Substituted imidazolecarboxamide as bruton's tyrosine kinase inhibitors

Abstract

Abstract: Provided is a series of substituted imidazolecarboxamide compounds of formula I as BTK (Burton's Tyrosine Kinase) inhibitors, non-receptor tyrosine kinases of the Tee family implicated in the maturation of B cells and the activation of mast cells: [Image disponible dans le document PDF, Image available in the PDF document] Also provided are pharmaceutical compounds containing such substituted imidazolecarboxamide compounds of formula I as well as uses thereof for the treatment of autoimmune disease, inflammatory disease, cancer and allergies.

Description

Substituted imidazolecarboxamide as Bruton's Tyrosine Kinase inhibitors TECHNICAL FIELD The application relates to a series of substituted imidazolecarboxamide compounds of formula I as 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. [Image disponible dans le document PDF, Image available in the PDF document] BACKGROUND ART BTK (Bruton's Tyrosine Kinase) is a non-receptor tyrosine kinase of the Tec family (Bradshaw et al, Cell Signal, 2010, 22, 1175-1184.). It plays an important role in the maturation of B cellsand the activation of mast cells. 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 Srchomology 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, lupusand 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. BTK inhibitors such as Ibrutinib (Structure A. Panet al, Chem Med Chem., 2007, 2, 58-61; Lee A. Honigberg et al, PNAS, 2010, 107, 13075-13080.), Acalabrutinib (Structure B, Barf et al, J Pharmacol Exp Ther., 2017, 363, 240-252; Robert B. Kargbo, ACS Med Chem Lett., 2017, 8, 911- 913.) have demonstrated their effectiveness in the treatment of various cancers. [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] А В Several other candidates (Bradshawet al. Nat Chem Biol., 2015, 11, 525-531; US9447106 B2; CN103848810 A1) in different stages of clinical trials are being tested for various diseases CA 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 The present application disloses compounds as protein kinase BTK inhibitors which may be used for the treatment of autoimmune disease, inflammatory disease, cancer and potentially allergies. In one aspect, the present application provides a compound represented by Formula I, or a pharmaceutically acceptable salt, active metabolite, tautomer, stereoisomer, or prodrug thereof. [Image disponible dans le document PDF, Image available in the PDF document] wherein R1 is selected from aryl, C1-6 alkyl, C1-6 alkyl substituted with halogen, C1-6 alkoxy, C3-6 cycloalkyl; aryl independently substituted with halogen, cyano, C1-6 alkoxy, (C1-4) fluoroalkyl; n is an integer that is selected from 0, 1, 2, 3; R2, R3, R4, R5 are independently selected from the groups consisting of hydrogen, halogen, C1-4 fluoroalkyls, cyano, C1-6 alkyl, C3-6 cycloalkyls and C1-6 alkoxy; X is selected from a 4-8 membered nitrogen-containing heterocyclyl where the said nitrogen atom is substituted with Y; an aryl that is substituted with -NR6Y, or an aryl that may be independently substituted with halogen, cyano, C1-6 alkoxy, (C1-4) fluoroalkyl along with -NR6Y; an heteroaryl that is substituted with -NR6Y, or a heteroaryl that may be independently substituted with halogen, cyano, C1-6 alkoxy, (C1-4) fluoroalkyls along with -NR6Y; a group of -(CH2)mNR6Y and m is an integer selected from any of from 1 to 3; a nitrogen-containing spiral heterocyclyl where the said nitrogen is substituted with Y; R6 is selected from the group consisting of hydrogen, C1-6 alkyl and C1-6 alkyl substituted with halogen and C1-6 alkoxys; Y is selected from the group consisting of -CN, -C(=O)P, -S(=O)P and -S(=O)2P; [Image disponible dans le document PDF, Image available in the PDF document] P is selected from and Rx is selected from the group consisting of H, cyano, halogen, C1-6 alkyl, C1-6 alkoxy, C3-6 cycloalkyl, phenyl, -(CH2)mNR10R11, C1-6 alkyl substituted with halogen, hydroxy; R7 is selected from hydrogen, halogen, cyano, <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkyl, <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkyl substituted with groups selected from F, hydroxyl and C1-6 alkoxy; C3-6 cycloalkyl, C3-6 cycloalkyl substituted with F; R8 and R9 are independently selected from hydrogen; halogen; cyano; CF3; aryl; aryl substituted with halogen, cyano, C1-6 alkyl, C1-6 alkoxy; heteroaryl; heteroaryl substituted with halogen, cyano, C1-6 alkyl, C1-6 alkoxy; C1-6 alkyl; C1-6 alkyl substituted with C1-6 alkoxy, -NR10R11, halogen, hydroxyl, C6 or C10 aryl, and heteroaryl; C3-6 cycloalkyl; C3-6 cycloalkyl substituted with halogen; C2-6 alkenyl; C2-6 alkenyl substituted with C1-6 alkoxy, -NR10R11, halogen, hydroxyl, aryl and heteroaryl; R10 and R11 are each independently selected from hydrogen, C1-6 alkyl, C3-6 cycloalkyl; or together with the nitrogen they substitute form a 4-6 membered heterocycloalkyl; m is an integer selected from 1, 2 or 3; and Z is selected from NH or CH2. In some embodiments, the above mentioned aryl may be C6 or C10 aryl; the above mentioned heteroaryl may be heteroaryl having one cycle with 5 to 10, 5 to 8, or 5 to 6 ring atoms at least one of which is a heteroatom selected from O, N, and S (excluding the circumstance of two O atoms and / or S atoms are adjacent); the above said spiral heterocyclyl may have two cycles at least one of which is 4-8 membered heterocyclyl containing N atom. In one embodiment of formula I, X is selected from the group consisting of [Image disponible dans le document PDF, Image available in the PDF document] wherein R12 is selected from H, F, C1-6 alkyl, C1-6 alkyl substituted with halogen, C1-6-alkoxy; and R12 may substitute more than one position; or in the above heterocyclyls, R12 may form a double bond in the ring it attaches to, or form a 3-6 membered ring fused or spiraled with the ring it attaches to. In another embodiment of formula I, R6 is hydrogen; R12 is hydrogen; R2, R3, R4, and R5 are H, and n is selected from 0, 1. In another embodiment of formula I, X is selected from [Image disponible dans le document PDF, Image available in the PDF document] wherein Y is -C(=O)P or CN; R9, R8 R9, RX, and Rx is selected from the group consisting of H, C1-6 alkyl, C1-6 alkyl substituted with halogen, and C3-6 cycloalkyl; R7 is selected from hydrogen, halogen, cyano, C1-6 alkyl, C1-6 alkyl substituted with halogen; and R8 and R9 are independently selected from the group consisting of hydrogen, halogen, C1-6 alkyl, C1-6 alkyl substituted with halogen or -NR10R11; and C3-6 cycloalkyl; <semantics>R10<annotation encoding="application / x-tex">R_{10}< / annotation>< / semantics> and <semantics>R11<annotation encoding="application / x-tex">R_{11}< / annotation>< / semantics> are independently selected from <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkyl. In another embodiment of formula I, X is selected from [Image disponible dans le document PDF, Image available in the PDF document] Wherein Y is <semantics>−C(=O)P<annotation encoding="application / x-tex">-C(=O)P< / annotation>< / semantics> or CN; CA [Image disponible dans le document PDF, Image available in the PDF document] P is selected from , and Rx is selected H, CH3, CF3 or cyclopropyl; R7 is selected from hydrogen, methyl, halogen or cyano; R8 and R9 are independently selected from hydrogen, CF3, CH3, C2H5, isobutyl, cyclopropyl or -(CH2)mN(CH3)2 and m is an integer selected from any of from 1 to 3. In another embodiment of formula I, X is selected from [Image disponible dans le document PDF, Image available in the PDF document] Y is <semantics>−C(=O)P<annotation encoding="application / x-tex">-C(=O)P< / annotation>< / semantics>; [Image disponible dans le document PDF, Image available in the PDF document] P is selected from , and Rx is selected from H or CH3; R7 is selected from hydrogen, F, or cyano; R8 and R9 are independently selected from hydrogen or CF3. In another embodiment of formula I, R1 is selected from the group consisting of C1-6 alkyl, C1-6 alkoxy, C3-6 cycloalkyl, and [Image disponible dans le document PDF, Image available in the PDF document] wherein R13, R14, R15, R16, R17 are independently selected from the group consisting of H; cyano; C1-6 alkyl; C1-6 alkyl substituted with halogen, particularly C1-6 alkyl substituted with F; C1-6 alkoxy; halogen; C6 or C10 aryl; C6 or C10 aryl independently substituted with halogen, C1-6 alkyl, C1-6 alkoxy, cyano, or trifluloromethyl; heteroaryl, particularly a five-membered or six-membered heteroaryl, or a bicycle heteroaryl where the five-membered or six-membered ring fused with each other. [Image disponible dans le document PDF, Image available in the PDF document] In another embodiment of formula I, R1 is , wherein, <semantics>R13<annotation encoding="application / x-tex">R_{13}< / annotation>< / semantics>, <semantics>R14<annotation encoding="application / x-tex">R_{14}< / annotation>< / semantics>, <semantics>R15<annotation encoding="application / x-tex">R_{15}< / annotation>< / semantics>, <semantics>R16<annotation encoding="application / x-tex">R_{16}< / annotation>< / semantics> and <semantics>R17<annotation encoding="application / x-tex">R_{17}< / annotation>< / semantics> are independently selected from H, halogen, cyano, C1-6 alkoxy, C1-6 alkyl substituted by halogen. [Image disponible dans le document PDF, Image available in the PDF document] In another embodiment of formula I, R1 is , wherein, R15 is selected from H, halogen, C1-6 alkoxy, cyano, C1-6 alkyl substituted by halogen, and R13, R14, R16 and R17 are H. In another embodiment of formula I, R15 is selected from the group consisting of H, CH3, CH2CH3, OCH3, F, Cl, Br, CN and CF3; and R13, R14, R16 and R17 are H. For example, in formula I, R13, R14, R15, R16 and R17 are H. In another embodiment of formula I, R15 is selected from the group consisting of H, CH3, CH2CH3, OCH3, F, Cl, Br, CN and CF3; R2 or R3 is C1-6 alkoxy; and R13, R14, R16 and R17 are H. In another embodiment of formula I, X is selected from [Image disponible dans le document PDF, Image available in the PDF document] wherein Y is -C(=O)P, where ... P is selected from <semantics>R7<annotation encoding="application / x-tex">R_7< / annotation>< / semantics> <semantics>R9<annotation encoding="application / x-tex">R_9< / annotation>< / semantics>, or <semantics>R7<annotation encoding="application / x-tex">R_7< / annotation>< / semantics> <semantics>R8<annotation encoding="application / x-tex">R_8< / annotation>< / semantics>, and Rx is selected from the group consisting of H, CH3, CF3 and cyclopropyl, -(CH2)mNR10R11 wherein m is an integer selected from 1, 2, 3; n is 0; Z is CH2; R1 is: [Image disponible dans le document PDF, Image available in the PDF document] wherein R13, R14, R15, R16 and R17 are independently selected from H, OCH3, F, Cl, Br, CF3 and CN; R2 is H or methoxy, R3, R4, R5 are H; R7 is selected from hydrogen, cyano, and halogen; R8 and R9 are independently selected from hydrogen, CF3, CH3, cyclopropyl and C1-6 alkyl substituted with -NR10R11; and R10, R11 are independently selected from C1-6 alkyl. In another embodiment of formula I, X is selected from [Image disponible dans le document PDF, Image available in the PDF document] Wherein Y is <semantics>−C(=O)P<annotation encoding="application / x-tex">-C(=O)P< / annotation>< / semantics> where [Image disponible dans le document PDF, Image available in the PDF document] P is selected from n is 0; Z is CH2; R1 is phenyl; R2 is H or methoxy, R3, R4, R5 are H; R7 is selected from hydrogen, cyano, and halogen; R8 and R9 are independently selected from hydrogen, CF3, CH3, cyclopropyl. In another embodiment of formula I, X is selected from [Image disponible dans le document PDF, Image available in the PDF document] Wherein Y is <semantics>−C(=O)P<annotation encoding="application / x-tex">-C(=O)P< / annotation>< / semantics> where [Image disponible dans le document PDF, Image available in the PDF document] P is selected from n is 1 Z is NH; <semantics>𝑹1<annotation encoding="application / x-tex">\mathbf{R}_1< / annotation>< / semantics> is phenyl; R2 is H or methoxy, R3, R4, R5 are H; R7 is selected from hydrogen, cyano, and halogen; R8 and R9 are independently selected from hydrogen, CF3, CH3, cyclopropyl. In some embodiments, some specific compounds within formula I are selected from the followings: 8-(1-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2- b]pyridazine-3-carboxamide 8-(1-(but-2-ynoyl)piperidin-4-yl)-2-(4-phenoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2- b]pyridazine-3-carboxamide 8-(1-(3-methylbut-2-enoyl)piperidin-4-yl)-2-(4-phenoxyphenyl)-5,6,7,8- tetrahydroimidazo[1,2-b]pyridazine-3-carboxamide 8-(1-methacryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2- b]pyridazine-3-carboxamide (E)-8-(1-(but-2-enoyl)piperidin-4-yl)-2-(4-phenoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2- b]pyridazine-3-carboxamide (E)-8-(1-(pent-2-enoyl)piperidin-4-yl)-2-(4-phenoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2- b]pyridazine-3-carboxamide (E)-8-(1-(2-cyano-4-methylpent-2-enoyl)piperidin-4-yl)-2-(4-phenoxyphenyl)-5,6,7,8- tetrahydroimidazo[1,2-b]pyridazine-3-carboxamide 2-(4-phenoxyphenyl)-8-(1-propioloylpiperidin-4-yl)-5,6,7,8-tetrahydroimidazo[1,2- b]pyridazine-3-carboxamide (E)-8-(1-(2-cyano-3-cyclopropylacryloyl)piperidin-4-yl)-2-(4-phenoxyphenyl)-5,6,7,8- tetrahydroimidazo[1,2-b]pyridazine-3-carboxamide 8-(1-acryloylpiperidin-4-yl)-2-(4-(4-fluorophenoxy)phenyl)-5,6,7,8-tetrahydroimidazo[1,2- b]pyridazine-3-carboxamide 8-(1-(but-2-ynoyl)piperidin-4-yl)-2-(4-(4-fluorophenoxy)phenyl)-5,6,7,8- tetrahydroimidazo[1,2-b]pyridazine-3-carboxamide (E)-2-(4-(4-fluorophenoxy)phenyl)-8-(1-(4,4,4-trifluorobut-2-enoyl)piperidin-4-yl)-5,6,7,8- tetrahydroimidazo[1,2-b]pyridazine-3-carboxamide 8-(1-acryloylpiperidin-4-yl)-2-(4-(4-methoxyphenoxy)phenyl)-5,6,7,8- tetrahydroimidazo[1,2-b]pyridazine-3-carboxamide 8-(1-(but-2-ynoyl)piperidin-4-yl)-2-(4-(4-methoxyphenoxy)phenyl)-5,6,7,8- tetrahydroimidazo[1,2-b]pyridazine-3-carboxamide <semantics>(E)−2−(4−(4−methoxyphenoxy)phenyl)−8−(1−(4,4,4−trifluorobut−2−enoyl)piperidin−4−yl)−<annotation encoding="application / x-tex">(E)-2-(4-(4-methoxyphenoxy)phenyl)-8-(1-(4,4,4-trifluorobut-2-enoyl)piperidin-4-yl)-< / annotation>< / semantics> 5,6,7,8-tetrahydroimidazo[1,2-b]pyridazine-3-carboxamide 8-(1-(2-fluoroacryloyl)piperidin-4-yl)-2-(4-phenoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2- b]pyridazine-3-carboxamide (E)-2-(4-phenoxyphenyl)-8-(1-(4,4,4-trifluorobut-2-enoyl)piperidin-4-yl)-5,6,7,8- tetrahydroimidazo[1,2-b]pyridazine-3-carboxamide 2-(4-phenoxyphenyl)-8-(1-propioloylpiperidin-4-yl)-5,6,7,8-tetrahydroimidazo|1,2- b]pyridazine-3-carboxamide 8-(2-acrylamidophenyl)-2-(4-phenoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2-b]pyridazine- 3-carboxamide 8-(1-acryloylazetidin-3-yl)-2-(4-phenoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2- b]pyridazine-3-carboxamide 8-(1-(but-2-ynoyl)azetidin-3-yl)-2-(4-phenoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2- b]pyridazine-3-carboxamide (E)-2-(4-phenoxyphenyl)-8-(1-(4,4,4-trifluorobut-2-enoyl)azetidin-3-yl)-5,6,7,8- tetrahydroimidazo[1,2-b]pyridazine-3-carboxamide 8-(4-acrylamidophenyl)-2-(4-phenoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2-b]pyridazine- 3-carboxamide 8-(1-cyanopiperidin-4-yl)-2-(4-phenoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2- b]pyridazine-3-carboxamide (E)-8-(1-(4-(dimethylamino)but-2-enoyl)piperidin-4-yl)-2-(4-phenoxyphenyl)-5,6,7,8- tetrahydroimidazo[1,2-b]pyridazine-3-carboxamide 7-(1-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole- 3-carboxamide 8-(1-acryloylpiperidin-4-yl)-2-(4-methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2- b]pyridazine-3-carboxamide 7-(1-acryloylpiperidin-4-yl)-2-(3-methoxy-4-phenoxyphenyl)-6,7-dihydro-5H-pyrrolo[1,2- a]imidazole-3-carboxamide 8-(1-acryloylpiperidin-4-yl)-2-(3-methoxy-4-phenoxyphenyl)-5,6,7,8- tetrahydroimidazo[1,2-b]pyridazine-3-carboxamide. In a further aspect, the application provides a pharmaceutical composition which includes an effective amount of a compound of the application, 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 application 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 application or a pharmaceutically acceptable salt, active metabolite, tautomer, stereoisomer, or prodrug thereof, or a pharmaceutical composition of this application. In another aspect, the application 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 application or a pharmaceutically acceptable salt, active metabolite, tautomer, stereoisomer, or prodrug thereof, or a pharmaceutical composition of this application. In a further aspect, the application provides a use of a compound of the application, 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 application provides a use of a compound of the application, 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 application provides a use of a compound of the application, 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 application provides a compound of the application, or a pharmaceutically acceptable salt, active metabolite, tautomer, stereoisomer, or prodrug thereof, for inhibiting BTK. In another aspect, the application provides a compound of the application, 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 application provides a compound of the application, 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, for example BTK mediated 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. Certain Chemical Terminology The present application 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., Annu Rep Med Chem., 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. 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 4TH ED". Vols. A (2000) and B (2001), Plenum Press, New York. Unless otherwise indicated, conventional methods of mass spectroscopy, NMR, HPLC, IR and UV / Vis 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, CH2O is equivalent to OCH2. Unless otherwise noted, the use of general chemical terms, such as though not limited to "alkyl", "aryl" are 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 stereocenters 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 application 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 "<semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>" 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, "C1-6 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, iso-butyl, 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 nonfused 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 six-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 to heteroalicyclyl groups having one cycle. Herein, whenever the number of carbon atoms in a heterocycle is indicated (e.g., C3-6 heterocycle), at least one non-carbon atom (the heteroatom) must be present in the ring. Designations such as "C3-6 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" includes 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 nonfused 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 nonlimiting example of a single ring aryl group includes phenyl; a fused ring aryl group includes naphthyl, phenanthrenyl, anthracenyl, azulenyl; and a nonfused biaryl group includes biphenyl. The term "heteroaryl" as used herein, alone or in combination, refers to optionally substituted aromatic mono-radicals containing from about five to about twenty, for example, five to twelve, five to ten, five or six skeletal ring atoms, where one or more, for example one to four, one to three, or one to two of the ring atoms is a heteroatom independently selected from among oxygen, nitrogen, sulfur, phosphorous, silicon, selenium and tin but not limited to these atoms and with the proviso that the ring of said group does not contain two adjacent O or S atoms. Heteroaryl includes monocyclic heteroaryl (having one ring), bicyclic heteroaryl (having two rings), or polycyclic heteroaryl (having more than two rings). In embodiments in which two or more heteroatoms are present in the ring, the two or more heteroatoms can be the same as each another, or some or all of the two or more heteroatoms can each be different from the others. Ividual rings may be alicyclic, heterocyclic, aromatic, heteroaromatic or any combination thereof. A single ring heteroaryl (monocyclic heteroaryl) includes but not limited to those having five to about twelve, or five to about ten, or five to seven, or six ring atoms. A non-limiting example of a single ring heteroaryl group includes pyridyl; fused ring heteroaryl groups include benzimidazolyl, quinolinyl, acridinyl, and a non-fused bi-heteroaryl group includes bipyridinyl. Further examples of heteroaryls include, without limitation, furanyl, thienyl, oxazolyl, acridinyl, phenazinyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzothiophenyl, benzoxadiazolyl, benzotriazolyl, imidazolyl, indolyl, isoxazolyl, isoquinolinyl, indolizinyl, isothiazolyl, isoindolyloxadiazolyl, indazolyl, pyridyl, pyridazyl, pyrimidyl, pyrazinyl, pyrrolyl, pyrazolyl, purinyl, phthalazinyl, pteridinyl, quinolinyl, quinazolinyl, quinoxalinyl, triazolyl, tetrazolyl, thiazolyl, triazinyl, thiadiazolyl and the like, and their oxides, such as for example pyridyl-N-oxide and the like. The term "alkyl" as used herein, alone or in combination, refers to an optionally substituted straightchain, or optionally substituted branchedchain saturated hydrocarbon monoradical having, for example, from one to about eighteen, or one to about ten carbon atoms, or one to six 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-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-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, tert-butoxy and the like. The term "alkenyl" as used herein, alone or in combination, refers to an optionally substituted straight-chain, or optionally substituted branchedchain 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, or two to about four carbon atoms. The group may be in either the cis or trans conformation about the double bond(s), and should be understood to include both isomers. Examples include, but are not limited to ethenyl (-CH=CH2), 1-propenyl (-CH2CH=CH2), isopropenyl [-C(CH3)=CH2], 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 application, 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 ed.; 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 application, 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 application 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 application, which, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this application or a pharmaceutically active metabolite or residue thereof. Particularly favored derivatives or prodrugs are those that increase the bioavailability of the compounds of this application 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. IC50 means the concentration of a particular compound that inhibits 50% of a specific measured activity. Embodiment The novel features of the application are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present application will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the application are utilized. Some embodiments of the present application have been shown and described herein by way of example only. It should be understood that various alternatives to the embodiments of the application described herein may be employed in practicing the application. Those ordinary skilled in the art will appreciate that numerous variations, changes, and substitutions are possible without departing from the application. It is intended that the following claims define the scope of aspects of the application and that methods and structures within the scope of these claims and their equivalents be covered thereby. Description of Scheme I. [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] С In Scheme I, m or n is a number selected from 0 or 1. Examples: Example 1: 8-(1-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)-5,6,7,8- tetrahydroimidazo[1,2-b]pyridazine-3-carboxamide [Image disponible dans le document PDF, Image available in the PDF document] Step A: Preparation of methyl 3-oxo-3-(4-phenoxyphenyl)propanoate [Image disponible dans le document PDF, Image available in the PDF document] To a stirred suspension of NaH (60% dispersion in mineral oil; 565.3 g, 14.13 mol) in N, N- dimethylformamide (DMF) (3 L) at 0 °C was added dropwise the solution of 1-(4- phenoxyphenyl)ethanone (2.0 kg, 9.42 mol) in N, N-dimethylformamide (2 L). After 30 minutes, dimethylcarbonate (4.2 kg, 47.11 mol) was added next. The mixture was allowed to warm to room temperature over a 2 hs period, then poured into 1:1 water / saturated sodium bicarbonate. I mol / L cooled glacial acetic acid was added dropwise until pH 6-7, then extracted with ethyl acetate (3×2000 mL). The combined organic layer was washed with saturated brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by chromatography with petroleum ether and ethyl acetate (20:1) to afford product as a yellow oil (2.3 kg, 90%). 1H NMR (600 MHz, DMSO-<semantics>d6<annotation encoding="application / x-tex">d6< / annotation>< / semantics>) <semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics> 8.00-7.96 (m, 2H), 7.47 (t, <semantics>J=8.0<annotation encoding="application / x-tex">J = 8.0< / annotation>< / semantics> Hz, 2H), 7.26 (t, <semantics>J=7.4<annotation encoding="application / x-tex">J = 7.4< / annotation>< / semantics> Hz, 1H), 7.16-7.12 (m, 2H), 7.05 (d, <semantics>J=8.8<annotation encoding="application / x-tex">J = 8.8< / annotation>< / semantics> Hz, 2H), 4.16 (s, 2H), 3.65 (s, 3H). MS (ESI, <semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>): 271.1 [M+H]+. Step B: Preparation of methyl 2-bromo-3-oxo-3-(4-phenoxyphenyl)propanoate [Image disponible dans le document PDF, Image available in the PDF document] To a solution of the product of Step A (1.0 kg, 3.70 mol) in CHCl3 (5 L) was added N- bromosuccinimide (NBS) (231.5 g, 4.07 mol) and azobisisobutyronitrile (AIBN) (303.7 g, 1.85 mol). The reaction mixture was refluxing for 6 hs. Then the CHCl3 was evaporated. The residue was diluted with 1500 mL ethyl acetate. The mixture was washed with aqueous 5% HCl (2×1000 mL) and 500 mL water, then dried over anhydrous sodium sulfate. Evaporation of the solvent gave the crude product as oil, the crude residue was flash chromatographed with ethyl acetate and petroleum ether (1:10) to get desired product as yellow oil (1.1 kg, 85%). 1H NMR (400 MHz, DMSO-d6) δ 8.10-8.03 (m, 2H), 7.53-7.46 (m, 2H), 7.33-7.26 (m, 1H), 7.20-7.15 (m, 2H), 7.11- 7.06 (m, 2H), 6.63 (s, 1H), 3.75 (s, 3H). MS (ESI, <semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>): 349.9 [M+H]+. Step C: Preparation of diethyl (2-oxotetrahydrofuran-3-yl)phosphonate [Image disponible dans le document PDF, Image available in the PDF document] A mixture of triethylphosphite (3.3 kg, 20.01 mol) and α-bromo-γ-butyrolactone (3.0 kg, 18.21 mol) was heated to reflux. After 4 h the mixture was allowed to cool to room temperature, then rotary evaporated to remove ethyl bromide. The resulting mixture was then purified by flash chromatography on silica gel with ethyl acetate and dichloromethane (1:1) to get product as colorless oil (3.5 kg, 86%). 1H NMR (400 MHz, CDCl3) <semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics> 4.45-4.37 (m, 1H), 4.35-4.27 (m, 1H), <semantics>4.25−4.11<annotation encoding="application / x-tex">4.25-4.11< / annotation>< / semantics> (m, 4H), <semantics>3.11−2.96<annotation encoding="application / x-tex">3.11-2.96< / annotation>< / semantics> (m, 1H), <semantics>2.62−2.49<annotation encoding="application / x-tex">2.62-2.49< / annotation>< / semantics> (m, 2H), <semantics>1.32<annotation encoding="application / x-tex">1.32< / annotation>< / semantics> (td, <semantics>J=7.1<annotation encoding="application / x-tex">J = 7.1< / annotation>< / semantics>, <semantics>3.4<annotation encoding="application / x-tex">3.4< / annotation>< / semantics> Hz, 6H). MS (ESI, <semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>): 233.1 [M+H]+. Step D: Preparation of tert-butyl 4-(2-oxodihydrofuran-3(2H)-ylidene)piperidine-1-carboxylate [Image disponible dans le document PDF, Image available in the PDF document] To a slurry of tetrahydrofuran-washed sodium hydride (60% dispersion in mineral oil; 602.2 g, 15.06 mol) was added diethyl (2-oxotetrahydrofuran-3-yl)phosphonate (3.3 kg, 15.06 mol) as a solution in dry tetrahydrofuran (3 L) dropwise over 70 min at 10°C. The mixture was stirred for 30 min before the addition of tert-butyl 4-oxopiperidine-1-carboxylate (2.0 kg, 10.01 mol) as a solution in tetrahydrofuran (2 L). The mixture was then stirred for 2 hs before the addition of dichloromethane (2 L) followed by water (5 L). The tetrahydrofuran was then removed under reduced pressure, the aqueous residue extracted with dichloromethane (3×1000 ml), then washed with water (2 × 1000 ml) and dried over anhydrous Na2SO4. Then residue was evaporated, and purified by column chromatography on silica gel with ethyl acetate and petroleum ether (1:2) to give product as a white solid (1.5 kg, 56%). 1H NMR (400 MHz, CDCl3) <semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics> 4.33 (t, <semantics>J=7.5<annotation encoding="application / x-tex">J = 7.5< / annotation>< / semantics> Hz, 2H), <semantics>3.54<annotation encoding="application / x-tex">3.54< / annotation>< / semantics> (t, <semantics>J=5.9<annotation encoding="application / x-tex">J = 5.9< / annotation>< / semantics> Hz, <semantics>2H<annotation encoding="application / x-tex">2H< / annotation>< / semantics>), <semantics>3.47<annotation encoding="application / x-tex">3.47< / annotation>< / semantics> (t, <semantics>J=5.9<annotation encoding="application / x-tex">J = 5.9< / annotation>< / semantics> Hz, <semantics>2H<annotation encoding="application / x-tex">2H< / annotation>< / semantics>), <semantics>3.12−3.05<annotation encoding="application / x-tex">3.12-3.05< / annotation>< / semantics> (m, <semantics>2H<annotation encoding="application / x-tex">2H< / annotation>< / semantics>), <semantics>2.91<annotation encoding="application / x-tex">2.91< / annotation>< / semantics> (t, <semantics>J=7.5<annotation encoding="application / x-tex">J = 7.5< / annotation>< / semantics> Hz, <semantics>2H<annotation encoding="application / x-tex">2H< / annotation>< / semantics>), <semantics>2.33<annotation encoding="application / x-tex">2.33< / annotation>< / semantics> <semantics>(t,J=5.8 Hz,2H),1.48 (s, 9H). MS (ESI, m / z):268.1 [M+H]+.<annotation encoding="application / x-tex">(t, J = 5.8 \text{ Hz}, 2\text{H}), 1.48 \text{ (s, 9H)}. \text{ MS (ESI, } m / z): 268.1 \text{ [M+H]}^+.< / annotation>< / semantics> Step E: Preparation of tert-butyl 4-(2-oxotetrahydrofuran-3-yl)piperidine-1-carboxylate [Image disponible dans le document PDF, Image available in the PDF document] To a solution of the product of step D (1.5 kg, 5.61 mol) in ethyl acetate (4 L) was added 10% Pd / C (300.0 g, 20%) at room temperature. The mixture was stirred for 3 hs under H2. The mixture was passed through Celite, and the solid was washed with ethyl acetate, and filtrate was concentrated under vacuum to get desired product (1.5 kg, 99%). 1H NMR (400 MHz, CDCl3) <semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics> 4.37-4.29 (m, 1H), 4.25-4.08 (m, 3H), 2.79-2.64 (m, 2H), 2.59-2.44 (m, 1H), 2.33-2.19 (m, 1H), 2.12-2.02 (m, 1H), 2.01-1.84 (m, 2H), 1.59-1.51 (m, 1H), 1.46 (s, 9H), 1.37-1.21 (m, 2H). MS <semantics>(ESI,m / z)<annotation encoding="application / x-tex">(ESI, m / z)< / annotation>< / semantics>: 270.1 <semantics>[M+H]+<annotation encoding="application / x-tex">[M+H]^+< / annotation>< / semantics>. Step F: Preparation of 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)-4-hydroxybutanoic acid [Image disponible dans le document PDF, Image available in the PDF document] The product of step E (1.0 kg, 3.71 mmol), H2O (2 L), and sodium hydroxide (297.1 g, 7.4 mol) were added in a round bottom flask. This reaction mixture was stirred at room temperature overnight. The clear reaction mixture was then extracted with ethyl acetate. The aqueous layer was isolated and acidified to pH 3-4 with concentrated HCl, then extracted with 3 ×1000 mL of dichloromethane. The organic phase was washed with saturated brine and then dried over anhydrous Na2SO4. The organic phase was concentrated in vacuo to get product as a white solid <semantics>(1.0 kg,93%)<annotation encoding="application / x-tex">(1.0 \text{ kg}, 93\%)< / annotation>< / semantics>. 1H NMR (600 MHz, DMSO-d6) <semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics> 12.12 (s, 1H), 4.45 (s, 1H), 3.94 (s, 2H), 3.40 (s, 1H), 3.30 (s, 1H), 2.65 (s, 2H), 2.20 (s, 1H), 1.69-1.56 (m, 4H), 1.55-1.48 (m, 1H), 1.38 (s, 9H), 1.14-0.99 (m, 2H). MS (ESI, <semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>): 288.2 [M+H]+. Step <semantics>𝑮<annotation encoding="application / x-tex">\mathbf{G}< / annotation>< / semantics> Preparation of 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)-4-((tert- butyldimethylsilyl)oxy)butanoic acid [Image disponible dans le document PDF, Image available in the PDF document] The tert-butyldimethylsilylchloride (597.9 g, 3.97 mol) was added to a mixture of the product of step F (950.1 g, 3.31 mmol) and Imidazole (450.0 g, 6.6mol) in N, N-dimethylformamide (3 L). The reaction mixture was stirred at 30°C for 5hs under Argon atmosphere, then poured into a separatory funnel containing 1000 mL of brine and extracted 4 times with 2 L of dichloromethane. The organic fractions were combined, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude product, the residue was purified via flash chromatography eluting with dichloromethane and methanol (20:1) to give the product as a clear colorless oil (4.4 g, 78%). 1H NMR (400 MHz, CDCl3) <semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics> 4.12 (t, <semantics>J<annotation encoding="application / x-tex">J< / annotation>< / semantics> = 8.0 Hz, 1H), 3.58-3.69 (m, 2H), 2.66 (t, <semantics>J=12.0<annotation encoding="application / x-tex">J = 12.0< / annotation>< / semantics> Hz, 2H), 2.39-2.41 (m, 1H), 1.81-1.90 (m, 1H), 1.68-1.77 (m, 3H), 1.61 (d, <semantics>J=16.0 Hz<annotation encoding="application / x-tex">J = 16.0 \text{ Hz}< / annotation>< / semantics>, 1H), 1.44 (s, 9H), 1.16-1.35 (m, 3H), 0.87 (s, 9H), 0.03 (s, 6H). MS (ESI, <semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>): 402.2 <semantics>[M+H]+<annotation encoding="application / x-tex">[M+H]^{+}< / annotation>< / semantics> Step H: Preparation of tert-butyl 4-(11,11,12,12-tetramethyl-3,6-dioxo-4-(4-phenoxybenzoyl)- 2,5,10-trioxa-11-silatridecan-7-yl)piperidine-1-carboxylate [Image disponible dans le document PDF, Image available in the PDF document] To a solution of the product of step G (138.0 g, 343.71 mmol) and N, N-diisopropylethylamine (DIEA) (55.5 g, 429.61 mmol) in acetonitrile (500 mL) was added the product of step B (100.0 g, 286.41 mmol). The mixture was stirred at 30°C for 3 hs. The solvent was removed by rotorary evaporation and the residue taken up in EA, washed with 0.1 N HCl, and brine. The organic fractions were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude product, the residue was purified via flash chromatography eluting with ethyl acetate and petroleum ether (1:10) to give the product as a clear colorless oil (150 g, 78%). 1H NMR (400 MHz, CDCl3) <semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics> 7.97 (dd, <semantics>J=12.0<annotation encoding="application / x-tex">J = 12.0< / annotation>< / semantics>, 4.0 Hz, 2H), 7.41 (t, <semantics>J=8.0<annotation encoding="application / x-tex">J = 8.0< / annotation>< / semantics> Hz, 2H), 7.23 (t, <semantics>J=8.0<annotation encoding="application / x-tex">J = 8.0< / annotation>< / semantics> Hz, 1H), 7.08 (d, <semantics>J=8.0<annotation encoding="application / x-tex">J = 8.0< / annotation>< / semantics> Hz, 2H), 7.00 (d, <semantics>J=8.0<annotation encoding="application / x-tex">J = 8.0< / annotation>< / semantics> Hz, 2H), 6.25 (s, 1H), 4.12 (s, 2H), 3.78 (s, 3H), 3.65 (dt, <semantics>J=12.0,8.0,4.0 Hz,1H,3.51−3.60 (m, 1H),2.56−2.65 (m, 3H),1.73−1.87 (m, 3H),1.60−1.69 (m, 1H)<annotation encoding="application / x-tex">J = 12.0, 8.0, 4.0 \text{ Hz}, 1\text{H}, 3.51-3.60 \text{ (m, 1H)}, 2.56-2.65 \text{ (m, 3H)}, 1.73-1.87 \text{ (m, 3H)}, 1.60-1.69 \text{ (m, 1H)}< / annotation>< / semantics> 2H), 1.44 (d, <semantics>J=1.3<annotation encoding="application / x-tex">J = 1.3< / annotation>< / semantics> Hz, 9H), 1.12-1.36 (m, 3H), 0.85 (d, <semantics>J=12.0<annotation encoding="application / x-tex">J = 12.0< / annotation>< / semantics> Hz, 9H), 0.02 (s, 3H), -0.02 (d, <semantics>J=8.0 Hz,3H<annotation encoding="application / x-tex">J = 8.0 \text{ Hz}, 3\text{H}< / annotation>< / semantics>). MS (ESI, <semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>): 670.3 [M+H]+. Step I: Preparation of tert-butyl 4-(3-((tert-butyldimethylsilyl)oxy)-1-(5-(methoxycarbonyl)-4- (4-phenoxyphenyl)-1H-imidazol-2-yl)propyl)piperidine-1-carboxylate [Image disponible dans le document PDF, Image available in the PDF document] To a slurry of ammonium acetate (132.6 g, 1.72 mol) in xylenes (400 mL) was added the product of step H (96.0 g, 143.31 mmol). The mixture was stirred at 140°C for 4 hs. The solution was cooled to room temperature and evaporated. The residue was dissolved in ethyl acetate and washed with saturated brine. The organic phase was dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography with ethyl acetate and petroleum ether (1:5) to give the product as a clear colorless oil (37 g, 39%). H NMR (400 MHz, CDCl3) <semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics> 9.71 (s, 1H), 7.93 (d, <semantics>J<annotation encoding="application / x-tex">J< / annotation>< / semantics> = 8.0 Hz, 2H), 7.34 (t, <semantics>J<annotation encoding="application / x-tex">J< / annotation>< / semantics> = 8.0 Hz, 2H), 7.11 (t, <semantics>J<annotation encoding="application / x-tex">J< / annotation>< / semantics> = 8.0 Hz, 1H), <semantics>7.02−7.06<annotation encoding="application / x-tex">7.02-7.06< / annotation>< / semantics> (m, 4H), <semantics>4.12<annotation encoding="application / x-tex">4.12< / annotation>< / semantics> (dd, <semantics>J=16.0<annotation encoding="application / x-tex">J = 16.0< / annotation>< / semantics>, <semantics>8.0<annotation encoding="application / x-tex">8.0< / annotation>< / semantics> Hz, 2H), <semantics>3.84<annotation encoding="application / x-tex">3.84< / annotation>< / semantics> (s, 3H), <semantics>3.65<annotation encoding="application / x-tex">3.65< / annotation>< / semantics> (dt, <semantics>J=8.0<annotation encoding="application / x-tex">J = 8.0< / annotation>< / semantics>, <semantics>4.0<annotation encoding="application / x-tex">4.0< / annotation>< / semantics> Hz, 1H), <semantics>3.44−3.49<annotation encoding="application / x-tex">3.44-3.49< / annotation>< / semantics> (m, 1H), <semantics>2.79−2.84<annotation encoding="application / x-tex">2.79-2.84< / annotation>< / semantics> (m, 1H), <semantics>2.67−2.63<annotation encoding="application / x-tex">2.67-2.63< / annotation>< / semantics> (m, 2H), <semantics>1.90−2.09<annotation encoding="application / x-tex">1.90-2.09< / annotation>< / semantics> (m, 3H), <semantics>1.85<annotation encoding="application / x-tex">1.85< / annotation>< / semantics> (d, <semantics>J=12.0<annotation encoding="application / x-tex">J=12.0< / annotation>< / semantics> Hz, 1H), 1.44 (s, 9H), 1.26 (t, <semantics>J=8.0<annotation encoding="application / x-tex">J = 8.0< / annotation>< / semantics> Hz, 1H), 1.20 (dt, <semantics>J=8.0<annotation encoding="application / x-tex">J = 8.0< / annotation>< / semantics>, 4.0 Hz, 2H), 0.89 (s, 9H), 0.03 (d, <semantics>J=<annotation encoding="application / x-tex">J =< / annotation>< / semantics> 4.0 Hz, 6H). MS (ESI, <semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>): 650.3 [M+H]+. Step J: Preparation of tert-butyl 4-(1-(1-amino-5-(methoxycarbonyl)-4-(4-phenoxyphenyl)-1H- imidazol-2-yl)-3-((tert-butyldimethylsilyl)oxy)propyl)piperidine-1-carboxylate [Image disponible dans le document PDF, Image available in the PDF document] Boc Lithium hexamethyldisilazane (85 mL of a 1 M solution intetrahydrofuran, 85.31 mmol) was slowly added to the product of step I (37.0 g, 56.91 mmol) in anhydrous N, N-dimethylformamide (500 mL) at 0 °C. After the mixture was stirred for 30 min, O-(diphenylphosphinyl) hydroxylamine (26.5 g, 113.86 mmol) was added, followed by stirring at room temperature for 4 hs (in cases where the reaction mixture became too viscous, additional N, N-dimethylformamide was added). The reaction was quenched with water until a clear solution was formed, then concentrated to dryness under reduced pressure. The residue was washed several times with ethyl acetate or dichloromethane. The combined organic fractions were concentrated in vacuo and purified by flash chromatography on silica gel with ethyl acetate and petroleum ether (1:3) to give the product as a clear colorless oil (29 g, 76%). 1H NMR (400 MHz, CDCl3) δ 7.63-7.58 (m, 2H), 7.37-7.30 (m, 2H), 7.10 (t, <semantics>J=7.4<annotation encoding="application / x-tex">J = 7.4< / annotation>< / semantics> Hz, 1H), 7.06-6.98 (m, 4H), 5.58 (s, 2H), 4.18-3.97 (m, 2H), 3.77 (s, 3H), 3.66-3.57 (m, 1H), 3.38-3.28 (m, 2H), 2.75-2.57 (m, 2H), 2.03-1.98 (m, 2H), 1.97-1.87 (m, 2H), 1.43 (s, 9H), 1.28-1.18 (m, 3H), 0.85 (s, 9H), 0.01-(-0.04) (m, 6H). MS (ESI, <semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>): 665.3 [M+H]+. Step K: Preparation of tert-buty14-(1-(1-amino-5-(methoxycarbonyl)-4-(4-phenoxyphenyl)-1H- imidazol-2-yl)-3-hydroxypropyl)piperidine-1-carboxylate [Image disponible dans le document PDF, Image available in the PDF document] To a solution of the product of step J (29.0 g, 43.61 mmol) in tetrahydrofuran (150 mL) was added a 1M solution of tetrabutylammonium fluoride in tetrahydrofuran (66 mL, 65.41 mmol) at RT. The solution was stirred for 2 hs and diluted with 100 mL ethyl acetate solution. The organic layer was separated and washed with <semantics>H2O<annotation encoding="application / x-tex">H_2O< / annotation>< / semantics> (3×200 mL). The water extract was washed with ethyl acetate solution (2×150 mL), and the organic layers were combined and dried over anhydrous Na2SO4. The solvent was evaporated in vacuo, and purified by flash chromatography on silica gel with dichloromethane and methanol (30:1) to give the product as a clear colorless oil (22 g, 91%). 1H NMR (400 MHz, CDCl3) <semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics> 7.64-7.59 (m, 2H), 7.37-7.32 (m, 2H), 7.12 (t, <semantics>J=7.4<annotation encoding="application / x-tex">J = 7.4< / annotation>< / semantics> Hz, 1H), <semantics>7.07−6.99<annotation encoding="application / x-tex">7.07-6.99< / annotation>< / semantics> (m, 4H), <semantics>5.52<annotation encoding="application / x-tex">5.52< / annotation>< / semantics> (s, 2H), <semantics>4.24−3.95<annotation encoding="application / x-tex">4.24-3.95< / annotation>< / semantics> (m, 2H), <semantics>3.79<annotation encoding="application / x-tex">3.79< / annotation>< / semantics> (s, 3H), <semantics>3.69−3.59<annotation encoding="application / x-tex">3.69-3.59< / annotation>< / semantics> (m, 1H), <semantics>3.51−3.40<annotation encoding="application / x-tex">3.51-3.40< / annotation>< / semantics> (m, 1H), 3.38-3.28 (m, 1H), 2.76-2.56 (m, 2H), 2.12-1.98 (m, 3H), 1.96-1.86 (m, 1H), 1.44 (s, 9H), 1.38-1.29 (m, 1H), 1.26-1.14 (m, 2H). MS (ESI, <semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>): 551.2 [M+H]+. Step L: Preparation of tert-butyl 4-(1-(1-amino-5-(methoxycarbonyl)-4-(4-phenoxyphenyl)-1H- imidazol-2-yl)-3-((methylsulfonyl)oxy)propyl)piperidine-1-carboxylate [Image disponible dans le document PDF, Image available in the PDF document] Methanesulfonyl chloride (6.0 g, 51.94 mmol) was added via syringe into a stirred mixture of the product of step K (22.1 g, 39.95 mmol) and N, N-diisopropylethylamine (7.8 g, 59.93 mmol) in dichloromethane (100 ml) maintained at 0 °C. The mixture was stirred at room temperature for 3 h (TLC monitoring) and then partitioned between dichloromethane and water. The organic phase was dried, then evaporated to afford a white solid, the crude product was passed through a column of silica gel with dichloromethane and methanol (20:1) to afford the desired product as a colorless oil (21 g, 83%). 1H NMR (400 MHz, CDCl3) <semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics> 7.65-7.61 (m, 2H), 7.36-7.32 (m, 2H), 7.12 (s, 1H), <semantics>7.06−7.01<annotation encoding="application / x-tex">7.06-7.01< / annotation>< / semantics> (m, 4H), <semantics>5.36<annotation encoding="application / x-tex">5.36< / annotation>< / semantics> (s, 2H), <semantics>4.25−4.14<annotation encoding="application / x-tex">4.25-4.14< / annotation>< / semantics> (m, 2H), <semantics>4.01<annotation encoding="application / x-tex">4.01< / annotation>< / semantics> (td, <semantics>J=9.8<annotation encoding="application / x-tex">J = 9.8< / annotation>< / semantics>, <semantics>3.9<annotation encoding="application / x-tex">3.9< / annotation>< / semantics> Hz, 2H), <semantics>3.79<annotation encoding="application / x-tex">3.79< / annotation>< / semantics> (s, 3H), <semantics>3.47 (dd, J=13.7,5.9 Hz,1H),2.94 (s, 3H),2.66 (s, 1H),2.45−2.32 (m, 1H),2.25 (dt, J=14.6,14.6)<annotation encoding="application / x-tex">3.47 \text{ (dd, } J = 13.7, 5.9 \text{ Hz}, 1\text{H}), 2.94 \text{ (s, 3H)}, 2.66 \text{ (s, 1H)}, 2.45-2.32 \text{ (m, 1H)}, 2.25 \text{ (dt, } J = 14.6, 14.6)< / annotation>< / semantics> 4.9 Hz, 1H), 1.89 (d, <semantics>J=12.3<annotation encoding="application / x-tex">J = 12.3< / annotation>< / semantics> Hz, 2H), 1.44 (s, 9H), 1.35-1.25 (m, 4H). MS (ESI, <semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>): 629.3 <semantics>[M+H]+<annotation encoding="application / x-tex">[M+H]^{+}< / annotation>< / semantics>. Step M: Preparation of methyl 8-(1-(tert-butoxycarbonyl)piperidin-4-yl)-2-(4-phenoxyphenyl)- 5,6,7,8-tetrahydroimidazo[1,2-b]pyridazine-3-carboxylate [Image disponible dans le document PDF, Image available in the PDF document] N, N-diisopropylethylamine (8.2 g, 63.61 mmol) and 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran(32 mL, 31.81 mmol) were added to the solution of the product of step L (20.0 g, 31.81 mmol) in anhydrous tetrahydrofuran(100 mL), the mixture was heated to 50°C for 2 hs, then cooled to r.t., concentrated and purified by flash column chromatography with dichloromethane and methanol (10:1) to give the desired product (11 g, 64%). 1H NMR (600 MHz, CDCl3) <semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics> 7.64 (d, <semantics>J=7.9<annotation encoding="application / x-tex">J = 7.9< / annotation>< / semantics> Hz, 2H), 7.34 (t, <semantics>J=7.4<annotation encoding="application / x-tex">J = 7.4< / annotation>< / semantics> Hz, 2H), 7.11 (t, <semantics>J=7.4<annotation encoding="application / x-tex">J = 7.4< / annotation>< / semantics> Hz, 1H), 7.07-7.02 (m, 4H), 7.01 (s, 1H), 4.17 (s, 2H), 3.78 (s, 3H), 3.50-3.44 (m, 1H), 3.38-3.31 (m, 1H), 3.09 (s, 1H), 2.71 (s, 2H), 2.41 (s, 1H), 2.12-2.02 (m, 1H), 1.98-1.89 (m, 1H), 1.77-1.71 (m, 1H), 1.61 (s, 1H), 1.45 (s, 9H), 1.42-1.32 (m, 2H). MS (ESI, <semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>): 533.2 [M+H]+. Step N: Preparation of 8-(1-(tert-butoxycarbonyl)piperidin-4-yl)-2-(4-phenoxyphenyl)-5,6,7,8- tetrahydroimidazo[1,2-b]pyridazine-3-carboxylic acid [Image disponible dans le document PDF, Image available in the PDF document] To a solution of the product of step M (10.0 g, 18.77 mmol) in tetrahydrofuran(60 mL) was added LiOH (2.25 g, 93.87 mmol) in water (10 mL), the mixture was heated at 50°C for 3 hs. After cooled to r.t., the mixture was acidified to pH 3-4 with concentrated HCl and then extracted with 3×100mL of dichloromethane. The organic phase was washed with saturated brine and then dried over anhydrous Na2SO4. The organic phase was concentrated in vacuo to afford 11 g crude product. The residue was used to next step without further purification. MS (ESI, <semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>): 519.3 [M+H]+. Step O: Preparation of tert-butyl 4-(3-carbamoyl-2-(4-phenoxyphenyl)-5,6,7,8- tetrahydroimidazo[1,2-b]pyridazin-8-yl)piperidine-1-carboxylate [Image disponible dans le document PDF, Image available in the PDF document] To the solution of the product of step N (11.0 g, 21.21 mmol) in dichloromethane (60 mL) was added N, N-diisopropylethylamine (11.0 g, 84.84 mmol). After 5 min, NII4Cl (4.54 g, 84.84 mmol) and HATU (12.1 g, 31.82 mmol) was added. The reaction mixture was continued to stir at room temperature for 2 hs. 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 (3×100 mL) with brine solution. The organic phase was dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by chromatography with dichloromethane and methanol (40:1) to give product as an off-white solid (7 g, 64%). 1H NMR (600 MHz, CDCl3) <semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics> <semantics>7.63−7.55<annotation encoding="application / x-tex">7.63-7.55< / annotation>< / semantics> (m, 2H), <semantics>7.38−7.29<annotation encoding="application / x-tex">7.38-7.29< / annotation>< / semantics> (m, 2H), <semantics>7.15−7.07<annotation encoding="application / x-tex">7.15-7.07< / annotation>< / semantics> (m, 1H), <semantics>7.00<annotation encoding="application / x-tex">7.00< / annotation>< / semantics> (dt, <semantics>J=16.0<annotation encoding="application / x-tex">J = 16.0< / annotation>< / semantics>, <semantics>8.0<annotation encoding="application / x-tex">8.0< / annotation>< / semantics> Hz, 4H), <semantics>6.88<annotation encoding="application / x-tex">6.88< / annotation>< / semantics> (dd, <semantics>J=13.0,6.2 Hz,1H<annotation encoding="application / x-tex">J = 13.0, 6.2 \text{ Hz}, 1\text{H}< / annotation>< / semantics>), 6.26 (s, 1H), 5.70 (s, 1H), 4.14 (s, 2H), 3.66-3.57 (m, 2H), 3.47-3.39 (m, 1H), 3.34-3.24 (m, 1H), 3.11 (dd, <semantics>J=14.8<annotation encoding="application / x-tex">J = 14.8< / annotation>< / semantics>, 7.4 Hz, 2H), 2.73 (d, <semantics>J=57.5<annotation encoding="application / x-tex">J = 57.5< / annotation>< / semantics> Hz, 2H), 2.38-2.34 (m, 1H), 2.05-2.00 (m, 1H), 1.92-1.86 (m, 1H), 1.71 (d, <semantics>J=12.3<annotation encoding="application / x-tex">J = 12.3< / annotation>< / semantics> Hz, 1H), 1.43 (s, 9H). MS (ESI, <semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>): 518.3 [M+H]+. Step P: Preparation of 2-(4-phenoxyphenyl)-8-(piperidin-4-yl)-5,6,7,8-tetrahydroimidazo[1,2- blpyridazine-3-carboxamide [Image disponible dans le document PDF, Image available in the PDF document] To a solution of the product of step O (5.0 g, crude) in EtOH (2 mL) was added 33% HCl / EtOH (20 mL) at room temperature. The mixture was stirred for 3 hs, then concentrated under vacuum to get 6.5 g crude product. The residue was used to next step without further purification. 1H NMR <semantics>(600 MHz, DMSO−d6)δ8.46 (s, 1H),7.98 (s, 1H),7.84 (d, J=8.7 Hz, 2H),7.51 (s, 1H),7.40 (dd, 1H)<annotation encoding="application / x-tex">(600 \text{ MHz}, \text{ DMSO}-d6) \delta 8.46 \text{ (s, 1H)}, 7.98 \text{ (s, 1H)}, 7.84 \text{ (d, } J = 8.7 \text{ Hz, 2H)}, 7.51 \text{ (s, 1H)}, 7.40 \text{ (dd, 1H)}< / annotation>< / semantics> <semantics>J=8.2,7.6 Hz,2H,7.14 (t, J=7.4 Hz,1H),7.04 (d, J=7.8 Hz,2H),6.99 (d, J=8.7 Hz,2H),<annotation encoding="application / x-tex">J = 8.2, 7.6 \text{ Hz}, 2\text{H}, 7.14 \text{ (t, } J = 7.4 \text{ Hz}, 1\text{H}), 7.04 \text{ (d, } J = 7.8 \text{ Hz}, 2\text{H}), 6.99 \text{ (d, } J = 8.7 \text{ Hz}, 2\text{H}),< / annotation>< / semantics> 6.70 (s, 1H), 3.38-3.30 (m, 1H), 3.27-3.16 (m, 2H), 3.12 (s, 1H), 3.04-2.97 (m, 1H), 2.86-2.77 (m, 1H), 2.76-2.68 (m, 1H), 2.26-2.17 (m, 1H), 1.96-1.86 (m, 2H), 1.78-1.65 (m, 2H), 1.62-1.47 (m, 2H). MS (ESI, <semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>): 418.2 [M+H]+. Step <semantics>𝑶<annotation encoding="application / x-tex">\mathbf{O}< / annotation>< / semantics> Preparation of 8-(1-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)-5,6,7,8- tetrahydroimidazo[1,2-b]pyridazine-3-carboxamide [Image disponible dans le document PDF, Image available in the PDF document] The mixture of the product of step P (200.0 mg, 0.48 mmol) and triethylamine(290.88 mg, 2.88 mmol) in dichloromethane (10 mL) was cooled to -60 °C, then the solution of propencyl chloride (52.1 mg, 0.57mmol) in dichloromethane (1 mL) was added slowly, LC-MS was tracking, at the end of the reaction, 1 mL MeOH was added, the mixture was concentrated under vacuum to get crude product. The residue was purified by flash chromatography on silica gel with dichloromethane and methanol (40:1) to get product as a white solid (38 mg, 19%). 1H NMR (400 MHz, MeOD) <semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics> 8.48 (s, 1H), 7.62-7.54 (m, 2H), 7.46-7.39 (m, 2H), 7.26-7.18 (m, 1H), 7.16-7.04 (m, 4H), 6.81-6.73 (m, 1H), 6.23-6.14 (m, 1H), 5.77-5.70 (m, 1H), 4.75-4.60 (m, 1H), 4.35-4.13 <semantics>(m,3H),3.79(d,J=4.2Hz,1H),3.32−3.13(m,1H),2.86−2.68(m,2H),2.66−2.58(m,2H),1.95−1.00(m,3H),3.79(d,J=4.2Hz,1H),3.32−3.13(m,1H),2.86−2.68(m,2H),2.66−2.58(m,2H),1.95−1.00(m,2H),2.86−2.<annotation encoding="application / x-tex">(m, 3H), 3.79 (d, J = 4.2 Hz, 1H), 3.32-3.13 (m, 1H), 2.86-2.68 (m, 2H), 2.66-2.58 (m, 2H), 1.95-1.00 (m, 3H), 3.79 (d, J = 4.2 Hz, 1H), 3.32-3.13 (m, 1H), 2.86-2.68 (m, 2H), 2.66-2.58 (m, 2H), 1.95-1.00 (m, 2H), 2.86-2.< / annotation>< / semantics> 1.82 (m, 1H), 1.58-1.31 (m, 3H). MS (ESI, <semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>): 418.2 [M+H]+. [Image disponible dans le document PDF, Image available in the PDF document] 1a 1H NMR (600 MHz, CDCl3) <semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics> 7.56 (s, 2H), 7.42 (s, 1H), 7.36 (t, <semantics>J=7.9<annotation encoding="application / x-tex">J = 7.9< / annotation>< / semantics> Hz, 2H), 7.14 (t, <semantics>J=7.9<annotation encoding="application / x-tex">J = 7.9< / annotation>< / semantics> Hz, 2H), 7.14 (t, <semantics>J=7.9<annotation encoding="application / x-tex">J = 7.9< / annotation>< / semantics> Hz, 2H), 7.14 (t, <semantics>J=7.9<annotation encoding="application / x-tex">J = 7.9< / annotation>< / semantics> Hz, 2H), 7.14 (t, <semantics>J=7.9<annotation encoding="application / x-tex">J = 7.9< / annotation>< / semantics> Hz, 2H), 7.14 (t, <semantics>J=7.<annotation encoding="application / x-tex">J = 7.< / annotation>< / semantics> <semantics>=7.4 Hz,1H,7.07−7.04 (m, 4H),6.60−6.54 (m, 1H),6.26 (d, J=16.9 Hz,1H),5.99 (s, 1H),5.67 (m, 1H)<annotation encoding="application / x-tex">= 7.4 \text{ Hz}, 1 \text{H}, 7.07-7.04 \text{ (m, 4H)}, 6.60-6.54 \text{ (m, 1H)}, 6.26 \text{ (d, } J = 16.9 \text{ Hz}, 1 \text{H)}, 5.99 \text{ (s, 1H)}, 5.67 \text{ (m, 1H)}< / annotation>< / semantics> <semantics>(d,J=10.5 Hz,1H),5.30 (s, 1H),4.79−4.72 (dd, J=32.3,12.8 Hz,1H),4.08−4.00 (m, 1H),3.46−4.00 (m, 1H)<annotation encoding="application / x-tex">(d, J = 10.5 \text{ Hz}, 1\text{H}), 5.30 \text{ (s, 1H)}, 4.79-4.72 \text{ (dd, } J = 32.3, 12.8 \text{ Hz}, 1\text{H}), 4.08-4.00 \text{ (m, 1H)}, 3.46-4.00 \text{ (m, 1H)}< / annotation>< / semantics> 3.44 (m, 1H), 3.15 -3.05 (m, 2H), 2.67-2.50 (m, 2H), 2.08-2.05 (m, 1H), 1.91-1.78 (m, 2H), 1.55- 1.53 (m, 1H), 1.50-1.46 (m, 1H), 1.42-1.40 (m, 1H). [Image disponible dans le document PDF, Image available in the PDF document] 1b 1H NMR (600 MHz, CDCl3) <semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics> 7.56 (s, 2H), 7.36 (t, <semantics>J<annotation encoding="application / x-tex">J< / annotation>< / semantics> = 7.8 Hz, 2H), 7.14 (t, <semantics>J<annotation encoding="application / x-tex">J< / annotation>< / semantics> = 7.4 Hz, 1H), 7.06 (dd, <semantics>J=11.6<annotation encoding="application / x-tex">J = 11.6< / annotation>< / semantics>, 8.3 Hz, 4H), 6.63-6.52 (m, 1H), 6.26 (d, <semantics>J=16.8<annotation encoding="application / x-tex">J = 16.8< / annotation>< / semantics> Hz, 1H), 5.99 (s, 1H), 5.67 (d, <semantics>J=10.5 Hz<annotation encoding="application / x-tex">J = 10.5 \text{ Hz}< / annotation>< / semantics>, 1H), 5.30 (s, 1H), 4.75 (dd, <semantics>J=33.1<annotation encoding="application / x-tex">J = 33.1< / annotation>< / semantics>, 12.1 Hz, 1H), 4.08-4.00 (m, 1H), 3.44 (s, 1H), <semantics>3.35<annotation encoding="application / x-tex">3.35< / annotation>< / semantics> (t, <semantics>J=11.4<annotation encoding="application / x-tex">J = 11.4< / annotation>< / semantics> Hz, 1H), <semantics>3.15−3.05<annotation encoding="application / x-tex">3.15-3.05< / annotation>< / semantics> (m, 2H), <semantics>2.68−2.45<annotation encoding="application / x-tex">2.68-2.45< / annotation>< / semantics> (m, 2H), <semantics>2.06<annotation encoding="application / x-tex">2.06< / annotation>< / semantics> (s, 1H), <semantics>1.96−1.75<annotation encoding="application / x-tex">1.96-1.75< / annotation>< / semantics> (m, 2H), 1.53 (s, 1H), 1.49 (d, <semantics>J=6.7<annotation encoding="application / x-tex">J = 6.7< / annotation>< / semantics> Hz, 1H), 1.41 (d, <semantics>J=14.1<annotation encoding="application / x-tex">J = 14.1< / annotation>< / semantics> Hz, 1H). Compound example 1 was separated into two enantiomeric stereoisomers compound 1a (peak 1, levoisomer, retention time at 7.9 min in chiral analysis), and compound 1b (peak 2, dextroisomer, retention time at 9.12 min in chiral analysis) by chiral prep-HPLC. The chiral separation conditions are shown below. [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] The specific rotation of compound 1a and compound 1b was measured by polarimeter. Specific rotation measurement conditions are shown below. [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] Example 2: 8-[1-(1-Oxo-but-2-ynyl)-piperidin-4-yl]-2-(4-phenoxy-phenyl)-5,6,7,8-tetrahydro- imidazo[1,2-b]pyridazine-3-carboxamide [Image disponible dans le document PDF, Image available in the PDF document] Preparation of 8-[1-(1-Oxo-but-2-ynyl)-piperidin-4-yl]-2-(4-phenoxy-phenyl)-5,6,7,8- tetrahydro-imidazo[1,2-b]pyridazine-3-carboxamide [Image disponible dans le document PDF, Image available in the PDF document] To the solution of the product (200.0 mg, 0.48 mmol) of step P of example 1 in dry N, N- dimethylformamide (10 mL) was added N, N-diisopropylethylamine (371.5 mg, 2.88 mmol). After 5 min, but-2-ynoic acid (47.8 mg, 0.57 mmol) and HATU (273.1 mg, 0.72 mmol) was added. The reaction mixture was continued to stir at room temperature for 2 hs. Dichloromethane and water were added. The layers were separated, the aqueous phase was extracted with dichloromethane. CA The combined organic phases were washed three times <semantics>(3×50 mL)<annotation encoding="application / x-tex">(3\times50 \text{ mL})< / annotation>< / semantics> with brine solution. The organic phase was dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by chromatography with dichloromethane and methanol (25:1) to give product as an off-white solid (54 mg, 23%). 1H NMR (400 MHz, DMSO-d6) <semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics> 8.24 (s, 1H), 7.95 (s, 1H), 7.87 (dd, <semantics>J=8.8,1.3<annotation encoding="application / x-tex">J = 8.8, 1.3< / annotation>< / semantics> Hz, 2H), 7.52 (s, 1H), 7.46 (dd, <semantics>J=8.4<annotation encoding="application / x-tex">J = 8.4< / annotation>< / semantics>, 7.6 Hz, 2H), 7.20 (t, <semantics>J=7.4<annotation encoding="application / x-tex">J = 7.4< / annotation>< / semantics> Hz, 1H), 7.10 (d, <semantics>J=7.8<annotation encoding="application / x-tex">J = 7.8< / annotation>< / semantics> Hz, 2H), 7.07-7.01 (m, 2H), 6.63-6.55 (m, 1H), 4.51-4.27 (m, 2H), 3.81-3.60 (m, 2H), 3.20 (dd, <semantics>J=<annotation encoding="application / x-tex">J =< / annotation>< / semantics> 12.9, 5.7 Hz, 3H), 3.12-3.00 (m, 1H), 2.34 (s, 1H), 2.07 (t, <semantics>J=6.1<annotation encoding="application / x-tex">J = 6.1< / annotation>< / semantics> Hz, 3H), 1.98-1.95 (m, 2H), 1.86-1.70 (m, 1H), 1.63-1.46 (m, 2H). MS (ESI, <semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>): 484.2 [M+H]+. Example 3: 8-(1-(3-methylbut-2-enoyl)piperidin-4-yl)-2-(4-phenoxyphenyl)-5,6,7,8- tetrahydroimidazo[1,2-b]pyridazine-3-carboxamide [Image disponible dans le document PDF, Image available in the PDF document] peridin-4-yl)-2-(4-phenoxyphenyl)-5,6,7,8- tetrahydroimidazo[1,2-b]pyridazine-3-carboxamide [Image disponible dans le document PDF, Image available in the PDF document] The mixture of the product (200.0 mg, 0.48 mmol) of step P of example 1 and triethylamine(290.88 mg, 2.88 mmol) in dichloromethane (10 mL) was cooled to -60°C, then the solution of 3-methylbut-2-enoyl chloride (62.47 mg, 0.53mmol) in dichloromethane (1 mL) was added slowly, LC-MS was tracking, at the end of the reaction, 1 mL MeOH was added, the mixture was concentrated under vacuum to get crude product. The residue was purified by flash chromatography on silica gel withdichloromethane and methanol (25:1) to get product as a white solid (43 mg, 18%). 1H NMR (400 MHz, MeOD) <semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics> 7.54 (dd, <semantics>J=8.7,1.9<annotation encoding="application / x-tex">J = 8.7, 1.9< / annotation>< / semantics> Hz, 2H), 7.30-7.21 (m, 2H), 7.02 (dd, <semantics>J=10.6<annotation encoding="application / x-tex">J = 10.6< / annotation>< / semantics>, 4.2 Hz, 1H), 6.95-6.85 (m, 4H), 5.75 (d, <semantics>J=8.1<annotation encoding="application / x-tex">J = 8.1< / annotation>< / semantics> Hz, 1H), 4.51 (dd, <semantics>J=<annotation encoding="application / x-tex">J =< / annotation>< / semantics> 24.3, 13.1 Hz, 1H), 3.94 (dd, <semantics>J=24.1<annotation encoding="application / x-tex">J = 24.1< / annotation>< / semantics>, 13.0 Hz, 1H), 3.34 (dt, <semantics>J=13.6<annotation encoding="application / x-tex">J = 13.6< / annotation>< / semantics>, 4.0 Hz, 1H), 3.13 (t, <semantics>J=13.6<annotation encoding="application / x-tex">J = 13.6< / annotation>< / semantics>, 4.0 Hz, 1H), 3.13 (t, <semantics>J=13.6<annotation encoding="application / x-tex">J = 13.6< / annotation>< / semantics>, 4.0 Hz, 1H), 3.13 (t, <semantics>J=13.6<annotation encoding="application / x-tex">J = 13.6< / annotation>< / semantics>, 4.0 Hz, 1H), 3.13 (t, <semantics>J=13.6<annotation encoding="application / x-tex">J = 13.6< / annotation>< / semantics>, 4.0 Hz, 11.2 Hz, 1H), 3.05 (t, <semantics>J=9.6<annotation encoding="application / x-tex">J = 9.6< / annotation>< / semantics> Hz, 1H), 3.02-2.88 (m, 1H), 2.65-2.47 (m, 1H), 2.44-2.26 (m, 1H), 1.92 (dd, <semantics>J=10.1<annotation encoding="application / x-tex">J = 10.1< / annotation>< / semantics>, 3.7 Hz, 1H), 1.77-1.67 (m, 8H), 1.43-1.26 (m, 3H). MS (ESI, <semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>): 500.3 <semantics>[M+H]+<annotation encoding="application / x-tex">[M+H]^+< / annotation>< / semantics> Example 4: 8-[1-(2-Methyl-acryloyl)-piperidin-4-yl]-2-(4-phenoxy-phenyl)-5,6,7,8-tetrahydro- imidazo[1,2-b]pyridazine-3-carboxamide [Image disponible dans le document PDF, Image available in the PDF document] Preparation of 8-[1-(2-Methyl-acryloyl)-piperidin-4-yl]-2-(4-phenoxy-phenyl)-5,6,7,8- tetrahydro-imidazo[1,2-b]pyridazine-3-carboxamide [Image disponible dans le document PDF, Image available in the PDF document] The mixture of the product (200.0 mg, 0.48 mmol) of step P of example 1 and triethylamine(290.8 mg, 2.88 mmol) in dichloromethane (10 mL) was cooled to -60 °C, then the solution of methacryloyl chloride (55 mg, 0.53 mmol) in dichloromethane (1 mL) was added slowly, LC-MS was tracking, at the end of the reaction, 1 mL MeOH was added, the mixture was concentrated under vacuum to get 420 mg crude. The crude was purified by flash chromatography on silica gel with dichloromethane and methanol (25:1) to get product as a white solid (38 mg, 16%). 1H NMR (400 MHz, MeOD) <semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics> 7.57-7.51 (m, 2H), 7.28-7.21 (m, 2H), 7.05-6.98 (m, 1H), <semantics>6.95−6.84<annotation encoding="application / x-tex">6.95-6.84< / annotation>< / semantics> (m, 4H), <semantics>5.09<annotation encoding="application / x-tex">5.09< / annotation>< / semantics> (s, 1H), <semantics>4.92<annotation encoding="application / x-tex">4.92< / annotation>< / semantics> (s, 1H), <semantics>4.44<annotation encoding="application / x-tex">4.44< / annotation>< / semantics> (d, <semantics>J=12.3<annotation encoding="application / x-tex">J = 12.3< / annotation>< / semantics> Hz, 1H), <semantics>3.95<annotation encoding="application / x-tex">3.95< / annotation>< / semantics> (dd, <semantics>J=22.7<annotation encoding="application / x-tex">J = 22.7< / annotation>< / semantics>, <semantics>13.7<annotation encoding="application / x-tex">13.7< / annotation>< / semantics> Hz, 1H), <semantics>3.35−3.30<annotation encoding="application / x-tex">3.35-3.30< / annotation>< / semantics> (m, 1H), <semantics>3.15−3.09<annotation encoding="application / x-tex">3.15-3.09< / annotation>< / semantics> (m, 1H), <semantics>3.03<annotation encoding="application / x-tex">3.03< / annotation>< / semantics> (d, <semantics>J=11.5<annotation encoding="application / x-tex">J = 11.5< / annotation>< / semantics> Hz, 2H), <semantics>2.63−2.61<annotation encoding="application / x-tex">2.63-2.61< / annotation>< / semantics> (m, 1H), <semantics>2.41−1.00<annotation encoding="application / x-tex">2.41-1.00< / annotation>< / semantics> 2.34 (m, 1H), 1.96-1.86 (m, 1H), 1.82 (s, 3H), 1.76-1.66 (m, 2H), 1.39-1.28 (m, 3H). MS (ESI, <semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>): 486.3 [M+H]+. Example 5: 8-(1-But-2-enoyl-piperidin-4-yl)-2-(4-phenoxy-phenyl)-5,6,7,8-tetrahydro-imidazo[1,2- b]pyridazine-3-carboxamide [Image disponible dans le document PDF, Image available in the PDF document] Preparation of (E)-8-(1-(but-2-enoyl)piperidin-4-yl)-2-(4-phenoxyphenyl)-5,6,7,8- tetrahydroimidazo[1,2-b]pyridazine-3-carboxamide CÆ [Image disponible dans le document PDF, Image available in the PDF document] The mixture of the product of step P of example 1 (200.0 mg, 0.48 mmol) and triethylamine(290.8 mg, 2.88 mmol) in dichloromethane (10 mL)was cooled to -60°C, then the solution of (E)-but-2-enoyl chloride (55 mg, 0.53 mmol) in dichloromethane (1 mL) was added slowly, LC-MS was tracking, at the end of the reaction, 1 mL MeOH was added, the mixture was concentrated under vacuum to get crude product. The residue was purified by flash chromatography on silica gel with dichloromethane and methanol (25:1) to get product as a white solid (41 mg, 17.6%). 1H NMR (400 MHz, MeOD) δ 7.60-7.49 (m, 2H), 7.32-7.22 (m, 2H), 7.02 <semantics>(t,J=7.4 Hz,1H),6.96−6.86 (m, 4H),6.73−6.64 (m, 1H),6.42−6.31 (m, 1H),4.59−4.49 (m, 1H),<annotation encoding="application / x-tex">(t, J = 7.4 \text{ Hz}, 1\text{H}), 6.96-6.86 \text{ (m, 4H)}, 6.73-6.64 \text{ (m, 1H)}, 6.42-6.31 \text{ (m, 1H)}, 4.59-4.49 \text{ (m, 1H)},< / annotation>< / semantics> <semantics>4.14−4.04<annotation encoding="application / x-tex">4.14-4.04< / annotation>< / semantics> (m, 1H), <semantics>3.36−3.33<annotation encoding="application / x-tex">3.36-3.33< / annotation>< / semantics> (m, 1H), <semantics>3.14<annotation encoding="application / x-tex">3.14< / annotation>< / semantics> (t, <semantics>J=11.3<annotation encoding="application / x-tex">J = 11.3< / annotation>< / semantics> Hz, 1H), <semantics>3.0−2.94<annotation encoding="application / x-tex">3.0-2.94< / annotation>< / semantics> (m, 2H), <semantics>2.68−2.49<annotation encoding="application / x-tex">2.68-2.49< / annotation>< / semantics> (m, 1H), 2.40 (s, 1H), 1.92 (d, <semantics>J=4.6<annotation encoding="application / x-tex">J = 4.6< / annotation>< / semantics> Hz, 1H), 1.82-1.72 (m, 5H), 1.44-1.27 (m, 3H). MS (ESI, <semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>): 486.3 [M+H]+. Example 6: (E)-8-(1-(pent-2-enoyl)piperidin-4-yl)-2-(4-phenoxyphenyl)-5,6,7,8- tetrahydroimidazo[1,2-b]pyridazine-3-carboxamide [Image disponible dans le document PDF, Image available in the PDF document] Preparation of (E)-8-(1-(pent-2-enoyl)piperidin-4-yl)-2-(4-phenoxyphenyl)-5,6,7,8- tetrahydroimidazo[1,2-b]pyridazine-3-carboxamide [Image disponible dans le document PDF, Image available in the PDF document] To the solution of the product (200.0 mg, 0.48 mmol) of step P of example 1 in dry N, N- dimethylformamide (10 mL) was added N, N-diisopropylethylamine (371.5 mg, 2.88 mmol). After CA 5 min, (E)-pent-2-enoic acid (34 mg, 0.34 mmol) and HATU (273 mg, 0.72 mmol) was added. The reaction mixture was continued to stir at room temperature for 2 hS. Ethyl acetate and water were added. The layers were separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed three times <semantics>(3×50 mL)<annotation encoding="application / x-tex">(3\times50 \text{ mL})< / annotation>< / semantics> with brine solution. The organic phase was dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by chromatography with dichloromethane and methanol (25:1) to give product as an off-white solid (32 mg, 22%). 1H NMR (400 MHz, MeOD) <semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics> 7.54 (d, <semantics>J<annotation encoding="application / x-tex">J< / annotation>< / semantics> = 8.7 Hz, 2H), 7.30-7.22 (m, 2H), 7.02 (t, <semantics>J=7.4 Hz<annotation encoding="application / x-tex">J = 7.4 \text{ Hz}< / annotation>< / semantics>, 1H), 6.97-6.85 (m, 4H), 6.74-6.67 (m, 1H), 6.35-6.28 (m, 1H), 4.60-4.50 (m, 1H), 4.14- 4.01 (m, 1H), 3.37-3.32 (m, 1H), 3.19-3.11 (m, 1H), 3.10-2.93 (m, 2H), 2.70-2.49 (m, 1H), 2.40 (s, 1H), 2.15 (dd, <semantics>J=12.3<annotation encoding="application / x-tex">J = 12.3< / annotation>< / semantics>, 6.5 Hz, 2H), 1.92 (d, <semantics>J=5.3<annotation encoding="application / x-tex">J = 5.3< / annotation>< / semantics> Hz, 1H), 1.76 (d, <semantics>J=11.5<annotation encoding="application / x-tex">J = 11.5< / annotation>< / semantics> Hz, 2H), 1.45- 1.27 (m, 3H), 0.98 (dd, <semantics>J=11.1<annotation encoding="application / x-tex">J = 11.1< / annotation>< / semantics>, 7.2 Hz, 3H). MS (ESI, <semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>): 500.3 [M+H]+. Example 7: 8-[1-(2-Cyano-4-methyl-pent-2-enoyl)-piperidin-4-yl]-2-(4-phenoxy-phenyl)-5,6,7,8- tetrahydro-imidazo[1,2-b]pyridazine-3-carboxamide [Image disponible dans le document PDF, Image available in the PDF document] Step A: Preparation of 8-(1-(2-cyanoacetyl)piperidin-4-yl)-2-(4-phenoxyphenyl)-5,6,7,8- tetrahydroimidazo[1,2-b]pyridazine-3-carboxamide [Image disponible dans le document PDF, Image available in the PDF document] To the solution of 1.0 g (2.41 mmol) of the product of step P of example 1 in dry N, N- dimethylformamide (20 mL) was added N, N-diisopropylethylamine (1.8 g, 14.41 mmol). After 5 min, 2-cyanoacetic acid (244.5 mg, 2.87 mmol) and HATU (1.4 g, 3.61 mmol) was added. The reaction mixture was continued to stir at room temperature for 2 hs. Ethyl acetate and water were added. The layers were separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed three times (3×50 mL) with brine solution. The organic phase was dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by chromatography with dichloromethane and methanol (25:1) to give product as an off-white solid (950 mg, crude). Step B: Preparation of 8-[1-(2-cyano-4-methyl-pent-2-enoyl)-piperidin-4-yl]-2-(4-phenoxy- phenyl)-5,6,7,8-tetrahydro-imidazo[1,2-b]pyridazine-3-carboxamide [Image disponible dans le document PDF, Image available in the PDF document] To the solution of isobutyraldehyde (29.7 mg, 0.41 mmol) in dry dichloromethane (10 mL) at <semantics>0∘<annotation encoding="application / x-tex">0^{\circ}< / annotation>< / semantics>C was added pyrrolidine (180 µL, 2.01 mmol) and then trimethyl chlorosilane(280 µL, 2.01 mmol). The ice bath was removed and the reaction mixture was stirred for 10 min followed by the additions of 200 mg (0.41 mmol) of the product of step A of example 7. The reaction solution was stirred for 1 h. Ethyl acetate and water was added. The layers were separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed three times (3×50 mL) with brine solution. The organic phase was dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by chromatography with dichloromethane and methanol (27:1) to afford product as a white solid (45 mg, 20%). 1H NMR (400 MHz, MeOD) <semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics> 7.60-7.50 <semantics>(m,2H),7.31−7.21(m,2H),7.02(t,J=7.4Hz,1H),6.96−6.85(m,4H),6.70(d,J=10.2Hz,1H),<annotation encoding="application / x-tex">(m, 2H), 7.31-7.21 (m, 2H), 7.02 (t, J = 7.4 Hz, 1H), 6.96-6.85 (m, 4H), 6.70 (d, J = 10.2 Hz, 1H),< / annotation>< / semantics> 4.41 (s, 1H), 3.99 (dd, <semantics>J=19.5<annotation encoding="application / x-tex">J = 19.5< / annotation>< / semantics>, 12.4 Hz, 1H), 3.38-3.32 (m, 1H), 3.19-3.02 (m, 3H), 2.41 (d, <semantics>J=19.5<annotation encoding="application / x-tex">J = 19.5< / annotation>< / semantics>, 12.4 Hz, 1H), 3.38-3.32 (m, 1H), 3.19-3.02 (m, 3H), 2.41 (d, <semantics>J=19.5<annotation encoding="application / x-tex">J = 19.5< / annotation>< / semantics>, 12.4 Hz, 1H), 3.38-3.32 (m, 1H), 3.19-3 3.5 Hz, 1H), 2.00-1.89 (m, 1H), 1.76 (dd, <semantics>J=10.1<annotation encoding="application / x-tex">J = 10.1< / annotation>< / semantics>, 3.5 Hz, 2H), 1.42 (d, <semantics>J=7.3<annotation encoding="application / x-tex">J = 7.3< / annotation>< / semantics> Hz, 3H), 1.30- 1.24 (m, 1H), 1.04 (d, <semantics>J=6.6<annotation encoding="application / x-tex">J = 6.6< / annotation>< / semantics> Hz, 6H). MS (ESI, <semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>): 539.3 [M+H]+. Example 8: 8-[1-(2-Cyano-3-cyclopropyl-acryloyl)-piperidin-4-yl]-2-(4-phenoxy-phenyl)-5,6,7,8- tetrahydro-imidazo[1,2-b]pyridazine-3-carboxamide [Image disponible dans le document PDF, Image available in the PDF document] Preparation of 8-[1-(2-cyano-3-cyclopropyl-acryloyl)-piperidin-4-yl]-2-(4-phenoxy-phenyl)- 5,6,7,8-tetrahydro-imidazo[1,2-b]pyridazine-3-carboxamide [Image disponible dans le document PDF, Image available in the PDF document] To the solution of cyclopropanecarbaldehyde (29.1 mg, 0.41 mmol) in dry dichloromethane (10 mL) at 0°C was added pyrrolidine (180 <semantics>μ<annotation encoding="application / x-tex">\mu< / annotation>< / semantics>L, 2.01 mmol) and then trimethyl chlorosilane(280 <semantics>μ<annotation encoding="application / x-tex">\mu< / annotation>< / semantics>L, 2.01 mmol). The ice bath was removed and the reaction mixture was stirred for 10 min followed by the additions of the product (200 mg, 0.41 mmol) of step A of example 7. The reaction solution was stirred for 1 h. Ethyl acetate and water was added. The layers were separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed three times (3×50 mL) with brine solution. The organic phase was dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by chromatography with dichloromethane and methanol (27:1) to afford product as a white solid (42 mg, 19 %). <semantics>1<annotation encoding="application / x-tex">^{1}< / annotation>< / semantics>H NMR (400 MHz, MeOD) <semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics> 7.58-7.50 <semantics>(m,2H),7.26 (dd, J=10.7,5.3 Hz,2H),7.05−6.98 (m, 1H),6.96−6.85 (m, 4H),6.39 (d, J=11.0)<annotation encoding="application / x-tex">(m, 2H), 7.26 \text{ (dd, } J = 10.7, 5.3 \text{ Hz}, 2H), 7.05-6.98 \text{ (m, 1H)}, 6.96-6.85 \text{ (m, 4H)}, 6.39 \text{ (d, } J = 11.0)< / annotation>< / semantics> Hz, 1H), <semantics>4.49−4.47<annotation encoding="application / x-tex">4.49-4.47< / annotation>< / semantics> (m, 1H), <semantics>4.19−3.85<annotation encoding="application / x-tex">4.19-3.85< / annotation>< / semantics> (m, 1H), <semantics>3.33<annotation encoding="application / x-tex">3.33< / annotation>< / semantics> (dd, <semantics>J=9.6<annotation encoding="application / x-tex">J = 9.6< / annotation>< / semantics>, <semantics>4.1<annotation encoding="application / x-tex">4.1< / annotation>< / semantics> Hz, 1H), <semantics>3.19−2.96<annotation encoding="application / x-tex">3.19-2.96< / annotation>< / semantics> (m, 3H), 2.80-2.59 (m, 1H), 2.40 (s, 1H), 2.03-1.86 (m, 2H), 1.82-1.67 (m, 2H), 1.50-1.30 (m, 3H), 1.11 <semantics>(dd,J=7.7,2.3 Hz,2H),0.85−0.72 (m, 2H).MS (ESI, m / z):537.3 [M+H]+.<annotation encoding="application / x-tex">(dd, J = 7.7, 2.3 \text{ Hz}, 2H), 0.85-0.72 \text{ (m, 2H)}. MS \text{ (ESI, } m / z\text{)}: 537.3 \text{ [M+H]}^+.< / annotation>< / semantics> Example 9: 8-[1-(2-Fluoro-acryloyl)-piperidin-4-yl]-2-(4-phenoxy-phenyl)-5,6,7,8-tetrahydro- imidazo[1,2-b]pyridazine-3-carboxamide [Image disponible dans le document PDF, Image available in the PDF document] Preparation of 8-[1-(2-fluoro-acryloyl)-piperidin-4-yl]-2-(4-phenoxy-phenyl)-5,6,7,8- tetrahydro-imidazo[1,2-b]pyridazine-3-carboxamide [Image disponible dans le document PDF, Image available in the PDF document] C / To the solution of the product (200.0 mg, 0.48 mmol) of step P of example 1 in dry <semantics>N<annotation encoding="application / x-tex">N< / annotation>< / semantics>, <semantics>N<annotation encoding="application / x-tex">N< / annotation>< / semantics>- dimethylformamide (10 mL) was added N, N-diisopropylethylamine (371.5 mg, 2.88 mmol). After 5 min, 2-fluoroacrylic acid (51.8 mg, 0.57 mmol) and HATU (273.1 mg, 0.72 mmol) was added. The reaction mixture was continued to stir at room temperature for 2 h. Ethyl acetate and water were added. The layers were separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed three times <semantics>(3×50 mL)<annotation encoding="application / x-tex">(3\times50 \text{ mL})< / annotation>< / semantics> with brine solution. The organic phase was dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by chromatography with dichloromethane and methanol (25:1) to give product as an off-white solid (37 mg, 16%). 1H NMR (400 MHz, MeOD) <semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics> 7.59-7.49 (m, 2H), 7.30-7.20 (m, 2H), 7.01 (t, <semantics>J=<annotation encoding="application / x-tex">J =< / annotation>< / semantics> 7.4 Hz, 1H), 6.96-6.84 (m, 4H), 5.09 (s, 1H), 5.05 (d, <semantics>J=3.7<annotation encoding="application / x-tex">J = 3.7< / annotation>< / semantics> Hz, 1H), 4.97 (d, <semantics>J=3.8<annotation encoding="application / x-tex">J = 3.8< / annotation>< / semantics> Hz, 1H), 4.40 (s, 1H), 3.99 (dd, <semantics>J=14.3<annotation encoding="application / x-tex">J = 14.3< / annotation>< / semantics>, 7.1 Hz, 1H), 3.32 (s, 1H), 3.13 (s, 3H), 2.80-2.55 (m, 1H), 2.45- 2.38 (M, 1H), 1.93-1.90 (M, 1H), 1.82-1.66 (m, 2H), 1.52-1.25 (m, 4H). MS (ESI, m / z): 490.2 <semantics>[M+H]+<annotation encoding="application / x-tex">[M+H]^{+}< / annotation>< / semantics>. Example 10: 2-(4-Phenoxy-phenyl)-8-[1-(4,4,4-trifluoro-but-2-enoyl)-piperidin-4-yl]-5,6,7,8- tetrahydro-imidazo[1,2-b]pyridazine-3-carboxamide [Image disponible dans le document PDF, Image available in the PDF document] Preparation of 2-(4-phenoxy-phenyl)-8-[1-(4,4,4-trifluoro-but-2-enoyl)-piperidin-4-yl]-5,6,7,8- tetrahydro-imidazo[1,2-b]pyridazine-3-carboxamide [Image disponible dans le document PDF, Image available in the PDF document] To the solution of the product (200.0 mg, 0.48 mmol) of step P of example 1 in dry N, N- dimethylformamide (10 mL) was added N, N-diisopropylethylamine (371.5 mg, 2.88 mmol). After 5 min, (E)-4,4,4-trifluorobut-2-enoic acid (80.5 mg, 0.57 mmol) and HATU (273.1 mg, 0.72 mmol) was added. The reaction mixture was continued to stir at room temperature for 2 hs. Ethyl acetate and water were added. The layers were separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed three times (3×50 mL) with brine solution. The organic phase was dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by chromatography with dichloromethane and methanol (25:1) to give product as an off- white solid (54 mg, 21%). 1H NMR (400 MHz, MeOD) <semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics> 7.58-7.50 (m, 2H), 7.29-7.21 (m, 2H), <semantics>7.20−7.11<annotation encoding="application / x-tex">7.20-7.11< / annotation>< / semantics> (m, 1H), <semantics>7.05−6.97<annotation encoding="application / x-tex">7.05-6.97< / annotation>< / semantics> (m, 1H), <semantics>6.94−6.84<annotation encoding="application / x-tex">6.94-6.84< / annotation>< / semantics> (m, 4H), <semantics>6.62−6.51<annotation encoding="application / x-tex">6.62-6.51< / annotation>< / semantics> (m, 1H), <semantics>4.53<annotation encoding="application / x-tex">4.53< / annotation>< / semantics> (dd, <semantics>J=25.1<annotation encoding="application / x-tex">J = 25.1< / annotation>< / semantics>, CA 13.2 Hz, 1H), 3.98 (dd, <semantics>J=24.9<annotation encoding="application / x-tex">J = 24.9< / annotation>< / semantics>, 13.6 Hz, 1H), 3.34-3.29 (M, 1H), 3.14-2.88 (m, 3H), 2.71-2.53 (m, 1H), 2.42-2.36 (m, 1H), 2.00-1.85 (m, 1H), 1.83-1.66 (m, 2H), 1.47-1.26 (m, 3H). MS (ESI, <semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>): 540.2 [M+H]+. [Image disponible dans le document PDF, Image available in the PDF document] 10a 1H NMR (600 MHz, CDCl3) <semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics> 7.55 (t, <semantics>J<annotation encoding="application / x-tex">J< / annotation>< / semantics> = 8.4 Hz, 2H), 7.44 (d, <semantics>J<annotation encoding="application / x-tex">J< / annotation>< / semantics> = 22.0 Hz, 1H), 7.36 (t, <semantics>J<annotation encoding="application / x-tex">J< / annotation>< / semantics> <semantics>=7.7 Hz,2H,7.15 (t, J=7.4 Hz,1H),7.06 (dd, J=11.1,8.3 Hz,4H),6.97 (t, J=14.1 Hz,1H),<annotation encoding="application / x-tex">= 7.7 \text{ Hz}, 2\text{H}, 7.15 \text{ (t, } J = 7.4 \text{ Hz}, 1\text{H}), 7.06 \text{ (dd, } J = 11.1, 8.3 \text{ Hz}, 4\text{H}), 6.97 \text{ (t, } J = 14.1 \text{ Hz}, 1\text{H}),< / annotation>< / semantics> <semantics>6.72−6.66<annotation encoding="application / x-tex">6.72-6.66< / annotation>< / semantics> (m, 1H), <semantics>5.98<annotation encoding="application / x-tex">5.98< / annotation>< / semantics> (s, 1H), <semantics>5.36<annotation encoding="application / x-tex">5.36< / annotation>< / semantics> (s, 1H), <semantics>4.77−4.70<annotation encoding="application / x-tex">4.77-4.70< / annotation>< / semantics> (m, 1H), <semantics>4.00−3.91<annotation encoding="application / x-tex">4.00-3.91< / annotation>< / semantics> (m, 1H), <semantics>3.47<annotation encoding="application / x-tex">3.47< / annotation>< / semantics> (dd, <semantics>J=<annotation encoding="application / x-tex">J =< / annotation>< / semantics> 15.7, 8.2 Hz, 2H), 3.35 (t, <semantics>J=11.2<annotation encoding="application / x-tex">J = 11.2< / annotation>< / semantics> Hz, 1H), 3.23-3.07 (m, 2H), 2.68 (q, <semantics>J=13.2<annotation encoding="application / x-tex">J = 13.2< / annotation>< / semantics> Hz, 1H), 2.54 <semantics>(dd,J=26.3,13.5Hz,1H),2.07(s,1H),1.97−1.83(m,2H),1.55−1.38(m,2H).<annotation encoding="application / x-tex">(dd, J = 26.3, 13.5 Hz, 1H), 2.07 (s, 1H), 1.97-1.83 (m, 2H), 1.55-1.38 (m, 2H).< / annotation>< / semantics> [Image disponible dans le document PDF, Image available in the PDF document] 10b 1H NMR (600 MHz, CDCl3) <semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics> 7.55 (t, <semantics>J<annotation encoding="application / x-tex">J< / annotation>< / semantics> = 8.4 Hz, 2H), 7.45 (d, <semantics>J<annotation encoding="application / x-tex">J< / annotation>< / semantics> = 21.4 Hz, 1H), 7.37 (t, <semantics>J<annotation encoding="application / x-tex">J< / annotation>< / semantics> <semantics>=7.8 Hz,2H,7.15 (t, J=7.4 Hz,1H),7.06 (dd, J=11.6,8.5 Hz,4H),6.96 (d, J=13.8 Hz,1H),<annotation encoding="application / x-tex">= 7.8 \text{ Hz}, 2\text{H}, 7.15 \text{ (t, } J = 7.4 \text{ Hz}, 1\text{H}), 7.06 \text{ (dd, } J = 11.6, 8.5 \text{ Hz}, 4\text{H}), 6.96 \text{ (d, } J = 13.8 \text{ Hz}, 1\text{H}),< / annotation>< / semantics> <semantics>6.74−6.65<annotation encoding="application / x-tex">6.74-6.65< / annotation>< / semantics> (m, 1H), <semantics>5.97<annotation encoding="application / x-tex">5.97< / annotation>< / semantics> (s, 1H), <semantics>5.35<annotation encoding="application / x-tex">5.35< / annotation>< / semantics> (s, 1H), <semantics>4.77−4.70<annotation encoding="application / x-tex">4.77-4.70< / annotation>< / semantics> (m, 1H), <semantics>4.00−3.91<annotation encoding="application / x-tex">4.00-3.91< / annotation>< / semantics> (m, 1H), <semantics>3.47<annotation encoding="application / x-tex">3.47< / annotation>< / semantics> (dd, <semantics>J=<annotation encoding="application / x-tex">J =< / annotation>< / semantics> 16.4, 8.2 Hz, 2H), 3.35 (t, <semantics>J=11.2<annotation encoding="application / x-tex">J = 11.2< / annotation>< / semantics> Hz, 1H), 3.19-3.10 (m, 2H), 2.68 (q, <semantics>J=13.1<annotation encoding="application / x-tex">J = 13.1< / annotation>< / semantics> Hz, 1H), 2.63- 2.45 (m, 1H), 2.07 (s, 1H), 1.99-1.79 (m, 2H), 1.56-1.39 (m, 2H). Compound example 10 was separated into two enantiomeric stereoisomers compound 10a (peak 1, levoisomer, retention time at 7.8 min in chiral analysis), and compound 10b (peak 2, dextroisomer, retention time at 8.9 min in chiral analysis) by chiral prep-HPLC. The chiral separation conditions are shown below. [Image disponible dans le document PDF, Image available in the PDF document] Sample solution 5 mg / mL The chiral analysis condition is shown below. [Image disponible dans le document PDF, Image available in the PDF document] The specific rotation of compound 10a and compound 10b was measured by polarimeter. Specific rotation measurement conditions are shown below. [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] Example 11: 2-(4-phenoxyphenyl)-8-(1-propioloylpiperidin-4-yl)-5,6,7,8-tetrahydroimidazo[1,2- b]pyridazine-3-carboxamide [Image disponible dans le document PDF, Image available in the PDF document] Preparation of 2-(4-phenoxyphenyl)-8-(1-propioloylpiperidin-4-yl)-5,6,7,8- tetrahydroimidazo[1,2-b]pyridazine-3-carboxamide [Image disponible dans le document PDF, Image available in the PDF document] To the solution of the product (200.0 mg, 0.48 mmol) of step P of example 1 in dry N, N- dimethylformamide (10 mL) was added N, N-diisopropylethylamine (371.5 mg, 2.88 mmol). After 5 min, propiolic acid (167.3 mg, 0.57 mmol) and HATU (273 mg, 0.72 mmol) was added. The reaction mixture was continued to stir at room temperature for 2 hs. Ethyl acetate and water were added. The layers were separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed three times (3×50 mL) with brine solution. The organic phase was dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by chromatography with dichloromethane and methanol (25:1) to give product as an off-white solid (54 mg, 23%). 1H NMR (600 MHz, MeOD) <semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics> 7.64 (d, <semantics>J=8.2<annotation encoding="application / x-tex">J = 8.2< / annotation>< / semantics> Hz, 2H), 7.36 (t, <semantics>J=7.6<annotation encoding="application / x-tex">J = 7.6< / annotation>< / semantics> Hz, 2H), 7.13 (t, <semantics>J=7.4<annotation encoding="application / x-tex">J = 7.4< / annotation>< / semantics> Hz, 1H), 7.01 (dd, <semantics>J=17.4<annotation encoding="application / x-tex">J = 17.4< / annotation>< / semantics>, 8.1 Hz, 4H), 4.62-4.42 (m, 2H), 3.97 (d, <semantics>J=10.9<annotation encoding="application / x-tex">J = 10.9< / annotation>< / semantics> Hz, 1H), 3.46 (d, <semantics>J=13.8<annotation encoding="application / x-tex">J = 13.8< / annotation>< / semantics> Hz, 1H), 3.28-3.14 (m, 3H), 2.79-2.67 (m, 1H), 2.50 (s, 1H), 2.04 (d, <semantics>J=13.8<annotation encoding="application / x-tex">J = 13.8< / annotation>< / semantics> Hz, 1H), 3.28-3.14 (m, 3H), 2.79-2.67 (m, 1H), 2.50 (s, 1H), 2.04 (d, <semantics>J=13.8<annotation encoding="application / x-tex">J = 13.8< / annotation>< / semantics> Hz, 1H), 3.28-3.14 (m, 3H), 2.79-2 10.5 Hz, 1H), 1.93-1.80 (m, 2H), 1.55 (d, <semantics>J=12.0<annotation encoding="application / x-tex">J = 12.0< / annotation>< / semantics> Hz, 1H), 1.52-1.31 (m, 2H). MS (ESI, <semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>): 470.2 [M+H]+. Examples 12: 8-(1-acryloylpiperidin-4-yl)-2-(4-(4-fluorophenoxy)phenyl)-5,6,7,8- tetrahydroimidazo[1,2-b]pyridazine-3-carboxamide [Image disponible dans le document PDF, Image available in the PDF document] Step A: Preparation of methyl 3-(4-(4-fluorophenoxy)phenyl)-3-oxopropanoate [Image disponible dans le document PDF, Image available in the PDF document] To a stirred suspension of NaH (60% dispersion in mineral oil; 469.0 g, 11.73 mol) in N, N- dimethylformamide(3 L) at 0°C was added dropwise 1-(4-(4-fluorophenoxy)phenyl)ethan-1-one (1.8 kg, 7.82 mol) dissolved in N,N-dimethylformamide(2 L). After 30 minutes, the mixture was cooled to 0°C and dimethylcarbonate (3.5 kg, 39.01 mol) was added. The mixture was allowed to warm to room temperature over a 2-hour period and then poured into water / saturated sodium bicarbonate (1:1). The aqueous layer was extracted with ethyl acetate, and 1 mol / L cooled glacial acetic acid was added dropwise until pH 6-7. The residue was extracted with ethyl acetate (3×1500 mL), the combined organic layer was washed with saturated brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by chromatography with petroleum ether and ethyl acetate (12:1) to afford product as a yellow oil (2.1 kg, 93%). 1H NMR (400 MHz, DMSO- d6) <semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics> 7.99 (d, <semantics>J=8.9<annotation encoding="application / x-tex">J = 8.9< / annotation>< / semantics> 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, <semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>): 289.1 [M+H]+. Step B: Preparation of methyl 2-bromo-3-(4-(4-fluorophenoxy)phenyl)-3-oxopropanoate [Image disponible dans le document PDF, Image available in the PDF document] To a solution of the product of step A of example 12 (1.0 kg, 3.47 mol) in CHCl3 (5 L) was added N-bromosuccinimide (217.0 g, 3.82 mol) and azobisisobutyronitrile (284.8 g, 1.73 mol). The reaction mixture was refluxing for 6 hs. Then the CHCl3 was evaporated. The residue was diluted with 100 mL ethyl acetate. The mixture was washed with aqueous 5% HCl (2×1000 mL) and 500 mL water and then dried over anhydrous sodium sulfate. Evaporation of the solvent gave the crude product as oil, the crude residue was flash chromatographed with ethyl acetate and petroleum ether (1:10) to get the product as yellow oil (1.0 kg, 78%). 1H NMR (600 MHz, CDCl3) <semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics> 7.97 (d, <semantics>J=7.8<annotation encoding="application / x-tex">J = 7.8< / annotation>< / semantics> Hz, 2H), 7.13-7.09 (m, 2H), 7.08-7.04 (m, 2H), 6.98 (d, <semantics>J=7.8<annotation encoding="application / x-tex">J = 7.8< / annotation>< / semantics> Hz, 2H), 5.63 (s, 1H), 3.83 (s, 3H). MS (ESI, <semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>): 367.9 [M+H]+. Step C: Preparation of tert-butyl 4-(4-(4-(4-fluorophenoxy)benzoyl)-11,11,12,12-tetramethyl- 3,6-dioxo-2,5,10-trioxa-11-silatridecan-7-yl)piperidine-1-carboxylate [Image disponible dans le document PDF, Image available in the PDF document] To a solution of the product of step G of example 1 (39.4 g, 98.05 mmol) and N, N- disopropylethylamine (15.8 g, 122.56 mmol) in acetonitrile (500 ml) was added the product of step B of example 12 (30.0 g, 81.71 mmol). The mixture was stirred at 30°C for 3 hs. The solvent was removed by rotorary evaporation and the residue taken up inethyl acetate, washed with 0.1 N HCl, and brine. The organic fractions were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude product which was purified via flash chromatography eluting with ethyl acetate and petroleum ether (1:10) to give the product as a clear colorless oil (46 g, 81.8%). 1H NMR (400 MHz, CDCl3) <semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics> 8.00-7.91 (m, 2H), 7.12-7.02 (m, 4H), <Formule mathématique disponible dans le document PDF, Math available in the PDF document>6.95 \text{ (d, } J = 8.9 \text{ Hz, } 2\text{H)}, 6.23 \text{ (s, } 1\text{H)}, 4.16\text{-}4.02 \text{ (m, } 2\text{H)}, 3.76 \text{ (s, } 3\text{H)}, 3.68\text{-}3.58 \text{ (m, } 1\text{H)}, 3.58\text{-}3.58 \text{ (m, } 1\text{H)}, 3.58\text{-}3.58 \text{ (m, } 1\text{H)}, 3.58\text{-}3.58 \text{ ( 3.48 (m, 1H), 2.70-2.51 (m, 3H), 1.90-1.78 (m, 2H), 1.74-1.65 (m, 1H), 1.61 (d, <semantics>J=8.5<annotation encoding="application / x-tex">J = 8.5< / annotation>< / semantics> Hz, 2H), 1.43 (d, <semantics>J=1.4<annotation encoding="application / x-tex">J = 1.4< / annotation>< / semantics> Hz, 9H), 1.28-1.21 (m, 2H), 0.83 (d, <semantics>J=13.4<annotation encoding="application / x-tex">J = 13.4< / annotation>< / semantics> Hz, 9H), 0-(-0.05) (m, 6H). MS (ESI, <semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>): 574.2 [M+H]+. Step <semantics>𝑫<annotation encoding="application / x-tex">\mathbf{D}< / annotation>< / semantics>: Preparation of tert-butyl 4-(3-((tert-butyldimethylsilyl)oxy)-1-(4-(4-(4- fluorophenoxy)phenyl)-5-(methoxycarbonyl)-1H-imidazol-2-yl)propyl)piperidine-1-carboxylate [Image disponible dans le document PDF, Image available in the PDF document] To a slurry of ammonium acetate (49.7 g, 1.72 mol) in xylenes (150 mL) was added the product of step C of example 12 (36.0 g, 52.33 mmol). The mixture was stirred at 140°C, for 4 hs. The solution was cooled to room temperature and the solvent was evaporated. The residue was dissolved in EA and washed with saturated brine. The organic phase was dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography with ethyl acetate and petroleum ether (1:5) to give the product as a clear colorless oil (14 g, 33%). 1H NMR (600 MHz, CDCl3) <semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics> 10.06 (s, 1H), 7.88 (d, <semantics>J<annotation encoding="application / x-tex">J< / annotation>< / semantics> = 6.7 Hz, 2H), 7.02-6.97 (m, 6H), 4.11- 4.04 (m, 2H), 3.81 (s, 3H), 3.64-3.60 (m, 1H), 2.80 (s, 1H), 2.64 (s, 2H), 2.02-1.95 (m, 4H), 1.83 <semantics>(d,J=12.0 Hz,1H),1.66 (s, 1H),1.42 (s, 9H),1.16 (d, J=9.3 Hz,2H),0.86 (s, 9H),0.00 (s, 6H).<annotation encoding="application / x-tex">(d, J = 12.0 \text{ Hz}, 1H), 1.66 \text{ (s, 1H)}, 1.42 \text{ (s, 9H)}, 1.16 \text{ (d, } J = 9.3 \text{ Hz}, 2H), 0.86 \text{ (s, 9H)}, 0.00 \text{ (s, 6H)}.< / annotation>< / semantics> MS (ESI, <semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>): 668.4 [M+H]+. Step E: Preparation of tert-butyl 4-(1-(1-amino-4-(4-(4-fluorophenoxy)phenyl)-5- (methoxycarbonyl)-1H-imidazol-2-yl)-3-((tert-butyldimethylsilyl)oxy)propyl)piperidine-1- carboxylate [Image disponible dans le document PDF, Image available in the PDF document] Lithium hexamethyldisilazane (18 mL of a 1 M solution intetrahydrofuran, 17.97 mmol) was slowly added to the product of step D of example 12 (8.0 g, 11.98 mmol) in anhydrous N,N- dimethylformamide (100 mL) at 0 <semantics>∘<annotation encoding="application / x-tex">^{\circ}< / annotation>< / semantics>C. After the mixture was stirred for 30 min, O- (diphenylphosphinyl) hydroxylamine (5.6 g, 23.96 mmol) was added at 0°C, followed by stirring at room temperature for 4 hs (in cases where the reaction mixture became too viscous, additional N,N-dimethylformamidewas added). The reaction was quenched with water until a clear solution was formed and concentrated to dryness under reduced pressure. The residue was washed several times with ethyl acetate or dichloromethane. The combined organic fractions were concentrated in vacuo and purified by flash chromatography on silica gel with ethyl acetate and petroleum ether (1:3) to give the product as a clear colorless oil (6.4 g, 78%). 1H NMR (600 MHz, CDCl3) <semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics> 7.60 <semantics>(d,J=7.9 Hz,2H),7.04−6.98 (m, 4H),6.96 (d, J=7.9 Hz,2H),5.58 (s, 2H),4.18−3.95 (m, 2H),<annotation encoding="application / x-tex">(d, J = 7.9 \text{ Hz}, 2H), 7.04-6.98 \text{ (m, 4H)}, 6.96 \text{ (d, } J = 7.9 \text{ Hz}, 2H), 5.58 \text{ (s, 2H)}, 4.18-3.95 \text{ (m, 2H)},< / annotation>< / semantics> 3.77 (s, 3H), 3.66-3.56 (m, 1H), 3.34 (d, <semantics>J=6.3<annotation encoding="application / x-tex">J = 6.3< / annotation>< / semantics> Hz, 2H), 2.72-2.57 (m, 2H), 2.04-1.99 (m, 2H), <semantics>1.98−1.88 (m, 2H),1.43 (s, 9H),1.38−1.34 (m, 1H),1.27−1.16 (m, 2H),0.85 (s, 9H),−0.01 (d, J=0.01)<annotation encoding="application / x-tex">1.98-1.88 \text{ (m, 2H)}, 1.43 \text{ (s, 9H)}, 1.38-1.34 \text{ (m, 1H)}, 1.27-1.16 \text{ (m, 2H)}, 0.85 \text{ (s, 9H)}, -0.01 \text{ (d, } J = 0.01)< / annotation>< / semantics> 17.7 Hz, 6H). MS (ESI, <semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>): 683.4 [M+H]+. Step F: Preparation of tert-butyl 4-(1-(1-amino-4-(4-(4-fluorophenoxy)phenyl)-5- (methoxycarbonyl)-1H-imidazol-2-yl)-3-hydroxypropyl)piperidine-1-carboxylate [Image disponible dans le document PDF, Image available in the PDF document] __C To a solution of the product of step E of example 12 (6.4 g, 9.37 mmol) in tetrahydrofuran (50 mL) was added a 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran (14 mL, 14.05) mmol) at RT. The solution was stirred for 2 hs and diluted with 100 mL ethyl acetate solution. The organic layer was separated and washed with H2O (3×200 mL). The water extract was washed with ethyl acetate solution (<semantics>2×150<annotation encoding="application / x-tex">2\times150< / annotation>< / semantics> mL), and the organic layers were combined and dried over anhydrous Na2SO4. The solvent was evaporated in vacuo, and purified by flash chromatography on silica gel with dichloromethane and methanol (35:1) to give the product as a clear colorless oil <semantics>(5.1g,95%)<annotation encoding="application / x-tex">(5.1g, 95\%)< / annotation>< / semantics>. 1H NMR <semantics>(600 MHz,CDCl3)δ7.61 (d, J=7.9 Hz, 2H),7.06−6.99 (m, 4H),6.97 (d, 3.16 (d, 3.16 (d, 3.16 (d, 3.16 (d, 3.16 (d, 3.16 (d, 3.16 (d, <annotation encoding="application / x-tex">(600 \text{ MHz}, \text{CDCl}_3) \delta 7.61 \text{ (d, } J = 7.9 \text{ Hz, 2H)}, 7.06-6.99 \text{ (m, 4H)}, 6.97 \text{ (d, } 3.16 \text{ (d, } 3.16 \text{ (d, } 3.16 \text{ (d, } 3.16 \text{ (d, } 3.16 \text{ (d, } 3.16 \text{ (d, } 3.16 \text{ (d, }< / annotation>< / semantics> <semantics>J=7.8 Hz<annotation encoding="application / x-tex">J = 7.8 \text{ Hz}< / annotation>< / semantics>, 2H), 5.52 (s, 2H), 4.20-3.98 (m, 2H), 3.79 (s, 3H), 3.68-3.60 (m, 1H), 3.50-3.42 (m, 1H), 3.36-3.30 (m, 1H), 2.76-2.58 (m, 2H), 2.11-1.98 (m, 3H), 1.94-1.86 (m, 1H), 1.63 (s, 1H), 1.44 (s, 9H), 1.35-1.30 (m, 1H), 1.26-1.16 (m, 2H). MS (ESI, <semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>): 569.3 [M+H]+. Step <semantics>G<annotation encoding="application / x-tex">G< / annotation>< / semantics>: Preparation of methyl 8-(1-(tert-butoxycarbonyl)piperidin-4-yl)-2-(4-(4- fluorophenoxy)phenyl)-5,6,7,8-tetrahydroimidazo[1,2-b]pyridazine-3-carboxylate [Image disponible dans le document PDF, Image available in the PDF document] Methanesulfonyl chloride (1.3 g, 11.43 mmol) was added via syringe into a stirred mixture of the product of step F of example 12 (5.0 g, 8.79 mmol) and N, N-diisopropylethylamine (3.4 g, 26.38 mmol) in dichloromethane (100 ml) maintained at 0°C. Then the mixture was stirred at room temperature overnight (TLC monitoring) and then partitioned between dichloromethane and water. The organic phase was dried and evaporated to afford a white solid. The crude intermediate was dissolved in tetrahydrofuran(20 mL), 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran(11 mL, 11.48 mmol) and N, N-diisopropylethylamine (2.0 g, 15.31 mmol) was added to the mixture, which was stirred 3hs, then partitioned between dichloromethane and water. The organic phase was dried and evaporated to afford a white solid, then passed through a column of silica gel with dichloromethane and methanol (30:1) to afford the desired product as a colorless oil (3.5 g, 72%). 1H NMR (600 MHz, CDCl3) <semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics> 7.65-7.61 (m, 2H), 7.06-7.01 (m, 4H), 6.99-6.95 (m, 2H), 4.17 (s, 2H), 3.78 (s, 3H), 3.51-3.43 (m, 1H), 3.38-3.32 (m, 1H), 3.11 (s, 1H), 2.71 (s, 2H), 2.42 (s, 1H), 2.10-2.02 (m, 1H), 1.98-1.90 (m, 1H), 1.77-1.71 (m, 1H), 1.45 (s, 9H), 1.42- 1.24 (m, 3H). MS (ESI, <semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>): 551.3 [M+H]+. Step H: Preparation of tert-butyl 4-(3-carbamoyl-2-(4-(4-fluorophenoxy)phenyl)-5,6,7,8- tetrahydroimidazo[1,2-b]pyridazin-8-yl)piperidine-1-carboxylate [Image disponible dans le document PDF, Image available in the PDF document] To a solution of the product of step G of example 12 (3.4 g, 6.17 mmol) in tetrahydrofuran(20 mL) was added LiOH (739.3 mg, 30.87 mmol) in water (5 mL), the mixture was heated at 50°C for 3 hs, then cooled to r.t. The mixture acidified to pH 3-4 with concentrated HCl and then extracted with 3×100mL of dichloromethane. The organic phase was washed with saturated brine and then dried over anhydrous Na2SO4. The organic phase was concentrated in vacuo to afford 3.7 g crude product. The residue was used to next step without further purification. Step Preparation of 8-(1-(tert-butoxycarbonyl)piperidin-4-yl)-2-(4-(4- fluorophenoxy)phenyl)-5,6,7,8-tetrahydroimidazo[1,2-b]pyridazine-3-carboxylic acid [Image disponible dans le document PDF, Image available in the PDF document] To the solution of the product of step H of example 12 (3.5 g, 6.52 mmol) in dichloromethane (30 mL) was added N, N-diisopropylethylamine (3.4 g, 26.09 mmol). After 5 min, NH4Cl (1.4 g, 26.09 mmol) and HATU (3.72 g, 9.78 mmol) was added. The reaction mixture was continued to stir at room temperature for 2 hs. Dichloromethane and water were added. The layers were separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed three times (3×50 mL) with brine solution. The organic phase was dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by chromatography with dichloromethane and methanol (40:1) to give product as an off-white solid (2.3 g, 65%). 1H NMR <semantics>(400 MHz,CDCl3)δ7.59−7.55 (m, 2H),7.26 (s, 1H),7.07−7.00 (m, 6H),6.09 (s, 1H),5.42 (s, 1H),<annotation encoding="application / x-tex">(400 \text{ MHz}, \text{CDCl}_3) \delta 7.59-7.55 \text{ (m, 2H)}, 7.26 \text{ (s, 1H)}, 7.07-7.00 \text{ (m, 6H)}, 6.09 \text{ (s, 1H)}, 5.42 \text{ (s, 1H)},< / annotation>< / semantics> 4.17 (s, 2H), 3.50-3.41 (m, 1H), 3.39-3.29 (m, 1H), 3.15-3.06 (m, 1H), 2.76-2.64 (m, 2H), 2.44- 2.34 (m, 1H), 2.11-2.02 (m, 1H), 1.99-1.87 (m, 1H), 1.76-1.68 (m, 2H), 1.45 (s, 9H), 1.42-1.25 (m, 2H). MS (ESI, <semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>): 536.3 [M+H]+. Step J: Preparation of 2-(4-(4-fluorophenoxy)phenyl)-8-(piperidin-4-yl)-5,6,7,8- tetrahydroimidazo[1,2-b]pyridazine-3-carboxamide [Image disponible dans le document PDF, Image available in the PDF document] To a solution of the product of step I of example 12 (2.3 g, 4.29 mmol) in EtOH (15 mL) was added 33% HCl / EtOH (10 mL) at room temperature in reaction still. The mixture was stirred for 3 hs. the mixture was concentrated under vacuum to get 3.5 g crude product. The residue was used to next step without further purification. MS (ESI, <semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>): 436.2 [M+H]+. Step K: Preparation of 8-(1-acryloylpiperidin-4-yl)-2-(4-(4-fluorophenoxy)phenyl)-5,6,7,8- tetrahydroimidazo|1,2-b|pyridazine-3-carboxamide [Image disponible dans le document PDF, Image available in the PDF document] The mixture of the product of step J of example 12 (200.0 mg, 0.46 mmol) and triethylamine(278.7) mg, 2.76 mmol) in dichloromethane (5 mL) was cooled to -60°C. Then the solution of propencyl chloride (45.0 mg, 0.51 mmol) in dichloromethane (3 mL) was added slowly, LC-MS was tracking, at the end of the reaction, 1 mL MeOH was added, the mixture was concentrated under vacuum to get 700 mg crude, and purified by flash chromatography on silica gel with dichloromethane and methanol (40:1) to get product as a white solid (41 mg, 30%). 1H NMR (400 MHz, MeOD) <semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics> 7.54 <semantics>(d,J=8.4 Hz,2H),7.05−6.92 (m, 4H),6.86 (d, J=8.7 Hz,2H),6.71−6.61 (m, 1H),6.10−6.03 (m, 1H)<annotation encoding="application / x-tex">(d, J = 8.4 \text{ Hz}, 2H), 7.05-6.92 \text{ (m, 4H)}, 6.86 \text{ (d, } J = 8.7 \text{ Hz}, 2H), 6.71-6.61 \text{ (m, 1H)}, 6.10-6.03 \text{ (m, 1H)}< / annotation>< / semantics> 1H), 5.65-5.58 (m, 1H), 4.60-4.51 (m, 1H), 4.12-4.03 (m, 1H), 3.37-3.31 (m, 1H), 3.19-2.97 (m, 3H), <semantics>2.70−2.52<annotation encoding="application / x-tex">2.70-2.52< / annotation>< / semantics> (m, 1H), <semantics>2.46−2.34<annotation encoding="application / x-tex">2.46-2.34< / annotation>< / semantics> (m, 1H), <semantics>1.91<annotation encoding="application / x-tex">1.91< / annotation>< / semantics> (d, <semantics>J=4.4<annotation encoding="application / x-tex">J = 4.4< / annotation>< / semantics> Hz, 1H), <semantics>1.78−1.72<annotation encoding="application / x-tex">1.78-1.72< / annotation>< / semantics> (m, 2H), <semantics>1.42−1.30<annotation encoding="application / x-tex">1.42-1.30< / annotation>< / semantics> (m, 3H). MS (ESI, <semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>): 490.2 [M+H]+. Example 13: 8-(1-(but-2-ynoyl)piperidin-4-yl)-2-(4-(4-fluorophenoxy)phenyl)-5,6,7,8- tetrahydroimidazo[1,2-b]pyridazine-3-carboxamide [Image disponible dans le document PDF, Image available in the PDF document] Preparation of 8-(1-(but-2-ynoyl)piperidin-4-yl)-2-(4-(4-fluorophenoxy)phenyl)-5,6,7,8- tetrahydroimidazo|1,2-b|pyridazine-3-carboxamide [Image disponible dans le document PDF, Image available in the PDF document] To the solution of the product (200 mg, 0.46 mmol) of step J of example 12 in dry N, N- dimethylformamide (5 mL) was added N, N-diisopropylethylamine (356.0 mg, 2.76 mmol). After 5 min, but-2-ynoic acid (46.3 mg, 0.55 mmol) and HATU (262.2 mg, 0.69 mmol) was added. The C reaction mixture was continued to stir at room temperature for 2 hs. Ethyl acetate and water were added. The layers were separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed three times (3×50 mL) with brine solution. The organic phase was dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by chromatography with dichloromethane and methanol (25:1) to give product as an off-white solid <semantics>(56 mg,24%)<annotation encoding="application / x-tex">(56 \text{ mg}, 24\%)< / annotation>< / semantics>. 1H NMR <semantics>(400 MHz,DMSO−d6)δ7.89 (s, 1H),7.83−7.76 (m, 2H),7.46 (s, 1H),<annotation encoding="application / x-tex">(400 \text{ MHz}, \text{DMSO}-d6) \delta 7.89 \text{ (s, 1H)}, 7.83-7.76 \text{ (m, 2H)}, 7.46 \text{ (s, 1H)},< / annotation>< / semantics> <semantics>7.27−7.21<annotation encoding="application / x-tex">7.27-7.21< / annotation>< / semantics> (m, 2H), <semantics>7.12−7.06<annotation encoding="application / x-tex">7.12-7.06< / annotation>< / semantics> (m, 2H), <semantics>6.96<annotation encoding="application / x-tex">6.96< / annotation>< / semantics> (d, <semantics>J=8.7<annotation encoding="application / x-tex">J = 8.7< / annotation>< / semantics> Hz, 2H), <semantics>6.55<annotation encoding="application / x-tex">6.55< / annotation>< / semantics> (d, <semantics>J=9.6<annotation encoding="application / x-tex">J = 9.6< / annotation>< / semantics> Hz, 1H), <semantics>4.42−4.25<annotation encoding="application / x-tex">4.42-4.25< / annotation>< / semantics> (m, 2H), 3.16-3.08 (m, 2H), 3.03 (d, <semantics>J=9.3<annotation encoding="application / x-tex">J = 9.3< / annotation>< / semantics> Hz, 1H), 2.70-2.56 (m, 1H), 2.27 (s, 1H), 2.01 (d, <semantics>J=<annotation encoding="application / x-tex">J =< / annotation>< / semantics> 4.6 Hz, 3H), 1.97-1.84 (m, 2H), 1.75-1.64 (m, 1H), 1.51-1.43 (m, 1H), 1.34-1.21 (m, 3H). MS <semantics>(ESI,m / z)<annotation encoding="application / x-tex">(ESI, m / z)< / annotation>< / semantics>: 502.2 [M+H]+. Example 14: (E)-2-(4-(4-fluorophenoxy)phenyl)-8-(1-(4,4,4-trifluorobut-2-enoyl)piperidin-4-yl)-5,6,7,8- tetrahydroimidazo[1,2-b]pyridazine-3-carboxamide [Image disponible dans le document PDF, Image available in the PDF document] Preparation of (E)-2-(4-(4-fluorophenoxy)phenyl)-8-(1-(4,4,4-trifluorobut-2-enoyl)piperidin-4- yl)-5,6,7,8-tetrahydroimidazo[1,2-b]pyridazine-3-carboxamide [Image disponible dans le document PDF, Image available in the PDF document] To the solution of the product of step J of example 12 (200 mg, 0.46 mmol) in dry N, N- dimethylformamide (5 mL) was added N, N-diisopropylethylamine (356.0 mg, 2.76 mmol). After 5 min, (E)-4,4,4-trifluorobut-2-enoic acid (83.6 mg, 0.60 mmol) and HATU (262.2 mg, 0.69 mmol) was added. The reaction mixture was continued to stir at room temperature for 2 h. Ethyl acetate and water were added. The layers were separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed three times (3 <semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics> 50 mL) with brine solution. The organic phase was dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by chromatography with dichloromethane and methanol (25:1) to give product as an off- white solid (56 mg, 24%). 1H NMR (400 MHz, CDCl3) <semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics> 7.58-7.55 (m, 2H), 7.28-7.22 (m, 1H), 7.06-6.96 (m, 6H), 6.72-6.64 (m, 1H), 6.16 (s, 1H), 5.58 (s, 1H), 4.82-4.65 (m, 1H), 4.06-3.98 (m, ( 1H), 3.40 (s, 1H), 3.39-3.29 (m, 1H), 3.18-3.08 (m, 2H), 2.74-2.61 (m, 1H), 2.59-2.45 (m, 1H), <semantics>2.12−2.02<annotation encoding="application / x-tex">2.12-2.02< / annotation>< / semantics> (m, 1H), <semantics>1.98−1.76<annotation encoding="application / x-tex">1.98-1.76< / annotation>< / semantics> (m, 3H), <semantics>1.65−1.57<annotation encoding="application / x-tex">1.65-1.57< / annotation>< / semantics> (m, 1H), <semantics>1.55−1.41<annotation encoding="application / x-tex">1.55-1.41< / annotation>< / semantics> (m, 2H). MS (ESI, <semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>): <semantics>558.2<annotation encoding="application / x-tex">558.2< / annotation>< / semantics> <semantics>[M+H]+<annotation encoding="application / x-tex">[M+H]^{+}< / annotation>< / semantics> Example 15: 8-(1-acryloylpiperidin-4-yl)-2-(4-(4-methoxyphenoxy)phenyl)-5,6,7,8- tetrahydroimidazo[1,2-b]pyridazine-3-carboxamide [Image disponible dans le document PDF, Image available in the PDF document] Step A: Preparation of methyl 3-(4-(4-methoxyphenoxy)phenyl)-3-oxopropanoate [Image disponible dans le document PDF, Image available in the PDF document] To a stirred suspension of NaH (60% dispersion in mineral oil; 495.3 g, 12.38 mol) in N, N- dimethylformamide(3 L) at 0°C was added dropwise 1-(4-phenoxyphenyl)ethanone (2.0 kg, 8.26) mol) dissolved in N, N-dimethylformamide(2 L). After 30 minutes, the mixture was cooled to 0 °C and dimethylcarbonate (3.7 kg, 41.28 mol) was added. The mixture was allowed to warm to room temperature over a 2hs period and then poured into water / saturated sodium bicarbonate (1:1). The aqueous layer was extracted with ethyl acetate, and after removal of the solvent under vacuum, the crude residue was flash chromatographed with ethyl acetate and petroleum ether (1:10) to give product as yellow oil (2.2 kg, 88%). 1H NMR (400 MHz, DMSO-d6) <semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics> 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, <semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>): 301.1 <semantics>[M+H]+<annotation encoding="application / x-tex">[M+H]^+< / annotation>< / semantics> Step B: Preparation of methyl 2-bromo-3-(4-(4-methoxyphenoxy)phenyl)-3-oxopropanoate [Image disponible dans le document PDF, Image available in the PDF document] To a solution of the product of step A of example 15 (1.0 kg, 3.33 mol) in CHCl3 (5 L) was added N-bromosuccinimide (651.9 g, 3.66 mol) and azobisisobutyronitrile (273.4 g, 1.66 mol). The reaction mixture was refluxing for 6 hs. Then the CHCl3 was evaporated. The residue was diluted with 100 mL ethyl acetate. The mixture was washed with aqueous 5% HCl (2×1000 mL) and 500 mL water and then dried over anhydrous sodium sulfate. Evaporation of the solvent gave the crude product as oil, the crude residue was flash chromatographed with ethyl acetate and petroleum ether (1:10) to give product as yellow oil (980 g, 77%). 1H NMR (400 MHz, CDCl3) <semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics> 7.99-7.91 (m, 2H), 7.04-6.99 (m, 2H), 6.97-6.92 (m, 4H), 5.64 (s, 1H), 3.82 (d, <semantics>J=1.3<annotation encoding="application / x-tex">J = 1.3< / annotation>< / semantics> Hz, 6H). MS (ESI, <semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>): 380.0 [M+H]+. Step C: Preparation of tert-butyl 4-(4-(4-methoxyphenoxy)benzoyl)-11,11,12,12- tetramethyl-3,6-dioxo-2,5,10-trioxa-11-silatridecan-7-yl)piperidine-1-carboxylate [Image disponible dans le document PDF, Image available in the PDF document] The product of step G (38.1 g, 94.94 mmol) of example 1 and The product of step B of example 15 (30.0 g, 79.11 mmol) were taken up in acetonitrile (250 mL), then N, N-diisopropylethylamine (15.3 g, 118.66 mmol) was added and the solution stirred at 30 °C for 3 hs. The solvent was removed by rotorary evaporation and the residue taken up in ethyl acetate, washed with 0.1 N HCl, and brine. The organic fractions were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude product which was purified via flash chromatography eluting with ethyl acetate and petroleum ether (1:10) to give the product as a clear colorless oil (48) g, 87%). 1H NMR (400 MHz, CDCl3) <semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics> 7.93 (d, <semantics>J=8.7<annotation encoding="application / x-tex">J = 8.7< / annotation>< / semantics> Hz, 2H), 7.00 (d, <semantics>J=8.7<annotation encoding="application / x-tex">J = 8.7< / annotation>< / semantics> Hz, 2H), 6.92 <semantics>(dd,J=10.1,5.2 Hz,4H),6.23 (s, 1H),4.09 (d, J=4.9 Hz,2H),3.87−3.72 (m, 6H),3.65−3.60 (m, 1H)<annotation encoding="application / x-tex">(dd, J = 10.1, 5.2 \text{ Hz}, 4H), 6.23 \text{ (s, 1H)}, 4.09 \text{ (d, } J = 4.9 \text{ Hz}, 2H), 3.87-3.72 \text{ (m, 6H)}, 3.65-3.60 \text{ (m, 1H)}< / annotation>< / semantics> 1H), <semantics>3.58−3.46<annotation encoding="application / x-tex">3.58-3.46< / annotation>< / semantics> (m, 1H), <semantics>2.62<annotation encoding="application / x-tex">2.62< / annotation>< / semantics> (d, <semantics>J=11.0<annotation encoding="application / x-tex">J = 11.0< / annotation>< / semantics> Hz, 1H), <semantics>2.59−2.48<annotation encoding="application / x-tex">2.59-2.48< / annotation>< / semantics> (m, 1H), <semantics>1.92−1.77<annotation encoding="application / x-tex">1.92-1.77< / annotation>< / semantics> (m, 2H), <semantics>1.77−1.77<annotation encoding="application / x-tex">1.77-1.77< / annotation>< / semantics> 1.67 (m, 2H), 1.68-1.55 (m, 2H), 1.42 (s, 9H), 1.34-1.18 (m, 2H), 0.86-0.80 (m, 9H), -0.01 (dd, J = 17.6, 6.6 Hz, 6H). MS (ESI, <semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>): 700.3 [M+H]+. Step D: Preparation of tert-butyl 4-(3-((tert-butyldimethylsilyl)oxy)-1-(5-(methoxycarbonyl)-4- (4-(4-methoxyphenoxy)phenyl)-1H-imidazol-2-yl)propyl)piperidine-1-carboxylate [Image disponible dans le document PDF, Image available in the PDF document] To a slurry of ammonium acetate (37.9 g, 491.76 mmol) in xylenes (150 mL) was added the product of step C of example 15 (24.0 g, 40.98 mmol). The mixture was stirred at 140 °C. for 4 hours. The solution was cooled to room temperature and the solvent was evaporated. The residue was dissolved in EA and washed with saturated brine. The organic phase was dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography with ethyl acetate and petroleum ether (1:5) to give the product as a clear colorless oil (8 g, 28%). 1H NMR (400 MHz, CDCl3) <semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics> 10.09 (s, 1H), 7.86 (d, <semantics>J<annotation encoding="application / x-tex">J< / annotation>< / semantics> = 8.6 Hz, 2H), 7.01-6.95 (m, 4H), 6.87 (d, <semantics>J=9.0 Hz<annotation encoding="application / x-tex">J = 9.0 \text{ Hz}< / annotation>< / semantics>, 2H), 4.14-4.00 (m, 2H), 3.80 (d, <semantics>J=5.2 Hz<annotation encoding="application / x-tex">J = 5.2 \text{ Hz}< / annotation>< / semantics>, 6H), 3.64-3.58 (m, 1H), 3.48-3.42 (m, 1H), 2.83-2.78 (m, 1H), 2.69-2.59 (m, 2H), 2.08-1.89 (m, 4H), 1.87-1.80 (m, 1H), 1.42 (s, 9H), 1.21- 1.12 (m, 2H), 0.87 (s, 9H), -0.00 (t, <semantics>J=4.2 Hz<annotation encoding="application / x-tex">J = 4.2 \text{ Hz}< / annotation>< / semantics>, 6H).MS (ESI, <semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>): 650.3 [M+H]+. Step E: Preparation of tert-buty1 4-(1-(1-amino-5-(methoxycarbonyl)-4-(4-(4- methoxyphenoxy)phenyl)-1H-imidazol-2-yl)-3-((tert-butyldimethylsilyl)oxy)propyl)piperidine- 1-carboxylate [Image disponible dans le document PDF, Image available in the PDF document] Lithium hexamethyldisilazane (17 mL of a 1 M solution in tetrahydrofuran, 16.98 mmol) was slowly added to the product of step D of example 15 (7.7g, 11.32 mmol) in anhydrous N, N- dimethylformamide(150 mL) at 0 °C. After the mixture was stirred for 30 min, O- (diphenylphosphinyl) hydroxylamine (5.3 g, 22.65 mmol) was added at 0°C, followed by stirring at room temperature for 4-6 h (in cases where the reaction mixture became too viscous, additional <semantics>N<annotation encoding="application / x-tex">N< / annotation>< / semantics>, <semantics>N<annotation encoding="application / x-tex">N< / annotation>< / semantics>-dimethylformamidewas added). The reaction was quenched with water until a clear solution was formed and concentrated to dryness under reduced pressure. The residue was washed several times with ethyl acetate or dichloromethane. The combined organic fractions were concentrated in vacuo and purified by flash chromatography on silica gel with ethyl acetate and petroleum ether (1:3) to give the product as a clear colorless oil (7 g, 89%). 1H NMR (400 MHz, CDCl3) δ 7.63- 7.57 (m, 2H), 7.06-7.01 (m, 2H), 7.00-6.95 (m, 2H), 6.94-6.88 (m, 2H), 5.60 (s, 2H), 4.24-3.96 (m, 2H), 3.86-3.78 (m, 6H), 3.68-3.60 (m, 1H), 3.41-3.31 (m, 2H), 2.78-2.58 (m, 2H), 2.08-2.01 (m, 2H), 2.00-1.90 (m, 2H), 1.46 (s, 9H), 1.42-1.35 (m, 1H), 1.31-1.18 (m, 2H), 0.88 (s, 9H), 0.04-(- 0.01) (m, 6H). MS (ESI, <semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>): 695.4 [M+H]+. Step Preparation of tert-butyl 4-(1-(1-amino-5-(methoxycarbonyl)-4-(4-(4- methoxyphenoxy)phenyl)-1H-imidazol-2-yl)-3-hydroxypropyl)piperidine-1-carboxylate [Image disponible dans le document PDF, Image available in the PDF document] To a solution of the product of step E of example 15 (6.0 g, 8.63 mmol) in tetrahydrofuran (50 mL) was added a 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran (13 mL, 12.94) mmol) at RT. The solution was stirred for 2 hs and diluted with 100 mL ethyl acetate solution. The organic layer was separated and washed with <semantics>H2O<annotation encoding="application / x-tex">H_2O< / annotation>< / semantics> (3×200 mL). The water extract was washed with ethyl acetate solution (<semantics>2×150<annotation encoding="application / x-tex">2 \times 150< / annotation>< / semantics> mL), and the organic layers were combined and dried over anhydrous Na2SO4. The solvent was evaporated in vacuo, and purified by flash chromatography on silica gel with dichloromethane and methanol (25:1) to give the product as a clear colorless oil (4.5 g, 89%). 1H NMR (400 MHz, CDCl3) <semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics> 7.58 (d, <semantics>J<annotation encoding="application / x-tex">J< / annotation>< / semantics> = 8.7 Hz, 2H), 7.04-6.98 (m, 2H), 6.95 (d, <semantics>J=8.7 Hz<annotation encoding="application / x-tex">J = 8.7 \text{ Hz}< / annotation>< / semantics>, 2H), 6.92-6.87 (m, 2H), 5.52 (s, 2H), 4.20-4.09 (m, 1H), 4.08-3.96 (m, 1H), 3.83-3.76 (m, 6H), 3.66-3.60 (m, 1H), 3.49-3.41 (m, 1H), 3.35-3.29 (m, 1H), 2.73-2.58 (m, 2H), 2.09-1.99 (m, 3H), 1.94-1.87 (m, 1H), 1.44 (s, 9H), 1.34-1.19 (m, 3H). MS (ESI, <semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>): 581.3 [M+H]+. Step G: Preparation of methyl 8-(1-(tert-butoxycarbonyl)piperidin-4-yl)-2-(4-(4- methoxyphenoxy)phenyl)-5,6,7,8-tetrahydroimidazo[1,2-b]pyridazine-3-carboxylate [Image disponible dans le document PDF, Image available in the PDF document] Methanesulfonyl chloride (1.2 g, 10.33 mmol) was added via syringe into a stirred mixture of the product of step F of example 15 (4.0 g, 6.89 mmol) and N, N-diisopropylethylamine (3.5 g, 27.55 mmol) in dichloromethane (30 ml) maintained at 0°C. The mixture was stirred at room temperature for 3 hs (TLC monitoring) and then partitioned between dichloromethane and water. The organic phase was dried and evaporated to afford an oil. The crude intermediatewas dissolved in tetrahydrofuran (20 mL), 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran(10 mL, 10.33 mmol) and N, N-diisopropylethylamine (3.5 g, 27.55 mmol) was added to the mixture, which was stirred 3hs, then partitioned between dichloromethane and water. The organic phase was dried and evaporated to afford a white solid, then passed through a column of silica gel with dichloromethane and methanol (25:1) to afford the desired product as a colorless oil(2.3 g, 59%). 1H NMR (400 MHz, CDCl3) <semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics> 7.60 (d, <semantics>J=8.7<annotation encoding="application / x-tex">J = 8.7< / annotation>< / semantics> Hz, 2H), 7.03-6.99 (m, 2H), 6.96-6.93 (m, 2H), 6.91-6.87 (m, 2H), 4.16 (s, 2H), 3.81 (s, 3H), 3.77 (s, 3H), 3.51-3.42 (m, 1H), 3.38-3.29 (m, 1H), <semantics>3.10 (d, J=3.8 Hz, 1H),2.78−2.62 (m, 2H),2.41 (s, 1H),2.08−2.02 (m, 1H),1.99−1.90 (m, 1H),<annotation encoding="application / x-tex">3.10 \text{ (d, } J = 3.8 \text{ Hz, } 1\text{H}), 2.78-2.62 \text{ (m, } 2\text{H}), 2.41 \text{ (s, } 1\text{H}), 2.08-2.02 \text{ (m, } 1\text{H}), 1.99-1.90 \text{ (m, } 1\text{H}),< / annotation>< / semantics> 1.77-1.70 (m, 1H), 1.45 (s, 9H), 1.36-1.23 (m, 3H).MS (ESI, <semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>): 563.3 [M+H]+. Step H: Preparation of 8-(1-(tert-butoxycarbonyl)piperidin-4-yl)-2-(4-(4- methoxyphenoxy)phenyl)-5,6,7,8-tetrahydroimidazo[1,2-b]pyridazine-3-carboxylic acid [Image disponible dans le document PDF, Image available in the PDF document] To a solution of the product of step G of example 15 (2.3 g, 4.09 mmol) in tetrahydrofuran(10 mL) was added LiOH (489.4 mg, 20.44 mmol) in water (5 mL), the mixture was heated at 50°C for 3 hs. Then cooled to r.t.. The mixture acidified to pH 3-4 with concentrated HCl and then extracted with 3×100mL of dichloromethane. The organic phase was washed with saturated brine and then dried over anhydrous Na2SO4. The organic phase was concentrated in vacuo to afford 2.5 g crude product. The residue was used to next step without further purification. MS (ESI, <semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>): 549.3 [M+H]+. Step I: Preparation of tert-butyl 4-(3-carbamoyl-2-(4-(4-methoxyphenoxy)phenyl)-5,6,7,8- tetrahydroimidazo[1,2-b]pyridazin-8-yl)piperidine-1-carboxylate [Image disponible dans le document PDF, Image available in the PDF document] To the solution of the product of step H of example 15 (2.5 g, 4.56 mmol) in dichloromethane (30 mL) was added N, N-diisopropylethylamine (2.4 g, 18.23 mmol). After 5 min, NH4Cl (975.0 mg, 18.23 mmol) and HATU (2.6 g, 6.84 mmol) was added. The reaction mixture was continued to stir at room temperature for 2 h. Dichloromethane and water were added. The layers were separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed three times (3×50 mL) with brine solution. The organic phase was dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by chromatography with dichloromethane and methanol (40:1) to give product as an off-white solid (2.1 g, 95%). 1H NMR (400 MHz, CDCl3) δ 7.55-7.49 (m, 2H), 7.38 (s, 1H), 7.02-6.97 (m, 4H), 6.93-6.87 (m, 2H), 5.99 (s, 1H), 5.38 (s, 1H), 4.16 (s, 2H), 3.82 (s, 3H), 3.48-3.40 (m, 1H), 3.39-3.29 (m, 1H), 3.14-3.04 (m, 1H), 2.76-2.62 (m, 2H), 2.46-2.32 (m, 1H), 2.12-2.01 (m, 1H), 1.99-1.87 (m, 1H), 1.75-1.64 (m, 2H), 1.45 (s, 9H), 1.44-1.41 (m, 1H), 1.40-1.32 (m, 1H). MS (ESI, <semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>): 548.3 [M+H]+. Step J: Preparation of 8-(1-acryloylpiperidin-4-yl)-2-(4-(4-methoxyphenoxy)phenyl)-5,6,7,8- tetrahydroimidazo[1,2-b]pyridazine-3-carboxamide [Image disponible dans le document PDF, Image available in the PDF document] To a solution of the product of step I of example 15 (5.0 g, crude) in EtOH (2 mL) was added 33% HCl / EtOH (10 mL) at room temperature in reaction still. The mixture was stirred for 3 hs. the mixture was concentrated under vacuum to get 6.5 g crude. The residue was used to next step without further purification. MS (ESI, <semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>): 448.2 [M+H]-. Step K: Preparation of 8-(1-acryloylpiperidin-4-yl)-2-(4-(4-methoxyphenoxy)phenyl)-5,6,7,8- tetrahydroimidazo[1,2-b]pyridazine-3-carboxamide [Image disponible dans le document PDF, Image available in the PDF document] The mixture of the product of step J of example 15 (200 mg, 0.45 mmol) and triethylamine(271.3 mg, 2.68 mmol) in dichloromethane (5 mL)was cooled to -60°C. Then the solution of propencyl chloride (40.4 mg, 0.45 mmol) in dichloromethane (1 mL) was added slowly, LC-MS was tracking, at the end of the reaction, 1 mL MeOH was added, the mixture was concentrated under vacuum to get crude product, and purified by flash chromatography on silica gel with dichloromethane and methanol (40:1) to get white solid (53 mg, 23%). 1H NMR (400 MHz, CDCl3) <semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics> 7.52 (d, <semantics>J=6.1<annotation encoding="application / x-tex">J = 6.1< / annotation>< / semantics> Hz, 2H), 7.00-6.94 (m, 4H), 6.92-6.86 (m, 2H), 6.0-6.51 (m, 1H), 6.27-6.19 (m, 1H), 5.68-5.62 (m, 1H), 4.79-4.63 (m, 1H), 4.10-3.94 (m, 1H), 3.80 (s, 3H), 3.40 (s, 1H), 3.36-3.26 (m, 1H), 3.14- 3.01 (m, 2H), 2.65-2.55 (m, 1H), 2.53-2.41 (m, 1H), 2.08-1.96 (m, 1H), 1.91-1.85 (m, 1H), 1.85- 1.73 (m, 1H), 1.48-1.42 (m, 1H), 1.42-1.35 (m, 2H). MS (ESI, <semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>): 502.2 [M+H]+. Example 16: 8-(1-(but-2-ynoyl)piperidin-4-yl)-2-(4-(4-methoxyphenoxy)phenyl)-5,6,7,8- tetrahydroimidazo[1,2-b]pyridazine-3-carboxamide [Image disponible dans le document PDF, Image available in the PDF document] Preparation of 8-(1-(but-2-ynoyl)piperidin-4-yl)-2-(4-(4-methoxyphenoxy)phenyl)-5,6,7,8- tetrahydroimidazo[1,2-b]pyridazine-3-carboxamide [Image disponible dans le document PDF, Image available in the PDF document] , To the solution of the product (200 mg, 0.45 mmol) of step J of example 15 in dry N, N- dimethylformamide (5 mL) was added N, N-diisopropylethylamine (346.5 mg, 2.68 mmol). After 5 min, but-2-ynoic acid (45.0 mg, 0.54 mmol) and HATU (256.5 mg, 0.67 mmol) was added. The reaction mixture was continued to stir at room temperature for 2 h. Ethyl acetate and water were added. The layers were separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed three times <semantics>(3×50 mL)<annotation encoding="application / x-tex">(3 \times 50 \text{ mL})< / annotation>< / semantics> with brine solution. The organic phase was dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by chromatography with dichloromethane and methanol (25:1) to give product as an off-white solid (58 mg, 25%). 1H NMR (400 MHz, CDCl3) <semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics> 7.55-7.48 (m, 2H), 7.40-7.30 (m, 1H), 6.99 (t, <semantics>J=<annotation encoding="application / x-tex">J =< / annotation>< / semantics> 8.0 Hz, 4H), 6.94-6.87 (m, 2H), 6.09 (s, 1H), 5.49 (s, 1H), 4.70-4.55 (m, 1H), 4.50-4.36 (m, 1H), 3.82 (s, 3H), 3.44 (s, 1H), 3.38-3.28 (m, 1H), 3.19-3.03 (m, 2H), 2.66-2.58 (m, 1H), 2.55-2.46 (m, 1H), 2.05-1.97 (m, 4H), 1.96-1.84 (m, 2H), 1.51 (s, 1H), 1.45-1.39 (m, 2H).MS (ESI, <semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>): 514.2 <semantics>[M+H]+<annotation encoding="application / x-tex">[M+H]^+< / annotation>< / semantics> Example 17: (E)-2-(4-(4-methoxyphenoxy)phenyl)-8-(1-(4,4,4-trifluorobut-2-enoyl)piperidin-4-yl)- 5,6,7,8-tetrahydroimidazo[1,2-b]pyridazine-3-carboxamide [Image disponible dans le document PDF, Image available in the PDF document] Preparation of <semantics>(E)<annotation encoding="application / x-tex">(E)< / annotation>< / semantics>-2-<semantics>(4<annotation encoding="application / x-tex">(4< / annotation>< / semantics>-<semantics>(4<annotation encoding="application / x-tex">(4< / annotation>< / semantics>-methoxyphenoxy)phenyl)-8-<semantics>(1<annotation encoding="application / x-tex">(1< / annotation>< / semantics>-<semantics>(4<annotation encoding="application / x-tex">(4< / annotation>< / semantics>,4,4-trifluorobut-2- enoyl)piperidin-4-yl)-5,6,7,8-tetrahydroimidazo[1,2-b]pyridazine-3-carboxamide [Image disponible dans le document PDF, Image available in the PDF document] To the solution of the product (200 mg, 0.45 mmol) of step J of example 15 in dry N, N- dimethylformamide (10 mL) was added N, N-diisopropylethylamine (346.5 mg, 2.68 mmol). After 5 min, (E)-4,4,4-trifluorobut-2-enoic acid (75.1 mg, 0.54 mmol) and HATU (256.5 mg, 0.67 mmol) was added. The reaction mixture was continued to stir at room temperature for 2 h. Ethyl acetate and water were added. The layers were separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed three times (3×50 mL) with brine solution. The organic phase was dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by chromatography with dichloromethane and methanol (25:1) to give product as an off- white solid (63 mg, 24%). 1H NMR (400 MHz, CDCl3) <semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics> 7.56-7.48 (m, 2H), 6.99-6.94 (m, 4H), 6.91-6.87 (m, 2H), 6.68-6.60 (m, 2H), 6.34 (s, 1H), 5.61 (s, 1H), 4.76-4.62 (m, 1H), 4.00-3.87 (m, 1H), 3.80 (s, 3H), 3.69-3.63 (m, 2H), 3.44 (s, 1H), 3.31 (s, 1H), 3.17-3.12 (m, 3H), 2.70-2.63 (m, 1H), 2.54-2.46 (m, 1H), 2.08-2.00 (m, 1H), 1.96-1.83 (m, 2H), 1.62-1.56 (m, 1H). MS (ESI, <semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>): 570.2 [M+H]+. Example 18: 8-(1-acryloylazetidin-3-yl)-2-(4-phenoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2- blpyridazine-3-carboxamide [Image disponible dans le document PDF, Image available in the PDF document] Step A: Preparation of tert-butyl 3-(2-oxodihydrofuran-3(2H)-ylidene)azetidine-1-carboxylate [Image disponible dans le document PDF, Image available in the PDF document] To a slurry of tetrahydrofuran-washed sodium hydride (60% dispersion in mineral oil; 385.5 g, 9.64 mol) was added diethyl (2-oxotetrahydrofuran-3-yl) phosphonate (2.2 kg, 9.64 mol) as a solution in dry tetrahydrofuran (3 L) dropwise over 70 min at 10 °C. The mixture was stirred for 30 min before the addition of tert-butyl 3-oxoazetidine-1-carboxylate (1.1 kg, 6.43 mol) as a solution in tetrahydrofuran (2 L). The mixture was then stirred for 2 h before the addition of dichloromethane (2 L) followed by water (5 L). The tetrahydrofuran was then removed under reduced pressure, the aqueous residue extracted with dichloromethane (3×1000 ml), then washed with water (2×1000 ml) and dried (anhydrous Na2SO4) before evaporating to dryness to give a yellow oil, then purified by column chromatography on silica gel with ethyl acetate and petroleum ether (1:2) to give product as a white solid (920 g, 59%). <semantics>1<annotation encoding="application / x-tex">^{1}< / annotation>< / semantics>H NMR (400 MHz, CDCl3) <semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics> 4.91-4.82 <semantics>(m,2H),4.59−4.56(m,2H),4.40(t,J=7.4Hz,2H),2.85−2.80(m,2H),1.45(s,9H).MS(ESI,2H),4.59−4.56(m,2H),4.59−4.56(m,2H),4.40(t,J=7.4Hz,2H),2.85−2.80(m,2H),1.45(s,9H).<annotation encoding="application / x-tex">(m, 2H), 4.59-4.56 (m, 2H), 4.40 (t, J = 7.4 Hz, 2H), 2.85-2.80 (m, 2H), 1.45 (s, 9H). MS (ESI, 2H), 4.59-4.56 (m, 2H), 4.59-4.56 (m, 2H), 4.40 (t, J = 7.4 Hz, 2H), 2.85-2.80 (m, 2H), 1.45 (s, 9H).< / annotation>< / semantics> <semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>): 240.1 [M+H]+. Step B: Preparation of tert-butyl 3-(2-oxotetrahydrofuran-3-yl)azetidine-1-carboxylate [Image disponible dans le document PDF, Image available in the PDF document] To a solution of the product of step A of example 18 (800 g, 3.34 mol) in ethyl acetate (4 L) was added 10% Pd / C (160.3 g, 20%) at room temperature. The mixture was stirred for 3 hs under H2. The mixture was passed through Celite, and the solid was washed with ethyl acetate, and filtrate was concentrated under vacuum to get desired product (800 g, 99%). 1H NMR (400 MHz, CDCl3) <semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics> 4.34-4.27 (m, 1H), 4.20-4.13 (m, 1H), 4.07 (t, <semantics>J<annotation encoding="application / x-tex">J< / annotation>< / semantics> = 8.6 Hz, 1H), 3.98 (t, <semantics>J<annotation encoding="application / x-tex">J< / annotation>< / semantics> = 8.4 Hz, 1H), 3.87- 3.75 (m, 1H), 3.64-3.57 (m, 1H), 2.84-2.67 (m, 2H), 2.43-2.31 (m, 1H), 2.01-1.89 (m, 1H), 1.35 (s, 9H). MS (ESI, <semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>): 242.1 [M+H]+. Step C: Preparation of 2-(1-(tert-butoxycarbonyl)azetidin-3-yl)-4-hydroxybutanoic acid [Image disponible dans le document PDF, Image available in the PDF document] The product of step B of example 18 (350 g, 1.45 mmol), H2O (500 mL), and sodiumhydroxide (116.1 g, 2.90 mol) were added in a round bottom flask. This reaction mixture was stirred at room temperature overnight. The clear reaction mixture was then extracted with ethyl acetate, the aqueous layer was isolated and acidified to pH 3-4 with concentrated HCl and then extracted with 100 mL of dichloromethane. The organic phase was washed with saturated brine and then dried over anhydrous Na2SO4. The organic phase was concentrated in vacuo to get product as a White solid (345 g, 91%). MS (ESI, <semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>): 260.2 [M+H]+. Step D: Preparation of 2-(1-(tert-butoxycarbonyl)azetidin-3-yl)-4-((tert- butyldimethylsilyl)oxy)butanoic acid [Image disponible dans le document PDF, Image available in the PDF document] Tert-butyldimethylsilylchloride (273.2 g, 1.57 mol) was added to a mixture of the product of step C of example 18 (340 g, 1.31 mmol) and imidazole (178.5 g, 2.62 mol) in N, N- dimethylformamide (3 L). The reaction mixture was stirred at 30°C for 5h under argon atmosphere and poured into a separatory funnel containing 400 mL of brine and extracted 4 times with 2 L dichloromethane. The organic fractions were combined, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude product which was purified via flash chromatography eluting with ethyl acetate and petroleum ether (1:2) to give the product as a clear colorless oil (crude 400 g). MS (ESI, <semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>): 374.2 [M+H]+. Step E: Preparation of tert-butyl 3-(11,11,12,12-tetramethyl-3,6-dioxo-4-(4-phenoxybenzoyl)- 2,5,10-trioxa-11-silatridecan-7-yl)azetidine-1-carboxylate [Image disponible dans le document PDF, Image available in the PDF document] The product of step B (30.0 g, 85.92 mmol) of example 1 and the product of step D of example 18 (38.5 g, 103.10 mmol) were taken up in acetonitrile (250 mL), then N, N-diisopropylethylamine (16.7 g, 128.87 mmol) was added and the solution stirred at 30°C for 3 hs. The solvent was removed by rotorary evaporation and the residue taken up in ethyl acetate, washed with 0.1 N HCl, and brine. The organic fractions were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude product which was purified via flash chromatography eluting with ethyl acetate and petroleum ether (1:20) to give the product as a clear colorless oil (46.3 g, 83%). 1H NMR (400 MHz, CDCl3) <semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics> 7.93 (d, <semantics>J=8.8<annotation encoding="application / x-tex">J = 8.8< / annotation>< / semantics> Hz, 2H), 7.37 (t, <semantics>J=7.9<annotation encoding="application / x-tex">J = 7.9< / annotation>< / semantics> Hz, 2H), 7.19 (t, <semantics>J=7.4<annotation encoding="application / x-tex">J = 7.4< / annotation>< / semantics> Hz, 1H), 7.05 (d, <semantics>J=8.0<annotation encoding="application / x-tex">J = 8.0< / annotation>< / semantics> Hz, 2H), 6.97 (d, <semantics>J=8.9<annotation encoding="application / x-tex">J = 8.9< / annotation>< / semantics> Hz, 2H), 6.22 (s, 1H), 4.03-3.94 (m, 2H), 3.68-3.59 (m, 3H), 2.94-2.86 (m, 1H), 2.83-2.75 (m, 1H), 1.93-1.80 (m, 1H), 1.71-1.59 (m, 1H), 1.39 (s, 9H), 0.83 (d, <semantics>J=7.3<annotation encoding="application / x-tex">J = 7.3< / annotation>< / semantics> Hz, 9H), 0.01-(-0.04) (m, 6H).MS (ESI, <semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>): 642.3 [M+H]+. Step F: Preparation of methyl 2-(1-(1-(tert-butoxycarbonyl)azetidin-3-yl)-3-((tert- butyldimethylsilyl)oxy)propyl)-4-(4-phenoxyphenyl)-1H-imidazole-5-carboxylate [Image disponible dans le document PDF, Image available in the PDF document] To a slurry of ammonium acetate (57.6 g, 747.86 mmol) in xylenes (400 mL) was added the product of step E of example 18 (40.0 g, 62.32 mmol). The mixture was stirred at 140°C for 4 hours. The solution was cooled to room temperature and evaporated. The residue was dissolved in ethyl acetate and washed with saturated brine. The organic phase was dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography with ethyl acetate and petroleum ether (1:5) to give the product as a clear colorless oil (18 g, 46%). 1H NMR (400 MHz, CDCl3) <semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics> 10.15 (s, 1H), 7.98-7.91 (m, 2H), 7.38-7.31 (m, 2H), 7.16-7.08 (m, 1H), <semantics>7.07−7.01<annotation encoding="application / x-tex">7.07-7.01< / annotation>< / semantics> (m, 4H), <semantics>4.14−3.97<annotation encoding="application / x-tex">4.14-3.97< / annotation>< / semantics> (m, 2H), <semantics>3.84<annotation encoding="application / x-tex">3.84< / annotation>< / semantics> (d, <semantics>J=5.2<annotation encoding="application / x-tex">J = 5.2< / annotation>< / semantics> Hz, 3H), <semantics>3.77−3.65<annotation encoding="application / x-tex">3.77-3.65< / annotation>< / semantics> (m, 3H), <semantics>3.63−3.54<annotation encoding="application / x-tex">3.63-3.54< / annotation>< / semantics> (m, 1H), 3.27-3.16 (m, 1H), 3.14-3.01 (m, 1H), 1.96-1.74 (m, 2H), 1.43 (s, 9H), 0.98-0.82 (m, 9H), 0.19-0.05 (m, 7H). MS (ESI, <semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>): 622.3 [M+H]+. Step G: Preparation of methyl 1-amino-2-(1-(1-(tert-butoxycarbonyl)azetidin-3-yl)-3-((tert- butyldimethylsilyl)oxy)propyl)-4-(4-phenoxyphenyl)-1H-imidazole-5-carboxylate [Image disponible dans le document PDF, Image available in the PDF document] _ C Lithium hexamethyldisilazane (20 mL of a 1 M solution intetrahydrofuran, 19.29 mmol) was slowly added to the product of step F of example 18 (8.0 g, 12.86 mmol) in anhydrous N, N- dimethylformamide (60 mL) at 0 <semantics>∘<annotation encoding="application / x-tex">^{\circ}< / annotation>< / semantics>C. After the mixture was stirred for 30 min, O- (diphenylphosphinyl) hydroxylamine (6.0 g, 25.73 mmol) was added at 0°C, followed by stirring at room temperature for 4-6 hs (in cases where the reaction mixture became too viscous, additional N, N-dimethylformamidewas added). The reaction was quenched with water until a clear solution was formed and concentrated to dryness under reduced pressure. The residue was washed several times with ethyl acetate or dichloromethane. The combined organic fractions were concentrated in vacuo and purified by flash chromatography on silica gel with ethyl acetate and petroleum ether (1:3) to give the product as a clear colorless oil (6.4 g, 78%). 1H NMR (400 MHz, CDCl3) <semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics> 7.63- 7.54 (m, 2H), 7.38-7.29 (m, 2H), 7.11 (t, <semantics>J=7.4<annotation encoding="application / x-tex">J = 7.4< / annotation>< / semantics> Hz, 1H), 7.06-6.97 (m, 4H), 5.66 (s, 2H), 4.07 (t, <semantics>J=7.7 Hz<annotation encoding="application / x-tex">J = 7.7 \text{ Hz}< / annotation>< / semantics>, 1H), 3.88 (t, <semantics>J=8.5 Hz<annotation encoding="application / x-tex">J = 8.5 \text{ Hz}< / annotation>< / semantics>, 1H), 3.82-3.75 (m, 3H), 3.73-3.64 (m, 3H), 3.58-3.53 (m, 1H), 3.52-3.43 (m, 1H), 3.12 (s, 1H), 1.87-1.80 (m, 2H), 1.42 (s, 9H), 0.88-0.75 (m, 9H), 0.03-(-0.05) (m, 6H). MS (ESI, <semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>): 637.3 [M+H]+. Step H: Preparation of methyl 1-amino-2-(1-(1-(tert-butoxycarbonyl)azetidin-3-yl)-3- hydroxypropyl)-4-(4-phenoxyphenyl)-1H-imidazole-5-carboxylate [Image disponible dans le document PDF, Image available in the PDF document] To a solution of the product of step G of example 18 (6.0 g, 9.24 mmol) in tetrahydrofuran (50 mL) was added a 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran (11 mL, 11.08 mmol) at RT. The solution was stirred for 2 hs and diluted with 100 mL ethyl acetate solution. The organic layer was separated and washed with H2O (3×200 mL). The water extract was washed with ethyl acetate solution (2×150 mL), and the organic layers were combined and dried over anhydrous Na2SO4. The solvent was evaporated in vacuo, and purified by flash chromatography on silica gel with dichloromethane and methanol (40:1) to give the product as a clear colorless oil <semantics>(4 g,81%)<annotation encoding="application / x-tex">(4 \text{ g}, 81\%)< / annotation>< / semantics>. 1H NMR <semantics>(400 MHz,CDCl3)δ7.63−7.56 (m, 2H),7.38−7.31 (m, 2H),7.12 (t, J=7.4 (m, 2H))<annotation encoding="application / x-tex">(400 \text{ MHz}, \text{CDCl}_3) \delta 7.63-7.56 \text{ (m, 2H)}, 7.38-7.31 \text{ (m, 2H)}, 7.12 \text{ (t, } J = 7.4 \text{ (m, 2H)})< / annotation>< / semantics> Hz, 1H), 7.07-6.96 (m, 4H), 5.75 (s, 2H), 4.08 (t, <semantics>J=8.4<annotation encoding="application / x-tex">J = 8.4< / annotation>< / semantics> Hz, 1H), 3.90 (t, <semantics>J=8.4<annotation encoding="application / x-tex">J = 8.4< / annotation>< / semantics> Hz, 1H), 3.78 (s, 3H), 3.75-3.66 (m, 2H), 3.64-3.58 (m, 1H), 3.56-3.50 (m, 1H), 3.45-3.36 (m, 1H), 3.19-3.12 (m, 1H), 1.93-1.80 (m, 2H), 1.41 (s, 9H). MS (ESI, <semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>): 523.2 [M+H]+. Step I: Preparation of methyl 8-(1-(tert-butoxycarbonyl)azetidin-3-yl)-2-(4-phenoxyphenyl)- 5,6,7,8-tetrahydroimidazo[1,2-b]pyridazine-3-carboxylate [Image disponible dans le document PDF, Image available in the PDF document] Methanesulfonyl chloride (1.3 g, 11.48 mmol) was added via syringe into a stirred mixture of the product of step H of example 18 (4.0 g, 7.65 mmol) and N, N-diisopropylethylamine (2.0 g, 15.31 mmol) in dichloromethane (70 ml) maintained at 0°C. The mixture was stirred at room temperature for 3 hs (TLC monitoring) and then partitioned between dichloromethane and water. The organic phase was dried and evaporated to afford a white oil, The crude intermediate was dissolved in tetrahydrofuran(20 mL), 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran(11 mL, 11.48 mmol) and N, N-diisopropylethylamine (2.0 g, 15.31 mmol) was added to the mixture, which was stirred 3hs, then partitioned between dichloromethane and water. The organic phase was dried and evaporated to afford a white solid, then passed through a column of silica gel with dichloromethane and methanol (30:1) to afford the desired product as a colorless oil (3.4 g, 88%). 1H NMR (600 MHz, CDCl3) <semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics> 7.65 (d, <semantics>J<annotation encoding="application / x-tex">J< / annotation>< / semantics> = 7.8 Hz, 2H), 7.34 (t, <semantics>J<annotation encoding="application / x-tex">J< / annotation>< / semantics> = 7.4 Hz, 2H), 7.11 (t, <semantics>J=7.4<annotation encoding="application / x-tex">J = 7.4< / annotation>< / semantics> Hz, 1H), 7.05 (d, <semantics>J=8.1<annotation encoding="application / x-tex">J = 8.1< / annotation>< / semantics> Hz, 2H), 7.01 (d, <semantics>J=7.8<annotation encoding="application / x-tex">J = 7.8< / annotation>< / semantics> Hz, 2H), 4.23 (s, 1H), 4.16 (d, <semantics>J=7.4<annotation encoding="application / x-tex">J = 7.4< / annotation>< / semantics> Hz, 2H), 4.23 (s, 1H), 4.16 (d, <semantics>J=7.4<annotation encoding="application / x-tex">J = 7.4< / annotation>< / semantics> Hz, 2H), 4.23 (s, 1H), 4.16 (d, <semantics>J=7.4<annotation encoding="application / x-tex">J = 7.4< / annotation>< / semantics> Hz, 2H), 4.23 (s, 1H <semantics>=8.4 Hz,1H),4.02 (t, J=8.4 Hz,1H),3.82 (t, J=6.8 Hz,1H),3.78 (s, 3H),3.47 (s, 1H),3.42<annotation encoding="application / x-tex">= 8.4 \text{ Hz}, 1\text{H}), 4.02 \text{ (t, } J = 8.4 \text{ Hz}, 1\text{H)}, 3.82 \text{ (t, } J = 6.8 \text{ Hz}, 1\text{H)}, 3.78 \text{ (s, 3H)}, 3.47 \text{ (s, 1H)}, 3.42< / annotation>< / semantics> <semantics>3.36 (m, 1H),3.31−3.24 (m, 1H),2.90 (s, 1H),2.21 (d, J=6.7 Hz, 1H),1.78 (s, 1H),1.44 (s, 9H).<annotation encoding="application / x-tex">3.36 \text{ (m, 1H)}, 3.31-3.24 \text{ (m, 1H)}, 2.90 \text{ (s, 1H)}, 2.21 \text{ (d, } J = 6.7 \text{ Hz, 1H)}, 1.78 \text{ (s, 1H)}, 1.44 \text{ (s, 9H)}.< / annotation>< / semantics> MS (ESI, <semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>): 505.2 [M+H]+. Step J: Preparation of 8-(1-(tert-butoxycarbonyl)azetidin-3-yl)-2-(4-phenoxyphenyl)-5,6,7,8- tetrahydroimidazo[1,2-b]pyridazine-3-carboxylic acid [Image disponible dans le document PDF, Image available in the PDF document] To a solution of the product of step I of example 18 (2.0 g, 3.96 mmol) in tetrahydrofuran(10 mL) was added LiOH (474.6 mg, 19.82 mmol) in water (5 mL), the mixture was heated at 50°C for 3 hs, then cooled to r.t. The mixture acidified to pH 3-4 with concentrated HCl and then extracted with dichloromethane (3×100 mL). The organic phase was washed with saturated brine and then dried over anhydrous Na2SO4. The organic phase was concentrated in vacuo to afford 2.4 g crude product. The residue was used to next step without further purification. MS (ESI, <semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>): 505.2 [M+H]+. Step K: Preparation of tert-butyl 3-(3-carbamoyl-2-(4-phenoxyphenyl)-5,6,7,8- tetrahydroimidazo[1,2-b]pyridazin-8-yl)azetidine-1-carboxylate [Image disponible dans le document PDF, Image available in the PDF document] To the solution of the product of step J of example 18 (2.4 g, 4.89 mmol) in dichloromethane (30 mL) was added N, N-diisopropylethylamine (2.5 g, 19.57 mmol). After 5 min, NH4Cl (1.1 g, 19.57 mmol) and HATU (2.8 g, 7.34 mmol) was added. The reaction mixture was continued to stir at room temperature for 2 hs. Dichloromethane and water were added. The layers were separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed three times (3×50 mL) with brine solution. The organic phase was dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by chromatography with dichloromethane and methanol (40:1) to give product as an off-white solid (1.7 g, 71%). 1H NMR (400 MHz, MeOD) <semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics> 7.70-7.63 (m, 2H), 7.39-7.31 (m, 2H), 7.15-7.07 (m, 1H), 7.06-6.99 (m, 2H), 6.99-6.94 (m, 2H), <semantics>4.09 (d, J=6.5 Hz, 2H),4.00 (t, J=8.5 Hz, 1H),3.89 (s, 1H),3.46−3.40 (m, 1H),3.30−3.17 (m, 1H)<annotation encoding="application / x-tex">4.09 \text{ (d, } J = 6.5 \text{ Hz, } 2\text{H)}, 4.00 \text{ (t, } J = 8.5 \text{ Hz, } 1\text{H)}, 3.89 \text{ (s, } 1\text{H)}, 3.46-3.40 \text{ (m, } 1\text{H)}, 3.30-3.17 \text{ (m, } 1\text{H)}< / annotation>< / semantics> 2H), 3.08-2.96 (m, 1H), 2.22-2.15 (m, 1H), 1.80-1.65 (m, 1H), 1.42 (s, 9H). MS (ESI, m / z): 288.2 <semantics>[M+H]+<annotation encoding="application / x-tex">[M+H]^{+}< / annotation>< / semantics>. Step L: Preparation of 2-(4-phenoxyphenyl)-8-(piperidin-4-yl)-5,6,7,8-tetrahydroimidazo[1,2- b]pyridazine-3-carboxamide [Image disponible dans le document PDF, Image available in the PDF document] To a solution of the product of step K of example 18 (1.5 g, 3.06 mmol) in dichloromethane (10 mL) was added CF3COOH (2 mL) at room temperature in reaction still. The mixture was stirred for 30 min, and concentrated under vacuum to get 2.3 g crude. The residue was used to next step without further purification. 1H NMR (600 MHz, MeOD) <semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics> 8.58 (s, 1H), 7.71 (d, <semantics>J<annotation encoding="application / x-tex">J< / annotation>< / semantics> = 8.1 Hz, 2H), 7.37 (t, <semantics>J=7.6<annotation encoding="application / x-tex">J = 7.6< / annotation>< / semantics> Hz, 2H), 7.14 (t, <semantics>J=7.3<annotation encoding="application / x-tex">J = 7.3< / annotation>< / semantics> Hz, 1H), 7.03 (d, <semantics>J=7.9<annotation encoding="application / x-tex">J = 7.9< / annotation>< / semantics> Hz, 2H), 6.99 (d, <semantics>J=8.1<annotation encoding="application / x-tex">J = 8.1< / annotation>< / semantics> Hz, 2H), <semantics>4.37<annotation encoding="application / x-tex">4.37< / annotation>< / semantics> (t, <semantics>J=9.3<annotation encoding="application / x-tex">J = 9.3< / annotation>< / semantics> Hz, 1H), <semantics>4.22<annotation encoding="application / x-tex">4.22< / annotation>< / semantics> (t, <semantics>J=7.9<annotation encoding="application / x-tex">J = 7.9< / annotation>< / semantics> Hz, 2H), <semantics>4.13<annotation encoding="application / x-tex">4.13< / annotation>< / semantics> (t, <semantics>J=9.2<annotation encoding="application / x-tex">J = 9.2< / annotation>< / semantics> Hz, 1H), <semantics>3.47−3.39<annotation encoding="application / x-tex">3.47-3.39< / annotation>< / semantics> (m, 2H), <semantics>3.31−3.39<annotation encoding="application / x-tex">3.31-3.39< / annotation>< / semantics> 3.25 (m, 1H), 2.23-2.13 (m, 1H), 1.71-1.63 (m, 1H). MS (ESI, <semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>): 390.2 [M+H]+. Step M: Preparation of 8-(1-acryloylazetidin-3-yl)-2-(4-phenoxyphenyl)-5,6,7,8- tetrahydroimidazo[1,2-b]pyridazine-3-carboxamide [Image disponible dans le document PDF, Image available in the PDF document] The mixture of the product of step L of example 18 (200.0 mg, 0.51 mmol) and triethylamine(207.8 mg, 2.05 mmol) in dichloromethane (5 mL) was cooled to -60°C. Then the solution of propenoyl chloride (46.5 mg, 0.51mmol) in dichloromethane (1 mL) was added slowly, LC-MS was tracking, at the end of the reaction, 1 mL MeOH was added, the mixture was concentrated under vacuum to get crude product. And the residue was purified by flash chromatography on silica gelwith dichloromethane and methanol (30:1) to get product (48 mg, 21%) as a white solid. 1H NMR (600 MHz, DMSO-d6) <semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics> 7.84-7.80 (m, 2H), 7.41 (t, <semantics>J=7.8<annotation encoding="application / x-tex">J = 7.8< / annotation>< / semantics> Hz, 2H), <semantics>7.15<annotation encoding="application / x-tex">7.15< / annotation>< / semantics> (t, <semantics>J=7.3<annotation encoding="application / x-tex">J = 7.3< / annotation>< / semantics> Hz, 1H), <semantics>7.04<annotation encoding="application / x-tex">7.04< / annotation>< / semantics> (d, <semantics>J=8.0<annotation encoding="application / x-tex">J = 8.0< / annotation>< / semantics> Hz, 2H), <semantics>6.99<annotation encoding="application / x-tex">6.99< / annotation>< / semantics> (d, <semantics>J=8.0<annotation encoding="application / x-tex">J = 8.0< / annotation>< / semantics> Hz, 2H), <semantics>6.39−6.31<annotation encoding="application / x-tex">6.39-6.31< / annotation>< / semantics> (m, 1H), 6.13-6.08 (m, 1H), 5.69-5.62 (m, 1H), 4.48-4.40 (m, 1H), 4.32-4,21 (m, 1H), 4.19-4.06 (m, 1H), 4.06 (s, 1H), 4.04-3.84 (m, 1H), 3.32-3.28 (m, 1H), 3.21-3.15 (m, 1H), 2.92 (s, 1H), 2.14-2.01 (m, 1H), 1.61-1.50 (m, 1H). MS (ESI, <semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>): 444.2 [M+H]+. Example 19: CA [Image disponible dans le document PDF, Image available in the PDF document] 1 [Image disponible dans le document PDF, Image available in the PDF document] To the solution of the product of step L of example 18 (350.1 mg, 0.89 mmol) in dry N, N- dimethylformamide (5 mL) was added N, N-diisopropylethylamine (464.6 mg, 3.59 mmol). After 5 min, but-2-ynoic acid (83.1 mg, 0.98 mmol) and HATU (512.5 mg, 1.35 mmol) was added. The reaction mixture was continued to stir at room temperature for 2 h. Ethyl acetate and water were added. The layers were separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed three times (3×50 mL) with brine solution. The organic phase was dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by chromatography with dichloromethane and methanol (40:1) to give product as an off-white solid <semantics>(64 mg,15%)<annotation encoding="application / x-tex">(64 \text{ mg}, 15\%)< / annotation>< / semantics>. 1H NMR <semantics>(400 MHz,CDCl3)δ7.65−7.56 (m, 2H),7.40−7.32 (m, 2H),7.17−7.10 (m, 2H)<annotation encoding="application / x-tex">(400 \text{ MHz}, \text{CDCl}_3) \delta 7.65-7.56 \text{ (m, 2H)}, 7.40-7.32 \text{ (m, 2H)}, 7.17-7.10 \text{ (m, 2H)}< / annotation>< / semantics> 1H), 7.08-7.01 (m, 4H), 5.83 (s, 1H), 4.53-4.35 (m, 1H), 4.33-4.21 (m, 1H), 4.18-4.07 (m, 2H), <semantics>3.88 (dd, J=10.4,6.0 Hz, 1H),3.47−3.22 (m, 3H),3.10−2.87 (m, 1H),2.26−2.10 (m, 1H),1.96 (d, 1.88 (dd, J=10.4,6.0 Hz, 1.88 (dd, J=10.4,6.0 Hz, 1.8<annotation encoding="application / x-tex">3.88 \text{ (dd, } J = 10.4, 6.0 \text{ Hz, } 1\text{H}), 3.47-3.22 \text{ (m, } 3\text{H)}, 3.10-2.87 \text{ (m, } 1\text{H)}, 2.26-2.10 \text{ (m, } 1\text{H)}, 1.96 \text{ (d, } 1.88 \text{ (dd, } J = 10.4, 6.0 \text{ Hz, } 1.88 \text{ (dd, } J = 10.4, 6.0 \text{ Hz, } 1.8< / annotation>< / semantics> <semantics>J=1.7 Hz,3H,1.79−1.64 (m, 1H). MS (ESI, m / z):514.2 [M+H]+.<annotation encoding="application / x-tex">J = 1.7 \text{ Hz}, 3\text{H}, 1.79-1.64 \text{ (m, 1H)}. \text{ MS (ESI, } m / z): 514.2 \text{ [M+H]}^+.< / annotation>< / semantics> Example 20: (E)-2-(4-phenoxyphenyl)-8-(1-(4,4,4-trifluorobut-2-enoyl)azetidin-3-yl)-5,6,7,8- tetrahydroimidazo[1,2-b]pyridazine-3-carboxamide [Image disponible dans le document PDF, Image available in the PDF document] C / Preparation of (E)-2-(4-phenoxyphenyl)-8-(1-(4,4,4-trifluorobut-2-enoyl)azetidin-3-yl)-5,6,7,8- tetrahydroimidazo[1,2-b]pyridazine-3-carboxamide [Image disponible dans le document PDF, Image available in the PDF document] To the solution of the product of step L of example 18 (350 mg, 0.89 mmol) in dry N, N- dimethylformamide (5 mL) was added N, N-diisopropylethylamine (464.5 mg, 3.59 mmol). After 5 min, (E)-4,4,4-trifluorobut-2-enoic acid (138.5 mg, 0.98 mmol) and HATU (512.5 mg, 1.35 mmol) was added. The reaction mixture was continued to stir at room temperature for 2 hs. Ethyl acetate and water were added. The layers were separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed three times (3×50 mL) with brine solution. The organic phase was dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by chromatography with dichloromethane and methanol (40:1) to give product as an off-white solid (67 mg, 14%). 1H NMR (400 MHz, CDCl3) <semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics> 7.55-7.46 (m, 2H), 7.32-7.24 (m, 2H), 7.10-7.03 (m, 1H), 7.00-6.89 (m, 5H), 6.70-6.59 (m, 2H), 6.55-6.49 (m, 1H), 5.82 (s, 1H), 4.57 (dd, <semantics>J=9.4<annotation encoding="application / x-tex">J = 9.4< / annotation>< / semantics>, 5.9 Hz, 1H), 4.47-4.39 (m, 1H), 4.30 (t, <semantics>J=8.6<annotation encoding="application / x-tex">J = 8.6< / annotation>< / semantics> Hz, 1H), 4.14 (dd, <semantics>J=13.7,6.0 Hz,1H<annotation encoding="application / x-tex">J = 13.7, 6.0 \text{ Hz}, 1\text{H}< / annotation>< / semantics>), 3.91 (dd, <semantics>J=10.8,6.0 Hz,1H<annotation encoding="application / x-tex">J = 10.8, 6.0 \text{ Hz}, 1\text{H}< / annotation>< / semantics>), 3.52-3.48 (m, 1H), 3.40-3.29 (m, 1H), 3.25- 3.19 (m, 1H), 2.99 (p, <semantics>J=7.5<annotation encoding="application / x-tex">J = 7.5< / annotation>< / semantics> Hz, 1H), 2.93-2.75 (m, 1H), 2.16-2.08 (m, 1H), 1.69-1.58 (m, 1H).MS (ESI, <semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>): 570.2 [M+H]+. Example 21: 8-(1-acryloylpyrrolidin-3-yl)-2-(4-phenoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2- blpyridazine-3-carboxamide [Image disponible dans le document PDF, Image available in the PDF document] Step A: Preparation of tert-butyl (E)-3-(2-oxodihydrofuran-3(2H)-ylidene)pyrrolidine-1- carboxylate [Image disponible dans le document PDF, Image available in the PDF document] To a slurry of tetrahydrofuran-washed sodium hydride (60% dispersion in mineral oil; 32.4 g, 809.83 mmol) was added diethyl (2-oxotetrahydrofuran-3-yl)phosphonate (180 g, 809.83 mmol) as a solution in dry tetrahydrofuran (3 L) dropwise over 70 min at 10 °C. The mixture was stirred for 30 min before the addition of tert-butyl 3-oxopyrrolidine-1-carboxylate (100 g, 539.89 mol) as a solution in tetrahydrofuran (2 L). The mixture was then stirred for 2 h before the addition of dichloromethane (2 L) followed by water (5 L). The tetrahydrofuran was then removed under reduced pressure, the aqueous residue extracted with dichloromethane (3×1000 ml), then washed with water (2×1000 ml) and dried (anhydrous Na2SO4) before evaporating to dryness to give a yellow oil, then purified by column chromatography on silica gel with ethyl acetate and petroleum ether (1:2) to give product as a white solid (34 g, 24%). 1H NMR (400 MHz, CDCl3) <semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics> 4.49 (s, 2H), 4.41 (t, <semantics>J=7.5<annotation encoding="application / x-tex">J = 7.5< / annotation>< / semantics> Hz, 2H), 3.59 (t, <semantics>J=7.0<annotation encoding="application / x-tex">J = 7.0< / annotation>< / semantics> Hz, 2H), 2.89-2.85 (m, 2H), 2.70-2.62 (m, 2H), 1.48 (s, 9H).MS (ESI, <semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>): 254.1 [M+H]+. Step B: Preparation of tert-butyl 3-(2-oxotetrahydrofuran-3-yl)pyrrolidine-1-carboxylate [Image disponible dans le document PDF, Image available in the PDF document] To a solution of the product of step A of example 21 (34 g, 3.34 mol) in ethyl acetate (4 L) was added 10% Pd / C (3.4 g, 10%) at room temperature. The mixture was stirred for 3 hs under H2. The mixture was passed through Celite, and the solid was washed with ethyl acetate, and filtrate was concentrated under vacuum to get desired product (32.5 g, 94%). 1H NMR (600 MHz, CDCl3) <semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics> <semantics>4.26<annotation encoding="application / x-tex">4.26< / annotation>< / semantics> (s, 1H), <semantics>4.12<annotation encoding="application / x-tex">4.12< / annotation>< / semantics> (d, <semantics>J=7.9<annotation encoding="application / x-tex">J = 7.9< / annotation>< / semantics> Hz, 1H), <semantics>3.50−3.36<annotation encoding="application / x-tex">3.50-3.36< / annotation>< / semantics> (m, 2H), <semantics>3.25−3.14<annotation encoding="application / x-tex">3.25-3.14< / annotation>< / semantics> (m, 1H), <semantics>2.93<annotation encoding="application / x-tex">2.93< / annotation>< / semantics> (t, <semantics>J=9.3<annotation encoding="application / x-tex">J = 9.3< / annotation>< / semantics> Hz, 1H), <semantics>2.47−2.34<annotation encoding="application / x-tex">2.47-2.34< / annotation>< / semantics> (m, 1H), <semantics>2.27<annotation encoding="application / x-tex">2.27< / annotation>< / semantics> (d, <semantics>J=6.1<annotation encoding="application / x-tex">J = 6.1< / annotation>< / semantics> Hz, 2H), <semantics>2.20<annotation encoding="application / x-tex">2.20< / annotation>< / semantics> (s, 1H), <semantics>2.00−1.90<annotation encoding="application / x-tex">2.00-1.90< / annotation>< / semantics> (m, 1H), <semantics>1.77−1.61<annotation encoding="application / x-tex">1.77-1.61< / annotation>< / semantics> (m, 1H), 1.35 (s, 9H).MS (ESI, <semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>): 256.1 [M+H]+. Step C: Preparation of 2-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-4-hydroxybutanoic acid [Image disponible dans le document PDF, Image available in the PDF document] The product of step B of example 21 (16.5 g, 64.63 mmol), H2O (100 mL), and sodium hydroxide (5.7 g, 129.25 mol) were added in a round bottom flask. This reaction mixture was stirred at room temperature overnight. The clear reaction mixture was then extracted with ethyl acetate, the aqueous layer was isolated and acidified to pH 3-4 with concentrated HCl and then extracted with 100 mL of dichloromethane. The organic phase was washed with saturated brine and then dried over anhydrous Na2SO4. The organic phase was concentrated in vacuo to give product as an oil <semantics>(17.5 g,91%)<annotation encoding="application / x-tex">(17.5 \text{ g}, 91\%)< / annotation>< / semantics>. 1H NMR <semantics>(400 MHz,CDCl3)δ4.36 (d,J=5.2 Hz,1H),4.25−4.17 (m, 1H),3.86−100 m<annotation encoding="application / x-tex">(400 \text{ MHz}, \text{CDCl}_3) \delta 4.36 \text{ (d}, J = 5.2 \text{ Hz}, 1\text{H}), 4.25-4.17 \text{ (m, 1H)}, 3.86-100 \text{ m}< / annotation>< / semantics> 3.70 (m, 2H), 3.53-3.48 (m, 2H), 3.29 (d, <semantics>J=8.6<annotation encoding="application / x-tex">J = 8.6< / annotation>< / semantics> Hz, 1H), 3.04 (d, <semantics>J=8.0<annotation encoding="application / x-tex">J = 8.0< / annotation>< / semantics> Hz, 1H), 2.53-2.49 (m, 1H), 2.44-2.37 (m, 2H), 1.90-1.83 (m, 1H), 1.46 (s, 9H). MS (ESI, <semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>): 274.2 [M+H]+. Step D: Preparation of 2-(1-(tert-butoxycarbonyl) pyrrolidin-3-yl)-4-((tert- butyldimethylsilyl)oxy)butanoic acid [Image disponible dans le document PDF, Image available in the PDF document] Tert-Butyldimethylsilylchloride (17.5 g, 76.83 mol) was added to a mixture of the product of step C of example 21 (17.5 g, 64.03 mmol) and imidazole (8.7 g, 128.05 mol) in <semantics>N<annotation encoding="application / x-tex">N< / annotation>< / semantics>, <semantics>N<annotation encoding="application / x-tex">N< / annotation>< / semantics>- dimethylformamide (300 mL). The reaction mixture was stirred at 30 °C for 5hs under argon atmosphere, then poured into a separatory funnel containing 400 mL of brine and extracted 4 times with 200 mL of dichloromethane. The organic fractions were combined, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude product which was purified via flash chromatography eluting with dichloromethane and methanol (30:1) to give the product as a clear colorless oil (crude 14 g). MS (ESI, <semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>): 388.3 [M+H]+. Step E: Preparation of tert-butyl 3-(11,11,12,12-tetramethyl-3,6-dioxo-4-(4-phenoxybenzoyl)- 2,5,10-trioxa-11-silatridecan-7-yl)pyrrolidine-1-carboxylate [Image disponible dans le document PDF, Image available in the PDF document] The product of step B (7.4 g, 21.08 mmol) of example 1 and the product of step D of example 21 (12.3 g, 31.62 mmol) were taken up in acetonitrile (250 mL), then N, N-diisopropylethylamine (5.5 g, 42.16 mmol) was added and the solution stirred at 30°C for 3 hs. The solvent was removed by rotorary evaporation and the residue taken up in ethyl acetate, washed with 0.1 N HCl, and brine. The organic fractions were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude product which was purified via flash chromatography eluting with ethyl acetate and petroleum ether <semantics>(1:20)<annotation encoding="application / x-tex">(1:20)< / annotation>< / semantics> to give the product as a clear colorless oil <semantics>(6 g,43%)<annotation encoding="application / x-tex">(6 \text{ g}, 43\%)< / annotation>< / semantics>. 1H NMR (600 MHz, CDCl3) <semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics> 7.98 (d, <semantics>J<annotation encoding="application / x-tex">J< / annotation>< / semantics> = 8.4 Hz, 2H), 7.42 (t, <semantics>J<annotation encoding="application / x-tex">J< / annotation>< / semantics> = 7.6 Hz, 2H), 7.24 (t, <semantics>J<annotation encoding="application / x-tex">J< / annotation>< / semantics> = 7.3 Hz, 1H), <semantics>7.09<annotation encoding="application / x-tex">7.09< / annotation>< / semantics> (d, <semantics>J=7.9<annotation encoding="application / x-tex">J = 7.9< / annotation>< / semantics> Hz, 2H), <semantics>7.01<annotation encoding="application / x-tex">7.01< / annotation>< / semantics> (d, <semantics>J=8.4<annotation encoding="application / x-tex">J = 8.4< / annotation>< / semantics> Hz, 2H), <semantics>6.25<annotation encoding="application / x-tex">6.25< / annotation>< / semantics> (d, <semantics>J=7.7<annotation encoding="application / x-tex">J = 7.7< / annotation>< / semantics> Hz, 1H), <semantics>3.79<annotation encoding="application / x-tex">3.79< / annotation>< / semantics> (s, 3H), 3.73-3.56 (m, 3H), 3.52-3.43 (m, 1H), 3.24 (s, 1H), 3.09-2.89 (m, 1H), 2.63 (s, 1H), 2.52-2.35 (m, 1H), 2.05 (s, 1H), 1.93 (s, 1H), 1.87-1.71 (m, 1H), 1.45 (s, 9H), 1.26 (s, 1H), 0.87-0.84 (m, 6H), <semantics>0.04<annotation encoding="application / x-tex">0.04< / annotation>< / semantics>-(-0.03) (m, 6H). MS (ESI, <semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>): 666.3 [M+H]+. Step F: Preparation of methyl 2-(1-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-((tert- butyldimethylsilyl)oxy)propyl)-4-(4-phenoxyphenyl)-1H-imidazole-5-carboxylate [Image disponible dans le document PDF, Image available in the PDF document] To a slurry of ammonium acetate (6 g, 9.15 mmol) in xylenes (40 mL) was added the product of step E of example 21 (8.5 g, 109.78 mmol). The mixture was stirred at 140°C. For 4 hours. The solution was cooled to room temperature and evaporated. The residue was dissolved in ethyl- acetate and washed with saturated brine. The organic phase was dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography with ethyl acetate and petroleum ether (1:20) to give the product as a clear colorless oil (2.5 g, 43%). 1H NMR (600 MHz, CDCl3) <semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics> 7.89 (d, <semantics>J=7.8<annotation encoding="application / x-tex">J = 7.8< / annotation>< / semantics> Hz, 2H), 7.29 (t, <semantics>J=7.4<annotation encoding="application / x-tex">J = 7.4< / annotation>< / semantics> Hz, 2H), 7.06 (t, <semantics>J=7.3<annotation encoding="application / x-tex">J = 7.3< / annotation>< / semantics> Hz, 1H), 7.00 (d, <semantics>J=6.7<annotation encoding="application / x-tex">J = 6.7< / annotation>< / semantics> Hz, 4H), 3.79 (s, 3H), 3.68-3.57 (m, 2H), 3.46-3.32 (m, 3H), 3.17 (t, <semantics>J=15.7<annotation encoding="application / x-tex">J = 15.7< / annotation>< / semantics> Hz, 1H), 2.99-2.83 (m, 3H), 2.64 (s, 1H), 1.90 (s, 3H), 1.75 (s, 2H), 1.42 (d, <semantics>J=11.9<annotation encoding="application / x-tex">J = 11.9< / annotation>< / semantics> Hz, 9H), 1.38 <semantics>(d,J−6.5 Hz,2H),0.86 (s, 9H),0.00 (d, J−4.7 Hz,6H). MS (ESI, m / z):636.3 [M+H]−.<annotation encoding="application / x-tex">(d, J-6.5 \text{ Hz}, 2\text{H}), 0.86 \text{ (s, 9H)}, 0.00 \text{ (d, } J-4.7 \text{ Hz}, 6\text{H}). \text{ MS (ESI, } m / z): 636.3 \text{ [M+H]}^-.< / annotation>< / semantics> Step G: Preparation of methyl 1-amino-2-(1-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-((tert-butoxycarbonyl)pyrrolidin-3-yl)-3-((tert-butoxycarbonyl)pyrrolidin-3-yl)-3-((tert-butoxycarbonyl)pyrrolidin-3-yl)-3-((tert-butoxy butyldimethylsilyl)oxy)propyl)-4-(4-phenoxyphenyl)-1H-imidazole-5-carboxylate [Image disponible dans le document PDF, Image available in the PDF document] Lithium hexamethyldisilazane (6 mL of a 1 M solution in tetrahydrofuran, 5.89 mmol) was slowly added to the product of step F of example 21 (2.5 g, 3.93 mmol) in anhydrous N, N- dimethylformamide(30 mL) at 0 °C. After the mixture was stirred for 30 min, O- (diphenylphosphinyl) hydroxylamine (1.8 g, 7.86 mmol) was added, followed by stirring at room temperature for 5 hs (in cases where the reaction mixture became too viscous, additional N,N- dimethylformamidewas added). The reaction was quenched with water until a clear solution was formed and concentrated to dryness under reduced pressure. The residue was washed several times with ethyl acetate or dichloromethane. The combined organic fractions were concentrated in vacuo and purified by flash chromatography on silica gel with ethyl acetate and petroleum ether (1:3) to give the product as a clear colorless oil (1.5 g, 58%). 1H NMR (400 MHz, CDCl3) <semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics> 7.62-7.59 (m, 2H), 7.33 (t, <semantics>J=7.0<annotation encoding="application / x-tex">J = 7.0< / annotation>< / semantics> Hz, 2H), 7.10 (t, <semantics>J=7.4<annotation encoding="application / x-tex">J = 7.4< / annotation>< / semantics> Hz, 1H), 7.05-6.99 (m, 4H), 5.69-5.52 (m, 2H), 3.77 (s, 3H), 3.71-3.58 (m, 2H), 3.50-3.44 (m, 1H), 3.43-3.32 (m, 2H), 3.26-3.14 (m, 1H), 3.12-2.98 (m, 1H), 2.77-2.65 (m, 1H), 2.04 (s, 2H), 1.97-1.85 (m, 1H), 1.83-1.69 (m, 1H), 1.47-1.41 (m, 9H), 0.85 (s, 9H), 0.01-(-0.04) (m, 6H). MS (ESI, <semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>): 651.3 [M+H]+. Step H: Preparation of methyl 1-amino-2-(1-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3- hydroxypropyl)-4-(4-phenoxyphenyl)-1H-imidazole-5-carboxylate [Image disponible dans le document PDF, Image available in the PDF document] To a solution of the product of step G of example 21 (1.5 g, 2.30 mmol) in tetrahydrofuran (20 mL) was added a 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran (2.5 mL, 2.5 mmol) at RT. The solution was stirred for 2 h and diluted with 100 mL ethyl acetate solution. The organic layer was separated and washed with H2O (3×200 mL). The water extract was washed with ethyl acetate solution (2×150 mL), and the organic layers were combined and dried over anhydrous Na2SO4. The solvent was evaporated in vacuo, and purified by flash chromatography on silica gel with dichloromethane and methanol (30:1) to give the product as a clear colorless oil (1.0 g, 80%). 1H NMR (600 MHz, CDCl3) <semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics> 7.64-7.55 (m, 2H), 7.32 (t, <semantics>J=7.9<annotation encoding="application / x-tex">J = 7.9< / annotation>< / semantics> Hz, 2H), 7.10 (t, <semantics>J=7.9<annotation encoding="application / x-tex">J = 7.9< / annotation>< / semantics> Hz, 2H), 7.10 (t, <semantics>J=7.9<annotation encoding="application / x-tex">J = 7.9< / annotation>< / semantics> Hz, 2H), 7.10 (t, <semantics>J=7.9<annotation encoding="application / x-tex">J = 7.9< / annotation>< / semantics> Hz, 2H), 7.10 (t, <semantics>J=7.9<annotation encoding="application / x-tex">J = 7.9< / annotation>< / semantics> Hz, 2H), 7.10 (t, <semantics>J=7.<annotation encoding="application / x-tex">J = 7.< / annotation>< / semantics> <semantics>=7.4 Hz,1H,7.05−6.96 (m, 4H),5.74−5.60 (m, 2H),3.76 (s, 3H),3.70−3.53 (m, 2H),3.49−3.23<annotation encoding="application / x-tex">= 7.4 \text{ Hz}, 1\text{H}, 7.05-6.96 \text{ (m, 4H)}, 5.74-5.60 \text{ (m, 2H)}, 3.76 \text{ (s, 3H)}, 3.70-3.53 \text{ (m, 2H)}, 3.49-3.23< / annotation>< / semantics> (m, 4H), 3.19-3.13 (m, 1H), 3.07-3.01 (m, 1H), 2.88-2.69 (m, 1H), 2.06-1.90 (m, 2H), 1.80-1.69 (m, 1H).MS (ESI, <semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>): 537.3 [M+H]+. Step I: Preparation of methyl 8-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-2-(4-phenoxyphenyl)- 5,6,7,8-tetrahydroimidazo[1,2-b]pyridazine-3-carboxylate [Image disponible dans le document PDF, Image available in the PDF document] Methanesulfonyl chloride (320.2 mg, 2.80 mmol) was added via syringe into a stirred mixture ____ of the product of step H of example 21 (1.0 g, 1.86 mmol) and N, N-diisopropylethylamine (481.7 mg, 3.37 mmol) in dichloromethane (10 ml) maintained at 0°C. The mixture was stirred at room temperature for 3 hs (TLC monitoring) and then partitioned between dichloromethane and water. The organic phase was dried and evaporated to afford a yellow oil. The crude intermediate was dissolved in tetrahydrofuran(10 mL), 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran(2 mL, 2 mmol) and N, N-diisopropylethylamine (481.7 g, 3.37 mmol) was added to the mixture, which was stirred 3hs, then partitioned between dichloromethane and water. The organic phase was dried and evaporated to afford a white solid, then passed through a column of silica gel with dichloromethane and methanol (30:1) to afford the desired product as a colorless oil (650 mg, 56%). 1H NMR (600 MHz, CDCl3) <semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics> 7.74-7.60 (m, 2H), 7.34 (t, <semantics>J<annotation encoding="application / x-tex">J< / annotation>< / semantics> = 7.9 Hz, 2H), 7.10 <semantics>(dd,J=13.4,6.0 Hz,1H),7.08−7.00 (m, 4H),3.78 (s, 3H),3.65−3.50 (m, 3H),3.42−3.32 (m, 1H),<annotation encoding="application / x-tex">(dd, J = 13.4, 6.0 \text{ Hz}, 1\text{H}), 7.08-7.00 \text{ (m, 4H)}, 3.78 \text{ (s, 3H)}, 3.65-3.50 \text{ (m, 3H)}, 3.42-3.32 \text{ (m, 1H)},< / annotation>< / semantics> <semantics>3.32−3.22<annotation encoding="application / x-tex">3.32-3.22< / annotation>< / semantics> (m, 1H), <semantics>3.10<annotation encoding="application / x-tex">3.10< / annotation>< / semantics> (t, <semantics>J−10.0<annotation encoding="application / x-tex">J-10.0< / annotation>< / semantics> Hz, 1H), <semantics>2.50<annotation encoding="application / x-tex">2.50< / annotation>< / semantics> (d, <semantics>J−4.8<annotation encoding="application / x-tex">J-4.8< / annotation>< / semantics> Hz, 1H), <semantics>2.49−2.30<annotation encoding="application / x-tex">2.49-2.30< / annotation>< / semantics> (m, 1H), <semantics>2.20−1.00<annotation encoding="application / x-tex">2.20-1.00< / annotation>< / semantics> 2.11 (m, 1H), 2.07-1.75 (m, 3H), 1.45 (s, 9H). MS (ESI, <semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>): 519.3 [M+H]+. Step J: Preparation of 8-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-2-(4-phenoxyphenyl)-5,6,7,8- tetrahydroimidazo[1,2-b]pyridazine-3-carboxylic acid [Image disponible dans le document PDF, Image available in the PDF document] To a solution of the product of step I of example 21 (650 mg, 1.25 mmol) in tetrahydrofuran(10 mL) / water (3 mL) was added LiOH (150.1 mg, 6.27 mmol) in water (1 mL), the mixture was heated at 50°C for 3 hs, and then cooled to r.t. The mixture acidified to pH 3-4 with concentrated HCl and then extracted with 3×100mL of dichloromethane. The organic phase was washed with saturated brine and then dried over anhydrous Na2SO4. The organic phase was concentrated in vacuo to afford 600 mg crude product. The residue was used to next step.MS (ESI, <semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>): 505.2 <semantics>[M+H]+<annotation encoding="application / x-tex">[M+H]^{+}< / annotation>< / semantics>. Step K: Preparation of tert-butyl 3-(3-carbamoyl-2-(4-phenoxyphenyl)-5,6,7,8- tetrahydroimidazo[1,2-b]pyridazin-8-yl)pyrrolidine-1-carboxylate [Image disponible dans le document PDF, Image available in the PDF document] To the solution of the product of step J of example 21 (600 mg, 1.19 mmol) in dichloromethane (10 mL) was added N, N-diisopropylethylamine (614.7 mg, 4.76 mmol). After 5 min, NH4Cl (254.4 mg, 4.76 mmol) and HATU (678.2 mg, 1.78 mmol) was added. The reaction mixture was continued to stir at room temperature for 2 hs. Dichloromethane and water were added. The layers were separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed three times (3×50 mL) with brine solution. The organic phase was dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by chromatography with dichloromethane and methanol (40:1) to afford the desired product as a colorless oil (280 mg, 46%). 1H NMR (600 MHz, CDCl3) <semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics> 7.60 (d, <semantics>J=8.5<annotation encoding="application / x-tex">J = 8.5< / annotation>< / semantics> Hz, 2H), 7.33 (t, <semantics>J=7.9<annotation encoding="application / x-tex">J = 7.9< / annotation>< / semantics> Hz, 2H), 7.11 (t, <semantics>J<annotation encoding="application / x-tex">J< / annotation>< / semantics> <semantics>=7.4 Hz,1H,7.01 (d, J=7.8 Hz,4H),6.87 (s, 1H),5.80 (s, 1H),3.59 (dd, J=13.2,6.5 Hz,1H),<annotation encoding="application / x-tex">= 7.4 \text{ Hz}, 1\text{H}, 7.01 \text{ (d, } J = 7.8 \text{ Hz}, 4\text{H}), 6.87 \text{ (s, 1H)}, 5.80 \text{ (s, 1H)}, 3.59 \text{ (dd, } J = 13.2, 6.5 \text{ Hz}, 1\text{H}),< / annotation>< / semantics> <semantics>3.54−3.48<annotation encoding="application / x-tex">3.54-3.48< / annotation>< / semantics> (m, 1H), <semantics>3.42<annotation encoding="application / x-tex">3.42< / annotation>< / semantics> (d, <semantics>J=6.0<annotation encoding="application / x-tex">J = 6.0< / annotation>< / semantics> Hz, 1H), <semantics>3.32−3.22<annotation encoding="application / x-tex">3.32-3.22< / annotation>< / semantics> (m, 2H), <semantics>3.11−3.06<annotation encoding="application / x-tex">3.11-3.06< / annotation>< / semantics> (m, 2H), <semantics>2.71−2.52<annotation encoding="application / x-tex">2.71-2.52< / annotation>< / semantics> (m, 1H), 2.34 (d, <semantics>J=5.7<annotation encoding="application / x-tex">J = 5.7< / annotation>< / semantics> Hz, 2H), 2.13 (s, 1H), 1.95-1.80 (m, 2H), 1.43 (s, 11H). MS (ESI, <semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>): 504.3 <semantics>[M+H]+<annotation encoding="application / x-tex">[M+H]^+< / annotation>< / semantics> Step L: Preparation of 2-(4-phenoxyphenyl)-8-(pyrrolidin-3-yl)-5,6,7,8-tetrahydroimidazo[1,2- blpyridazine-3-carboxamide [Image disponible dans le document PDF, Image available in the PDF document] To a solution of the product of step K of example 21 (280 mg, 0.55 mmol) in dichloromethane (10 mL) was added CF3COOH (2 mL) at room temperature in reaction still. The mixture was stirred for 30 min, and concentrated under vacuum to get 540 mg crude. The residue was used to next step without further purification. MS (ESI, <semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>): 404.2 [M+H]+. Step <semantics>𝑴<annotation encoding="application / x-tex">\mathbf{M}< / annotation>< / semantics>: Preparation of 8-(1-acryloylpyrrolidin-3-yl)-2-(4-phenoxyphenyl)-5,6,7,8- tetrahydroimidazo[1,2-b]pyridazine-3-carboxamide [Image disponible dans le document PDF, Image available in the PDF document] The mixture of the product of step L of example 21 (220.0 mg, 0.55 mmol) and triethylamine(220.7 mg, 2.18 mmol) in dichloromethane (5 mL) was cooled to -60°C. Then the solution of propenoyl chloride (49.5 mg, 0.55mmol) in dichloromethane(1 mL) was added slowly, LC-MS was tracking, at the end of the reaction, 1 mL MeOH was added, the mixture was concentrated under vacuum to get 320 mg crude, and purified by flash chromatography on silica gel with dichloromethane and methanol (40:1) to get product as a white solid (48 mg, 21%). 1H NMR (400 MHz, CDCl3) <semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics> 7.64-7.55 (m, 2H), 7.37-7.32 (m, 2H), 7.12 (ddd, <semantics>J=7.2,5.1,1.8<annotation encoding="application / x-tex">J = 7.2, 5.1, 1.8< / annotation>< / semantics> Hz, CA 1H), <semantics>7.03<annotation encoding="application / x-tex">7.03< / annotation>< / semantics> (dt, <semantics>J=5.0<annotation encoding="application / x-tex">J = 5.0< / annotation>< / semantics>, <semantics>4.6<annotation encoding="application / x-tex">4.6< / annotation>< / semantics> Hz, 4H), <semantics>6.42−6.28<annotation encoding="application / x-tex">6.42-6.28< / annotation>< / semantics> (m, 2H), <semantics>5.93<annotation encoding="application / x-tex">5.93< / annotation>< / semantics> (s, 1H), <semantics>5.69−5.61<annotation encoding="application / x-tex">5.69-5.61< / annotation>< / semantics> (m, 1H), <semantics>3.89−3.66<annotation encoding="application / x-tex">3.89-3.66< / annotation>< / semantics> (m, 2H), 3.49-3.28 (m, 3H), 3.27-3.15 (m, 1H), 3.13-2.96 (m, 1H), 2.86-2.63 (m, 1H), 2.36-2.25 (m, 1H), 2.23-2.02 (m, 2H), 1.92-1.83 (m, 1H). MS (ESI, <semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>): 458.2 [M+H]+. Scheme II [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] Example 22: Preparation of 8-(2-acrylamidophenyl)-2-(4-phenoxyphenyl)-5,6,7,8- tetrahydroimidazo[1,2-b]pyridazine-3-carboxamide [Image disponible dans le document PDF, Image available in the PDF document] Experimental Section: Step A: Preparation of methyl 2-(2-nitrophenyl)acetate [Image disponible dans le document PDF, Image available in the PDF document] 2-Nitrophenylacetic acid (300 g, 1.66 mol) was set stirring in 500 mL of methanol. Sulfurous dichloride (591.3 g, 4.97 mol) was added and the mixture heated to reflux. After 4 h the mixture was cooled and evaporated under reduced pressure to give a clear yellow oil. The oil was taken up in ethyl acetate and washed with saturated NaHCO3. The organics were dried over anhydrous Na2SO4 and evaporated to give product as a clear orange liquid (320 g, 99%). 1H NMR (400 MHz, CDCl3) <semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics> 8.13-8.07 (m, 1H), 7.63-7.56 (m, 1H), 7.50-7.44 (m, 1H), 7.39-7.34 (m, 1H), 4.03 (s, 2H), 3.70 (s, 3H). MS (ESI, m / z): 196.1 [M+H]+. Step B: Preparation of methyl 4-((tert-butyldimethylsilyl)oxy)-2-(2-nitrophenyl)butanoate [Image disponible dans le document PDF, Image available in the PDF document] A solution of the product of step A of example 22 (100.0 g, 512.36 mmol) and t-BuOK (115.0 g, 1.02 mol) in N, N-dimethylformamide (1500 mL) was stirred at room temperature for 1 hs. Then (2-bromo-ethoxy)-tert-butyl-dimethyl-silane (196.1 g, 819.78 mmol) was added slowly at 0°C to this solution. The mixture was stirred at room temperature overnight, then poured into water (500 mL). The aqueous phase was extracted with ethyl acetate (3×500 mL), and the organic layer was washed with saturated NH4Cl (500 mL), water (3×500 mL), brine (500 mL), dried with anhydrous Na2SO4, and evaporated to get crude product. It was purified by flash chromatography with ethyl acetate and petroleum ether (1:20) to obtain the desired product as a clear orange liquid (103 g, 56%). 1H NMR (600 MHz, CDCl3) <semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics> 7.91-7.87 (m, 1H), 7.59-7.54 (m, 1H), 7.52-7.49 (m, 1H), <semantics>7.44−7.38<annotation encoding="application / x-tex">7.44-7.38< / annotation>< / semantics> (m, 1H), <semantics>4.39<annotation encoding="application / x-tex">4.39< / annotation>< / semantics> (t, <semantics>J=7.2<annotation encoding="application / x-tex">J = 7.2< / annotation>< / semantics> Hz, 1H), <semantics>3.68−3.64<annotation encoding="application / x-tex">3.68-3.64< / annotation>< / semantics> (m, 4H), <semantics>3.54−3.50<annotation encoding="application / x-tex">3.54-3.50< / annotation>< / semantics> (m, 1H), <semantics>2.47−2.41<annotation encoding="application / x-tex">2.47-2.41< / annotation>< / semantics> (m, 1H), 2.06-1.95 (m, 1H), 0.86 (s, 9H), -0.00 (d, <semantics>J=7.0 Hz<annotation encoding="application / x-tex">J = 7.0 \text{ Hz}< / annotation>< / semantics>, 6H). MS (ESI, m / z): 354.2 [M+H]+. Step C: Preparation of 4-((tert-butyldimethylsilyl)oxy)-2-(2-nitrophenyl)butanoic acid [Image disponible dans le document PDF, Image available in the PDF document] To a solution of the ester product of step B of example 22 (50 g, 5.7 mmol) in tetrahydrofuran (500 mL) was added a solution of aqueous 10% KOH (250 mL). The reaction mixture was stirred until complete consumption of the ester. Water was added and the reaction mixture was acidified to pH 5-6 with 1 M HCl. The mixture was extracted with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuo to get the product as a colorless oil (41 g, 85%), which was used for the next step without further purification. 1H NMR (600 MHz, CDCl3) δ 7.96-7.92 (m, 1H), 7.61-7.56 (m, 1H), 7.52-7.48 (m, 1H), 7.47-7.40 <semantics>(m,1H),4.42(t,J=6.9Hz,1H),3.73−3.67(m,1H),3.54−3.51(m,1H),2.52−2.43(m,1H),2.07−<annotation encoding="application / x-tex">(m, 1H), 4.42 (t, J = 6.9 Hz, 1H), 3.73-3.67 (m, 1H), 3.54-3.51 (m, 1H), 2.52-2.43 (m, 1H), 2.07-< / annotation>< / semantics> 1.97 (m, 1H), 0.86 (s, 9H), 0.00 (d, <semantics>J=9.2<annotation encoding="application / x-tex">J = 9.2< / annotation>< / semantics> Hz, 6H). MS (ESI, m / z): 340.2 [M+H]+. Step D: Preparation of 1-methoxy-1,3-dioxo-3-(4-phenoxyphenyl)propan-2-yl 4-((tert- butyldimethylsilyl)oxy)-2-(2-nitrophenyl)butanoate [Image disponible dans le document PDF, Image available in the PDF document] The product of step B (20.0 g, 57.28 mmol) of example 1 and the product of step C of example 22 (21.39 g, 63.00 mmol) were taken up in acetonitrile (250 mL), then N, N-diisopropylethylamine (11.1 mL, 85.92 mmol) was added and the solution stirred at 30°C for 3 hs. The solvent was removed by rotorary evaporation and the residue taken up in ethyl acetate, washed with 0.1 N HCl, and brine. The organic fractions were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude product which was purified via flash chromatography eluting with ethyl acetate and petroleum ether (1:20) to give the product as a clear orange oil (23 g, 66%). 1H NMR (400 MHz, CDCl3) <semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics> 7.97-7.81 (m, 3H), 7.63-7.49 (m, 2H), 7.45-7.38 (m, 3H), <semantics>7.26−7.20<annotation encoding="application / x-tex">7.26-7.20< / annotation>< / semantics> (m, 1H), <semantics>7.11−7.06<annotation encoding="application / x-tex">7.11-7.06< / annotation>< / semantics> (m, 2H), <semantics>6.96−6.88<annotation encoding="application / x-tex">6.96-6.88< / annotation>< / semantics> (m, 2H), <semantics>6.19<annotation encoding="application / x-tex">6.19< / annotation>< / semantics> (d, <semantics>J=1.9<annotation encoding="application / x-tex">J = 1.9< / annotation>< / semantics> Hz, 1H), <semantics>4.57<annotation encoding="application / x-tex">4.57< / annotation>< / semantics> (t, <semantics>J=7.1<annotation encoding="application / x-tex">J = 7.1< / annotation>< / semantics> Hz, 1H), 3.79-3.72 (m, 3H), 3.72-3.66 (m, 1H), 3.54-3.48 (m, 1H), 2.58-2.45 (m, 1H), 2.13-1.97 (m, 111), 0.84 (t, <semantics>J=2.1 Hz<annotation encoding="application / x-tex">J = 2.1 \text{ Hz}< / annotation>< / semantics>, 911), -0.01-(-0.04) (m, 611). MS (ESI, m / z): 608.2 [M+II]+. C Step E: Preparation of methyl 2-(3-((tert-butyldimethylsilyl)oxy)-1-(2-nitrophenyl)propyl)-4- (4-phenoxyphenyl)-1H-imidazole-5-carboxylate [Image disponible dans le document PDF, Image available in the PDF document] To a slurry of ammonium acetate (18.26 g, 236.95 mmol) in xylenes (50 mL) was added the product of step D of example 22 (12 g, 19.75 mmol). The mixture was stirred at 140°C for 4 hs. The solution was cooled to room temperature and the solvent was evaporated. The residue was dissolved in ethyl acetate and washed with saturated brine. The organic phase was dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography with ethyl acetate and petroleum ether (1:5) to give the product as a clear yellow oil (2.5 g, 21%). 1H NMR (600 MHz, CDCl3) <semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics> 10.12 (s, 1H), 7.97 (d, <semantics>J=8.5<annotation encoding="application / x-tex">J = 8.5< / annotation>< / semantics> Hz, 2H), 7.84 (d, <semantics>J=8.5<annotation encoding="application / x-tex">J = 8.5< / annotation>< / semantics> Hz, 2H), 7.84 (d, <semantics>J=8.5<annotation encoding="application / x-tex">J = 8.5< / annotation>< / semantics> Hz, 2H), 7.84 (d, <semantics>J=8.5<annotation encoding="application / x-tex">J = 8.5< / annotation>< / semantics> Hz, 2H), 7.84 (d, <semantics>J=8.5<annotation encoding="application / x-tex">J = 8.5< / annotation>< / semantics> Hz, 2H), 7.84 (d, <semantics>J=8.<annotation encoding="application / x-tex">J = 8.< / annotation>< / semantics> <semantics>=8.0 Hz,1H,7.70 (d, J=7.8 Hz,1H),7.55 (t, J=7.6 Hz,2H),7.40−7.31 (m, 3H),7.11 (t, J=7.8 Hz,1H),7.55 (t, J=7.6 Hz,2H),7.40−7.31 (m, 3H),7<annotation encoding="application / x-tex">= 8.0 \text{ Hz}, 1\text{H}, 7.70 \text{ (d, } J = 7.8 \text{ Hz}, 1\text{H}), 7.55 \text{ (t, } J = 7.6 \text{ Hz}, 2\text{H}), 7.40-7.31 \text{ (m, 3H)}, 7.11 \text{ (t, } J = 7.8 \text{ Hz}, 1\text{H}), 7.55 \text{ (t, } J = 7.6 \text{ Hz}, 2\text{H}), 7.40-7.31 \text{ (m, 3H)}, 7< / annotation>< / semantics> 7.4 Hz, 1H), 7.06-6.99 (m, 3H), 4.96 (t, <semantics>J=7.2<annotation encoding="application / x-tex">J = 7.2< / annotation>< / semantics> Hz, 1H), 3.82 (s, 3H), 3.68-3.63 (m, 1H), 3.58- 3.54 (m, 1H), 2.67-3.64 (m, 1H), 2.35-2.30 (m, 1H), 0.87 (s, 9H), 0.01-(-0.03) (m, 6H). MS (ESI, <semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>): 588.3 <semantics>[M+H]+<annotation encoding="application / x-tex">[M+H]^+< / annotation>< / semantics>. Step F: Preparation of methyl 1-amino-2-(3-((tert-butyldimethylsilyl)oxy)-1-(2- nitrophenyl)propyl)-4-(4-phenoxyphenyl)-1H-imidazole-5-carboxylate [Image disponible dans le document PDF, Image available in the PDF document] Lithium hexamethyldisilazane (6.3 mL of a 1 M solution intetrahydrofuran, 2.77 mmol) was slowly added to the product of step E of example 22 (2.5 g, 4.25 mmol) in anhydrous N, N- dimethylformamide (10 mL) at <semantics>0∘<annotation encoding="application / x-tex">0^{\circ}< / annotation>< / semantics>C. After the mixture was stirred for 30 min, O- (diphenylphosphinyl) hydroxylamine (1.98 g, 8.51 mmol) was added at 0°C, followed by stirring at room temperature for 4 hs (in cases where the reaction mixture became too viscous, additional N, N-dimethylformamide was added). The reaction was quenched with water until a clear solution was formed and concentrated to dryness under reduced pressure. The residue was washed several times with ethyl acetate or dichloromethane. The combined organic fractions were concentrated in vacuo and purified by flash chromatography on silica gel with ethyl acetate and petroleum ether (1:3) to give the product as a clear colorless oil (2.3 g, 89%). 1H NMR (600 MHz, CDCl3) <semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics> 7.79- 7.76 (m, 1H), 7.70-7.65 (m, 3H), 7.51-7.44 (m, 1H), 7.37-7.31 (m, 3H), 7.13-7.09 (m, 1H), 7.06- 7.00 (m, 4H), 5.33-5.29 (m, 1H), 5.13 (s, 2H), 3.78-3.72 (m, 4H), 3.71-3.66 (m, 1H), 2.64-2.58 (m, 1H), 2.32-2.27 (m, 1H), 0.85 (s, 9H), 0.00-(-0.04) (m, 6H). MS (ESI, m / z): 603.3 [M+H]+. Step G: Preparation of methyl 1-amino-2-(3-hydroxy-1-(2-nitrophenyl)propyl)-4-(4- phenoxyphenyl)-1H-imidazole-5-carboxylate [Image disponible dans le document PDF, Image available in the PDF document] To a solution of the product of step F of example 22 (2.3 g, 3.82 mmol) in tetrahydrofuran (20 mL) was added a 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran (10 mL, 10 mmol) at r.t. The solution was stirred for 2 hs and diluted with 100 mL ethyl acetate solution. The organic layer was separated and washed with H2O (3×100 mL). The water extract was washed with ethyl acetate solution (<semantics>2×50<annotation encoding="application / x-tex">2\times50< / annotation>< / semantics> mL), and the organic layers were combined and dried over anhydrous Na2SO4. The solvent was evaporated in vacuo, and the residue was purified via flash chromatography eluting with ethyl acetate and petroleum ether (1:1) to give the product as a clear orange oil (1.3 g, 69%). 1H NMR (400 MHz, CDCl3) <semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics> 7.85 (d, <semantics>J=7.9<annotation encoding="application / x-tex">J = 7.9< / annotation>< / semantics> Hz, 1H), 7.69-7.62 (m, 2H), 7.55-7.49 (m, 2H), 7.40-7.30 (m, 3H), 7.13 (t, <semantics>J=7.4<annotation encoding="application / x-tex">J = 7.4< / annotation>< / semantics> Hz, 1H), 7.08-6.98 (m, 4H), 5.30 (dd, <semantics>J=<annotation encoding="application / x-tex">J =< / annotation>< / semantics> 8.9, 5.0 Hz, 1H), 5.15 (s, 2H), 3.76 (s, 3H), 3.74-3.63 (m, 2H), 2.64-2.53 (m, 1H), 2.50-2.37 (m, 1H). MS (ESI, m / z): 489.2 [M+H]+. Step H: Preparation of methyl 1-amino-2-(3-((methylsulfonyl)oxy)-1-(2-nitrophenyl)propyl)-4- (4-phenoxyphenyl)-1H-imidazole-5-carboxylate [Image disponible dans le document PDF, Image available in the PDF document] Methanesulfonyl chloride (365.7 mg, 3.19 mmol) was added via syringe into a stirred mixture of the product of step G of example 22 (1.3 g, 2.66 mmol) and N, N-disopropylethylamine (687.9 mg, 5.32 mmol) in dichloromethane (3 ml) maintained at 0°C. The mixture was stirred at room temperature for 3 hs (TLC monitoring) and then partitioned between dichloromethane and water. The organic phase was dried and evaporated to afford a white solid which was passed through a column of silica gel with dichloromethane and methanol (40:1) to afford the desired product as a colorless oil (1.2 g, 79%). 1H NMR (600 MHz, CDCl3) <semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics> 7.85 (d, <semantics>J<annotation encoding="application / x-tex">J< / annotation>< / semantics> = 8.1 Hz, 1H), 7.69 (d, <semantics>J<annotation encoding="application / x-tex">J< / annotation>< / semantics> = 8.5 Hz, 2H), 7.61 (d, <semantics>J=7.9<annotation encoding="application / x-tex">J = 7.9< / annotation>< / semantics> Hz, 1H), 7.51 (t, <semantics>J=7.6<annotation encoding="application / x-tex">J = 7.6< / annotation>< / semantics> Hz, 1H), 7.40-7.33 (m, 3H), 7.13 (t, <semantics>J=7.4<annotation encoding="application / x-tex">J = 7.4< / annotation>< / semantics> Hz, 1H), 7.08-7.02 (m, 4H), 5.37-5.31 (m, 1H), 5.10 (s, 2H), 4.43-4.34 (m, 2H), 3.75 (s, 3H), 3.03 (s, 3H), 2.92-2.83 (m, 1H), 2.60-2.50 (m, 1H). MS (ESI, m / z): 567.2 [M+H]+. Step I: Preparation of methyl 8-(2-nitrophenyl)-2-(4-phenoxyphenyl)-5,6,7,8- tetrahydroimidazo[1,2-b]pyridazine-3-carboxylate [Image disponible dans le document PDF, Image available in the PDF document] CA The crude the product of step H of example 22 (1.0 g, 1.76 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL), N, N-diisopropylethylamine (456.2 mg, 3.5 mmol) and TBAF (4mL, 1mol / L tetrahydrofuransolution) were added, then heated to 30°C for 3 hs, concentrated and purified by flash column chromatography with dichloromethane and methanol (40:1) to give the desired product (300 mg, 36%). 1H NMR (400 MHz, CDCl3) <semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics> 8.00 (dd, <semantics>J<annotation encoding="application / x-tex">J< / annotation>< / semantics> = 8.2, 1.3 Hz, 1H), 7.60- 7.50 (m, 3H), 7.45-7.38 (m, 1H), 7.34-7.29 (m, 2H), 7.22 (t, <semantics>J=3.4<annotation encoding="application / x-tex">J = 3.4< / annotation>< / semantics> Hz, 1H), 7.15-7.07 (m, 2H), <semantics>7.04−6.95<annotation encoding="application / x-tex">7.04-6.95< / annotation>< / semantics> (m, 4H), <semantics>5.05<annotation encoding="application / x-tex">5.05< / annotation>< / semantics> (t, <semantics>J=7.4<annotation encoding="application / x-tex">J = 7.4< / annotation>< / semantics> Hz, 1H), <semantics>3.82<annotation encoding="application / x-tex">3.82< / annotation>< / semantics> (s, 3H), <semantics>3.62−3.44<annotation encoding="application / x-tex">3.62-3.44< / annotation>< / semantics> (m, 2H), <semantics>2.75−2.68<annotation encoding="application / x-tex">2.75-2.68< / annotation>< / semantics> (m, 1H), <semantics>2.29−2.18<annotation encoding="application / x-tex">2.29-2.18< / annotation>< / semantics> (m, 1H). MS (ESI, m / z): <semantics>471.2<annotation encoding="application / x-tex">471.2< / annotation>< / semantics> [M+H]+. Step J: Preparation of 8-(2-nitrophenyl)-2-(4-phenoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2- b]pyridazine-3-carboxylic acid [Image disponible dans le document PDF, Image available in the PDF document] To a solution of the product of step I of example 22 (300 mg, 0.64 mmol) in tetrahydrofuran (10 mL) was added LiOH (76.6 mg, 3.19 mmol) in water (1 mL), the mixture was heated at 50°C for 3 hs, then cooled to r.t. The mixture acidified to pH 3-4 with concentrated HCl and then extracted with 3×100mL of dichloromethane. The organic phase was washed with saturated brine and then dried over anhydrous Na2SO4. The organic phase was concentrated in vacuo to afford 340 mg crude product. The residue was used to next step without further purification. MS (ESI, <semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>): 457.2 <semantics>[M+H]+<annotation encoding="application / x-tex">[M+H]^+< / annotation>< / semantics>. Step K: Preparation of 8-(2-nitrophenyl)-2-(4-phenoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2- b]pyridazine-3-carboxamide [Image disponible dans le document PDF, Image available in the PDF document] To the solution of the product of step J of example 22 (340 mg, 0.74 mmol) in dichloromethane (10 mL) was added N, N-diisopropylethylamine (385.1 mg, 2.98 mmol). After 5 min, NH4Cl (159.4 mg, 2.98 mmol) and HATU (424.8 mg, 1.12 mmol) was added. The reaction mixture was continued to stir at room temperature for 2 hs. Dichloromethane and water were added. The layers were separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed three times (3×50 mL) with brine solution. The organic phase was dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by chromatography with dichloromethane and methanol (40:1) to give product as an off-white solid (290 mg, 85%). 1H NMR (600 MHz, CDCl3) <semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics> 7.96 (d, <semantics>J=8.1<annotation encoding="application / x-tex">J = 8.1< / annotation>< / semantics> Hz, 1H), 7.56 (t, <semantics>J=7.5<annotation encoding="application / x-tex">J = 7.5< / annotation>< / semantics> Hz, 1H), 7.52 (d, <semantics>J=7.8<annotation encoding="application / x-tex">J = 7.8< / annotation>< / semantics> Hz, 2H), 7.41 (t, <semantics>J=7.8<annotation encoding="application / x-tex">J = 7.8< / annotation>< / semantics> Hz, 1H), 7.32 (t, <semantics>J=7.3<annotation encoding="application / x-tex">J = 7.3< / annotation>< / semantics> Hz, 2H), 7.22 (d, <semantics>J=7.8<annotation encoding="application / x-tex">J = 7.8< / annotation>< / semantics> Hz, 1H), 7.11 (t, <semantics>J=7.4<annotation encoding="application / x-tex">J = 7.4< / annotation>< / semantics> Hz, 1H), 7.04 (s, 1H), 6.98 (d, <semantics>J=8.2<annotation encoding="application / x-tex">J = 8.2< / annotation>< / semantics> Hz, 4H), 6.78 (s, 1H), 5.65 (s, 1H), 4.97 (t, <semantics>J=7.7<annotation encoding="application / x-tex">J = 7.7< / annotation>< / semantics> Hz, 1H), 3.56 <semantics>(d,J=12.7 Hz,1H),3.47(d,J=4.5 Hz,1H),2.74−2.62(m,1H),2.28−2.21(m,1H).<annotation encoding="application / x-tex">(d, J = 12.7 \text{ Hz}, 1\text{H}), 3.47 (d, J = 4.5 \text{ Hz}, 1\text{H}), 2.74-2.62 (m, 1\text{H}), 2.28-2.21 (m, 1\text{H}).< / annotation>< / semantics> MS (ESI, <semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>): 456.2 [M+H]+. Step L: Preparation of 8-(2-aminophenyl)-2-(4-phenoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2- b]pyridazine-3-carboxamide [Image disponible dans le document PDF, Image available in the PDF document] To a solution of the product of step K of example 22 (330 mg, crude) in MeOH (10 mL) was added 10% Pd / C (100 mg, 30%) at room temperature. The mixture was stirred for 3 hs under H2. The mixturewas cooled to r.t. The mixture was passed through Celite, and the solid was washed with ethyl acetate, and filtrate was concentrated under vacuum to get 300 mg crude. The residue was used to next step without further purification. MS (ESI, m / z): 426.2 [M+H]+. Step <semantics>𝑴<annotation encoding="application / x-tex">\mathbf{M}< / annotation>< / semantics>: Preparation of 8-(2-acrylamidophenyl)-2-(4-phenoxyphenyl)-5,6,7,8- tetrahydroimidazo[1,2-b]pyridazine-3-carboxamide [Image disponible dans le document PDF, Image available in the PDF document] The mixture of the product of step L of example 22 (70 mg, 0.16 mmol) and triethylamine (33.36) mg, 0.33 mmol) in dichloromethane (2 mL) was cooled to -60°C. Then the solution of propencyl chloride (19.36 mg, 0.21 mmol) in dichloromethane (1 mL) was added slowly, LC-MS was tracking, at the end of the reaction, 1 mL MeOH was added, the mixture was concentrated under vacuum to get crude product and purified by flash chromatography on silica gel with dichloromethane and methanol (40:1) to get product as a white solid (11 mg, 14%). 1H NMR (600 MHz, MeOD) <semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics> 7.58 (d, <semantics>J=8.2<annotation encoding="application / x-tex">J = 8.2< / annotation>< / semantics> Hz, 2H), 7.42 (d, <semantics>J=7.8<annotation encoding="application / x-tex">J = 7.8< / annotation>< / semantics> Hz, 1H), 7.37-7.30 (m, 3H), 7.26 (t, <semantics>J=<annotation encoding="application / x-tex">J =< / annotation>< / semantics> 7.5 Hz, 1H), 7.14-7.08 (m, 2H), 7.00 (d, <semantics>J=8.0<annotation encoding="application / x-tex">J = 8.0< / annotation>< / semantics> Hz, 2H), 6.95 (d, <semantics>J=8.3<annotation encoding="application / x-tex">J = 8.3< / annotation>< / semantics> Hz, 2H), 6.51-6.43 (m, 1H), <semantics>6.39−6.33<annotation encoding="application / x-tex">6.39-6.33< / annotation>< / semantics> (m, 1H), <semantics>5.83−5.77<annotation encoding="application / x-tex">5.83-5.77< / annotation>< / semantics> (m, 1H), <semantics>4.65<annotation encoding="application / x-tex">4.65< / annotation>< / semantics> (t, <semantics>J=7.4<annotation encoding="application / x-tex">J = 7.4< / annotation>< / semantics> Hz, 1H), <semantics>3.51−3.45<annotation encoding="application / x-tex">3.51-3.45< / annotation>< / semantics> (m, 1H), <semantics>3.40−3.33<annotation encoding="application / x-tex">3.40-3.33< / annotation>< / semantics> (m, 1H), 2.44-2.36 (m, 1H), 2.10-1.99 (m, 1H). MS (ESI, m / z): 480.2 [M+H]+. Example 23: 8-(4-acrylamidophenyl)-2-(4-phenoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2- b]pyridazine-3-carboxamide [Image disponible dans le document PDF, Image available in the PDF document] Step A: Preparation of methyl 2-(4-nitrophenyl)acetate [Image disponible dans le document PDF, Image available in the PDF document] 4-Nitrophenylacetic acid (240 g, 1.33 mol) was set stirring in 400 mL of methanol. Sulfurous dichloride (472.8 g, 3.98 mol) was added and the mixture heated to reflux. After 4 h the mixture was cooled and evaporated under reduced pressure to give a clear yellow oil. The oil was brought up in ethyl acetate and washed with saturated NaHCO3. The organics were dried (anhydrous Na2SO4) and evaporated to give the ester as a clear orange liquid (256 g, 99%). MS (ESI, m / z): 196.1 [M+H]+. Step B: Preparation of methyl 4-((tert-butyldimethylsilyl)oxy)-2-(4-nitrophenyl)butanoate [Image disponible dans le document PDF, Image available in the PDF document] A solution of the product of step A of example 23 (100.0 g, 512.36 mmol) and t-BuOK (115.0 g, 1.02 mol) in N, N-dimethylformamide (1500 mL) was stirred at room temperature for 1h. Then (2-bromo-ethoxy)-tert-butyl-dimethyl-silane (196.1 g, 819.78 mmol) was added slowly at 0 °C to this solution. The mixture was stirred at room temperature overnight and poured into water (500 mL). The aqueous phase was extracted with ethyl acetate (<semantics>3×500<annotation encoding="application / x-tex">3\times500< / annotation>< / semantics> mL), and the organic layer was washed with saturated NH4Cl (500 mL), water (3×500 mL), brine (500 mL), dried with anhydrous Na2SO4, and evaporated to get crude product. It was purified by flash chromatography with ethyl acetate and petroleum ether (1:3) to obtain the desired product as a clear orange liquid (96 g, 53%). 1H NMR (600 MHz, CDCl3) <semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics> 8.17 (d, <semantics>J<annotation encoding="application / x-tex">J< / annotation>< / semantics> = 8.7 Hz, 2H), 7.47 (d, <semantics>J<annotation encoding="application / x-tex">J< / annotation>< / semantics> = 8.7 Hz, 2H), 3.97 (t, <semantics>J<annotation encoding="application / x-tex">J< / annotation>< / semantics> = 7.5 Hz, 1H), 3.66 (s, 3H), 3.64-3.59 (m, 1H), 3.47-3.43 (m, 1H), 2.38-2.29 (m, 1H), 1.96-1.90 (m, 1H), 0.88 (s, 9H), -0.01 (d, <semantics>J=7.0<annotation encoding="application / x-tex">J = 7.0< / annotation>< / semantics> Hz, 6H).MS (ESI, m / z): 354.2 [M+H]+. Step C: Preparation of 4-((tert-butyldimethylsilyl)oxy)-2-(4-nitrophenyl)butanoic acid [Image disponible dans le document PDF, Image available in the PDF document] To a solution of the product of step B of example 23 (75 g, 8.55 mmol) in tetrahydrofuran (500 mL) was added a solution of aqueous 10% KOH (250 mL). The reaction mixture was stirred until complete consumption of the ester. Water was added and the reaction mixture was acidified to pH 5-6 with 1 M HCl. The mixture was extracted with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuo to get the product as a colorless oil (60 g, 81%), which was used for the next step without further purification. 1H NMR (600 MHz, DMSO-d6) <semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics> 12.66 (s, 1H), 8.22 (d, <semantics>J=8.7<annotation encoding="application / x-tex">J = 8.7< / annotation>< / semantics> Hz, 2H), 7.58 (d, <semantics>J=8.7<annotation encoding="application / x-tex">J = 8.7< / annotation>< / semantics> Hz, 2H), 3.86 (t, <semantics>J=7.5<annotation encoding="application / x-tex">J = 7.5< / annotation>< / semantics> Hz, 1H), 3.60-3.56 (m, 1H), 3.50-3.46 (m, 1H), 2.30-2.19 (m, 1H), 1.94-1.84 (m, 1H), 0.86 (s, 9H), -0.01 (d, <semantics>J=7.5<annotation encoding="application / x-tex">J = 7.5< / annotation>< / semantics> Hz, 6H). MS (ESI, m / z): 340.2 [M+H]+. Step D: Preparation of 1-methoxy-1,3-dioxo-3-(4-phenoxyphenyl)propan-2-yl 4-((tert- butyldimethylsilyl)oxy)-2-(4-nitrophenyl)butanoate [Image disponible dans le document PDF, Image available in the PDF document] The product of step B (37.7 g, 105.96 mmol) of example 1 and the product of step C of example 23 (40.2 g, 127.16 mmol) were taken up in acetonitrile (250 mL), then N, N-diisopropylethylamine (20.5 g, 158.94 mmol) was added and the solution stirred at 30°C for 3 hs. The solvent was removed by rotorary evaporation and the residue taken up in ethyl acetate, washed with 0.1 N HCl, and brine. The organic fractions were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude product which was purified via flash chromatography eluting with ethyl acetate and petroleum ether (1:20) to give the product as a clear orange oil (33.1) g, 51%). 1H NMR (600 MHz, CDCl3) <semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics> 8.18 (d, <semantics>J<annotation encoding="application / x-tex">J< / annotation>< / semantics> = 8.4 Hz, 1H), 8.13 (d, <semantics>J<annotation encoding="application / x-tex">J< / annotation>< / semantics> = 8.4 Hz, 1H), 7.87 (d, <semantics>J=8.6 Hz<annotation encoding="application / x-tex">J = 8.6 \text{ Hz}< / annotation>< / semantics>, 1H), 7.81 (d, <semantics>J=8.6 Hz<annotation encoding="application / x-tex">J = 8.6 \text{ Hz}< / annotation>< / semantics>, 1H), 7.51 (d, <semantics>J=8.4 Hz<annotation encoding="application / x-tex">J = 8.4 \text{ Hz}< / annotation>< / semantics>, 1H), 7.46 (d, <semantics>J=8.4 Hz<annotation encoding="application / x-tex">J = 8.4 \text{ Hz}< / annotation>< / semantics>, 1H), 7.44- 7.40 (m, 2H), 7.27-7.21 (m, 1H), 7.07 (t, <semantics>J=8.8 Hz<annotation encoding="application / x-tex">J = 8.8 \text{ Hz}< / annotation>< / semantics>, 2H), 6.94 (d, <semantics>J=8.6 Hz<annotation encoding="application / x-tex">J = 8.6 \text{ Hz}< / annotation>< / semantics>, 1H), 6.88 (d, <semantics>J=8.6 Hz<annotation encoding="application / x-tex">J = 8.6 \text{ Hz}< / annotation>< / semantics> Hz, 1H), 6.22 (d, <semantics>J=5.5<annotation encoding="application / x-tex">J = 5.5< / annotation>< / semantics> Hz, 1H), 4.18-4.15 (m, 1H), 3.79-3.76 (m, 3H), 3.69-3.64 (m, 1H), 3.49- <semantics>3.44 (m, 1H),2.48−2.38 (m, 1H),2.06−1.96 (m, 1H),0.87 (d, J=9.6 Hz, 9H),0.06−0.03 (m, 6H).<annotation encoding="application / x-tex">3.44 \text{ (m, 1H)}, 2.48-2.38 \text{ (m, 1H)}, 2.06-1.96 \text{ (m, 1H)}, 0.87 \text{ (d, } J = 9.6 \text{ Hz, 9H)}, 0.06-0.03 \text{ (m, 6H)}.< / annotation>< / semantics> MS (ESI, <semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>): 608.2 [M+H]+. Step E: Preparation of methyl 2-(3-((tert-butyldimethylsilyl)oxy)-1-(4-nitrophenyl)propyl)-4- (4-phenoxyphenyl)-1H-imidazole-5-carboxylate [Image disponible dans le document PDF, Image available in the PDF document] To a slurry of ammonium acetate (50.2 g, 651.60 mmol) in xylenes (350 mL) was added the product of step D of example 23 (33.0 g, 54.30 mmol). The mixture was stirred at 140 °C for 4 hs. The solution was cooled to room temperature and the solvent was evaporated. The residue was dissolved in ethyl acetate and washed with saturated brine. The organic phase was dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography with ethyl acetate and petroleum ether (1:5) to give the product as a clear yellow oil (9.6 g, 30%). 1H NMR (600 MHz, CDCl3) <semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics> 9.81 (s, 1H), 8.16 (d, <semantics>J<annotation encoding="application / x-tex">J< / annotation>< / semantics> = 8.4 Hz, 2H), 7.91 (d, <semantics>J<annotation encoding="application / x-tex">J< / annotation>< / semantics> = 8.4 Hz, 2H), 7.49 (d, <semantics>J=8.4<annotation encoding="application / x-tex">J = 8.4< / annotation>< / semantics> Hz, 2H), 7.32 (t, <semantics>J=7.8<annotation encoding="application / x-tex">J = 7.8< / annotation>< / semantics> Hz, 2H), 7.09 (t, <semantics>J=7.5<annotation encoding="application / x-tex">J = 7.5< / annotation>< / semantics> Hz, 1H), 7.02 (t, <semantics>J=7.8<annotation encoding="application / x-tex">J = 7.8< / annotation>< / semantics> Hz, 2H), 7.09 (t, <semantics>J=7.5<annotation encoding="application / x-tex">J = 7.5< / annotation>< / semantics> Hz, 1H), 7.02 (t, <semantics>J=7.8<annotation encoding="application / x-tex">J = 7.8< / annotation>< / semantics> Hz, 2H), 7.09 (t, <semantics>J=7.5<annotation encoding="application / x-tex">J = 7.5< / annotation>< / semantics> Hz, 1H), 7.02 (t, <semantics>J<annotation encoding="application / x-tex">J< / annotation>< / semantics> <semantics>=7.3 Hz,4H,4.47 (t, J=7.3 Hz,1H),3.80 (s, 3H),3.64−3.58 (m, 1H),3.57−3.53 (m, 1H),2.54−1.58 (m, 1H),3.57−3.53 (m, 1H),3.57−3.53 (m, 1H),3.57<annotation encoding="application / x-tex">= 7.3 \text{ Hz}, 4\text{H}, 4.47 \text{ (t, } J = 7.3 \text{ Hz}, 1\text{H}), 3.80 \text{ (s, } 3\text{H}), 3.64-3.58 \text{ (m, } 1\text{H}), 3.57-3.53 \text{ (m, } 1\text{H}), 2.54-1.58 \text{ (m, } 1\text{H}), 3.57-3.53 \text{ (m, } 1\text{H}), 3.57-3.53 \text{ (m, } 1\text{H}), 3.57< / annotation>< / semantics> 2.45 (m, 1H), 2.25-2.16 (m, 1H), 0.88 (s, 9H), 0.01 (d, <semantics>J=7.1<annotation encoding="application / x-tex">J = 7.1< / annotation>< / semantics> Hz, 6H). MS (ESI, m / z): 588.3 <semantics>[M+H]+<annotation encoding="application / x-tex">[M+H]^+< / annotation>< / semantics>. Step F: Preparation of methyl 1-amino-2-(3-((tert-butyldimethylsilyl)oxy)-1-(4- nitrophenyl)propyl)-4-(4-phenoxyphenyl)-1H-imidazole-5-carboxylate [Image disponible dans le document PDF, Image available in the PDF document] Lithium hexamethyldisilazane (24.5 mL of a 1 M solution intetrahydrofuran, 24.49 mmol) was slowly added to the product of step E of example 23 (9.6 g, 16.33 mmol) in anhydrous N, N- dimethylformamide (100 mL) at 0°C. After the mixture was stirred for 30 min, O- (diphenylphosphinyl) hydroxylamine (7.3 g, 32.67 mmol) was added at 0°C, followed by stirring at room temperature for 3 hs (in cases where the reaction mixture became too viscous, additional N, N-dimethylformamidewas added). The reaction was quenched with water until a clear solution was formed and concentrated to dryness under reduced pressure. The residue was washed several times with ethyl acetate or dichloromethane. The combined organic fractions were concentrated in vacuo and purified by flash chromatography on silica gel with ethyl acetate and petroleum ether (1:3) to give the product as a clear colorless oil (3.5 g, 35%). III NMR (600 MIIz, CDCl3) <semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics> 8.16 <semantics>(d,J=8.3 Hz,2H),7.67(d,J=8.4 Hz,2H),7.59(d,J=8.3 Hz,2H),7.36(t,J=7.6 Hz,2H),<annotation encoding="application / x-tex">(d, J = 8.3 \text{ Hz}, 2H), 7.67 (d, J = 8.4 \text{ Hz}, 2H), 7.59 (d, J = 8.3 \text{ Hz}, 2H), 7.36 (t, J = 7.6 \text{ Hz}, 2H),< / annotation>< / semantics> 7.13 (t, <semantics>J=7.4<annotation encoding="application / x-tex">J = 7.4< / annotation>< / semantics> Hz, 1H), 7.08-7.03 (m, 4H), 5.20 (s, 2H), 4.90 (t, <semantics>J=7.7<annotation encoding="application / x-tex">J = 7.7< / annotation>< / semantics> Hz, 1H), 3.77 (s, 3H), 3.70-3.62 (m, 1H), 3.58-3.55 (m, 1H), 2.60-2.54 (m, 1H), 2.26-2.21 (m, 1H), 0.90 (s, 9H), 0.01 (d, <semantics>J=6.8 Hz,6H<annotation encoding="application / x-tex">J = 6.8 \text{ Hz}, 6\text{H}< / annotation>< / semantics>). MS (ESI, m / z): <semantics>603.3 [M+H]+<annotation encoding="application / x-tex">603.3 \text{ [M+H]}^+< / annotation>< / semantics>. Step G: Preparation of methyl 1-amino-2-(3-hydroxy-1-(4-nitrophenyl)propyl)-4-(4- phenoxyphenyl)-1H-imidazole-5-carboxylate [Image disponible dans le document PDF, Image available in the PDF document] To a solution of the product of step F of example 23 (3.0g, 4.98 mmol) in tetrahydrofuran (20 mL) was added a 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran (5 mL, 5 mmol) at r.t. The solution was stirred for 2 hs and diluted with 100 mL ethyl acetate solution. The organic layer was separated and washed with <semantics>H2O<annotation encoding="application / x-tex">H_2O< / annotation>< / semantics> (3×100 mL). The water extract was washed with ethyl- acetate solution (2×50 mL), and the organic layers were combined and dried over anhydrous Na2SO4. The solvent was evaporated in vacuo, and the residue was purified via flash chromatography eluting with ethyl acetate and petroleum ether (1:1) to give the product as a clear orange oil (2.3 g, 76%). 1H NMR (400 MHz, CDCl3) <semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics> 8.13 (d, <semantics>J<annotation encoding="application / x-tex">J< / annotation>< / semantics> = 8.8 Hz, 2H), 7.65 (d, <semantics>J<annotation encoding="application / x-tex">J< / annotation>< / semantics> = 8.8 Hz, 2H), 7.53 (d, <semantics>J=8.8<annotation encoding="application / x-tex">J = 8.8< / annotation>< / semantics> Hz, 2H), 7.38-7.30 (m, 2H), 7.11 (t, <semantics>J=7.4<annotation encoding="application / x-tex">J = 7.4< / annotation>< / semantics> Hz, 1H), 7.07-6.99 (m, 4H), <semantics>4.92−4.83<annotation encoding="application / x-tex">4.92-4.83< / annotation>< / semantics> (m, 1H), <semantics>3.75<annotation encoding="application / x-tex">3.75< / annotation>< / semantics> (s, 3H), <semantics>3.60<annotation encoding="application / x-tex">3.60< / annotation>< / semantics> (t, <semantics>J=5.4<annotation encoding="application / x-tex">J = 5.4< / annotation>< / semantics> Hz, 2H), <semantics>2.56−2.48<annotation encoding="application / x-tex">2.56-2.48< / annotation>< / semantics> (m, 1H), <semantics>2.36−2.22<annotation encoding="application / x-tex">2.36-2.22< / annotation>< / semantics> (m, 1H). <semantics>MS<annotation encoding="application / x-tex">MS< / annotation>< / semantics> (ESI, m / z): 489.2 [M+H]+. Step H: Preparation of methyl 1-amino-2-(3-((methylsulfonyl)oxy)-1-(4-nitrophenyl)propyl)-4- (4-phenoxyphenyl)-1H-imidazole-5-carboxylate [Image disponible dans le document PDF, Image available in the PDF document] Methanesulfonyl chloride (809.0 mg, 7.06 mmol) was added via syringe into a stirred mixture of the product of step G of example 23 (2.3 g, 4.71 mmol) and N, N-diisopropylethylamine (1.22 g, 9.42 mmol) in dichloromethane (3 ml) maintained at 0 °C. The mixture was stirred at room temperature for 3 hs (TLC monitoring) and then partitioned between dichloromethane and water. The organic phase was dried and evaporated to afford a white solid which was passed through a column of silica gel with dichloromethane and methanol (40:1) to afford the desired product as a colorless oil (2.1 g, 78%). 1H NMR (600 MHz, CDCl3) <semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics> 8.16 (d, <semantics>J<annotation encoding="application / x-tex">J< / annotation>< / semantics> = 8.3 Hz, 2H), 7.68 (d, <semantics>J<annotation encoding="application / x-tex">J< / annotation>< / semantics> = 8.3 Hz, 2H), 7.61 (d, <semantics>J=8.3<annotation encoding="application / x-tex">J = 8.3< / annotation>< / semantics> Hz, 2H), 7.36 (t, <semantics>J=7.7<annotation encoding="application / x-tex">J = 7.7< / annotation>< / semantics> Hz, 2H), 7.13 (t, <semantics>J=7.4<annotation encoding="application / x-tex">J = 7.4< / annotation>< / semantics> Hz, 1H), 7.08-7.02 (m, 4H), 5.25 (s, 2H), 4.93-4.86 (m, 1H), 4.34-4.28 (m, 1H), 4.26-4.23 (m, 1H), 3.77 (s, 3H), 2.99 (s, 3H), 2.90-2.82 (m, 1H), 2.48-2.39 (m, 1H). MS (ESI, m / z): 567.2 [M+H]+. Step ľ Preparation of methyl 8-(4-nitrophenyl)-2-(4-phenoxyphenyl)-5,6,7,8- tetrahydroimidazo[1,2-b]pyridazine-3-carboxylate [Image disponible dans le document PDF, Image available in the PDF document] The crude the product of step H of example 23 (2.0 g, 3.53 mmol) was dissolved in anhydrous tetrahydrofuran(20 mL), N, N-diisopropylethylamine (912.5 mg, 7.06 mmol) and TBAF (4 mL, 1mol / L tetrahydrofuransolution) were added, then heated to 30 °C for 3 hs, concentrated and purified by flash column chromatography with dichloromethane and methanol (30:1) to give the desired product (0.56 g, 37%). 1H NMR (400 MHz, CDCl3) <semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics> 8.16-8.10 (m, 2H), 7.70-7.63 (m, 2H), <semantics>7.39−7.31<annotation encoding="application / x-tex">7.39-7.31< / annotation>< / semantics> (m, 4H), <semantics>7.17−7.09<annotation encoding="application / x-tex">7.17-7.09< / annotation>< / semantics> (m, 1H), <semantics>7.08−7.01<annotation encoding="application / x-tex">7.08-7.01< / annotation>< / semantics> (m, 4H), <semantics>5.51<annotation encoding="application / x-tex">5.51< / annotation>< / semantics> (dd, <semantics>J=4.5<annotation encoding="application / x-tex">J = 4.5< / annotation>< / semantics>, <semantics>1.4<annotation encoding="application / x-tex">1.4< / annotation>< / semantics> Hz, 1H), <semantics>4.06−100<annotation encoding="application / x-tex">4.06-100< / annotation>< / semantics> 3.99 (m, 1H), 3.87-3.80 (m, 1H), 3.78 (s, 3H), 1.96-1.86 (m, 2H).MS (ESI, m / z): 471.2 [M+H]+. Step J: Preparation of 8-(4-nitrophenyl)-2-(4-phenoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2- blpyridazine-3-carboxylic acid [Image disponible dans le document PDF, Image available in the PDF document] To a solution of the product of step I of example 23 (560 mg, 1.19 mmol) in tetrahydrofuran (10 mL) was added LiOH (142.5 mg, 5.95 mmol) in water (2 mL), the mixture was heated at 50°C for 3 hs. Then cooled to r.t. The mixture acidified to pH 3-4 with concentrated HCl, then extracted with dichloromethane (3×100 mL). The organic phase was washed with saturated brine and then dried over anhydrous Na2SO4. The organic phase was concentrated in vacuo to afford 300 mg crude product. The residue was used to next step without further purification. MS (ESI, <semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>): 457.2 <semantics>[M+H]+<annotation encoding="application / x-tex">[M+H]^{+}< / annotation>< / semantics>. Step K: Preparation of 8-(4-nitrophenyl)-2-(4-phenoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2- blpyridazine-3-carboxamide [Image disponible dans le document PDF, Image available in the PDF document] To the solution of the product of step J of example 23 (260 mg, 0.57 mmol) in dichloromethane (10 mL) was added N, N-diisopropylethylamine (294.5 mg, 2.28 mmol). After 5 min, NH4Cl (121.5 mg, 2.28 mmol) and HATU (324.8 mg, 0.85 mmol) were added. The reaction mixture was continued to stir at room temperature for 2 hs. Dichloromethane and water were added. The layers were separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed three times <semantics>(3×50 mL)<annotation encoding="application / x-tex">(3\times50 \text{ mL})< / annotation>< / semantics> with brine solution. The organic phase was dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by chromatography with dichloromethane and methanol (40:1) to give product as an off-white solid (200 mg, 77%). 1H NMR (600 MHz, CDCl3) <semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics> 8.14 (d, <semantics>J<annotation encoding="application / x-tex">J< / annotation>< / semantics> = 8.5 Hz, 2H), 7.57 (d, <semantics>J<annotation encoding="application / x-tex">J< / annotation>< / semantics> = 8.3 Hz, 2H), 7.40-7.30 (m, 4H), 7.15 (t, <semantics>J=7.4<annotation encoding="application / x-tex">J = 7.4< / annotation>< / semantics> Hz, 1H), 7.08 (d, <semantics>J=8.3<annotation encoding="application / x-tex">J = 8.3< / annotation>< / semantics> Hz, 2H), 7.05 (d, <semantics>J=8.0<annotation encoding="application / x-tex">J = 8.0< / annotation>< / semantics> Hz, 2H), 5.85 (s, 1H), 5.60 (s, 1H), 5.45 (s, 1H), 1.73 (t, <semantics>J=6.0<annotation encoding="application / x-tex">J = 6.0< / annotation>< / semantics> Hz, 2H), 1.49 (t, <semantics>J=6.0<annotation encoding="application / x-tex">J = 6.0< / annotation>< / semantics> Hz, 2H). MS (ESI, m / z): 456.2 [M+H]+. Step L: Preparation of 8-(4-aminophenyl)-2-(4-phenoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2- b]pyridazine-3-carboxamide [Image disponible dans le document PDF, Image available in the PDF document] To a solution of the product of step K of example 23 (200 mg, crude) in MeOH (10 mL) was added Pd / C 10% (100 mg, 30%) at room temperature. The mixture was stirred for 3 hs under H2. And then cooled to r.t. The mixture was passed through Celite, and the solid was washed with ethyl acetate, and filtrate was concentrated under vacuum to get 65 mg crude. The residue was used to next step without further purification. MS (ESI, m / z): 426.2 [M+H]+. Step M: Preparation of 8-(4-acrylamidophenyl)-2-(4-phenoxyphenyl)-5,6,7,8- tetrahydroimidazo[1,2-b]pyridazine-3-carboxamide [Image disponible dans le document PDF, Image available in the PDF document] The mixture of the product of step L of example 23 (65 mg, 0.15 mmol) and triethylamine (23.2) mg, 0.23 mmol) in dichloromethane (5 mL) was cooled to -60°C. Then the solution of propencyl chloride (13.8 mg, 0.15 mmol) in dichloromethane (1 mL) was added slowly, LC-MS was tracking, at the end of the reaction, 1 mL MeOH was added, the mixture was concentrated under vacuum to get crude product and purified by flash chromatography on silica gel with dichloromethane and methanol (40:1) to get product as a white solid (23 mg, 23%). 1H NMR (600 MHz, MeOD) <semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics> 7.58 <semantics>(d,J=8.2 Hz,2H),7.42(d,J=7.8 Hz,1H),7.38−7.31(m,3H),7.26(t,J=7.5 Hz,1H),7.11(t,J=7.5 Hz,1H),7.11(t,J=7.5 Hz,1H),7.11(t,J=7.5 Hz,1H),7.11<annotation encoding="application / x-tex">(d, J = 8.2 \text{ Hz}, 2\text{H}), 7.42 (d, J = 7.8 \text{ Hz}, 1\text{H}), 7.38-7.31 (m, 3\text{H}), 7.26 (t, J = 7.5 \text{ Hz}, 1\text{H}), 7.11 (t, J = 7.5 \text{ Hz}, 1\text{H}), 7.11 (t, J = 7.5 \text{ Hz}, 1\text{H}), 7.11 (t, J = 7.5 \text{ Hz}, 1\text{H}), 7.11< / annotation>< / semantics> <semantics>J=7.6 Hz<annotation encoding="application / x-tex">J = 7.6 \text{ Hz}< / annotation>< / semantics>, 2H), <semantics>7.00 (d, J=8.0 Hz<annotation encoding="application / x-tex">7.00 \text{ (d, } J = 8.0 \text{ Hz}< / annotation>< / semantics>, 2H), <semantics>6.95 (d, J=8.3 Hz<annotation encoding="application / x-tex">6.95 \text{ (d, } J = 8.3 \text{ Hz}< / annotation>< / semantics>, 2H), <semantics>6.47 (dd, J=16.9,10.3 Hz<annotation encoding="application / x-tex">6.47 \text{ (dd, } J = 16.9, 10.3 \text{ Hz}< / annotation>< / semantics>, 1H), 6.36 (d, <semantics>J=17.0<annotation encoding="application / x-tex">J = 17.0< / annotation>< / semantics> Hz, 1H), 5.80 (d, <semantics>J=10.2<annotation encoding="application / x-tex">J = 10.2< / annotation>< / semantics> Hz, 1H), 4.65 (t, <semantics>J=7.4<annotation encoding="application / x-tex">J = 7.4< / annotation>< / semantics> Hz, 1H), 3.48 (dd, <semantics>J=10.2<annotation encoding="application / x-tex">J = 10.2< / annotation>< / semantics> Hz, 1H), 4.65 (t, <semantics>J=10.4<annotation encoding="application / x-tex">J = 10.4< / annotation>< / semantics> Hz, 1H), 3.48 (dd, <semantics>J=10.4<annotation encoding="application / x-tex">J = 10.4< / annotation>< / semantics> Hz, 1H), 4.65 (t, <semantics>J=10.4<annotation encoding="application / x-tex">J = 10.4< / annotation>< / semantics> Hz, 1H), 4.65 (t, <semantics>J<annotation encoding="application / x-tex">J< / annotation>< / semantics> 13.6, 3.6 Hz, 1H), 3.40-3.33 (m, 1H), 2.44-2.36 (m, 1H), 2.10-1.99 (m, 1H). MS (ESI, m / z): 480.2 <semantics>[M+H]+<annotation encoding="application / x-tex">[M+H]^+< / annotation>< / semantics> Example 24: 8-(1-cyanopiperidin-4-yl)-2-(4-phenoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2- b]pyridazine-3-carboxamide [Image disponible dans le document PDF, Image available in the PDF document] Preparation of 8-(1-cyanopiperidin-4-yl)-2-(4-phenoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2- b]pyridazine-3-carboxamide [Image disponible dans le document PDF, Image available in the PDF document] To the solution of the product (200.0 mg, 0.48 mmol) of step P of example 1 in tetrahydrofuran (20 mL) was added N, N-diisopropylethylamine (371.5 mg, 2.88 mmol). After BrCN (76.1 mg, 0.72 mmol) was added. The reaction mixture was continued to stir at room temperature for 8 hs. 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 Na2SO4, filtered and concentrated. The residue was purified by chromatography with dichloromethane and methanol (25:1) to give product as an off-white solid (45 mg, 21%). 1H NMR (600 MHz, CDCl3) <semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics> 7.58-7.53 (m, 2H), 7.39 <semantics>(d,J=6.3 Hz,1H),7.38−7.33 (m, 2H),7.14 (t, J=7.4 Hz,1H),7.07−7.03 (m, 4H),6.05 (s, 1H),<annotation encoding="application / x-tex">(d, J = 6.3 \text{ Hz}, 1\text{H}), 7.38-7.33 \text{ (m, 2H)}, 7.14 \text{ (t, } J = 7.4 \text{ Hz}, 1\text{H)}, 7.07-7.03 \text{ (m, 4H)}, 6.05 \text{ (s, 1H)},< / annotation>< / semantics> 5.57 (s, 1H), 3.50-3.42 (m, 3H), 3.38-3.31 (m, 1H), 3.13 - 3.03 (m, 3H), 2.38-2.33 (m, 1H), 2.11- <semantics>2.07 (m, 1H),1.98−1.90 (m, 1H),1.79 (d, J=13.1 Hz, 1H),1.69−1.60 (m, 2H),1.52−1.49 (m, 1H).<annotation encoding="application / x-tex">2.07 \text{ (m, 1H)}, 1.98-1.90 \text{ (m, 1H)}, 1.79 \text{ (d, } J = 13.1 \text{ Hz, 1H)}, 1.69-1.60 \text{ (m, 2H)}, 1.52-1.49 \text{ (m, 1H)}.< / annotation>< / semantics> MS (ESI, <semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>): 443.2 [M+H]+. Example 25: C. (E)-8-(1-(4-(dimethylamino)but-2-enoyl)piperidin-4-yl)-2-(4-phenoxyphenyl)-5,6,7,8- tetrahydroimidazo[1,2-b]pyridazine-3-carboxamide [Image disponible dans le document PDF, Image available in the PDF document] Preparation of (E)-8-(1-(4-(dimethylamino)but-2-enoyl)piperidin-4-yl)-2-(4-phenoxyphenyl)- 5,6,7,8-tetrahydroimidazo[1,2-b]pyridazine-3-carboxamide [Image disponible dans le document PDF, Image available in the PDF document] To the solution of the product (200.0 mg, 0.48 mmol) of step P of example 1 in dry N, N- dimethylformamide (10 mL) was added N, N-diisopropylethylamine (371.5 mg, 2.88 mmol). After 5 min, (E)-4-(dimethylamino)but-2-enoic acid (68.1 mg, 0.52 mmol) and HATU (273.1 mg, 0.72 mmol) was added. The reaction mixture was continued to stir at room temperature for 2 hs. Ethyl acetate and water were added. The layers were separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed three times (3×50 mL) with brine solution. The organic phase was dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by chromatography with dichloromethane and methanol (10:1) to give product as an off-white solid (31 mg, 12%). 1H NMR (600 MHz, DMSO-d6) <semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics> 7.81 (d, <semantics>J<annotation encoding="application / x-tex">J< / annotation>< / semantics> = 8.7 Hz, 2H), 7.40 (t, <semantics>J=7.9<annotation encoding="application / x-tex">J = 7.9< / annotation>< / semantics> Hz, 2H), 7.14 (t, <semantics>J=7.3<annotation encoding="application / x-tex">J = 7.3< / annotation>< / semantics> Hz, 1H), 7.04-6.97 (m, 4H), 6.59-6.57 (m, 2H), 4.54- <semantics>4.45 (m, 2H),4.15−3.99 (m, 2H),3.31 (d, J=9.5 Hz, 1H),3.17 (d, J=4.8 Hz, 3H),3.03 (s, 2H),<annotation encoding="application / x-tex">4.45 \text{ (m, 2H)}, 4.15-3.99 \text{ (m, 2H)}, 3.31 \text{ (d, } J = 9.5 \text{ Hz, 1H)}, 3.17 \text{ (d, } J = 4.8 \text{ Hz, 3H)}, 3.03 \text{ (s, 2H)},< / annotation>< / semantics> 2.87 (s, 2H), 2.54 (s, 6H), 2.51 (d, <semantics>J=1.6<annotation encoding="application / x-tex">J = 1.6< / annotation>< / semantics> Hz, 2H), 2.24 (s, 2H). MS (ESI, <semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>): 529.3 [M+H]+. Scheme III [Image disponible dans le document PDF, Image available in the PDF document] . CA mmol) at r.t. The solution was stirred for 2 hs and diluted with 100 mL ethyl acetate solution. The organic layer was separated and washed with H2O (3×200 mL). The water extract was washed with ethyl acetate solution (2×150 mL), and the organic layers were combined and dried over anhydrous Na2SO4. The solvent was evaporated in vacuo, and purified by flash chromatography on silica gel with dichloromethane and methanol (30:1) to give the product as a clear colorless oil <semantics>(2.5 g,89%)<annotation encoding="application / x-tex">(2.5 \text{ g}, 89\%)< / annotation>< / semantics>. 1H NMR (600 MHz, CDCl3) <semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics> 7.84 (d, <semantics>J=6.1 Hz,2H),7.33(t,<math>J=7.7 Hz,2H),7.11<annotation encoding="application / x-tex">J = 6.1 \text{ Hz}, 2\text{H}), 7.33 (t, J = 7.7 \text{ Hz}, 2\text{H}), 7.11< / annotation>< / semantics> <semantics>(d,J=6.6 Hz,1H),7.03−7.00 (m, 4H),4.02 (s, 1H),3.80 (s, 3H),3.67−3.60 (m, 1H),3.52−3.45 (s, 3H)<annotation encoding="application / x-tex">(d, J = 6.6 \text{ Hz}, 1\text{H}), 7.03-7.00 \text{ (m, 4H)}, 4.02 \text{ (s, 1H)}, 3.80 \text{ (s, 3H)}, 3.67-3.60 \text{ (m, 1H)}, 3.52 - 3.45 \text{ (s, 3H)}< / annotation>< / semantics> (m, 1H), 2.82 (s, 1H), 2.62 (s, 2H), 2.24-2.08 (m, 2H), 2.03-1.97 (m, 2H), 1.96-1.88 (m, 1H), 1.85- 1.80 (m, 1H), 1.42 (s, 9H), 1.19-1.08 (m, 2H). MS (ESI, <semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>): 536.3 [M+H]+. Step B: Preparation oftert-butyl 4-(1-(5-(methoxycarbonyl)-4-(4-phenoxyphenyl)-1H-imidazol- 2-vl)-3-((methylsulfonyl)oxy)propyl)piperidine-1-carboxylate [Image disponible dans le document PDF, Image available in the PDF document] Methanesulfonyl chloride (801.9 mg, 7.00 mmol) was added via syringe into a stirred mixture of the product of step A (2.5 g, 4.67 mmol) of example 26 and N, N-diisopropylethylamine (1.2 g, 9.33 mmol) in dichloromethane (100 ml) maintained at 0°C. The mixture was stirred at room temperature for 3 h (TLC monitoring) and then partitioned between dichloromethane and water. The organic phase was dried, then evaporated to afford a white solid, the crude product was passed through a column of silica gel with dichloromethane and methanol (20:1) to afford the desired product as a colorless oil (1.6 g, 56%). MS (ESI, <semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>): 614.2 [M+H]+. Step C: Preparation of methyl 7-(1-(tert-butoxycarbonyl)piperidin-4-yl)-2-(4-phenoxyphenyl)- 6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-3-carboxylate [Image disponible dans le document PDF, Image available in the PDF document] N, N-diisopropylethylamine (505.0 mg, 3.91 mmol) and 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran(2.6 mL, 2.61 mmol) were added to the solution of the product of step B (1.6 g, 2.61 mmol) of example 26 in anhydrous tetrahydrofuran (20 mL), the mixture was heated to 50°C for 2 hs, then cooled to r.t., concentrated and purified by flash column chromatography with dichloromethane and methanol (10:1) to give the desired product (1.1 g, 81%). 1H NMR (600) MHz, CDCl3) <semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics> 7.79 (d, <semantics>J=8.6<annotation encoding="application / x-tex">J = 8.6< / annotation>< / semantics> Hz, 2H), 7.33 (t, <semantics>J=7.9<annotation encoding="application / x-tex">J = 7.9< / annotation>< / semantics> Hz, 2H), 7.10 (t, <semantics>J=7.3<annotation encoding="application / x-tex">J = 7.3< / annotation>< / semantics> Hz, 1H), 7.07- 6.98 (m, 4H), 4.30-4.26 (m, 1H), 4.21-4.16 (m, 2H), 3.80 (s, 3H), 3.08 (s, 1H), 2.75-2.63 (m, 3H), 2.39-2.33 (m, 1H), 2.08 (s, 1H), 1.93 (s, 1H), 1.55 (s, 1H), 1.45 (s, 9H), 1.40-1.27 (m, 3H). MS <semantics>(ESI,m / z)<annotation encoding="application / x-tex">(ESI, m / z)< / annotation>< / semantics>: 518.3 <semantics>[M+H]+<annotation encoding="application / x-tex">[M+H]^+< / annotation>< / semantics>. Step D: Preparation of 7-(1-(tert-butoxycarbonyl)piperidin-4-yl)-2-(4-phenoxyphenyl)-6,7- dihydro-5H-pyrrolo[1,2-a]imidazole-3-carboxylic acid [Image disponible dans le document PDF, Image available in the PDF document] To a solution of the product of step C (1.1 g, 2.13 mmol) of example 26 in tetrahydrofuran (30 mL) was added LiOH (254.5 mg, 10.63 mmol) in water (5 mL), the mixture was heated at 50°C for 3 hs. After cooled to r.t., The mixture was acidified to pH 3-4 with concentrated HCl and then extracted with dichloromethane (3×100 mL). The organic phase was washed with saturated brine and then dried over anhydrous Na2SO4. The organic phase was concentrated in vacuo to afford 1 g crude product. The residue was used to next step without further purification. MS (ESI, <semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>): 504.2 [M+H]+. Step E: Preparation of tert-butyl 4-(3-carbamoyl-2-(4-phenoxyphenyl)-6,7-dihydro-5H- pyrrolo[1,2-a]imidazol-7-yl)piperidine-1-carboxylate [Image disponible dans le document PDF, Image available in the PDF document] ___ To the solution of the product of step D (300.0 mg, 0.59 mmol) of example 26 in dichloromethane (20 mL) was added N, N-diisopropylethylamine (308.0 mg, 2.38 mmol). After 5 min, NH4Cl (127.5 mg, 2.38 mmol) and HATU (339.8 mg, 0.89 mmol) was added. The reaction mixture was continued to stir at room temperature for 2 hs. 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 (3×100 mL) with brine solution. The organic phase was dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by chromatography with dichloromethane and methanol (40:1) to give product as an off-white solid (165 mg, 55%). 1H NMR (400 MHz, CDCl3) <semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics> 7.55 (d, <semantics>J<annotation encoding="application / x-tex">J< / annotation>< / semantics> = 8.3 Hz, 2H), 7.36 (t, <semantics>J<annotation encoding="application / x-tex">J< / annotation>< / semantics> = 7.7 Hz, 2H), <semantics>7.14<annotation encoding="application / x-tex">7.14< / annotation>< / semantics> (t, <semantics>J=7.3<annotation encoding="application / x-tex">J = 7.3< / annotation>< / semantics> Hz, <semantics>1<annotation encoding="application / x-tex">1< / annotation>< / semantics>H), <semantics>7.05<annotation encoding="application / x-tex">7.05< / annotation>< / semantics> (t, <semantics>J=8.8<annotation encoding="application / x-tex">J = 8.8< / annotation>< / semantics> Hz, <semantics>4<annotation encoding="application / x-tex">4< / annotation>< / semantics>H), <semantics>4.41−4.28<annotation encoding="application / x-tex">4.41-4.28< / annotation>< / semantics> (m, <semantics>1<annotation encoding="application / x-tex">1< / annotation>< / semantics>H), <semantics>4.27−4.03<annotation encoding="application / x-tex">4.27-4.03< / annotation>< / semantics> (m, <semantics>3<annotation encoding="application / x-tex">3< / annotation>< / semantics>H), <semantics>3.75−3.68<annotation encoding="application / x-tex">3.75-3.68< / annotation>< / semantics> <semantics>(m,1H),3.20−3.15(m,1H),3.06(d,J=6.7Hz,1H),2.75−2.57(m,3H),2.41−2.32(m,1H),2.04<annotation encoding="application / x-tex">(m, 1H), 3.20-3.15 (m, 1H), 3.06 (d, J = 6.7 Hz, 1H), 2.75-2.57 (m, 3H), 2.41-2.32 (m, 1H), 2.04< / annotation>< / semantics> (s, 1H), 1.91 (s, 1H), 1.56 (d, <semantics>J=12.5<annotation encoding="application / x-tex">J = 12.5< / annotation>< / semantics> Hz, 1H), 1.44 (s, 9H). MS (ESI, <semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>): 503.3 [M+H]+. Step F: Preparation of 2-(4-phenoxyphenyl)-7-(piperidin-4-yl)-6,7-dihydro-5H-pyrrolo[1,2- alimidazole-3-carboxamide [Image disponible dans le document PDF, Image available in the PDF document] To a solution of the product of step E (165 mg, crude) of example 26 in EtOH (10 mL) was added CF3COOH (2 mL) at room temperature. The mixture was stirred for 3 hs, then concentrated under vacuum to get 116 mg crude product. The residue was used to next step without further purification. MS (ESI, <semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>): 403.2 [M+H]+. Step G: Preparation of 7-(1-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)-6,7-dihydro-5H- pyrrolo[1,2-a]imidazole-3-carboxamide [Image disponible dans le document PDF, Image available in the PDF document] The mixture of the product of step F (116.0 mg, 0.28 mmol) of example 26 and triethylamine (116.7 mg, 1.15 mmol) in dichloromethane (10 mL) was cooled to 0°C, then the solution of propenoyl chloride (28.7 mg, 0.32 mmol) in dichloromethane (1 mL) was added slowly, LC-MS was tracking, at the end of the reaction, 1 mL MeOH was added, the mixture was concentrated under vacuum to get crude product. The residue was purified by flash chromatography on silica gel with dichloromethane and methanol (40:1) to get product as a white solid (69 mg, 52%). 1H NMR (600 MHz, CDCl3) <semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics> 7.56 (d, <semantics>J<annotation encoding="application / x-tex">J< / annotation>< / semantics> = 8.4 Hz, 2H), 7.38-7.35 (m, 2H), 7.16-7.14 (m, 1H), 7.08- 7.04 (m, 4H), 6.59-6.54 (m, 1H), 6.27-6.24 (m, 1H), 5.67-5.66 (m, 1H), 4.74 (s, 1H), 4.35 (s, 1H), 4.22 (s, 1H), 4.04 (s, 1H), 3.07-3.03 (m, 2H), 2.72-2.66 (m, 1H), 2.62 (s, 1H), 2.39-2.33 (m, 1H), 2.32-2.18 (m, 1H), 2.09-2.07 (m, 1H), 2.02-1.96 (m, 1H), 1.86 (s, 1H), 1.71-1.65 (m, 1H). MS <semantics>(ESI,m / z)<annotation encoding="application / x-tex">(ESI, m / z)< / annotation>< / semantics>: 457.2 <semantics>[M+H]+<annotation encoding="application / x-tex">[M+H]^+< / annotation>< / semantics>. Scheme IV [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] Example 27: 8-(1-acryloylpiperidin-4-yl)-2-(4-methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2- b]pyridazine-3-carboxamide [Image disponible dans le document PDF, Image available in the PDF document] Step A: Preparation ofmethyl 2-bromo-3-(4-methoxyphenyl)-3-oxopropanoate [Image disponible dans le document PDF, Image available in the PDF document] To a solution of methyl 3-(4-methoxyphenyl)-3-oxopropanoate (40.0 g, 192.11 mmol) in methyl tert-butyl ether (500 mL) was added N-bromosuccinimide (41.0 g, 230.53 mmol) and CH3COONH4 (2.9 g, 38.42 mmol). The reaction mixture was stirred for 3 hs at r.t. The mixture was washed with water (3×500 mL), then dried over anhydrous sodium sulfate. Evaporation of the solvent gave the crude product as oil, the crude residue was flash chromatographed with ethyl acetate and petroleum ether (1:10) to give product as yellow oil (48 g, 87%). 1H NMR (600 MHz, CDCl3) <semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics> 7.93 (d, <semantics>J=8.7<annotation encoding="application / x-tex">J = 8.7< / annotation>< / semantics> Hz, 2H), 6.92 (d, <semantics>J=8.7<annotation encoding="application / x-tex">J = 8.7< / annotation>< / semantics> Hz, 2H), 5.65 (s, 1H), 3.84 (s, 3H), 3.77 (s, 3H). MS (ESI, <semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>): 287.9 [M+H]+. Step B: Preparation of tert-butyl 4-(4-(4-methoxybenzoyl)-11,11,12,12-tetramethyl-3,6-dioxo- 2,5,10-trioxa-11-silatridecan-7-yl) piperidine-1-carboxylate [Image disponible dans le document PDF, Image available in the PDF document] The product of step G (52.5 g, 130.61 mmol) of example 1 and the product of step A (25.0 g, 87.07 mmol) of example 27 were taken up in acetonitrile (400 mL), then N, N- disopropylethylamine (22.5 g, 174.15 mmol) was added and the solution stirred at 30°C for 3 hs. The solvent was removed by rotorary evaporation and the residue taken up in ethyl acetate, washed with 0.1 N HCl and brine. The organic fractions were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude product which was purified via flash chromatography with ethyl acetate and petroleum ether (1:10) to give the product as a clear colorless oil (43 g, 81%). 1H NMR (600 MHz, CDCl3) <semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics> 7.96 (d, <semantics>J=8.7<annotation encoding="application / x-tex">J = 8.7< / annotation>< / semantics> Hz, 2H), 6.94 (d, <semantics>J=8.7<annotation encoding="application / x-tex">J = 8.7< / annotation>< / semantics> Hz, 2H), 6.25 (s, 1H), 4.22-3.97 (m, 2H), 3.87 (s, 3H), 3.76 (s, 3H), 3.72 (s, 2H), 3.65-3.61 (m, 1H), <semantics>3.58−3.50<annotation encoding="application / x-tex">3.58-3.50< / annotation>< / semantics> (m, 1H), <semantics>2.75−2.51<annotation encoding="application / x-tex">2.75-2.51< / annotation>< / semantics> (m, 3H), <semantics>1.83<annotation encoding="application / x-tex">1.83< / annotation>< / semantics> (s, 2H), <semantics>1.62−1.60<annotation encoding="application / x-tex">1.62-1.60< / annotation>< / semantics> (m, 1H), <semantics>1.43<annotation encoding="application / x-tex">1.43< / annotation>< / semantics> (d, <semantics>J=3.4<annotation encoding="application / x-tex">J = 3.4< / annotation>< / semantics> Hz, 9H), 1.33-1.17 (m, 2H), 0.85-0.82 (m, 9H), 0.01-(-0.04) (m, 6H). MS (ESI, <semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>): 608.3 [M+H]+. Step C: Preparation of tert-butyl 4-(3-((tert-butyldimethylsilyl)oxy)-1-(5-(methoxycarbonyl)-4- (4-methoxyphenyl)-1H-imidazol-2-yl)propyl)piperidine-1-carboxylate [Image disponible dans le document PDF, Image available in the PDF document] To a slurry of ammonium acetate (65.5 g, 848.94 mmol) in xylenes (400 mL) was added the product of step B (43.0 g, 70.75 mmol) of example 27. The mixture was stirred at 140° C for 4 hours. The solution was cooled to room temperature and the solvent was evaporated. The residue was dissolved in ethyl acetate and washed with saturated brine. The organic phase was dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography with ethyl acetate and petroleum ether (1:5) to give the product as a clear colorless oil (9 g, 21%). 1H NMR (600 MHz, CDCl3) <semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics> 7.86-7.55 (m, 2H), 6.92 (d, <semantics>J<annotation encoding="application / x-tex">J< / annotation>< / semantics> – 8.3 Hz, 2H), 4.22- 3.95 (m, 2H), 3.83-3.81 (m, 6H), 3.63-3.59 (m, 1H), 3.50-3.42 (m, 1H), 2.82-2.78 (m, 1H), 2.63- 2.41 (m, 3H), 2.03-1.93 (m, 3H), 1.84-1.82 (m, 1H), 1.42 (s, 9H), 1.21-1.09 (m, 2H), 0.87 (s, 9H), 0.00 (s, 6H). MS (ESI, <semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>): 588.3 [M+H]+. Step D: Preparation of tert-butyl 4-(1-(1-amino-5-(methoxycarbonyl)-4-(4-methoxyphenyl)-1H- imidazol-2-yl)-3-((tert-butyldimethylsilyl)oxy)propyl)piperidine-1-carboxylate [Image disponible dans le document PDF, Image available in the PDF document] Lithium hexamethyldisilazane (23 mL of a 1 M solution in tetrahydrofuran, 22.96 mmol) was slowly added to the product of step C (9.1 g, 15.31 mmol) of example 27 in anhydrous N, N- dimethylformamide(150 mL) at 0 °C. After the mixture was stirred for 30 min, O- (diphenylphosphinyl) hydroxylamine (7.1 g, 30.62 mmol) was added at 0°C, followed by stirring at room temperature for 4-6 hs (in cases where the reaction mixture became too viscous, additional N, N-dimethylformamidewas added). The reaction was quenched with water until a clear solution was formed and concentrated to dryness under reduced pressure. The residue was washed several times with ethyl acetate or dichloromethane. The combined organic fractions were concentrated in vacuo and purified by flash chromatography on silica gel with ethyl acetate and petroleum ether (1:3) to give the product as a clear colorless oil (7.5 g, 81%). 1H NMR (400 MHz, CDCl3) <semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics> 7.57 <semantics>(d,J=8.6 Hz,2H),6.91(d,J=8.6 Hz,2H),5.57(s,2H),4.11(s,1H),4.00(s,1H),3.82(s,3H),<annotation encoding="application / x-tex">(d, J = 8.6 \text{ Hz}, 2H), 6.91 (d, J = 8.6 \text{ Hz}, 2H), 5.57 (s, 2H), 4.11 (s, 1H), 4.00 (s, 1H), 3.82 (s, 3H),< / annotation>< / semantics> 3.76 (s, 3H), 3.63-3.57 (m, 1H), 3.36-3.30 (m, 2H), 2.78-2.53 (m, 2H), 2.04-1.97 (m, 2H), 1.98- 1.86 (m, 2H), 1.43 (s, 9H), 1.38-1.33 (m, 1H), 1.29-1.19 (m, 2H), 0.85 (s, 9H), -0.01 (d, <semantics>J=11.5<annotation encoding="application / x-tex">J = 11.5< / annotation>< / semantics> Hz, 6H). MS (ESI, <semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>): 603.3 [M+H]+. Step E: Preparation oftert-butyl 4-(1-(1-amino-5-(methoxycarbonyl)-4-(4-methoxyphenyl)-1H- imidazol-2-yl)-3-hydroxypropyl)piperidine-1-carboxylate [Image disponible dans le document PDF, Image available in the PDF document] To a solution of the product of step D (7.5 g, 12.44 mmol) of example 27 in tetrahydrofuran (50 mL) was added a 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran (13 mL, 12.44 mmol) at r.t. The solution was stirred for 2 hs and diluted with 100 mL ethyl acetate. The organic layer was separated and washed with <semantics>H2O<annotation encoding="application / x-tex">H_2O< / annotation>< / semantics> (3×200 mL). The water extract was washed with ethyl acetate (2×150 mL), and the organic layers were combined and dried over anhydrous Na2SO4. The solvent was evaporated in vacuo, and purified by flash chromatography on silica gel with dichloromethane and methanol (25:1) to give the product as a clear colorless oil (5 g, 82%). 1H NMR (400 MHz, CDCl3) <semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics> 7.56 (d, <semantics>J<annotation encoding="application / x-tex">J< / annotation>< / semantics> = 8.5 Hz, 2H), 6.90 (d, <semantics>J<annotation encoding="application / x-tex">J< / annotation>< / semantics> = 8.5 Hz, 2H), 5.53 (s, 2H), 4.11 <semantics>(dd,J=14.0,7.0 Hz,1H),4.00(s,1H),3.82(s,3H),3.76(s,3H),3.57(s,1H),3.40(s,1H),3.29<annotation encoding="application / x-tex">(dd, J = 14.0, 7.0 \text{ Hz}, 1\text{H}), 4.00 (s, 1\text{H}), 3.82 (s, 3\text{H}), 3.76 (s, 3\text{H}), 3.57 (s, 1\text{H}), 3.40 (s, 1\text{H}), 3.29< / annotation>< / semantics> <Formule mathématique disponible dans le document PDF, Math available in the PDF document>(td, J - 9.1, 5.2 \text{ Hz}, 1\text{H}), 2.78-2.54 \text{ (m, 2H)}, 2.01 \text{ (dd, } J - 9.5, 5.3 \text{ Hz}, 3\text{H}), 1.90 \text{ (s, 1H)}, 1.43 \text{ (s, 1H)}, 1.43 \text{ (s, 1H)}, 1.43 \text{ (s, 1H)}, 1.43 \text{ (s, 1H)}, 1.43 \text{ (s, 1H)}, 1.43 \text{ (s, 9H), 1.31 (d, <semantics>J=11.8<annotation encoding="application / x-tex">J = 11.8< / annotation>< / semantics> Hz, 1H), 1.28-1.17 (m, 2H). MS (ESI, <semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>): 489.3 [M+H]+. Step F: Preparation of methyl 8-(1-(tert-butoxycarbonyl)piperidin-4-yl)-2-(4-methoxyphenyl)- 5,6,7,8-tetrahydroimidazo[1,2-b]pyridazine-3-carboxylate [Image disponible dans le document PDF, Image available in the PDF document] Methanesulfonyl chloride (2.3 g, 20.47 mmol) was added via syringe into a stirred mixture of the product of step E (5.0 g, 10.23 mmol) of example 27 and N, N-diisopropylethylamine (3.3 g, 25.58 mmol) in dichloromethane (50 ml) maintained at 0°C. The mixture was stirred at room temperature for 3 hs (TLC monitoring) and then partitioned between dichloromethane and water. The organic phase was dried and evaporated to afford an oil. The crude intermediate was dissolved in tetrahydrofuran (20 mL), 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran (10 mL, 10.23 mmol) and N, N-diisopropylethylamine (3.3 g, 25.58 mmol) was added to the mixture, which was stirred 3hs, then partitioned between dichloromethane and water. The organic phase was dried and evaporated to afford a white solid, then passed through a column of silica gel with dichloromethane and methanol (25:1) to afford the desired product as a colorless oil (2.0 g, 41%). 1H NMR (600 MHz, CDCl3) <semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics> 7.59 (d, <semantics>J=8.7<annotation encoding="application / x-tex">J = 8.7< / annotation>< / semantics> Hz, 2H), 6.91 (d, <semantics>J=8.7<annotation encoding="application / x-tex">J = 8.7< / annotation>< / semantics> Hz, 2H), 4.16 (s, 2H), 3.83 (s, 3H), 3.76 (s, 3H), 3.49-3.42 (m, 1H), 3.34-3.31 (m, 1H), 3.08 (s, 1H), 2.68 (s, 2H), 2.39 (s, 1H), <semantics>2.08−2.01<annotation encoding="application / x-tex">2.08-2.01< / annotation>< / semantics> (m, 1H), <semantics>1.95−1.88<annotation encoding="application / x-tex">1.95-1.88< / annotation>< / semantics> (m, 1H), <semantics>1.73<annotation encoding="application / x-tex">1.73< / annotation>< / semantics> (d, <semantics>J=12.5<annotation encoding="application / x-tex">J = 12.5< / annotation>< / semantics> Hz, 1H), <semantics>1.44<annotation encoding="application / x-tex">1.44< / annotation>< / semantics> (s, 9H), <semantics>1.41<annotation encoding="application / x-tex">1.41< / annotation>< / semantics> (d, <semantics>J=9.4<annotation encoding="application / x-tex">J = 9.4< / annotation>< / semantics> Hz, 1H), 1.32 (s, 1H), 1.28 (s, 1H). MS (ESI, <semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>): 471.3 [M+H]+. Step G: Preparation of 8-(1-(tert-butoxycarbonyl)piperidin-4-yl)-2-(4-methoxyphenyl)-5,6,7,8- tetrahydroimidazo[1,2-b]pyridazine-3-carboxylic acid [Image disponible dans le document PDF, Image available in the PDF document] To a solution of the product of step F (2.0 g, 4.25 mmol) of example 27 in tetrahydrofuran (30 mL) was added LiOH (1.1 g, 42.50 mmol) in water (10 mL), the mixture was heated at 50°C for 3 hs. Then cooled to r.t. The mixture acidified to pH 3-4 with concentrated HCl and then extracted with dichloromethane (3×100 mL). The organic phase was washed with saturated brine and then dried over anhydrous Na2SO4. The organic phase was concentrated in vacuo to afford 2.1 g crude product. The residue was used to next step without further purification. MS (ESI, <semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>): 457.2 <semantics>[M+H]+<annotation encoding="application / x-tex">[M+H]^{+}< / annotation>< / semantics>. Step H: Preparation of tert-butyl 4-(3-carbamoyl-2-(4-methoxyphenyl)-5,6,7,8- tetrahydroimidazo[1,2-b]pyridazin-8-yl)piperidine-1-carboxylate [Image disponible dans le document PDF, Image available in the PDF document] CA To the solution of the product of step G (1.0 g, 2.19 mmol) of example 27 in dichloromethane (30 mL) was added N, N-diisopropylethylamine (1.4 g, 10.95 mmol). After 5 min, NH4Cl (468.6 mg, 8.76 mmol) and HATU (1.3 g, 3.29 mmol) was added. The reaction mixture was continued to stir at room temperature for 2 h. Dichloromethane and water were added. The layers were separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed three times (3×50 mL) with brine solution. The organic phase was dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by chromatography with dichloromethane and methanol (40:1) to give product as an off-white solid (630 mg, 63%). 1H NMR (600 MHz, CDCl3) <semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics> 7.51 (d, <semantics>J=8.6<annotation encoding="application / x-tex">J = 8.6< / annotation>< / semantics> Hz, 2H), 6.96 (d, <semantics>J=8.7<annotation encoding="application / x-tex">J = 8.7< / annotation>< / semantics> Hz, 2H), 4.16 (s, 2H), 3.83 (s, 3H), 3.45-3.37 (m, 1H), <semantics>3.36−3.27<annotation encoding="application / x-tex">3.36-3.27< / annotation>< / semantics> (m, 1H), <semantics>3.11<annotation encoding="application / x-tex">3.11< / annotation>< / semantics> (d, <semantics>J=3.7<annotation encoding="application / x-tex">J = 3.7< / annotation>< / semantics> Hz, 1H), <semantics>2.69<annotation encoding="application / x-tex">2.69< / annotation>< / semantics> (s, 2H), <semantics>2.39<annotation encoding="application / x-tex">2.39< / annotation>< / semantics> (s, 1H), <semantics>2.07−2.01<annotation encoding="application / x-tex">2.07-2.01< / annotation>< / semantics> (m, 1H), <semantics>1.97−1.09<annotation encoding="application / x-tex">1.97-1.09< / annotation>< / semantics> 1.88 (m, 1H), 1.71-1.69 (m, 1H), 1.44 (s, 9H), 1.43-1.41 (m, 1H), 1.36 (s, 1H), 1.32 (s, 1H). <semantics>MS(ESI,m / z)<annotation encoding="application / x-tex">MS(ESI, m / z)< / annotation>< / semantics>: 456.3 <...

Claims

<pat:ClaimStatement>What is claimed is:< / pat:ClaimStatement> <pat:Claims com:id="claims"> <pat:Claim com:id="CLM-00001"> <pat:ClaimNumber>1< / pat:ClaimNumber> <pat:ClaimText>1. A compound represented by Formula I, or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, [Image disponible dans le document PDF, Image available in the PDF document] wherein <semantics>R1<annotation encoding="application / x-tex">R_1< / annotation>< / semantics> is selected from the group consisting of <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkyl; <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkyl substituted with the substituents selected from the group consisting of halogen, C1-6 alkoxy, and C3-6 cycloalkyl; and [Image disponible dans le document PDF, Image available in the PDF document] .1 wherein R13, R14, R15, R16, R17 are independently selected from the group consisting of H; cyano; C1-6 alkyl; C1-6 alkyl substituted with halogen; C1-6 alkoxy; halogen; C6 or C10 aryl; C6 or C10 aryl substituted with halogen, C1-6 alkyl, C1-6 alkoxy, cyano, or trifluloromethyl; a five-membered or six-membered heteroaryl, and a bicyclic heteroaryl in which five-membered and six-membered rings are fused with each other; n is an integer that is selected from 0, 1, 2, or 3; R2, R3, R4, R5 are independently selected from the group consisting of hydrogen, halogen, C1- 4 fluoroalkyls, cyano, C1-6 alkyl, C3-6 cycloalkyls and C1-6 alkoxy; X is selected from the group consisting of: [Image disponible dans le document PDF, Image available in the PDF document] , and an aryl substituted with -NR6Y, wherein <semantics>R12<annotation encoding="application / x-tex">R_{12}< / annotation>< / semantics> is selected from H, F, <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkyl, <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkyl substituted with halogen, <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkoxy; and R12 forms a double bond in the ring it attaches to, or forms a 3-6 membered ring fused or spiraled with the ring it attaches to; <semantics>R6<annotation encoding="application / x-tex">R_6< / annotation>< / semantics> is selected from the group consisting of hydrogen, <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkyl and <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkyl substituted with halogen and <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkoxys; Y is selected from the group consisting of -CN, -C(=O)P, -S(=O)P and -S(=O)2P; [Image disponible dans le document PDF, Image available in the PDF document] P is selected from Rx is selected from the group consisting of H, cyano, halogen, C1-6 alkyl, C1-6 alkoxy, <semantics>C3−6<annotation encoding="application / x-tex">C_{3-6}< / annotation>< / semantics> cycloalkyl, phenyl, <semantics>−(CH2)mNR10R11<annotation encoding="application / x-tex">-(CH_2)_mNR_{10}R_{11}< / annotation>< / semantics>, <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkyl substituted with halogen, and hydroxy; <semantics>R7<annotation encoding="application / x-tex">R_7< / annotation>< / semantics> is selected from the group consisting of hydrogen, halogen, cyano, <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkyl, <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkyl substituted with groups selected from F, hydroxyl and C1-6 alkoxy; C3-6 cycloalkyl, and C3-6 cycloalkyl substituted with F; R8 and R9 are independently selected from the group consisting of hydrogen; halogen; cyano; CF3; aryl; aryl substituted with halogen, cyano, C1-6 alkyl, C1-6 alkoxy; heteroaryl; heteroaryl substituted with halogen, cyano, C1-6 alkyl, C1-6 alkoxy; C1-6 alkyl; C1-6 alkyl substituted with C1-6 alkoxy, -NR10R11, halogen, hydroxyl, C6 or C10 aryl, and heteroaryl; C3-6 cycloalkyl; C3- 6 cycloalkyl substituted with halogen; <semantics>C2−6<annotation encoding="application / x-tex">C_{2-6}< / annotation>< / semantics> alkenyl; <semantics>C2−6<annotation encoding="application / x-tex">C_{2-6}< / annotation>< / semantics> alkenyl substituted with <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkoxy, - <semantics>NR10R11<annotation encoding="application / x-tex">NR_{10}R_{11}< / annotation>< / semantics>, halogen, hydroxyl, aryl and heteroaryl; <semantics>R10<annotation encoding="application / x-tex">R_{10}< / annotation>< / semantics> and <semantics>R11<annotation encoding="application / x-tex">R_{11}< / annotation>< / semantics> are each independently selected from hydrogen, <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkyl, <semantics>C3−6<annotation encoding="application / x-tex">C_{3-6}< / annotation>< / semantics> cycloalkyl; or together with the nitrogen they substitute to form a 4-6 membered heterocycloalkyl; m is an integer selected from 1, 2 or 3; and Z is selected from NH or CH2. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00002"> <pat:ClaimNumber>2< / pat:ClaimNumber> <pat:ClaimText>2. A compound of claim 1, wherein Z is NH. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00003"> <pat:ClaimNumber>3< / pat:ClaimNumber> <pat:ClaimText>3. A compound of claim 1, wherein Z is CH2. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00004"> <pat:ClaimNumber>4< / pat:ClaimNumber> <pat:ClaimText>4. A compound of any one of claims 1 to 3, wherein n is 0 or 1. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00005"> <pat:ClaimNumber>5< / pat:ClaimNumber> <pat:ClaimText>5. A compound of any one of claims 1 to 4, wherein R13, R14, R15, R16, R17 are independently selected from the group consisting of H; cyano; <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkyl; <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkyl substituted with F; <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkoxy; halogen; C6 or C10 aryl; C6 or C10 aryl substituted with halogen, C1-6 alkyl, C1-6 alkoxy, cyano, or trifluloromethyl; a five-membered or six-membered heteroaryl; and a bicyclic heteroaryl in which five-membered and six-membered rings are fused with each other. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00006"> <pat:ClaimNumber>6< / pat:ClaimNumber> <pat:ClaimText>6. A compound of any one of claims 1 to 5, wherein R6 is hydrogen; R12 is hydrogen; and R2, R3, R4, R5 are H. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00007"> <pat:ClaimNumber>7< / pat:ClaimNumber> <pat:ClaimText>7. A compound of any one of claims 1 to 6, wherein X is selected from the group consisting of [Image disponible dans le document PDF, Image available in the PDF document] wherein Y is <semantics>−C(=O)P<annotation encoding="application / x-tex">-C(=O)P< / annotation>< / semantics> or CN; P is selected from <semantics>R7<annotation encoding="application / x-tex">R_7< / annotation>< / semantics> <semantics>R9<annotation encoding="application / x-tex">R_9< / annotation>< / semantics> or <semantics>R7<annotation encoding="application / x-tex">R_7< / annotation>< / semantics> <semantics>R9<annotation encoding="application / x-tex">R_9< / annotation>< / semantics> and Rx is selected from the group consisting of H, C1-6 alkyl, C1-6 alkyl substituted with halogen, and C3-6 cycloalkyl; R7 is selected from the group comprising hydrogen, halogen, cyano, C1-6 alkyl, and C1-6 alkyl substituted with halogen; and R8 and R9 are independently selected from the group consisting of hydrogen, halogen, C1-6 alkyl, C1-6 alkyl substituted with halogen or -NR10R11; and C3-6 cycloalkyl; and <semantics>R10<annotation encoding="application / x-tex">R_{10}< / annotation>< / semantics> and <semantics>R11<annotation encoding="application / x-tex">R_{11}< / annotation>< / semantics> are independently selected from <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkyl. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00008"> <pat:ClaimNumber>8< / pat:ClaimNumber> <pat:ClaimText>8. A compound of any one of claims 1 to 7, wherein X is selected from the group consisting of [Image disponible dans le document PDF, Image available in the PDF document] wherein Y is <semantics>−C(=O)P<annotation encoding="application / x-tex">-C(=O)P< / annotation>< / semantics> or CN; [Image disponible dans le document PDF, Image available in the PDF document] Rx is selected from the group consisting of H, CH3, CF3 and cyclopropyl; R7 is selected from the group consisting of hydrogen, methyl, halogen and cyano; R8 and R9 are independently selected from the group consisting of hydrogen, CF3, CH3, C2H5, isobutyl, cyclopropyl, and -(CH2)mN(CH3)2; and m is an integer selected from 1 to 3. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00009"> <pat:ClaimNumber>9< / pat:ClaimNumber> <pat:ClaimText>9. A compound of any one of claims 1 to 8, wherein X is selected from the group consisting of [Image disponible dans le document PDF, Image available in the PDF document] Y is <semantics>−C(=O)P<annotation encoding="application / x-tex">-C(=O)P< / annotation>< / semantics>; [Image disponible dans le document PDF, Image available in the PDF document] P is selected from and Rx is selected from H or CH3; R7 is selected from the group comprising hydrogen, F, and cyano; R8 and R9 are independently selected from hydrogen or CF3. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00010"> <pat:ClaimNumber>10< / pat:ClaimNumber> <pat:ClaimText>10. A compound of any one of claims 1 to 9, wherein [Image disponible dans le document PDF, Image available in the PDF document] <semantics>R1<annotation encoding="application / x-tex">R_1< / annotation>< / semantics> is wherein R13, R14, R15, R16 and R17 are independently selected from the group consisting of H, halogen, <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkyl, <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkoxy, <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkyl substituted by halogen, and CN. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00011"> <pat:ClaimNumber>11< / pat:ClaimNumber> <pat:ClaimText>11. A compound of any one of claims 1 to 10, wherein R15 is selected from the group consisting of H, CH3, CH2CH3, OCH3, F, Cl, Br, CN and CF3; and <semantics>R13<annotation encoding="application / x-tex">R_{13}< / annotation>< / semantics>, <semantics>R14<annotation encoding="application / x-tex">R_{14}< / annotation>< / semantics>, <semantics>R16<annotation encoding="application / x-tex">R_{16}< / annotation>< / semantics> and <semantics>R17<annotation encoding="application / x-tex">R_{17}< / annotation>< / semantics> are H. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00012"> <pat:ClaimNumber>12< / pat:ClaimNumber> <pat:ClaimText>12. A compound of any one of claims 1 to 11, wherein R15 is selected from the group consisting of H, CH3, CH2CH3, OCH3, F, Cl, Br, CN and CF3; and each of <semantics>R13<annotation encoding="application / x-tex">R_{13}< / annotation>< / semantics>, <semantics>R14<annotation encoding="application / x-tex">R_{14}< / annotation>< / semantics>, <semantics>R16<annotation encoding="application / x-tex">R_{16}< / annotation>< / semantics> and <semantics>R17<annotation encoding="application / x-tex">R_{17}< / annotation>< / semantics> are H. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00013"> <pat:ClaimNumber>13< / pat:ClaimNumber> <pat:ClaimText>13. A compound of claim 12, wherein R13, R14, R15, R16 and R17 are H. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00014"> <pat:ClaimNumber>14< / pat:ClaimNumber> <pat:ClaimText>14. A compound of any one of claims 1 to 13, wherein <semantics>R2<annotation encoding="application / x-tex">R_2< / annotation>< / semantics> or <semantics>R3<annotation encoding="application / x-tex">R_3< / annotation>< / semantics> is <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkoxy. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00015"> <pat:ClaimNumber>15< / pat:ClaimNumber> <pat:ClaimText>15. A compound of claim 1, wherein X is selected from the group consisting of [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] wherein Y is -C(=O)P, where [Image disponible dans le document PDF, Image available in the PDF document] P is selected from , and Rx is selected from the group consisting of H, CH3, CF3, cyclopropyl, and -(CH2)mNR10R11 wherein m is an integer selected from 1, 2, or 3; n is 0; Z is CH2; R1 is: [Image disponible dans le document PDF, Image available in the PDF document] wherein R13, R14, R15, R16 and R17 are independently selected from the group consisting of H, OCH3, F, Cl, Br, CF3 and CN; R2 is H or methoxy; each of R3, R4, and R5 are H; R7 is selected from the group consisting of hydrogen, cyano, and halogen; R8 and R9 are independently selected from the group consisting of hydrogen, CF3, CH3, cyclopropyl, and <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkyl substituted with -NR10R11; and <semantics>R10<annotation encoding="application / x-tex">R_{10}< / annotation>< / semantics>, <semantics>R11<annotation encoding="application / x-tex">R_{11}< / annotation>< / semantics> are independently selected from <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkyl. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00016"> <pat:ClaimNumber>16< / pat:ClaimNumber> <pat:ClaimText>16. A compound of claim 1, wherein X is selected from the group consisting of [Image disponible dans le document PDF, Image available in the PDF document] , and [Image disponible dans le document PDF, Image available in the PDF document] wherein Y is <semantics>−C(=O)P<annotation encoding="application / x-tex">-C(=O)P< / annotation>< / semantics> where [Image disponible dans le document PDF, Image available in the PDF document] P is selected from , n is 0; Z is CH2; <semantics>R1<annotation encoding="application / x-tex">R_1< / annotation>< / semantics> is phenyl; R2 is H or methoxy, each of R3, R4, and R5 are H; R7 is selected from the group consisting of hydrogen, cyano, and halogen; and R8 and R9 are independently selected from the group consisting of hydrogen, CF3, CH3, and cyclopropyl. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00017"> <pat:ClaimNumber>17< / pat:ClaimNumber> <pat:ClaimText>17. A compound of claim 1, wherein X is selected from the group consisting of [Image disponible dans le document PDF, Image available in the PDF document] , and wherein Y is <semantics>−C(=O)P<annotation encoding="application / x-tex">-C(=O)P< / annotation>< / semantics> where [Image disponible dans le document PDF, Image available in the PDF document] P is selected from , n is 1 Z is NH; R1 is phenyl; R2 is H or methoxy, R3, R4, R5 are H; R7 is selected from the group consisting of hydrogen, cyano, and halogen; and R8 and R9 are independently selected from the group consisting of hydrogen, CF3, CH3, and cyclopropyl. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00018"> <pat:ClaimNumber>18< / pat:ClaimNumber> <pat:ClaimText>18. A compound of claim 1, wherein the compound is selected from the group consisting of: 8-(1-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2- b]pyridazine-3-carboxamide, racemate 8-(1-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2- b]pyridazine-3-carboxamide, levoisomer 8-(1-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2- b]pyridazine-3-carboxamide, dextroisomer 8-(1-(but-2-ynoyl)piperidin-4-yl)-2-(4-phenoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2- b]pyridazine-3-carboxamide 8-(1-(3-methylbut-2-enoyl)piperidin-4-yl)-2-(4-phenoxyphenyl)-5,6,7,8- tetrahydroimidazo[1,2-b]pyridazine-3-carboxamide 8-(1-methacryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2- b]pyridazine-3-carboxamide (E)-8-(1-(but-2-enoyl)piperidin-4-yl)-2-(4-phenoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2- b]pyridazine-3-carboxamide (E)-8-(1-(pent-2-enoyl)piperidin-4-yl)-2-(4-phenoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2- b]pyridazine-3-carboxamide (E)-8-(1-(2-cyano-4-methylpent-2-enoyl)piperidin-4-yl)-2-(4-phenoxyphenyl)-5,6,7,8- tetrahydroimidazo[1,2-b]pyridazine-3-carboxamide $2\hbox{-}(4\hbox{-phenoxyphenyl})\hbox{-}8\hbox{-}(1\hbox{-propioloylpiperidin-}4\hbox{-}yl)\hbox{-}5,6,7,8\hbox{-tetrahydroimidazo} [1,2\hbox{-}2]$ b]pyridazine-3-carboxamide (E)-8-(1-(2-cyano-3-cyclopropylacryloyl)piperidin-4-yl)-2-(4-phenoxyphenyl)-5,6,7,8- tetrahydroimidazo[1,2-b]pyridazine-3-carboxamide 8-(1-acryloylpiperidin-4-yl)-2-(4-(4-fluorophenoxy)phenyl)-5,6,7,8-tetrahydroimidazo[1,2- b]pyridazine-3-carboxamide 8-(1-(but-2-ynoyl)piperidin-4-yl)-2-(4-(4-fluorophenoxy)phenyl)-5,6,7,8- tetrahydroimidazo[1,2-b]pyridazine-3-carboxamide (E)-2-(4-(4-fluorophenoxy)phenyl)-8-(1-(4,4,4-trifluorobut-2-enoyl)piperidin-4-yl)-5,6,7,8- tetrahydroimidazo[1,2-b]pyridazine-3-carboxamide 8-(1-acryloylpiperidin-4-yl)-2-(4-(4-methoxyphenoxy)phenyl)-5,6,7,8- tetrahydroimidazo[1,2-b]pyridazine-3-carboxamide 8-(1-(but-2-ynoyl)piperidin-4-yl)-2-(4-(4-methoxyphenoxy)phenyl)-5,6,7,8- tetrahydroimidazo[1,2-b]pyridazine-3-carboxamide (E)-2-(4-(4-methoxyphenoxy)phenyl)-8-(1-(4,4,4-trifluorobut-2-enoyl)piperidin-4-yl)- 5,6,7,8-tetrahydroimidazo[1,2-b]pyridazine-3-carboxamide 8-(1-(2-fluoroacryloyl)piperidin-4-yl)-2-(4-phenoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2- b]pyridazine-3-carboxamide (E)-2-(4-phenoxyphenyl)-8-(1-(4,4,4-trifluoro-but-2-enoyl)piperidin-4-yl)-5,6,7,8- tetrahydroimidazo[1,2-b]pyridazine-3-carboxamide, racemate 2-(4-Phenoxy-phenyl)-8-[1-(4,4,4-trifluoro-but-2-enoyl)-piperidin-4-yl]-5,6,7,8-tetrahydro- imidazo[1,2-b]pyridazine-3-carboxamide, levoisomer 2-(4-Phenoxy-phenyl)-8-[1-(4,4,4-trifluoro-but-2-enoyl)-piperidin-4-yl]-5,6,7,8-tetrahydro- imidazo[1,2-b]pyridazine-3-carboxamide, dextroisomer 8-(2-acrylamidophenyl)-2-(4-phenoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2-b]pyridazine- 3-carboxamide 8-(1-acryloylazetidin-3-yl)-2-(4-phenoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2- b]pyridazine-3-carboxamide 8-(1-(but-2-ynoyl)azetidin-3-yl)-2-(4-phenoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2- b]pyridazine-3-carboxamide (E)-2-(4-phenoxyphenyl)-8-(1-(4,4,4-trifluorobut-2-enoyl)azetidin-3-yl)-5,6,7,8- tetrahydroimidazo[1,2-b]pyridazine-3-carboxamide 8-(4-acrylamidophenyl)-2-(4-phenoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2-b]pyridazine- 3-carboxamide 8-(1-cyanopiperidin-4-yl)-2-(4-phenoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2- b]pyridazine-3-carboxamide (E)-8-(1-(4-(dimethylamino)but-2-enoyl)piperidin-4-yl)-2-(4-phenoxyphenyl)-5,6,7,8- tetrahydroimidazo[1,2-b]pyridazine-3-carboxamide 7-(1-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole- 3-carboxamide 8-(1-acryloylpiperidin-4-yl)-2-(4-methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2- b]pyridazine-3-carboxamide 7-(1-acryloylpiperidin-4-yl)-2-(3-methoxy-4-phenoxyphenyl)-6,7-dihydro-5H-pyrrolo[1,2- a]imidazole-3-carboxamide, and 8-(1-acryloylpiperidin-4-yl)-2-(3-methoxy-4-phenoxyphenyl)-5,6,7,8- tetrahydroimidazo[1,2-b]pyridazine-3-carboxamide; or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00019"> <pat:ClaimNumber>19< / pat:ClaimNumber> <pat:ClaimText>19. A pharmaceutical composition comprising a compound, a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof as claimed in any one of claims 1 to 18, and a pharmaceutically acceptable carrier. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00020"> <pat:ClaimNumber>20< / pat:ClaimNumber> <pat:ClaimText>20. A use of a compound as claimed in any one of claims 1 to 18 in the preparation of a medicament for inhibiting the activity of BTK. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00021"> <pat:ClaimNumber>21< / pat:ClaimNumber> <pat:ClaimText>21. A use of a compound as claimed in any one of claims 1 to 18 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. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00022"> <pat:ClaimNumber>22< / pat:ClaimNumber> <pat:ClaimText>22. A use of a compound as claimed in any one of claims 1 to 18 in the preparation of a medicament for the treatment of a disease 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, central nerve system lymphoma, primary central nerve system lymphoma, Ocular lymphoma, Waldenström's macroglobulinemia, lupus erythematosus, rheumatoid arthritis, Urticaria, Crohn's disease, psoriasis, multiple sclerosis, and asthma. < / pat:ClaimText> < / pat:Claim> < / pat:Claims>