heterocycles; and when X 3 When R is CH2, CH2CH2, O, O-CH2*, NH, or NH-CH2*, 2 To bond to X via a ring carbon atom ("C-link") 3 4-12 membered monocyclic or bicyclic nitrogen-containing heterocycles, 4-7 membered monocyclic or oxygen-containing heterocycles, or 3-12 membered monocyclic or bicyclic carbocyclic groups; By R 2 The N-linked 4-12 member monocyclic or bicyclic nitrogen-containing heterocycles, the 4-7 member oxygen-containing heterocycles, and the 3-12 member monocyclic or bicyclic carbon rings represented by R 4 The indicated group is substituted and optionally further replaced by one or two groups derived from R. 10 The group to be represented is substituted; The C-linked 4-12 member monocyclic or bicyclic nitrogen-containing heterocycle is R 5 The indicated group is N-substituted and optionally further substituted by one or two R groups. 10 The group to be represented is substituted; R 4 for , , or ; R 5 for , , or ; Each R 6 Independently H, C1-C3 alkyl, C1-C3 haloalkyl, N(R) a )2 or CH2N(R a )2, where each R a Independently, it is either H or methyl; Each R 6' It is independently H, C1-C3 alkyl, or C1-C3 haloalkyl; Each R 7 Independently, it is H, C1-C2 alkyl, or C1-C2 fluoroalkyl; and Each R 10 It can be F or methyl.

3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 11 It can be H or NH2.

4. The compound of claim 1, wherein the compound is represented by formula (II): (II), Or its pharmaceutically acceptable salt.

5. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein (R) 1 ) q -Het- is selected from: ; ; ; ; ; ; and .

6. The compound of claim 1, wherein the compound is represented by formula (III): (III), Or its pharmaceutically acceptable salt.

7. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein: X 0 For CH, X 1 Let C and X be the values ​​of C and X respectively. 2 For N and X 4 Let N be the number of people in the group. X 3 It does not exist, and is O, O-CH2*, NH, or NH-CH2*, where "*" indicates that it is related to R. 2 The connection point; When X 3 When it does not exist, R 2 It is bonded to the double-ring nucleus or X-linked ring via nitrogen atom ("N-link") 3 4-12 membered monocyclic or bicyclic nitrogen-containing heterocycles; and when X 3 When R is O, O-CH2* or NH-CH2*, 2 To bond to X via a ring carbon atom ("C-link") 3 4-12 membered monocyclic or bicyclic nitrogen-containing heterocycles, 4-7 membered monocyclic or oxygen-containing heterocycles, or 3-12 membered monocyclic or bicyclic carbocyclic groups; By R 2 The N-linked 4-12 member monocyclic or bicyclic nitrogen-containing heterocycle, the 4-7 member monocyclic oxygen-containing heterocycle, and the 3-12 member monocyclic or bicyclic carbon ring represented by R 4 The indicated group is substituted, and optionally further replaced by one or two groups derived from R. 10 The group to be represented is substituted; The C-linked 4-12 member monocyclic or bicyclic nitrogen-containing heterocycle is R 5 The indicated group is N-substituted and optionally further substituted by one or two R groups. 10 The group substitution is indicated.

8. The compound of claim 1, wherein the compound is represented by formula (V): (V)， Or its pharmaceutically acceptable salt.

9. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein X 3 For key and R 2 It is a 4-12 membered monocyclic or bicyclic nitrogen-containing heterocycle bonded to a bicyclic core via its cyclic nitrogen atom, and is composed of R 2 The 4-12 member monocyclic or bicyclic nitrogen-containing heterocycles represented by R 4 The indicated group is substituted and optionally further replaced by one or two groups derived from R. 10 The group substitution is indicated.

10. The compound of claim 9 or a pharmaceutically acceptable salt thereof, wherein X 3 For key and R 2 It is a 7-10 membered bicyclic nitrogen-containing heterocycle bonded to a bicyclic core via its cyclic nitrogen atom, and is composed of R 2 The 7-10 member bicyclic nitrogen-containing heterocycle represented by R 4 The indicated group is substituted and optionally further replaced by one or two groups derived from R. 10 The group substitution is indicated.

11. The compound of claim 10 or a pharmaceutically acceptable salt thereof, wherein R 2 The 7-10 membered bicyclic nitrogen-containing heterocycle indicated is R 4 The indicated group is substituted and optionally further replaced by R. 10 The group represented is a substituted azaspiro[2,4]heptane subunit.

12. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein X 3 For key and R 2 It is a 4-7 membered monocyclic nitrogen-containing heterocycle bonded to a bicyclic core via its cyclic nitrogen atom, and is composed of R 2 The 4-7 member monocyclic nitrogen-containing heterocycles represented by R 4 The indicated group is substituted and optionally further replaced by R. 10 The group substitution is indicated.

13. The compound of claim 12 or a pharmaceutically acceptable salt thereof, wherein R 2 The 4-7 membered monocyclic nitrogen-containing heterocycles indicated are azapyrocyclic butyl, pyrrolidinyl, piperidinyl, azapyrocyclic heptyl, or oxazolidinyl heptyl, each represented by R. 4 The indicated group is substituted and optionally further replaced by one or two groups derived from R. 10 The group substitution is indicated.

14. The compound of claim 1, wherein the compound is represented by a structural formula selected from the following: and Or its pharmaceutically acceptable salt.

15. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 6 It is H, CH3 or CH2Cl and p is 2.

16. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 4 The values ​​are 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.

17. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 4 The possible values ​​are CH2NHC(O)C≡CH, CH2NHC(O)CH=CH2, N(CH3)C(O)C≡CH, or CH2N(R). 7 )C(O)CH=CHCH2Cl.

18. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein X 3 For O, O-CH2*, O-CH2CH2*, NH, NH-CH2*, N(CH3) or CH2N(CH3)-*, R 2 To bond to X via a ring carbon atom ("C-link") 3 The 4-12 member monocyclic or bicyclic nitrogen-containing heterocycle, and the C-linked 4-12 member nitrogen-containing heterocycle is R 5 The indicated group is N-substituted and optionally further substituted by one to three R groups. 10 The group substitution is indicated.

19. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein X 3 For O, O-CH2*, NH or NH-CH2*, R 2 To bond to X via a ring carbon atom ("C-link") 3 The 4-12 member nitrogen-containing heterocycle, and the C-linked 4-12 member nitrogen-containing heterocycle is R 5 The indicated group is N-substituted and optionally further substituted by one or two R groups. 10 The group substitution is indicated.

20. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein X 3 It is O or O-CH2*.

21. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 The C-linked 4-12-membered nitrogen-containing heterocycle indicated is optionally 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 one epoxide or one cyclic sulfur atom, and is composed of R 2 The C-linked 4-12-membered nitrogen-containing heterocycle represented by R 5 The indicated group is N-substituted and optionally further substituted by one or two R groups. 10 The group substitution is indicated.

22. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 The C-linked 4-12 nitrogen-containing heterocycles represented are azaspiro[3.3]heptanediol, azaspiro[3.5]nonanediol, azaspiro[4.4]nonanediol, azaspiro[3.4]octanediol, azahexacyclic butyl, pyridinediol, piperidinyl, azahexacyclic heptyl, diazaheptyl, morpholinyl, octahydrocyclopentadien[c]pyrrolediol, oxazolidinyl heptyl, azabicyclo[3.2.0]heptanediol, azabicyclo[2.2.1]heptanediol, Azabicyclo[3.1.1]heptane, azabicyclo[3.2.1]octane, azabicyclo[4.2.0]octane, azatricyclo[4.1.1.03,7]octane, azabicyclo[3.2.0]heptane, azabicyclo[2.1.1]heptane, azabicyclo[2.1.1]hexane, azabicyclo[3.1.0]hexane, 2λ2-azaspiro[3.4]octane or octahydrocyclopentadien[c]pyrrole, and composed of R 2 The C-linked 4-12-membered nitrogen-containing heterocycle represented by R 5 The indicated group is N-substituted and optionally further substituted by one or two R groups. 10 The group substitution is indicated.

23. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 The C-linked 4-12 nitrogen-containing heterocycles represented are azapyrocyclobutane, pyridine, piperidinyl, azapyrocycloheptane, azapyrocycloheptane, azabicyclo[3.2.1]octane, azatricyclo[4.1.1.03,7]octane, azabicyclo[3.2.0]heptane, azabicyclo[3.1.0]hexane, 2λ2-azaspiro[3.4]octane, or octahydrocyclopentadien[c]pyrrole, and are composed of R 2 The C-linked 4-12-membered nitrogen-containing heterocycle represented by R 5 The indicated group is N-substituted and optionally further substituted by one or two R groups. 10 The group substitution is indicated.

24. The compound of claim 22 or a pharmaceutically acceptable salt thereof, wherein R 2 The C-linked 4-12 member monocyclic or bicyclic nitrogen-containing heterocycles represented are selected from: , , , , , , , , , , , , , , , , , , , , , , , , , , , and The "**" indicates the relationship with X. 3 The connection point; and "***" indicates the connection with R. 5 The connection point, where R is the connection point. 2 Each group represented may optionally be further defined by one or two R groups. 10 The group substitution is indicated.

25. The compound of claim 23 or a pharmaceutically acceptable salt thereof, wherein R 2 The C-linked 4-12 member monocyclic or bicyclic nitrogen-containing heterocycles represented are selected from: , , , , , , , , , , , and The "**" indicates the relationship with X. 3 The connection point; and "***" indicates the connection with R. 5 The connection point, where R is the connection point. 2 Each group represented may optionally be further defined by one or two R groups. 10 The group substitution is indicated.

26. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the bond to X 3 by R 2 The stereochemical configuration of the cyclic carbon atom in the C-linked 4-12 member nitrogen-containing heterocycle is represented by R.

27. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the bond to X 3 by R 2 The stereochemical configuration of the ring carbon atom in the C-linked 4-12 member nitrogen-containing heterocycle is represented as S.

28. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 6 and R 6 'Independently H, CH3 or CH2Cl and p is 2.' 29. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 5 For 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 .

30. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 5 For 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 or COCF=CHCH2Cl.

31. The compound of claim 30 or a pharmaceutically acceptable salt thereof, wherein R 5 The possible values ​​are SO2CH=CH2, SO2CH=CHCH3, COCH=CH2, COCF=CH2, COCH=CHCH2Cl, CO-C≡CH, or CO-C≡CCH3.

32. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein X 3 For O, O-CH2*, NH or NH-CH2*, R 2 It is a 3-12 membered monocyclic or bicyclic carbocyclic group, a 4-7 membered monocyclic or bicyclic oxygen-containing heterocyclic group, or a 5-6 membered heteroaryl group, and is composed of R 2 The 3-12 member monocyclic or bicyclic carbocyclic rings, the 4-7 member monocyclic or bicyclic oxygen-containing heterocycles, and the 5-6 member heteroaryl groups represented by R 4 The indicated group is substituted and optionally further replaced by one to three groups derived from R. 10 The group substitution is indicated.

33. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein X 3 For O, O-CH2*, NH or NH-CH2*, R 2 It is a 4-7 membered monocyclic or bicyclic oxygen-containing heterocycle or a 5-6 membered heteroaryl group, and is composed of R 2 The 4-7 member monocyclic or bicyclic oxygen-containing heterocycles and the 5-6 member heteroaryl groups represented by R 4 The indicated group is substituted and optionally further replaced by one to three groups derived from R. 10 The group substitution is indicated.

34. The compound of claim 33 or a pharmaceutically acceptable salt thereof, wherein the 4-7 membered monocyclic or bicyclic oxyheterocyclic ring is an oxabicyclo[3.1.1]heptane subunit or a tetrahydro-2H-pyran subunit, each being R 4 The indicated group is substituted and optionally further replaced by one or two groups derived from R. 10 The indicated group is substituted; and the 5-6 membered heteroaryl group is replaced by R. 4 The indicated group is substituted and optionally further replaced by one to three groups derived from R. 10 The group represented is a pyridyl group that has been substituted.

35. The compound of claim 33 or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from: , and , Each was R 4 The indicated group is substituted and optionally further replaced by one or two groups derived from R. 10 The group substitution is indicated.

36. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein X 3 For O, O-CH2*, NH or NH-CH2*, R 2 It is a 3-12 member monocyclic or bicyclic carbocyclic group, and is composed of R 2 The 3-12 cyclic monocyclic or bicyclic carbon rings represented by R 4 The indicated group is substituted and optionally further replaced by one or two groups derived from R. 10 The group substitution is indicated.

37. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein X 3 It is O or O-CH2*.

38. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 It is a phenylene, C3-C7 cycloalkylene, or C6-C9 bicyclic saturated carbon ring, and is composed of R 2 The phenylene, the C3-C7 cycloalkylene, and the C6-C9 bicyclic saturated carbon ring represented by R 4 The indicated group is substituted and optionally further replaced by one or two groups derived from R. 10 The group substitution is indicated.

39. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 For R 4 The indicated group is substituted and optionally further replaced by one or two groups derived from R. 10 The indicated group is a substituted phenylene or a C4-C7 cycloalkylene group.

40. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein X 3 It is O.

41. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 It is phenylene, cyclobutylene, cyclohexylene, cyclopentylene, cyclopropylene, bicyclo[3.3.1]heptanediol, bicyclo[2.2.1]heptanediol, bicyclo[4.1.0]heptanediol, or bicyclo[2.1.1]hexanediol, each of which is R 4 The indicated group is substituted and optionally further replaced by one or two groups derived from R. 10 The group substitution is indicated.

42. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 For R 4 The indicated group is substituted and optionally further replaced by one or two groups derived from R. 10 The group represented is a substituted phenylene, cyclobutylene, cyclohexylene, or bicyclic [3.3.1]heptane subunit.

43. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 for , , , , , , , , , or The "**" indicates the relationship with X. 3 The connection point; and "***" indicates the connection with R. 4 The connection point, where R is the connection point. 2 The indicated group is optionally represented by one or two R groups. 10 The group substitution is indicated.

44. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 for , , or , of which R 2 The indicated group is optionally represented by one or two R groups. 10 The group substitution is indicated.

45. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 6 It can be H, CN, CH3, CH2Cl, CF3 or CH2N(R) a )2 and R 6’ It can be H, CH3, CH2Cl, CF3, or cyclopropyl.

46. ​​The compound of claim 45 or a pharmaceutically acceptable salt thereof, wherein R a Each is independently selected from -CH3 and cyclopropyl.

47. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 6 and R 6 It can be H, CH3 or CH2Cl independently.

48. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 4 For 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=CHCH3, 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.

49. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 4 For NHCOCH=CH2, N(CH3)COCH=CH2, NHCOCH=CHCH3, N(CH3)COCH=CHCH3, N(H)COC≡CH, N(CH3)COC≡CH, N(H)COC≡CCH 3. N(CH3)COC≡CCH3, N(CH2CH2F)COCH=CH2, N(CH2CH2F)COCH=CHCH3, N(CH2CH2F)COC≡CH or N(CH2CH2F)COC≡CCH3.

50. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 4 It is NHC(O)C≡CH, NHC(O)C≡CCH3, NHC(O)CH=CH2, N(CH3)COCH=CH2, N(CH3)COC≡CCH3 or N(CH2CH2F)COCH=CH2.

51. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the bond to X 3 by R 2 The stereochemical configuration of the cyclic carbon atom in the C-linked 3-12-membered carbon ring is represented by R.

52. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the bond to X 3 by R 2 The stereochemical configuration of the cyclic carbon atom in the C-linked 3-12 membered carbon ring is represented as S.

53. The compound of claim 36 or a pharmaceutically acceptable salt thereof, wherein X 3 and R 4 The orientation is reversed.

54. The compound of claim 36 or a pharmaceutically acceptable salt thereof, wherein X 3 and R 4 The orientation is cis.

55. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein X 3 It is O-CH2CH2*, and R 2 For R 4 The indicated group is substituted and optionally further replaced by one or two groups derived from R. 10 The group represented is a C1-C3 alkyl group substituted with R. 2 It does not exist and X 3 Directly connected to R 4 .

56. The compound of claim 55 or a pharmaceutically acceptable salt thereof, R 2 Selected from -CH2- , -CH2CH(CH3)- ,in" "Indicates with X" 3 The connection point, and " "Indicates to R" 4 The connection point.

57. The compound of claim 56 or a pharmaceutically acceptable salt thereof, wherein R 4 It is N(CH3)C(O)CH=CH2.

58. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 It is H or C1-C3 alkyl, C1-C3 fluoroalkyl or 4-7 membered monocyclic oxygen-containing heterocycle.

59. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 It can be H, CH3, CH(CH3)2, CHF2, CF3, oxetane, or tetrahydrofuranyl.

60. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 It can be H, CH3, CH(CH3)2, CHF2, oxocyclic butyl or tetrahydrofuranyl.

61. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 0 It can be H, F, CN, CH3, CF3, cyclopropyl, or phenyl.

62. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 0 It can be H, F, CN, CH3 or CF3.

63. The compound of any one of claims 1-62 or a pharmaceutically acceptable salt thereof, wherein R 7 Selected from H, CH3, CH2CH3, CH2CHF2 and cyclopropyl.

64. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 8 It can be H or CH3.

65. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 10 It can be F, Cl, CH3 or cyclopropyl.

66. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 14 It is Cl.

67. The compound of claim 1, wherein the compound is represented by formula (XV): (XV), Or its pharmaceutically acceptable salt, wherein: R 0 It can be H, a halogenated group, or a cyclopropyl group; X 3 It is O or O-CH2*; R 2 It is a 4-7 member monocyclic or bicyclic saturated carbocyclic group, and is composed of R 2 The 4-7 cyclic monocyclic or bicyclic saturated carbocyclic group represented by R 4 The indicated group is substituted and optionally further replaced by one or two R groups. 10 Replace, or R 2 To bond to X via a ring carbon atom ("C-link") 3 The 7-9 member bicyclic nitrogen-containing heterocycle, and the C-linked 7-9 member bicyclic nitrogen-containing heterocycle is R 5 The indicated group is substituted and optionally further replaced by one or two R groups. 10 replace; R 4 For N(R) 7 C(O)C≡CCH3、N(R) 7 C(O)CH=CH2, R 5 For C(O)CH=CH2, R 7 It is H, C1-C2 alkyl, or C1-C2 haloalkyl; and R 10 It is a C1-C3 alkyl group.

68. The compound of claim 67 or a pharmaceutically acceptable salt thereof, wherein X 3 It is O.

69. The compound of claim 67 or a pharmaceutically acceptable salt thereof, wherein R 2 It is a cyclobutylene, cyclohexylene, cyclopentylene, or bicyclic [2.1.1]hexane subunit, each of which is R 4 The indicated group is substituted and optionally further replaced by one or two R groups. 10 replace.

70. The compound of claim 67 or a pharmaceutically acceptable salt thereof, wherein R 2 for , , or , of which R 2 The indicated group is optionally further defined by one or two R groups. 10 The group substitution is indicated.

71. The compound of claim 67 or a pharmaceutically acceptable salt thereof, wherein R 2 It is an azirbicyclo[3.2.1]octane subunit, an azirbicyclo[3.1.1]heptane subunit, or an azirbicyclo[3.2.0]heptane subunit, each of which is R 5 The indicated group is substituted and optionally further replaced by one or two R groups. 10 replace.

72. The compound of claim 71 or a pharmaceutically acceptable salt thereof, wherein R 2 for , or The "**" indicates the relationship with X. 3 The connection point; and "***" indicates the connection with R. 5 The connection point, where R is the connection point. 2 Each group represented may optionally be further defined by one or two R groups. 10 The group substitution is indicated.

73. The compound of claim 67 or a pharmaceutically acceptable salt thereof, wherein R 7 It can be H, CH3 or CH2CHF2.

74. The compound of claim 67 or a pharmaceutically acceptable salt thereof, wherein R 10 It is CH3.

75. A pharmaceutical composition comprising the compound of any one of claims 1-74 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

76. Use of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-74, or the pharmaceutical composition according to claim 75, in the preparation of a medicament for treating a condition responsive to Bruton's tyrosine kinase inhibition.

77. The use as described in claim 76, wherein the condition is an autoimmune disease.

78. The use as described in claim 77, wherein the autoimmune disease is rheumatoid arthritis.

79. The use as described in claim 77, wherein the autoimmune disease is systemic lupus erythematosus.

80. The use as claimed in claim 76, wherein the condition is atopic dermatitis.

81. The use as described in claim 76, wherein the disease is leukemia or lymphoma.

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