Substituted 1H-imidazo[1,2-b]pyrazole-3-carboxamides as Bruno's tyrosine kinase inhibitors

Abstract

The present application discloses a substituted 1H-imidazo[1,2-b]pyrazole-3-carboxamide compound represented by Formula I as a kinase inhibitor, particularly a Bruno's tyrosine kinase (BTK) inhibitor, a preparation method thereof, and the use of the compound in treating autoimmune diseases, inflammatory diseases, cancer, and potential allergies. #imgabs0#

Description

Technical Field

[0001] The present invention relates to a series of substituted 1H-imidazo[1,2-b]pyrazole-3-carboxamide compounds of formula I as kinase inhibitors, particularly Bruno's Tyrosine Kinase (BTK) inhibitors, and methods for their preparation and use in the treatment of autoimmune diseases, inflammatory diseases, cancer and potential allergies.

[0002] Background Art

[0003] Bruno's tyrosine kinase (BTK) is a non-receptor tyrosine kinase belonging to the Tec family (Bradshaw et al, Cell Signal, 2010, 22, 1175-184). It plays an important role in the maturation of B cells, bone marrow cells, mast cells and platelets. BTK is an essential kinase in the B cell receptor (BCR) signaling pathway and is the driving force of CLL and other B cell malignancies (Treon SP et al, New England journal of Medicine, 2015, 373, 584-586; Treon SP et al, New England journal of Medicine, 2015, 372, 1430-1440; Cao Y et al, British Journal of Haematology, 2015, 170, 134-138; Carrie J Li et al, Molecular Cancer Therapeutics, 2018). It is mainly expressed in hematopoietic cells such as B cells, mast cells and macrophages, and is present in tissues including bone marrow, lymph nodes and spleen. They participate in signal transduction caused by almost all types of extracellular stimuli transmitted by growth factor receptors, cytokine receptors, G-protein coupled receptors, antigen-receptors and integrins (Qiu et al, Oncogene, 2000, 19, 5651-5661). Structurally, it is characterized by having a pleckstrin homology domain, a Src homology 3 domain, a Src homology 2 domain and a Src homology 1 domain (kinase domain). The pleckstrin homology domain binds to phosphatidylinositol (3,4,5)-triphosphate (PIP3), inducing BTK to phosphorylate phospholipase Cγ, which then hydrolyzes phosphatidylinositol 4,5-bisphosphate (PIP2) into two second messengers, inositol triphosphate (IP3) and diacylglycerol (DAG), thereby regulating downstream B cell signaling. Abnormal BTK activation is the main cause of autoimmune diseases such as rheumatoid arthritis, osteoporosis, and lupus, and is associated with many cancers. BTK gene mutations are directly associated with the immunodeficiency disease X-linked agammaglobulinemia (XLA). Patients with this disease have immature B cells in the bone marrow, but they do not mature further and enter the circulation.

[0004] Several small molecule BTK inhibitors have been reported. As a first-generation BTK inhibitor, ibrutinib (Structure A, Lee A. Honigberg et al, Proceedings of the National Academy of Sciences of the United States of America, 2010, 107, 13075-13080) has been used clinically to treat chronic lymphocytic leukemia (CLL), mantle cell lymphoma and Waldenstrom macroglobulinemia (Novero A et al, Experimental Hematology & Oncology, 2014, 3, 1-7; Treon SP et al, New England journal of Medicine, 2015, 372, 1430-40; Wang ML et al, New England journal of Medicine, 2013, 369, 507-16; Brown JR et al, Blood, 2015, 125, 2915-22). However, ibrutinib has been shown to have some adverse side effects, such as vomiting, nausea, bleeding, rash, diarrhea, and atrial fibrillation, some of which are severe. These adverse reactions are partly due to its off-target effects on epidermal growth factor receptor and Tec family proteins other than BTK (Schwartzberg PL et al, Nature Reviews Immunology, 2005, 5, 284-295; Byrd JC et al, New England journal of Medicine, 2013, 369, 32-42; Rai K, Journal of Hematology & Oncology, 2015, 8, 85; Treon SP et al, New England journal of Medicine, 2015, 372, 1430-1440; Brown JR et al, Blood, 2015, 125, 2915-2922; Wu JJ et al, Journal of Hematology & Oncology, 2016, 21, 2-4). Based on these findings, more selective BTK inhibitors are being explored.

[0005] Acalabrutinib (ACP-196, structure B, Barf et al, Journal of Pharmacology and Experimental Therapeutics, 2017, 363, 240-252; Robert B. Kargbo, ACS Medicinal Chemistry Letters, 2017, 8, 911-913) is a novel, irreversible, second-generation BTK inhibitor that is more selective than ibrutinib (Covey T et al, Cancer Research, 2015, 75, 2596; Wu J et al, Journal of Hematology & Oncology, 2016, 9, 21).

[0006] ONO / GS-4059 (Structure C) is another novel, highly potent and selective BTK inhibitor. Its antitumor activity has been studied in preclinical models (Yasuhiro T et al, Cancer Research, 2013, 73, 2452) and clinical trials for the treatment of B-cell malignancies (Dyer M HC et al, Journal of Clinical Oncology, 2014, 32, 8553; Rule S SN et al, Blood, 2013, 122, 4397; Jones R et al, Blood, 2015, 126, 1749).

[0007] Zanubrutinib (BGB-3111, structure D, WO2014 / 173289A1; WO2018 / 137681A1; Guo YH et al, Journal of Medicinal Chemistry, 2019, 62, 7923-7940) is another more selective and investigational second-generation irreversible BTK inhibitor reported. Compared with ibrutinib, it has good oral bioavailability and lower off-target inhibitory activity (Tam C et al, Blood, 2015, 126, 832; Na L et al, Cancer Research, 2015, 75, 2597).

[0008] Several other candidates (Bradshaw et al. Nat Chem Biol, 2015, 11(7), 525-531; US9447106 B2; CN103848810 A1) are in various stages of clinical trials and are being tested for a variety of diseases, including cancer and autoimmune diseases. All of these indicate that BTK inhibitors can be used to treat a variety of diseases, including cancer, allergies, and autoimmune diseases.

[0009] Summary of the Invention

[0010] The present invention describes compounds that are inhibitors of protein kinases, particularly BTK, and that can be used to treat autoimmune diseases, inflammatory diseases, cancer, and allergies.

[0011] In one aspect, the present invention provides a compound represented by Formula I or a pharmaceutically acceptable salt, active metabolite, tautomer, stereoisomer or prodrug thereof:

[0012]

[0013] in

[0014] R1 is selected from H, C 1-6 Alkyl and C 1-6 Cycloalkyl;

[0015] R2 and R3 are independently selected from hydrogen; halogen; cyano; CF3; aryl, independently hydrogen, -NR6Y, cyano, C 1-6 Alkoxy, F-substituted C 1-6 Alkyl substituted aryl; heteroaryl, independently substituted by halogen, -NR6Y; cyano, C 1-6 Alkoxy, F-substituted C 1-6 Alkyl-substituted heteroaryl; nitrogen-containing C 4-7 Heterocycloalkyl, wherein the N atom is substituted by Y; C 1-6 Alkyl; C 1-6 Alkoxy, NR6Y substituted C 1-6 Alkyl; C 3-6 Cycloalkyl, C substituted by NR6Y 3-6 Cycloalkyl; or R2 and R3 may together form a 5-8 membered saturated carbon ring, which may be substituted by NR6Y or the ring contains a nitrogen atom substituted by Y; or R2 and R3 together form an aromatic ring such as a benzene ring, which is independently substituted by halogen, cyano, CF3, C 1-6 Alkyl, C 1-6 Alkoxy and NR6Y substitution;

[0016] R6 is selected from hydrogen; C 1-6 Alkyl; selected from F, hydroxy and C1-6 Alkoxy substituted C 1-6 Alkyl; C 3-6 Cycloalkyl; C substituted by F 3-6 Cycloalkyl;

[0017] Y is selected from -CN, -C(=O)P, -S(=O)P and -S(=O)2P; wherein

[0018] P is selected from and

[0019] Rx is selected from H, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, phenyl, -(CH2) m NR 10 R 11 , C substituted by halogen or hydroxyl 1-6 alkyl;

[0020] m is an integer selected from 1, 2, and 3;

[0021] R7 is selected from hydrogen; halogen; cyano; C 1-6 Alkyl; selected from F, hydroxy and C 1-6 Alkoxy substituted C 1-6 Alkyl; C 3-6 Cycloalkyl; C substituted by F 3-6 Cycloalkyl;

[0022] R8 and R9 are independently selected from hydrogen; halogen; cyano; CF3; aryl; independently hydrogen, halogen, cyano, C 1-6 alkyloxy and CF3 substituted aryl; heteroaryl; independently hydrogen, halogen, cyano, C 1-6 Alkoxy and CF3 substituted heteroaryl; C 1-6 Alkyl; C 1-6 Alkoxy, NR 10 R 11 , halogen, hydroxyl, C6 or C 10 Aryl, and heteroaryl substituted C 1-6 Alkyl; C 3-6 Cycloalkyl; C substituted by halogen 3-6 Cycloalkyl; C 2-6 Alkenyl; C 1-6 Alkoxy, NR 10 R 11 , halogen, hydroxyl, C6 or C 10 Aryl, and heteroaryl substituted C 2-6 alkenyl;

[0023] R 10 and R 11are each independently selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl; or together with the nitrogen they replace form a 4-6 membered heterocycloalkyl;

[0024] R4 is selected from aryl, C 1-6 Alkyl, (C 1-4 ) fluoroalkyl, C 3-6 Cycloalkyl; independently substituted by halogen, cyano, C 1-6 Alkoxy, (C 1-4 ) aryl substituted with fluoroalkyl;

[0025] R5 can be substituted at any suitable position on the phenyl ring to which it is attached and is selected from hydrogen, halogen, (C 1-4 ) fluoroalkyl, cyano, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy.

[0026] In one embodiment, in Formula I, R1 is H or methyl; the remaining groups are as defined above.

[0027] In one embodiment, in Formula I:

[0028] R1 is H;

[0029] R2 is selected from:

[0030]

[0031] where R 12 Independently selected from H, F, C 1-6 Alkyl; halogen, C 1-6 Alkoxy and NR6R7 substituted C 1-6 alkyl; and R 12 can be substituted at more than one position; or in the case of a heterocycle, R 12 A double bond can be formed in the ring, or a fused or spiro 3-6 membered ring can be formed with the original ring;

[0032] R3 is H;

[0033] R4 is C 1-6 Alkyl, C 1-6 Cycloalkyl or

[0034]

[0035] in

[0036] R 13 、R 14 、R 15 、R 16 and R 17independently selected from H; halogen; CN; C 1-6 Alkyl; C 1-6 Alkoxy; C substituted by halogen 1-6 alkyl;

[0037] R5 is H;

[0038] R6 is selected from hydrogen; C 1-6 Alkyl; selected from F, hydroxy and C 1-6 Alkoxy substituted C 1-6 Alkyl; C 3-6 Cycloalkyl; C substituted by F 3-6 Cycloalkyl.

[0039] R7 is selected from hydrogen; halogen; cyano; C 1-6 Alkyl; selected from F, hydroxy and C 1-6 Alkoxy substituted C 1-6 Alkyl; C 3-6 Cycloalkyl; C substituted by F 3-6 Cycloalkyl;

[0040] In another embodiment, in Formula I:

[0041] R1 is H;

[0042] R2 is selected from:

[0043]

[0044] R3 is H;

[0045] R4 is:

[0046]

[0047] in

[0048] R 13 、R 14 、R 15 、R 16 and R 17 Independently selected from H, OCH3, F, Cl, Br, CF3 and CN;

[0049] The remaining groups are as defined above.

[0050] In another embodiment, in Formula I:

[0051] R1 is H;

[0052] R2 is selected from:

[0053]

[0054] Y is -C(=O)P; wherein

[0055] P is selected from and

[0056] R7 is selected from hydrogen, cyano and CF3;

[0057] R8 and R9 are independently selected from hydrogen, CF3, CH3, cyclopropyl and NR 10 R 11 Substituted C 1-6 alkyl;

[0058] Rx is selected from H, CH3, CF3, cyclopropyl and -(CH2) m NR 10 R 11 ,in

[0059] R 10 and R 11 are each independently selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl; or together with the nitrogen they replace form a 4-6 membered heterocycloalkyl;

[0060] m is an integer selected from 1, 2, and 3;

[0061] R3 is H and R4 is phenyl;

[0062] R5 is H.

[0063] In another embodiment, in Formula I:

[0064] R1 is H;

[0065] R2 and R3 together with the double bond they replace form a nitrogen-containing heterocycloalkyl group, wherein the N atom is substituted by Y (Formula II); or form a benzene ring, which is substituted by NR6Y at any position of the ring (Formula III);

[0066]

[0067] wherein n1 and n2 are independently selected from integers of 0, 1, and 2;

[0068] R4, R6 and Y are as defined above.

[0069] In another embodiment, in Formula I:

[0070] R1 is H;

[0071] R2 is selected from:

[0072]

[0073] wherein Y is -C(=O)P;

[0074] P is selected from and

[0075] R7 is selected from hydrogen or cyano;

[0076] R8 and R9 are independently selected from hydrogen, CF3, CH3 and NR 10 R 11 Substituted C 1-6 alkyl;

[0077] Rx is selected from H, CH3, CF3;

[0078] R 10 and R 11 All are methyl;

[0079] R3 is H and R4 is phenyl;

[0080] R5 is H.

[0081] In another embodiment, in Formula I:

[0082] R1 is H;

[0083] R2 is selected from:

[0084]

[0085] Where Y is CN;

[0086] R3 is H and R4 is phenyl;

[0087] R5 is H.

[0088] In another embodiment, in Formula II:

[0089] R1 is H;

[0090] R4 is phenyl;

[0091] Y is -C(=O)P;

[0092] P is selected from

[0093] R9 is selected from hydrogen, CF3, CH3 and NR 10 R 11 Substituted C 1-6 alkyl.

[0094] In another embodiment, in Formula III:

[0095] R1 is H;

[0096] R4 is phenyl;

[0097] Y is -C(=O)P;

[0098] P is selected from

[0099] R9 is selected from hydrogen, CF3, CH3 and NR 10 R 11 Substituted C 1-6 alkyl;

[0100] R 10 and R 11 All are methyl;

[0101] R6 is H or methyl.

[0102] In one embodiment, in Formula I:

[0103] R1 is H;

[0104] R2 is selected from:

[0105]

[0106] wherein Y is -C(=O)P;

[0107] P is and

[0108] Rx is selected from H, CH3;

[0109] R3 is H and R4 is phenyl;

[0110] R5 is H.

[0111] In one embodiment, in Formula I:

[0112] R1 is H;

[0113] R2 is

[0114] wherein Y is -C(=O)P;

[0115] P is selected from and

[0116] R9 is selected from hydrogen, CF3;

[0117] Rx is selected from H, CH3;

[0118] R3 is H and R4 is phenyl;

[0119] R5 is H.

[0120] In another embodiment, the present invention provides the following compounds of formula I:

[0121] 7-(1-Acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide

[0122] (E)-7-(1-(But-2-enoyl)piperidin-4-yl)-2-(4-phenoxyphenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide

[0123] 7-(1-Methacrylpiperidin-4-yl)-2-(4-phenoxyphenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide

[0124] 7-(1-(3-methylbut-2-enoyl)piperidin-4-yl)-2-(4-phenoxyphenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide

[0125] 7-(1-(But-2-ynyl)piperidin-4-yl)-2-(4-phenoxyphenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide

[0126] 2-(4-phenoxyphenyl)-7-(1-propioloylpiperidin-4-yl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide

[0127] (E)-7-(1-(Pent-2-enoyl)piperidin-4-yl)-2-(4-phenoxyphenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide

[0128] 7-(1-Acryloylpiperidin-4-yl)-1-methyl-2-(4-phenoxyphenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide

[0129] 7-(1-(But-2-ynyl)piperidin-4-yl)-1-methyl-2-(4-phenoxyphenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide

[0130] (E)-2-(4-phenoxyphenyl)-7-(1-(4,4,4-trifluorobut-2-enoyl)piperidin-4-yl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide

[0131] (E)-7-(1-(4-(dimethylamino)but-2-enoyl)piperidin-4-yl)-2-(4-phenoxyphenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide

[0132] 7-(1-cyanopiperidin-4-yl)-2-(4-phenoxyphenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide

[0133] 7-(1-Acryloylpiperidin-4-yl)-2-(4-(4-fluorophenoxy)phenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide

[0134] 7-(1-(But-2-ynyl)piperidin-4-yl)-2-(4-(4-fluorophenoxy)phenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide

[0135] 2-(4-(4-fluorophenoxy)phenyl)-7-(1-propioloylpiperidin-4-yl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide

[0136] (E)-2-(4-(4-fluorophenoxy)phenyl)-7-(1-(4,4,4-trifluorobut-2-enoyl)piperidin-4-yl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide

[0137] 7-(1-Acryloylpiperidin-4-yl)-2-(4-(2,4-difluorophenoxy)phenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide

[0138] 7-(1-(But-2-ynyl)piperidin-4-yl)-2-(4-(2,4-difluorophenoxy)phenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide

[0139] 2-(4-(2,4-difluorophenoxy)phenyl)-7-(1-propioloylpiperidin-4-yl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide

[0140] 7-(1-Acryloylpiperidin-4-yl)-2-(4-(4-methoxyphenoxy)phenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide

[0141] 7-(1-(But-2-ynyl)piperidin-4-yl)-2-(4-(4-methoxyphenoxy)phenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide

[0142] 2-(4-(4-methoxyphenoxy)phenyl)-7-(1-propioloylpiperidin-4-yl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide

[0143] 7-(1-Acryloylpiperidin-4-yl)-2-(4-(2-methoxyphenoxy)phenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide

[0144] 7-(1-(But-2-ynyl)piperidin-4-yl)-2-(4-(2-methoxyphenoxy)phenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide

[0145] 2-(4-(2-methoxyphenoxy)phenyl)-7-(1-propioloylpiperidin-4-yl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide

[0146] 7-(1-Acryloylpiperidin-4-yl)-2-(4-(2-fluorophenoxy)phenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide

[0147] 7-(1-(But-2-ynyl)piperidin-4-yl)-2-(4-(2-fluorophenoxy)phenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide

[0148] 2-(4-(2-fluorophenoxy)phenyl)-7-(1-propioloylpiperidin-4-yl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide

[0149] 7-(1-Acryloylpiperidin-4-yl)-2-(4-(4-chlorophenoxy)phenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide

[0150] 2-(4-(4-chlorophenoxy)phenyl)-7-(1-propioloylpiperidin-4-yl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide

[0151] 7-(1-Acryloylpiperidin-4-yl)-2-(4-(4-bromophenoxy)phenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide

[0152] 7-(1-Acryloylpiperidin-4-yl)-2-(4-(p-tolyloxy)phenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide

[0153] 7-(1-Acryloylpyrrolidin-3-yl)-2-(4-phenoxyphenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide

[0154] 7-(1-(But-2-ynyl)pyrrolidin-3-yl)-2-(4-phenoxyphenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide

[0155] 2-(4-phenoxyphenyl)-7-(1-propioloylpyrrolidin-3-yl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide

[0156] 7-(1-Acryloylpyrrolidin-3-yl)-2-(4-(4-fluorophenoxy)phenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide

[0157] 7-(1-(But-2-ynyl)pyrrolidin-3-yl)-2-(4-(4-fluorophenoxy)phenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide

[0158] 2-(4-(4-fluorophenoxy)phenyl)-7-(1-propioloylpyrrolidin-3-yl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide

[0159] 2-(4-(2,4-difluorophenoxy)phenyl)-7-(1-propioloylpyrrolidin-3-yl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide

[0160] 7-(1-Acryloylpyrrolidin-3-yl)-2-(4-(4-methoxyphenoxy)phenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide

[0161] 7-(1-(But-2-ynyl)pyrrolidin-3-yl)-2-(4-(4-methoxyphenoxy)phenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide

[0162] 2-(4-(4-methoxyphenoxy)phenyl)-7-(1-propioloylpyrrolidin-3-yl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide

[0163] 7-(1-Acryloylpyrrolidin-3-yl)-2-(4-(2-methoxyphenoxy)phenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide

[0164] 7-(1-(But-2-ynyl)pyrrolidin-3-yl)-2-(4-(2-methoxyphenoxy)phenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide

[0165] 2-(4-(2-methoxyphenoxy)phenyl)-7-(1-propioloylpyrrolidin-3-yl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide

[0166] 7-(1-Acryloylpyrrolidin-3-yl)-2-(4-(2-fluorophenoxy)phenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide

[0167] 7-(1-(But-2-ynyl)pyrrolidin-3-yl)-2-(4-(2-fluorophenoxy)phenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide

[0168] (E)-2-(4-(p-Tolyloxy)phenyl)-7-(1-(4,4,4-trifluorobut-2-enoyl)pyrrolidin-3-yl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide

[0169] 7-(1-Acryloylazetidin-3-yl)-2-(4-phenoxyphenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide

[0170] 7-(1-(But-2-ynyl)azetidin-3-yl)-2-(4-phenoxyphenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide

[0171] 2-(4-phenoxyphenyl)-7-(1-propioloylazetidin-3-yl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide

[0172] (E)-2-(4-phenoxyphenyl)-7-(1-(4,4,4-trifluorobut-2-enoyl)azetidin-3-yl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide

[0173] 7-(1-Acryloylazetidin-3-yl)-2-(4-(4-fluorophenoxy)phenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide

[0174] 7-(1-(But-2-ynyl)azetidin-3-yl)-2-(4-(4-fluorophenoxy)phenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide

[0175] 2-(4-(4-fluorophenoxy)phenyl)-7-(1-propioloylazetidin-3-yl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide

[0176] 7-(1-Acryloylazetidin-3-yl)-2-(4-(2-methoxyphenoxy)phenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide

[0177] 7-(1-(But-2-ynyl)azetidin-3-yl)-2-(4-(2-methoxyphenoxy)phenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide

[0178] 2-(4-(2-methoxyphenoxy)phenyl)-7-(1-propioloylazetidin-3-yl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide

[0179] 7-(4-Acrylamidophenyl)-2-(4-phenoxyphenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide

[0180] 2-(4-phenoxyphenyl)-7-(4-propiolamidophenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide

[0181] 7-(3-Acrylamidophenyl)-2-(4-phenoxyphenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide

[0182] 8-Acryloyl-2-(4-phenoxyphenyl)-6,7,8,9-tetrahydro-1H-imidazo[1',2':1,5]pyrazolo[4,3-c]pyridine-3-carboxamide

[0183] (E)-8-(4-(Dimethylamino)but-2-enoyl)-2-(4-phenoxyphenyl)-6,7,8,9-tetrahydro-1H-imidazo[1',2':1,5]pyrazolo[4,3-c]pyridine-3-carboxamide

[0184] 9-Acryloyl-2-(4-phenoxyphenyl)-1,6,7,8,9,10-hexahydroimidazo[1',2':1,5]pyrazolo[4,3-c]azepine-3-carboxamide

[0185] 8-Acryloyl-2-(4-phenoxyphenyl)-1,6,7,8,9,10-hexahydroimidazo[1',2':1,5]pyrazolo[3,4-d]azepine-3-carboxamide.

[0186] In another aspect, the present invention provides a pharmaceutical composition comprising an effective amount of a compound of the present invention or a pharmaceutically acceptable salt, active metabolite, tautomer, stereoisomer or prodrug thereof and a pharmaceutically acceptable carrier.

[0187] In some embodiments, the pharmaceutical composition is in a form suitable for administration, including but not limited to oral administration, parenteral administration, topical administration, and rectal administration. In further or other embodiments, the pharmaceutical composition is in the form of tablets, capsules, pills, powders, sustained-release formulations, solutions, and suspensions, sterile solutions, suspensions, or emulsions for parenteral injection, ointments or creams for topical administration, or suppositories for rectal administration. In further or other embodiments, the pharmaceutical composition is in a unit dosage form suitable for single administration of a precise dose. In further or other embodiments, the amount of the compound of Formula I is in the range of about 0.001 mg / kg body weight / day to about 1000 mg / kg body weight / day. In further or other embodiments, the amount of the compound of Formula I ranges from about 0.001 g / day to about 7 g / day. In further or other embodiments, a dosage level below the lower limit of the above range may be sufficient. In further or other embodiments, a dosage level above the upper limit of the above range may be required. In further or other embodiments, the compound of Formula I is administered in a single dose, once daily. In further or additional embodiments, the compound of formula I is administered in multiple doses, more than once per day. In further or additional embodiments, the pharmaceutical composition further comprises at least one therapeutic agent.

[0188] In another aspect, the present invention provides a method for preventing or treating a subject having or at risk of a BTK-mediated disease or condition, comprising administering to the subject an effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, active metabolite, tautomer, stereoisomer or prodrug thereof, or a pharmaceutical composition of the present invention.

[0189] In another aspect, the present invention provides a method for preventing or treating a subject having or at risk of the following diseases or conditions, wherein the diseases or conditions are selected from autoimmune diseases, inflammatory diseases, cancer, allergies, diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphocytic leukemia, mantle cell lymphoma, splenic marginal zone lymphoma, large B-cell lymphoma, lupus erythematosus, rheumatoid arthritis, Crohn's disease, psoriasis, multiple sclerosis, asthma, etc., the method comprising administering to the subject an effective amount of a compound of the present invention or a pharmaceutically acceptable salt, active metabolite, tautomer, stereoisomer or prodrug thereof, or a pharmaceutical composition of the present invention.

[0190] In another aspect, the present invention provides use of a compound of the present invention, or a pharmaceutically acceptable salt, active metabolite, tautomer, stereoisomer, or prodrug thereof, in the preparation of a medicament for inhibiting BTK activity.

[0191] In another aspect, the present invention provides use of a compound of the present invention, or a pharmaceutically acceptable salt, active metabolite, tautomer, stereoisomer, or prodrug thereof, in the preparation of a medicament for treating a disease or condition that may benefit from inhibition of BTK.

[0192] In another aspect, the present invention provides use of a compound of the present invention or a pharmaceutically acceptable salt, active metabolite, tautomer, stereoisomer or prodrug thereof in the preparation of a medicament for treating the following diseases or conditions, wherein the diseases or conditions are selected from autoimmune diseases, inflammatory diseases, cancer, allergies, diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphocytic leukemia, mantle cell lymphoma, splenic marginal zone lymphoma, large B-cell lymphoma, lupus erythematosus, rheumatoid arthritis, Crohn's disease, psoriasis, multiple sclerosis, asthma, and the like.

[0193] In another aspect, the present invention provides a compound of the present invention, or a pharmaceutically acceptable salt, active metabolite, tautomer, stereoisomer, or prodrug thereof, for use in inhibiting BTK.

[0194] In another aspect, the present invention provides a compound of the present invention, or a pharmaceutically acceptable salt, active metabolite, tautomer, stereoisomer, or prodrug thereof, for use in treating a disease or condition that may benefit from inhibition of BTK.

[0195] In another aspect, the present invention provides a compound of the present invention or a pharmaceutically acceptable salt, active metabolite, tautomer, stereoisomer or prodrug thereof for use in treating a disease or condition selected from the group consisting of autoimmune diseases, inflammatory diseases, cancer, allergies, diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphocytic leukemia, mantle cell lymphoma, splenic marginal zone lymphoma, large B-cell lymphoma, lupus erythematosus, rheumatoid arthritis, Crohn's disease, psoriasis, multiple sclerosis, asthma, and the like.

[0196] In some embodiments, the subject is a mammal, such as a human.

[0197] In some embodiments, the aforementioned diseases or conditions that may benefit from BTK inhibition include, but are not limited to, cancer, autoimmune diseases, inflammatory diseases, and allergies. Such diseases include, but are not limited to, diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphocytic leukemia, mantle cell lymphoma, splenic marginal zone lymphoma, large B-cell lymphoma, lupus erythematosus, rheumatoid arthritis, Crohn's disease, psoriasis, multiple sclerosis, asthma, and the like. Detailed Description of the Invention

[0199] The section headings used herein are for organizational purposes only and should not be construed as limitations on the subject matter described. All documents or portions of documents cited in this application, including but not limited to patents, patent applications, articles, books, manuals, and treatises, are incorporated herein by reference in their entirety for any purpose.

[0200] Some chemical terms

[0201] The present invention also includes isotope-labeled compounds. Common isotope atoms include but are not limited to 2 H. 3 H. 13 C. 14 C. 17 O. 18 O. 15 N, etc. These atoms are identical to their most abundant atoms in nature but have different mass numbers. The application of isotope labeling in drug discovery has been reported (Elmore, Charles S, Annual Report of Medicinal Chemistry, 2009, 44, 515-534).

[0202] Unless otherwise defined, all technical and scientific terms used herein have the same meanings as commonly understood by those skilled in the art to which the claimed subject matter belongs. Unless otherwise indicated, all patents, patent applications, and publications cited herein are incorporated by reference in their entirety. If multiple definitions of a term are used herein, the definitions in this section shall prevail.

[0203] It should be understood that the above overview and the detailed description below are exemplary and for explanation only and do not limit the subject matter of the present invention in any way. In this application, unless otherwise specifically stated, the use of the singular also includes the plural. It should also be noted that, unless the context clearly dictates otherwise, as used in the specification and claims, the singular forms "a", "an", "the", or "said" include plural referents. It should also be noted that, unless otherwise stated, the use of "or" or "alternatively" means "and / or". In addition, the use of the term "including" and other forms is not restrictive. Similarly, the use of the term "comprising" and other forms is not restrictive.

[0204] The following references can be found in the literature (including Carey and Sundberg "ADVANCED ORGANIC CHEMISTRY 4 THDefinitions of standard chemical terms can be found in "Chemicals of the Present Invention," ed." Vols. A (2000) and B (2001), Plenum Press, New York). Unless otherwise indicated, conventional methods within the skill of the art, such as mass spectrometry, NMR, HPLC, IR and UV / Vis spectroscopy and pharmacological methods, are employed. Unless specific definitions are provided, the nomenclature employed in connection with analytical chemistry, organic synthetic chemistry, and pharmaceutical and medicinal chemistry described herein, as well as the experimental procedures and techniques thereof, are those known in the art. Standard techniques can be used in chemical syntheses, chemical analyses, pharmaceutical preparation, formulation and delivery, and treatment of patients. For example, the manufacturer's instructions for use of the kits can be utilized, or the reactions and purification techniques can be performed in a manner known in the art or as described herein. The techniques and methods described above can generally be performed according to conventional methods well known in the art, as described in the various general and more specific references cited and discussed in this specification.

[0205] When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes chemically equivalent substituents that would result if the structure were written from right to left. For example, CH2O is equivalent to OCH2.

[0206] Unless otherwise indicated, general chemical terms such as, but not limited to, "alkyl" and "aryl" are equivalent to their optionally substituted forms. For example, "alkyl" as used herein includes optionally substituted alkyl.

[0207] The compounds described herein may have one or more stereogenic centers, and each center may exist in the form of R or S configuration or a combination thereof. Similarly, the compounds described herein may have one or more double bonds, and each double bond may exist in the form of E (trans) or Z (cis) configuration or a combination thereof. A specific stereoisomer described should be understood to include all possible stereoisomers, including positional isomers, diastereomers, enantiomers or epimers and mixtures thereof. Therefore, the compounds described herein include all configurationally different stereoisomers, positional isomers, diastereomers, enantiomers and epimers and their corresponding mixtures. Racemates (mixtures of S and R forms), diastereomers and single S or R isomers may exist. The present invention is intended to illustrate that the compounds claimed herein may be mixtures of diastereomers, racemates or single S or R isomers.

[0208] The term "optionally" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, according to the definitions below, "alkyl optionally substituted with" means "alkyl" or "alkyl substituted with."

[0209] As used herein, a group referred to as "C1-C6" refers to a group having from 1 to 6 carbon atoms in the moiety, i.e., groups containing 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, and 6 carbon atoms. Thus, by way of example only, "C1-C6 alkyl" means that there are from 1 to 6 carbon atoms in the alkyl group, i.e., the alkyl group is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and isomers thereof.

[0210] As used herein, the terms "ring," "cyclic," and "membered ring," alone or in combination, refer to any covalently closed structure as described herein, including alicyclic, heterocyclic, aromatic, heteroaromatic, and polycyclic fused or non-fused ring systems. The ring may be optionally substituted. The ring may form part of a fused ring system. The term "membered" refers to the number of skeletal atoms comprising the ring. Thus, by way of example only, cyclohexane, pyridine, pyran, and pyrimidine are 6-membered rings.

[0211]

[0046] The term "fused," as used herein, alone or in combination, refers to ring structures wherein two or more rings have one or more bonds in common.

[0212] The term "heterocyclyl," as used herein, alone or in combination, refers to an aliphatic heterocyclic group. When the number of carbon atoms in a heterocycle is indicated herein (e.g., a C3-C6 heterocycle), at least one non-carbon atom (heteroatom) must be present in the ring. For example, the designation "C3-C6 heterocycle" refers only to the number of carbon atoms in the ring, not the total number of atoms in the ring. For example, the designation "4-8 membered heterocycle" refers to the total number of atoms contained in the ring (i.e., a four-, five-, six-, seven-, or eight-membered ring in which at least one atom is a carbon atom, at least one atom is a heteroatom, and the remaining 2 to 6 atoms are carbon atoms or heteroatoms). For heterocycles having two or more heteroatoms, the two or more heteroatoms may be the same or different. A heterocycle may be optionally substituted. It may be bonded to the heterocycle (i.e., attached to or further substituted with the parent molecule) via a heteroatom or carbon atom. A "heterocycle" in which the ring is saturated is referred to as a heterocycloalkyl.

[0213] The term "spiroheterocyclyl" as used herein, alone or in combination, refers to a polycyclic ring radical in which two rings have one carbon atom in common and at least one ring-forming atom is a heteroatom. A spiroheterocyclyl can have two or more rings, each of which can be a 4-8 membered ring. A spiroheterocyclyl can be optionally substituted. It can be combined with a spiroheterocycle (i.e., connected to or further substituted with the parent molecule) via a heteroatom or carbon atom. "Spiroheterocycle" includes heterocycloalkyl.

[0214] The term "cycloalkyl" as used herein, alone or in combination, refers to an optionally substituted monovalent saturated hydrocarbon ring that may include other non-ring carbon atoms (e.g., methylcyclopropyl) as substituents. A cycloalkyl group may have 3 to about 10, or 3 to about 8, or 3 to about 6, or 3 to 5 ring atoms. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0215] The term "aryl" as used herein, alone or in combination, refers to an optionally substituted aromatic hydrocarbon radical having 6 to about 20 ring-forming carbon atoms, and includes fused aromatic rings and non-fused aromatic rings. A fused aromatic ring group contains 2 to 4 fused rings, wherein the connected ring is an aromatic ring, and the other independent rings can be an alicyclic ring, a heterocyclic ring, an aromatic ring, a heteroaromatic ring, or any combination thereof. In addition, the term aryl also includes fused rings and non-fused rings. Moreover, the term aryl includes monocyclic, bicyclic, tricyclic, or more rings. Aryl (e.g., monocyclic aryl) contains, for example, 6 to about 12, or 6 to about 10, or 6 to about 8 ring-forming carbon atoms. Non-limiting examples of monocyclic aryl include phenyl; fused ring aryl includes naphthyl, phenanthrenyl, anthracenyl, azulenyl; and non-fused biaryl includes biphenyl.

[0216] The term "alkyl" as used herein, alone or in combination, refers to an optionally substituted straight chain or optionally substituted branched monovalent saturated hydrocarbon having 1 to about 18 carbon atoms, or 1 to about 10 carbon atoms, or 1 to about 6 carbon atoms. "Lower alkyl" as used herein, alone or in combination, refers to an alkyl group having a relatively small number of carbon atoms, for example, 1 to about 8 carbon atoms, preferably 1 to about 6 carbon atoms, or 1 to about 4 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, and the like.

[0217] The "alkyl group" used in combination includes, but is not limited to, the "alkyl group" included in the "alkoxy group".

[0218] The term "alkoxy" as used herein, alone or in combination, refers to an alkyl ether radical (O-alkyl). Non-limiting examples of alkoxy include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, and the like.

[0219] The term "alkenyl", as used herein, alone or in combination, refers to an optionally substituted straight or optionally substituted branched monovalent hydrocarbon radical having one or more C=C double bonds and having, for example, 2 to about 18 carbon atoms, or 2 to about 10 carbon atoms, or 2 to about 6 carbon atoms. The double bond in this group can be in a cis or trans conformation and should be understood to include both isomers. Examples include, but are not limited to, vinyl (-CH=CH2), 1-propenyl (-CH2CH=CH2), isopropenyl [-C(CH3)=CH2], butenyl, and 1,3-butadienyl, etc. The term "alkenyl" where no numerical range is specified is also encompassed by this definition.

[0220]

[0046] The terms "halogen," "halo," or "halide," as used herein, alone or in combination, refer to fluoro, chloro, bromo, and iodo.

[0221] Hydroxyl refers to an -OH group.

[0222] Cyano refers to a -CN group.

[0223] In the molecular structures shown herein, when asymmetric centers are present, solid wedges indicate bonds pointing toward the top of the paper and dashed wedges indicate bonds pointing toward the back of the paper. Solid bond lines generally indicate all possible isomers.

[0224] Certain drug terms

[0225] The terms "subject," "patient," or "individual" as used herein with respect to an individual suffering from a disease, disorder, condition, etc., include mammals and non-mammals. Examples of mammals include, but are not limited to, any member of the class Mammalia: humans, non-human primates (e.g., chimpanzees and other ape and monkey species); farm animals, such as cattle, horses, sheep, goats, pigs; domestic animals, such as rabbits, dogs, and cats; laboratory animals, including rodents, such as rats, mice, and guinea pigs, etc. Examples of non-mammals include, but are not limited to, birds and fish, etc. In one embodiment of the methods and compositions provided herein, the mammal is a human.

[0226] As used herein, the terms "treat," "treat," "treat," and other similar synonyms include alleviating, alleviating, or ameliorating the symptoms of a disease or condition, preventing other symptoms, ameliorating or preventing the underlying metabolic causes of symptoms, inhibiting the disease or condition, such as arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, alleviating the condition caused by the disease or condition, or suspending the symptoms of the disease or condition, and are intended to include prevention. The term also includes obtaining a therapeutic benefit and / or a prophylactic benefit. The therapeutic benefit refers to curing or ameliorating the underlying condition being treated. Moreover, a therapeutic benefit is achieved by curing or ameliorating one or more physiological symptoms associated with the underlying condition, such that although the patient may still be affected by the underlying condition, an improvement in the patient's condition is observed. With respect to prophylactic benefit, the composition can be administered to a patient at risk for a particular disease, or to a patient who reports the presence of one or more physiological symptoms of the disease, even if a diagnosis of the disease has not yet been made.

[0227] As used herein, the terms "effective amount," "therapeutically effective amount," or "pharmaceutically effective amount" refer to an amount of at least one agent or compound that, upon administration, is sufficient to provide some relief from one or more symptoms of the disease or condition being treated. The result can be a reduction and / or alleviation of the signs, symptoms, or causes of the disease, or any other desired change in a biological system. For example, an "effective amount" for therapeutic use is the amount of a composition comprising a compound disclosed herein that is required to provide a clinically significant disease-modifying effect. Techniques such as dose escalation studies can be used to determine an appropriate "effective" amount in any individual case.

[0228] As used herein, the terms "administering," "administration," and the like refer to methods capable of delivering a compound or composition to a desired biological site of action. These methods include, but are not limited to, oral routes, intraduodenal routes, parenteral injections (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular injection or infusion), topical, and rectal administration. Those skilled in the art are familiar with administration techniques that can be used for the compounds and methods described herein, such as those discussed in Goodman and Gilman, The Pharmacological Basis of Therapeutics, current edition; Pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, Pa. In a preferred embodiment, the compounds and compositions described herein are administered orally.

[0229] The term "acceptable" with respect to a formulation, composition or ingredient, as used herein, means having no long-term detrimental effect on the general health of the subject being treated.

[0230] As used herein, the term "pharmaceutically acceptable" refers to a substance (such as a carrier or diluent) that does not affect the biological activity or properties of the compounds described herein and is relatively non-toxic, i.e., the substance can be administered to a subject without causing adverse biological effects or interacting in a deleterious manner with any components included in the composition.

[0231] The term "pharmaceutical composition" as used herein refers to a biologically active compound optionally mixed with at least one pharmaceutically acceptable chemical component, including but not limited to carriers, stabilizers, diluents, dispersants, suspending agents, thickeners and / or excipients.

[0232] As used herein, the term "carrier" refers to relatively nontoxic chemical compounds or agents that facilitate the introduction of a compound into cells or tissues.

[0233] As used herein, the term "pharmaceutically acceptable salt" refers to a salt that retains the biological effectiveness of the free acid and free base of the specified compound and has no adverse biological or other effects. The compounds described herein may have acidic or basic groups and can therefore react with any of a variety of inorganic or organic bases and inorganic and organic acids to form pharmaceutically acceptable salts. These salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or by reacting the purified compound in its free base form with a suitable organic or inorganic acid separately and isolating the salt thus formed. Examples of pharmaceutically acceptable salts include those prepared by reactions between the compounds described herein and inorganic or organic acids or inorganic or organic bases.

[0234] As used herein, the term "tautomer" refers to isomers that are readily interconvertible from the compounds of the present invention by, for example, hydrogen atom migration or proton migration.

[0235] The term "prodrug" as used herein refers to any pharmaceutically acceptable salt, ester, salt of an ester, or other derivative of a compound of the invention that, upon administration to a recipient, is capable of providing, directly or indirectly, a compound of the invention or a pharmaceutically active metabolite or residue thereof. Particularly preferred derivatives or prodrugs are those that increase the bioavailability of the compound of the invention when administered to a patient (e.g., make an orally administered compound more readily absorbed into the blood), or those that promote delivery of the parent compound to biological compartments (e.g., the brain or lymphatic system).

[0236] As used herein, the term "active metabolite" refers to a biologically active derivative of a compound that is formed when the compound is metabolized.

[0237] As used herein, the term "metabolic" refers to all processes by which an organism changes a particular substance (including but not limited to hydrolysis reactions and enzyme-catalyzed reactions).

[0238] IC 50 It refers to the concentration of a particular compound that inhibits a specific measured activity by 50%. DETAILED DESCRIPTION

[0239] The novel features of the present invention are particularly set forth in the appended claims. Exemplary embodiments utilizing the principles of the present invention are set forth in the following detailed description, and the features and advantages of the present invention may be better understood by reference to the detailed description.

[0240] While some embodiments of the present invention have been shown and described herein, these embodiments are provided as examples only. It will be understood that variations of the embodiments of the present invention described herein may also be used to practice the present invention. One of ordinary skill in the art will appreciate that numerous variations, changes, and substitutions may occur without departing from the scope of the present invention. It will be understood that the scope of protection of various aspects of the present invention is determined by the claims, and that methods and structures within the scope of these claims, as well as equivalent methods and structures, are intended to be encompassed by the claims of the present invention.

[0241] Compounds of Formula I can generally be prepared by the chemical routes depicted in Schemes 1 to 3. Specific examples are provided below.

[0242] Treatment of phenyl ketone 1 with sodium hydride and dimethyl carbonate yields β-ketoester 2. Treatment of ester 2 with ammonia in 1,4-dioxane at elevated temperature yields the corresponding amide 3, which reacts with CuBr2 in ethyl acetate to yield 1-bromoamide 4. Separately, aminopyrazole 9 is prepared by reacting ketone 5 with diethyl cyanomethylphosphonate and NaH in THF to yield nitrile 6, which is then hydrogenated to yield nitrile 7. Treatment of nitrile 7 with ethyl formate and a base in THF yields 1-cyanoaldehyde 8, which is condensed with hydrazine in ethanol to yield aminopyrazole 9. Treatment of aminopyrazole 9 with 1-bromoamide 4 yields 1H-imidazo[1,2-b]pyrazole-3-carboxamide 10. Treatment of carboxamide 10 with HCl yields the hydrochloride salt 11. Final compounds 12a or 12b can be prepared under the conditions described below, but are not limited to the conditions specified.

[0243] Plan-1

[0244]

[0245] Plan-1 continued

[0246]

[0247] In Scheme-1, where m is 0, n can only be selected from the number 1. When m is 1, n is selected from the numbers 1 and 2. Compounds 9a and 9b can be prepared in a manner similar to that of preparing compounds 12a and 12b.

[0248] Plan-2

[0249]

[0250] Plan-3

[0251]

[0252] In Scheme-3, n is selected from the numbers 1 and 2.

[0253] Plan-4

[0254]

[0255] Example:

[0256] Example 1: 7-(1-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)-1H-imidazo[1,2-b]pyrrolidone Azole-3-carboxamide

[0257] Step A: Preparation of methyl 3-oxo-3-(4-phenoxyphenyl)propionate

[0258]

[0259] To a suspension of NaH (60% dispersion in mineral oil; 26.3 g, 659.6 mmol) in anhydrous N,N-dimethylformamide (DMF, 300 mL) was added dropwise a solution of 1-(4-phenoxyphenyl)ethan-1-one (70 g, 329.8 mmol) in anhydrous DMF (50 mL) at 0°C with stirring. After 30 minutes, dimethyl carbonate (118.8 g, 1.32 mol) was added dropwise at 0°C. The system was warmed to room temperature over 2 hours, and the reaction mixture was poured into a 1:1 water / saturated sodium bicarbonate solution. The aqueous phase was extracted with ethyl acetate (3 x 500 mL). The combined organic phases were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by chromatography using petroleum ether and ethyl acetate (10:1) to yield the desired product, methyl 3-oxo-3-(4-phenoxyphenyl)propanoate, as a yellow solid (81 g, 90%). 1H NMR(600MHz,DMSO-d6)δ8.00-7.96(m,2H),7.47(t,J=8.0Hz,2H),7.26(t,J=7 .4Hz,1H),7.16-7.12(m,2H),7.05(d,J=8.8Hz,2H),4.16(s,2H),3.65(s,3H). MS(ESI,m / z):271.3[M+H] + .

[0260] Step B: Preparation of 3-oxo-3-(4-phenoxyphenyl)propionamide

[0261]

[0262] To a solution of the product from Example 1, Step A (81 g, 0.30 mol) in 1,4-dioxane (100 mL) was added 7M NH3 / 1,4-dioxane (100 mL) in a 300 mL sealed tube at room temperature. The tube was sealed and the mixture was stirred at 95°C for 12 hours, then cooled to room temperature. The mixture was concentrated under vacuum. The residue was purified by chromatography using petroleum ether and ethyl acetate (1:1) to give the desired product, 3-oxo-3-(4-phenoxyphenyl)propionamide, as a white solid (40 g, 53%). 1 HNMR (400MHz, DMSO-d6) δ8.01-7.97(m,2H),7.48-7.43(m,2H),7.29-7.25(m,1H),7.16-7.12(m,2H),7.07-7.04(m,2H),3.81(s,2H). MS(ESI,m / z):256.3[M+H] + .

[0263] Step C: Preparation of 2-bromo-3-oxo-3-(4-phenoxyphenyl)propionamide

[0264]

[0265] CuBr2 (38 g, 0.17 mol) was added to a solution of the product of Example 1, Step B (40 g, 0.16 mol) in ethyl acetate (500 ml). The mixture was stirred at 50 ° C until no further changes were observed by TLC. The mixture was filtered through celite. The filtrate was diluted with ethyl acetate and water. After separation, the organic phase was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by chromatography using petroleum ether and ethyl acetate (3:2) to give the target product, 2-bromo-3-oxo-3-(4-phenoxyphenyl)propionamide, as a white solid (48 g, 90.6%). MS (ESI, m / z): 335.2 [M + H] + .

[0266] Step D: Preparation of tert-butyl 4-(cyanomethylene)piperidine-1-carboxylate

[0267]

[0268] To a suspension of NaH (60% dispersion in mineral oil; 64 g, 1.6 mol) in anhydrous tetrahydrofuran (THF, 500 mL) was added a solution of diethyl cyanomethylphosphonate (304 g, 1.7 mol) in anhydrous THF (200 mL) dropwise with stirring at 10°C. After 30 minutes, tert-butyl 4-oxopiperidine-1-carboxylate (262 g, 1.32 mol) was added dropwise at 10°C. The system temperature was raised to room temperature over 2 hours and then quenched with ice water. The aqueous layer was extracted with ethyl acetate, the solvent was removed under vacuum, and the residue was recrystallized from petroleum ether and ethyl acetate (10:1) to obtain the desired product, tert-butyl 4-(cyanomethylene)piperidine-1-carboxylate, as a white solid (260 g, 89%). 1 H NMR (400MHz, CDCl3) δ5.09 (s, 1H), 3.43-3.31 (m, 4H), 2.46-2.37 (m, 2H), 2.20 (t, J = 5.6Hz, 2H), 1.33 (s, 9H). MS(ESI,m / z):223.3[M+H] + .

[0269] Step E: Preparation of tert-butyl 4-(cyanomethyl)piperidine-1-carboxylate

[0270]

[0271] Under N2 protection, 10% Pd / C (8 g, 10%) was added to a solution of the product of Example 1, Step D (80 g, 0.36 mol) in ethyl acetate (1000 mL). The suspension was degassed under vacuum and purged with H2 several times. Stirred under H2 at room temperature for 5 hours. The mixture was passed through celite and the filter cake was washed with ethyl acetate. The filtrate was concentrated under vacuum to give the desired product, tert-butyl 4-(cyanomethyl)piperidine-1-carboxylate, as a white solid (61 g, 74.4%). 1 H NMR (400MHz, CDCl3) δ4.08 (s, 2H), 2.77-2.52 (m, 2H), 2.25 (d, J = 6.4Hz, 2H), 1.82-1.68 (m, 3H), 1.40 (s, 9H), 1.26-1.12 (m, 2H). MS(ESI,m / z):225.3[M+H] + .

[0272] Step F: Preparation of tert-butyl 4-(1-cyano-2-oxoethyl)piperidine-1-carboxylate

[0273]

[0274] The product (61g, 0.27mol) of Example 1 Step E in anhydrous THF (250mL) solution was cooled to -85°C (liquid nitrogen / ethanol bath), then n-BuLi (n-BuLi, 2.5M n-hexane solution, 544mL, 1.35mol) was added dropwise to the system and insulated and stirred for 30 minutes. Ethyl formate (61g, 0.81mol) was then added dropwise to the reaction solution, warming to ice / water bath temperature, insulated and stirred for 30 minutes. The product was then quenched with ice / water, acidified to pH 5-6 with concentrated HCl, and extracted with ethyl acetate. The organic phase was washed with saturated common salt water, dried over anhydrous Na2SO4, filtered and concentrated to give 118g crude product 4-(1-cyano-2-oxoethyl)piperidine-1-carboxylic acid tert-butyl esters. The residue was directly used in the next step.

[0275] Step G: Preparation of tert-butyl 4-(5-amino-1H-pyrazol-4-yl)piperidine-1-carboxylate

[0276]

[0277] The product of Example 1, Step F (118 g, 0.47 mol) and hydrazine hydrate (80%, 300 mL) were heated to 80° C. in ethanol (300 mL) and reacted for 10 hours. The reaction was then cooled to room temperature, and the solvent was removed under vacuum. The crude residue was purified by chromatography using petroleum ether and ethyl acetate (1:5) to give the desired product, tert-butyl 4-(5-amino-1H-pyrazol-4-yl)piperidine-1-carboxylate, as a yellow solid (31 g, 43% yield over two steps). 1 H NMR (400MHz, DMSO-d6) δ7.12(s,1H),4.04-3.93(m,2H),2.74(s,2H),2.49-2.42(m,1H),1.79-1.72(m,2H),1.40(s,9H),1.31-1.20(m,2H). MS(ESI,m / z):267.3[M+H] + .

[0278] Step H: Preparation of 4-(3-carbamoyl-2-(4-phenoxyphenyl)-1H-imidazo[1,2-b]pyrazol-7-yl) Piperidine-1-carboxylic acid tert-butyl ester

[0279]

[0280] The product from Example 1, Step G (31 g, 0.12 mol) and the product from Example 1, Step C (31 g, 0.10 mol) were heated to reflux in ethanol (500 mL) and reacted overnight. The reaction solution was then cooled to room temperature, and the solvent was removed under vacuum. The crude residue was purified by chromatography using petroleum ether and ethyl acetate (3:2) to obtain the desired product, tert-butyl 4-(3-carbamoyl-2-(4-phenoxyphenyl)-1H-imidazo[1,2-b]pyrazol-7-yl)piperidine-1-carboxylate, as a yellow solid (10 g, 17%). 1 HNMR(400MHz,DMSO-d6)δ12.09(s,1H),8.38(s,1H),7.84(d,J=8.7Hz,2H),7.70(s,1H),7.54(s,1H),7.45(t,J=7.9Hz,2H),7.2 1(t,J=7.4Hz,1H),7.14-7.04(m,4H),4.12-3.96(m,2H),2.91-2.70(m,3H),1.93-1.85(m,2H),1.65-1.52(m,2H),1.41(s,9H). MS(ESI,m / z):502.6[M+H] + .

[0281] Step I: Preparation of 2-(4-phenoxyphenyl)-7-(piperidin-4-yl)-1H-imidazo[1,2-b]pyrazole-3-carboxylate amine

[0282]

[0283] To a solution of the product from Example 1, Step H (10 g, 19.9 mmol) in ethanol (2 mL) was added 33% HCl / EtOH (10 mL) at room temperature. The mixture was stirred for 3 hours, then concentrated under vacuum to afford 9.5 g of crude 2-(4-phenoxyphenyl)-7-(piperidin-4-yl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide. The residue was used directly in the next step. MS (ESI, m / z): 402.6 [M+H] + .

[0284] Step J: Preparation of 7-(1-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)-1H-imidazo[1,2-b]pyrrolidone Azole-3-carboxamide

[0285]

[0286] A solution of the product from Example 1, Step I (180 mg, 0.44 mmol) in THF / H₂O (3:1, 4 mL) was basified with NaHCO₃ to pH 7-8. The mixture was then cooled to 0°C, and a solution of acryloyl chloride (60 mg, 0.66 mmol) in THF (1 mL) was slowly added. The reaction mixture was stirred at 0°C for 1 hour. Dichloromethane and water were then added to the reaction mixture, the layers were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with saturated brine (3 × 50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by chromatography using dichloromethane and methanol (30:1) to afford 7-(1-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide as an off-white solid (80 mg, 39.2%). 1 H NMR (400MHz, CDCl3) δ10.48(s,1H),8.81(s,1H),7.80-7.75(m,2H),7.51(s,1H),7.39-7.3 3(m,2H),7.15(t,J=7.4Hz,1H),7.07-7.02(m,2H),7.00-6.96(m,2H),6.57-6.48(m,1H),6. 14-6.07(m,1H),5.64(d,J=1.8Hz,1H),5.62(d,J=1.9Hz,1H),4.77-4.65(m,1H),4.10-3.98 (m,1H),3.23-3.10(m,1H),2.94-2.81(m,1H),2.70(s,1H),1.95(s,3H),1.90-1.80(m,1H). MS(ESI,m / z):456.5[M+H] + .

[0287] Example 2: E )-7-(1-(but-2-enoyl)piperidin-4-yl)-2-(4-phenoxyphenyl)-1H-imidazo [1,2-b]pyrazole-3-carboxamide

[0288]

[0289] A solution of the product from Example 1, Step 1 (180 mg, 0.44 mmol) in THF / H₂O (3:1, 4 mL) was basified to pH 7-8 with NaHCO₃. The mixture was then cooled to 0°C and a solution of (E)-but-2-enoyl chloride (69 mg, 0.66 mmol) in THF (1 mL) was slowly added. The reaction mixture was stirred at 0°C for 1 hour. Dichloromethane and water were then added to the reaction mixture, the layers were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with saturated brine (3×50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by chromatography with dichloromethane and methanol (30:1) to give (E)-7-(1-(but-2-enoyl)piperidin-4-yl)-2-(4-phenoxyphenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide as an off-white solid (85 mg, 40.4%). 1 H NMR(400MHz,DMSO-d6)δ12.12(s,1H),8.38(s,1H),7.88-7.80(m,2H),7.71(s,1H),7.5 4(s,1H),7.49-7.41(m,2H),7.24-7.18(m,1H),7.13-7.06(m,4H),6.73-6.64(m,1H),6 .58-6.52(m,1H),4.60-4.48(m,1H),4.23-4.09(m,1H),3.20-3.03(m,1H),2.92-2.81( m,1H),2.69(s,1H),1.98-1.89(m,2H),1.84(dd,J=6.7,1.3Hz,3H),1.68-1.54(m,2H). MS(ESI,m / z):470.5[M+H] + .

[0290] Example 3: 7-(1-methacryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)-1H-imidazo[1,2-b] Pyrazole-3-carboxamide

[0291]

[0292] A solution of the product from Example 1, Step I (180 mg, 0.44 mmol) in THF / H₂O (3:1, 4 mL) was basified with NaHCO₃ to pH 7-8. The mixture was then cooled to 0°C, and a solution of methacryloyl chloride (69 mg, 0.66 mmol) in THF (1 mL) was slowly added. The reaction mixture was stirred at 0°C for 1 hour. Dichloromethane and water were then added to the reaction mixture, the layers separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with saturated brine (3 × 50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by chromatography using dichloromethane and methanol (30:1) to afford 7-(1-methacryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide as an off-white solid (90 mg, 42.7%). 1 HNMR(600MHz,DMSO-d6)δ12.12(s,1H),8.39(s,1H),7.84(d,J=8.5Hz,2H),7.7 2(s,1H),7.55(s,1H),7.45(t,J=7.7Hz,2H),7.21(t,J=7.3Hz,1H),7.12-7.07 (m,4H),5.17(s,1H),5.03(s,1H),4.46(s,1H),3.96(s,1H),3.14(s,1H),2.93 -2.84(m,1H),2.74(s,1H),1.98-1.91(m,2H),1.88(s,3H),1.67-1.58(m,2H). MS (ESI, m / z): 470.5 [M+H] + .

[0293] Example 4: 7-(1-(3-methylbut-2-enoyl)piperidin-4-yl)-2-(4-phenoxyphenyl)-1H-imidazo [1,2-b]pyrazole-3-carboxamide

[0294]

[0295] A solution of the product from Example 1, Step 1 (180 mg, 0.44 mmol) in THF / H2O (3:1, 4 mL) was basified to pH 7-8 with NaHCO3. The mixture was then cooled to 0°C and a solution of 3-methylbut-2-enoyl chloride (78 mg, 0.66 mmol) in THF (1 mL) was slowly added. The reaction mixture was stirred at 0°C for 1 hour. Dichloromethane and water were then added to the reaction solution, the layers were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with saturated brine (3×50 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by chromatography with dichloromethane and methanol (30:1) to give 7-(1-(3-methylbut-2-enoyl)piperidin-4-yl)-2-(4-phenoxyphenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide as an off-white solid (88 mg, 40.6%). 1 H NMR(400MHz,DMSO-d6)δ12.10(s,1H),8.37(s,1H),7.89-7.79(m,2H),7.70(s,1 H),7.54(s,1H),7.49-7.41(m,2H),7.21(t,J=7.4Hz,1H),7.14-7.05(m,4H),5.9 2(s,1H),4.57-4.44(m,1H),4.04-3.91(m,1H),3.15-3.03(m,1H),2.90-2.79(m, 1H),2.74-2.61(m,1H),1.98-1.89(m,2H),1.87-1.76(m,6H),1.66-1.51(m,2H). MS(ESI,m / z):484.6[M+H] + .

[0296] Example 5: 7-(1-(but-2-ynyl)piperidin-4-yl)-2-(4-phenoxyphenyl)-1H-imidazo[1,2- b]pyrazole-3-carboxamide

[0297]

[0298] A solution of the product from Example 1, Step 1 (180 mg, 0.44 mmol) in DMF (5 mL) was basified to pH 7-8 with N,N-diisopropylethylamine. After 5 minutes, 2-butynoic acid (55 mg, 0.66 mmol) and HATU (184 mg, 0.48 mmol) were added. The reaction mixture was stirred at room temperature for another 30 minutes. Dichloromethane and water were then added to the reaction mixture. The layers were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with saturated brine (3 x 50 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by chromatography using dichloromethane and methanol (30:1) to afford 7-(1-(but-2-ynyl)piperidin-4-yl)-2-(4-phenoxyphenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide as an off-white solid (105 mg, 51.2%). 1 H NMR (400MHz, DMSO-d6) δ12.12(s,1H),8.37(s,1H),7.84(d,J=8.7Hz,2H),7.71(s,1H),7.55(s,1H),7.45(t,J=7.9Hz,2H),7.21(t,J=7.4Hz,1H), 7.14-7.05(m,4H),4.46-4.30(m,2H),3.28-3.16(m,1H),2.93-2.82(m,1 H),2.81-2.71(m,1H),2.03(s,3H),2.00-1.86(m,2H),1.77-1.52(m,2H). MS(ESI,m / z):468.5[M+H] + .

[0299] Example 6: 2-(4-phenoxyphenyl)-7-(1-propioloylpiperidin-4-yl)-1H-imidazo[1,2-b]pyrrolidone Azole-3-carboxamide

[0300]

[0301] A solution of the product from Example 1, Step 1 (180 mg, 0.44 mmol) in DMF (5 mL) was basified to pH 7-8 with N,N-diisopropylethylamine. After 5 minutes, propiolic acid (46 mg, 0.66 mmol) and HATU (184 mg, 0.48 mmol) were added. The reaction mixture was stirred at room temperature for another 30 minutes. Dichloromethane and water were then added to the reaction mixture. The layers were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with saturated brine (3 x 50 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by chromatography using dichloromethane and methanol (30:1) to afford 2-(4-phenoxyphenyl)-7-(1-propioloylpiperidin-4-yl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide as an off-white solid (112 mg, 56.1%). 1 H NMR (400MHz, DMSO-d6) δ12.12(s,1H),8.37(s,1H),7.88-7.80(m,2H),7.71(s,1H),7.55(s,1H),7.50-7.40(m,2H),7.21(t,J=7.4Hz ,1H),7.13-7.06(m,4H),4.54(s,1H),4.46-4.29(m,2H),3.32-3.23(m,1H),2.95-2.75(m,2H),2.02-1.87(m,2H),1.79-1.54(m,2H). MS(ESI,m / z):454.5[M+H] + .

[0302] Example 7: (E)-7-(1-(pent-2-enoyl)piperidin-4-yl)-2-(4-phenoxyphenyl)-1H-imidazo [1,2-b]pyrazole-3-carboxamide

[0303]

[0304] A solution of the product from Example 1, Step 1 (180 mg, 0.44 mmol) in DMF (5 mL) was basified to pH 7-8 with N,N-diisopropylethylamine. After 5 minutes, (E)-2-pentenoic acid (66 mg, 0.66 mmol) and HATU (184 mg, 0.48 mmol) were added. The reaction mixture was stirred at room temperature for another 30 minutes. Dichloromethane and water were then added to the reaction mixture. The layers were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with saturated brine (3 x 50 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by chromatography using dichloromethane and methanol (30:1) to afford (E)-7-(1-(pent-2-enoyl)piperidin-4-yl)-2-(4-phenoxyphenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide as an off-white solid (102 mg, 47.9%).1 H NMR (600MHz, DMSO-d6) δ12.12(s,1H),8.37(s,1H),7.83(d,J=8.7Hz,2H),7.69(s,1H),7.53(s, 1H),7.44(t,J=8.0Hz,2H),7.20(t,J=7.4Hz,1H),7.09(t,J=8.7Hz,4H),6.74-6.68(m,1H),6.5 1-6.46(m,1H),4.59-4.50(m,1H),4.20-4.10(m,1H),3.16-3.08(m,1H),2.89-2.82(m,1H),2.7 3-2.64(m,1H),2.23-2.15(m,2H),1.97-1.88(m,2H),1.67-1.53(m,2H),1.01(t,J=7.4Hz,3H). MS(ESI,m / z):484.6[M+H] + .

[0305] Example 8: 7-(1-acryloylpiperidin-4-yl)-1-methyl-2-(4-phenoxyphenyl)-1H-imidazo[1, 2-b]pyrazole-3-carboxamide

[0306]

[0307] To a solution of the product from Example 1, Step J (100 mg, 0.22 mmol) in DMF (2 mL) was added NaHCO₃ (74 mg, 0.88 mmol) and CH₃I (62 mg, 0.44 mmol). The reaction mixture was stirred at room temperature for 3 hours. It was then quenched with saturated sodium bicarbonate solution, and dichloromethane and water were added. The layers were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with saturated brine (3 × 20 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by chromatography using dichloromethane and methanol (40:1) to afford 7-(1-acryloylpiperidin-4-yl)-1-methyl-2-(4-phenoxyphenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide as an off-white solid (32 mg, 31.0%). 1H NMR (600MHz, DMSO-d6) δ8.14(s,1H),7.64(s,1H),7.62(s,1H),7.54(d,J=8.4Hz,2H),7.48(t, J=7.7Hz,2H),7.24(t,J=7.3Hz,1H),7.16(d,J=8.2Hz,2H),7.09(d,J=8.4Hz,2H),6.89-6.83(m ,1H),6.15-6.09(m,1H),5.71-5.66(m,1H),4.59-4.52(m,1H),4.20-4.13(m,1H),3.56(s,3H), 3.24-3.17(m,1H),3.16-3.09(m,1H),2.80-2.73(m,1H),2.00-1.92(m,2H),1.63-1.49(m,2H). MS(ESI,m / z):470.5[M+H] + .

[0308] Example 9: 7-(1-(But-2-ynyl)piperidin-4-yl)-1-methyl-2-(4-phenoxyphenyl)-1H-imidazole 1,2-b]pyrazole-3-carboxamide

[0309]

[0310] To a solution of the product of Example 5 (100 mg, 0.21 mmol) in DMF (2 mL) were added NaHCO₃ (72 mg, 0.84 mmol) and CH₃I (61 mg, 0.42 mmol). The reaction mixture was stirred at room temperature for another 3.5 hours. The mixture was quenched with saturated sodium bicarbonate solution. Dichloromethane and water were added, the layers were separated, the aqueous phase was extracted with dichloromethane, and the combined organic phases were washed with saturated brine (3×20 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by chromatography using dichloromethane and methanol (40:1) to give 7-(1-(but-2-ynyl)piperidin-4-yl)-1-methyl-2-(4-phenoxyphenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide as an off-white solid (42 mg, 40.8%). 1H NMR(400MHz,DMSO-d6)δ8.14(s,1H),7.65(s,1H),7.63(s,1H),7.56-7.51(m,2H ),7.50-7.43(m,2H),7.23(t,J=7.4Hz,1H),7.17-7.13(m,2H),7.11-7.05(m,2H) ,4.47-4.32(m,2H),3.55(s,3H),3.31-3.20(m,1H),3.17-3.07(m,1H),2.85-2. 75(m,1H),2.04(s,3H),2.01-1.89(m,2H),1.68-1.55(m,1H),1.54-1.42(m,1H). MS(ESI,m / z):482.5[M+H] + .

[0311] Example 10: (E)-2-(4-phenoxyphenyl)-7-(1-(4,4,4-trifluorobut-2-enoyl)piperidin-4-yl)- 1H-Imidazolo[1,2-b]pyrazole-3-carboxamide

[0312]

[0313] A solution of the product from Example 1, Step 1 (180 mg, 0.44 mmol) in DMF (5 mL) was basified to pH 7-8 with N,N-diisopropylethylamine. After 5 minutes, (E)-4,4,4-trifluoro-2-butenoic acid (92 mg, 0.66 mmol) and HATU (184 mg, 0.48 mmol) were added. The reaction mixture was stirred at room temperature for an additional 10 minutes. Dichloromethane and water were added, the layers were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with saturated brine (3 x 50 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by chromatography with dichloromethane and methanol (10:1) to give (E)-2-(4-phenoxyphenyl)-7-(1-(4,4,4-trifluorobut-2-enoyl)piperidin-4-yl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide as an off-white solid (103 mg, 44.8%). 1H NMR (400MHz, DMSO-d6) δ12.09(s,1H),8.36(s,1H),7.86-7.81(m,2H),7.71(s,1H),7.54(s,1H),7.48-7.39(m,3H),7.23-7.18(m,1H),7.12-7. 07(m,4H),6.82-6.71(m,1H),4.60-4.46(m,1H),4.19-4.06(m,1H),3.2 7-3.15(m,1H),2.95-2.74(m,2H),2.02-1.90(m,2H),1.77-1.56(m,2H). MS(ESI,m / z):524.5[M+H] + .

[0314] Example 11: (E)-7-(1-(4-(dimethylamino)but-2-enoyl)piperidin-4-yl)-2-(4-phenoxybenzene 1H-imidazo[1,2-b]pyrazole-3-carboxamide

[0315]

[0316] A solution of the product from Example 1, Step 1 (180 mg, 0.44 mmol) in DMF (5 mL) was basified to pH 7-8 with N,N-diisopropylethylamine. After 5 minutes, (E)-4-(dimethylamino)-2-butenoic acid (87 mg, 0.66 mmol) and HATU (184 mg, 0.48 mmol) were added. The reaction mixture was stirred at room temperature for an additional 10 minutes. Dichloromethane and water were added, the layers were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with saturated brine (3 x 50 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by chromatography with dichloromethane and methanol (10:1) to give (E)-7-(1-(4-(dimethylamino)but-2-enoyl)piperidin-4-yl)-2-(4-phenoxyphenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide as an off-white solid (90 mg, 39.2%). 1H NMR(600MHz,DMSO-d6)δ8.37(s,1H),7.83(d,J=8.7Hz,2H),7.69(s,1H),7.54(s,1 H),7.45(t,J=7.9Hz,2H),7.21(t,J=7.4Hz,1H),7.12-7.07(m,4H),6.69-6.57(m,2 H),4.57-4.50(m,1H),4.16-4.08(m,1H),3.19-3.12(m,1H),3.09(d,J=5.8Hz,2H), 2.92-2.84(m,1H),2.76-2.67(m,1H),2.19(s,6H),1.94(s,2H),1.68-1.55(m,2H). MS(ESI,m / z):513.6[M+H] + .

[0317] Example 12: 7-(1-cyanopiperidin-4-yl)-2-(4-phenoxyphenyl)-1H-imidazo[1,2-b]pyrazole-3- Formamide

[0318]

[0319] A solution of the product from Example 1, Step I (180 mg, 0.44 mmol) in THF (5 mL) was basified to pH 7-8 with N,N-diisopropylethylamine. The mixture was then cooled to 0°C, and a solution of cyanogen bromide (52 mg, 0.49 mmol) in THF (1 mL) was slowly added. The reaction mixture was stirred at 0°C for 1 hour. Dichloromethane and water were added, the layers were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with saturated brine (3 x 50 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by chromatography using dichloromethane and methanol (20:1) to give 7-(1-cyanopiperidin-4-yl)-2-(4-phenoxyphenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide as a yellow solid (106 mg, 55.4%). 1 H NMR (600MHz, DMSO-d6) δ12.14(s,1H),8.36(s,1H),7.85(d,J=8.7Hz,2H),7.71(s,1H),7.55(s,1H),7.45(t,J=7.9Hz,2H),7.21(t ,J=7.4Hz,1H),7.13-7.07(m,4H),3.48-3.41(m,2H),3.21-3.13(m,2H),2.78-2.70(m,1H),1.96-1.90(m,2H),1.84-1.74(m,2H). MS(ESI,m / z):427.5[M+H] + .

[0320] Example 13: 7-(1-acryloylpiperidin-4-yl)-2-(4-(4-fluorophenoxy)phenyl)-1H-imidazo[1, 2-b]pyrazole-3-carboxamide

[0321]

[0322] Step A: Preparation of methyl 3-(4-(4-fluorophenoxy)phenyl)-3-oxopropanoate

[0323]

[0324] To a solution of NaH (60% dispersion in mineral oil; 24 g, 0.60 mol) in anhydrous DMF (300 mL) was added dropwise a solution of 1-(4-(4-fluorophenoxy)phenyl)ethanone (70 g, 0.30 mol) in anhydrous DMF (50 mL) at 0°C with stirring. After 30 minutes, dimethyl carbonate (108 g, 1.2 mol) was added dropwise at 0°C. The temperature was allowed to rise to room temperature over 2 hours, and the reaction mixture was poured into a 1:1 water / saturated sodium bicarbonate solution. The aqueous layer was extracted with ethyl acetate (3 x 500 mL). The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by chromatography using petroleum ether and ethyl acetate (10:1) to afford the desired product, methyl 3-(4-(4-fluorophenoxy)phenyl)-3-oxopropanoate, as a yellow solid (83 g, 96.0%). 1 H NMR (400MHz, DMSO-d6) δ7.99 (d, J = 8.9 Hz, 2H), 7.34-7.28 (m, 2H), 7.24-7.18 (m, 2H), 7.07-7.02 (m, 2H), 4.17 (s, 2H), 3.66 (s, 3H). MS(ESI,m / z):289.3[M+H] + .

[0325] Step B: Preparation of 3-(4-(4-fluorophenoxy)phenyl)-3-oxopropionamide

[0326]

[0327] To a solution of the product from Example 13, Step A (83 g, 0.29 mol) in 1,4-dioxane (100 mL) was added 7M NH3 / 1,4-dioxane (100 mL) in a 300 mL sealed tube at room temperature. The tube was sealed and the mixture was stirred at 95°C for 12 hours, then cooled to room temperature. The mixture was concentrated under vacuum. The residue was purified by chromatography using petroleum ether and ethyl acetate (1:1) to give the desired product, 3-(4-(4-fluorophenoxy)phenyl)-3-oxopropanamide, as a light yellow solid (50 g, 63.1%). 1H NMR (600MHz, DMSO-d6) δ7.98 (d, J = 8.8 Hz, 2H), 7.29 (d, J = 8.7 Hz, 2H), 7.23-7.18 (m, 2H), 7.05-7.02 (m, 2H), 3.81 (s, 2H). MS(ESI,m / z):274.3[M+H] + .

[0328] Step C: Preparation of 2-bromo-3-(4-(4-fluorophenoxy)phenyl)-3-oxopropionamide

[0329]

[0330] CuBr2 (45 g, 0.20 mol) was added to a solution of the product of Example 13 Step B (50 g, 0.18 mol) in ethyl acetate (500 ml). The mixture was stirred at 50 ° C until no further changes were observed by TLC. The mixture was filtered through celite. The filtrate was diluted with ethyl acetate and water. After separation, the organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by chromatography using petroleum ether and ethyl acetate (3:2) to give the target product, 2-bromo-3-(4-(4-fluorophenoxy)phenyl)-3-oxopropanamide, as a yellow solid (60 g, 94.6%). MS (ESI, m / z): 353.2 [M + H] + .

[0331] Step D: Preparation of 4-(3-carbamoyl-2-(4-(4-fluorophenoxy)phenyl)-1H-imidazo[1,2-b]pyrrolidone tert-Butyl oxazol-7-yl)piperidine-1-carboxylate

[0332]

[0333] The product from Example 1, Step G (10 g, 0.037 mol) and the product from Example 13, Step C (10 g, 0.03 mol) were heated to reflux in ethanol (100 mL) overnight. The reaction was then cooled to room temperature, and the solvent was removed under vacuum. The crude residue was purified by chromatography using petroleum ether and ethyl acetate (3:2) to afford the desired product, tert-butyl 4-(3-carbamoyl-2-(4-(4-fluorophenoxy)phenyl)-1H-imidazo[1,2-b]pyrazol-7-yl)piperidine-1-carboxylate, as a yellow solid (2.5 g, 12.8%). 1H NMR (600MHz, DMSO-d6) δ12.09(s,1H),8.37(s,1H),7.84(d,J=8.2Hz,2H),7.70(s,1H),7.53(s,1H),7.29(t,J=8.4Hz,2H),7.18-7.14 (m,2H),7.07(d,J=8.1Hz,2H),4.04(s,2H),2.82-2.71(m,2H),2.02-1.95(m,1H),1.92-1.85(m,2H),1.63-1.54(m,2H),1.41(s,9H). MS(ESI,m / z):520.6[M+H] + .

[0334] Step E: Preparation of 2-(4-(4-fluorophenoxy)phenyl)-7-(piperidin-4-yl)-1H-imidazo[1,2-b]pyrazole- 3-Formamide

[0335]

[0336] To a solution of the product from Example 13, Step D (2.5 g, 4.8 mmol) in EtOH (2 mL) was added a 33% HCl / EtOH solution (10 mL) at room temperature. The mixture was stirred for 3 hours, then concentrated under vacuum to yield 2.4 g of crude 2-(4-(4-fluorophenoxy)phenyl)-7-(piperidin-4-yl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide. The residue was used directly in the next step.

[0337] Step F: Preparation of 7-(1-acryloylpiperidin-4-yl)-2-(4-(4-fluorophenoxy)phenyl)-1H-imidazo[1, 2-b]pyrazole-3-carboxamide

[0338]

[0339] The product from Example 13, Step E (180 mg, 0.43 mmol) was dissolved in THF / H₂O (3:1, 4 mL) and basified with NaHCO₃ to pH 7-8. The mixture was then cooled to 0°C and a solution of acryloyl chloride (58 mg, 0.64 mmol) in THF (1 mL) was slowly added. The reaction mixture was stirred at 0°C for 1 hour. Dichloromethane and water were then added to the reaction mixture. The layers were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with saturated brine (3 x 50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by chromatography using dichloromethane and methanol (30:1) to afford 7-(1-acryloylpiperidin-4-yl)-2-(4-(4-fluorophenoxy)phenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide as an off-white solid (84 mg, 41.3%). 1H NMR(400MHz,DMSO-d6)δ12.10(s,1H),8.36(s,1H),7.86-7.79(m,2H),7.70(s,1H),7 .54(s,1H),7.31-7.25(m,2H),7.19-7.12(m,2H),7.08-7.04(m,2H),6.90-6.80(m,1 H),6.14-6.07(m,1H),5.70-5.64(m,1H),4.58-4.49(m,1H),4.20-4.09(m,1H),3.21 -3.09(m,1H),2.92-2.83(m,1H),2.78-2.67(m,1H),1.99-1.88(m,2H),1.62(s,2H). MS(ESI,m / z):474.5[M+H] + .

[0340] Example 14: 7-(1-(But-2-ynyl)piperidin-4-yl)-2-(4-(4-fluorophenoxy)phenyl)-1H-imidazole 1,2-b]pyrazole-3-carboxamide

[0341]

[0342] A solution of the product from Example 13, Step E (180 mg, 0.43 mmol) in DMF (5 mL) was basified to pH 7-8 with N,N-diisopropylethylamine. After 5 minutes, 2-butynoic acid (54 mg, 0.64 mmol) and HATU (180 mg, 0.47 mmol) were added. The reaction mixture was stirred at room temperature for another 30 minutes. Dichloromethane and water were then added to the reaction mixture. The layers were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with saturated brine (3 x 50 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by chromatography using dichloromethane and methanol (30:1) to afford 7-(1-(but-2-ynyl)piperidin-4-yl)-2-(4-(4-fluorophenoxy)phenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide as an off-white solid (118 mg, 56.5%). 1HNMR(400MHz,DMSO-d6)δ12.10(s,1H),8.35(s,1H),7.83(d,J=8.8Hz,2H),7.70(s,1H),7.54(s,1H),7.35-7.24(m,2H),7.21-7.13(m,2H),7.07 (d,J=8.8Hz,2H),4.45-4.30(m,2H),3.27-3.17(m,1H),2.94-2.82(m,1H ),2.82-2.70(m,1H),2.03(s,3H),1.97-1.84(m,2H),1.76-1.50(m,2H). MS(ESI,m / z):486.5[M+H] + .

[0343] Example 15: 2-(4-(4-fluorophenoxy)phenyl)-7-(1-propioloylpiperidin-4-yl)-1H-imidazo[1, 2-b]pyrazole-3-carboxamide

[0344]

[0345] A solution of the product from Example 13, Step E (180 mg, 0.43 mmol) in DMF (5 mL) was basified to pH 7-8 with N,N-diisopropylethylamine. After 5 minutes, propiolic acid (45 mg, 0.64 mmol) and HATU (180 mg, 0.47 mmol) were added. The reaction mixture was stirred at room temperature for an additional 30 minutes. Dichloromethane and water were then added to the reaction mixture. The layers were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with saturated brine (3 x 50 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by chromatography using dichloromethane and methanol (30:1) to afford 2-(4-(4-fluorophenoxy)phenyl)-7-(1-propioloylpiperidin-4-yl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide as an off-white solid (120 mg, 59.4%). 1 H NMR (600MHz, DMSO-d6) δ8.64(d,J=8.8Hz,2H),8.53(s,1H),7.30(t,J=8.7Hz,2H),7.22-7.19(m,2H),7.17(d,J=8.6Hz,2H),4.58(s,1H),4.55 -4.51(m,1H),4.47-4.42(m,1H),3.64-3.57(m,1H),3.45-3.38(m,1H) ,2.98-2.90(m,1H),2.11(s,1H),2.08-2.03(m,2H),1.96-1.92(m,1H). MS(ESI,m / z):472.5[M+H] + .

[0346] Example 16: ( E )-2-(4-(4-fluorophenoxy)phenyl)-7-(1-(4,4,4-trifluorobut-2-enoyl)piperidin- 4-amino)-1H-imidazo[1,2-b]pyrazole-3-carboxamide

[0347]

[0348] A solution of the product from Example 13, Step E (180 mg, 0.43 mmol) in DMF (5 mL) was basified to pH 7-8 with N,N-diisopropylethylamine. After 5 minutes, (E)-4,4,4-trifluoro-2-butenoic acid (90 mg, 0.64 mmol) and HATU (180 mg, 0.47 mmol) were added. The reaction mixture was stirred at room temperature for 10 minutes. Dichloromethane and water were then added to the reaction mixture. The layers were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with saturated brine (3 x 50 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by chromatography with dichloromethane and methanol (10:1) to give (E)-2-(4-(4-fluorophenoxy)phenyl)-7-(1-(4,4,4-trifluoro-2-butenoyl)piperidin-4-yl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide as an off-white solid (121 mg, 52.2%). 1 H NMR(400MHz,DMSO-d6)δ12.10(s,1H),8.36(s,1H),7.86-7.78(m,2H),7.70( s,1H),7.54(s,1H),7.46-7.38(m,1H),7.34-7.24(m,2H),7.19-7.12(m,2H) ,7.10-7.04(m,2H),6.82-6.70(m,1H),4.59-4.46(m,1H),4.18-4.06(m,1H) ,3.27-3.16(m,1H),2.94-2.76(m,2H),2.01-1.90(m,2H),1.74-1.56(m,2H). MS (ESI, m / z): 542.5 [M+H] + .

[0349] Example 17: 7-(1-acryloylpiperidin-4-yl)-2-(4-(2,4-difluorophenoxy)phenyl)-1H-imidazo [1,2-b]pyrazole-3-carboxamide

[0350]

[0351] Step A: Preparation of methyl 3-(4-(2,4-difluorophenoxy)phenyl)-3-oxopropanoate

[0352]

[0353] To a suspension of NaH (60% dispersion in mineral oil; 23 g, 0.56 mol) in anhydrous DMF (300 mL) was added dropwise a solution of 1-(4-(2,4-difluorophenoxy)phenyl)ethanone (70 g, 0.28 mol) in anhydrous DMF (50 mL) at 0°C with stirring. After 30 minutes, dimethyl carbonate (101 g, 1.12 mol) was added dropwise to the reaction mixture at 0°C. The system temperature was allowed to rise to room temperature over 2 hours, and the reaction mixture was then poured into a 1:1 water / saturated sodium bicarbonate solution. The aqueous layer was extracted with ethyl acetate (3 x 500 mL). The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by chromatography using petroleum ether and ethyl acetate (10:1) to give the desired product, methyl 3-(4-(2,4-difluorophenoxy)phenyl)-3-oxopropanoate, as a yellow solid (81 g, 94.5%). MS (ESI, m / z): 307.3 [M+H] + .

[0354] Step B: Preparation of 3-(4-(2,4-difluorophenoxy)phenyl)-3-oxopropionamide

[0355]

[0356] To a solution of the product from Example 17, Step A (81 g, 0.26 mol) in 1,4-dioxane (100 mL) was added 7M NH3 / 1,4-dioxane (100 mL) in a 300 mL sealed tube at room temperature. The tube was sealed and the mixture was stirred at 95°C for 12 hours, then cooled to room temperature. The mixture was concentrated under vacuum. The residue was purified by chromatography using petroleum ether and ethyl acetate (1:1) to give the desired product, 3-(4-(2,4-difluorophenoxy)phenyl)-3-oxopropanamide, as a light yellow solid (48 g, 63.4%). 1 H NMR (400MHz, DMSO-d6) δ7.98 (d, J = 8.9 Hz, 2H), 7.56-7.51 (m, 1H), 7.46-7.39 (m, 1H), 7.24-7.17 (m, 1H), 7.06 (s, 1H), 7.04 (s, 1H), 3.82 (s, 2H). MS(ESI,m / z):292.3[M+H] + .

[0357] Step C: Preparation of 2-bromo-3-(4-(2,4-difluorophenoxy)phenyl)-3-oxopropionamide

[0358]

[0359] CuBr2 (40 g, 0.18 mol) was added to a solution of the product of Example 17 Step B (48 g, 0.16 mol) in ethyl acetate (500 ml). The mixture was stirred at 50 ° C until no further changes were observed by TLC. The mixture was filtered through celite. The filtrate was diluted with ethyl acetate and water. After separation, the organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by chromatography using petroleum ether and ethyl acetate (3:2) to give the target product, 2-bromo-3-(4-(2,4-difluorophenoxy)phenyl)-3-oxopropanamide, as a yellow solid (50 g, 84.4%). MS (ESI, m / z): 371.1 [M + H] + .

[0360] Step D: Preparation of 4-(3-carbamoyl-2-(4-(2,4-difluorophenoxy)phenyl)-1H-imidazo[1,2-b] tert-Butyl pyrazol-7-yl)piperidine-1-carboxylate

[0361]

[0362] The product from Example 1, Step G (10 g, 0.037 mol) and the product from Example 17, Step C (11 g, 0.03 mol) were heated to reflux in ethanol (100 mL) overnight. The reaction was then cooled to room temperature, and the solvent was removed under vacuum. The crude residue was purified by chromatography using petroleum ether and ethyl acetate (3:2) to afford the desired product, tert-butyl 4-(3-carbamoyl-2-(4-(2,4-difluorophenoxy)phenyl)-1H-imidazo[1,2-b]pyrazol-7-yl)piperidine-1-carboxylate, as a yellow solid (3.2 g, 16.1%). 1 H NMR (400MHz, DMSO-d6) δ12.10(s,1H),8.36(s,1H),7.82(d,J=8.8Hz,2H),7.70(s,1H),7.56-7.48(m,2H),7.43-7.36(m,1H),7. 23-7.15(m,1H),7.05(d,J=8.8Hz,2H),4.10-4.00(m,2H),2.91-2.70(m,3H),1.93-1.85(m,2H),1.65-1.51(m,2H),1.41(s,9H). MS(ESI,m / z):538.6[M+H] + .

[0363] Step E: Preparation of 2-(4-(2,4-difluorophenoxy)phenyl)-7-(piperidin-4-yl)-1H-imidazo[1,2-b]pyrrolidone Azole-3-carboxamide

[0364]

[0365] To a solution of the product from Example 17, Step D (3.2 g, 5.9 mmol) in ethanol (2 mL) was added a 33% HCl / EtOH solution (10 mL) at room temperature. The mixture was stirred for 3 hours, then concentrated under vacuum to yield 3.0 g of crude 2-(4-(2,4-difluorophenoxy)phenyl)-7-(piperidin-4-yl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide. The residue was used directly in the next step.

[0366] Step F: Preparation of 7-(1-acryloylpiperidin-4-yl)-2-(4-(2,4-difluorophenoxy)phenyl)-1H-imidazole 1,2-b]pyrazole-3-carboxamide

[0367]

[0368] A solution of the product from Example 17, Step E (180 mg, 0.41 mmol) in THF / H₂O (3:1, 4 mL) was basified with NaHCO₃ to pH 7-8. The mixture was then cooled to 0°C, and a solution of acryloyl chloride (56 mg, 0.62 mmol) in THF (1 mL) was slowly added. The reaction mixture was stirred at 0°C for 1 hour. Dichloromethane and water were then added to the reaction mixture. The layers were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with saturated brine (3 x 50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by chromatography using dichloromethane and methanol (30:1) to afford 7-(1-acryloylpiperidin-4-yl)-2-(4-(2,4-difluorophenoxy)phenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide as an off-white solid (96 mg, 47.8%). 1 H NMR (600MHz, DMSO-d6) δ12.11(s,1H),8.34(s,1H),7.80(d,J=8.5Hz,2H),7.69(s,1H),7. 55-7.51(m,2H),7.43-7.37(m,1H),7.19(t,J=7.7Hz,1H),7.04(d,J=8.5Hz,2H),6.88-6.8 1(m,1H),6.14-6.08(m,1H),5.70-5.65(m,1H),4.59-4.50(m,1H),4.18-4.10(m,1H),3.20 -3.11(m,1H),2.91-2.83(m,1H),2.78-2.69(m,1H),1.98-1.89(m,2H),1.69-1.56(m,2H). MS(ESI,m / z):492.5[M+H] + .

[0369] Example 18: 7-(1-(but-2-ynyl)piperidin-4-yl)-2-(4-(2,4-difluorophenoxy)phenyl)-1H- imidazo[1,2-b]pyrazole-3-carboxamide

[0370]

[0371] A solution of the product from Example 17, Step E (180 mg, 0.41 mmol) in DMF (5 mL) was basified to pH 7-8 with N,N-diisopropylethylamine. After 5 minutes, 2-butynoic acid (52 mg, 0.62 mmol) and HATU (171 mg, 0.45 mmol) were added. The reaction mixture was stirred at room temperature for 30 minutes. Dichloromethane and water were then added to the reaction mixture. The layers were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with saturated brine (3 x 50 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by chromatography with dichloromethane and methanol (30:1) to give 7-(1-(but-2-ynyl)piperidin-4-yl)-2-(4-(2,4-difluorophenoxy)phenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide as an off-white solid (120 mg, 58.2%). 1 H NMR(600MHz,DMSO-d6)δ12.11(s,1H),8.34(s,1H),7.81(d,J=8.5Hz,2H),7.70(s,1 H),7.57-7.50(m,2H),7.43-7.37(m,1H),7.19(t,J=8.5Hz,1H),7.05(d,J=8.5Hz,2H ),4.43-4.31(m,2H),3.25-3.18(m,1H),2.91-2.83(m,1H),2.79-2.72(m,1H),2.03 (s,3H),1.97-1.92(m,1H),1.91-1.87(m,1H),1.73-1.64(m,1H),1.61-1.53(m,1H). MS(ESI,m / z):504.5[M+H] + .

[0372] Example 19: 2-(4-(2,4-difluorophenoxy)phenyl)-7-(1-propioloylpiperidin-4-yl)-1H-imidazo [1,2-b]pyrazole-3-carboxamide

[0373]

[0374] A solution of the product from Example 17, Step E (180 mg, 0.41 mmol) in DMF (5 mL) was basified to pH 7-8 with N,N-diisopropylethylamine. After 5 minutes, propiolic acid (43 mg, 0.62 mmol) and HATU (171 mg, 0.45 mmol) were added. The reaction mixture was stirred at room temperature for another 30 minutes. Dichloromethane and water were then added to the reaction mixture. The layers were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with saturated brine (3 x 50 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by chromatography using dichloromethane and methanol (30:1) to afford 2-(4-(2,4-difluorophenoxy)phenyl)-7-(1-propioloylpiperidin-4-yl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide as an off-white solid (116 mg, 57.8%). 1 H NMR (400MHz, DMSO-d6) δ12.11(s,1H),8.35(s,1H),7.81(d,J=8.7Hz,2H),7.71(s,1H),7.57-7.47(m,2H),7.44-7.35(m,1H),7.19(t,J=8.3 Hz,1H),7.05(d,J=8.7Hz,2H),4.54(s,1H),4.46-4.28(m,2H),3.32-3.23(m,1H),2.98-2.74(m,2H),2.01-1.87(m,2H),1.77-1.51(m,2H). MS(ESI,m / z):490.5[M+H] + .

[0375] Example 20: 7-(1-acryloylpiperidin-4-yl)-2-(4-(4-methoxyphenoxy)phenyl)-1H-imidazo [1,2-b]pyrazole-3-carboxamide

[0376]

[0377] Step A: Preparation of methyl 3-(4-(4-methoxyphenoxy)phenyl)-3-oxopropanoate

[0378]

[0379] To a suspension of NaH (60% dispersion in mineral oil; 23 g, 0.58 mol) in anhydrous DMF (300 mL) was added dropwise a solution of 1-(4-(4-methoxyphenoxy)phenyl)ethanone (70 g, 0.29 mol) in anhydrous DMF (50 mL) at 0°C with stirring. After 30 minutes, dimethyl carbonate (104 g, 1.16 mol) was added to the reaction mixture at 0°C. The system was warmed to room temperature over 2 hours, and the reaction mixture was then poured into a 1:1 water / saturated sodium bicarbonate solution. The aqueous layer was extracted with ethyl acetate (3 x 500 mL). The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by chromatography using petroleum ether and ethyl acetate (10:1) to yield the desired product, methyl 3-(4-(4-methoxyphenoxy)phenyl)-3-oxopropanoate, as a yellow solid (85 g, 97.6%). 1 H NMR (400MHz, DMSO-d6) δ7.95 (d, J = 8.9 Hz, 2H), 7.14-7.07 (m, 2H), 7.05-6.93 (m, 4H), 4.15 (s, 2H), 3.78 (s, 3H), 3.64 (s, 3H). MS(ESI,m / z):301.3[M+H] + .

[0380] Step B: Preparation of 3-(4-(4-methoxyphenoxy)phenyl)-3-oxopropionamide

[0381]

[0382] To a solution of the product of Example 20 Step A (85 g, 0.28 mol) in 1,4-dioxane (100 mL) was added 7M NH3 / 1,4-dioxane (100 mL) in a 300 mL sealed tube at room temperature. The tube was sealed and the mixture was stirred at 95 ° C for 12 hours and then cooled to room temperature. The mixture was concentrated under vacuum to obtain a crude product. The residue was purified by chromatography using petroleum ether and ethyl acetate (1:1) to obtain the target product, 3-(4-(4-methoxyphenoxy)phenyl)-3-oxopropanamide, as a light yellow solid (50 g, 61.9%). 1 H NMR (600MHz, DMSO-d6) δ7.97 (d, J = 8.8 Hz, 2H), 7.10 (s, 2H), 7.02 (d, J = 9.0 Hz, 2H), 6.98 (d, J = 8.8 Hz, 2H), 3.81 (s, 2H), 3.78 (s, 3H). MS(ESI,m / z):286.3[M+H] + .

[0383] Step C: Preparation of 2-bromo-3-(4-(4-methoxyphenoxy)phenyl)-3-oxopropionamide

[0384]

[0385] CuBr2 (42 g, 0.19 mol) was added to a solution of the product of Example 20 Step B (50 g, 0.17 mol) in ethyl acetate (500 ml). The mixture was stirred at 50 ° C until no further changes were observed by TLC. The mixture was filtered through celite. The filtrate was diluted with ethyl acetate and water. After separation, the organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by chromatography using petroleum ether and ethyl acetate (3:2) to give the target product, 2-bromo-3-(4-(4-methoxyphenoxy)phenyl)-3-oxopropanamide, as a yellow solid (55 g, 88.8%). MS (ESI, m / z): 365.2 [M + H] + .

[0386] Step D: Preparation of 4-(3-carbamoyl-2-(4-(4-methoxyphenoxy)phenyl)-1H-imidazo[1,2-b] tert-Butyl pyrazol-7-yl)piperidine-1-carboxylate

[0387]

[0388] The product from Example 1, Step G (10 g, 0.037 mol) and the product from Example 20, Step C (11 g, 0.03 mol) were heated to reflux in ethanol (100 mL) overnight. The reaction was then cooled to room temperature, and the solvent was removed under vacuum. The crude residue was purified by chromatography using petroleum ether and ethyl acetate (3:2) to afford the desired product, tert-butyl 4-(3-carbamoyl-2-(4-(4-methoxyphenoxy)phenyl)-1H-imidazo[1,2-b]pyrazol-7-yl)piperidine-1-carboxylate, as a yellow solid (2.8 g, 14.2%). 1 H NMR (400MHz, DMSO-d6) δ12.08(s,1H),8.37(s,1H),7.80(d,J=8.7Hz,2H),7.69(s,1H),7.53(s,1H),7.11-7.06(m,2H),7 .03-6.98(m,4H),4.09-3.98(m,2H),3.77(s,3H),2.92-2.68(m,3H),1.93-1.84(m,2H),1.64-1.51(m,2H),1.41(s,9H). MS(ESI,m / z):532.6[M+H] + .

[0389] Step E: Preparation of 2-(4-(4-methoxyphenoxy)phenyl)-7-(piperidin-4-yl)-1H-imidazo[1,2-b]pyrrolidone Azole-3-carboxamide

[0390]

[0391] To a solution of the product from Example 20, Step D (2.8 g, 5.3 mmol) in ethanol (2 mL) was added 33% HCl / EtOH (10 mL) at room temperature. The mixture was stirred for 3 hours, then concentrated under vacuum to yield 2.6 g of crude 2-(4-(4-methoxyphenoxy)phenyl)-7-(piperidin-4-yl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide. The residue was used directly in the next step.

[0392] Step F: Preparation of 7-(1-acryloylpiperidin-4-yl)-2-(4-(4-methoxyphenoxy)phenyl)-1H-imidazole 1,2-b]pyrazole-3-carboxamide

[0393]

[0394] A solution of the product from Example 20, Step E (180 mg, 0.42 mmol) in THF / H₂O (3:1, 4 mL) was basified with NaHCO₃ to pH 7-8. The mixture was then cooled to 0°C, and a solution of acryloyl chloride (57 mg, 0.63 mmol) in THF (1 mL) was slowly added. The reaction mixture was stirred at 0°C for 1 hour. Dichloromethane and water were then added to the reaction mixture. The layers were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with saturated brine (3 x 50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by chromatography using dichloromethane and methanol (30:1) to afford 7-(1-acryloylpiperidin-4-yl)-2-(4-(4-methoxyphenoxy)phenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide as an off-white solid (123 mg, 60.3%). 1 H NMR (400MHz, DMSO-d6) δ12.08(s,1H),8.35(s,1H),7.79(d,J=8.8Hz,2H),7.68(s,1H ),7.53(s,1H),7.10-7.05(m,2H),7.03-6.98(m,4H),6.89-6.80(m,1H),6.14-6.08(m ,1H),5.70-5.65(m,1H),4.59-4.49(m,1H),4.20-4.10(m,1H),3.77(s,3H),3.22-3.1 0(m,1H),2.92-2.82(m,1H),2.78-2.68(m,1H),1.98-1.89(m,2H),1.69-1.54(m,2H). MS(ESI,m / z):486.5[M+H] + .

[0395] Example 21: 7-(1-(But-2-ynyl)piperidin-4-yl)-2-(4-(4-methoxyphenoxy)phenyl)-1H- imidazo[1,2-b]pyrazole-3-carboxamide

[0396]

[0397] A solution of the product from Example 20, Step E (180 mg, 0.42 mmol) in DMF (5 mL) was basified to pH 7-8 with N,N-diisopropylethylamine. After 5 minutes, 2-butynoic acid (53 mg, 0.63 mmol) and HATU (176 mg, 0.46 mmol) were added. The reaction mixture was stirred at room temperature for an additional 30 minutes. Dichloromethane and water were then added to the reaction mixture. The layers were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with saturated brine (3 x 50 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by chromatography using dichloromethane and methanol (30:1) to afford 7-(1-(but-2-ynyl)piperidin-4-yl)-2-(4-(4-methoxyphenoxy)phenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide as an off-white solid (142 mg, 67.9%). 1 H NMR (400MHz, DMSO-d6) δ12.09(s,1H),8.35(s,1H),7.79(d,J=8.8Hz,2H),7.68(s,1H),7.54(s,1H),7.15-7.06(m,2H),7.04-6.98(m,4H),4 .44-4.31(m,2H),3.78(s,3H),3.27-3.16(m,1H),2.92-2.82(m,1H), 2.81-2.71(m,1H),2.03(s,3H),1.98-1.84(m,2H),1.75-1.50(m,2H). MS(ESI,m / z):498.6[M+H] + .

[0398] Example 22: 2-(4-(4-methoxyphenoxy)phenyl)-7-(1-propioloylpiperidin-4-yl)-1H-imidazo [1,2-b]pyrazole-3-carboxamide

[0399]

[0400] A solution of the product from Example 20, Step E (180 mg, 0.42 mmol) in DMF (5 mL) was basified to pH 7-8 with N,N-diisopropylethylamine. After 5 minutes, propiolic acid (44 mg, 0.63 mmol) and HATU (176 mg, 0.46 mmol) were added. The reaction mixture was stirred at room temperature for an additional 30 minutes. Dichloromethane and water were then added to the reaction mixture. The layers were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with saturated brine (3 x 50 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by chromatography using dichloromethane and methanol (30:1) to afford 2-(4-(4-methoxyphenoxy)phenyl)-7-(1-propioloylpiperidin-4-yl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide as an off-white solid (136 mg, 67.0%). 1 H NMR(400MHz, CDCl3)δ8.35(s,1H),7.84-7.77(m,2H),7.69(s,1H),7.55(s,1H),7.12-7.06(m,2H),7.05-6.98(m,4H),4 .55(s,1H),4.45-4.28(m,2H),3.78(s,3H),3.31-3.22(m,1H),2.94-2.75(m,2H),2.01-1.88(m,2H),1.78-1.53(m,2H). MS(ESI,m / z):484.5[M+H] + .

[0401] Example 23: 7-(1-acryloylpiperidin-4-yl)-2-(4-(2-methoxyphenoxy)phenyl)-1H-imidazo [1,2-b]pyrazole-3-carboxamide

[0402]

[0403] Step A: Preparation of methyl 3-(4-(2-methoxyphenoxy)phenyl)-3-oxopropanoate

[0404]

[0405] To a suspension of NaH (60% dispersion in mineral oil; 23 g, 0.58 mol) in anhydrous DMF (300 mL) was added dropwise a solution of 1-(4-(2-methoxyphenoxy)phenyl)ethanone (70 g, 0.29 mol) in anhydrous DMF (50 mL) at 0°C with stirring. After 30 minutes, dimethyl carbonate (104 g, 1.16 mol) was added dropwise at 0°C. The system was warmed to room temperature over 2 hours, and the reaction mixture was poured into a 1:1 water / saturated sodium bicarbonate solution. The aqueous layer was extracted with ethyl acetate (3 x 500 mL). The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by chromatography using petroleum ether and ethyl acetate (10:1) to yield the desired product, methyl 3-(4-(2-methoxyphenoxy)phenyl)-3-oxopropanoate, as a yellow solid (84 g, 96.4%). 1 H NMR(400MHz,DMSO-d6)δ7.97-7.91(m,2H),7.33-7.27(m,1H),7.24-7.15(m,2H ),7.06-7.01(m,1H),6.94-6.88(m,2H),4.15(s,2H),3.73(s,3H),3.65(s,3H). MS(ESI,m / z):301.3[M+H] + .

[0406] Step B: Preparation of 3-(4-(2-methoxyphenoxy)phenyl)-3-oxopropionamide

[0407]

[0408] To a solution of the product of Example 23 Step A (85 g, 0.28 mol) in 1,4-dioxane (100 mL) was added 7 M NH 3 / 1,4-dioxane (100 mL) in a 300 mL sealed tube at room temperature. The tube was sealed and the mixture was stirred at 95 ° C for 12 hours and then cooled to room temperature. The mixture was concentrated under vacuum to obtain a crude product. The residue was purified by chromatography using petroleum ether and ethyl acetate (1: 1) to obtain the target product, 3- (4- (2-methoxyphenoxy) phenyl) -3- oxopropanamide, as a light yellow solid (53 g, 66.3%). 1 H NMR(400MHz,DMSO-d6)δ7.95-7.90(m,2H),7.30-7.27(m,1H),7.23-7.20(m,1H),7.18 -7.15(m,1H),7.06-7.00(m,1H),6.90(s,1H),6.87(s,1H),3.79(s,2H),3.73(s,3H). MS(ESI,m / z):286.3[M+H] + .

[0409] Step C: Preparation of 2-bromo-3-(4-(2-methoxyphenoxy)phenyl)-3-oxopropionamide

[0410]

[0411] CuBr2 (42 g, 0.19 mol) was added to a solution of the product of Example 23 Step B (50 g, 0.17 mol) in ethyl acetate (500 ml). The mixture was stirred at 50 ° C until no further changes were observed by TLC. The mixture was filtered through celite. The filtrate was diluted with ethyl acetate and water. After separation, the organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by chromatography using petroleum ether and ethyl acetate (3:2) to give the target product, 2-bromo-3-(4-(2-methoxyphenoxy)phenyl)-3-oxopropanamide, as a yellow solid (58 g, 93.7%). MS (ESI, m / z): 365.2 [M + H] + .

[0412] Step D: Preparation of 4-(3-carbamoyl-2-(4-(2-methoxyphenoxy)phenyl)-1H-imidazo[1,2-b] tert-Butyl pyrazol-7-yl)piperidine-1-carboxylate

[0413]

[0414] The product from Example 1, Step G (10 g, 0.037 mol) and the product from Example 23, Step C (11 g, 0.03 mol) were heated to reflux in ethanol (100 mL) overnight. The reaction was then cooled to room temperature, and the solvent was removed under vacuum. The crude residue was purified by chromatography using petroleum ether and ethyl acetate (3:2) to afford the desired product, tert-butyl 4-(3-carbamoyl-2-(4-(2-methoxyphenoxy)phenyl)-1H-imidazo[1,2-b]pyrazol-7-yl)piperidine-1-carboxylate, as a yellow solid (3.3 g, 16.8%). 1 H NMR(400MHz,DMSO-d6)δ12.06(s,1H),8.34(s,1H),7.76-7.73(m,2H),7. 67(s,1H),7.52(s,1H),7.29-7.25(m,1H),7.23-7.21(m,1H),7.15-7.12( m,1H),7.04-7.01(m,1H),6.91-6.87(m,2H),4.09-3.99(m,2H),3.76(s,3 H),2.93-2.71(m,3H),1.91-1.85(m,2H),1.62-1.54(m,2H),1.41(s,9H). MS (ESI, m / z): 532.6 [M+H] + .

[0415] Step E: Preparation of 2-(4-(2-methoxyphenoxy)phenyl)-7-(piperidin-4-yl)-1H-imidazo[1,2-b]pyrrolidone Azole-3-carboxamide

[0416]

[0417] To a solution of the product from Example 23, Step D (3.3 g, 6.2 mmol) in ethanol (2 mL) was added 33% HCl / EtOH (10 mL) at room temperature. The mixture was stirred for 3 hours and then concentrated under vacuum to yield 3.0 g of crude 2-(4-(2-methoxyphenoxy)phenyl)-7-(piperidin-4-yl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide. The residue was used directly in the next step.

[0418] Step F: Preparation of 7-(1-acryloylpiperidin-4-yl)-2-(4-(2-methoxyphenoxy)phenyl)-1H-imidazole 1,2-b]pyrazole-3-carboxamide

[0419]

[0420] A solution of the product from Example 23, Step E (180 mg, 0.42 mmol) in THF / H₂O (3:1, 4 mL) was basified with NaHCO₃ to pH 7-8. The mixture was then cooled to 0°C, and a solution of acryloyl chloride (57 mg, 0.63 mmol) in THF (1 mL) was slowly added. The reaction mixture was stirred at 0°C for 1 hour. Dichloromethane and water were then added to the reaction mixture. The layers were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with saturated brine (3 x 50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by chromatography using dichloromethane and methanol (30:1) to afford 7-(1-acryloylpiperidin-4-yl)-2-(4-(2-methoxyphenoxy)phenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide as an off-white solid (127 mg, 62.3%). 1H NMR(600MHz,DMSO-d6)δ12.06(s,1H),8.34(s,1H),7.74(d,J=8.7Hz,2H),7.66(s,1H),7.52(s,1H),7.2 7(t,J=7.7Hz,1H),7.22(d,J=8.0Hz,1H),7.13(d,J=7.6Hz,1H),7.03(t,J=7.6Hz,1H),6.89(d,J=8.7Hz, 2H),6.87-6.82(m,1H),6.12-6.09(m,1H),5.68-5.66(m,1H),4.58-4.49(m,1H),4.18-4.09(m,1H),3.7 6(s,3H),3.20-3.11(m,1H),2.89-2.85(m,1H),2.78-2.68(m,1H),1.96-1.89(m,2H),1.68-1.53(m,2H). MS(ESI,m / z):486.5[M+H] + .

[0421] Example 24: 7-(1-(But-2-ynyl)piperidin-4-yl)-2-(4-(2-methoxyphenoxy)phenyl)-1H- imidazo[1,2-b]pyrazole-3-carboxamide

[0422]

[0423] A solution of the product from Example 23, Step E (180 mg, 0.42 mmol) in DMF (5 mL) was basified to pH 7-8 with N,N-diisopropylethylamine. After 5 minutes, 2-butynoic acid (53 mg, 0.63 mmol) and HATU (176 mg, 0.46 mmol) were added. The reaction mixture was stirred at room temperature for an additional 30 minutes. Dichloromethane and water were then added to the reaction mixture. The layers were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with saturated brine (3 x 50 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by chromatography using dichloromethane and methanol (30:1) to afford 7-(1-(but-2-ynyl)piperidin-4-yl)-2-(4-(2-methoxyphenoxy)phenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide as an off-white solid (138 mg, 66.0%). 1H NMR (400MHz, DMSO-d6) δ12.07(s,1H),8.34(s,1H),7.75(d,J=8.8Hz,2H),7.68(s,1 H),7.54(s,1H),7.30-7.20(m,2H),7.16-7.12(m,1H),7.06-7.01(m,1H),6.92-6.87 (m,2H),4.44-4.31(m,2H),3.77(s,3H),3.26-3.17(m,1H),2.92-2.82(m,1H),2.81 -2.71(m,1H),2.03(s,3H),1.99-1.85(m,2H),1.75-1.64(m,1H),1.63-1.51(m,1H). MS(ESI,m / z):498.6[M+H] + .

[0424] Example 25: 2-(4-(2-methoxyphenoxy)phenyl)-7-(1-propioloylpiperidin-4-yl)-1H-imidazo [1,2-b]pyrazole-3-carboxamide

[0425]

[0426] A solution of the product from Example 23, Step E (180 mg, 0.42 mmol) in DMF (5 mL) was basified to pH 7-8 with N,N-diisopropylethylamine. After 5 minutes, propiolic acid (44 mg, 0.63 mmol) and HATU (176 mg, 0.46 mmol) were added. The reaction mixture was stirred at room temperature for an additional 30 minutes. Dichloromethane and water were then added to the reaction mixture. The layers were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with saturated brine (3 x 50 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by chromatography using dichloromethane and methanol (30:1) to afford 2-(4-(2-methoxyphenoxy)phenyl)-7-(1-propioloylpiperidin-4-yl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide as an off-white solid (136 mg, 67.0%). 1H NMR(400MHz,DMSO-d6)δ12.07(s,1H),8.34(s,1H),7.75(d,J=8.7Hz,2H),7 .68(s,1H),7.54(s,1H),7.30-7.19(m,2H),7.16-7.11(m,1H),7.06-7.00( m,1H),6.90(d,J=8.7Hz,2H),4.54(s,1H),4.44-4.27(m,2H),3.77(s,3H), 3.32-3.22(m,1H),2.93-2.75(m,2H),2.01-1.85(m,2H),1.77-1.53(m,2H). MS (ESI, m / z): 484.5 [M+H] + .

[0427] Example 26: 7-(1-acryloylpiperidin-4-yl)-2-(4-(2-fluorophenoxy)phenyl)-1H-imidazo[1, 2-b]pyrazole-3-carboxamide

[0428]

[0429] Step A: Preparation of methyl 3-(4-(2-fluorophenoxy)phenyl)-3-oxopropanoate

[0430]

[0431] To a suspension of NaH (60% dispersion in mineral oil; 24 g, 0.60 mol) in anhydrous DMF (300 mL) was added dropwise a solution of 1-(4-(2-fluorophenoxy)phenyl)ethanone (70 g, 0.30 mol) in anhydrous DMF (50 mL) at 0°C with stirring. After 30 minutes, dimethyl carbonate (108 g, 1.2 mol) was added dropwise at 0°C. The system was warmed to room temperature over 2 hours, and the reaction mixture was poured into a 1:1 water / saturated sodium bicarbonate solution. The aqueous layer was extracted with ethyl acetate (3 x 500 mL). The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by chromatography using petroleum ether and ethyl acetate (10:1) to yield the desired product, methyl 3-(4-(2-fluorophenoxy)phenyl)-3-oxopropanoate, as a yellow solid (81 g, 93.7%). 1 H NMR (400MHz, DMSO-d6) δ8.03-7.96(m,2H),7.50-7.42(m,1H),7.39-7.27(m,3H),7.09-7.03(m,2H),4.18(s,2H),3.65(s,3H). MS(ESI,m / z):289.3[M+H] + .

[0432] Step B: Preparation of 3-(4-(2-fluorophenoxy)phenyl)-3-oxopropionamide

[0433]

[0434] To a solution of the product of Example 26 Step A (81 g, 0.28 mol) in 1,4-dioxane (100 mL) was added 7M NH3 / 1,4-dioxane (100 mL) in a 300 mL sealed tube at room temperature. The tube was sealed and the mixture was stirred at 95 ° C for 12 hours and then cooled to room temperature. The mixture was concentrated under vacuum to obtain a crude product. The residue was purified by chromatography using petroleum ether and ethyl acetate (1:1) to obtain the target product, 3-(4-(2-fluorophenoxy)phenyl)-3-oxopropanamide, as a light yellow solid (46 g, 59.9%). 1 H NMR(600MHz,DMSO-d6)δ7.99(d,J=8.7Hz,2H),7.58(s,1H),7.44(d,J=8.5Hz,1H) ,7.34(s,1H),7.32-7.28(m,2H),7.09(s,1H),7.04(d,J=8.8Hz,2H),3.82(s,2H). MS(ESI,m / z):274.3[M+H] + .

[0435] Step C: Preparation of 2-bromo-3-(4-(2-fluorophenoxy)phenyl)-3-oxopropionamide

[0436]

[0437] CuBr2 (41 g, 0.18 mol) was added to a solution of the product of Example 26 Step B (46 g, 0.17 mol) in ethyl acetate (500 ml). The mixture was stirred at 50 ° C until no further changes were observed by TLC. The mixture was filtered through celite. The filtrate was diluted with ethyl acetate and water. After separation, the organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by chromatography using petroleum ether and ethyl acetate (3:2) to give the target product, 2-bromo-3-(4-(2-fluorophenoxy)phenyl)-3-oxopropanamide, as a yellow solid (52 g, 86.8%). MS (ESI, m / z): 353.2 [M + H] + .

[0438] Step D: Preparation of 4-(3-carbamoyl-2-(4-(2-fluorophenoxy)phenyl)-1H-imidazo[1,2-b]pyrrolidone tert-Butyl oxazol-7-yl)piperidine-1-carboxylate

[0439]

[0440] The product from Example 1, Step G (10 g, 0.037 mol) and the product from Example 26, Step C (10 g, 0.03 mol) were heated to reflux in ethanol (100 mL) overnight. The reaction was then cooled to room temperature, and the solvent was removed under vacuum. The crude residue was purified by chromatography using petroleum ether and ethyl acetate (3:2) to afford the desired product, tert-butyl 4-(3-carbamoyl-2-(4-(2-fluorophenoxy)phenyl)-1H-imidazo[1,2-b]pyrazol-7-yl)piperidine-1-carboxylate, as a yellow solid (3.3 g, 17.2%). 1 H NMR (400MHz, DMSO-d6) δ12.10(s,1H),8.36(s,1H),7.82(d,J=8.9Hz,2H),7.70(s,1H),7.54(s,1H),7.48-7.40(m,1H),7.33- 7.27(m,3H),7.05(d,J=8.8Hz,2H),4.11-3.98(m,2H),2.90-2.70(m,3H),1.94-1.83(m,2H),1.65-1.51(m,2H),1.41(s,9H). MS(ESI,m / z):[M+H] + .

[0441] Step E: Preparation of 2-(4-(2-fluorophenoxy)phenyl)-7-(piperidin-4-yl)-1H-imidazo[1,2-b]pyrazole- 3-Formamide

[0442]

[0443] To a solution of the product from Example 26, Step D (3.3 g, 6.4 mmol) in ethanol (2 mL) was added 33% HCl / EtOH (10 mL) at room temperature. The mixture was stirred for 3 hours, then concentrated under vacuum to yield 2.4 g of crude 2-(4-(2-fluorophenoxy)phenyl)-7-(piperidin-4-yl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide. The residue was used directly in the next step.

[0444] Step F: Preparation of 7-(1-acryloylpiperidin-4-yl)-2-(4-(2-fluorophenoxy)phenyl)-1H-imidazo[1, 2-b]pyrazole-3-carboxamide

[0445]

[0446] A solution of the product from Example 26, Step E (180 mg, 0.43 mmol) in THF / H₂O (3:1, 4 mL) was basified with NaHCO₃ to pH 7-8. The mixture was then cooled to 0°C, and a solution of acryloyl chloride (58 mg, 0.64 mmol) in THF (1 mL) was slowly added. The reaction mixture was stirred at 0°C for 1 hour. Dichloromethane and water were then added to the reaction mixture. The layers were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with saturated brine (3 x 50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by chromatography using dichloromethane and methanol (30:1) to afford 7-(1-acryloylpiperidin-4-yl)-2-(4-(2-fluorophenoxy)phenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide as an off-white solid (125 mg, 61.4%). 1 H NMR (400MHz, DMSO-d6) δ12.12(s,1H),8.37(s,1H),7.82(d,J=8.8Hz,2H),7.71(s,1H), 7.54(s,1H),7.48-7.39(m,1H),7.33-7.26(m,3H),7.05(d,J=8.8Hz,2H),6.89-6.79(m, 1H),6.16-6.07(m,1H),5.71-5.63(m,1H),4.61-4.49(m,1H),4.20-4.09(m,1H),3.21-3 .10(m,1H),2.93-2.82(m,1H),2.78-2.67(m,1H),1.99-1.88(m,2H),1.70-1.55(m,2H). MS(ESI,m / z):474.5[M+H] + .

[0447] Example 27: 7-(1-(But-2-ynyl)piperidin-4-yl)-2-(4-(2-fluorophenoxy)phenyl)-1H-imidazole 1,2-b]pyrazole-3-carboxamide

[0448]

[0449] A solution of the product from Example 26, Step E (180 mg, 0.43 mmol) in DMF (5 mL) was basified to pH 7-8 with N,N-diisopropylethylamine. After 5 minutes, 2-butynoic acid (54 mg, 0.64 mmol) and HATU (180 mg, 0.47 mmol) were added. The reaction mixture was stirred at room temperature for an additional 30 minutes. Dichloromethane and water were then added to the reaction mixture. The layers were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with saturated brine (3 x 50 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by chromatography using dichloromethane and methanol (30:1) to afford 7-(1-(but-2-ynyl)piperidin-4-yl)-2-(4-(2-fluorophenoxy)phenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide as an off-white solid (131 mg, 62.7%). 1 HNMR(400MHz,DMSO-d6)δ12.12(s,1H),8.37(s,1H),7.83(d,J=8.7Hz,2H) ,7.72(s,1H),7.55(s,1H),7.47-7.39(m,1H),7.34-7.25(m,3H),7.06(d, J=8.7Hz,2H),4.47-4.30(m,2H),3.27-3.16(m,1H),2.93-2.82(m,1H),2. 81-2.70(m,1H),1.99-1.84(m,2H),1.76-1.65(m,1H),1.63-1.51(m,1H). MS(ESI,m / z):486.5[M+H] + .

[0450] Example 28: 2-(4-(2-fluorophenoxy)phenyl)-7-(1-propioloylpiperidin-4-yl)-1H-imidazo[1, 2-b]pyrazole-3-carboxamide

[0451]

[0452] A solution of the product from Example 26, Step E (180 mg, 0.43 mmol) in DMF (5 mL) was basified to pH 7-8 with N,N-diisopropylethylamine. After 5 minutes, propiolic acid (45 mg, 0.64 mmol) and HATU (180 mg, 0.47 mmol) were added. The reaction mixture was stirred at room temperature for another 30 minutes. Dichloromethane and water were then added to the reaction mixture. The layers were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with saturated brine (3 x 50 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by chromatography using dichloromethane and methanol (30:1) to afford 2-(4-(2-fluorophenoxy)phenyl)-7-(1-propioloylpiperidin-4-yl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide as an off-white solid (136 mg, 67.1%). 1 H NMR(600MHz,DMSO-d6)δ12.14(s,1H),8.34(s,1H),7.82(d,J=7.7Hz,2H),7.71(s,1H) ,7.56(s,1H),7.48-7.41(m,1H),7.33-7.27(m,3H),7.06(d,J=7.8Hz,2H),4.54(s,1H) ,4.44-4.38(m,1H),4.36-4.31(m,1H),3.32-3.24(m,1H),2.93-2.86(m,1H),2.84-2. 77(m,1H),2.00-1.95(m,1H),1.94-1.89(m,1H),1.76-1.67(m,1H),1.66-1.57(m,1H). MS(ESI,m / z):472.5[M+H] + .

[0453] Example 29: 7-(1-acryloylpiperidin-4-yl)-2-(4-(4-chlorophenoxy)phenyl)-1H-imidazo[1, 2-b]pyrazole-3-carboxamide

[0454]

[0455] Step A: Preparation of methyl 3-(4-(4-chlorophenoxy)phenyl)-3-oxopropanoate

[0456]

[0457] To a suspension of NaH (60% dispersion in mineral oil; 23 g, 0.56 mol) in anhydrous DMF (300 mL) was added dropwise a solution of 1-(4-(4-chlorophenoxy)phenyl)ethanone (70 g, 0.28 mol) in anhydrous DMF (50 mL) at 0°C with stirring. After 30 minutes, dimethyl carbonate (101 g, 1.2 mol) was added dropwise at 0°C. The system was warmed to room temperature over 2 hours, and the reaction mixture was poured into a 1:1 water / saturated sodium bicarbonate solution. The aqueous layer was extracted with ethyl acetate (3 x 500 mL). The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by chromatography using petroleum ether and ethyl acetate (10:1) to yield the desired product, methyl 3-(4-(4-chlorophenoxy)phenyl)-3-oxopropanoate, as a white solid (82 g, 96.1%). MS (ESI, m / z): 305.7 [M+H] + .

[0458] Step B: Preparation of 3-(4-(4-chlorophenoxy)phenyl)-3-oxopropionamide

[0459]

[0460] To a solution of the product of Example 29 Step A (82 g, 0.27 mol) in 1,4-dioxane (100 mL) was added 7M NH3 / 1,4-dioxane (100 mL) in a 300 mL sealed tube at room temperature. The tube was sealed and the mixture was stirred at 95 ° C for 12 hours and then cooled to room temperature. The mixture was concentrated under vacuum to obtain a crude product. The residue was purified by chromatography with petroleum ether and ethyl acetate (1: 1) to give the target product 3- (4- (4-chlorophenoxy) phenyl) -3-oxopropanamide as a light yellow solid (48 g, 61.5%). MS (ESI, m / z): 290.7 [M + H] + .

[0461] Step C: Preparation of 2-bromo-3-(4-(4-chlorophenoxy)phenyl)-3-oxopropionamide

[0462]

[0463] CuBr2 (41 g, 0.18 mol) was added to a solution of the product of Example 29 Step B (48 g, 0.16 mol) in ethyl acetate (500 ml). The mixture was stirred at 50 ° C until no further changes were observed by TLC. The mixture was filtered through celite. The filtrate was diluted with ethyl acetate and water. After separation, the organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by chromatography using petroleum ether and ethyl acetate (3:2) to give the target product, 2-bromo-3-(4-(4-chlorophenoxy)phenyl)-3-oxopropanamide, as a yellow solid (50 g, 84.7%). MS (ESI, m / z): 369.6 [M + H] + .

[0464] Step D: Preparation of 4-(3-carbamoyl-2-(4-(4-chlorophenoxy)phenyl)-1H-imidazo[1,2-b]pyrrolidone tert-Butyl oxazol-7-yl)piperidine-1-carboxylate

[0465]

[0466] The product from Example 1, Step G (8.5 g, 0.032 mol) and the product from Example 29, Step C (10 g, 0.027 mol) were heated to reflux in ethanol (100 mL) overnight. The reaction was then cooled to room temperature, and the solvent was removed under vacuum. The crude residue was purified by chromatography using petroleum ether and ethyl acetate (3:2) to afford the desired product, tert-butyl 4-(3-carbamoyl-2-(4-(4-chlorophenoxy)phenyl)-1H-imidazo[1,2-b]pyrazol-7-yl)piperidine-1-carboxylate, as an off-white solid (3.0 g, 20.7%). 1 H NMR (400MHz, DMSO-d6) δ12.11(s,1H),8.38(s,1H),7.86(d,J=8.5Hz,2H),7.71(s,1H),7.54(s,1H),7.49(d,J=8.8Hz ,2H),7.12(d,J=8.6Hz,4H),4.11-3.98(m,2H),2.90-2.70(m,3H),1.94-1.84(m,2H),1.64-1.54(m,2H),1.41(s,9H). MS(ESI,m / z):537.0[M+H] + .

[0467] Step E: Preparation of 2-(4-(4-chlorophenoxy)phenyl)-7-(piperidin-4-yl)-1H-imidazo[1,2-b]pyrazole- 3-Formamide

[0468]

[0469] To a solution of the product from Example 29, Step D (3.0 g, 5.6 mmol) in ethanol (2 mL) was added 33% HCl / EtOH (10 mL) at room temperature. The mixture was stirred for 3 hours, then concentrated under vacuum to yield 2.5 g of crude 2-(4-(4-chlorophenoxy)phenyl)-7-(piperidin-4-yl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide. The residue was used directly in the next step.

[0470] Step F: Preparation of 7-(1-acryloylpiperidin-4-yl)-2-(4-(4-chlorophenoxy)phenyl)-1H-imidazo[1, 2-b]pyrazole-3-carboxamide

[0471]

[0472] A solution of the product from Example 29, Step E (180 mg, 0.33 mmol) in THF / H₂O (3:1, 4 mL) was basified with NaHCO₃ to pH 7-8. The mixture was then cooled to 0°C, and a solution of acryloyl chloride (45 mg, 0.50 mmol) in THF (1 mL) was slowly added. The reaction mixture was stirred at 0°C for 1 hour. Dichloromethane and water were then added to the reaction mixture. The layers were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with saturated brine (3 x 50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by chromatography using dichloromethane and methanol (30:1) to afford 7-(1-acryloylpiperidin-4-yl)-2-(4-(4-chlorophenoxy)phenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide as an off-white solid (109 mg, 67.7%). 1 H NMR (400MHz, DMSO-d6) δ12.13(s,1H),8.37(s,1H),7.86(d,J=8.8Hz,2H),7.70(s ,1H),7.54(s,1H),7.51-7.46(m,2H),7.15-7.09(m,4H),6.90-6.80(m,1H),6.16- 6.07(m,1H),5.71-5.65(m,1H),4.60-4.48(m,1H),4.19-4.09(m,1H),3.17(d,J= 5.2Hz,1H),2.93-2.84(m,1H),2.79-2.69(m,1H),1.98-1.90(m,2H),1.63(s,2H). MS(ESI,m / z):490.2[M+H] + .

[0473] Example 30: 2-(4-(4-chlorophenoxy)phenyl)-7-(1-propioloylpiperidin-4-yl)-1H-imidazo[1, 2-b]pyrazole-3-carboxamide

[0474]

[0475] A solution of the product from Example 29, Step E (180 mg, 0.33 mmol) in DMF (5 mL) was basified to pH 7-8 with N,N-diisopropylethylamine. After 5 minutes, propiolic acid (34 mg, 0.49 mmol) and HATU (139 mg, 0.36 mmol) were added. The reaction mixture was stirred at room temperature for an additional 30 minutes. Dichloromethane and water were then added to the reaction mixture. The layers were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with saturated brine (3 x 50 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by chromatography using dichloromethane and methanol (30:1) to afford 2-(4-(4-chlorophenoxy)phenyl)-7-(1-propioloylpiperidin-4-yl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide as an off-white solid (120 mg, 75.0%). 1 H NMR (600MHz, DMSO-d6) δ12.14(s,1H),8.38(s,1H),7.86(d,J=8.3Hz,2H),7.72(s, 1H),7.56(s,1H),7.49(d,J=8.5Hz,2H),7.13(t,J=7.8Hz,4H),4.54(s,1H),4.44- 4.39(m,1H),4.37-4.31(m,1H),3.31-3.24(m,1H),2.94-2.86(m,1H),2.85-2.77( m,1H),2.00-1.95(m,1H),1.94-1.89(m,1H),1.76-1.68(m,1H),1.66-1.58(m,1H). MS(ESI,m / z):488.1[M+H] + .

[0476] Example 31: 7-(1-acryloylpiperidin-4-yl)-2-(4-(4-bromophenoxy)phenyl)-1H-imidazo[1, 2-b]pyrazole-3-carboxamide

[0477]

[0478] Step A: Preparation of methyl 3-(4-(4-bromophenoxy)phenyl)-3-oxopropanoate

[0479]

[0480] To a suspension of NaH (60% dispersion in mineral oil; 19 g, 0.48 mol) in anhydrous DMF (300 mL) was added dropwise a solution of 1-(4-(4-bromophenoxy)phenyl)ethanone (70 g, 0.24 mol) in anhydrous DMF (50 mL) at 0°C with stirring. After 30 minutes, dimethyl carbonate (87 g, 0.96 mol) was added dropwise at 0°C. The system was warmed to room temperature over 2 hours, and the reaction mixture was poured into a 1:1 water / saturated sodium bicarbonate solution. The aqueous layer was extracted with ethyl acetate (3 x 500 mL). The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by chromatography using petroleum ether and ethyl acetate (10:1) to yield the desired product, methyl 3-(4-(4-bromophenoxy)phenyl)-3-oxopropanoate, as a pale yellow solid (80 g, 95.3%). MS (ESI, m / z): 350.2 [M+H] + .

[0481] Step B: Preparation of 3-(4-(4-bromophenoxy)phenyl)-3-oxopropionamide

[0482]

[0483] To a solution of the product of Example 31 Step A (80 g, 0.23 mol) in 1,4-dioxane (100 mL) was added 7M NH3 / 1,4-dioxane (100 mL) in a 300 mL sealed tube at room temperature. The tube was sealed and the mixture was stirred at 95 ° C for 12 hours and then cooled to room temperature. The mixture was concentrated under vacuum to obtain a crude product. The residue was purified by chromatography with petroleum ether and ethyl acetate (1: 1) to give the target product 3- (4- (4-bromophenoxy) phenyl) -3-oxopropanamide as a light yellow solid (45 g, 58.8%). MS (ESI, m / z): 335.2 [M + H] + .

[0484] Step C: Preparation of 2-bromo-3-(4-(4-bromophenoxy)phenyl)-3-oxopropionamide

[0485]

[0486] CuBr2 (33 g, 0.15 mol) was added to a solution of the product of Example 31 Step B (45 g, 0.13 mol) in ethyl acetate (500 ml). The mixture was stirred at 50 ° C until no further changes were observed by TLC. The mixture was filtered through celite. The filtrate was diluted with ethyl acetate and water. After separation, the organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by chromatography using petroleum ether and ethyl acetate (3:2) to give the target product, 2-bromo-3-(4-(4-bromophenoxy)phenyl)-3-oxopropanamide, as a yellow solid (52 g, 93.5%). MS (ESI, m / z): 414.1 [M + H] + .

[0487] Step D: Preparation of 4-(2-(4-(4-bromophenoxy)phenyl)-3-carbamoyl-1H-imidazo[1,2-b]pyrrolidone tert-Butyl oxazol-7-yl)piperidine-1-carboxylate

[0488]

[0489] The product from Example 1, Step G (8.0 g, 0.03 mol) and the product from Example 31, Step C (10 g, 0.024 mol) were heated to reflux in ethanol (100 mL) overnight. The reaction was then cooled to room temperature, and the solvent was removed under vacuum. The crude residue was purified by chromatography using petroleum ether and ethyl acetate (3:2) to afford the desired product, tert-butyl 4-(2-(4-(4-bromophenoxy)phenyl)-3-carbamoyl-1H-imidazo[1,2-b]pyrazol-7-yl)piperidine-1-carboxylate, as an off-white solid (2.8 g, 16.1%). 1 H NMR (600MHz, DMSO-d6) δ12.12(s,1H),8.41(s,1H),7.87(t,J=5.7Hz,2H),7.72(s,1H),7.63-7.58(m,2H),7.54(s,1H),7.13( d,J=8.7Hz,2H),7.09-7.04(m,2H),4.11-4.00(m,2H),2.91-2.72(m,3H),1.92-1.86(m,2H),1.65-1.55(m,2H),1.42(s,9H). MS(ESI,m / z):581.5[M+H] + .

[0490] Step E: Preparation of 2-(4-(4-bromophenoxy)phenyl)-7-(piperidin-4-yl)-1H-imidazo[1,2-b]pyrazole- 3-Formamide

[0491]

[0492] To a solution of the product from Example 31, Step D (2.8 g, 4.8 mmol) in ethanol (2 mL) was added 33% HCl / EtOH (10 mL) at room temperature. The mixture was stirred for 3 hours, then concentrated under vacuum to yield 2.0 g of crude 2-(4-(4-bromophenoxy)phenyl)-7-(piperidin-4-yl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide. The residue was used directly in the next step.

[0493] Step F: Preparation of 7-(1-acryloylpiperidin-4-yl)-2-(4-(4-bromophenoxy)phenyl)-1H-imidazo[1, 2-b]pyrazole-3-carboxamide

[0494]

[0495] A solution of the product from Example 31, Step E (180 mg, 0.37 mmol) in THF / H₂O (3:1, 4 mL) was basified with NaHCO₃ to pH 7-8. The mixture was then cooled to 0°C, and a solution of acryloyl chloride (51 mg, 0.56 mmol) in THF (1 mL) was slowly added. The reaction mixture was stirred at 0°C for 1 hour. Dichloromethane and water were then added to the reaction mixture. The layers were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with saturated brine (3 x 50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by chromatography using dichloromethane and methanol (30:1) to afford 7-(1-acryloylpiperidin-4-yl)-2-(4-(4-bromophenoxy)phenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide as an off-white solid (118 mg, 58.9%). 1 H NMR (400MHz, DMSO-d6) δ12.13(s,1H),8.37(s,1H),7.89-7.83(m,2H),7.71(s,1H),7. 64-7.57(m,2H),7.54(s,1H),7.17-7.10(m,2H),7.08-7.02(m,2H),6.90-6.80(m,1H) ,6.14-6.07(m,1H),5.69-5.65(m,1H),4.62-4.49(m,1H),4.21-4.08(m,1H),3.22-3. 10(m,1H),2.93-2.83(m,1H),2.79-2.68(m,1H),1.98-1.90(m,2H),1.69-1.56(m,2H). MS(ESI,m / z):534.1[M+H] + .

[0496] Example 32: 7-(1-acryloylpiperidin-4-yl)-2-(4-(p-tolyloxy)phenyl)-1H-imidazo[1, 2-b]pyrazole-3-carboxamide

[0497]

[0498] Step A: Preparation of methyl 3-oxo-3-(4-(p-tolyloxy)phenyl)propanoate

[0499]

[0500] To a suspension of NaH (60% dispersion in mineral oil; 25 g, 0.62 mol) in anhydrous DMF (300 mL) was added dropwise a solution of 1-(4-(p-tolyloxy)phenyl)ethanone (70 g, 0.31 mol) in anhydrous DMF (50 mL) at 0°C with stirring. After 30 minutes, dimethyl carbonate (111 g, 1.24 mol) was added dropwise at 0°C. The system was warmed to room temperature over 2 hours, and the reaction mixture was poured into a 1:1 water / saturated sodium bicarbonate solution. The aqueous layer was extracted with ethyl acetate (3 x 500 mL). The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by chromatography using petroleum ether and ethyl acetate (10:1) to yield the desired product, methyl 3-oxo-3-(4-(p-tolyloxy)phenyl)propanoate, as an off-white solid (82 g, 93.2%). MS (ESI, m / z): 285.3 [M+H] + .

[0501] Step B: Preparation of 3-oxo-3-(4-(p-tolyloxy)phenyl)propionamide

[0502]

[0503] To a solution of the product of Example 32 Step A (82 g, 0.29 mol) in 1,4-dioxane (100 mL) was added 7M NH3 / 1,4-dioxane (100 mL) in a 300 mL sealed tube at room temperature. The tube was sealed and the mixture was stirred at 95 ° C for 12 hours and then cooled to room temperature. The mixture was concentrated under vacuum to obtain a crude product. The residue was purified by chromatography with petroleum ether and ethyl acetate (1: 1) to give the target product, 3-oxo-3-(4-(p-tolyloxy)phenyl)propanamide, as a light yellow solid (40 g, 51.5%). MS (ESI, m / z): 270.3 [M + H] + .

[0504] Step C: Preparation of 2-bromo-3-oxo-3-(4-(p-tolyloxy)phenyl)propionamide

[0505]

[0506] CuBr2 (36 g, 0.16 mol) was added to a solution of the product of Example 32 Step B (40 g, 0.15 mol) in ethyl acetate (500 ml). The mixture was stirred at 50 ° C until no further changes were observed by TLC. The mixture was filtered through celite. The filtrate was diluted with ethyl acetate and water. After separation, the organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by chromatography using petroleum ether and ethyl acetate (3:2) to give the target product, 2-bromo-3-oxo-3-(4-(p-tolyloxy)phenyl)propionamide, as a yellow solid (48 g, 92.8%). MS (ESI, m / z): 349.2 [M + H] + .

[0507] Step D: Preparation of 4-(3-carbamoyl-2-(4-(p-tolyloxy)phenyl)-1H-imidazo[1,2-b]pyrrolidone tert-Butyl oxazol-7-yl)piperidine-1-carboxylate

[0508]

[0509] The product from Example 1, Step G (8.0 g, 0.03 mol) and the product from Example 32, Step C (8.4 g, 0.024 mol) were heated to reflux overnight in ethanol (100 mL). The reaction was then cooled to room temperature, and the solvent was removed under vacuum. The crude residue was purified by chromatography using petroleum ether and ethyl acetate (3:2) to afford the desired product, tert-butyl 4-(3-carbamoyl-2-(4-(p-tolyloxy)phenyl)-1H-imidazo[1,2-b]pyrazol-7-yl)piperidine-1-carboxylate, as an off-white solid (3.0 g, 19.4%). 1 H NMR (400MHz, DMSO-d6) δ12.08(s,1H),8.39(s,1H),7.82(d,J=8.6Hz,2H),7.70(s,1H),7.53(s,1H),7.25(d,J=8.2Hz,2H),7 .06-6.98(m,4H),4.05(d,J=9.3Hz,2H),2.93-2.70(m,3H),2.32(s,3H),1.93-1.85(m,2H),1.65-1.53(m,2H),1.41(s,9H). MS(ESI,m / z):516.6[M+H] + .

[0510] Step E: Preparation of 7-(piperidin-4-yl)-2-(4-(p-tolyloxy)phenyl)-1H-imidazo[1,2-b]pyrazole- 3-Formamide

[0511]

[0512] To a solution of the product from Example 32, Step D (3.0 g, 5.8 mmol) in ethanol (2 mL) was added 33% HCl / EtOH (10 mL) at room temperature. The mixture was stirred for 3 hours, then concentrated under vacuum to yield 2.6 g of crude product, 7-(piperidin-4-yl)-2-(4-(p-tolyloxy)phenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide. The residue was used directly in the next step.

[0513] Step F: Preparation of 7-(1-acryloylpiperidin-4-yl)-2-(4-(p-tolyloxy)phenyl)-1H-imidazo[1, 2-b]pyrazole-3-carboxamide

[0514]

[0515] A solution of the product from Example 32, Step E (180 mg, 0.43 mmol) in THF / H₂O (3:1, 4 mL) was basified with NaHCO₃ to pH 7-8. The mixture was then cooled to 0°C, and a solution of acryloyl chloride (59 mg, 0.65 mmol) in THF (1 mL) was slowly added. The reaction mixture was stirred at 0°C for 1 hour. Dichloromethane and water were then added to the reaction mixture. The layers were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with saturated brine (3 x 50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by chromatography using dichloromethane and methanol (30:1) to afford 7-(1-acryloylpiperidin-4-yl)-2-(4-(p-tolyloxy)phenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide as an off-white solid (115 mg, 56.5%). 1 H NMR (400MHz, CDCl3) δ11.33(s,1H),8.83(s,1H),7.71(d,J=8.8Hz,2H),7.48(s,1 H),7.13(d,J=8.3Hz,2H),6.91-6.83(m,4H),6.52-6.43(m,1H),6.07-6.00(m,1H ),5.71(s,1H),5.61-5.56(m,1H),4.70-4.60(m,1H),4.04-3.95(m,1H),3.17-3. 06(m,1H),2.89-2.77(m,1H),2.70-2.59(m,1H),2.34(s,3H),1.96-1.81(m,4H). MS(ESI,m / z):470.5[M+H] + .

[0516] Example 33: 7-(1-acryloylpyrrolidin-3-yl)-2-(4-phenoxyphenyl)-1H-imidazo[1,2-b] Pyrazole-3-carboxamide

[0517]

[0518] Step A: Preparation of tert-butyl 3-(cyanomethylene)pyrrolidine-1-carboxylate

[0519]

[0520] To a suspension of NaH (60% dispersion in mineral oil; 48 g, 1.2 mol) in anhydrous THF (500 mL) was added a solution of diethyl cyanomethylphosphonate (230 g, 1.3 mol) in anhydrous THF (200 mL) with stirring at 10°C. After 30 minutes, tert-butyl 3-oxopyrrolidine-1-carboxylate (185 g, 1.0 mol) was added dropwise at 10°C. The mixture was allowed to warm to room temperature over 2 hours and then quenched with ice / water. The aqueous layer was extracted with ethyl acetate, and after removing the solvent under vacuum, the crude residue was recrystallized from petroleum ether and ethyl acetate (10:1) to give the target product, tert-butyl 3-(cyanomethylene)pyrrolidine-1-carboxylate, as a white solid (180 g, 86.5%). 1 H NMR (400MHz, CDCl3) δ 5.78-5.70 (m, 1H), 4.12 (s, 2H), 3.45 (t, J = 7.2Hz, 2H), 2.78 (s, 2H), 1.48 (d, J = 2.2Hz, 1H), 1.42 (s, 9H). MS(ESI,m / z):209.3[M+H] + .

[0521] Step B: Preparation of tert-butyl 3-(cyanomethyl)pyrrolidine-1-carboxylate

[0522]

[0523] To a solution of the product from Example 33, Step A (180 g, 0.86 mol) in ethyl acetate (1500 mL) was added 10% Pd / C (18 g, 10%) under N2 protection. The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred at room temperature under H2 for 5 hours. The mixture was passed through celite, the solid was washed with ethyl acetate, and the filtrate was concentrated under vacuum to afford the desired product, tert-butyl 3-(cyanomethyl)pyrrolidine-1-carboxylate, as a white solid (170 g, 94.0%). 1 H NMR (600MHz, DMSO-d6) δ3.44(dd,J=18.1,10.1Hz,1H),3.39-3.34(m,1H),3.24-3.15(m,1H),2.92(t,J=8.1Hz, 1H), 2.65 (t, J = 6.4Hz, 2H), 2.45 (dt, J = 14.9, 7.4Hz, 1H), 2.00 (d, J = 4.9Hz, 1H), 1.65-1.54 (m, 1H), 1.39 (s, 9H). MS(ESI,m / z):211.3[M+H]+ .

[0524] Step C: Preparation of tert-butyl 3-(1-cyano-2-oxoethyl)pyrrolidine-1-carboxylate

[0525]

[0526] The product of embodiment 33 step B (170g, 0.81mol) anhydrous THF (500mL) solution is cooled to -85 ℃ (liquid nitrogen / ethanol bath), then n-BuLi (2.5M normal hexane solution, 1.6L, 4.05mol) is added dropwise in the system, insulated and stirred for 30 minutes. Then ethyl formate (180g, 2.43mol) is added dropwise in the reaction solution, warming up to ice / water bath temperature, insulated and stirred for 30 minutes. Then it is quenched with ice / water, acidified to pH 5-6 with concentrated HCl, and extracted with ethyl acetate. The organic phase is washed with saturated common salt water, through anhydrous Na SO Drying, filtered and concentrated to obtain 203g crude product 3-(1-cyano-2-oxoethyl) pyrrolidine-1-carboxylic acid tert-butyl esters. Residue is directly used in the next step.

[0527] Step D: Preparation of tert-butyl 3-(5-amino-1H-pyrazol-4-yl)pyrrolidine-1-carboxylate

[0528]

[0529] The product of Example 33, Step C (203 g, 0.85 mol) and hydrazine hydrate (80%, 500 mL) were heated to 80° C. in ethanol (500 mL) and reacted for 10 hours. The reaction was then cooled to room temperature, and the solvent was removed under vacuum. The crude residue was purified by chromatography using petroleum ether and ethyl acetate (1:5) to give the desired product, tert-butyl 3-(5-amino-1H-pyrazol-4-yl)pyrrolidine-1-carboxylate, as a yellow solid (80 g, 39.1% yield over two steps). 1 H NMR(400MHz, DMSO-d6)δ7.23(d,J=1.4Hz,1H),3.68-3.60(m,1H),3.43(t,J=9.2Hz,1H),3.31-3.21( m,1H),3.18-3.06(m,1H),3.05-2.99(m,1H),2.11(d,J=5.8Hz,1H),1.89-1.76(m,1H),1.44(s,9H). MS(ESI,m / z):253.3[M+H] + .

[0530] Step E: Preparation of 3-(3-carbamoyl-2-(4-phenoxyphenyl)-1H-imidazo[1,2-b]pyrazol-7-yl) Pyrrolidine-1-carboxylic acid tert-butyl ester

[0531]

[0532] The product from Example 33, Step D (10 g, 39.6 mmol) and the product from Example 1, Step C (11 g, 31.7 mmol) were heated to reflux in ethanol (200 mL) overnight. The reaction was then cooled to room temperature, and the solvent was removed under vacuum. The crude residue was purified by chromatography using petroleum ether and ethyl acetate (3:2) to afford the desired product, tert-butyl 3-(3-carbamoyl-2-(4-phenoxyphenyl)-1H-imidazo[1,2-b]pyrazol-7-yl)pyrrolidine-1-carboxylate, as a yellow solid (2.6 g, 13.5%). 1 H NMR(600MHz,DMSO-d6)δ12.32(s,1H),8.35(s,1H),7.87(d,J=8.6Hz,2H),7.7 2(s,1H),7.58(s,1H),7.45(t,J=7.9Hz,2H),7.21(t,J=7.4Hz,1H),7.13-7.07 (m,4H),3.73-3.64(m,1H),3.33-3.25(m,1H),3.22(t,J=9.9Hz,1H),2.23-2. 14(m,1H),2.12-2.04(m,1H),1.41(d,J=9.4Hz,9H),1.30(s,1H),1.26(s,1H). MS (ESI, m / z): 488.6 [M+H] + .

[0533] Step F: Preparation of 2-(4-phenoxyphenyl)-7-(pyrrolidin-3-yl)-1H-imidazo[1,2-b]pyrazole-3-carboxylate Amide

[0534]

[0535] To a solution of the product from Example 33, Step E (2.6 g, 5.33 mmol) in ethanol (2 mL) was added 33% HCl / EtOH (5 mL) at room temperature. The mixture was stirred for 3 hours, then concentrated under vacuum to yield 2.4 g of crude 2-(4-phenoxyphenyl)-7-(pyrrolidin-3-yl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide. The residue was used directly in the next step.

[0536] Step G: Preparation of 7-(1-acryloylpyrrolidin-3-yl)-2-(4-phenoxyphenyl)-1H-imidazo[1,2-b] Pyrazole-3-carboxamide

[0537]

[0538] A solution of the product from Example 33, Step F (180 mg, 0.46 mmol) in THF / H₂O (3:1, 4 mL) was basified with NaHCO₃ to pH 7-8. The mixture was then cooled to 0°C, and a solution of acryloyl chloride (63 mg, 0.70 mmol) in THF (1 mL) was slowly added. The reaction mixture was stirred at 0°C for 1 hour. Dichloromethane and water were then added to the reaction mixture. The layers were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with saturated brine (3 x 50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by chromatography using dichloromethane and methanol (30:1) to afford 7-(1-acryloylpyrrolidin-3-yl)-2-(4-phenoxyphenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide as an off-white solid (132 mg, 65.0%). 1 HNMR(400MHz,DMSO-d6)δ12.18(s,1H),8.34(s,1H),7.90-7.83(m,2H),7.72(s,1H),7.60(d,J=5 .0Hz,1H),7.49-7.42(m,2H),7.20(t,J=7.4Hz,1H),7.12-7.07(m,4H),6.66-6.57(m,1H),6.21- 6.11(m,1H),5.71-5.64(m,1H),4.04-3.98(m,0.5H),3.94-3.88(m,0.5H),3.81-3.59(m,2H),3. 58-3.50(m,1H),3.49-3.43(m,1H),2.34-2.27(m,0.5H),2.26-2.12(m,1H),2.11-2.00(m,0.5H). MS(ESI,m / z):442.5[M+H] + .

[0539] Example 34: 7-(1-(But-2-ynyl)pyrrolidin-3-yl)-2-(4-phenoxyphenyl)-1H-imidazo[1, 2-b]pyrazole-3-carboxamide

[0540]

[0541] A solution of the product from Example 33, Step F (180 mg, 0.46 mmol) in DMF (5 mL) was basified to pH 7-8 with N,N-diisopropylethylamine. After 5 minutes, 2-butynoic acid (58 mg, 0.69 mmol) and HATU (192 mg, 0.51 mmol) were added. The reaction mixture was stirred at room temperature for an additional 30 minutes. Dichloromethane and water were then added to the reaction mixture. The layers were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with saturated brine (3 x 50 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by chromatography using dichloromethane and methanol (30:1) to afford 7-(1-(but-2-ynyl)pyrrolidin-3-yl)-2-(4-phenoxyphenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide as an off-white solid (135 mg, 64.7%). 1 H NMR (600MHz, DMSO-d6) δ12.20 (s, 1H), 8.35 (s, 1H), 7.90-7.84 (m, 2H), 7.75 (d, J = 3. 0Hz,1H),7.61(d,J=9.3Hz,1H),7.45(t,J=7.7Hz,2H),7.21(t,J=7.2Hz,1H),7.13-7 .08(m,4H),4.04-3.99(m,0.5H),3.88-3.78(m,1H),3.64-3.51(m,1.5H),3.50-3.38 (m,1H),3.33-3.25(m,1H),2.31-2.19(m,1H),2.18-2.09(m,1H),2.05-1.97(m,3H). MS(ESI,m / z):454.5[M+H] + .

[0542] Example 35: 2-(4-phenoxyphenyl)-7-(1-propioloylpyrrolidin-3-yl)-1H-imidazo[1,2-b] Pyrazole-3-carboxamide

[0543]

[0544] A solution of the product from Example 33, Step F (180 mg, 0.46 mmol) in DMF (5 mL) was basified to pH 7-8 with N,N-diisopropylethylamine. After 5 minutes, propiolic acid (48 mg, 0.69 mmol) and HATU (192 mg, 0.51 mmol) were added. The reaction mixture was stirred at room temperature for an additional 30 minutes. Dichloromethane and water were then added to the reaction mixture. The layers were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with saturated brine (3 x 50 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by chromatography using dichloromethane and methanol (30:1) to afford 2-(4-phenoxyphenyl)-7-(1-propioloylpyrrolidin-3-yl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide as an off-white solid (132 mg, 65.3%). 1 H NMR(600MHz,DMSO-d6)δ12.20(s,1H),8.35(s,1H),7.90-7.82(m,2H),7.75(s,1H),7.6 2(d,J=6.6Hz,1H),7.45(t,J=7.9Hz,2H),7.21(t,J=7.4Hz,1H),7.13-7.08(m,4H),4.52 -4.44(m,1H),4.08-4.02(m,0.5H),3.90-3.80(m,1H),3.69-3.56(m,1.5H),3.53-3.40( m,1H),3.39-3.36(m,0.5H),3.33-3.27(m,0.5H),2.32-2.22(m,1H),2.21-2.09(m,1H). MS(ESI,m / z):440.5[M+H] + .

[0545] Example 36: 7-(1-acryloylpyrrolidin-3-yl)-2-(4-(4-fluorophenoxy)phenyl)-1H-imidazo [1,2-b]pyrazole-3-carboxamide

[0546]

[0547] Step A: Preparation of 3-(3-carbamoyl-2-(4-(4-fluorophenoxy)phenyl)-1H-imidazo[1,2-b]pyrrolidone tert-Butyl oxazol-7-yl)pyrrolidine-1-carboxylate

[0548]

[0549] The product of Example 33, Step D (10 g, 39.6 mmol) and the product of Example 13, Step C (11 g, 31.7 mmol) were heated to reflux in ethanol (200 mL) overnight. The reaction was then cooled to room temperature and the solvent removed under vacuum. The crude residue was purified by chromatography using petroleum ether and ethyl acetate (3:2) to give the desired product, tert-butyl 3-(3-carbamoyl-2-(4-(4-fluorophenoxy)phenyl)-1H-imidazo[1,2-b]pyrazol-7-yl)pyrrolidine-1-carboxylate, as a yellow solid (3.1 g, 15.5%). MS (ESI, m / z): 506.5 [M+H] + .

[0550] Step B: Preparation of 2-(4-(4-fluorophenoxy)phenyl)-7-(pyrrolidin-3-yl)-1H-imidazo[1,2-b]pyrrolidone Azole-3-carboxamide

[0551]

[0552] To a solution of the product from Example 36, Step A (3.1 g, 6.1 mmol) in EtOH (2 mL) was added 33% HCl / EtOH (5 mL) at room temperature. The mixture was stirred for 3 hours, then concentrated under vacuum to yield 2.8 g of crude 2-(4-(4-fluorophenoxy)phenyl)-7-(pyrrolidin-3-yl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide. The residue was used directly in the next step.

[0553] Step C: Preparation of 7-(1-acryloylpyrrolidin-3-yl)-2-(4-(4-fluorophenoxy)phenyl)-1H-imidazolyl [1,2-b]pyrazole-3-carboxamide

[0554]

[0555] A solution of the product from Example 36, Step B (180 mg, 0.44 mmol) in THF / H₂O (3:1, 4 mL) was basified with NaHCO₃ to pH 7-8. The mixture was then cooled to 0°C, and a solution of acryloyl chloride (60 mg, 0.67 mmol) in THF (1 mL) was slowly added. The reaction mixture was stirred at 0°C for 1 hour. Dichloromethane and water were then added to the reaction mixture. The layers were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with saturated brine (3 x 50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by chromatography using dichloromethane and methanol (30:1) to afford 7-(1-acryloylpyrrolidin-3-yl)-2-(4-(4-fluorophenoxy)phenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide as an off-white solid (106 mg, 52.3%). 1H NMR (400MHz, DMSO-d6) δ12.18(d,J=16.0Hz,1H),8.34(s,1H),7.85(d,J=8.7Hz,2H),7.73(s,1H),7.61(d, J=5.0Hz,1H),7.34-7.24(m,2H),7.19-7.13(m,2H),7.10-7.05(m,2H),6.67-6.57(m,1H),6.19-6.11(m,1 H),5.71-5.63(m,1H),4.05-3.98(m,0.5H),3.94-3.87(m,0.5H),3.78(t,J=7.9Hz,0.5H),3.71-3.58(m,1 H),3.57-3.45(m,1H),3.43-3.35(m,1.5H),2.34-2.26(m,0.5H),2.26-2.13(m,1H),2.11-2.01(m,0.5H). MS(ESI,m / z):460.5[M+H] + .

[0556] Example 37: 7-(1-(but-2-ynyl)pyrrolidin-3-yl)-2-(4-(4-fluorophenoxy)phenyl)-1H-imidazole Azo[1,2-b]pyrazole-3-carboxamide

[0557]

[0558] A solution of the product from Example 36, Step B (180 mg, 0.44 mmol) in DMF (5 mL) was basified to pH 7-8 with N,N-diisopropylethylamine. After 5 minutes, 2-butynoic acid (56 mg, 0.67 mmol) and HATU (184 mg, 0.48 mmol) were added. The reaction mixture was stirred at room temperature for an additional 30 minutes. Dichloromethane and water were then added to the reaction mixture. The layers were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with saturated brine (3 x 50 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by chromatography using dichloromethane and methanol (30:1) to afford 7-(1-(but-2-ynyl)pyrrolidin-3-yl)-2-(4-(4-fluorophenoxy)phenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide as an off-white solid (127 mg, 61.2%). 1HNMR(400MHz,DMSO-d6)δ12.19(s,1H),8.33(s,1H),7.89-7.81(m,2H),7.72(s, 1H),7.60(d,J=6.0Hz,1H),7.33-7.25(m,2H),7.20-7.13(m,2H),7.10-7.05(m,2 H),4.04-3.97(m,0.5H),3.87-3.76(m,1H),3.66-3.52(m,1.5H),3.49-3.40(m, 1H),3.31-3.23(m,1H),2.31-2.17(m,1H),2.16-2.07(m,1H),2.04-1.97(m,3H). MS(ESI,m / z):472.5[M+H] + .

[0559] Example 38: 2-(4-(4-fluorophenoxy)phenyl)-7-(1-propioloylpyrrolidin-3-yl)-1H-imidazo [1,2-b]pyrazole-3-carboxamide

[0560]

[0561] A solution of the product from Example 36, Step B (180 mg, 0.44 mmol) in DMF (5 mL) was basified to pH 7-8 with N,N-diisopropylethylamine. After 5 minutes, propiolic acid (47 mg, 0.67 mmol) and HATU (184 mg, 0.48 mmol) were added. The reaction mixture was stirred at room temperature for another 30 minutes. Dichloromethane and water were then added to the reaction mixture. The layers were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with saturated brine (3 x 50 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by chromatography using dichloromethane and methanol (30:1) to afford 2-(4-(4-fluorophenoxy)phenyl)-7-(1-propioloylpyrrolidin-3-yl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide as an off-white solid (125 mg, 62.1%). 1H NMR(400MHz,DMSO-d6)δ12.19(s,1H),8.33(s,1H),7.87-7.83(m,2H),7.73(s,1 H),7.61(d,J=4.4Hz,1H),7.32-7.24(m,2H),7.19-7.13(m,2H),7.10-7.06(m,2 H),4.51-4.43(m,1H),4.08-3.99(m,0.5H),3.90-3.76(m,1H),3.69-3.54(m,1. 5H),3.52-3.39(m,1H),3.30-3.26(m,1H),2.33-2.20(m,1H),2.17-2.08(m,1H). MS(ESI,m / z):458.5[M+H] + .

[0562] Example 39: 2-(4-(2,4-difluorophenoxy)phenyl)-7-(1-propioloylpyrrolidin-3-yl)-1H-imidazole 1,2-b]pyrazole-3-carboxamide

[0563]

[0564] Step A: Preparation of 3-(3-carbamoyl-2-(4-(2,4-difluorophenoxy)phenyl)-1H-imidazo[1,2-b] tert-Butyl pyrazol-7-yl)pyrrolidine-1-carboxylate

[0565]

[0566] The product of Example 33, Step D (10 g, 39.6 mmol) and the product of Example 17, Step C (12 g, 31.7 mmol) were heated to reflux in ethanol (200 mL) overnight. The reaction was then cooled to room temperature, and the solvent was removed under vacuum. The crude residue was purified by chromatography using petroleum ether and ethyl acetate (3:2) to give the desired product, tert-butyl 3-(3-carbamoyl-2-(4-(2,4-difluorophenoxy)phenyl)-1H-imidazo[1,2-b]pyrazol-7-yl)pyrrolidine-1-carboxylate, as a yellow solid (3.5 g, 16.9%). 1H NMR(400MHz,DMSO-d6)δ12.17(s,1H),8.33(s,1H),7.87-7.80(m,2H),7.72( s,1H),7.58(s,1H),7.55-7.49(m,1H),7.44-7.36(m,1H),7.24-7.15(m,1H), 7.06(d,J=8.7Hz,2H),3.75-3.62(m,1H),3.46(t,J=9.4Hz,1H),3.22(t,J=9. 8Hz, 1H), 2.54 (s, 1H), 2.25-2.12 (m, 1H), 2.08 (s, 2H), 1.41 (d, J = 6.0Hz, 9H). MS (ESI, m / z): 524.5 [M+H] + .

[0567] Step B: Preparation of 2-(4-(2,4-difluorophenoxy)phenyl)-7-(pyrrolidin-3-yl)-1H-imidazo[1,2-b] Pyrazole-3-carboxamide

[0568]

[0569] To a solution of the product from Example 39, Step A (3.5 g, 6.7 mmol) in ethanol (2 mL) was added 33% HCl / EtOH (5 mL) at room temperature. The mixture was stirred for 3 hours, then concentrated under vacuum to afford 3.0 g of crude 2-(4-(2,4-difluorophenoxy)phenyl)-7-(pyrrolidin-3-yl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide. The residue was used directly in the next step.

[0570] Step C: Preparation of 2-(4-(2,4-difluorophenoxy)phenyl)-7-(1-propioloylpyrrolidin-3-yl)-1H-imidazole Azo[1,2-b]pyrazole-3-carboxamide

[0571]

[0572] A solution of the product from Example 39, Step B (180 mg, 0.43 mmol) in DMF (5 mL) was basified to pH 7-8 with N,N-diisopropylethylamine. After 5 minutes, propiolic acid (45 mg, 0.64 mmol) and HATU (180 mg, 0.47 mmol) were added. The reaction mixture was stirred at room temperature for an additional 30 minutes. Dichloromethane and water were then added to the reaction mixture. The layers were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with saturated brine (3 x 50 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by chromatography using dichloromethane and methanol (30:1) to afford 2-(4-(2,4-difluorophenoxy)phenyl)-7-(1-propioloylpyrrolidin-3-yl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide as an off-white solid (105 mg, 51.9%).1 HNMR(400MHz,DMSO-d6)δ12.19(s,1H),8.32(s,1H),7.86-7.80(m,2H),7.73(s,1H), 7.61(d,J=4.5Hz,1H),7.57-7.49(m,1H),7.44-7.36(m,1H),7.23-7.16(m,1H),7.09- 7.03(m,2H),4.51-4.43(m,1H),4.08-3.99(m,0.5H),3.89-3.78(m,1H),3.66-3.55( m,1.5H),3.51-3.42(m,1H),3.31-3.25(m,1H),2.34-2.19(m,1H),2.18-2.06(m,1H). MS(ESI,m / z):476.5[M+H] + .

[0573] Example 40: 7-(1-acryloylpyrrolidin-3-yl)-2-(4-(4-methoxyphenoxy)phenyl)-1H-imidazole 1,2-b]pyrazole-3-carboxamide

[0574]

[0575] Step A: Preparation of 3-(3-carbamoyl-2-(4-(4-methoxyphenoxy)phenyl)-1H-imidazo[1,2-b] tert-Butyl pyrazol-7-yl)pyrrolidine-1-carboxylate

[0576]

[0577] The product of Example 33, Step D (10 g, 39.6 mmol) and the product of Example 20, Step C (11 g, 31.7 mmol) were heated to reflux in ethanol (200 mL) overnight. The reaction was then cooled to room temperature, and the solvent was removed under vacuum. The crude residue was purified by chromatography using petroleum ether and ethyl acetate (3:2) to give the desired product, tert-butyl 3-(3-carbamoyl-2-(4-(4-methoxyphenoxy)phenyl)-1H-imidazo[1,2-b]pyrazol-7-yl)pyrrolidine-1-carboxylate, as a yellow solid (3.0 g, 14.6%). 1H NMR(600MHz,DMSO-d6)δ12.15(d,J=5.1Hz,1H),8.34(s,1H),7.82(d,J=8.6Hz,2H) ,7.71(s,1H),7.57(s,1H),7.08(d,J=8.9Hz,2H),7.01(dd,J=8.5,4.2Hz,4H),3.77 (s,3H),3.73-3.63(m,1H),3.45(s,1H),3.31-3.26(m,1H),3.22(t,J=9.8Hz,1H),2 .17(dd,J=22.6,6.3Hz,1H),2.12-2.03(m,1H),1.41(d,J=9.3Hz,9H),1.23(s,1H). MS(ESI,m / z):518.6[M+H] + .

[0578] Step B: Preparation of 2-(4-(4-methoxyphenoxy)phenyl)-7-(pyrrolidin-3-yl)-1H-imidazo[1,2-b] Pyrazole-3-carboxamide

[0579]

[0580] To a solution of the product from Example 40, Step A (3.0 g, 7.2 mmol) in EtOH (2 mL) was added 33% HCl / EtOH (5 mL) at room temperature. The mixture was stirred for 3 hours. The mixture was then concentrated under vacuum to yield 2.8 g of crude 2-(4-(4-methoxyphenoxy)phenyl)-7-(pyrrolidin-3-yl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide. The residue was used directly in the next step.

[0581] Step C: Preparation of 7-(1-acryloylpyrrolidin-3-yl)-2-(4-(4-methoxyphenoxy)phenyl)-1H-imidazole Azo[1,2-b]pyrazole-3-carboxamide

[0582]

[0583] A solution of the product from Example 40, Step B (180 mg, 0.43 mmol) in THF / H₂O (3:1, 4 mL) was basified with NaHCO₃ to pH 7-8. The mixture was then cooled to 0°C, and a solution of acryloyl chloride (58 mg, 0.65 mmol) in THF (1 mL) was slowly added. The reaction mixture was stirred at 0°C for 1 hour. Dichloromethane and water were then added to the reaction mixture. The layers were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with saturated brine (3 × 50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by chromatography using dichloromethane and methanol (30:1) to afford 7-(1-acryloylpyrrolidin-3-yl)-2-(4-(4-methoxyphenoxy)phenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide as an off-white solid (137 mg, 67.4%). 1 H NMR (400MHz, DMSO-d6) δ12.15(s,1H),8.34(s,1H),7.81(d,J=8.7Hz,2H),7.72(s,1H),7.60(d,J =5.0Hz,1H),7.08(d,J=9.0Hz,2H),7.04-6.97(m,4H),6.66-6.56(m,1H),6.20-6.11(m,1H),5.71 -5.63(m,1H),4.05-3.98(m,0.5H),3.96-3.86(m,0.5H),3.81-3.72(m,4H),3.72-3.59(m,1H),3. 57-3.44(m,1H),3.42-3.36(m,1H),2.35-2.26(m,0.5H),2.25-2.11(m,1H),2.10-1.98(m,0.5H). MS(ESI,m / z):472.5[M+H] + .

[0584] Example 41: 7-(1-(but-2-ynyl)pyrrolidin-3-yl)-2-(4-(4-methoxyphenoxy)phenyl)- 1H-Imidazolo[1,2-b]pyrazole-3-carboxamide

[0585]

[0586] A solution of the product from Example 40, Step B (180 mg, 0.43 mmol) in DMF (5 mL) was basified to pH 7-8 with N,N-diisopropylethylamine. After 5 minutes, 2-butynoic acid (54 mg, 0.65 mmol) and HATU (180 mg, 0.47 mmol) were added. The reaction mixture was stirred at room temperature for an additional 30 minutes. Dichloromethane and water were then added to the reaction mixture. The layers were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with saturated brine (3 x 50 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by chromatography using dichloromethane and methanol (30:1) to afford 7-(1-(but-2-ynyl)pyrrolidin-3-yl)-2-(4-(4-methoxyphenoxy)phenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide as an off-white solid (132 mg, 63.3%). 1 H NMR(400MHz,DMSO-d6)δ12.17(s,1H),8.33(s,1H),7.88-7.78(m,2H),7.7 2(s,1H),7.60(d,J=6.1Hz,1H),7.13-7.06(m,2H),7.05-6.98(m,4H),4.0 5-3.98(m,0.5H),3.88-3.79(m,1H),3.78(s,3H),3.65-3.39(m,2.5H),3. 31-3.23(m,1H),2.30-2.18(m,1H),2.17-2.09(m,1H),2.04-1.96(m,3H). MS (ESI, m / z): 484.5 [M+H] + .

[0587] Example 42: 2-(4-(4-methoxyphenoxy)phenyl)-7-(1-propioloylpyrrolidin-3-yl)-1H-imidazole 1,2-b]pyrazole-3-carboxamide

[0588]

[0589] A solution of the product from Example 40, Step B (180 mg, 0.43 mmol) in DMF (5 mL) was basified to pH 7-8 with N,N-diisopropylethylamine. After 5 minutes, propiolic acid (45 mg, 0.65 mmol) and HATU (180 mg, 0.47 mmol) were added. The reaction mixture was stirred at room temperature for another 30 minutes. Dichloromethane and water were then added to the reaction mixture. The layers were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with saturated brine (3 x 50 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by chromatography using dichloromethane and methanol (30:1) to afford 2-(4-(4-methoxyphenoxy)phenyl)-7-(1-propioloylpyrrolidin-3-yl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide as an off-white solid (137 mg, 67.7%). 1 HNMR(400MHz,DMSO-d6)δ12.17(s,1H),8.32(s,1H),7.85-7.78(m,2H),7.72(s ,1H),7.60(d,J=4.5Hz,1H),7.11-7.06(m,2H),7.04-6.98(m,4H),4.51-4.43( m,1H),4.07-4.00(m,0.5H),3.89-3.79(m,1H),3.77(s,3H),3.69-3.54(m,1.5 H),3.52-3.39(m,1H),3.32-3.26(m,1H),2.33-2.20(m,1H),2.19-2.08(m,1H). MS (ESI, m / z): 470.5 [M+H] + .

[0590] Example 43: 7-(1-acryloylpyrrolidin-3-yl)-2-(4-(2-methoxyphenoxy)phenyl)-1H-imidazole 1,2-b]pyrazole-3-carboxamide

[0591]

[0592] Step A: Preparation of 3-(3-carbamoyl-2-(4-(2-methoxyphenoxy)phenyl)-1H-imidazo[1,2-b] tert-Butyl pyrazol-7-yl)pyrrolidine-1-carboxylate

[0593]

[0594] The product of Example 33, Step D (10 g, 39.6 mmol) and the product of Example 23, Step C (11 g, 31.7 mmol) were heated to reflux in ethanol (200 mL) overnight. The reaction was then cooled to room temperature, and the solvent was removed under vacuum. The crude residue was purified by chromatography using petroleum ether and ethyl acetate (3:2) to give the desired product, tert-butyl 3-(3-carbamoyl-2-(4-(2-methoxyphenoxy)phenyl)-1H-imidazo[1,2-b]pyrazol-7-yl)pyrrolidine-1-carboxylate, as a yellow solid (3.8 g, 18.5%). 1 H NMR (400MHz, DMSO-d6) δ12.14(d,J=3.8Hz,1H),8.34(s,1H),7.78(d,J=8.8Hz,2 H),7.71(s,1H),7.57(s,1H),7.27-7.20(m,2H),7.16-7.12(m,1H),7.06-7.00( m,1H),6.91(d,J=8.8Hz,2H),3.77(s,3H),3.74-3.63(m,2H),3.52-3.40(m,2H) ,3.33-3.28(m,1H),3.25-3.18(m,1H),2.11-2.02(m,1H),1.41(d,J=5.7Hz,9H). MS (ESI, m / z): 518.6 [M+H] + .

[0595] Step B: Preparation of 2-(4-(2-methoxyphenoxy)phenyl)-7-(pyrrolidin-3-yl)-1H-imidazo[1,2-b] Pyrazole-3-carboxamide

[0596]

[0597] To a solution of the product from Example 43, Step A (3.8 g, 7.3 mmol) in ethanol (2 mL) was added 33% HCl / EtOH (5 mL) at room temperature. The mixture was stirred for 3 hours. The mixture was then concentrated under vacuum to yield 3.4 g of crude 2-(4-(2-methoxyphenoxy)phenyl)-7-(pyrrolidin-3-yl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide. The residue was used directly in the next step.

[0598] Step C: Preparation of 7-(1-acryloylpyrrolidin-3-yl)-2-(4-(2-methoxyphenoxy)phenyl)-1H-imidazole Azo[1,2-b]pyrazole-3-carboxamide

[0599]

[0600] A solution of the product from Example 43, Step B (180 mg, 0.43 mmol) in THF / H₂O (3:1, 4 mL) was basified with NaHCO₃ to pH 7-8. The mixture was then cooled to 0°C, and a solution of acryloyl chloride (58 mg, 0.65 mmol) in THF (1 mL) was slowly added. The reaction mixture was stirred at 0°C for 1 hour. Dichloromethane and water were then added to the reaction mixture. The layers were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with saturated brine (3 × 50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by chromatography using dichloromethane and methanol (30:1) to afford 7-(1-acryloylpyrrolidin-3-yl)-2-(4-(2-methoxyphenoxy)phenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide as an off-white solid (135 mg, 66.4%). 1 H NMR (600MHz, DMSO-d6) δ12.15(s,1H),8.32(s,1H),7.77(d,J=8.7Hz,2H),7.69(s,1H),7.59(d,J=7.7Hz,1H),7.27(t,J =7.3Hz,1H),7.22(d,J=7.8Hz,1H),7.14(d,J=7.9Hz,1H),7.03(t,J=7.5Hz,1H),6.92-6.88(m,2H),6.65-6.56(m,1H),6 .18-6.12(m,1H),5.70-5.64(m,1H),4.04-3.98(m,0.5H),3.93-3.87(m,0.5H),3.76(s,3H),3.70-3.58(m,1H),3.53(t ,J=9.8Hz,0.5H),3.50-3.43(m,0.5H),3.41-3.35(m,2H),2.33-2.27(m,0.5H),2.24-2.12(m,1H),2.09-2.00(m,0.5H). MS(ESI,m / z):472.5[M+H] + .

[0601] Example 44: 7-(1-(But-2-ynyl)pyrrolidin-3-yl)-2-(4-(2-methoxyphenoxy)phenyl)- 1H-Imidazolo[1,2-b]pyrazole-3-carboxamide

[0602]

[0603] A solution of the product from Example 43, Step B (180 mg, 0.43 mmol) in DMF (5 mL) was basified to pH 7-8 with N,N-diisopropylethylamine. After 5 minutes, 2-butynoic acid (54 mg, 0.65 mmol) and HATU (180 mg, 0.47 mmol) were added. The reaction mixture was stirred at room temperature for an additional 30 minutes. Dichloromethane and water were then added to the reaction mixture. The layers were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with saturated brine (3 x 50 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by chromatography using dichloromethane and methanol (30:1) to afford 7-(1-(but-2-ynyl)pyrrolidin-3-yl)-2-(4-(2-methoxyphenoxy)phenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide as an off-white solid (136 mg, 65.2%). 1 H NMR(400MHz,DMSO-d6)δ12.20(s,1H),8.30(s,1H),7.81-7.75(m,2H),7.72(s,1H),7.61( d,J=5.4Hz,1H),7.30-7.19(m,2H),7.19-7.11(m,1H),7.07-6.99(m,1H),6.95-6.88(m,2 H),4.05-3.98(m,0.5H),3.87-3.79(m,1H),3.77(s,3H),3.54-3.50(m,1H),3.50-3.32(m ,2H),3.32-3.23(m,0.5H),2.31-2.18(m,1H),2.19-2.06(m,1H),2.00(d,J=15.9Hz,3H). MS(ESI,m / z):484.5[M+H] + .

[0604] Example 45: 2-(4-(2-methoxyphenoxy)phenyl)-7-(1-propioloylpyrrolidin-3-yl)-1H-imidazole 1,2-b]pyrazole-3-carboxamide

[0605]

[0606] A solution of the product from Example 43, Step B (180 mg, 0.43 mmol) in DMF (5 mL) was basified to pH 7-8 with N,N-diisopropylethylamine. After 5 minutes, propiolic acid (45 mg, 0.65 mmol) and HATU (180 mg, 0.47 mmol) were added. The reaction mixture was stirred at room temperature for an additional 30 minutes. Dichloromethane and water were then added to the reaction mixture. The layers were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with saturated brine (3 x 50 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by chromatography using dichloromethane and methanol (30:1) to afford 2-(4-(2-methoxyphenoxy)phenyl)-7-(1-propioloylpyrrolidin-3-yl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide as an off-white solid (133 mg, 65.7%). 1 HNMR(600MHz,DMSO-d6)δ12.16(s,1H),8.31(s,1H),7.79-7.74(m,2H),7.71(s,1H),7.60(d,J=6 .5Hz,1H),7.27(t,J=7.8Hz,1H),7.22(d,J=8.1Hz,1H),7.14(d,J=7.8Hz,1H),7.03(t,J=7.6Hz, 1H),6.93-6.88(m,2H),4.50-4.42(m,1H),4.06-4.00(m,0.5H),3.88-3.80(m,1H),3.77(s,3H), 3.68-3.56(m,2H),3.45-3.32(m,1H),3.32-3.26(m,0.5H),2.31-2.20(m,1H),2.18-2.09(m,1H). MS(ESI,m / z):470.5[M+H] + .

[0607] Example 46: 7-(1-acryloylpyrrolidin-3-yl)-2-(4-(2-fluorophenoxy)phenyl)-1H-imidazo [1,2-b]pyrazole-3-carboxamide

[0608]

[0609] Step A: Preparation of 3-(3-carbamoyl-2-(4-(2-fluorophenoxy)phenyl)-1H-imidazo[1,2-b]pyrrolidone tert-Butyl oxazol-7-yl)pyrrolidine-1-carboxylate

[0610]

[0611] The product of Example 33, Step D (10 g, 39.6 mmol) and the product of Example 26, Step C (11 g, 31.7 mmol) were heated to reflux in ethanol (200 mL) overnight. The reaction was then cooled to room temperature, and the solvent was removed under vacuum. The crude residue was purified by chromatography using petroleum ether and ethyl acetate (3:2) to give the desired product, tert-butyl 3-(3-carbamoyl-2-(4-(2-fluorophenoxy)phenyl)-1H-imidazo[1,2-b]pyrazol-7-yl)pyrrolidine-1-carboxylate, as a yellow solid (3.2 g, 16.0%). 1 H NMR(400MHz,DMSO-d6)δ12.21(s,1H),8.34(s,1H),7.88-7.82(m,2H),7.7 2(s,1H),7.58(s,1H),7.48-7.40(m,1H),7.33-7.28(m,3H),7.06(d,J=8.7 Hz,2H),3.75-3.63(m,1H),3.50-3.42(m,2H),3.31-3.26(m,1H),3.22(t, J=9.8Hz,1H),2.20-2.11(m,1H),2.09-2.01(m,1H),1.41(d,J=6.0Hz,9H). MS (ESI, m / z): 506.5 [M+H] + .

[0612] Step B: Preparation of 2-(4-(2-fluorophenoxy)phenyl)-7-(pyrrolidin-3-yl)-1H-imidazo[1,2-b]pyrrolidone Azole-3-carboxamide

[0613]

[0614] To a solution of the product from Example 46, Step A (3.2 g, 6.3 mmol) in ethanol (2 mL) was added 33% HCl / EtOH (5 mL) at room temperature. The mixture was stirred for 3 hours. The mixture was then concentrated under vacuum to yield 3.0 g of crude 2-(4-(2-fluorophenoxy)phenyl)-7-(pyrrolidin-3-yl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide. The residue was used directly in the next step.

[0615] Step C: Preparation of 7-(1-acryloylpyrrolidin-3-yl)-2-(4-(2-fluorophenoxy)phenyl)-1H-imidazolyl [1,2-b]pyrazole-3-carboxamide

[0616]

[0617] A solution of the product from Example 46, Step B (180 mg, 0.39 mmol) in THF / H₂O (3:1, 4 mL) was basified with NaHCO₃ to pH 7-8. The mixture was then cooled to 0°C, and a solution of acryloyl chloride (53 mg, 0.59 mmol) in THF (1 mL) was slowly added. The reaction mixture was stirred at 0°C for 1 hour. Dichloromethane and water were then added to the reaction mixture. The layers were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with saturated brine (3 x 50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by chromatography using dichloromethane and methanol (30:1) to afford 7-(1-acryloylpyrrolidin-3-yl)-2-(4-(2-fluorophenoxy)phenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide as an off-white solid (123 mg, 68.7%). 1 H NMR (400MHz, DMSO-d6) δ12.20(s,1H),8.34(s,1H),7.84(d,J=8.1Hz,2H),7.73(s,1H),7.61( d,J=4.4Hz,1H),7.43(d,J=9.7Hz,1H),7.30(s,3H),7.07(d,J=7.2Hz,2H),6.67-6.56(m,1H), 6.21-6.11(m,1H),5.67(t,J=8.2Hz,1H),4.02(t,J=7.4Hz,0.5H),3.95-3.88(m,0.5H),3.82- 3.58(m,2H),3.57-3.45(m,2H),2.36-2.26(m,0.5H),2.25-2.12(m,1H),2.09-1.99(m,0.5H). MS(ESI,m / z):460.5[M+H] + .

[0618] Example 47: 7-(1-(but-2-ynyl)pyrrolidin-3-yl)-2-(4-(2-fluorophenoxy)phenyl)-1H-imidazole Azo[1,2-b]pyrazole-3-carboxamide

[0619]

[0620] A solution of the product from Example 46, Step B (180 mg, 0.39 mmol) in DMF (5 mL) was basified to pH 7-8 with N,N-diisopropylethylamine. After 5 minutes, 2-butynoic acid (50 mg, 0.59 mmol) and HATU (163 mg, 0.43 mmol) were added. The reaction mixture was stirred at room temperature for an additional 30 minutes. Dichloromethane and water were then added to the reaction mixture. The layers were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with saturated brine (3 x 50 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by chromatography using dichloromethane and methanol (30:1) to afford 7-(1-(but-2-ynyl)pyrrolidin-3-yl)-2-(4-(2-fluorophenoxy)phenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide as an off-white solid (118 mg, 64.2%). 1 HNMR(600MHz,DMSO-d6)δ12.20(s,1H),8.34(s,1H),7.85(t,J=7.4Hz,2H),7 .75(s,1H),7.61(d,J=9.4Hz,1H),7.49-7.42(m,1H),7.33-7.27(m,3H),7.1 0-7.05(m,2H),4.05-3.98(m,0.5H),3.87-3.77(m,1H),3.65-3.37(m,3H),3 .31-3.25(m,0.5H),2.30-2.19(m,1H),2.17-2.08(m,1H),2.06-1.95(m,3H). MS (ESI, m / z): 472.5 [M+H] + .

[0621] Example 48: ( E )-2-(4-(p-tolyloxy)phenyl)-7-(1-(4,4,4-trifluorobut-2-enoyl)pyrrole alkyl-3-yl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide

[0622]

[0623] Step A: Preparation of 3-(3-carbamoyl-2-(4-(p-tolyloxy)phenyl)-1H-imidazo[1,2-b]pyrrolidone tert-Butyl oxazol-7-yl)pyrrolidine-1-carboxylate

[0624]

[0625] The product from Example 33, Step D (10 g, 39.6 mmol) and the product from Example 32, Step C (11 g, 31.7 mmol) were heated to reflux in ethanol (200 mL) overnight. The reaction was then cooled to room temperature, and the solvent was removed under vacuum. The crude residue was purified by chromatography using petroleum ether and ethyl acetate (3:2) to afford the desired product, tert-butyl 3-(3-carbamoyl-2-(4-(p-tolyloxy)phenyl)-1H-imidazo[1,2-b]pyrazol-7-yl)pyrrolidine-1-carboxylate, as an off-white solid (3.5 g, 17.6%). 1 H NMR (600MHz, DMSO-d6) δ12.19(s,1H),8.36(s,1H),7.84(d,J=8.7Hz,2H),7.72( s,1H),7.58(s,1H),7.25(d,J=8.3Hz,2H),7.05(d,J=8.4Hz,2H),7.01(d,J=8.3H z,2H),3.75-3.63(m,1H),3.49-3.43(m,1H),3.36-3.26(m,2H),3.23(t,J=9.8H z,1H),2.32(s,3H),2.23-2.12(m,1H),2.12-2.02(m,1H),1.41(d,J=8.7Hz,9H). MS (ESI, m / z): 502.2 [M+H] + .

[0626] Step B: Preparation of 7-(pyrrolidin-3-yl)-2-(4-(p-tolyloxy)phenyl)-1H-imidazo[1,2-b]pyrrolidone Azole-3-carboxamide

[0627]

[0628] To a solution of the product from Example 48, Step A (3.5 g, 7.0 mmol) in ethanol (2 mL) was added 33% HCl / EtOH (5 mL) at room temperature. The mixture was stirred for 3 hours. The mixture was then concentrated under vacuum to yield 3.0 g of crude product, 7-(pyrrolidin-3-yl)-2-(4-(p-tolyloxy)phenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide. The residue was used directly in the next step.

[0629] Step C: Preparation ( E )-2-(4-(p-tolyloxy)phenyl)-7-(1-(4,4,4-trifluorobut-2-enoyl)pyrrole alkyl-3-yl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide

[0630]

[0631] A solution of the product from Example 48, Step B (180 mg, 0.45 mmol) in DMF (5 mL) was basified to pH 7-8 with N,N-diisopropylethylamine. After 5 minutes, (E)-4,4,4-trifluoro-2-butenoic acid (94 mg, 0.67 mmol) and HATU (187 mg, 0.49 mmol) were added. The reaction mixture was stirred at room temperature for 10 minutes. Dichloromethane and water were then added to the reaction mixture. The layers were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with saturated brine (3 x 50 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by chromatography using dichloromethane and methanol (10:1) to give (E)-2-(4-(p-tolyloxy)phenyl)-7-(1-(4,4,4-trifluorobut-2-enoyl)pyrrolidin-3-yl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide as an off-white solid (125 mg, 53.2%). 1 H NMR(400MHz,DMSO-d6)δ12.27-12.17(m,1H),8.39(s,1H),7.91-7.86(m,2H),7.78(s,1 H),7.68(d,J=5.0Hz,1H),7.31(d,J=8.3Hz,2H),7.24-7.16(m,1H),7.13-7.09(m,2H), 7.06(d,J=8.3Hz,2H),6.92-6.81(m,1H),4.19-4.13(m,0.5H),4.04-3.89(m,1H),3.81 -3.72(m,1H),3.71-3.65(m,0.5H),3.61-3.45(m,2H),2.38(s,3H),2.34-2.07(m,2H). MS(ESI,m / z):524.5[M+H] + .

[0632] Example 49: 7-(1-acryloylazetidin-3-yl)-2-(4-phenoxyphenyl)-1H-imidazo[1, 2-b]pyrazole-3-carboxamide

[0633]

[0634] Step A: Preparation of tert-butyl 3-(cyanomethylene)azetidine-1-carboxylate

[0635]

[0636] Under stirring at 10 ° C, to a suspension of NaH (60% mineral oil dispersion; 48g, 1.2mol) in anhydrous THF (500mL) was added dropwise anhydrous THF (200mL) of diethyl cyanomethylphosphonate (230g, 1.3mol). After 30 minutes, 3-oxoazetidine-1-carboxylic acid tert-butyl ester (171g, 1.0mol) was added dropwise at 10 ° C. The mixture was allowed to warm to room temperature within 2 hours and then quenched with ice / water. The water layer was extracted with ethyl acetate, and after removing the solvent under vacuum, the crude residue was recrystallized from petroleum ether and ethyl acetate (10: 1) to obtain the target product 3- (cyanomethylene) azetidine-1-carboxylic acid tert-butyl ester as a white solid (167g, 86.1%). 1 H NMR (400MHz, DMSO-d6) δ5.87-5.78(m,1H),4.70-4.48(m,4H),1.40(s,9H). MS(ESI,m / z):195.2[M+H] + .

[0637] Step B: Preparation of tert-butyl 3-(cyanomethyl)azetidine-1-carboxylate

[0638]

[0639] Under N2 protection, Pd / C (17 g, 10%) was added to a solution of the product (167 g, 0.86 mol) of Example 49 Step A in ethyl acetate (1500 mL). The suspension was degassed under vacuum and purged several times with H2. The mixture was stirred at room temperature under H2 for 5 hours. The mixture was passed through diatomaceous earth, the solid was washed with ethyl acetate, and the filtrate was concentrated under vacuum to give the target product, tert-butyl 3-(cyanomethyl)azetidine-1-carboxylate, as a white solid (163 g, 96.6%). 1 H NMR (400MHz, DMSO-d6) δ3.95 (s, 2H), 3.63-3.50 (m, 2H), 2.85-2.79 (m, 3H), 1.37 (s, 9H). MS(ESI,m / z):197.2[M+H] + .

[0640] Step C: Preparation of tert-butyl 3-(1-cyano-2-oxoethyl)azetidine-1-carboxylate

[0641]

[0642] The product of embodiment 49 step C (163g, 0.83mol) anhydrous THF (500mL) solution is cooled to -85 DEG C (liquid nitrogen / ethanol bath), then n-BuLi (2.5M normal hexane solution, 1.7L, 4.15mol) is added dropwise into the system, insulated and stirred for 30 minutes.Then ethyl formate (184g, 2.49mol) is added dropwise into the reaction solution, it is warming up to ice / water bath temperature, insulated and stirred for 30 minutes, then quenched with ice / water, acidified to pH 5-6 with concentrated HCl, and extracted with ethyl acetate.Organic phase is washed with saturated common salt water, through anhydrous NaSODrying, filtered and concentrated, obtains 195g crude product 3- (1- cyano -2- oxoethyl) azetidine -1- carboxylic acid tert-butyl esters.Residue is directly used in next step.

[0643] Step D: Preparation of tert-butyl 3-(5-amino-1H-pyrazol-4-yl)azetidine-1-carboxylate

[0644]

[0645] The product from Example 49, Step C (195 g, 0.87 mol) and hydrazine hydrate (80%, 500 mL) were heated to 80° C. in ethanol (500 mL) and reacted for 10 hours. The reaction solution was then cooled to room temperature, and the solvent was removed under vacuum. The crude residue was purified by chromatography using petroleum ether and ethyl acetate (1:5) to obtain the desired product, tert-butyl 3-(5-amino-1H-pyrazol-4-yl)azetidine-1-carboxylate, as a yellow solid (83 g, 42.0% yield over two steps). 1 H NMR (600MHz, DMSO-d6) δ11.37(s,1H),7.39(s,1H),4.43(s,2H),4.13(s,2H),3.72(s,2H),3.59-3.51(m,1H),1.39(s,9H). MS(ESI,m / z):239.3[M+H] + .

[0646] Step E: Preparation of 3-(3-carbamoyl-2-(4-phenoxyphenyl)-1H-imidazo[1,2-b]pyrazol-7-yl) tert-Butyl azetidine-1-carboxylate

[0647]

[0648] The product from Example 49, Step D (10 g, 42.0 mmol) and the product from Example 1, Step C (11 g, 33.6 mmol) were heated to reflux in ethanol (200 mL) overnight. The reaction was then cooled to room temperature, and the solvent was removed under vacuum. The crude residue was purified by chromatography using petroleum ether and ethyl acetate (3:2) to afford the desired product, tert-butyl 3-(3-carbamoyl-2-(4-phenoxyphenyl)-1H-imidazo[1,2-b]pyrazol-7-yl)azetidine-1-carboxylate, as a yellow solid (3.2 g, 16.1%). 1 H NMR(400MHz,DMSO-d6)δ12.35(s,1H),8.33(s,1H),7.89-7.83(m,2H),7.74(s,1H),7.71(s,1H),7.49-7.42(m,2H ),7.24-7.18(m,1H),7.12-7.07(m,4H),4.18(t,J=7.9Hz,2H),3.99-3.90(m,2H),3.89-3.82(m,1H),1.41(s,9H). MS(ESI,m / z):474.5[M+H] + .

[0649] Step F: Preparation of 7-(azetidin-3-yl)-2-(4-phenoxyphenyl)-1H-imidazo[1,2-b]pyrazole- 3-Formamide

[0650]

[0651] To a solution of the product from Example 49, Step E (3.2 g, 6.76 mmol) in EtOH (2 mL) was added 33% HCl / EtOH (5 mL) at room temperature. The mixture was stirred for 3 hours and then concentrated under vacuum to yield 2.9 g of crude product, 7-(azetidin-3-yl)-2-(4-phenoxyphenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide. The residue was used directly in the next step.

[0652] Step G: Preparation of 7-(1-acryloylazetidin-3-yl)-2-(4-phenoxyphenyl)-1H-imidazo[1, 2-b]pyrazole-3-carboxamide

[0653]

[0654] A solution of the product from Example 49, Step F (180 mg, 0.48 mmol) in THF / H₂O (3:1, 4 mL) was basified with NaHCO₃ to pH 7-8. The mixture was then cooled to 0°C and a solution of acryloyl chloride (65 mg, 0.72 mmol) in THF (1 mL) was slowly added. The reaction mixture was stirred at 0°C for 1 hour. Dichloromethane and water were then added to the reaction mixture, the layers were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with saturated brine (3 × 50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by chromatography using dichloromethane and methanol (30:1) to give 7-(1-acryloylazetidin-3-yl)-2-(4-phenoxyphenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide as an off-white solid (126 mg, 61.15%). 1 H NMR (400MHz, DMSO-d6) δ12.39(s,1H),8.31(s,1H),7.85(d,J=8.7Hz,2H),7.74(s,1H),7.71(s,1H),7.45(t,J=7.9Hz,2H),7.21(t,J=7.4Hz,1H ),7.10(d,J=8.6Hz,4H),6.40-6.30(m,1H),6.17-6.08(m,1H),5.71-5. 65(m,1H),4.56(t,J=8.3Hz,1H),4.35-4.23(m,2H),4.05-3.92(m,2H). MS(ESI,m / z):428.5[M+H] + .

[0655] Example 50: 7-(1-(But-2-ynyl)azetidin-3-yl)-2-(4-phenoxyphenyl)-1H-imidazole 1,2-b]pyrazole-3-carboxamide

[0656]

[0657] A solution of the product from Example 49, Step F (180 mg, 0.48 mmol) in DMF (5 mL) was basified to pH 7-8 with N,N-diisopropylethylamine. After 5 minutes, 2-butynoic acid (61 mg, 0.72 mmol) and HATU (201 mg, 0.53 mmol) were added. The reaction mixture was stirred at room temperature for another 30 minutes. Dichloromethane and water were then added to the reaction mixture, the layers were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with saturated brine (3×50 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by chromatography using dichloromethane and methanol (30:1) to afford 7-(1-(but-2-ynyl)azetidin-3-yl)-2-(4-phenoxyphenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide as an off-white solid (128 mg, 60.4%). 1 HNMR(600MHz,DMSO-d6)δ8.31(s,1H),7.87(d,J=8.5Hz,2H),7.69(s,1H),7.45(t,J=7.8Hz,2H),7.21(d,J =7.3Hz,1H),7.11-7.08(m,4H),4.45(t,J=8.3Hz,1H),4.26-4.19(m,2H),4.00-3.94(m,2H),2.00(s,3H). MS(ESI,m / z):440.5[M+H] + .

[0658] Example 51: 2-(4-phenoxyphenyl)-7-(1-propioloylazetidin-3-yl)-1H-imidazo[1, 2-b]pyrazole-3-carboxamide

[0659]

[0660] A solution of the product from Example 49, Step F (180 mg, 0.48 mmol) in DMF (5 mL) was basified to pH 7-8 with N,N-diisopropylethylamine. After 5 minutes, propiolic acid (51 mg, 0.72 mmol) and HATU (201 mg, 0.53 mmol) were added. The reaction mixture was stirred at room temperature for another 30 minutes. Dichloromethane and water were then added to the reaction mixture, the layers were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with saturated brine (3 × 50 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by chromatography using dichloromethane and methanol (30:1) to afford 2-(4-phenoxyphenyl)-7-(1-propioloylazetidin-3-yl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide as an off-white solid (135 mg, 65.8%). 1H NMR(400MHz,DMSO-d6)δ12.40(s,1H),8.32(s,1H),7.92-7.80(m,2H),7.75(s,1H),7.72(s,1H),7.49-7.42(m,2H ),7.21(t,J=7.4Hz,1H),7.13-7.08(m,4H),4.53-4.47(m,1H),4.44(s,1H),4.34-4.22(m,2H),4.06-3.96(m,2H). MS(ESI,m / z):426.4[M+H] + .

[0661] Example 52: ( E )-2-(4-phenoxyphenyl)-7-(1-(4,4,4-trifluorobut-2-enoyl)azetidine- 3-amino)-1H-imidazo[1,2-b]pyrazole-3-carboxamide

[0662]

[0663] A solution of the product from Example 49, Step F (180 mg, 0.48 mmol) in DMF (5 mL) was basified to pH 7-8 with N,N-diisopropylethylamine. After 5 minutes, HATU (202 mg, 0.53 mmol) and (E)-4,4,4-trifluoro-2-butenoic acid (101 mg, 0.72 mmol) were added. The reaction mixture was stirred at room temperature for 10 minutes. Dichloromethane and water were then added to the reaction mixture. The layers were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with saturated brine (3 x 50 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by chromatography with dichloromethane and methanol (10:1) to give (E)-2-(4-phenoxyphenyl)-7-(1-(4,4,4-trifluorobut-2-enoyl)azetidin-3-yl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide as an off-white solid (125 mg, 52.3%). 1 H NMR (400MHz, DMSO-d6) δ12.36(s,1H),8.32(s,1H),7.88-7.82(m,2H),7.75(s,1H),7.73(s,1H),7.49-7.42(m,2H),7.21(t,J=7.4 Hz,1H),7.13-7.06(m,4H),6.93-6.77(m,2H),4.69(t,J=8.7Hz,1H),4.45-4.38(m,1H),4.34(t,J=9.3Hz,1H),4.12-3.95(m,2H). MS(ESI,m / z):496.5[M+H] + .

[0664] Example 53: 7-(1-acryloylazetidin-3-yl)-2-(4-(4-fluorophenoxy)phenyl)-1H-imidazole 1,2-b]pyrazole-3-carboxamide

[0665]

[0666] Step A: Preparation of 3-(3-carbamoyl-2-(4-(4-fluorophenoxy)phenyl)-1H-imidazo[1,2-b]pyrrolidone tert-Butyl oxazol-7-yl)azetidine-1-carboxylate

[0667]

[0668] The product from Example 49, Step D (10 g, 42.0 mmol) and the product from Example 13, Step C (12 g, 33.6 mmol) were heated to reflux in ethanol (200 mL) overnight. The reaction was then cooled to room temperature, and the solvent was removed under vacuum. The crude residue was purified by chromatography using petroleum ether and ethyl acetate (3:2) to afford the desired product, tert-butyl 3-(3-carbamoyl-2-(4-(4-fluorophenoxy)phenyl)-1H-imidazo[1,2-b]pyrazol-7-yl)azetidine-1-carboxylate, as a yellow solid (3.7 g, 18.0%). 1 H NMR (400MHz, DMSO-d6) δ12.31(s,1H),8.34(s,1H),7.85(d,J=8.7Hz,2H),7.74(s,1H),7.70(s,1H),7.29(t,J=8.7Hz,2H ),7.19-7.13(m,2H),7.08(d,J=8.7Hz,2H),4.19(t,J=7.9Hz,2H),3.96(t,J=7.1Hz,2H),3.92-3.82(m,1H),1.41(s,9H). MS(ESI,m / z):492.5[M+H] + .

[0669] Step B: Preparation of 7-(azetidin-3-yl)-2-(4-(4-fluorophenoxy)phenyl)-1H-imidazo[1,2-b] Pyrazole-3-carboxamide

[0670]

[0671] To a solution of the product from Example 53, Step A (3.7 g, 7.5 mmol) in ethanol (2 mL) was added 33% HCl / EtOH (10 mL) at room temperature. The mixture was stirred for 3 hours and then concentrated under vacuum to afford 3.2 g of crude product, 7-(azetidin-3-yl)-2-(4-(4-fluorophenoxy)phenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide. The residue was used directly in the next step.

[0672] Step C: Preparation of 7-(1-acryloylazetidin-3-yl)-2-(4-(4-fluorophenoxy)phenyl)-1H-imidazole Azo[1,2-b]pyrazole-3-carboxamide

[0673]

[0674] A solution of the product from Example 53, Step B (180 mg, 0.46 mmol) in THF / H₂O (3:1, 4 mL) was basified with NaHCO₃ to pH 7-8. The mixture was then cooled to 0°C and a solution of acryloyl chloride (62 mg, 0.69 mmol) in THF (1 mL) was slowly added. The reaction mixture was stirred at 0°C for 1 hour. Dichloromethane and water were then added to the reaction mixture, the layers were separated, the aqueous phase was extracted with dichloromethane, the organic phases were combined, washed with saturated brine (3 × 50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by chromatography using dichloromethane and methanol (30:1) to give 7-(1-acryloylazetidin-3-yl)-2-(4-(4-fluorophenoxy)phenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide as an off-white solid (141 mg, 68.8%). 1 H NMR (400MHz, DMSO-d6) δ12.38(s,1H),8.32(s,1H),7.84(t,J=5.8Hz,2H),7.74(s,1H),7.72(s,1H),7.33-7.24(m,2H),7.19-7.13(m,2H),7 .08(d,J=8.8Hz,2H),6.40-6.31(m,1H),6.16-6.09(m,1H),5.71-5.66(m,1H),4.56(t,J=8.3Hz,1H),4.36-4.19(m,2H),4.06-3.94(m,2H). MS(ESI,m / z):446.4[M+H] + .

[0675] Example 54: 7-(1-(But-2-ynyl)azetidin-3-yl)-2-(4-(4-fluorophenoxy)phenyl)- 1H-Imidazolo[1,2-b]pyrazole-3-carboxamide

[0676]

[0677] A solution of the product from Example 53, Step B (180 mg, 0.46 mmol) in DMF (5 mL) was basified to pH 7-8 with N,N-diisopropylethylamine. After 5 minutes, 2-butynoic acid (58 mg, 0.69 mmol) and HATU (192 mg, 0.51 mmol) were added. The reaction mixture was stirred at room temperature for 30 minutes. Dichloromethane and water were then added to the reaction mixture. The layers were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with saturated brine (3 x 50 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by chromatography with dichloromethane and methanol (30:1) to give 7-(1-(but-2-ynyl)azetidin-3-yl)-2-(4-(4-fluorophenoxy)phenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide as an off-white solid (143 mg, 68.1%). 1 H NMR (400MHz, DMSO-d6) δ12.38(s,1H),8.31(s,1H),7.88-7.82(m,2H),7.74(s,1H),7.71(s,1H),7.33-7.26(m,2H ),7.20-7.13(m,2H),7.12-7.06(m,2H),4.46(t,J=8.3Hz,1H),4.26-4.19(m,2H),4.04-3.92(m,2H),2.01(s,3H). MS(ESI,m / z):458.5[M+H] + .

[0678] Example 55: 2-(4-(4-fluorophenoxy)phenyl)-7-(1-propioloylazetidin-3-yl)-1H-imidazole 1,2-b]pyrazole-3-carboxamide

[0679]

[0680] A solution of the product from Example 53, Step B (180 mg, 0.46 mmol) in DMF (5 mL) was basified to pH 7-8 with N,N-diisopropylethylamine. After 5 minutes, propiolic acid (48 mg, 0.69 mmol) and HATU (192 mg, 0.51 mmol) were added. The reaction mixture was stirred at room temperature for another 30 minutes. Dichloromethane and water were then added to the reaction mixture, the layers were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with saturated brine (3 × 50 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by chromatography using dichloromethane and methanol (30:1) to give 2-(4-(4-fluorophenoxy)phenyl)-7-(1-propioloylazetidin-3-yl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide as an off-white solid (140 mg, 68.6%). 1HNMR(400MHz,DMSO-d6)δ12.39(s,1H),8.31(s,1H),7.88-7.82(m,2H),7.75(s,1H),7.72(s,1H),7.32-7.25(m,2H) ,7.20-7.14(m,2H),7.09(d,J=8.7Hz,2H),4.50(t,J=8.3Hz,1H),4.44(s,1H),4.34-4.23(m,2H),4.06-3.95(m,2H). MS(ESI,m / z):444.4[M+H] + .

[0681] Example 56: 7-(1-acryloylazetidin-3-yl)-2-(4-(2-methoxyphenoxy)phenyl)-1H- imidazo[1,2-b]pyrazole-3-carboxamide

[0682]

[0683] Step A: Preparation of 3-(3-carbamoyl-2-(4-(2-methoxyphenoxy)phenyl)-1H-imidazo[1,2-b] tert-Butyl pyrazol-7-yl)azetidine-1-carboxylate

[0684]

[0685] The product from Example 49, Step D (10 g, 42.0 mmol) and the product from Example 23, Step C (12 g, 33.6 mmol) were heated to reflux in ethanol (200 mL) overnight. The reaction was then cooled to room temperature, and the solvent was removed under vacuum. The crude residue was purified by chromatography using petroleum ether and ethyl acetate (3:2) to afford the desired product, tert-butyl 3-(3-carbamoyl-2-(4-(2-methoxyphenoxy)phenyl)-1H-imidazo[1,2-b]pyrazol-7-yl)azetidine-1-carboxylate, as a yellow solid (3.8 g, 18.0%). 1 H NMR (400MHz, DMSO-d6) δ12.28(s,1H),8.31(s,1H),7.76(d,J=8.9Hz,2H),7.71(s,1H),7.69(s,1H),7.28-7.20(m,2H),7.16-7.12( m,1H),7.06-7.00(m,1H),6.93-6.88(m,2H),4.18(t,J=7.7Hz,2H),3.98-3.90(m,2H),3.90-3.83(m,1H),3.77(s,3H),1.40(s,9H). MS(ESI,m / z):504.5[M+H] + .

[0686] Step B: Preparation of 7-(azetidin-3-yl)-2-(4-(2-methoxyphenoxy)phenyl)-1H-imidazo[1, 2-b]pyrazole-3-carboxamide

[0687]

[0688] To a solution of the product from Example 56, Step A (3.8 g, 7.5 mmol) in ethanol (2 mL) was added 33% HCl / EtOH (5 mL) at room temperature. The mixture was stirred for 3 hours. The mixture was then concentrated under vacuum to give 3.2 g of crude product, 7-(azetidin-3-yl)-2-(4-(2-methoxyphenoxy)phenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide. The residue was used directly in the next step.

[0689] Step C: Preparation of 7-(1-acryloylazetidin-3-yl)-2-(4-(2-methoxyphenoxy)phenyl)- 1H-Imidazolo[1,2-b]pyrazole-3-carboxamide

[0690]

[0691] A solution of the product from Example 56, Step B (180 mg, 0.45 mmol) in THF / H₂O (3:1, 4 mL) was basified with NaHCO₃ to pH 7-8. The mixture was then cooled to 0°C, and a solution of acryloyl chloride (61 mg, 0.67 mmol) in THF (1 mL) was slowly added. The reaction mixture was stirred at 0°C for 1 hour. Dichloromethane and water were then added to the reaction mixture, the layers were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with saturated brine (3 × 50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by chromatography using dichloromethane and methanol (30:1) to afford 7-(1-acryloylazetidin-3-yl)-2-(4-(2-methoxyphenoxy)phenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide as an off-white solid (135 mg, 65.6%). 1 H NMR(400MHz,DMSO-d6)δ12.34(s,1H),8.30(s,1H),7.78-7.73(m,2H),7.71 (s,1H),7.70(s,1H),7.30-7.20(m,2H),7.15-7.11(m,1H),7.06-7.00(m,1H ),6.93-6.87(m,2H),6.40-6.30(m,1H),6.15-6.08(m,1H),5.70-5.65(m,1H ), 4.55 (t, J = 8.3Hz, 1H), 4.35-4.21 (m, 2H), 4.06-3.90 (m, 2H), 3.76 (s, 3H). MS (ESI, m / z): 458.5 [M+H] + .

[0692] Example 57: 7-(1-(but-2-ynyl)azetidin-3-yl)-2-(4-(2-methoxyphenoxy)benzene 1H-imidazo[1,2-b]pyrazole-3-carboxamide

[0693]

[0694] A solution of the product from Example 56, Step B (180 mg, 0.45 mmol) in DMF (5 mL) was basified to pH 7-8 with N,N-diisopropylethylamine. After 5 minutes, 2-butynoic acid (56 mg, 0.67 mmol) and HATU (188 mg, 0.49 mmol) were added. The reaction mixture was stirred at room temperature for 30 minutes. Dichloromethane and water were then added to the reaction mixture. The layers were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with saturated brine (3 x 50 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by chromatography with dichloromethane and methanol (30:1) to give 7-(1-(but-2-ynyl)azetidin-3-yl)-2-(4-(2-methoxyphenoxy)phenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide as an off-white solid (136 mg, 64.4%). 1 H NMR(600MHz,DMSO-d6)δ12.34(s,1H),8.29(s,1H),7.76(d,J=8.6Hz,2H),7 .71(s,1H),7.69(s,1H),7.27(t,J=7.8Hz,1H),7.22(d,J=8.1Hz,1H),7.14 (d,J=7.8Hz,1H),7.03(t,J=7.6Hz,1H),6.91(d,J=8.6Hz,2H),4.44(t,J=8 .2Hz,1H),4.26-4.19(m,2H),3.99-3.93(m,2H),3.76(s,3H),2.00(s,3H). MS(ESI,m / z):470.5[M+H] + .

[0695] Example 58: 2-(4-(2-methoxyphenoxy)phenyl)-7-(1-propioloylazetidin-3-yl)-1H- imidazo[1,2-b]pyrazole-3-carboxamide

[0696]

[0697] A solution of the product from Example 56, Step B (180 mg, 0.45 mmol) in DMF (5 mL) was basified to pH 7-8 with N,N-diisopropylethylamine. After 5 minutes, propiolic acid (47 mg, 0.67 mmol) and HATU (188 mg, 0.49 mmol) were added. The reaction mixture was stirred at room temperature for another 30 minutes. Dichloromethane and water were then added to the reaction mixture, the layers were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with saturated brine (3 × 50 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by chromatography using dichloromethane and methanol (30:1) to afford 2-(4-(2-methoxyphenoxy)phenyl)-7-(1-propioloylazetidin-3-yl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide as an off-white solid (131 mg, 63.9%). 1 H NMR(600MHz,DMSO-d6)δ12.35(s,1H),8.29(s,1H),7.76(d,J=8.5Hz,2H),7 .72(s,1H),7.70(s,1H),7.27(t,J=7.8Hz,1H),7.22(d,J=8.2Hz,1H),7.14 (d,J=7.8Hz,1H),7.03(t,J=7.6Hz,1H),6.91(d,J=8.5Hz,2H),4.49(t,J=8 .3Hz,1H),4.43(s,1H),4.30-4.22(m,2H),4.03-3.96(m,2H),3.76(s,3H). MS(ESI,m / z):456.5[M+H] + .

[0698] Example 59: 7-(4-acrylamidophenyl)-2-(4-phenoxyphenyl)-1H-imidazo[1,2-b]pyrazole- 3-Formamide

[0699]

[0700] Step A: Preparation of 4-(4-nitrophenyl)-1H-pyrazol-3-amine

[0701]

[0702] In a sealed tube, a solution of 4-nitrophenylacetonitrile (20 g, 0.12 mol) in DMF / DMA (100 mL) was heated at 90°C for 8 hours. The mixture was then dissolved in ethanol (50 mL) and hydrazine hydrate (80%, 50 mL) was added. The reaction was refluxed overnight. The solvent was removed under vacuum, and the crude residue was purified by chromatography using petroleum ether and ethyl acetate (1:5) to give the desired product, 4-(4-nitrophenyl)-1H-pyrazol-3-amine, as a yellow solid (15 g, 61.2%). 1H NMR (600MHz, DMSO-d6) δ8.16 (d, J = 8.5 Hz, 2H), 7.90 (s, 1H), 7.77 (d, J = 8.5 Hz, 2H). MS(ESI,m / z):205.2[M+H] + .

[0703] Step B: Preparation of 7-(4-nitrophenyl)-2-(4-phenoxyphenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide amine

[0704]

[0705] The product from Example 59, Step A (15 g, 73.5 mmol) and the product from Example 1, Step C (20 g, 58.8 mmol) were heated to reflux in ethanol (200 mL) overnight. The reaction was then cooled to room temperature, and the solvent was removed under vacuum. The crude residue was purified by chromatography using petroleum ether and ethyl acetate (3:2) to afford the desired product, 7-(4-nitrophenyl)-2-(4-phenoxyphenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide, as a yellow solid (6.7 g, 20.7%). 1 H NMR(600MHz,DMSO-d6)δ12.91(s,1H),8.45(s,1H),8.24-8.15(m,3H),7.99(d,J=7 .1Hz,2H),7.87(d,J=8.1Hz,3H),7.46(d,J=6.6Hz,2H),7.22(s,1H),7.12(s,4H). MS(ESI,m / z):440.4[M+H] + .

[0706] Step C: Preparation of 7-(4-aminophenyl)-2-(4-phenoxyphenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxylate amine

[0707]

[0708] Under N2 protection, 10% Pd / C (0.7 g, 10%) was added to a solution of the product of Example 59, Step B (6.7 g, 15.2 mmol) in methanol (20 mL). The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred at room temperature under H2 for 5 hours. The mixture was passed through celite, the solid was washed with methanol, and the filtrate was concentrated under vacuum to give the desired product, 7-(4-aminophenyl)-2-(4-phenoxyphenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide, as a yellow solid (5.8 g, 93.2%). MS (ESI, m / z): 410.4 [M+H] + .

[0709] Step D: Preparation of 7-(4-acrylamidophenyl)-2-(4-phenoxyphenyl)-1H-imidazo[1,2-b]pyrazole- 3-Formamide

[0710]

[0711] A solution of the product from Example 59, Step C (180 mg, 0.44 mmol) in THF / H₂O (3:1, 4 mL) was basified with NaHCO₃ to pH 7-8. The mixture was then cooled to 0°C, and a solution of acryloyl chloride (60 mg, 0.66 mmol) in THF (1 mL) was slowly added. The reaction mixture was stirred at 0°C for 1 hour. Dichloromethane and water were then added to the reaction mixture, the layers were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with saturated brine (3 × 50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by chromatography using dichloromethane and methanol (30:1) to afford 7-(4-acrylamidophenyl)-2-(4-phenoxyphenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide as a yellow solid (87 mg, 42.7%). 1 H NMR (400MHz, DMSO-d6) δ10.15(s,1H),8.31(s,1H),8.17(s,1H),7.87(d,J=8.7Hz,2H),7.80(s,1H),7.70(s,4H) ,7.46(t,J=8.0Hz,2H),7.22(s,1H),7.13-7.09(m,5H),6.49-6.40(m,1H),6.29-6.21(m,1H),5.77-5.72(m,1H). MS(ESI,m / z):464.5[M+H] + .

[0712] Example 60: 2-(4-phenoxyphenyl)-7-(4-propiolamidophenyl)-1H-imidazo[1,2-b]pyrazole- 3-Formamide

[0713]

[0714] A solution of the product from Example 59, Step C (180 mg, 0.44 mmol) in DMF (5 mL) was basified to pH 7-8 with N,N-diisopropylethylamine. After 5 minutes, propiolic acid (46 mg, 0.66 mmol) and HATU (183 mg, 0.48 mmol) were added. The reaction mixture was stirred at room temperature for another 30 minutes. Dichloromethane and water were then added to the reaction mixture, the layers were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with saturated brine (3×50 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by chromatography using dichloromethane and methanol (30:1) to give 2-(4-phenoxyphenyl)-7-(4-propiolamidophenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide as a yellow solid (131 mg, 64.6%). MS (ESI, m / z): 462.5 [M+H] + .

[0715] Example 61: 7-(3-acrylamidophenyl)-2-(4-phenoxyphenyl)-1H-imidazo[1,2-b]pyrazole- 3-Formamide

[0716]

[0717] Step A: Preparation of 4-(3-nitrophenyl)-1H-pyrazol-5-amine

[0718]

[0719] In a sealed tube, a solution of 3-nitrophenylacetonitrile (20 g, 0.12 mol) in DMF / DMA (100 mL) was heated at 90°C for 8 hours. The mixture was then dissolved in ethanol (50 mL) and hydrazine hydrate (80%, 50 mL) was added. The reaction was refluxed overnight. The solvent was removed under vacuum, and the crude residue was purified by chromatography using petroleum ether and ethyl acetate (1:5) to give the desired product, 4-(3-nitrophenyl)-1H-pyrazol-5-amine, as a yellow solid (16 g, 65.3%). MS (ESI, m / z): 205.2 [M+H] + .

[0720] Step B: Preparation of 7-(3-nitrophenyl)-2-(4-phenoxyphenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide amine

[0721]

[0722] The product from Example 61, Step A (16 g, 78.4 mmol) and the product from Example 1, Step C (21 g, 62.7 mmol) were heated to reflux in ethanol (200 mL) overnight. The reaction was then cooled to room temperature, and the solvent was removed under vacuum. The crude residue was purified by chromatography using petroleum ether and ethyl acetate (3:2) to afford the desired product, 7-(3-nitrophenyl)-2-(4-phenoxyphenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide, as a yellow solid (8.3 g, 24.1%). 1 H NMR (600MHz, DMSO-d6) δ12.82(s,1H),8.51(s,1H),8.40(s,1H),8.24(s,1H),8.19(d,J=7.8Hz,1H),7.96-7.92(m,1H),7 .91-7.86(m,2H),7.78(s,1H),7.65(t,J=7.9Hz,1H),7.46(t,J=7.4Hz,2H),7.21(t,J=7.4Hz,1H),7.12(d,J=7.9Hz,4H). MS(ESI,m / z):440.4[M+H] + .

[0723] Step C: Preparation of 7-(3-aminophenyl)-2-(4-phenoxyphenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxylate amine

[0724]

[0725] Under N2 protection, 10% Pd / C (0.8 g, 10%) was added to a solution of the product of Example 61, Step B (8.3 g, 18.9 mmol) in methanol (20 mL). The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred at room temperature under H2 for 5 hours. The mixture was passed through celite, the solid was washed with methanol, and the filtrate was concentrated under vacuum to give the desired product, 7-(3-aminophenyl)-2-(4-phenoxyphenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide, as a yellow solid (7.5 g, 96.9%). MS (ESI, m / z): 410.4 [M+H] + .

[0726] Step D: Preparation of 7-(3-acrylamidophenyl)-2-(4-phenoxyphenyl)-1H-imidazo[1,2-b]pyrazole- 3-Formamide

[0727]

[0728] The product from Example 61, Step C (180 mg, 0.44 mmol) in THF / H₂O (3:1, 4 mL) was basified with NaHCO₃ to pH 7-8. The mixture was then cooled to 0°C and a solution of acryloyl chloride (60 mg, 0.66 mmol) in THF (1 mL) was slowly added. The reaction mixture was stirred at 0°C for 1 hour. Dichloromethane and water were then added to the reaction mixture, the layers were separated, the aqueous phase was extracted with dichloromethane, and the combined organic phases were washed three times with saturated brine (3×50 mL). The organic phases were dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by chromatography using dichloromethane and methanol (30:1) to afford 7-(3-acrylamidophenyl)-2-(4-phenoxyphenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide as a yellow solid (93 mg, 45.6%). 1 HNMR(400MHz,DMSO-d6)δ12.56(s,1H),10.12(s,1H),8.29(s,1H),8.05(s,1H),7.89-7.85(m,2H),7.56-7.41(m,5H),7.35(t,J =7.8Hz,1H),7.25-7.15(m,2H),7.14-7.10(m,3H),7.07-7.02(m,1H),6.52-6.42(m,1H),6.32-6.25(m,1H),5.82-5.73(m,1H). MS(ESI,m / z):464.5[M+H] + .

[0729] Example 62: 8-Acryloyl-2-(4-phenoxyphenyl)-6,7,8,9-tetrahydro-1H-imidazo[1',2':1, 5]pyrazolo[4,3-c]pyridine-3-carboxamide

[0730]

[0731] Step A: Preparation of tert-butyl 3-amino-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate

[0732]

[0733] tert-Butyl 3-cyano-4-oxopiperidine-1-carboxylate (50 g, 0.22 mol) and hydrazine hydrate (80%, 150 mL) were heated to 80°C in ethanol (150 mL) and reacted for 10 hours. The reaction was then cooled to room temperature and the solvent removed under vacuum. The crude residue was purified by chromatography using petroleum ether and ethyl acetate (1:5) to obtain the desired product, tert-butyl 3-amino-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate, as a yellow solid (45 g, 84.7%). 1H NMR (600MHz, CDCl3) δ4.15 (s, 2H), 3.51 (s, 2H), 2.49 (t, J = 5.5Hz, 2H), 1.39 (s, 9H). MS(ESI,m / z):239.3[M+H] + .

[0734] Step B: Preparation of 3-carbamoyl-2-(4-phenoxyphenyl)-1,6,7,9-tetrahydro-8H-imidazo[1',2': tert-Butyl 1,5]pyrazolo[4,3-c]pyridine-8-carboxylate

[0735]

[0736] The product from Example 62, Step A (10 g, 42.0 mmol) and the product from Example 1, Step C (11 g, 33.6 mmol) were heated to reflux in ethanol (200 mL) overnight. The reaction was then cooled to room temperature, and the solvent was removed under vacuum. The crude residue was purified by chromatography using petroleum ether and ethyl acetate (3:2) to afford the desired product, tert-butyl 3-carbamoyl-2-(4-phenoxyphenyl)-1,6,7,9-tetrahydro-8H-imidazo[1',2':1,5]pyrazolo[4,3-c]pyridine-8-carboxylate, as a yellow solid (3.7 g, 18.6%). 1 H NMR (400MHz, DMSO-d6) δ12.11(s,1H),8.37(s,1H),7.88(d,J=8.8Hz,2H),7.72(s,1H),7.49-7.40(m,2H),7.2 1(t,J=7.4Hz,1H),7.13-7.05(m,4H),4.48(s,2H),3.67(t,J=5.7Hz,2H),2.77(t,J=5.6Hz,2H),1.44(s,9H). MS(ESI,m / z):474.5[M+H] + .

[0737] Step C: Preparation of 2-(4-phenoxyphenyl)-6,7,8,9-tetrahydro-1H-imidazo[1',2':1,5]pyrazolo[4, 3-c]pyridine-3-carboxamide

[0738]

[0739] To a solution of the product from Example 62, Step B (3.2 g, 6.76 mmol) in ethanol (2 mL) was added 33% HCl / EtOH (5 mL) at room temperature. The mixture was stirred for 3 hours, then concentrated under vacuum to yield 2.9 g of crude 2-(4-phenoxyphenyl)-6,7,8,9-tetrahydro-1H-imidazo[1',2':1,5]pyrazolo[4,3-c]pyridine-3-carboxamide. The residue was used directly in the next step.

[0740] Step D: Preparation of 8-acryloyl-2-(4-phenoxyphenyl)-6,7,8,9-tetrahydro-1H-imidazo[1',2':1, 5]pyrazolo[4,3-c]pyridine-3-carboxamide

[0741]

[0742] A solution of the product from Example 62, Step C (180 mg, 0.48 mmol) in THF / H₂O (3:1, 4 mL) was basified with NaHCO₃ to pH 7-8. The mixture was then cooled to 0°C and a solution of acryloyl chloride (65 mg, 0.72 mmol) in THF (1 mL) was slowly added. The reaction mixture was stirred at 0°C for 1 hour. Dichloromethane and water were then added to the reaction mixture. The layers were separated and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with saturated brine (3 x 50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by chromatography with dichloromethane and methanol (30:1) to give 8-acryloyl-2-(4-phenoxyphenyl)-6,7,8,9-tetrahydro-1H-imidazo[1′,2′:1,5]pyrazolo[4,3-c]pyridine-3-carboxamide as an off-white solid (136 mg, 66.0%). 1 H NMR (400MHz, DMSO-d6) δ12.13(s,1H),8.37(s,1H),7.89(d,J=8.7Hz,2H),7.72(s,1H),7.46(t,J=7.9Hz,2H),7.22(t,J=7.4Hz,1H),7. 10(t,J=8.4Hz,4H),7.00-6.89(m,1H),6.21-6.07(m,1H),5.77-5.70(m,1H),4.73-4.62(m,2H),3.93-3.84(m,2H),2.90-2.76(m,2H). MS(ESI,m / z):428.5[M+H] + .

[0743] Example 63: ( E )-8-(4-(dimethylamino)but-2-enoyl)-2-(4-phenoxyphenyl)-6,7,8,9- Tetrahydro-1H-imidazo[1',2':1,5]pyrazolo[4,3-c]pyridine-3-carboxamide

[0744]

[0745] A solution of the product from Example 62, Step C (180 mg, 0.48 mmol) in DMF (5 mL) was basified to pH 7-8 with N,N-diisopropylethylamine. After 5 minutes, (E)-4-(dimethylamino)-2-butenoic acid (93 mg, 0.72 mmol) and HATU (201 mg, 0.53 mmol) were added. The reaction mixture was stirred at room temperature for 10 minutes. Dichloromethane and water were then added to the reaction mixture. The layers were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with saturated brine (3 x 50 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by chromatography using dichloromethane and methanol (10:1) to give (E)-8-(4-(dimethylamino)but-2-enoyl)-2-(4-phenoxyphenyl)-6,7,8,9-tetrahydro-1H-imidazo[1′,2′:1,5]pyrazolo[4,3-c]pyridine-3-carboxamide as an off-white solid (86 mg, 41.9%). 1 H NMR(600MHz,DMSO-d6)δ8.37(s,1H),7.91-7.86(m,2H),7.72(s,1H),7.4 9-7.43(m,2H),7.22(t,J=7.4Hz,1H),7.14-7.06(m,4H),6.77-6.58(m,2H ),4.69(s,1H),4.64(s,1H),3.90-3.84(m,2H),3.08(d,J=6.0Hz,1H),3. 06-3.02(m,1H),2.87-2.84(m,1H),2.82-2.75(m,1H),2.20-2.13(m,6H). MS(ESI,m / z):428.5[M+H] + .

[0746] Example 64: 9-Acryloyl-2-(4-phenoxyphenyl)-1,6,7,8,9,10-hexahydroimidazo[1',2':1, 5]Pyrazolo[4,3-c]azepine-3-carboxamide

[0747]

[0748] Step A: Preparation of tert-butyl 3-bromo-4-oxoazepane-1-carboxylate and tert-butyl 4-bromo-5-oxoazepane- tert-Butyl 1-carboxylate

[0749]

[0750] To a solution of tert-butyl 4-oxoazepane-1-carboxylate (100 g, 0.46 mol) in dichloromethane (500 mL) was added p-toluenesulfonic acid (8.0 g, 0.046 mol). The mixture was then cooled to 0 ° C and NBS (92 g, 0.50 mol) was slowly added. The mixture was allowed to warm to room temperature over 24 hours and then quenched with 1: 1 water / saturated sodium bicarbonate solution. The aqueous layer was extracted with dichloromethane. The organic phases were combined, washed with saturated brine (3 × 100 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by chromatography using petroleum ether and ethyl acetate (5:1) to give crude product tert-butyl 3-bromo-4-oxoazepane-1-carboxylate as a yellow oily liquid (40 g, 29.8%) and crude product tert-butyl 4-bromo-5-oxoazepane-1-carboxylate as a yellow oily liquid (80 g, 59.7%). The residue was used directly in the next step. MS (ESI, m / z): 293.2 [M+H] + .

[0751] Step B: Preparation of tert-butyl 3-cyano-4-oxoazepane-1-carboxylate

[0752]

[0753] To a solution of tert-butyl 3-bromo-4-oxoazepane-1-carboxylate (40 g, 0.14 mol) in DMSO (50 mL) was added NaCN (7.4 g, 0.15 mol). The mixture was stirred at room temperature overnight. The mixture was then used directly in the next step. MS (ESI, m / z): 238.3 [M+H] + .

[0754] Step C: Preparation of tert-butyl 3-amino-2,6,7,8-tetrahydropyrazolo[4,3-c]azepine-5(4H)-carboxylate

[0755]

[0756] To a solution of the mixture from Step B of Example 64 in ethanol (200 mL) was added hydrazine hydrate (80%, 200 mL). The mixture was then heated to 80°C and reacted for 6 hours. The reaction was then cooled to room temperature and the solvent was removed under vacuum to give the crude product, tert-butyl 3-amino-2,6,7,8-tetrahydropyrazolo[4,3-c]azepine-5(4H)-carboxylate, as a yellow oily liquid (30 g). The mixture was then used directly in the next step. MS (ESI, m / z): 253.3 [M+H] + .

[0757] Step D: Preparation of 3-carbamoyl-2-(4-phenoxyphenyl)-1,7,8,10-tetrahydroimidazo[1',2':1, tert-Butyl 5]pyrazolo[4,3-c]azepine-9(6H)-carboxylate

[0758]

[0759] The product from Step C of Example 64 (30 g, 0.12 mol) and the product from Step C of Example 1 (32 g, 0.09 mol) were heated to reflux in ethanol (200 mL) overnight. The reaction was then cooled to room temperature, and the solvent was removed under vacuum. The crude residue was purified by chromatography using petroleum ether and ethyl acetate (2:1) to afford the desired product, tert-butyl 3-carbamoyl-2-(4-phenoxyphenyl)-1,7,8,10-tetrahydroimidazo[1',2':1,5]pyrazolo[4,3-c]azepine-9(6H)-carboxylate, as a yellow solid (0.8 g, 1.3%). MS (ESI, m / z): 488.5 [M+H] + .

[0760] Step E: Preparation of 2-(4-phenoxyphenyl)-1,6,7,8,9,10-hexahydroimidazo[1',2':1,5]pyrazolo [4,3-c]azepine-3-carboxamide

[0761]

[0762] To a solution of the product from Example 64, Step D (0.8 g, 1.64 mmol) in dichloromethane (2 mL) was added 33% HCl / EtOH (5 mL) at room temperature. The mixture was stirred for 3 hours, then concentrated under vacuum to afford 2-(4-phenoxyphenyl)-1,6,7,8,9,10-hexahydroimidazo[1',2':1,5]pyrazolo[4,3-c]azepine-3-carboxamide (0.7 g). The residue was used directly in the next step.

[0763] Step F: Preparation of 9-acryloyl-2-(4-phenoxyphenyl)-1,6,7,8,9,10-hexahydroimidazo[1',2': 1,5]pyrazolo[4,3-c]azepine-3-carboxamide

[0764]

[0765] A solution of the product from Example 64, Step E (200 mg, 0.52 mmol) in THF / H₂O (3:1, 8 mL) was basified with NaHCO₃ to pH 7-8. The mixture was then cooled to 0°C and a solution of acryloyl chloride (70 mg, 0.77 mmol) in THF (2 mL) was slowly added. The reaction mixture was stirred at 0°C for 1 hour. Dichloromethane and water were then added to the reaction mixture. The layers were separated and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with saturated brine (3 x 50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by chromatography with dichloromethane and methanol (20:1) to give 9-acryloyl-2-(4-phenoxyphenyl)-1,6,7,8,9,10-hexahydroimidazo[1′,2′:1,5]pyrazolo[4,3-c]azepine-3-carboxamide as a white solid (90 mg, 39.3%). 1H NMR(400MHz,DMSO-d6)δ12.39-11.97(m,1H),8.36-8.23(m,1H),7.93-7.83(m,2H),7.75-7.66(m,1H),7.49-7.41(m,2H),7.25-7.18(m,1H),7.1 4-7.06(m,4H),6.95-6.75(m,1H),6.14-6.02(m,1H),5.70-5.60(m,1H) ,4.71-4.59(m,2H),3.90(s,1H),3.83(s,1H),2.94(s,2H),1.77(s,2H). MS(ESI,m / z):442.5[M+H] + .

[0766] Example 65: 8-Acryloyl-2-(4-phenoxyphenyl)-1,6,7,8,9,10-hexahydroimidazo[1',2':1, 5]pyrazolo[3,4-d]azepine-3-carboxamide

[0767]

[0768] Step A: Preparation of tert-butyl 4-cyano-5-oxoazepane-1-carboxylate

[0769]

[0770] To a solution of tert-butyl 4-bromo-5-oxoazepane-1-carboxylate (80 g, 0.28 mol), the product of Example 64, Step A, in DMSO (70 mL), was added NaCN (14.8 g, 0.30 mol). The mixture was stirred at room temperature overnight. The mixture was then used directly in the next step. MS (ESI, m / z): 238.3 [M+H] + .

[0771] Step B: Preparation of tert-butyl 3-amino-4,5,7,8-tetrahydropyrazolo[3,4-d]azepine-6(2H)-carboxylate

[0772]

[0773] To a solution of the mixture from Step A of Example 65 in ethanol (300 mL) was added hydrazine hydrate (80%, 300 mL). The mixture was then heated to 80°C and reacted for 6 hours. The reaction was then cooled to room temperature and the solvent was removed under vacuum to give the crude product, tert-butyl 3-amino-4,5,7,8-tetrahydropyrazolo[3,4-d]azepane-6(2H)-carboxylate, as a yellow oily liquid (75 g). The mixture was then used directly in the next step. MS (ESI, m / z): 253.3 [M+H] + .

[0774] Step C: Preparation of 3-carbamoyl-2-(4-phenoxyphenyl)-6,7,9,10-tetrahydroimidazo[1',2':1, tert-Butyl 5]pyrazolo[3,4-d]azepine-8(1H)-carboxylate

[0775]

[0776] The product from Example 65, Step B (75 g, 0.30 mol) and the product from Example 1, Step C (79 g, 0.24 mol) were heated to reflux in ethanol (300 mL) overnight. The reaction was then cooled to room temperature, and the solvent was removed under vacuum. The crude residue was purified by chromatography using petroleum ether and ethyl acetate (2:1) to afford the desired product, tert-butyl 3-carbamoyl-2-(4-phenoxyphenyl)-6,7,9,10-tetrahydroimidazo[1',2':1,5]pyrazolo[3,4-d]azepan-8(1H)-carboxylate, as a yellow solid (1.5 g, 1.0%). MS (ESI, m / z): 488.5 [M+H] + .

[0777] Step D: Preparation of 2-(4-phenoxyphenyl)-1,6,7,8,9,10-hexahydroimidazo[1',2':1,5]pyrazolo [3,4-d]azepine-3-carboxamide

[0778]

[0779] To a solution of the product from Example 65, Step C (1.5 g, 3.08 mmol) in dichloromethane (5 mL) was added 33% HCl / EtOH (10 mL) at room temperature. The mixture was stirred for 3 hours, then concentrated under vacuum to afford 0.7 g of crude 2-(4-phenoxyphenyl)-1,6,7,8,9,10-hexahydroimidazo[1',2':1,5]pyrazolo[3,4-d]azepane-3-carboxamide. The residue was used directly in the next step.

[0780] Step E: Preparation of 8-acryloyl-2-(4-phenoxyphenyl)-1,6,7,8,9,10-hexahydroimidazo[1',2': 1,5]pyrazolo[3,4-d]azepine-3-carboxamide

[0781]

[0782] A solution of the product from Example 65, Step D (200 mg, 0.52 mmol) in THF / H2O (3:1, 8 mL) was basified with NaHCO3 to pH 7-8. The mixture was then cooled to 0°C and a solution of acryloyl chloride (70 mg, 0.77 mmol) in THF (2 mL) was slowly added. The reaction mixture was stirred at 0°C for 1 hour. Dichloromethane and water were then added to the reaction mixture, the layers were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with saturated brine (3 x 50 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by chromatography with dichloromethane and methanol (20:1) to give 8-acryloyl-2-(4-phenoxyphenyl)-1,6,7,8,9,10-hexahydroimidazo[1′,2′:1,5]pyrazolo[3,4-d]azepine-3-carboxamide as a white solid (103 mg, 45.0%).1 H NMR (400MHz, DMSO-d6) δ12.03(s,1H),8.35(s,1H),7.86(d,J=8.4Hz,2H),7.70(s,1H),7.45(t,J=7.8Hz,2H),7.21(t,J=7.4Hz,1H) ,7.09(t,J=7.3Hz,4H),6.99-6.85(m,1H),6.24-6.14(m,1H),5.78-5.66(m,1H),3.89-3.67(m,4H),2.98-2.89(m,2H),2.78(s,2H). MS(ESI,m / z):442.5[M+H] + .

[0783] Table 1 Structures of representative compounds

[0784]

[0785]

[0786]

[0787]

[0788]

[0789] Example 66 BTK (EGFR, BMX, or ITK, etc.) kinase assay

[0790] This assay was performed in-house.

[0791] Internal procedures:

[0792] The kinase inhibitory activity of the compounds was evaluated using enzyme-linked immunosorbent assay (ELISA). BTK (EGFR, BMX or ITK, etc.) kinases were purchased from Carna Bioscience (Kobe, Japan). A total of 10 ng / mL anti-phosphotyrosine (PY713) antibody (abcam, Cambridge Science Park, UK) was pre-coated in a 96-well ELISA plate. The kinases were incubated with the indicated drugs in 1× reaction buffer (50 mmol / L HEPES pH 7.4, 20 mmol / L MgCl2, 0.1 mmol / L MnCl2, 1 mmol / L DTT) containing 20 μmol / L substrate (NH2-ETVYSEVRK-biotin) at 25°C for 1 hour. Then, a total of 3 μmol / L ATP was added and the reaction was allowed to continue for 2 hours. The reaction products were transferred to a 96-well ELISA plate containing the antibody and incubated at 25°C for 30 min. After incubation, the wells were washed with PBS and then incubated with horseradish peroxidase (HRP)-labeled streptavidin. The wells were visualized using 3,3',5,5'-tetramethylbenzidine (TMB) and the absorbance was read at 450 nm using a multimode plate reader (PerkinElmer, USA).

[0793] Table II BTK inhibition by representative compounds

[0794]

[0795]

[0796] Table III: Selectivity of representative compounds for BTK and EGFR inhibition

[0797]

[0798]

[0799] Table IV: Selectivity of representative compounds for BTK and BMX inhibition

[0800]

[0801] Table V: Selectivity of representative compounds for BTK and ITK inhibition

[0802]

[0803]

[0804] Example 67 Cell Antiproliferative Activity Assay

[0805] Reaction procedure:

[0806] Spin down the suspended cells and resuspend them in growth medium and count them using a cell counter. Dilute the cell suspension in growth medium to the desired concentration. Remove 95 μl of the cell suspension and place it in a 96-well plate. Add 5 μl of 20X compound to the 96-well plate. The final DMSO concentration in each well is 0.1%. Incubate at 37°C, 5% CO2 for 72 hours. Allow the assay plate to equilibrate to room temperature before measurement. Add 50 μl of CellTiter-Glo to each well. Reagents were added. The contents were mixed on an orbital shaker for 2 minutes to induce cell lysis. Incubated at room temperature for 10 minutes to stabilize the luminescent signal. Luminescence was recorded using an EnVision Multilabel Reader (PerkinElmer).

[0807] Cell viability (CV%) was calculated relative to vehicle (DMSO) treated control wells using the following formula: Cell viability (%) = (RLU compound - RLU blank) / (RLU control - RLU blank) * 100%. Data were analyzed using Graphpad 7.0, fitting a 4-parameter equation to generate concentration response curves.

[0808] Table VI Antiproliferative activity of representative compounds

[0809]

Claims

1. A compound represented by formula I or a pharmaceutically acceptable salt thereof: in R1 is selected from H, C 1-6 alkyl; R3 is selected from hydrogen; R2 is selected from aryl or halogen, cyano, C 1-6 Alkoxy, -NR6Y, F substituted C 1-6 Alkyl substituted aryl, the aryl selected from phenyl; nitrogen-containing C 4-7 Heterocycloalkyl, wherein the nitrogen atom is substituted by Y; or R2 and R3 together form a nitrogen-containing C 4-7 Heterocycloalkyl, wherein the nitrogen atom is substituted by Y; R6 is selected from hydrogen; C 1-6 Alkyl; selected from F, hydroxy and C 1-6 Alkoxy substituted C 1-6 Alkyl; C 3-6 Cycloalkyl; C substituted by F 3-6 Cycloalkyl; Y is selected from -CN, -C(=O)P; wherein P is selected from and R7 is selected from hydrogen; halogen; cyano; C 1-6 Alkyl; selected from F, hydroxy and C 1-6 Alkoxy substituted C 1-6 Alkyl; C 3-6 Cycloalkyl; C substituted by F 3-6 Cycloalkyl; R8 and R9 are independently selected from hydrogen; halogen; cyano; CF3; C 1-6 Alkyl; C 1-6 Alkoxy, NR 10 R 11 , halogen, hydroxy substituted C 1-6 Alkyl; C 3-6 Cycloalkyl; C substituted by halogen 3-6 Cycloalkyl; C 2-6 Alkenyl; C 1-6 Alkoxy, NR 10 R 11 , halogen, hydroxy substituted C 2-6 alkenyl; Rx is selected from H, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, -(CH2) m NR 10 R 11 , C substituted by halogen or hydroxyl 1-6 alkyl; R 10 and R 11 are each independently selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl; or together with the nitrogen they replace form a 4-6 membered heterocycloalkyl; m is an integer selected from 1, 2, and 3; R4 is in, R 13 、R 14 、R 15 、R 16 and R 17 independently selected from H; halogen; CN; C 1-6 Alkyl; C 1-6 Alkoxy; C substituted by halogen 1-6 alkyl; R5 is selected from hydrogen.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein in Formula I, R1 is H or methyl; and R2, R3, R4 and R5 are as defined in claim 1.

3. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein in Formula I, R1 is H or methyl; R3 is hydrogen; and R2, R4 and R5 are as defined in claim 1.

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein in Formula I, R2 is selected from: where R 12 are independently selected from H; R6 and R7 are independently selected from hydrogen; C 1-6 Alkyl; selected from F, hydroxy and C 1-6 Alkoxy substituted C 1-6 Alkyl; C 3-6 Cycloalkyl; C substituted by F 3-6 Cycloalkyl.

5. The compound according to claim 4 or a pharmaceutically acceptable salt thereof, wherein in Formula I, R2 is selected from: where R 12 and Y as defined in claim 4.

6. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein in Formula I, R 12 is hydrogen, and R6 is hydrogen.

7. A compound represented by formula I or a pharmaceutically acceptable salt thereof: in R1 is selected from H, C 1-6 alkyl; R3 is selected from hydrogen; R2 is selected from aryl or halogen, cyano, C 1-6 Alkoxy, -NR6Y, F substituted C 1-6 Alkyl substituted aryl, the aryl selected from phenyl; nitrogen-containing C 4-7 Heterocycloalkyl, wherein the nitrogen atom is substituted by Y; or R2 and R3 together form a nitrogen-containing C 4-7 Heterocycloalkyl, wherein the nitrogen atom is substituted by Y; R6 is selected from hydrogen; C 1-6 Alkyl; selected from F, hydroxy and C 1-6 Alkoxy substituted C 1-6 Alkyl; C 3-6 Cycloalkyl; C substituted by F 3-6 Cycloalkyl; Y is selected from -CN, -C(=O)P; wherein P is selected from in R7 is selected from hydrogen; cyano; C 1-6 Alkyl; is selected from halogen, hydroxy and C 1-6 Alkoxy substituted C 1-6 alkyl; R8 is selected from hydrogen; C 1-6 Alkyl; is selected from halogen, hydroxy and C 1-6 Alkoxy substituted C 1-6 alkyl; R9 is selected from hydrogen; C 1-6 Alkyl; C 1-6 Alkoxy, NR 10 R 11 , halogen, hydroxy substituted C 1-6 alkyl; Rx is selected from H, C 1-6 alkyl; R 10 and R 11 are each independently selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl; or together with the nitrogen they replace form a 4-6 membered heterocycloalkyl; m is an integer selected from 1, 2, and 3; R4 is in, R 13 、R 14 、R 15 、R 16 and R 17 independently selected from H; halogen; CN; C 1-6 Alkyl; C 1-6 Alkoxy; C substituted by halogen 1-6 alkyl; R5 is selected from hydrogen.

8. The compound according to claim 7 or a pharmaceutically acceptable salt thereof, wherein R7 is selected from hydrogen or methyl; R8 is selected from hydrogen or methyl; R9 is selected from hydrogen; methyl; ethyl; -CF3; -CH2NR 10 R 11 , R 10 and R 11 All are methyl; Rx is selected from H or -CH3.

9. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 13 、R 14 、R 15 、R 16 and R 17 independently selected from H; halogen and C 1-6 Alkoxy.

10. The compound according to claim 9 or a pharmaceutically acceptable salt thereof, wherein R 13 、R 14 、R 15 、R 16 and R 17 Independently selected from H; F; Cl; Br and -OCH3.

11. The following compound or a pharmaceutically acceptable salt thereof: 7-(1-Acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide (E)-7-(1-(But-2-enoyl)piperidin-4-yl)-2-(4-phenoxyphenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide 7-(1-Methacrylpiperidin-4-yl)-2-(4-phenoxyphenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide 7-(1-(3-methylbut-2-enoyl)piperidin-4-yl)-2-(4-phenoxyphenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide 7-(1-(But-2-ynyl)piperidin-4-yl)-2-(4-phenoxyphenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide 2-(4-phenoxyphenyl)-7-(1-propioloylpiperidin-4-yl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide (E)-7-(1-(Pent-2-enoyl)piperidin-4-yl)-2-(4-phenoxyphenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide 7-(1-Acryloylpiperidin-4-yl)-1-methyl-2-(4-phenoxyphenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide 7-(1-(But-2-ynyl)piperidin-4-yl)-1-methyl-2-(4-phenoxyphenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide (E)-2-(4-phenoxyphenyl)-7-(1-(4,4,4-trifluorobut-2-enoyl)piperidin-4-yl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide (E)-7-(1-(4-(dimethylamino)but-2-enoyl)piperidin-4-yl)-2-(4-phenoxyphenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide 7-(1-cyanopiperidin-4-yl)-2-(4-phenoxyphenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide 7-(1-Acryloylpiperidin-4-yl)-2-(4-(4-fluorophenoxy)phenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide 7-(1-(But-2-ynyl)piperidin-4-yl)-2-(4-(4-fluorophenoxy)phenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide 2-(4-(4-fluorophenoxy)phenyl)-7-(1-propioloylpiperidin-4-yl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide (E)-2-(4-(4-fluorophenoxy)phenyl)-7-(1-(4,4,4-trifluorobut-2-enoyl)piperidin-4-yl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide 7-(1-Acryloylpiperidin-4-yl)-2-(4-(2,4-difluorophenoxy)phenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide 7-(1-(But-2-ynyl)piperidin-4-yl)-2-(4-(2,4-difluorophenoxy)phenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide 2-(4-(2,4-difluorophenoxy)phenyl)-7-(1-propioloylpiperidin-4-yl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide 7-(1-Acryloylpiperidin-4-yl)-2-(4-(4-methoxyphenoxy)phenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide 7-(1-(But-2-ynyl)piperidin-4-yl)-2-(4-(4-methoxyphenoxy)phenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide 2-(4-(4-methoxyphenoxy)phenyl)-7-(1-propioloylpiperidin-4-yl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide 7-(1-Acryloylpiperidin-4-yl)-2-(4-(2-methoxyphenoxy)phenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide 7-(1-(But-2-ynyl)piperidin-4-yl)-2-(4-(2-methoxyphenoxy)phenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide 2-(4-(2-methoxyphenoxy)phenyl)-7-(1-propioloylpiperidin-4-yl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide 7-(1-Acryloylpiperidin-4-yl)-2-(4-(2-fluorophenoxy)phenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide 7-(1-(But-2-ynyl)piperidin-4-yl)-2-(4-(2-fluorophenoxy)phenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide 2-(4-(2-fluorophenoxy)phenyl)-7-(1-propioloylpiperidin-4-yl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide 7-(1-Acryloylpiperidin-4-yl)-2-(4-(4-chlorophenoxy)phenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide 2-(4-(4-chlorophenoxy)phenyl)-7-(1-propioloylpiperidin-4-yl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide 7-(1-Acryloylpiperidin-4-yl)-2-(4-(4-bromophenoxy)phenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide 7-(1-Acryloylpiperidin-4-yl)-2-(4-(p-tolyloxy)phenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide 7-(1-Acryloylpyrrolidin-3-yl)-2-(4-phenoxyphenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide 7-(1-(But-2-ynyl)pyrrolidin-3-yl)-2-(4-phenoxyphenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide 2-(4-phenoxyphenyl)-7-(1-propioloylpyrrolidin-3-yl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide 7-(1-Acryloylpyrrolidin-3-yl)-2-(4-(4-fluorophenoxy)phenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide 7-(1-(But-2-ynyl)pyrrolidin-3-yl)-2-(4-(4-fluorophenoxy)phenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide 2-(4-(4-fluorophenoxy)phenyl)-7-(1-propioloylpyrrolidin-3-yl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide 2-(4-(2,4-difluorophenoxy)phenyl)-7-(1-propioloylpyrrolidin-3-yl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide 7-(1-Acryloylpyrrolidin-3-yl)-2-(4-(4-methoxyphenoxy)phenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide 7-(1-(But-2-ynyl)pyrrolidin-3-yl)-2-(4-(4-methoxyphenoxy)phenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide 2-(4-(4-methoxyphenoxy)phenyl)-7-(1-propioloylpyrrolidin-3-yl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide 7-(1-Acryloylpyrrolidin-3-yl)-2-(4-(2-methoxyphenoxy)phenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide 7-(1-(But-2-ynyl)pyrrolidin-3-yl)-2-(4-(2-methoxyphenoxy)phenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide 2-(4-(2-methoxyphenoxy)phenyl)-7-(1-propioloylpyrrolidin-3-yl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide 7-(1-Acryloylpyrrolidin-3-yl)-2-(4-(2-fluorophenoxy)phenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide 7-(1-(But-2-ynyl)pyrrolidin-3-yl)-2-(4-(2-fluorophenoxy)phenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide (E)-2-(4-(p-Tolyloxy)phenyl)-7-(1-(4,4,4-trifluorobut-2-enoyl)pyrrolidin-3-yl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide 7-(1-Acryloylazetidin-3-yl)-2-(4-phenoxyphenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide 7-(1-(But-2-ynyl)azetidin-3-yl)-2-(4-phenoxyphenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide 2-(4-phenoxyphenyl)-7-(1-propioloylazetidin-3-yl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide (E)-2-(4-phenoxyphenyl)-7-(1-(4,4,4-trifluorobut-2-enoyl)azetidin-3-yl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide 7-(1-Acryloylazetidin-3-yl)-2-(4-(4-fluorophenoxy)phenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide 7-(1-(But-2-ynyl)azetidin-3-yl)-2-(4-(4-fluorophenoxy)phenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide 2-(4-(4-fluorophenoxy)phenyl)-7-(1-propioloylazetidin-3-yl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide 7-(1-Acryloylazetidin-3-yl)-2-(4-(2-methoxyphenoxy)phenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide 7-(1-(But-2-ynyl)azetidin-3-yl)-2-(4-(2-methoxyphenoxy)phenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide 2-(4-(2-methoxyphenoxy)phenyl)-7-(1-propioloylazetidin-3-yl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide 7-(4-Acrylamidophenyl)-2-(4-phenoxyphenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide 2-(4-phenoxyphenyl)-7-(4-propiolamidophenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide 7-(3-Acrylamidophenyl)-2-(4-phenoxyphenyl)-1H-imidazo[1,2-b]pyrazole-3-carboxamide 8-Acryloyl-2-(4-phenoxyphenyl)-6,7,8,9-tetrahydro-1H-imidazo[1',2':1,5]pyrazolo[4,3-c]pyridine-3-carboxamide (E)-8-(4-(dimethylamino)but-2-enoyl)-2-(4-phenoxyphenyl)-6,7,8,9-tetrahydro-1H-imidazolyl [1',2':1,5]pyrazolo[4,3-c]pyridine-3-carboxamide 9-Acryloyl-2-(4-phenoxyphenyl)-1,6,7,8,9,10-hexahydroimidazo[1',2':1,5]pyrazolo[4,3-c]azepine-3-carboxamide 8-Acryloyl-2-(4-phenoxyphenyl)-1,6,7,8,9,10-hexahydroimidazo[1',2':1,5]pyrazolo[3,4-d]azepine-3-carboxamide.

12. A pharmaceutical composition comprising the compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

13. Use of the compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for inhibiting BTK activity.

14. Use of the compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a disease selected from the group consisting of autoimmune diseases, inflammatory diseases, cancer and allergies.

15. The use according to claim 14, wherein the disease is selected from follicular lymphoma, chronic lymphocytic leukemia, mantle cell lymphoma, splenic marginal zone lymphoma, large B-cell lymphoma, lupus erythematosus, rheumatoid arthritis, Crohn's disease, psoriasis, multiple sclerosis and asthma.

16. The use according to claim 14, wherein the disease is selected from diffuse large B-cell lymphoma.

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