Pyrazolo[3,4-d]pyridazinone compound, preparation method therefor, pharmaceutical composition thereof and use thereof

Abstract

Provided in the present invention are a pyrazolo[3,4-d]pyridazinone compound, a preparation method therefor, a pharmaceutical composition thereof and the use thereof. Specifically, the compound of the present invention has a structure as shown in the following formula (I) or (II), has a function of inhibiting the activity of a DDR1 kinase, and can be used for treating various diseases associated with abnormal expression or activity of a DDR1 protease, for example, same can be used for preparing a pharmaceutical composition for treating autoimmune diseases.

Description

Pyrazolo[3,4-d]pyridazinone compounds, preparation methods, pharmaceutical compositions and applications thereof Technical Field

[0001] The present invention relates to the field of medicinal chemistry. Specifically, the present invention provides a class of pyrazolo[3,4-d]pyridazinone compounds, a preparation method thereof, a pharmaceutical composition and applications thereof. The compounds can effectively inhibit the activity of DDR1 kinase and can be used to treat various diseases associated with abnormal expression or activity of DDR1 protease, such as autoimmune diseases. Background Art

[0002] Autoimmune diseases (AIDs) are diseases caused by the body's immune system being misdirected to attack the host itself. They include over 100 conditions, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), inflammatory bowel disease (IBD), and multiple sclerosis (MS). AIDs represent a significant and growing unmet clinical need. AIDs affect approximately 5% to 8% of the global population, causing significant suffering. The increasing disability and mortality rates reflect the significant challenges faced in treating AIDs, which also represent a major global socioeconomic issue. The pathogenesis of AIDs is exceptionally complex, primarily involving abnormalities in the function of T lymphocytes, B lymphocytes, and macrophages, as well as the overexpression of proinflammatory cytokines. These diseases are often primary, with complex etiologies and challenging treatment, posing a serious threat to human health. Currently, steroids and nonsteroidal anti-inflammatory drugs (NSAIDs) and traditional disease-modifying anti-rheumatic drugs (DMARDs) are widely used in the clinic to treat AID. However, long-term use of these therapies often leads to serious adverse reactions in patients, and patient compliance is also poor, limiting their widespread clinical application. Therefore, finding new drugs with significant efficacy and few adverse reactions has become a clinical problem that needs to be addressed. The pathological mechanism of AID is complex, and patients are highly heterogeneous. Even the same disease manifestations are often caused by different molecular signaling abnormalities, inducing inflammatory pathological effects through specific signal transduction pathways. Therefore, there is a lack of classification and stratification of sensitive populations within the patient population with the same disease manifestations, resulting in the general low efficiency of drug treatment for AID.

[0003] Discoidin domain receptors (DDRs) are members of the transmembrane receptor tyrosine kinase (RTK) superfamily. Unlike typical RTKs that use peptidic growth factors as ligands, DDR1 primarily targets type I and IV collagen. Activation of DDR1 leads to overexpression of downstream phosphorylation pathways. Through signaling proteins such as nuclear factor-κB (NF-κB), p38 mitogen-activated protein kinase (MAPK), and c-Jun N-terminal kinase (JNK), as well as their associated downstream cytokines, DDR1 promotes cell adhesion, migration, proliferation, apoptosis, survival, and differentiation, and regulates extracellular matrix remodeling. While classic tyrosine kinases exhibit rapid phosphorylation and short duration of action, DDR1 typically undergoes a very slow phosphorylation process, and its effects persist for a long time after activation. DDR1 is significantly associated with diseases such as atherosclerosis and fibrosis, and is overexpressed in various organ inflammatory responses, such as microglial inflammation, hepatitis, and nephritis. DDR1 not only induces the secretion of inflammatory factors but, more importantly, enhances the effects of other stimuli, such as proinflammatory cytokines or bacterial products. As an emerging and promising target for anti-inflammatory and anti-autoimmune diseases, DDR1 has garnered increasing attention from both academia and industry. Currently, no therapeutic agents targeting DDR1 for AIDs have been approved for marketing.

[0004] Studies have shown that the types of autoimmune diseases involving DDR1 kinase include (but are not limited to): rheumatoid arthritis, systemic lupus erythematosus, lupus nephritis, scleroderma, polymyositis, dermatomyositis, Sjögren's syndrome, Graves' disease, Hashimoto's thyroiditis, vasculitis, glomerulonephritis (kidney inflammation), antiphospholipid antibody syndrome, autoimmune liver disease, inflammatory bowel disease and multiple sclerosis.

[0005] Therefore, it is of great significance to develop DDR1 inhibitors with immunosuppressive activity. Summary of the Invention

[0006] The present invention aims to provide a class of pyrazolo[3,4-d]pyridazinone compounds, a preparation method, a pharmaceutical composition and an application thereof, wherein the compounds can effectively inhibit the activity of DDR1 kinase.

[0007] In the first aspect of the present invention, there is provided a compound as shown in formula (I) and a pharmaceutically acceptable salt thereof,

[0008] in,

[0009] X is selected from NH, S, O;

[0010] Selected from:

[0011] a substituted or unsubstituted C6-C12 aryl group, a substituted or unsubstituted 4-12 membered heterocyclic group, or a substituted or unsubstituted 5-12 membered heteroaryl group, wherein the heterocyclic group and the heteroaryl group contain 1-4 heteroatoms selected from oxygen, sulfur and nitrogen as the ring skeleton; wherein the substitution refers to that the group A is substituted by one or more L groups, and each L is independently selected from the following group: a C1-C12 straight chain or branched alkyl group, a C1-C6 straight chain or branched haloalkyl group, a C1-C6 straight chain or branched alkylthio group, a C1-C6 straight chain or branched alkoxy group, a C1-C6 straight chain or branched haloalkoxy group, a C1-C6 straight chain or branched haloalkylthio group, NO2, NH2, -NHC(O)R 1 、-C(O)NHR 1 、-NHC(O)OR 1 、-COR 1 、-SO2R 1 , -SF5, C3-C8 cycloalkyl (including saturated or partially unsaturated), C6-C10 aryl, phenoxy, benzyloxy, NHC(O)benzyl, C(O)-5-7 membered heterocyclic group; and said L may be further substituted by 1-3 Re; said Re is selected from the following group: halogen, trifluoromethyl, difluoromethyl, C1-C4 straight chain or branched alkyl; or any two substituents L located at adjacent atoms may together form a 5-12 membered heterocyclic group;

[0012] Among them, R 1 is H, C1-C4 alkyl, C1-C4 haloalkyl, -NR 2 R 3 ; R 2 、R 3 Each independently represents H, C1-C4 alkyl, or the R 2 and R 3 Together they constitute a 5-12 membered heterocyclic group;

[0013] R5 is selected from the group consisting of: H, halogen, and halogen-substituted C1-C4 alkyl.

[0014] In another preferred embodiment, X is O.

[0015] In another preferred embodiment, the Selected from:

[0016] substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl;

[0017] The substitution mentioned herein refers to the substitution of group A by one or more L groups, and each L is independently selected from the following groups: halogen, trifluoromethyl, difluoromethyl, C1-C12 straight or branched alkyl, C1-C6 straight or branched alkoxy, C1-C6 straight or branched alkylthio, C3-C12 cycloalkyl, -SO2R 1 、-COR 1 NHCOOR 1 , nitro, amino, trifluoromethoxy, trifluoromethylthio, pentafluorosulfur, C6-C10 aryl, phenoxy; and the L can be further substituted by 1-3 Re; the Re is selected from the following group: halogen, trifluoromethyl, difluoromethyl, C1-C4 straight or branched alkyl; or any two substituents L located at adjacent atoms can together form a 5-8 membered heterocyclic group; wherein R 1 As mentioned above.

[0018] In another preferred embodiment, L is independently selected from the following group: halogen, trifluoromethyl, difluoromethyl, C1-C6 linear or branched alkyl, C3-C6 cyclic hydrocarbon group, nitro, amino, pentafluorinated sulfur group, trifluoromethoxy, trifluoromethylthio, -SO2R 1 ; and said L may be further substituted by 1-3 Re; said Re is selected from the following group: halogen, trifluoromethyl;

[0019] Among them, R 1 Each independently selected from the following group: H, C1-C4 alkyl, trifluoromethyl, -NR 2 R 3 ; R 2 、R 3 Each independently represents H, methyl, or the R 2 and R 3 Together they constitute a 5-6 membered heterocyclic group.

[0020] In another preferred embodiment, Selected from the following structural fragments:

[0021] In the second aspect of the present invention, there is provided a compound as shown in formula (II) and a pharmaceutically acceptable salt thereof,

[0022] in,

[0023] X is selected from NH, S, O;

[0024] R 4is a substituted or unsubstituted C6-C12 aryl group, a substituted or unsubstituted C4-C12 cycloalkyl group, a substituted or unsubstituted 4-12 membered heterocyclyl group, or a substituted or unsubstituted 5-12 membered heteroaryl group, wherein the heterocyclyl group and the heteroaryl group contain 1-4 heteroatoms selected from oxygen, sulfur and nitrogen as the ring skeleton, wherein the substitution refers to that one or more hydrogen atoms on the group are replaced by a substituent selected from the group consisting of halogen and halogen-substituted C1-C4 alkyl;

[0025] Selected from:

[0026] a substituted or unsubstituted C6-C12 aryl group, a substituted or unsubstituted 4-12 membered heterocyclic group, or a substituted or unsubstituted 5-12 membered heteroaryl group, wherein the heterocyclic group and the heteroaryl group contain 1-4 heteroatoms selected from oxygen, sulfur and nitrogen as the ring skeleton; wherein the substitution refers to that one or more hydrogen atoms on the group are replaced by substituents independently selected from the following groups: a C1-C12 straight chain or branched alkyl group, a C1-C6 straight chain or branched haloalkyl group, a C1-C6 straight chain or branched alkylthio group, a C1-C6 straight chain or branched alkoxy group, a C1-C6 straight chain or branched haloalkoxy group, a C1-C6 straight chain or branched haloalkylthio group, NO2, NH2, -NHC(O)R 1 、-C(O)NHR 1 、-NHC(O)OR 1 、-COR 1 、-SO2R 1 , -SF5, C3-C8 cycloalkyl (including saturated or partially unsaturated), C6-C10 aryl, phenoxy, benzyloxy, NHC(O)benzyl, C(O)-5-7 membered heterocyclic group; and the substituents may be further substituted by 1-3 Re; the Re is selected from the following group: halogen, trifluoromethyl, difluoromethyl, C1-C4 straight or branched alkyl; or any two substituents located at adjacent atoms may together constitute a 5-12 membered heterocyclic group or C6-C10 aryl;

[0027] L is selected from C1-C6 straight chain or branched alkylthio, C1-C6 straight chain or branched alkoxy, C1-C6 straight chain or branched fluoroalkoxy, -SO2R 1 , -SF5, cyclopropane, NO2, benzyloxy, NH2, NHC(O)benzyl, phenyl, C(O)-5-7 membered heterocyclic group; and said L may be further substituted by 1-3 Re; said Re is selected from the following group: halogen, trifluoromethyl, difluoromethyl, C1-C4 straight chain or branched alkyl;

[0028] Among them, R 1 C1-C4 alkyl, C1-C4 haloalkyl, -NR 2 R 3 ; R2 、R 3 Each independently represents H, C1-C4 alkyl, or the R 2 and R 3 Together they constitute a 5-12 membered heterocyclic group.

[0029] In another preferred embodiment, the R 4 Selected from the following groups: substituted or unsubstituted phenyl, substituted or unsubstituted C4-C7 cycloalkyl, substituted or unsubstituted 4-7 membered heterocyclyl; wherein the substitution refers to that one or more hydrogen atoms on the group are replaced by a substituent selected from the following group: trifluoromethyl, difluoromethyl, halogen.

[0030] In another preferred embodiment, the R 4 Select from the following groups:

[0031] In another preferred embodiment, the Selected from:

[0032] substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl;

[0033] The substitution refers to that one or more hydrogen atoms on the group are replaced by substituents independently selected from the following groups: halogen, halogen-substituted C1-C4 alkyl, C1-C12 straight or branched alkyl, C1-C6 straight or branched alkoxy, C1-C6 straight or branched alkylthio, unsubstituted or substituted by one or more R 1 Substituted C3-C12 carbocyclic group (including saturated or partially unsaturated), -SO2R 1 、-COR 1 NHCOOR 1 , nitro, amino, trifluoromethoxy, trifluoromethylthio, pentafluorinated sulfenyl, C6-C10 aryl, phenoxy; wherein any two substituents located on adjacent atoms can together form a 5-12 membered heterocyclic group;

[0034] Among them, R 1 C1-C4 alkyl, C1-C4 haloalkyl, -NR 2 R 3 ; R 2 、R 3 Each independently represents H, C1-C4 alkyl, or the R 2 and R 3 Together they constitute a 5-12 membered heterocyclic group.

[0035] In another preferred embodiment, Selected from the following structural fragments:

[0036] In the third aspect of the present invention, there is provided the use of the compound of formula (I) and its pharmaceutically acceptable salt as described in the first aspect of the present invention or the compound of formula (II) and its pharmaceutically acceptable salt as described in the second aspect of the present invention, for preparing a pharmaceutical composition for treating a disease associated with DDR1 enzyme activity or expression, wherein the disease associated with DDR1 enzyme activity or expression is selected from the following group: rheumatoid arthritis, systemic lupus erythematosus, lupus nephritis, scleroderma, polymyositis, dermatomyositis, Sjögren's syndrome, Graves' disease, Hashimoto's thyroiditis, psoriasis, vitiligo, asthma, psoriasis, idiopathic pulmonary fibrosis, vasculitis, glomerulonephritis (kidney inflammation), antiphospholipid antibody syndrome, autoimmune liver disease, inflammatory bowel disease and multiple sclerosis; preferably, the disease is rheumatoid arthritis or systemic lupus erythematosus.

[0037] In another preferred embodiment, the use further comprises:

[0038] (a) preparing DDR1 targeted inhibitors;

[0039] (b) preparing an in vitro reagent for inhibiting DDR1 enzyme activity;

[0040] (c) preparing an in vitro reagent for inhibiting T and B lymphocyte proliferation;

[0041] (d) preparing a pharmaceutical composition for treating a disease associated with overactivation of T and B lymphocytes; preferably, the disease is an autoimmune disease, more preferably selected from the group consisting of rheumatoid arthritis, systemic lupus erythematosus, lupus nephritis, scleroderma, Sjögren's syndrome, psoriasis, vitiligo, asthma, psoriasis, idiopathic pulmonary fibrosis, antiphospholipid antibody syndrome, autoimmune liver disease, inflammatory bowel disease and multiple sclerosis.

[0042] In a fourth aspect of the present invention, a pharmaceutical composition is provided, comprising: (i) an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a compound of formula (II) or a pharmaceutically acceptable salt thereof; and (ii) a pharmaceutically acceptable carrier.

[0043] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features described in detail below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be listed here one by one. BRIEF DESCRIPTION OF THE DRAWINGS

[0044] Figure 1. Therapeutic effect of A048 administered by oral gavage on the bovine type II collagen-induced arthritis model in mice.

[0045] Figure 2. Therapeutic effect of A048 administered by oral gavage on the MRL / lpr spontaneous systemic lupus erythematosus mouse model.

[0046] Figure 3. Body weight of mice three days before the single-dose toxicity study of A048. DETAILED DESCRIPTION

[0047] After extensive and intensive research, including extensive screening and testing, the inventors have developed a class of pyrazolo[3,4-d]pyridazinone compounds, which they discovered possess DDR1 kinase and immunosuppressive activity. Furthermore, these compounds exhibit excellent inhibitory activity against DDR1 kinase and T / B lymphocyte proliferation at relatively low concentrations, making them potentially useful in treating related autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, psoriasis, inflammatory bowel disease, lupus nephritis, asthma, psoriasis, idiopathic pulmonary fibrosis, multiple sclerosis, and vitiligo. Based on these findings, the inventors completed the present invention.

[0048] the term

[0049] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0050] As used herein, when used in reference to a specific recited value, the term "about" means that the value may vary by no more than 1% from the recited value. For example, as used herein, the expression "about 100" includes all values ​​between 99 and 101 (e.g., 99.1, 99.2, 99.3, 99.4, etc.).

[0051] As used herein, the terms "comprising" or "including" may be open, semi-closed, or closed. In other words, the terms also include "consisting essentially of" or "consisting of."

[0052] As used herein, the term "room temperature" or "normal temperature" refers to a temperature of 4-40°C, preferably, 25±5°C.

[0053] As used herein, the term "C1-C6 alkyl" refers to a straight or branched chain alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, and isohexyl, or similar groups. The definition of "C1-C6 alkyl" includes "C1-C4 alkyl."

[0054] The term "C6-C12 aryl" refers to a monocyclic or fused bicyclic ring having 6-12 carbon atoms, a substituent having a conjugated π electron system, such as phenyl and naphthyl, or similar groups. The definition of "C6-C12 aryl" includes "C6-C10 aryl".

[0055] The term "C6-C12 arylene" refers to a group formed by losing a hydrogen atom from a C6-C12 aryl group, including monocyclic or bicyclic arylene groups, such as phenylene, naphthylene, or the like. The definition of "C6-C12 arylene" includes "C6-C10 arylene."

[0056] The term "5-12 membered heteroaryl" refers to an unsaturated ring system substituent having a 5-12 membered monocyclic or fused polycyclic ring and having one or more heteroatoms selected from O, S, N or P on the ring system, preferably a 5-10 membered monocyclic or fused bicyclic ring and having 1-5 heteroatoms selected from O, S, N or P on the ring system, further preferably a 5-8 membered monocyclic heteroaryl or an 8-10 membered bicyclic heteroaryl, most preferably a 5-6 membered monocyclic heteroaryl, a benzo 5-6 membered monocyclic heteroaryl, a 5-6 membered monocyclic heteroaryl and a 5-6 membered monocyclic heteroaryl, such as pyridyl, thienyl, furyl, pyrrolyl, thiazolyl, imidazolyl, benzofuranyl, indolyl, indazolyl, isoindolyl, benzimidazolyl, benzothienyl, benzothiazolyl, quinolyl, isoquinolyl, benzopyrimidinyl and benzopyranyl, or similar groups.

[0057] The term "C3-C8 cycloalkyl" refers to a saturated carbocyclic group having 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, or similar groups. The definition of "C3-C8 cycloalkyl" includes "C3-C6 cycloalkyl".

[0058] The term "C3-C8 cycloalkylene" refers to a group formed by the loss of a hydrogen atom from a C3-C8 cycloalkyl group, such as cyclopropylene, cyclobutylene, cyclopentylene, and cyclohexylene, or similar groups. The definition of "C3-C8 cycloalkylene" includes "C3-C6 cycloalkylene."

[0059] The term "C3-C8 cycloalkenyl" refers to a carbocyclic group having 3-8 carbon atoms and containing 1-3 double bonds, but not having a completely conjugated π-electron system, such as cyclopropenyl, cyclobutenyl, cyclohexadienyl, and cycloheptatrienyl, or similar groups. The definition of "C3-C8 cycloalkenyl" includes "C3-C6 cycloalkenyl."

[0060] The term "3-12 membered heterocyclyl" refers to a saturated ring system substituent having a 3-12 membered monocyclic or fused bicyclic ring with one or more (preferably 1-5) heteroatoms selected from O, S, N, or P, such as piperidinyl, pyrrolidinyl, piperazinyl, tetrahydrofuranyl, morpholinyl, or the like. The definition of "3-12 membered heterocyclyl" includes "4-7 membered heterocyclyl."

[0061] The term "halogen" refers to fluorine, chlorine, bromine or iodine; preferably fluorine, chlorine or bromine.

[0062] The term "C1-C6 alkoxy" refers to a straight or branched chain alkoxy group having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and tert-butoxy, or similar groups. The definition of "C1-C6 alkoxy" includes "C1-C4 alkoxy".

[0063] In the present invention, the terms "comprising", "including" or "comprising" indicate that various components can be used together in the mixture or composition of the present invention. Therefore, the terms "consisting mainly of" and "consisting of" are included in the term "comprising".

[0064] In the present invention, the term "pharmaceutically acceptable" refers to a substance that is suitable for use in humans and / or animals without excessive adverse side effects (such as toxicity, irritation, and allergic reactions), that is, has a reasonable benefit / risk ratio.

[0065] As used herein, the term "effective amount" refers to an amount of a therapeutic agent that treats, alleviates, or prevents a target disease or condition, or an amount that exhibits a detectable therapeutic or preventive effect. The precise effective amount for a given subject depends on the subject's size and health, the nature and severity of the condition, and the therapeutic agent and / or combination of therapeutic agents selected for administration. Therefore, it is not useful to specify an exact effective amount in advance. However, for a given condition, the effective amount can be determined by routine experimentation and is within the judgment of the clinician.

[0066] As used herein, unless otherwise specified, the term "substituted" refers to a group where one or more hydrogen atoms are replaced by a substituent selected from the group consisting of halogen, unsubstituted or halogenated C1-C6 alkyl, unsubstituted or halogenated C2-C6 acyl, or unsubstituted or halogenated C1-C6 alkyl-hydroxy.

[0067] Unless otherwise specified, all compounds mentioned in the present invention are intended to include all possible optical isomers, such as single chiral compounds or mixtures of various chiral compounds (i.e., racemates). In all compounds of the present invention, each chiral carbon atom may optionally be in the R configuration or the S configuration, or a mixture of the R and S configurations.

[0068] As used herein, the term "compound of the present invention" refers to a compound of Formula I. The term also includes various crystalline forms, pharmaceutically acceptable salts, hydrates or solvates of the compound of Formula I.

[0069] As used herein, the term "pharmaceutically acceptable salt" refers to a salt formed by a compound of the present invention with an acid or base that is suitable for use as a drug. Pharmaceutically acceptable salts include inorganic salts and organic salts. A preferred class of salts is a salt formed by a compound of the present invention with an acid. Suitable acids for forming salts include, but are not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, and phosphoric acid; organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzenesulfonic acid, and benzenesulfonic acid; and acidic amino acids such as aspartic acid and glutamic acid. Suitable bases for forming salts include, but are not limited to, sodium hydroxide, potassium hydroxide, lithium hydroxide, etc.

[0070] Compounds of formula I

[0071] The present invention provides a compound shown in the following formula I:

[0072] in,

[0073] X is selected from NH, S, O;

[0074] Selected from:

[0075] a substituted or unsubstituted C6-C12 aryl group, a substituted or unsubstituted 4-12 membered heterocyclic group, or a substituted or unsubstituted 5-12 membered heteroaryl group, wherein the heterocyclic group and the heteroaryl group contain 1-4 heteroatoms selected from oxygen, sulfur and nitrogen as the ring skeleton; wherein the substitution refers to that one or more hydrogen atoms on the group are replaced by substituents independently selected from the following groups: halogen, halogen-substituted C1-C4 alkyl, C1-C12 straight or branched alkyl, C1-C6 straight or branched alkoxy, C1-C6 straight or branched alkylthio, unsubstituted or replaced by one or more R 1 Substituted C3-C12 cyclic hydrocarbon group (including saturated or partially unsaturated), -SO2R 1 、-COR 1 NHCOOR 1 , nitro, amino, trifluoromethoxy, trifluoromethylthio, pentafluorosulfur, C6-C10 aryl, phenoxy; or any two substituents located on adjacent atoms can together form a 5-12 membered heterocyclic group;

[0076] Among them, R 1 C1-C4 alkyl, C1-C4 haloalkyl, -NR 2 R 3 ; R 2 、R 3 Each independently is a C1-C4 alkyl group, or the R 2 and R 3 Together they constitute a 5-12 membered heterocyclic group;

[0077] R5 is selected from the group consisting of: H, halogen, and halogen-substituted C1-C4 alkyl.

[0078] In another preferred embodiment, the Selected from:

[0079] substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl;

[0080] The substitution refers to that one or more hydrogen atoms on the group are replaced by substituents independently selected from the following groups: halogen, trifluoromethyl, difluoromethyl, C1-C12 straight or branched alkyl, C1-C6 straight or branched alkoxy, C1-C6 straight or branched alkylthio, C3-C12 cycloalkyl, -SO2R 1 、-COR 1 NHCOOR 1 , nitro, amino, trifluoromethoxy, trifluoromethylthio, pentafluorosulfur, C6-C10 aryl, phenoxy; or any two substituents located at adjacent atoms can together form a 5-8 membered heterocyclic group.

[0081] The inventors have found that when the benzene ring at the head has a specific substitution pattern, a compound with significantly improved pharmacokinetics can be obtained. In another preferred embodiment, the compound of formula (I) is selected from the following group:

[0082] Compound of formula II

[0083] The present invention provides a compound shown in the following formula II:

[0084] in,

[0085] X is selected from NH, S, O;

[0086] R 4 is a substituted or unsubstituted C6-C12 aryl group, a substituted or unsubstituted C4-C12 cycloalkyl group, a substituted or unsubstituted 4-12 membered heterocyclyl group, or a substituted or unsubstituted 5-12 membered heteroaryl group, wherein the heterocyclyl group and the heteroaryl group contain 1-4 heteroatoms selected from oxygen, sulfur and nitrogen as the ring skeleton, wherein the substitution refers to that one or more hydrogen atoms on the group are replaced by a substituent selected from the group consisting of halogen and halogen-substituted C1-C4 alkyl;

[0087] Selected from:

[0088] a substituted or unsubstituted C6-C12 aryl group, a substituted or unsubstituted 4-12 membered heterocyclic group, or a substituted or unsubstituted 5-12 membered heteroaryl group, wherein the heterocyclic group and the heteroaryl group contain 1-4 heteroatoms selected from oxygen, sulfur and nitrogen as the ring skeleton; wherein the substitution refers to that one or more hydrogen atoms on the group are replaced by substituents independently selected from the following groups: halogen, halogen-substituted C1-C4 alkyl, C1-C12 straight or branched alkyl, C1-C6 straight or branched alkoxy, C1-C6 straight or branched alkylthio, unsubstituted or replaced by one or more R 1 Substituted C3-C12 carbocyclic group (including saturated or partially unsaturated), -SO2R 1 、-COR 1 NHCOOR 1 , nitro, amino, trifluoromethoxy, trifluoromethylthio, pentafluorinated sulfenyl, C6-C10 aryl, phenoxy; wherein any two substituents located on adjacent atoms can together form a 5-12 membered heterocyclic group;

[0089] L is selected from C1-C6 straight chain or branched alkylthio, C1-C6 straight chain or branched alkoxy, C1-C6 straight chain or branched fluoroalkoxy, -SO2R 1 , -SF5, cyclopropane, NO2, benzyloxy, NH2, NHC(O)benzyl, phenyl, C(O)-5-7 membered heterocyclic group; and said L may be further substituted by 1-3 Re; said Re is selected from the following group: halogen, trifluoromethyl, difluoromethyl, C1-C4 straight chain or branched alkyl;

[0090] Among them, R 1 C1-C4 alkyl, C1-C4 haloalkyl, -NR 2 R 3 ; R 2 、R 3 Each independently represents H, C1-C4 alkyl, or the R 2 and R 3 Together they constitute a 5-12 membered heterocyclic group.

[0091] By introducing specific substituents into the A ring (such as C1-C6 straight or branched alkylthio, -SO2R 1 In another preferred embodiment, L is selected from C1-C6 linear or branched alkylthio, -SO2R 1 、-SF5.

[0092] In another preferred embodiment, said L is a 4-substituent.

[0093] In another preferred embodiment, the compound of formula (II) is selected from the following group:

[0094] Preparation method of compound of formula (I) or (II)

[0095] The present invention also provides a method for preparing the compounds of general formula (I) and (II), and the reaction scheme is as follows:.

[0096] Among them, A ring, R 2 The definitions of and X are the same as those described above.

[0097] The reaction steps are described in detail as follows:

[0098] Step a: Disperse A-1 in a solvent, add potassium carbonate and ethyl bromoacetate and react at room temperature to obtain compound A-2, wherein the solvent is DMF;

[0099] Step b: dissolving A-2 in a solvent, adding DBU and heating to react to obtain compound A-3, wherein the solvent is toluene;

[0100] Step c: dissolving A-3 in a solvent, adding palladium acetate, a phosphine ligand, molybdenum hexacarbonyl, and an amino compound, and heating the reaction to obtain compound A-4, wherein the solvent is DMF;

[0101] Step d: A-4 is dissolved in a solvent, sodium hydride and acetonitrile are added, and the mixture is reacted at room temperature to obtain compound AX, wherein the solvent is tetrahydrofuran;

[0102] Step e: dissolving the amino compound in a solvent, adding sodium nitrite, sodium acetate, and ethyl 2-chloroacetoacetate, and reacting at room temperature to obtain compound C-2, wherein the solvent is hydrochloric acid / water;

[0103] Step f: Dissolve AX and C-2 in a solvent, add triethylamine, and react at room temperature to obtain compound R-1, wherein the solvent is dichloromethane.

[0104] Step g: dissolve R-1 in a solvent, add hydrazine hydrate, and heat to react to obtain compound R-2, wherein the solvent is ethanol.

[0105] Step g: dissolve R-2 in a solvent, add hydrochloric acid, and heat under microwave to react to obtain the target compound, wherein the solvent is ethanol.

[0106] DDR1 inhibitors and their applications

[0107] The compounds of the present invention can inhibit the activity of DDR1 kinase. For example, the compounds of the present invention can be used to inhibit the activity of DDR1 kinase in cells, individuals or patients in need of inhibition of the enzyme by administering an inhibitory amount of the compounds of the present invention to the cells, individuals or patients.

[0108] As DDR1 kinase inhibitors, the compounds of the present invention are suitable for treating various autoimmune diseases associated with abnormal expression or activity of DDR1 kinase. The autoimmune diseases associated with DDR1 kinase activity or expression include, but are not limited to, rheumatoid arthritis, systemic lupus erythematosus, lupus nephritis, scleroderma, polymyositis, dermatomyositis, Sjögren's syndrome, Graves' disease, Hashimoto's thyroiditis, psoriasis, vitiligo, asthma, psoriasis, idiopathic pulmonary fibrosis, vasculitis, glomerulonephritis (kidney inflammation), antiphospholipid antibody syndrome, autoimmune liver disease, inflammatory bowel disease, and multiple sclerosis.

[0109] The compounds of the present invention may also be used in combination therapy, ie, in combination with one or more other agents or therapeutic approaches, for the treatment of autoimmune diseases, disorders or conditions associated with DDR1 kinase.

[0110] The pharmaceutical composition of the present invention comprises a safe and effective amount of a compound of the present invention or a pharmacologically acceptable salt thereof, and a pharmacologically acceptable excipient or carrier. "Safe and effective amount" means an amount of the compound sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, more preferably 5-200 mg of the compound of the present invention per dose. Preferably, "one dose" is one capsule or tablet.

[0111] "Pharmaceutically acceptable carriers" refer to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds. Some examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as Tween ), wetting agents (such as sodium lauryl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0112] There is no particular limitation on the administration of the compound or pharmaceutical composition of the present invention. Representative administration routes include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.

[0113] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and acacia; (c) humectants, for example, glycerol; (d) disintegrants, for example, agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solubilizers, for example, paraffin; (f) absorption accelerators, for example, quaternary ammonium compounds; (g) wetting agents, for example, cetyl alcohol and glyceryl monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

[0114] Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifying agents, and the release of the active compound or compounds in such compositions can be delayed in a certain portion of the digestive tract. Examples of useful encapsulating components are polymeric substances and waxes. If desired, the active compound can also be microencapsulated with one or more of the above-mentioned excipients.

[0115] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage form may contain an inert diluent conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil, or mixtures thereof.

[0116] Besides such inert diluents, the composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and flavoring agents.

[0117] Suspensions, in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0118] Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0119] Dosage forms for topical administration of the compounds of this invention include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required.

[0120] The compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds.

[0121] When using a pharmaceutical composition, a safe and effective amount of the compound of the present invention is administered to a mammal (e.g., a human) in need of treatment, wherein the dosage is a pharmaceutically effective dosage. For a 60 kg human, the daily dosage is generally 1 to 2000 mg, preferably 5 to 500 mg. Of course, the specific dosage will also take into account factors such as the route of administration and the patient's health condition, all of which are within the skill of a skilled physician.

[0122] The main advantages of the present invention include:

[0123] 1. The compounds of the present invention have excellent DDR1 kinase inhibitory activity, providing more options for the treatment of various diseases related to abnormal expression or activity of DDR1 kinase, especially autoimmune diseases.

[0124] 2. The compounds of the present invention are superior to the clinical immunosuppressive drug cyclosporin A in significantly inhibiting the proliferation activity of T and B lymphocytes in vitro, and have low killing effects on normal cells and good safety.

[0125] 3. The compounds of the present invention have shown excellent therapeutic effects in animal experiments and are superior to existing drugs for treating immune diseases.

[0126] Below in conjunction with specific implementation, further elaborate the present invention.It should be understood that these embodiments are only used to illustrate the present invention and are not used to limit the scope of the present invention.The experimental method of not indicating specific conditions in the following examples is usually according to normal conditions, such as the conditions described in Sambrook et al., Molecular Cloning: A Laboratory Manual (New York:Cold Spring Harbor Laboratory Press, 1989), or according to the conditions recommended by the manufacturer.In the embodiment, the yield percentage of chemical experiment is calculated by molar ratio, and the reagent solution percentage of pharmacological experiment is calculated by volume.

[0127] Unless otherwise specified, the starting materials used in the present invention were purchased commercially.

[0128] Certain abbreviations used in the reaction schemes and examples are defined as follows:

[0129] Example 1 Preparation of Compound 2-(4-amino-7-oxo-2-(4-(trifluoromethyl)phenyl)-6,7-dihydro-2H-pyrazolo[3,4-d]pyridazin-3-yl)-3-methyl-N-(3-(trifluoromethyl)phenyl)benzofuran-6-carboxamide (A001)

[0130] Reaction 1.1

[0131] Step 1: Preparation of 2-(2-cyanoacetyl)-3-methyl-N-(3-(trifluoromethyl)phenyl)benzofuran-6-carboxamide (A-5)

[0132] 4-Bromo-2-hydroxyacetophenone A-1 (6.14 g, 28.56 mmol), ethyl bromoacetate (7.16 g, 42.84 mmol), and K2CO3 (11.84 g, 85.69 g) were placed in a round-bottom flask. DMF was added and stirred at room temperature for 4 h. After TLC confirmed the reaction was complete, EA was added and the mixture was extracted with water (3 × 30 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to afford the crude white solid A-2. The yield for this step was 86%. A-2 (1.88 g, 6.24 mmol) was dissolved in toluene and DBU (1.43 g, 9.39 mmol) was added. The mixture was refluxed at 100°C for 2 h. The reaction was confirmed to be complete by TLC. The reaction solution was evaporated under reduced pressure and then purified by column chromatography (PE / EA = 20:1) to afford A-3, a white solid. The yield for this step was 80%. 1 HNMR(400MHz,Chloroform-d)δ7.71(d,J=1.6Hz,1H),7.49(d,J=8.3Hz,1H),7.43(dd,J=8.4,1. 7Hz,1H),7.26(s,2H),4.45(q,J=7.1Hz,2H),1.45(t,J=7.1Hz,3H).LRMS(ESI,m / z):282.0[MH] - .

[0133] A-3 (316.28 mg, 1.12 mmol), m-trifluoromethylaniline (150 mg, 0.93 mmol), molybdenum hexacarbonyl (122.89 mg, 0.47 mmol), DBU (212.59 mg, 1.4 mmol), palladium acetate (6.27 mg, 3 mmol%), and CATACXIUM A (20.03 mg, 6 mmol%) were sequentially dissolved in DMF, protected with Ar, and reacted at 120°C for 16 h. EA was added, and the mixture was extracted with water (3 × 30 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and evaporated under reduced pressure, followed by column chromatography (PE / EA = 4:1) to afford A-4 as a white solid. The yield for this step was 61%. 1 H NMR (400MHz, DMSO-d6) δ10.65(s,1H),8.32-8.22(m,2H),8.07(d,J=8.2Hz,1H),7.97(s,2H),7.61(t,J=8.0Hz,1 H),7.47(d,J=7.7Hz,1H),4.38(q,J=7.1Hz,2H),2.58(s,3H),1.36(t,J=7.1Hz,3H).LRMS(ESI,m / z):390.0[MH] - .

[0134] A-4 (5 g, 12.78 mmol) and NaH (1.28 g, 60% in oil, 31.94 mmol) were added to a two-necked flask under Ar protection. Ultra-dry acetonitrile (2.1 g, 51.11 mmol) and tetrahydrofuran (20 mL) were added and reacted at room temperature overnight. TLC confirmed the completion of the reaction. Dilute hydrochloric acid was added to adjust the pH to around neutral. A yellow solid precipitated, which was filtered and dried to obtain a yellow solid A-5. The reaction yield for this step was 89%. 1 H NMR (400MHz, DMSO-d6) δ10.69(s,1H),8.33(s,1H),8.29(s,1H),8.09(d,J=8.3Hz,1H),8.05(d,J=8.5Hz,1H),8.01(dd ,J=8.3,1.3Hz,1H),7.63(t,J=8.0Hz,1H),7.49(d,J=7.5Hz,1H),4.69(s,2H),2.62(s,3H).LRMS(ESI,m / z):385.0[MH] - .

[0135] The intermediates in the table below were prepared according to the synthesis method of A-5

[0136] Reaction 1.2

[0137] Step 2: Preparation of ethyl 2-chloro-2-(2-(4-(trifluoromethyl)phenyl)hydrazinomethylene)acetate (C-2-pCF3)

[0138] 4-Trifluoromethylaniline (1 g, 6.21 mmol) was dissolved in H2O / HCl (8 mL, H2O / HCl = 3:1) and sodium nitrite (471 mg, 6.83 mmol) was added dropwise on an ice bath. After reacting at 0°C for 1 h, sodium acetate (560 mg, 6.83 mmol) and ethyl 2-chloroacetoacetate (1.12 g, 6.83 mmol) were added. The reaction was continued at room temperature for 5 h. The mixture was diluted with water and extracted with EA (3 × 20 mL). The organic phases were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (PE:EA = 10:1) to obtain C-2-pCF3 as a yellow solid. The yield of this step was 95%. LRMS (ESI, m / z): 295.8 [M+H] + The remaining C-2 intermediates were prepared according to this synthetic method.

[0139] Reaction 1.3

[0140] Step 3: Preparation of ethyl 4-cyano-5-(3-methyl-6-((3-(trifluoromethyl)phenyl)carbamoyl)benzofuran-2-yl)-1-(4-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxylate (R-1-pCF3)

[0141] Dissolve A-5 and TEA in DCM and stir at room temperature for 30 minutes. Slowly add C-2-pCF3 and continue stirring at room temperature for 6 hours. After the reaction, the product R-1-pCF3 is obtained by silica gel column chromatography (PE:EA = 5:1) as a pale yellow solid. The yield of this step is 58%. 1 H NMR (500MHz, DMSO-d6) δ10.58(s,1H),8.25(d,J=2.3Hz,1H),8.20(s,1H),8.10-8.05(m,1H),8.02(dd,J=8.2,1.4Hz,1H),7.93(dd,J=8.4, 3.4Hz, 2H), 7.76 (d, J = 8.4Hz, 2H), 7.61 (t, J = 8.1Hz, 1H), 7.47 (d, J = 8.0Hz, 1H), 4.46 (q, J = 7.1Hz, 2H), 2.24 (s, 3H), 1.38 (t, J = 7.1Hz, 3H).

[0142] Reaction 1.4

[0143] Step 4: Preparation of 2-(4-cyano-3-(hydrazide)-1-(4-(trifluoromethyl)phenyl)-1H-pyrazol-5-yl)-3-methyl-N-(3-(trifluoromethyl)phenyl)benzofuran-6-carboxamide (R-2-pCF3)

[0144] Dissolve R-1-pCF3 in EtOH and slowly add excess NH2NH2·H2O dropwise. Reflux at 70°C for 2 h. After the reaction, spin dry to obtain the product R-2-pCF3 as a pale yellow solid, which does not require further purification.

[0145] React 1.5

[0146] Step 5: Preparation of 2-(4-amino-7-oxo-2-(4-(trifluoromethyl)phenyl)-6,7-dihydro-2H-pyrazolo[3,4-d]pyridazin-3-yl)-3-methyl-N-(3-(trifluoromethyl)phenyl)benzofuran-6-carboxamide (A001)

[0147] Place R-2-pCF3 in a microwave reaction tube, dissolve in EtOH, slowly add excess 12N HCl dropwise, and stir at 108°C for 3 h. After the reaction, the product is purified by silica gel column chromatography (DCM:MeOH = 40:1) to obtain a pale yellow solid. The yield for this step is 64%. 1 H NMR (500MHz, DMSO-d6) δ11.55(s,1H),10.59(s,1H),8.27(d,J=5.1Hz,2H),8.09(dd,J=8.2,2.2Hz,1H),8.00(dd,J=8.3,1.4Hz,1H),7.89(d, J=8.4Hz,2H),7.86(d,J=8.2Hz,1H),7.72(d,J=8.3Hz,2H),7.61(t,J=8.0Hz,1H),7.46(d,J=7.7Hz,1H),5.31(d,J=8.2Hz,2H),2.03(s,3H). 13C NMR(126MHz,DMSO-d6)δ165.22,154.79,154.06,143.61,143.11,141.97,139.89,139.51,1 32.16,131.72,129.86,129.50(q,J=32.1Hz),129.34(d,J=31.5Hz),127.44,126.78(d,J=3. 4Hz),125.49,124.13(q,J=272.2Hz),123.59(q,J=272.6Hz),123.81,122.93,120.74,120. 44,119.98(d,J=3.9Hz),116.41(d,J=3.8Hz),115.34,111.08,8.24.HRMS[ESI]:calculated for C 29 H 19 F6N6O3[M+H] + :613.1417,found:613.1418.

[0148] Example 2 Preparation of Compound 2-(4-amino-7-oxo-2-(3-(trifluoromethyl)phenyl)-6,7-dihydro-2H-pyrazolo[3,4-d]pyridazin-3-yl)-3-methyl-N-(3-(trifluoromethyl)phenyl)benzofuran-6-carboxamide (A002)

[0149] Compound A002 was prepared in the same manner as in Example 1 except that C-2-mCF3 was used instead of C-2-pCF3. The product was a light yellow solid. The reaction yield of this step was 68%. 1 H NMR (500MHz, DMSO-d6) δ11.55(s,1H),10.61(s,1H),8.30-8.22(m,2H),8.09(t,J=4.9Hz,1H),8.03-7.97(m,1H),7.91-7.85(m,2H),7 .84(d,J=8.2Hz,1H),7.79-7.74(m,1H),7.71(t,J=7.9Hz,1H),7.61(t,J=8.0Hz,1H),7.46(d,J=7.7Hz,1H),5.34(s,2H),2.03(s,3H). 13CNMR(126MHz,DMSO-d6)δ165.71,155.31,154.52,143.97,143.63,140.38,139.95,139.82,132. 59,132.16,131.38,130.53(d,J=32.8Hz),130.35,129.82(d,J=30.6Hz),129.11,128.04,126.6 0,124.63(q,J=272.1Hz),124.31,123.75(q,J=272.7Hz),123.41,122.24(d,J=3.0Hz),121.10, 121.02,120.48(d,J=4.4Hz),116.91(d,J=3.9Hz),115.69,111.48,8.69.HRMS[ESI]:calculated for C 29 H 19 F6N6O3[M+H] + :613.1417,found:613.1409.

[0150] Example 3 Preparation of Compound 2-(4-amino-2-(3-isopropylphenyl)-7-oxo-6,7-dihydro-2H-pyrazolo[3,4-d]pyridazin-3-yl)-3-methyl-N-(3-(trifluoromethyl)phenyl)benzofuran-6-carboxamide (A003)

[0151] Except for replacing C-2-pCF3 with C-2-miPr, compound A003 was prepared in the same manner as Example 1. The product was a light yellow solid, and the reaction yield of this step was 55%. 1 H NMR (500MHz, DMSO-d6) δ11.51 (s, 1H), 10.61 (s, 1H), 8.27 (d, J = 11.3Hz, 2H), 8. 09(d,J=8.2Hz,1H),7.99(d,J=8.2Hz,1H),7.82(d,J=8.2Hz,1H),7.61(t,J=8. 0Hz,1H),7.46(d,J=7.7Hz,1H),7.40(d,J=7.7Hz,1H),7.33(t,J=6.9Hz,2H),7 .20(s,1H),5.29(s,2H),2.91-2.70(m,1H),1.97(s,3H),0.95(d,J=6.9Hz,6H). 13C NMR(126MHz,DMSO-d6)δ165.24,154.97,154.00,149.84,143.19,143.08,140.15,1 39.91,138.78,131.90,131.77,129.85,129.45,129.10(q,J=31.6Hz),127.66,127. 04,124.14(q,J=272.2Hz),123.81,122.89,122.00,121.95,120.44,120.11,119.9 6,116.42(d,J=4.3Hz),115.04,111.02,32.93,23.26,8.04.HRMS[ESI]:calculated for C 31 H 26 F3N6O3[M+H] + :587.2013,found:587.2005.

[0152] Example 4 Preparation of Compound 2-(4-amino-2-(3-(tert-butyl)phenyl)-7-oxo-6,7-dihydro-2H-pyrazolo[3,4-d]pyridazin-3-yl)-3-methyl-N-(3-(trifluoromethyl)phenyl)benzofuran-6-carboxamide (A004)

[0153] Compound A004 was prepared in the same manner as Example 1 except that C-2-mtBu was used instead of C-2-pCF3. The product was a light yellow solid. The reaction yield of this step was 59%. 1 H NMR (600MHz, DMSO-d6) δ11.51(s,1H),10.61(s,1H),8.27(d,J=16.4Hz,2H),8.09(d,J=8.4Hz,1H),7.99(d,J=8.2Hz,1H),7.82(d,J=8. 2Hz,1H),7.61(t,J=8.0Hz,1H),7.51-7.43(m,3H),7.40(d,J=7.8Hz,1H),7.26(d,J=2.1Hz,1H),5.30(s,2H),1.96(s,3H),1.02(s,9H). 13C NMR(151MHz,DMSO-d6)δ165.23,154.97,154.03,152.06,143.21,143.07,140.23 ,139.91,138.55,131.84,129.89,129.35,129.34(q,J=31.6Hz),127.04,126.15, 124.16(q,J=272.5Hz),123.83,122.91,121.80,121.19,120.43,120.12,120.02, 116.42(d,J=3.6Hz),115.05,111.00,34.35,30.53,8.03.HRMS[ESI]:calculated for C 32 H 28 F3N6O3[M+H] + :601.2169,found:601.2178.

[0154] Example 5 Preparation of Compound 2-(4-amino-2-(3-(methylsulfonyl)phenyl)-7-oxo-6,7-dihydro-2H-pyrazolo[3,4-d]pyridazin-3-yl)-3-methyl-N-(3-(trifluoromethyl)phenyl)benzofuran-6-carboxamide (A005)

[0155] Compound A005 was prepared in the same manner as Example 1 except that C-2-mSO2Me was used instead of C-2-pCF3. The product was a light yellow solid. The reaction yield of this step was 68%. 1 H NMR (500MHz, DMSO-d6) δ11.55(s,1H),10.61(s,1H),8.28(d,J=2.0Hz,1H),8.25(d,J=1.4 Hz,1H),8.09(dd,J=8.2,2.0Hz,1H),8.05(t,J=2.0Hz,1H),8.03(dt,J=7.6,1.5Hz,1H),7. 99(dd,J=8.2,1.5Hz,1H),7.84(d,J=8.2Hz,1H),7.80(dt,J=8.2,1.5Hz,1H),7.76(t,J=7. 9Hz,1H),7.61(t,J=8.0Hz,1H),7.49-7.44(m,1H),5.34(s,2H),3.12(s,3H),2.04(s,3H). 13C NMR(126MHz,DMSO-d6)δ165.72,155.28,154.55,144.05,143.62,142.44,140.39, 139.92,139.72,132.62,132.19,131.42,130.35,129.82(q,J=31.1Hz),129.80,1 28.26,128.01,124.63(q,J=272.3Hz),124.30,123.77,123.43,121.15,121.09,1 20.46,116.90(d,J=3.6Hz),115.76,111.55,43.62,8.74.HRMS[ESI]:calculated for C 29 H 22 F3N6O5S[M+H] + :623.1319,found:623.1328.

[0156] Example 6 Preparation of Compound 2-(4-amino-2-(4-cyclopropylphenyl)-7-oxo-6,7-dihydro-2H-pyrazolo[3,4-d]pyridazin-3-yl)-3-methyl-N-(3-(trifluoromethyl)phenyl)benzofuran-6-carboxamide (A006)

[0157] Compound A006 was prepared in the same manner as Example 1 except that C-2-pcPr was used instead of C-2-pCF3. The product was a light yellow solid, and the reaction yield was 52%. 1 H NMR(500MHz,DMSO-d6)δ11.50(s,1H),10.61(s,1H),8.29(s,1H),8.27(s,1H),8 .10(d,J=8.1Hz,1H),7.99(d,J=9.0Hz,1H),7.85(d,J=8.2Hz,1H),7.63(t,J=8. 0Hz,1H),7.48(d,J=8.1Hz,1H),7.34(d,J=8.2Hz,2H),7.17(d,J=8.3Hz,2H),5. 24(s,2H),2.00(s,3H),1.98-1.90(m,1H),1.01-0.96(m,2H),0.73-0.67(m,2H). 13C NMR(126MHz,DMSO-d6)δ165.80,155.41,154.44,146.13,143.63,143.48,140 .56,140.41,136.68,132.49,132.20,130.36,129.83(q,J=31.7Hz),127.37, 126.54,124.84,124.63(q,J=272.3Hz),124.28,123.38,121.12,120.47,116 .87(d,J=3.8Hz),115.49,111.55,15.31,10.61,8.65.HRMS[ESI]:calculated for C 31 H 24 F3N6O3[M+H] + :585.1856,found:585.1862.

[0158] Example 7 Preparation of Compound 2-(4-amino-2-(3-cyclopropylphenyl)-7-oxo-6,7-dihydro-2H-pyrazolo[3,4-d]pyridazin-3-yl)-3-methyl-N-(3-(trifluoromethyl)phenyl)benzofuran-6-carboxamide (A007)

[0159] Compound A007 was prepared in the same manner as in Example 1 except that C-2-mcPr was used instead of C-2-pCF3. The product was a light yellow solid. The reaction yield of this step was 71%. 1 H NMR (600MHz, DMSO-d6) δ11.51(s,1H),10.62(s,1H),8.28(d,J=2.0Hz,1H),8.26(d,J=1.4Hz ,1H),8.11-8.07(m,1H),8.00(dd,J=8.2,1.5Hz,1H),7.84(d,J=8.2Hz,1H),7.61(t,J=8.0H z,1H),7.48-7.45(m,1H),7.32(t,J=7.8Hz,1H),7.26-7.19(m,2H),7.05(t,J=2.0Hz,1H),5 .28(s,2H),2.00(s,3H),1.90(tt,J=8.3,5.0Hz,1H),0.87-0.82(m,2H),0.44-0.39(m,2H). 13C NMR(151MHz,DMSO-d6)δ165.74,155.41,154.44,146.10,143.66,143.52,140.55, 140.40,139.44,132.43,132.20,130.35,129.82(q,J=31.4Hz),129.66,127.47,12 4.63(q,J=272.4Hz),124.28,123.40,121.76,121.02,120.60,120.46(d,J=3.4Hz) ,116.88(d,J=4.3Hz),115.52,111.51,15.15,10.19,8.61.HRMS[ESI]:calculated for C 31 H 24 F3N6O3[M+H] + :585.1856,found:585.1856.

[0160] Example 8 Preparation of Compound 2-(4-amino-7-oxo-2-(3-sulfonamidophenyl)-6,7-dihydro-2H-pyrazolo[3,4-d]pyridazin-3-yl)-3-methyl-N-(3-(trifluoromethyl)phenyl)benzofuran-6-carboxamide (A008)

[0161] Compound A008 was prepared in the same manner as in Example 1 except that C-2-mSO2NH2 was used instead of C-2-pCF3. The product was a light yellow solid. The reaction yield of this step was 64%. 1 H NMR(500MHz,DMSO-d6)δ10.70(s,1H),8.31(d,J=1.9Hz,1H),8.29(d,J=1.4Hz ,1H),8.14(t,J=2.0Hz,1H),8.12(dd,J=7.9,2.0Hz,1H),8.02(dd,J=8.3,1.4 Hz,1H),7.93(dt,J=7.8,1.4Hz,1H),7.85(d,J=8.2Hz,1H),7.65-7.58(m,4H) ,7.52(dd,J=7.4,1.7Hz,1H),7.45(d,J=8.0Hz,1H),4.74(s,2H),2.06(s,3H). 13C NMR(151MHz,DMSO-d6)δ165.33,154.61,154.15,145.59,139.99,139.01, 132.19,131.75,130.68,130.38,129.84,129.36(q,J=31.3Hz),127.21,1 26.47,125.26,124.18(q,J=272.3Hz),123.89,123.10,123.03,122.33,120.72,119.98,116.50(d,J=3.7Hz),111.20,8.36.HRMS[ESI]:calculated for C 28 H 21 F3N7O5S[M+H] + :624.1271,found:624.1279.

[0162] Example 9 Preparation of Compound 2-(4-amino-2-(4-(methylthio)phenyl)-7-oxo-6,7-dihydro-2H-pyrazolo[3,4-d]pyridazin-3-yl)-3-methyl-N-(3-(trifluoromethyl)phenyl)benzofuran-6-carboxamide (A009)

[0163] Compound A009 was prepared in the same manner as in Example 1 except that C-2-pSMe was used instead of C-2-pCF3. The product was a light yellow solid, and the reaction yield was 63%. 1 H NMR (600MHz, DMSO-d6) δ11.53(s,1H),10.63(s,1H),8.28(d,J=2.1Hz,1H),8.26(d,J=1.4Hz,1H),8.08(dd,J=8.0,2.0Hz,1H),7.98(dd,J=8.2,1.5Hz, 1H),7.84(d,J=8.2Hz,1H),7.61(t,J=8.0Hz,1H),7.47(d,J=7.7Hz,1H),7. 42-7.38(m,2H),7.35-7.29(m,2H),5.27(s,2H),2.47(s,3H),2.02(s,3H). 13C NMR(151MHz,DMSO-d6)δ165.34,154.93,154.02,143.19,143.09,140.55,1 39.94,135.54,132.05,131.76,129.91,129.36(q,J=31.5Hz),126.99,125. 90,124.98,124.17(q,J=272.3Hz),123.83,122.94,120.69,120.11,120.03,116.41(d,J=4.0Hz),115.07,111.11,14.21,8.27.HRMS[ESI]:calculated for C 29 H 22 F3N6O3S[M+H] + :591.1421,found:591.1419.

[0164] Example 10 Preparation of Compound 2-(4-amino-2-(3-(methylthio)phenyl)-7-oxo-6,7-dihydro-2H-pyrazolo[3,4-d]pyridazin-3-yl)-3-methyl-N-(3-(trifluoromethyl)phenyl)benzofuran-6-carboxamide (A010)

[0165] Compound A010 was prepared in the same manner as in Example 1 except that C-2-mSMe was used instead of C-2-pCF3. The product was a light yellow solid, and the reaction yield was 58%. 1 H NMR(500MHz,DMSO-d6)δ11.52(s,1H),10.64(s,1H),8.28(s,1H),8.26(s,1H), 8.11-8.07(m,1H),8.00(d,J=8.2Hz,1H),7.85(d,J=8.2Hz,1H),7.61(t,J=8.0H z,1H),7.47(d,J=7.8Hz,1H),7.39(t,J=7.9Hz,1H),7.34(d,J=8.2Hz,1H),7.29 (d,J=2.0Hz,1H),7.22(d,J=8.0Hz,1H),5.29(s,2H),2.26(s,3H),2.04(s,3H). 13C NMR(126MHz,DMSO-d6)δ165.34,154.96,154.05,143.24,143.18,140.19,140.01, 139.89,139.45,132.02,131.75,129.87,129.83,129.36(q,J=32.5Hz),127.20,1 26.72,124.19(q,J=272.2Hz),123.98,123.10,121.09,120.71,120.60,120.35,1 20.02,116.55(d,J=4.0Hz),115.13,111.19,14.20,8.26.HRMS[ESI]:calculated for C 29 H 22 F3N6O3S[M+H] + :591.1421,found:591.1422.

[0166] Example 11 Preparation of Compound 2-(2-(4-acetylphenyl)-4-amino-7-oxo-6,7-dihydro-2H-pyrazolo[3,4-d]pyridazin-3-yl)-3-methyl-N-(3-(trifluoromethyl)phenyl)benzofuran-6-carboxamide (A011)

[0167] Compound A011 was prepared in the same manner as in Example 1 except that C-2-pAc was used instead of C-2-pCF3. The product was a light yellow solid, and the reaction yield was 73%. 1 H NMR (600MHz, DMSO-d6) δ11.51(s,1H),10.60(s,1H),8.26-8.24(m,2H),8.05(dd,J=8.1,2.1Hz,1H),7.98-7.94(m,2H),7.8 2(d,J=8.2Hz,1H),7.57(t,J=8.0Hz,1H),7.54-7.50(m,2H),7.42(d,J=7.7Hz,2H),5.26(s,2H),2.22(s,3H),2.02(s,3H). 13C NMR(151MHz,DMSO-d6)δ165.26,156.93,154.86,154.03,143.32,143.15,139 .92,139.82,138.32,132.05,131.75,129.84,129.31(q,J=31.3Hz),127.61,1 27.09,124.49,124.13(q,J=272.0Hz),123.79,122.94,120.70,120.28,119. 96,116.38(d,J=3.7Hz),115.24,111.14,14.81,8.28.HRMS[ESI]:calculated for C 30 H 20 F3N6O4[MH] - :585.1504,found:585.1501.

[0168] Example 12 Preparation of Compound 2-(2-(3-acetylphenyl)-4-amino-7-oxo-6,7-dihydro-2H-pyrazolo[3,4-d]pyridazin-3-yl)-3-methyl-N-(3-(trifluoromethyl)phenyl)benzofuran-6-carboxamide (A012)

[0169] Compound A012 was prepared in the same manner as in Example 1 except that C-2-mAc was used instead of C-2-pCF3. The product was a light yellow solid. The reaction yield of this step was 69%. 1 H NMR(500MHz,DMSO-d6)δ11.52(s,1H),10.62(s,1H),8.28(s,1H),8.25(d,J=1.5Hz,1H),8 .08(dd,J=8.3,2.2Hz,1H),7.98(dd,J=8.2,1.5Hz,1H),7.83(d,J=8.2Hz,1H),7.73(t,J=2 .0Hz,1H),7.70(dt,J=8.0,1.3Hz,1H),7.61(t,J=8.0Hz,1H),7.47(d,J=7.8Hz,1H),7.37( t,J=8.0Hz,1H),7.24(ddd,J=8.0,2.2,1.0Hz,1H),5.28(s,2H),2.02(s,3H),1.85(s,3H). 13CNMR(126MHz,DMSO-d6)δ165.33,154.97,154.01,143.23,143.08,141.09,140.03 ,139.94,139.60,138.88,131.99,131.76,129.55(q,J=29.6Hz),129.17,127.02, 125.26,124.17(q,J=272.1Hz),123.81,122.92,122.42,120.74,120.62,120.20, 120.00,116.39(d,J=3.8Hz),115.11,111.05,10.91,8.22.HRMS[ESI]:calculated for C 30 H 20 F3N6O4[MH] - :585.1504,found:585.1508.

[0170] Example 13 Preparation of Compound 2-(4-amino-2-(4-nitrophenyl)-7-oxo-6,7-dihydro-2H-pyrazolo[3,4-d]pyridazin-3-yl)-3-methyl-N-(3-(trifluoromethyl)phenyl)benzofuran-6-carboxamide (A013)

[0171] Compound A013 was prepared in the same manner as in Example 1 except that C-2-pNO2 was used instead of C-2-pCF3. The product was a light yellow solid, and the reaction yield was 67%. 1 H NMR (500MHz, DMSO-d6) δ11.57(s,1H),10.60(s,1H),8.35-8.31(m,2H),8.27(t,J=2.0Hz,1H),8.26(d,J=1.4Hz,1H),8.09(dd,J=8.1,2.3Hz,1H),8 .00(dd,J=8.2,1.5Hz,1H),7.86(d,J=8.2Hz,1H),7.79-7.74(m,2H),7.6 1(t,J=8.0Hz,1H),7.47(dd,J=7.7,1.8Hz,1H),5.35(s,2H),2.06(s,3H). 13C NMR(126MHz,DMSO-d6)δ165.25,154.76,154.11,147.36,143.85,143.56,14 3.13,139.92,139.36,132.21,131.79,129.91,129.36(q,zJ=31.6Hz),127. 69,125.83,125.01,124.17(q,J=272.3Hz),123.84,122.97,120.81,120.70 ,120.03,116.43(d,J=3.6Hz),115.48,111.18,8.39.HRMS[ESI]:calculated for C 28 H 19 F3N7O5[M+H] + :590.1394,found:590.1398.

[0172] Example 14 Preparation of Compound 2-(4-amino-2-(3-nitrophenyl)-7-oxo-6,7-dihydro-2H-pyrazolo[3,4-d]pyridazin-3-yl)-3-methyl-N-(3-(trifluoromethyl)phenyl)benzofuran-6-carboxamide (A014)

[0173] Compound A014 was prepared in the same manner as in Example 1 except that C-2-mNO2 was used instead of C-2-pCF3. The product was a light yellow solid, and the reaction yield was 71%. 1 H NMR (500MHz, DMSO-d6) δ11.57(s,1H),10.62(s,1H),8.38(t,J=2.2Hz,1H),8.33(ddd,J=8.3 ,2.3,1.0Hz,1H),8.28(t,J=2.0Hz,1H),8.25(d,J=1.4Hz,1H),8.09(dd,J=8.1,2.1Hz,1H),8 .00(dd,J=8.2,1.5Hz,1H),7.89(ddd,J=8.1,2.2,1.0Hz,1H),7.85(d,J=8.2Hz,1H),7.76(t ,J=8.2Hz,1H),7.61(t,J=8.0Hz,1H),7.47(dd,J=7.7,1.6Hz,1H),5.35(s,2H),2.06(s,3H). 13C NMR(126MHz,DMSO-d6)δ165.27,154.80,154.12,148.01,143.63,143.17,139.93 ,139.47,139.31,132.20,131.75,131.13,130.73,129.90,129.35(q,J=31.4Hz), 127.67,124.19,124.17(q,J=272.3Hz),123.85,122.97,120.75,120.02(d,J=3. 2Hz),119.85,116.44(d,J=3.9Hz),115.34,111.10,8.35.HRMS[ESI]:calculated for C 28 H 19 F3N7O5[M+H] + :590.1394,found:590.1392.

[0174] Example 15 Preparation of 2-(4-amino-2-(4-(tert-butyl)phenyl)-7-oxo-6,7-dihydro-2H-pyrazolo[3,4-d]pyridazin-3-yl)-3-methyl-N-(3-(trifluoromethyl)phenyl)benzofuran-6-carboxamide (A015)

[0175] Compound A015 was prepared in the same manner as Example 1 except that C-2-ptBu was used instead of C-2-pCF3. The product was a light yellow solid, and the reaction yield was 60%. 1 H NMR (600MHz, DMSO-d6) δ11.52(s,1H),10.62(s,1H),8.32-8.27(m,2H),8.10(d,J=7.3Hz,1H),8.00(dd,J=8.2,1.4Hz,1H),7.85(d,J=8. 2Hz,1H),7.63(t,J=8.0Hz,1H),7.50(d,J=8.8Hz,2H),7.49-7.46(m,1H),7.41(d,J=8.7Hz,2H),5.25(s,2H),1.97(s,3H),1.27(s,9H). 13C NMR(151MHz,DMSO-d6)δ165.31,154.97,154.01,152.20,143.18,143.09,140.1 3,139.96,136.47,132.06,131.77,129.90,129.37(q,J=31.4Hz),126.91,126. 25,124.38,124.17(q,J=272.3Hz),124.12,123.81,122.95,120.66,120.00,11 6.40(d,J=4.2Hz),115.12,111.16,34.57,30.90,8.10.HRMS[ESI]:calculated for C 32 H 26 F3N6O3[MH] - :599.2024,found:599.2021.

[0176] Example 16 Preparation of 2-(4-amino-2-(4-(methylsulfonyl)phenyl)-7-oxo-6,7-dihydro-2H-pyrazolo[3,4-d]pyridazin-3-yl)-3-methyl-N-(3-(trifluoromethyl)phenyl)benzofuran-6-carboxamide (A016)

[0177] Compound A016 was prepared in the same manner as in Example 1 except that C-2-pSO2Me was used instead of C-2-pCF3. The product was a light yellow solid, and the reaction yield was 57%. 1 H NMR (600MHz, DMSO-d6) δ11.57(s,1H),10.70(s,1H),8.31(s,2H),8.12(d,J=8.9Hz,1H),8.07-8.00(m,3H),7.86(d,J =8.2Hz,1H),7.81-7.72(m,2H),7.61(t,J=8.0Hz,1H),7.47(d,J=7.7Hz,1H),5.33(s,2H),3.29(s,3H),2.04(s,3H). 13C NMR(151MHz,DMSO-d6)δ165.42,154.93,154.18,143.78,143.30,142.64,141.36 ,140.11,139.48,132.23,131.81,129.90,129.37(q,J=31.6Hz),128.61,127.68 ,125.63,124.28(q,J=272.3Hz),124.09,123.26,120.82,120.66,120.20-119.8 7(m),116.65(d,J=4.3Hz),115.48,111.45,43.27,8.41.HRMS[ESI]:calculated for C 29 H 20 F3N6O5S[MH] - :621.1173,found:621.1167.

[0178] Example 17 Preparation of 2-(4-amino-7-oxo-2-(pyridin-3-yl)-6,7-dihydro-2H-pyrazolo[3,4-d]pyridazin-3-yl)-3-methyl-N-(3-(trifluoromethyl)phenyl)benzofuran-6-carboxamide (A017)

[0179] Compound A017 was prepared in the same manner as in Example 1 except that C-2-py was used instead of C-2-pCF3. The product was a light yellow solid, and the reaction yield was 65%. 1 H NMR (600MHz, DMSO-d6) δ11.56(s,1H),10.62(s,1H),8.70-8.66(m,2H),8.29(s,1H),8.25(s,1H),8.10(d,J=8.2Hz,1H),8.02-7.98 (m,2H),7.86(d,J=8.2Hz,1H),7.63(t,J=8.0Hz,1H),7.58(dd,J=8.3,4.8Hz,1H),7.48(d,J=7.7Hz,1H),5.36(s,2H),2.06(s,3H). 13C NMR(126MHz,DMSO-d6)δ165.29,154.82,154.08,150.42,145.31,143.73,143 .17,139.96,139.44,135.72,132.61,132.17,131.73,129.87,129.35(q,J=31 .7Hz),127.80,124.34,124.17(q,J=272.6Hz),123.84,122.99,120.71,120.5 1,119.99,116.43(d,J=4.6Hz),115.18,111.08,8.32.HRMS[ESI]:calculated for C 27 H 17 F3N7O3[MH] - :544.135,found:544.1346.

[0180] Example 18 Preparation of 2-(4-amino-7-oxo-2-(piperidin-4-yl)-6,7-dihydro-2H-pyrazolo[3,4-d]pyridazin-3-yl)-3-methyl-N-(3-(trifluoromethyl)phenyl)benzofuran-6-carboxamide (A018)

[0181] Compound A018 was prepared in the same manner as in Example 1 except that C-2-piperidine was used instead of C-2-pCF3. The product was a light yellow solid, and the reaction yield was 68%. 1 H NMR(600MHz,DMSO-d6)δ11.43(s,1H),10.89(d,J=3.6Hz,1H),9.32(s,1H),8.45(s,1H ),8.38(s,1H),8.20(d,J=8.2Hz,1H),8.11(dd,J=8.3,1.5Hz,1H),7.93(d,J=8.2Hz,1H ),7.61(t,J=8.0Hz,1H),7.46(d,J=7.7Hz,1H),5.15(s,2H),4.79-4.58(m,1H),3.42-3 .36(m,2H),3.14-2.92(m,2H),2.44-2.34(m,2H),2.29(s,3H),2.15(d,J=35.8Hz,2H). 13C NMR (126MHz, DMSO-d6) δ165.40,154.96,154.38,143.26,142.36,140.09,139.23,132.04,131.82,129.79,129.29(q,J=30.6,30.0Hz),126.57 ,124.19(q,J=271.7Hz),123.97,122.87,120.63,120.57,119.93,116.56,113.93,111.57,55.38,45.24,41.78,8.72.HRMS[ESI]:calculated for C 27 H 23 F3N7O3[MH] - :550.182,found:550.182.

[0182] Example 19 Preparation of Compound 2-(4-amino-2-(4-(benzyloxy)phenyl)-7-oxo-6,7-dihydro-2H-pyrazolo[3,4-d]pyridazin-3-yl)-3-methyl-N-(3-(trifluoromethyl)phenyl)benzofuran-6-carboxamide (A019)

[0183] Compound A019 was prepared in the same manner as Example 1 except that C-2-pOBn was used instead of C-2-pCF3. The product was a light yellow solid, and the reaction yield was 76%. 1 H NMR (500MHz, DMSO-d6) δ11.50 (s, 1H), 10.62 (s, 1H), 8.29 (d, J = 2.1Hz, 1H), 8.27 (d,J=1.4Hz,1H),8.10(d,J=8.4Hz,1H),7.99(dd,J=8.2,1.5Hz,1H),7.83(d,J=8 .2Hz,1H),7.62(t,J=8.0Hz,1H),7.47(d,J=7.7Hz,1H),7.44-7.34(m,6H),7.31( tt,J=7.3,1.5Hz,1H),7.11-7.07(m,2H),5.25(s,2H),5.11(s,2H),2.00(s,3H). 13C NMR(126MHz,DMSO)δ165.36,158.75,154.99,154.00,143.21,142.92,140.17, 139.98,136.45,131.99,131.78,129.91,129.38(q,J=31.7Hz),128.43,127.98 127.90,127.06,126.10,124.18(q,J=272.3Hz),123.82,122.91,120.63,120.02,1 19.97,116.41(d,J=4.6Hz),115.40,114.90,111.10,69.60.HRMS[ESI]:calculated for C 35 H 26 F3N6O4[M+H] + :651.1962,found:651.1958.

[0184] Example 20 Preparation of Compound 2-(4-amino-2-(3-(benzyloxy)phenyl)-7-oxo-6,7-dihydro-2H-pyrazolo[3,4-d]pyridazin-3-yl)-3-methyl-N-(3-(trifluoromethyl)phenyl)benzofuran-6-carboxamide (A020)

[0185] Compound A020 ​​was prepared in the same manner as Example 1 except that C-2-mOBn was used instead of C-2-pCF3. The product was a light yellow solid. The reaction yield of this step was 69%. 1 H NMR (500MHz, DMSO-d6) δ11.55(s,1H),10.64(s,1H),8.31-8.26(m,2H),8.09(d,J=8.3Hz,1H),8.01(d,J=8.2Hz,1H),7.86(d,J=8.2Hz,1H),7. 62(t,J=8.0Hz,1H),7.47(d,J=7.8Hz,1H),7.39-7.26(m,6H),7.13-7.0 9(m,2H),7.01(d,J=7.7Hz,1H),5.32(s,2H),4.97(s,2H),2.02(s,3H). 13C NMR(126MHz,DMSO-d6)δ165.32,158.67,154.96,154.04,143.23,143.13,139.99,139.96,1 39.85,136.35,132.05,131.79,130.39,129.93,129.39(q,J=31.6Hz),128.44,127.95,127 .57,127.14,124.20(t,J=272.8Hz),123.85,122.96,120.68,120.33,120.04(d,J=3.2Hz), 116.45(d,J=4.3Hz),116.87,116.26,115.11,111.13,69.57,8.23.HRMS[ESI]:calculated for C 35 H 26 F3N6O4[M+H] + :651.1962,found:651.1963.

[0186] Example 21 Preparation of Compound 2-(4-amino-7-oxo-2-(4-((trifluoromethyl)thio)phenyl)-6,7-dihydro-2H-pyrazolo[3,4-d]pyridazin-3-yl)-3-methyl-N-(3-(trifluoromethyl)phenyl)benzofuran-6-carboxamide (A021)

[0187] Compound A021 was prepared in the same manner as in Example 1 except that C-2-pSCF3 was used instead of C-2-pCF3. The product was a light yellow solid, and the reaction yield was 74%. 1 H NMR (500MHz, DMSO-d6) δ11.56(s,1H),10.61(s,1H),8.28(t,J=2.0Hz,1H),8.26(d,J=1.3Hz,1H),8.09(dd,J=8.0,2.4Hz,1H),8.0 0(dd,J=8.2,1.5Hz,1H),7.86-7.82(m,3H),7.66-7.62(m,2H),7.61(d,J=8.0Hz,1H),7.50-7.44(m,1H),5.33(s,2H),1.98(s,3H). 13C NMR(126MHz,DMSO-d6)δ165.27,154.82,154.06,143.61,143.14,141.15,139.93,13 9.65,137.17,132.18,131.77,129.91,129.43(q,J=308.2Hz),129.37(q,J=31.5Hz), 127.49,126.02,124.61,124.17(q,J=272.1Hz),123.82,122.96,120.69,120.03(d,J =3.3Hz),120.33,116.42(d,J=4.0Hz),115.27,111.14,8.20.HRMS[ESI]:calculated for C 29 H 19 F6N6O3S[M+H] + :645.1138,found:645.1138.

[0188] Example 22 Preparation of Compound 2-(4-amino-7-oxo-2-(3-((trifluoromethyl)thio)phenyl)-6,7-dihydro-2H-pyrazolo[3,4-d]pyridazin-3-yl)-3-methyl-N-(3-(trifluoromethyl)phenyl)benzofuran-6-carboxamide (A022)

[0189] Compound A022 was prepared in the same manner as in Example 1 except that C-2-mSCF3 was used instead of C-2-pCF3. The product was a light yellow solid, and the reaction yield was 72%. 1 H NMR (500MHz, DMSO-d6) δ11.55(s,1H),10.62(s,1H),8.28(t,J=2.0Hz,1H),8.25(d,J=1.4Hz,1H),8.09(dd,J=8.0,2.0Hz,1H),7.99(dd,J=8.2, 1.5Hz,1H),7.86-7.79(m,3H),7.79-7.73(m,1H),7.67(t,J=8.0Hz,1H) ,7.61(t,J=8.0Hz,1H),7.47(d,J=7.7Hz,1H),5.32(s,2H),1.96(s,3H). 13C NMR (126MHz, DMSO-d6) δ165.27,154.85,154.07,143.51,143.17,139.92,139.63,139.57,13 7.05,132.03,131.88,131.80,131.15,129.91,129.36(q,J=30.1Hz),129.14(q,J=308.5Hz) ,127.89,127.64,124.42(d,J=2.4Hz),124.17(q,J=272.6Hz),123.85,122.89,120.60,120. 30,120.03(d,J=4.4Hz),116.43(d,J=4.9Hz),115.16,111.05,8.09.HRMS[ESI]:calculated for C 29 H 19 F6N6O3S[M+H] + :645.1138,found:645.1141.

[0190] Example 23 Preparation of Compound 2-(4-amino-2-(4-methoxyphenyl)-7-oxo-6,7-dihydro-2H-pyrazolo[3,4-d]pyridazin-3-yl)-3-methyl-N-(3-(trifluoromethyl)phenyl)benzofuran-6-carboxamide (A023)

[0191] Compound A023 was prepared in the same manner as in Example 1 except that C-2-pOMe was used instead of C-2-pCF3. The product was a light yellow solid, and the reaction yield was 55%. 1 H NMR(500MHz,DMSO-d6)δ11.49(s,1H),10.61(s,1H),8.28(t,J=2.0Hz,1H),8 .26(d,J=1.4Hz,1H),8.09(dd,J=8.2,2.0Hz,1H),7.98(dd,J=8.2,1.5Hz,1H ),7.83(d,J=8.2Hz,1H),7.61(t,J=8.0Hz,1H),7.47(d,J=7.8Hz,1H),7.42- 7.38(m,2H),7.03-6.99(m,2H),5.28-5.18(m,2H),3.76(s,3H),2.01(s,3H). 13C NMR(126MHz,DMSO-d6)δ165.32,159.64,154.94,153.96,143.16,142.86,1 40.14,139.93,131.96,131.80,131.74,129.88,129.33(d,J=31.6Hz),126. 99,126.05,124.14(q,J=272.3Hz),123.78,122.86,120.60,119.92,116.37(d,J=4.2Hz),114.87,114.48,111.06,55.49,8.19.HRMS[ESI]:calculated for C 29 H 22 F3N6O4[M+H] + :575.1649,found:575.1649.

[0192] Example 24 Preparation of Compound 2-(4-amino-2-(3-methoxyphenyl)-7-oxo-6,7-dihydro-2H-pyrazolo[3,4-d]pyridazin-3-yl)-3-methyl-N-(3-(trifluoromethyl)phenyl)benzofuran-6-carboxamide (A024)

[0193] Compound A024 was prepared in the same manner as in Example 1 except that C-2-mOMe was used instead of C-2-pCF3. The product was a light yellow solid. The reaction yield of this step was 51%. 1 H NMR(500MHz,DMSO-d6)δ11.52(s,1H),10.62(s,1H),8.28(t,J=2.0Hz,1H),8.26(d, J=1.4Hz,1H),8.09(dd,J=8.1,2.1Hz,1H),7.99(dd,J=8.2,1.5Hz,1H),7.84(d,J=8 .2Hz,1H),7.61(t,J=8.0Hz,1H),7.49-7.45(m,1H),7.36(t,J=8.1Hz,1H),7.07-7. 03(m,2H),7.00(ddd,J=8.0,2.0,0.9Hz,1H),5.28(s,2H),3.65(s,3H),2.04(s,3H). 13C NMR(126MHz,DMSO-d6)δ165.29,159.56,154.92,153.98,143.17,143.07,139.96,13 9.93,139.83,132.02,131.70,130.31,129.87,129.34(q,J=31.5Hz),127.09,124.15 (q,J=272.3Hz),123.79,122.91,120.60,120.24,119.98(d,J=4.9Hz),116.52,116.3 9(d,J=3.8Hz),115.40,115.09,111.03,110.15,55.39,8.19.HRMS[ESI]:calculated for C 29 H 22 F3N6O4[M+H] + :575.1649,found:575.1650.

[0194] Example 25 Preparation of Compound 2-(4-amino-7-oxo-2-(4-(trifluoromethoxy)phenyl)-6,7-dihydro-2H-pyrazolo[3,4-d]pyridazin-3-yl)-3-methyl-N-(3-(trifluoromethyl)phenyl)benzofuran-6-carboxamide (A025)

[0195] Compound A025 was prepared in the same manner as in Example 1 except that C-2-pOCF3 was used instead of C-2-pCF3. The product was a light yellow solid. The reaction yield of this step was 69%. 1 H NMR (500MHz, DMSO-d6) δ11.54(s,1H),10.67(s,1H),8.30(s,1H),8.28(d,J=1.4Hz,1H),8.11(d,J=8.2Hz,1H),8.01(dd,J=8.1 ,1.4Hz,1H),7.84(d,J=8.2Hz,1H),7.66-7.58(m,3H),7.52(d,J=8.6Hz,2H),7.47(d,J=7.7Hz,1H),5.30(s,2H),2.00(s,3H). 13C NMR (126MHz, DMSO) δ165.29,154.85,154.05,148.45,143.36,143.16,139.97,139.6 6,137.68,132.10,131.74,129.86,129.31(q,J=31.5Hz),127.46,126.91,124.17(q ,J=272.3Hz),123.89,123.01,122.04,120.67,120.26,120.00(d,J=2.5Hz),119.89 (q,J=257.4Hz),116.46(d,J=3.9Hz),115.11,111.17,8.22.HRMS[ESI]:calculated for C 29 H 19 F6N6O4[M+H] + :629.1366,found:629.1368.

[0196] Example 26 Preparation of Compound 2-(4-amino-7-oxo-2-(3-(trifluoromethoxy)phenyl)-6,7-dihydro-2H-pyrazolo[3,4-d]pyridazin-3-yl)-3-methyl-N-(3-(trifluoromethyl)phenyl)benzofuran-6-carboxamide (A026)

[0197] Compound A026 was prepared in the same manner as in Example 1 except that C-2-mOCF3 was used instead of C-2-pCF3. The product was a light yellow solid. The reaction yield of this step was 58%. 1 H NMR (500MHz, DMSO-d6) δ11.55(s,1H),10.65(s,1H),8.29(t,J=2.1Hz,1H),8.26(d,J=1.4Hz,1H),8.10(dd,J=8.2,2.0Hz,1H),8.01(dd,J=8.2,1.5 Hz,1H),7.84(d,J=8.2Hz,1H),7.67-7.59(m,2H),7.55(dt,J=8.3,1.3Hz ,1H),7.54-7.51(m,2H),7.46(d,J=8.4Hz,1H),5.33(s,2H),2.01(s,3H). 13C NMR (126MHz, DMSO-d6) δ165.26,154.84,154.08,148.15,143.45,143.16,139.95,139. 54,132.05,131.76,131.50,129.88,129.35(q,J=31.4Hz),127.60,124.18(q,J=272.4H z),124.00,123.86,122.94,122.30,120.59,120.42,120.01(d,J=3.6Hz),119.78(q,J =257.6Hz),117.89,116.45(d,J=3.9Hz),115.17,111.05,8.16.HRMS[ESI]:calculated for C 29 H 19 F6N6O4[M+H] + :629.1366,found:629.1366.

[0198] Example 27 Preparation of Compound 2-(4-amino-2-(4-aminophenyl)-7-oxo-6,7-dihydro-2H-pyrazolo[3,4-d]pyridazin-3-yl)-3-methyl-N-(3-(trifluoromethyl)phenyl)benzofuran-6-carboxamide (A027)

[0199] A013 was dissolved in MeOH, an appropriate amount of Pd / C was added, and H2 was introduced. The reaction was refluxed at 80°C for 12 h. After completion of the reaction, the filtrate was collected by filtration through celite, dried, and purified by silica gel column chromatography (DCM:MeOH = 20:1) to obtain the product A027 as a pale yellow solid. The yield for this step was 80%. 1 H NMR(600MHz,DMSO-d6)δ11.44(s,1H),10.63(s,1H),8.29(t,J=1.9Hz,1H),8 .27(d,J=1.4Hz,1H),8.09(dd,J=8.4,2.0Hz,1H),7.98(dd,J=8.2,1.5Hz,1H ),7.83(d,J=8.2Hz,1H),7.61(t,J=8.0Hz,1H),7.47(dd,J=7.9,1.7Hz,1H), 7.09-7.05(m,2H),6.54-6.50(m,2H),5.53(s,2H),5.18(s,2H),1.99(s,3H). 13C NMR(151MHz,DMSO)δ165.85,155.49,154.38,150.20,143.64,142.94,141.06, 140.44,132.32,132.26,130.35,129.81(q,J=31.6Hz),127.71,126.93,125.8 4,124.63(q,J=272.4Hz),124.26,123.33,121.00,120.43(d,J=3.3Hz),120.0 6,116.84(d,J=3.9Hz),115.11,113.83,111.50,8.64.HRMS[ESI]:calculated for C 28 H 21 F3N7O3[M+H] + :560.1652,found:560.1652.

[0200] Example 28 Preparation of Compound 2-(4-amino-2-(3-aminophenyl)-7-oxo-6,7-dihydro-2H-pyrazolo[3,4-d]pyridazin-3-yl)-3-methyl-N-(3-(trifluoromethyl)phenyl)benzofuran-6-carboxamide (A028)

[0201] A014 was dissolved in MeOH, an appropriate amount of Pd / C was added, and H2 was introduced. The reaction was refluxed at 80°C for 12 h. After completion of the reaction, the filtrate was collected by filtration through celite, dried, and purified by silica gel column chromatography (DCM:MeOH = 20:1) to obtain the product A028 as a pale yellow solid. The yield for this step was 83%. 1 H NMR (600MHz, DMSO-d6) δ11.48(s,1H),10.64(s,1H),8.29(t,J=2.0Hz,1H),8.27(d,J=1. 4Hz, 1H), 8.09 (dd, J=8.3, 2.2Hz, 1H), 7.99 (dd, J=8.2, 1.5Hz, 1H), 7.84 (d, J=8.2Hz, 1H), 7.61(t,J=8.0Hz,1H),7.46(dd,J=7.7,1.8Hz,1H),7.01(t,J=8.0Hz,1H),6.74(t,J=2.2H z,1H),6.60(ddd,J=8.4,2.3,1.0Hz,1H),6.39(ddd,J=8.2,2.2,0.9Hz,1H),2.04(s,3H). 13CNMR(151MHz,DMSO-d6)δ165.84,155.45,154.40,150.25,143.64,143.27,140.74, 140.44,140.13,132.38,132.24,130.34,130.01,129.81(q,J=31.6Hz),127.18,124 .63(q,J=272.4Hz),124.27,123.34,121.05,120.44(d,J=3.9Hz),120.34,116.85( d,J=3.8Hz),115.38,115.00,111.57,111.35,110.00,8.68.HRMS[ESI]:calculated for C 28 H 21 F3N7O3[M+H] + :560.1652,found:560.1652.

[0202] Example 29 Preparation of Compound (Benzyl 4-(4-amino-3-(3-methyl-6-((3-(trifluoromethyl)phenyl)carbamoyl)benzofuran-2-yl)-7-oxo-6,7-dihydro-2H-pyrazolo[3,4-d]pyridazin-2-yl)phenyl)carbamate (A029)

[0203] Compound A029 was prepared in the same manner as in Example 1 except that C-2-pNHCbz was used instead of C-2-pCF3. The product was a light yellow solid. The reaction yield of this step was 65%. 1 H NMR (500MHz, DMSO-d6) δ11.51(s,1H),10.61(s,1H),10.07(s,1H),8.28(t,J=2. 0Hz, 1H), 8.26 (d, J = 1.4Hz, 1H), 8.09 (dd, J = 8.1, 2.4Hz, 1H), 7.98 (dd, J = 8.2, 1. 5Hz,1H),7.83(d,J=8.2Hz,1H),7.61(t,J=8.0Hz,1H),7.56-7.52(m,2H),7.47( dd,J=7.7,1.6Hz,1H),7.43-7.35(m,7H),5.27(s,2H),5.14(s,2H),2.01(s,3H). 13C NMR(126MHz,DMSO-d6)δ165.32,154.93,153.98,153.23,143.17,142.95,140.06,139.95 ,136.30,133.12,131.97,131.75,129.87,129.35(q,J=31.5Hz),128.43,128.19,128.10 ,126.96,125.30,124.16(q,J=272.4Hz),123.78,122.88,120.62,120.02,119.97(d,J=3 .5Hz),118.20,116.39(q,J=4.2Hz),114.90,111.04,66.02,8.22.HRMS[ESI]:calculated for C 36 H 27 F3N7O5[M+H] + :694.2020,found:694.2018.

[0204] Example 30 Preparation of the compound benzyl (3-(4-amino-3-(3-methyl-6-((3-(trifluoromethyl)phenyl)carbamoyl)benzofuran-2-yl)-7-oxo-6,7-dihydro-2H-pyrazolo[3,4-d]pyridazin-2-yl)phenyl)carbamate (A030)

[0205] Compound A030 was prepared in the same manner as in Example 1 except that C-2-mNHCbz was used instead of C-2-pCF3. The product was a light yellow solid. The reaction yield was 70%. 1 H NMR(500MHz,DMSO-d6)δ11.52(s,1H),10.61(s,1H),10.06(s,1H),8.28(s,1H) ,8.26(s,1H),8.08(d,J=8.3Hz,1H),7.99(dd,J=8.2,1.5Hz,1H),7.84(d,J=8.2 Hz,1H),7.80(t,J=2.2Hz,1H),7.61(t,J=8.0Hz,1H),7.50-7.44(m,2H),7.40-7 .28(m,6H),7.01(dd,J=8.0,2.1Hz,1H),5.26(s,2H),5.10(s,2H),2.04(s,3H). 13C NMR(126MHz,DMSO-d6)δ165.36,154.96,154.09,153.18,143.22,143.16,140.15,139.98,139.90, 139.26,136.27,131.94,131.84,129.93,129.85,129.38(q,J=31.4Hz),128.47,128.33,128.16,1 27.08,124.20(q,J=272.4Hz),123.84,122.88,120.66,120.29,120.03(d,J=3.6Hz),118.62(d,J= 2.7Hz),118.06,116.43(d,J=4.3Hz),115.15,113.94,111.11,66.04,8.26.HRMS[ESI]:calculated for C 36 H 27 F3N7O5[M+H] + :694.2020,found:694.2024.

[0206] Example 31 Preparation of Compound 2-(4-amino-2-(4-(dimethylcarbamoyl)phenyl)-7-oxo-6,7-dihydro-2H-pyrazolo[3,4-d]pyridazin-3-yl)-3-methyl-N-(3-(trifluoromethyl)phenyl)benzofuran-6-carboxamide (A031)

[0207] Compound A031 was prepared in the same manner as in Example 1 except that C-2-pCONMe2 was used instead of C-2-pCF3. The product was a light yellow solid. The reaction yield of this step was 78%. 1 H NMR (500MHz, DMSO-d6) δ11.56(s,1H),10.63(s,1H),8.29(s,1H),8.26(d,J=1.4Hz,1H),8.09(dd,J=8.1,2.1Hz,1H),7.99(dd,J=8.3,1.4Hz,1 H),7.85(d,J=8.2Hz,1H),7.61(t,J=8.0Hz,1H),7.54-7.49(m,4H),7.4 7(d,J=7.9Hz,1H),5.34(s,2H),2.96(s,3H),2.85(s,3H),2.02(s,3H). 13C NMR(126MHz,DMSO-d6)δ168.83,165.30,154.89,154.02,143.36,143.18,139.95 ,139.87,139.31,137.34,132.10,131.77,129.91,129.36(q,J=31.4Hz),128.12, 127.28,124.62,124.17(q,J=272.3Hz),123.81,122.95,120.70,120.22,120.00( d,J=3.0Hz),116.39(d,J=4.8Hz),115.14,111.06,,8.27.HRMS[ESI]:calculated for C 31 H 25 F3N7O4[M+H] + :616.1915,found:616.1917.

[0208] Example 32 Preparation of Compound 2-(4-amino-2-(3-(dimethylcarbamoyl)phenyl)-7-oxo-6,7-dihydro-2H-pyrazolo[3,4-d]pyridazin-3-yl)-3-methyl-N-(3-(trifluoromethyl)phenyl)benzofuran-6-carboxamide (A032)

[0209] Compound A032 was prepared in the same manner as in Example 1 except that C-2-mCONMe2 was used instead of C-2-pCF3. The product was a light yellow solid. The reaction yield of this step was 74%. 1 H NMR (500MHz, DMSO-d6) δ11.56(s,1H),10.63(s,1H),8.29(s,1H),8.25(d,J=1.4Hz,1H),8.10(d,J=8.3Hz,1H),7.99(dd,J=8.3,1.5Hz,1H ),7.84(d,J=8.2Hz,1H),7.62(t,J=8.0Hz,1H),7.59-7.55(m,2H),7.54-7.45(m,3H),5.35(s,2H),2.88(s,3H),2.55(s,3H),2.02(s,3H). 13C NMR (126MHz, DMSO-d6) δ168.31,165.26,154.90,154.01,143.30,143.20,139.94,139.89 ,138.58,137.64,132.00,131.82,129.91,129.87,129.35(q,J=31.4Hz),128.15,127.43 ,125.70,124.17(q,J=272.1Hz),123.82,123.19,122.94,120.58,120.20,120.04(d,J=4 .3Hz),116.41(d,J=3.8Hz),115.05,111.02,38.38,34.65,8.28.HRMS[ESI]:calculated for C 31 H 25 F3N7O4[M+H] + :616.1915,found:616.1916.

[0210] Example 33 Preparation of Compound 2-(2-([1,1'-biphenyl]-4-yl)-4-amino-7-oxo-6,7-dihydro-2H-pyrazolo[3,4-d]pyridazin-3-yl)-3-methyl-N-(3-(trifluoromethyl)phenyl)benzofuran-6-carboxamide (A033)

[0211] Compound A033 was prepared in the same manner as in Example 1 except that C-2-pPh was used instead of C-2-pCF3. The product was a light yellow solid, and the reaction yield was 77%. 1 H NMR(500MHz,DMSO-d6)δ11.54(s,1H),10.60(s,1H),8.28(d,J=1.8Hz,1H),8.2 7(d,J=2.4Hz,1H),8.08(d,J=8.5Hz,1H),7.98(dd,J=8.2,1.5Hz,1H),7.85(d, J=8.2Hz,1H),7.82-7.79(m,2H),7.72-7.69(m,2H),7.61(t,J=8.0Hz,1H),7.5 8-7.54(m,2H),7.48-7.44(m,3H),7.41-7.37(m,1H),5.30(s,2H),2.05(s,3H). 13C NMR (126MHz, DMSO) δ165.31,154.94,154.04,143.26,143.20,140.87,140.02,139.94, 138.31,138.12,132.07,131.80,129.90,129.34(q,J=30.8Hz),129.07,128.17,127.5 0,127.07,126.80,125.03,124.17(q,J=272.0Hz),123.80,122.94,120.71,120.20,12 0.00(d,J=3.5Hz),116.39(d,J=3.5Hz),115.18,111.12,8.29.HRMS[ESI]:calculated for C 34 H 24 F3N6O3[M+H] + :621.1856,found:621.1858.

[0212] Example 34 Preparation of Compound 2-(2-([1,1'-biphenyl]-3-yl)-4-amino-7-oxo-6,7-dihydro-2H-pyrazolo[3,4-d]pyridazin-3-yl)-3-methyl-N-(3-(trifluoromethyl)phenyl)benzofuran-6-carboxamide (A034)

[0213] Compound A034 was prepared in the same manner as in Example 1 except that C-2-mPh was used instead of C-2-pCF3. The product was a light yellow solid, and the reaction yield was 72%. 1 H NMR (500MHz, DMSO-d6) δ11.55(s,1H),10.63(s,1H),8.30(d,J=1.5Hz,1H),8.29(s,1H),8.09(d, J=8.3Hz,1H),8.02(dd,J=8.2,1.3Hz,1H),7.86(d,J=8.3Hz,1H),7.76(dt,J=7.8,1.4Hz,1H),7. 67(t,J=2.0Hz,1H),7.61(t,J=8.0Hz,1H),7.57(t,J=7.9Hz,1H),7.49(ddd,J=8.1,2.2,1.1Hz,1 H),7.46(dd,J=7.7,1.7Hz,1H),7.39-7.36(m,2H),7.36-7.32(m,3H),5.35(s,2H),2.05(s,3H). 13C NMR(126MHz,DMSO-d6)165.29,154.99,154.12,143.26,141.32,140.11,139.96,139.40,1 38.46,132.11,131.86,130.16,129.91,129.37(q,J=31.6Hz),129.04,128.18,127.66,12 7.16,126.66,124.18(q,J=272.3Hz),123.83,123.37,123.01,122.53,120.64,120.41,12 0.02(d,J=3.6Hz),116.43(d,J=4.5,3.9Hz),115.23,111.14,8.22.HRMS[ESI]:calculated for C 34 H 24 F3N6O3[M+H] + :621.1856,found:621.1854.

[0214] Example 35 Preparation of Compound 2-(4-amino-2-(1-naphthyl)-7-oxo-6,7-dihydro-2H-pyrazolo[3,4-d]pyridazin-3-yl)-3-methyl-N-(3-(trifluoromethyl)phenyl)benzofuran-6-carboxamide (A035)

[0215] Compound A035 was prepared in the same manner as Example 1 except that C-2-αNp was used instead of C-2-pCF3. The product was a light yellow solid, and the reaction yield was 69%. 1 H NMR (500MHz, DMSO-d6) δ11.60(s,1H),10.54(s,1H),8.23(t,J=2.1Hz,1H),8.11(d,J=8.3Hz,1H),8.08-8.01(m,3H ),7.87(dd,J=8.2,1.5Hz,1H),7.70-7.66(m,2H),7.62-7.55(m,4H),7.46-7.41(m,2H),5.36(s,2H),1.95(s,3H). 13C NMR(126MHz,DMSO-d6)δ165.23,155.09,153.88,143.42,139.92,139.84,134.86,133.46 ,131.83,131.57,130.65,129.89,129.67,129.36(q,J=31.8Hz),128.67,128.27,127.94, 127.13,125.36,125.19,124.19(q,J=272.1Hz),123.84,122.76,122.07,120.50,120.20 ,120.01(d,J=3.6Hz),116.44(d,J=3.8Hz),114.60,110.72,8.50.HRMS[ESI]:calculated for C 32 H 22 F3N6O3[M+H] + :595.1700,found:595.1704.

[0216] Example 36 Preparation of Compound 2-(4-amino-2-(2-naphthyl)-7-oxo-6,7-dihydro-2H-pyrazolo[3,4-d]pyridazin-3-yl)-3-methyl-N-(3-(trifluoromethyl)phenyl)benzofuran-6-carboxamide (A036)

[0217] Compound A036 was prepared in the same manner as in Example 1 except that C-2-βNp was used instead of C-2-pCF3. The product was a light yellow solid, and the reaction yield was 66%. 1 H NMR (500MHz, DMSO-d6) δ11.55(s,1H),10.58(s,1H),8.26(t,J=2.1Hz,1H),8.22(d,J=1.5Hz,1H),8.18(d,J=2.2Hz,1H),8.06(dd,J=8.2,2.1Hz ,1H),8.01-7.94(m,4H),7.80(d,J=8.2Hz,1H),7.63-7.56(m,3H),7.49 (dd,J=8.8,2.2Hz,1H),7.46(d,J=7.8Hz,1H),5.33(s,2H),2.00(s,3H). 13C NMR (126MHz, DMSO-d6) δ165.77,155.43,154.50,143.79,143.71,140.50,140.40,136 .83,132.94,132.51,132.21,130.35,129.81(q,J=31.4Hz),129.77,128.83,128.29,1 28.08,127.91,127.80,124.63(q,J=272.6Hz),124.26,124.19,123.38,122.46,121.1 2,120.73,120.46,116.85(d,J=4.1Hz),115.63,111.53,8.77.HRMS[ESI]:calculated for C 32 H 22 F3N6O3[M+H] + :595.1700,found:595.1700.

[0218] Example 37 Preparation of Compound 2-(4-amino-2-(4-(N,N-dimethylsulfonamido)phenyl)-7-oxo-6,7-dihydro-2H-pyrazolo[3,4-d]pyridazin-3-yl)-3-methyl-N-(3-(trifluoromethyl)phenyl)benzofuran-6-carboxamide (A037)

[0219] Compound A037 was prepared in the same manner as Example 1 except that C-2-pSO2NMe2 was used instead of C-2-pCF3. The product was a light yellow solid, and the reaction yield was 63%. 1 H NMR (500MHz, DMSO-d6) δ11.58(s,1H),10.62(s,1H),8.28(t,J=2.1Hz,1H),8.26(d,J=1.5Hz,1H),8.09(dt,J=8.4,1.2Hz,1H),8.00(dd,J= 8.2,1.5Hz,1H),7.88-7.83(m,3H),7.76-7.73(m,2H),7.62(t,J=8.0Hz,1H),7.47(d,J=7.7Hz,1H),5.37(s,2H),2.59(s,6H),2.00(s,3H). 13C NMR(126MHz,DMSO-d6)δ165.28,154.82,154.10,143.73,143.17,142.15,139.94, 139.58,135.24,132.22,131.80,129.93,129.37(q,J=31.4,30.8Hz),128.93,127. 60,125.63,124.18(q,J=272.1Hz),123.85,122.99,120.76,120.47,120.05(d,J= 4.2Hz),116.43(d,J=3.7Hz),115.30,111.13,37.55,8.27.HRMS[ESI]:calculated for C 30 H 25 F3N7O5S[M+H] + :652.1584,found:652.1585.

[0220] Example 38 Preparation of Compound 2-(4-amino-2-(3-(N,N-dimethylsulfonamido)phenyl)-7-oxo-6,7-dihydro-2H-pyrazolo[3,4-d]pyridazin-3-yl)-3-methyl-N-(3-(trifluoromethyl)phenyl)benzofuran-6-carboxamide (A038)

[0221] Compound A038 was prepared in the same manner as in Example 1, except that C-2-mSO2NMe2 was used instead of C-2-pCF3. The product was a light yellow solid, and the reaction yield was 70%. 1 H NMR (500MHz, DMSO-d6) δ11.58(s,1H),10.65(s,1H),8.29(s,1H),8.27(s,1H),8.10(d,J=8.4Hz,1H),8.02-7.98(m,1H),7.93(d,J=7.9 Hz,1H),7.88-7.79(m,3H),7.75(d,J=1.9Hz,1H),7.61(t,J=8.0Hz,1H),7.46(d,J=7.7Hz,1H),5.35(s,2H),2.35(s,6H),2.02(s,3H). 13CNMR(126MHz,DMSO-d6)δ165.24,154.90,154.12,143.57,143.22,139.96,139.62,13 9.37,136.04,132.16,131.77,131.15,129.90,129.37(q,J=31.3Hz),129.35,128.34 ,127.57,124.19(q,J=272.3Hz),123.87,123.45,123.03,120.64,120.55,120.03(d, J=2.5Hz),116.48(d,J=3.9Hz),115.40,111.15,37.16,8.19.HRMS[ESI]:calculated for C 30 H 25 F3N7O5S[M+H] + :652.1584,found:652.1582.

[0222] Example 39 Preparation of Compound 2-(4-amino-7-oxo-2-(4-phenoxyphenyl)-6,7-dihydro-2H-pyrazolo[3,4-d]pyridazin-3-yl)-3-methyl-N-(3-(trifluoromethyl)phenyl)benzofuran-6-carboxamide (A039)

[0223] Compound A039 was prepared in the same manner as in Example 1 except that C-2-pOPh was used instead of C-2-pCF3. The product was a light yellow solid. The reaction yield of this step was 67%. 1 H NMR(500MHz,DMSO-d6)δ11.52(s,1H),10.62(s,1H),8.28(t,J=2.1Hz,1H), 8.27(d,J=1.5Hz,1H),8.11-8.08(m,1H),7.99(dd,J=8.2,1.5Hz,1H),7.85( d,J=8.2Hz,1H),7.62(t,J=8.0Hz,1H),7.50-7.46(m,3H),7.44-7.39(m,2H ),7.18(tt,J=7.6,1.1Hz,1H),7.07-7.03(m,4H),5.29(s,2H),2.04(s,3H). 13C NMR(151MHz,DMSO-d6)δ165.33,157.58,155.62,154.94,154.03,143.21,143.07,14 0.03,139.96,133.92,132.02,131.82,130.29,129.94,129.37(q,J=31.3Hz),127.2 3,126.64,124.36,124.18(q,J=272.5Hz),123.83,122.91,120.69,120.12,120.05, 119.40,118.62,116.41(d,J=3.8Hz),114.94,111.08,8.29.HRMS[ESI]:calculated for C 34 H 24 F3N6O4[M+H] + :637.1806,found:637.1809.

[0224] Example 40 Preparation of Compound 2-(4-amino-7-oxo-2-(3-phenoxyphenyl)-6,7-dihydro-2H-pyrazolo[3,4-d]pyridazin-3-yl)-3-methyl-N-(3-(trifluoromethyl)phenyl)benzofuran-6-carboxamide (A040)

[0225] Compound A040 was prepared in the same manner as in Example 1 except that C-2-mOPh was used instead of C-2-pCF3. The product was a light yellow solid, and the reaction yield was 63%. 1 H NMR (600MHz, DMSO-d6) δ11.51(s,1H),10.65(s,1H),8.30(s,1H),8.23(d,J=1.5Hz,1H),8.11 (d,J=8.3Hz,1H),8.03(dd,J=8.1,1.5Hz,1H),7.87(d,J=8.1Hz,1H),7.62(t,J=8.0Hz,1H),7 .53(t,J=8.2Hz,1H),7.48(d,J=7.7Hz,1H),7.31(dd,J=7.9,2.1Hz,1H),7.21-7.15(m,3H),7 .09(t,J=7.4Hz,1H),6.85(t,J=2.2Hz,1H),6.77(d,J=7.9Hz,2H),5.26(s,2H),1.98(s,3H). 13C NMR(151MHz,DMSO-d6)δ165.37,157.47,155.19,154.92,154.05,143.23,143.21,139.99 ,139.95,139.83,132.08,131.84,131.27,130.14,129.97,129.40(q,J=31.4Hz),127.18, 124.37,124.22(q,J=272.0Hz),123.89,122.99,120.78,120.22,120.08(d,J=2.6Hz),11 9.43,119.22,116.48(d,J=4.0Hz),115.12,113.51,111.12,8.20.HRMS[ESI]:calculated for C 34 H 24 F3N6O4[M+H] + :637.1806,found:637.1806.

[0226] Example 41 Preparation of Compound 2-(4-amino-2-(4-(4-morpholinecarbonyl)phenyl)-7-oxo-6,7-dihydro-2H-pyrazolo[3,4-d]pyridazin-3-yl)-3-methyl-N-(3-(trifluoromethyl)phenyl)benzofuran-6-carboxamide (A041)

[0227] Compound A041 was prepared in the same manner as in Example 1 except that C-2-pCOMor was used instead of C-2-pCF3. The product was a light yellow solid. The reaction yield of this step was 69%. 1 H NMR (600MHz, DMSO-d6) δ11.54(s,1H),10.61(s,1H),8.28(s,1H),8.25(s,1H),8.09(d,J=8.2Hz,1H),8.00(d,J=8.2Hz,1H),7.85(d,J=8. 2Hz,1H),7.61(t,J=8.0Hz,1H),7.56-7.50(m,4H),7.47(d,J=7.8Hz,1H),5.31(s,2H),3.68-3.46(m,6H),3.30-3.22(m,2H),2.04(s,3H). 13C NMR (126MHz, DMSO) δ167.81,165.29,154.91,154.04,143.39,143.21,139.95,139.84 ,139.56,136.41,132.09,131.79,129.92,129.38(q,J=31.6Hz),128.29,127.33,124 .76,124.18(q,J=272.3Hz),123.83,122.96,120.74,120.31,120.03(d,J=3.4Hz),11 6.42(d,J=3.8Hz),115.14,111.02,65.94,47.60,42.07,8.32.HRMS[ESI]:calculated for C 33 H 27 F3N7O5[M+H] + :658.2020,found:658.2018.

[0228] Example 42 Preparation of Compound 2-(4-amino-2-(4-(morpholinesulfonyl)phenyl)-7-oxo-6,7-dihydro-2H-pyrazolo[3,4-d]pyridazin-3-yl)-3-methyl-N-(3-(trifluoromethyl)phenyl)benzofuran-6-carboxamide (A042)

[0229] Compound A042 was prepared in the same manner as in Example 1 except that C-2-pSO2Mor was used instead of C-2-pCF3. The product was a light yellow solid. The reaction yield of this step was 64%. 1 H NMR (500MHz, DMSO-d6) δ11.57(s,1H),10.58(s,1H),8.27(t,J=2.0Hz,1H),8.25(d,J=1.4Hz,1H),8.08(dd,J=8.1,2.1Hz,1H),8.00(dd,J=8.2,1.5Hz,1 H),7.87-7.83(m,3H),7.78-7.74(m,2H),7.61(t,J=8.0Hz,1H),7.46(d,J= 7.8Hz,1H),5.37(s,2H),3.70-3.46(m,4H),2.98-2.74(m,4H),2.03(s,3H). 13C NMR(126MHz,DMSO-d6)δ165.24,154.83,154.09,143.75,143.19,142.40,139.95, 139.56,135.24,132.23,131.79,129.90,129.37(q,J=31.7Hz),129.03,127.68,12 5.75,124.19(q,J=272.2Hz),123.86,123.02,120.74,120.51,120.03(d,J=4.2Hz) ,116.47(d,J=3.8Hz),115.30,111.05,65.21,45.92,8.33.HRMS[ESI]:calculated for C 32 H 27 F3N7O6S[M+H] + :694.1690,found:694.1699.

[0230] Example 43 Preparation of Compound 2-(4-amino-7-oxo-2-(3-(pentafluoro-16-sulfonyl)phenyl)-6,7-dihydro-2H-pyrazolo[3,4-d]pyridazin-3-yl)-3-methyl-N-(3-(trifluoromethyl)phenyl)benzofuran-6-carboxamide (A043)

[0231] Compound A043 was prepared in the same manner as in Example 1 except that C-2-pSF5 was used instead of C-2-pCF3. The product was a light yellow solid, and the reaction yield was 51%. 1 H NMR (600MHz, DMSO-d6) δ11.57(s,1H),10.61(s,1H),8.29-8.27(m,2H),8.11-8.05(m,3H),8.01(dd,J=8.2,1.5Hz, 1H),7.87(d,J=8.2Hz,1H),7.75-7.72(m,2H),7.61(t,J=8.0Hz,1H),7.48-7.45(m,1H),5.33(s,2H),2.04(s,3H). 13C NMR(126MHz,DMSO-d6)δ165.25,154.79,154.14,152.47(t,J=17.0Hz),143.75,1 43.14,141.54,139.93,139.42,132.24,131.78,129.92,129.37(q,J=31.6Hz),1 27.53,125.51,124.17(q,J=272.3Hz),123.84,123.01,120.83,120.58,120.04( d,J=5.8Hz),116.43(d,J=3.8Hz),115.48,111.16,8.30.HRMS[ESI]:calculated for C 28 H 19 F8N6O3S[M+H] + :671.1106,found:671.1108.

[0232] Example 44 Preparation of compound 2-(4-amino-7-oxo-2-(3-(pentafluoro-16-sulfonyl)phenyl)-6,7-dihydro-2H-pyrazolo[3,4-d]pyridazin-3-yl)-3-methyl-N-(3-(trifluoromethyl)phenyl)benzofuran-6-carboxamide (A044) Compound A044 was prepared in the same manner as in Example 1, except that C-2-mSF5 was used instead of C-2-pCF3. The product was a light yellow solid, and the reaction yield of this step was 53%. 1 H NMR (500MHz, DMSO-d6) δ11.56(s,1H),10.62(s,1H),8.28(t,J=2.0Hz,1H),8.24(d,J=1.5Hz,1H),8.09(dd,J=8.0,2.1Hz,1H),8.05(dd,J=8.3, 2.3Hz,1H),8.02-7.98(m,2H),7.87-7.82(m,2H),7.75(t,J=8.2Hz,1H) ,7.61(t,J=8.0Hz,1H),7.46(d,J=7.7Hz,1H),5.36(s,2H),2.03(s,3H).

[0233] 13C NMR (126MHz, DMSO-d6) δ165.25, 154.84, 154.13, 152.55 (t, J = 17.6Hz), 143.58, 143.20 ,139.94,139.39,139.06,132.12,131.73,130.94,129.89,128.81,129.37(q,J=31.5H z),127.76,126.72,124.18(q,J=272.5Hz),123.85,122.95,122.58,120.65,120.62,1 20.02(d,J=3.6Hz),116.45(d,J=3.9Hz),115.28,111.01,8.19.HRMS[ESI]:calculated for C 28 H 19 F8N6O3S[M+H] + :671.1106,found:671.1106.

[0234] Example 45 Preparation of Compound 2-(4-amino-2-(4-(N,N-dimethylsulfonamido)phenyl)-7-oxo-6,7-dihydro-2H-pyrazolo[3,4-d]pyridazin-3-yl)-N-(3-fluoro-5-(trifluoromethyl)phenyl)-3-methylbenzofuran-6-carboxamide (A045)

[0235] Compound A045 was prepared in the same manner as in Example 1, except that C-2-pSO2NMe2 was used instead of C-2-pCF3 and AF-2 was used instead of A-5. The product was a light yellow solid, and the reaction yield of this step was 55%. 1 H NMR (800MHz, DMSO-d6) δ11.56(s,1H),10.77(s,1H),8.25(s,1H),8.09-8.05(m,2H),7.99(d,J=8.1Hz,1 H),7.89-7.84(m,3H),7.76-7.72(m,2H),7.42(d,J=8.3Hz,1H),5.35(s,2H),2.60(s,6H),2.01(s,3H). 13C NMR(201MHz,DMSO-d6)δ165.47,162.02(d,J=243.9Hz),154.79,154.06,143.72,143.1 5,142.13,141.86(d,J=11.5Hz),139.72,135.25,132.02,131.78,130.93(dd,J=32.4,9 .7Hz),128.92,127.54,125.62,123.28(dd,J=272.1,3.1Hz),122.97,120.85,120.48,1 15.31,112.62,111.18,110.48(d,J=26.5Hz),107.37(dd,J=25.8,3.8Hz),37.54,8.26. 19 F NMR(471MHz,DMSO-d6)δ-61.47,-109.23(t,J=10.0Hz).HRMS[ESI]:calculated for C 30 H 24 F4N7O5S[M+H] + :670.1490,found:670.1492.

[0236] Example 46 Preparation of Compound 2-(4-amino-2-(3-(N,N-dimethylsulfonamido)phenyl)-7-oxo-6,7-dihydro-2H-pyrazolo[3,4-d]pyridazin-3-yl)-N-(3-fluoro-5-(trifluoromethyl)phenyl)-3-methylbenzofuran-6-carboxamide (A046)

[0237] Compound A046 was prepared in the same manner as in Example 1, except that C-2-mSO2NMe2 was used instead of C-2-pCF3 and AF-2 was used instead of A-5. The product was a light yellow solid, and the reaction yield of this step was 62%. 1 H NMR (800MHz, DMSO-d6) δ11.57(s,1H),10.80(s,1H),8.26(d,J=1.4Hz,1H),8.09-8.07(m,2H),8.00(dd,J=8.2,1.5Hz,1H),7.94(ddd,J=8.0 ,2.2,1.1Hz,1H),7.86(dt,J=7.9,1.4Hz,1H),7.85(d,J=8.1Hz,1H),7.82(t,J=7.9Hz,1H),7.75(t,J=2.0Hz,1H),2.36(s,6H),2.03(s,3H). 13C NMR(126MHz,DMSO-d6)δ165.43,162.00(d,J=243.9Hz),154.85,154.06,143.54,143.18,1 41.86(d,J=11.4Hz),139.73,139.33,136.01,131.97,131.70,131.13,130.91(dd,J=32.9 ,10.1Hz),129.33,128.33,127.49,123.42,123.35(qd,J=272.7,3.3Hz),123.00,120.73, 120.55,115.38,112.63,111.18,110.48(d,J=26.4Hz),107.35(d,J=23.3Hz),37.13,8.16. 19 F NMR(471MHz,DMSO-d6)δ-61.49,-109.25(t,J=10.0Hz).HRMS[ESI]:calculated for C 30 H 24 F4N7O5S[M+H] + :670.1490,found:670.1495.

[0238] Example 47 Preparation of Compound 2-(4-amino-2-(4-(morpholinesulfonyl)phenyl)-7-oxo-6,7-dihydro-2H-pyrazolo[3,4-d]pyridazin-3-yl)-N-(3-fluoro-5-(trifluoromethyl)phenyl)-3-methylbenzofuran-6-carboxamide (A047)

[0239] Compound A047 was prepared in the same manner as Example 1, except that C-2-pSO2Mor was used instead of C-2-pCF3 and AF-2 was used instead of A-5. The product was a light yellow solid, and the reaction yield of this step was 58%. 1 H NMR (800MHz, DMSO-d6) δ11.58(s,1H),10.82(s,1H),8.27(d,J=1.4Hz,1H),8.11-8.07(m,2H),8.02(dd,J=8.2,1.5Hz,1H),7.86(d,J=4 .5Hz,1H),7.85-7.84(m,2H),7.77-7.75(m,2H),7.39(dt,J=8.4,2.0Hz,1H),3.58(t,J=4.8Hz,4H),2.85(t,J=4.8Hz,4H),2.04(s,3H). 13C NMR(201MHz,DMSO-d6)δ165.89,161.99(d,J=243.8Hz),155.20,154.53,144.14,143.71,142 .83,141.93(d,J=11.4Hz),140.08,135.74,132.46,132.24,130.89(qd,J=32.6,9.7Hz),129 .49,128.22,126.24,123.53,123.38(qd,J=272.5,3.3Hz),121.27,121.05,115.65,112.69( t, J=3.8Hz), 110.52 (d, J=26.3Hz), 111.62, 107.76 (dd, J=25.1, 3.2Hz), 65.66, 46.37, 8.78. 19 F NMR(471MHz,DMSO-d6)δ-61.48,-109.32(t,J=9.7Hz).HRMS[ESI]:calculated for C 32 H 26 F4N7O6S[M+H] + :712.1596,found:712.1597.

[0240] Example 48 Preparation of Compound 2-(4-amino-2-(4-(tert-butyl)phenyl)-7-oxo-6,7-dihydro-2H-pyrazolo[3,4-d]pyridazin-3-yl)-N-(3-fluoro-5-(trifluoromethyl)phenyl)-3-methylbenzofuran-6-carboxamide (A048)

[0241] Compound A048 was prepared in the same manner as in Example 1, except that C-2-ptBu was used instead of C-2-pCF3 and AF-2 was used instead of A-5. The product was a light yellow solid, and the reaction yield was 66%. 1 H NMR (800MHz, DMSO-d6) δ11.51(s,1H),10.76(s,1H),8.28(d,J=1.5Hz,1H),8.08-8.05(m,2H),7.98(dd,J=8.1, 1.5Hz,1H),7.85(d,J=8.1Hz,1H),7.50-7.48(m,2H),7.42-7.39(m,3H),5.24(s,2H),1.96(s,3H),1.26(s,9H). 13C NMR(201MHz,DMSO-d6)δ165.50,162.02(d,J=244.0Hz),154.95,153.98,152.20,143.16 ,143.09,141.88(d,J=11.4Hz),140.28,136.46,131.99,131.62,130.93(qd,J=32.9,10 .5Hz),126.85,126.24,124.12,123.35(qd,J=272.2,4.1Hz),122.94,120.75,120.02,1 15.13, 112.58, 110.43 (d, J = 26.5Hz), 111.20, 107.32 (d, J = 25.2Hz), 34.57, 30.90, 8.09. 19 F NMR(753MHz,DMSO-d6)δ-61.50,-109.24(t,J=9.6Hz).HRMS[ESI]:calculated for C 32 H 27 F4N6O3[M+H] + :619.2075,found:619.2079.

[0242] Example 49 Preparation of Compound 2-(4-amino-2-(3-(tert-butyl)phenyl)-7-oxo-6,7-dihydro-2H-pyrazolo[3,4-d]pyridazin-3-yl)-N-(3-fluoro-5-(trifluoromethyl)phenyl)-3-methylbenzofuran-6-carboxamide (A049)

[0243] Compound A049 was prepared in the same manner as in Example 1, except that C-2-mtBu was used instead of C-2-pCF3 and AF-2 was used instead of A-5. The product was a light yellow solid, and the reaction yield was 62%. 1 H NMR (800MHz, DMSO-d6) δ11.51(s,1H),10.77(s,1H),8.24(d,J=1.6Hz,1H),8.07(d,J=13.2Hz,2H),7.98(dd,J=8.2,1.5Hz,1H),7.83(d,J=8. 1Hz,1H),7.48(dt,J=7.9,1.5Hz,1H),7.45(t,J=7.8Hz,1H),7.41-7.39(m,2H),7.25(t,J=1.9Hz,1H),5.31(s,2H),1.97(s,3H),1.02(s,9H). 13C NMR(201MHz,DMSO)δ165.47,162.03(d,J=243.9Hz),155.00,154.03,152.09,143.24,143.1 0,141.88(d,J=11.5Hz),140.42,138.57,132.10,131.46,130.94(qd,J=32.9,10.0Hz),129 .39,127.02,126.18,123.37(qd,J=272.6,3.1Hz),122.95,121.83,121.21,120.55,120.17 ,115.09,112.64,111.09,110.49(d,J=26.4Hz),107.35(d,J=24.9Hz),34.37,30.54,8.04. 19 F NMR(753MHz,DMSO-d6)δ-61.50,-109.25(t,J=10.0Hz).HRMS[ESI]:calculated for C 32 H 27 F4N6O3[M+H] + :619.2075,found:619.2078.

[0244] Example 50 Preparation of Compound 2-(4-amino-2-(4-(N,N-dimethylsulfonamido)phenyl)-7-oxo-6,7-dihydro-2H-pyrazolo[3,4-d]pyridazin-3-yl)-3-methyl-N-(3-(trifluoromethyl)phenyl)benzo[b]thiophene-6-carboxamide (A050)

[0245] Compound A050 was prepared in the same manner as in Example 1, except that C-2-pSO2NMe2 was used instead of C-2-pCF3 and AS-4 was used instead of A-5. The product was a light yellow solid, and the reaction yield of this step was 52%. 1 H NMR (800MHz, DMSO-d6) δ11.49(s,1H),10.66(s,1H),8.65(d,J=1.5Hz,1H),8.27(t,J=2.1Hz,1H),8.08(dt,J=8.2,1.3Hz,1H),8.04(dd,J=8.4,1.6Hz, 1H),8.01(d,J=8.4Hz,1H),7.83-7.80(m,2H),7.74-7.72(m,2H),7.62(t,J =8.0Hz,1H),7.47(d,J=7.7Hz,1H),5.11(s,2H),2.58(s,6H),2.20(s,3H). 13C NMR(151MHz,DMSO-d6)δ165.58,155.06,143.40,143.31,141.81,141.20,139.96 ,139.94,136.52,135.15,132.07,130.96,129.97,129.38(q,J=31.6Hz),128.71, 126.08,124.22,124.16(q,J=272.3Hz),123.86,123.69,123.35,122.62,120.04 (d,J=3.0Hz),116.25(d,J=3.9Hz),114.78,37.53,12.64.HRMS[ESI]:calculated for C 30 H 25 F3N7O4S2[M+H] + :668.1356,found:668.1355.

[0246] Example 51 Preparation of Compound 2-(4-amino-2-(3-(N,N-dimethylsulfonamido)phenyl)-7-oxo-6,7-dihydro-2H-pyrazolo[3,4-d]pyridazin-3-yl)-3-methyl-N-(3-(trifluoromethyl)phenyl)benzo[b]thiophene-6-carboxamide (A051)

[0247] Compound A051 was prepared in the same manner as in Example 1, except that C-2-mSO2NMe2 was used instead of C-2-pCF3 and AS-4 was used instead of A-5. The product was a light yellow solid, and the reaction yield was 49%. 1 H NMR (800MHz, DMSO-d6) δ11.49(s,1H),10.67(s,1H),8.65(d,J=1.7Hz,1H),8.28(t ,J=2.0Hz,1H),8.10(dd,J=8.1,2.1Hz,1H),8.05(dd,J=8.4,1.6Hz,1H),7.99(d,J =8.4Hz,1H),7.97(dt,J=6.3,2.4Hz,1H),7.81-7.78(m,2H),7.72(q,J=1.4Hz,1H) ,7.62(t,J=8.0Hz,1H),7.49-7.46(m,1H),5.10(s,2H),2.22(s,6H),2.20(s,3H). 13C NMR(151MHz,DMSO-d6)δ165.44,155.11,143.33,143.25,141.23,139.99,139.94,138 .98,136.57,135.42,131.92,130.97,130.86,129.95,129.84,129.38(q,J=31.6Hz), 128.18,124.23,124.15(q,J=272.2Hz),124.02,123.80,123.72,123.22,122.53,120 .04(d,J=3.4Hz),116.32(d,J=3.9Hz),114.82,37.01,12.56.HRMS[ESI]:calculated for C 30 H 25 F3N7O4S2[M+H] + :668.1356,found:668.1354.

[0248] Example 52 Preparation of Compound 2-(4-amino-2-(4-(morpholinesulfonyl)phenyl)-7-oxo-6,7-dihydro-2H-pyrazolo[3,4-d]pyridazin-3-yl)-3-methyl-N-(3-(trifluoromethyl)phenyl)benzo[b]thiophene-6-carboxamide (A052)

[0249] Compound A052 was prepared in the same manner as in Example 1, except that C-2-pSO2Mor was used instead of C-2-pCF3 and AS-4 was used instead of A-5. The product was a light yellow solid, and the reaction yield was 54%. 1 H NMR (800MHz, DMSO-d6) δ11.51(s,1H),10.65(s,1H),8.65(d,J=1.5Hz,1H),8.27( t,J=2.0Hz,1H),8.07(dd,J=8.1,2.1Hz,1H),8.04(dd,J=8.4,1.6Hz,1H),8.00(d ,J=8.4Hz,1H),7.83-7.79(m,2H),7.77-7.73(m,2H),7.62(t,J=8.0Hz,1H),7.47 (d,J=7.7Hz,1H),5.12(s,2H),3.59-3.55(m,4H),2.85-2.81(m,4H),2.20(s,3H). 13C NMR(201MHz,DMSO-d6)δ165.57,155.09,143.45,143.34,142.07,141.20,139.97,1 39.96,136.57,135.19,132.09,131.06,129.99,129.43(q,J=31.4Hz),128.83,126 .23,124.25,124.18(q,J=272.3Hz),123.90,123.74,123.35,122.62,120.07(d,J= 3.0Hz),116.31(d,J=3.9Hz),114.83,65.20,45.90,12.67.HRMS[ESI]:calculated for C 32 H 27 F3N7O5S2[M+H] + :710.1462,found:710.1465.

[0250] Example 53 Preparation of Compound 2-(4-amino-2-(4-(N,N-dimethylsulfonamido)phenyl)-7-oxo-6,7-dihydro-2H-pyrazolo[3,4-d]pyridazin-3-yl)-N-cyclohexyl-3-methylbenzofuran-6-carboxamide (A053)

[0251] Compound A053 was prepared in the same manner as in Example 1, except that C-2-pSO2NMe2 was used instead of C-2-pCF3 and ACy-2 was used instead of A-5. The product was a light yellow solid, and the reaction yield was 57%. 1 H NMR (800MHz, DMSO-d6) δ11.55(s,1H),8.28(d,J=7.9Hz,1H),8.07(d,J=1.5Hz,1H ),7.86(dd,J=8.2,1.4Hz,1H),7.85-7.83(m,2H),7.74(d,J=8.1Hz,1H),7.73-7.7 0(m,2H),5.32(s,2H),3.81-3.76(m,1H),2.58(s,6H),1.97(s,3H),1.86-1.80(m ,2H),1.77-1.71(m,2H),1.64-1.58(m,1H),1.35-1.27(m,4H),1.16-1.09(m,1H). 13CNMR(201MHz,DMSO-d6)δ164.63,154.81,154.17,143.69,143.14,142.15,138.97,135.17,132.90,130.90,128.88 ,127.76,125.58,122.62,120.32,115.16,110.47,48.54,37.53,32.43,25.27,24.97,8.25.HRMS[ESI]:calculated for C 29 H 32 N7O5S[M+H] + :590.2180,found:590.2182.

[0252] Example 54 Preparation of Compound 2-(4-amino-2-(3-(N,N-dimethylsulfonamido)phenyl)-7-oxo-6,7-dihydro-2H-pyrazolo[3,4-d]pyridazin-3-yl)-N-cyclohexyl-3-methylbenzofuran-6-carboxamide (A054)

[0253] Compound A054 was prepared in the same manner as in Example 1, except that C-2-mSO2NMe2 was used instead of C-2-pCF3 and ACy-2 was used instead of A-5. The product was a light yellow solid, and the reaction yield of this step was 55%. 1 H NMR (800MHz, DMSO-d6) δ11.54(s,1H),8.30(d,J=7.9Hz,1H),8.08(d,J=1.5Hz,1H),7.90( ddd,J=8.0,2.2,1.1Hz,1H),7.87-7.83(m,2H),7.79(t,J=7.9Hz,1H),7.73(t,J=2.0Hz,1 H),7.71(d,J=8.1Hz,1H),5.28(s,2H),3.81-3.75(m,1H),2.34(s,6H),1.97(s,3H),1.85 -1.82(m,2H),1.76-1.71(m,2H),1.63-1.59(m,1H),1.35-1.27(m,4H),1.16-1.10(m,1H). 13C NMR(201MHz,DMSO-d6)δ164.62,154.86,154.17,143.52,143.15,139.34,139.00,136.00,132.87,131.09,130.85,129.28,128 .29,127.67,123.41,122.64,120.33,120.20,115.27,110.48,48.56,37.14,32.43,25.27,24.97,8.15.HRMS[ESI]:calculated for C 29 H 32 N7O5S[M+H] + :590.2180,found:590.2179.

[0254] Example 55 Preparation of Compound 2-(4-amino-2-(4-(morpholinesulfonyl)phenyl)-7-oxo-6,7-dihydro-2H-pyrazolo[3,4-d]pyridazin-3-yl)-N-cyclohexyl-3-methylbenzofuran-6-carboxamide (A055)

[0255] Compound A055 was prepared in the same manner as in Example 1, except that C-2-pSO2Mor was used instead of C-2-pCF3 and ACy-2 was used instead of A-5. The product was a light yellow solid, and the reaction yield was 67%. 1 H NMR(800MHz,DMSO-d6)δ11.55(s,1H),8.26(d,J=7.9Hz,1H),8.07(s,1H),7.8 6(d,J=8.2Hz,1H),7.85-7.82(m,2H),7.75-7.72(m,3H),5.32(s,2H),3.81-3. 75(m,1H),3.61-3.57(m,4H),2.87-2.84(m,4H),1.98(s,3H),1.85-1.80(m,2H ),1.76-1.71(m,2H),1.63-1.58(m,1H),1.35-1.27(m,4H),1.16-1.10(m,1H). 13C NMR(201MHz,DMSO-d6)δ165.14,155.27,154.65,144.19,143.61,142.84,139.41,135.67,133.45,131.35,129.46,128.23 ,126.12,123.12,120.80,120.75,115.69,110.92,65.67,49.02,46.37,32.88,25.75,25.44,8.74.HRMS[ESI]:calculated for C 31 H 34 N7O6S[M+H] + :632.2286,found:632.2285.

[0256] Example 56 Preparation of Compound 2-(4-amino-2-(4-(tert-butyl)phenyl)-7-oxo-6,7-dihydro-2H-pyrazolo[3,4-d]pyridazin-3-yl)-N-cyclohexyl-3-methylbenzofuran-6-carboxamide (A057)

[0257] Compound A057 was prepared in the same manner as in Example 1, except that C-2-ptBu was used instead of C-2-pCF3 and ACy-2 was used instead of A-5. The product was a light yellow solid, and the reaction yield was 59%. 1 H NMR (800MHz, DMSO-d6) δ11.50(s,1H),8.28(d,J=7.9Hz,1H),8.11(d,J=1.4Hz,1H ),7.86(dd,J=8.1,1.5Hz,1H),7.72(d,J=8.2Hz,1H),7.49-7.46(m,2H),7.40-7.3 7(m,2H),5.19(s,2H),3.81-3.75(m,1H),1.92(s,3H),1.86-1.79(m,2H),1.78-1 .70(m,2H),1.64-1.58(m,1H),1.36-1.27(m,4H),1.25(s,9H),1.16-1.10(m,1H). 13C NMR(201MHz,DMSO-d6)δ165.18,155.43,154.57,152.63,143.61,143.52,139.98,136.94,133.25,131.35,127.51,126.69 ,124.55,123.04,120.70,120.30,115.50,111.01,49.01,35.04,32.90,31.38,25.74,25.43,8.55.HRMS[ESI]:calculated for C 31 H 35 N6O3[M+H] + :539.2765,found:539.2766.

[0258] Example 57 Preparation of Compound 2-(4-amino-2-(4-(tert-butyl)-3-chlorophenyl)-7-oxo-6,7-dihydro-2H-pyrazolo[3,4-d]pyridazin-3-yl)-N-(3-fluoro-5-(trifluoromethyl)phenyl)-3-methylbenzofuran-6-carboxamide (A058)

[0259] Compound A058 was prepared in the same manner as in Example 1, except that C-2-ptBu-mCl was used instead of C-2-pCF3 and AF-2 was used instead of A-5. The product was a light yellow solid, and the reaction yield was 67%. 1 H NMR (600MHz, DMSO-d6) δ11.54(s,1H),10.78(s,1H),8.29(d,J=1.4Hz,1H),8.08-8.05(m,2H),8.00(dd,J=8.2,1.5Hz,1H),7.88(d,J=8.2Hz,1H ),7.61(d,J=2.4Hz,1H),7.54(d,J=8.7Hz,1H),7.42(dt,J=8.5,2.0Hz,1H),7.36(dd,J=8.6,2.4Hz,1H),5.28(s,2H),2.03(s,3H),1.42(s,9H). 13C NMR(201MHz,DMSO-d6)δ165.55,162.06(d,J=243.9Hz),154.88,154.07,147.21,143.35,143.17 ,141.88(d,J=11.4Hz),139.82,137.67,132.95,132.00,131.77,130.98(qd,J=33.0,10.4Hz),12 8.90,127.44,127.14,123.38(qd,J=272.3,3.6Hz),123.01,122.85,120.88,120.43,115.29,112 .65(t,J=3.2Hz),111.25,110.51(d,J=26.5Hz),107.41(dd,J=25.2,3.3Hz),35.92,29.13,8.24. 19 FNMR(471MHz,DMSO-d6)δ-61.48,-109.23(t,J=9.8Hz).HRMS[ESI]:calculated for C 32 H 26 ClF4N6O3[M+H] + :653.1686,found:653.1689.

[0260] Example 58 Preparation of Compound 2-(4-amino-2-(3-bromo-4-(tert-butyl)phenyl)-7-oxo-6,7-dihydro-2H-pyrazolo[3,4-d]pyridazin-3-yl)-N-(3-fluoro-5-(trifluoromethyl)phenyl)-3-methylbenzofuran-6-carboxamide (A059)

[0261] Compound A059 was prepared in the same manner as in Example 1, except that C-2-ptBu-mBr was used instead of C-2-pCF3 and AF-2 was used instead of A-5. The product was a light yellow solid, and the reaction yield was 68%. 1 H NMR (600MHz, DMSO-d6) δ11.54(s,1H),10.78(s,1H),8.29(d,J=1.5Hz,1H),8.09-8.05(m,2H),8.01(dd,J=8.2,1.5Hz,1H),7 .89(d,J=8.1Hz,1H),7.81(d,J=2.4Hz,1H),7.54(d,J=8.7Hz,1H),7.44-7.39(m,2H),5.28(s,2H),2.03(s,3H),1.45(s,9H). 13CNMR(201MHz,DMSO-d6)δ165.52,162.04(d,J=243.9Hz),154.85,154.06,148.45,143.33 ,143.14,141.87(d,J=11.6Hz),139.80,137.53,131.99,131.74,131.00,128.94,127.08, 124.04(qd,J=272.6,3.2Hz),123.16,122.98,121.56,120.85,120.43,115.28,112.63(t, J=3.5Hz), 111.23, 110.48 (d, J=26.7Hz), 107.39 (dd, J=25.5, 3.2Hz), 36.44, 29.20, 8.22. 19 F NMR(471MHz,DMSO-d6)δ-61.48,-109.23(t,J=9.9Hz).HRMS[ESI]:calculated for C 32 H 26 BrF4N6O3[M+H] + :697.1180,found:697.1183.

[0262] Example 59 Preparation of Compound 2-(4-amino-2-(4-(tert-butyl)-3-fluorophenyl)-7-oxo-6,7-dihydro-2H-pyrazolo[3,4-d]pyridazin-3-yl)-N-(3-fluoro-5-(trifluoromethyl)phenyl)-3-methylbenzofuran-6-carboxamide (A060)

[0263] Compound A060 was prepared in the same manner as in Example 1, except that C-2-ptBu-mF was used instead of C-2-pCF3 and AF-2 was used instead of A-5. The product was a light yellow solid, and the reaction yield was 68%. 1 H NMR (800MHz, DMSO-d6) δ11.54(s,1H),10.77(s,1H),8.29(d,J=1.4Hz,1H),8.08-8.05(m,2H),8.00(dd,J=8.2,1.5H z,1H),7.88(d,J=8.2Hz,1H),7.44-7.38(m,3H),7.23(dd,J=8.5,2.3Hz,1H),5.28(s,2H),2.03(s,3H),1.32(s,9H). 13C NMR (201MHz, DMSO-d6) δ165.49,162.02(d,J=243.9Hz),160.68(d,J=249.0Hz),154.84,154.03,143.27,143.12,141.87(d,J =11.4Hz),139.86,138.05(d,J=11.0Hz),137.86(d,J=11.5Hz),131.97,131.72,130.91(qd,J=32.6,10.4Hz),128.26(d,J=6 .5Hz),127.10,123.35(qd,J=272.3,3.2Hz),122.96,120.83,120.34,120.13(d,J=2.2Hz),115.23,112.91(d,J=28.9Hz),11 2.61 (t, J = 3.1Hz), 111.21, 110.45 (d, J = 26.5Hz), 107.34 (dd, J = 24.8, 3.0Hz), 34.10 (d, J = 2.2Hz), 29.45 (d, J = 2.7Hz), 8.18. 19 F NMR(753MHz,DMSO-d6)δ-61.51,-107.37,-109.24(t,J=9.6Hz).HRMS[ESI]:calculated for C 32 H 26 F5N6O3[M+H] + :637.1981,found:637.1981.

[0264] Example 60 Preparation of Compound 2-(4-amino-2-(4-(tert-butyl)phenyl)-7-oxo-6,7-dihydro-2H-pyrazolo[3,4-d]pyridazin-3-yl)-N-(3-fluoro-5-(trifluoromethyl)phenyl)-3-methylbenzo[b]thiophene-6-carboxamide (A061)

[0265] Compound A061 was prepared in the same manner as in Example 1, except that C-2-ptBu was used instead of C-2-pCF3 and ASF-3 was used instead of A-5. The product was a light yellow solid, and the reaction yield was 57%. 1H NMR (800MHz, DMSO-d6) δ11.44(s,1H),10.82(s,1H),8.65(d,J=1.5Hz,1H),8.06-8.04(m,2H),8.03(dd,J=8.4, 1.6Hz,1H),8.02(d,J=8.4Hz,1H),7.47-7.44(m,2H),7.43-7.39(m,3H),5.00(s,2H),2.20(s,3H),1.23(s,9H). 13 C NMR(201MHz,DMSO-d6)δ165.79,162.06(d,J=243.9Hz),155.22,152.10,143.35,142.7 8,141.88(d,J=11.4Hz),141.36,139.87,136.16,131.56,130.99(qd,J=32.5,9.6Hz),1 30.21,126.07,124.72,124.68,124.16,123.40,123.36(qd,J=272.6,2.9Hz),122.74,1 14.50, 112.51, 110.37 (d, J = 26.3Hz), 107.40 (dd, J = 24.9, 2.9Hz), 34.56, 30.92, 12.58. 19 F NMR(753MHz,DMSO-d6)δ-61.50,-109.15(t,J=9.1Hz).HRMS[ESI]:calculated for C 32 H 25 F4N6O2S[MH] - :633.1701,found:633.1700.

[0266] Example 61 Preparation of Compound 2-(4-amino-7-oxo-2-(4-(1-(trifluoromethyl)cyclopropyl)phenyl)-6,7-dihydro-2H-pyrazolo[3,4-d]pyridazin-3-yl)-N-(3-fluoro-5-(trifluoromethyl)phenyl)-3-methylbenzofuran-6-carboxamide (A062)

[0267] Compound A062 was prepared in the same manner as in Example 1, except that C-2-pcPr-CF3 was used instead of C-2-pCF3 and AF-2 was used instead of A-5. The product was a light yellow solid, and the reaction yield of this step was 51%. 1H NMR (800MHz, DMSO-d6) δ11.53(s,1H),10.76(s,1H),8.27(d,J=1.5Hz,1H),8.08-8.05(m,2H),7.99(dd,J=8.1,1.5Hz,1H),7.85(d,J=8.2H z,1H),7.58-7.56(m,2H),7.52-7.49(m,2H),7.41(dt,J=8.5,2.0Hz,1H),5.28(s,2H),1.95(s,3H),1.35-1.33(m,2H),1.16-1.14(m,2H). 13 C NMR(201MHz,DMSO-d6)δ165.50,162.03(d,J=243.9Hz),154.88,154.00,143.32,143.14,141.87(d ,J=11.5Hz),140.05,138.84,136.59,132.03,131.99,131.69,130.94(qd,J=32.7,9.6Hz),127.11 ,126.31(q,J=273.5Hz),124.68,123.36(qd,J=272.5,3.3Hz),122.95,120.76,120.17,115.20,11 2.59, 111.22, 110.44 (d, J = 26.4Hz), 107.35 (dd, J = 25.4, 2.8Hz), 27.21 (q, J = 33.1Hz), 9.82, 8.09. 19 F NMR(753MHz,DMSO-d6)δ-61.50,-68.37,-109.23(t,J=9.4Hz).HRMS[ESI]:calculated for C 32 H 20 F7N6O3[MH] - :669.1491,found:669.1494.

[0268] Example 62 Preparation of Compound 2-(4-amino-2-(4-(N,N-dimethylsulfonamido)phenyl)-7-oxo-6,7-dihydro-2H-pyrazolo[3,4-d]pyridazin-3-yl)-N-(3-fluoro-5-(trifluoromethyl)phenyl)-3-methylbenzo[b]thiophene-6-carboxamide (A063)

[0269] Compound A063 was prepared in the same manner as in Example 1, except that C-2-pSO2NMe2 was used instead of C-2-pCF3 and ASF-3 was used instead of A-5. The product was a light yellow solid, and the reaction yield of this step was 49%.1 H NMR (800MHz, DMSO-d6) δ11.50(s,1H),10.83(s,1H),8.65(t,J=1.2Hz,1H),8.07-8.01(m,4H),7.83- 7.80(m,2H),7.74-7.71(m,2H),7.42(dt,J=8.5,2.0Hz,1H),5.11(s,2H),2.58(s,6H),2.20(s,3H). 13 C NMR(201MHz,DMSO-d6)δ165.78,162.05(d,J=243.9Hz),155.05,143.40,143.29,141.88 (d,J=11.4Hz),141.80,141.37,139.97,136.54,135.21,131.66,131.00(qd,J=33.1,8. 8Hz),130.92,128.69,126.09,124.17,124.09,123.43,123.35(qd,J=272.2,3.4Hz),12 2.72,114.80,112.49,110.35(d,J=26.3Hz),107.37(dd,J=26.0,3.4Hz),37.52,12.63. 19 F NMR(753MHz,DMSO-d6)δ-61.49,-109.16(t,J=9.8Hz).HRMS[ESI]:calculated for C 30 H 24 F4N7O4S2[M+H] + :686.1262,found:686.1264.

[0270] Example 63 Preparation of Compound 2-(4-amino-2-(4-(morpholinesulfonyl)phenyl)-7-oxo-6,7-dihydro-2H-pyrazolo[3,4-d]pyridazin-3-yl)-N-(3-fluoro-5-(trifluoromethyl)phenyl)-3-methylbenzo[b]thiophene-6-carboxamide (A064)

[0271] Compound A064 was prepared in the same manner as in Example 1, except that C-2-pSO2Mor was used instead of C-2-pCF3 and ASF-3 was used instead of A-5. The product was a light yellow solid, and the reaction yield of this step was 52%. 1H NMR (800MHz, DMSO-d6) δ11.51(s,1H),10.81(s,1H),8.64(d,J=1.5Hz,1H),8.06-8.03(m,3H),8.01(d,J=8.4Hz,1H),7.82-7 .80(m,2H),7.76-7.73(m,2H),7.41(dt,J=8.4,2.0Hz,1H),5.12(s,2H),3.59-3.55(m,4H),2.86-2.80(m,4H),2.20(s,3H). 13 CNMR(201MHz,DMSO-d6)δ165.77,162.08(d,J=244.0Hz),155.09,143.45,143.34,142.06, 141.38,141.89(d,J=11.5Hz),139.99,136.60,135.20,131.67,131.03,131.01(qd,J=32. 7,10.1Hz),128.83,126.25,124.21,124.12,123.43,122.72,122.69(qd,J=272.3,3.7Hz) ,114.83,112.53,110.40(d,J=26.5Hz),107.40(dd,J=25.3,2.9Hz),65.21,45.91,12.67. 19 F NMR(753MHz,DMSO-d6)δ-61.50,-109.15(t,J=10.1Hz).HRMS[ESI]:calculated for C 32 H 26 F4N7O5S2[M+H] + :728.1367,found:728.1364.

[0272] Example 64 Preparation of Compound 2-(4-amino-2-(4-(tert-butyl)phenyl)-7-oxo-6,7-dihydro-2H-pyrazolo[3,4-d]pyridazin-3-yl)-N-(4,4-difluorocyclohexyl)-3-methylbenzofuran-6-carboxamide (A065)

[0273] Compound A065 was prepared in the same manner as in Example 1, except that C-2-ptBu was used instead of C-2-pCF3 and ACyF-2 was used instead of A-5. The product was a light yellow solid, and the reaction yield was 68%. 1H NMR (500MHz, DMSO-d6) δ11.50(s,1H),8.38(d,J=7.6Hz,1H),8.12(s,1H),7.86(d,J=8.2Hz,1H),7.74(d,J=8.3Hz,1H),7 .52-7.45(m,2H),7.41-7.36(m,2H),5.20(s,2H),4.07-3.98(m,1H),2.12-1.86(m,9H),1.71-1.60(m,2H),1.25(s,9H). 13 C NMR (126MHz, DMSO-d6) δ165.20,154.96,154.08,152.17,143.14,143.05,139.62,136.46,132.44,131.04,127.01,126.2 2,124.09,122.59,120.31,119.85,115.04,110.63,46.02,34.57,31.66(t,J=24.3Hz), 30.90,27.94(d,J=9.1Hz),8.07. 19 F NMR(471MHz, DMSO-d6)δ-92.FF28(d,J=233.1Hz),-98.83(d,J=233.8Hz).HRMS[ESI]:calculated for C 31 H 33 F2N6O3[M+H] + :575.2577,found:575.2579.

[0274] Example 65 Preparation of Compound 2-(4-amino-2-(4-(tert-butyl)phenyl)-7-oxo-6,7-dihydro-2H-pyrazolo[3,4-d]pyridazin-3-yl)-3-methyl-N-(tetrahydro-2H-pyran-4-yl)benzofuran-6-carboxamide (A066)

[0275] Compound A066 was prepared in the same manner as in Example 1, except that C-2-ptBu was used instead of C-2-pCF3 and APO-2 was used instead of A-5. The product was a light yellow solid, and the reaction yield was 66%. 1H NMR (500MHz, DMSO-d6) δ11.50(s,1H),8.40(d,J=7.6Hz,1H),8.12(s,1H),7.87(d,J=8.1Hz,1H),7.74(d,J=8.2Hz,1H),7.52-7.45(m,2H),7 .42-7.34(m,2H),5.20(s,2H),4.08-3.97(m,1H),3.92-3.84(m,2H), 3.42-3.36(m,2H),1.92(s,3H),1.81-1.73(m,2H),1.64-1.54(m,2H). 13 C NMR (126MHz, DMSO-d6) δ164.96,154.96,154.09,152.16,143.15,143.06,139.60,136.47,132.53,131.02,127.02,126 .23,124.09,122.57,120.31,119.86,115.04,110.58,66.18,45.95,34.57,32.43,30.90,8.08.HRMS[ESI]:calculated for C 30 H 33 N6O4[M+H] + :541.2558,found:541.2560.

[0276] Example 66 Preparation of Compound 2-(4-amino-7-oxo-2-(4-(1-(trifluoromethyl)cyclopropyl)phenyl)-6,7-dihydro-2H-pyrazolo[3,4-d]pyridazin-3-yl)-3-methyl-N-(tetrahydro-2H-pyran-4-yl)benzofuran-6-carboxamide (A067)

[0277] Compound A067 was prepared in the same manner as in Example 1, except that C-2-pcPr-CF3 was used instead of C-2-pCF3 and APO-2 was used instead of A-5. The product was a light yellow solid, and the reaction yield of this step was 67%. 1H NMR (800MHz, DMSO-d6) δ11.52(s,1H),8.39(d,J=7.6Hz,1H),8.11(d,J=1.5Hz,1H) ,7.87(dd,J=8.2,1.4Hz,1H),7.74(d,J=8.2Hz,1H),7.57-7.54(m,2H),7.50-7.47( m,2H),5.23(s,2H),4.06-4.00(m,1H),3.91-3.85(m,2H),3.42-3.37(m,2H),1.92( s,3H),1.79-1.75(m,2H),1.63-1.56(m,2H),1.35-1.33(m,2H),1.17-1.14(m,2H). 13 C NMR (201MHz, DMSO) δ164.94,154.89,154.11,143.29,143.12,139.36,138.84,136.54,132.59,132.01,131.01,127.27,126 .30(q,J=273.4Hz),124.64,122.58,120.30,120.01,115.10,110.58,66.18,45.95,32.43,27.21(q,J=33.2Hz),9.80,8.08. 19 F NMR(471MHz,DMSO-d6)δ-68.38.HRMS[ESI]:calculated for C 30 H 28 F3N6O4[M+H] + :593.2119,found:593.2120.

[0278] Example 67 Preparation of Compound 2-(4-amino-2-(4-(tert-butyl)phenyl)-7-oxo-6,7-dihydro-2H-pyrazolo[3,4-d]pyridazin-3-yl)-N-cyclobutyl-3-methylbenzofuran-6-carboxamide (A068)

[0279] Compound A068 was prepared in the same manner as in Example 1, except that C-2-ptBu was used instead of C-2-pCF3 and ACb-2 was used instead of A-5. The product was a light yellow solid, and the reaction yield was 63%. 1H NMR (600MHz, DMSO-d6) δ11.50(s,1H),8.69(d,J=7.5Hz,1H),8.11-8.10(m,1H),7.86(dd,J=8.2,1.4Hz,1H),7.73(d,J=8.2Hz,1H),7.50-7.46 (m,2H),7.40-7.37(m,2H),5.20(s,2H),4.48-4.40(m,1H),2.26-2.19( m,2H),2.13-2.04(m,2H),1.93(s,3H),1.73-1.63(m,2H),1.25(s,9H). 13 C NMR(151MHz,DMSO-d6)δ164.61,154.95,154.09,152.15,143.15,143.05,139.58,136.48,132.37,131.02,127.02,126 .22,124.09,122.51,120.32,119.86,115.02,110.51,44.69,34.56,30.91,30.09,14.73,8.09.HRMS[ESI]:calculated for C 29 H 31 N6O3[M+H] + :511.2452,found:511.2451.

[0280] Example 68 Preparation of Compound 2-(4-amino-2-(4-(tert-butyl)phenyl)-7-oxo-6,7-dihydro-2H-pyrazolo[3,4-d]pyridazin-3-yl)-N-cyclopentyl-3-methylbenzofuran-6-carboxamide (A069)

[0281] Compound A069 was prepared in the same manner as in Example 1, except that C-2-ptBu was used instead of C-2-pCF3 and ACp-2 was used instead of A-5. The product was a light yellow solid, and the reaction yield was 64%. 1H NMR (600MHz, DMSO-d6) δ11.49(s,1H),8.36(d,J=7.2Hz,1H),8.11(s,1H),7.86(dd,J=8.2,1.4Hz,1H),7.72(d,J=8.2Hz,1H),7.51-7.45(m ,2H),7.41-7.36(m,2H),5.20(s,2H),4.25(dt,J=10.6,6.8Hz,1H),1.92(s,3H),1.91-1.85(m,2H),1.75-1.66(m,2H),1.59-1.50(m,4H). 13 C NMR(151MHz,DMSO-d6)δ165.26,154.95,154.09,152.15,143.14,143.04,139.50,136.47,132.69,130.87,127.03,126 .22,124.07,122.58,120.22,119.84,115.01,110.54,51.09,34.56,32.13,30.90,23.66,8.08.HRMS[ESI]:calculated for C 30 H 33 N6O3[M+H] + :525.2609,found:525.2609.

[0282] Example 69 Preparation of Compound 2-(4-amino-2-(4-(tert-butyl)phenyl)-7-oxo-6,7-dihydro-2H-pyrazolo[3,4-d]pyridazin-3-yl)-N-cyclohexyl-3-methylbenzofuran-6-carboxamide (A070)

[0283] Compound A070 was prepared in the same manner as in Example 1 except that C-2-ptBu was substituted for C-2-pCF3 and ACh-2 was substituted for A-5. The product was a light yellow solid. The reaction yield of this step was 59%. 1H NMR (500MHz, DMSO-d6) δ11.51(s,1H),8.34(d,J=7.9Hz,1H),8.11(d,J=1.5Hz,1H ),7.85(dd,J=8.2,1.4Hz,1H),7.72(d,J=8.2Hz,1H),7.50-7.45(m,2H),7.41-7.3 5(m,2H),5.21(s,2H),4.03-3.94(m,1H),1.92(s,3H),1.89-1.82(m,2H),1.70-1 .63(m,2H),1.62-1.54(m,4H),1.54-1.48(m,2H),1.48-1.39(m,2H),1.25(s,9H). 13 C NMR(151MHz,DMSO-d6)δ164.46,154.95,154.09,152.15,143.14,143.04,139.48,136.46,132.85,130.84,127.03,126 .22,124.07,120.21,119.83,115.02,110.53,50.60,34.56,34.31,30.90,27.84,23.96,8.07.HRMS[ESI]:calculated for C 32 H 37 N6O3[M+H] + :553.2922,found:553.2923.

[0284] Example 70 Preparation of Compound N-((1r,3S,5R)-adamantan-1-yl)-2-(4-amino-2-(4-(tert-butyl)phenyl)-7-oxo-6,7-dihydro-2H-pyrazolo[3,4-d]pyridazin-3-yl)-3-methylbenzofuran-6-carboxamide (A071)

[0285] Compound A071 was prepared in the same manner as Example 1, except that C-2-ptBu was used instead of C-2-pCF3 and AAd-2 was used instead of A-5. The product was a light yellow solid, and the reaction yield of this step was 63%. 1H NMR(500MHz,DMSO-d6)δ11.51(s,1H),8.07(d,J=1.4Hz,1H),7.80(dd,J=8.2,1.4Hz,1H),7.72-7.67(m,2H),7.50- 7.46(m,2H),7.40-7.36(m,2H),5.19(s,2H),2.10-2.08(m,6H),2.07-2.03(m,4H),1.69-1.63(m,6H),1.25(s,9H). 13 C NMR(151MHz,DMSO-d6)δ165.36,154.95,154.01,152.15,143.11,143.04,139.40,136.44,133.87,130.63,127.02,126.21 ,124.05,122.68,120.07,119.81,115.03,110.68,51.67,40.87,36.09,34.56,30.90,28.90,8.05.HRMS[ESI]:calculated for C 35 H 39 N6O3[M+H] + :591.3078,found:591.3081.

[0286] Example 71 Preparation of Compound 2-(4-amino-2-(4-(tert-butyl)phenyl)-7-oxo-6,7-dihydro-2H-pyrazolo[3,4-d]pyridazin-3-yl)-N-(3,3-difluorocyclobutyl)-3-methylbenzofuran-6-carboxamide (A072)

[0287] Compound A072 was prepared in the same manner as in Example 1, except that C-2-ptBu was used instead of C-2-pCF3 and ACbF-2 was used instead of A-5. The product was a light yellow solid, and the reaction yield was 55%. 1 H NMR (800MHz, DMSO-d6) δ11.50(s,1H),8.90(d,J=6.6Hz,1H),8.11(d,J=1.5Hz,1H),7.86(dd,J=8.2,1.4Hz,1H),7.77(d,J=8.2Hz,1H), 7.50-7.46(m,2H),7.40-7.37(m,2H),5.21(s,2H),4.33-4.27(m,1H),3.00-2.93(m,2H),2.81-2.72(m,1H),1.94(s,3H),1.25(s,9H). 13C NMR (201MHz, DMSO-d6)) δ165.67,154.94,154.07,152.16,143.15,143.05,139.78,136.47,131.75,131.32,126.96,126.22,124.09,122. 44,120.47,119.89,119.55(dd,J=282.7,268.0Hz),115.04,110.57,42.03(t,J=22.3Hz),34.56,34.46(dd,J=19.7,5.6Hz),30.90,8.09. 19 F NMR(753MHz, DMSO-d6)δ-81.89(d,J=193.9Hz),-96.86(dp,J=196.0,16.6Hz).HRMS[ESI]:calculated for C 29 H 29 F2N6O3[M+H] + :547.2264,found:547.2262.

[0288] Example 72 Compound 2-(4-amino-7-oxo-2-(4-(pentafluoro-λ 6 Preparation of 6-methylbenzofuran-2H-pyrazolo[3,4-d]pyridazin-3-yl)-N-(3-fluoro-5-(trifluoromethyl)phenyl)-3-methylbenzofuran-6-carboxamide (A073)

[0289] Compound A073 was prepared in the same manner as in Example 1, except that C-2-pSF5 was used instead of C-2-pCF3 and AF-2 was used instead of A-5. The product was a light yellow solid, and the reaction yield was 58%. 1 H NMR(800MHz,DMSO-d6)δ11.57(s,1H),10.76(s,1H),8.27(d,J=1.4Hz,1H),8.09-8.05(m,4H),8 .00(dd,J=8.2,1.5Hz,1H),7.89(d,J=8.2Hz,1H),7.75-7.72(m,2H),5.33(s,2H),2.04(s,3H). 13C NMR(201MHz,DMSO-d6)δ165.45,162.02(d,J=243.8Hz),154.76,154.10,152.47(t,J=17 .6,16.8Hz),143.74,143.12,141.85(d,J=11.4Hz),141.53,139.57,132.00,131.80,130 .93(qd,J=33.0,9.9Hz),127.47,125.50,123.35(qd,J=273.0,3.9Hz),123.00,120.92,1 20.59,115.49,112.62,111.22,110.47(d,J=26.4Hz),107.36(dd,J=24.6,3.7Hz),8.29. 19 F NMR(753MHz, DMSO-d6)δ85.80(p,J=151.6Hz),64.17(d,J=151.4Hz),-61.50,-109.25(t,J=10.4Hz).HRMS[ESI]:calculated for C 28 H 18 F9N6O3S[M+H] + :689.1012,found:689.1013.

[0290] Example 73 Compound 2-(4-amino-7-oxo-2-(4-(pentafluoro-λ 6 Preparation of 6-methyl-1-thiophene-2-ol (4-[4-(2-thiazolyl)sulfonyl)phenyl)-6,7-dihydro-2H-pyrazolo[3,4-d]pyridazin-3-yl)-N-cyclobutyl-3-methylbenzofuran-6-carboxamide (A074)

[0291] Compound A074 was prepared in the same manner as in Example 1, except that C-2-pSF5 was used instead of C-2-pCF3 and ACb-2 was used instead of A-5. The product was a light yellow solid, and the reaction yield was 50%. 1 H NMR (800MHz, DMSO-d6) δ11.56(s,1H),8.69(d,J=7.5Hz,1H),8.10(d,J=1.5Hz,1H),8.08-8.05(m,2H),7.88(dd,J=8.2,1.4Hz,1H),7.77( d,J=8.1Hz,1H),7.73-7.70(m,2H),5.30(s,2H),4.47-4.40(m,1H),2.25-2.20(m,2H),2.11-2.05(m,2H),2.01(s,3H),1.72-1.64(m,2H). 13C NMR(201MHz,DMSO-d6)δ164.55,154.77,154.22,152.58-152.27(m),143.71,143.11,141.54,138.87,132.56,1 31.02,127.64,127.55-127.36(m),125.46,122.59,120.47,120.45,115.37,110.51,44.70,30.08,14.73,8.29. 19 F NMR (753MHz, DMSO-d6) δ85.82 (p, J = 151.4Hz), 64.18 (d, J = 150.7Hz). HRMS [ESI]: calculated for C 25 H 22 F5N6O3S[M+H] + :581.1389,found:581.1387.

[0292] Example 74 Compound 2-(4-amino-7-oxo-2-(4-(pentafluoro-λ 6 Preparation of 6-methyl-1-thiazolyl-2-yl)-4-thiazolyl-1-sulfonyl)phenyl)-6,7-dihydro-2H-pyrazolo[3,4-d]pyridazin-3-yl)-N-cyclopentyl-3-methylbenzofuran-6-carboxamide (A075)

[0293] Compound A075 was prepared in the same manner as in Example 1, except that C-2-pSF5 was used instead of C-2-pCF3 and ACp-2 was used instead of A-5. The product was a light yellow solid, and the reaction yield was 57%. 1 H NMR (500MHz, DMSO-d6) δ11.55(s,1H),8.36(d,J=7.2Hz,1H),8.11(d,J=1.4Hz,1H),8.09-8.04(m,2H),7.88(dd,J=8.2,1.4Hz,1H),7.76(d, J=8.2Hz,1H),7.74-7.69(m,2H),5.29(s,2H),4.25(h,J=6.9Hz,1H),2.00(s,3H),1.94-1.85(m,2H),1.76-1.65(m,2H),1.61-1.49(m,4H). 13C NMR (126MHz, DMSO-d6) δ165.19,154.77,154.22,143.71,143.10,141.53,138.80,132.87,130.87,127 .65,127.57-127.32(m),125.44,122.66,120.43,120.38,115.38,110.55,51.11,32.13,23.67,8.27. 19 F NMR(471MHz, DMSO-d6)δ85.83(d,J=151.0Hz),64.19(d,J=150.9Hz).HRMS[ESI]:calculated for C 26 H 24 F-5N6O3S[M+H] + :595.1545,found:595.1544.

[0294] Example 75 Compound 2-(4-amino-7-oxo-2-(4-(pentafluoro-λ 6 Preparation of 6-methyl-1-thiazolyl-2-yl-4-thiazolyl-1-sulfonyl)phenyl)-6,7-dihydro-2H-pyrazolo[3,4-d]pyridazin-3-yl)-N-cyclohexyl-3-methylbenzofuran-6-carboxamide (A076)

[0295] Compound A076 was prepared in the same manner as in Example 1, except that C-2-pSF5 was used instead of C-2-pCF3 and ACy-2 was used instead of A-5. The product was a light yellow solid, and the reaction yield was 51%. 1 H NMR (800MHz, DMSO-d6) δ11.55(s,1H),8.28(d,J=7.9Hz,1H),8.10(d,J=1.4Hz ,1H),8.07-8.05(m,2H),7.88(dd,J=8.2,1.4Hz,1H),7.76(d,J=8.1Hz,1H),7. 72-7.70(m,2H),5.28(s,2H),3.81-3.75(m,1H),1.99(s,3H),1.85-1.82(m,2H ),1.76-1.72(m,2H),1.63-1.59(m,1H),1.36-1.27(m,4H),1.16-1.09(m,1H). 13C NMR(201MHz,DMSO-d6)δ164.63,154.77,154.23,152.55-152.24(m),143.71,143.10,141.52,138.80,132.96,130. 87,127.64,127.51-127.38(m),125.44,122.63,120.42,120.38,115.39,110.54,48.55,32.42,25.27,24.96,8.26. 19 F NMR(753MHz,DMSO-d6)δ85.83(p,J=151.5Hz),64.18(d,J=150.3Hz).HRMS[ESI]:calculated for C 27 H 26 F5N6O3S[M+H] + :609.1702,found:609.1703.

[0296] Example 76 Compound 2-(4-amino-7-oxo-2-(4-(pentafluoro-λ 6 Preparation of 6-methyl-1-thiazolyl-2-thiazolyl-4-sulfonyl)phenyl)-6,7-dihydro-2H-pyrazolo[3,4-d]pyridazin-3-yl)-N-cyclohexyl-3-methylbenzofuran-6-carboxamide (A077)

[0297] Compound A077 was prepared in the same manner as Example 1 except that C-2-pSF5 was used instead of C-2-pCF3 and ACh-2 was used instead of A-5. The product was a light yellow solid, and the reaction yield was 55%. 1 H NMR (500MHz, DMSO-d6) δ11.55(s,1H),8.33(d,J=7.9Hz,1H),8.10(d,J=1.4Hz ,1H),8.08-8.03(m,2H),7.87(dd,J=8.2,1.4Hz,1H),7.75(d,J=8.2Hz,1H),7. 73-7.69(m,2H),5.28(s,2H),4.04-3.93(m,1H),1.99(s,3H),1.90-1.81(m,2H ),1.71-1.63(m,2H),1.63-1.55(m,4H),1.54-1.48(m,2H),1.48-1.39(m,2H). 13C NMR (126MHz, DMSO) δ164.39,154.78,154.23,143.72,143.10,141.52,138.78,133.04,130.85,127.65, 127.54-127.34(m),125.44,122.65,120.42,120.37,115.39,110.54,50.63,34.32,27.84,23.97,8.26. 19 F NMR(471MHz, DMSO-d6)δ85.82(p,J=151.0Hz),64.18(d,J=150.8Hz).HRMS[ESI]:calculated for C 28 H 28 F5N6O3S[M+H] + :623.1858,found:623.1860.

[0298] Example 77 Compound 2-(4-amino-7-oxo-2-(4-(pentafluoro-λ 6 Preparation of 6-methyl-1-thiophene-2-yl)-4-nitro-2-thiazolyl-1-sulfonyl)phenyl)-6,7-dihydro-2H-pyrazolo[3,4-d]pyridazin-3-yl)-N-(3,3-difluorocyclobutyl)-3-methylbenzofuran-6-carboxamide (A079)

[0299] Compound A079 was prepared in the same manner as in Example 1, except that C-2-pSF5 was used instead of C-2-pCF3 and ACbF-2 was used instead of A-5. The product was a light yellow solid, and the reaction yield was 45%. 1 H NMR (800MHz, DMSO-d6) δ11.56(s,1H),8.91(d,J=6.6Hz,1H),8.10(d,J=1.4Hz,1H),8.08-8.04(m,2H),7.88(dd,J=8.2,1.5Hz,1 H),7.80(d,J=8.2Hz,1H),7.73-7.69(m,2H),5.30(s,2H),4.33-4.27(m,1H),3.00-2.93(m,2H),2.81-2.73(m,2H),2.01(s,3H). 13CNMR(201MHz,DMSO-d6)δ165.63,154.78,154.20,152.58-152.30(m),143.72,143.12,141.54,139.08,131.94,131.34,127.59,125 .47,122.52,120.64,120.49,119.56(dd,J=282.5,268.0Hz),115.40,110.57,42.03(t,J=22.2Hz),34.49(dd,J=19.7,5.5Hz),8.30. 19 F NMR (753MHz, DMSO-d6) δ85.82 (p, J = 151.3Hz), 64.18 (d, J = 151.1Hz), -81.92 (dt, J = 194.0, 14.4Hz), -96.87 (dp, J = 196.1, 16.6Hz). HRMS [ESI]: calculated for C 25 H 20 F7N6O3S[M+H] + :617.1200,found:617.1199.

[0300] Example 78 Compound 2-(4-amino-7-oxo-2-(4-(pentafluoro-λ 6 Preparation of 6-methyl-1-thiophene-2-yl)-4-nitro-2-thiazolyl-1-sulfonyl)phenyl)-6,7-dihydro-2H-pyrazolo[3,4-d]pyridazin-3-yl)-N-(4,4-difluorocyclohexyl)-3-methylbenzofuran-6-carboxamide (A080)

[0301] Compound A080 was prepared in the same manner as in Example 1, except that C-2-pSF5 was used instead of C-2-pCF3 and ACyF-2 was used instead of A-5. The product was a light yellow solid, and the reaction yield was 69%. 1 H NMR (800MHz, DMSO-d6) δ8.38(d,J=7.7Hz,1H),8.11(d,J=1.5Hz,1H),8.07-8.05(m,2H),7.88(dd,J=8.1,1.4Hz,1H),7.77(d,J=8.2Hz ,1H),7.73-7.69(m,2H),5.29(s,2H),4.05-3.99(m,1H),2.10-2.04(m,2H),2.01-1.92(m,5H),1.92-1.86(m,2H),1.69-1.62(m,2H). 13C NMR(201MHz,DMSO-d6)δ165.12,154.77,154.20,152.55-152.29(m),143.72,143.10,141.52,138.91,132.62,131.03,127.53 -127.37(m),127.45,125.45,122.65,120.45,120.43,115.40,110.63,46.03,31.67(t,J=23.9Hz),27.94(d,J=9.1Hz),8.26. 19 F NMR (753MHz, DMSO-d6) δ85.82 (p, J = 151.0Hz), 64.17 (d, J = 151.0Hz), -92.28 (d, J = 233.6Hz), -98.90 (d, J = 229.1Hz). HRMS [ESI]: calculated for C 27 H 24 F7N6O3S[M+H] + :645.1513,found:645.1512.

[0302] Example 79 Compound 2-(4-amino-7-oxo-2-(4-(pentafluoro-λ 6 Preparation of 6-methyl-N-(tetrahydro-2H-pyran-4-yl)benzofuran-6-carboxamide (A081)

[0303] Compound A081 was prepared in the same manner as in Example 1, except that C-2-pSF5 was used instead of C-2-pCF3 and APO-2 was used instead of A-5. The product was a light yellow solid, and the reaction yield was 72%. 1 H NMR (800MHz, DMSO-d6) δ11.56(s,1H),8.39(d,J=7.7Hz,1H),8.11(d,J=1.4Hz,1H),8.08-8.05(m,2H),7.89(dd,J=8.1,1.4Hz,1H),7.77(d,J=8.2H z,1H),7.73-7.70(m,2H),5.29(s,2H),4.06-4.00(m,1H),3.90-3.86(m,2 H),3.42-3.36(m,2H),2.00(s,3H),1.79-1.75(m,2H),1.63-1.56(m,2H). 13C NMR(201MHz,DMSO-d6)δ164.89,154.78,154.22,152.56-152.25(m),143.72,143.10,141.52,138.88,132.7 0,131.01,127.62,127.54-127.36(m),125.45,122.63,120.45,115.40,110.58,66.18,45.97,32.42,8.27. 19 F NMR(753MHz, DMSO-d6)δ85.83(p,J=151.4Hz),64.18(d,J=151.2Hz).HRMS[ESI]:calculated for C 26 H 24 F5N6O4S[M+H] + :611.1494,found:644.1494.

[0304] Example 80 Preparation of Compound 2-(4-amino-2-(4-(difluoromethyl)phenyl)-7-oxo-6,7-dihydro-2H-pyrazolo[3,4-d]pyridazin-3-yl)-N-(3-fluoro-5-(trifluoromethyl)phenyl)-3-methylbenzofuran-6-carboxamide (A082)

[0305] Compound A082 was prepared in the same manner as in Example 1, except that C-2-pCHF2 was substituted for C-2-pCF3 and AF-2 was substituted for A-5. The product was a light yellow solid, and the reaction yield of this step was 61%. 1 H NMR (800MHz, DMSO-d6) δ11.54(s,1H),10.76(s,1H),8.25(d,J=1.6Hz,1H),8.08-8.04(m,2H),7.98(dd,J=8.2,1.5Hz,1H),7.86(d, J=8.1Hz,1H),7.71-7.68(m,2H),7.65-7.62(m,2H),7.41(dt,J=8.4,2.0Hz,1H),7.09(t,J=55.7Hz,1H),5.31(s,2H),2.02(s,3H). 13C NMR(201MHz,DMSO-d6)δ165.49,162.02(d,J=243.9Hz),154.86,154.03,143.46,143.17,141.87 (d,J=11.5Hz),140.72,139.87,134.83(t,J=22.5Hz),131.99,131.69,130.93(qd,J=32.7,9.7Hz ),127.30,127.07(t,J=6.0Hz),125.18,123.36(qd,J=272.3,3.5Hz),122.95,120.83,120.37,11 5.26, 114.15 (t, J = 236.7Hz), 112.61, 111.16, 110.46 (d, J = 26.4Hz), 107.35 (d, J = 24.8Hz), 8.25. 19 F NMR(753MHz,DMSO-d6)δ-61.50,-109.25(t,J=10.3Hz),-110.52,-110.59.HRMS[ESI]:calculated for C 29 H 18 F6N6O3[M+H] + :613.1417,found:613.1417.

[0306] Pharmacological experiments

[0307] Evaluation of in vitro immunosuppressive activity of biologically active compounds 1

[0308] 1. Experimental Materials

[0309] Female BALB / c mice, 6–8 weeks old, were purchased from Shanghai Slake Laboratory Animal Co., Ltd. Concanavalin A (ConA), bacterial lipopolysaccharide (LPS), and MTT were purchased from Sigma; fetal bovine serum (FBS) was purchased from Hyclone. 3 H-thymidine nucleotide 3 H-TdR (1 μCi / mL) was purchased from PerkinElmer; dimethyl sulfoxide (DMSO) was purchased from Sinopharm Chemical Reagent Co., Ltd.

[0310] 2. Experimental methods:

[0311] [I] MTT assay to detect the non-specific toxicity of compounds to mouse spleen lymphocytes

[0312] Succinate dehydrogenase in the mitochondria of living cells reduces methylthiazolyl blue (MTT) to water-insoluble, blue-purple formazan crystals, whereas dead cells do not. Dissolving the formazan in DMSO and measuring its absorbance at 570 nm indirectly reflects the number of viable cells. Within a certain cell population range, the amount of MTT crystals formed is proportional to the cell number. This assay can be used for cytotoxicity analysis.

[0313] Mouse spleen was prepared into a single cell suspension with a concentration of 8 × 10 5 The cells were plated in 96-well plates, and different concentrations of positive control drugs (cyclosporine A, CsA) and compounds (final concentrations of 100, 40, 16, 2.56, 1.024, 0.41, and 0.164 μM) were added in a volume of 200 μL / well. Corresponding blank controls (cell culture medium without cells) and cell controls (cells only without compounds) were also set up. The cells were cultured in a 37°C, 5% CO2 incubator for 48 hours. 4 hours before the end of the culture, a 5 mg / mL MTT solution was added. At the end of the culture, the supernatant was discarded, 150 μL DMSO was added to each well to dissolve the purple crystals, and the OD value was measured at 570 nM on a microplate reader to calculate the CC of the compound. 50 value.

[0314] [two] 3 H-TdR incorporation assay to determine the effects of compounds on the proliferation of mouse primary spleen lymphocytes induced by mitogens or cluster of differentiation 3

[0315] Mouse spleen was prepared into a single cell suspension with a concentration of 5.5×10 5 Each well was inoculated with 20 μg / mL LPS or 1 μg / mL ConA, and different concentrations of positive control drug (CsA) and compound (final concentrations of 20, 8, 3.2, 1.28, 0.512, 0.205, 0.082, and 0.033 μM) were added and cultured for 48 hours. 8 hours before the end of the culture, 25 μL was added to each well. 3 The cells were harvested onto a glass fiber membrane using a cell harvester, and scintillation fluid was added to measure the amount of 3H-TdR incorporated into the cellular DNA using a Beta counter (MicroBeta Trilux, PerkinElmer). The cpm value represented the cell proliferation.

[0316] 3. Experimental results:

[0317] The results showed (Table 1) that this class of compounds had excellent immunosuppressive activity against T and B lymphocytes.

[0318] Table 1. In vitro immunosuppressive activity test of compounds

[0319] a Comp.2 is the compound reported in J.Med.Chem.2022,65,103-119

[0320] Cyclosporine A (CsA) is a classic immunosuppressive compound and was used as a positive control drug in this experiment. As can be seen from the results in Table 1, this series of compounds has good activity and selectivity against ConA-induced T lymphocyte proliferation and LPS-induced B lymphocyte proliferation. Each compound of the present invention has a better effect than the prior art compounds, especially the closest compound in the prior art, Comp.2. a effect.

[0321] In vitro enzyme activity test of biological activity example 2

[0322] Mobility Shift Assay was used to screen the inhibitory effects of compounds on DDR1 enzyme.

[0323] The general method is as follows:

[0324] 1. Prepare 1x kinase base buffer and stop buffer

[0325] 1x Kinase Base Buffer: 50 mM HEPES, pH 7.5; 0.0015% Brij-35

[0326] Stop buffer: 100 mM HEPES, pH 7.5; 0.015% Brij-35; 0.2% Coating Reagent #3; 50 mM EDTA

[0327] 2. Prepare the compound

[0328] Dilute the compound in DMSO to 50 times the maximum inhibitor concentration required in the reaction. Transfer 100 μL of this compound dilution to a 96-well plate. Add 100 μL of DMSO to two empty wells on the same 96-well plate for a no-compound control and a no-enzyme control, marking this plate as the source plate. (3) Prepare the intermediate plate. Transfer 10 μL of compound from the source plate to a new 96-well plate to serve as the intermediate plate. Add 90 μL of 1x kinase buffer to each well of the intermediate plate. Mix the compound on the intermediate plate on a shaker for 10 minutes.

[0329] 3. Prepare the assay plate

[0330] Transfer 5 μL per well from the 96-well intermediate plate to the 384-well plate in duplicate.

[0331] 4. Kinase reaction

[0332] Prepare a 2.5x enzyme solution by adding kinase to 1x kinase base buffer. Prepare a 2.5x peptide solution by adding FAM-labeled peptide and ATP to 1x kinase base buffer. The assay plate already contains 5 μL of compound in 10% DMSO. Transfer the 2.5x enzyme solution to the assay plate and add 10 μL of 2.5x enzyme solution to each well of a 384-well assay plate. Incubate at room temperature for 10 minutes. Transfer the 2.5x peptide solution to the assay plate and add 10 μL of 2.5x peptide solution to each well of the 384-well assay plate. Incubate the kinase reaction and stop it at 28°C for the desired time. Add 25 μL of stop buffer to stop the reaction.

[0333] 5. Reading and curve fitting

[0334] Copy the conversion data from Caliper; convert the conversion values ​​to inhibition values, Percent inhibition = (max-conversion) / (max-min)*100. "max" represents the DMSO control; "min" represents the low control; fit the data in XLFit Excel add-in version 5.4.0.8 to obtain IC 50 The formula used is: Y = Bottom + (Top - Bottom) / (1 + (IC 50 / X)^HillSlope).

[0335] Table 2. Inhibitory activity of compounds against DDR1 kinase

[0336] The results showed that the compounds of the present invention have good biological activity, and their inhibitory activity against DDR1 kinase is IC 50 The values ​​were <100 nM, and some compounds were even <10 nM.

[0337] Biological Activity Example 3 Pharmacokinetic Experiment in Mice

[0338] 1. Experimental Materials

[0339] BALB / c female mice, 6-8 weeks old, were purchased from Shanghai Slake Laboratory Animal Co., Ltd.

[0340] 2. Experimental methods

[0341] The compounds were administered to mice by intravenous injection and oral gavage, respectively. Blood was then collected at different time points. After the blood was processed, the concentration of the test substance in mouse plasma was determined by LC-MS / MS and the in vivo pharmacokinetic parameters were calculated.

[0342] The experimental procedures were as follows: First, the compounds were dissolved in 10% DMSO + 40% PEG400 + 50% water for injection to obtain clear, neutral solutions of varying concentrations, which were then administered orally to mice. Blood samples were collected from the jugular vein at various time points after intravenous and oral administration. The blood samples were anticoagulated with sodium heparin and placed on ice. Plasma was separated by centrifugation and analyzed using LC-MS / MS.

[0343] 3. The experimental results are shown in Table 3:

[0344] Table 3 Pharmacokinetic parameters of Comp.2, A043 and A048 in mice

[0345] a Comp.2 is a compound reported in J.Med.Chem.2022,65,103-119. After oral administration of 5 mg / kg of the compound, the plasma exposure was essentially zero, indicating that the compound has poor pharmacokinetic properties.

[0346] The results showed that the compounds A043 and A048 of the present invention both had improved pharmacokinetics compared to Comp.2, while Comp.2 had almost no plasma exposure after oral administration, suggesting that the compounds of the present invention had unexpected pharmacokinetic improvements.

[0347] Biological Activity Example 4 In vivo pharmacodynamic evaluation in a rheumatoid arthritis mouse (CIA) model

[0348] 1. Experimental Materials

[0349] DBA / 1 mice, male, 4 weeks old, were purchased from Beijing Weitonglihua Laboratory Animal Technology Co., Ltd. Type II collagen was purchased from Chondrex; Freund's complete adjuvant (CFA) and Freund's incomplete adjuvant (IFA) were purchased from Sigma; and methotrexate was purchased from Furen Pharmaceutical.

[0350] 2. Experimental methods:

[0351] (1) Modeling agent configuration

[0352] 10 mg of bovine type II collagen was swollen in 2.5 ml of 0.1 M glacial acetic acid at 4°C overnight to prepare a 4 mg / ml solution, which was fully emulsified with an equal volume of CFA or IFA.

[0353] (2) Establishment and evaluation of collagen-induced arthritis model in mice

[0354] The modeling agent fully emulsified with CFA was injected subcutaneously at the base of the mouse tail in 50 μl. 21 days later, the modeling agent fully emulsified with IFA was injected subcutaneously at the base of the mouse tail in 50 μL for booster immunization. 14 days after booster immunization, the mice were grouped according to the arthritis score standard (Table 3). The normal control group, model group, positive drug group (methotrexate 1 mg / kg), and A048 group (10 mg / kg, 3 mg / kg, 1 mg / kg) treatment groups were set up, and the drugs were administered orally by gavage.

[0355] Table 3. Arthritis scoring criteria

[0356] (3) Detection of spleen lymphocyte proliferation in CIA mice

[0357] Lymphocytes from each group of mice were prepared and stimulated with LPS (10ug / ml), ConA (1ug / ml), anti-CD3 (5ug / ml), and bovine type II collagen (100ug / ml). ConA and LPS stimulation lasted for 48 hours, anti-CD3 antibody stimulation for 72 hours, and bovine type II collagen stimulation for 96 hours. 3 The cell proliferation was detected by H incorporation method.

[0358] 3. Experimental results:

[0359] The experimental results are shown in Figure 1. A048 can significantly improve the pathogenesis index of CIA mice, inhibit the proliferation response of mouse lymphocytes induced by LPS, ConA and anti-CD3 antibodies, and inhibit the specific proliferation response of mouse lymphocytes induced by bovine type II collagen, showing significant in vivo immunosuppressive activity.

[0360] Biological Activity Example 5 In vivo pharmacodynamic evaluation in a mouse model of systemic lupus erythematosus

[0361] Urinary protein is one of the main manifestations of systemic lupus erythematosus and lupus nephritis. It is an important indicator affecting renal function and an important parameter for judging the efficacy and severity of the disease. In addition, the ratio of urine protein to creatinine is an important indicator for detecting kidney damage.

[0362] 1. Experimental Materials

[0363] MRL / lpr spontaneous systemic lupus erythematosus mice, 6–7 weeks old, were purchased from Shanghai Slake Laboratory Animal Co., Ltd. Creatinine assay kit was purchased from Nanjing Jiancheng Biological Company, and Coomassie Brilliant Blue was purchased from Tiangen Biochemical Technology Co., Ltd.

[0364] 2. Experimental methods

[0365] (1) Proteinuria and urine creatinine determination

[0366] At least 10 μL of urine was collected from each mouse using the bladder massage method. The urine protein content was determined by Coomassie Brilliant Blue, and the urine creatinine level was determined by a creatinine kit.

[0367] (2) Grouping and drug administration

[0368] Starting at 9 weeks of age, mice were treated with A048 orally. Mice were divided into a model group, a positive drug group (prednisone acetate, 2 mg / kg), and an A048 treatment group (10 mg / kg, 3 mg / kg, and 1 mg / kg), with 8 mice per group. Urinary protein and creatinine levels were measured weekly to investigate the therapeutic effect of A048 on mice with systemic lupus erythematosus.

[0369] 3. Experimental results:

[0370] The results are shown in Figure 2. A048 can significantly reduce the proteinuria level (Figure 2A) and urine protein to creatinine ratio (Figure 2B) of MRL / lpr mice, indicating that A048 has a good therapeutic effect on spontaneous systemic lupus erythematosus in MRL / lpr mice and has good application prospects in the clinical treatment and adjuvant treatment of systemic lupus erythematosus and lupus nephritis.

[0371] Biological Activity Example 6 Acute Toxicity Evaluation of A048 in Mice

[0372] 1. Experimental Materials

[0373] Female BALB / c mice were purchased from Shanghai Lingchang Biotechnology Co., Ltd.

[0374] 2. Experimental methods:

[0375] The acute toxicity of compound A048 after a single dose was investigated. BALB / c mice were randomly divided into four groups based on body weight: a normal control group and A048 2000 mg / kg, 600 mg / kg, and 200 mg / kg groups, with four mice in each group. Dosing was performed once on the day of grouping. Immediately after dosing, the animals were observed for any toxic reactions. The activity of the mice was closely monitored within 4 hours of dosing. Thereafter, the mice were observed twice daily for survival and weight changes were monitored regularly.

[0376] 3. Experimental results

[0377] The experimental results, shown in Figure 3, showed no significant abnormalities in activity within 4 hours of A048 administration. No animals died during the dosing period, and animal weight began to recover starting on the third day of dosing. These results demonstrate the compound's good safety.

[0378] All documents mentioned in this application are incorporated herein by reference, just as if each document were incorporated herein by reference individually. It should also be understood that after reading the above teachings of the present invention, those skilled in the art may make various changes or modifications to the present invention, and that such equivalents also fall within the scope of the claims appended hereto.

Claims

1. A compound as represented by formula (I) and a pharmaceutically acceptable salt thereof, in, X is selected from NH, S, O; Selected from: a substituted or unsubstituted C6-C12 aryl group, a substituted or unsubstituted 4-12 membered heterocyclic group, or a substituted or unsubstituted 5-12 membered heteroaryl group, wherein the heterocyclic group and the heteroaryl group contain 1-4 heteroatoms selected from oxygen, sulfur and nitrogen as the ring skeleton; wherein the substitution refers to that the group A is substituted by one or more L groups, and each L is independently selected from the following group: a C1-C12 straight chain or branched alkyl group, a C1-C6 straight chain or branched haloalkyl group, a C1-C6 straight chain or branched alkylthio group, a C1-C6 straight chain or branched alkoxy group, a C1-C6 straight chain or branched haloalkoxy group, a C1-C6 straight chain or branched haloalkylthio group, NO2, NH2, -NHC(O)R 1 、-C(O)NHR 1 、-NHC(O)OR 1 、-COR 1 、-SO2R 1 , -SF5, C3-C8 cycloalkyl (including saturated or partially unsaturated), C6-C10 aryl, phenoxy, benzyloxy, NHC(O)benzyl, C(O)-5-7 membered heterocyclic group; and said L may be further substituted by 1-3 Re; said Re is selected from the following group: halogen, trifluoromethyl, difluoromethyl, C1-C4 straight chain or branched alkyl; or any two substituents L located at adjacent atoms may together form a 5-12 membered heterocyclic group; Among them, R 1 is H, C1-C4 alkyl, C1-C4 haloalkyl, -NR 2 R 3 ; R 2 、R 3 Each independently represents H, C1-C4 alkyl, or the R 2 and R 3 Together they constitute a 5-12 membered heterocyclic group; R5 is selected from the group consisting of: H, halogen, and halogen-substituted C1-C4 alkyl.

2. The compound according to claim 1 and a pharmaceutically acceptable salt thereof, wherein The Selected from: substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl; The substitution mentioned herein refers to the substitution of group A by one or more L groups, and each L is independently selected from the following groups: halogen, trifluoromethyl, difluoromethyl, C1-C12 straight or branched alkyl, C1-C6 straight or branched alkoxy, C1-C6 straight or branched alkylthio, C3-C12 cycloalkyl, -SO2R 1 、-COR 1 NHCOOR 1 , nitro, amino, trifluoromethoxy, trifluoromethylthio, pentafluorosulfur, C6-C10 aryl, phenoxy; and the L can be further substituted by 1-3 Re; the Re is selected from the following group: halogen, trifluoromethyl, difluoromethyl, C1-C4 straight or branched alkyl; or any two substituents L located at adjacent atoms can together form a 5-8 membered heterocyclic group; wherein R 1 As claimed in claim 1.

3. The compound according to claim 1 and a pharmaceutically acceptable salt thereof, wherein Selected from the following structural fragments:

4. A compound represented by formula (II) and a pharmaceutically acceptable salt thereof, in, X is selected from NH, S, O; R 4 is a substituted or unsubstituted C6-C12 aryl group, a substituted or unsubstituted C4-C12 cycloalkyl group, a substituted or unsubstituted 4-12 membered heterocyclyl group, or a substituted or unsubstituted 5-12 membered heteroaryl group, wherein the heterocyclyl group and the heteroaryl group contain 1-4 heteroatoms selected from oxygen, sulfur and nitrogen as the ring skeleton, wherein the substitution refers to that one or more hydrogen atoms on the group are replaced by a substituent selected from the group consisting of halogen and halogen-substituted C1-C4 alkyl; Selected from: a substituted or unsubstituted C6-C12 aryl group, a substituted or unsubstituted 4-12 membered heterocyclic group, or a substituted or unsubstituted 5-12 membered heteroaryl group, wherein the heterocyclic group and the heteroaryl group contain 1-4 heteroatoms selected from oxygen, sulfur and nitrogen as the ring skeleton; wherein the substitution refers to that one or more hydrogen atoms on the group are replaced by substituents independently selected from the following groups: a C1-C12 straight chain or branched alkyl group, a C1-C6 straight chain or branched haloalkyl group, a C1-C6 straight chain or branched alkylthio group, a C1-C6 straight chain or branched alkoxy group, a C1-C6 straight chain or branched haloalkoxy group, a C1-C6 straight chain or branched haloalkylthio group, NO2, NH2, -NHC(O)R 1 、-C(O)NHR 1 、-NHC(O)OR 1 、-COR 1 、-SO2R 1 , -SF5, C3-C8 cycloalkyl (including saturated or partially unsaturated), C6-C10 aryl, phenoxy, benzyloxy, NHC(O)benzyl, C(O)-5-7 membered heterocyclic group; and the substituents may be further substituted by 1-3 Re; the Re is selected from the following group: halogen, trifluoromethyl, difluoromethyl, C1-C4 straight or branched alkyl; or any two substituents located at adjacent atoms may together constitute a 5-12 membered heterocyclic group or C6-C10 aryl; L is selected from C1-C6 straight chain or branched alkylthio, C1-C6 straight chain or branched alkoxy, C1-C6 straight chain or branched fluoroalkoxy, -SO2R 1 , -SF5, cyclopropane, NO2, benzyloxy, NH2, NHC(O)benzyl, phenyl, C(O)-5-7 membered heterocyclic group; and said L may be further substituted by 1-3 Re; said Re is selected from the following group: halogen, trifluoromethyl, difluoromethyl, C1-C4 straight chain or branched alkyl; Among them, R 1 C1-C4 alkyl, C1-C4 haloalkyl, -NR 2 R 3 ; R 2 、R 3 Each independently represents H, C1-C4 alkyl, or the R 2 and R 3 Together they constitute a 5-12 membered heterocyclic group.

5. The compound according to claim 4 and a pharmaceutically acceptable salt thereof, wherein: R 4 Selected from the following groups: substituted or unsubstituted phenyl, substituted or unsubstituted C4-C7 cycloalkyl, substituted or unsubstituted 4-7 membered heterocyclyl; wherein the substitution refers to that one or more hydrogen atoms on the group are replaced by a substituent selected from the following group: trifluoromethyl, difluoromethyl, halogen.

6. The compound according to claim 4 and a pharmaceutically acceptable salt thereof, wherein: R 4 Select from the following groups:

7. The compound according to claim 1 or 4 and a pharmaceutically acceptable salt thereof, wherein: Select from the following groups:

8. Use of the compound of formula (I) and a pharmaceutically acceptable salt thereof according to claim 1 or the compound of formula (II) and a pharmaceutically acceptable salt thereof according to claim 4, characterized in that: For preparing a pharmaceutical composition for treating a disease associated with DDR1 enzyme activity or expression, wherein the disease associated with DDR1 enzyme activity or expression is selected from the following group: rheumatoid arthritis, systemic lupus erythematosus, lupus nephritis, scleroderma, polymyositis, dermatomyositis, Sjögren's syndrome, Graves' disease, Hashimoto's thyroiditis, psoriasis, vitiligo, asthma, psoriasis, idiopathic pulmonary fibrosis, vasculitis, glomerulonephritis (kidney inflammation), antiphospholipid antibody syndrome, autoimmune liver disease, inflammatory bowel disease and multiple sclerosis; preferably, the disease is rheumatoid arthritis or systemic lupus erythematosus.

9. The use according to claim 8, characterized in that Also includes: (a) preparing DDR1 targeted inhibitors; (b) preparing an in vitro reagent for inhibiting DDR1 enzyme activity; (c) preparing an in vitro reagent for inhibiting T and B lymphocyte proliferation; (d) preparing a pharmaceutical composition for treating a disease associated with overactivation of T and B lymphocytes; preferably, the disease is an autoimmune disease, more preferably selected from the group consisting of rheumatoid arthritis, systemic lupus erythematosus, lupus nephritis, scleroderma, Sjögren's syndrome, psoriasis, vitiligo, asthma, psoriasis, idiopathic pulmonary fibrosis, antiphospholipid antibody syndrome, autoimmune liver disease, inflammatory bowel disease and multiple sclerosis.

10. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises: (i) an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a compound of formula (II) or a pharmaceutically acceptable salt thereof; and (ii) a pharmaceutically acceptable carrier.

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