WO2022012550A1

WO2022012550A1 - Substituted 1h-imidazo [1, 2-b] pyrazole-3-carboxamide as bruton's tyrosine kinase inhibitors

Info

Publication number: WO2022012550A1
Application number: PCT/CN2021/106090
Authority: WO
Inventors: Yuqin JIANG; Dandan Zhang; Qingjie Ding; Chunhua MA; Guiqing Xu; Wei Li; Shouning YANG; Yang Li; Chenchen Zhang; Lu Zhao; Zongjing HAO; Xin Shi; Peipei SHI
Original assignee: Henan Normal University; Henan Zhiwei Biomedicine Co., Ltd.
Priority date: 2020-07-13
Filing date: 2021-07-13
Publication date: 2022-01-20
Also published as: CN116018138A

Abstract

This application discloses a series of substituted 1H-imidazo [1, 2-b] pyrazole-3-carboxamide compounds represented by formula I as kinase inhibitors, in particular BTK (Bruton's Tyrosine Kinase) inhibitors, and the methods of making and using the same for the treatment of autoimmune disease, inflammatory disease, cancer and potentially allergies.

Description

Substituted 1H-imidazo [1, 2-b] pyrazole-3-carboxamide as Bruton’s Tyrosine Kinase inhibitors

TECHNICAL FIELD

The invention relates to a series of substituted 1H-imidazo [1, 2-b] pyrazole-3-carboxamide compounds of formula I as kinase inhibitors, in particular BTK (Bruton’s Tyrosine Kinase) inhibitors, and the methods of making and using the same for the treatment of autoimmune disease, inflammatory disease, cancer and potentially allergies.

BACKGROUND OF ART

Bruton’s Tyrosine Kinase (BTK) is a non-receptor tyrosine kinase of the Tec family (Bradshaw et al, Cell Signal, 2010, 22, 1175-184) . It plays an important role in the maturation of B cells, myeloid cells, mast cells, and platelets. BTK is an essential kinase in the B cell receptor (BCR) signaling pathway and a driving force for 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 primarily expressed in hematopoietic cells such as B cell, mast cell and microphages and exists in tissues including bone marrow, lymph nodes and spleens. They participate in signal transduction in response to virtually all types of extracellular stimuli which are 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 features 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 phosphatidylinositol (3, 4, 5) -triphosphate (PIP3) and induces BTK to phosphorylate phospholipase C gamma which then hydrolyzes phosphatidylinositol 4, 5-biphosphate (PIP2) into two secondary messengers, inositol triphosphate (IP3) and diacylglycerol (DAG) which in turn modulate downstream B cell signaling. Dysfunctional BTK activation has been the culprit of autoimmune disease such as rheumatoid arthritis, osteoporosis, lupus and implicated in many cancers. Mutations of BTK gene are directly implicated in the immunodeficiency disease X-linked agammaglobulinemia (XLA) . Patients with this disease have premature B cells in their bone marrow but they never mature and enter into circulation.

Several small molecule BTK inhibitors have been reported. 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) , as the first-generation BTK inhibitor, has been in clinical use for the treatment of chronic lymphocytic leukemia (CLL) , mantle cell lymphoma, and Waldenstrom’s 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 demonstrated some untoward side effects such as vomit, nausea, bleeding, rash, diarrhea and atrial fibrillation with some of them being serious. These adverse effects are partly due to its off-target effects on the epidermis 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 the findings, more selective BTK inhibitors are being explored.

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, which 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) .

ONO/GS-4059 (Structure C) is another novel highly potent and selective BTK inhibitor. Its anti-tumor activities were studied in preclinical models (Yasuhiro T et al, Cancer Research, 2013, 73, 2452) and in the 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) .

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

Several other candidates (Bradshaw et al. Nat Chem Biol, 2015, 11 (7) , 525-531; US9447106 B2; CN103848810 A1) in different stages of clinical trials are being tested for various diseases including cancer and autoimmune diseases. All these point to the potential application of BTK inhibition in the treatment of various diseases in the area of cancer, allergy and auto-immune diseases.

SUMMARY OF INVENTION

The present invention describes compounds as protein kinase, particularly BTK inhibitors which may be used for the treatment of autoimmune disease, inflammatory disease, cancer and potentially allergies.

In one aspect, the invention provides the compound represented by Formula I, the pharmaceutically acceptable salt, active metabolite, tautomer, stereoisomer and prodrug thereof.

wherein

R ₁ is selected from H, and C _1-6 alkyl, C _1-6 cycloalkyl;

R ₂ and R ₃ are independently selected from hydrogen; halogen; cyano; CF ₃, aryl, aryl substituted independently with -NR ₆Y, hydrogen, cyano, C _1-6 alkoxy, C _1-6 alkyl substituted with F;heteroaryl, heteroaryl substituted independently with -NR ₆Y, halogen, cyano, C _1-6 alkoxy, C _1-6 alkyl substituted with F; Nitrogen containing C _4-7 heterocycloalkyl where the N atom is substituted with Y; C _1-6 alkyl; C _1-6 alkyl substituted with C _1-6 alkoxy, NR ₆Y; C _3-6 cycloalkyl, C _3- ₆ cycloalkyl substituted with NR ₆Y; Or R ₂ and R ₃ can together form a 5-8 member saturated carbon cycle which may be substituted with NR ₆Y or in the ring contain a nitrogen atom that is substituted with Y; Or R ₂ and R ₃ together form an aryl ring such as phenyl that is substituted independently with halogen, cyano, CF ₃, C _1-6 alkyl, C _1-6 alkoxy and NR ₆Y;

R ₆ is selected from hydrogen, C _1-6 alkyl, C _1-6 alkyl substituted with groups selected from F, hydroxyl and C _1-6 alkoxy; C _3-6 cycloalkyl, C _3-6 cycloalkyl substituted with F;

Y is selected from the groups consisting of -CN, -C (=O) P, -S (=O) P and -S (=O) ₂P; where

P is selected from

and

Rx is selected from the group consisting of H, cyano, C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, phenyl, - (CH ₂) _mNR ₁₀R ₁₁, C _1-6 alkyl substituted with halogen, hydroxy;

m is an integer selected from 1, 2, 3;

R ₇ is selected from hydrogen, halogen, cyano, C _1-6 alkyl, C _1-6 alkyl substituted with groups selected from F, hydroxyl and C _1-6 alkoxy; C _3-6 cycloalkyl, C _3-6 cycloalkyl substituted with F;

R ₈ and R ₉ are independently selected from hydrogen; halogen; cyano; CF ₃; aryl; aryl independently substituted with hydrogen, halogen, cyano, C _1-6 alkoxy and CF ₃; heteroaryl; heteroaryl independently substituted with hydrogen, halogen, cyano, C _1-6 alkoxy and CF ₃; C _1-6 alkyl; C _1-6 alkyl substituted with C _1-6 alkoxy, NR ₁₀R ₁₁, halogen, hydroxyl, C ₆ or C ₁₀ aryl, and heteroaryl; C _3-6 cycloalkyl; C _3-6 cycloalkyl substituted with halogen; C _2-6 alkenyl; C _2-6 alkenyl substituted with C _1-6 alkoxy, NR ₁₀R ₁₁, halogen, hydroxyl, C ₆ or C ₁₀ aryl and heteroaryl;

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 substitute form a 4-6 membered heterocycloalkyl;

R ₄ is selected from aryl, C _1-6 alkyl, (C _1-4) fluoroalkyls, C _3-6 cycloalkyls; aryl independently substituted with halogen, cyano, C _1-6 alkoxy, (C _1-4) fluoroalkyls;

R ₅ can substitute any suitable position of the phenyl ring it attaches and is selected from groups of hydrogen, halogen, (C _1-4) fluoroalkyls, cyano, C _1-6 alkyl, C _3-6 cycloalkyls, C _1-6 alkoxy;

In one embodiment in Formula I, R ₁ is H or methyl. The rest of the groups are as defined above.

In another embodiment of Formula I,

R ₁ is H;

R ₂ is selected from the group consisting of:

Wherein R ₁₂ is independently selected from H, F, C _1-6 alkyl, C _1-6 alkyl substituted with halogen, C _1-6 alkoxy, and NR ₆R ₇; and R ₁₂ may substitute more than one position; or in the heterocycle cases R ₁₂ may form a double bond in the ring, or form a 3-6 membered ring fused or spiraled with the original ring;

R ₃ is H;

R ₄ is C _1-6 alkyl, C _1-6 cycloalkyl and

Wherein,

R ₁₃, R ₁₄, R ₁₅, R ₁₆ and R ₁₇ are independently selected from the group consisting of H; halogen; CN; C _1-6 alkyl; C _1-6 alkoxy, C _1-6 alkyl substituted with halogen;

R ₅ is H;

R ₆ is selected from hydrogen, C _1-6 alkyl, C _1-6 alkyl substituted with groups selected from F, hydroxyl and C _1-6 alkoxy; C _3-6 cycloalkyl, C _3-6 cycloalkyl substituted with F.

In another embodiment of Formula I,

R ₁ is H;

R ₂ is selected from the group consisting of:

R ₃ is H;

R4 is:

wherein,

R ₁₃, R ₁₄, R ₁₅, R ₁₆ and R ₁₇ are independently selected from H, OCH ₃, F, Cl, Br, CF ₃ and CN.

The rest of the groups is as defined above.

In another embodiment of Formula I,

R ₁ is H;

R ₂ is selected from

Y is -C (=O) P; where

P is selected from

and

R ₇ is selected from hydrogen, cyano, and CF ₃;

R ₈ and R ₉ are independently selected from hydrogen, CF ₃, CH ₃, cyclopropyl and C _1-6 alkyl substituted with NR ₁₀R ₁₁.

Rx is selected from the group consisting of H, CH ₃, CF ₃ and cyclopropyl, -(CH ₂) _mNR ₁₀R ₁₁ wherein

m is an integer selected from 1, 2, 3;

R ₃ is H and R ₄ is phenyl;

R ₅ is H;

In another embodiment of Formula I wherein

R ₁ is H;

R ₂ and R ₃ together with the pyrazole ring they substitute form a nitrogen containing heterocycloalkyl where the N atom is substituted with Y (Formula II) or form a phenyl ring that is substituted at any position of the ring with NR ₆Y (Formula III) ;

Wherein n ₁ and n ₂ are integers that are independently selected from 0, 1, 2;

R ₄, R ₆ and Y are as defined above.

In another embodiment of Formula I, wherein

R ₁ is H;

R ₂ is selected from

Wherein Y is -C (=O) P;

P is selected from

and

R ₇ is selected from hydrogen or cyano;

R ₈ and R ₉ are independently selected from hydrogen, CF ₃, CH ₃ and C _1-6 alkyl substituted with NR ₁₀R ₁₁;

Rx is selected from the group consisting of H, CH ₃, CF ₃;

R ₃ is H and R ₄ is phenyl;

R ₅ is H;

In another embodiment of Formula I, wherein

R ₁ is H;

R ₂ is selected from

Wherein Y is CN;

R ₃ is H and R ₄ is phenyl;

R ₅ is H;

In another embodiment of Formula II,

R ₁ is H;

R ₄ is phenyl;

Y is -C (=O) P;

P is selected from

R ₉ is selected from hydrogen, CF ₃, CH ₃ and C _1-6 alkyl substituted with NR ₁₀R ₁₁;

In another embodiment of Formula III, wherein

R ₁ is H;

R ₄ is phenyl;

Y is -C (=O) P;

P is selected from

R ₉ is selected from hydrogen, CF ₃, CH ₃ and C _1-6 alkyl substituted with NR ₁₀R ₁₁; R ₆is H or methyl;

In another embodiment of Formula I, wherein

R ₁ is H;

R ₂ is selected from

Wherein Y is -C (=O) P;

P is

and

Rx is selected from the group consisting of H, CH ₃;

R ₃ is H and R ₄ is phenyl;

R ₅ is H;

In another embodiment of Formula I, wherein

R ₁ is H;

R ₂ is

Wherein Y is -C (=O) P;

P is selected from

and

R ₉ is selected from hydrogen, CF ₃;

Rx is selected from the group consisting of H, CH ₃;

R ₃ is H and R ₄ is phenyl;

R ₅ is H;

In another embodiment of Formula I, the present invention provides the following compounds.

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-methacryloylpiperidin-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-ynoyl) 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-ynoyl) 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-ynoyl) 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-ynoyl) 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-ynoyl) 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-ynoyl) 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-ynoyl) 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-ynoyl) 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-ynoyl) 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-ynoyl) 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-ynoyl) 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-ynoyl) 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-ynoyl) 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-ynoyl) 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-ynoyl) 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-imidazo [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

In a further aspect, the invention provides a pharmaceutical composition which includes an effective amount of a compound of the invention, or a pharmaceutically acceptable salt, active metabolite, tautomer, stereoisomer, or prodrug thereof, and a pharmaceutically acceptable carrier.

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 additional embodiments, the pharmaceutical composition is in the form of a tablet, capsule, pill, powder, sustained release formulation, solution and suspension, for parenteral injection as a sterile solution, suspension or emulsion, for topical administration as an ointment or cream or for rectal administration as a suppository. In further or additional embodiments, the pharmaceutical composition is in unit dosage forms suitable for single administration of precise dosages. In further or additional embodiments, the amount of compound of formula I is in the range of about 0.001 to about 1000 mg/kg body weight/day. In further or additional embodiments, the amount of compound of formula I is about 0.001 to about 7 g/day. In further or additional embodiments, dosage levels below the lower limit of the aforesaid range may be more than adequate. In further or additional embodiments, dosage levels above the upper limit of the aforesaid range may be required. In further or additional 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.

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

In another aspect, the invention provides a method for preventing or treating a subject suffering from or at risk of a disease or disorder selected from the group consisting of an autoimmune disease, inflammatory disease, cancer, allergy, diffused large B cell lymphoma, follicular lymphoma, chronic lymphocytic leukemia, mantel cell lymphoma, splenic marginal zone lymphoma, large B cell lymphoma, lupus erythematosus, rheumatoid arthritis, Crohn’s disease, psoriasis, multiple sclerosis, asthma etc., comprising administering to said subject an effective amount of a compound of this invention or a pharmaceutically acceptable salt, active metabolite, tautomer, stereoisomer, or prodrug thereof, or a pharmaceutical composition of this invention.

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

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

In another aspect, the invention provides a use of a compound of the invention, or a pharmaceutically acceptable salt, active metabolite, tautomer, stereoisomer, or prodrug thereof, in the preparation of a medicament for treating a disease or disorder selected from the group consisting of an autoimmune disease, inflammatory disease, cancer, allergy, diffused large B cell lymphoma, follicular lymphoma, chronic lymphocytic leukemia, mantel cell lymphoma, splenic marginal zone lymphoma, large B cell lymphoma, lupus erythematosus, rheumatoid arthritis, Crohn’s disease, psoriasis, multiple sclerosis, asthma etc.

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

In another aspect, the invention provides a compound of the invention, or a pharmaceutically acceptable salt, active metabolite, tautomer, stereoisomer, or prodrug thereof, for the treatment of a disease or disorder that may benefit from the inhibition of BTK.

In another aspect, the invention provides a compound of the invention, or a pharmaceutically acceptable salt, active metabolite, tautomer, stereoisomer, or prodrug thereof, for treating a disease or disorder selected from the group consisting of an autoimmune disease, inflammatory disease, cancer, allergy, diffused large B cell lymphoma, follicular lymphoma, chronic lymphocytic leukemia, mantel cell lymphoma, splenic marginal zone lymphoma, large B cell lymphoma, lupus erythematosus, rheumatoid arthritis, Crohn’s disease, psoriasis, multiple sclerosis, asthma etc.

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

In some embodiments, the foregoing disease or condition includes but not limit to cancer, autoimmune disease, inflammatory disease and allergy. Such diseases include but not limit to diffused large B cell lymphoma, follicular lymphoma, chronic lymphocytic leukemia, mantel cell lymphoma, splenic marginal zone lymphoma, large B cell lymphoma, lupus erythematosus, rheumatoid arthritis, Crohn’s disease, psoriasis, multiple sclerosis, asthma etc.

DETAILED DESCRIPTION

The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described. All documents, or portions of documents, cited in the application including, without limitation, patents, patent applications, articles, books, manuals, and treatises are hereby expressly incorporated by reference in their entirety for any purpose.

Certain Chemical Terminology

The present invention also intended to include isotopically labeled compounds. The commonly seen isotopic atoms include but not limited to ²H, ³H, ¹³C, ¹⁴C, ¹⁷O, ¹⁸O, ¹⁵N etc. These atoms are the same as their naturally richest atom but have a different mass number. Applications of isotopically labeling in drug discovery are reported (Elmore, Charles S, Annual Report of Medicinal Chemistry, 2009, 44, 515-534) .

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which the claimed subject matter belongs. All patents, patent applications, published materials referred to throughout the entire disclosure herein, unless noted otherwise, are incorporated by reference in their entirety. In the event that there is a plurality of definitions for terms herein, those in this section prevail.

It is to be understood that the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of any subject matter claimed. In this application, the use of the singular includes the plural unless specifically stated otherwise. It must be noted that, as used in the specification and the appended claims, the singular forms "a" , "an" and "the" include plural referents unless the context clearly dictates otherwise. It should also be noted that use of "or" means "and/or" unless stated otherwise. Furthermore, use of the term "including" as well as other forms, such as "include" , "includes" , and "included" is not limiting. Likewise, use of the term "comprising" as well as other forms, such as "comprise" , "comprises" , and "comprised" is not limiting.

Definition of standard chemistry terms may be found in reference works, including Carey and Sundberg "ADVANCED ORGANIC CHEMISTRY 4 ^TH ED. " Vols. A (2000) and B (2001) , Plenum Press, New York. Unless otherwise indicated, conventional methods of mass spectroscopy, NMR, HPLC, IR and UV/V is spectroscopy and pharmacology, within the skill of the art are employed. Unless specific definitions are provided, the nomenclature employed in connection with, and the laboratory procedures and techniques of, analytical chemistry, synthetic organic chemistry, and medicinal and pharmaceutical chemistry described herein are those known in the art. Standard techniques can be used for chemical syntheses, chemical analyses, pharmaceutical preparation, formulation, and delivery, and treatment of patients. Reactions and purification techniques can be performed, e.g., using kits of manufacturer's specifications or as commonly accomplished in the art or as described herein. The foregoing techniques and procedures can be generally performed of conventional methods well known in the art and as described in various general and more specific references that are cited and discussed throughout the present specification.

Where substituent groups are specified by their conventional chemical formulas, written from left to right, they equally encompass the chemically identical substituents that would result from writing the structure from right to left. As a non-limiting example, CH ₂O is equivalent to OCH ₂.

Unless otherwise noted, the use of general chemical terms, such as though not limited to "alkyl" , "aryl" is equivalent to their optionally substituted forms. For example, "alkyl" as used herein, includes optionally substituted alkyl.

The compounds presented herein may possess one or more stereo centers and each center may exist in the R or S configuration, or combinations thereof. Likewise, the compounds presented herein may possess one or more double bonds and each may exist in the E (trans) or Z (cis) configuration, or combinations thereof. Presentation of one particular stereoisomer should be understood to include all possible stereoisomers, including regioisomers, diastereomers, enantiomers or epimers and mixtures thereof. Thus, the compounds presented herein include all separate configurational stereoisomeric, regioisomeric, diastereomeric, enantiomeric, and epimeric forms as well as the corresponding mixtures thereof. A racemate (a mixture of S and R form) , diastereomers and single isomers of either S or R can exist. It is the intention of the invention that compounds claimed here could be a mixture of diastereomers, a racemate or a single isomer of either S or R.

The term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. For example, "alkyl optionally substituted with…. " means either "alkyl" or "substituted alkyl with……" as defined below.

As used herein, a group designated as "C ₁-C ₆" indicates that there are one to six 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, "C ₁-C ₆ alkyl" indicates that there are one to six carbon atoms in the alkyl group, i.e. the alkyl group is selected from among methyl, ethyl, propyl, iso-propyl, n-butyl, isobutyl, sec-butyl, and t-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl and the isomers thereof.

The terms "cycle" , "cyclic" , "ring" and "membered ring" as used herein, alone or in combination, refer to any covalently closed structure, including alicyclic, heterocyclic, aromatic, heteroaromatic and polycyclic fused or non-fused ring systems as described herein. Rings can be optionally substituted. Rings can form part of a fused ring system. The term "membered" is meant to denote the number of skeletal atoms that constitute the ring. Thus, by way of example only, cyclohexane, pyridine, pyran and pyrimidine are 6-membered rings.

The term "fused" as used herein, alone or in combination, refers to cyclic structures in which two or more rings share one or more bonds.

The term "heterocyclyl" as used herein, alone or in combination, refers collectively to heteroalicyclyl groups. Herein, whenever the number of carbon atoms in a heterocycle is indicated (e.g. C ₃-C ₆ heterocycle) , at least one non-carbon atom (the heteroatom) must be present in the ring. Designations such as "C ₃-C ₆ heterocycle" refer only to the number of carbon atoms in the ring and do not refer to the total number of atoms in the ring. Designations such as "4-8 membered heterocycle" refer to the total number of atoms that are 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 two to six atoms are either carbon atoms or heteroatoms) . For heterocycles having two or more heteroatoms, those two or more heteroatoms can be the same or different from one another. Heterocycles can be optionally substituted. Bonding (i.e. attachment to a parent molecule or further substitution) to a heterocycle can be via a heteroatom or a carbon atom. The "heterocycle" wherein the ring is saturated is called as heterocycloalkyl.

The term "spiral heterocyclyl" as used herein, alone or in combination, refers to a polycyclyl wherein two rings share a carbon atom and at least one ring atom is a heteroatom. The spiral heterocyclyl may have two or more cycles, each of them may be 4-8 membered cycles. Spiral heterocyclyl can be optionally substituted. Bonding (i.e. attachment to a parent molecule or further substitution) to a spiral heterocycle can be via a heteroatom or a carbon atom. The "spiral heterocycle" includes heterocycloalkyl.

The term "cycloalkyl" as used herein, alone or in combination, refers to an optionally substituted, saturated, hydrocarbon monoradical ring which may include additional, non-ring carbon atoms as substituents (e.g. methylcyclopropyl) . The cycloalkyl may have three to about ten, or three to about eight, or three to about six, or three to five ring atoms. The examples include but not limited to cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

The term "aryl" as used herein, alone or in combination, refers to an optionally substituted aromatic hydrocarbon radical of six to about twenty ring carbon atoms, and includes fused and non-fused aryl rings. A fused aryl ring radical contains from two to four fused rings where the ring of attachment is an aryl ring, and the other individual rings may be alicyclic, heterocyclic, aromatic, heteroaromatic or any combination thereof. Further, the term aryl includes fused and non-fused rings. Moreover, the term aryl includes but not limited to monocycle, bicycle and tricycle or more cycles. The aryl (for example monocyclic aryl) contains, for example, from six to about twelve, or six to about ten, or six to about eight ring carbon atoms. A non-limiting example of a single ring aryl group includes phenyl; a fused ring aryl group includes naphthyl, phenanthrenyl, anthracenyl, azulenyl; and a non-fused bi-aryl group includes biphenyl.

The term "alkyl" as used herein, alone or in combination, refers to an optionally substituted straight-chain, or optionally substituted branched-chain saturated hydrocarbon monoradical having, for example, from one to about eighteen, or one to about ten carbon atoms, or one to six carbon atoms. The term "lower alkyl" as used herein, alone or in combination, refers to an alkyl having relatively less carbon atoms, for example having one to about eight carbon atoms, preferably having one to about six, or one to about four carbon atoms. Examples of alkyl include, but are not limited to methyl, ethyl, n-propyl, isopropyl, 2-methyl-l-propyl, 2-methyl-2-propyl, 2-methyl-l-butyl, 3-methyl-l-butyl, 2-methyl-3-butyl, 2, 2-dimethyl-l-propyl, 2-methyl-l-pentyl, 3-methyl-1-pentyl, 4-methyl-l-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2, 2-dimethyl-l-butyl, 3, 3-dimethyl-1-butyl, 2-ethyl-l-butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl and hexyl, and the like.

The "alkyl" as used in combination includes but not limited to the "alkyl" included in "alkoxy" .

The term "alkoxy" as used herein, alone or in combination, refers to an alkyl ether radical, O-alkyl. Non-limiting examples of alkoxy radicals include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tertbutoxy and the like.

The term "alkenyl" as used herein, alone or in combination, refers to an optionally substituted straight-chain, or optionally substituted branched-chain hydrocarbon monoradical having one or more carbon-carbon double-bonds and having, for example, from two to about eighteen or two to about ten carbon atoms, or two to about six carbon atoms. The group may be in either the cis or trans conformation about the double bonds, and should be understood to include both isomers. Examples include, but are not limited to ethenyl (-CH=CH ₂) , 1-propenyl (-CH ₂CH=CH ₂) , isopropenyl [-C (CH ₃) =CH ₂] , butenyl, 1, 3-butadienyl and the like. The present definition also covers the occurrence of the term "alkenyl" where no numerical range is designated.

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

Hydroxy or hydroxyl refers to a group of -OH.

Cyano refers to a group of -CN.

In the molecular structures shown in the invention, when asymmetric centers appear, a solid wedge means the bond is pointing to the top of the paper while a dotted wedge means the bond is pointing to the back of the paper. A solid bond line usually means all possible isomers.

Certain Pharmaceutical Terminology

The term "subject" , "patient" or "individual" as used herein in reference to individuals suffering from a disease, a disorder, a condition, and the like, encompasses mammals and non-mammals. Examples of mammals include, but are not limited to, any member of the Mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like. Examples of non-mammals include, but are not limited to, birds, fish and the like. In one embodiment of the methods and compositions provided herein, the mammal is a human.

The terms "treat, " "treating" or "treatment, " and other grammatical equivalents as used herein, include alleviating, abating or ameliorating a disease or condition symptoms, preventing additional symptoms, ameliorating or preventing the underlying metabolic causes of symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition, and are intended to include prophylaxis. The terms further include achieving a therapeutic benefit and/or a prophylactic benefit. By therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient may still be afflicted with the underlying disorder. For prophylactic benefit, the compositions may be administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease may not have been made.

The terms "effective amount" , "therapeutically effective amount" or "pharmaceutically effective amount" as used herein, refer to a sufficient amount of at least one agent or compound being administered which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result can be reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an "effective amount" for therapeutic uses is the amount of the composition comprising a compound as disclosed herein required to provide a clinically significant decrease in a disease. An appropriate "effective" amount in any individual case may be determined using techniques, such as a dose escalation study.

The terms "administer, " "administering" , "administration, " and the like, as used herein, refer to the methods that may be used to enable delivery of compounds or compositions to the desired site of biological action. These methods include, but are not limited to oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular or infusion) , topical and rectal administration. Those of skill in the art are familiar with administration techniques that can be employed with the compounds and methods described herein, e.g., as 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 preferred embodiments, the compounds and compositions described herein are administered orally.

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

The term "pharmaceutically acceptable" as used herein, refers to a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compounds described herein, and is relatively nontoxic, i.e., the material may be administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.

The term "pharmaceutical composition, " as used herein, refers to a biologically active compound, optionally mixed with at least one pharmaceutically acceptable chemical component, such as, though not limited to carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and/or excipients.

The term "carrier" as used herein, refers to relatively nontoxic chemical compounds or agents that facilitate the incorporation of a compound into cells or tissues.

The term "pharmaceutically acceptable salt" as used herein, refers to salts that retain the biological effectiveness of the free acids and bases of the specified compound and that are not biologically or otherwise undesirable. Compounds described herein may possess acidic or basic groups and therefore may react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt. These salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or by separately reacting a purified compound in its free base form with a suitable organic or inorganic acid, and isolating the salt thus formed. Examples of pharmaceutically acceptable salts include those salts prepared by reaction of the compounds described herein with a mineral or organic acid or an inorganic or organic base.

The term "tautomer" as used herein refers to an isomer readily interconverted from a compound of this invention by e.g., migration of a hydrogen atom or proton.

The term "prodrug" as used herein, refers to any pharmaceutically acceptable salt, ester, salt of an ester or other derivative of a compound of this invention, which, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this invention or a pharmaceutically active metabolite or residue thereof. Particularly favored derivatives or prodrugs are those that increase the bioavailability of the compounds of this invention when such compounds are administered to a patient (e.g. by allowing orally administered compound to be more readily absorbed into blood) or which enhance delivery of the parent compound to a biological compartment (e.g. the brain or lymphatic system) .

The term "active metabolite" , as used herein, refers to a biologically active derivative of a compound that is formed when the compound is metabolized.

The term "metabolized" , as used herein, refers to the sum of the processes (including, but not limited to, hydrolysis reactions and reactions catalyzed by enzymes) by which a particular substance is changed by an organism.

IC ₅₀ means the concentration of a particular compound that inhibits 50 %of a specific measured activity.

Embodiments The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized.

Some embodiments of the present invention have been shown and described herein by way of example only. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. Those ordinary skilled in the art will appreciate that numerous variations, changes, and substitutions are possible without departing from the invention. It is intended that the following claims define the scope of aspects of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.

The compounds of Formula I can generally be made by the chemistry route described in Schemes 1-3. Particular examples are provided in the following text.

Treatment of phenylketone 1 with sodium hydride and dimethylcarbonate gave β-ketoester 2. Treatment of ester 2 with ammonia in 1, 4-dioxane at elevated temperature gave the corresponding amide 3 that reacted with CuBr ₂ in ethyl acetate to give 1-bromoamide 4. On the other hand, aminopyrazole 9 was made by reacting ketone 5 with diethyl (cyanomethyl) phosphonate and NaH in THF gave nitrile 6 which was hydrogenated to give nitrile 7. Treatement of nitrile 7 with ethyl fromate and base in THF gave 1-cyanyo aldehyde 8 which condenses with hydrazine in EtOH provided aminopyrazole 9. Treatement of aminopyrazole 9 with 1-bromoamide 4 gave 1H-imidazo [1, 2-b] pyrazole-3-carboxamide 10. Treatment of carboxamide 10 with HCl to give the hydrochloride 11. Under conditions decribed below but not limited to the specified conditions, final compound either 12a or 12b could be prepared.

Scheme-1

Scheme-1 continued.

In Scheme-1, when m is 0, n can only choose the number 1. When m is 1, n is a number selected from 1, and 2. By a similar way to the preparation of compounds 12a and 12b, compounds 9a and 9b could be prepared.

Scheme-2

Scheme-3

In Scheme-3, n is a number selected from 1, and 2.

Scheme-4

Examples:

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

Step A: Preparation of methyl-3-oxo-3- (4-phenoxyphenyl) propanoate

To a stirred suspension of NaH (60 %dispersion in mineral oil; 26.3 g, 659.6 mmol) in anhydrous N, N-dimethylformamide (DMF, 300 mL) at 0 ℃ was added dropwise 1- (4-phenoxyphenyl) ethan-1-one (70 g, 329.8 mmol) dissolved in anhydrous DMF (50 mL) . After 30 minutes, the mixture was cooled to 0 ℃ and dimethyl carbonate (118.8 g, 1.32 mol) was added neat. The mixture was allowed to warm to room temperature for 2 hours and then poured into 1: 1 water/saturated sodium bicarbonate solution. The aqueous layer was extracted with ethyl acetate (3 × 500 mL) . The combined organic layer was washed with saturated brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by chromatography with petroleum ether and ethyl acetate (10: 1) to give the desired product methyl-3-oxo-3- (4-phenoxyphenyl) propanoate as a yellow solid (81 g, 90 %) . ¹H NMR (600 MHz, DMSO-d6) δ 8.00-7.96 (m, 2H) , 7.47 (t, J = 8.0 Hz, 2H) , 7.26 (t, J = 7.4 Hz, 1H) , 7.16-7.12 (m, 2H) , 7.05 (d, J = 8.8 Hz, 2H) , 4.16 (s, 2H) , 3.65 (s, 3H) . MS (ESI, m/z) : 271.3 [M+H] ⁺.

Step B: Preparation of 3-oxo-3- (4-phenoxyphenyl) propanamide

To a solution of the product of step A of example 1 (81 g, 0.30 mol) in 1, 4-dioxane (100 mL) was added 7 M NH ₃/1, 4-dioxane (100 mL) at room temperature in a 300 mL of sealed tube. The mixture was stirred at 95 ℃ for 12 hs, then it was cooled to room temperature. The mixture was concentrated under vacuum The residue was purified by chromatography with petroleum ether and ethyl acetate (1: 1) to give the desired product 3-oxo-3- (4- phenoxyphenyl) propanamide as a white solid (40 g, 53 %) . ¹H NMR (400 MHz, 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] ⁺.

Step C: Preparation of 2-bromo-3-oxo-3- (4-phenoxyphenyl) propanamide

CuBr ₂ (38 g, 0.17 mol) was added to a solution of the product of step B of example 1 (40 g, 0.16 mol) in ethyl acetate (500 ml) . The mixture was stirred at 50 ℃ until no further TLC changes were observed. The mixture was filtrated through celite. The filtrate was diluted with ethyl acetate and H ₂O. After the layers were separated, the organic layer was washed with brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by chromatography with petroleum ether and ethyl acetate (3: 2) to give the desired product 2-bromo-3-oxo-3- (4-phenoxyphenyl) propanamide as a white solid (48 g, 90.6 %) . MS (ESI, m/z) : 335.2 [M+H] ⁺.

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

To a stirred suspension of NaH (60 %dispersion in mineral oil; 64 g, 1.6 mol) in anhydrous tetrahydrofuran (THF, 500 mL) at 10 ℃ was added dropwise diethyl (cyanomethyl) phosphonate (304 g, 1.7 mol) dissolved in anhydrous THF (200 mL) . After 30 minutes, the mixture was cooled to 10 ℃ and tert-butyl 4-oxopiperidine-1-carboxylate (262 g, 1.32 mol) was added neat. The mixture was allowed to warm to room temperature over a 2 hs period and then quenched with ice/water. The aqueous layer was extracted with ethyl acetate, and after removal of the solvent under vacuum, the crude residue was recrystallized from petroleum ether and ethyl acetate (10: 1) to give the desired product tert-butyl 4- (cyanomethylene) piperidine-1-carboxylate as a white solid (260 g, 89 %) . ¹H NMR (400 MHz, CDCl ₃) δ 5.09 (s, 1H) , 3.43-3.31 (m, 4H) , 2.46-2.37 (m, 2H) , 2.20 (t, J = 5.6 Hz, 2H) , 1.33 (s, 9H) . MS (ESI, m/z) : 223.3 [M+H] ⁺.

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

To a solution of the product of step D of example 1 (80 g, 0.36 mol) in ethyl acetate (1000 mL) was added 10 %Pd/C (8 g, 10 %) under N ₂. The suspension was degassed under vacuum and purged with H ₂ several times. The mixture was stirred under H ₂ balloon at room temperature for 5 hs. The mixture was passed through celite, and the solid 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 %) . ¹H NMR (400 MHz, CDCl ₃) δ 4.08 (s, 2H) , 2.77-2.52 (m, 2H) , 2.25 (d, J = 6.4 Hz, 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] ⁺.

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

A solution of the product of step E of example 1 (61 g, 0.27 mol) in anhydrous THF (250 mL) was cooled to -85 ℃ (liquid nitrogen/ethanol bath) and treated with n-Butyllithium (n-BuLi, 2.5 M in hexane, 544 mL, 1.35 mol) dropwise and allowed to stir for 30 minutes. The reaction was then treated with ethyl formate (61 g, 0.81 mol) and allowed to warm to ice/water bath temperature and stirred for 30 min. Then it was quenched with ice/water and acidified to pH 5-6 with concentrated HCl and extracted with ethyl acetate. The organic phase was washed with saturated brine and then dried over anhydrous Na ₂SO ₄, filtered and concentrated to get 118 g crude tert-butyl 4- (1-cyano-2-oxoethyl) piperidine-1-carboxylate. The residue was used to next step directly.

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

A solution of the product of step F of example 1 (118 g, 0.47 mol) and hydrazine hydrate (80 %, 300 mL) in ethanol (300 mL) was heated to 80 ℃ for 10 hs. The reaction was then cooled to room temperature and the solvent was removed under vacuum, the crude residue was purified by chromatography with 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, the yield of the two steps was 43 %) . ¹H NMR (400 MHz, DMSO-d6) δ 7.12 (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] ⁺.

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

A solution of the product of step G of example 1 (31 g, 0.12 mol) and the product of step C of example 1 (31 g, 0.10 mol) in ethanol (500 mL) was heated to reflux for overnight. The reaction was then cooled to room temperature and the solvent was removed under vacuum, the crude residue was purified by chromatography with petroleum ether and ethyl acetate (3: 2) to give 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 %) . ¹H NMR (400 MHz, DMSO-d6) δ 12.09 (s, 1H) , 8.38 (s, 1H) , 7.84 (d, J = 8.7 Hz, 2H) , 7.70 (s, 1H) , 7.54 (s, 1H) , 7.45 (t, J = 7.9 Hz, 2H) , 7.21 (t, J = 7.4 Hz, 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] ⁺.

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

To a solution of the product of step H of example 1 (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 hs, then the mixture was concentrated under vacuum to get 9.5 g crude 2- (4-phenoxyphenyl) -7-(piperidin-4-yl) -1H-imidazo [1, 2-b] pyrazole-3-carboxamide. The residue was used to next step directly. MS (ESI, m/z) : 402.6 [M+H] ⁺.

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

The mixture of the product of step I of example 1 (180 mg, 0.44 mmol) in THF/H ₂O (3: 1, 4 mL) was alkalified to pH 7-8 with NaHCO ₃. Then the mixture was cooled to 0 ℃, and the solution of acryloyl chloride (60 mg, 0.66 mmol) in THF (1 mL) was added slowly. The reaction mixture was continued to stir for 1 h at 0 ℃. Dichloromethane and water were added. The layers were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed three times with brine solution (3 × 50 mL) . The organic phase was dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by chromatography with dichloromethane and methanol (30: 1) to give 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 %) . ¹H NMR (400 MHz, CDCl ₃) δ 10.48 (s, 1H) , 8.81 (s, 1H) , 7.80-7.75 (m, 2H) , 7.51 (s, 1H) , 7.39-7.33 (m, 2H) , 7.15 (t, J = 7.4 Hz, 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 = 1.8 Hz, 1H) , 5.62 (d, J = 1.9 Hz, 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] ⁺.

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

The mixture of the product of step I of example 1 (180 mg, 0.44 mmol) in THF/H ₂O (3: 1, 4 mL) was alkalified to pH 7-8 with NaHCO ₃. Then the mixture was cooled to 0 ℃, and the solution of (E) -but-2-enoyl chloride (69 mg, 0.66 mmol) in THF (1 mL) was added slowly. The reaction mixture was continued to stir for 1 h at 0 ℃. Dichloromethane and water were added. The layers were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed three times with brine (3 × 50 mL) . The organic phase was dried over anhydrous Na ₂SO ₄, 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 %) . ¹H NMR (400 MHz, DMSO-d6) δ 12.12 (s, 1H) , 8.38 (s, 1H) , 7.88-7.80 (m, 2H) , 7.71 (s, 1H) , 7.54 (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, 1.3 Hz, 3H) , 1.68-1.54 (m, 2H) . MS (ESI, m/z) : 470.5 [M+H] ⁺.

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

The mixture of the product of step I of example 1 (180 mg, 0.44 mmol) in THF/H ₂O (3: 1, 4 mL) was alkalified to pH 7-8 with NaHCO ₃. Then the mixture was cooled to 0 ℃, and the solution of meth-acryloyl chloride (69 mg, 0.66 mmol) in THF (1 mL) was added slowly. The reaction mixture was continued to stir for 1 h at 0 ℃. Dichloromethane and water were added. The layers were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed three times with brine (3 × 50 mL) . The organic phase was dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by chromatography with dichloromethane and methanol (30: 1) to give 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 %) . ¹H NMR (600 MHz, DMSO-d6) δ 12.12 (s, 1H) , 8.39 (s, 1H) , 7.84 (d, J = 8.5 Hz, 2H) , 7.72 (s, 1H) , 7.55 (s, 1H) , 7.45 (t, J = 7.7 Hz, 2H) , 7.21 (t, J = 7.3 Hz, 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] ⁺.

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

The mixture of the product of step I of example 1 (180 mg, 0.44 mmol) in THF/H ₂O (3: 1, 4 mL) was alkalified to pH 7-8 with NaHCO ₃. Then the mixture was cooled to 0 ℃, and the solution of 3-methylbut-2-enoyl chloride (78 mg, 0.66 mmol) in THF (1 mL) was added slowly. The reaction mixture was continued to stir for 1 h at 0 ℃. Dichloromethane and water were added. The layers were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed three times with brine (3 × 50 mL) . The organic phase was dried over anhydrous Na ₂SO ₄, 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 %) . ¹H NMR (400 MHz, DMSO-d6) δ 12.10 (s, 1H) , 8.37 (s, 1H) , 7.89-7.79 (m, 2H) , 7.70 (s, 1H) , 7.54 (s, 1H) , 7.49-7.41 (m, 2H) , 7.21 (t, J = 7.4 Hz, 1H) , 7.14-7.05 (m, 4H) , 5.92 (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] ⁺.

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

The mixture of the product of step I of example 1 (180 mg, 0.44 mmol) in DMF (5 mL) was alkalified to pH 7-8 with N, N-diisopropylethylamine. After 5 min, but-2-ynoic acid (55 mg, 0.66 mmol) and HATU (184 mg, 0.48 mmol) were added. The reaction mixture was continued to stir at room temperature for 30 min. Dichloromethane and water were added. The layers were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed three times with brine solution (3 × 50 mL) . The organic phase was dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by chromatography with dichloromethane and methanol (30: 1) to give 7- (1- (but-2-ynoyl) piperidin-4-yl) -2- (4-phenoxyphenyl) -1H-imidazo [1, 2-b] pyrazole-3-carboxamide as an off-white solid (105 mg, 51.2 %) . ¹H NMR (400 MHz, DMSO-d6) δ 12.12 (s, 1H) , 8.37 (s, 1H) , 7.84 (d, J = 8.7 Hz, 2H) , 7.71 (s, 1H) , 7.55 (s, 1H) , 7.45 (t, J = 7.9 Hz, 2H) , 7.21 (t, J = 7.4 Hz, 1H) , 7.14-7.05 (m, 4H) , 4.46-4.30 (m, 2H) , 3.28-3.16 (m, 1H) , 2.93-2.82 (m, 1H) , 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] ⁺.

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

The mixture of the product of step I of example 1 (180 mg, 0.44 mmol) in DMF (5 mL) was alkalified to pH 7-8 with N, N-diisopropylethylamine. After 5 min, propiolic acid (46 mg, 0.66 mmol) and HATU (184 mg, 0.48 mmol) were added. The reaction mixture was continued to stir at room temperature for 30 min. Dichloromethane and water were added. The layers were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed three times with brine solution (3 × 50 mL) . The organic phase was dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by chromatography with dichloromethane and methanol (30: 1) to give 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 %) . ¹H NMR (400 MHz, DMSO-d6) δ 12.12 (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 = 7.4 Hz, 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] ⁺.

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

The mixture of the product of step I of example 1 (180 mg, 0.44 mmol) in DMF (5 mL) was alkalified to pH 7-8 with N, N-diisopropylethylamine. After 5 min, (E) -pent-2-enoic acid (66 mg, 0.66 mmol) and HATU (184 mg, 0.48 mmol) were added. The reaction mixture was continued to stir at room temperature for 30 min. Dichloromethane and water were added. The layers were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed three times with brine solution (3 × 50 mL) . The organic phase was dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by chromatography with dichloromethane and methanol (30: 1) to give (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 %) . ¹H NMR (600 MHz, DMSO-d6) δ 12.12 (s, 1H) , 8.37 (s, 1H) , 7.83 (d, J = 8.7 Hz, 2H) , 7.69 (s, 1H) , 7.53 (s, 1H) , 7.44 (t, J = 8.0 Hz, 2H) , 7.20 (t, J = 7.4 Hz, 1H) , 7.09 (t, J = 8.7 Hz, 4H) , 6.74-6.68 (m, 1H) , 6.51-6.46 (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) , 2.73-2.64 (m, 1H) , 2.23-2.15 (m, 2H) , 1.97-1.88 (m, 2H) , 1.67-1.53 (m, 2H) , 1.01 (t, J = 7.4 Hz, 3H) . MS (ESI, m/z) : 484.6 [M+H] ⁺.

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

The mixture of the product of step J of example 1 (100 mg, 0.22 mmol) in DMF (2 mL) was added NaHCO ₃ (74 mg, 0.88 mmol) and CH ₃I (62 mg, 0.44 mmol) . The reaction mixture was continued to stir at room temperature for 3 hs. The mixture was quenched with saturated sodium bicarbonate. Dichloromethane and water were added. The layers were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed three times with brine solution (3 × 20 mL) . The organic phase was dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by chromatography with dichloromethane and methanol (40: 1) to give 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 (600 MHz, DMSO-d6) δ 8.14 (s, 1H) , 7.64 (s, 1H) , 7.62 (s, 1H) , 7.54 (d, J = 8.4 Hz, 2H) , 7.48 (t, J = 7.7 Hz, 2H) , 7.24 (t, J = 7.3 Hz, 1H) , 7.16 (d, J = 8.2 Hz, 2H) , 7.09 (d, J = 8.4 Hz, 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] ⁺.

Example 9: 7- (1- (but-2-ynoyl) piperidin-4-yl) -1-methyl-2- (4-phenoxyphenyl) -1H- imidazo [1, 2-b] pyrazole-3-carboxamide

The mixture of the product of example 5 (100 mg, 0.21 mmol) in DMF (2 mL) was added NaHCO ₃ (72 mg, 0.84 mmol) and CH ₃I (61 mg, 0.42 mmol) . The reaction mixture was continued to stir at room temperature for 3.5 hs. The mixture was quenched with saturated sodium bicarbonate. Dichloromethane and water were added. The layers were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed three times with brine solution (3 × 20 mL) . The organic phase was dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by chromatography with dichloromethane and methanol (40: 1) to give 7- (1- (but-2-ynoyl) 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 (400 MHz, DMSO-d6) δ 8.14 (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 = 7.4 Hz, 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] ⁺.

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

The mixture of the product of step I of example 1 (180 mg, 0.44 mmol) in DMF (5 mL) was alkalified to pH 7-8 with N, N-diisopropylethylamine. After 5 min, (E) -4, 4, 4-trifluorobut-2-enoic acid (92 mg, 0.66 mmol) and HATU (184 mg, 0.48 mmol) were added. The reaction mixture was continued to stir at room temperature for 10 min. Dichloromethane and water were added. The layers were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed three times with brine solution (3 × 50 mL) . The organic phase was dried over anhydrous Na ₂SO ₄, 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 (400 MHz, DMSO-d6) δ 12.09 (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) , 3.27-3.15 (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] ⁺.

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

The mixture of the product of step I of example 1 (180 mg, 0.44 mmol) in DMF (5 mL) was alkalified to pH 7-8 with N, N-diisopropylethylamine. After 5 min, (E) -4- (dimethylamino) but-2-enoic acid (87 mg, 0.66 mmol) and HATU (184 mg, 0.48 mmol) were added. The reaction mixture was continued to stir at room temperature for 10 min. Dichloromethane and water were added. The layers were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed three times with brine solution (3 × 50 mL) . The organic phase was dried over anhydrous Na ₂SO ₄, 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 (600 MHz, DMSO-d6) δ 8.37 (s, 1H) , 7.83 (d, J = 8.7 Hz, 2H) , 7.69 (s, 1H) , 7.54 (s, 1H) , 7.45 (t, J = 7.9 Hz, 2H) , 7.21 (t, J = 7.4 Hz, 1H) , 7.12-7.07 (m, 4H) , 6.69-6.57 (m, 2H) , 4.57-4.50 (m, 1H) , 4.16-4.08 (m, 1H) , 3.19-3.12 (m, 1H) , 3.09 (d, J = 5.8 Hz, 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] ⁺.

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

The mixture of the product of step I of example 1 (180 mg, 0.44 mmol) in THF (5 mL) was alkalified to pH 7-8 with N, N-diisopropylethylamine. Then the mixture was cooled to 0 ℃, and the solution of cyanic bromide (52 mg, 0.49 mmol) in THF (1 mL) was added slowly. The reaction mixture was continued to stir for 1 h at 0 ℃. Dichloromethane and water were added. The layers were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed three times with brine solution (3 × 50 mL) . The organic phase was dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by chromatography with 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 %) . ¹H NMR (600 MHz, DMSO-d6) δ 12.14 (s, 1H) , 8.36 (s, 1H) , 7.85 (d, J = 8.7 Hz, 2H) , 7.71 (s, 1H) , 7.55 (s, 1H) , 7.45 (t, J = 7.9 Hz, 2H) , 7.21 (t, J = 7.4 Hz, 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] ⁺.

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

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

To a stirred suspension of NaH (60 %dispersion in mineral oil; 24 g, 0.60 mol) in anhydrous DMF (300 mL) at 0 ℃ was added dropwise 1- (4- (4-fluorophenoxy) phenyl) ethan-1-one (70 g, 0.30 mol) dissolved in anhydrous DMF (50 mL) . After 30 minutes, the mixture was cooled to 0 ℃ and dimethyl carbonate (108 g, 1.2 mol) was added neat. The mixture was allowed to warm to room temperature for 2 hs and then poured into 1: 1 water/saturated bicarbonate. The aqueous layer was extracted with ethyl acetate (3 × 500 mL) . The combined organic layer was washed with saturated brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by chromatography with petroleum ether and ethyl acetate (10: 1) to give the desired product methyl 3- (4- (4-fluorophenoxy) phenyl) -3-oxopropanoate as a yellow solid (83 g, 96.0 %) . ¹H NMR (400 MHz, DMSO-d6) δ 7.99 (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] ⁺.

Step B: Preparation of 3- (4- (4-fluorophenoxy) phenyl) -3-oxopropanamide

To a solution of the product of step A of example 13 (83 g, 0.29 mol) in 1, 4-dioxane (100 mL) was added 7 M NH ₃/1, 4-dioxane (100 mL) at room temperature in a 300 mL of sealed tube. The mixture was stirred at 95 ℃ for 12 hs, then it was cooled to room temperature. The mixture was concentrated under vacuum to get crude. The residue was purified by chromatography with 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 (600 MHz, DMSO-d6) δ 7.98 (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] ⁺.

Step C: Preparation of 2-bromo-3- (4- (4-fluorophenoxy) phenyl) -3-oxopropanamide

CuBr ₂ (45 g, 0.20 mol) was added to a solution of the product of step B of example 13 (50 g, 0.18 mol) in ethyl acetate (500 ml) . The mixture was stirred at 50 ℃ until no further TLC changes were observed. The mixture was filtrated through celite. The filtrate was diluted with ethyl acetate and H ₂O. After the layers were separated, the organic layer was washed with brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by chromatography with petroleum ether and ethyl acetate (3: 2) to give the desired 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] ⁺.

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

A solution of the product of step G of example 1 (10 g, 0.037 mol) and the product of step C of example 13 (10 g, 0.03 mol) in ethanol (100 mL) was heated to reflux for overnight. The reaction was then cooled to room temperature and the solvent was removed under vacuum, the crude residue was purified by chromatography with petroleum ether and ethyl acetate (3: 2) to give 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 (600 MHz, DMSO-d6) δ 12.09 (s, 1H) , 8.37 (s, 1H) , 7.84 (d, J = 8.2 Hz, 2H) , 7.70 (s, 1H) , 7.53 (s, 1H) , 7.29 (t, J = 8.4 Hz, 2H) , 7.18-7.14 (m, 2H) , 7.07 (d, J = 8.1 Hz, 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] ⁺.

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

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

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

The mixture of the product of step E of example 13 (180 mg, 0.43 mmol) in THF/H ₂O (3: 1, 4 mL) was alkalified to pH 7-8 with NaHCO ₃. Then the mixture was cooled to 0 ℃, and the solution of acryloyl chloride (58 mg, 0.64 mmol) in THF (1 mL) was added slowly. The reaction mixture was continued to stir for 1 h at 0 ℃. Dichloromethane and water were added. The layers were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed three times with brine solution (3 × 50 mL) . The organic phase was dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by chromatography with dichloromethane and methanol (30: 1) to give 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 (400 MHz, DMSO-d6) δ 12.10 (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, 1H) , 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] ⁺.

Example 14: 7- (1- (but-2-ynoyl) piperidin-4-yl) -2- (4- (4-fluorophenoxy) phenyl) -1H- imidazo [1, 2-b] pyrazole-3-carboxamide

The mixture of the product of step E of example 13 (180 mg, 0.43 mmol) in DMF (5 mL) was alkalified to pH 7-8 with N, N-diisopropylethylamine. After 5 min, but-2-ynoic acid (54 mg, 0.64 mmol) and HATU (180 mg, 0.47 mmol) were added. The reaction mixture was continued to stir at room temperature for 30 min. Dichloromethane and water were added. The layers were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed three times (3 × 50 mL) with brine solution. The organic phase was dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by chromatography with dichloromethane and methanol (30: 1) to give 7- (1- (but-2-ynoyl) 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 %) . ¹H NMR (400 MHz, DMSO-d6) δ 12.10 (s, 1H) , 8.35 (s, 1H) , 7.83 (d, J = 8.8 Hz, 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 = 8.8 Hz, 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] ⁺.

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

The mixture of the product of step E of example 13 (180 mg, 0.43 mmol) in DMF (5 mL) was alkalified to pH 7-8 with N, N-diisopropylethylamine. After 5 min, propiolic acid (45 mg, 0.64 mmol) and HATU (180 mg, 0.47 mmol) were added. The reaction mixture was continued to stir at room temperature for 30 min. Dichloromethane and water were added. The layers were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed three times with brine solution (3 × 50 mL) . The organic phase was dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by chromatography with dichloromethane and methanol (30: 1) to give 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 %) . ¹H NMR (600 MHz, DMSO-d6) δ 8.64 (d, J = 8.8 Hz, 2H) , 8.53 (s, 1H) , 7.30 (t, J = 8.7 Hz, 2H) , 7.22-7.19 (m, 2H) , 7.17 (d, J = 8.6 Hz, 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] ⁺.

Example 16: (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

The mixture of the product of step E of example 13 (180 mg, 0.43 mmol) in DMF (5 mL) was alkalified to pH 7-8 with N, N-diisopropylethylamine. After 5 min, (E) -4, 4, 4-trifluorobut-2-enoic acid (90 mg, 0.64 mmol) and HATU (180 mg, 0.47 mmol) were added. The reaction mixture was continued to stir at room temperature for 10 min. Dichloromethane and water were added. The layers were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed three times (3 × 50 mL) with brine solution. The organic phase was dried over anhydrous Na ₂SO ₄, 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-trifluorobut-2-enoyl) piperidin-4-yl) -1H-imidazo [1, 2-b] pyrazole-3-carboxamide as an off-white solid (121 mg, 52.2 %) . ¹H NMR (400 MHz, DMSO-d6) δ 12.10 (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] ⁺.

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

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

To a stirred suspension of NaH (60 %dispersion in mineral oil; 23 g, 0.56 mol) in anhydrous DMF (300 mL) at 0 ℃ was added dropwise 1- (4- (2, 4-difluorophenoxy) phenyl) ethan-1-one (70 g, 0.28 mol) dissolved in anhydrous DMF (50 mL) . After 30 minutes, the mixture was cooled to 0 ℃ and dimethyl carbonate (101 g, 1.12 mol) was added neat. The mixture was allowed to warm to room temperature for 2 hs and then poured into 1: 1 water/saturated bicarbonate. The aqueous layer was extracted with ethyl acetate (3 ×500 mL) . The combined organic layer was washed with saturated brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by chromatography with 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] ⁺.

Step B: Preparation of 3- (4- (2, 4-difluorophenoxy) phenyl) -3-oxopropanamide

To a solution of the product of step A of example 17 (81 g, 0.26 mol) in 1, 4-dioxane (100 mL) was added 7 M NH ₃/1, 4-dioxane (100 mL) at room temperature in a 300 mL of sealed tube. The mixture was stirred at 95 ℃ for 12 hs, then it was cooled to room temperature. The mixture was concentrated under vacuum to get crude. The residue was purified by chromatography with 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 %) . ¹H NMR (400 MHz, DMSO-d6) δ 7.98 (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] ⁺.

Step C: Preparation of 2-bromo-3- (4- (2, 4-difluorophenoxy) phenyl) -3-oxopropanamide

CuBr ₂ (40 g, 0.18 mol) was added to a solution of the product of step B of example 17 (48 g, 0.16 mol) in ethyl acetate (500 ml) . The mixture was stirred at 50 ℃ until no further TLC changes were observed. The mixture was filtrated through celite. The filtrate was diluted with ethyl acetate and H ₂O. After the layers were separated, the organic layer was washed with brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by chromatography with petroleum ether and ethyl acetate (3: 2) to give the desired 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] ⁺.

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

A solution of the product of step G of example 1 (10 g, 0.037 mol) and the product of step C of example 17 (11 g, 0.03 mol) in ethanol (100 mL) was heated to reflux for overnight. The reaction was then cooled to room temperature and the solvent was removed under vacuum, the crude residue was purified by chromatography with petroleum ether and ethyl acetate (3: 2) to give 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 %) . ¹H NMR (400 MHz, DMSO-d6) δ 12.10 (s, 1H) , 8.36 (s, 1H) , 7.82 (d, J = 8.8 Hz, 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 = 8.8 Hz, 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] ⁺.

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

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

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

The mixture of the product of step E of example 17 (180 mg, 0.41 mmol) in THF/H ₂O (3: 1, 4 mL) was alkalified to pH 7-8 with NaHCO ₃. Then the mixture was cooled to 0 ℃, and the solution of acryloyl chloride (56 mg, 0.62 mmol) in THF (1 mL) was added slowly. The reaction mixture was continued to stir for 1 h at 0 ℃. Dichloromethane and water were added. The layers were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed three times with brine solution (3 × 50 mL) . The organic phase was dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by chromatography with dichloromethane and methanol (30: 1) to give 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 %) . ¹H NMR (600 MHz, DMSO-d6) δ 12.11 (s, 1H) , 8.34 (s, 1H) , 7.80 (d, J = 8.5 Hz, 2H) , 7.69 (s, 1H) , 7.55-7.51 (m, 2H) , 7.43-7.37 (m, 1H) , 7.19 (t, J = 7.7 Hz, 1H) , 7.04 (d, J = 8.5 Hz, 2H) , 6.88-6.81 (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] ⁺.

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

The mixture of the product of step E of example 17 (180 mg, 0.41 mmol) in DMF (5 mL) was alkalified to pH 7-8 with N, N-diisopropylethylamine. After 5 min, but-2-ynoic acid (52 mg, 0.62 mmol) and HATU (171 mg, 0.45 mmol) were added. The reaction mixture was continued to stir at room temperature for 30 min. Dichloromethane and water were added. The layers were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed three times with brine solution (3 × 50 mL) . The organic phase was dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by chromatography with dichloromethane and methanol (30: 1) to give 7- (1- (but-2-ynoyl) 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 %) . ¹H NMR (600 MHz, DMSO-d6) δ 12.11 (s, 1H) , 8.34 (s, 1H) , 7.81 (d, J = 8.5 Hz, 2H) , 7.70 (s, 1H) , 7.57-7.50 (m, 2H) , 7.43-7.37 (m, 1H) , 7.19 (t, J = 8.5 Hz, 1H) , 7.05 (d, J = 8.5 Hz, 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] ⁺.

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

The mixture of the product of step E of example 17 (180 mg, 0.41 mmol) in DMF (5 mL) was alkalified to pH 7-8 with N, N-diisopropylethylamine. After 5 min, propiolic acid (43 mg, 0.62 mmol) and HATU (171 mg, 0.45 mmol) were added. The reaction mixture was continued to stir at room temperature for 30 min. Dichloromethane and water were added. The layers were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed three times with brine solution (3 × 50 mL) . The organic phase was dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by chromatography with dichloromethane and methanol (30: 1) to give 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 %) . ¹H NMR (400 MHz, DMSO-d6) δ 12.11 (s, 1H) , 8.35 (s, 1H) , 7.81 (d, J = 8.7 Hz, 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 = 8.7 Hz, 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] ⁺.

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

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

To a stirred suspension of NaH (60 %dispersion in mineral oil; 23 g, 0.58 mol) in anhydrous DMF (300 mL) at 0 ℃ was added dropwise 1- (4- (4-methoxyphenoxy) phenyl) ethan- 1-one (70 g, 0.29 mol) dissolved in anhydrous DMF (50 mL) . After 30 minutes, the mixture was cooled to 0 ℃ and dimethyl carbonate (104 g, 1.16 mol) was added neat. The mixture was allowed to warm to room temperature for 2 hs and then poured into 1: 1 water/saturated bicarbonate. The aqueous layer was extracted with ethyl acetate (3 × 500 mL) . The combined organic layer was washed with saturated brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by chromatography with petroleum ether and ethyl acetate (10: 1) to give the desired product methyl 3- (4- (4-methoxyphenoxy) phenyl) -3-oxopropanoate as a yellow solid (85 g, 97.6 %) . ¹H NMR (400 MHz, DMSO-d6) δ 7.95 (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] ⁺.

Step B: Preparation of 3- (4- (4-methoxyphenoxy) phenyl) -3-oxopropanamide

To a solution of the product of step A of example 20 (85 g, 0.28 mol) in 1, 4-dioxane (100 mL) was added 7 M NH ₃/1, 4-dioxane (100 mL) at room temperature in a 300 mL of sealed tube. The mixture was stirred at 95 ℃ for 12 hs, then it was cooled to room temperature. The mixture was concentrated under vacuum to get crude. The residue was purified by chromatography with petroleum ether and ethyl acetate (1: 1) to give the desired product 3- (4- (4-methoxyphenoxy) phenyl) -3-oxopropanamide as a light yellow solid (50 g, 61.9 %) . ¹H NMR (600 MHz, DMSO-d6) δ 7.97 (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] ⁺.

Step C: Preparation of 2-bromo-3- (4- (4-methoxyphenoxy) phenyl) -3-oxopropanamide

CuBr ₂ (42 g, 0.19 mol) was added to a solution of the product of step B of example 20 (50 g, 0.17 mol) in ethyl acetate (500 ml) . The mixture was stirred at 50 ℃ until no further TLC changes were observed. The mixture was filtrated through celite. The filtrate was diluted with ethyl acetate and H ₂O. After the layers were separated, the organic layer was washed with brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by chromatography with petroleum ether and ethyl acetate (3: 2) to give the desired 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] ⁺.

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

A solution of the product of step G of example 1 (10 g, 0.037 mol) and the product of step C of example 20 (11 g, 0.03 mol) in ethanol (100 mL) was heated to reflux for overnight. The reaction was then cooled to room temperature and the solvent was removed under vacuum, the crude residue was purified by chromatography with petroleum ether and ethyl acetate (3: 2) to give 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 %) . ¹H NMR (400 MHz, DMSO-d6) δ 12.08 (s, 1H) , 8.37 (s, 1H) , 7.80 (d, J = 8.7 Hz, 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] ⁺.

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

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

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

The mixture of the product of step E of example 20 (180 mg, 0.42 mmol) in THF/H ₂O (3: 1, 4 mL) was alkalified to pH 7-8 with NaHCO ₃. Then the mixture was cooled to 0 ℃, and the solution of acryloyl chloride (57 mg, 0.63 mmol) in THF (1 mL) was added slowly. The reaction mixture was continued to stir for 1 h at 0 ℃. Dichloromethane and water were added. The layers were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed three times with brine solution (3 × 50 mL) . The organic phase was dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by chromatography with dichloromethane and methanol (30: 1) to give 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 %) . ¹H NMR (400 MHz, DMSO-d6) δ 12.08 (s, 1H) , 8.35 (s, 1H) , 7.79 (d, J = 8.8 Hz, 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) , 3.22-3.10 (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] ⁺.

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

The mixture of the product of step E of example 20 (180 mg, 0.42 mmol) in DMF (5 mL) was alkalified to pH 7-8 with N, N-diisopropylethylamine. After 5 min, but-2-ynoic acid (53 mg, 0.63 mmol) and HATU (176 mg, 0.46 mmol) were added. The reaction mixture was continued to stir at room temperature for 30 min. Dichloromethane and water were added. The layers were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed three times with brine solution (3 × 50 mL) . The organic phase was dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by chromatography with dichloromethane and methanol (30: 1) to give 7- (1- (but-2-ynoyl) 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 %) . ¹H NMR (400 MHz, DMSO-d6) δ 12.09 (s, 1H) , 8.35 (s, 1H) , 7.79 (d, J = 8.8 Hz, 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] ⁺.

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

The mixture of the product of step E of example 20 (180 mg, 0.42 mmol) in DMF (5 mL) was alkalified to pH 7-8 with N, N-diisopropylethylamine. After 5 min, propiolic acid (44 mg, 0.63 mmol) and HATU (176 mg, 0.46 mmol) were added. The reaction mixture was continued to stir at room temperature for 30 min. Dichloromethane and water were added. The layers were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed three times with brine solution (3 × 50 mL) . The organic phase was dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by chromatography with dichloromethane and methanol (30: 1) to give 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 %) . ¹H NMR (400 MHz, CDCl ₃) δ 8.35 (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] ⁺.

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

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

To a stirred suspension of NaH (60 %dispersion in mineral oil; 23 g, 0.58 mol) in anhydrous DMF (300 mL) at 0℃ was added dropwise 1- (4- (2-methoxyphenoxy) phenyl) ethan-1-one (70 g, 0.29 mol) dissolved in anhydrous DMF (50 mL) . After 30 minutes, the mixture was cooled to 0 ℃ and dimethyl carbonate (104 g, 1.16 mol) was added neat. The mixture was allowed to warm to room temperature for 2 hs and then poured into 1: 1 water/saturated bicarbonate. The aqueous layer was extracted with ethyl acetate (3 × 500 mL) . The combined organic layer was washed with saturated brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by chromatography with petroleum ether and ethyl acetate (10: 1) to give the desired product methyl 3- (4- (2-methoxyphenoxy) phenyl) -3-oxopropanoate as a yellow solid (84 g, 96.4 %) . ¹H NMR (400 MHz, DMSO-d6) δ 7.97-7.91 (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] ⁺.

Step B: Preparation of 3- (4- (2-methoxyphenoxy) phenyl) -3-oxopropanamide

To a solution of the product of step A of example 23 (85 g, 0.28 mol) in 1, 4-dioxane (100 mL) was added 7 M NH ₃/1, 4-dioxane (100 mL) at room temperature in a 300 mL of sealed tube. The mixture was stirred at 95 ℃ for 12 hs, then it was cooled to room temperature. The mixture was concentrated under vacuum to get crude. The residue was purified by chromatography with petroleum ether and ethyl acetate (1: 1) to give the desired product 3- (4- (2-methoxyphenoxy) phenyl) -3-oxopropanamide as a light-yellow solid (53 g, 66.3 %) . ¹H NMR (400 MHz, DMSO-d6) δ 7.95-7.90 (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] ⁺.

Step C: Preparation of 2-bromo-3- (4- (2-methoxyphenoxy) phenyl) -3-oxopropanamide

CuBr ₂ (42 g, 0.19 mol) was added to a solution of the product of step B of example 23 (50 g, 0.17 mol) in ethyl acetate (500 ml) . The mixture was stirred at 50 ℃ until no further TLC changes were observed. The mixture was filtrated through celite. The filtrate was diluted with ethyl acetate and H ₂O. After the layers were separated, the organic layer was washed with brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by chromatography with petroleum ether and ethyl acetate (3: 2) to give the desired 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] ⁺.

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

A solution of the product of step G of example 1 (10 g, 0.037 mol) and the product of step C of example 23 (11 g, 0.03 mol) in ethanol (100 mL) was heated to reflux for overnight. The reaction was then cooled to room temperature and the solvent was removed under vacuum, the crude residue was purified by chromatography with petroleum ether and ethyl acetate (3: 2) to give 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 %) . ¹H NMR (400 MHz, DMSO-d6) δ 12.06 (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, 3H) , 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] ⁺.

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

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

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

The mixture of the product of step E of example 23 (180 mg, 0.42 mmol) in THF/H ₂O (3: 1, 4 mL) was alkalified to pH 7-8 with NaHCO ₃. Then the mixture was cooled to 0 ℃, and the solution of acryloyl chloride (57 mg, 0.63 mmol) in THF (1 mL) was added slowly. The reaction mixture was continued to stir for 1 h at 0 ℃. Dichloromethane and water were added. The layers were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed three times with brine solution (3 × 50 mL) . The organic phase was dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by chromatography with dichloromethane and methanol (30: 1) to give 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 (600 MHz, DMSO-d6) δ 12.06 (s, 1H) , 8.34 (s, 1H) , 7.74 (d, J = 8.7 Hz, 2H) , 7.66 (s, 1H) , 7.52 (s, 1H) , 7.27 (t, J = 7.7 Hz, 1H) , 7.22 (d, J = 8.0 Hz, 1H) , 7.13 (d, J = 7.6 Hz, 1H) , 7.03 (t, J = 7.6 Hz, 1H) , 6.89 (d, J = 8.7 Hz, 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) , 3.76 (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] ⁺.

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

The mixture of the product of step E of example 23 (180 mg, 0.42 mmol) in DMF (5 mL) was alkalified to pH 7-8 with N, N-diisopropylethylamine. After 5 min, but-2-ynoic acid (53 mg, 0.63 mmol) and HATU (176 mg, 0.46 mmol) were added. The reaction mixture was continued to stir at room temperature for 30 min. Dichloromethane and water were added. The layers were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed three times with brine solution (3 × 50 mL) . The organic phase was dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by chromatography with dichloromethane and methanol (30: 1) to give 7- (1- (but-2-ynoyl) 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 (400 MHz, DMSO-d6) δ 12.07 (s, 1H) , 8.34 (s, 1H) , 7.75 (d, J = 8.8 Hz, 2H) , 7.68 (s, 1H) , 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] ⁺.

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

The mixture of the product of step E of example 23 (180 mg, 0.42 mmol) in DMF (5 mL) was alkalified to pH 7-8 with N, N-diisopropylethylamine. After 5 min, propiolic acid (44 mg, 0.63 mmol) and HATU (176 mg, 0.46 mmol) were added. The reaction mixture was continued to stir at room temperature for 30 min. Dichloromethane and water were added. The layers were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed three times with brine solution (3 × 50 mL) . The organic phase was dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by chromatography with dichloromethane and methanol (30: 1) to give 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 (400 MHz, DMSO-d6) δ 12.07 (s, 1H) , 8.34 (s, 1H) , 7.75 (d, J = 8.7 Hz, 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 = 8.7 Hz, 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] ⁺.

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

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

To a stirred suspension of NaH (60 %dispersion in mineral oil; 24 g, 0.60 mol) in anhydrous DMF (300 mL) at 0 ℃ was added dropwise 1- (4- (2-fluorophenoxy) phenyl) ethan-1-one (70 g, 0.30 mol) dissolved in anhydrous DMF (50 mL) . After 30 minutes, the mixture was cooled to 0 ℃ and dimethyl carbonate (108 g, 1.2 mol) was added neat. The mixture was allowed to warm to room temperature for 2 hs and then poured into 1: 1 water/saturated bicarbonate. The aqueous layer was extracted with ethyl acetate (3 × 500 mL) . The combined organic layer was washed with saturated brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by chromatography with petroleum ether and ethyl acetate (10: 1) to give the desired product methyl 3- (4- (2-fluorophenoxy) phenyl) -3-oxopropanoate as a yellow solid (81 g, 93.7 %) . ¹H NMR (400 MHz, DMSO-d6) δ 8.03-7.96 (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] ⁺.

Step B: Preparation of 3- (4- (2-fluorophenoxy) phenyl) -3-oxopropanamide

To a solution of the product of step A of example 26 (81 g, 0.28 mol) in 1, 4-dioxane (100 mL) was added 7 M NH ₃/1, 4-dioxane (100 mL) at room temperature in a 300 mL of sealed tube. The mixture was stirred at 95 ℃ for 12 hs, then it was cooled to room temperature. The mixture was concentrated under vacuum to get crude. The residue was purified by chromatography with petroleum ether and ethyl acetate (1: 1) to give the desired product 3- (4- (2-fluorophenoxy) phenyl) -3-oxopropanamide as a light-yellow solid (46 g, 59.9 %) . ¹H NMR (600 MHz, DMSO-d6) δ 7.99 (d, J = 8.7 Hz, 2H) , 7.58 (s, 1H) , 7.44 (d, J = 8.5 Hz, 1H) , 7.34 (s, 1H) , 7.32-7.28 (m, 2H) , 7.09 (s, 1H) , 7.04 (d, J = 8.8 Hz, 2H) , 3.82 (s, 2H) . MS (ESI, m/z) : 274.3 [M+H] ⁺.

Step C: Preparation of 2-bromo-3- (4- (2-fluorophenoxy) phenyl) -3-oxopropanamide

CuBr ₂ (41 g, 0.18 mol) was added to a solution of the product of step B of example 26 (46 g, 0.17 mol) in ethyl acetate (500 ml) . The mixture was stirred at 50 ℃ until no further TLC changes were observed. The mixture was filtrated through celite. The filtrate was diluted with ethyl acetate and H ₂O. After the layers were separated, the organic layer was washed with brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by chromatography with petroleum ether and ethyl acetate (3: 2) to give the desired 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] ⁺.

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

A solution of the product of step G of example 1 (10 g, 0.037 mol) and the product of step C of example 26 (10 g, 0.03 mol) in ethanol (100 mL) was heated to reflux for overnight. The reaction was then cooled to room temperature and the solvent was removed under vacuum, the crude residue was purified by chromatography with petroleum ether and ethyl acetate (3: 2) to give 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 %) . ¹H NMR (400 MHz, DMSO-d6) δ 12.10 (s, 1H) , 8.36 (s, 1H) , 7.82 (d, J = 8.9 Hz, 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 = 8.8 Hz, 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] ⁺.

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

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

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

The mixture of the product of step E of example 26 (180 mg, 0.43 mmol) in THF/H ₂O (3: 1, 4 mL) was alkalified to pH 7-8 with NaHCO ₃. Then the mixture was cooled to 0 ℃, and the solution of acryloyl chloride (58 mg, 0.64 mmol) in THF (1 mL) was added slowly. The reaction mixture was continued to stir for 1 h at 0 ℃. Dichloromethane and water were added. The layers were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed three times with brine solution (3 × 50 mL) . The organic phase was dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by chromatography with dichloromethane and methanol (30: 1) to give 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 %) . ¹H NMR (400 MHz, DMSO-d6) δ 12.12 (s, 1H) , 8.37 (s, 1H) , 7.82 (d, J = 8.8 Hz, 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 = 8.8 Hz, 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] ⁺.

Example 27: 7- (1- (but-2-ynoyl) piperidin-4-yl) -2- (4- (2-fluorophenoxy) phenyl) -1H- imidazo [1, 2-b] pyrazole-3-carboxamide

The mixture of the product of step E of example 26 (180 mg, 0.43 mmol) in DMF (5 mL) was alkalified to pH 7-8 with N, N-diisopropylethylamine. After 5 min, but-2-ynoic acid (54 mg, 0.64 mmol) and HATU (180 mg, 0.47 mmol) were added. The reaction mixture was continued to stir at room temperature for 30 min. Dichloromethane and water were added. The layers were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed three times with brine solution (3 × 50 mL) . The organic phase was dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by chromatography with dichloromethane and methanol (30: 1) to give 7- (1- (but-2-ynoyl) 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 %) . ¹H NMR (400 MHz, DMSO-d6) δ 12.12 (s, 1H) , 8.37 (s, 1H) , 7.83 (d, J = 8.7 Hz, 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 = 8.7 Hz, 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] ⁺.

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

The mixture of the product of step E of example 26 (180 mg, 0.43 mmol) in DMF (5 mL) was alkalified to pH 7-8 with N, N-diisopropylethylamine. After 5 min, propiolic acid (45 mg, 0.64 mmol) and HATU (180 mg, 0.47 mmol) were added. The reaction mixture was continued to stir at room temperature for 30 min. Dichloromethane and water were added. The layers were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed three times with brine solution (3 × 50 mL) . The organic phase was dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by chromatography with dichloromethane and methanol (30: 1) to give 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 %) . ¹H NMR (600 MHz, DMSO-d6) δ 12.14 (s, 1H) , 8.34 (s, 1H) , 7.82 (d, J = 7.7 Hz, 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 = 7.8 Hz, 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] ⁺.

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

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

To a stirred suspension of NaH (60 %dispersion in mineral oil; 23 g, 0.56 mol) in anhydrous DMF (300 mL) at 0 ℃ was added dropwise 1- (4- (4-chlorophenoxy) phenyl) ethan-1-one (70 g, 0.28 mol) dissolved in anhydrous DMF (50 mL) . After 30 minutes, the mixture was cooled to 0 ℃ and dimethyl carbonate (101 g, 1.2 mol) was added neat. The mixture was allowed to warm to room temperature for 2 hs and then poured into 1: 1 water/saturated bicarbonate. The aqueous layer was extracted with ethyl acetate (3 × 500 mL) . The combined organic layer was washed with saturated brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by chromatography with petroleum ether and ethyl acetate (10: 1) to give 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] ⁺.

Step B: Preparation of 3- (4- (4-chlorophenoxy) phenyl) -3-oxopropanamide

To a solution of the product of step A of example 29 (82 g, 0.27 mol) in 1, 4-dioxane (100 mL) was added 7 M NH ₃/1, 4-dioxane (100 mL) at room temperature in a 300 mL of sealed tube. The mixture was stirred at 95 ℃ for 12 hs, then it was cooled to room temperature. The mixture was concentrated under vacuum to get crude. The residue was purified by chromatography with petroleum ether and ethyl acetate (1: 1) to give the desired 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] ⁺.

Step C: Preparation of 2-bromo-3- (4- (4-chlorophenoxy) phenyl) -3-oxopropanamide

CuBr ₂ (41 g, 0.18 mol) was added to a solution of the product of step B of example 29 (48 g, 0.16 mol) in ethyl acetate (500 ml) . The mixture was stirred at 50 ℃ until no further TLC changes were observed. The mixture was filtrated through celite. The filtrate was diluted with ethyl acetate and H ₂O. After the layers were separated, the organic layer was washed with brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by chromatography with petroleum ether and ethyl acetate (3: 2) to give the desired 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] ⁺.

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

A solution of the product of step G of example 1 (8.5 g, 0.032 mol) and the product of step C of example 29 (10 g, 0.027 mol) in ethanol (100 mL) was heated to reflux for overnight. The reaction was then cooled to room temperature and the solvent was removed under vacuum, the crude residue was purified by chromatography with petroleum ether and ethyl acetate (3: 2) to give 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 %) . ¹H NMR (400 MHz, DMSO-d6) δ 12.11 (s, 1H) , 8.38 (s, 1H) , 7.86 (d, J = 8.5 Hz, 2H) , 7.71 (s, 1H) , 7.54 (s, 1H) , 7.49 (d, J = 8.8 Hz, 2H) , 7.12 (d, J = 8.6 Hz, 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] ⁺.

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

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

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

The mixture of the product of step E of example 29 (180 mg, 0.33 mmol) in THF/H ₂O (3: 1, 4 mL) was alkalified to pH 7-8 with NaHCO ₃. Then the mixture was cooled to 0 ℃, and the solution of acryloyl chloride (45 mg, 0.50 mmol) in THF (1 mL) was added slowly. The reaction mixture was continued to stir for 1 h at 0 ℃. Dichloromethane and water were added. The layers were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed three times with brine solution (3 × 50 mL) . The organic phase was dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by chromatography with dichloromethane and methanol (30: 1) to give 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 %) . ¹H NMR (400 MHz, DMSO-d6) δ 12.13 (s, 1H) , 8.37 (s, 1H) , 7.86 (d, J = 8.8 Hz, 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 = 5.2 Hz, 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] ⁺.

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

The mixture of the product of step E of example 29 (180 mg, 0.33 mmol) in DMF (5 mL) was alkalified to pH 7-8 with N, N-diisopropylethylamine. After 5 min, propiolic acid (34 mg, 0.49 mmol) and HATU (139 mg, 0.36 mmol) were added. The reaction mixture was continued to stir at room temperature for 30 min. Dichloromethane and water were added. The layers were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed three times with brine solution (3 × 50 mL) . The organic phase was dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by chromatography with dichloromethane and methanol (30: 1) to give 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 %) . ¹H NMR (600 MHz, DMSO-d6) δ 12.14 (s, 1H) , 8.38 (s, 1H) , 7.86 (d, J = 8.3 Hz, 2H) , 7.72 (s, 1H) , 7.56 (s, 1H) , 7.49 (d, J = 8.5 Hz, 2H) , 7.13 (t, J = 7.8 Hz, 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] ⁺.

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

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

To a stirred suspension of NaH (60 %dispersion in mineral oil; 19 g, 0.48 mol) in anhydrous DMF (300 mL) at 0 ℃ was added dropwise 1- (4- (4-bromophenoxy) phenyl) ethan- 1-one (70 g, 0.24 mol) dissolved in anhydrous DMF (50 mL) . After 30 minutes, the mixture was cooled to 0 ℃ and dimethyl carbonate (87 g, 0.96 mol) was added neat. The mixture was allowed to warm to room temperature for 2 hs and then poured into 1: 1 water/saturated bicarbonate. The aqueous layer was extracted with ethyl acetate (3 × 500 mL) . The combined organic layer was washed with saturated brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by chromatography with petroleum ether and ethyl acetate (10: 1) to give the desired product methyl 3- (4- (4-bromophenoxy) phenyl) -3-oxopropanoate as a light-yellow solid (80 g, 95.3 %) . MS (ESI, m/z) : 350.2 [M+H] ⁺.

Step B: Preparation of 3- (4- (4-bromophenoxy) phenyl) -3-oxopropanamide

To a solution of the product of step A of example 31 (80 g, 0.23 mol) in 1, 4-dioxane (100 mL) was added 7 M NH ₃/1, 4-dioxane (100 mL) at room temperature in a 300 mL of sealed tube. The mixture was stirred at 95 ℃ for 12 hs, then it was cooled to room temperature. The mixture was concentrated under vacuum to get crude. The residue was purified by chromatography with petroleum ether and ethyl acetate (1: 1) to give the desired 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] ⁺.

Step C: Preparation of 2-bromo-3- (4- (4-bromophenoxy) phenyl) -3-oxopropanamide

CuBr ₂ (33 g, 0.15 mol) was added to a solution of the product of step B of example 31 (45 g, 0.13 mol) in ethyl acetate (500 ml) . The mixture was stirred at 50 ℃ until no further TLC changes were observed. The mixture was filtrated through celite. The filtrate was diluted with ethyl acetate and H ₂O. After the layers were separated, the organic layer was washed with brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by chromatography with petroleum ether and ethyl acetate (3: 2) to give the desired 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] ⁺.

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

A solution of the product of step G of example 1 (8.0 g, 0.03 mol) and the product of step C of example 31 (10 g, 0.024 mol) in ethanol (100 mL) was heated to reflux for overnight. The reaction was then cooled to room temperature and the solvent was removed under vacuum, the crude residue was purified by chromatography with petroleum ether and ethyl acetate (3: 2) to give 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 %) . ¹H NMR (600 MHz, DMSO-d6) δ 12.12 (s, 1H) , 8.41 (s, 1H) , 7.87 (t, J = 5.7 Hz, 2H) , 7.72 (s, 1H) , 7.63-7.58 (m, 2H) , 7.54 (s, 1H) , 7.13 (d, J = 8.7 Hz, 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] ⁺.

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

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

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

The mixture of the product of step E of example 31 (180 mg, 0.37 mmol) in THF/H ₂O (3: 1, 4 mL) was alkalified to pH 7-8 with NaHCO ₃. Then the mixture was cooled to 0 ℃, and the solution of acryloyl chloride (51 mg, 0.56 mmol) in THF (1 mL) was added slowly. The reaction mixture was continued to stir for 1 h at 0 ℃. Dichloromethane and water were added. The layers were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed three times with brine solution (3 × 50 mL) . The organic phase was dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by chromatography with dichloromethane and methanol (30: 1) to give 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 %) . ¹H NMR (400 MHz, DMSO-d6) δ 12.13 (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] ⁺.

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

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

To a stirred suspension of NaH (60 %dispersion in mineral oil; 25 g, 0.62 mol) in anhydrous DMF (300 mL) at 0 ℃ was added dropwise 1- (4- (p-tolyloxy) phenyl) ethan-1-one (70 g, 0.31 mol) dissolved in anhydrous DMF (50 mL) . After 30 minutes, the mixture was cooled to 0 ℃ and dimethyl carbonate (111 g, 1.24 mol) was added neat. The mixture was allowed to warm to room temperature for 2 hs and then poured into 1: 1 water/saturated bicarbonate. The aqueous layer was extracted with ethyl acetate (3 × 500 mL) . The combined organic layer was washed with saturated brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by chromatography with petroleum ether and ethyl acetate (10: 1) to give 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] ⁺.

Step B: Preparation of 3-oxo-3- (4- (p-tolyloxy) phenyl) propanamide

To a solution of the product of step A of example 32 (82 g, 0.29 mol) in 1, 4-dioxane (100 mL) was added 7 M NH ₃/1, 4-dioxane (100 mL) at room temperature in a 300 mL of sealed tube. The mixture was stirred at 95 ℃ for 12 hs, then it was cooled to room temperature. The mixture was concentrated under vacuum to get crude. The residue was purified by chromatography with petroleum ether and ethyl acetate (1: 1) to give the desired 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] ⁺.

Step C: Preparation of 2-bromo-3-oxo-3- (4- (p-tolyloxy) phenyl) propanamide

CuBr ₂ (36 g, 0.16 mol) was added to a solution of the product of step B of example 32 (40 g, 0.15 mol) in ethyl acetate (500 ml) . The mixture was stirred at 50 ℃ until no further TLC changes were observed. The mixture was filtrated through celite. The filtrate was diluted with ethyl acetate and H ₂O. After the layers were separated, the organic layer was washed with brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by chromatography with petroleum ether and ethyl acetate (3: 2) to give the desired product 2-bromo-3-oxo-3- (4- (p-tolyloxy) phenyl) propanamide as a yellow solid (48 g, 92.8 %) . MS (ESI, m/z) : 349.2 [M+H] ⁺.

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

A solution of the product of step G of example 1 (8.0 g, 0.03 mol) and the product of step C of example 32 (8.4 g, 0.024 mol) in ethanol (100 mL) was heated to reflux for overnight. The reaction was then cooled to room temperature and the solvent was removed under vacuum, the crude residue was purified by chromatography with petroleum ether and ethyl acetate (3: 2) to give 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 %) . ¹H NMR (400 MHz, DMSO-d6) δ 12.08 (s, 1H) , 8.39 (s, 1H) , 7.82 (d, J = 8.6 Hz, 2H) , 7.70 (s, 1H) , 7.53 (s, 1H) , 7.25 (d, J = 8.2 Hz, 2H) , 7.06-6.98 (m, 4H) , 4.05 (d, J = 9.3 Hz, 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] ⁺.

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

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

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

The mixture of the product of step E of example 32 (180 mg, 0.43 mmol) in THF/H ₂O (3: 1, 4 mL) was alkalified to pH 7-8 with NaHCO ₃. Then the mixture was cooled to 0 ℃, and the solution of acryloyl chloride (59 mg, 0.65 mmol) in THF (1 mL) was added slowly. The reaction mixture was continued to stir for 1 h at 0 ℃. Dichloromethane and water were added. The layers were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed three times with brine solution (3 × 50 mL) . The organic phase was dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by chromatography with dichloromethane and methanol (30: 1) to give 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 %) . ¹H NMR (400 MHz, CDCl ₃) δ 11.33 (s, 1H) , 8.83 (s, 1H) , 7.71 (d, J = 8.8 Hz, 2H) , 7.48 (s, 1H) , 7.13 (d, J = 8.3 Hz, 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] ⁺.

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

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

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

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

To a solution of the product of step A of example 33 (180 g, 0.86 mol) in ethyl acetate (1500 mL) was added 10 %Pd/C (18 g, 10 %) under N ₂. The suspension was degassed under vacuum and purged with H ₂ several times. The mixture was stirred under H ₂ balloon at room temperature for 5 hs. The mixture was passed through celite, and the solid was washed with ethyl acetate, and filtrate was concentrated under vacuum to give the desired product tert-butyl 3- (cyanomethyl) pyrrolidine-1-carboxylate as a white solid (170 g, 94.0 %) . ¹H NMR (600 MHz, DMSO-d6) δ 3.44 (dd, J = 18.1, 10.1 Hz, 1H) , 3.39-3.34 (m, 1H) , 3.24-3.15 (m, 1H) , 2.92 (t, J = 8.1 Hz, 1H) , 2.65 (t, J = 6.4 Hz, 2H) , 2.45 (dt, J = 14.9, 7.4 Hz, 1H) , 2.00 (d, J = 4.9 Hz, 1H) , 1.65-1.54 (m, 1H) , 1.39 (s, 9H) . MS (ESI, m/z) : 211.3 [M+H] ⁺.

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

A solution of the product of step B of example 33 (170 g, 0.81 mol) in anhydrous THF (500 mL) was cooled to -85 ℃ (Liquid nitrogen/ethanol bath) and treated with n-BuLi (2.5 M in hexane, 1.6 L, 4.05 mol) dropwise and allowed to stir cold for 30 minutes. The reaction was then treated with ethyl formate (180 g, 2.43 mol) and allowed to warm to ice/water bath temperature and stirred for 30 min at which point it was quenched with ice/water and acidified to pH 5-6 with concentrated HCl and extracted with ethyl acetate. The organic phase was washed with saturated brine and then dried over anhydrous Na ₂SO ₄, filtered and concentrated to get 203 g crude tert-butyl 3- (1-cyano-2-oxoethyl) pyrrolidine-1-carboxylate. The residue was used to next step directly.

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

A solution of the product of step C of example 33 (203 g, 0.85 mol) and hydrazine hydrate (80 %, 500 mL) in ethanol (500 mL) was heated to 80 ℃ for 10 hs. The reaction was then cooled to room temperature and the solvent was removed under vacuum, the crude residue was purified by chromatography with 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, the yield of the two steps was 39.1 %) . ¹H NMR (400 MHz, DMSO-d6) δ 7.23 (d, J = 1.4 Hz, 1H) , 3.68-3.60 (m, 1H) , 3.43 (t, J = 9.2 Hz, 1H) , 3.31-3.21 (m, 1H) , 3.18-3.06 (m, 1H) , 3.05-2.99 (m, 1H) , 2.11 (d, J = 5.8 Hz, 1H) , 1.89-1.76 (m, 1H) , 1.44 (s, 9H) . MS (ESI, m/z) : 253.3 [M+H] ⁺.

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

A solution of the product of step D of example 33 (10 g, 39.6 mmol) and the product of step C of example 1 (11 g, 31.7 mmol) in ethanol (200 mL) was heated to reflux for overnight. The reaction was then cooled to room temperature and the solvent was removed under vacuum, the crude residue was purified by chromatography with petroleum ether and ethyl acetate (3: 2) to give 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 %) . ¹H NMR (600 MHz, DMSO-d6) δ 12.32 (s, 1H) , 8.35 (s, 1H) , 7.87 (d, J = 8.6 Hz, 2H) , 7.72 (s, 1H) , 7.58 (s, 1H) , 7.45 (t, J = 7.9 Hz, 2H) , 7.21 (t, J = 7.4 Hz, 1H) , 7.13-7.07 (m, 4H) , 3.73-3.64 (m, 1H) , 3.33- 3.25 (m, 1H) , 3.22 (t, J = 9.9 Hz, 1H) , 2.23-2.14 (m, 1H) , 2.12-2.04 (m, 1H) , 1.41 (d, J = 9.4 Hz, 9H) , 1.30 (s, 1H) , 1.26 (s, 1H) . MS (ESI, m/z) : 488.6 [M+H] ⁺.

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

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

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

The mixture of the product of step F of example 33 (180 mg, 0.46 mmol) in THF/H ₂O (3: 1, 4 mL) was alkalified to pH 7-8 with NaHCO ₃. Then the mixture was cooled to 0 ℃, and the solution of acryloyl chloride (63 mg, 0.70 mmol) in THF (1 mL) was added slowly. The reaction mixture was continued to stir for 1 h at 0 ℃. Dichloromethane and water were added. The layers were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed three times with brine solution (3 × 50 mL) . The organic phase was dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by chromatography with dichloromethane and methanol (30: 1) to give 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 %) . ¹H NMR (400 MHz, DMSO-d6) δ 12.18 (s, 1H) , 8.34 (s, 1H) , 7.90-7.83 (m, 2H) , 7.72 (s, 1H) , 7.60 (d, J = 5.0 Hz, 1H) , 7.49-7.42 (m, 2H) , 7.20 (t, J = 7.4 Hz, 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] ⁺.

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

The mixture of the product of step F of example 33 (180 mg, 0.46 mmol) in DMF (5 mL) was alkalified to pH 7-8 with N, N-diisopropylethylamine. After 5 min, but-2-ynoic acid (58 mg, 0.69 mmol) and HATU (192 mg, 0.51 mmol) were added. The reaction mixture was continued to stir at room temperature for 30 min. Dichloromethane and water were added. The layers were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed three times with brine solution (3 × 50 mL) . The organic phase was dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by chromatography with dichloromethane and methanol (30: 1) to give 7- (1- (but-2-ynoyl) pyrrolidin-3-yl) -2- (4-phenoxyphenyl) -1H-imidazo [1, 2-b] pyrazole-3-carboxamide as an off-white solid (135 mg, 64.7 %) . ¹H NMR (600 MHz, DMSO-d6) δ 12.20 (s, 1H) , 8.35 (s, 1H) , 7.90-7.84 (m, 2H) , 7.75 (d, J = 3.0 Hz, 1H) , 7.61 (d, J = 9.3 Hz, 1H) , 7.45 (t, J = 7.7 Hz, 2H) , 7.21 (t, J = 7.2 Hz, 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] ⁺.

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

The mixture of the product of step F of example 33 (180 mg, 0.46 mmol) in DMF (5 mL) was alkalified to pH 7-8 with N, N-diisopropylethylamine. After 5 min, propiolic acid (48 mg, 0.69 mmol) and HATU (192 mg, 0.51 mmol) were added. The reaction mixture was continued to stir at room temperature for 30 min. Dichloromethane and water were added. The layers were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed three times (3 × 50 mL) with brine solution. The organic phase was dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by chromatography with dichloromethane and methanol (30: 1) to give 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 %) . ¹H NMR (600 MHz, DMSO-d6) δ 12.20 (s, 1H) , 8.35 (s, 1H) , 7.90-7.82 (m, 2H) , 7.75 (s, 1H) , 7.62 (d, J = 6.6 Hz, 1H) , 7.45 (t, J = 7.9 Hz, 2H) , 7.21 (t, J = 7.4 Hz, 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] ⁺.

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

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

A solution of the product of step D of example 33 (10 g, 39.6 mmol) and the product of step C of example 13 (11 g, 31.7 mmol) in ethanol (200 mL) was heated to reflux for overnight. The reaction was then cooled to room temperature and the solvent was removed under vacuum, the crude residue was purified by chromatography with 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] ⁺.

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

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

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

The mixture of the product of step B of example 36 (180 mg, 0.44 mmol) in THF/H ₂O (3: 1, 4 mL) was alkalified to pH 7-8 with NaHCO ₃. Then the mixture was cooled to 0 ℃, and the solution of acryloyl chloride (60 mg, 0.67 mmol) in THF (1 mL) was added slowly. The reaction mixture was continued to stir for 1 h at 0 ℃. Dichloromethane and water were added. The layers were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed three times with brine solution (3 × 50 mL) . The organic phase was dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by chromatography with dichloromethane and methanol (30: 1) to give 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 (400 MHz, DMSO-d6) δ 12.18 (d, J = 16.0 Hz, 1H) , 8.34 (s, 1H) , 7.85 (d, J = 8.7 Hz, 2H) , 7.73 (s, 1H) , 7.61 (d, J = 5.0 Hz, 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, 1H) , 5.71-5.63 (m, 1H) , 4.05-3.98 (m, 0.5H) , 3.94-3.87 (m, 0.5H) , 3.78 (t, J = 7.9 Hz, 0.5H) , 3.71-3.58 (m, 1H) , 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] ⁺.

Example 37: 7- (1- (but-2-ynoyl) pyrrolidin-3-yl) -2- (4- (4-fluorophenoxy) phenyl) -1H- imidazo [1, 2-b] pyrazole-3-carboxamide

The mixture of the product of step B of example 36 (180 mg, 0.44 mmol) in DMF (5 mL) was alkalified to pH 7-8 with N, N-diisopropylethylamine. After 5 min, but-2-ynoic acid (56 mg, 0.67 mmol) and HATU (184 mg, 0.48 mmol) were added. The reaction mixture was continued to stir at room temperature for 30 min. Dichloromethane and water were added. The layers were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed three times with brine solution (3 × 50 mL) . The organic phase was dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by chromatography with dichloromethane and methanol (30: 1) to give 7- (1- (but-2-ynoyl) 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 %) . ¹H NMR (400 MHz, DMSO-d6) δ 12.19 (s, 1H) , 8.33 (s, 1H) , 7.89-7.81 (m, 2H) , 7.72 (s, 1H) , 7.60 (d, J = 6.0 Hz, 1H) , 7.33-7.25 (m, 2H) , 7.20-7.13 (m, 2H) , 7.10-7.05 (m, 2H) , 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] ⁺.

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

The mixture of the product of step B of example 36 (180 mg, 0.44 mmol) in DMF (5 mL) was alkalified to pH 7-8 with N, N-diisopropylethylamine. After 5 min, propiolic acid (47 mg, 0.67 mmol) and HATU (184 mg, 0.48 mmol) were added. The reaction mixture was continued to stir at room temperature for 30 min. Dichloromethane and water were added. The layers were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed three times with brine solution (3 × 50 mL) . The organic phase was dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by chromatography with dichloromethane and methanol (30: 1) to give 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 (400 MHz, DMSO-d6) δ 12.19 (s, 1H) , 8.33 (s, 1H) , 7.87-7.83 (m, 2H) , 7.73 (s, 1H) , 7.61 (d, J = 4.4 Hz, 1H) , 7.32-7.24 (m, 2H) , 7.19-7.13 (m, 2H) , 7.10-7.06 (m, 2H) , 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] ⁺.

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

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

A solution of the product of step D of example 33 (10 g, 39.6 mmol) and the product of step C of example 17 (12 g, 31.7 mmol) in ethanol (200 mL) was heated to reflux for overnight. The reaction was then cooled to room temperature and the solvent was removed under vacuum, the crude residue was purified by chromatography with 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 (400 MHz, DMSO-d6) δ 12.17 (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 = 8.7 Hz, 2H) , 3.75-3.62 (m, 1H) , 3.46 (t, J = 9.4 Hz, 1H) , 3.22 (t, J = 9.8 Hz, 1H) , 2.54 (s, 1H) , 2.25-2.12 (m, 1H) , 2.08 (s, 2H) , 1.41 (d, J = 6.0 Hz, 9H) . MS (ESI, m/z) : 524.5 [M+H] ⁺.

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

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

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

The mixture of the product of step B of example 39 (180 mg, 0.43 mmol) in DMF (5 mL) was alkalified to pH 7-8 with N, N-diisopropylethylamine. After 5 min, propiolic acid (45 mg, 0.64 mmol) and HATU (180 mg, 0.47 mmol) were added. The reaction mixture was continued to stir at room temperature for 30 min. Dichloromethane and water were added. The layers were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed three times with brine solution (3 × 50 mL) . The organic phase was dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by chromatography with dichloromethane and methanol (30: 1) to give 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 %) . ¹H NMR (400 MHz, DMSO-d6) δ 12.19 (s, 1H) , 8.32 (s, 1H) , 7.86-7.80 (m, 2H) , 7.73 (s, 1H) , 7.61 (d, J = 4.5 Hz, 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] ⁺.

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

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

A solution of the product of step D of example 33 (10 g, 39.6 mmol) and the product of step C of example 20 (11 g, 31.7 mmol) in ethanol (200 mL) was heated to reflux for overnight. The reaction was then cooled to room temperature and the solvent was removed under vacuum, the crude residue was purified by chromatography with 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 (600 MHz, DMSO-d6) δ 12.15 (d, J = 5.1 Hz, 1H) , 8.34 (s, 1H) , 7.82 (d, J = 8.6 Hz, 2H) , 7.71 (s, 1H) , 7.57 (s, 1H) , 7.08 (d, J = 8.9 Hz, 2H) , 7.01 (dd, J = 8.5, 4.2 Hz, 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 = 9.8 Hz, 1H) , 2.17 (dd, J = 22.6, 6.3 Hz, 1H) , 2.12-2.03 (m, 1H) , 1.41 (d, J = 9.3 Hz, 9H) , 1.23 (s, 1H) . MS (ESI, m/z) : 518.6 [M+H] ⁺.

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

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

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

The mixture of the product of step B of example 40 (180 mg, 0.43 mmol) in THF/H ₂O (3: 1, 4 mL) was alkalified to pH 7-8 with NaHCO ₃. Then the mixture was cooled to 0 ℃, and the solution of acryloyl chloride (58 mg, 0.65 mmol) in THF (1 mL) was added slowly. The reaction mixture was continued to stir for 1 h at 0 ℃. Dichloromethane and water were added. The layers were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed three times with brine solution (3 × 50 mL) . The organic phase was dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by chromatography with dichloromethane and methanol (30: 1) to give 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 %) . ¹H NMR (400 MHz, DMSO-d6) δ 12.15 (s, 1H) , 8.34 (s, 1H) , 7.81 (d, J = 8.7 Hz, 2H) , 7.72 (s, 1H) , 7.60 (d, J = 5.0 Hz, 1H) , 7.08 (d, J = 9.0 Hz, 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] ⁺.

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

The mixture of the product of step B of example 40 (180 mg, 0.43 mmol) in DMF (5 mL) was alkalified to pH 7-8 with N, N-diisopropylethylamine. After 5 min, but-2-ynoic acid (54 mg, 0.65 mmol) and HATU (180 mg, 0.47 mmol) were added. The reaction mixture was continued to stir at room temperature for 30 min. Dichloromethane and water were added. The layers were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed three times with brine solution (3 × 50 mL) . The organic phase was dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by chromatography with dichloromethane and methanol (30: 1) to give 7- (1- (but-2-ynoyl) 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 %) . ¹H NMR (400 MHz, DMSO-d6) δ 12.17 (s, 1H) , 8.33 (s, 1H) , 7.88-7.78 (m, 2H) , 7.72 (s, 1H) , 7.60 (d, J = 6.1 Hz, 1H) , 7.13-7.06 (m, 2H) , 7.05-6.98 (m, 4H) , 4.05-3.98 (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] ⁺.

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

The mixture of the product of step B of example 40 (180 mg, 0.43 mmol) in DMF (5 mL) was alkalified to pH 7-8 with N, N-diisopropylethylamine. After 5 min, propiolic acid (45 mg, 0.65 mmol) and HATU (180 mg, 0.47 mmol) were added. The reaction mixture was continued to stir at room temperature for 30 min. Dichloromethane and water were added. The layers were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed three times (3 × 50 mL) with brine solution. The organic phase was dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by chromatography with dichloromethane and methanol (30: 1) to give 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 %) . ¹H NMR (400 MHz, DMSO-d6) δ 12.17 (s, 1H) , 8.32 (s, 1H) , 7.85-7.78 (m, 2H) , 7.72 (s, 1H) , 7.60 (d, J = 4.5 Hz, 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, 1.5H) , 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] ⁺.

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

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

A solution of the product of step D of example 33 (10 g, 39.6 mmol) and the product of step C of example 23 (11 g, 31.7 mmol) in ethanol (200 mL) was heated to reflux for overnight. The reaction was then cooled to room temperature and the solvent was removed under vacuum, the crude residue was purified by chromatography with 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 %) . ¹H NMR (400 MHz, DMSO-d6) δ 12.14 (d, J = 3.8 Hz, 1H) , 8.34 (s, 1H) , 7.78 (d, J = 8.8 Hz, 2H) , 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 = 8.8 Hz, 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 = 5.7 Hz, 9H) . MS (ESI, m/z) : 518.6 [M+H] ⁺.

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

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

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

The mixture of the product of step B of example 43 (180 mg, 0.43 mmol) in THF/H ₂O (3: 1, 4 mL) was alkalified to pH 7-8 with NaHCO ₃. Then the mixture was cooled to 0 ℃, and the solution of acryloyl chloride (58 mg, 0.65 mmol) in THF (1 mL) was added slowly. The reaction mixture was continued to stir for 1 h at 0 ℃. Dichloromethane and water were added. The layers were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed three times with brine solution (3 × 50 mL) . The organic phase was dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by chromatography with dichloromethane and methanol (30: 1) to give 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 %) . ¹H NMR (600 MHz, DMSO-d6) δ 12.15 (s, 1H) , 8.32 (s, 1H) , 7.77 (d, J = 8.7 Hz, 2H) , 7.69 (s, 1H) , 7.59 (d, J = 7.7 Hz, 1H) , 7.27 (t, J = 7.3 Hz, 1H) , 7.22 (d, J = 7.8 Hz, 1H) , 7.14 (d, J = 7.9 Hz, 1H) , 7.03 (t, J = 7.5 Hz, 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 = 9.8 Hz, 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] ⁺.

Example 44: 7- (1- (but-2-ynoyl) pyrrolidin-3-yl) -2- (4- (2-methoxyphenoxy) phenyl) -1H- imidazo [1, 2-b] pyrazole-3-carboxamide

The mixture of the product of step B of example 43 (180 mg, 0.43 mmol) in DMF (5 mL) was alkalified to pH 7-8 with N, N-diisopropylethylamine. After 5 min, but-2-ynoic acid (54 mg, 0.65 mmol) and HATU (180 mg, 0.47 mmol) were added. The reaction mixture was continued to stir at room temperature for 30 min. Dichloromethane and water were added. The layers were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed three times with brine solution (3 × 50 mL) . The organic phase was dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by chromatography with dichloromethane and methanol (30: 1) to give 7- (1- (but-2-ynoyl) 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 %) . ¹H NMR (400 MHz, DMSO-d6) δ 12.20 (s, 1H) , 8.30 (s, 1H) , 7.81-7.75 (m, 2H) , 7.72 (s, 1H) , 7.61 (d, J = 5.4 Hz, 1H) , 7.30-7.19 (m, 2H) , 7.19-7.11 (m, 1H) , 7.07-6.99 (m, 1H) , 6.95-6.88 (m, 2H) , 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 = 15.9 Hz, 3H) . MS (ESI, m/z) : 484.5 [M+H] ⁺.

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

The mixture of the product of step B of example 43 (180 mg, 0.43 mmol) in DMF (5 mL) was alkalified to pH 7-8 with N, N-diisopropylethylamine. After 5 min, propiolic acid (45 mg, 0.65 mmol) and HATU (180 mg, 0.47 mmol) were added. The reaction mixture was continued to stir at room temperature for 30 min. Dichloromethane and water were added. The layers were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed three times with brine solution (3 × 50 mL) . The organic phase was dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by chromatography with dichloromethane and methanol (30: 1) to give 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 %) . ¹H NMR (600 MHz, DMSO-d6) δ 12.16 (s, 1H) , 8.31 (s, 1H) , 7.79-7.74 (m, 2H) , 7.71 (s, 1H) , 7.60 (d, J = 6.5 Hz, 1H) , 7.27 (t, J = 7.8 Hz, 1H) , 7.22 (d, J = 8.1 Hz, 1H) , 7.14 (d, J = 7.8 Hz, 1H) , 7.03 (t, J = 7.6 Hz, 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] ⁺.

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

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

A solution of the product of step D of example 33 (10 g, 39.6 mmol) and the product of step C of example 26 (11 g, 31.7 mmol) in ethanol (200 mL) was heated to reflux for overnight. The reaction was then cooled to room temperature and the solvent was removed under vacuum, the crude residue was purified by chromatography with 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 %) . ¹H NMR (400 MHz, DMSO-d6) δ 12.21 (s, 1H) , 8.34 (s, 1H) , 7.88-7.82 (m, 2H) , 7.72 (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 = 9.8 Hz, 1H) , 2.20-2.11 (m, 1H) , 2.09-2.01 (m, 1H) , 1.41 (d, J = 6.0 Hz, 9H) . MS (ESI, m/z) : 506.5 [M+H] ⁺.

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

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

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

The mixture of the product of step B of example 46 (180 mg, 0.39 mmol) in THF/H ₂O (3: 1, 4 mL) was alkalified to pH 7-8 with NaHCO ₃. Then the mixture was cooled to 0 ℃, and the solution of acryloyl chloride (53 mg, 0.59 mmol) in THF (1 mL) was added slowly. The reaction mixture was continued to stir for 1 h at 0 ℃. Dichloromethane and water were added. The layers were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed three times with brine solution (3 × 50 mL) . The organic phase was dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by chromatography with dichloromethane and methanol (30: 1) to give 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 %) . ¹H NMR (400 MHz, DMSO-d6) δ 12.20 (s, 1H) , 8.34 (s, 1H) , 7.84 (d, J = 8.1 Hz, 2H) , 7.73 (s, 1H) , 7.61 (d, J = 4.4 Hz, 1H) , 7.43 (d, J = 9.7 Hz, 1H) , 7.30 (s, 3H) , 7.07 (d, J = 7.2 Hz, 2H) , 6.67-6.56 (m, 1H) , 6.21-6.11 (m, 1H) , 5.67 (t, J = 8.2 Hz, 1H) , 4.02 (t, J = 7.4 Hz, 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] ⁺.

Example 47: 7- (1- (but-2-ynoyl) pyrrolidin-3-yl) -2- (4- (2-fluorophenoxy) phenyl) -1H- imidazo [1, 2-b] pyrazole-3-carboxamide

The mixture of the product of step B of example 46 (180 mg, 0.39 mmol) in DMF (5 mL) was alkalified to pH 7-8 with N, N-diisopropylethylamine. After 5 min, but-2-ynoic acid (50 mg, 0.59 mmol) and HATU (163 mg, 0.43 mmol) were added. The reaction mixture was continued to stir at room temperature for 30 min. Dichloromethane and water were added. The layers were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed three times with brine solution (3 × 50 mL) . The organic phase was dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by chromatography with dichloromethane and methanol (30: 1) to give 7- (1- (but-2-ynoyl) 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 %) . ¹H NMR (600 MHz, DMSO-d6) δ 12.20 (s, 1H) , 8.34 (s, 1H) , 7.85 (t, J = 7.4 Hz, 2H) , 7.75 (s, 1H) , 7.61 (d, J = 9.4 Hz, 1H) , 7.49-7.42 (m, 1H) , 7.33-7.27 (m, 3H) , 7.10-7.05 (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] ⁺.

Example 48: (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

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

A solution of the product of step D of example 33 (10 g, 39.6 mmol) and the product of step C of example 32 (11 g, 31.7 mmol) in ethanol (200 mL) was heated to reflux for overnight. The reaction was then cooled to room temperature and the solvent was removed under vacuum, the crude residue was purified by chromatography with petroleum ether and ethyl acetate (3: 2) to give 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 %) . ¹H NMR (600 MHz, DMSO-d6) δ 12.19 (s, 1H) , 8.36 (s, 1H) , 7.84 (d, J = 8.7 Hz, 2H) , 7.72 (s, 1H) , 7.58 (s, 1H) , 7.25 (d, J = 8.3 Hz, 2H) , 7.05 (d, J = 8.4 Hz, 2H) , 7.01 (d, J = 8.3 Hz, 2H) , 3.75-3.63 (m, 1H) , 3.49-3.43 (m, 1H) , 3.36-3.26 (m, 2H) , 3.23 (t, J = 9.8 Hz, 1H) , 2.32 (s, 3H) , 2.23-2.12 (m, 1H) , 2.12-2.02 (m, 1H) , 1.41 (d, J = 8.7 Hz, 9H) . MS (ESI, m/z) : 502.2 [M+H] ⁺.

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

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

Step C: Preparation of (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

The mixture of the product of step B of example 48 (180 mg, 0.45 mmol) in DMF (5 mL) was alkalified to pH 7-8 with N, N-diisopropylethylamine. After 5 min, (E) -4, 4, 4-trifluorobut-2-enoic acid (94 mg, 0.67 mmol) and HATU (187 mg, 0.49 mmol) were added. The reaction mixture was continued to stir at room temperature for 10 min. Dichloromethane and water were added. The layers were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed three times with brine solution (3 × 50 mL) . The organic phase was dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by chromatography with 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 %) . ¹H NMR (400 MHz, DMSO-d6) δ12.27-12.17 (m, 1H) , 8.39 (s, 1H) , 7.91-7.86 (m, 2H) , 7.78 (s, 1H) , 7.68 (d, J = 5.0 Hz, 1H) , 7.31 (d, J = 8.3 Hz, 2H) , 7.24-7.16 (m, 1H) , 7.13-7.09 (m, 2H) , 7.06 (d, J = 8.3 Hz, 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] ⁺.

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

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

To a stirred suspension of NaH (60 %dispersion in mineral oil; 48 g, 1.2 mol) in anhydrous THF (500 mL) at 10 ℃ was added dropwise diethyl (cyanomethyl) phosphonate (230 g, 1.3 mol) dissolved in anhydrous THF (200 mL) . After 30 minutes, the mixture was cooled to 10 ℃ and tert-butyl 3-oxoazetidine-1-carboxylate (171 g, 1.0 mol) was added neat. The mixture was allowed to warm to room temperature over a 2 hs period and then quenched with ice/water. The aqueous layer was extracted with ethyl acetate, and after removal of the solvent under vacuum, the crude residue was recrystallized from petroleum ether and ethyl acetate (10: 1) to give the desired product tert-butyl 3- (cyanomethylene) azetidine-1-carboxylate as a white solid (167 g, 86.1 %) . White solid. ¹H NMR (400 MHz, DMSO-d6) δ 5.87-5.78 (m, 1H) , 4.70-4.48 (m, 4H) , 1.40 (s, 9H) . MS (ESI, m/z) : 195.2 [M+H] ⁺.

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

To a solution of the product of step A of example 49 (167 g, 0.86 mol) in ethyl acetate (1500 mL) was added Pd/C (17 g, 10 %) under N ₂. The suspension was degassed under vacuum and purged with H ₂ several times. The mixture was stirred under H ₂ balloon at room temperature for 5 hs. The mixture was passed through celite, and the solid was washed with ethyl acetate, and filtrate was concentrated under vacuum to give the desired product tert-butyl 3- (cyanomethyl) azetidine-1-carboxylate as a white solid (163 g, 96.6 %) . ¹H NMR (400 MHz, DMSO-d6) δ 3.95 (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] ⁺.

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

A solution of the product of step C of example 49 (163 g, 0.83 mol) in anhydrous THF (500 mL) was cooled to -85 ℃ (Liquid nitrogen/ethanol bath) and treated with n-BuLi (2.5 M in hexane, 1.7 L, 4.15 mol) dropwise and allowed to stir cold for 30 minutes. The reaction was then treated with ethyl formate (184 g, 2.49 mol) and allowed to warm to ice/water bath temperature and stirred for 30 min at which point it was quenched with ice/water and acidified to pH 5-6 with concentrated HCl and extracted with ethyl acetate. The organic phase was washed with saturated brine and then dried over anhydrous Na ₂SO ₄, filtered and concentrated to get 195 g crude tert-butyl 3- (1-cyano-2-oxoethyl) azetidine-1-carboxylate. The residue was used to next step directly.

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

A solution of the product of step C of example 49 (195 g, 0.87 mol) and hydrazine hydrate (80 %, 500 mL) in ethanol (500 mL) was heated to 80 ℃ for 10 hs. The reaction was then cooled to room temperature and the solvent was removed under vacuum, the crude residue was purified by chromatography with petroleum ether and ethyl acetate (1: 5) to give the desired product tert-butyl 3- (5-amino-1H-pyrazol-4-yl) azetidine-1-carboxylate as a yellow solid (83 g, the yield of the two steps was 42.0 %) . ¹H NMR (600 MHz, DMSO-d6) δ 11.37 (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] ⁺.

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

A solution of the product of step D of example 49 (10 g, 42.0 mmol) and the product of step C of example 1 (11 g, 33.6 mmol) in ethanol (200 mL) was heated to reflux for overnight. The reaction was then cooled to room temperature and the solvent was removed under vacuum, the crude residue was purified by chromatography with petroleum ether and ethyl acetate (3: 2) to give 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 %) . ¹H NMR (400 MHz, DMSO-d6) δ 12.35 (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 = 7.9 Hz, 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] ⁺.

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

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

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

The mixture of the product of step F of example 49 (180 mg, 0.48 mmol) in THF/H ₂O (3: 1, 4 mL) was alkalified to pH 7-8 with NaHCO ₃. Then the mixture was cooled to 0 ℃, and the solution of acryloyl chloride (65 mg, 0.72 mmol) in THF (1 mL) was added slowly. The reaction mixture was continued to stir for 1 h at 0 ℃. Dichloromethane and water were added. The layers were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed three times with brine solution (3 × 50 mL) . The organic phase was dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by chromatography with 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 %) . ¹H NMR (400 MHz, DMSO-d6) δ 12.39 (s, 1H) , 8.31 (s, 1H) , 7.85 (d, J = 8.7 Hz, 2H) , 7.74 (s, 1H) , 7.71 (s, 1H) , 7.45 (t, J = 7.9 Hz, 2H) , 7.21 (t, J = 7.4 Hz, 1H) , 7.10 (d, J = 8.6 Hz, 4H) , 6.40-6.30 (m, 1H) , 6.17-6.08 (m, 1H) , 5.71-5.65 (m, 1H) , 4.56 (t, J = 8.3 Hz, 1H) , 4.35-4.23 (m, 2H) , 4.05-3.92 (m, 2H) . MS (ESI, m/z) : 428.5 [M+H] ⁺.

Example 50: 7- (1- (but-2-ynoyl) azetidin-3-yl) -2- (4-phenoxyphenyl) -1H-imidazo [1, 2- b] pyrazole-3-carboxamide

The mixture of the product of step F of example 49 (180 mg, 0.48 mmol) in DMF (5 mL) was alkalified to pH 7-8 with N, N-diisopropylethylamine. After 5 min, but-2-ynoic acid (61 mg, 0.72 mmol) and HATU (201 mg, 0.53 mmol) were added. The reaction mixture was continued to stir at room temperature for 30 min. Dichloromethane and water were added. The layers were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed three times with brine solution (3 × 50 mL) . The organic phase was dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by chromatography with dichloromethane and methanol (30: 1) to give 7- (1- (but-2-ynoyl) azetidin-3-yl) -2- (4-phenoxyphenyl) -1H-imidazo [1, 2-b] pyrazole-3-carboxamide as an off-white solid (128 mg, 60.4 %) . ¹H NMR (600 MHz, DMSO-d6) δ 8.31 (s, 1H) , 7.87 (d, J = 8.5 Hz, 2H) , 7.69 (s, 1H) , 7.45 (t, J = 7.8 Hz, 2H) , 7.21 (d, J = 7.3 Hz, 1H) , 7.11-7.08 (m, 4H) , 4.45 (t, J = 8.3 Hz, 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] ⁺.

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

The mixture of the product of step F of example 49 (180 mg, 0.48 mmol) in DMF (5 mL) was alkalified to pH 7-8 with N, N-diisopropylethylamine. After 5 min, propiolic acid (51 mg, 0.72 mmol) and HATU (201 mg, 0.53 mmol) were added. The reaction mixture was continued to stir at room temperature for 30 min. Dichloromethane and water were added. The layers were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed three times (3 × 50 mL) with brine solution. The organic phase was dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by chromatography with dichloromethane and methanol (30: 1) to give 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 (400 MHz, DMSO-d6) δ 12.40 (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 = 7.4 Hz, 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] ⁺.

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

The mixture of the product of step F of example 49 (180 mg, 0.48 mmol) in DMF (5 mL) was alkalified to pH 7-8 with N, N-diisopropylethylamine. After 5 min, HATU (202 mg, 0.53 mmol) and (E) -4, 4, 4-trifluorobut-2-enoic acid (101 mg, 0.72 mmol) were added. The reaction mixture was continued to stir at room temperature for 10 min. Dichloromethane and water were added. The layers were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed three times with brine solution (3 × 50 mL) . The organic phase was dried over anhydrous Na ₂SO ₄, 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 %) . ¹H NMR (400 MHz, DMSO-d6) δ 12.36 (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 = 8.7 Hz, 1H) , 4.45-4.38 (m, 1H) , 4.34 (t, J = 9.3 Hz, 1H) , 4.12-3.95 (m, 2H) . MS (ESI, m/z) : 496.5 [M+H] ⁺.

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

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

A solution of the product of step D of example 49 (10 g, 42.0 mmol) and the product of step C of example 13 (12 g, 33.6 mmol) in ethanol (200 mL) was heated to reflux for overnight. The reaction was then cooled to room temperature and the solvent was removed under vacuum, the crude residue was purified by chromatography with 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) azetidine-1-carboxylate as a yellow solid (3.7 g, 18.0 %) . ¹H NMR (400 MHz, DMSO-d6) δ 12.31 (s, 1H) , 8.34 (s, 1H) , 7.85 (d, J = 8.7 Hz, 2H) , 7.74 (s, 1H) , 7.70 (s, 1H) , 7.29 (t, J = 8.7 Hz, 2H) , 7.19-7.13 (m, 2H) , 7.08 (d, J = 8.7 Hz, 2H) , 4.19 (t, J = 7.9 Hz, 2H) , 3.96 (t, J = 7.1 Hz, 2H) , 3.92-3.82 (m, 1H) , 1.41 (s, 9H) . MS (ESI, m/z) : 492.5 [M+H] ⁺.

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

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

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

The mixture of the product of step B of example 53 (180 mg, 0.46 mmol) in THF/H ₂O (3: 1, 4 mL) was alkalified to pH 7-8 with NaHCO ₃. Then the mixture was cooled to 0 ℃, and the solution of acryloyl chloride (62 mg, 0.69 mmol) in THF (1 mL) was added slowly. The reaction mixture was continued to stir for 1 h at 0 ℃. Dichloromethane and water were added. The layers were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed three times with brine solution (3 × 50 mL) . The organic phase was dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by chromatography with 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 %) . ¹H NMR (400 MHz, DMSO-d6) δ 12.38 (s, 1H) , 8.32 (s, 1H) , 7.84 (t, J = 5.8 Hz, 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 = 8.8 Hz, 2H) , 6.40-6.31 (m, 1H) , 6.16-6.09 (m, 1H) , 5.71-5.66 (m, 1H) , 4.56 (t, J = 8.3 Hz, 1H) , 4.36-4.19 (m, 2H) , 4.06-3.94 (m, 2H) . MS (ESI, m/z) : 446.4 [M+H] ⁺.

Example 54: 7- (1- (but-2-ynoyl) azetidin-3-yl) -2- (4- (4-fluorophenoxy) phenyl) -1H- imidazo [1, 2-b] pyrazole-3-carboxamide

The mixture of the product of step B of example 53 (180 mg, 0.46 mmol) in DMF (5 mL) was alkalified to pH 7-8 with N, N-diisopropylethylamine. After 5 min, but-2-ynoic acid (58 mg, 0.69 mmol) and HATU (192 mg, 0.51 mmol) were added. The reaction mixture was continued to stir at room temperature for 30 min. Dichloromethane and water were added. The layers were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed three times with brine solution (3 × 50 mL) . The organic phase was dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by chromatography with dichloromethane and methanol (30: 1) to give 7- (1- (but-2-ynoyl) 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 %) . ¹H NMR (400 MHz, DMSO-d6) δ 12.38 (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 = 8.3 Hz, 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] ⁺.

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

The mixture of the product of step B of example 53 (180 mg, 0.46 mmol) in DMF (5 mL) was alkalified to pH 7-8 with N, N-diisopropylethylamine. After 5 min, propiolic acid (48 mg, 0.69 mmol) and HATU (192 mg, 0.51 mmol) were added. The reaction mixture was continued to stir at room temperature for 30 min. Dichloromethane and water were added. The layers were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed three times with brine solution (3 × 50 mL) . The organic phase was dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by chromatography with 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 %) . ¹H NMR (400 MHz, DMSO-d6) δ 12.39 (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 = 8.7 Hz, 2H) , 4.50 (t, J = 8.3 Hz, 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] ⁺.

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

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

A solution of the product of step D of example 49 (10 g, 42.0 mmol) and the product of step C of example 23 (12 g, 33.6 mmol) in ethanol (200 mL) were heated to reflux for overnight. The reaction was then cooled to room temperature and the solvent was removed under vacuum, the crude residue was purified by chromatography with 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) azetidine-1-carboxylate as a yellow solid (3.8 g, 18.0 %) . ¹H NMR (400 MHz, DMSO-d6) δ 12.28 (s, 1H) , 8.31 (s, 1H) , 7.76 (d, J = 8.9 Hz, 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 = 7.7 Hz, 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] ⁺.

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

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

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

The mixture of the product of step B of example 56 (180 mg, 0.45 mmol) in THF/H ₂O (3: 1, 4 mL) was alkalified to pH 7-8 with NaHCO ₃. Then the mixture was cooled to 0 ℃, and the solution of acryloyl chloride (61 mg, 0.67 mmol) in THF (1 mL) were added slowly. The reaction mixture was continued to stir for 1 h at 0 ℃. Dichloromethane and water were added. The layers were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed three times with brine solution (3 × 50 mL) . The organic phase was dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by chromatography with dichloromethane and methanol (30: 1) to give 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 %) . ¹H NMR (400 MHz, DMSO-d6) δ 12.34 (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 = 8.3 Hz, 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] ⁺.

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

The mixture of the product of step B of example 56 (180 mg, 0.45 mmol) in DMF (5 mL) was alkalified to pH 7-8 with N, N-diisopropylethylamine. After 5 min, but-2-ynoic acid (56 mg, 0.67 mmol) and HATU (188 mg, 0.49 mmol) were added. The reaction mixture was continued to stir at room temperature for 30 min. Dichloromethane and water were added. The layers were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed three times with brine solution (3 × 50 mL) . The organic phase was dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by chromatography with dichloromethane and methanol (30: 1) to give 7- (1- (but-2-ynoyl) 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 %) . ¹H NMR (600 MHz, DMSO-d6) δ 12.34 (s, 1H) , 8.29 (s, 1H) , 7.76 (d, J = 8.6 Hz, 2H) , 7.71 (s, 1H) , 7.69 (s, 1H) , 7.27 (t, J = 7.8 Hz, 1H) , 7.22 (d, J = 8.1 Hz, 1H) , 7.14 (d, J = 7.8 Hz, 1H) , 7.03 (t, J = 7.6 Hz, 1H) , 6.91 (d, J = 8.6 Hz, 2H) , 4.44 (t, J = 8.2 Hz, 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] ⁺.

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

The mixture of the product of step B of example 56 (180 mg, 0.45 mmol) in DMF (5 mL) was alkalified to pH 7-8 with N, N-diisopropylethylamine. After 5 min, propiolic acid (47 mg, 0.67 mmol) and HATU (188 mg, 0.49 mmol) were added. The reaction mixture was continued to stir at room temperature for 30 min. Dichloromethane and water were added. The layers were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed three times with brine solution (3 × 50 mL) . The organic phase was dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by chromatography with dichloromethane and methanol (30: 1) to give 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 %) . ¹H NMR (600 MHz, DMSO-d6) δ 12.35 (s, 1H) , 8.29 (s, 1H) , 7.76 (d, J = 8.5 Hz, 2H) , 7.72 (s, 1H) , 7.70 (s, 1H) , 7.27 (t, J = 7.8 Hz, 1H) , 7.22 (d, J = 8.2 Hz, 1H) , 7.14 (d, J = 7.8 Hz, 1H) , 7.03 (t, J = 7.6 Hz, 1H) , 6.91 (d, J = 8.5 Hz, 2H) , 4.49 (t, J = 8.3 Hz, 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] ⁺.

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

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

In a sealed tube, 4-nitrobenzacetonitrile (20 g, 0.12 mol) and DMF/DMA (100 mL) were heated for 8 h at 90 ℃. Then the mixture was dissolved in ethanol (50 mL) and hydrazine hydrate (80 %, 50 mL) was added. The reaction was refluxed overnight. The solvent was removed in vacuo, the crude residue was purified by chromatography with 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 (600 MHz, DMSO-d6) δ 8.16 (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] ⁺.

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

A solution of the product of step A of example 59 (15 g, 73.5 mmol) and the product of step C of example 1 (20 g, 58.8 mmol) in ethanol (200 mL) was heated to reflux for overnight. The reaction was then cooled to room temperature and the solvent was removed under vacuum, the crude residue was purified by chromatography with petroleum ether and ethyl acetate (3: 2) to give 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 %) . ¹H NMR (600 MHz, DMSO-d6) δ 12.91 (s, 1H) , 8.45 (s, 1H) , 8.24-8.15 (m, 3H) , 7.99 (d, J = 7.1 Hz, 2H) , 7.87 (d, J = 8.1 Hz, 3H) , 7.46 (d, J = 6.6 Hz, 2H) , 7.22 (s, 1H) , 7.12 (s, 4H) . MS (ESI, m/z) : 440.4 [M+H] ⁺.

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

To a solution of the product of step B of example 59 (6.7 g, 15.2 mmol) in MeOH (20 mL) was added 10 %Pd/C (0.7 g, 10 %) under N ₂. The suspension was degassed under vacuum and purged with H ₂ several times. The mixture was stirred under H ₂ balloon at room temperature for 5 hs. The mixture was passed through celite, and the solid was washed with methyl alcohol, and 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] ⁺.

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

The mixture of the product of step C of example 59 (180 mg, 0.44 mmol) in THF/H ₂O (3: 1, 4 mL) was alkalified to pH 7-8 with NaHCO ₃. Then the mixture was cooled to 0 ℃, and the solution of acryloyl chloride (60 mg, 0.66 mmol) in THF (1 mL) was added slowly. The reaction mixture was continued to stir for 1 h at 0 ℃. Dichloromethane and water were added. The layers were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed three times with brine solution (3 × 50 mL) . The organic phase was dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by chromatography with dichloromethane and methanol (30: 1) to give 7- (4-acrylamidophenyl) -2- (4-phenoxyphenyl) -1H-imidazo [1, 2-b] pyrazole-3-carboxamide as a yellow solid (87 mg, 42.7 %) . ¹H NMR (400 MHz, DMSO-d6) δ 10.15 (s, 1H) , 8.31 (s, 1H) , 8.17 (s, 1H) , 7.87 (d, J = 8.7 Hz, 2H) , 7.80 (s, 1H) , 7.70 (s, 4H) , 7.46 (t, J = 8.0 Hz, 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] ⁺.

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

The mixture of the product of step C of example 59 (180 mg, 0.44 mmol) in DMF (5 mL) was alkalified to pH 7-8 with N, N-diisopropylethylamine. After 5 min, propiolic acid (46 mg, 0.66 mmol) and HATU (183 mg, 0.48 mmol) were added. The reaction mixture was continued to stir at room temperature for 30 min. Dichloromethane and water were added. The layers were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed three times with brine solution (3 × 50 mL) . The organic phase was dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by chromatography with 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] ⁺.

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

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

In a sealed tube, 3-nitrobenzacetonitrile (20 g, 0.12 mol) and DMF/DMA (100 mL) were heated for 8 h at 90 ℃. Then the mixture was dissolved in ethanol (50 mL) and hydrazine hydrate (80 %, 50 mL) was added. The reaction was refluxed overnight. The solvent was removed in vacuo, the crude residue was purified by chromatography with 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] ⁺.

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

A solution of the product of step A of example 61 (16 g, 78.4 mmol) and the product of step C of example 1 (21 g, 62.7 mmol) in ethanol (200 mL) was heated to reflux for overnight. The reaction was then cooled to room temperature and the solvent was removed under vacuum, the crude residue was purified by chromatography with petroleum ether and ethyl acetate (3: 2) to give 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 %) . ¹H NMR (600 MHz, DMSO-d6) δ 12.82 (s, 1H) , 8.51 (s, 1H) , 8.40 (s, 1H) , 8.24 (s, 1H) , 8.19 (d, J = 7.8 Hz, 1H) , 7.96-7.92 (m, 1H) , 7.91-7.86 (m, 2H) , 7.78 (s, 1H) , 7.65 (t, J = 7.9 Hz, 1H) , 7.46 (t, J = 7.4 Hz, 2H) , 7.21 (t, J = 7.4 Hz, 1H) , 7.12 (d, J = 7.9 Hz, 4H) . MS (ESI, m/z) : 440.4 [M+H] ⁺.

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

To a solution of the product of step B of example 61 (8.3 g, 18.9 mmol) in MeOH (20 mL) was added 10 %Pd/C (0.8 g, 10 %) under N ₂. The suspension was degassed under vacuum and purged with H ₂ several times. The mixture was stirred under H ₂ balloon at room temperature for 5 hs. The mixture was passed through celite, and the solid was washed with methyl alcohol, and 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] ⁺.

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

The mixture of the product of step C of example 61 (180 mg, 0.44 mmol) in THF/H ₂O (3: 1, 4 mL) was alkalified to pH 7-8 with NaHCO ₃. Then the mixture was cooled to 0 ℃, and the solution of acryloyl chloride (60 mg, 0.66 mmol) in THF (1 mL) was added slowly. The reaction mixture was continued to stir for 1 h at 0 ℃. Dichloromethane and water were added. The layers were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed three times with brine solution (3 × 50 mL) . The organic phase was dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by chromatography with dichloromethane and methanol (30: 1) to give 7- (3-acrylamidophenyl) -2- (4-phenoxyphenyl) -1H-imidazo [1, 2-b] pyrazole-3-carboxamide as a yellow solid (93 mg, 45.6 %) . ¹H NMR (400 MHz, DMSO-d6) δ 12.56 (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 = 7.8 Hz, 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] ⁺.

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

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

A solution of tert-butyl 3-cyano-4-oxopiperidine-1-carboxylate (50 g, 0.22 mol) and hydrazine hydrate (80 %, 150 mL) in ethanol (150 mL) was heated to 80 ℃ for 10 hs. The reaction was then cooled to room temperature and the solvent was removed under vacuum, the crude residue was purified by chromatography with petroleum ether and ethyl acetate (1: 5) to give 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 (600 MHz, CDCl ₃) δ 4.15 (s, 2H) , 3.51 (s, 2H) , 2.49 (t, J = 5.5 Hz, 2H) , 1.39 (s, 9H) . MS (ESI, m/z) : 239.3 [M+H] ⁺.

Step B: Preparation of 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

A solution of the product of step A of example 62 (10 g, 42.0 mmol) and the product of step C of example 1 (11 g, 33.6 mmol) in ethanol (200 mL) was heated to reflux for overnight. The reaction was then cooled to room temperature and the solvent was removed under vacuum, the crude residue was purified by chromatography with petroleum ether and ethyl acetate (3: 2) to give 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 %) . ¹H NMR (400 MHz, DMSO-d6) δ 12.11 (s, 1H) , 8.37 (s, 1H) , 7.88 (d, J = 8.8 Hz, 2H) , 7.72 (s, 1H) , 7.49-7.40 (m, 2H) , 7.21 (t, J = 7.4 Hz, 1H) , 7.13-7.05 (m, 4H) , 4.48 (s, 2H) , 3.67 (t, J = 5.7 Hz, 2H) , 2.77 (t, J = 5.6 Hz, 2H) , 1.44 (s, 9H) . MS (ESI, m/z) : 474.5 [M+H] ⁺.

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

To a solution of the product of step B of example 62 (3.2 g, 6.76 mmol) in EtOH (2 mL) was added 33 %HCl/EtOH (5 mL) at room temperature in reaction still. The mixture was stirred for 3 hs, then the mixture was concentrated under vacuum to get 2.9 g 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 to next step directly.

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

The mixture of the product of step C of example 62 (180 mg, 0.48 mmol) in THF/H ₂O (3: 1, 4 mL) was alkalified to pH 7-8 with NaHCO ₃. Then the mixture was cooled to 0 ℃, and the solution of acryloyl chloride (65 mg, 0.72 mmol) in THF (1 mL) was added slowly. The reaction mixture was continued to stir for 1 h at 0 ℃. Dichloromethane and water were added. The layers were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed three times with brine solution (3 × 50 mL) . The organic phase was dried over anhydrous Na ₂SO ₄, 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 %) . ¹H NMR (400 MHz, DMSO-d6) δ 12.13 (s, 1H) , 8.37 (s, 1H) , 7.89 (d, J = 8.7 Hz, 2H) , 7.72 (s, 1H) , 7.46 (t, J = 7.9 Hz, 2H) , 7.22 (t, J = 7.4 Hz, 1H) , 7.10 (t, J = 8.4 Hz, 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] ⁺.

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

The mixture of the product of step C of example 62 (180 mg, 0.48 mmol) in DMF (5 mL) was alkalified to pH 7-8 with N, N-diisopropylethylamine. After 5 min, (E) -4- (dimethylamino) but-2-enoic acid (93 mg, 0.72 mmol) and HATU (201 mg, 0.53 mmol) were added. The reaction mixture was continued to stir at room temperature for 10 min. Dichloromethane and water were added. The layers were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed three times with brine solution (3 × 50 mL) . The organic phase was dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by chromatography with 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 %) . ¹H NMR (600 MHz, DMSO-d6) δ 8.37 (s, 1H) , 7.91-7.86 (m, 2H) , 7.72 (s, 1H) , 7.49-7.43 (m, 2H) , 7.22 (t, J = 7.4 Hz, 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 = 6.0 Hz, 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] ⁺.

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

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

To a solution of tert-butyl 4-oxoazepane-1-carboxylate (100 g, 0.46 mol) in DCM (500 mL) was added p-toluenesulfonic acid (8.0 g, 0.046 mol) . Then the mixture was cooled to 0 ℃, and NBS (92 g, 0.50 mol) was added slowly. The mixture was allowed to warm to room temperature over a 24 hs period and then quenched with 1: 1 water/saturated sodium bicarbonate solution. The aqueous layer was extracted with dichloromethane. The combined organic phases were washed three times with brine solution (3 × 100 mL) . The organic phase was dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by chromatography with petroleum ether and ethyl acetate (5: 1) to give the crude tert-butyl 3-bromo-4-oxoazepane-1-carboxylate as the yellow oily liquid (40 g, 29.8 %) and the crude tert-butyl 4-bromo-5-oxoazepane-1-carboxylate as the yellow oily liquid (80 g, 59.7 %) . The residue was used to next step directly. MS (ESI, m/z) : 293.2 [M+H] ⁺.

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

To a solution of the product of step A of example 64 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 overnight at room temperature. Then the mixture was used to next step directly. MS (ESI, m/z) : 238.3 [M+H] ⁺.

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

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

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

A solution of the product of step C of example 64 (30 g, 0.12 mol) and the product of step C of example 1 (32 g, 0.09 mol) in ethanol (200 mL) was heated to reflux for overnight. The reaction was then cooled to room temperature and the solvent was removed under vacuum, the crude residue was purified by chromatography with petroleum ether and ethyl acetate (2: 1) to give 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] ⁺.

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

To a solution of the product of step D of example 64 (0.8 g, 1.64 mmol) in dichloromethane (2 mL) was added 33 %HCl/EtOH (5 mL) at room temperature in reaction still. The mixture was stirred for 3 hs, then the mixture was concentrated under vacuum to get 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 to next step directly.

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

The mixture of the product of step E of example 64 (200 mg, 0.52 mmol) in THF/H ₂O (3: 1, 8 mL) was alkalified to pH 7-8 with NaHCO ₃. Then the mixture was cooled to 0 ℃, and the solution of acryloyl chloride (70 mg, 0.77 mmol) in THF (2 mL) was added slowly. The reaction mixture was continued to stir for 1 h at 0 ℃. Dichloromethane and water were added. The layers were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed three times with brine solution (3 × 50 mL) . The organic phase was dried over anhydrous Na ₂SO ₄, 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 (400 MHz, DMSO-d6) δ 12.39-11.97 (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) , 7.14-7.06 (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] ⁺.

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

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

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

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

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

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

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

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

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

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

The mixture of the product of step D of example 65 (200 mg, 0.52 mmol) in THF/H ₂O (3: 1. 8 mL) was alkalified to pH 7-8 with NaHCO ₃. Then the mixture was cooled to 0 ℃, and the solution of acryloyl chloride (70 mg, 0.77 mmol) in THF (2 mL) was added slowly. The reaction mixture was continued to stir for 1 h at 0 ℃. Dichloromethane and water were added. The layers were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed three times with brine solution (3 × 50 mL) . The organic phase was dried over anhydrous Na ₂SO ₄, 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 %) . ¹H NMR (400 MHz, DMSO-d6) δ 12.03 (s, 1H) , 8.35 (s, 1H) , 7.86 (d, J = 8.4 Hz, 2H) , 7.70 (s, 1H) , 7.45 (t, J = 7.8 Hz, 2H) , 7.21 (t, J = 7.4 Hz, 1H) , 7.09 (t, J = 7.3 Hz, 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] ⁺.

Table I The structure of representative compounds

Example 66 BTK (EGFR, BMX, or ITK, etc) Kinase Assay

The assay was conducted in house.

In house procedure:

Kinase inhibitory activities of compounds were evaluated using the enzyme-linked immunosorbent assay (ELISA) . The kinase enzyme of BTK (EGFR, BMX, or ITK, etc) was purchased from Carna Bioscience (Kobe, Japan) . A total of 10 ng/mL antiphosphotyrosine (PY713) antibody (abcam, Cambridge Science Park, UK) was precoated in 96-well ELISA plates. Active kinases were incubated with indicated drugs in 1 × reaction buffer (50 mmol/L HEPES pH 7.4, 20 mmol/L MgCl ₂, 0.1 mmol/L MnCl ₂, 1 mmol/L DTT) containing 20 μmol/L substrate (NH ₂-ETVYSEVRK-biotin) at 25 ℃ for 1 h. Then, a total of 3 μmol/L ATP was added and the reaction was continued for 2 hs. The products of reaction were transfered into 96-well ELISA plates containing antibody and incubated at 25 ℃ for 30 min. After incubation, the wells were washed with PBS and then incubated with horseradish peroxidase (HRP) -conjugated streptavidin. The wells were visualized using 3, 3', 5, 5'-tetramethylbenzidine (TMB) , and the absorbance was read with a multimode plate reader (PerkinElmer, USA) at 450 nm.

Table II, BTK inhibition of representative compounds

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

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

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

Example 67 Cell Proliferation Assay

Reaction Procedure:

Spin down suspension cells and resuspend in growth medium, then count with cell counter. Dilute cell suspensions in growth medium to desired density. The cell suspensions of 95 μl were taken to 96-well plate. Add 5μl 20X compounds into the 96-well plate. Final DMSO concentration in each well was 0.1%. Incubate at 37 ℃, 5%CO ₂ for 72 h. Equilibrate the assay plate to room temperature before measurement. Add 50 μl of

Reagent into each well. Mix contents for 2 minutes on an orbital shaker to induce cell lysis. Incubate at room temperature for 10 minutes to stabilize luminescent signal. Record luminescence using EnVision Multilabel Reader (PerkinElmer) .

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

Table Ⅵ Cell proliferation of representative compounds

Claims

A compound represented by Formula I, or the pharmaceutically acceptable salt, active metabolite, tautomer, stereoisomer, or prodrug thereof;

wherein

R ₁ is selected from H, C _1-6 alkyl and C _1-6 cycloalkyl;

R ₂ and R ₃ are independently selected from hydrogen; halogen; cyano; CF ₃, aryl, aryl substituted independently with halogen, cyano, C _1-6 alkoxy, -NR ₆Y, C _1-6 alkyl substituted with F; heteroaryl optionally substituted independently with halogen, cyano, C _1-6 alkoxy, -NR ₆Y, C _1- ₆ alkyl substituted with F; nitrogen containing C _4-7 heterocycloalkyl where the N atom is substituted with Y; C _1-6 alkyl; C _1-6 alkyl substituted with C _1-6 alkoxy, NR ₆Y; C _3-6 cycloalkyl, C _3-6 cycloalkyl substituted with NR ₆Y; Or R ₂ and R ₃ can together form a 5-8 member saturated carbon cycle which may be substituted with NR ₆Y or in the ring contain a nitrogen atom that is substituted with Y; Or R ₂ and R ₃ together form a nitrogen containing C _4-7 heterocycloalkyl where the N atom is substituted with Y;

R ₆ is selected from hydrogen, C _1-6 alkyl, C _1-6 alkyl substituted with groups selected from F, hydroxyl, C _1-6 alkoxy, C _3-6 cycloalkyl, C _3-6 cycloalkyl substituted with F;

Y is selected from the groups consisting of -CN, -C (=O) P, -S (=O) P and -S (=O) ₂P; where

P is selected from
and

R ₇ is selected from hydrogen, halogen, cyano, C _1-6 alkyl, C _1-6 alkyl substituted with groups selected from F, hydroxyl and C _1-6 alkoxy; C _3-6 cycloalkyl, C _3-6 cycloalkyl substituted with F;

R ₈ and R ₉ are independently selected from hydrogen; halogen; cyano; CF ₃; aryl; aryl independently substituted with hydrogen, halogen, cyano, C _1-6 alkoxy and CF ₃; heteroaryl; heteroaryl independently substituted with hydrogen, halogen, cyano, C _1-6 alkoxy and CF ₃; C _1-6 alkyl; C _1-6 alkyl substituted with C _1-6 alkoxy, NR ₁₀R ₁₁, halogen, hydroxyl, C ₆ or C ₁₀ aryl, and heteroaryl; C _3-6 cycloalkyl; C _3-6 cycloalkyl substituted with halogen; C _2-6 alkenyl; C _2-6 alkenyl substituted with C _1-6 alkoxy, NR ₁₀R ₁₁, halogen, hydroxyl, C ₆ or C ₁₀ aryl and heteroaryl;

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 substitute form a 4-6 membered heterocycloalkyl;

Rx is selected from the group consisting of H, cyano, C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, phenyl, - (CH ₂) _mNR ₁₀R ₁₁, C _1-6 alkyl substituted with halogen, hydroxy;

m is an integer selected from 1, 2, 3;

R ₄ is selected from aryl, C _1-6 alkyl, (C _1-4) fluoroalkyls, C _3-6 cycloalkyls; aryl substituted with halogen, cyano, C _1-6 alkoxy, (C _1-4) fluoroalkyls;

R ₅ can substitute any suitable position of the phenyl ring it attaches and is selected from groups of hydrogen, halogen, (C _1-4) fluoroalkyls, cyano, C _1-6 alkyl, C _3-6 cycloalkyls, C _1-6 alkoxy.
The compound of claim 1, wherein in Formula I, R ₁ is H or methyl; and R ₂, R ₃, R ₄, and R ₅ are defined as claim 1.
The compound of claim 2, wherein in Formula I, R ₁ is H or methyl; R ₃ is hydrogen, and R ₂, R ₄, and R ₅ are defined as in claim 1.
The compound of any of the preceding claims, wherein in Formula I,

R ₂ is selected from the group consisting of,

Wherein R ₁₂ is independently selected from H, F, C _1-6 alkyl, C _1-6 alkyl substituted with halogen, C _1-6 alkoxy, and NR ₆R ₇; and R ₁₂ may substitute more than one position; or where in the nitrogen containing heterocycloalkyl, R ₁₂ may form a double bond in the ring, or form a 3-6 membered ring fused or spiraled with the original ring;

R ₆ and R ₇ are independently selected from hydrogen, C _1-6 alkyl, C _1-6 alkyl substituted with groups selected from F, hydroxyl and C _1-6 alkoxy; C _3-6 cycloalkyl, C _3-6 cycloalkyl substituted with F.
The compound of claim 4, wherein in Formula I, R ₂ is selected from the group consisting of

where R ₁₂ and Y are defined as claim 4.
The compound of any of the preceding claims, wherein in Formula I, R ₁₂ is hydrogen, and R ₆ is hydrogen.
The compound of any of the preceding claims, wherein in Formula I, in R ₂,

Y is selected from the groups consisting of -CN, -C (=O) P, -S (=O) P and -S (=O) ₂P; where

P is selected from
wherein

R ₇ is selected from hydrogen, CN, C _1-6 alkyl, C _1-6 alkyl substituted with groups selected from halogen, hydroxyl and C _1-6 alkoxy;

R ₈ is selected from hydrogen, C _1-6 alkyl, C _1-6 alkyl substituted with groups selected from halogen, hydroxyl and C _1-6 alkoxy;

R ₉ is selected from hydrogen; C _1-6 alkyl; C _1-6 alkyl substituted with C _1-6 alkoxy, NR ₁₀R ₁₁, halogen, hydroxyl;

Rx is selected from the group consisting of H, C _1-6 alkyl.
The compound of claim 7, wherein

R ₇ is selected from hydrogen, methyl;

R ₈ is selected from hydrogen, methyl;

R ₉ is selected from hydrogen; methyl; ethyl; -CF ₃; -CH ₂NR ₁₀R ₁₁, R ₁₀ and R ₁₁ are both methyl;

Rx is selected from the group consisting of H and -CH ₃.
The compound of any of the preceding claims, wherein in Formula I,

R ₄ is

wherein,

R ₁₃, R ₁₄, R ₁₅, R ₁₆ and R ₁₇ are independently selected from the group consisting of H; halogen; CN; C _1-6 alkyl; C _1-6 alkoxy, C _1-6 alkyl substituted with halogen.
The compound of claim 9, wherein R ₁₃, R ₁₄, R ₁₅, R ₁₆ and R ₁₇ are independently selected from the group consisting of H; halogen and C _1-6 alkoxy.
The compound of claim 10, wherein R ₁₃, R ₁₄, R ₁₅, R ₁₆ and R ₁₇ are independently selected from the group consisting of H; F; Cl; Br and -OCH ₃.
A compound selected from the following, or a pharmaceutically acceptable salt, active metabolite, tautomer, stereoisomer, or prodrug 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-methacryloylpiperidin-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-ynoyl) 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-ynoyl) 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-ynoyl) 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-ynoyl) 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-ynoyl) 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-ynoyl) 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-ynoyl) 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-ynoyl) 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-ynoyl) 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-ynoyl) 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-ynoyl) 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-ynoyl) 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-ynoyl) 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-ynoyl) 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-ynoyl) 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-imidazo [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.
A pharmaceutical composition comprising a compound, a pharmaceutically acceptable salt, active metabolite, tautomer, stereoisomer, or prodrug thereof as claimed in any of the preceding claims, and a pharmaceutically acceptable carrier.
Use of a compound as claimed in any of claims 1 to 12 in the preparation of a medicament for inhibiting the activity of BTK.
Use of a compound as claimed in any of claims 1 to 12 in the preparation of a medicament for the treatment of a disease selected from the group consisting of an autoimmune disease, inflammatory disease, cancer and allergy.
The use of claim 15, wherein the disease is selected from the group consisting of diffused large B cell lymphoma, follicular lymphoma, chronic lymphocytic leukemia, mantel cell lymphoma, splenic marginal zone lymphoma, large B cell lymphoma, lupus erythematosus, rheumatoid arthritis, Crohn’s disease, psoriasis, multiple sclerosis and asthma.