HK1193090A - Heterocyclic compounds as pi3 kinase inhibitors - Google Patents

Description

Heterocyclic compounds as PI3 kinase inhibitors

Technical Field

The present invention relates generally to compounds useful for treating disorders mediated by lipid kinases (lipid kinases), such as inflammation, immunological disorders and cancer, and more particularly to compounds that inhibit the activity of PI3 kinase. The invention also relates to methods of using the compounds for in vitro, in situ, and in vivo diagnosis or treatment of mammalian cells or associated pathological conditions.

Background

Phosphatidylinositol (PI), a phospholipid found in cell membranes, plays an important role in intracellular signal transduction. Cellular signaling through 3' -phosphorylated inositol phosphates has been shown to be involved in a number of cellular processes, such as malignant transformation, growth factor signaling, inflammation and immunity (Rameh et al (1999) J. biol Chem,274: 8347-8350). The enzyme responsible for the production of these phosphorylated signaling products, phosphatidylinositol 3-kinase (also known as PI 3-kinase or PI3K), was originally identified as having activity related to the viral oncogene protein and growth factor receptor tyrosine kinase that phosphorylates Phosphatidylinositol (PI) and its phosphorylated derivatives on the 3' -hydroxyl of the inositol ring (Panayotou et al (1992) trends cell Biol2: 358-60).

Phosphoinositide 3-kinases (PI3K) are lipid kinases that phosphorylate lipids located on the 3-hydroxyl residue of the inositol ring of phosphoinositides (Whitman et al (1988) Nature,332: 664). The 3' -phosphorylated phospholipids produced by PI 3-kinase (PIP3) act as second messengers that recruit kinases such as Akt and phosphoinositide-dependent kinase-1 (PDK1) with lipid binding domains, including the Plekstrin Homology (PH) domain. Binding of Akt to membrane PIP3 translocates Akt to the plasma membrane, thereby contacting Akt with PDK1, which is responsible for activating Akt. The tumor suppressor phosphatase PTEN dephosphorylates PIP3 and thus acts as a negative regulator of Akt activation. The PI 3-kinases Akt and PDK1 are important in the regulation of a number of cellular processes including cell cycle regulation, proliferation, survival, apoptosis and motility, and are important components of the molecular mechanisms of diseases such as Cancer, diabetes and immune inflammation (Vivanco et al (2002) Nature Rev. Cancer2:489; Phillips et al (1998) Cancer83: 41).

PI3 kinase is a heterodimer composed of p85 and p110 subunits (Otsu et al (1991) Cell65:91-104; Hiles et al (1992) Cell70: 419-29). Four different class I PI3K have been identified, designated PI3K α (alpha), β (beta), δ (delta), and γ (gamma), respectively, each of which consists of a different catalytic and regulatory subunit of 110 kDa. More specifically, three of the catalytic subunits, i.e., p110 α, p110 β, and p110 δ, each interact with the same catalytic subunit p 85; whereas p110 γ interacts with a different regulatory subunit p 101. The expression pattern of each of these PI3K in mammalian cells and tissues is also different.

The p110 delta isoform has been shown to be involved in biological functions associated with immune-inflammatory diseases including signaling from B-cell receptors, T-cell receptors, FcR signaling of mast cells and monocytes/macrophages, and osteoclast function/RANKL signaling (Berndt et al (2010) NatureChemical Biology; Williams et al (2010) Chem. & biol.17:123-134; Chantry et al (1997) journal. of biol. chem.272(31):19236-19241; Deane J and Fruman DA (2004) Annu. Rev. Immunol.2004.22:563-98; Janas et al (2008) the journal of Immunology 180:739-746; Marone R et al (biochem. Biophy.acta,1784: 159-185. PI 83. K) and selective elimination of the delta gene introduced or the delta I K mutant of T-signaling by almost complete deletion of cells and proliferation of the delta mutant also rendered cells inactive by the introduction of PI3, and proliferation almost complete elimination of the mutant.

Summary of The Invention

The present invention relates to heterocyclic (including 4-substituted pyrimidine) compounds of formula I having PI3 kinase inhibitory activity and binding selectively to the p110 δ isoform relative to the p110 α isoform.

The compounds of formula I have the structure:

and stereoisomers, geometric isomers, tautomers and pharmaceutically acceptable salts thereof. The various substituents are as defined herein.

Another aspect of the invention provides a pharmaceutical composition comprising a compound of formula I and a pharmaceutically acceptable carrier, glidant, diluent, or excipient. Another aspect of the invention provides a pharmaceutical composition further comprising a chemotherapeutic agent.

Another aspect of the invention provides a method of preparing a pharmaceutical composition comprising combining a compound of formula I with a pharmaceutically acceptable carrier.

Another aspect of the invention provides the use of a compound of formula I in the manufacture of a medicament for the treatment of a disease or disorder selected from cancer, immune disorders, cardiovascular disease, viral infection, inflammation, metabolic/endocrine function disorders and neurological disorders and mediated by PI3 kinase (including selective inhibition of the p110 δ isoform).

The invention also relates to methods of using compounds of formula I for in vitro, in situ, and in vivo diagnosis or treatment of mammalian cells, biological, or associated pathological conditions such as cancer, systemic and local inflammation, immune-inflammatory diseases such as rheumatoid arthritis, immunosuppression, organ transplant rejection (organ transplant rejection), allergy, ulcerative colitis, crohn's disease, dermatitis, asthma, systemic lupus erythematosus, sjogren's syndrome, multiple sclerosis, scleroderma/systemic sclerosis, Idiopathic Thrombocytopenic Purpura (ITP), anti-neutrophil cytoplasmic antibody (ANCA) vasculitis, Chronic Obstructive Pulmonary Disease (COPD), psoriasis, and methods of using compounds of formula I for overall joint protection.

Another aspect of the invention provides a method of treating a disease or disorder comprising administering a compound of formula I to a patient having a disease or disorder selected from cancer, immune disorders, cardiovascular disease, viral infection, inflammation, metabolic/endocrine dysfunction and neurological disorders and mediated by the p110 δ, β or α isoform of PI3 kinase. In another aspect, the disease or disorder is an immune disorder. The method may further comprise administering an additional therapeutic agent selected from the group consisting of chemotherapeutic agents, anti-inflammatory agents, immunomodulatory agents, neurotropic factors (neurotropic factors), agents for treating cardiovascular diseases, agents for treating liver diseases, antiviral agents, agents for treating hematologic disorders, agents for treating diabetes, and agents for treating immunodeficiency disorders.

Methods of treating cancer include where the cancer is breast cancer, ovarian cancer, cervical cancer, prostate cancer, testicular cancer, genitourinary tract cancer, esophageal cancer, laryngeal cancer, glioblastoma, neuroblastoma, gastric cancer, skin cancer, keratoacanthoma, lung cancer, epidermoid carcinoma, large cell carcinoma, non-small cell lung cancer (NSCLC), small cell carcinoma, lung adenocarcinoma, bone cancer, colon cancer, adenoma, pancreatic cancer, adenoma, thyroid cancer, follicular carcinoma, undifferentiated carcinoma (undivided carcinoma), papillary carcinoma, seminoma, melanoma, sarcoma, bladder cancer, liver and biliary tract cancer, kidney cancer, pancreatic cancer, myeloid disorders, lymphoma, hairy cell carcinoma, buccal cavity cancer, nasopharyngeal carcinoma, pharyngeal cancer, lip cancer, tongue cancer, oral cancer, small bowel cancer, colon-rectal cancer, large bowel cancer, rectal cancer, cancer of the brain and central nervous system, Hodgkin's disease (Hodgkin's), colon-rectal cancer, colorectal cancer, cancer of the brain and central nervous system, cancer of the esophagus cancer, cancer of the larynx, or colon-rectum, or prostate cancer, or colorectal cancer, or a cancer, or, Methods of leukemia, bronchial carcinoma, thyroid carcinoma, hepatic and intrahepatic bile duct carcinoma, hepatocellular carcinoma, gastric carcinoma, glioma/glioblastoma, endometrial carcinoma, melanoma, renal and renal pelvis carcinoma, bladder carcinoma, uterine body (uterine corppus) carcinoma, cervical carcinoma, multiple myeloma, acute myelogenous leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, lymphocytic leukemia, myelogenous leukemia, oral and pharyngeal carcinoma, non-hodgkin's lymphoma, melanoma, or villous colon adenoma (villous colon adenomona).

In another embodiment, the disease or disorder is systemic and local inflammation, arthritis, inflammation associated with immune suppression, organ transplant rejection, allergy, ulcerative colitis, crohn's disease, dermatitis, asthma, systemic lupus erythematosus, sjogren's syndrome, multiple sclerosis, scleroderma/systemic sclerosis, Idiopathic Thrombocytopenic Purpura (ITP), anti-neutrophil cytoplasmic antibody (ANCA) vasculitis, Chronic Obstructive Pulmonary Disease (COPD), psoriasis.

Another aspect of the invention provides a kit for treating a disorder mediated by the p110 δ isoform of PI3 kinase, comprising: a first pharmaceutical composition comprising a compound of formula I; and instructions for use.

Other aspects of the invention include: (i) a method of preventing or treating a condition, disorder or disease mediated by activation of PI3K kinase in a subject in need of such treatment, which method comprises administering to said subject an effective amount of a compound of formula I, in free form or in pharmaceutically acceptable salt form, for use as a medicament, in any of the methods set forth herein; (ii) a compound of formula I in free form or in pharmaceutically acceptable salt form for use as a medicament, in particular for use in one or more phosphatidylinositol 3-kinase (PI3K) -mediated diseases in any of the methods set forth herein; (iii) use of a compound of formula I, in free form or in pharmaceutically acceptable salt form, in any of the methods set forth herein, particularly for the treatment of one or more phosphatidylinositol 3-kinase mediated diseases; (iv) use of a compound of formula I, in free form or in pharmaceutically acceptable salt form, in any of the methods set forth herein, particularly for the manufacture of a medicament for the treatment of one or more phosphatidylinositol 3-kinase mediated diseases.

Detailed description of exemplary embodiments

Reference will now be made in detail to certain embodiments of the invention, examples of which are illustrated in the accompanying structures and formulas. While the invention will be described in conjunction with the enumerated embodiments, it will be understood that the invention is not limited to those embodiments. On the contrary, the invention is intended to cover all alternatives, modifications and equivalents, which may be included within the scope of the invention as defined by the appended claims. Those of skill in the art will recognize many methods and materials similar or equivalent to those described herein that can be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described. Where one or more of the documents, patents, and similar materials incorporated herein are different from or contradictory to this application (including but not limited to defined terms, usage of terms, described techniques, etc.), the present invention shall control.

Definition of

The term "alkyl" as used herein refers to 1 to 12 carbon atoms (C)₁-C₁₂) Wherein the alkyl group may be optionally independently substituted with one or more substituents described below. In another embodiment, alkyl is 1 to 8 carbon atoms (C) ₁-C₈) Or 1 to 6 carbon atoms (C)₁-C₆) In (1). Examples of alkyl groups include, but are not limited to, methyl (Me, -CH)₃) Ethyl (Et-CH)₂CH₃) 1-propyl (n-Pr, n-propyl, -CH)₂CH₂CH₃) 2-propyl (i-Pr, i-propyl, -CH (CH)₃)₂) 1-butyl (n-Bu, n-butyl, -CH)₂CH₂CH₂CH₃) 2-methyl-1-propyl (i-Bu, i-butyl, -CH)₂CH(CH₃)₂) 2-butyl (s-Bu, sec-butyl, -CH (CH)₃)CH₂CH₃) 2-methyl-2-propyl (t-Bu, t-butyl, -C (CH)₃)₃) 1-pentyl (n-pentyl, -CH)₂CH₂CH₂CH₂CH₃) 2-pentyl (-CH (CH)₃)CH₂CH₂CH₃) 3-pentyl (-CH (CH)₂CH₃)₂) 2-methyl-2-butyl (-C (CH)₃)₂CH₂CH₃) 3-methyl-2-butyl (-CH (CH)₃)CH(CH₃)₂) 3-methyl-1-butyl (-CH)₂CH₂CH(CH₃)₂) 2-methyl-1-butyl (-CH)₂CH(CH₃)CH₂CH₃) 1-hexyl (-CH)₂CH₂CH₂CH₂CH₂CH₃) 2-hexyl (-CH (CH)₃)CH₂CH₂CH₂CH₃) 3-hexyl (-CH (CH)₂CH₃)(CH₂CH₂CH₃) 2-methyl-2-pentyl (-C (CH))₃)₂CH₂CH₂CH₃) 3-methyl-2-pentyl (-CH (CH)₃)CH(CH₃)CH₂CH₃) 4-methyl-2-pentyl (-CH (CH)₃)CH₂CH(CH₃)₂) 3-methyl-3-pentyl (-C (CH)₃)(CH₂CH₃)₂) 2-methyl-3-pentyl (-CH (CH)₂CH₃)CH(CH₃)₂) 2, 3-dimethyl-2-butyl (-C (CH)₃)₂CH(CH₃)₂) 3, 3-dimethyl-2-butyl (-CH (CH)₃)C(CH₃)₃1-heptyl, 1-octyl, and the like.

The term "alkylene" as used herein refers to 1 to 12 carbon atoms (C)₁-C₁₂) Wherein the alkylene group may be optionally independently substituted with one or more substituents described below. In another embodiment, alkylene is 1 to 8 carbon atoms (C) ₁-C₈) Or 1 to 6 carbon atoms (C)₁-C₆) In (1). Examples of alkylene groups include, but are not limited to, methylene (-CH)₂-) ethylene (-CH₂CH₂-) propylene (-CH)₂CH₂CH₂-) and the like.

The term "alkenyl" refers to a group having at least one site of unsaturation, i.e., a carbon-carbon sp²2 to 8 carbon atoms (C) of a double bond₂-C₈) Wherein the alkenyl group may be optionally substituted independently with one or more substituents described herein, including groups having "cis" and "trans" orientations or "E" and "Z" orientations. Examples include, but are not limited to, vinyl (-CH ═ CH)₂) Allyl (-CH)₂CH＝CH₂) And the like.

The term "alkenylene" refers to a compound having at least one site of unsaturation, i.e., a carbon-carbon sp²2 to 8 carbon atoms (C) of a double bond₂-C₈) Wherein the alkenyl group may be optionally substituted, including having a "cis" or branched divalent hydrocarbon groupGroups of formula "and" trans "orientation or" E "and" Z "orientation. Examples include, but are not limited to, ethenylene (-CH-), allyl (-CH-)₂CH-) and the like.

The term "alkynyl" refers to 2 to 8 carbon atoms (C) having at least one site of unsaturation, i.e., a carbon-carbon sp triple bond₂-C₈) Wherein the alkynyl group may be optionally independently substituted with one or more substituents described herein. Examples include, but are not limited to, ethynyl (-C ≡ CH), propynyl (propargyl, -CH) ₂C.ident.CH) and the like.

The term "alkynylene" refers to 2 to 8 carbon atoms (C) having at least one site of unsaturation, i.e., a carbon-carbon sp triple bond₂-C₈) Wherein the alkynyl group may be optionally substituted. Examples include, but are not limited to, ethynylene (-C ≡ C-), propynyl (propargylene, -CH)₂C.ident.C-), and the like.

The terms "carbocycle", "carbocyclyl", "carbocyclic ring" and "cycloalkyl" refer to monovalent non-aromatic saturated or partially unsaturated compounds having 3 to 12 carbon atoms (C)₃-C₁₂) Or a bicyclic ring having 7 to 12 carbon atoms. Bicyclic carbocycles having 7 to 12 atoms may be substituted by, for example, bicyclo [4,5 ]]、[5,5]、[5,6]Or [6,6 ]]Arranged in the form of a system, the bicyclic carbocyclic ring having 9 or 10 ring atoms may be bicyclic [5,6 ]]Or [6,6 ]]Arranged in the form of a system, or in the form of a bridged system, e.g. bicyclo [2.2.1]Heptane, bicyclo [2.2.2]Octane and bicyclo [3.2.2]Nonane. Examples of monocyclic carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, adamantyl, and the like.

"aryl" means 6 to 20 carbon atoms (C) derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system₆-C₂₀) A monovalent aromatic hydrocarbon group of (2). Some aryl groups are represented in the example structures as "Ar". Aryl includes bicyclic radicals comprising an aromatic ring fused to a saturated, partially unsaturated ring or an aromatic carbon ring. Typical aryl groups include, but are not limited to, groups derived from benzene (phenyl), substituted benzenes, naphthalenes, anthracenes, biphenyls, indenyls, indanyl, 1, 2-dihydronaphthalene, 1,2,3, 4-tetrahydronaphthyl, and the like. Aryl is optionally independently substituted with one or more substituents described herein.

"arylene" means 6 to 20 carbon atoms (C) derived by the removal of two hydrogen atoms from two carbon atoms of a parent aromatic ring system₆-C₂₀) A divalent aromatic hydrocarbon group of (1). Some arylene groups are represented as "Ar" in the example structures. Arylene includes bicyclic radicals comprising an aromatic ring fused to a saturated, partially unsaturated ring or an aromatic carbon ring. Typical arylene groups include, but are not limited to, groups derived from benzene (phenylene), substituted benzenes, naphthalene, anthracene, biphenyl, indenylene, indanyl, 1, 2-dihydronaphthalene, 1,2,3, 4-tetrahydronaphthyl, and the like. Arylene is optionally substituted.

The terms "heterocycle", "heterocyclyl" and "heterocyclic ring" are used interchangeably herein and refer to a saturated or partially unsaturated (i.e., having one or more double and/or triple bonds within the ring) carbocyclic group in which at least one ring atom is a heteroatom selected from nitrogen, oxygen, phosphorus and sulfur, the remaining ring atoms being 3 to about 20 ring atoms of C, wherein one or more ring atoms are optionally independently substituted with one or more substituents described below. The heterocyclic ring may be a monocyclic ring having 3 to 7 ring members (2 to 6 carbon atoms and 1 to 4 heteroatoms selected from N, O, P and S) or a bicyclic ring having 7 to 10 ring members (4 to 9 carbon atoms and 1 to 6 heteroatoms selected from N, O, P and S), for example: bicyclo [4,5 ]]、[5,5]、[5,6]Or [6,6 ]]Provided is a system. Heterocycles are described in the following documents: paquette, leoa., "Modern Heterocyclic Chemistry" (w.a. benjamin, new york, 1968), in particular chapters 1, 3, 4, 6, 7 and 9; "heterocyclic Chemistry," A series of monographs (The Chemistry of Heterocyclic Compounds,Aseries of Monographs)”(John Wiley&Sons, new york, 1950 to date), particularly volumes 13, 14, 16, 19 and 28; and j.am.chem.soc. (1960)82: 5566. "Heterocyclyl" also includes groups in which the heterocyclic group is fused to a saturated, partially unsaturated ring or an aromatic carbocyclic or heterocyclic ring. Examples of heterocycles include, but are not limited to, pyrrolidinyl, tetrahydrofuryl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thia Alkyl, piperazinyl, homopiperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepinyl, thiepanyl, oxazepanyl, and oxazepanylOxazepinyl, diazaRadical, sulfur nitrogen heteroRadicals (thiazepinyl), 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, diAlkyl, 1, 3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuryl, dihydroisoquinolinyl, tetrahydroisoquinolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 2-oxa-5-azabicyclo [2.2.2]Octane, 3-oxa-8-azabicyclo [3.2.1]Octane, 8-oxa-3-azabicyclo [3.2.1]Octane, 6-oxa-3-azabicyclo [3.1.1]Heptane, 2-oxa-5-azabicyclo [2.2.1]Heptane, 3-azabicyclo [3.1.0]Hexane radical, 3-azabicyclo [4.1.0 ]]Heptylalkyl, azabicyclo [2.2.2]A hexyl group, a 3H-indolyl group,Quinolizinyl and N-pyridylurea. Spiro groups are also included within the scope of this definition. Examples of heterocyclyl groups in which 1 or 2 ring carbon atoms are substituted by oxo (= O) groups are pyrimidinone groups and 1, 1-dioxo-thiomorpholinyl groups. The heterocyclic groups herein are optionally substituted independently with one or more substituents described herein.

The term "heteroaryl" refers to a monovalent aromatic group of a 5-, 6-, or 7-membered ring, including fused ring systems of 5-20 atoms (wherein at least one ring is aromatic), which contains one or more heteroatoms independently selected from nitrogen, oxygen, and sulfur. Examples of heteroaryl groups are pyridyl (including, e.g., 2-hydroxypyridyl), imidazolyl, imidazopyridyl, pyrimidinyl (including, e.g., 4-hydroxypyrimidinyl), pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furanyl, thienyl, iso-pyridylAzolyl, thiazolyl,A diazolyl group,Oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, cinnolinyl, indazolyl,Oxadiazolyl, triazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxanylAzolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. Heteroaryl groups are optionally independently substituted with one or more substituents described herein.

In the possible placeIn this case, the heterocyclic or heteroaryl group may be carbon (carbon-linked) or nitrogen (nitrogen-linked) bonded. Carbon-bonded heterocycles or heteroaryls are, for example, but not limited to, in the 2, 3, 4, 5 or 6 position of pyridine, in the 3, 4, 5 or 6 position of pyridazine, in the 2, 4, 5 or 6 position of pyrimidine, in the 2, 3, 5 or 6 position of pyrazine, in the 2, 3, 4 or 5 position of furan, tetrahydrofuran, thiophene, pyrrole or tetrahydropyrrole, In the 2, 4 or 5 position of oxazole, imidazole or thiazole, isoThe linkage is made at the 3, 4 or 5 position of the oxazole, pyrazole or isothiazole, at the 2 or 3 position of the aziridine, at the 2, 3 or 4 position of the azetidine, at the 2, 3, 4, 5, 6, 7 or 8 position of the quinoline or at the 1, 3, 4, 5, 6, 7 or 8 position of the isoquinoline. The ring nitrogen atom of the heterocycle or heteroaryl may be bonded to an oxygen to form an N-oxide.

Nitrogen-bonded heterocycles or heteroaryls are, for example, but not limited to, aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline, 1H-indazole, benzimidazole in position 1, isoindole or isoindoline in position 2, morpholine in position 4 and carbazole or β -carboline in position 9.

The term "treatment" refers to both therapeutic treatment and prophylactic or preventative measures, wherein a subject is prevented or slowed (or reduced) from occurring or spreading an undesired physiological change or disorder, such as cancer. For purposes of the present invention, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), including both perceptible and imperceptible. "treatment" also means a prolonged survival compared to the expected survival without receiving treatment. Those in need of treatment include those already with the condition or disorder as well as those susceptible to the condition or disorder or those in which the condition or disorder is prevented.

The phrase "therapeutically effective amount" means an amount of a compound of the invention that (i) treats or prevents a particular disease, condition, or disorder, (ii) attenuates, ameliorates, or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition, or disorder described herein. In the case of cancer, a therapeutically effective amount of the drug may reduce the number of cancer cells; reducing the size of the tumor; inhibit (i.e., slow to some extent and preferably stop) cancer cell infiltration into peripheral organs; inhibit (i.e., slow to some extent and preferably stop) tumor metastasis; inhibit tumor growth to some extent; and/or alleviate one or more symptoms associated with cancer to some extent. To the extent that the drug can prevent the growth and/or kill existing cancer cells, it can be a cytostatic agent and/or a cytotoxic agent. For the treatment of cancer, efficacy can be measured, for example, by assessing time to disease progression (TTP) and/or determining Response Rate (RR).

As used herein, "inflammatory disorder" refers to any disease, disorder or syndrome in which an excessive or uncontrolled inflammatory response results in an excessive inflammatory condition, host tissue damage or loss of tissue function. "inflammatory disorders" also refer to pathological conditions mediated by leukocyte influx and/or neutrophil chemotaxis.

As used herein, "inflammation" refers to a localized protective response triggered by injury or destruction of tissue that serves to destroy, dilute, or separate (isolate) damaging substances and damaged tissue. Inflammation is apparently associated with leukocyte influx and/or neutrophil chemotaxis. Inflammation can be caused by pathogenic microbial and viral infections, as well as by non-infectious means such as reperfusion after trauma or myocardial infarction or stroke, immune response to foreign antigens, and autoimmune response. Thus, inflammatory disorders that may be treated with compounds of formula I include disorders associated with a response to a specific defense system as well as disorders associated with a response to a non-specific defense system.

By "specific defense system" is meant components of the immune system that respond to the presence of specific antigens. Examples of inflammation caused by the response of a specific defense system include classical responses to foreign antigens, autoimmune diseases, and delayed-type hypersensitivity responses mediated by T-cells. Chronic inflammatory diseases, rejection of solid transplanted tissues and organs such as kidney and bone marrow transplants, and Graft Versus Host Disease (GVHD) are further examples of inflammatory responses of specific defense systems.

The term "non-specific defense system" as used herein refers to inflammatory disorders mediated by immune memory-free leukocytes (e.g., granulocytes and macrophages). Examples of inflammation caused at least in part by a reaction of the non-specific defense system include inflammation associated with conditions such as: adult (acute) respiratory distress syndrome (ARD) or multiple organ injury syndrome; reperfusion injury; acute glomerulonephritis; reactive arthritis (reactive arthritis); skin diseases with acute inflammatory components; acute purulent meningitis or other central nervous system inflammatory disorders such as stroke; heat damage; inflammatory bowel disease; syndrome associated with granulocyte metastasis associated syndrome; and cytokine-induced toxicity.

As used herein, "autoimmune disease" refers to any group of disorders in which tissue damage is associated with a humoral or cell-mediated response to the body's own components.

As used herein, "allergic disease" refers to any condition, tissue damage or loss of tissue function resulting from an allergic reaction. As used herein, "arthritic disease" refers to any disease characterized by inflammatory damage to joints attributable to various etiologies. As used herein, "dermatitis" refers to any of a large group of diseases characterized by inflammation of the skin attributable to various etiologies. As used herein, "graft rejection" refers to any immune response against transplanted tissue, such as organs or cells (e.g., bone marrow), characterized by loss of function, pain, swelling, leukocytosis, and thrombocytopenia of the transplanted and surrounding tissues. The therapeutic methods of the present invention include methods for treating disorders associated with inflammatory cell activation.

"inflammatory cell activation" refers to the induction of a stimulus for a proliferative cell response, including but not limited to a cytokine, antigen, or autoantibody, the production of soluble mediators, including but not limited to cytokines, oxygen radicals, enzymes, prostanoids, or vasoactive amines, or the cell surface expression of new or increased amounts of mediators, including but not limited to major histocompatibility antigens or cell adhesion molecules, in inflammatory cells, including but not limited to monocytes, macrophages, T lymphocytes, B lymphocytes, granulocytes (i.e., polymorphonuclear leukocytes such as neutrophils, basophils, and eosinophils), mast cells, dendritic cells, langerhans cells, and endothelial cells. It is understood by those skilled in the art that activation of one or a combination of these phenotypes in these cells can contribute to the initiation, perpetuation, or worsening of an inflammatory disorder.

The term "NSAID" is an acronym for "nonsteroidal anti-inflammatory drug" and is a therapeutic agent with analgesic, antipyretic (reducing elevated temperature and alleviating pain without compromising consciousness) and anti-inflammatory (reducing inflammation) at higher doses. The term "non-steroidal" is used to distinguish these drugs from steroids which (among a wide range of other effects) have similar eicosanoid-inhibiting, anti-inflammatory effects. NSAIDs are not narcotics and are therefore not common as analgesics. NSAIDs include aspirin, ibuprofen, and naproxen. NSAIDs are generally indicated for the treatment of acute or chronic conditions in which pain and inflammation are present. NSAIDs are generally indicated for symptomatic relief of the following conditions: rheumatoid arthritis, osteoarthritis, inflammatory joint diseases (e.g. ankylosing spondylitis, psoriatic arthritis, Reiter's syndrome, acute gout, dysmenorrhea), osteoarthritis, rheumatoid arthritis, osteoarthritis, rheumatoid arthritis Migratory bone pain, headache and migraine, postoperative pain, mild to moderate pain due to inflammation and tissue injury, fever, ileus, and renal colic. Most NSAIDs act as non-selective inhibitors of cyclooxygenase, which inhibits both the cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) isozymes. Cyclooxygenase catalyzed by arachidonic acid (which is itself catalyzed by phospholipase A)₂Derived from a cellular phospholipid bilayer) to form prostaglandins and thromboxanes. Prostaglandins (among other things) act as messenger molecules in inflammatory processes. COX-2 inhibitors include celecoxib, etoricoxib, lumiracoxib, parecoxib, rofecoxib, and valdecoxib.

The term "cancer" refers to or describes a physiological condition in mammals that is typically characterized by uncontrolled cell growth. A "tumor" comprises one or more cancer cells. Examples of cancer include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia or lymphoid malignancies (lymphoid malignanes). More specific examples of such cancers include squamous cell cancer (e.g., epithelial squamous cell cancer), lung cancer (including small-cell lung cancer, non-small cell lung cancer ("NSCLC"), adenocarcinoma of the lung, and squamous carcinoma of the lung), peritoneal cancer, hepatocellular cancer, gastric cancer (including gastrointestinal cancer), pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, renal cancer, prostate cancer, vulvar cancer, thyroid cancer, liver cancer, anal cancer, penile cancer, head and neck cancer, multiple myeloma, acute myelogenous leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, lymphocytic leukemia, myelogenous leukemia, oral and pharyngeal cancer, non-hodgkin's lymphoma, melanoma, and villous colon adenoma.

"chemotherapeutic agents" are chemical compounds that can be used to treat cancer regardless of mechanism of action. Types of chemotherapeutic agents include, but are not limited to: alkylating agents, antimetabolites, spindle poison plant alkaloids, cytotoxic/antitumor antibiotics, topoisomerase inhibitors, antibodies, photosensitizers, and kinasesAnd (3) an inhibitor. Chemotherapeutic agents include compounds used in "targeted therapy" and conventional chemotherapy. Examples of chemotherapeutic agents include: erlotinib (b)Genentech/OSI Pharm), docetaxelSanofi-Aventis), 5-FU (fluorouracil, 5-fluorouracil, CAS number 51-21-8), gemcitabine (Gemcitabine)Lilly), PD-0325901(CAS number 391210-10-9, Pfizer), cisplatin (cis-diamine, dichloroplatinum (II), CAS number 15663-27-1), carboplatin (CAS number 41575-94-4), paclitaxel (r) (paclitaxel: (r) ((r))Bristol-Myers Squibb Oncology, Princeton, N.J.), Trastuzumab (R) (R.B.C.)Genentech), temozolomide (4-methyl-5-oxo-2, 3,4,6, 8-pentaazabicyclo [4.3.0]Nonane-2, 7, 9-triene-9-carboxamide, CAS number 85622-93-1,schering Plough), tamoxifen ((Z) -2- [4- (1, 2-diphenylbut-1-enyl) phenoxy]-N, N-dimethylethylamine,) And doxorubicin (c) ((c))) Akti-1/2, HPPD and rapamycin.

Further examples of chemotherapeutic agents include: oxaliplatin (A) Sanofi), bortezomib (Millennium Pharm.)、sutent(SU11248, Pfizer), letrozole (I), (II), (III), (Novartis), imatinib mesylate (Novartis), XL-518(Mek inhibitor, Exelixis, WO2007/044515), ARRY-886(Mek inhibitor, AZD6244, Array BioPharma, Astra Zeneca), SF-1126(PI3K inhibitor, Semaform Pharmaceuticals), BEZ-235(PI3K inhibitor, Novartis), XL-147(PI3K inhibitor, Exelixis), PTK787/ZK222584(Novartis), fulvestrant: (fulvestrant)AstraZeneca), leucovorin (leucovorin), rapamycin (sirolimus,wyeth), lapatinib (GSK572016 (Glaxo Smith Kline), Lonafanib (Sarasar @)^TMSCH66336, Schering Plough), Sorafenib (sorafenib) ((Schering Plough)BAY43-9006, Bayer Labs), gefitinib (B)AstraZeneca), irinotecan (A)CPT-11, Pfizer), tipifarnib (ZARNESTRA)^TM,Johnson&Johnson)、ABRAXANE^TM(Cremophor-free), albumin-modified nanoparticulate formulations of paclitaxel (American Pharmaceutical Partners, Schaumberg, Il), vandetanib (rINN, ZD6474,AstraZeneca), chlorambucil (chlorenbucil), AG1478, AG1571(SU5271; Sugen), temsirolimus (Tacrolimus)Wyeth), pazopanib (GlaxoSmithKline), Kamamide (C.E.)Telik), thiotepa and cyclophosphamide (C: (A)) (ii) a Alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzotepa, carboquone, meturedpa, and uredepa; aziridines and methylolmelamines including hexamethylmelamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide and trimethylolmelamine; polyacetylens (acetogenin) (especially bullatacin and bullatacin); camptothecin (including the synthetic analog topotecan); bryostatins; callystatin; CC-1065 (including its aldorexin, kazelaixin, and bizelaixin synthetic analogs); cryptophycins (especially cryptophycin1 and cryptophycin 8); dolastatin; duocarmycins (including the synthetic analogs KW-2189 and CB1-TM 1); eiscosahol (eleutherobin); coprinus atrata base (pancratistatin); eleutherobin (sarcodictyin); spongistatin; nitrogen mustards such as chlorambucil, chlorophosphamide, estramustine, ifosfamide, mechlorethamine hydrochloride, melphalan, neomustard, benzene mustard cholesterol, pine Benzene mustard, three mustard cyclophosphamide, uracil mustard; nitrosoureas such as carmustine, chlorouramicin, fotemustine, lomustine, nimustine and ranimustine; antibiotics such as enediyne (enediyne) antibiotics (e.g., calicheamicin γ 1I, calicheamicin ω I1(Angew chem. Intl. Ed. Engl. (1994)33: 183-186); enediyne anthracyclines, enediyne anthracyclines A; bisphosphonates such as clodronate; epothilones; and neocarzinostamycin chromophore and related chromoprotein enediyne antibiotics chromophore), aclacinomycin (aclacinomysins), actinomycin, authramycin, azaserine, bleomycin, actinomycin C, carabicin, nordaunordaunorubicin, carzinomycin, chromomycins, dactinomycin, daunorubicin, ditrithromycin, 6-diazo-5-oxo-L-norleucine, morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolidino-doxorubicin, and doxorubicin) & doxorubicin, Epirubicin, esorubicin, idarubicin, nemorubicin, maselomycin, mitomycins such as mitomycin C, mycophenolic acid, norubicin, olivomycin, pellomycin, pofiomycin, puromycin, triiron doxorubicin, rodobicin, streptomycin, streptozotocin, tubercidin, ubenimex, setastin, zorubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens such as carpoterone, drostandrosterone propionate, epitioandrostanol, meperidine, and testolactone; anti-adrenalines such as aminoglutethimide, mitotane, trostane, folic acid supplements such as frolicic acid; acetic acid glucurolactone; (ii) an aldophosphamide glycoside; (ii) aminolevulinic acid; eniluracil; amsacrine, bestraucil, bisantrene, edatrexate (edatraxate), defofamine; colchicine; diazaquinone; elfornitine; ammonium etiolate; an epothilone; etoglut; gallium nitrate; a hydroxyurea; mushroom (Lentinus edodes) A polysaccharide; lonidamine (lonidainine); maytansinoids (maytansinoids) such as maytansine and maytansinol; mitoguazone; mitoxantrone; mopidanmol; nitrerine; pentostatin; methionine; pirarubicin; losoxanthraquinone; podophyllinic acid; 2-ethyl hydrazide; procarbazine;polysaccharide complex (JHS Natural Products, Eugene, OR); lezoxan; rhizomycin; a texaphyrin; a germanium spiroamine; alternarionic acid; a tri-imine quinone; 2, 2' -trichlorotriethylamine; trichothecenes (especially T-2 toxin, veracurin A, bacillocin A (roridin A) and anguidine); urethane; vindesine; dacarbazine; mannomustine; dibromomannitol; dibromodulcitol; pipobroman; a polycytidysine; arabinoside ("Ara-C"); cyclophosphamide; thiotepa; 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin and carboplatin; vinblastine; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; vinorelbineNoxiaoling; (ii) teniposide; edatrexae; daunomycin; aminopterin; capecitabineRoche); ibandronate; CPT-11; topoisomerase inhibitor RFS 2000; difluoromethyl ornithine (DMFO); retinoids such as retinoic acid; and pharmaceutically acceptable salts, acids and derivatives of any of the foregoing.

Also included in the definition of "chemotherapeutic agent" are: (i) anti-hormonal substances such as antiestrogens and Selective Estrogen Receptor Modulators (SERMs) that exert a modulating or suppressing effect of hormones on tumors include, for example, tamoxifen (includingTamoxifen citrate), raloxifene, droloxifene, 4-hydroxy tamoxifen, trovaxifenKeoxifene, LY117018, onapristone and(toremifene citrate); (ii) aromatase inhibitors which inhibit aromatase which regulates estrogen production in the adrenal gland, e.g. 4(5) -imidazoles, aminoglutethimide,(megestrol acetate),(exemestane; Pfizer), formestane, fatrozole,(vorozole),(letrozole; Novartis) and(anastrozole; AstraZeneca); (iii) antiandrogens such as flutamide, nilutamide, bicalutamide, leuprolide and goserelin; and troxacitabine (1, 3-dioxolane nucleoside cytosine analogues); (iv) protein kinase inhibitors such as MEK inhibitors (WO 2007/044515); (v) a lipid kinase inhibitor; (vi) antisense oligonucleotides, particularly those that inhibit the expression of genes involved in signaling pathways of abnormal cell proliferation, e.g., PKC- α, Raf, and H-Ras, e.g., oblimersen (R) ((R)) Genta Inc.); (vii) ribozymes such as VEGF expression inhibitors (e.g.,) And inhibitors of HER2 expression; (viii) vaccines, e.g. gene therapy vaccines, e.g.AndrIL-2; topoisomerase 1 inhibitors such asrmRH; (ix) anti-angiogenic agents such as bevacizumabGenentech); and pharmaceutically acceptable salts, acids and derivatives of any of the foregoing.

Also included within the definition of "chemotherapeutic agent" are therapeutic antibodies such as alemtuzumab (Campath), bevacizumab (bGenentech); cetuximab (Imclone); panitumumab (A)Amgen), rituximab (Genentech/Biogen Idec), pertuzumab (pertuzumab) (OMNITARG)^TM2C4, Genentech), trastuzumab (Genentech), tositumomab (Bexxar, Corixia), and antibody drug conjugate gemtuzumab ozolomicin (b.i.)Wyeth)。

Humanized monoclonal antibodies having therapeutic potential as chemotherapeutic agents for use in combination with the PI3K inhibitors of the invention include: alemtuzumab, aprezumab, aselizumab, atlizumab, bapidizumab, bevacizumab, bivatuzumab-DM 1, meclizumab, cetilizumab, peslizumab, cidfusituzumab, cidfutuzumab, cidtuzumab, daclizumab, eculizumab, efuzumab, epratuzumab, elizumab (erlizumab), nonvzuzumab, aryltuzumab, gemtuzumab ozolomide, influzumab olmicin, ipiuzumab, lepuzumab, labuzumab, lintuzumab, matuzumab, metuzumab, motavizumab, natalizumab, nimotuzumab, nolovizumab, nuzumab, aurilizumab, omalizumab, pertuzumab, paclizumab, cfb, resuzumab, rituximab, rituzumab, ritujvizumab, and ritujvizu, Celizumab, matuzumab, tacatuzumab tetraxetan, taduzumab, talilizumab, tefralizumab, tollizumab, trastuzumab, simon interleukin mab, tucusituzumab, umavivizumab, Ulizumab, and Visizumab (visilizumab).

The term "hematopoietic malignancy" refers to a cancer or hyperproliferative disorder that develops during hematopoiesis involving cells such as leukocytes, lymphocytes, natural killer cells, plasma cells, and myeloid cells, e.g., neutrophils and monocytes. Hematopoietic Malignancies include diseases listed in the WHO classification of human Hematopoietic Malignancies; tumors of Hematopoietic and Lymphoid Tissues with morphological codes of the international classification of disease (ICD-O) (Jaffe E.S., Harris N.L., Stein H., Vardiman J.W (eds.) (2001): the World Health organization classification of Tumors (World Health organization classification of Tumors), Pathology and Genetics of Tumors of hematopoetic and Lymphoid Tissues. IARC Press: Lyon). For malignant tumors, behavior is coded as/3, for low or undetermined potential lesions, as/1.

Hematopoietic malignancies include:

I. chronic myeloproliferative disease

Chronic myelogenous leukemia-ICD-O9875/3

Chronic neutrophilic leukemia (Chronic neutrophilic leukemia) -ICD-O9963/3

Chronic eosinophilic leukemia (Chronic eosinophilic leukemia)/hypereosinophilic syndrome-ICD-O9964/3

Polycythemia vera-ICD-O9950/3

Chronic idiopathic myelofibrosis-ICD-O9961/3

Essential thrombocytosis (Essential thrombocytemia) -ICD-O9962/3

Chronic myeloproliferative disease, non-classifiable-ICD-O9975/3

Myelodysplastic/myeloproliferative disorders

Chronic myelo-monocytic leukemia-ICD-O9980/3

Atypical chronic myelogenous leukemia-ICD-O9876/3

Juvenile granule-single cell leukemia-ICD-O9946/3

Myelodysplastic/myeloproliferative disorders, non-classifiable-ICD-O9975/3

Myelodysplastic syndrome

Intractable anemia-ICD-O9980/3

Annular iron granulocytic Refractory anemia (reflectory anemia with ringedsideroblast) -ICD-O9982/3

Refractory cytopenia with multilineage dyslasia (refractory cytopenia with multilineage dyslasia) -ICD-O9985/3

Refractory anemia with immature cell excess (cultured anemia) -ICD-O9983/3

Myelodysplastic syndrome-ICD-O9986/3 associated with isolated del (5q) chromosomal abnormalities

Myelodysplastic syndrome, classifiable 9989/3

Acute myelogenous leukemia

Acute myeloid leukemia with recurrent cytogenetic abnormalities

AML companion t (8;21) (q22; q22), AML1/ETO-ICD-O9896/3

AML with inv (16) (p13q22) or t (16;16) (p13; q22), CBFb/MYH11-ICD-O9871/3

Acute promyelocytic leukemia (AML with t (15;17) (q22; q12), PML-RARa and variants) -ICD-O9866/3

AML with 11q23(MLL) abnormality-ICD-O9897/3

Acute myelogenous leukemia multisystem abnormality-ICD-O9895/3

Acute myelogenous leukemia and myelodysplastic syndrome, treatment-related ICD-O9920/3

Acute myeloid leukemia not otherwise classified

Acute myelogenous leukemia, very poorly differentiated-ICD-O9872/3

Acute myeloid leukemia, not accompanied by mature-ICD-O9873/3

Acute myeloid leukemia with maturation-ICD-O9874/3

Acute myelomonocytic leukemia-ICD-O9867/3

Acute monocytic and monocytic leukemia-ICD-O9891/3

Acute erythroleukemia (Acute erythroid leukemia) -ICD-O9840/3

Acute megakaryocytic leukemia-ICD-O9910/3

Acute basophilic leukemia (Acute basophilic leukemia) -ICD-O9870/3

Acute myeloproliferative disorder with myelofibrosis (Acute panmyeloiosis with myelofibrosis) -ICD-O9931/3

Medullary sarcoma (Myeloid sarcoma) -ICD-O9930/3

Acute leukemia with unknown pedigree-ICD-O9805/3

V.B-cell tumors

Precursor hematopoietic system tumor (Precursor hematopoietic neoplasms)

Precursor B lymphoblastic leukemia (Precursor B lymphoblastic leukemia)/-ICD-O9835/3

lymphoma-ICD-O9728/3

Tumor of mature hematopoietic system

Chronic lymphocytic leukemia/-ICD-O9823/3

Small lymphocytic lymphoma-ICD-O9670/3

Hematopoietic promyelocytic leukemia (myelogenous leukemia) -ICD-O9833/3

Lymphoplasmacytic lymphoma (Lymphoplasmacytic lymphoma) -ICD-O9671/3

Splenic marginal zone lymphoma (Splendic marginal zone lymphoma) -ICD-O9689/3

Hairy cell leukemia-ICD-O9940/3

Plasma cell myeloma-ICD-O9732/3

Solitary plasmacytoma of bone-ICD-O9731/3

Extraosseous plasmacytoma (Extraosseous plasmacytoma) -ICD-O9734/3

Extranodal marginal zone hematopoietic lymphoma of mucosa-associated lymphoid tissue (MALT-lymphoma) -ICD-O9699/3

Lymphomas of hematopoietic system of the Nodal marginal zone (Nodal marginal zone hematopoietic lymphomas) -ICD-O9699/3

Follicular lymphoma-ICD-O9690/3

Mantle cell lymphoma-ICD-O9673/3

Diffuse large hematopoietic system lymphoma (Difose large hematopoietic lymphoma) -ICD-O9680/3

Mediastinal (thymic) large cell lymphoma (mediastinal (thymic) large cell lymphoma) -ICD-O9679/3

Intravascular large hematopoietic lymphoma (Intravascular large hematopoietic lymphoma) -ICD-O9680/3

Primary effusion lymphoma (Primary effusivity lymphoma) -ICD-O9678/3

Burkitt's lymphoma/-ICD-O9687/3

leukemia-ICD-O9826/3

Hematopoietic system proliferation without determining the possibility of malignancy (hematopoietic promoters of uncertain malignant potential)

Lymphomatoid granulomatosis (Lymphomatoid granulomatosis) -ICD-O9766/1

Polymorphic form of-ICD-O9970/1 in post-transplant lymphoproliferative disorder

T-cell and NK-cell tumors

Precursor T-cell tumors

Precursor T primitive lymphocytic leukemia/-ICD-O9837/3

lymphoma-ICD-O9729/3

Primitive NK cell lymphoma (blast NK-cell lymphoma) -ICD-O9727/3

Mature T-cell and NK-cell tumors

T-cell prolymphocytic leukemia-ICD-O9834/3

T-cell large granular lymphocytic leukemia (T-cell large granular lymphocytic leukemia) -ICD-O9831/3

Aggressive NK cell leukemia (Aggressive NK cell leukemia) -ICD-O9948/3

Adult T-cell leukemia/lymphoma-ICD-O9827/3

Extranodal NK/T cell lymphoma, nasal-ICD-O9719/3

Enteropathy type T-cell lymphoma-ICD-09717/3

Hepatosplenic T-cell lymphoma-ICD-O9716/3

Subcutaneous lipodermitis-like T-cell lymphoma-ICD-O9708/3

Mycosis fungoides-ICD-O9700/3

Sedri syndrome-ICD-O9701/3

Primary anaplastic large cell lymphoma-ICD-O9718/3

Peripheral T-cell lymphoma, unspecified-ICD-O9702/3

Angioimmunoblastic T-cell lymphoma (Angioimmunoblastic T-celllymphoma) -ICD-O9705/3

Anaplastic large cell lymphoma-ICD-O9714/3

Uncertain malignant potential of T-cell proliferation (T-cell proliferation of uncertain malignant potential)

Lymphoma-like papulosis-ICD-O9718/1

VII Hodgkin's lymphoma

Nodular lymphocytes are major Hodgkin lymphoma (Nodula lymphocypredominant Hodgkin lymphoma) -ICD-O9659/3

Classical Hodgkin lymphoma-ICD-O9650/3

Nodule sclerosing classic Hodgkin lymphoma (Nodula sclerosisal Hodgkin lymphoma) -ICD-O9663/3

Lymphocyte-enriched classical Hodgkin lymphoma-ICD-O9651/3

Mixed cell type classical Hodgkin lymphoma (Mixed cellular lymphoma) -ICD-O9652/3

Lymphocyte-depleting classical Hodgkin lymphoma (lymphoma) -ICD-O9653/3

Histiocytic and dendritic cell tumors

Macrophage/histiocytoma

Histiocytic sarcoma-ICD-O9755/3

Dendritic cell tumor

Langerhans cell histiocytosis-ICD-O9751/1

Langerhans cell sarcoma-ICD-O9756/3

Staggered dendritic cell sarcoma/tumor-ICD-O9757/3/1

Follicular dendritic cell sarcoma/tumor-ICD-O9758/3/1

Dendritic cell sarcoma, unspecified-ICD-O9757/3

IX. mastocytosis

Mastocytosis of the skin

Static systemic mastocytosis (index system mastocytosis) -ICD-O9741/1

Systemic mastocytosis with associated clonal hematopoietic non-mast cell line disease-ICD-O9741/3

Invasive systemic mastocytosis (invasive system stocytosis) -ICD-O9741/3

Mast cell leukemia-ICD-O9742/3

mastocytosis-ICD-O9740/3

Cutaneous external mast cell tumor-ICD-O9740/1

"metabolites" are products produced by the metabolism of a given compound or salt thereof in the body. Metabolites of a compound can be identified by conventional techniques known in the art and their activity determined using assays such as those described herein. Such products may result, for example, from oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage, etc. of the administered compound. Accordingly, the present invention includes metabolites of the compounds of the present invention, including compounds produced by a method comprising contacting a compound of the present invention with a mammal for a period of time sufficient to produce a metabolite thereof.

The term "package insert" refers to instructions typically included in commercial packaging for therapeutic products that contain information about the indications, usage, dosage, administration, contraindications, and/or concerns about the use of such therapeutic products.

The term "chiral" refers to molecules that have mirror partners non-superimposability, while the term "achiral" refers to molecules that can be superimposed with their mirror partners.

The term "stereoisomers" refers to compounds that have the same chemical constitution, but differ in the spatial arrangement of the atoms or groups. Stereoisomers include enantiomers and diastereomers.

"diastereomer" refers to a stereoisomer having two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers can be separated under high resolution analytical procedures such as electrophoresis and chromatography. Diastereomers include geometric isomers, cis/trans and E/Z isomers, and atropisomers.

"enantiomer" refers to two stereoisomers of a compound that are nonsuperimposable mirror images of each other.

The stereochemical definitions and conventions used herein generally follow the edition S.P. Parker, McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of organic Compounds", John Wiley & Sons, Inc., New York, 1994. The compounds of the invention may contain asymmetric or chiral centers and may therefore exist in different stereoisomeric forms. All stereoisomeric forms of the compounds of the present invention (including but not limited to diastereomers, enantiomers and atropisomers as well as mixtures thereof such as racemic mixtures) are integral to the present invention. Many organic compounds exist in optically active form, i.e., they have the ability to rotate the plane of plane polarized light. In describing optically active compounds, the prefixes D and L or R and S are used to designate the absolute configuration of the molecule at its chiral center. The sign of rotation of the compound to plane polarized light is named with the prefixes d and l or (+) and (-), with (-) or l meaning that the compound is left-handed. Compounds prefixed with (+) or d are dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. A particular stereoisomer may also be referred to as an enantiomer, and mixtures of such isomers are often referred to as enantiomeric mixtures. A 50:50 mixture of enantiomers is referred to as a racemic mixture or racemate, which may occur in the absence of stereoselectivity or stereospecificity in the chemical reaction or process. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomers without optical activity.

The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that are interconvertible by a low energy barrier. For example, proton tautomers (also referred to as prototropic tautomers) include interconversion by proton migration, such as keto-enol and imine-enamine isomerizations. Valence tautomers (valencetatomer) include interconversion by recombination of some of the bonding electrons.

The phrase "pharmaceutically acceptable salt" as used herein refers to pharmaceutically acceptable organic or inorganic salts of the compounds of the present invention. Examples of salts include, but are not limited to, sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate ", ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., 1, 1' -methylene-bis (2-hydroxy-3-naphthoate)). Pharmaceutically acceptable salts may involve inclusion of another molecule such as an acetate ion, succinate ion, or other counterion. The counterion may be any organic or inorganic moiety that stabilizes the charge on the parent compound. In addition, pharmaceutically acceptable salts may also have more than one charged atom in their structure. Where the pharmaceutically acceptable salt has multiple charged atoms, there may be multiple counterions. Thus, a pharmaceutically acceptable salt may have one or more charged atoms and/or one or more counterions.

If the compound of the invention is a base, the desired pharmaceutically acceptable salt may be prepared by any suitable method available in the art, for example by treating the free base with an inorganic acid such as hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid, methanesulphonic acid, phosphoric acid and the like or with an organic acid such as acetic acid, trifluoroacetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, a pyranosidyl acid (glucuronic acid) such as glucuronic acid or galacturonic acid, an alpha hydroxy acid such as citric acid or tartaric acid, an amino acid such as aspartic acid or glutamic acid, an aromatic acid such as benzoic acid or cinnamic acid, a sulphonic acid such as p-toluenesulphonic acid or ethanesulphonic acid and the like.

If the compound of the invention is an acid, the desired pharmaceutically acceptable salt may be prepared by any suitable method, for example, by treating the free acid with an inorganic or organic base such as an amine (primary, secondary or tertiary), an alkali metal hydroxide or alkaline earth metal hydroxide, and the like. Illustrative examples of suitable salts include, but are not limited to, organic salts derived from amino acids such as glycine and arginine, ammonia, primary, secondary and tertiary amines, and cyclic amines such as piperidine, morpholine, and piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium.

The phrase "pharmaceutically acceptable" means that the substance or composition is chemically and/or toxicologically compatible with the other ingredients comprising the formulation and/or the mammal being treated therewith.

"solvate" refers to an association or complex of one or more solvent molecules with a compound of the invention. Examples of solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine.

The terms "compound of the invention" and "compound of formula I" in the singular or plural include compounds of formula I as well as stereoisomers, tautomers, solvates, metabolites and pharmaceutically acceptable salts and prodrugs thereof.

Any chemical formula or structure given herein, including the compound of formula I, also represents hydrates, solvates and polymorphs of the compound, as well as mixtures thereof.

Any formulae or structures given herein, including compounds of formula I, also represent isotopically labeled as well as unlabeled forms of the compounds. Isotopically-labeled compounds have the structure depicted in the structural formulae except that one or more atoms are replaced by an atom having a selected atomic mass or number of atoms. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as, but not limited to, 2H (deuterium, D), 3H (tritium), 11C, 13C, 14C, 15N, 18F, 31P, 32P, 35S, 36Cl and 125I. Various isotopically-labeled compounds of the present invention, for example, those into which radioactive isotopes such as 3H, 13C, and 14C are incorporated. Such isotopically labeled compounds are useful in metabolic studies, reaction kinetic studies, detection or imaging techniques such as Positron Emission Tomography (PET) or Single Photon Emission Computed Tomography (SPECT), including drug or substrate tissue distribution assays, or in the radiation treatment of patients. Deuterium labeled or substituted therapeutic compounds of the invention have improved DMPK (drug metabolism and pharmacokinetics) properties, relating to distribution, metabolism and excretion (ADME). Substitution with heavier isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements. The 18F labeled compounds are useful for PET or SPECT studies. Isotopically labeled compounds of the present invention, and prodrugs thereof, can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations below, by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent. In addition, substitution with heavier isotopes, particularly deuterium (i.e., 2H or D), may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements or an improved therapeutic index. It is to be understood that deuterium is in this case considered as a substituent in the compound of formula (I). The concentration of such heavier isotopes, in particular deuterium, can be defined by the isotopic enrichment factor. In the compounds of the present invention, any atom not specifically designated as a particular isotope represents any stable isotope of that atom. Unless otherwise indicated, when a position is specifically designated as "H" or "hydrogen," the position is understood to have hydrogen in its natural abundance isotopic composition. Thus, in the compounds of the present invention, any atom specifically designated as deuterium (D) represents deuterium.

Heterocyclic compounds of the invention

Compounds of formula I include compounds having the formula:

and stereoisomers, geometric isomers, tautomers and pharmaceutically acceptable salts thereof, wherein:

Z¹is CR¹Or N;

Z²is CR²Or N;

Z³is CR³Or N;

Z⁴is CR⁴Or N;

wherein Z¹、Z²、Z³And Z⁴None, one or both are N;

wherein (i) X¹Is NR¹⁰And X²Is N, (ii) X¹Is S and X²Is CR¹¹，(iii)X¹Is O and X²Is CR¹¹Or (iv) X¹Is NR¹⁰And X²Is CR¹¹；

Or at X¹Z in the case of N¹And X¹Form optionally substituted by one or more R¹²A group-substituted 5-, 6-or 7-membered heteroaryl or heterocyclyl ring;

R⁵and R⁶Independently selected from H, C₁-C₁₂Alkyl radical, C₂-C₈Alkenyl and C₂-C₈Alkynyl, wherein alkyl, alkenyl and alkynyl are optionally substituted with one or more groups independently selected from: F. cl, Br, I, -CN, -CO₂H、-COCH₃、-COC(CH₃)₃、-CO₂CH₃、-CONH₂、-CONHCH₃、-CON(CH₃)₂、-NO₂、-NH₂、-NHCH₃、-N(CH₃)₂、-NHCOCH₃、-NHS(O)₂CH₃、-N(CH₃)C(CH₃)₂CONH₂、-N(CH₃)CH₂CH₂S(O)₂CH₃、=O、-OH、-OCH₃、-OCH₂CH₃、-OCH(CH₃)₂、-S(O)₂N(CH₃)₂、-SCH₃and-S (O)₂CH₃；

Or R⁵And R⁶Form optionally substituted by one or more R¹²A group-substituted 5-or 6-membered heteroaryl or heterocyclyl ring;

R¹、R²、R³、R⁴and R¹²Independently selected from H, F, Cl, Br, I, -CH₃、-CH₂CH₃、-C(CH₃)₃、-CH₂OH、-CH₂CH₂OH、-C(CH₃)₂OH、-CH₂OCH₃、-CN、-CF₃、-CO₂H、-COCH₃、-COC(CH₃)₃、-CO₂CH₃、-CONH₂、-CONHCH₃、-CON(CH₃)₂、-CONHCH₂CH₂OCH₃、-CON(CH₂CH₂)₂O、-CON(CH₂CH₂)₂N(CH₃)、-C(CH₃)₂CONH₂、-NO₂、-NH₂、-NHCH₃、-N(CH₃)₂、-NHCOCH₃、-NHS(O)₂CH₃、-N(CH₃)C(CH₃)₂CONH₂、-N(CH₃)CH₂CH₂S(O)₂CH₃、=O、-OH、-OCH₃、-OCF₃、-S(O)₂N(CH₃)₂、-SCH₃and-S (O)₂CH₃(ii) a Or

R¹、R²、R³、R⁴And R¹²Independently selected from heterocyclyl having 3 to 20 ring atoms or heteroaryl having 5 to 20 ring atoms, optionally substituted with one or more groups selected from: F. cl, Br, I, -CH ₃、-CH₂CH₃、-C(CH₃)₃、-CH₂OH、-CH₂CH₂OH、-C(CH₃)₂OH、-CH₂OCH₃、-CN、-CF₃、-CO₂H、-COCH₃、-COC(CH₃)₃、-CO₂CH₃、-CONH₂、-CONHCH₃、-CON(CH₃)₂、-CONHCH₂CH₂OCH₃、-CON(CH₂CH₂)₂O、-CON(CH₂CH₂)₂N(CH₃)、-C(CH₃)₂CONH₂、-NO₂、-NH₂、-NHCH₃、-N(CH₃)₂、-NHCOCH₃、-NHS(O)₂CH₃、-N(CH₃)C(CH₃)₂CONH₂、-N(CH₃)CH₂CH₂S(O)₂CH₃、=O、-OH、-OCH₃、-OCF₃、-S(O)₂N(CH₃)₂、-SCH₃、-S(O)₂CH₃；

Y is a heterocyclyl having 3 to 20 ring atoms or a heteroaryl having 5 to 20 ring atoms, optionally substituted with one or more groups selected from: F. cl, Br, I, -CH₃、-CH₂CH₃、-C(CH₃)₃、-CH₂OH、-CH₂CH₂OH、-C(CH₃)₂OH、-CH₂OCH₃、-CN、-CF₃、-CO₂H、-COCH₃、-COC(CH₃)₃、-CO₂CH₃、-CONH₂、-CONHCH₃、-CON(CH₃)₂、-CONHCH₂CH₂OCH₃、-CON(CH₂CH₂)₂O、-CON(CH₂CH₂)₂N(CH₃)、-C(CH₃)₂CONH₂、-NO₂、-NH₂、-NHCH₃、-N(CH₃)₂、-NHCOCH₃、-NHS(O)₂CH₃、-N(CH₃)C(CH₃)₂CONH₂、-N(CH₃)CH₂CH₂S(O)₂CH₃、=O、-OH、-OCH₃、-OCF₃、-S(O)₂N(CH₃)₂、-SCH₃、-S(O)₂CH₃Optionally substituted with-NHCOCH₃Substituted benzo [ d ]]Thiazol-2-yl, cyclopropyl, cyclobutyl, 1-dioxo-thiopyran-4-yl, indolyl, oxetanyl, morpholino and optionally substituted by F, Cl, Br, I, -OH, -CN or-CH₃Substituted phenyl;

or R⁶And Y is optionally substituted with one or more R¹²A group-substituted 5-or 6-membered heteroaryl or heterocyclyl ring;

R¹⁰is H, C₁-C₁₂Alkyl radical, C₂-C₈Alkenyl radical, C₂-C₈Alkynyl, C₆-C₂₀Aryl radical, C₃-C₁₂Carbocyclyl, heterocyclyl having 3 to 20 ring atoms, heteroaryl having 5 to 20 ring atoms, - (C)₁-C₁₂Alkylene group) - (C₃-C₁₂Carbocyclyl), - (C)₁-C₁₂Alkylene) - (heterocyclic group having 3-20 ring atoms), - (C)₁-C₁₂Alkylene) -C (= O) - (heterocyclic group having 3 to 20 ring atoms), - (C₁-C₁₂Alkylene group) - (C₆-C₂₀Aryl), - (C)₆-C₂₀Aryl radicals) - (heteroaryl having 5 to 20 ring atoms), - (C)₆-C₂₀Aryl) - (heterocyclic radical having 3-20 ring atoms) and- (C)₁-C₁₂Alkylene) - (heteroaryl having 5-20 ring atoms), wherein alkyl, alkenyl, alkynyl, alkylene, carbocyclyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one or more groups independently selected from: F. cl, Br, I, -CH ₃、-CH₂CH₃、-CH(CH₃)₂、-C(CH₃)₃、-CH₂OH、-CH₂CH₂OH、-C(CH₃)₂OH、-CH₂OCH₃、-CN、-CH₂CH₂CN、-CH₂F、-CHF₂、-CH₂CONH₂、-CF₃、-CO₂H、-COCH₃、-COC(CH₃)₂OH、-COCH₂N(CH₃)₂、-COC(CH₃)₃、-CO₂CH₃、-CO₂C(CH₃)₃、-CONH₂、-CONHCH₃、-CON(CH₃)₂、-C(CH₃)₂CONH₂、-NO₂、-NH₂、-NHCH₃、-N(CH₃)₂、-NHCOCH₃、-NHS(O)₂CH₃、-N(CH₃)C(CH₃)₂CONH₂、-N(CH₃)CH₂CH₂S(O)₂CH₃、=O、-OH、-OCH₃、-S(O)₂N(CH₃)₂、-SCH₃、-S(O)₂CH₃Cyclopropyl, cyclobutyl, oxetanyl, morpholino and 1, 1-dioxo-thiopyran-4-yl; and is

R¹¹Is H, F, Cl, Br, I, CN, -N (R)⁵)₂、-OR⁵、C₁-C₁₂Alkyl radical, C₂-C₈Alkenyl radical, C₂-C₈Alkynyl, C₆-C₂₀Aryl radical, C₃-C₁₂Carbocyclyl, heterocyclyl having 3 to 20 ring atoms, heteroaryl having 5 to 20 ring atoms, - (C)₁-C₁₂Alkylene group) - (C₃-C₁₂Carbocyclyl), - (C)₁-C₁₂Alkylene) - (heterocyclic group having 3-20 ring atoms), - (C)₁-C₁₂Alkylene) -C (= O) - (heterocyclic group having 3 to 20 ring atoms), - (C₁-C₁₂Alkylene group) - (C₆-C₂₀Aryl) and- (C)₁-C₁₂Alkylene) - (heteroaryl having 5-20 ring atoms), wherein alkyl, alkenyl, alkynyl, alkylene, carbocyclyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one or more groups independently selected from: F. cl, Br, I, -CH₃、-CH₂CH₃、-C(CH₃)₃、-CH₂OH、-CH₂CH₂OH、-C(CH₃)₂OH、-CH₂OCH₃、-CN、-CH₂F、-CHF₂、-CF₃、-CO₂H、-COCH₃、-COC(CH₃)₃、-CO₂CH₃、-CONH₂、-CONHCH₃、-CON(CH₃)₂、-C(CH₃)₂CONH₂、-NO₂、-NH₂、-NHCH₃、-N(CH₃)₂、-NHCOCH₃、-NHS(O)₂CH₃、-N(CH₃)C(CH₃)₂CONH₂、-N(CH₃)CH₂CH₂S(O)₂CH₃、=O、-OH、-OCH₃、-S(O)₂N(CH₃)₂、-SCH₃、-S(O)₂CH₃Cyclopropyl, cyclobutyl, oxetanyl, morpholino and 1, 1-dioxo-thiopyran-4-yl.

Exemplary embodiments of compounds of formula I include those wherein Y has the structure:

wherein the wavy line represents the attachment site;

R⁷、R⁸and R⁹Independently selected from H, F, Cl, Br, I, -CH₃、-CH₂CH₃、-C(CH₃)₃、-CH₂OH、-CH₂CH₂OH、-C(CH₃)₂OH、-CH₂OCH₃、-CN、-CF₃、-CO₂H、-COCH₃、-COC(CH₃)₃、-CO₂CH₃、-CONH₂、-CONHCH₃、-CON(CH₃)₂、-CONHCH₂CH₂OCH₃、-CON(CH₂CH₂)₂O、-CON(CH₂CH₂)₂N(CH₃)、-C(CH₃)₂CONH₂、-NO₂、-NH₂、-NHCH₃、-N(CH₃)₂、-NHCOCH₃、-NHS(O)₂CH₃、-N(CH₃)C(CH₃)₂CONH₂、-N(CH₃)CH₂CH₂S(O)₂CH₃、=O、-OH、-OCH₃、-OCF₃、-S(O)₂N(CH₃)₂、-SCH₃、-S(O)₂CH₃Cyclopropyl, cyclobutyl, oxetanyl, morpholino and 1, 1-dioxo-thiopyran-4-yl;

or: (iv) r⁶And R⁹Or (v) R ⁸And R⁹Form optionally substituted by one or more R¹²A group-substituted 5-or 6-membered heteroaryl or heterocyclyl ring.

Exemplary embodiments of compounds of formula I include those of formulae Ia-d:

exemplary embodiments of compounds of formula I include those wherein Z¹Is CR¹；Z²Is CR²；Z³Is CR³(ii) a And Z is⁴Is CR⁴An embodiment of (1).

Exemplary embodiments of compounds of formula I include those wherein R¹、R²、R³And R⁴Independently selected from H, F, Cl, -CH₃And embodiments of-CN.

Exemplary embodiments of compounds of formula I include those wherein R¹、R²、R³And R⁴Embodiments in which one or more is F or Cl.

Exemplary embodiments of compounds of formula I include those wherein R¹Is an optionally substituted cyclopropyl, cyclobutyl, 1-dioxo-thiopyran-4-yl, indazolyl, oxetanyl, morpholino, phenyl, pyranyl, pyrazolyl or pyridyl group.

Exemplary embodiments of compounds of formula I include those wherein R⁵is-CH₃And R is⁶Is an embodiment of H.

Exemplary embodiments of compounds of formula I include those wherein R⁷Is an embodiment of H.

Exemplary embodiments of compounds of formula I include embodiments wherein Y is [1,3,5] triazine, pyridyl, or pyridazinone.

Exemplary embodiments of compounds of formula I include those wherein R⁵And R⁶Form optionally substituted by one or more R ¹²Embodiments of a 5-or 6-membered heteroaryl or heterocyclyl ring substituted with a group.

Exemplary embodiments of compounds of formula I include those wherein R⁶And R⁹Form optionally substituted by one or more R¹²Embodiments of a 5-or 6-membered heteroaryl or heterocyclyl ring substituted with a group.

Exemplary embodiments of compounds of formula I include those wherein R⁶And R⁹Embodiments that form an imidazolyl, piperidonyl, pyrrolidinyl, or pyrazolyl ring.

Exemplary embodiments of compounds of formula I include those wherein R⁸And R⁹Form optionally substituted by one or more R¹²Embodiments of a 5-or 6-membered heteroaryl or heterocyclyl ring substituted with a group.

Exemplary embodiments of compounds of formula I include those wherein R⁸And R⁹Embodiments that form an imidazolyl, piperidonyl, pyrrolidinyl, or pyrazolyl ring.

Exemplary embodiments of compounds of formula I include those wherein X¹Is N and Z¹Is C, X¹And Z¹Form optionally substituted by one or more R¹²Embodiments of a 5-, 6-or 7-membered heteroaryl or heterocyclyl ring substituted with a group.

Exemplary embodiments of compounds of formula I include those wherein R¹⁰Is optionally substituted with one or more substituents selected from F, Cl and CH₃Embodiments of phenyl substituted with the group of (1).

Exemplary embodiments of compounds of formula I include those wherein R ¹⁰Is an optionally substituted heterocyclic group having 3 to 20 ring atoms.

Exemplary embodiments of compounds of formula I include:

and stereoisomers, geometric isomers, tautomers and pharmaceutically acceptable salts thereof, wherein:

Z¹is CR¹Or N;

Z²is CR²Or N;

Z³is CR³Or N;

Z⁴is CR⁴Or N;

wherein Z¹、Z²、Z³And Z⁴None, one or both are N;

wherein (i) X¹Is NR¹⁰And X²Is N, (ii) X¹Is S and X²Is CR¹¹，(iii)X¹Is O and X²Is CR¹¹Or (iv) X¹Is NR¹⁰And X²Is CR¹¹；

R⁵And R⁶Independently selected from H, C₁-C₁₂Alkyl radical, C₂-C₈Alkenyl and C₂-C₈Alkynyl, wherein alkyl, alkenyl and alkynyl are optionally substituted with one or more groups independently selected from: F. cl, Br, I, -CN, -CO₂H、-COCH₃、-COC(CH₃)₃、-CO₂CH₃、-CONH₂、-CONHCH₃、-CON(CH₃)₂、-NO₂、-NH₂、-NHCH₃、-N(CH₃)₂、-NHCOCH₃、-NHS(O)₂CH₃、-N(CH₃)C(CH₃)₂CONH₂、-N(CH₃)CH₂CH₂S(O)₂CH₃、=O、-OH、-OCH₃、-OCH₂CH₃、-OCH(CH₃)₂、-S(O)₂N(CH₃)₂、-SCH₃and-S (O)₂CH₃；

R¹、R²、R³、R⁴、R⁷、R⁸、R⁹And R¹²Independently selected from H, F, Cl, Br, I, -CH₃、-CH₂CH₃、-C(CH₃)₃、-CH₂OH、-CH₂CH₂OH、-C(CH₃)₂OH、-CH₂OCH₃、-CN、-CF₃、-CO₂H、-COCH₃、-COC(CH₃)₃、-CO₂CH₃、-CONH₂、-CONHCH₃、-CON(CH₃)₂、-C(CH₃)₂CONH₂、-NO₂、-NH₂、-NHCH₃、-N(CH₃)₂、-NHCOCH₃、-NHS(O)₂CH₃、-N(CH₃)C(CH₃)₂CONH₂、-N(CH₃)CH₂CH₂S(O)₂CH₃、=O、-OH、-OCH₃、-OCF₃、-S(O)₂N(CH₃)₂、-SCH₃、-S(O)₂CH₃Cyclopropyl, cyclobutyl, oxetanyl, morpholino and 1, 1-dioxo-thiopyran-4-yl;

or R⁶And R⁹Or R⁸And R⁹Form optionally substituted by one or more R¹²A group-substituted 5-or 6-membered heteroaryl or heterocyclyl ring;

R¹⁰is H, C₁-C₁₂Alkyl radical, C₂-C₈Alkenyl radical, C₂-C₈Alkynyl, C₆-C₂₀Aryl radical, C₃-C₁₂Carbocyclyl, C₂-C₂₀Heterocyclic group, C₁-C₂₀Heteroaryl, - (C)₁-C₁₂Alkylene group) - (C₃-C₁₂Carbocyclyl), - (C)₁-C₁₂Alkylene group) - (C₂-C₂₀Heterocyclyl), - (C) ₁-C₁₂Alkylene) -C (= O) - (C)₂-C₂₀Heterocyclyl), - (C)₁-C₁₂Alkylene group) - (C₆-C₂₀Aryl), - (C)₆-C₂₀Aryl group) - (C₁-C₂₀Heteroaryl), - (C)₆-C₂₀Aryl group) - (C₂-C₂₀Heterocyclyl) and- (C)₁-C₁₂Alkylene group) - (C₁-C₂₀Heteroaryl), wherein alkyl, alkenyl, alkynyl, alkylene, carbocyclyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one or more groups independently selected from: F. cl, Br, I, -CH₃、-CH₂CH₃、-C(CH₃)₃、-CH₂OH、-CH₂CH₂OH、-C(CH₃)₂OH、-CH₂OCH₃、-CN、-CH₂F、-CHF₂、-CF₃、-CO₂H、-COCH₃、-COC(CH₃)₃、-CO₂CH₃、-CONH₂、-CONHCH₃、-CON(CH₃)₂、-C(CH₃)₂CONH₂、-NO₂、-NH₂、-NHCH₃、-N(CH₃)₂、-NHCOCH₃、-NHS(O)₂CH₃、-N(CH₃)C(CH₃)₂CONH₂、-N(CH₃)CH₂CH₂S(O)₂CH₃、=O、-OH、-OCH₃、-S(O)₂N(CH₃)₂、-SCH₃、-S(O)₂CH₃Cyclopropyl, cyclobutyl, oxetanyl, morpholino and 1, 1-dioxo-thiopyran-4-yl; and is

R¹¹Is H, F, Cl, Br, I, CN, -N (R)⁵)₂、-OR⁵、C₁-C₁₂Alkyl radical, C₂-C₈Alkenyl radical, C₂-C₈Alkynyl, C₆-C₂₀Aryl radical, C₃-C₁₂Carbocyclyl, C₂-C₂₀Heterocyclic group, C₁-C₂₀Heteroaryl, - (C)₁-C₁₂Alkylene group) - (C₃-C₁₂Carbocyclyl), - (C)₁-C₁₂Alkylene group) - (C₂-C₂₀Heterocyclyl), - (C)₁-C₁₂Alkylene) -C (= O) - (C)₂-C₂₀Heterocyclyl), - (C)₁-C₁₂Alkylene group) - (C₆-C₂₀Aryl) and- (C)₁-C₁₂Alkylene group) - (C₁-C₂₀Heteroaryl), wherein alkyl, alkenyl, alkynyl, alkylene, carbocyclyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one or more groups independently selected from: F. cl, Br, I, -CH₃、-CH₂CH₃、-C(CH₃)₃、-CH₂OH、-CH₂CH₂OH、-C(CH₃)₂OH、-CH₂OCH₃、-CN、-CH₂F、-CHF₂、-CF₃、-CO₂H、-COCH₃、-COC(CH₃)₃、-CO₂CH₃、-CONH₂、-CONHCH₃、-CON(CH₃)₂、-C(CH₃)₂CONH₂、-NO₂、-NH₂、-NHCH₃、-N(CH₃)₂、-NHCOCH₃、-NHS(O)₂CH₃、-N(CH₃)C(CH₃)₂CONH₂、-N(CH₃)CH₂CH₂S(O)₂CH₃、=O、-OH、-OCH₃、-S(O)₂N(CH₃)₂、-SCH₃、-S(O)₂CH₃Cyclopropyl, cyclobutyl, oxetanyl, morpholino and 1, 1-dioxo-thiopyran-4-yl.

Exemplary embodiments of the compounds of formula I include the compounds in tables 1, 2 and 3.

Exemplary embodiments of compounds of formula I include those wherein R¹⁰Is CH₃Or optionally substituted phenyl and wherein the phenyl is substituted with one or more groups selected from F, Cl and CH₃Embodiments substituted with the group of (1).

Exemplary embodiments of compounds of formula I include those wherein R¹⁰Is optionally substituted C₂-C₂₀Heterocyclyl and wherein R¹⁰Is an embodiment of 4-piperidinyl.

Exemplary embodiments of compounds of formula I include those wherein R¹⁰Is an optionally substituted heterocyclic group having 3 to 20 ring atoms and wherein R¹⁰Is an embodiment of 4-piperidinyl.

The compounds of formula I according to the invention may contain asymmetric or chiral centers and thus exist in different stereoisomeric forms. All stereoisomeric forms of the compounds of the present invention (including but not limited to diastereomers, enantiomers and atropisomers and mixtures thereof such as racemic mixtures) form part of the present invention.

In addition, the present invention also includes all geometric and positional isomers. For example, if the compounds of formula I have double bonds or fused rings, the cis-and trans-forms and mixtures thereof are also included within the scope of the present invention. Single positional isomers and mixtures of positional isomers are also included within the scope of the present invention.

In the structures shown herein, without giving the stereochemistry of any particular chiral atom, then all stereoisomers are considered and included in the compounds of the present invention. Where stereochemistry is given by a solid wedge or dashed line representing a particular configuration, then stereoisomers are so given and defined.

The compounds of the present invention may exist in unsolvated forms as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and both solvated and unsolvated forms are encompassed by the present invention.

The compounds of the invention may also exist in different tautomeric forms, all such forms being included within the scope of the invention. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that are interconvertible by a low energy barrier. For example, proton tautomers (also referred to as proton translocating tautomers) include interconversion by proton translocation, such as keto-enol and imine-enamine isomerizations. Valence tautomers include interconversion by recombination of some of the bonding electrons.

The invention also includes isotopically-labeled compounds of the invention, which are identical to those recited herein, except that one or more atoms are replaced by an atom having an atomic mass or number of atoms different from the atomic mass or number of atoms usually found in nature. All isotopes of any particular atom or element given and their uses are included within the scope of the compounds of the present invention. Examples of isotopes that can be incorporated into the compounds of the invention include hydrogen, carbonIsotopes of nitrogen, oxygen, phosphorus, fluorine, chlorine and iodine, e.g.²H、³H、¹¹C、¹³C、¹⁴C、¹³N、¹⁵N、¹⁵O、¹⁷O、¹⁸O、³²P、³³P、³⁵S、¹⁸F、³⁶Cl、¹²³I and¹²⁵I. certain isotopically-labeled compounds of the invention (e.g., with³H and¹⁴c-labeled ones) can be used for compound and/or substrate tissue distribution studies. Tritiated (a)³H) And carbon-14 (¹⁴C) Isotopes can be used to facilitate preparation and detection. In addition, the heavy isotopes such as deuterium (i.e.,²H) substitution may provide certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements), and thus substitution with heavier isotopes may be preferred in some circumstances. Positron emitting isotopes such as¹⁵O、¹³N、¹¹C and¹⁸f can be used in Positron Emission Tomography (PET) studies to detect substrate receptor occupancy. Isotopically labeled compounds of the present invention can generally be prepared by carrying out procedures analogous to those disclosed in the schemes and/or examples below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

Biological evaluation

The relative efficacy of a compound of formula I as an inhibitor of enzyme activity (or other biological activity) can be determined by determining the concentration of each compound that inhibits activity to a given degree and then comparing the results. Typically, the preferred assay is the concentration that inhibits 50% of the activity in a biochemical assay, i.e., the 50% inhibitory concentration or "IC₅₀". The IC may be completed using conventional techniques known in the art₅₀And (4) measuring the value. In general, IC can be determined by measuring the activity of a given enzyme in the presence of a range of concentrations of the inhibitor of interest₅₀. The experimentally obtained values of the enzyme activity were then plotted against the inhibitor concentration used. Will exhibit 50% inhibition of enzyme activity (versus the absence of any inhibition)Activity ratio in the case of agent) as IC₅₀The value is obtained. Similarly, other inhibitory concentrations can be determined by appropriate activity assays. For example, in some cases, it is desirable to determine the 90% inhibitory concentration, i.e., IC₉₀And the like.

Accordingly, a "selective PI3K δ inhibitor" may be understood to mean exhibiting a 50% Inhibitory Concentration (IC) against PI3K δ₅₀) At a concentration that is at least 10-fold lower than the IC50 value of any or all other class I PI3K family members.

The PI3 kinase activity of the compounds of formula I can be determined using a number of direct and indirect assays. The ability of certain exemplary compounds described herein to inhibit PI3K α, β, γ, and δ isoforms was determined (example 901). IC50 values for inhibition of PI3K δ ranged from less than 1nM (sodium moles) to about 10 μ M (micromolar). Certain exemplary compounds of the invention have a PI3K delta inhibitory IC of less than 10nM₅₀The value is obtained. The compounds are selective for the p110 δ (delta) isoform, which is a class Ia PI3 kinase, relative to the other class Ia PI3 kinases, and thus for the p110 δ isoform, relative to both the p110 α (alpha) isoform and the p110 β (beta) isoform. In particular, they are selective for p110 δ (delta) over p110 α (alpha). The compounds are also selective for the p110 δ isoform over p110 γ (gamma), a class Ib kinase. Such as biochemical IC₅₀As illustrated by the ratio of values (example 901), the compounds of formula I of the present invention exhibit at least 10-fold selectivity for the p110 δ (delta) isoform over the p110 α (alpha) isoform of PI3 kinase.

Certain compounds of formula I have antiproliferative activity in the treatment of hyperproliferative disorders, such as cancer. The compounds of formula I inhibit tumor growth in mammals and are useful for treating human cancer patients. The compounds of formula I can be tested for their in vitro cell proliferation activity and in vivo tumor growth inhibition according to the methods described in the following documents: WO2006/046031, US2008/0039459, US2008/0076768, US2008/0076758, WO2008/070740, WO2008/073785, which are incorporated herein by reference.

Drug-induced immunosuppression of the compounds of the present invention can be assessed using in vivo functional assays such as rodent models of induced arthritis and therapeutic or prophylactic treatments for assessing disease scores, T cell dependent antibody responses (TDAR) and Delayed Type Hypersensitivity (DTH). Other in vivo systems including murine models of host defense against infection or tumor resistance (Burleson GR, Dean JH, and Munson AE. methods in immunological biology, Vol.1. Wiley-Liss, New York, 1995) are contemplated to elucidate the nature or mechanism of the observed immunosuppression. In vivo test systems can be supplemented with well established in vitro or ex vivo functional assays for assessing immunocompetence. These assays may include measurements of B or T cell proliferation in response to a mitogen or specific antigen, signaling through the PI3K pathway in B or T cells or immortalized B or T cell lines, cell surface markers in response to B or T cell signaling, Natural Killer (NK) cell activity, mast cell degranulation, macrophage phagocytosis or killing activity, and measurement of neutrophil oxidative burst and/or chemotaxis. In each of these assays, it may involve measuring cytokine production by specific effector cells (e.g., lymphocytes, NK, monocytes/macrophages, neutrophils). In vitro and ex vivo assays can be used in preclinical and clinical trials using lymphoid tissues and/or peripheral blood (House RV. "Theory and practice of cytokine assessment in immunotoxicology" (1999) Methods19:17-27; Hubbard AK. "effect of xenobiotics on macrophage function: evaluation in vitro Methods" (1999) Methods;19:8-16; Lebrec H et al (2001) diagnostics 158: 25-29).

A detailed study of collagen-induced arthritis (CIA) using a 6-week model of human arthritis mimicking the autoimmune mechanism, rat and mouse models (example 902). Collagen-induced arthritis (CIA) is one of the most commonly used animal models of human Rheumatoid Arthritis (RA). The inflammation of the joints that occurs in animals with CIA is quite similar to that observed in patients with RA. Blocking Tumor Necrosis Factor (TNF) is an effective treatment of CIA, just as it is a very effective therapy in the treatment of RA patients. CIA is mediated by both T-cells and antibodies (B-cells). Macrophages are thought to play an important role in mediating tissue damage during disease development. CIA is induced by immunizing animals with collagen emulsified in Complete Freund's Adjuvant (CFA). Induction is most often performed in DBA/l mouse strains, but the disease can also be induced in Lewis mice.

There is good evidence that B-cells play a key role in the pathogenesis of autoimmune and/or inflammatory diseases. B cell depleting protein-based therapeutics such as Rituxan are effective against autoantibody driven inflammatory diseases such as rheumatoid arthritis (Rastetter et al (2004) Annu RevMed55: 477). CD69 is an early activation marker in leukocytes including T cells, thymocytes, B cells, NK cells, neutrophils, and eosinophils. The CD69 human whole blood assay (example 903) determined the ability of compounds to inhibit the production of CD69 by B lymphocytes in human whole blood activated by cross-linking surface IgM with goat F (ab') 2 anti-human IgM.

T-cell dependent antibody response (TDAR) is a predictive assay for immune function testing when the potential immunotoxic effects of a compound need to be investigated. The IgM-Plaque Forming Cell (PFC) assay using Sheep Red Blood Cells (SRBC) is a currently widely accepted and validated standard test. TDAR has been shown to be a highly predictive assay for the detection of somatic exposure immunotoxicity in mice based on the US National ToxicogyProgramm (NTP) database (M.I.Luster et al (1992) fundam. appl. Toxicol.18: 200-. The utility of this assay derives from the fact that it is a measure of the body integrity involving a number of important components of the immune response. TDAR depends on the following function of the cell compartments: (1) antigen presenting cells, such as macrophages or dendritic cells; (2) t-helper cells, which are key players in the origin of the response and in isotype switching; and (3) B-cells, which are the final effector cells and are responsible for antibody production. Chemically induced changes in either compartment can result in significant changes in the overall TDAR (m.p. holsapple: g.r.burleson, j.h.dean and a.e.munson, editors, modern methods in immunology, volume 1, Wiley-light Publishers, new york, NY (1995), pages 71-108). Typically, the assay is performed in the form of an ELISA for measuring soluble antibodies (R.J.Smiialowzc et al (2001) Toxicol.Sci.61:164-175) or in the form of a plaque (or antibody) forming cell assay for detecting plasma cells secreting antigen-specific antibodies (L.Guo et al (2002) Toxicol.appl.Pharmacol.181: 219-227). The antigen of choice is either a whole cell (e.g., sheep red blood cells) or a soluble protein antigen (T.Miller et al (1998) Toxicol. Sci.42: 129-135).

Exemplary compounds of formula I in tables 1, 2 and 3 were prepared, characterized and tested for inhibition and selectivity to PI3K δ according to the methods of the present invention, and these compounds have the following structures and corresponding names (chem biodraw Ultra, version 11.0, Cambridge soft corp., Cambridge MA).

TABLE 1.

TABLE 2.

TABLE 3

Administration of Compounds of formula I

The compounds of formula I of the present invention may be administered by a route appropriate to the condition being treated. Suitable routes include oral, parenteral (including subcutaneous, intramuscular, intravenous, intraarterial, intradermal, intrathecal and epidural), transdermal, rectal, nasal, topical (including buccal and sublingual), vaginal, intraperitoneal, intrapulmonary and intranasal. For local immunosuppressive therapy, the compound may be administered by intralesional administration, including perfusion with the inhibitor prior to transplantation or contacting the graft with the inhibitor. It will be appreciated that the preferred route may vary, for example, depending on the condition of the recipient. In the case where the compound is administered orally, it may be formulated with a pharmaceutically acceptable carrier or excipient as a pill, capsule, tablet, or the like. Where the compound is administered parenterally, it may be formulated in a pharmaceutically acceptable parenteral vehicle and in injectable unit dosage forms, as described in detail below.

The dosage for treating a human patient may vary from about 10mg to about 1000mg of the compound of formula I. A typical dose may be from about 100mg to about 300mg of the compound. The dose may be administered once daily (QID), twice daily (BID), or more frequently, depending on the pharmacokinetic and pharmacodynamic properties, including absorption, distribution, metabolism, and excretion of the particular compound. In addition, toxicity factors may also affect the dosage and administration regimen. When administered orally, the pills, capsules or tablets may be ingested daily or less frequently for a prescribed period of time. The protocol may be repeated for a number of treatment cycles.

Methods of treatment with compounds of formula I

The compounds of formula I of the present invention are useful in the treatment of human or animal patients suffering from diseases or disorders caused by abnormal cell growth, function or behaviour associated with PI3 kinase, in particular with the p110 δ (delta) isoform of PI3 kinase, such as immune disorders, cardiovascular diseases, viral infections, inflammation, metabolism/endocrine disorders or neurological disorders, and therefore may be treated by a method comprising administering thereto a compound of the present invention as defined above. A human or animal patient suffering from cancer may also be treated with a method comprising administering thereto a compound of the invention as defined above. The condition of the patient can thus be improved or improved.

The compounds of formula I are useful for in vitro, in situ and in vivo diagnosis or treatment of mammalian cells, biological or related pathological conditions such as systemic and local inflammation, immune-inflammatory diseases such as rheumatoid arthritis, immune suppression, organ transplant rejection, allergy, ulcerative colitis, crohn's disease, dermatitis, asthma, systemic lupus erythematosus, sjogren's syndrome, multiple sclerosis, scleroderma/systemic sclerosis, Idiopathic Thrombocytopenic Purpura (ITP), anti-neutrophil cytoplasmic antibody (ANCA) vasculitis, Chronic Obstructive Pulmonary Disease (COPD), psoriasis, for total joint protection.

The compounds of formula I are useful in the treatment of diseases such as: arthritic diseases such as rheumatoid arthritis, monoarthritis, osteoarthritis, gouty arthritis, spondylitis; behcet's disease; sepsis, septic shock, endotoxic shock, gram negative sepsis (gram negative sepsis), gram positive sepsis (gram positive sepsis), and toxic shock syndrome; multiple organ injury syndrome secondary to sepsis, trauma, or hemorrhage; ophthalmic disorders such as allergic conjunctivitis, vernal conjunctivitis, uveitis, and thyroid-associated eye disease; eosinophilic granuloma; lung or respiratory system disorders such as asthma, chronic bronchitis, allergic rhinitis, ARDS, chronic inflammatory diseases of the lung (e.g., chronic obstructive pulmonary disease), silicosis, pulmonary sarcoidosis, pleuritis, alveolitis, vasculitis, emphysema, pneumonia, bronchiectasis, and pulmonary oxygen toxicity (pulmony oxygen toxicity); reperfusion injury of the myocardium, brain or limbs; fibrosis such as cystic fibrosis; keloid formation or scar tissue formation; atherosclerosis; autoimmune diseases such as Systemic Lupus Erythematosus (SLE), autoimmune thyroiditis, multiple sclerosis, some forms of diabetes and raynaud's syndrome; and graft rejection disorders such as GVHD and allograft rejection; chronic glomerulonephritis; inflammatory bowel diseases such as Chronic Inflammatory Bowel Disease (CIBD), crohn's disease, ulcerative colitis, and necrotizing enterocolitis; inflammatory dermatoses such as contact dermatitis, atopic dermatitis, psoriasis or urticaria; fever and myalgia due to infection; inflammatory disorders of the central or peripheral nervous system such as meningitis, encephalitis, and brain or spinal cord injury due to minor trauma; sjogren's syndrome; diseases involving leukocyte extravasation (leukocyte diapedesis); alcoholic hepatitis; bacterial pneumonia; antigen-antibody complex mediated diseases; hypovolemic shock; type I diabetes; acute and delayed type hypersensitivity reactions; disease states due to leukocyte dyscrasia (leucocyte dyscrasia) and metastasis; heat damage; syndromes associated with granulocyte metastasis; and cytokine-induced toxicity.

The methods of the invention have utility in treating individuals suffering from or likely to experience reperfusion injury, i.e., injury resulting from a condition in which a tissue or organ has experienced ischemia for a period of time, followed by reperfusion. The term "ischemia" refers to ischemia of local tissue caused by an occlusion of arterial blood flow. Transient ischemia, followed by reperfusion, characteristically results in neutrophil activation and migration through the endothelium of the vessels in the affected area. Accumulation of activated neutrophils in turn leads to the production of reactive oxygen metabolites that damage the components of the involved tissue or organ. This "reperfusion injury" phenomenon is commonly associated with conditions such as vascular stroke (including global and focal ischemia), hemorrhagic shock, myocardial ischemia or infarction, organ transplantation, and cerebral vasospasm. For example, reperfusion injury occurs at the end of a heart bypass procedure or during cardiac arrest, when reperfusion begins once the heart is prevented from receiving blood. Inhibition of PI3K δ activity is expected to lead to a reduction in the amount of reperfusion injury in such cases.

The methods of the invention comprise treating cancer with a compound of formula I, wherein the cancer is breast cancer, ovarian cancer, cervical cancer, prostate cancer, testicular cancer, genitourinary tract cancer, esophageal cancer, laryngeal cancer, glioblastoma, neuroblastoma, gastric cancer, skin cancer, keratoacanthoma, lung cancer, epidermoid carcinoma, large cell carcinoma, non-small cell lung cancer (NSCLC), small cell carcinoma, lung adenocarcinoma, bone cancer, colon cancer, adenoma, pancreatic cancer, adenoma, thyroid cancer, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, sarcoma, bladder cancer, liver cancer and biliary passages, kidney cancer, pancreatic cancer, myeloid disorders, lymphoma, hairy cell carcinoma, buccal cavity cancer, nasopharyngeal cancer, pharyngeal cancer, lip cancer, tongue cancer, mouth cancer, small intestine cancer, colon-rectal cancer, large intestine cancer, rectal cancer, cancers of the brain and central nervous system, cancer, colon cancer, and cervical cancer, Hodgkin's disease, leukemia, bronchial carcinoma, thyroid carcinoma, cancer of the liver and intrahepatic bile ducts, hepatocellular carcinoma, gastric carcinoma, glioma/glioblastoma, endometrial carcinoma, melanoma, renal and renal pelvis cancers, bladder cancer, uterine corpus carcinoma, cervical cancer, multiple myeloma, acute myelogenous leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, lymphocytic leukemia, myeloid leukemia, oral and pharyngeal cancers, non-hodgkin's lymphoma, melanoma, and villous colon adenoma.

The methods of the invention comprise administering a compound of formula I to treat a hematopoietic malignancy selected from leukemia, non-hodgkin's lymphoma, diffuse large hematopoietic lymphoma, follicular lymphoma, mantle cell lymphoma, Chronic Lymphocytic Leukemia (CLL), multiple myeloma, Acute Myelogenous Leukemia (AML), and Myeloid Cell Leukemia (MCL).

The invention also includes compounds of formula I for use as a medicament.

The invention also includes the use of a compound of formula I for the treatment of a disease or disorder selected from cancer, immune disorders, cardiovascular disease, viral infection, inflammation, metabolic/endocrine function disorders and neurological disorders and mediated by the p110 δ isoform of PI3 kinase.

The invention also includes compounds of formula I for use in the treatment of a disease or disorder selected from cancer, immune disorders, cardiovascular disease, viral infection, inflammation, metabolic/endocrine function disorders and neurological disorders and mediated by the p110 δ isoform of PI3 kinase.

The invention also includes the use of a compound of formula I for the manufacture of a medicament.

The invention also includes the use of a compound of formula I in the manufacture of a medicament for the treatment of cancer, immune disorders, cardiovascular disease, viral infection, inflammation, metabolism/endocrine function disorders and neurological disorders.

Pharmaceutical preparation

For the therapeutic treatment (including prophylactic treatment) of mammals, including humans, with a compound of formula I, the compound of formula I is typically formulated as a pharmaceutical composition according to standard pharmaceutical practice. According to this aspect of the invention there is provided a pharmaceutical composition comprising a compound of the invention in association with a pharmaceutically acceptable diluent or carrier.

Typical formulations are prepared by mixing a compound of the invention with a carrier, diluent or excipient. Suitable carriers, diluents and excipients are well known to those skilled in the art and include materials such as carbohydrates, waxes, water soluble and/or swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water and the like. The particular carrier, diluent or excipient employed will depend upon the means and purpose for which the compounds of the present invention are to be employed. The solvent is generally selected on the basis of solvents recognized by those skilled in the art as being safe for administration to mammals (GRAS). Generally, safe solvents are non-toxic aqueous solvents such as water and other non-toxic solvents that are soluble or miscible in water. Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycol (e.g., PEG400, PEG300), and the like, and mixtures thereof. The formulations may also contain one or more buffers, stabilisers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifying agents (glidants), glidants, processing aids (processing aids), colorants, sweeteners, flavoring agents (flavoring agents), flavouring agents and other additives known to provide an elegant form to a drug (i.e. a compound of the invention or a pharmaceutical composition thereof) or to aid in the manufacture of a pharmaceutical product (i.e. a medicament).

The formulations may be prepared using conventional dissolution and mixing procedures. For example, the starting drug (i.e., a compound of the invention or a stabilized form of the compound (e.g., a complex with a cyclodextrin derivative or other known complexant) is dissolved in a suitable solvent in the presence of one or more of the above-mentioned excipients.

The pharmaceutical composition (or formulation) for use can be packaged in a variety of ways depending on the method used to administer the drug. Generally, articles for dispensing include containers having a pharmaceutical formulation in a suitable form therein. Suitable containers are well known to those skilled in the art and include materials such as bottles (plastic and glass), sachets, ampoules, plastic bags, metal cartridges, and the like. The container may also include tamper-proof means for preventing inadvertent access to the contents of the package. In addition, the container also has a label placed thereon describing the contents of the container. The label may also include appropriate warnings.

Pharmaceutical formulations of the compounds of the present invention may be prepared for various routes and types of administration. For example, a compound of formula I having the desired purity may be admixed in the form of a lyophilized formulation, a milled powder or an aqueous solution, optionally with pharmaceutically acceptable diluents, carriers, excipients or stabilizers (Remington's Pharmaceutical Sciences (1980), 16 th edition, Osol, a. Can be formulated at ambient temperature, at a suitable pH and at the desired purity in admixture with a physiologically acceptable carrier, i.e. a carrier which is non-toxic to the recipient at the dosages and concentrations employed. The pH of the formulation depends primarily on the particular application and concentration of the compound, but may vary from about 3 to about 8. Formulation in acetate buffer at pH5 is one suitable embodiment.

The compounds can generally be stored in the form of solid compositions, freeze-dried preparations or in the form of aqueous solutions.

The pharmaceutical compositions of the present invention will be formulated, administered and administered in a manner consistent with good medical practice (i.e., the amount, concentration, schedule, process, medium and route of administration). Factors to be considered in this context include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the etiology of the disorder, the site of delivery of the active agent, the method of administration, the schedule of administration, and other factors known to medical practitioners. A "therapeutically effective amount" of a compound to be administered will be determined by such considerations and is the minimum amount required to prevent, ameliorate or treat the hyperproliferative disorder.

As a general proposition, the initial pharmaceutically effective amount/dose of inhibitor administered parenterally will be in the range of about 0.01-100mg/kg patient body weight/day, i.e., about 0.1-20mg/kg patient body weight/day, with a typical initial range of 0.3-15 mg/kg/day for the compound used.

Acceptable diluents, carriers, excipients and stabilizers are nontoxic to recipients at the dosages and concentrations employed, and include: buffers such as phosphates, citrates and other organic acids; antioxidants, including ascorbic acid and methionine; preservatives (for example octadecyl dimethyl benzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butanol or benzyl alcohol; Alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counterions such as sodium; metal complexes (e.g., zinc-protein complexes); and/or nonionic surfactants such as TWEEN^TM、PLURONICS^TMOr polyethylene glycol (PEG). The active pharmaceutical ingredient may also be entrapped in microcapsules, for example prepared by coacervation techniques or interfacial polymerization methods, such as hydroxymethylcellulose or gelatin-microcapsules and poly (methylmethacylate) microcapsules, respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nanoparticles and nanocapsules) or in macroemulsions (macroemulsions). This technique is disclosed in Remington's Pharmaceutical Sciences, 16 th edition, Osol, A. edition (1980).

Sustained release formulations of the compounds of formula I can be prepared. Suitable examples of sustained release formulations include semipermeable matrices of solid hydrophobic polymers containing a compound of formula I, which matrices are in the form of shaped articles, e.g., films, or microcapsules. Examples of sustained release matrices include polyesters, hydrogels (e.g., poly (2-hydroxyethyl methacrylate) or poly (vinyl alcohol)), polylactide (US3773919), copolymers of L-glutamic acid and γ -ethyl-L-glutamate, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers such as LUPRON DEPOT^TM(injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate) and poly-D- (-) -3-hydroxybutyric acid.

The formulations include those suitable for use in the routes of administration detailed herein. The formulations may be conveniently presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Techniques and formulations are generally found in Remington's Pharmaceutical Sciences (Mack Publishing co., Easton, PA). Such methods include the step of bringing into association the active ingredient with the carrier, which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.

Formulations of a compound of formula I suitable for oral administration may be prepared in the form of discrete units such as pills, capsules, cachets or tablets, each containing a predetermined amount of a compound of formula I. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form, such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surfactant or dispersing agent. Molded tablets may be prepared by molding in a suitable machine the powdered active ingredient moistened with an inert liquid diluent. The tablets may optionally be coated or scored and optionally formulated for slow or controlled release of the active ingredient therefrom. Tablets, troches (troche), aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules such as gelatin capsules, syrups or elixirs may be prepared for oral use. Formulations of a compound of formula I for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents including sweetening agents, flavouring agents, colouring agents and preserving agents in order to provide palatable preparations. Tablets containing the active ingredient in admixture with pharmaceutically acceptable non-toxic excipients which are suitable for the manufacture of tablets are acceptable. These excipients may be, for example: inert diluents, such as calcium or sodium carbonate, lactose, calcium or sodium phosphate; granulating and disintegrating agents, such as corn starch or alginic acid; binding agents, such as starch, gelatin or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or they may be coated by known techniques, including microencapsulation, to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed alone or with a wax.

For the treatment of the eye or other external tissues, such as the mouth and skin, the formulations may be applied in the form of a topical ointment or cream containing one or more active ingredients in an amount of, for example, 0.075-20% w/w. When formulated in an ointment, the active ingredient may be used with a paraffinic or water-miscible ointment base. Alternatively, the active ingredient may be formulated in a cream with an oil-in-water cream base. If desired, the aqueous phase of the cream base may include polyhydric alcohols, i.e., alcohols having two or more hydroxyl groups such as propylene glycol, butane 1, 3-diol, mannitol, sorbitol, glycerol, and polyethylene glycols (including PEG400), and mixtures thereof. Topical formulations may desirably include compounds that enhance the absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such skin penetration enhancers include dimethyl sulfoxide and related analogs. The oily phase of the emulsions of the invention may be constituted in a known manner by known ingredients, including mixtures of at least one emulsifier with a fat or an oil or both. The hydrophilic emulsifier included together with the lipophilic emulsifier functions as a stabilizer. One or more emulsifiers, with or without one or more stabilizers, together constitute a so-called emulsifying wax, which together with oils and fats constitutes a so-called emulsifying ointment base, which forms the oily dispersed phase of the cream. Emulsifiers and emulsion stabilizers suitable for use in the formulations of the present invention include 60、80. Cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glycerol monostearate, and sodium lauryl sulfate.

Aqueous suspensions of the compounds of formula I contain the active ingredient in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients include: suspending agents, such as sodium carboxymethylcellulose, croscarmellose, povidone, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing or wetting agents such as naturally-occurring phosphatides (e.g., lecithin), condensation products of an alkylene oxide with fatty acids (e.g., polyoxyethylene stearate), condensation products of ethylene oxide with long chain aliphatic alcohols (e.g., heptadecaethyleneoxycetanol), condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides (e.g., polyoxyethylene sorbitan monooleate). The aqueous suspensions may also contain one or more preservatives, for example ethyl or n-propyl p-hydroxybenzoate, one or more colouring agents, one or more flavouring agents and one or more sweetening agents, such as sucrose or saccharin.

Pharmaceutical compositions of the compounds of formula I may be in the form of sterile injectable preparations, such as sterile injectable aqueous or oleaginous suspensions. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a parenterally-acceptable non-toxic diluent or solvent, for example as a solution in 1, 3-butanediol, or as a lyophilized powder. Among the acceptable vehicles and solvents that may be employed are water, ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending vehicle. For this purpose, any bland fixed oil may be employed including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid may likewise be used in the preparation of injectables.

The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. For example, a time release formulation for oral administration to humans may contain about 1-1000mg of the active substance complexed with a suitable, convenient amount of carrier material, which may be from about 5% to about 95% (weight: weight) of the total composition. The pharmaceutical composition can be prepared to provide an easily measurable amount for administration. For example, an aqueous solution for intravenous infusion may contain about 3-500 μ g of active ingredient per mL of solution, thereby allowing an appropriate volume to be infused at a rate of about 30 mL/hour.

Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and sterile aqueous and non-aqueous suspensions which may contain suspending agents and thickening agents.

Formulations suitable for topical administration to the eye also include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingredient. The active ingredient is preferably present in such formulations at a concentration of about 0.5-20% w/w, such as about 0.5-10% w/w, for example about 1.5% w/w.

Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavoured base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.

Formulations for rectal administration may be presented as suppositories with a suitable base comprising, for example, cocoa butter or a salicylate.

Formulations suitable for intrapulmonary or nasal administration have, for example, a particle size of 0.1 to 500 microns (including particle sizes in increments of microns in the range of 0.1 to 500 microns, such as 0.5, 1, 30 microns, 35 microns, etc.), which are administered by rapid inhalation through the nasal passages or by inhalation through the mouth to reach the alveolar sacs. Suitable formulations include aqueous or oily solutions of the active ingredient. Formulations suitable for aerosol or dry powder administration may be prepared according to conventional methods and may be delivered with other therapeutic agents, such as the compounds described below for the treatment or prevention of the disorders described below.

Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.

The formulations may be packaged in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (freeze-dried) condition requiring only the addition of the sterile liquid carrier for injections, for example water, immediately prior to use. Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules and tablets of the type previously described. Preferred unit dose formulations are those containing a daily dose or unit daily sub-dose, or a suitable fraction thereof, of the active ingredient as hereinbefore described.

The present invention also provides a veterinary composition comprising at least one active ingredient as defined above and a veterinary carrier therefor. Veterinary carriers are substances used for the purpose of administering the composition, and may be solid, liquid or gaseous substances which are otherwise inert or acceptable in the veterinary art and are compatible with the active ingredient. These veterinary compositions may be administered parenterally, orally or by any other desired route.

Combination therapy

The compounds of formula I may be used alone or in combination with other therapeutic agents for the treatment of diseases or disorders described herein, such as inflammation or hyperproliferative disorders (e.g., cancer). In certain embodiments, the compounds of formula I are used in combination with a second therapeutic compound having anti-inflammatory or anti-hyperproliferative properties or for the treatment of inflammation, immune response disorders, or hyperproliferative disorders (e.g., cancer) in a pharmaceutical combination formulation or in a dosage regimen in the form of a combination therapy. The second therapeutic agent may be an NSAID anti-inflammatory agent. The second therapeutic agent may be a chemotherapeutic agent. The second compound in the pharmaceutical combination formulation or dosing regimen preferably has complementary activities to the compound of formula I such that they do not adversely affect each other. Such compounds are suitably present in the combination in an amount effective for the intended purpose. In one embodiment, the compositions of the present invention comprise a compound of formula I, or a stereoisomer, tautomer, or pharmaceutically acceptable salt or prodrug thereof, in combination with a therapeutic agent, such as an NSAID.

The combination therapy may be administered in a simultaneous or sequential regimen. When administered sequentially, the combination may be administered in the form of two or more administrations. Combined administration includes co-administration using separate formulations or a single pharmaceutical formulation, and sequential administration in any order, preferably over a period of time when both (or all) active agents exert their biological activity simultaneously.

Suitable dosages for any of the above co-administered agents are those presently used, and may be reduced due to the combined effect (synergy) of the newly identified agent and the other therapeutic agent or treatment.

Combination therapy may provide a "synergistic effect" and prove to be "synergistic", i.e., the effect achieved when the active ingredients are used together is greater than the sum of the effects produced by the separate use of the compounds. (1) When the active ingredients are co-formulated in a combined unit dose formulation and administered or delivered simultaneously; (2) when the active ingredients are delivered alternately or in parallel in separate formulations; or (3) when the active ingredients are administered using some other regimen, a synergistic effect can be achieved. When delivered in alternation therapy, synergy can be achieved when the compounds are administered or delivered sequentially, e.g., by different injections in separate syringes, separate pills or capsules, or separate infusions. In general, in alternation therapy, the effective doses of each active ingredient are administered sequentially, i.e. sequentially, whereas in combination therapy, the effective doses of two or more active ingredients are administered together.

In a particular embodiment of therapy, the compounds of formula I, or stereoisomers, tautomers, or pharmaceutically acceptable salts or prodrugs thereof, may be used in combination with other therapeutic agents, hormones, or antibody substances, such as those described herein, as well as in combination with surgical therapy and radiation therapy. Accordingly, the combination therapies of the present invention comprise administering at least one compound of formula I, or a stereoisomer, tautomer, or pharmaceutically acceptable salt or prodrug thereof, and using at least one other cancer treatment method. The amounts of the one or more compounds of formula I and the one or more other pharmaceutically active chemotherapeutic agents, as well as the relative timing of administration, are selected to achieve the desired combination therapeutic effect.

Metabolites of compounds of formula I

The in vivo metabolites of formula I described herein also fall within the scope of the present invention. Such products may result, for example, from oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage, etc. of the administered compound. Accordingly, the present invention includes metabolites of the compounds of formula I, including compounds produced by a method comprising contacting a compound of the present invention with a mammal for a period of time sufficient to produce a metabolite thereof.

Metabolites are typically identified by the following methods: preparation of a radiolabel for a compound of the invention (e.g.,¹⁴c or³H) Is administered parenterally to an animal such as a rat, mouse, guinea pig, monkey or human in detectable doses (e.g., greater than about 0.5mg/kg), allowed to exist for a sufficient period of time to metabolize (typically about 30 seconds to 30 hours) and the conversion products are isolated from urine, blood or other biological samples. Since they are labeled, these products are easily isolated (others are isolated by using antibodies that bind to epitopes retained in the metabolite). The structure of the metabolites is determined by conventional means such as MS, LC/MS or NMR analysis. In general, analysis of metabolites is performed in the same manner as conventional drug metabolism studies well known to those skilled in the art. Metabolites may be used in a discriminatory assay for therapeutic administration of the compounds of the invention, as long as no other metabolite is found in vivo.

Article of manufacture

In another embodiment of the invention, an article of manufacture or "kit" is provided that contains materials useful for treating the diseases or disorders described above. In one embodiment, the kit comprises a container containing a compound of formula I. The kit may further comprise a label or package insert located on or associated with the container. The term "package insert" refers to instructions typically included in commercial packaging for therapeutic products that contain information about the indications, usage, dosage, administration, contraindications, and/or concerns about the use of such therapeutic products. Such containers include, for example, bottles, vials, syringes, blister packs, and the like. The container may be formed from a variety of materials such as glass or plastic. The container may contain a compound of formula I or a formulation thereof effective to treat the condition and may have a sterile access port (e.g., the container may be an intravenous solution bag or vial having a stopper pierceable by a hypodermic injection needle). At least one active agent in the composition is a compound of formula I. The label or package insert indicates that the composition is used to treat a selected condition, such as cancer. In addition, the label or package insert may also indicate that the patient being treated is a patient suffering from a disorder such as a hyperproliferative disorder, neurodegeneration, cardiac hypertrophy, pain, migraine or a neurotrauma disease or event. In one embodiment, the label or package insert indicates that compositions comprising a compound of formula I are useful for treating disorders caused by abnormal cell growth. The label or package insert may also indicate that the composition may be used to treat other disorders. Alternatively or additionally, the article of manufacture may further comprise a second container comprising a pharmaceutically acceptable buffer, such as bacteriostatic water for injection (BWFI), phosphate buffered saline, ringer's solution, and dextrose solution. It may further include other substances desirable from a commercial or user standpoint, including other buffers, diluents, filters, needles, and syringes.

The kit may further comprise instructions for administering the compound of formula I and, if present, the second pharmaceutical formulation. For example, if the kit comprises a first composition comprising a compound of formula I and a second pharmaceutical formulation, the kit may further comprise instructions for administering the first and second pharmaceutical compositions simultaneously, sequentially or separately to a patient in need thereof.

In another embodiment, the kit is suitable for delivering a solid oral form of a compound of formula I, such as a tablet or capsule. Such kits preferably comprise a plurality of unit doses. Such kits may include a card having a dosage directed to its intended use. An example of such a kit is a "blister pack". Blister packs are well known in the packaging industry and are widely used for packaging pharmaceutical unit dosage forms. If desired, a memory aid, such as in the form of a number, letter, or other indicia, can be provided or a calendar insert can be used that indicates the day of the treatment schedule on which the dose can be administered.

According to one embodiment, a kit may comprise (a) a first container having a compound of formula I contained therein; and optionally (b) a second container having a second pharmaceutical formulation contained therein, wherein the second pharmaceutical formulation comprises a second compound having anti-hyperproliferative activity. Alternatively or additionally, the kit may further comprise a third container comprising a pharmaceutically acceptable buffer, such as bacteriostatic water for injection (BWFI), phosphate buffered saline, ringer's solution, and dextrose solution. It may further include other substances desirable from a commercial or user standpoint, including other buffers, diluents, filters, needles, and syringes.

In certain additional embodiments, wherein the kit comprises a compound of formula I and a second therapeutic agent, the kit may comprise containers for holding separate compositions, such as separate bottles or separate foil packets, but the separate compositions may also be contained in a single non-separate container. Typically, the kit contains instructions for administering the separate components. The kit form is particularly advantageous when the separate components are preferably administered in different dosage forms, e.g., oral and parenteral dosage forms, are administered at different dosage intervals, or when the prescribing physician desires to dose-escalate the components of the combination.

Preparation of Compounds of formula I

Heterocyclic compounds of formula I, for example 4-substituted pyrimidine compounds, may be synthesized using synthetic routes that include methods analogous to those well known in the chemical arts, particularly those described with reference to the description included herein and described for other heterocycles in the following documents: comprehensive heterocyclic Chemistry II, editors Katritzky and Rees, Elsevier,1997, e.g., volume 3; liebigs Annalen der Chemie, (9):1910-16, (1985); helvetica ChimicaActa,41:1052-60, (1958); Arzneimittel-Forschung,40(12):1328-31, (1990), each of which is incorporated herein by reference. The starting materials are generally available from commercial sources such as Aldrich Chemicals (Milwaukee, Wis.) or can be readily synthesized by methods well known to those skilled in the art (e.g., by methods generally described in Louis F. Fieser and Mary Fieser, Reagents for Organic Synthesis, Vol. 1-23, Wiley, N.Y. (1967. 2006 edition) or Beilsteins Handbuch der organischen Chemie,4, Aufl. editor. Springer-Verlag, Berlin (including Books) (also available from the Beilstein online database)).

Synthetic chemical Transformations and protecting group methodologies (protection and deprotection) as well as the necessary reagents and intermediates for the Synthesis of compounds of formula I are known in the art and include, for example, those described in R.Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T.W.Greene and P.G.M.Wuts, Protective Groups in Organic Synthesis, 3 rd edition, John Wiley and Sons (1999); and L.Patuette editors, Encyclopedia of Reagentsfor Organic Synthesis, John Wiley and Sons (1995) and subsequent versions thereof.

The compounds of formula I can be prepared individually or in the form of a compound library comprising at least 2, e.g. 5-1,000 compounds or 10-100 compounds. Libraries of compounds of formula I can be prepared by combinatorial 'split and mix' methods or by multiple parallel syntheses using solution phase or solid phase chemistry using procedures known to those skilled in the art. Thus, according to another aspect of the present invention, there is provided a compound library comprising at least 2 compounds or pharmaceutically acceptable salts thereof.

In the preparation of compounds of formula I, protection of intermediate remote (remote) functional groups, such as primary or secondary amines, may be required. The need for such protection will vary depending on the nature of the remote functionality and the conditions of the preparation process. Suitable amino-protecting groups include acetyl, trifluoroacetyl, tert-Butoxycarbonyl (BOC), benzyloxycarbonyl (CBz) and 9-fluorenylmethyleneoxycarbonyl (Fmoc). The need for such protection can be readily determined by those skilled in the art. For a general description of protecting Groups and their use, see t.w. greene, Protective Groups in Organic Synthesis, John Wiley & Sons, new york, 1991.

For illustrative purposes, schemes 1-17 show general methods for preparing compounds of formula I, e.g., 4-substituted pyrimidine compounds, as well as key intermediates. For a more detailed description of the individual reaction steps, see general procedures and the examples section. It will be appreciated by those skilled in the art that other synthetic routes may be used to synthesize the compounds of the invention. Although specific starting materials and reagents are described and discussed in the general procedures, examples and flow diagrams, other starting materials and reagents may be readily substituted to provide various derivative bicyclic and/or reaction conditions. In addition, many of the exemplary compounds prepared by the methods described herein can be further modified in accordance with the disclosure herein using conventional chemical methods well known to those skilled in the art.

In the following schemes 1-17:

Z₁-Z₄= as defined before

R¹³= suitable groups such as substituted alkyl and the like

R¹= suitable groups such as unsubstituted or substituted aromatic cyclic, acyclic or cyclic ether, alkyl or cycloalkyl, heteroaryl, piperidine, cyclicAs amine.

R²= suitable groups such as small alkyl, cycloalkyl, OH or ether.

R³= suitable groups such as H, alkyl or NH ₂。

The compound of formula (I) may be according toScheme 1Obtained from compounds of formula (II) by nucleophilic aromatic substitution reactions or other methods described in the literature. Typical reaction conditions are in the presence of a base such as DIPEA in a dipolar solvent such as bisHalogenated heterocycles are used in alkanes, n-butanol and heated at temperatures of 90-140 ℃ under microwave radiation or thermal heating.

Scheme 1

Compounds of formula (Ia) wherein Het is 2-aminopyridinyl, or at R, are obtainable⁶And R⁹In the case of rings forming a 5-or 6-membered heteroaryl or heterocycle, according toFlow chart 2Obtained from compounds of formula (III) wherein X is halogen such as bromide, chloride, iodide or a suitable leaving group such as mesylate, by alkylation reactions or other methods described in the literature. Typical reaction conditions are the use of a base such as Cs in an aprotic dipolar solvent such as DMF or DMSO under microwave irradiation or thermal heating at a temperature of 0-140 deg.C₂CO₃、K₂CO₃Or NaH.

Flow chart 2

Wherein X¹Is NR¹⁰、X²Is N, R⁶Compounds of formula (Ib) which are H and the N-linked heterocycle is purineFlow chart 3Obtained from compounds of formula (IIa) by nucleophilic aromatic substitution reactions or other methods described in the literature. Typical reaction conditions are in the presence of a base such as DIPEA in a dipolar solvent such as bis 6-chloro-9H-purine was used in the alkane or n-butanol and heated at a temperature of 100 ℃ and 140 ℃ under microwave irradiation or thermal heating. 6-chloro-9H-purine carrying an N-protecting group such as THP (tetrahydropyranyl) at position 9 may also be used under the reaction conditions reported above. The THP groups can be removed during post-treatment, for example by using a strong cation column (SCX-2).

Flow chart 3

The compound of formula (Ic) is wherein R¹⁰Is C-linked piperidine and R¹³Being substituted alkyl is a compound of formula I, which may be according toFlow chart 4Obtained from compounds of formula (Id) by reductive amination reactions or other methods described in the literature. The reaction can be carried out by using the appropriate aldehyde or ketone, followed by the addition of a reducing agent such as sodium triacetoxyborohydride. Alternatively, substituted carboxylic acids, acid chlorides, halides, isocyanides may be reacted with a compound of formula (Id) under suitable reaction conditions to give compounds wherein R is¹³A compound of formula (Ic) which is a suitable group as defined hereinbefore.

Flow chart 4

The compound of formula (Id) may be prepared according toFlow chart 5From a compound of formula (Ie) wherein Pg is a suitable protecting group such as Boc. Removal of the Boc group can be achieved, for example, by using TFA in DCM at a temperature from 0 ℃ to room temperature.

Flow chart 5

The compound of formula (If) corresponds to wherein R¹⁰Is C-linked piperidine and R¹³Is a substituted alkyl group, which may be according toFlow chart 6Obtained from compounds of formula (Ig) by reductive amination with the appropriate aldehyde or ketone, followed by addition of a reducing agent such as sodium triacetoxyborohydride. Alternatively, substituted carboxylic acids, acid chlorides, halides and isocyanides may be reacted with compounds of formula (Ig) under suitable reaction conditions as described in the literature to give compounds wherein R is¹³A compound of formula (If) which is a suitable group as defined hereinbefore.

Flow chart 6

The compound of formula (Ig) may be according toFlow chart 7From a compound of formula (Ih) wherein Pg is a suitable protecting group such as Boc or CBZ. Removal of the Boc group can be achieved, for example, by using TFA in DCM at a temperature from 0 ℃ to RT. The CBZ group can be removed, for example, by using Pd/C in the presence of HCl, at RT, using a protic solvent such as EtOH or IMS, under a hydrogen atmosphere.

Flow chart 7

The compound of formula (IIa) may be according toFlow chart 8Deprotection by an N-Pg group is obtained from compounds of formula (III) wherein Pg is a suitable N-protecting group, typically Boc or CBZ. For example, the Boc group can be removed by using TFA in DCM at a temperature from 0 ℃ to RT. For example, the CBZ group can be removed by using Pd/C in the presence of HCl, at RT, using a protic solvent such as EtOH or IMS, under a hydrogen atmosphere.

Flow chart 8

Compounds of formula (III) wherein Pg is a suitable N-protecting group, typically Boc or CBZ, may be prepared according toFlow chart 9Obtained from the compound of formula (IV) by a cyclization reaction. Typical reaction conditions are heating for a period of time from 2h to 48h at a temperature of from 60 to 90 ℃ using an acid such as acetic acid, hydrochloric acid or p-toluenesulfonic acid.

Flow chart 9

Compounds of formula (IV) wherein Pg is a suitable N-protecting group, typically Boc or CBZ, may be prepared according toFlow chart 10Obtained from the compound of formula (V) by amide coupling reactions or other methods described in the literature. Typical reaction conditions are at 0 ℃ in the presence of a coupling agent such as HObt or HOAt, in the presence of N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride and in the presence of a base such as triethylamine or 4-methylmorpholine in a dipolar aprotic solvent such as DCMTo RT using a suitable amino acid bearing a suitable protecting group such as Boc or CBZ on the amino moiety for a period of 2h to 48 h.

Flow chart 10

Compounds of formula (III) wherein Pg is a suitable N-protecting group, typically Boc or CBZ, may be prepared according toFlow chart 11Obtained from the compound of formula (V) by an amide coupling reaction followed by a cyclization reaction, without separation of the chain intermediates. Typical reaction conditions for the amide coupling step are the use of a suitable amino acid bearing a suitable protecting group such as Boc or CBZ on the amino moiety for a period of 2h to 48h in the presence of a coupling reagent such as HOBt or HOAt, in the presence of N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride and in the presence of a base such as triethylamine or 4-methylmorpholine in a dipolar aprotic solvent such as DCM at a temperature of 0 ℃ to RT. Typical reaction conditions for the cyclisation step are heating with acetic acid at a temperature of 60-90 ℃ for a period of 2h to 48 h.

Flow chart 11

The compound of formula (V) may be according toFlow chart 12Obtained from the compound of formula (VI) by reduction of the nitro group. Typical reaction conditions are in a hydrogen atmosphere, in a solvent such as IMS or EtOAc, at RT using a catalyst such as Pd/C or PtO₂For a period of time from 2h to 72 h. An alternative reaction condition may be the use of iron powder and ammonium chloride in a mixture of MeOH and water heated to reflux for a period of 2 to 5 hours.

Flow chart12

The compound of formula (VI) may be according toFlow chart 13Obtained from a compound of formula (VII) by nucleophilic aromatic substitution or transition metal catalyzed coupling reaction. Typical reaction conditions are heating in a solvent such as DMF or NMP at RT or at a temperature of 80-120 ℃ or under microwave irradiation using a base such as potassium carbonate, triethylamine or sodium tert-butoxide for a period of 2h to 20 h. Alternative reaction conditions are to use LiHMDS as a base at-78 ℃ and then add the appropriate primary amine NH in a solvent such as THF₂R¹⁰Or using palladium-mediated reaction conditions, e.g. with Pd (OAc)₂As catalyst, (R) -BINAP or (S) -BINAP was used as ligand, NH in toluene was used₂R¹⁰Heating at 90-140 deg.C.

Flow chart 13

The compounds of the formula (IIb) correspond to the formula in which X¹Is CR¹According to formula II, which can beFlow of FIG. 14 is a flowchartObtained from the compound of formula (VIII) by reduction of an azide. Typical reaction conditions are to use triphenylphosphine in a THF/water mixture as solvent, with heating at RT or at a temperature of 60-80 ℃ for 2h to 8 h. Alternatively, the reduction may be achieved by hydrogenation in the presence of a Pd catalyst such as Pd/C in a protic solvent such as ethanol.

Flow chart 14

The compound of formula (VIII) may be according toFlow chart 15Obtained from a compound of formula (IX) by converting an alcohol group to an azide group. Typical reaction conditions are those in which the appropriate alcohol is reacted under Mitsunobu reaction conditions (DIAD, PPh)₃And diphenyl phosphorazidate) in a solvent such as bis (methyl ethyl phosphorazidate)And (3) reacting in alkane. Alternatively, the conversion may be accomplished by using a base such as DBU in the presence of diphenyl phosphorazidate in THF. Wherein R is⁵The compound of formula (VIII) being H may be according toFlow chart 15By conversion of the alcohol function into a good leaving group such as a mesylate followed by reaction with an azide as nucleophile⁵A compound of formula (IX) which is H.

Flow chart 15

The compound of formula (IX) may be according toFlow chart 16Obtained from the compound of formula (X) by adding an organometallic substance, such as a Grignard reagent, to the aldehyde group. Typical reaction conditions are the use of organometallic species in solvents such as THF or diethyl ether at low temperatures, typically at-78 ℃.

Flow chart 16

Wherein R is⁵The compound of formula (IXa) which is H can be prepared according toFlow chart 17From formula (X) by reduction of aldehyde groupsThe compound is obtained. Typical reaction conditions are the use of tetrabutylammonium borohydride (nBu) as reducing agent in THF as solvent₄NBH₄)。

Flow chart 17

Separation method

In the process for preparing the compounds of the formula I, the reaction products can advantageously be separated from one another and/or from the starting materials. The desired product of each step or series of steps is isolated and/or purified to the desired degree of homogeneity using techniques conventional in the art. Typically, such separations include heterogeneous extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography. Chromatography may include any number of methods, including, for example: reverse phase chromatography and normal phase chromatography; size exclusion chromatography; ion exchange; high, medium and low pressure liquid chromatography methods and apparatus; small scale analytical chromatography; simulated Moving Bed (SMB) and preparative thin or thick layer chromatography, as well as small scale thin layer and flash chromatography techniques.

Another class of separation methods includes treating the mixture with reagents selected to combine or otherwise enable the separation of the desired product, unreacted starting materials, reaction byproducts, and the like. Such agents include adsorbents or absorbents such as activated carbon, molecular sieves, ion exchange media, and the like. Alternatively, the reagent may be an acid (in the case of a basic substance), a base (in the case of an acidic substance), a binding reagent such as an antibody, a binding protein, a selective chelating agent such as a crown ether, a liquid/liquid ion extraction reagent (LIX), or the like. The choice of a suitable separation method depends on the nature of the substances involved, such as boiling point and molecular weight in distillation and sublimation, presence or absence of polar functional groups in chromatography, stability of the substances in heterogeneous extraction in acidic and basic media, etc.

Mixtures of diastereomers may be separated into their individual diastereomers on the basis of their physicochemical differences by methods well known to those skilled in the art, such as chromatography and/or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., a chiral auxiliary (auxiliary) such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers and converting each diastereomer to the corresponding pure enantiomer. In addition, some of the compounds of the present invention may be atropisomers (e.g., substituted biaryls), which are also considered part of the present invention. Enantiomers can also be separated using a chiral HPLC column.

The individual stereoisomers, e.g., enantiomers, substantially free of their stereoisomers can be obtained by resolving racemic mixtures using methods such as diastereomer formation with optical resolving agents (Eliel, E. and Wilen, S. "Stereochemistry of Organic Compounds," John Wiley & Sons, Inc., New York, 1994; Lochmuller, C.H., (1975) J.Chromatogr.,113(3): 283-. The racemic mixture of the chiral compounds of the present invention can be separated and isolated by any suitable method, including: (1) formation of ionic diastereomeric salts with chiral compounds and separation by fractional crystallization or other means, (2) formation of diastereomeric compounds with chiral derivatizing reagents, separation of the diastereomers, and conversion to pure stereoisomers, and (3) separation of substantially pure or enriched stereoisomers directly under chiral conditions. See: "drug Stereochemistry, Analytical Methods and pharmacy," Irving W.Wainer, ed, Marcel Dekker, Inc., New York (1993).

In process (1), diastereomeric salts can be formed by reacting an enantiomerically pure chiral base such as brucine, quinine, ephedrine, strychnine, α -methyl- β -phenylethylamine (amphetamine), and the like, with an asymmetric compound bearing an acidic functional group such as a carboxylic acid and a sulfonic acid. Diastereomeric salts can be separated by fractional crystallization or ion chromatography. For the separation of optical isomers of amino compounds, the addition of chiral carboxylic or sulfonic acids such as camphorsulfonic acid, tartaric acid, mandelic acid or lactic acid can lead to the formation of diastereomeric salts.

Alternatively, by process (2), the substrate to be resolved is reacted with one enantiomer of a chiral compound to form a diastereomeric pair (e. and Wilen, s. "Stereochemistry of organic compounds", John Wiley&Sons, inc.,1994, p.322). Diastereomeric compounds can be formed by the following method: asymmetric compounds are reacted with enantiomerically pure chiral derivatizing agents such as menthyl derivatives followed by separation and hydrolysis of the diastereomers to give pure or enriched enantiomers. Methods for determining optical purity include the preparation of chiral esters such as menthyl esters, e.g., (-) menthyl chloroformate (Jacob III.J.org.chem. (1982)47:4165), in the presence of a base or Mosher esters (α -methoxy- α - (trifluoromethyl) phenyl acetate of the racemic mixture), and analysis¹HNMR spectroscopy confirmed the presence of two atropisomeric enantiomers or diastereomers. The stable diastereomers of the atropisomeric compounds can be separated and isolated by normal phase and reverse phase chromatography according to the procedure used for the separation of the atropisomeric naphthyl-isoquinolines (WO 96/15111). By (3), a racemic mixture of the two enantiomers can be separated by Chromatography using a chiral stationary phase ("chiral liquid Chromatography" (1989) edited by W.J.Lough, Chapman and Hall, New York; Okamoto, J.Chromatogr., (1990)513: 375-. Enriched or purified enantiomers can be distinguished by methods for distinguishing other chiral molecules with asymmetric carbon atoms, such as optical rotation and circular dichroism.

Examples

The chemical reactions described in the examples can be readily adapted to prepare many other PI3K inhibitors of the invention, and alternative methods for preparing the compounds of the invention are considered to be within the scope of the invention. For example, the synthesis of non-exemplary compounds of the invention may be successfully carried out by adjustments apparent to those skilled in the art, for example by reacting suitably protected reactive functional groups with other suitable reagents known in the art other than those described, and/or by routine adjustments to reaction conditions. Alternatively, other reactions disclosed herein or known in the art will be recognized as also useful for preparing other compounds of the invention.

¹The H NMR spectra were recorded at ambient temperature with an NMR spectrometer including a Varian Unity Inova (400MHz) spectrometer with a three-line resonant 5mm probe. Chemical shifts are expressed in ppm relative to tetramethylsilane. The following abbreviations are used: br = broad singlet, s = singlet, d = doublet, dd = doublet, t = triplet, q = quartet, m = multiplet.

Can be used for measuring retention time (R)_T) And high pressure liquid chromatography/mass spectrometry (LCMS) experiments of the relevant mass ions. The spectrometer may have an electrospray source operating in positive and negative modes. Additional detection is achieved with an evaporative light scattering detector.

Chiral SFCs (supercritical fluid chromatography) can be used to separate enantiomers (Liu et al (2003) chromatography 58(11/12): 775-779).

The microwave experiment is carried out by using CEM Explorer, Smith Synthesizer or BiotageInitiator^TM(which uses single mode resonator and dynamic zone tuning, both of which give reproducibility and contrast). Temperatures of 40-250 ℃ and pressures of up to 20 bar can be achieved.

All reactions were carried out under an inert, i.e. argon or nitrogen atmosphere, unless otherwise stated.

The enantiomeric purity of the final compound was determined by three methods: method A, method B and method C.

Method a involves derivatizing a precursor amine sample with the chiral aryl fluoride (S) -2- (5-fluoro-2, 4-dinitrophenylamino) propanamide (known as Marfey' S reagent). The% de of the resulting adduct was calculated by integration of the peak area (identified by mass spectrometry) in the UV trace of LCMS of the crude sample. When measured by chiral HPLC of the final compound, inS reaction of intermediate amines with a number of hinge-type conjugate (hingbiner) heteroaromatic chlorides_NNo chiral attack was observed after Ar reaction.

Method B% ee of many final compounds was measured by chiral HPLL (chiral AGP5 μm150mm × 4.0mm column 426, T =35 ℃; run time 40min; isocratic elution-solvent =98% water 2% methanol 0.1% formic acid).

Method C% ee of many final compounds was measured by chiral SFC (Berger analysis SFC using Waters ZQ Mass spectrometer column size: 4.6 mm. times.50 mm,3 micron. screening column: Chiralpak AD, Chiralpak IC, Chiralpak AS, Chiralcel OJ, LuxCellulose-1, Lux Cellulose-4; flow rate: 5mL/min

Mobile phase A is CO₂Mobile phase B methanol (0.1% NH)₄OH), ethanol (0.1% NH)₄OH) or isopropanol (0.1% NH)₄OH). Gradient: 10-65% in 1.8 min, hold for 0.7 min. UV: 254nm

Method D involves derivatization of a sample of precursor amines with (R) -and (S) -methoxyphenylacetic acid. The% de of the amide obtained was calculated by integration of the peak area (identified by mass spectrometry) in the LCMS UV trace of the sample.

Abbreviations

AcOH acetic acid, BINAP 2,2 '-bis (diphenylphosphino) -1, 1' -binaphthyl, CH₃CN acetonitrile, Cs₂CO₃Cesium carbonate, CuI cuprous iodide, DBU 1, 8-diazabicyclo [5.4.0 ]]Undec-7-ene, DCE dichloroethane, DIBAL-H diisobutylaluminum hydride, DCM dichloromethane, DIPEA diisopropylethylamine, DMAP 4-dimethylaminopyridine, DME dimethoxyethane, DMF dimethylformamide, DMSO dimethyl sulfoxide, EDCI 1-ethyl-3- (3' -dimethylaminopropyl) carbodiimide, EtOAc ethyl acetate, Et₃N triethylamine, H or hr H HATU (2- (7-aza-1H-benzotriazol-1-yl) -1,1,3, 3-tetramethylurea hexafluorophosphate) ) HCl, hydrochloric acid, HCO₂H is formic acid, HOAt is 1-hydroxy-7-azabenzotriazole, HOBt is hydroxyBenzotriazole, HM-N:HM-N is a modified form of diatomaceous earth effective for adsorbing aqueous samples, HPLC: high performance liquid chromatography, IMS: Industrial methylated spirits (Industrial methyl ethyl spirites), LCMS: liquid chromatography mass spectrometry, LiHMDS: Lithium bis (trimethylsilyl) amide, M: mol, min: min, mL: mL, PBA: 3-chloroperbenzoic acid, MeOH: methanol, MgSO₄Magnesium sulfate and NaHCO₃Sodium bicarbonate, NaOH, sodium hydroxide and Na₂SO₄Sodium sulfate, NBS N-bromosuccinimide, NH₃Ammonia, NH₄Cl ammonium chloride, NMP N-methylpyrrolidone, NMR nuclear magnetic resonance, Pd/C Palladium on carbon (Palladium on carbon), Pd₂dba₃Tris (dibenzylideneacetone) dipalladium (0); Pd (OAc)₂Palladium (II) acetate, Pd (PPh)₃)₄Tetrakis (triphenylphosphine) palladium (0), PdCl₂{P^tBu₂(Ph-_p-NMe₂)}₂Bis (di-tert-butyl (4-dimethylaminophenyl) phosphine) palladium (II) dichloride, PTFE, polytetrafluoroethylene, PtO₂Platinum oxide, RT: room temperature, Si-PPC: pre-packed silica flash column:SPE,Biotageor ISCOSCX-2 column, Strong ion exchange column, TBME, tert-butyl methyl ether, TFA, trifluoroacetic acid, THF, tetrahydrofuran, Xantphos, 9-dimethyl-4, 5-bis (diphenylphosphino) xanthene

Example 1(S) -1- (7-methyl-1-phenyl-1H-benzimidazol-2-yl) ethylamine

Step 1 (2-methyl-6-nitrophenyl) phenylamine

2-bromo-1-methyl-3-nitrobenzene (1.0g,4.63mmol), aniline (506. mu.L, 5.56mmol), Cs₂CO₃A mixture of (2.11g,6.48mmol) and (R) -BINAP (5mol%,143mg,0.23mmol) in toluene (10mL) was degassed with a stream of nitrogen, then Pd (OAc) was added₂(25mg,0.11mmol) and stirred at 110 ℃ under a nitrogen atmosphere for 20 h. After cooling to RT, the mixture was partitioned between EtOAc and water. The organic layer was washed with brine and then dried (Na)₂SO₄) And concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient elution with 0-35% DCM in cyclohexane) to give (2-methyl-6-nitrophenyl) phenylamine as a red solid (981mg, 93%). LCMS R_T3.88min[M+H]⁺229.1

Step 2 3-methyl-N²-phenyl-1, 2-diamines

A mixture of (2-methyl-6-nitrophenyl) phenylamine (981mg,4.3mmol) and 10% Pd/C (981mg) in EtOAc (20mL) was degassed with a stream of nitrogen and then stirred at RT for 4h under a hydrogen atmosphere. The suspension is then filtered over a PTFE frit and the filtrate is concentrated in vacuo to give 3-methyl-N²Phenyl-1, 2-diamine as a yellow solid (852mg, 100%). LCMS R_T3.02min[M+H]⁺199.0

Step 3 [ (S) -1- (7-methyl-1-phenyl-1H-benzimidazol-2-yl) ethyl ] carbamic acid benzyl ester

To 3-methyl-N²To a solution of (S) -2-benzyloxycarbonylaminopropionic acid (1.44g,6.45mmol), HOBt (639mg,4.73mmol), 4-methylmorpholine (1.04mL,9.46mmol) and N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride (1.24g,6.45mmol) in dry DCM (20mL) was added (852mg,4.3mmol) phenyl-benzene-1, 2-diamine. The mixture was stirred at RT for 6.5h, then partitioned between DCM (100mL) and water. The organic layer was then washed with brine and dried (Na)₂SO₄) And concentrated in vacuo. The resulting residue was dissolved in AcOH (10mL) and heated to 65 ℃ for 18 h. After cooling to RT, the volatiles were removed under reduced pressure and the residue was diluted with EtOAc (100 mL). The organic layer was washed with saturated NaHCO₃The solution was then washed with brine and then dried (Na)₂SO₄) And concentrated in vacuo to give [ (S) -1- (7-methyl-1-phenyl-1H-benzimidazol-2-yl) ethyl]Benzyl carbamate as a brown foam (1.5g, 90%). LCMS R_T3.07min[M+H]⁺386.2。

Step 4 [ (S) -1- (7-methyl-1-phenyl-1H-benzimidazol-2-yl) ethyl]A mixture of benzyl carbamate (1.5g,3.89mmol) and 10% Pd/C (150mg) in IMS (25mL) was degassed with a stream of nitrogen and, after addition of HCl (1M,2.5mL), stirred at RT (room temperature) under a hydrogen atmosphere for 5.5 h. Then the suspension is applied The pad was filtered and the filtrate was concentrated in vacuo. The resulting residue was partitioned between DCM (dichloromethane) and water, then the organic layer was washed with saturated NaHCO₃The solution is washed and dried (Na)₂SO₄) And concentrated in vacuo to give (S) -1- (7-methyl-1-phenyl-1H-benzimidazol-2-yl) ethylamine as a brown solid (1.41g, 96%). LCMS R_T2.07min[M-NH₂]⁺235.1

Example 2(R) -1- (4-methyl-1-phenyl-1H-benzimidazol-2-yl) ethylamine

Step 1 (3-methyl-2-nitrophenyl) phenylamine

1-bromo-3-methyl-2-nitrobenzene (1g,4.63mmol), aniline (422. mu.L, 4.63mmol), Cs₂CO₃A mixture of (2.11g,6.48mmol) and (R) -BINAP (5mol%,143mg,0.23mmol) in toluene (20mL) was degassed with a stream of nitrogen, then Pd (OAc) was added₂(25mg,0.11mmol) and stirred at 110 ℃ under a nitrogen atmosphere for 18 h. After cooling to RT, the mixture was partitioned between EtOAc and water. The organic layer was washed with brine and then dried (Na)₂SO₄) And concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient elution with 0-35% DCM in cyclohexane) to give (3-methyl-2-nitrophenyl) phenylamine as a red oil (931mg, 88%). LCMS R_T3.97min[M+H]⁺229.1。

Step 2 3-methyl-N¹-phenyl-1, 2-diamines

A mixture of (3-methyl-2-nitrophenyl) phenylamine (931mg,4.08mmol) and 10% Pd/C (465mg) in EtOAc (20mL) was degassed with a stream of nitrogen and stirred at RT for 4h under a hydrogen atmosphere. The suspension is then filtered over a PTFE frit and the filtrate is concentrated in vacuo to give 3-methyl-N ¹-phenyl-benzene-1, 2-diamine as an off-white solid (763mg, 94%). LCMS R_T3.37min[M+H]⁺199.0。

Step 3 [ (R) -1- (4-methyl-1-phenyl-1H-benzimidazol-2-yl) ethyl ] carbamic acid tert-butyl ester

To 3-methyl-N¹To a solution of (R) -phenyl-1, 2-diamine (381mg,1.92mmol) in dry DCM (10mL) were added (R) -2-tert-butoxycarbonylaminopropionic acid (399mg,2.11mmol), HOBt (285mg,2.11mmol), 4-methylmorpholine (464. mu.L, 4.22mmol) and N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride (404mg,2.11mmol) and the mixture was stirred at RT for 2 h. After this time, additional (R) -2-tert-butoxycarbonylaminopropionic acid (145mg,0.77mmol) and N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride (148mg,0.77mmol) were added. Stirring was continued for 20h, then additional (R) -2-tert-butoxycarbonylaminopropionic acid (545mg,2.88mmol), HOBt (285mg,2.11mmol), 4-methylmorpholine (464. mu.L, 4.22mmol) and N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride (553mg,2.88mmol) were added. Stirring was continued for 24h, then the crude mixture was purified by column chromatography (Si-PCC with gradient elution of 0-40% EtOAc in cyclohexane) to afford [ (R) -1- (2-methyl-6-phenylaminophenylcarbamoyl) ethyl ]Tert-butyl carbamate as an orange oil (456mg, 64%). LCMS R_T3.69min[M+H]⁺370.2

A solution of the product thus obtained (456mg) in AcOH (5mL) was heated to 70 ℃ for 2 h 45 min, then allowed to cool to RT and stand at RT for 18 h. The volatiles were removed in vacuo and the residue was dissolved in EtOAc (75mL) and saturated NaHCO₃The solution was washed and then dried (Na)₂SO₄) And concentrated in vacuo to give [ (R) -1- (4-methyl-1-phenyl-1H-benzimidazol-2-yl) ethyl]Tert-butyl carbamate (404mg, 60%). LCMS R_T3.11min[M+H]⁺352.2。

Step 4 to [ (R) -1- (4-methyl-1-phenyl-1H-benzimidazol-2-yl) ethyl]Tert-butyl carbamate (404mg,1.15mmol) in DCM (5mL) was added TFA (1mL) and the mixture was stirred at RT for 3 h. Additional TFA (0.5mL) was added and stirring was continued for 30 min. Volatiles were removed under reduced pressure and the residue was dissolved in a small amount of DCM and loaded onto a SCX-2 column. The column was first washed with 10% MeOH in DCM and 2M NH₃The product was eluted with MeOH to give (R) -1- (4-methyl-1-phenyl-1H-benzimidazol-2-yl) ethylamine as a brown solid (273mg, 94%). LCMS R_T2.14[M-NH₂]⁺235.1

Example 3(S) -1- (4-methyl-1-phenyl-1H-benzimidazol-2-yl) ethylamine

Step 1 [ (S) -1- (4-methyl-1-phenyl-1H-benzimidazol-2-yl) ethyl ] carbamic acid tert-butyl ester

To 3-methyl-N¹To a solution of (S) -phenyl-1, 2-diamine (381mg,1.92mmol) in dry DCM (10mL) were added (S) -2-tert-butoxycarbonylaminopropionic acid (399mg,2.11mmol), HOBt (285mg,2.11mmol), 4-methylmorpholine (464. mu.L, 4.22mmol) and N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride (405mg,2.11 mmol). The mixture was stirred at RT for 2h, then additional (S) -2-tert-butoxycarbonylaminopropionic acid (145mg,0.77mmol) and N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride (148mg,0.77mmol) were added. Stirring was continued for 18h, then additional (S) -2-tert-butoxycarbonylaminopropionic acid (545mg,2.88mmol), HOBt (285mg,2.11mmol), 4-methylmorpholine (464. mu.L, 4.22mmol) and N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride (553mg,2.88mmol) were added. Stirring was continued for 24h, then the crude mixture was purified by column chromatography (Si-PCC with a ring of 0-40% EtOAc)Gradient elution with hexane solution) to give [ (S) -1- (2-methyl-6-phenylaminophenylcarbamoyl) ethyl]Tert-butyl carbamate as orange oil (395mg, 56%). LCMS R_T3.69min[M+H]⁺370.2。

A solution of the product thus obtained (395mg) in AcOH (10mL) was heated to 70 ℃ for 2 hours 45 minutes. After cooling to RT, the volatiles were removed under reduced pressure, the residue was dissolved in EtOAc (75mL) and saturated NaHCO ₃The solution was washed and then dried (Na)₂SO₄) And concentrated in vacuo to give [ (S) -1- (4-methyl-1-phenyl-1H-benzimidazol-2-yl) ethyl]Tert-butyl carbamate (380mg, 56%). LCMS R_T3.15min[M+H]⁺352.2。

Step 2 to [ (S) -1- (4-methyl-1-phenyl-1H-benzimidazol-2-yl) ethyl]To a solution of tert-butyl carbamate (380mg,1.08mmol) in DCM (5mL) was added TFA (1mL) and the mixture was stirred at RT for 3 h. Additional TFA (0.5mL) was added and stirring was continued for 30 min. The volatiles were removed under reduced pressure, then the residue was dissolved in a small amount of DCM and loaded onto a SCX-2 column, which was initially washed with 10% MeOH in DCM. With 2M NH₃The product was eluted with MeOH to give (S) -1- (4-methyl-1-phenyl-1H-benzimidazol-2-yl) ethylamine as a brown solid (222mg, 82%). LCMS R_T2.16[M-NH₂]⁺235.1

Example 41- (1-phenyl-1H-benzo [ d ]]Imidazol-2-yl) ethylamine

Step 1 [1- (2-Phenylaminophenylcarbamoyl) ethyl ] carbamic acid tert-butyl ester

N-phenyl-1, 2-diamine (1.84g,0.01mol), racemic (R/S) -2-tert-butoxycarbonylaminopropionic acid (1.89g,0.01mol), N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride (1.92g), 4-methylmorpholine (1.0g,0.01mol), and HOBt (1.53g,0.01mol) were suspended in THF (10mL) under a nitrogen atmosphere. The resulting mixture was stirred at RT for 12 h. After this time, additional N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride (500mg X3) and (R/S) -2-tert-butoxycarbonylaminopropionic acid (500mg) were added and the mixture was stirred for an additional 4 h. The reaction mixture was then partitioned between water and EtOAc. The organic layer was separated and dried (MgSO) ₄) The residue was purified by column chromatography (Si-PCC ISCO24g column, gradient elution with 0-20% EtOAc in cyclohexane). The product containing fractions were combined and concentrated in vacuo to give [1- (2-phenylaminophenylcarbamoyl) ethyl]Tert-butyl carbamate as a white crystalline solid (3.07g, 86%). LCMS R_T3.61min[M+H-^tBu]⁺300.1。

Step 2 reaction of [1- (2-phenylaminophenylcarbamoyl) ethyl group]Tert-butyl carbamate (400mg,1.59mmol) was suspended in AcOH (4mL) and the resulting mixture was heated at 80 ℃ for 12h, at which time the mixture became clear. The cooled solution was diluted with toluene and the volatiles were removed under reduced pressure. The resulting residue was stirred with TFA (4mL) for 2h and the resulting solution was loaded onto a SCX-2 column, which was initially washed with MeOH. With 2M NH₃The product was eluted with MeOH, which was further purified by column chromatography (Si-PCC gradient eluted with 0-6% MeOH in DCM) to afford 1- (1-phenyl-1H-benzo [ d ]]Imidazol-2-yl) ethylamine as a white crystalline solid (211 m)_g,80%)。LCMS:R_T0.27min[M-NH₂]⁺221.1. Can resolve and separate enantiomer (S) -1- (1-phenyl-1H-benzo [ d)]Imidazol-2-yl) ethylamine and (R) -1- (1-phenyl-1H-benzo [ d]Imidazol-2-yl) ethylamine. Alternatively, (S) -1- (1-phenyl-1H-benzo [ d ] can be prepared from enantiomerically pure (S) -2-tert-butoxycarbonylaminopropionic acid ]Imidazol-2-yl) ethylamine.

Example 52-bromomethyl-1-phenyl-1H-benzimidazoles

To a stirred solution of (1-phenyl-1H-benzimidazol-2-yl) methanol (240mg,1.02mmol) and triphenylphosphine (295mg,1.12mmol) in DCM (10mL) was added NBS (200mg,1.12mmol) and the mixture was stirred at RT for 3H. The volatiles were evaporated under reduced pressure and the residue was purified by column chromatography (Si-PCC, gradient eluted with 0-5% MeOH in DCM) to give 2-bromomethyl-1-phenyl-1H-benzimidazole as a colorless oil (0.636g, quantitative yield). LCMS R_T3.31min[M+H]⁺386.8/388.8

Example 64- [2- ((S) -1-aminoethyl) benzimidazol-1-yl]Piperidine-1-carboxylic acid tert-butyl ester

Step 1 tert-butyl 4- [2- ((S) -1-benzyloxycarbonylaminoethyl) benzimidazol-1-yl ] piperidine-1-carboxylate

A mixture of (S) -2-benzyloxycarbonylaminopropionic acid (230mg,1.03mmol), tert-butyl 4- (2-aminophenylamino) piperidine-1-carboxylate (200mg,0.686mmol), HOBt (102mg,0.755mmol), 4-methylmorpholine (166. mu.L, 1.51mmol) and N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride (197mg,1.03mmol) in DCM (7mL) was stirred at RT for 3 h. The reaction mixture was then diluted with additional DCM and the organic layer was washed with water, then dried and concentrated in vacuo to give 4- [2- ((S) - 2-benzyloxycarbonylaminopropionylamino) phenylamino]Tert-butyl piperidine-1-carboxylate as a purple/brown oil (436mg, quantitative yield). LCMS R_T3.66min[M+H]⁺497.2.

A solution of the compound thus obtained (0.686mmol) in AcOH (5mL) was stirred at 60 ℃ for 18 h. After cooling to RT, the volatiles were evaporated under reduced pressure and the residue was taken up in EtOAc and saturated NaHCO₃The solutions were partitioned. The organic layer was washed with brine and dried (Na)₂SO₄) And then concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient eluted with 0-100% EtOAc in cyclohexane) to afford 4- [2- ((S) -1-benzyloxycarbonylaminoethyl) benzimidazol-1-yl]Tert-butyl piperidine-1-carboxylate as a light orange oil (308mg, 94% yield over two steps). LCMS R_T3.06min[M+H]⁺479.1。

Step 2-purging of Nitrogen with 4- [2- ((S) -1-benzyloxycarbonylaminoethyl) benzimidazol-1-yl]To a solution of tert-butyl piperidine-1-carboxylate (308mg,0.644mmol) in IMS (10mL) was added 10% Pd/C (32mg) and the reaction mixture was stirred at RT under a hydrogen atmosphere for 2 h. Subsequently, an additional 10% Pd/C (41 mg after 2h, 33mg after 4 h) was added and the reaction mixture was stirred at RT for 17h under a hydrogen atmosphere. The suspension was filtered with PTFE frit and washed with additional IMS. The filtrate was concentrated in vacuo to give 4- [2- ((S) -1-aminoethyl) benzimidazol-1-yl ]Tert-butyl piperidine-1-carboxylate as a pale yellow oil (202 mg). LCMS R_T2.34min[M+H]⁺345.2

Example 7(S) -1- (7-fluoro-1-phenyl-1H-benzimidazol-2-yl) ethylamine

(S) -1- (7-fluoro-1-phenyl-1H-benzimidazol-2-yl) ethylamine

Step 1 (2-fluoro-6-nitrophenyl) phenylamine

A mixture of 1, 2-difluoro-3-nitrobenzene (690. mu.L, 6.29mmol), aniline (600. mu.L, 6.60mmol) and potassium carbonate (1.74g,12.57mmol) in DMSO (3mL) was stirred at RT for 3h and then heated to 90 ℃ for 4 h. After cooling to RT, the reaction mixture was partitioned between EtOAc and water. The organic layer was then washed with brine and dried (Na)₂SO₄) And concentrated in vacuo, and the resulting residue was purified by column chromatography (Si-PCC, gradient elution of 0-20% EtOAc in cyclohexane, followed by Si-PCC, gradient elution of 0-50% DCM in cyclohexane) to give (2-fluoro-6-nitrophenyl) phenylamine as an orange/red oil (563mg, 39%).

¹HNMR(CDCl₃,400MHz):δ8.70(1H,s),8.00(1H,d,J=8.66Hz),7.36-7.23(3H,m),7.09(lH，t，J＝7.41Hz)，7.03-6.89(3H，m).

Step 2 3-fluoro-N²-phenyl-1, 2-diamines

A mixture of (2-fluoro-6-nitrophenyl) phenylamine (558mg,6.57mmol) and 10% Pd/C (115mg) in IMS (20mL) was degassed with a stream of nitrogen and stirred at RT for 2h under a hydrogen atmosphere. The suspension was then filtered over PTFE frit and the filtrate was concentrated in vacuo to give 3-fluoro-N²Phenyl-1, 2-diamine as a white solid (468mg, 96%). ¹H NMR(CDCl₃,400MHz):δ7.24-7.16(2H,m),7.04-6.96(1H,m),6.83(1H,t,J=7.37Hz),6.66(2H,d,J=7.95Hz),6.59-6.48(2H,m),5.16(1H,bs),3.96(2H,s)。

Step 3 [ (S) -1- (7-fluoro-1-phenyl-1H-benzimidazol-2-yl) ethyl ] carbamic acid tert-butyl ester

The reaction mixture was purified by reacting (S) -2-tert-butoxycarbonylaminopropionic acid (480mg,2.53mmol) and 3-fluoro-N²A mixture of-phenyl-benzene-1, 2-diamine (466mg,2.30mmol), HOAt (345mg,2.53mmol), 4-methylmorpholine (560. mu.L, 5.07mmol) and N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride (486mg,2.53mmol) in DCM (15mL) was stirred at RT for 2 h. The reaction mixture was then partitioned between additional DCM and NaHCO₃The aqueous solution was partitioned. The organic layer was dried and concentrated in vacuo, and the resulting residue (1.0g) was dissolved in AcOH (20mL) and stirred at 70 ℃ for 18 h. After cooling to RT, the volatiles were evaporated under reduced pressure and the residue was taken up in EtOAc and saturated NaHCO₃The solutions were partitioned. The organic layer was washed with water, then brine, then dried (Na)₂SO₄) And concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient elution with 0-30% EtOAc in DCM) to afford [ (S) -1- (7-fluoro-1-phenyl-1H-benzimidazol-2-yl) ethyl]Tert-butyl carbamate as a yellow/orange oil (631mg, 77%). LCMS R_T3.64min[M+H]⁺356.0。

Step 4 to [ (S) -1- (7-fluoro-1-phenyl-1H-benzimidazol-2-yl) ethyl]To a solution of tert-butyl carbamate (625mg) in DCM (3mL) was added TFA (3mL) and the resulting mixture was stirred at RT for 3 h. Loading the crude reaction mixture into SCX-2 column. The column was washed with MeOH, 2M NH₃The product eluted with MeOH. The product containing fractions were combined and concentrated in vacuo to give (S) -1- (7-fluoro-1-phenyl-1H-benzimidazol-2-yl) ethylamine as a light orange oil (372mg, 83%). LCMS R_T1.97 and 2.11min [ M + H]⁺255.9。

Example 8(S) -1- (6-fluoro-1-phenyl-1H-benzimidazol-2-yl) ethylamine

Step 1 (5-fluoro-2-nitrophenyl) phenylamine

LiHMDS (1.0M in THF, 12.57mL) was added dropwise to a stirred solution of aniline (600. mu.L, 6.60mmol) in dry THF (10mL) at-78 ℃ under a nitrogen atmosphere. After 30min, a solution of 2, 4-difluoro-1-nitrobenzene (690 μ L,6.29mmol) in THF (10mL) was added and stirring continued for 1 h. The solution was poured onto NH₄Aqueous Cl (100mL) and extracted with EtOAc (. times.3). The combined organic layers were dried and concentrated in vacuo and the resulting residue was purified by column chromatography (Si-PCC, gradient eluted with 0-30% EtOAc in cyclohexane) to give (5-fluoro-2-nitrophenyl) phenylamine as a yellow/orange solid (1.37g, 94%).¹H NMR(CDCl₃,400MHz):δ9.66(1H,s),8.28(1H,dd,J=9.48,6.01Hz),7.47(2H,t,J=7.63Hz),7.36-7.24(3H,m),6.82(1H,dd,J=11.38,2.61Hz),6.53-6.44(1H,m)。

Step 2: 4-fluoro-N²-phenyl-1, 2-diamines

A mixture of (5-fluoro-2-nitrophenyl) phenylamine (1.37g,5.90mmol) in IMS (50mL) and EtOAc (50mL) was degassed with a stream of nitrogen, then 10% Pd/C (138mg) was added and stirred at RT for 4h under a hydrogen atmosphere. The suspension is then filtered over a PTFE frit and the filtrate is concentrated in vacuo to give 4-fluoro-N ²Phenyl-1, 2-diamine as a red oil (1.19g, quantitative yield). LCMS R_T2.87min[M+H]⁺203.1。

Step 3 [ (S) -1- (6-fluoro-1-phenyl-1H-benzimidazol-2-yl) ethyl ] carbamic acid tert-butyl ester

Reacting 4-fluoro-N²A mixture of-phenyl-benzene-1, 2-diamine (1.19g,5.88mmol), (S) -2-tert-butoxycarbonylaminopropionic acid (1.22g,6.47mmol), HOAt (881mg,6.47mmol), 4-methylmorpholine (1.42mL,12.95mmol) and N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride (1.24g,6.47mmol) in DCM (30mL) was stirred at RT for 21 h. The reaction mixture was then partitioned between additional DCM and NaHCO₃The aqueous solution was partitioned. The organic layer was dried and concentrated in vacuo, and the resulting residue (2.40g) was dissolved in AcOH (50mL) and stirred at 60 ℃ for 48 h. After cooling to RT, the volatiles were evaporated under reduced pressure and the residue was taken up in EtOAc and saturated NaHCO₃The solutions were partitioned. The organic layer was washed with brine and dried (Na)₂SO₄) And then concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient elution with 0-50% EtOAc in DCM) to afford [ (S) -1- (6-fluoro-1-phenyl-1H-benzimidazol-2-yl) ethyl]Tert-butyl carbamate as yellow foam (1.20g, 57%). LCMS R_T3.50min[M+H]⁺356.2

Step 4 to [ (S) -1- (6-fluoro-1-phenyl-1H-benzimidazol-2-yl) ethyl ]To a solution of tert-butyl carbamate (1.20g,3.38mmol) in DCM (5mL) was added TFA (5mL) and the resulting mixture was stirred at RT for 1.5 h. Loading the crude reaction mixture intoSCX-2 column. The column was washed with MeOH, 2M NH₃The product eluted with MeOH. The product-containing fractions were combined and concentrated in vacuo to give (S) -1- (6-fluoro-1-phenyl-1H-benzimidazol-2-yl) ethylamine as a yellow oil (861mg, quantitative yield). LCMS R_T1.97And 2.19min [ M + H]⁺256.2

Example 9(S) -1- (4-chloro-1-phenyl-1H-benzimidazol-2-yl) ethylamine

Step 1 (3-chloro-2-nitrophenyl) phenylamine

LiHMDS (1.0M in THF, 23mL) was added to a stirred solution of aniline (1.12g,12.0mmol) in THF (15mL) at-78 deg.C under a nitrogen atmosphere. Stirring was continued for 30min, then 1-chloro-3-fluoro-2-nitrobenzene (1.92g,10.9mmol) in THF (15mL) was added. The reaction mixture was stirred at-78 ℃ for 30min, then slowly warmed to RT and stirred at RT for 2 h. The reaction mixture was poured onto NH₄Cl in saturated solution, then extracted with EtOAc (× 2). The combined organic layers were washed with brine and then dried (Na)₂SO₄) And concentrated in vacuo to give (3-chloro-2-nitrophenyl) phenylamine as a dark brown oil (2.85) _gQuantitative yield).¹HNMR(CDCl₃,400MHz):δ7.41-7.25(3H,m),7.23-7.12(5H,m),6.96-6.91(1H,m)。

Step 2-3-chloro-N¹-phenyl-1, 2-diamines

To a mixture of (3-chloro-2-nitrophenyl) phenylamine (0.0109mol) in MeOH (150mL) and water (50mL) was added NH₄Cl (3.51g,0.0656mol) and iron powder (2.45g,0.0438mol) and the reaction mixture was heated to reflux temperatureThe degree reaches 3 h. After cooling to RT, the solid was usedThe pad was filtered off and washed with additional MeOH. The filtrate was concentrated in vacuo and then partitioned between EtOAc and water. The aqueous phase was further extracted with EtOAc and the combined organic layers were washed with brine and then dried (Na)₂SO₄) And vacuum concentrating to obtain 3-chloro-N¹Phenyl-1, 2-diamine as a light brown solid (2.61g, quantitative yield). LCMS R_T3.72min[M+H]⁺219.0

Step 3 [ (S) -1- (2-chloro-6-phenylaminophenylcarbamoyl) ethyl ] carbamic acid tert-butyl ester

To 3-chloro-N cooled to 0 ℃ under a nitrogen atmosphere¹A mixture of (1.72g,7.87mmol) of (S) -2-tert-butoxycarbonylaminopropionic acid (1.64g,8.65mmol), HOAt (1.18g,8.65mmol) and N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride (1.66g,8.65mmol) in DCM (40mL) was added Et₃N (3.3mL,0.0236 mol). The reaction mixture was stirred at 0 ℃ for 5min, then slowly warmed to RT and stirred for a further 16 h. The resulting mixture was purified in DCM and saturated NaHCO ₃The solutions were partitioned. The organic layer was washed with brine and then dried (Na)₂SO₄) And concentrated in vacuo. The residue thus obtained was purified by column chromatography (Si-PCC,0-2%2M NH)₃Gradient elution in DCM/MeOH) to give [ (S) -1- (2-chloro-6-phenylaminophenylcarbamoyl) ethyl]Tert-butyl carbamate as an off-white solid (1.60g, 52% yield in three steps). LCMS R_T3.75min[M+H]⁺390.2。

Step 4 [ (S) -1- (4-chloro-1-phenyl-1H-benzimidazol-2-yl) ethyl ] carbamic acid tert-butyl ester

Reacting [ (S) -1- (2-chloro-6-phenylaminophenylcarbamoyl) ethyl]A solution of tert-butyl carbamate (1.58g,4.05mmol) in AcOH (25mL) was stirred at 65 ℃ for 18 h. After cooling to RT, the volatiles were evaporated under reduced pressure and the residue was taken up in EtOAc and saturated NaHCO₃The solutions were partitioned. The aqueous phase was further extracted with EtOAc and the combined organic layers were washed with brine and then dried (Na)₂SO₄) And concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC with 0-2%2M NH)₃Gradient elution in DCM/MeOH) to give [ (S) -1- (4-chloro-1-phenyl-1H-benzimidazol-2-yl) ethyl ] ethyl]Tert-butyl carbamate as an off-white solid (1.41g, 93%). LCMS R_T3.90min[M+H]⁺372.2。

Step 5 to [ (S) -1- (4-chloro-1-phenyl-1H-benzimidazol-2-yl) ethyl ]To a solution of tert-butyl carbamate (1.40g,3.76mmol) in DCM (20mL) was added TFA (20mL) and the resulting mixture was stirred at RT for 20 min. Volatiles were removed under reduced pressure and the resulting residue was taken up in DCM and saturated NaHCO₃The solutions were partitioned. The aqueous layer was further extracted with DCM, and the combined organic layers were dried (Na)₂SO₄) And concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC with 0-8%2M NH)₃MeOH in DCM) to give (S) -1- (4-chloro-1-phenyl-1H-benzimidazol-2-yl) ethylamine as a white solid (680mg, 67%). LCMS R_T2.23min[M+H]⁺272.1

Example 10(S) -1- (3-phenyl-3H-imidazo [4, 5-b)]Pyridin-2-yl) ethylamine

Step 1 (3-nitropyridin-2-yl) phenylamine

2-chloro-3-nitropyridine (3.49g,22.0mmol), aniline (2mL,22.0mmol) and Et₃A mixture of N (3.1mL,22.0mmol) in NMP (7mL) was stirred under nitrogen at 100 ℃ for 1.5 h. Add additional Et₃N (0.2mL) and aniline (0.1mL), stirring was continued for another 30 min. The mixture was then partitioned between EtOAc and water. The aqueous phase was further extracted with EtOAc and the combined organic layers were washed with brine and then dried (Na)₂SO₄) And concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient eluted with 10-100% DCM in pentane) to give (3-nitropyridin-2-yl) phenylamine as a red crystalline solid (2.49g, 58%). LCMS R _T3.53min[M+H]⁺216.0。

Step 2N²-phenylpyridine-2, 3-diamine

A mixture of (3-nitropyridin-2-yl) phenylamine (2.49g,0.0116mol) and 10% Pd/C (40mg) in EtOAc (100mL) was degassed with a stream of nitrogen and then stirred at RT under a hydrogen atmosphere for 16 h. The suspension is then appliedPad filtration, then vacuum concentration of the filtrate to give N²Phenylpyridine-2, 3-diamine as a white solid (2.06g, 96%). LCMS R_T1.15min[M+H]⁺186.0。

Step 3 [ (S) -tert-butyl 1- (3-phenyl-3H-imidazo [4,5-b ] pyridin-2-yl) ethyl ] carbamate

To N cooled to 0 ℃ under a nitrogen atmosphere²A mixture of (E) -phenylpyridine-2, 3-diamine (2.00g,0.011mol), (S) -2-tert-butoxycarbonylaminopropionic acid (3.06g,0.0162mol), HOBt (2.19g,0.0162mol) and N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride (3.10g,0.0162mol) in DCM (80mL) was added Et₃N (4.5mL,0.0324 mol). The reaction mixture was stirred at 0 ℃ for 5min, then slowly warmed to RT and stirred for further 20 h. The resulting mixture was washed with EtOAc and saturated NaHCO₃The solutions were partitioned. The aqueous phase was further extracted with EtOAc and the combined organic layers were washed with brine and then dried (Na)₂SO₄) And concentrated in vacuo. The residue thus obtained was purified by column chromatography (Si-PCC with 0-5%2M NH) ₃Gradient elution in DCM/MeOH) to give [ (S) -1- (2-phenylaminopyridin-3-ylcarbamoyl) ethyl]Tert-butyl carbamate as a pale pink solid (2.05g,4.56 mmol). LCMS R_T3.75min[M+H]⁺390.2

A solution of the compound thus obtained (4.56mmol) in AcOH (8mL) was stirred at 65 ℃ for 5 h. After cooling to RT, the volatiles were evaporated under reduced pressure and the residue was taken up in DCM and saturated NaHCO₃The solutions were partitioned. The aqueous phase was further extracted with DCM and the combined organic layers were washed with brine and dried (Na)₂SO₄) And then concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC with 0-5%2M NH)₃Gradient elution in DCM/MeOH) to give [ (S) -1- (3-phenyl-3H-imidazo [4, 5-b)]Pyridin-2-yl) ethyl]Tert-butyl carbamate as a pink foam (1.78 g). LCMS R_T3.02min[M+H-^tBu]⁺283.1

Step 4, mixing [ (S) -1- (3-phenyl-3H-imidazo [4,5-b ]]Pyridin-2-yl) ethyl]A solution of tert-butyl carbamate (1.77g) in DCM (4mL) was added to TFA (20mL) and the resulting mixture was stirred at RT for 15 min. Volatiles were removed under reduced pressure and the resulting residue was taken up in DCMAnd saturated NaHCO₃The solutions were partitioned. The aqueous phase was further extracted with DCM, and the combined organic layers were dried (Na) ₂SO₄) And then concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC with 0-8%2M NH)₃Gradient elution with MeOH in DCM) to give (S) -1- (3-phenyl-3H-imidazo [4, 5-b)]Pyridin-2-yl) ethylamine as a colorless gum (540mg, 20% yield in three steps). LCMS R_T1.65min[M-NH₂]⁺222.0。

Example 112- ((S) -1-aminoethyl) -3-phenyl-3H-benzimidazole-5-carbonitrile

Step 1-4-Nitro-3-phenylaminobenzonitrile

A suspension of 3-fluoro-4-nitrobenzonitrile (1.66g,10.0mmol) in DMSO (5mL) was purged with a stream of argon, then aniline (1.82mL,20.0mmol) was added, and the mixture was stirred at 120 ℃ under an argon atmosphere for 1 h. After cooling to RT, the reaction mixture was taken up in EtOAc (75mL) and KHSO₄The aqueous solution (100mL) was partitioned. The organic layer was then washed with brine and dried (Na)₂SO₄) And concentrated in vacuo. The resulting residue was triturated with ether to give 4-nitro-3-phenylaminobenzonitrile as red crystals (2.35g, 98%).¹H NMR(CDCl₃,400MHz):δ9.48(1H,bs),8.29(1H,d,J=8.76Hz),7.53-7.40(3H,m),7.35(1H,t,J=7.52Hz),7.29-7.22(2H,m),6.97(1H,d,J=8.79Hz)。

Step 2-4-amino-3-phenylaminobenzonitrile

A solution of 4-nitro-3-phenylaminobenzonitrile (560mg,2.34mmol) in EtOAc (30mL) was degassed with a stream of nitrogen and then PtO was added₂(44mg) and stirred at RT for 2h under a hydrogen atmosphere. Then the suspension is appliedPad filtration and concentration of the filtrate in vacuo afforded 4-amino-3-phenylaminobenzonitrile as a purple solid (500mg, quantitative yield). LCMS R _T3.20min[M+H]⁺210.1。

Step 3 [ (S) -1- (4-cyano-2-phenylaminophenylcarbamoyl) ethyl ] carbamic acid tert-butyl ester

A mixture of 4-amino-3-phenylaminobenzonitrile (490mg,2.34mmol), (S) -2-tert-butoxycarbonylaminopropionic acid (490mg,2.57mol), HOAt (380mg,2.79mmol), N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride (540mg,2.81mol) and 4-methylmorpholine (560. mu.L, 5.15mmol) in THF (5mL) was stirred under an argon atmosphere at RT for 48 h. The crude reaction mixture was then washed with EtOAc and saturated NaHCO₃The solutions were partitioned. The aqueous phase was further extracted with EtOAc and the combined organic layers were washed with brine and then dried (Na)₂SO₄) And concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient eluted with 0-10% EtOAc in DCM) to afford [ (S) -1- (4-cyano-2-phenylaminophenylcarbamoyl) ethyl]Tert-butyl carbamate as creamy foam (800mg, 89%). LCMS R_T3.62min[M+H]⁺381.2。

Step 4 reaction of [ (S) -1- (4-cyano-2-phenylaminophenylcarbamoyl) ethyl group]Dissolution of tert-butyl carbamate (750mg,1.97mmol) in AcOH (3mL)The solution was stirred at 80 ℃ for 18 h. After cooling to RT, the volatiles were evaporated under reduced pressure to give [ (S) -1- (6-cyano-1-phenyl-1H-benzimidazol-2-yl) ethyl ] ethyl ]Tert-butyl carbamate (1.97mmol) was used in the subsequent step without any further purification. LCMS R_T3.55min[M+H]⁺363.2。

Reacting [ (S) -1- (6-cyano-1-phenyl-1H-benzimidazol-2-yl) ethyl]A solution of tert-butyl carbamate (1.97mmol) in TFA (3mL) was stirred at RT for 30 min. Removing volatile substances under reduced pressure, and loading the obtained residue onSCX-2 column. The column was washed with MeOH, 2M NH₃The product eluted with MeOH. The product was further purified by column chromatography (Si-PCC, gradient eluted with 0-10% MeOH in DCM) to give 2- ((S) -1-aminoethyl) -3-phenyl-3H-benzimidazole-5-carbonitrile as a white crystalline solid (415mg, 80% yield over two steps). LCMS R_T1.99min[M+H]⁺263.2

Example 12(S) -1- (1-phenyl-1H-benzimidazol-2-yl) propylamine

Step 1 [ (S) -1- (1-phenyl-1H-benzimidazol-2-yl) propyl ] carbamic acid tert-butyl ester

A mixture of N-phenylbenzene-1, 2-diamine (1.0g,5.43mmol), (S) -2-tert-butoxycarbonylaminobutyric acid (1.21g,5.97mmol), HOAt (813mg,5.97mmol), N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride (1.15g,5.97mmol) and 4-methylmorpholine (1.31mL,11.95mmol) in DCM (20mL) at RTStirring for 2 h. The crude reaction mixture was diluted with DCM (100mL) and then saturated NaHCO ₃The solution was then washed with brine and dried (Na)₂SO₄) And concentrated in vacuo. The resulting residue was dissolved in AcOH (20mL) and heated to 70 ℃ for 18 h. After cooling to RT, the volatiles were evaporated under reduced pressure and the residue was dissolved in EtOAc (150mL) with saturated NaHCO₃And (4) washing the solution. The organic layer was then washed with brine and dried (Na)₂SO₄) And then concentrated in vacuo. The resulting residue was absorbed onto HM-N and purified by column chromatography twice (Si-PCC, gradient eluted with 0-50% EtOAc in cyclohexane) to give [ (S) -1- (1-phenyl-1H-benzimidazol-2-yl) propyl ] ester]Carbamic acid tert-butyl ester (1.76 g). LCMS R_T3.23min[M+H-^tBu]⁺352.2

Step 2 to [ (S) -1- (1-phenyl-1H-benzimidazol-2-yl) propyl ] methyl]To a solution of tert-butyl carbamate (1.76g) in DCM (10mL) was added TFA (7.5mL) and the mixture was stirred at RT for 4 h. Volatiles were removed under reduced pressure and the resulting residue was dissolved in DCM and saturated NaHCO₃And (4) washing the solution. The two-phase system was stirred for 20min, and then the organic layer was dried (Na)₂SO₄) And concentrated in vacuo to give (S) -1- (1-phenyl-1H-benzimidazol-2-yl) propylamine as a brown oil (1.1g, 81% yield in three steps). LCMS R_T2.02min[M+H]⁺252.2

Example 13(S) -1- (6-methyl-1-phenyl-1H-benzimidazol-2-yl) ethylamine

Step 1 (5-methyl-2-nitrophenyl) phenylamine

A solution of 2-fluoro-4-methyl-1-nitrobenzene (1.0g,6.45mmol) in DMSO (3mL) was purged with a stream of nitrogen, then phenylamine (1.18mL,12.9mmol) was added, then stirred in a sealed tube at 100 ℃ for 20 h. After cooling to RT, the reaction mixture was partitioned between EtOAc (125mL) and water (150 mL). The organic layer was then washed with water (150 mL. times.3) then brine, then dried (Na)₂SO₄) And concentrated in vacuo to give (5-methyl-2-nitrophenyl) phenylamine as a red solid (1.5g, quantitative yield).¹H NMR(DMSO,400MHz):δ9.40(1H,s),8.03(1H,d,J=8.70Hz),7.45-7.39(2H,m),7.35-7.30(2H,m),7.21(1H,t,J=7.33Hz),6.98(1H,s),6.72-6.68(1H,m),2.24(3H,s)。

Step 2: 4-methyl-N²-phenyl-1, 2-diamines

A mixture of (5-methyl-2-nitrophenyl) phenylamine (1.5g,6.57mmol) and 10% Pd/C (750mg) in EtOAc (25mL) was degassed with a stream of nitrogen and stirred at RT for 5h under a hydrogen atmosphere. The suspension is then filtered over a PTFE frit and the filtrate is concentrated in vacuo to give 4-methyl-N²Phenyl-1, 2-diamine as a brown solid (1.29g, 99%). LCMS R_T2.61min[M+H]⁺199.2。

Step 3 [ (S) -1- (6-methyl-1-phenyl-1H-benzimidazol-2-yl) ethyl ] carbamic acid tert-butyl ester

4-methyl-N²-phenyl-benzene-1, 2-diamine (600mg,3.03mmol), (S) -2-tert-butoxycarbonylaminopropionic acid (861mg,4.55mmol), HOAt (453mg,3.33mmol), N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride (874mg,4.55mmol) and 4-methylmorpholine (S-H-L-methyl-L-alanine) 0.74mL,6.67mmol) in dry DCM (20Ml) was stirred at RT for 1.5 h. Volatiles were removed under reduced pressure and the resulting residue was dissolved in AcOH (10mL) and heated to 70 ℃ for 20 h. After cooling to RT, the volatiles were removed in vacuo, the residue was dissolved in EtOAc (100mL) and saturated NaHCO₃The solution was washed (2X 100 mL). The organic layer was then washed with brine and dried (Na)₂SO₄) And then concentrated in vacuo. The resulting residue was taken up on HM-N and the solvent was removed in vacuo. The product was purified by column chromatography (Si-PCC, gradient eluted with 10-60% EtOAc in cyclohexane) to afford [ (S) -1- (6-methyl-1-phenyl-1H-benzimidazol-2-yl) ethyl]Tert-butyl carbamate (969mg, 92%). LCMS R_T3.10min[M+H-^tBu]⁺352.1。

Step 4 to [ (S) -1- (6-methyl-1-phenyl-1H-benzimidazol-2-yl) ethyl]To a solution of tert-butyl carbamate (969mg,2.76mmol) in DCM (7.5mL) was added TFA (2.5mL) and the mixture was stirred at RT for 20 h. Volatiles were removed under reduced pressure and the resulting residue was dissolved in DCM (30mL) and saturated NaHCO₃The solution was washed (40 mL). The two-phase system was stirred for 10min, and then the organic layer was dried (Na)₂SO₄) And concentrated in vacuo to give (S) -1- (6-methyl-1-phenyl-1H-benzimidazol-2-yl) ethylamine as a brown solid (583mg, 84%). LCMS R _T3.02min[M+H]⁺252.2

Example 14(S) -1- (5-methyl-1-phenyl-1H-benzimidazol-2-yl) ethylamine

Step 1 (4-methyl-2-nitrophenyl) phenylamine

A solution of 1-fluoro-4-methyl-2-nitrobenzene (1.0g,6.45mmol) in DMSO (3mL) was purged with a stream of nitrogen, followed by addition of aniline (1.18mL,12.9mmol) and stirring in a sealed tube at 100 ℃ for 20 h. After cooling to RT, the reaction mixture was partitioned between EtOAc (200mL) and water (150 mL). The organic layer was then washed with water (150 mL. times.3) then brine, then dried (Na)₂SO₄) And concentrated in vacuo, and the resulting residue was purified by column chromatography (Si-PCC, gradient eluted with 0-40% DCM in cyclohexane) to give (4-methyl-2-nitrophenyl) phenylamine as a red oil (1.41g, 96%).¹H NMR(DMSO,400MHz):δ9.21(1H,s),7.94-7.91(1H,m),7.43-7.26(5H,m),7.19-7.12(2H,m),2.27(3H,s)。

Step 2: 4-methyl-N¹-phenyl-1, 2-diamines

A mixture of (4-methyl-2-nitrophenyl) phenylamine (1.41g,6.18mmol) and 10% Pd/C (140mg) in EtOAc (30mL) was degassed with a stream of nitrogen and stirred at RT for 5h under a hydrogen atmosphere. The suspension is then filtered over a PTFE frit and the filtrate is concentrated in vacuo to give 4-methyl-N¹-phenyl-benzene-1, 2-diamine as an off-white solid (1.18g, 96%). LCMS R_T3.08min[M+H]⁺199.1。

Step 3 [ (S) -1- (5-methyl-1-phenyl-1H-benzimidazol-2-yl) ethyl ] carbamic acid tert-butyl ester

4-methyl-N¹-phenyl-benzene-1, 2-diamine (500mg,2.52mmol), (S) -2-tert-butoxycarbonylaminopropionic acid (524mg,2.77mmol), HOAt (377mg,2.77mmol), N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride (532mg,2.77mmol) and 4-methylmorpholine (0.609mL,5.54mmol) in dry DCM (20mL) were stirred at RT for 20 h. The reaction mixture was diluted with DCM (100mL) and saturated NaHCO₃And (4) washing the solution. The organic layer was then dried and concentrated in vacuo. The resulting residue was dissolved in AcOH (10mL) and heated to 70 ℃ for 20 h. After cooling to RT, the volatiles were removed in vacuo, the residue was dissolved in EtOAc and saturated NaHCO₃The solution was washed (2X 100 mL). The organic layer was then washed with brine and dried (Na)₂SO₄) And then concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC gradient eluted with 10-60% EtOAc in cyclohexane) to afford [ (S) -1- (5-methyl-1-phenyl-1H-benzimidazol-2-yl) ethyl]Tert-butyl carbamate (912mg, quantitative yield). LCMS R_T3.02min[M+H-^tBu]⁺352.1。

Step 4 to [ (S) -1- (5-methyl-1-phenyl-1H-benzimidazol-2-yl) ethyl]To a solution of tert-butyl carbamate (912mg,2.59mmol) in DCM (10mL) was added TFA (5mL) and the mixture was stirred at RT for 2 h. Volatiles were removed under reduced pressure and the resulting residue was dissolved in DCM (40mL) and saturated NaHCO ₃The solution was washed (50 mL). The two-phase system was stirred for 10min, and then the organic layer was dried (Na)₂SO₄) And concentrated in vacuo to give (S) -1- (5-methyl-1-phenyl-1H-benzimidazol-2-yl) ethylamine (617mg, 95%). LCMS R_T2.10 and 2.23min [ M-NH ]₂]⁺252.0。

Example 15(S) -1- (4-fluoro-1-phenyl-1H-benzimidazol-2-yl) ethylamine

Step 1 (3-fluoro-2-nitrophenyl) phenylamine

Sodium tert-butoxide (1.2g,12.58mmol) was added in portions to a stirred solution of 1, 3-difluoro-2-nitrobenzene (1g,6.29mmol) and aniline (1.15mL,12.58mmol) in anhydrous DMF (5mL) under a nitrogen atmosphere at RT and stirring was continued for 20 h. The mixture was poured onto NH₄Aqueous Cl and extracted with EtOAc (150 mL). The organic layer was washed with brine, then dried and concentrated in vacuo, and the resulting residue was purified by column chromatography (Si-PCC, gradient eluted with 0-15% EtOAc in cyclohexane) to give (3-fluoro-2-nitrophenyl) phenylamine as a red solid (1.06g, 73%). LCMS R_T3.80min。

Step 2 3-fluoro-N¹-phenyl-1, 2-diamines

A mixture of (3-fluoro-2-nitrophenyl) phenylamine (1.06g,4.56mmol) and 10% Pd/C (100mg) in EtOAc (20mL) was degassed with a stream of nitrogen and stirred at RT for 7h under a hydrogen atmosphere. The suspension was then filtered with a PTFE frit and the filtrate was concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient elution with 0-20% EtOAc in cyclohexane) to provide 3-fluoro-N ¹-phenyl-benzene-1, 2-diamine (440mg, 48%). LCMS R_T3.46min[M+H]⁺203.1。

Step 3, adding 3-fluoro-N¹A mixture of-phenyl-benzene-1, 2-diamine (440mg,2.18mmol), (S) -2-tert-butoxycarbonylaminopropionic acid (454mg,2.40mmol), HOAt (327mg,2.40mmol), N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride (460mg,2.40mmol) and 4-methylmorpholine (0.527mL,4.79mmol) in anhydrous DCM (20mL) was stirred at RT for 2 h. The reaction mixture was diluted with DCM (100mL) and saturated NaHCO₃And (4) washing the solution. The organic layer was then dried and concentrated in vacuo. The resulting residue was dissolved in AcOH (10mL) and heated to 70 ℃ for 2h, then 80 ℃ for 20 h. After cooling to RT, TFA (20mL) was added and the mixture was washed with waterStir at RT for 1 hour 20 minutes. The volatiles were then removed in vacuo, the residue was dissolved in DCM (100mL) and saturated NaHCO was used₃And (4) washing the solution. The organic layer was then washed with brine and dried (Na)₂SO₄) And then concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient eluted with 0-10% MeOH in TBME) to give (S) -1- (4-fluoro-1-phenyl-1H-benzimidazol-2-yl) ethylamine as a brown oil (396mg, 71%). LCMS R_T2.01min[M-NH₂]⁺239.1。

Example 16[ (S) -1- ((R) -1-piperidin-3-yl-1H-benzimidazol-2-yl) ethyl ]- (9H-purin-6-yl) amines

Step 1 (R) -3- (2-nitrophenylamino) piperidine-1-carboxylic acid tert-butyl ester

A mixture of 1-fluoro-2-nitrobenzene (1.41g,10.0mmol), (R) -3-aminopiperidine-1-carboxylic acid tert-butyl ester (2g,10.0mmol) and potassium carbonate (152mg,11.0mmol) in DMF (18mL) was heated to 120 ℃ under microwave radiation for 30 min. The reaction mixture was partitioned between EtOAc (150mL) and water. The organic layer was washed with brine and dried (Na)₂SO₄) And then concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, eluent 10% EtOAc in DCM) to give (R) -3- (2-nitrophenylamino) piperidine-1-carboxylic acid tert-butyl ester as an orange oil (2.48g, 77%). LCMS R_T3.95min[M+H-^tBu]⁺266.2。

Step 2 (R) -3- (2-aminophenylamino) piperidine-1-carboxylic acid tert-butyl ester

A mixture of (R) -tert-butyl 3- (2-nitrophenylamino) piperidine-1-carboxylate (2.48g,7.72mmol) and 10% Pd/C (250mg) in EtOAc (50mL) was degassed with a stream of nitrogen and stirred at RT for 20h under a hydrogen atmosphere. The suspension was then filtered with a PTFE frit and the filtrate was concentrated in vacuo to give (R) -3- (2-aminophenylamino) piperidine-1-carboxylic acid tert-butyl ester as a clear glass (2.25g, quantitative yield). LCMS R_T2.64min[M+H-Boc]⁺192.1。

Step 3 (R) -3- [2- ((S) -1-benzyloxycarbonylaminoethyl) benzimidazol-1-yl ] piperidine-1-carboxylic acid tert-butyl ester

A mixture of (R) -tert-butyl 3- (2-aminophenylamino) piperidine-1-carboxylate (2.25g,7.72mmol), (S) -2-benzyloxycarbonylaminopropionic acid (1.9g,8.49mmol), HOAt (1.16g,8.49mmol), N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride (1.63g,8.49mmol) and 4-methylmorpholine (1.87mL,16.98mmol) in anhydrous DCM (50mL) was stirred at RT for 1.5 h. The reaction mixture was diluted with DCM (200mL), with 10% citric acid solution and then saturated NaHCO₃The solution was then washed with brine. The organic layer was then dried and concentrated in vacuo. The resulting residue was dissolved in AcOH (20mL) and heated at 70 ℃ for 20h, then 80 ℃ for 2 h. After cooling to RT, the volatiles were then removed in vacuo, the residue was dissolved in EtOAc (200mL) and saturated NaHCO₃The solution was washed (100 mL. times.2). The organic layer was then washed with brine and dried (Na)₂SO₄) And then concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC gradient eluted with 0-50% EtOAc in cyclohexane) to yield (R) -3- [2- ((S) -1-benzyloxycarbonylaminoethyl) benzimidazol-1-yl]Tert-butyl piperidine-1-carboxylate as a white foam (2.75g, 74%). LCMS R_T3.16min[M+H]⁺479.1。

Step 4 (R) -3- [2- ((S) -1-aminoethyl) benzimidazol-1-yl ] piperidine-1-carboxylic acid tert-butyl ester

Reacting (R) -3- [2- ((S) -1-benzyloxycarbonylaminoethyl) benzimidazol-1-yl]A mixture of tert-butyl piperidine-1-carboxylate (2.75g,5.75mmol), 10% Pd/C (275mg) and AcOH (4mL) in EtOAc (40mL) was purged with a stream of nitrogen and then stirred at RT for 20h under a hydrogen atmosphere. The suspension was then filtered with a PTFE frit and the filtrate was concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC,0-10%2M NH)₃Gradient eluent in DCM/MeOH) to give (R) -3- [2- ((S) -1-aminoethyl) benzimidazol-1-yl]Tert-butyl piperidine-1-carboxylate as a white foam (1.65g, 83%). LCMS R_T2.30min[M+H-^tBu]⁺289.2。

Step 5 (R) -tert-butyl 3- (2- { (S) -1- [9- (tetrahydropyran-2-yl) -9H-purin-6-ylamino ] ethyl } benzimidazol-1-yl) piperidine-1-carboxylate

Reacting (R) -3- [2- ((S) -1-aminoethyl) benzimidazol-1-yl]A mixture of piperidine-1-carboxylic acid tert-butyl ester (1.65g,4.79mmol), 6-chloro-9- (tetrahydropyran-2-yl) -9H-purine (1.14g,4.79mmol) and DIPEA (2.5mL,14.4mmol) in IMS (10mL) was stirred in a sealed vial at 90 ℃ for 48H. After cooling to RT, the volatiles were removed under reduced pressure and the resulting residue was purified by column chromatography (Si-PCC, gradient elution with 0-10% MeOH in EtOAc). The product-containing fractions were concentrated in vacuo to give (R) -3- (2- { (S) -1- [9- (tetrahydropyran-2-yl) -9H-purin-6-yl Amino group]Ethyl } benzimidazol-1-yl) piperidine-1-carboxylic acid tert-butyl ester as a white foam (2.27g, 87%). LCMS R_T2.88min[M+H]⁺547.1。

Step 6 Synthesis of (R) -3- (2- { (S) -1- [9- (tetrahydropyran-2-yl) -9H-purin-6-ylamino]Ethyl } benzimidazol-1-yl) piperidine-1-carboxylic acid tert-butyl ester (2.27g,4.15mmol) in DCM (25mL) TFA (15mL) was added and the mixture was stirred at RT for 1 h. Removing volatile substances under reduced pressure, and loading the obtained residue onSCX-2 column. The column was washed with a 1:1 mixture of MeOH: DCM, 2M NH₃The product was eluted with MeOH (100mL) in DCM (150 mL). The product containing fractions were combined and concentrated in vacuo to give [ (S) -1- ((R) -1-piperidin-3-yl-1H-benzimidazol-2-yl) ethyl)]- (9H-purin-6-yl) amine as a pale yellow solid (1.53g, quantitative yield). LCMS R_T1.63min[M+H]⁺363.2。

Example 17(S) -1- [1- (tetrahydropyran-4-yl) -1H-benzimidazol-2-yl]Ethyl amine

Step 1 (2-Nitrophenyl) (tetrahydropyran-4-yl) amine

A solution of tetrahydropyran-4-ylamine (0.75g,7.44mmol) in DMF (2mL) was added to a mixture of 1-fluoro-2-nitrobenzene (1.00g,7.09mmol) and potassium carbonate (2.94g,21.3mmol) in DMF (10 mL). The reaction mixture was heated under microwave irradiation at 135 ℃ for 1h, and then the volatiles were removed under vacuum. The resulting residue was partitioned between EtOAc and water. The aqueous phase is further treated with EtOAc (× 2) extraction and the combined organic layers were washed with brine and then dried (Na)₂SO₄) And concentrated in vacuo to give (2-nitrophenyl) (tetrahydropyran-4-yl) amine as a yellow solid (1.58g, quantitative yield).¹H NMR(CDCl₃,400MHz):δ8.18(1H,d,J=8.65Hz),8.09(1H,s),7.42(1H,t,J=7.81Hz),6.87(1H,d,J=8.70Hz),6.64(1H,t,J=7.72),4.06-3.98(2H,m),3.79-3.68(1H,m),3.57(2H,t,J=11.32Hz),2.14-2.01(2H,m),1.74-1.61(2H,m)。

Step 2N- (tetrahydropyran-4-yl) benzene-1, 2-diamine

A mixture of (2-nitrophenyl) (tetrahydropyran-4-yl) amine (1.58g,7.09mmol) and 10% Pd/C (400mg) in EtOAc (30mL) was degassed with a stream of nitrogen and stirred at RT under a hydrogen atmosphere for 3 days. The suspension was then filtered through a celite pad and the filtrate was concentrated in vacuo to give N- (tetrahydropyran-4-yl) benzene-1, 2-diamine as a colorless oil (quantitative yield).¹H NMR(CDCl₃,400MHz):δ6.83-6.64(4H,m),4.01(2H,d,J=11.69Hz),3.57-3.41(3H,m),3.40-3.19(3H,bs),2.08-1.99(2H,m),1.59-1.46(2H,m)。

Step 3 { (S) -1- [2- (tetrahydropyran-4-ylamino) phenylcarbamoyl ] ethyl } carbamic acid tert-butyl ester

Et at 0 ℃ under nitrogen atmosphere₃N (2.6mL,18.9mmol) was added to a stirred mixture of N- (tetrahydropyran-4-yl) benzene-1, 2-diamine (1.21g,6.29mmol), (S) -2-tert-butoxycarbonylaminopropionic acid (1.31g,6.92mmol), HOAt (0.94g,6.92mmol) and N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride (1.33g,6.92mmol) in anhydrous DCM (30 mL). At 0 deg.CStirring was continued for 10min, then the mixture was slowly warmed to RT and stirred at RT for 4 h. The reaction mixture was washed with DCM and saturated NaHCO ₃The solutions were partitioned. The aqueous phase was further extracted with DCM, and the combined organic layers were washed with brine and dried (Na)₂SO₄) And concentrated in vacuo. The residue was purified by column chromatography (Si-PCC with 0-4%2 MNH)₃Gradient elution in DCM/MeOH) to give { (S) -1- [2- (tetrahydropyran-4-ylamino) phenylcarbamoyl]Ethyl } carbamic acid tert-butyl ester as a white solid (1.91g, 83%). LCMS R_T2.78min[M+H-^tBu]⁺308.1。

Step 4 { (S) -1- [1- (tetrahydropyran-4-yl) -1H-benzimidazol-2-yl ] ethyl } carbamic acid tert-butyl ester

Reacting { (S) -1- [2- (tetrahydropyran-4-ylamino) phenylcarbamoyl]Tert-butyl ethyl } carbamate (1.90g,5.23mmol) was dissolved in AcOH (30mL) and heated to 70 ℃ for 18 h. The volatiles were then removed in vacuo and the residue was taken up in DCM and saturated NaHCO₃The solutions were partitioned. The aqueous phase was further extracted with DCM (× 2), and the combined organic layers were washed with brine and dried (Na)₂SO₄) And concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC with 0-4%2M NH)₃Gradient elution in DCM/MeOH) to give { (S) -1- [1- (tetrahydropyran-4-yl) -1H-benzimidazol-2-yl]Ethyl } carbamic acid tert-butyl ester as a white foam (1.40g, 77%). LCMS R _T2.23min[M+H-^tBu]⁺290.1。

Step 5 Synthesis of { (S) -1- [1- (tetrahydropyran-4-yl) -1H-benzimidazol-2-yl]Ethyl } carbamic acid tert-butyl ester (1.80g,5.22mmol) in DCM (25mL) was added TFA (10mL) and the mixture was stirred at RT for 1 h. Volatiles were removed under reduced pressure and the resulting residue was taken up in DCM and saturated NaHCO₃The solutions were partitioned. Feeding the aqueous phase intoStep (d) was extracted with DCM (× 2), and the combined organic layers were dried (Na)₂SO₄) And concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC,0-10%2M NH)₃Gradient eluent in DCM/MeOH). The product containing fractions were concentrated in vacuo to give (S) -1- [1- (tetrahydropyran-4-yl) -1H-benzimidazol-2-yl]Ethylamine as a pale yellow solid (415mg, 32%). LCMS R_T0.27min[M+Na]⁺268.1。

Example 18(S) -1- [1- (tetrahydropyran-3-yl) -1H-benzimidazol-2-yl]Ethyl amine

Step 1 (2-Nitrophenyl) (tetrahydropyran-3-yl) amine

A solution of tetrahydropyran-3-ylamine (0.43g,4.05mmol) in DMF (2mL) was added to a mixture of 1-fluoro-2-nitrobenzene (0.57g,4.05mmol) and potassium carbonate (1.68g,12.1mmol) in DMF (10 mL). The reaction mixture was heated under microwave irradiation at 135 ℃ for 1 h. Additional tetrahydropyran-3-ylamine (40mg) was added and microwave irradiation continued at 135 ℃ for another 30 min. The volatiles were then removed under vacuum and the resulting residue was partitioned between EtOAc and water. The aqueous phase was further extracted with EtOAc (× 2), the combined organic layers were washed with brine and then dried (Na) ₂SO₄) And concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient eluted with 0-2% MeOH in DCM) to give (2-nitrophenyl) (tetrahydropyran-3-yl) amine as an orange oil (0.73g, 81%). LCMS R_T3.31min[M+H]⁺223.2。

Step 2N- (tetrahydropyran-3-yl) benzene-1, 2-diamine

A mixture of (2-nitrophenyl) (tetrahydropyran-3-yl) amine (0.72g,3.24mmol) and 10% Pd/C (200mg) in EtOAc (30mL) was degassed with a stream of nitrogen and stirred at RT under a hydrogen atmosphere for 3 days. The suspension was then filtered through a celite pad and the filtrate was concentrated in vacuo to give N- (tetrahydropyran-3-yl) benzene-1, 2-diamine as a colorless oil (quantitative yield).¹H NMR(CDCl₃,400MHz):δ6.80(1H,t,J=7.55Hz),6.75-6.62(3H,m),4.00(1H,d,J=11.24Hz),3.84-3.71(1H,m),3.67-3.16(6H,m),2.07-1.92(1H,m),1.87-1.73(1H,m),1.72-1.56(2H,m)。

Step 3 { (S) -1- [2- (tetrahydropyran-3-ylamino) phenylcarbamoyl ] ethyl } carbamic acid tert-butyl ester

Et at 0 ℃ under nitrogen atmosphere₃N (1.6mL,11.3mmol) was added to a stirred mixture of N- (tetrahydropyran-3-yl) benzene-1, 2-diamine (0.61g,3.17mmol), (S) -2-tert-butoxycarbonylaminopropionic acid (0.78g,4.14mmol), HOAt (0.56g,4.14mmol), and N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride (0.79g,4.14mmol) in anhydrous DCM (20 mL). Stirring was continued at 0 ℃ for 10min, then the mixture was slowly warmed to RT and stirred at RT for 3 h. The reaction mixture was washed with DCM and saturated NaHCO ₃The solutions were partitioned. The aqueous phase was further extracted with DCM (× 2), the combined organic layers were washed with brine and then dried (Na)₂SO₄) And concentrated in vacuo. The residue was purified by column chromatography (Si-PCC with 0-4%2 MNH)₃Gradient elution in DCM/MeOH) to give { (S) -1- [2- (tetrahydropyran-3-ylamino) phenylcarbamoyl]Ethyl } carbamic acid tert-butyl ester as a white solid (0.96g, 70%). LCMS R_T3.00min[M+H]⁺364.1。

Step 4 { (S) -1- [1- (tetrahydropyran-3-yl) -1H-benzimidazol-2-yl ] ethyl } carbamic acid tert-butyl ester

Reacting { (S) -1- [2- (tetrahydropyran-3-ylamino) phenylcarbamoyl]Ethyl } carbamic acid tert-butyl ester (0.95g,2.61mmol) was dissolved in AcOH (20mL) and heated to 70 ℃ for 38 h. The volatiles were then removed in vacuo and the residue was taken up in DCM and saturated NaHCO₃The solutions were partitioned. The aqueous phase was further extracted with DCM (× 2), and the combined organic layers were washed with brine and dried (Na)₂SO₄) And concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC with 0-4%2M NH)₃Gradient elution in DCM/MeOH) to give { (S) -1- [1- (tetrahydropyran-3-yl) -1H-benzimidazol-2-yl]Ethyl } carbamic acid tert-butyl ester as a light brown solid (0.73g, 81%). LCMS R _T2.35min[M+H-^tBu]⁺290.0。

Step 5 Synthesis of { (S) -1- [1- (tetrahydropyran-3-yl) -1H-benzimidazol-2-yl]Ethyl } carbamic acid tert-butyl ester (720mg,2.08mmol) in DCM (5mL) was added TFA (15mL) and the mixture was stirred at RT for 20 min. Volatiles were removed under reduced pressure and the resulting residue was taken up in DCM and saturated NaHCO₃The solutions were partitioned. The aqueous phase was further extracted with DCM (× 2) and the combined organic layers were dried (Na)₂SO₄) And concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC,0-10%2M NH)₃Gradient eluent in DCM/MeOH). The product containing fractions were concentrated in vacuo to give (S) -1- [1- (tetrahydropyran-3-yl) -1H-benzimidazol-2-yl]Ethylamine as an oil (305mg, 60%). LCMS R_T1.85min[M-NH₂]⁺229.1。

Example 19(S) -1- (7-chloro-1-phenyl-1H-benzimidazol-2-yl)Ethyl amine

Step 1 (2-chloro-6-nitrophenyl) phenylamine

A solution of 1-chloro-2-fluoro-3-nitrobenzene (983mg,5.60mmol) in DMSO (3mL) was purged with a stream of nitrogen, then aniline (1.0mL,11.2mmol) was added, which was then stirred in a sealed tube at 100 ℃ for 3 h. After cooling to RT, the reaction mixture was partitioned between EtOAc and water. The organic layer was then washed with saturated KHSO₄The solution (. times.3) was then washed with water, then brine, and dried (Na) ₂SO₄) And concentrated in vacuo to give (2-chloro-6-nitrophenyl) phenylamine as a dark orange oil (1.35g, 97%).¹H NMR(CDCl₃,400MHz):δ8.15(1H,s),8.03(1H,dd,J=8.40,1.49Hz),7.63(1H,d,J=7.90Hz),7.32-7.23(2H,m),7.08-6.99(2H,m),6.86(2H,d,J=7.90Hz)。

Step 2-3-chloro-N²-phenyl-1, 2-diamines

To a mixture of (2-chloro-6-nitrophenyl) phenylamine (676mg,2.72mmol) in MeOH (45mL) and water (15mL) was added NH₄Cl (872mg,16.31mol) and iron powder (607mg,10.87mmol) and the reaction mixture was heated to reflux temperature for 4 h. After cooling to RT, the solid was usedThe pad was filtered off and washed with additional MeOH. Concentrating the filtrate in vacuoCondensed and then partitioned between EtOAc and water. The aqueous phase was further extracted with EtOAc and the combined organic layers were washed with brine and then dried (Na)₂SO₄) And concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC gradient eluted with 50-100% DCM in cyclohexane). The product containing fractions were concentrated in vacuo to give 3-chloro-N²-phenyl-benzene-1, 2-diamine as a light orange solid (500mg, 84%). LCMS R_T3.45min[M+H]⁺219.1。

Step 3 [ (S) -1- (7-chloro-1-phenyl-1H-benzimidazol-2-yl) ethyl ] carbamic acid tert-butyl ester

Reacting 3-chloro-N²A mixture of-phenyl-benzene-1, 2-diamine (495mg,2.26mmol), (S) -2-tert-butoxycarbonylaminopropionic acid (470mg,2.48mmol), HOAt (338mg,2.48mmol), N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride (477mg,2.48mmol) and 4-methylmorpholine (0.550mL,4.97mmol) in anhydrous DCM (15mL) was stirred at RT for 19 h. The reaction mixture was diluted with DCM (100mL) and saturated NaHCO ₃And (4) washing the solution. The organic layer was then dried and concentrated in vacuo. The resulting residue was dissolved in AcOH (20mL) and heated at 70 ℃ for 22 h. After cooling to RT, the volatiles were removed in vacuo and the residue was purified by column chromatography (Si-PCC, gradient elution of 0-30% EtOAc in DCM) to give [ (S) -1- (7-chloro-1-phenyl-1H-benzimidazol-2-yl) ethyl]Tert-butyl carbamate as light yellow oil (quantitative yield). LCMS R_T3.83min[M+H-^tBu]⁺316.0。

Step 4 to [ (S) -1- (7-chloro-1-phenyl-1H-benzimidazol-2-yl) ethyl]To a solution of tert-butyl carbamate (2.26mmol) in DCM (5mL) was added TFA (5mL) and the mixture was stirred at RT for 3 h. Loading the crude reaction mixture intoSCX-2 column, wash column with MeOH, 2M NH₃The product eluted with MeOH. The product containing fractions were combined and concentrated in vacuo to give (S) -1- (7-chloro-1-phenyl-1H-benzimidazol-2-yl) ethylamine as a light orange oil (482mg, 78%). LCMS R_T2.11and2.24min[M+H]⁺271.9

Example 204-chloro-5H-pyrrolo [3,2-d]Pyrimidines

Step 1:2- (2-cyanovinylamino) malonic acid diethyl ester

To a 500-mL round bottom flask was placed an iso-flask in ethanol (100mL)Oxazole (25g,354.76mmol,1.00equiv,98%) and sodium ethoxide (124mL, 21%). The resulting solution was stirred at 0 ℃ for 30 min. Then acetic acid (6.9mL,98%), sodium acetate (20.5g,244.91mmol,0.69equiv,98%) and diethyl 2-aminomalonate hydrochloride (48g,222.26mmol,0.63equiv,98%) were added. The resulting solution was allowed to react for an additional 48h at room temperature with stirring, concentrated in vacuo, dissolved in 200mL of dichloromethane, washed with 2X 100mL of water, dried over anhydrous sodium sulfate and concentrated to give 30g (37%) of diethyl 2- (2-cyanovinylamino) malonate as a yellow oil.

Step 2 3-amino-1H-pyrrole-2-carboxylic acid ethyl ester

A1000-mL round bottom flask was charged with a solution of diethyl 2- (2-cyanovinylamino) malonate (30g,119.3mmol,1.00equiv,90%) in ethanol (420mL) and sodium ethoxide (80mL, 21%). The resulting solution was stirred at room temperature for 3 days. After addition of acetic acid (15mL), the resulting mixture was concentrated in vacuo, dissolved in 200mL of dichloromethane, washed with 2 × 100mL of saturated aqueous sodium bicarbonate solution and 1 × 100mL of brine, dried over anhydrous sodium sulfate and concentrated. The residue is dried under HV to yield 10g (49%) of ethyl 3-amino-1H-pyrrole-2-carboxylate as orange syrup.

Step 3H-pyrrolo [3,2-d ] pyrimidin-4 (5H) -one

To a 250-mL round bottom flask was placed a solution of ethyl 3-amino-1H-pyrrole-2-carboxylate (10g,58.38mmol,1.00equiv,90%) in ethanol (150mL) and formamidine acetate (10g,94.13mmol,1.61equiv, 98%). The resulting solution was stirred at reflux for 16 h. The precipitate was collected by filtration, washed with ethanol and dried under reduced pressure to give 5g (61%) of 3H-pyrrolo [3,2-d ] pyrimidin-4 (5H) -one as a grey solid.

Step 4A 50-mL round-bottom flask was charged with a solution of 3H-pyrrolo [3,2-d ] pyrimidin-4 (5H) -one (5g,35.52mmol,1.00equiv,96%) in trichlorophosphate (20 mL). The resulting solution was stirred at reflux for 1h, concentrated under vacuum, dissolved in 100mL ethyl acetate, washed with 2X 100mL10% aqueous sodium bicarbonate and 1X 100mL brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied to a silica gel column and eluted with ethyl acetate/petroleum ether (1:8) to give 2g (36%) of 4-chloro-5H-pyrrolo [3,2-d ] pyrimidine as a yellow solid.

Example 21N- (1- (3-phenyl-1-tosyl-1H-indol-2-yl) ethyl) -9H-purin-6-amine

Step 1 3-phenyl-1- (toluene-4-sulfonyl) -1H-indole-2-carboxylic acid ethyl ester

To a stirred solution of ethyl 3-phenyl-1H-indole-2-carboxylate (3.99g,15.0mmol) in DMF (25mL) cooled to 0 deg.C under a nitrogen atmosphere was added NaH (60% in mineral oil, 720mg,18.0 mmol). After stirring at RT for 10min, the reaction mixture was cooled to 0 ℃ and 4-methylbenzenesulfonyl chloride (3.44g,18.0mmol) in DMF (15mL) was added. Stirring was continued at RT for 16h, then the mixture was poured into 1.0M HCl and extracted with EtOAc (× 2). The combined organic layers were washed with water and then dried (Na)₂SO₄) And concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient eluted with 30-100% DCM in pentane) to give 3-phenyl-1- (toluene-4-sulfonyl) -1H-indole-2-carboxylic acid ethyl ester as a colorless oil (3.25g, 52%).¹H NMR(CDCl₃,400MHz):δ8.08(1H,d,J=8.43Hz),7.92(2H,d,J=8.37Hz),7.53-7.36(7H,m),7.28-7.21(3H,m),4.35(2H,q,J=7.15Hz),2.36(3H,s),1.25(3H,t,J=7.14Hz)。

Step 2 [ 3-phenyl-1- (toluene-4-sulfonyl) -1H-indol-2-yl ] methanol

To a stirred solution of ethyl 3-phenyl-1- (toluene-4-sulfonyl) -1H-indole-2-carboxylate (3.24g,7.72mmol) in toluene (40mL) cooled to-78 deg.C under a nitrogen atmosphere was added 1.0M DIBAL-H in toluene (23.2mL,23.2 mmol). The reaction mixture was stirred at-78 deg.C Stirring for 15min, and stirring at-10 deg.C for 30 min. After re-cooling to-78 ℃, the reaction mixture was quenched with water (20mL) and then allowed to warm to RT. The mixture was partitioned between EtOAc and 1.0M HCl and the aqueous phase was extracted with additional EtOAc (× 3). The combined organic layers were washed with water and then dried (Na)₂SO₄) And concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient eluted with 30-100% DCM in pentane) to give [ 3-phenyl-1- (toluene-4-sulfonyl) -1H-indol-2-yl]Methanol as a white foam (2.49g, 85%). LCMS R_T4.77min[M+Na]⁺400.1。

Step 3-3-phenyl-1- (toluene-4-sulfonyl) -1H-indole-2-carbaldehyde

To a stirred solution of oxalyl chloride (1.37g,10.8mmol) in DCM (30mL) cooled to-78 deg.C under a nitrogen atmosphere was added DMSO (1.50mL,21.6 mmol). Stirring at-78 deg.C for 10min, adding [ 3-phenyl-1- (toluene-4-sulfonyl) -1H-indol-2-yl]A solution of methanol (2.27g,6.01mmol) in DCM (20mL) was stirred for 1.5 h. Triethylamine was then added and after stirring at-78 ℃ for 10min, the mixture was slowly warmed to RT. The reaction mixture was then poured into 1.0M aqueous HCl and extracted with DCM (× 3). The combined organic layers were washed with water, then brine and dried (Na) ₂SO₄) And concentrated in vacuo to give 3-phenyl-1- (toluene-4-sulfonyl) -1H-indole-2-carbaldehyde as a gum which was then solidified by spinning to give an off-white solid (2.26g, 100%).¹H NMR(CDCl₃,400MHz):δ10.22(1H,s),8.31(1H,d,J=8.56Hz),7.86-7.81(2H,m),7.60-7.41(7H,m),7.33-7.21(3H,m),2.37(3H,s)。

Step 4 1- [ 3-phenyl-1- (toluene-4-sulfonyl) -1H-indol-2-yl ] ethanol

To a solution of 3-phenyl-1- (toluene-4-sulfonyl) -1H-indole-2-carbaldehyde (2.11g,5.62mmol) in THF (30mL) cooled to-78 ℃ and under a nitrogen atmosphere was added a 3.0M solution of MeMgBr in ether (2.6 mL). The mixture was stirred at 0 ℃ for 30min, then an additional 3.0M solution of MeMgBr in ether (0.3mL) was added. After stirring for 15min, the reaction mixture was poured onto NH₄Cl in saturated solution and extracted with EtOAc (× 2). The combined organic layers were washed with water and then dried (Na)₂SO₄) And concentrated in vacuo. The crude material was combined with a second crude reaction mixture obtained according to the same procedure (starting from 140mg,3.73mmol 3-phenyl-1- (toluene-4-sulfonyl) -1H-indole-2-carbaldehyde) and the combined batch was purified by column chromatography (Si-PCC, gradient eluted with 20-100% DCM in pentane) to give the title compound as a gum which solidified upon standing (2.02g, 86%).¹H NMR(CDCl₃,400MHz):δ8.07(1H,d,J=8.35),7.80-7.75(2H,m),7.51-7.38(5H,m),7.33-7.26(2H,m),7.20-7.14(3H,m),5.25-5.15(1H,m),4.06(1H,d,J=11.01Hz),2.31(3H,s),1.70(3H,d,J=6.88Hz)。

Step 5-2- (1-azidoethyl) -3-phenyl-1- (toluene-4-sulfonyl) -1H-indole

DIAD (1.80g,8.89mmol) was placed in a nitrogen atmosphere at 0 deg.CA solution in an alkane (5mL) was added to triphenylphosphine (2.33g,8.89mmol) in bisIn an alkane (20 mL). After stirring for 10min, add1- [ 3-phenyl-1- (toluene-4-sulfonyl) -1H-indol-2-yl in an alkane (15mL)]Ethanol (1.74g,4.44mmol) was then added to the reaction mixtureDiphenyl phosphorazidate (1.47g,5.53mmol) in an alkane (5 mL). Stirring was continued for 16H at 20 ℃ then the crude reaction mixture was diluted with DCM and purified by column chromatography (Si-PCC, gradient eluting with 10-100% DCM in pentane) to give 2- (1-azidoethyl) -3-phenyl-1- (toluene-4-sulfonyl) -1H-indole as a gum (1.39g, 75%). LCMS R_T4.77min[M-N₃]⁺374.1。

Step 6- [ 3-phenyl-1- (toluene-4-sulfonyl) -1H-indol-2-yl ] ethylamine

A mixture of 2- (1-azidoethyl) -3-phenyl-1- (toluene-4-sulfonyl) -1H-indole (1.34g,3.22mmol) and 10% Pd/C (200mg) in EtOAc (80mL) was degassed with a stream of nitrogen and stirred at RT for 20H under a hydrogen atmosphere. The suspension was then filtered and the filtrate was concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient eluted with 0-10% MeOH in DCM) to give 1- [ 3-phenyl-1- (toluene-4-sulfonyl) -1H-indol-2-yl ]Ethylamine as a white solid (960mg, 76%).¹H NMR(CDCl₃,400MHz):δ8.18(1H,d,J=8.44Hz),7.73(2H,d,J=8.44Hz),7.49-7.15(10H,m),4.72(1H,q,J=6.96Hz),2.35(3H,s),1.45(3H,d,J=7.40Hz)

Step 7-1- [ 3-phenyl-1- (toluene-4-sulfonyl) -1H-indol-2-yl]A mixture of ethylamine (294mg,0.753mmol), 6-chloro-9H-purine (140mg,0.903mmol), and DIPEA (0.20mL,1.13mmol) in n-butanol (1.5mL) was stirred in a sealed tube at 120 deg.C for 56H. After cooling to RT, the crude reaction mixture is loadedSCX-2 column, wash it with MeOH, 2M NH₃The product eluted with MeOH. The product containing fractions were combined and concentrated under reduced pressure. The residue was purified by column chromatography (Si-PCC with 0-7%2 MNH)₃Gradient MeOH in DCM) to give N- (1- (3-phenyl-1-tosyl-1H-indol-2-yl) ethyl) -9H-purin-6-amine as a yellow solid (350mg, 91%). LCMS R_T3.31min[M+H]⁺509.1

Example 229- ((3-phenyl-1-tosyl-1H-indol-2-yl) methyl) -9H-purine_-6_-Amines as pesticides

Step 1: 2-bromomethyl-3-phenyl-1- (toluene-4-sulfonyl) -1H-indole

To [ 3-phenyl-1- (toluene-4-sulfonyl) -1H-indol-2-yl under a nitrogen atmosphere at RT]To a solution of methanol (1.31g,3.47mmol) and triphenylphosphine (1.09g,4.16mmol) in DCM (30mL) was added NBS (240mg,4.16mmol) and stirring was continued for 2 h. Volatiles were removed under reduced pressure and the resulting residue was purified by column chromatography (Si-PCC, gradient eluted with 30-100% DCM in pentane) to give 2-bromomethyl-3-phenyl-1- (toluene-4-sulfonyl) -1H-indole as a gum (440mg, 29%). ¹H NMR(CDCl₃,400MHz):δ8.16(1H,dt,J=8.48,0.84Hz),7.92-7.88(2H,m),7.60-7.49(4H,m),7.48-7.37(3H,m),7.28-7.22(3H,m),5.05(2H,s),2.38(3H,s)。

Step 2 to a stirred mixture of 9H-purin-6-ylamine (130mg,0.976mmol) in DMF (5mL) under an argon atmosphereNaH (60% in mineral oil, 40mg,0.976mmol) was added. After stirring at RT for 10min, 2-bromomethyl-3-phenyl-1- (toluene-4-sulfonyl) -1H-indole (430mg,0.976mmol) in DMF (10mL) was added and stirring continued for 15 min. Loading the crude reaction mixture intoSCX-2 column, wash it with MeOH, 2M NH₃The product eluted with MeOH. The product containing fractions were combined and concentrated under reduced pressure. The resulting residue was purified by column chromatography (Si-PCC, gradient eluted with 0-10% MeOH in DCM) to give 9- ((3-phenyl-1-tosyl-1H-indol-2-yl) methyl) -9H-purin-6-amine as a white solid (370mg, 77%). LCMS R_T3.16min[M+H]⁺495.1

Example 231- (3-phenylbenzo [ b ]]Thien-2-yl) ethylamine

Step 1- (3-phenylbenzo [ b ] thiophen-2-yl) ethanol

To 3-phenylbenzo [ b ] in a nitrogen atmosphere cooled to-78 deg.C]Thiophene-2-carbaldehyde (430mg,1.87mmol) in THF (10mL) was added 3.0M MeMgBr in ether (1.24mL) and stirring was continued for 30 min. Reacting the mixture with NH₄A saturated solution of Cl (20mL) was quenched and slowly warmed to RT. The mixture was extracted with EtOAc (× 2), the combined organic layers were washed with water and then dried (Na) ₂SO₄) And concentrated in vacuo to give 1- (3-phenylbenzo [ b ]]Thiophen-2-yl) ethanol as a white solid (472mg, quantitative yield).¹H NMR(CDCl₃,400MHz):δ7.88-7.84(1H,m),7.52-7.28(8H,m),5.21(1H,q,J=6.35Hz),2.03(1H,s),1.59(3H,d,J=6.63Hz)。

Step 2-2- (1-azidoethyl) -3-phenylbenzo [ b ] thiophene

DIAD (556mg,2.75mmol) was added to triphenylphosphine (722mg,2.75mmol) in bis at 0 ℃ under a nitrogen atmosphereIn an alkane (5 mL). After stirring for 10min, 1- (3-phenylbenzo [ b ] was added]Thien-2-yl) ethanol (350mg,1.37mmol), followed by diphenyl phosphorazidate (454mg,1.65mmol) was added. Stirring was continued at 20 ℃ for 16h, and the volatiles were then concentrated in vacuo. The crude reaction mixture was purified by column chromatography (Si-PCC, gradient eluted with 0-20% DCM in cyclohexane) to afford 2- (1-azidoethyl) -3-phenylbenzo [ b ]]Thiophene as a colorless oil (211mg, 55%).¹H NMR(CDCl₃,400MHz):δ7.88(1H,d,J=7.87Hz),7.54-7.42(4H,m),7.41-7.29(4H,m),4.97(1H,q,J=6.80Hz),1.58(3H,d,J=6.80Hz)。

Step 3, reacting 2- (1-azidoethyl) -3-phenylbenzo [ b ]]Thiophene (211mg,0.756mmol) was dissolved in a mixture of THF (4mL) and water (0.27mL) and triphenylphosphine (237mg,0.91mmol) was added. The mixture was stirred at RT for 1h, then additional triphenylphosphine (237mg) was added. Stirring was continued for 1h and the crude reaction mixture was loadedSCX-2 column, wash it with MeOH, 2M NH₃The product eluted with MeOH. The product containing fractions were combined and concentrated under reduced pressure. The resulting residue was purified by column chromatography (Si-PCC with a gradient elution of 0-8% MeOH in DCM) to provide 1- (3-phenylbenzo [ b ] ]Thien-2-yl) ethylamine as a white solid (160mg, 83%).¹H NMR(CDCl₃,400MHz):δ7.84(1H,dd,J=7.63,1.55Hz),7.52-7.27(8H,m),4.56-4.44(1H,br),1.76(2H,s),1.47(3H,d,J=6.21Hz)。

Example 241- (3-phenylbenzofuran-2-yl) ethylamine

Step 1- (3-phenylbenzofuran-2-yl) ethanol

Tetrabutylammonium borohydride (nBu)₄NBH₄) (750mg,2.91mmol) was added to a solution of 1- (3-phenylbenzofuran-2-yl) ethanone (459mg,1.94mmol) in THF (9mL) and IMS (1mL) and the mixture was stirred at RT for 1 h. The reaction mixture was then quenched by addition of MeOH and the volatiles were removed under reduced pressure. The resulting residue was purified by column chromatography (Si-PCC gradient eluted with 0-40% EtOAc in cyclohexane) to give 1- (3-phenylbenzofuran-2-yl) ethanol as an oil (452mg, 98%). LCMS R_T3.57min[M-OH]⁺221.1

Step 2-2- (1-azidoethyl) -3-phenylbenzofuran

DBU (155. mu.L, 1.04mmol) was added dropwise to a solution of 1- (3-phenylbenzofuran-2-yl) ethanol (206mg,0.864mmol) and diphenyl phosphorazidate (255. mu.L, 1.04mmol) in anhydrous THF (7mL) at 0 ℃ under a nitrogen atmosphere. After stirring at 0 ℃ for 30min, the mixture was slowly warmed to RT and stirring was continued for 1.5 h. Additional diphenyl phosphorazidate (255. mu.L, 1.04mmol) and DBU (155. mu.L, 1.04mmol) were added and stirring continued for 18 h. Removing volatility under reduced pressureMaterial, the resulting residue was purified by column chromatography (Si-PCC, gradient eluted with 0-30% EtOAc in cyclohexane) to give the title compound as an oil (186mg, 82%). LCMS R _T4.48min[M+H-N₂]⁺236.1。

Step 3 triphenylphosphine (231mg,0.883mmol) was added to a solution of 2- (1-azidoethyl) -3-phenylbenzofuran (186mg,0.706mmol) in THF (9mL) and water (1 mL). The mixture was heated at 60 ℃ for 2h and then cooled to RT. Volatiles were removed under reduced pressure and the resulting residue was purified by column chromatography (Si-PCC gradient eluted with 0-10% MeOH in EtOAc) to give 1- (3-phenylbenzofuran-2-yl) ethylamine as an oil (327mg, quantitative yield). LCMS R_T2.21min[M-NH₂]⁺221.1

Example 25Methanesulfonic acid (3-phenylbenzofuran-2-yl) methyl ester

Methanesulfonyl chloride (160. mu.L, 2.05mmol) was added dropwise to a solution of (3-phenylbenzofuran-2-yl) methanol (367mg,1.64mmol) and DIPEA (343. mu.L, 1.97mmol) in anhydrous DCM (10mL) at 0 ℃. Stirring was continued at 0 ℃ for 15min, then the mixture was slowly warmed to RT. After stirring at RT for 2h, additional methanesulfonyl chloride (80. mu.L, 1.03mmol) and DIPEA (172. mu.L, 0.99mmol) were added and stirring continued for 1.5 h. The reaction mixture was diluted with DCM and the organic layer was washed with water and then dried (Na)₂SO₄) And concentrated in vacuo to give (3-phenylbenzofuran-2-yl) methyl methanesulfonate as an oil (443mg, 89%).¹H NMR(DMSO,400MHz):δ7.71-7.64(2H,m),7.62-7.56(4H,m),7.52-7.41(2H,m),7.37-7.32(1H,m),4.98(2H,s),3.89(3H,s)

Example 26(3-Phenylbenzo [ b ]]Thien-2-yl) methylamines

Step 1 (3-phenylbenzo [ b ] thiophen-2-yl) methyl methanesulfonate

Methanesulfonyl chloride (127. mu.L, 1.63mmol) was added dropwise to (3-phenylbenzo [ b ] at 0 deg.C]Thien-2-yl) methanol (356mg,1.48mmol) and DIPEA (322. mu.L, 1.85mmol) in dry DCM (10 mL). Stirring was continued at 0 ℃ for 15min, then the mixture was slowly warmed to RT. After stirring at RT for 2.5h, additional methanesulfonyl chloride (1 drop) was added and stirring was continued for 1 h. The reaction mixture was diluted with DCM and the organic layer was washed with water and then dried (Na)₂SO₄) And concentrated in vacuo to give methanesulfonic acid (3-phenylbenzo [ b ]]Thiophen-2-yl) methyl ester as a yellow oil (408mg, 87%).¹H NMR(DMSO,400MHz):δ8.07-8.02(1H,m),7.62-7.56(2H,m),7.55-7.37(6H,m),4.96(2H,s),3.33(3H,s)。

Step 2-azidomethyl-3-phenylbenzo [ b ] thiophene

Sodium azide (179mg,2.76mmol) was added to methanesulfonic acid 3-phenylbenzo [ b ]]Thien-2-ylmethyl ester (828mg,1.84mmol) in DMF (10mL) and the mixture was stirred at RT for 18 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine and then dried (Na)₂SO₄) And concentrated in vacuo, and the resulting residue purified by column chromatography (Si-PCC, gradient elution with 0-35% DCM in cyclohexane) to afford 2-azidomethyl-3-phenylbenzo [ b ]]Thiophene as a clear oil (244mg, 50%). LCMS R _T4.46min[M+H-N₂]⁺237.8。

Step 3, in a nitrogen atmosphere, reacting 2-azidomethyl-3-phenylbenzo [ b ]]A solution of thiophene (244mg,0.92mmol) in THF (10mL) was treated with a solution of triphenylphosphine (302mg,1.15mmol) in water (1 mL). The mixture was heated to 60 ℃ for 2h and then cooled to RT. Volatile materials were removed under reduced pressure and the residue obtained was loaded ontoSCX-2 column, wash it with MeOH, 2M NH₃The product eluted with MeOH. The product containing fractions were combined and concentrated in vacuo to give (3-phenylbenzo [ b ]]Thien-2-yl) methylamine (288mg, quantitative yield). LCMS R_T2.15min[M-N₃]⁺223.0

Example 27Methanesulfonic acid (3-o-tolylbenzo [ b ]]Thien-2-yl) methyl ester

Step 1 3-o-tolylbenzo [ b ] thiophene-2-carbaldehyde

Reacting 3-bromobenzo [ b]Thiophene-2-carbaldehyde (500mg,2.07mmol), 2-methylphenylboronic acid (394mg,2.90mmol), Pd (PPh)₃)₄(243mg,0.21mmol)、Cs₂CO₃(2.02g,6.21mmol) in bisThe mixture in alkane (12mL) and water (4mL) was degassed with a stream of nitrogen and then heated with microwave radiation in a sealed tube at 130 ℃ for 45 min. The reaction mixture was extracted with EtOAc, then the organic layer was washed with water, then brine, and dried (Na)₂SO₄) And concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient eluted with 0-70% DCM in cyclohexane) to give the title compound (quantitative yield). LCMS R _T4.16min。

Step 2 (3-o-tolylbenzo [ b ] thiophen-2-yl) methanol

Tetrabutylammonium borohydride (nBu)₄NBH₄) (800mg,3.10mmol) was added to 3-o-tolylbenzo [ b ] at RT]Thiophene-2-carbaldehyde (2.07mmol) in THF (10mL) and IMS (1mL) and the mixture was stirred at RT for 1 h. The reaction mixture was then quenched by addition of MeOH and the volatiles were removed under reduced pressure. The resulting residue was purified by column chromatography (Si-PCC gradient eluted with 0-30% EtOAc in cyclohexane) to afford the title compound as an oil (432mg, 82% over 2 steps). LCMS R_T3.74min[M-OH]⁺237.1。

Step 3 Methanesulfonyl chloride (158. mu.L, 2.04mmol) was added dropwise to (3-o-tolylbenzo [ b ] at RT]Thien-2-yl) methanol (432mg,1.70mmol) and DIPEA (385. mu.L, 2.21mmol) in dry DCM (10 mL). Stirring was continued for 18h at RT, then the reaction mixture was washed with water and then dried (Na)₂SO₄) And concentrated in vacuo to give methanesulfonic acid (3-o-tolylbenzo [ b ]]Thiophen-2-yl) methyl ester as a brown oil (424mg, 75%).¹H NMR(DMSO,400MHz):δ8.05(1H,d,J=8.04Hz),7.45-7.40(3H,m),7.38-7.32(2H,m),7.21(1H,d,J=7.40Hz),7.12(1H,d,J=7.98Hz),4.82(1H,d,J=12.41Hz),4.76(1H,d,J=12.41Hz),3.32(3H,s),1.99(3H,s)

Example 28(S) -1- (6-fluoro-1-phenyl-1H-benzo [ d)]Imidazol-2-yl) propan-1-amine

Step 1 (S) -1- (6-fluoro-1-phenyl-1H-benzo [ d ] imidazol-2-yl) propylcarbamic acid tert-butyl ester

4-fluoro-N from example 8 ²A mixture of-phenyl-benzene-1, 2-diamine (199mg,0.984mmol), (S) -2-tert-butoxycarbonylaminobutyric acid (219mg,1.08mmol), HOAt (147mg,1.08mmol), 4-methylmorpholine (0.238mL,2.16mmol) and N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride (207mg,1.08mmol) in DCM (5mL) was stirred at RT for 2 h. The reaction mixture was then washed with DCM (50mL) and saturated NaHCO₃The solutions were partitioned. The organic layer was dried (Na)₂SO₄) And concentrated in vacuo, the resulting residue was dissolved in AcOH (10mL) and stirred at 70 ℃ for 18 h. After cooling to RT, the volatiles were evaporated in vacuo and the residue was taken up in DCM (50mL) and saturated NaHCO₃The solutions were partitioned. The organic layer was washed with brine and dried (Na)₂SO₄) And then concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC gradient eluted with 0-50% EtOAc in cyclohexane) to yield (S) -1- (6-fluoro-1-phenyl-1H-benzo [ d%]Imidazol-2-yl) propylcarbamic acid tert-butyl ester as a beige solid (234mg, 64%). LCMS R_T3.82min[M+H]⁺370.5

Step 2 to (S) -1- (6-fluoro-1-phenyl-1H-benzo [ d]Imidazol-2-yl) propylcarbamic acid tert-butyl ester (234mg,0.63mmol) in DCM (3mL) was added TFA (1.5mL) and the mixture was stirred at RT for 2 h. Volatiles were removed under reduced pressure and the resulting residue was purified in DCM (20mL) and saturated NaHCO ₃The solutions were partitioned. The two-phase system was stirred for 10min, and then the organic layer was dried (MgSO₄) And concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC with a gradient elution of 0-10% MeOH in DCM) to give (S) -1- (6-fluoro-1-phenyl-1H-benzo [ d ]]Imidazol-2-yl) propan-1-amine,as a colorless oil (42mg, 25%). LCMS R_T1.90min[M-NH₂]⁺253.0

Example 29(S) -1- (5-fluoro-1-phenyl-1H-benzo [ d)]Imidazol-2-yl) ethylamine

Step 1 (S) -tert-butyl 1- (5-fluoro-2- (phenylamino) -1-oxopropan-2-ylcarbamate

Reacting 4-fluoro-N¹A mixture of-phenylbenzene-1, 2-diamine (866mg,4.3mmol), (S) -2-tert-butoxycarbonylaminopropionic acid (890mg,4.7mmol), HOAt (640mg,4.7mmol), 4-methylmorpholine (1.0mL,9.5mmol) and N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride (900mg,4.7mmol) in DCM (20mL) was stirred at RT for 2 h. The reaction mixture was then washed with DCM (50mL) and saturated NaHCO₃The solutions were partitioned. The organic layer was washed with brine and then dried (MgSO)₄) And concentrated in vacuo to give tert-butyl (S) -1- (5-fluoro-2- (phenylamino) -1-oxopropan-2-ylcarbamate (quantitative yield), which was used in the subsequent step without further purification. LCMS R _T3.83min[M+H]⁺374.1

Step 2 (S) -tert-butyl 1- (5-fluoro-1-phenyl-1H-benzo [ d ] imidazol-2-yl) ethylcarbamate

Reacting (S) -1- (5-fluoro-2- (phenylamino) -1-oxopropan-2-ylcarbamic acidA solution of tert-butyl ester (2.15mmol) in AcOH (10mL) was stirred at 70 ℃ for 18 h. After cooling to RT, the volatiles were evaporated under reduced pressure and the residue was taken up in EtOAc and saturated NaHCO₃The solutions were partitioned. The organic layer was washed with brine and dried (MgSO)₄) And then concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC gradient eluted with 0-40% EtOAc in cyclohexane) to yield (S) -1- (5-fluoro-1-phenyl-1H-benzo [ d ]]Imidazol-2-yl) ethylcarbamic acid tert-butyl ester as an orange oil (661mg, 86% yield in two steps). LCMS R_T3.52min[M+H]⁺356.1

Step 3 to (S) -1- (5-fluoro-1-phenyl-1H-benzo [ d]Imidazol-2-yl) ethylcarbamic acid tert-butyl ester (661mg,1.9mmol) in DCM (9mL) was added TFA (4.5mL) and the mixture was stirred at RT for 2 h. Volatiles were removed under reduced pressure and the resulting residue was purified in DCM (20mL) and saturated NaHCO₃The solutions (40mL) were partitioned between. The two-phase system was stirred for 10min, and then the organic layer was dried (MgSO₄) And concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC with a gradient elution of 0-10% MeOH in DCM) to give (S) -1- (5-fluoro-1-phenyl-1H-benzo [ d ] ]Imidazol-2-yl) ethylamine as a yellow oil (379mg, 78%). LCMS R_T1.77min[M+H]⁺256.2

Intermediates

The following intermediates may also be used in the synthesis of the compounds of the present invention:

(5-fluoro-2-nitrophenyl) phenylamine (alternative preparation)

To a solution of aniline (30.1mL,0.33mol) in THF (300mL) at-78 deg.C was added LiHMDS (408mL,1M solution in THF, 0.41mmol) at a rate such that T.ltoreq.65 deg.C. The reaction mixture was stirred at-78 ℃ for 30min and then at-78 ℃ at a rate such that T.ltoreq.65 ℃This was added to a solution of 2, 4-difluoronitrobenzene (50g,0.31mol) in THF (200 mL). The mixture was stirred at-78 ℃ for 2 h. The reaction mixture was diluted with water (300mL) and EtOAc (300mL), and the emulsion thus formed was usedAnd (5) filtering. The layers were separated and the aqueous fraction was extracted with EtOAc (3X 100 mL). The combined organic extracts were washed with brine and dried (MgSO)₄) And concentrated in vacuo. The resulting residue was stirred with pentane (300mL) for 16h, then filtered to give the title compound as a brown solid (50g, 68%).¹H NMR400MHz(CDCl₃)δ:9.64(1H,br s),8.26(1H,dd,J=9.5,6.0Hz),7.49-7.42(2H,m),7.32-7.25(3H,m),6.80(1H,dd,J=11.3,2.5Hz),6.51-6.45(1H,m)

4-fluoro-N-2-phenylbenzene-1, 2-diamine (alternative preparation)

To a solution of (5-fluoro-2-nitrophenyl) phenylamine (50g,0.22mol) in EtOAc (500mL) was added palladium on carbon (10% by weight, 5 g). The reaction mixture was stirred at RT under hydrogen atmosphere for 48 h. Mixing the mixture with Filtration and concentration of the filtrate in vacuo gave the title compound as a purple solid (40.1g, 92%).¹H NMR400MHz(CDCl₃)δ:7.28-7.21(2H,m),6.93-6.83(4H,m),6.72(1H,dd,J=8.6,5.6Hz),6.68-6.62(1H,m),5.29(1H,br s),3.49(2H,br s)。

[ (S) -1- (4-fluoro-2-phenylaminophenylcarbamoyl) ethyl ] carbamic acid tert-butyl ester (alternative preparation)

To a solution of 4-fluoro-N-2-phenylbenzene-1, 2-diamine (50g,0.25mol), L-Boc-ala-OH (46.8g,0.25mol), and HOAT (33.7g,0.25mol) in DCM (500mL) at 0 deg.C was added EDC in portions at a rate such that T.ltoreq.2 deg.C, and the reaction mixture was stirred at 0 deg.C for 30 min. Water (500mL) was added, allowing a white precipitate to form. The mixture was filtered and the filtrate was extracted with DCM (3X 100 mL). The combined organic fractions were washed with citric acid solution (10% by weight, 100mL) and then with saturated NaHCO₃The aqueous solution was then washed with brine and dried (MgSO)₄) And concentrated in vacuo. The residue was triturated with pentane to give the title compound as a violet solid (79g, 86%).¹H NMR400MHz(CDCl₃) δ:8.03(1H, br s),7.44(1H, dd, J =8.9,6.0Hz),7.29-7.23(2H, m),7.03-6.92(4H, m),6.64(1H, td, J =8.7,2.9Hz),6.21(1H, br s),4.93(1H, d, J =6.2Hz),4.22(1H, quintuple, 6.8Hz),1.44-1.38(12H, m). LCMS R_T=3.68min,[M+H-^tBu]⁺=318

(S) -1- (6-fluoro-1-phenyl-1H-benzimidazol-2-yl) ethylamine dihydrochloride (alternative preparation)

Reacting [ (S) -1- (4-fluoro-2-phenylaminophenylcarbamoyl) ethyl]Di-tert-butyl carbamate (40g,0.11mol) dissolved in HClAlkane solution (4N,135mL) and the reaction mixture was heated at 60 ℃ for 3 h. The reaction mixture was cooled to RT and seeded with crystals of the desired product, allowing the product to crystallize. The product was collected by filtration and dried in vacuo to give the title compound as a purple solid (31.2g, 89%).¹H NMR400MHz(DMSO-d₆) δ 8.94(3H, br s),7.81(1H, dd, J =8.8,4.9Hz),7.74-7.62(5H, m),7.25-7.18(1H, m),6.98(1H, dd, J =9.0,2.4),4.41(1H, five Hz)Heavy peak, J =6.3Hz),1.45(3H, d, J =6.4 Hz). LCMS R_T=2.02min,[M+H]⁺=256(10%)[M-NH₂]=239(100%)。

[ (S) -1- (6-fluoro-1-phenyl-1H-benzimidazol-2-yl) ethyl ] - [9- (tetrahydropyran-2-yl) -9H-purin-6-yl ] amine

To a solution of (S) -1- (6-fluoro-1-phenyl-1H-benzimidazol-2-yl) ethylamine dihydrochloride (30.7g,93.7mmol) in IPA (300mL) was added 6-chloro-9- (tetrahydropyran-2-yl) -9H-purine (26.9g,112.5mmol) and DIPEA (48mL,281.2mmol), and the reaction mixture was heated at 80 deg.C for 16H. The reaction mixture was concentrated in vacuo and the residue was dissolved in EtOAc (600 mL). The solution was washed with water and the organic fraction was separated. The organic fraction was washed with brine and dried (MgSO) ₄) And concentrated in vacuo. The residue obtained is treated by flash chromatography (SiO)₂Eluted with 0-10% methanol in EtOAc) to give the title compound as a yellow oil (30g,70%)¹H NMR400MHz(CDCl₃)δ8.25(1H,s),7.96(1H,s),7.70(1H,qn,J4.1Hz),7.37-7.58(5H,m),6.98-6.82(1H,m),6.52-6.66(1H,m),5.60-5.77(2H,m),4.12-4.19(1H,m),3.76(1H,td,J11.3,2.5Hz),1.91-2.13(4H,m),1.68-1.84(2H,m),1.60-1.68(3H,m)

3-phenyl-1- (toluene-4-sulfonyl) -1H-indole-2-carboxylic acid ethyl ester

To a stirred solution of ethyl 3-phenyl-1H-indole-2-carboxylate (3.99g,15.0mmol) in DMF (25mL) cooled to 0 ℃ under a nitrogen atmosphere was added NaH (60% in mineral oil, 720mg,18.0 mmol). After stirring at RT for 10min, the reaction mixture was cooled to 0 ℃ and 4-methylbenzenesulfonyl chloride (3) in DMF (15mL) was added.44g,18.0 mmol). Stirring was continued at RT for 16h, then the mixture was poured into 1.0M HCl and extracted with EtOAc (× 2). The combined organic fractions were washed with water and dried (Na)₂SO₄) And concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient eluted with 30-100% DCM in pentane) to give the title compound as a colorless oil (3.25g, 52%).¹H NMR(CDCl₃,400MHz):δ8.08(1H,d,J=8.43Hz),7.92(2H,d,J=8.37Hz),7.53-7.36(7H,m),7.28-7.21(3H,m),4.35(2H,q,J=7.15Hz),2.36(3H,s),1.25(3H,t,J=7.14Hz)

[ 3-phenyl-1- (toluene-4-sulfonyl) -1H-indol-2-yl ] methanol

To a stirred solution of ethyl 3-phenyl-1- (toluene-4-sulfonyl) -1H-indole-2-carboxylate (3.24g,7.72mmol) in toluene (40mL) at-78 deg.C under a nitrogen atmosphere was added a 1.0M solution of MDIBAL-H in toluene (23.2mL,23.2 mmol). The reaction mixture was stirred at-78 ℃ for 15min and then at-10 ℃ for 30 min. After re-cooling to-78 ℃, the reaction mixture was quenched with water (20mL) and then allowed to warm to RT. The mixture was partitioned between EtOAc and 1.0M HCl and the aqueous phase was extracted with additional EtOAc (× 3). The combined organic fractions were washed with water and dried (Na) ₂SO₄) And concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient eluted with 30-100% DCM in pentane) to give the title compound as a white foam (2.49g, 85%). LCMS (method C) R_T4.77min[M+Na]⁺400.1

3-phenyl-1- (toluene-4-sulfonyl) -1H-indole-2-carbaldehyde

To be at-7To a stirred solution of oxalyl chloride (1.37g,10.8mmol) in DCM (30mL) at 8 deg.C under nitrogen was added DMSO (1.50mL,21.6 mmol). Stirring at-78 deg.C for 10min, adding [ 3-phenyl-1- (toluene-4-sulfonyl) -1H-indol-2-yl]A solution of methanol (2.27g,6.01mmol) in DCM (20mL) was stirred for 1.5 h. Triethylamine was added and after stirring at-78 ℃ for 10min, the mixture was slowly warmed to RT. The reaction mixture was poured into 1.0M aqueous HCl and extracted with DCM (× 3). The combined organic layers were washed with water and then brine and dried (Na)₂SO₄) And concentrated in vacuo to give the title compound as a gum which then solidified upon standing to give an off-white solid (2.26g, 100%).¹H NMR(CDCl₃,400MHz):δ10.22(1H,s),8.31(1H,d,J=8.56Hz),7.86-7.81(2H,m),7.60-7.41(7H,m),7.33-7.21(3H,m),2.37(3H,s)

1- [ 3-phenyl-1- (toluene-4-sulfonyl) -1H-indol-2-yl ] ethanol

To a solution of 3-phenyl-1- (toluene-4-sulfonyl) -1H-indole-2-carbaldehyde (2.11g,5.62mmol) in THF (30mL) at-78 deg.C under a nitrogen atmosphere was added a 3.0M solution of methylmagnesium bromide in ether (2.6 mL). The mixture was stirred at 0 ℃ for 30min, then another 3.0M solution of methyl magnesium bromide in ether (0.3mL) was added. After 15min, the reaction mixture was poured onto NH ₄Cl in saturated solution and extracted with EtOAc (× 2). The combined organic fractions were washed with water and dried (Na)₂SO₄) And concentrated in vacuo. The crude material was combined with a second crude reaction mixture obtained according to the same procedure (starting from 140mg,3.73mmol 3-phenyl-1- (toluene-4-sulfonyl) -1H-indole-2-carbaldehyde) and the combined batch was purified by column chromatography (Si-PCC, gradient eluted with 20-100% DCM in pentane) to give the title compound as a gum which solidified upon standing (2.02g, 86%).¹H NMR(CDCl₃,400MHz):δ8.07(1H,d,J=8.35),7.80-7.75(2H,m),7.51-7.38(5H,m),7.33-7.26(2H,m),7.20-7.14(3H,m),5.25-5.15(1H,m),4.06(1H,d,J=11.01Hz),2.31(3H,s),1.70(3H,d,J=6.88Hz)

2- (1-azidoethyl) -3-phenyl-1- (toluene-4-sulfonyl) -1H-indole

DIAD (1.80g,8.89mmol) was placed in a nitrogen atmosphere at 0 deg.CA solution in an alkane (5mL) was added to triphenylphosphine (2.33g,8.89mmol) in bisIn an alkane (20 mL). Stirring for 10min, adding1- [ 3-phenyl-1- (toluene-4-sulfonyl) -1H-indol-2-yl in an alkane (15mL)]Ethanol (1.74g,4.44mmol) was then added to the reaction mixtureDiphenyl phosphorazidate (1.47g,5.53mmol) in an alkane (5 mL). The reaction mixture was stirred at 20 ℃ for 16h, then diluted with DCM and purified by column chromatography (Si-PCC gradient elution with 10-100% DCM in pentane) to give the title compound as a gum (1.39g, 75%). LCMS (method C) R _T4.77min[M-N₃]⁺374.1.

1- [ 3-phenyl-1- (toluene-4-sulfonyl) -1H-indol-2-yl ] ethylamine

A mixture of 2- (1-azidoethyl) -3-phenyl-1- (toluene-4-sulfonyl) -1H-indole (1.34g,3.22mmol) and 10% Pd/C (200mg) in EtOAc (80mL) was degassed with a stream of nitrogen and stirred at RT for 20H under a hydrogen atmosphere. The suspension was filtered and the filtrate was concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient eluted with 0-10% MeOH in DCM) to give the title compound as a white solid (960mg, 76%).¹H NMR(CDCl₃,400MHz):δ8.18(1H,d,J=8.44Hz),7.73(2H,d,J=8.44Hz),7.49-7.15(10H,m),4.72(1H,q,J=6.96Hz),2.35(3H,s),1.45(3H,d,J=7.40Hz)。

1- [ 3-phenyl-1- (toluene-4-sulfonyl) -1H-indol-2-yl ] ethyl } - (9H-purin-6-yl) amine

1- [ 3-phenyl-1- (toluene-4-sulfonyl) -1H-indol-2-yl]A mixture of ethylamine (294mg,0.75mmol), 6-chloro-9H-purine (140mg,0.90mmol) and DIPEA (0.20mL,1.13mmol) in n-butanol (1.5mL) was stirred in a sealed tube at 120 ℃ for 56H. After cooling to RT, the crude reaction mixture is loadedSCX-2 column, then MeOH washing and 2M NH₃The product eluted with MeOH. The product containing fractions were combined and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC with 0-7%2M NH)₃Gradient MeOH in DCM) to give the title compound as a yellow solid (350mg, 91%). LCMS (method C) R _T3.31min[M+H]⁺509.1。

2-bromomethyl-3-phenyl-1- (toluene-4-sulfonyl) -1H-indole

To a solution of [ 3-phenyl-1- (toluene-4-sulfonyl) -1H-indol-2-yl under an atmosphere of RT, nitrogen]To a solution of methanol (1.31g,3.47mmol) and triphenylphosphine (1.09g,4.16mmol) in DCM (30mL) was added NBS (240mg,4.16mmol) and stirring was continued for 2 h. Volatiles were removed under reduced pressure and the resulting residue was purified by column chromatography (Si-PCC, gradient eluted with 30-100% DCM in pentane) to give the title compound as a gum (440mg, 29%).¹H NMR(CDCl₃,400MHz):δ8.16(1H,dt,J=8.48,0.84Hz),7.92-7.88(2H,m),7.60-7.49(4H,m),7.48-7.37(3H,m),7.28-7.22(3H,m),5.05(2H,s),2.38(3H,s)

9- [ 3-phenyl-1- (toluene-4-sulfonyl) -1H-indol-2-ylmethyl ] -9H-purin-6-ylamine

To a stirred mixture of 9H-purin-6-ylamine (130mg,0.98mmol) in DMF (5mL) under an argon atmosphere was added NaH (60% in mineral oil, 40mg,0.98 mmol). After stirring at RT for 10min, 2-bromomethyl-3-phenyl-1- (toluene-4-sulfonyl) -1H-indole (430mg,0.98mmol) in DMF (10mL) was added and stirring continued for 15 min. Loading the crude reaction mixture intoSCX-2 column, then MeOH, 2M NH₃The product eluted with MeOH. The product containing fractions were combined and concentrated under reduced pressure. The resulting residue was purified by column chromatography (Si-PCC, gradient eluted with 0-10% MeOH in DCM) to give the title compound as a white solid (370mg, 77%). LCMS (method C) R _T3.16min[M+H]⁺495.1。

1- (3-phenylbenzo [ b ] thiophen-2-yl) ethanol

To 3-phenylbenzo [ b ] at-78 ℃ under a nitrogen atmosphere]Thiophene-2-carbaldehyde (430mg,1.87mmol) in THF (10mL) was added 3.0M methyl magnesium bromide in ether (1.24mL) and stirring was continued for 30 min. Reacting the mixture with NH₄A saturated solution of Cl (20mL) was quenched and slowly warmed to RT. The mixture was extracted with EtOAc (× 2), the combined organic fractions were washed with water and dried (Na)₂SO₄) And concentrated in vacuo to give the title compound as a white solid (472mg, quantitative yield).¹H NMR(CDCl₃,400MHz):δ7.88-7.84(1H,m),7.52-7.28(8H,m),5.21(1H,q,J=6.35Hz),2.03(1H,s),1.59(3H,d,J=6.63Hz)

2- (1-azidoethyl) -3-phenylbenzo [ b ] thiophene

DIAD (556mg,2.75mmol) was added to triphenylphosphine (722mg,2.75mmol) in bis at 0 ℃ under a nitrogen atmosphereIn an alkane (5 mL). After 10min, 1- (3-phenylbenzo [ b ] was added]Thien-2-yl) ethanol (350mg,1.37mmol), followed by diphenyl phosphorazidate (454mg,1.65mmol) was added. The reaction mixture was stirred at 20 ℃ for 16h and then concentrated in vacuo. The crude reaction mixture was purified by column chromatography (Si-PCC, gradient eluted with 0-20% DCM in cyclohexane) to give the title compound as a colourless oil (211mg, 55%).¹H NMR(CDCl₃,400MHz):δ7.88(1H,d,J=7.87Hz),7.54-7.42(4H,m),7.417.29(4H,m),4.97(1H,q,J=6.80Hz),1.58(3H,d,J=6.80Hz)。

1- (3-phenylbenzo [ b ] thiophen-2-yl) ethylamine

Reacting 2- (1-azidoethyl) -3-phenylbenzo [ b ] ]Thiophene (211mg,0.76mmol) was dissolved in a mixture of THF (4mL) and water (0.27mL) and triphenylphosphine (237mg,0.91mmol) was added. The mixture was stirred at RT for 1h, then additional triphenylphosphine (237mg) was added. The reaction mixture was stirred at RT for 1h and then loadedSCX-2 column, washing with MeOH, 2M NH₃The product eluted with MeOH. The product containing fractions were combined and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient eluted with 0-8% MeOH in DCM) to give the title compound as a white solid (160mg, 83%).¹H NMR(CDCl₃,400MHz):δ7.84(1H,dd,J=7.63,1.55Hz),7.52-7.27(8H,m),4.56-4.44(1H,br),1.76(2H,s),1.47(3H,d,J=6.21Hz)。

1- (3-phenylbenzofuran-2-yl) ethanol

Tetrabutylammonium borohydride (750mg,2.91mmol) was added to a solution of 1- (3-phenylbenzofuran-2-yl) ethanone (459mg,1.94mmol) in THF (9mL) and IMS (1mL) and the mixture was stirred at RT for 1 h. The reaction mixture was quenched by addition of MeOH and volatiles were removed under vacuum. The resulting residue was purified by column chromatography (Si-PCC gradient eluted with 0-40% EtOAc in cyclohexane) to afford the title compound as an oil (452mg, 98%). LCMS (method C) R_T3.57min[M-OH]⁺221.1

2- (1-azidoethyl) -3-phenylbenzofuran

DBU (155. mu.L, 1.04mmol) was added dropwise to a solution of 1- (3-phenylbenzofuran-2-yl) ethanol (206mg,0.86mmol) and diphenyl phosphorazidate (255. mu.L, 1.04mmol) in anhydrous THF (7mL) at 0 ℃ under a nitrogen atmosphere. After 30min at 0 ℃, the mixture was slowly warmed to RT and stirring was continued for 1.5 h. Additional diphenyl phosphorazidate (255. mu.L, 1.04mmol) and DBU (155. mu.L, 1.04mmol) were added and stirring continued for 18 h. The volatiles were removed in vacuo and the resulting residue was purified by column chromatography (Si-PCC gradient eluted with 0-30% EtOAc in cyclohexane) to give the title compound as an oil (186mg, 82%). LCMS (method C) R _T4.48min[M+H-N₂]⁺236.1

1- (3-phenylbenzofuran-2-yl) ethylamine

Triphenylphosphine (231mg,0.88mmol) was added to a solution of 2- (1-azidoethyl) -3-phenylbenzofuran (186mg,0.71mmol) in THF (9mL) and water (1 mL). The mixture was heated at 60 ℃ for 2h and then cooled to RT. The volatiles were removed in vacuo and the resulting residue was purified by column chromatography (Si-PCC, gradient elution with 0-10% MeOH in EtOAc) to give the title compound as an oil (327mg, quantitative yield). LCMS (method C) R_T2.21min[M-NH₂]⁺221.1

Methanesulfonic acid 3-phenylbenzofuran-2-ylmethyl ester

Methanesulfonyl chloride (160uL,2.05mmol) was added dropwise to (3-phenylbenzofuran-2-yl) methanol (367mg,1.64mmol) and DIPEA (343. mu.L, 1.97mmol) in anhydrous DCM (10mL) at 0 deg.CIn the solution of (1). Stirring was continued at 0 ℃ for 15min, then the mixture was slowly warmed to RT. After 2h at RT, additional methanesulfonyl chloride (80uL,1.03mmol) and DIPEA (172. mu.L, 0.99mmol) were added and stirring continued for 1.5 h. The reaction mixture was diluted with DCM and the organic fraction was washed with water and dried (Na)₂SO₄) And concentrated in vacuo to give the title compound as an oil (443mg, 89%).¹H NMR(DMSO-d₆,400MHz):δ7.71-7.64(2H,m),7.62-7.56(4H,m),7.52-7.41(2H,m),7.37-7.32(1H,m),4.98(2H,s),3.89(3H,s)

Methanesulfonic acid 3-phenylbenzo [ b ] thiophen-2-ylmethyl ester

Methanesulfonyl chloride (127. mu.L, 1.63mmol) was added dropwise to (3-phenylbenzo [ b ] at 0 deg.C ]Thien-2-yl) methanol (356mg,1.48mmol) and DIPEA (322. mu.L, 1.85mmol) in dry DCM (10 mL). Stirring was continued at 0 ℃ for 15min, then the mixture was slowly warmed to RT. After 2.5h at RT, additional methanesulfonyl chloride (1 drop) was added and stirring was continued for 1 h. The reaction mixture was diluted with DCM and the organic fraction was washed with water and dried (Na)₂SO₄) And concentrated in vacuo to give the title compound as a yellow oil (408mg, 87%).¹H NMR(DMSO-d₆,400MHz):δ8.07-8.02(1H,m),7.62-7.56(2H,m),7.55-7.37(6H,m),4.96(2H,s),3.33(3H,s)

2-azidomethyl-3-phenylbenzo [ b ] thiophenes

Sodium azide (179mg,2.76mmol) was added to methanesulfonic acid 3-phenylbenzo [ b ]]Thien-2-ylmethyl ester (828mg,1.84mmol) in DMF (10mL) and the mixture was stirred at RT for 18 h. The reaction mixture was diluted with water and washed with waterAnd (4) extracting the EtOAc. The organic fraction was washed with brine and dried (Na)₂SO₄) And concentrated in vacuo, and the resulting residue was purified by column chromatography (Si-PCC, gradient elution of 0-35% DCM in cyclohexane) to give the title compound as a clear oil (244mg, 50%). LCMS (method C) R_T4.46min[M+H-N₂]⁺237.8

(3-phenylbenzo [ b ] thiophen-2-yl) methylamines

Under a nitrogen atmosphere, reacting 2-azidomethyl-3-phenylbenzo [ b ]]A solution of thiophene (244mg,0.92mmol) in THF (10mL) was treated with a solution of triphenylphosphine (302mg,1.15mmol) in water (1 mL). The mixture was heated at 60 ℃ for 2h and then cooled to RT. Volatile materials were removed under vacuum and the resulting residue was loaded onto SCX-2 column, then MeOH, 2M NH₃The product eluted with MeOH. The product containing fractions were combined and concentrated in vacuo to give the title compound (288mg, quantitative yield). LCMS (method C) R_T2.15min[M-N₃]⁺223.0。

3-o-tolylbenzo [ b ] thiophene-2-carbaldehyde

Reacting 3-bromobenzo [ b]Thiophene-2-carbaldehyde (500mg,2.07mmol), 2-methylphenylboronic acid (394mg,2.90mmol), Pd (PPh)₃)₄(243mg,0.21mmol)、Cs₂CO₃A mixture (2.02g,6.21mmol) in dioxane (12mL) and water (4mL) was degassed with a stream of nitrogen and then heated with microwave radiation in a sealed test tube at 130 ℃ for 45 min. Mixing the reactionThe mixture was extracted with EtOAc, the organic fraction was washed with water and then brine, dried (Na)₂SO₄) And concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient eluted with 0-70% DCM in cyclohexane) to give the title compound (quantitative yield). LCMS (method C) R_T4.16min

(3-o-tolylbenzo [ b ] thiophen-2-yl) methanol

Tetrabutylammonium borohydride (800mg,3.10mmol) was added to 3-o-tolylbenzo [ b ] at RT]Thiophene-2-carbaldehyde (2.07mmol) in THF (10mL) and IMS (1mL) and the mixture was stirred at RT for 1 h. The reaction mixture was quenched by addition of MeOH and the volatiles were removed under reduced pressure. The resulting residue was purified by column chromatography (Si-PCC gradient eluted with 0-30% EtOAc in cyclohexane) to afford the title compound as an oil (432mg, 82% over 2 steps). LCMS (method C) R _T3.74min[M-OH]⁺237.1。

Methanesulfonic acid 3-o-tolylbenzo [ b ] thiophen-2-ylmethyl ester

Methanesulfonyl chloride (158. mu.L, 2.04mmol) was added dropwise to (3-o-tolylbenzo [ b ] at RT]Thien-2-yl) methanol (432mg,1.70mmol) and DIPEA (385. mu.L, 2.21mmol) in dry DCM (10 mL). Stirring was continued for 18h at RT, then the reaction mixture was washed with water and dried (Na)₂SO₄) And concentrated in vacuo to give the title compound as a brown oil (424mg, 75%).¹H NMR(DMSO-d₆,400MHz):δ8.05(1H,d,J=8.04Hz),7.45-7.40(3H,m),7.38-7.32(2H,m),7.21(1H,d,J=7.40Hz),7.12(1H,d,J=7.98Hz),4.82(1H,d,J=12.41Hz),4.76(1H,d,J=12.41Hz),3.32(3H,s),1.99(3H,s)

(3-Nitropyridin-2-yl) -o-tolylamine

Under a nitrogen atmosphere, 2-chloro-3-nitropyridine (4.13g,26.1mmol), o-tolylamine (3.4mL,31.3mmol) and Et₃A mixture of N (4.4mL,31.3mmol) in DMF (10mL) was stirred at 90 ℃ for 1 h. Additional o-tolylamine (2mL,18.2mmol) was added and stirring continued for 16 h. The mixture was partitioned between DCM and water. The aqueous phase was further extracted with DCM (× 3), the combined organic fractions were washed with brine and dried (Na)₂SO₄) And concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient eluted with 20-100% DCM in cyclohexane) to give the title compound as an orange solid (3.96g, 66%). LCMS (method C) R_T3.60min[M+H]⁺230.3

N²-o-tolylpyridine-2, 3-diamine

A mixture of (3-nitropyridin-2-yl) -o-tolylamine (3.96g,17.3mmol) in EtOAc (200mL) was degassed with a stream of nitrogen, then 10% Pd/C (700mg) was added and stirred at RT for 16h under a hydrogen atmosphere. The suspension was filtered and the filtrate was concentrated in vacuo to give the title compound as a white solid (2.02g, 59%). ¹H NMR(CDCl₃,400MHz):δ7.83(1H,d,J=4.94Hz),7.28-7.11(3H,m),7.01(1H,d,J=7.64Hz),6.93(1H,t,J=7.41Hz),6.79(1H,dd,J=7.63,4.96Hz),5.97(1H,s),3.43(2H,s),2.30(3H,s)。

[ (S) -1- (2-o-tolylaminopyridin-3-ylcarbamoyl) ethyl ] carbamic acid tert-butyl ester

Triethylamine (1.05mL,7.53mmol) was added to N at 0 deg.C under a nitrogen atmosphere²-o-tolylpyridine-2, 3-diamine (500mg,2.51mmol), (S) -2-tert-butoxycarbonylaminopropionic acid (520mg,2.76mmol), HOAt (380mg,2.76mmol), and N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride (530mg,2.76mmol) in a mixture of anhydrous DCM (20 mL). The reaction mixture was stirred at 0 ℃ for 10min and then slowly warmed to RT. Stirring was continued at RT for 16 h. The resulting mixture was partitioned between DCM and saturated NaHCO₃The aqueous solution was partitioned. The aqueous phase was further extracted with DCM and the combined organic fractions were washed with water and dried (Na)₂SO₄) And concentrated in vacuo to give the title compound. The crude material was used in the next step without further purification. The yield was considered quantitative. LCMS (method J) R_T2.19min[M+H]⁺371.1。

(S) -1- (3-o-tolyl-3H-imidazo [4,5-b ] pyridin-2-yl) ethylamine

Reacting [ (S) -1- (2-o-tolylaminopyridin-3-ylcarbamoyl) ethyl]A solution of tert-butyl carbamate (2.51mmol) in AcOH (20mL) was heated at 70 ℃ for 6 h. After cooling to RT, the volatiles were removed under reduced pressure and the residue was taken up in DCM and saturated NaHCO ₃The aqueous solution was partitioned. The aqueous phase was extracted with DCM and the combined organic fractions were washed with water and dried (Na)₂SO₄) And concentrated in vacuo to give [ (S) -1- (3-o-tolyl-3H-imidazo [4,5-b ]]Pyridin-2-yl) ethyl]Tert-butyl carbamate as brown oil (quantitative yield). To a solution of the compound thus obtained (2.51mmol) in DCM (25mL) was added TFA (10mL), and the mixture was mixedThe material was stirred at RT for 15 min. Volatiles were removed under vacuum, the resulting residue was dissolved in DCM and saturated NaHCO₃Aqueous (40mL) wash. The aqueous phase was further extracted with DCM (× 3) and the combined organic fractions were dried (Na)₂SO₄) And concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC with 0-8%2M NH)₃Gradient MeOH in DCM) to give the title compound as an oil (340mg, 54% over 3 steps). 1H NMR (CDCl)₃400MHz) delta 8.33(1H, d, J =4.83Hz),8.09(1H, d, J =8.00Hz),7.52-7.37(3H, m),7.33-7.21(2H, m),4.08(0.5H, q, J =6.75Hz),3.99(0.5H, q, J =6.72Hz),2.02(3H, s),1.50(1.5H, d, J =6.75Hz),1.41(1.5H, d, J =6.75 Hz). The signal is cleaved due to the presence of rotamers/tautomers.

[ (S) -1- (2-Phenylaminopyridin-3-ylcarbamoyl) propyl ] carbamic acid tert-butyl ester

Triethylamine (1.8mL,13.0mmol) was added to N at 0 deg.C under a nitrogen atmosphere²-phenylpyridine-2, 3-diamine (800mg,4.32mmol), (S) -2-tert-butoxycarbonylaminobutyric acid (960mg,4.75mmol), HOAt (650mg,4.75mmol) and N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride (910mg,4.75mmol) in a mixture of anhydrous DCM (25 mL). The reaction mixture was stirred at 0 ℃ for 10min and then slowly warmed to RT. Stirring was continued at RT for 16 h. After re-cooling to 0 deg.C, additional (S) -2-tert-butoxycarbonylaminobutyric acid (610mg), N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride (580mg), HOAt (410mg) and triethylamine (1.0mL) were added and stirring continued at RT for 1 h. The reaction mixture was then washed with DCM and saturated NaHCO₃The aqueous solution was partitioned. The aqueous phase was further extracted with DCM (× 3), the combined organic fractions were washed with water and dried (Na)₂SO₄) And concentrated in vacuo to give the title compound as a dark oil. The crude material was used without further purificationIn the subsequent steps. The yield was considered quantitative. LCMS (method J) R_T2.67min[M+H]⁺371.2。

[ (S) -1- (3-phenyl-3H-imidazo [4,5-b ] pyridin-2-yl) propyl ] carbamic acid tert-butyl ester

Reacting [ (S) -1- (2-phenylaminopyridin-3-ylcarbamoyl) propyl]A solution of tert-butyl carbamate (4.32mmol) in AcOH (30mL) was heated at 70 ℃ for 3 h. After cooling to RT, the volatiles were removed under reduced pressure and the residue was taken up in DCM and saturated NaHCO₃The aqueous solution was partitioned. The aqueous phase was extracted with DCM (× 3), the combined organic fractions were washed with water and dried (Na)₂SO₄) And concentrated in vacuo to give the title compound as an oil (1.27g, crude material). LCMS (method C) R_T3.24min[M+H]⁺353.4。

(S) -1- (3-phenyl-3H-imidazo [4,5-b ] pyridin-2-yl) propylamine

To [ (S) -1- (3-phenyl-3H-imidazo [4,5-b ]]Pyridin-2-yl) propyl]To a solution of tert-butyl carbamate (1.27g,3.60mmol) in DCM (25mL) was added TFA (10mL) and the mixture was stirred at RT for 15 min. Volatiles were removed under vacuum, the resulting residue was dissolved in DCM and saturated NaHCO₃And (4) washing the solution. The aqueous phase was extracted with DCM (× 3) and the combined organic fractions were dried (Na)₂SO₄) And concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC with 0-8%2M NH)₃Gradient MeOH in DCM) to give the title compound as a brown oil (440mg, 40% over 3 steps).¹H NMR(CDCl₃,400MHz):δ8.34(1H,d,J=4.82Hz),8.08(1H,d,J=8.00Hz),7.67-7.52(3H,m),7.45(2H,d,J=7.60Hz),7.30-7.22(1H,m),3.99(1H,t,J=6.70Hz),2.02-1.87(1H,m),1.83-1.69(3H,m),0.89(3H,t,J=7.40Hz)。

[ (S) -1- (6-fluoro-1-phenyl-1H-benzimidazol-2-yl) propyl ] carbamic acid tert-butyl ester

Reacting 4-fluoro-N²A mixture of-phenyl-benzene-1, 2-diamine (199mg,0.98mmol), (S) -2-tert-butoxycarbonylaminobutyric acid (219mg,1.08mmol), HOAt (147mg,1.08mmol), 4-methylmorpholine (0.238mL,2.16mmol) and N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride (207mg,1.08mmol) in DCM (5mL) was stirred at RT for 2 h. The reaction mixture was washed with DCM (50mL) and saturated NaHCO₃The solutions were partitioned. The organic layer was dried (Na)₂SO₄) Concentrated in vacuo, the resulting residue was dissolved in AcOH (10mL) and stirred at 70 ℃ for 18 h. After cooling to RT, the volatiles were evaporated under reduced pressure and the residue was taken up in DCM (50mL) and saturated NaHCO₃The aqueous solution was partitioned. The organic layer was washed with brine and dried (Na)₂SO₄) And then concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC gradient eluted with 0-50% EtOAc in cyclohexane) to give the title compound as a beige solid (234mg, 64%). LCMS (method C) R_T3.82min[M+H]⁺370.5。

(S) -1- (6-fluoro-1-phenyl-1H-benzimidazol-2-yl) propylamine

To [ (S) -1- (6-fluoro-1-phenyl-1H-benzimidazol-2-yl) propyl]To a solution of tert-butyl carbamate (234mg,0.63mmol) in DCM (3mL) was added TFA (1.5mL) and the mixture was taken up in RStirring for 2h under T. Volatiles were removed under vacuum and the resulting residue was taken up in DCM (20mL) and saturated NaHCO ₃The aqueous solution was partitioned. The two-phase system was stirred for 10min, then the organic fraction was dried (MgSO₄) And concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient eluted with 0-10% MeOH in DCM) to give the title compound as a colorless oil (42mg, 25%). LCMS (method B) R_T1.90min[M-NH₂]⁺253.0。

[ (S) -1- (5-fluoro-2-phenylaminophenylcarbamoyl) ethyl ] carbamic acid tert-butyl ester

Reacting 4-fluoro-N¹A mixture of-phenylbenzene-1, 2-diamine (866mg,4.3mmol), (S) -2-tert-butoxycarbonylaminopropionic acid (890mg,4.7mmol), HOAt (640mg,4.7mmol), 4-methylmorpholine (1.0mL,9.5mmol) and N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride (900mg,4.7mmol) in DCM (20mL) was stirred at RT for 2 h. The reaction mixture was washed with DCM and saturated NaHCO₃The aqueous solution was partitioned. The organic fraction was washed with brine and dried (MgSO)₄) And concentrated in vacuo to give the title compound as a yellow-orange solid (quantitative yield). The crude product was used in the next step without further purification. LCMS (method B) R_T3.83min[M+H]⁺374.1。

[ (S) -1- (5-fluoro-1-phenyl-1H-benzimidazol-2-yl) ethyl ] carbamic acid tert-butyl ester

Reacting [ (S) -1- (5-fluoro-2-phenylaminophenylcarbamoyl) ethyl ]A solution of tert-butyl carbamate (2.15mmol) in AcOH (10mL) was stirred at 70 ℃ for 18 h. After cooling to RTThe volatiles were evaporated in vacuo and the residue was taken up in EtOAc and saturated NaHCO₃The aqueous solution was partitioned. The organic fraction was washed with brine and dried (MgSO)₄) And concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient eluted with 0-40% EtOAc in cyclohexane) to give the title compound as an orange oil (661mg, 86% over two steps). LCMS (method J) R_T3.52min[M+H]⁺356.1。

(S) -1- (5-fluoro-1-phenyl-1H-benzimidazol-2-yl) ethylamine

To [ (S) -1- (5-fluoro-1-phenyl-1H-benzimidazol-2-yl) ethyl]To a solution of tert-butyl carbamate (661mg,1.9mmol) in DCM (9mL) was added TFA (4.5mL) and the mixture was stirred at RT for 2 h. Volatiles were removed under vacuum and the resulting residue was taken up in DCM (20mL) and saturated NaHCO₃The aqueous solution (40mL) was partitioned. The two-phase system was stirred for 10min, then the organic fraction was dried (MgSO₄) And concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient eluted with 0-10% MeOH in DCM) to give the title compound as a yellow oil (379mg, 78%). LCMS (method J) R_T1.77min[M+H]⁺256.2。

3- (2-aminophenylamino) benzonitrile

A mixture of 1-fluoro-2-nitrobenzene (2.00g,14.2mmol), 3-aminobenzonitrile (3.35g,28.3mmol) and potassium carbonate (5.88g,42.5mmol) in DMF (30mL) was stirred at 135 ℃ under a nitrogen atmosphere for 16 h. After cooling to RT, the reaction mixture was partitioned between DCM and water. The aqueous phase was extracted with DCM (× 3) and the combined organic fractions were dried (Na)₂SO₄) And concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient eluted with 25-100% DCM in cyclohexane) then loaded onto a SCX-2 column and washed with DCM to afford 3- (2-nitrophenylamino) benzonitrile as a bright orange foam (2.02g, 60%).

To a mixture of 3- (2-nitrophenylamino) benzonitrile (2.0g,8.40mmol) in a 3:1 mixture of MeOH: water (120mL) was added NH₄Cl (2.70g,0.05mol) and iron powder (1.88g,0.03mol), the reaction mixture was heated at reflux temperature for 1 h. After cooling to RT, the solid was usedThe pad was filtered off and washed with additional MeOH. The filtrate was concentrated in vacuo and the resulting residue partitioned between DCM and water. The aqueous phase was further extracted with DCM (× 3), the combined organic fractions were washed with brine and dried (Na)₂SO₄) And concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient eluted with 0-2% MeOH in DCM) to give the title compound as a yellow solid (185mg, 11%). LCMS (method J) R _T2.99min[M+H]⁺210.0。

{ (S) -1- [2- (3-cyanophenylamino) phenylcarbamoyl ] ethyl } carbamic acid tert-butyl ester

Triethylamine (0.35mL,2.59mmol) was added to a mixture of 3- (2-aminophenylamino) benzonitrile (177mg,0.85mmol), (S) -2-tert-butoxycarbonylaminopropionic acid (190mg,1.02mmol), HOAt (140mg,1.02mmol) and N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride (190mg,1.02mmol) in anhydrous DCM (10mL) at 0 deg.C under a nitrogen atmosphere. The reaction mixture was stirred at 0 ℃ for 10min and then slowly warmed to RT. Stirring was continued at RT for 16 h. The reaction mixture was then washed with DCM and saturated NaHCO₃The aqueous solution was partitioned. The aqueous phase is further treated with DCM extraction (. times.3), combined organic fractions were washed with water and dried (Na)₂SO₄) And concentrated in vacuo. The residue was purified by column chromatography (Si-PCC with 0-2%2 MNH)₃Gradient MeOH in DCM) to give the title compound as a yellow oil (290mg, 90%). The material was still impure and was used in the next step without further purification. LCMS (method J) R_T3.54min[M+H]⁺380.8

{ (S) -1- [1- (3-cyanophenyl) -1H-benzimidazol-2-yl ] ethyl } carbamic acid tert-butyl ester

Reacting { (S) -1- [2- (3-cyanophenylamino) phenylcarbamoyl ]A solution of tert-butyl ethyl carbamate (289mg,0.75mmol) in AcOH (3mL) was heated at 80 ℃ for 16 h. After cooling to RT, the volatiles were removed in vacuo, the residue was dissolved in DCM and washed with saturated NaHCO₃And (4) washing with an aqueous solution. The aqueous phase was further extracted with DCM (× 3) and the combined organic fractions were dried (Na)₂SO₄) And concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC with 0-2%2M NH)₃Gradient MeOH in DCM) to give the title compound (232mg, 86%). The material was still impure and was used in the next step without further purification. LCMS (method C) R_T3.54min[M+H]⁺363.4

3- [2- ((S) -1-aminoethyl) benzimidazol-1-yl ] benzonitrile

To { (S) -1- [1- (3-cyanophenyl) -1H-benzimidazol-2-yl]Ethyl } carbamic acid tert-butyl ester (200mg,0.55mmol) in DCM (2mL) was added TFA (5mL) and the mixture was stirred at RT for 15 min. In trueVolatiles were removed under air and the resulting residue was dissolved in DCM and saturated NaHCO₃And (4) washing with an aqueous solution. The aqueous phase was further extracted with DCM (× 3) and the combined organic fractions were dried (Na)₂SO₄) And concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC with 0-7%2M NH)₃Gradient MeOH in DCM) to give the title compound (58mg, 40%). ¹H NMR(CDCl₃,400MHz):δ7.93-7.66(6H,m),7.39-7.21(3H,m),7.08(1H,d,J=7.94Hz),4.16-4.05(1H,m),1.51(3H,d,J=7.36Hz)

(5-chloro-2-nitrophenyl) phenylamine

A mixture of 4-chloro-2-fluoro-1-nitrobenzene (983mg,5.60mmol) and aniline (1.0mL,11.20mmol) in DMSO (3mL) was heated at 110 ℃ for 4 h. After cooling to RT, the reaction mixture was partitioned between EtOAc and water. Subjecting the organic layer to KHSO₄Is washed with brine and then dried (Na)₂SO₄) And concentrated in vacuo to give the title compound as an orange solid (1.37g, 98%).¹H NMR(CDCl₃,400MHz):δ9.54(1H,s),8.16(1H,d,J=9.13Hz),7.46(2H,t,J=7.61Hz),7.32-7.22(3H,m),7.14(1H,d,J=2.14Hz),6.72(1H,dd,J=9.12,2.15Hz)

4-chloro-N²-phenyl-1, 2-diamines

To a mixture of (5-chloro-2-nitrophenyl) phenylamine (1.36g,5.47mmol) in a 3:1 mixture of MeOH: water (120mL) was added NH₄Cl (1.76g,32.81mmol) and iron powder (1.22g,21.88mmol) and the reaction mixture was heated at 90 ℃ for 2 h. After cooling to RT, the solid was usedThe pad was filtered off and washed with additional MeOH. The filtrate was concentrated in vacuo and the resulting residue partitioned between EtOAc and water. The aqueous phase was further extracted with EtOAc and the combined organic fractions were washed with brine and dried (Na)₂SO₄) And concentrated in vacuo. The resulting residue was purified by column chromatography (gradient elution of Si-PCC,0-100% DCM in cyclohexane) to give the title compound as a brown oil (980mg, 82%). LCMS (method C) R_T3.57min[M+H]⁺219.0

[ (S) -1- (6-chloro-1-phenyl-1H-benzimidazol-2-yl) ethyl ] carbamic acid tert-butyl ester

Reacting 4-chloro-N²A mixture of-phenyl-benzene-1, 2-diamine (975mg,4.46mmol), (S) -2-tert-butoxycarbonylaminopropionic acid (928mg,4.90mmol), HOAt (668mg,4.90mmol), 4-methylmorpholine (1.08mL,9.81mmol) and N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride (940mg,4.90mmol) in DCM (30mL) was stirred at RT for 19 h. The reaction mixture was washed with DCM and saturated NaHCO₃The aqueous solution was partitioned. The organic layer was washed with brine, dried and concentrated in vacuo to give [ (S) -1- (4-chloro-2-phenylaminophenylcarbamoyl) ethyl]Tert-butyl carbamate as a purple solid (quantitative yield). A solution of the compound thus obtained (4.46mmol) in AcOH (30mL) was heated at 70 ℃ for 22 h. After cooling to RT, the volatiles were removed in vacuo and the resulting residue was taken up in EtOAc and saturated NaHCO₃The aqueous solution was partitioned. The organic layer was washed with water, then brine, then dried (Na)₂SO₄) And concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient elution with 0-30% EtOAc in DCM) to give the title compound as a yellow solid (1.20g, 72% yield over two steps). LCMS (method C) R_T3.82min[M+H]⁺372.3

(S) -1- (6-chloro-1-phenyl-1H-benzimidazol-2-yl) ethylamine

To [ (S) -1- (6-chloro-1-phenyl-1H-benzimidazol-2-yl) ethyl]To a solution of tert-butyl carbamate (1.20g,3.23mmol) in DCM (5mL) was added TFA (5mL) and the mixture was stirred at RT for 3 h. Loading the crude mixture intoSCX-2 column, then MeOH, then 2M NH₃Washing with MeOH. The basic fractions were combined and concentrated in vacuo to give (S) -1- (6-chloro-1-phenyl-1H-benzimidazol-2-yl) ethylamine as a yellow oil (796mg, 91%).

LCMS (method C) R_T2.35min[M+H]⁺272.2

(5-fluoro-2-nitrophenyl) pyridin-3-ylamine

LiHMDS (1.0M in THF, 12.6mL,12.6mmol) was added dropwise to a stirred solution of pyridin-3-ylamine (621mg,6.60mmol) in anhydrous THF (10mL) at-78 deg.C under a nitrogen atmosphere. After stirring at-78 ℃ for 45min, a solution of 2, 4-difluoro-1-nitrobenzene (690. mu.L, 6.29mmol) in THF (10mL) was added and stirring continued for 1 h. Pour solution into NH₄Aqueous Cl (100mL) and extracted with EtOAc (. times.3). The combined organic fractions were washed with water and then brine and dried (Na)₂SO₄) And concentrated in vacuo. The resulting residue was triturated with EtOAc to give the title compound as a dark orange solid (638 mg). The mother liquor was concentrated under reduced pressure to give the title compound as a dark orange solid (648mg, Yield of the combined batch was 87%).¹H NMR(CDCl₃,400MHz):δ9.60(1H,br s),8.63(1H,s),8.56(1H,d,J=4.76Hz),8.35-8.27(1H,m),7.65(1H,d,J=8.20Hz),7.45-7.38(1H,m),6.75(1H,d,J=11.14Hz),6.57(1H,t,J=8.24Hz)

4-fluoro-N²-pyridin-3-ylphenyl-1, 2-diamine

A mixture of (5-fluoro-2-nitrophenyl) pyridin-3-ylamine (1.28g,5.49mmol) in EtOAc (60mL) was degassed with a stream of nitrogen, then 10% Pd/C (107mg) was added and stirred at RT for 2h under a hydrogen atmosphere. The resulting suspension was diluted with IMS (10mL) and stirred under an atmosphere of hydrogen for 56 h. The reaction mixture was filtered through a phase separator and the filtrate was concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient eluted with 0-20% MeOH in DCM) to give the title compound as a brown solid (1.03g, 92%).¹H NMR(CDCl₃,400MHz):δ8.24(1H,d,J=2.67Hz),8.14(1H,d,J=4.50Hz),7.20-7.05(2H,m),6.86(1H,dd,J=9.62,2.63Hz),6.79-6.65(2H,m),5.42(1H,s),3.50(2H,s)

{ (S) -1- [ 4-fluoro-2- (pyridin-3-ylamino) phenylcarbamoyl ] ethyl } carbamic acid tert-butyl ester

Reacting 4-fluoro-N²A mixture of-pyridin-3-ylphenyl-1, 2-diamine (1.03g,5.07mmol), (S) -2-tert-butoxycarbonylaminopropionic acid (1.05g,5.58mmol), HOAt (759mg,5.58mmol), 4-methylmorpholine (1.23mL,11.15mmol) and N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride (1.07g,5.58mmol) in DCM (30mL) was stirred at RT for 2 h. The reaction mixture was then washed with DCM and saturated NaHCO₃The solutions were partitioned. Precipitation occurred in the organic fractionMaterial, which was filtered off to give the title compound as a pale yellow solid (503 mg). The filtrate was dried (MgSO ₄) And concentrated in vacuo, and the resulting residue triturated with DCM to give the second title compound as a yellow solid (765mg; 67% yield for the combined batches).

LCMS (method C) R_T2.06min[M+H]⁺375.3

N- [ (S) -1- (6-fluoro-1-pyridin-3-yl-1H-benzimidazol-2-yl) ethyl ] acetamide

Reacting { (S) -1- [ 4-fluoro-2- (pyridin-3-ylamino) phenylcarbamoyl]A solution of tert-butyl ethyl carbamate (47mg,0.126mmol) in AcOH (1mL) was heated at 100 ℃ for 28h in a sealed test tube. In a separate vial, { (S) -1- [ 4-fluoro-2- (pyridin-3-ylamino) phenylcarbamoyl]Tert-butyl ethyl } carbamate (228mg,0.61mmol) was dissolved in AcOH (2mL) and heated at 100 ℃ for 17 h. After cooling to RT, the two reaction mixtures were combined and the volatiles were removed under vacuum. The resulting residue was washed with EtOAc and saturated NaHCO₃The aqueous solution was partitioned. The organic fraction was washed with water and then brine, dried (Na)₂SO₄) And concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient eluted with 0-10% MeOH in DCM) to give the title compound as an orange oil (126mg, 57%). LCMS (method C) R_T2.16min[M+H]⁺299.3。¹H NMR(CDCl₃,400MHz):δ8.84(1H,dd,J=4.82,1.02Hz),8.75(1H,s),7.95(1H,s),7.72-7.57(2H,m),7.47(1H,s),7.07(1H,td,J=9.15,2.31Hz),6.80(1H,d,J=8.61Hz),5.21-5.09(1H,m),1.96(3H,s),1.50(3H,d,J=6.99Hz)

(S) -1- (6-fluoro-1-pyridin-3-yl-1H-benzimidazol-2-yl) ethylamine

Reacting N- [ (S) -1- (6-fluoro-1-pyridin-3-yl-1H-benzimidazol-2-yl) ethyl]A mixture of acetamide (126mg) and 6N HCl (2mL) was heated in a sealed vial at 100 ℃ for 1 h. After cooling to RT, the crude reaction mixture was taken up in EtOAc and saturated NaHCO₃The aqueous solution was partitioned. The organic fraction was washed with water and then brine, dried (Na)₂SO₄) And concentrated in vacuo to give 10mg of crude material as an orange oil. The aqueous phase was back-extracted with DCM (× 3), the combined organic fractions were washed with brine and dried (Na)₂SO₄) And concentrated in vacuo to give 71mg of crude material as a colorless oil. The crude products were combined to give the title compound as a light orange oil (81mg, 75%).¹HNMR(CDCl₃,400MHz):δ8.82(1H,d,J=5.43Hz),8.75(1H,s),7.83(1H,d,J=8.06Hz),7.73(1H,dd,J=8.85,4.75Hz),7.61-7.56(1H,m),7.06(1H,t,J=9.26Hz),6.77(1H,d,J=8.49Hz),4.14-4.04(1H,m),1.50(3H,d,J=6.65Hz)

[ (R) -1- (6-fluoro-1-phenyl-1H-benzimidazol-2-yl) -2-methoxyethyl ] carbamic acid tert-butyl ester

Reacting 4-fluoro-N²A mixture of-phenyl-benzene-1, 2-diamine (450mg,2.2mmol), (S) -2-tert-butoxycarbonylamino-3-methoxypropionic acid (525mg,2.4mmol), HOAt (330mg,2.4mmol), 4-methylmorpholine (0.53mL,4.8mmol) and N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride (460mg,2.4mmol) in DCM (10mL) was stirred at RT for 18 h. The reaction mixture was washed with DCM and saturated NaHCO₃The aqueous solution was partitioned. The organic phase was washed with brine and dried (MgSO) ₄) Concentrated in vacuo and the residue purified by column chromatography (Si-PCC gradient eluted with 0-30% EtOAc in cyclohexane) to give [ (S) -1- (4-fluoro-2-phenylaminophenylcarbamoyl) -2-carbaldehydeOxyethyl radical]Tert-butyl carbamate (0.655g, 74%). A solution of the compound thus obtained (0.655g) in AcOH (10mL) was heated at 70 ℃ for 56 h. After cooling to RT, the volatiles were removed in vacuo and the resulting residue was taken up in DCM and saturated NaHCO₃The aqueous solution was partitioned. The organic layer was washed with brine and dried (MgSO)₄) And concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC gradient eluted with 0-30% EtOAc in cyclohexane) to afford the title compound (227mg, 28%). LCMS (method J) R_T3.59 and 3.70min [ M + H ]]⁺386.2

(R) -1- (6-fluoro-1-phenyl-1H-benzimidazol-2-yl) -2-methoxyethylamine

To [ (R) -1- (6-fluoro-1-phenyl-1H-benzimidazol-2-yl) -2-methoxyethyl]Tert-butyl carbamate (0.227g,0.59mmol) in DCM (4.5mL) was added TFA (2.5mL) and the mixture was stirred at RT for 2 h. Volatiles were removed in vacuo and the resulting residue was taken up in DCM and saturated NaHCO₃The aqueous solution was partitioned. The two-phase system was stirred for 10min, then the organic fraction was dried (MgSO ₄) And concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient eluted with 0-10% MeOH in DCM) to give the title compound as a colorless oil (110mg, 65%). LCMS (method B) R_T1.90min[M+H]⁺286.0。

[ (1R,2R) -2-benzyloxy-1- (6-fluoro-1-phenyl-1H-benzimidazol-2-yl) propyl ] carbamic acid tert-butyl ester

Reacting 4-fluoro-N²-phenyl-1, 2-diamine (525mg,2.6mmol), (2S,3R) -3-benzyloxy-2-tert-butoxyA mixture of alkylcarbonylaminobutanoic acid (880mg,2.9mmol), HOAt (390mg,2.9mmol), 4-methylmorpholine (0.60mL,5.7mmol) and N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride (560mg,2.9mmol) in DCM (13mL) was stirred at RT for 18 h. The reaction mixture was washed with DCM and saturated NaHCO₃The aqueous solution was partitioned. The organic phase was washed with brine and dried (MgSO)₄) Concentrated in vacuo and the residue purified by column chromatography (Si-PCC, gradient eluted with 0-30% EtOAc in cyclohexane) to give [ (1S,2R) -2-benzyloxy-1- (4-fluoro-2-phenylaminophenylcarbamoyl) propyl]Carbamic acid tert-butyl ester (1.32 g). LCMS (method B) R_T4.32min[M+H]⁺494.3。

A solution of the compound thus obtained (1.32g) in AcOH (13mL) was heated at 70 ℃ for 18 h. After cooling to RT, the volatiles were removed in vacuo and the resulting residue was taken up in DCM and saturated NaHCO ₃The aqueous solution was partitioned. The organic fraction was washed with brine and dried (MgSO)₄) And concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient eluted with 0-30% EtOAc in cyclohexane) to give the title compound as a yellow solid (971mg,79%) which was still impure and used in the next step without further purification. LCMS (method J) R_T4.28min[M+H]⁺476.2。

(1R,2R) -2-benzyloxy-1- (6-fluoro-1-phenyl-1H-benzimidazol-2-yl) propylamine

To [ (1R,2R) -2-benzyloxy-1- (6-fluoro-1-phenyl-1H-benzimidazol-2-yl) propyl ] group]To a solution of tert-butyl carbamate (0.971g,2.0mmol) in DCM (15mL) was added TFA (8mL) and the mixture was stirred at RT for 2 h. Volatiles were removed in vacuo and the resulting residue was taken up in DCM and saturated NaHCO₃The aqueous solution was partitioned. The two-phase system was stirred for 10min, then the organic fraction was dried (MgSO₄) And concentrated in vacuo.The resulting residue was purified by column chromatography (Si-PCC, gradient eluted with 0-10% MeOH in DCM) to give the title compound (100mg, 13%). LCMS (method C) R_T2.59min[M+H]⁺376.4。

[ (1R,2R) -2-benzyloxy-1- (6-fluoro-1-phenyl-1H-benzimidazol-2-yl) propyl ] - (7H-purin-6-yl) amine

A mixture of (1R,2R) -2-benzyloxy-1- (6-fluoro-1-phenyl-1H-benzimidazol-2-yl) propylamine (100mg,0.27mmol), 6-chloro-9- (tetrahydropyran-2-yl) -9H-purine (65mg,0.27mmol) and DIPEA (240. mu.L, 1.35mmol) in n-butanol (1mL) was heated at 90 ℃ for 18H in a sealed vial. After cooling to RT, the volatiles were removed under vacuum and the resulting residue was loaded SCX-2 column, then MeOH, then 2MNH₃Washing with MeOH. The product containing fractions were combined and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC,0-10%2M NH)₃Gradient MeOH in DCM) to give the title compound (128mg, 96%). LCMS (method J) R_T3.19min[M+H]⁺494.1。

[ (R) -2-benzyloxy-1- (6-fluoro-1-phenyl-1H-benzimidazol-2-yl) ethyl ] carbamic acid tert-butyl ester

Reacting 4-fluoro-N²-phenyl-1, 2-diamine (550mg,2.7mmol), (S) -3-benzyloxy-2-tert-butoxycarbonylaminopropionic acid (880mg,3.0mmol), HOAt (410mg,3.0mmol), 4-methylmorpholine (0.65mL,5.9mmol) and N- (3-dimethylaminopropyl) -N' -ethylcarbodiimideA mixture of imine hydrochloride (580mg,3.0mmol) in DCM (13mL) was stirred at RT for 18 h. The reaction mixture was washed with DCM and saturated NaHCO₃The aqueous solution was partitioned. The organic fraction was washed with brine and dried (MgSO)₄) Concentrated in vacuo and the residue purified by column chromatography (Si-PCC gradient eluted with 0-30% EtOAc in cyclohexane) to give [ (S) -2-benzyloxy-1- (4-fluoro-2-phenylaminophenylcarbamoyl) ethyl]Tert-butyl carbamate as a red oil (1.1g, 83%).

A solution of the compound thus obtained (1.1g) in AcOH (10mL) was heated at 70 ℃ for 96 h. After cooling to RT, the volatiles were removed in vacuo and the resulting residue was taken up in DCM and saturated NaHCO ₃The aqueous solution was partitioned. The organic fraction was washed with brine and dried (MgSO)₄) And concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient eluted with 0-30% EtOAc in cyclohexane) to give the title compound as an orange oil (797mg, 74%). LCMS (method J) R_T4.14min[M+H]⁺462.3。

(R) -2-benzyloxy-1- (6-fluoro-1-phenyl-1H-benzimidazol-2-yl) ethylamine

To [ (R) -2-benzyloxy-1- (6-fluoro-1-phenyl-1H-benzimidazol-2-yl) ethyl]To a solution of tert-butyl carbamate (0.797g,1.7mmol) in DCM (9mL) was added TFA (5mL) and the mixture was stirred at RT for 2 h. Volatiles were removed under reduced pressure and the resulting residue was taken up in DCM and saturated NaHCO₃The aqueous solution was partitioned. The two-phase system was stirred for 10min, then the organic fraction was dried (MgSO₄) And concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient eluted with 0-10% MeOH in DCM) to give the title compound (298mg, 49%). LCMS (method J) R_T2.02min[M+H]⁺362.2。

[ (R) -2-benzyloxy-1- (6-fluoro-1-phenyl-1H-benzimidazol-2-yl) ethyl ] - (7H-purin-6-yl) amine

A solution of (R) -2-benzyloxy-1- (6-fluoro-1-phenyl-1H-benzimidazol-2-yl) ethylamine (298mg,0.83mmol), 6-chloro-9- (tetrahydropyran-2-yl) -9H-purine (200mg,0.83mmol) and DIPEA (700. mu.L, 4.2mmol) in n-butanol (5mL) was heated in a sealed vial at 90 ℃ for 48H. After cooling to RT, the volatiles were removed under vacuum and the resulting residue was loaded SCX-2 column, then MeOH, then 2M NH₃Washing with MeOH. The product containing fractions were combined and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC,0-10%2M NH)₃Gradient eluent in DCM/MeOH) to give the title compound as a colorless oil (256mg, 64%). LCMS (method B) R_T3.26min[M+H]⁺480.2。

(2-bromo-3-fluoro-6-nitrophenyl) phenylamine

LiHMDS (1.0M THF solution, 16.8mL,16.8mmol) was added dropwise to a stirred solution of aniline (821mg,8.80mmol) in anhydrous THF (20mL) at-78 deg.C under a nitrogen atmosphere. After stirring at-78 ℃ for 10min, a solution of 2-bromo-1, 3-difluoro-4-nitrobenzene (2.0g,8.40mmol) in THF (10mL) was added and stirring continued at-78 ℃ for 30 min. The reaction mixture was quenched by addition of water and extracted with EtOAc (× 3). The combined organic fractions were washed with brine and dried (MgSO)₄) Concentrating under vacuum, and purifying the residue by column chromatography (Si-PCC, gradient elution with 0-100% DCM in cyclohexane) to obtainTo the title compound (2.4g, 91%).¹H NMR(CDCl₃,400MHz):δ8.48(1H,s),8.19-7.12(1H,m),7.33-7.25(2H,m),7.09(1H,t,J=7.41Hz),6.93-6.83(3H,m)。

3-bromo-4-fluoro-N²-phenyl-1, 2-diamines

To a mixture of (2-bromo-3-fluoro-6-nitrophenyl) phenylamine (2.4g,7.7mmol) in MeOH (40mL) and water (15mL) was added NH₄Cl (2.38g,46.3mmol) and iron powder (1.72g,30.9mmol) and the reaction mixture was heated at 90 ℃ for 1 h. After cooling to RT, the crude mixture is taken up The pad was filtered and the filtrate was concentrated in vacuo. The resulting residue was partitioned between EtOAc and water. The aqueous phase was extracted with EtOAc (× 3), the combined organic fractions were washed with brine and dried (MgSO)₄) And concentrated in vacuo to give the title compound (1.95g, 90%). LCMS (method C) R_T3.48min[M+H]⁺281.1/283.1。

(S) -1- (7-bromo-6-fluoro-1-phenyl-1H-benzimidazol-2-yl) ethylamine

Reacting 3-bromo-4-fluoro-N²A mixture of-phenyl-benzene-1, 2-diamine (500mg,1.79mmol), (S) -2-tert-butoxycarbonylaminopropionic acid (370mg,1.95mmol), HOAt (266mg,1.95mmol), 4-methylmorpholine (0.43mL,3.91mmol) and N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride (376mg,1.95mmol) in DCM (5mL) was stirred at RT for 2 h. The reaction mixture was diluted with water and extracted with DCM (× 3). The combined organic fractions were washed with brine and dried (M)_gSO4) and concentrated in vacuo.Dissolving the residue in IIAlkane (10mL) and HCl (12N,1.5mL) was added. The reaction mixture was stirred at RT for 18h and then made basic by addition of 1N NaOH. The aqueous phase was extracted with EtOAc (× 3), the combined organic fractions were washed with brine and dried (MgSO)₄) And concentrated under reduced pressure. The resulting residue was purified by column chromatography (Si-PCC, gradient eluted with 0-10% MeOH in DCM) to give (S) -1- (7-bromo-6-fluoro-1-phenyl-1H-benzimidazol-2-yl) ethylamine (102mg, 17%). LCMS (method C) R _T2.28min[M+H]⁺334.1/336.1. Chromatography purification also yielded (S) -2-amino-N- (3-bromo-4-fluoro-2-phenylaminophenyl) propionamide (384mg), which was dissolved in 4N HCl bisAlkane solution (10mL) and heated at 70 ℃ for 3 h. Volatiles were removed under vacuum to give (S) -1- (7-bromo-6-fluoro-1-phenyl-1H-benzimidazol-2-yl) ethylamine dihydrochloride (434mg, 60%).¹H NMR(DMSO-d₆,400MHz):δ8.84(2H,s),7.83(1H,dd,J=8.80,4.57Hz),7.71-7.58(5H,m),7.38(1H,dd,J=9.65,8.80Hz),4.17-4.07(1H,m),3.56(2H,s),1.42(3H,d,J=6.80Hz)

[ (S) -1- (7-bromo-6-fluoro-1-phenyl-1H-benzimidazol-2-yl) ethyl ] - [9- (tetrahydropyran-2-yl) -9H-purin-6-yl ] amine

A mixture of (S) -1- (7-bromo-6-fluoro-1-phenyl-1H-benzimidazol-2-yl) ethylamine (102mg,0.31mmol), 6-chloro-9- (tetrahydropyran-2-yl) -9H-purine (80mg,0.34mmol) and DIPEA (104 μ L,0.61mmol) in n-butanol (2mL) was heated at 90 ℃ for 18H in a sealed vial. After cooling to RT, the volatiles were removed in vacuo and the resulting residue was purified by column chromatography (Si-PCC, gradient elution with 0-10% MeOH in EtOAc) to afford the title compoundThe title compound (128mg, 78%). LCMS (method C) R_T3.57min[M+H]⁺536.3/538.3。

(2-chloro-3-fluoro-6-nitrophenyl) phenylamine

LiHMDS (1.0M THF solution, 10.3mL,10.3mmol) was added dropwise to a stirred solution of aniline (505mg,5.43mmol) in anhydrous THF (10mL) at-78 deg.C under a nitrogen atmosphere. After stirring at-78 ℃ for 10min, a solution of 2-chloro-1, 3-difluoro-4-nitrobenzene (1.0g,5.17mmol) in THF (5mL) was added and stirring continued at-78 ℃ for 30 min. The reaction mixture was quenched by addition of water and then extracted with EtOAc (× 3). The combined organic fractions were washed with brine and dried (MgSO) ₄) Concentrated in vacuo and the residue purified by column chromatography (Si-PCC, gradient elution with 0-70% EtOAc in cyclohexane) to afford the title compound (1.28g, 93%).¹H NMR(CDCl₃,400MHz):δ8.70(1H,s),8.15(1H,dd,J=9.44,5.61Hz),7.36-7.28(2H,m),7.12(1H,t,J=7.44Hz),6.98-6.86(3H,m)。

3-chloro-4-fluoro-N²-phenyl-1, 2-diamines

To a mixture of (2-chloro-3-fluoro-6-nitrophenyl) phenylamine (1.28g,4.8mmol) in MeOH (45mL) and water (15mL) was added NH₄Cl (1.48g,28.8mmol) and iron powder (1.07g,19.2mmol) and the reaction mixture was heated at 90 ℃ for 2 h. After cooling to RT, the crude mixture is taken upThe pad was filtered and the filtrate was concentrated in vacuo. The resulting residue was partitioned between EtOAc and water. The aqueous phase was extracted with EtOAc (. times.3) and the mixture was evaporatedThe organic fraction was washed with brine and dried (MgSO)₄) And concentrated in vacuo. The resulting residue was purified by column chromatography (gradient elution of Si-PCC in cyclohexane with 0-100% DCM) to give the title compound (918mg, 81%). LCMS (method C) R_T3.46min[M+H]⁺237.1/239.1。

(S) -1- (7-chloro-6-fluoro-1-phenyl-1H-benzimidazol-2-yl) ethylamine dihydrochloride

Reacting 3-chloro-4-fluoro-N²A mixture of-phenylbenzene-1, 2-diamine (300mg,1.26mmol), (S) -2-tert-butoxycarbonylaminopropionic acid (264mg,1.39mmol), HOAt (190mg,1.39mmol), 4-methylmorpholine (0.31mL,2.79mmol) and N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride (270mg,1.39mmol) in DCM (5mL) was stirred at RT for 18 h. The reaction mixture was washed with saturated NaHCO ₃Aqueous dilution and extraction with DCM (× 3). The combined organic fractions were washed with brine and dried (MgSO)₄) And concentrated in vacuo. The resulting residue was dissolved in AcOH (5mL) and the solution was heated at 70 ℃ for 36 h. The volatiles were removed under vacuum and the resulting residue was purified by column chromatography (Si-PCC gradient eluted with 0-100% EtOAc in cyclohexane) to afford impure [ (S) -1- (7-chloro-6-fluoro-1-phenyl-1H-benzimidazol-2-yl) ethyl]Tert-butyl carbamate. The product thus obtained was dissolved in 4N HCl in dioxane (7mL) and heated at 70 ℃ for 2 h. The volatiles were removed under vacuum to give (S) -1- (7-chloro-6-fluoro-1-phenyl-1H-benzimidazol-2-yl) ethylamine dihydrochloride as an off-white solid (368mg, 80% yield in three steps). LCMS (method C) R_T2.28min[M+H]⁺290.2。

[ (S) -1- (7-chloro-6-fluoro-1-phenyl-1H-benzimidazol-2-yl) ethyl ] - [9- (tetrahydropyran-2-yl) -9H-purin-6-yl ] amine

A mixture of (S) -1- (7-chloro-6-fluoro-1-phenyl-1H-benzimidazol-2-yl) ethylamine dihydrochloride (150mg,0.41mmol), 6-chloro-9- (tetrahydropyran-2-yl) -9H-purine (118mg,0.49mmol) and DIPEA (280. mu.L, 1.65mmol) in n-butanol (3mL) was heated at 90 ℃ in a sealed vial for 18H. After cooling to RT, the volatiles were removed under reduced pressure and the resulting residue was purified by column chromatography (Si-PCC, gradient elution of 0-10% MeOH in EtOAc) to give the title compound (166mg, 82%). LCMS (method B) R _T3.57min[M+H]⁺492.0/493.8。

(3-Nitropyridin-2-yl) -m-tolylamine

2-chloro-3-nitropyridine (2.28g,14.4mmol), m-tolylamine (2.78g,25.9mmol) and Et₃A mixture of N (3.6mL,25.9mmol) in DMF (10mL) was stirred at 90 ℃ under a nitrogen atmosphere for 16 h. The reaction mixture was partitioned between DCM and water. The aqueous phase was extracted with DCM (× 3) and the combined organic layers were dried (Na)₂SO₄) And concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient eluted with 30-100% DCM in cyclohexane) to give the title compound as an orange solid (2.31g, 70%). LCMS (method C) R_T3.81min[M+H]⁺230.1。

N²-m-tolylpyridine-2, 3-diamine

A mixture of (3-nitropyridin-2-yl) -m-tolylamine (2.30g,10.0mmol) in EtOAc (150mL) was degassed with a stream of nitrogen and then 1 was added0% Pd/C (400mg) and stirred at RT for 16h under a hydrogen atmosphere. The suspension was filtered and the filtrate was concentrated in vacuo to give the title compound as a white solid (1.88g, 94%). LCMS (method C) R_T1.60min[M+H]⁺200.1。

[ (S) -1- (2-m-tolylaminopyridin-3-ylcarbamoyl) ethyl ] carbamic acid tert-butyl ester

Triethylamine (1.7mL,12.0mmol) was added to N at 0 deg.C under a nitrogen atmosphere²-m-tolylpyridine-2, 3-diamine (600mg,3.01mmol), (S) -2-tert-butoxycarbonylaminopropionic acid (1.03g,5.42mmol), HOAt (740mg,5.42mmol), and N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride (1.04g,5.42mmol) in a mixture of anhydrous DCM (25 mL). The reaction mixture was stirred at 0 ℃ for 15min and then slowly warmed to RT. Stirring was continued at RT for 16 h. After the mixture was cooled again to 0 deg.C, additional (S) -2-tert-butoxycarbonylaminopropionic acid (220mg,1.20mmol), HOAt (160mg,1.20mmol), N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride (230mg,1.20mmol) and triethylamine (0.41mL,3.01mmol) were added. The reaction mixture was stirred at 0 ℃ for 15min and then slowly warmed to RT. Stirring was continued at RT for 72 h. The reaction mixture was washed with DCM and saturated NaHCO ₃The solutions were partitioned. The aqueous phase was extracted with DCM (× 3), the combined organic fractions were washed with water and dried (Na)₂SO₄) And concentrated in vacuo to give the title compound as an off-white foam. The crude material was used in the next step without further purification. The yield was considered quantitative. LCMS (method C) R_T2.70min[M+H]⁺371.3。

[ (S) -1- (3-m-tolyl-3H-imidazo [4,5-b ] pyridin-2-yl) ethyl ] carbamic acid tert-butyl ester

Reacting [ (S) -1- (2-m-tolylaminopyridin-3-ylcarbamoyl) ethyl]A solution of tert-butyl carbamate (3.01mmol) in AcOH (20mL) was heated at 70 ℃ under a nitrogen atmosphere for 2 h. After cooling to RT, the volatiles were removed in vacuo and the resulting residue was taken up in DCM and saturated NaHCO₃The aqueous solution was partitioned. The aqueous phase was extracted with DCM (× 3), the combined organic fractions were washed with water and dried (Na)₂SO₄) And concentrated in vacuo to give the title compound as an off-white foam (quantitative yield). LCMS (method C) R_T3.23min[M+H]⁺353.4。

(S) -1- (3-m-tolyl-3H-imidazo [4,5-b ] pyridin-2-yl) ethylamine

To [ (S) -1- (3-m-tolyl-3H-imidazo [4,5-b ]]Pyridin-2-yl) ethyl]To a solution of tert-butyl carbamate (3.01mmol) in DCM (25mL) was added TFA (10mL) and the mixture was stirred at RT for 15 min. Volatiles were removed in vacuo and the resulting residue was taken up in DCM and saturated NaHCO ₃The solutions were partitioned. The aqueous phase was extracted with DCM (× 3) and the combined organic fractions were dried (Na)₂SO₄) And concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC with 0-8%2M NH)₃Gradient MeOH in DCM) to give the title compound as a colorless oil (700mg, 92% yield in three steps). LCMS (method C) R_T1.91min[M+H]⁺253.2。

2-chloro-N- (4-fluoro-2-phenylaminophenyl) acetamide

Chloroacetyl chloride (0.68mL,8.58mmol) was added dropwise to a stirred 4-fluoro-N at 0 deg.C under a nitrogen atmosphere²-phenyl-benzene-1, 2-diamine (1.24g,6.13mmol) and pyridine (2.0mL,24.5mmol) in DCM (8 mL). After stirring at 0 ℃ for 20min, the mixture was slowly warmed to RT and stirring was continued at RT for 2 h. The mixture was partitioned between DCM and aqueous HCl cooled to 0 ℃ (1M,50mL) and the aqueous phase was further extracted with DCM (× 3). The combined organic fractions were washed with water and dried (Na)₂SO₄) And concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient eluted with 30-100% DCM in cyclohexane) to give the title compound as a white crystalline solid (750mg, 44%). LCMS (method C) R_T3.42min[M+H]⁺279.2。

2-chloromethyl-6-fluoro-1-phenyl-1H-benzimidazoles

2-chloro-N- (4-fluoro-2-phenylaminophenyl) acetamide (740mg,2.62mmol) was dissolved in AcOH (20mL) and the mixture was heated at 70 ℃ under a nitrogen atmosphere for 5 h. Volatiles were removed in vacuo and the resulting residue was taken up in DCM and saturated NaHCO ₃The aqueous solution was partitioned. The aqueous phase was extracted with DCM (× 3). The combined organic fractions were washed with water and dried (Na)₂SO₄) And concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient eluted with 0-5% MeOH in DCM) to give the title compound as a brown oil which crystallized on standing (570mg, 84%). LCMS (method C) R_T3.40min[M+H]⁺261.2。¹H NMR(CDCl₃,400MHz):δ7.75(1H,dd,J=8.87,4.76Hz),7.66-7.54(3H,m),7.47(2H,d,J=7.38Hz),7.07(1H,td,J=9.21,2.41Hz),6.84(1H,dd,J=8.54,2.41Hz),4.66(2H,s)。1

(5-fluoro-2-nitrophenyl) pyridin-2-yl-amines

LiHMDS (1.0M THF solution, 4.8mL,4.8mmol) was added dropwise to a stirred solution of pyridin-2-ylamine (269mg,2.86mmol) in anhydrous THF (10mL) at-78 deg.C under a nitrogen atmosphere. After stirring at-78 ℃ for 30min, 2, 4-difluoro-1-nitrobenzene (298. mu.L, 2.72mmol) was added and stirring continued at-78 ℃ for 30 min. The reaction mixture was slowly warmed to RT and after 30min by addition of NH₄Aqueous Cl (50mL) was quenched. The mixture was partitioned between EtOAc and water and then washed withAnd (5) filtering. The organic fraction was dried (Na)₂SO₄) Concentrated in vacuo and the resulting residue purified by column chromatography (Si-PCC gradient eluted with 0-40% EtOAc in cyclohexane) to give the title compound as an orange solid (258mg, 41%).¹H NMR(CDCl₃,400MHz):δ10.48(1H,s),8.82(1H,dd,J=12.32,2.77Hz),8.38(1H,dd,J=5.03,1.87Hz),8.34-8.25(1H,m),7.70-7.64(1H,m),7.03-6.94(2H,m),6.68-6.61(1H,m)。

4-fluoro-N²-pyridin-2-ylphenyl-1, 2-diamine

A mixture of (5-fluoro-2-nitrophenyl) pyridin-2-yl-amine (255mg,1.09mmol) in EtOAc (20mL) was degassed with a stream of nitrogen, then 10% Pd/C (28mg) was added and stirred at RT for 18h under a hydrogen atmosphere. The suspension was filtered through a phase separator and the filtrate was concentrated in vacuo to give the title compound as a black solid (241mg, quantitative yield). ¹H NMR(CDCl₃,400MHz):δ8.20-8.16(1H,m),7.51-7.44(1H,m),7.12-7.07(1H,m),6.78-6.72(3H,m),6.55(1H,dt,J=8.39,0.93Hz),6.22(1H,s),3.63(2H,s)。

(S) -2-amino-N- [ 4-fluoro-2- (pyridin-2-ylamino) phenyl ] propanamide

Reacting 4-fluoro-N²A mixture of-pyridin-2-ylphenyl-1, 2-diamine (241mg,1.19mmol), (S) -2-tert-butoxycarbonylaminopropionic acid (247mg,1.30mmol), HOAt (178mg,1.30mmol), 4-methylmorpholine (0.287mL,2.61mmol) and N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride (250mg,1.30mmol) in DCM (10mL) was stirred at RT for 2 h. The reaction mixture was washed with saturated NaHCO₃Aqueous dilution and extraction with DCM (× 3). The combined organic fractions were passed through a phase separator and concentrated in vacuo to give { (S) -1- [ 4-fluoro-2- (pyridin-2-ylamino) phenylcarbamoyl]Ethyl } carbamic acid tert-butyl ester as a light red solid (505mg, quantitative yield). LCMS (method B) R_T2.30min[M+H]⁺375.0。

A portion of the compound thus obtained (391mg) was reacted with 4M HCl bisAlkane solution (5mL) was treated and the mixture was heated in a sealed vial at 70 ℃ for 2 h. Volatiles were removed in vacuo and the resulting residue was taken up in DCM and saturated NaHCO₃The aqueous solution was partitioned. The organic layer was passed through a phase separator and concentrated in vacuo to give the title compound as a brown oil (190mg, 66%).¹H NMR(CDCl₃,400MHz):δ9.61(1H,s),8.20-8.17(1H,m),7.68(1H,dd,J=8.93,5.91Hz),7.48(1H,ddd,J=8.35,7.22,1.93Hz),7.32(1H,dd,J=9.79,2.61Hz),6.96(1H,s),6.87-6.81(1H,m),6.78-6.73(1H,m),6.58(1H,dt,J=8.35,0.92Hz),3.59(1H,q,J=7.16Hz),1.39(3H,d,J=7.01Hz)。

(S) -N- [ 4-fluoro-2- (pyridin-2-ylamino) phenyl ] -2- (9H-purin-6-ylamino) propionamide

Reacting (S) -2-amino-N- [ 4-fluoro-2- (pyridin-2-ylamino) phenyl]A mixture of propionamide (190mg,0.69mmol), 6-chloro-9- (tetrahydropyran-2-yl) -9H-purine (186mg,0.78mmol) and DIPEA (380. mu.L, 2.22mmol) in n-butanol (1.5mL) was heated at 90 ℃ for 65H in a sealed vial. After cooling to RT, the volatiles were removed under vacuum and the resulting residue was loadedSCX-2 column, then MeOH, then 2M NH₃Washing with MeOH. The product-containing fractions were combined and concentrated in vacuo to give the title compound as an orange/brown oil (263mg, 97%). LCMS (method C) R_T1.67min[M+H]⁺393.3。

4-trans- (5-fluoro-2-nitrophenylamino) cyclohexanecarbonitrile

2, 4-difluoro-1-nitrobenzene (505mg,3.17mmol), 4-aminocyclohexanecarbonitrile hydrochloride (510mg,3.17mmol) and NaHCO₃A mixture of (780mg,9.3mmol) in DMSO (5mL) was heated at 60 ℃ for 1h in a sealed vial. The reaction mixture was diluted with water and extracted with EtOAc (× 3). The combined organic fractions were washed with brine, dried and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC gradient eluted with 0-25% EtOAc in cyclohexane) to give the title compound as a light brown solid (500mg, 61%). ¹H NMR(CDCl₃,400MHz):δ8.29-8.10(2H,m),6.47(1H,dd,J=11.40,2.52Hz),6.42-6.34(1H,m),3.55-3.44(1H,m),2.66-2.55(1H,m),2.27-2.13(4H,m),1.87-1.72(2H,m),1.55-1.41(2H,m)。

4-trans- (2-amino-5-fluorophenylamino) cyclohexanecarbonitrile

A solution of 4-trans- (5-fluoro-2-nitrophenylamino) cyclohexanecarbonitrile (500mg,1.89mmol) in EtOAc (3mL) and EtOH (3mL) was degassed with a stream of argon and then PtO was added₂(50mg) and stirred at RT for 24h under a hydrogen atmosphere. The suspension was filtered and the filtrate was concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC gradient eluted with 0-80% EtOAc in cyclohexane) to afford the title compound (195mg, 44%). LCMS (method J) R_T2.07min[M+H]⁺234.2。

{ (S) -1- [2- (trans-4-cyanocyclohexylamino) -4-fluorophenylcarbamoyl ] ethyl } carbamic acid tert-butyl ester

A mixture of trans-4- (2-amino-5-fluorophenylamino) cyclohexanecarbonitrile (195mg,0.83mmol), (S) -2-tert-butoxycarbonylaminopropionic acid (174mg,0.92mmol), HOAt (125mg,0.92mmol), 4-methylmorpholine (0.20mL,1.83mmol) and N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride (192mg,1.0mmol) in THF (3mL) was stirred under a nitrogen atmosphere at RT for 18 h. The reaction mixture was partitioned between EtOAc and water. The organic fraction was washed with brine and dried (MgSO)₄) Concentrated in vacuo and the resulting residue purified by column chromatography (Si-PCC gradient eluted with 0-50% EtOAc in cyclohexane) to give the title compound as a white foam (199mg, 60%). LCMS (method B) R _T3.37[M+H]⁺405.2

Trans-4- [2- ((S) -1-aminoethyl) -6-fluorobenzoimidazol-1-yl ] cyclohexanecarbonitrile

Reacting { (S) -1- [2- (trans-4-cyanocyclohexylamino) -4-fluorophenylcarbamoyl]A mixture of tert-butyl ethyl } carbamate (195mg,0.48mmol) in AcOH (2mL) was heated at 80 ℃ under a nitrogen atmosphere for 1h, then at 90 ℃ for 2h, and finally at 110 ℃ for 16 h. Volatiles were removed under reduced pressure and the resulting residue was dissolved in 6N HCl (5mL) and heated at reflux temperature for 2 h. The volatiles were removed under vacuum and the resulting residue was dissolved in NaHCO₃Aqueous and extracted with EtOAc (× 3). The combined organic fractions were washed with water, dried and concentrated in vacuo to give the title compound as a brown solid (100mg, 72%). LCMS (method C) R_T2.01min[M+H]⁺287.1。

N²-cyclobutyl-4-fluorobenzene-1, 2-diamine

To a solution of 2, 4-difluoro-1-nitrobenzene (0.7mL,6.3mmol) in CH₃To a solution in CN (10mL) was added cyclobutylamine (0.54mL,6.3mmol) and DIPEA (1.1mL,6.3 mmol). The reaction mixture was stirred at RT for 18h, then concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient eluted with 0-10% EtOAc in cyclohexane) to afford cyclobutyl- (5-fluoro-2-nitrophenyl) amine as a yellow oil (1.38g, quantitative yield). To a solution of the product thus obtained (6.3mmol) in EtOAc (60mL) was added 10% Pd/C (150mg) and the reaction mixture was stirred at RT for 18h under a hydrogen atmosphere. Mixing the suspension with The pad was filtered and the filtrate was concentrated in vacuo to give the title compound as an orange oil (1.1g, quantitative yield).¹H NMR(CDCl₃,300MHz):δ6.63-6.56(1H,m),6.35-6.19(2H,m),3.92-3.78(1H,m),3.66-2.91(2H,m),2.53-2.36(2H,m),1.94-1.73(4H,m)。

[ (S) -1- (1-cyclobutyl-6-fluoro-1H-benzimidazol-2-yl) ethyl ] carbamic acid tert-butyl ester

Will N²A mixture of-cyclobutyl-4-fluorobenzene-1, 2-diamine (0.63g,3.5mmol), (S) -2-tert-butoxycarbonylaminopropionic acid (0.73g,3.9mmol), HOAt (0.53g,3.9mmol), 4-methylmorpholine (0.85mL,7.7mmol) and N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride (0.75g,3.9mmol) in DCM (12mL) was stirred at RT for 18 h. The reaction mixture was washed with DCM and saturated NaHCO₃The aqueous solution was partitioned. The organic fraction was washed with brine and dried (MgSO)₄) Concentrated in vacuo and the residue purified by column chromatography (Si-PCC gradient eluted with 0-30% EtOAc in cyclohexane) to give [ (S) -1- (2-cyclobutylamino-4-fluorophenylcarbamoyl) ethyl]Tert-butyl carbamate (853mg, 69%). LCMS (method J) R_T3.54min[M+H]⁺352.2。

The compound thus obtained was dissolved in AcOH (12mL) and heated at 70 ℃ for 18 h. After cooling to RT, the volatiles were evaporated in vacuo and the residue was taken up in DCM and saturated NaHCO₃The aqueous solution was partitioned. The organic fraction was washed with brine and dried (MgSO) ₄) And then concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient eluted with 0-30% EtOAc in cyclohexane) to give the title compound as a yellow oil (728mg, 62%). LCMS (method B) R_T2.96min[M+H]⁺334.2。

(S) -1- (1-cyclobutyl-6-fluoro-1H-benzimidazol-2-yl) ethylamine

To [ (S) -1- (1-cyclobutyl-6-fluoro-1H-benzimidazol-2-yl) ethyl]To a solution of tert-butyl carbamate (728mg,2.2mmol) in DCM (15mL) was added TFA (8mL) and the mixture was stirred at RT for 1 h. Volatiles were removed in vacuo and the resulting residue was taken up in DCM and saturated NaHCO₃The aqueous solution was partitioned. The two-phase system was stirred for 10min, and the organic layer was dried (MgSO₄) And concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient eluted with 0-10% MeOH in DCM) to give the title compound as a white solid (251mg, 49%). LCMS (method C) R_T2.07min[M+H]⁺234.1。

Cyclopropyl- (5-fluoro-2-nitrophenyl) amine

To a solution of 2, 4-difluoro-1-nitrobenzene (0.7mL,6.3mmol) in anhydrous CH₃To a solution of CN (10mL) was added cyclopropylamine (0.4mL,6.3mmol) and DIPEA (1.1mL,6.3 mmol). The reaction mixture was stirred at RT for 18h and then evaporated in vacuo. The resulting residue was purified by column chromatography (Si-PCC gradient eluted with 0-10% EtOAc in cyclohexane) to afford the title compound as a yellow solid (6.3mmol, quantitative yield). ¹H NMR(CDCl₃,300MHz):δ8.26-8.09(2H,m),6.95(1H,dd,J=11.43,2.68Hz),6.46-6.35(1H,m),2.60-2.50(1H,m),0.98-0.89(2H,m),0.71-0.63(2H,m)。

N²-cyclopropyl-4-fluorobenzene-1, 2-diamine

To a solution of cyclopropyl- (5-fluoro-2-nitrophenyl) amine (6.3mmol) in EtOAc (60mL) was added 10% Pd/C (150mg) and the reaction mixture was stirred at RT for 5h under a hydrogen atmosphere. Mixing the suspension withPad filtration and concentration of the filtrate in vacuo afforded the title compound as a brown oil (1.1g, quantitative yield).¹H NMR(CDCl₃,300MHz):δ6.76(1H,dd,J=10.85,2.76Hz),6.60(1H,dd,J=8.38,5.56Hz),6.34(1H,td,J=8.45,2.82Hz),4.15(1H,br s),3.03(2H,br s),2.45-2.36(1H,m),0.80-0.72(2H,m),0.56-0.49(2H,m)。

[ (S) -1- (1-cyclopropyl-6-fluoro-1H-benzimidazol-2-yl) ethyl ] carbamic acid tert-butyl ester

Will N²A mixture of-cyclopropyl-4-fluorobenzene-1, 2-diamine (0.724g,4.4mmol), (S) -2-tert-butoxycarbonylaminopropionic acid (0.91g,4.8mmol), HOAt (0.65g,4.8mmol), 4-methylmorpholine (1.1mL,9.7mmol) and N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride (0.92g,4.8mmol) in DCM (15mL) was stirred at RT for 18 h. The reaction mixture was washed with DCM and saturated NaHCO₃The aqueous solution was partitioned. The organic fraction was washed with brine and dried (MgSO)₄) Concentrated in vacuo and the residue purified by column chromatography (Si-PCC gradient eluted with 0-30% EtOAc in cyclohexane) to give [ (S) -1- (2-cyclopropylamino-4-fluorophenylcarbamoyl) ethyl]Tert-butyl carbamate as a brown oil (1.07g, 72%). LCMS (method B) R_T3.40min[M+H]⁺338.2.110180243

The compound thus obtained (1.07g) was dissolved in AcOH (15mL) and heated at 70 ℃ for 18 h. After cooling to RT, the volatiles were evaporated in vacuo and the resulting residue was taken up in DCM and saturated NaHCO ₃The aqueous solution was partitioned. The organic layer was washed with brine and dried (MgSO)₄) And then concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC gradient eluted with 0-30% EtOAc in cyclohexane) to give the title compound as a colorless oil: (414mg, 29%). LCMS (method C) R_T2.81min[M+H]⁺320.2。

(S) -1- (1-cyclopropyl-6-fluoro-1H-benzimidazol-2-yl) ethylamine

To [ (S) -1- (1-cyclopropyl-6-fluoro-1H-benzimidazol-2-yl) ethyl]To a solution of tert-butyl carbamate (414mg,1.3mmol) in DCM (7mL) was added TFA (3mL) and the mixture was stirred at RT for 1 h. Volatiles were removed in vacuo and the resulting residue was taken up in DCM and saturated NaHCO₃The aqueous solution was partitioned. The two-phase system was stirred for 10min, and then the organic layer was dried (MgSO₄) And concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient eluted with 0-10% MeOH in DCM) to give the title compound as a yellow oil (166mg, 58%). LCMS (method C) R_T1.66min[M+H]⁺220.1。

[ (S) -1- (6-fluoro-1-phenyl-1H-benzimidazol-2-yl) ethyl ] methylcarbamic acid tert-butyl ester

Reacting 4-fluoro-N²A mixture of-phenylbenzene-1, 2-diamine (450mg,2.2mmol), (S) -2- (tert-butoxycarbonylmethylamino) propionic acid (0.50g,2.4mmol), HOAt (0.33g,2.4mmol), 4-methylmorpholine (0.5mL,4.8mmol) and N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride (0.46g,2.4mmol) in DCM (10mL) was stirred at RT for 2 h. The reaction mixture was washed with DCM and saturated NaHCO ₃The aqueous solution was partitioned. The organic layer was washed with brine and dried (MgSO)₄) Concentrated in vacuo and the residue purified by column chromatography (Si-PCC gradient eluted with 0-30% EtOAc in cyclohexane) to give [ (S) -1- (4-fluoro-2-phenylaminophenylcarbamoyl)) Ethyl radical]Tert-butyl methylcarbamate (0.781g, 92%). LCMS (method J) R_T3.92min[M+H]⁺388.1。

The compound thus obtained (0.781g) was dissolved in AcOH (10mL) and heated at 70 ℃ for 18 h. After cooling to RT, the volatiles were evaporated in vacuo and the residue was taken up in DCM and saturated NaHCO₃The aqueous solution was partitioned. The organic fraction was washed with brine and dried (MgSO)₄) And concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient eluted with 0-30% EtOAc in cyclohexane) to give the title compound as an orange solid (264mg, 33%). LCMS (method B) R_T3.82min[M+H-^tBu]⁺314.0。

[ (S) -1- (6-fluoro-1-phenyl-1H-benzimidazol-2-yl) ethyl ] methylamine

To [ (S) -1- (6-fluoro-1-phenyl-1H-benzimidazol-2-yl) ethyl]To a solution of tert-butyl methylcarbamate (0.264g,0.72mmol) in DCM (8mL) was added TFA (4mL) and the mixture was stirred at RT for 1.5 h. Volatiles were removed in vacuo and the resulting residue was taken up in DCM and saturated NaHCO ₃The aqueous solution was partitioned. The two-phase system was stirred for 10 min, then the aqueous phase was extracted with DCM. The combined organic fractions were dried (MgSO)₄) And concentrated in vacuo to give the title compound as a colorless oil (102mg, 53%). LCMS (method J) R_T1.80min[M+H]⁺270.2。

[ (S) -3-benzyloxy-1- (4-fluoro-2-phenylaminophenylcarbamoyl) propyl ] carbamic acid tert-butyl ester

Reacting 4-fluoro-N²A mixture of-phenyl-benzene-1, 2-diamine (614mg,3.04mmol), (S) -4-benzyloxy-2-tert-butoxycarbonylaminobutyric acid (1.0g,3.3mmol), HOAt (0.450g,3.3mmol), 4-methylmorpholine (0.7mL,6.7mmol) and N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride (0.63g,3.3mmol) in DCM (15mL) was stirred at RT for 18 h. The reaction mixture was washed with DCM and saturated NaHCO₃The aqueous solution was partitioned. The organic fraction was washed with brine and dried (MgSO)₄) Concentrated in vacuo and the residue purified by column chromatography (Si-PCC gradient eluted with 0-30% EtOAc in cyclohexane) to give the title compound as a yellow oil (1.22g, 82%). LCMS (method J) R_T4.17min[M+H]⁺494.1。

(S) -3-benzyloxy-1- (6-fluoro-1-phenyl-1H-benzimidazol-2-yl) propylamine

Reacting [ (S) -3-benzyloxy-1- (4-fluoro-2-phenylaminophenylcarbamoyl) propyl ]Tert-butyl carbamate (1.22g,2.5mmol) in 4M HClThe solution in alkane solution (10mL) was heated at 70 ℃ for 2 h. After cooling to RT, the volatiles were concentrated in vacuo and the residue was taken up in DCM and saturated NaHCO₃The aqueous solution was partitioned. The organic fraction was washed with brine and dried (MgSO)₄) And then concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient eluted with 0-10% MeOH in DCM) to give the title compound as a colorless oil (639mg, 68%). LCMS (method B) R_T2.11 and 2.55min [ M + H]⁺376.2。

[ (S) -3-benzyloxy-1- (6-fluoro-1-phenyl-1H-benzimidazol-2-yl) propyl ] - (9H-purin-6-yl) amine

A mixture of (S) -3-benzyloxy-1- (6-fluoro-1-phenyl-1H-benzimidazol-2-yl) propylamine (639mg,1.7mmol), 6-chloro-9- (tetrahydropyran-2-yl) -9H-purine (410mg,1.7mmol) and DIPEA (1.5mL,8.5mmol) in n-butanol (6mL) was heated at 100 ℃ for 18H. After cooling to RT, the volatiles were removed under vacuum and the resulting residue was loadedSCX-2 column. The column was washed with MeOH, then 2M NH₃Washing with MeOH. The basic fractions were combined and concentrated in vacuo and the resulting residue was purified by column chromatography (Si-PCC,0-10%2 MNH)₃Gradient eluent in DCM/MeOH) to give the title compound as a white solid (703mg, 84%). LCMS (method C) R _T3.10min[M+H]⁺494.3。

(S) -2-amino-3-methyl-N- (2-phenylaminopyridin-3-yl) butanamide

Will N²A mixture of-phenylpyridine-2, 3-diamine (556mg,3.0mmol), (S) -2-tert-butoxycarbonylamino-3-methylbutyric acid (0.72g,3.3mmol), HOAt (0.450g,3.3mmol), 4-methylmorpholine (0.73mL,6.6mmol) and N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride (0.63g,3.3mmol) in DCM (15mL) was stirred at RT for 18 h. The reaction mixture was washed with DCM and saturated NaHCO₃The aqueous solution was partitioned. The organic layer was washed with brine and dried (MgSO)₄) Concentrated in vacuo and the residue purified by column chromatography (Si-PCC, gradient eluted with 0-30% EtOAc in cyclohexane) to give [ (S) -2-methyl-1- (2-phenylaminopyridin-3-ylcarbamoyl) propyl]Tert-butyl carbamate as white solid (1.13g, quantitative yield).

The compound thus obtained is reacted in 4M HClThe mixture in alkane solution (10mL) was heated at 70 ℃ for 2 h. After cooling to RT, the volatiles were removed under reduced pressure. The resulting residue was taken up in DCM and saturated NaHCO₃The aqueous solution was partitioned. The two-phase system was stirred for 10 min. The organic fraction was then washed with brine and dried (MgSO)₄) And concentrated in vacuo to give the title compound (quantitative yield). LCMS (method C) R _T1.17min[M+H]⁺285.3。

(S) -3-methyl-N- (2-phenylaminopyridin-3-yl) -2- (9H-purin-6-ylamino) butanamide

A mixture of (S) -2-amino-3-methyl-N- (2-phenylaminopyridin-3-yl) butanamide (3.0mmol), 6-chloro-9- (tetrahydropyran-2-yl) -9H-purine (720mg,3.0mmol) and DIPEA (2.6mL,15.0mmol) in N-butanol (12mL) was heated in a sealed vial at 100 ℃ for 18H. After cooling to RT, the volatiles were removed under vacuum and the resulting residue was loadedSCX-2 column. The column was washed with MeOH, then 2M NH₃Washing with MeOH. The basic fractions were combined, concentrated in vacuo and the residue purified by column chromatography (Si-PCC,0-10%2 MNH)₃Gradient eluent in DCM/MeOH) to give the title compound (821mg, 68% yield over two steps). LCMS (method J) R_T1.75min[M+H]⁺403.2。

(5-fluoro-2-nitrophenyl) pyridin-3-yl-amines

LiHMDS (1.0M in THF, 50mL,50mmol) was added dropwise to a stirred solution of pyridin-3-ylamine (2.5g,26.4mmol) in anhydrous THF (20mL) at-70 ℃ under a nitrogen atmosphere. After stirring at-78 ℃ for 10min, a solution of 2, 4-difluoro-1-nitrobenzene (4.0g,25.1mmol) in THF (40mL) was added dropwise at-78 ℃. The reaction mixture was slowly warmed to RT. After stirring for 4h at RT, by addition of NH ₄The crude mixture was quenched with aqueous Cl and the aqueous fraction was extracted with EtOAc. The combined organic fractions were washed with brine and dried (MgSO)₄) And concentrated in vacuo to give the title compound as a red solid (quantitative yield).¹H NMR(CDCl₃,300MHz):δ9.58(1H,br s),8.61(1H,d,J=2.64Hz),8.55(1H,d,J=4.76Hz),8.29(1H,dd,J=9.47,5.92Hz),7.66-7.61(1H,m),7.40(1H,dd,J=8.19,4.75Hz),6.74(1H,dd,J=10.95,2.62Hz),6.60-6.51(1H,m)。

4-fluoro-N²-pyridin-3-ylphenyl-1, 2-diamine

To a mixture of (5-fluoro-2-nitrophenyl) pyridin-3-yl-amine (25mmol) in EtOH (300mL) was added 10% Pd/C (1.0g) and the reaction mixture was stirred at RT for 18h under a hydrogen atmosphere. Additional Pd/C (1.0g) was added and stirring continued at RT for 2h under a hydrogen atmosphere. Mixing the suspension withPad filtration and concentration of the filtrate in vacuo afforded the title compound as a brown solid (quantitative yield).¹H NMR(CDCl₃,300MHz):δ8.27(1H,dd,J=2.64,0.91Hz),8.15(1H,dd,J=4.41,1.71Hz),7.20-7.09(2H,m),6.87(1H,dd,J=9.61,2.59Hz),6.80-6.68(2H,m),5.50(1H,br s),2.96(2H,br s)

(S) -1- (6-fluoro-1-pyridin-3-yl-1H-benzimidazol-2-yl) -2-methylpropylamine

To 4-fluoro-N at 0 DEG C²To a solution of (S) -2-tert-butoxycarbonylamino-3-methylbutyric acid (720mg,3.3mmol), HOAt (0.450g,3.3mmol) and N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride (0.63g,3.3mmol) in DCM (18mL) was added and the resulting mixture was stirred at 0 ℃ for 2 h. The reaction mixture was washed with DCM and saturated NaHCO₃The aqueous solution was partitioned. The organic layer was dried (MgSO ₄) Concentrated in vacuo and the residue purified by column chromatography (Si-PCC gradient eluted with 0-60% EtOAc in cyclohexane) to give { (S) -1- [ 4-fluoro-2- (pyridin-3-ylamino) phenylcarbamoyl]-tert-butyl 2-methylpropyl } carbamate (790 mg). LCMS (method J) R_T2.10min[M+H]⁺403.3

A solution of the compound thus obtained (790mg) in AcOH (15mL) was heated at 100 ℃ for 72h, then the volatiles were removed under vacuum. The resulting residue was taken up in DCM and saturated NaHCO₃The aqueous solution was partitioned. The two-phase system was stirred vigorously for 10 minutes, and then the organic fraction was dried (MgSO₄) And concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient eluted with 0-10% MeOH in DCM) and the relevant fractions were combined and concentrated in vacuo. The resulting residue (251mg) was dissolved in 6M HCl (6mL) and heated in a sealed tube at 100 ℃ for 1 h. The crude mixture was taken up in DCM and saturated NaHCO₃The aqueous solution was partitioned. The two-phase system was stirred vigorously for 10 minutes, and then the organic fraction was dried (MgSO₄) And concentrated in vacuo to give the title compound (135mg, 16% yield over four steps). LCMS (method J) R_T1.75min[M+H]⁺285.2

(R) -2-ethoxy-1- (6-fluoro-1-phenyl-1H-benzimidazol-2-yl) ethylamine

To 4-fluoro-N at 0 DEG C ²To a solution of-phenyl-benzene-1, 2-diamine (562mg,2.8mmol) in DCM (18mL) were added (S) -2-tert-butoxycarbonylamino-3-ethoxypropionic acid (720mg,3.1mmol), HOAt (0.420g,3.1mmol), and N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride (0.59g,3.1mmol), and the resulting mixture was stirred at 0 deg.C for 1 h. The reaction mixture was washed with DCM and saturated NaHCO₃The aqueous solution was partitioned. The organic fraction was washed with brine and dried (MgSO)₄) Concentrated in vacuo and the residue purified by column chromatography (Si-PCC gradient eluted with 0-30% EtOAc in cyclohexane) to give [ (S) -2-ethoxy-1- (4-fluoro-2-phenylaminophenylcarbamoyl) ethyl]Tert-butyl carbamate (770mg, 66%). LCMS (method B) R_T3.87min[M+H]⁺418.3

A solution of the compound thus obtained (770mg) in 4N HCl in dioxane (10mL) was heated at 70 ℃ for 2h, then volatiles were removed under vacuum. The resulting residue was purified by column chromatography (Si-PCC, gradient eluted with 0-10% MeOH in DCM) to give the title compound as an oil (510mg, 92%). LCMS (method B) R_T1.94min[M+H]⁺300.1

[ (S) -1- (7-cyclopropyl-6-fluoro-1-phenyl-1H-benzimidazol-2-yl) ethyl ] - [9- (tetrahydropyran-2-yl) -9H-purin-6-yl ] amine

Reacting [ (S) -1- (7-bromo-6-fluoro-1-phenyl-1H-benzimidazol-2-yl) ethyl]- [9- (tetrahydropyran-2-yl) -9H-purin-6-yl]Amine (50mg,0.09mmol), Cyclopropylboronic acid (10mg,0.12mmol) and Cs₂CO₃(46mg,0.14mmol) bis in 4:1Mixture in the mixture of alkane and water (2.5mL) was degassed with a stream of argon and Pd (PPh) was added₃)₄(5mg) and heated in a sealed vial at 100 ℃ for 18 h. Adding an additional site IICyclopropylboronic acid (10mg,0.12mmol) and Pd (PPh) in an alkane (0.25mL)₃)₄(5mg) and stirring was continued in a sealed vial at 100 ℃ for 3 h. The reaction mixture was diluted with water and extracted with EtOAc (× 3). The combined organic fractions were washed with brine and dried (MgSO)₄) And concentrated in vacuo. The resulting residue was purified by reverse phase HPLC (Phenomenex Gemini5 μm C18, 25min gradient elution: 10-90%,0.1% HCO₂H in acetonitrile/water) to give the title compound (20mg, 43%). LCMS (method C) R_T3.32min[M+H]⁺498.1。

6-fluoro-3-nitro-2-phenylaminobenzonitrile

LiHMDS (1.0M in THF, 38mL,38.0mmol) was added dropwise to a stirred solution of aniline (1.86g,19.9mmol) in anhydrous THF (30mL) at-78 deg.C under a nitrogen atmosphere. After stirring at-78 ℃ for 10min, a solution of 2, 6-difluoro-3-nitrobenzonitrile (3.5g,19.0mmol) in THF (15mL) was added and stirring continued at-78 ℃ for 30 min. The crude mixture was quenched with water and diluted with EtOAc. Using the obtained emulsion Pad filtration and separation of the organic fraction, washing with brine and drying (MgSO)₄) And concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC gradient eluted with 0-100% EtOAc in cyclohexane) to afford the title compound (2.7g, 55%).¹H NMR(CDCl₃,400MHz):δ9.94(1H,br s),8.51(1H,dd,J=9.50,5.88Hz),7.51-7.21(5H,m),6.68(1H,dd,J=9.50,7.46Hz)。

3-amino-6-fluoro-2-phenylaminobenzonitrile

To a mixture of 6-fluoro-3-nitro-2-phenylaminobenzonitrile (2.7g,10.5mmol) in a mixture of MeOH (50mL) and water (20mL) was added NH₄Cl (3.23g,62.9mmol) and iron powder (2.3g,41.9mmol) and the reaction mixture was heated at 90 ℃ for 1 h. After cooling to RT, the solid was usedThe pad was filtered off and the filtrate was concentrated in vacuo. The resulting residue was partitioned between EtOAc and water, and the aqueous phase was extracted with EtOAc (× 3). The combined organic fractions were washed with brine and dried (MgSO)₄) And concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC gradient eluted with 0-100% EtOAc in cyclohexane) to afford the title compound (930mg, 39%). LCMS (method B) R_T3.27min[M+H]⁺227.8。

[ (S) -1- (7-cyano-6-fluoro-1-phenyl-1H-benzimidazol-2-yl) ethyl ] carbamic acid tert-butyl ester

To a suspension of tert-butyl ((S) -1-carbamoylethyl) carbamate (1.12g,6.0mmol) in DCM (7mL) was added triethyloxytetrafluoroborate (969mg,5.1mmol) and the reaction mixture was stirred at RT for 3h, during which time the solid dissolved. The reaction mixture was concentrated in vacuo and the residue was dissolved in ethanol (7 mL). 3-amino-6-fluoro-2-phenylaminobenzonitrile (400mg,1.8mmol) was added and the reaction was heated at 75 ℃ for 1 h. The reaction mixture was concentrated in vacuo, the residue was dissolved in water and The product was extracted with EtOAc (3X 20 mL). The combined organic extracts were washed with brine and dried (MgSO)₄) And concentrated in vacuo. The residue obtained is treated by flash chromatography (SiO)₂Eluting with 0-100% EtOAc in cyclohexane) to give the title compound as a white solid (411mg, 61%). LCMS (method C) R_T=3.55min,[M+H]+=381。

(S) -1- (6-fluoro-1-pyridin-3-yl-1H-benzimidazol-2-yl) propylamine

To 4-fluoro-N at 0 DEG C²To a solution of (S) -2-tert-butoxycarbonylaminobutyric acid (650mg,3.2mmol), HOAt (440mg,3.2mmol) and N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride (610mg,3.2mmol) in DCM (18mL) was added pyridin-3-ylphenyl-1, 2-diamine (0.594g,2.9mmol) and the reaction mixture was stirred at 0 ℃ for 2 h. The crude mixture was taken up in DCM and saturated NaHCO₃The aqueous solution was partitioned. The organic phase was washed with brine and dried (MgSO)₄) Concentrated in vacuo and the residue purified by column chromatography (Si-PCC gradient eluted with 0-60% EtOAc in cyclohexane) to give { (S) -1- [ 4-fluoro-2- (pyridin-3-ylamino) phenylcarbamoyl]Propyl } carbamic acid tert-butyl ester (839mg, 75%). LCMS (method J) R_T0.69min[M+H]⁺389.2。

A solution of the compound thus obtained (839mg,2.2mmol) in AcOH (15mL) was heated at 100 ℃ for 18h, then the volatiles were removed under vacuum. The resulting residue was taken up in DCM and saturated NaHCO ₃The aqueous solution was partitioned. The two-phase system was stirred at RT for 10min, after which the organic fraction was separated off and dried (MgSO₄) And concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC gradient eluted with 0-10% MeOH in DCM) to afford 292mg of a brown solid. The compound thus obtained was dissolved in 6N aqueous HCl (6mL) and the solution was heated in a sealed vial at 100 ℃ for 1 h. After cooling to the temperature of the reaction mixture at RT,the reaction mixture was washed with DCM and saturated NaHCO₃The aqueous solution was partitioned. The two-phase system was stirred at RT for 10min, after which the organic fraction was separated off and dried (MgSO₄) And concentrated in vacuo to give the title compound (243mg, 41%). LCMS (method J) R_T1.57min[M+H]⁺271.3。

(2-Nitropyridin-3-yl) phenylamines

3-fluoro-2-nitropyridine (1.07g,6.75mmol), aniline (1.8mL,20.2mmol) and Et₃A mixture of N (2.8mL,20.2mmol) in DMF (10mL) was stirred under a nitrogen atmosphere at 100 ℃ for 16 h. After cooling to RT, the volatiles were removed under reduced pressure. The resulting residue was partitioned between DCM and water. The aqueous phase was further extracted with DCM (× 3) and the combined organic fractions were dried (Na)₂SO₄) And concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient eluted with 0-4% MeOH in DCM) to give the title compound as a red oil (2.24g, quantitative yield). LCMS (method C) R _T3.03min[M+H]⁺216.2。

N³-phenylpyridine-2, 3-diamine

A mixture of (2-nitropyridin-3-yl) phenylamine (6.75mmol) in EtOAc (40mL) was degassed with a stream of nitrogen, then 10% Pd/C (200mg) was added and stirred at RT for 16h under a hydrogen atmosphere. The suspension was filtered and the filtrate was concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient eluted with 0-10% MeOH in DCM) to give the title compound as a white solid (520mg, 42% yield over two steps).¹H NMR(CDCl₃,400MHz):δ7.92(1H,dd,J=4.98,1.64Hz),7.36(1H,ddd,J=7.62,1.65,0.69Hz),7.26-7.20(2H,m),6.90-6.85(1H,m),6.78-6.73(2H,m),6.68(1H,dd,J=7.61,4.98Hz),5.13(1H,br s),4.57(2H,br s)。

[ (S) -1- (3-Phenylaminopyridin-2-ylcarbamoyl) ethyl ] carbamic acid tert-butyl ester

Triethylamine (1.5mL,11.0mmol) was added to N at 0 deg.C under a nitrogen atmosphere³-phenylpyridine-2, 3-diamine (510mg,2.75mmol), (S) -2-tert-butoxycarbonylaminopropionic acid (0.94g,4.96mmol), HOAt (670mg,4.96mmol) and N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride (0.95g,4.96mmol) in a mixture of anhydrous DCM (30 mL). The reaction mixture was stirred at 0 ℃ for 10min and then slowly warmed to RT. Stirring was continued at RT for 18 h. The reaction mixture was washed with DCM and saturated NaHCO₃The aqueous solution was partitioned. The aqueous phase was further extracted with DCM (× 3), the combined organic fractions were washed with water and dried (Na)₂SO₄) And concentrated in vacuo to give the title compound as a light brown foam (1.17g, quantitative yield). LCMS (method C) R _T3.04min[M+H]⁺357.3。

[ (S) -1- (1-phenyl-1H-imidazo [4,5-b ] pyridin-2-yl) ethyl ] carbamic acid tert-butyl ester

Reacting [ (S) -1- (3-phenylaminopyridin-2-ylcarbamoyl) ethyl]A mixture of tert-butyl carbamate (980mg,2.75mmol) in AcOH (25mL) was heated at 75 ℃ under a nitrogen atmosphere for 10 h. Volatiles were removed in vacuo and the resulting residue was taken up in DCM and saturated NaHCO₃The aqueous solution was partitioned. The aqueous phase was further extracted with DCM (. times.3) and the combined organic fractions were washed with brineWashed with water, then brine, then dried (Na)₂SO₄) And concentrated in vacuo to give the title compound as a light brown foam (920mg, 99%). LCMS (method C) R_T2.88min[M+H]⁺339.3。

(S) -1- (1-phenyl-1H-imidazo [4,5-b ] pyridin-2-yl) ethylamine

To [ (S) -1- (1-phenyl-1H-imidazo [4,5-b ]]Pyridin-2-yl) ethyl]To a solution of tert-butyl carbamate (910mg,2.69mmol) in DCM (5mL) was added TFA (15mL) and the mixture was stirred at RT for 15 min. Volatiles were removed under vacuum, the resulting residue was dissolved in DCM and saturated NaHCO₃And (4) washing with an aqueous solution. The aqueous phase was further extracted with DCM (× 3) and the combined organic fractions were dried (Na)₂SO₄) And concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC,0-10%2M NH) ₃Gradient eluent in DCM/MeOH) to give the title compound as a brown solid (340mg, 53%).¹H NMR(CDCl₃,400MHz):δ8.55(1H,dd,J=4.78,1.56Hz),7.65-7.53(3H,m),7.45-7.37(3H,m),7.15(1H,dd,J=8.04,4.78Hz),4.18(1H,q,J=6.71Hz),3.49(2H,s),1.48(3H,d,J=6.71Hz)。

6-fluoro-3-nitro-2-phenylaminobenzoic acid

To a solution of 2, 6-difluoro-3-nitrobenzoic acid (5g,24.6mmol) in EtOH (25mL) and water (25mL) at 0 deg.C was added Et₃N (6.2mL,44.3mmol) and aniline (2.3g,24.6 mmol). The reaction mixture was heated at 70 ℃ for 4h under a nitrogen atmosphere. After cooling to RT, the pH of the solution was adjusted to 1 by adding 1N HCl. A precipitate is formed, which is collected by filtrationThe solid was washed with water to give the title compound (6.0g, 88%).¹H NMR(DMSO-d₆,400MHz):δ9.02(1H,s),8.18(1H,dd,J=9.29,5.78Hz),7.25-7.16(2H,m),7.05(1H,t,J=9.07Hz),7.00-6.91(3H,m)

6-fluoro-3-nitro-2-phenylaminobenzoic acid methyl ester

Trimethylsilyldiazomethane (2M in hexane, 7.24mL,14.5mmol) was added dropwise to a solution of 6-fluoro-3-nitro-2-phenylaminobenzoic acid (2.0g,7.24mmol) in MeOH (5mL) and DCM (40mL) at RT. The solution was stirred at RT for 45min, then volatiles were removed under reduced pressure to give the title compound (2.1g, quantitative yield).¹H NMR(CDCl₃,400MHz):δ9.67(1H,br s),8.32(1H,dd,J=9.47,5.75Hz),7.36-7.30(2H,m),7.23-7.07(3H,m),6.64(1H,dd,J=9.47,8.33Hz),3.27(3H,s)

3-amino-6-fluoro-2-phenylaminobenzoic acid methyl ester

To a mixture of methyl 6-fluoro-3-nitro-2-phenylaminobenzoate (2.1g,7.24mmol) in a mixture of MeOH (50mL) and water (15mL) was added NH₄Cl (2.23g,43.4mmol) and iron powder (1.61g,28.9mmol) and the reaction mixture was heated at 90 ℃ for 3 h. After cooling to RT, the suspension is taken up The pad was filtered and washed with additional MeOH. The filtrate was concentrated in vacuo to remove the organic solvent, and the resulting aqueous residue was extracted with EtOAc (× 3). The combined organic fractions were washed with brine and dried (MgSO)₄) And concentrated in vacuo to give the title compound as an orange oilIt solidified upon standing (2.0g, quantitative yield).¹H NMR(CDCl₃,400MHz):δ7.23-7.18(2H,m),7.13(1H,br s),6.89-6.80(3H,m),6.69-6.64(2H,m),3.83(3H,s)

2- ((S) -1-tert-Butoxycarbonylaminoethyl) -5-fluoro-3-phenyl-3H-benzimidazole-4-carboxylic acid methyl ester

A mixture of methyl 3-amino-6-fluoro-2-phenylanthranilate (2.0g,7.7mmol), (S) -2-tert-butoxycarbonylaminopropionic acid (1.6g,8.45mmol), HOAt (760mg,8.45mmol), 4-methylmorpholine (1.86mL,16.9mmol) and N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride (1.07g,8.45mmol) in DCM (20mL) was stirred at RT for 2 h. The reaction mixture was then washed with DCM and saturated NaHCO₃The aqueous solution was partitioned. The organic layer was washed with brine and dried (MgSO)₄) And concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient eluted with 0-100% EtOAc in cyclohexane) to afford methyl 3- ((S) -2-tert-butoxycarbonylaminopropionylamino) -6-fluoro-2-phenylanthranilate. LCMS (method B) R_T3.65min[M+H]⁺432.3。

A solution of the compound thus obtained in AcOH (15mL) was heated at 80 ℃ for 48 h. After cooling to RT, the volatile material was concentrated in vacuo and the residue was taken up in EtOAc and saturated NaHCO ₃The aqueous solution was partitioned. The aqueous phase was further extracted with EtOAc, and the combined organic fractions were washed with brine and dried (MgSO)₄) And then concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC gradient eluted with 0-100% EtOAc in cyclohexane) to afford the title compound (1.1g, 32%). LCMS (method C) R_T3.47min[M+H]⁺414.2。

5-fluoro-3-phenyl-2- { (S) -1- [9- (tetrahydropyran-2-yl) -9H-purin-6-ylamino ] ethyl } -3H-benzimidazole-4-carboxylic acid methyl ester

To a solution of methyl 2- ((S) -1-tert-butoxycarbonylaminoethyl) -5-fluoro-3-phenyl-3H-benzimidazole-4-carboxylate (1.1g,2.7mmol) in MeOH (20mL) was added 4N HCl in bisAlkane solution (5mL) and the reaction mixture was heated at 45 ℃ for 3 h. Volatiles were removed under reduced pressure and the resulting residue was treated with 6-chloro-9- (tetrahydropyran-2-yl) -9H-purine (825mg,3.46mmol) and DIPEA (1.8mL,10.6mmol) in n-butanol (10 mL). The reaction mixture was heated at 90 ℃ for 16h in a sealed vial. After cooling to RT, the volatiles were removed under reduced pressure and the resulting residue was purified by column chromatography (Si-PCC, gradient elution of 0-10% MeOH in EtOAc) to give the title compound (1.2g, 87%). LCMS (method C) R_T3.11min[M+H]⁺516.2。

5-fluoro-3-phenyl-2- { (S) -1- [9- (tetrahydropyran-2-yl) -9H-purin-6-ylamino ] ethyl } -3H-benzimidazole-4-carboxylic acid

Reacting 5-fluoro-3-phenyl-2- { (S) -1- [9- (tetrahydropyran-2-yl) -9H-purin-6-ylamino]Ethyl } -3H-benzimidazole-4-carboxylic acid methyl ester (580mg,1.13mmol) and LiOH. H₂A solution of O (94mg,2.25mmol) in MeOH (20mL) and water (2mL) was heated at 45 deg.C for 3 h. Addition of additional LiOH. H₂O (94mg), the mixture was heated at 80 ℃ for 16 h. Further adding LiOH. H₂After O (94mg), stirring was continued at 75 ℃ for 18 h. After cooling to RT, the pH of the mixture was adjusted to 4 by addition of 1N HCl. The organic solvent was removed under reduced pressure and EtOAc was added to the crude mixture. After sonication of the suspension, the organic solvent was removed in vacuo. By passingThe solid was collected by filtration and dried in vacuo to give the title compound (412mg, 73%). LCMS (method C) R_T2.40min[M+H]⁺502.0。

(3-fluoro-2-methyl-6-nitrophenyl) phenylamine

LiHMDS (1.0M THF solution, 12.9mL,12.9mmol) was added dropwise to a stirred solution of aniline (633mg,6.79mmol) in anhydrous THF (10mL) at-78 deg.C under a nitrogen atmosphere. After stirring at-78 ℃ for 10min, a solution of 1, 3-difluoro-2-methyl-4-nitrobenzene (1.12g,6.47mmol) in THF (5mL) was added and stirring continued for 30 min. The reaction mixture was quenched by addition of water and diluted with EtOAc. Using the obtained emulsion The organic fraction was filtered and separated, washed with brine and dried (MgSO)₄). The volatiles were removed under vacuum and the resulting residue was purified by column chromatography (Si-PCC gradient eluted with 0-100% EtOAc in cyclohexane) to give the title compound (1.5g, 94%).¹H NMR(CDCl₃,400MHz):δ8.74(1H,br s),8.07(1H,dd,J=9.34,5.86Hz),7.30-7.23(2H,m),7.03(1H,t,J=7.41Hz),6.85-6.78(3H,m),1.92(3H,d,J=2.87Hz)。

4-fluoro-3-methyl-N²-phenyl-1, 2-diamines

To a mixture of (3-fluoro-2-methyl-6-nitrophenyl) phenylamine (1.5g,6.1mmol) in a 3:1 mixture of MeOH in water (40mL) was added NH₄Cl (1.88g,36.5mmol) and iron powder (1.36g,24.4mmol) and the reaction mixture was heated at 90 ℃ for 1 h. After cooling to RT, the solid was usedThe pad was filtered off and washed with additional MeOH. The filtrate was concentrated in vacuo and the resulting residue partitioned between EtOAc and water. The aqueous phase was further extracted with EtOAc (× 3), the combined organic fractions were washed with brine and dried (MgSO)₄) And concentrated in vacuo to give the title compound as a pink solid (1.16g, 88%).¹H NMR(CDCl₃,400MHz):δ7.22-7.15(2H,m),6.88-6.77(2H,m),6.64-6.55(3H,m),5.03(1H,br s),3.68(2H,br s),2.11(3H,d,J=2.24Hz)。

(S) -1- (6-fluoro-7-methyl-1-phenyl-1H-benzimidazol-2-yl) ethylamine dihydrochloride

Reacting 4-fluoro-3-methyl-N²A mixture of-phenyl-benzene-1, 2-diamine (600mg,2.77mmol), (S) -2-tert-butoxycarbonylaminopropionic acid (577mg,3.05mmol), HOAt (415mg,3.05mmol), 4-methylmorpholine (0.67mL,6.1mmol) and N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride (586mg,3.05mmol) in DCM (10mL) was stirred at RT for 1 h. The reaction mixture was diluted with water and extracted with DCM (× 3). The combined organic fractions were washed with brine and dried (MgSO) ₄) And concentrated in vacuo.

The residue obtained is dissolved in 4N HCl bisAlkane solution (15mL) and the solution was heated at 70 ℃ for 2 h. The volatiles were removed in vacuo and the resulting residue was taken up in EtOAc and saturated NaHCO₃The aqueous solution was partitioned. The aqueous phase was further extracted with EtOAc, the combined organic fractions were washed with water, then brine and dried (MgSO)₄). Volatiles were removed under vacuum and the resulting residue was purified by column chromatography (Si-PCC with a gradient elution of 0-10% MeOH in DCM) to afford the title compoundThe title compound (662mg, 89%).¹H NMR(CDCl₃,400MHz):δ7.63-7.52(4H,m),7.46-7.36(2H,m),7.05-6.97(1H,m),3.93(1H,q,J=6.72Hz),1.77(3H,d,J=2.06Hz),1.44(3H,d,J=6.40Hz)。

(R) -1- (6-fluoro-7-methyl-1-phenyl-1H-benzimidazol-2-yl) -2-methoxyethylamine

Reacting 4-fluoro-3-methyl-N²A mixture of-phenyl-benzene-1, 2-diamine (560mg,2.59mmol), (S) -2-tert-butoxycarbonylamino-3-methoxypropionic acid (624mg,2.85mmol), HOAt (388mg,2.85mmol), 4-methylmorpholine (626. mu.L, 5.69mmol) and N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride (547mg,2.85mmol) in DCM (10mL) was stirred at RT for 1 h. The reaction mixture was partitioned between DCM and water. The aqueous phase was further extracted with DCM and the combined organic fractions were washed with brine and dried (MgSO)₄) And concentrated in vacuo. The residue obtained is dissolved in 4N HCl bis Alkane solution (5mL) and the mixture was heated at 70 ℃ for 2 h. The volatiles were removed in vacuo and the resulting residue was taken up in EtOAc and saturated NaHCO₃The aqueous solution was partitioned. The aqueous phase was further extracted with EtOAc, and the combined organic fractions were washed with brine and dried (MgSO)₄) And concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient eluted with 0-10% MeOH in DCM) to give the title compound (545mg, 70%). LCMS (method C) R_T3.95min[M+H]⁺300.2。

(3-chlorophenyl) - (3-nitropyridin-2-yl) amine

A mixture of 2-chloro-3-nitropyridine (317mg,2.0mmol), 3-chlorophenylamine (0.212mL,2.0mmol) and potassium carbonate (829mg,6.0mmol) in DMF (3mL) was heated at 140 ℃ for 30min with microwave radiation. After cooling to RT, the reaction mixture was partitioned between EtOAc and water. The aqueous phase was extracted with EtOAc (× 3), the combined organic fractions were washed with brine and dried (Na)₂SO₄) And concentrated in vacuo. The resulting brown oil (370mg) was purified by column chromatography (Si-PCC, gradient elution of 0-100% DCM in cyclohexane) to give the title compound as a red solid (111mg, 22%). LCMS (method B) R_T3.95min[M+H]⁺250.0。

N²- (3-chlorophenyl) pyridine-2, 3-diamine

To a mixture of (3-chlorophenyl) - (3-nitropyridin-2-yl) amine (111mg,0.45mmol) in 3:1 MeOH/water mixture (20mL) was added NH ₄Cl (154mg,2.88mmol) and iron powder (107mg,1.92mmol), the reaction mixture was heated at 90 ℃ for 3 h. After cooling to RT, the solid was usedThe pad was filtered off and the filtrate was concentrated in vacuo. The resulting residue was partitioned between EtOAc and water. The aqueous phase was further extracted with EtOAc (× 3), the combined organic fractions were washed with brine and dried (Na)₂SO₄) And concentrated in vacuo. The resulting brown oil was purified by column chromatography (Si-PCC, gradient eluted with 0-10% MeOH in DCM) to give the title compound as a brown solid (29mg, 30%). LCMS (method C) R_T1.84min[M+H]⁺220.1。

{ (S) -1- [3- (3-chlorophenyl) -3H-imidazo [4,5-b ] pyridin-2-yl ] ethyl } carbamic acid tert-butyl ester

Will N²A mixture of- (3-chlorophenyl) pyridine-2, 3-diamine (29mg,0.13mmol), (S) -2-tert-butoxycarbonylaminopropionic acid (27mg,0.15mmol), HOAt (20mg,0.15mmol), 4-methylmorpholine (32. mu.L, 0.29mmol) and N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride (28mg,0.15mmol) in DCM (5mL) was stirred at RT for 1h, then allowed to stand at RT for 64 h. The reaction mixture was washed with DCM and saturated NaHCO₃The solutions were partitioned. The organic fraction was washed with brine and dried (Na)₂SO₄) And concentrated in vacuo. The resulting brown oil was combined as { (S) -1- [2- (3-chlorophenylamino) pyridin-3-ylcarbamoyl ]Ethyl } carbamic acid tert-butyl ester (44mg) was dissolved in AcOH (3mL) and heated at 70 ℃ for 4 h. After cooling to RT, the volatiles were removed under vacuum. The resulting residue was washed with EtOAc and saturated NaHCO₃The aqueous solution was partitioned. The organic fraction was washed with water, then brine, then dried (Na)₂SO₄) And concentrated in vacuo. The resulting brown oil was purified by column chromatography (Si-PCC, gradient eluted with 0-5% MeOH in DCM) to give the title compound as an orange/brown oil (35mg, 72% over two steps). LCMS (method C) R_T3.34min[M+H]⁺373.2。

{ (S) -1- [3- (4-chlorophenyl) -3H-imidazo [4,5-b ] pyridin-2-yl ] ethyl } carbamic acid tert-butyl ester

Will N²A mixture of- (4-chlorophenyl) pyridine-2, 3-diamine (64mg,0.291mmol), (S) -2-tert-butoxycarbonylaminopropionic acid (61mg,0.32mmol), HOAt (44mg,0.32mmol), 4-methylmorpholine (70. mu.L, 0.641mmol) and N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride (61mg,0.32mmol) in DCM (10mL) was stirred at RT for 1h, then allowed to stand at RTAnd placing for 64 h. The reaction mixture was washed with DCM and saturated NaHCO₃The aqueous solution was partitioned. The organic fraction was washed with brine, dried and concentrated in vacuo. The resulting brown oil was combined as { (S) -1- [2- (4-chlorophenylamino) pyridin-3-ylcarbamoyl ]Ethyl } carbamic acid tert-butyl ester (136mg) was dissolved in AcOH (5mL) and heated at 70 ℃ for 4 h. After cooling to RT, the volatiles were removed under reduced pressure. The resulting residue was washed with EtOAc and saturated NaHCO₃The aqueous solution was partitioned. The organic fraction was washed with water and then brine, dried (Na)₂SO₄) And concentrated in vacuo. The resulting brown oil was purified by column chromatography (Si-PCC, gradient eluted with 0-5% MeOH in DCM) to give the title compound as an orange/brown oil (99mg, 91% over two steps). LCMS (method C) R_T3.33min[M+H]⁺373.2。

(5-fluoro-2-nitrophenyl) - (6-fluoropyridin-3-yl) amine

LiHMDS (1.0M in THF, 5.0mL,5.0mmol) was added dropwise to a stirred solution of 6-fluoropyridin-3-ylamine (294mg,2.63mmol) in anhydrous THF (5mL) at-78 deg.C under a nitrogen atmosphere. After stirring at-78 ℃ for 30min, a solution of 2, 4-difluoro-1-nitrobenzene (275 μ L,2.50mmol) in THF (5mL) was added and stirring continued at-78 ℃ for 1 h. Pour solution into NH₄Aqueous Cl and extracted with EtOAc (× 3). The combined organic fractions were washed with brine and dried (Na)₂SO₄) And concentrated in vacuo. The resulting residue was purified by column chromatography (gradient elution of Si-PCC,0-100% DCM in cyclohexane) to give the title compound as a yellow solid (571mg, 91%). LCMS (method C) R _T3.33min[M+H]⁺252.1。

4-fluoro-N²- (6-fluoropyridin-3-yl) benzene-1, 2-diamine

A mixture of (5-fluoro-2-nitrophenyl) - (6-fluoropyridin-3-yl) amine (571mg,2.27mmol) in EtOAc (40mL) was degassed with a stream of nitrogen, then 10% Pd/C (57mg) was added and stirred at RT for 22h under a hydrogen atmosphere. The mixture was filtered through a phase separator and the filtrate was concentrated in vacuo to give the title compound as a dark oil (524mg, quantitative yield). LCMS (method C) R_T2.39min[M+H]⁺222.2。

{ (S) -1- [ 4-fluoro-2- (6-fluoropyridin-3-ylamino) phenylcarbamoyl ] ethyl } carbamic acid tert-butyl ester

Reacting 4-fluoro-N²A mixture of (6-fluoropyridin-3-yl) benzene-1, 2-diamine (524mg,2.37mmol), (S) -2-tert-butoxycarbonylaminopropionic acid (493mg,2.61mmol), HOAt (355mg,2.61mmol), 4-methylmorpholine (575. mu.L, 5.21mmol) and N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride (500mg,2.61mmol) in DCM (20mL) was stirred at RT for 3 h. The reaction mixture was washed with DCM and saturated NaHCO₃The aqueous solution was partitioned. The organic layer was washed with brine and dried (Na)₂SO₄) And concentrated in vacuo to give the title compound as a yellow solid (973mg, quantitative yield). LCMS (method C) R_T3.25min[M+H]⁺393.3。

(S) -2-amino-N- [ 4-fluoro-2- (6-fluoropyridin-3-ylamino) phenyl ] propanamide

Reacting { (S) -1- [ 4-fluoro-2- (6-fluoropyridin-3-ylamino) phenylcarbamoyl ]Ethyl } carbamic acid tert-butyl esterA mixture of (276mg,0.70mmol) in DCM (1mL) and TFA (1mL) was stirred at RT for 3 h. Loading the reaction mixture intoSCX-2 column, then MeOH, then 2M NH₃Washing with MeOH. The basic fractions were combined and concentrated in vacuo to give the title compound as a yellow oil (193mg, 94%). LCMS (method C) R_T0.29 and 1.93min [ M + H ]]⁺293.2。

(S) -N- [ 4-fluoro-2- (6-fluoropyridin-3-ylamino) phenyl ] -2- (9H-purin-6-ylamino) propanamide

Reacting (S) -2-amino-N- [ 4-fluoro-2- (6-fluoropyridin-3-ylamino) phenyl]A mixture of propionamide (193mg,0.66mmol), 6-chloro-9- (tetrahydropyran-2-yl) -9H-purine (165mg,0.69mmol) and DIPEA (0.34mL,1.98mmol) in n-butanol (1mL) was heated at 100 ℃ for 16H in a sealed vial. After cooling to RT, the volatiles were removed under vacuum and the resulting residue was loadedSCX-2 column, then MeOH, then 2M NH₃Washing with MeOH. The basic fractions were combined and concentrated in vacuo to give the title compound as a red solid (255mg, 94%). LCMS (method C) R_T2.40min[M+H]⁺411.2。

{ (S) -1- [ 6-fluoro-1- (6-methoxypyridin-3-yl) -1H-benzimidazol-2-yl ] ethyl } carbamic acid tert-butyl ester

Reacting { (S) -1- [ 4-fluoro-2- (6-fluoropyridin-3-ylamino) Yl) phenylcarbamoyl]A suspension of tert-butyl ethyl carbamate (196mg,0.50mmol) in 0.5M NaOMe in MeOH (2.0mL,1.0mmol) was heated at 120 deg.C for 15min with microwave radiation. The crude reaction mixture was diluted with MeOH and loaded ontoSCX-2 column, then MeOH, then 2M NH₃Washing with MeOH. The basic fractions were combined and concentrated in vacuo and the resulting residue was purified by column chromatography (Si-PCC, gradient eluted with 0-5% MeOH in DCM) to give the title compound as a pink oil (52mg, 27%). LCMS (method C) R_T3.42min[M+H]⁺387.2。

(5-fluoro-2-nitrophenyl) - (5-fluoropyridin-2-yl) amine

LiHMDS (1.0M in THF, 4.0mL,4.0mmol) was added dropwise to a stirred solution of 5-fluoropyridin-2-ylamine (224mg,2.0mmol) in anhydrous THF (5mL) at-78 deg.C under a nitrogen atmosphere. After stirring at-78 ℃ for 15min, a solution of 2, 4-difluoro-1-nitrobenzene (0.22mL,2.0mmol) in THF (5mL) was added and stirring continued at-78 ℃ for 30 min. The mixture was slowly warmed to 0 ℃ and then the reaction mixture was poured onto NH₄Cl saturated solution (50 mL). The aqueous phase was extracted with EtOAc (× 3), the combined organic fractions were washed with water then brine, dried (Na)₂SO₄) And concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC gradient eluted with 0-40% EtOAc in cyclohexane) to give the title compound as an orange solid (34mg, 7%). LCMS (method C) R _T3.81min[M+H]⁺252.1。

4-fluoro-N²- (5-fluoropyridin-2-yl) benzene-1, 2-diamine

A mixture of (5-fluoro-2-nitrophenyl) - (5-fluoropyridin-2-yl) amine (34mg,0.14mmol) in EtOAc (5mL) was degassed with a stream of nitrogen, then 10% Pd/C (10mg) was added and stirred at RT for 3h under a hydrogen atmosphere. The mixture was filtered through a phase separator and the filtrate was concentrated in vacuo to give the title compound as a dark oil (30mg, quantitative yield). LCMS (method C) R_T1.95min[M+H]⁺222.2。

{ (S) -1- [ 6-fluoro-1- (5-fluoropyridin-2-yl) -1H-benzimidazol-2-yl ] ethyl } carbamic acid tert-butyl ester

Reacting 4-fluoro-N²A mixture of (5-fluoropyridin-2-yl) benzene-1, 2-diamine (30mg,0.136mmol), (S) -2-tert-butoxycarbonylaminopropionic acid (28mg,0.15mmol), HOAt (20mg,0.15mmol) and N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride (29mg,0.15mmol) in DCM (5mL) was stirred at 0 ℃ for 1 h. Additional (S) -2-tert-butoxycarbonylaminopropionic acid (5mg), HOAt (4mg), and N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride (5mg) were added and stirring was continued for 30 min. The reaction mixture was washed with DCM and saturated NaHCO₃The aqueous solution was partitioned. The organic layer was dried and concentrated in vacuo to give { (S) -1- [ 4-fluoro-2- (5-fluoropyridin-2-ylamino) phenylcarbamoyl ]Ethyl } carbamic acid tert-butyl ester as an orange oil. LCMS (method C) R_T3.51min[M+H]⁺393.1。

A mixture of the compound thus obtained in AcOH (5mL) was heated at 70 ℃ for 16 h. The volatiles were removed under reduced pressure and the resulting residue was washed with EtOAc and saturated NaHCO₃The aqueous solution was partitioned. The organic fraction was washed with water, then brine, then dried (Na)₂SO₄) And concentrated in vacuo. The resulting oil was purified by column chromatography (Si-PCC, usingGradient elution with 0-5% MeOH in DCM) gave the title compound as an orange oil (33mg, 65%). LCMS (method C) R_T3.38min[M+H]⁺375.2。

3- (5-fluoro-2-nitrophenylamino) azetidine-1-carboxylic acid tert-butyl ester

2, 4-difluoro-1-nitrobenzene (3.69g,23.2mmol), 3-aminoazetidine-1-carboxylic acid tert-butyl ester (4.0g,23.2mmol) and DIPEA (3.97mL,23.2mmol) in CH₃The mixture in CN (37mL) was stirred under nitrogen atmosphere at RT for 18 h. The volatiles were removed under vacuum and the resulting residue was purified by column chromatography (Si-PCC gradient eluted with 0-40% EtOAc in cyclohexane) to give the title compound as a yellow solid (4.84g, 67%). LCMS (method B) R_T3.80min[M+H]⁺312.1。

3- (2-amino-5-fluorophenylamino) azetidine-1-carboxylic acid tert-butyl ester

A mixture of tert-butyl 3- (5-fluoro-2-nitrophenylamino) azetidine-1-carboxylate (4.84g,15.54mmol) in EtOAc (100mL) was degassed with a stream of nitrogen, then 10% Pd/C (500mg) was added and stirred at RT under a hydrogen atmosphere for 16 h. An additional 10% Pd/C (500mg) was added and stirring continued under a hydrogen atmosphere for 6 h. The mixture was filtered and the filtrate was concentrated in vacuo to give the title compound as a brown foam (4.4g, quantitative yield). LCMS (method J) R _T2.39 and 2.60min [ M + H ]]⁺282.1。

3- [2- ((S) -2-Benzyloxycarbonylaminopropionylamino) -5-fluoro-phenylamino ] azetidine-1-carboxylic acid tert-butyl ester

A mixture of tert-butyl 3- (2-amino-5-fluorophenylamino) azetidine-1-carboxylate (15.5mmol), (S) -2-benzyloxycarbonylaminopropionic acid (3.81g,17.1mmol), HOAt (2.32g,17.1mmol), 4-methylmorpholine (3.75mL,34.1mmol) and N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride (3.27g,17.1mmol) in DCM (53mL) was stirred at RT for 2 h. The reaction mixture was washed with EtOAc and saturated NaHCO₃The aqueous solution was partitioned. The aqueous phase was further extracted with EtOAc (× 3), the combined organic fractions were washed with water then brine and then dried (Na)₂SO₄) And concentrated in vacuo to give the title compound as a yellow oil (quantitative yield). LCMS (method B) R_T3.63min[M+H]⁺487.3。

3- [2- ((S) -1-Benzyloxycarbonylaminoethyl) -6-fluorobenzoimidazol-1-yl ] azetidine-1-carboxylic acid tert-butyl ester

Reacting 3- [2- ((S) -2-benzyloxycarbonylaminopropionylamino) -5-fluoro-phenylamino]A mixture of azetidine-1-carboxylic acid tert-butyl ester (15.52mmol) in AcOH (110mL) was heated at 60 ℃ for 18h, at 70 ℃ for 24h, then at 80 ℃ for 6 h. The volatiles were removed in vacuo and the resulting residue was taken up in EtOAc and saturated NaHCO ₃The aqueous solution was partitioned. The aqueous phase was further extracted with EtOAc (× 3), the combined organic fractions were washed with water then brine and then dried (Na)₂SO₄) And concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC gradient eluted with 0-60% EtOAc in cyclohexane) to afford the title compound as a yellow oil (3.23g, 44%). LCMS (method J) R_T3.60min[M+H]⁺469.1。

3- [2- ((S) -1-aminoethyl) -6-fluorobenzoimidazol-1-yl ] azetidine-1-carboxylic acid tert-butyl ester

Reacting 3- [2- ((S) -1-benzyloxycarbonylaminoethyl) -6-fluorobenzoimidazol-1-yl]A mixture of tert-butyl azetidine-1-carboxylate (524mg,1.12mmol) in IMS (18mL) was degassed with a stream of nitrogen, then 10% Pd/C (100mg) was added and stirred at RT for 64h under a hydrogen atmosphere. The mixture was filtered, washed with IMS and the filtrate was concentrated in vacuo. With 3- [2- ((S) -1-benzyloxycarbonylaminoethyl) -6-fluorobenzoimidazol-1-yl]Tert-butyl azetidine-1-carboxylate (2.11g,4.5mmol) the same procedure was repeated and the two residues were combined. The product was purified by column chromatography (Si-PCC, gradient eluted with 0-10% MeOH in DCM) to give the title compound as a yellow foam (1.17g, 62%).¹H NMR(CDCl₃,300MHz):δ7.68(1H,dd,J=8.85,4.93Hz),7.45(1H,dd,J=9.04,2.37Hz),7.04(1H,td,J=9.19,2.31Hz),5.67-5.54(1H,m),4.56-4.43(4H,m),4.30(1H,q,J=6.64Hz),1.68(2H,br s),1.60-1.49(12H,m)。327301

2-chloro-N- (4-fluoro-2-phenylaminophenyl) acetamide

Chloroacetyl chloride (0.68mL,8.58mmol) was added dropwise to a stirred 4-fluoro-N at 0 deg.C under a nitrogen atmosphere²-phenyl-benzene-1, 2-diamine (1.24g,6.13mmol) and pyridine (2.0mL,24.5mmol) in DCM (8 mL). Stirring was continued for 20min at 0 ℃ and then for 2h at RT. The reaction mixture was partitioned between 1M aqueous HCl (50mL) and DCM, cooled to 0 ℃. The aqueous phase was further extracted with DCM (× 3), the combined organic fractions were washed with water and dried (Na)₂SO₄) And concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient eluted with 30-100% DCM in cyclohexane) to give the title compound as a white crystalline solid (750mg, 44%). LCMS (method C) R_T3.39min[M+H]⁺279.2。

2-chloromethyl-6-fluoro-1-phenyl-1H-benzimidazoles

A mixture of 2-chloro-N- (4-fluoro-2-phenylaminophenyl) acetamide (740mg,2.62mmol) in AcOH (20mL) was heated at 70 ℃ for 5h under a nitrogen atmosphere. Volatiles were removed in vacuo and the resulting residue was taken up in DCM and saturated NaHCO₃The aqueous solution was partitioned. The aqueous phase was further extracted with DCM (× 3), the combined organic fractions were washed with water and dried (Na)₂SO₄) And concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient eluted with 0-5% MeOH in DCM) to give the title compound as a brown oil which crystallized on standing (570mg, 84%). LCMS (method C) R _T3.40min[M+H]⁺261.2。

(5-fluoro-2-nitrophenyl) pyridin-2-yl-amine (preparation 1)

LiHMDS (1.0M in THF, 62mL,6.2mmol) was added dropwise to a stirred solution of pyridin-2-ylamine (3.1g,33mmol) in anhydrous THF (50mL) at-78 deg.C under a nitrogen atmosphere. After stirring at-78 ℃ for 30min, 2, 4-difluoro-1-nitrobenzene (3.4mL,31mmol) was added and stirring continued at-78 ℃ for 30 min. The reaction mixture was slowly warmed to RT and after 5h by addition of saturated NH₄Aqueous Cl (150mL) was quenched. The mixture was partitioned between EtOAc and water and then washed withAnd (5) filtering. The organic fraction was dried (MgSO)₄) Concentrated in vacuo and the resulting residue purified by column chromatography (Si-PCC, gradient elution of 0-50% DCM in cyclohexane) to give the title compound as an orange solid (3.9g, 54%).¹H NMR(CDCl₃,400MHz):δ10.48(1H,s),8.82(1H,dd,J=12.32,2.77Hz),8.38(1H,dd,J=5.03,1.87Hz),8.34-8.25(1H,m),7.70-7.64(1H,m),7.03-6.94(2H,m),6.68-6.61(1H,m)。

Preparation 2 sodium hydride (48.6g,60% by weight, 1.22mol) was added portionwise to a solution of 2-aminopyridine (57.2g,0.61mol) in THF (400mL) at 0 ℃ at a rate such that T.ltoreq.18 ℃. The reaction mixture was stirred at 0 ℃ for 10min and then added via cannula (cannula) to a solution of 2, 4-difluoronitrobenzene in THF (350mL) at-20 ℃ at a rate such that T.ltoreq.10 ℃. The reaction was stirred at-40 ℃ for 1h and then allowed to warm to RT. When the reaction reached RT, the temperature rose rapidly to 35 ℃ and effervescence was observed. The reaction mixture was poured onto ice (. about.2L) and the solid formed was collected by filtration. The solid was washed with pentane and dried in vacuo to give (5-fluoro-2-nitrophenyl) pyridin-2-yl-amine as a bright orange solid (139.3g, 94%).

4-fluoro-N²-pyridin-2-yl-benzene-1, 2-diamine

A mixture of (5-fluoro-2-nitrophenyl) pyridin-2-yl-amine (3.92g,17mmol) in EtOAc (150mL) was degassed with a stream of nitrogen, then 10% Pd/C (500mg) was added and stirred at RT for 18h under a hydrogen atmosphere. The suspension was filtered through a phase separator and the filtrate was concentrated in vacuo to give the title compound as a black solid (3.5g, quantitative yield).

[ (S) -tert-butyl 1- (6-fluoro-1-pyridin-2-yl-1H-benzimidazol-2-yl) ethyl ] carbamate (preparation 1)

To a solution of (S) -Boc-alaninamide (1.5g,7.9mmol) in anhydrous THF (20mL) under nitrogen atmosphere was added triethyloxy in one portionTetrafluoroborate (1.6g,8.3 mmol). The resulting mixture was stirred at RT for 2 h. Volatiles were removed under vacuum and the resulting residue was redissolved in anhydrous EtOH (20 mL). Adding 4-fluoro-N to the mixture²Pyridin-2-yl-benzene-1, 2-diamine (1.0g,4.9mmol) and the mixture was stirred at 75 ℃ for 16 h. Volatiles were removed in vacuo and the resulting residue was taken up in DCM and saturated NaHCO₃The aqueous solution was partitioned. The aqueous phase was further extracted with DCM and the combined organic fractions were washed with water and dried (MgSO)₄) And concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient eluted with 0-40% EtOAc in cHex) to give the title compound as an orange oil (1.6g, 92%). LCMS (method B) R _T3.21min[M+H]⁺357.0。

(preparation 2) to a suspension of (S) -Boc-alaninamide (79.4g,0.42mol) in DCM (750mL) was added triethyloxy-chlorideTetrafluoroborate (69.5g,0.37mol) and the reaction mixture was stirred at RT for 2h, during which time the solid dissolved. The reaction mixture was concentrated in vacuo and the residue was dissolved in ethanol (750 mL). (5-fluoro-2-nitrophenyl) pyridin-2-yl-amine (57.1g,0.28mol) was added and the reaction was heated at 70 ℃ for 1 h. The reaction mixture was concentrated in vacuo, the residue was dissolved in water and the product was extracted with EtOAc (3 × 150 mL). The combined organic extracts were washed with brine and dried (MgSO)₄) And concentrated in vacuo. The residue obtained is treated by flash chromatography (SiO)₂Cyclohexane with 0-100% EtOAcAlkane solution elution) to give the title compound as a white foam (60.3mg, 60%).

(S) -1- (6-fluoro-1-pyridin-2-yl-1H-benzimidazol-2-yl) ethylamine

To [ (S) -1- (6-fluoro-1-pyridin-2-yl-1H-benzimidazol-2-yl) ethyl]To a solution of tert-butyl carbamate (1.6g,4.5mmol) in DCM (24mL) was added TFA (12mL) and the mixture was stirred at RT for 1 h. Volatile materials were removed under vacuum and the resulting residue was loaded ontoSCX-2 column. The column was washed with MeOH, then 2M NH ₃Washing with MeOH. The basic fractions were combined and concentrated in vacuo to give the crude material as a yellow oil (764mg,66%), which was used without further purification. LCMS (method B) R_T1.63min[M+H]⁺256.9。

((S) -1-carbamoylpropyl) carbamic acid tert-butyl ester

To a solution of (S) -2-tert-butoxycarbonylaminobutyric acid (1.2g,5.8mmol) in anhydrous THF (20mL) cooled to-15 deg.C was added N-methylmorpholine (0.64mL,5.8mmol) and isobutyl chloroformate (0.75mL,5.8mmol) under a nitrogen atmosphere. After 2 min, 33% aqueous ammonia (0.5mL,8.7mmol) was added and the resulting mixture was stirred at-15 ℃ for 2 h. The reaction mixture was warmed to RT and then washed with EtOAc and saturated NaHCO₃The aqueous solution was partitioned. The combined organic fractions were washed with 5% NaHCO₃Aqueous solution, water washing, and drying (MgSO)₄) And concentrated in vacuo. The resulting white solid was used without further purification(1.0g,85%)。¹H NMR(CDCl₃,300MHz):δ6.15(1H,br s),5.63(1H,br s),5.08(1H,br s),4.05(1H,br s),1.95-1.80(1H,m),1.70-1.53(1H,m),1.40(9H,s),0.95(3H,d,J=6.71Hz)。327997

[ (S) -1- (6-fluoro-1-pyridin-2-yl-1H-benzimidazol-2-yl) propyl ] carbamic acid tert-butyl ester

To a solution of tert-butyl ((S) -1-carbamoyl-propyl) carbamate (510mg,2.5mmol) in anhydrous THF (8mL) under a nitrogen atmosphere was added triethyloxy in one portionTetrafluoroborate (520mg,2.7 mmol). The resulting mixture was stirred at RT for 2 h. Volatiles were removed under vacuum and the resulting residue was redissolved in anhydrous EtOH (8 mL). To the mixture was added 4-fluoro-N-2-pyridin-2-yl-benzene-1, 2-diamine (318mg,1.6mmol) and the mixture was stirred at 75 ℃ for 16 h. Volatiles were removed under reduced pressure and the resulting residue was taken up in DCM and saturated NaHCO ₃The aqueous solution was partitioned. The aqueous phase was further extracted with DCM and the combined organic fractions were washed with water and dried (MgSO)₄) And concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient eluted with 0-40% EtOAc in cHex) to give the title compound as an orange oil (0.557)_g94%). LCMS (method B) R_T3.45min[M+H]⁺371.1。

(S) -1- (6-fluoro-1-pyridin-2-yl-1H-benzimidazol-2-yl) propylamine

To [ (S) -1- (6-fluoro-1-pyridin-2-yl-1H-benzimidazol-2-yl)Propyl radical]To a solution of tert-butyl carbamate (557mg,1.5mmol) in DCM (8mL) was added TFA (4mL) and the mixture was stirred at RT for 1 h. Volatile materials were removed under vacuum and the resulting residue was loaded ontoSCX-2 column. The column was washed with MeOH, then 2M NH₃Washing with MeOH. The basic fractions were combined and concentrated in vacuo. The crude material was used in the next step without further purification. Yellow oil (349mg, 86%). LCMS (method B) R_T1.75min[M+H]⁺270.92。

((S) -1-carbamoyl-2-methoxyethyl) carbamic acid tert-butyl ester

To a solution of (S) -2-tert-butoxycarbonylamino-3-methoxypropionic acid (1.13g,5.2mmol) in anhydrous THF (20mL) at-15 deg.C under a nitrogen atmosphere were added N-methylmorpholine (0.57mL,5.2mmol) and isobutyl chloroformate (0.67mL,5.2 mmol). After 2 min, 33% aqueous ammonia (0.45mL,7.8mmol) was added and the resulting mixture was stirred at-15 ℃ for 2 h. The reaction mixture was warmed to RT and washed with EtOAc and saturated NaHCO ₃The aqueous solution was partitioned. The combined organic fractions were washed with 5% NaHCO₃Aqueous solution, water, and then dried (MgSO)₄) And concentrated in vacuo. The resulting pink oil was used without further purification (1.03g, 91%).¹H NMR(CDCl₃,300MHz):δ6.42(1H,br s),5.48(2H,br s),4.25(1H,br s),3.83-3.74(1H,m),3.52-3.41(1H,m),3.40(3H,s),1.42(9H,s)。

[ (R) -1- (6-fluoro-1-pyridin-2-yl-1H-benzimidazol-2-yl) -2-methoxyethyl ] carbamic acid tert-butyl ester

To a solution of tert-butyl ((S) -1-carbamoyl-2-methoxyethyl) carbamate (340mg,1.7mmol) in anhydrous THF (8mL) under a nitrogen atmosphere was added triethyloxy in one portionTetrafluoroborate (550mg,2.9 mmol). The resulting mixture was stirred at RT for 2 h. Volatiles were removed under vacuum and the resulting residue was redissolved in anhydrous EtOH (8 mL). To the mixture was added 4-fluoro-N-2-pyridin-2-yl-benzene-1, 2-diamine (340mg,1.7mmol) and the mixture was stirred at 75 ℃ for 16 h. Volatiles were removed under reduced pressure and the resulting residue was taken up in DCM and saturated NaHCO₃The aqueous solution was partitioned. The aqueous phase was further extracted with DCM and the combined organic fractions were washed with water and dried (MgSO)₄) And concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient eluted with 0-50% EtOAc in cHex) to give the title compound as an orange oil (557mg, 64%). LCMS (method B) R _T3.32min[M+H]⁺387.1。

(R) -1- (6-fluoro-1-pyridin-2-yl-1H-benzimidazol-2-yl) -2-methoxyethylamine

To [ (R) -1- (6-fluoro-1-pyridin-2-yl-1H-benzimidazol-2-yl) -2-methoxyethyl]To a solution of tert-butyl carbamate (419mg,1mmol) in DCM (6mL) was added TFA (3mL) and the mixture was stirred at RT for 2 h. Volatile materials were removed under vacuum and the resulting residue was loaded ontoSCX-2 column. The column was washed with MeOH, then 2M NH₃Washing with MeOH. The basic fractions were combined and concentrated in vacuo. The crude material was used in the next step without further purificationThe method comprises the following steps: yellow oil (135mg, 47%). LCMS (method B) R_T1.71min[M+H]⁺287.01。

((S) -2-benzyloxy-1-carbamoylethyl) carbamic acid tert-butyl ester

To a solution of (S) -3-benzyloxy-2- (tert-butoxycarbonylamino) propionic acid (0.98g,3.3mmol) in anhydrous THF (13mL) at-15 deg.C under a nitrogen atmosphere was added N-methylmorpholine (0.4mL,3.3mmol) and isobutyl chloroformate (0.4mL,3.3 mmol). After 2 min, 33% aqueous ammonia (0.3mL,5mmol) was added and the resulting mixture was stirred at-15 ℃ for 2 h. The reaction mixture was allowed to warm to RT and washed with EtOAc and saturated NaHCO₃The aqueous solution was partitioned. The combined organic fractions were washed with 5% NaHCO ₃Aqueous solution, water washing, and drying (MgSO)₄) And concentrated in vacuo. The resulting white solid was used without further purification (quantitative yield).¹H NMR(CDCl₃,300MHz):δ7.41-7.25(5H,m),6.42(1H,br s),5.48(2H,br s),4.55(2H,dd,J=22.,12Hz),4.30(1H,br s),3.95-3.85(1H,dd,J=9.5,3.9Hz),3.55(1H,dd,J=9.5,6.7Hz),1.42(9H,s)。

[ (R) -2-benzyloxy-1- (6-fluoro-1-pyridin-2-yl-1H-benzimidazol-2-yl) ethyl ] carbamic acid tert-butyl ester

To a solution of tert-butyl ((S) -2-benzyloxy-1-carbamoylethyl) carbamate (820mg,2.8mmol) in anhydrous THF (10mL) under a nitrogen atmosphere was added triethoxy oxide in one portionTetrafluoroborate (550mg,2.9 mmol). Will be describedThe mixture was stirred at RT for 2 h. Volatiles were removed under vacuum and the resulting residue was redissolved in anhydrous EtOH (10 mL). To the mixture was added 4-fluoro-N-2-pyridin-2-yl-benzene-1, 2-diamine (355mg,1.7mmol) and the mixture was stirred at 75 ℃ for 16 h. Volatiles were removed in vacuo and the resulting residue was taken up in DCM and saturated NaHCO₃The aqueous solution was partitioned. The aqueous phase was further extracted with DCM and the combined organic fractions were washed with water and dried (MgSO)₄) And concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient eluted with 0-30% EtOAc in cHex) to give the title compound as a yellow oil (420mg, 53%). LCMS (method B) R _T3.95min[M+H]⁺463.1。

(R) -2-benzyloxy-1- (6-fluoro-1-pyridin-2-yl-1H-benzimidazol-2-yl) ethylamine

To [ (R) -2-benzyloxy-1- (6-fluoro-1-pyridin-2-yl-1H-benzimidazol-2-yl) ethyl]To a solution of tert-butyl carbamate (420mg,0.91mmol) in DCM (6mL) was added TFA (3mL) and the mixture was stirred at RT for 2 h. Volatile materials were removed under vacuum and the resulting residue was loaded ontoSCX-2 column. The column was washed with MeOH, then 2M NH₃Washing with MeOH. The basic fractions were combined and concentrated in vacuo. The crude material was used in the next step without further purification. Yellow oil (284mg, 86%). LCMS (method B) R_T2.16min[M+H]⁺363.20。

[ (R) -2-benzyloxy-1- (6-fluoro-1-pyridin-2-yl-1H-benzimidazol-2-yl) ethyl ] (7H-purin-6-yl) amine

A mixture of (R) -2-benzyloxy-1- (6-fluoro-1-pyridin-2-yl-1H-benzimidazol-2-yl) ethylamine (284mg,0.78mmol), 6-chloro-9- (tetrahydropyran-2-yl) -9H-purine (190mg,0.78mmol), and DIPEA (0.7mL,3.9mmol) in IPA (1.5mL) was heated at 90 deg.C for 72H. After cooling to RT, the volatiles were removed under vacuum and the resulting residue was loadedSCX-2 column. The column was washed with MeOH, then 2M NH₃Washing with MeOH. The basic fractions were combined and concentrated in vacuo and the resulting residue was purified by column chromatography (Si-PCC, gradient elution with 0-2.5% MeOH in DCM) to give the title compound as a white solid (336mg, 90%). LCMS (method B) R _T2.94min[M+H]⁺481.1。

((S) -3-benzyloxy-1-carbamoylpropyl) carbamic acid tert-butyl ester

To a solution of (S) -4-benzyloxy-2-tert-butoxycarbonylaminobutyric acid (1.16g,3.7mmol) in dry THF (15mL) at-15 deg.C under a nitrogen atmosphere was added N-methylmorpholine (0.41mL,3.7mmol) and isobutyl chloroformate (0.51mL,3.7 mmol). After 2 min, 33% aqueous ammonia (0.34mL,5.6mmol) was added and the resulting mixture was stirred at-15 ℃ for 2 h. The reaction mixture was warmed to RT and washed with EtOAc and saturated NaHCO₃The aqueous solution was partitioned. The combined organic fractions were washed with 5% NaHCO₃Aqueous solution, water washing, and drying (MgSO)₄) And concentrated in vacuo. The resulting white solid was used without further purification (quantitative yield).¹H NMR(CDCl₃,300MHz):δ7.41-7.25(5H,m),6.38(1H,br s),5.75(1H,br s),5.38(1H,br s),4.55-4.45(2H,m),4.30(1H,br s),3.75-3.52(2H,m),2.10-2.00(2H,m),1.42(9H,s)。

[ (S) -3-benzyloxy-1- (6-fluoro-1-pyridin-2-yl-1H-benzimidazol-2-yl) propyl ] carbamic acid tert-butyl ester

To a solution of tert-butyl ((S) -3-benzyloxy-1-carbamoylpropyl) carbamate (840mg,2.7mmol) in anhydrous DCM (10mL) under a nitrogen atmosphere was added triethoxy oxide in one portionTetrafluoroborate (550mg,2.9 mmol). The resulting mixture was stirred at RT for 2 h. Volatiles were removed under vacuum and the resulting residue was redissolved in anhydrous EtOH (10 mL). To the mixture was added 4-fluoro-N-2-pyridin-2-yl-benzene-1, 2-diamine (345mg,1.7mmol) and the mixture was stirred at 75 ℃ for 16 h. Volatiles were removed in vacuo and the resulting residue was taken up in DCM and saturated NaHCO ₃The aqueous solution was partitioned. The aqueous phase was further extracted with DCM and the combined organic fractions were washed with water and dried (MgSO)₄) And concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient eluted with 0-30% EtOAc in cHex) to give the title compound as a yellow oil (546mg, 67%). LCMS (method B) R_T3.89min[M+H]⁺477.2。

(S) -3-benzyloxy-1- (6-fluoro-1-pyridin-2-yl-1H-benzimidazol-2-yl) propylamine

To [ (S) -3-benzyloxy-1- (6-fluoro-1-pyridin-2-yl-1H-benzimidazol-2-yl) propyl]To a solution of tert-butyl carbamate (546mg,1.1mmol) in DCM (10mL) was added TFA (5mL) and the mixture was stirred at RT for 1 h. Removing volatile matter under reduced pressureA volatile substance, loading the residue obtained toSCX-2 column. The column was washed with MeOH, then 2M NH₃Washing with MeOH. The basic fractions were combined and concentrated in vacuo. The crude material was used in the next step without further purification. A colorless oil (355mg, 86%). LCMS (method B) R_T1.89min[M+H]⁺377.3。

[ (S) -3-benzyloxy-1- (6-fluoro-1-pyridin-2-yl-1H-benzimidazol-2-yl) propyl ] (7H-purin-6-yl) amine

A mixture of (S) -3-benzyloxy-1- (6-fluoro-1-pyridin-2-yl-1H-benzimidazol-2-yl) propylamine (355mg,0.94mmol), 6-chloro-9- (tetrahydropyran-2-yl) -9H-purine (230mg,0.94mmol) and DIPEA (0.82mL,4.7mmol) in IPA (2mL) was heated at 90 deg.C for 16H. After cooling to RT, the volatiles were removed under vacuum and the resulting residue was loaded SCX-2 column. The column was washed with MeOH, then 2M NH₃Washing with MeOH. The basic fractions were combined, concentrated in vacuo, and the resulting residue was purified by column chromatography (Si-PCC, gradient eluted with 0-5% MeOH in DCM) to give the title compound as a yellow solid (465mg, 86%). LCMS (method B) R_T3.56min[M+H]⁺495.1。

2, 2-Dimethylpropanoic acid 2-bromoethyl ester

2, 2-dimethylpropionyl chloride (10mL,81.2mmol) was added dropwise over 10minTo an ice-cooled solution of 2-bromoethanol (5.48mL,77.4mmol) and DIPEA (20.8mL,121.8mmol) in DCM (150 mL). The reaction mixture was stirred in the ice bath for a further 15min and then at RT for 16 h. The reaction mixture was washed successively with 1M HCl, saturated NaHCO₃Aqueous solution and water wash. The organic fraction was dried (Na)₂SO₄) And then concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, eluent 1-6% EtOAc in cyclohexane) to give the title compound as a colorless oil (10.58g, 65%).¹H NMR(CDCl₃,300MHz):4.37(2H,t,J=6.0Hz),3.52(2H,t,J=6.0Hz),1.23(9H,s)。

2- ((R) -3-tert-Butoxycarbonylaminopiperidin-1-yl) ethyl 2, 2-dimethylpropionate

A mixture of 2-bromoethyl 2, 2-dimethylpropionate (2.3g,11mmol), (R) -tert-butyl piperidin-3-ylcarbamate (2g,10.0mmol), potassium carbonate (4.15g,30mmol) and sodium iodide (0.15g,1mmol) in DMF (20mL) was stirred at RT for 2 days. The reaction mixture was partitioned between water and EtOAc. The aqueous phase was extracted with EtOAc, the combined organic fractions were washed with water and then brine, then dried (Na) ₂SO₄) And concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC with eluent 10-40% EtOAc in cyclohexane) to afford the title compound as a colorless oil (2.884g, 88%).¹H NMR(CDCl₃,300MHz):5.09(1H,bs),4.25-4.07(2H,m),3.73(1H,bs),2.63-2.52(3H,m),2.49(1H,bs),2.31-2.24(1H,m),1.74-1.61(1H,m),1.59-1.49(3H,m),1.44(9H,s),1.21(9H,s)。

2- ((R) -3-Aminopiperidin-1-yl) ethyl 2, 2-dimethylpropionate

To an ice-cooled solution of 2- ((R) -3-tert-butoxycarbonylaminopiperidin-1-yl) ethyl 2, 2-dimethylpropionate (2.86g,8.72mmol) in DCM (100mL) was added TFA (25mL) and the mixture was stirred at RT for 3 h. Toluene was added and the volatiles were removed under vacuum. The residue obtained is dissolved in MeOH and loadedSCX-2 column. The column was washed with MeOH, 1M NH₃The product eluted with MeOH. The product containing fractions were combined and concentrated in vacuo to give the title compound as a colorless oil (1.678g, 84%).¹H NMR(CDCl₃,300MHz):4.18(2H,t,J=6.0Hz),2.89-2.77(2H,m),2.68-2.59&2.62(3H,m&t,J=6.0Hz),2.19-2.11(1H,m),2.00-1.94(1H,m),1.84-1.65(2H,m),1.60-1.46(1H,m),1.23(2H,bs),1.20(9H,s),1.15-1.03(1H,m)。

2- [ (R) -3- (5-fluoro-2-nitrophenylamino) piperidin-1-yl ] ethyl 2, 2-dimethylpropionate

To an ice-cooled solution of 2- ((R) -3-aminopiperidin-1-yl) ethyl 2, 2-dimethylpropionate (1.675g,7.33mmol) in DMF (30mL) were added 2, 4-difluoronitrobenzene (1.517g,9.54mmol) and potassium carbonate (2.03g,14.7 mmol). The reaction mixture was stirred at RT for 16h, then partitioned between water and EtOAc. The aqueous phase was extracted with EtOAc, the combined organic fractions were washed with water and then brine, then dried (Na) ₂SO₄) And concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, eluent 10-40% EtOAc in cyclohexane) to give the title compound as a yellow oil (2.533g, 94%). LCMS (method J) R_T2.31min[M+H]⁺368。

2- [ (R) -3- (2-amino-5-fluorophenylamino) piperidin-1-yl ] ethyl 2, 2-dimethylpropionate

To 2, 2-dimethylpropionic acid 2- [ (R) -3- (5-fluoro-2-nitrophenylamino) piperidin-1-yl]A solution of ethyl ester (2.53g,6.88mmol) in EtOAC (100mL) was added a slurry of 10% Pd/C (200mg) in IMS (20mL) and the reaction mixture was stirred at RT for 18h under a hydrogen atmosphere. Mixing the suspension withPad filtration and concentration of the filtrate in vacuo afforded the title compound as a purple oil (2.33g, 100%). LCMS (method J) R_T1.75min[M+H]⁺338。

2- { (R) -3- [2- ((S) -2-tert-Butoxycarbonylaminopropionylamino) -5-fluoro-phenylamino ] piperidin-1-yl } ethyl 2, 2-dimethylpropionate

To ice-cooled 2, 2-dimethylpropionic acid 2- [ (R) -3- (2-amino-5-fluorophenylamino) piperidin-1-yl group]To a mixture of ethyl ester (500mg,1.48mmol), (S) -2-tert-butoxycarbonylaminopropionic acid (309mg,1.63mmol) and HOAt (202mg,1.48mmol) in DCM (30mL) was added N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride (341mg,1.78 mmol). The reaction mixture was stirred in an ice bath for 1.5h, then diluted with DCM and over 2M Na ₂CO₃Then washed with water. The organic fraction was dried (Na)₂SO₄) And concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC gradient eluted with 50-100% EtOAc in cyclohexane) to give the title compound as a purple gum (quantitative yield). LCMS (method B) R_T2.50min[M+H]⁺509。

2- { (R) -3- [2- ((S) -2-Aminopropionylamino) -5-fluorophenylamino ] piperidin-1-yl } ethyl 2, 2-dimethylpropionate

To ice-cooled 2- { (R) -3- [2- ((S) -2-tert-Butoxycarbonylaminopropionylamino) -5-fluorophenylamino ] 2, 2-dimethylpropionic acid]-piperidin-1-yl } ethyl ester (0.74mmol) in DCM (20mL) was added TFA (5mL) and the mixture was stirred at RT for 1.5 h. Toluene was added and the volatiles were removed under vacuum. The residue obtained is dissolved in MeOH and loadedSCX-2 column. The column was washed with MeOH, 0.5M NH₃The product eluted with MeOH. The product containing fractions were combined and concentrated in vacuo to give the title compound as a violet oil (0.255g, 84% yield over 2 steps). LCMS (method J) R_T1.65min[M+H]⁺409。

2- [ (R) -3- (5-fluoro-2- { (S) -2- [9- (tetrahydropyran-2-yl) -9H-purin-6-ylamino ] propionylamino } phenylamino) piperidin-1-yl ] ethyl 2, 2-dimethylpropionate

2- { (R) -3- [2- ((S) -2-aminopropionylamino) -5-fluorophenylamino ] 2, 2-dimethylpropionic acid ]A mixture of piperidin-1-yl } ethyl ester (0.255g,0.62mmol), 6-chloro-9- (tetrahydropyran-2-yl) -9H-purine (0.149g,0.62mmol) and DIPEA (0.32mL,1.87mmol) in n-butanol (4mL) was stirred in a sealed vial at 100 ℃ for 2H and then at 90 ℃ for 16H. After cooling to RT, the volatiles were removed under vacuum and the resulting residue was purified by column chromatography (Si-PCC with 2-8%2M NH₃Gradient elution in DCM/MeOH) to give the title compound as a colorless gum(0.301g, 79%). LCMS (method J) R_T2.29min[M+H]⁺611。

2- { (R) -3- [2- ((S) -2-tert-Butoxycarbonylaminobutylamino) -5-fluorophenylamino ] piperidin-1-yl } ethyl 2, 2-dimethylpropionate

To ice-cooled 2, 2-dimethylpropionic acid 2- [ (R) -3- (2-amino-5-fluorophenylamino) piperidin-1-yl group]To a mixture of ethyl ester (500mg,1.48mmol), (S) -2-tert-butoxycarbonylaminobutyric acid (331mg,1.63mmol) and HOAt (202mg,1.48mmol) in DCM (30mL) was added N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride (341mg,1.78 mmol). The reaction mixture was stirred in an ice bath for 1h, then diluted with DCM and over 2M Na₂CO₃Then washed with water. The organic fraction was dried (Na)₂SO₄) And concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC gradient eluted with 50-80% EtOAc in cyclohexane) to give the title compound as a pink gum (0.734g, 95%). LCMS (method B) R _T2.56min[M+H]⁺523。

2- { (R) -3- [2- ((S) -2-Aminobutyrylamino) -5-fluorophenylamino ] piperidin-1-yl } ethyl 2, 2-dimethylpropionate

To ice-cooled 2- { (R) -3- [2- ((S) -2-tert-Butoxycarbonylaminobutylamino) -5-fluorophenylamino ] 2, 2-dimethylpropionic acid]Piperidin-1-yl } ethyl ester (0.732g,1.4mmol) in DCM (25mL) was added TFA (6mL) and the mixture was stirred at RT for 1.5 h. Toluene was added and the volatiles were removed in vacuo and the resulting residue was dissolved in MeOH and loaded ontoSCX-2 column. The column was washed with MeOH, 0.5M NH₃The product eluted with MeOH. The product containing fractions were combined and concentrated in vacuo to give the title compound as a brown gum (0.59g, 100%). LCMS (method B) R_T1.76min[M+H]⁺423。

2- [ (R) -3- (5-fluoro-2- { (S) -2- [9- (tetrahydropyran-2-yl) -9H-purin-6-ylamino ] butyrylamino } phenylamino) piperidin-1-yl ] ethyl 2, 2-dimethylpropionate

2- { (R) -3- [2- ((S) -2-aminobutyrylamino) -5-fluorophenylamino ] 2, 2-dimethylpropionic acid]A mixture of piperidin-1-yl } ethyl ester (0.588g,1.39mmol), 6-chloro-9- (tetrahydropyran-2-yl) -9H-purine (0.333g,1.39mmol) and DIPEA (0.71mL,4.15mmol) in n-butanol (6mL) was stirred in a sealed vial at 100 ℃ for 16H. After cooling to RT, the volatiles were removed in vacuo and the resulting residue was purified by column chromatography (Si-PCC with 2-10%2 MNH) ₃Gradient MeOH in DCM) to give the title compound as a pale brown gum (0.516g, 59%). LCMS (method B) R_T2.47min[M+H]⁺625。

2- ((S) -3-tert-Butoxycarbonylaminopiperidin-1-yl) ethyl 2, 2-dimethylpropionate

A mixture of 2-bromoethyl 2, 2-dimethylpropionate (2.3g,11mmol), (S) -piperidin-3-ylcarbamate tert-butyl ester (2g,10.0mmol), potassium carbonate (4.15g,30mmol) and sodium iodide (0.15g,1mmol) in DMF (20mL) was stirred at RT for 3 days. The reaction mixture was partitioned between water and EtOAc. The aqueous phase was extracted with EtOAcThe combined organic fractions were washed with water and then brine, and then dried (Na)₂SO₄) And concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC with eluent 10-40% EtOAc in cyclohexane) to afford the title compound as a colorless oil (3.23g, 98%).¹H NMR(CDCl₃,300MHz):5.08(1H,bs),4.27-4.07(2H,m),3.73(1H,bs),2.65-2.50(3H,m),2.48(1H,bs),2.30-2.24(1H,m),1.74-1.61(1H,m),1.58-1.47(3H,m),1.44(9H,s),1.21(9H,s)。

2- ((S) -3-amino-piperidin-1-yl) ethyl 2, 2-dimethylpropionate

To an ice-cooled solution of 2- ((S) -3-tert-butoxycarbonylaminopiperidin-1-yl) ethyl 2, 2-dimethylpropionate (2.54g,7.73mmol) in DCM (80mL) was added TFA (20mL) and the mixture was stirred at RT for 2 h. Toluene was added and the volatiles were removed under vacuum. The residue obtained is dissolved in MeOH and loaded SCX-2 column. The column was washed with MeOH, 1M NH₃The product eluted with MeOH. The product containing fractions were combined and concentrated in vacuo to give the title compound as a pale yellow oil (1.567g, 89%).¹H NMR(CDCl₃,300MHz):4.18(2H,t,J=6.0Hz),2.89-2.77(2H,m),2.68-2.59&2.62(3H,m&t,J=6.0Hz),2.20-2.12(1H,m),2.00-1.94(1H,m),1.82-1.65(2H,m),1.60-1.46(1H,m),1.28(2H,bs),1.20(9H,s),1.15-1.03(1H,m)。

2- [ (S) -3- (5-fluoro-2-nitrophenylamino) piperidin-1-yl ] ethyl 2, 2-dimethylpropionate

To an ice-cooled solution of 2- ((S) -3-aminopiperidin-1-yl) ethyl 2, 2-dimethylpropionate (1.565g,6.85mmol) in DMF (30mL) were added 2, 4-difluoronitrobenzene (1.517g,8.92mmol) and potassium carbonate (1.9g,13.8 mmol). The reaction mixture was stirred at RT for 16h, then partitioned between water and EtOAc. The aqueous phase was extracted with EtOAc, the combined organic fractions were washed with water and then brine, then dried (Na)₂SO₄) And concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC with 10-40% EtOAc in cyclohexane as eluent) to afford the title compound as a yellow oil (2.307g, 92%). LCMS (method J) R_T2.34min[M+H]⁺368。

2- [ (S) -3- (2-amino-5-fluorophenylamino) piperidin-1-yl ] ethyl 2, 2-dimethylpropionate

To 2, 2-dimethylpropionic acid 2- [ (S) -3- (5-fluoro-2-nitrophenylamino) piperidin-1-yl]To a solution of ethyl ester (2.3g,6.26mmol) in EtOAC (100mL) was added a slurry of 10% Pd/C (200mg) in IMS (20mL) and the reaction mixture was stirred at RT for 24h under a hydrogen atmosphere. Mixing the suspension with The pad was filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (Si-PCC with 2-6%2M NH)₃Gradient elution with MeOH in DCM) afforded the title compound as a colorless gum, as a dark red oil (1.464g, 69%). LCMS (method J) R_T1.71min[M+H]⁺338。

2- { (S) -3- [2- ((S) -2-tert-Butoxycarbonylaminopropionylamino) -5-fluorophenylamino ] piperidin-1-yl } ethyl 2, 2-dimethylpropionate

To ice-cooled 2, 2-dimethylpropionic acid 2- [ (S) -3- (2-amino-5-fluorophenylamino) piperidin-1-yl group]A mixture of ethyl ester (1.464g,4.34mmol), (S) -2-tert-butoxycarbonylaminopropionic acid (0.904g,4.77mmol) and HOAt (0.591g,4.34mmol) in DCM (40mL) was added portionwise over 10min to N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride (1.0g,5.21 mmol). The reaction mixture was stirred in an ice bath for 2h, then diluted with DCM and over 2M Na₂CO₃Then washed with water. The organic fraction was dried (Na)₂SO₄) And then concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC gradient eluted with 40-70% EtOAc in cyclohexane) to give the title compound as a dark red gum (2.054g, 93%). LCMS (method B) R_T2.46min[M+H]⁺509。

2- { (S) -3- [2- ((S) -2-Aminopropionylamino) -5-fluorophenylamino ] piperidin-1-yl } ethyl 2, 2-dimethylpropionate

To ice-cooled 2- { (S) -3- [2- ((S) -2-tert-Butoxycarbonylaminopropionylamino) -5-fluorophenylamino ] 2, 2-dimethylpropionic acid]Piperidin-1-yl } ethyl ester (2.054g,4.04mmol) in DCM (40mL) was added TFA (14mL) and the mixture was stirred at RT for 1.5 h. Toluene was added and the volatiles were removed under vacuum. The residue obtained is dissolved in MeOH and loadedSCX-2 column. The column was washed with MeOH, 0.5M NH₃The product eluted with MeOH. The product containing fractions were combined and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC with 2-10%2M NH)₃Gradient elution in DCM/MeOH) to give the title compound as a purple colorOil (1.443g, 87%). LCMS (method B) R_T1.60min[M+H]⁺409。

2- [ (S) -3- (5-fluoro-2- { (S) -2- [9- (tetrahydropyran-2-yl) -9H-purin-6-ylamino ] propionylamino } phenylamino) piperidin-1-yl ] ethyl 2, 2-dimethylpropionate

2- { (S) -3- [2- ((S) -2-aminopropionylamino) -5-fluorophenylamino ] 2, 2-dimethylpropionic acid]A mixture of piperidin-1-yl } ethyl ester (0.591g,1.45mmol), 6-chloro-9- (tetrahydropyran-2-yl) -9H-purine (0.346g,1.45mmol) and DIPEA (0.74mL,4.32mmol) in n-butanol (7mL) was stirred in a sealed vial at 90 ℃ for 16H. After cooling to RT, the volatiles were removed in vacuo and the resulting residue was purified by column chromatography (Si-PCC with 2-8%2 MNH) ₃Gradient MeOH in DCM) to give the title compound as a colorless gum (0.583g, 66%). LCMS (method J) R_T2.39min[M+H]⁺611。

2- { (S) -3- [2- ((S) -1-aminoethyl) -6-fluorobenzoimidazol-1-yl ] piperidin-1-yl } ethanol

2- { (S) -3- [2- ((S) -2-aminopropionylamino) -5-fluorophenylamino ] 2, 2-dimethylpropionic acid]A solution of piperidin-1-yl } ethyl ester (200mg,0.49mmol) in 6M aqueous HCl (8mL) was refluxed for 30 min. After cooling to RT, the volatiles were removed under vacuum and the resulting residue was taken up in twoAlkane/water (1:1) toSCX-2 column. Use the column twoAlkane/water (1:1) and then with bisAlkane wash and 10%880NH₃2 ofThe product was eluted with an alkane solution. The product containing fractions were purified by column chromatography (Si-PCC with 3-18%2M NH)₃Gradient MeOH in DCM) to give the title compound as a colorless gum (71.2mg, 47%). LCMS (method J) R_T0.39min[M+H]⁺307。

1-phenyl-1H-imidazo [4,5-c ] pyridine and 3-phenyl-3H-imidazo [4,5-c ] pyridine

1H-imidazo [4,5-c ] in pyridine (60m)]Pyridine (2.01g,0.0169mol), copper acetate (7.66g,42.2mmol) and phenylboronic acid (5.14g,042.2mmol) were stirred vigorously at 37 ℃ for 3 days in a flask open to the atmosphere. The mixture was cooled to RT and then partitioned between water and DCM (3 × 50 mL). The combined DCM extracts were washed with water and dried (Na) ₂SO₄) And concentrated in vacuo. The residue is purified by chromatography (SiO)₂0-6% (2M ammonia in methanol) in DCM) to give 1-phenyl-1H-imidazo [4, 5-c)]Pyridine (1.60g) and 3-phenyl-3H-imidazo [4, 5-c)]Pyridine (1.06g) as a white solid (81% combined).

1-phenyl-1H-imidazo [4, 5-c)]Pyridine LCMS (method H) R_T0.25min,[M+H]⁺196

3-phenyl-3H-imidazo [4, 5-c)]Pyridine LCMS (method H) R_T0.28min,[M+H]⁺196

1-phenyl-1H-imidazo [4,5-c ] pyridine-2-carbaldehyde

N-butyllithium (2.5M in hexane, 6.8mL,17.1mmol) was added to 1-phenyl-1H-imidazo [4,5-c ] at-78 deg.C under a nitrogen atmosphere]Pyridine (1.85g,9.48mmol) in THF (40 mL). The mixture was held at-78 ℃ for 15 minutes, then-10 ℃ for 10 minutes, then re-cooled to-78 ℃ and DMF (1.5mL,0.190mol) was added. The reaction mixture was stirred at-78 ℃ for 15 minutes and-10 ℃ for 10 minutes. The mixture was poured into aqueous hydrochloric acid (1M,80mL) and saturated NaHCO₃The resulting mixture was adjusted to pH8 with aqueous solution (50mL) and then extracted with EtOAc (3X 50 mL). The combined EtOAc extracts were dried (Na)₂SO₄) And concentrated in vacuo. The residue obtained is purified by chromatography (SiO)₂0-10% (2M ammonia in methanol) in DCM) to give the title compound containing methyl hemiacetal as a yellow solid (0.72g, 34%). LCMS (method H) R _t1.28min,[M+H]⁺224

1- (1-phenyl-1H-imidazo [4,5-c ] pyridin-2-yl) ethanol

Methylmagnesium bromide (3.0M in ether, 2.1mL,6.36mmol) was added to a stirred 1-phenyl-1H-imidazo [4,5-c ] at-78 deg.C under a nitrogen atmosphere]Pyridine-2-carbaldehyde (0.71g,3.18mmol) in THF (25 mL). The resulting mixture was stirred at-78 ℃ for 2h, then-10 ℃ for 20 min, then cooled again to-78 ℃ and additional methylmagnesium bromide (3.0M in ether, 1mL,3.00mmol) was added. The resulting mixture was stirred at-10 ℃ for 30 minutes and then poured into saturated ammonium chloride waterTo the solution (25mL), extract with EtOAc (3X 50 mL). The combined EtOAc extracts were dried (Na)₂SO₄) And concentrated in vacuo. The resulting residue was dissolved in THF (25mL), cooled to-78 deg.C, and methylmagnesium bromide (3.0M in ether, 2.1mL,6.36mmol) was added, followed by stirring at-78 deg.C for 30 minutes, followed by stirring at-10 deg.C for 1 h. The mixture was then poured into saturated aqueous ammonium chloride (25mL) and extracted with EtOAc (3X 50 mL). The combined EtOAc extracts were dried (Na)₂SO₄) And concentrated in vacuo. The residue obtained is purified by chromatography (SiO)₂0-10% (2M ammonia in methanol) in DCM) to give the title compound as a yellow oil (0.36g, 47%). LCMS (method H) R _t1.42min,[M+H]⁺240。

2- (1-azidoethyl) -1-phenyl-1H-imidazo [4,5-c ] pyridine

Diphenyl phosphorazidate (0.50g,1.81mmol) and diisopropyl azodicarboxylate (0.61g,3.01mmol) were added to stirred 1- (1-phenyl-1H-imidazo [4,5-c ] at 0 ℃ under a nitrogen atmosphere]Pyridin-2-yl) ethanol (0.36g,1.50mmol) and triphenylphosphine (0.79g,3.01mmol) in bisIn an alkane (15 mL). After the addition, the mixture was stirred at 20 ℃ for 16 h. Additional diphenyl phosphorazidate (0.25g,0.91mmol), triphenylphosphine (0.40g,1.53mmol) and diisopropyl azodicarboxylate (0.30g,1.48mmol) were added and the resulting mixture was stirred at 20 ℃ for 30 minutes. The reaction mixture was concentrated in vacuo and the residue was purified by chromatography (SiO)₂0-10% (2M ammonia in methanol) in DCM) to give the title compound as an oil (0.60g, contaminated with triphenylphosphine oxide). LCMS (method H) R_t1.86min,[M+H]⁺265

1- (1-phenyl-1H-imidazo [4,5-c ] pyridin-2-yl) ethylamine

Reacting 2- (1-azidoethyl) -1-phenyl-1H-imidazo [4, 5-c)]A mixture of pyridine (0.40g,1.50mmol) and 10% palladium on carbon (0.10g) in EtOAc (20mL) was stirred under an atmosphere of hydrogen, atmospheric pressure and at 20 ℃ for 16 h. The catalyst was removed by filtration, the filtrate was concentrated in vacuo and the resulting residue was purified by chromatography (SiO) ₂0-10% (2M ammonia in methanol) in DCM) to give the title compound as a white solid (0.194g, 54%). LCMS (method J) R_t0.26min,[M+H]⁺239。

1- (3-phenyl-3H-imidazo [4,5-c ] pyridin-2-yl) ethanones

LiHMDS (2.0M solution in THF/heptane/ethylbenzene, 3.9mL,7.79mmol) was added to a stirred 3-phenyl-3H-imidazo [4,5-c ] at-78 deg.C under a nitrogen atmosphere]Pyridine (0.95g,4.87mol) in THF (20 mL). The resulting mixture was stirred at-78 ℃ for 10 minutes and then at-10 ℃ for 15 minutes. The reaction mixture was cooled again to-78 deg.C, N-dimethylacetamide (0.72mL,7.79mmol) was added, followed by stirring at-78 deg.C for 5 minutes and then at-10 deg.C for 15 minutes. The reaction mixture was poured into saturated aqueous ammonium chloride (30mL) and extracted with EtOAc (3X 30 mL). The combined EtOAc extracts were dried (Na)₂SO₄) And concentrated in vacuo. The residue is purified by chromatography (SiO)₂0-4% (2M ammonia in methanol) in DCM) to give the title compound as an off-white solid (0.96g,76%) LCMS (method H): R_t1.76min,[M+H]⁺238

1- (3-phenyl-3H-imidazo [4,5-c ] pyridin-2-yl) ethanol

Sodium borohydride (0.27g,7.17mmol) was added to a stirred 1- (3-phenyl-3H-imidazo [4,5-c ] solution at 0 ℃ under a nitrogen atmosphere ]Pyridin-2-yl) ethanone (0.85g,3.58mmol) in methanol (20 mL). The reaction mixture was stirred for 15 min, then poured into saturated aqueous ammonium chloride and extracted with EtOAc (3 × 50 mL). The combined EtOAc extracts were washed with water and dried (Na)₂SO₄) And concentrated in vacuo to give the title compound as a white solid (0.74g, 87%). LCMS (method H) R_t1.76min,[M+H]⁺240。

2- (1-azidoethyl) -3-phenyl-3H-imidazo [4,5-c ] pyridine

Stirring 1- (3-phenyl-3H-imidazo [4,5-c ] at 0 ℃ under nitrogen]Pyridin-2-yl) ethanol (0.81g,3.39mmol) and triphenylphosphine (1.78g,6.77mmol) in bisTo a solution of diphenyl phosphorazidate (1.12g,4.06mmol) in an alkane (50mL) was added, followed by diisopropyl azodicarboxylate (1.37g,6.77 mmol). The reaction mixture was stirred at 20 ℃ for 16h, then diluted with DCM to dissolve all materials. Load it toSCX-2 column, washing with methanol, 2M NH₃The product was eluted with MeOH and then concentrated in vacuo. The residue is purified by chromatography (SiO)₂0-4% (2M ammonia in methanol) in DCM) to give the title compound as freeA colored oil (1.48g, contaminated with triphenylphosphine oxide). LCMS (method H) R_t1.79min,[M+H]⁺265。

1- (3-phenyl-3H-imidazo [4,5-c ] pyridin-2-yl) ethylamine

Reacting 2- (1-azidoethyl) -3-phenyl-3H-imidazo [4, 5-c)]A mixture of pyridine (0.89g,3.39mmol) and 10% palladium on carbon (0.20g) in EtOAc (40mL) was stirred under hydrogen atmosphere at atmospheric pressure and 20 ℃ for 3 h. The catalyst was removed by filtration and the filtrate was concentrated in vacuo. The residue obtained is purified by chromatography (SiO)₂0-10% (2M ammonia in methanol) in DCM) to give the title compound as a white solid (0.53g, 65%). LCMS (method H) R_t0.25min,[M+H]⁺239。

[ (S) -1- (3-cyano-4-fluoro-2-phenylaminophenylcarbamoyl) propyl ] carbamic acid tert-butyl ester

Triethylamine (0.55mL,3.96mmol) was added to a stirred mixture of 3-amino-6-fluoro-2-phenylaminobenzonitrile (0.30g,1.32mmol), (S) - (2-tert-butoxycarbonylamino) butyric acid (0.30g,1.45mmol), N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride (0.28g,1.45mmol) and HOAt (0.20g,1.45mmol) in DCM at 0 deg.C under nitrogen. The resulting mixture was stirred at 0 ℃ for 5 minutes and then at 20 ℃ for 16 h. The reaction mixture was cooled again to 0 ℃ and (S) -2-tert-butoxycarbonylaminobutyric acid (0.30g,1.45mmol), N- (3-dimethylaminopropyl) -N' ethylcarbodiimide hydrochloride (0.28g,1.45mmol), HOAt (0.20g,1.45mmol) and triethylamine (0.55mL,3.96mmol) were added successively and the resulting mixture was stirred at 20 ℃ for 24 h. Mixing the mixture in Saturated NaHCO₃Partition between aqueous solution (20mL) and DCM (3X 20 mL). The combined DCM extracts were washed with water and dried (Na)₂SO₄) And concentrated in vacuo to give the title compound as an off-white foam (0.64 g). LCMS (method H) R_t2.93min,[M+H]⁺413。

2- ((S) -1-amino-propyl) -5-fluoro-3-phenyl-3H-benzimidazole-4-carbonitrile

Reacting HCl at 20 deg.CAn alkane solution (4M,10mL,0.04mol) was added to [ (S) -1- (3-cyano-4-fluoro-2-phenylaminophenylcarbamoyl) propyl]Tert-butyl carbamate (0.54g,1.32mmol) in bisTo a solution in alkane (5mL), the resulting mixture was stirred at 80 ℃ for 17 h. After cooling, the reaction mixture was washed with saturated NaHCO₃Partition between aqueous (20mL) and EtOAc (3X 20 mL). The combined EtOAc extracts were dried (Na)₂SO₄) And concentrated in vacuo. The residue obtained is purified by chromatography (SiO)₂0-20% methanol in EtOAc) to give the title compound as an oil (0.27g,69%) LCMS (method H): R)_T2.03min,[M+H]⁺295。

(3-Nitro-pyridin-2-yl) -pyridin-2-yl-amines

2-chloro-3-nitropyridine (3.42g,21.60mmol) and pyridin-2-ylamine (6.09g,0.65mol) in DMF (20mL) were stirred together at 80 ℃ for 18 h. Will be reversedThe mixture is concentrated in vacuo and the residue is purified by chromatography (SiO)₂0-5% methanol in DCM) to give the title compound as an orange solid (1.68g, 36%). LCMS (method H) R _t1.45min,[M+H]⁺217。

N²-pyridin-2-yl-pyridine-2, 3-diamine

A mixture of (3-nitro-pyridin-2-yl) -pyridin-2-yl-amine (0.84g,3.89mmol) and 10% palladium on carbon (0.30g) in EtOAc (20mL) was stirred under an atmosphere of hydrogen, atmospheric pressure and at 20 ℃ for 16 h. The catalyst was removed by filtration and the filtrate was concentrated in vacuo to give the title compound as a green solid (0.63g, 88%). LCMS (method H) R_t1.87min,[M+H]⁺187。

[ (S) -1- (3-pyridin-2-yl-3H-imidazo [4,5-b ] pyridin-2-yl) ethyl ] carbamic acid tert-butyl ester

At 20 ℃ under nitrogen, the triethyl oxideTetrafluoroborate (1.08g,5.66mmol) was added to a solution of tert-butyl ((S) -1-carbamoylethyl) carbamate (1.00g,5.33mmol) in THF (15mL), and the resulting mixture was stirred for 2h, then concentrated in vacuo. Will N²A solution of-pyridin-2-yl-pyridine-2, 3-diamine (0.62g,3.33mmol) in ethanol (15mL) was added to the residue and the resulting solution was stirred at 75 ℃ for 16 h. The reaction mixture was concentrated in vacuo and the residue was taken up in DCM (3X 30mL) and saturated NaHCO₃The aqueous solution (30mL) was partitioned. The combined DCM extracts were dried (Na)₂SO₄) And vacuum concentrating. The residue obtained is purified by chromatography (SiO)₂0-5% (2M ammonia in methanol) in DCM) gave the title compound as an oil (1.11g, 98%). LCMS (method H) R _t2.73min,[M+H]⁺340。

(S) -1- (3-pyridin-2-yl-3H-imidazo [4,5-b ] pyridin-2-yl) ethylamine

Trifluoroacetic acid (20mL) was added to [ (S) -1- (3-pyridin-2-yl-3H-imidazo [4,5-b ]]Pyridin-2-yl) ethyl]A solution of tert-butyl carbamate (1.10g,3.24mmol) in DCM (10mL) was stirred for 30 min. The reaction mixture was concentrated in vacuo and the residue was purified by chromatography (SiO)₂0-10% (2M ammonia in methanol) in DCM) to give the title compound (0.145g, 19%). LCMS (method H) R_t0.26min,[M+H]⁺240。

(2-bromo-3-fluoro-6-nitro-phenyl) -pyridin-2-yl-amine

Potassium tert-butoxide (2.82g,25.2mmol) was added to a solution of 2-aminopyridine (1.25g,13.2mmol) in THF (40mL) at 0 deg.C and the reaction mixture was stirred at 0 deg.C for 30 min. 2-bromo-1, 3-difluoro-4-nitrobenzene (3g,12.6mmol) was added as a solution in THF (10mL) and the reaction mixture was stirred at 0 deg.C for 2 h. The reaction mixture was diluted with water and the product was extracted with EtOAc (3X 40 mL). The combined organic extracts were washed with brine and dried (MgSO)₄) And concentrated in vacuo. The residue obtained is treated by flash chromatography (SiO)₂Eluting with 0-100% EtOAc in cyclohexane) to give the title compound as a yellow solid (2.38g, 60%).¹H NMR400MHzδ(CDCl₃):8.16(1H,ddd,J=5.1,2.0,1.0Hz),8.08(1H,dd,J=9.3,5.6Hz),7.82(1H,br s),7.62(1H,ddd,J=8.1,7.3,1.8Hz),6.99(1H,dd,J=9.2,7.1Hz),6.91(1H,ddd,J=7.3,5.0,1Hz),6.82(1H,dt,J=8.3,1.0Hz)。

3-bromo-4-fluoro-N ²-pyridin-2-yl-benzene-1, 2-diamine

(2-bromo-3-fluoro-6-nitro-phenyl) -pyridin-2-yl-amine (3.68g,11.8mmol), iron powder (2.63g,47.2mmol) and ammonium chloride (3.63g,70.7mmol) in methanol (40mL) and water (15mL) were heated at 90 ℃ for 1.5 h. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was dissolved in water and extracted with EtOAc (3X 40 mL). The combined organic extracts were washed with brine and dried (MgSO)₄) And concentrated in vacuo. The residue obtained is treated by flash chromatography (SiO)₂Eluting with 0-10% methanol in EtOAc) to give the title compound as a white solid (2.5g, 75%).¹H NMR400MHzδ(CDCl₃):8.23-8.17(1H,m),7.48(1H,ddd,J=8.4,7.3,1.9Hz),6.94(1H,dd,J=8.8,7.9Hz),6.77(1H,ddd,J=7.2,5.0,1.0Hz),6.73(1H,dd,J=8.8,5.0Hz),6.31(1H,dt,J=8.3,1.0Hz),6.10(1H,br s),3.94(2H,br s)。

[ (S) -1- (7-bromo-6-fluoro-1-pyridin-2-yl-1H-benzimidazol-2-yl) ethyl ] carbamic acid tert-butyl ester

To a suspension of tert-butyl ((S) -1-carbamoylethyl) carbamate (1.0g,5.4mmol) in DCM (10mL) was added triethyloxyTetrafluoroborate (1.1g,5.78mmol) and the reaction mixture was stirred at RT for 2h during which time the solid dissolved.The reaction mixture was concentrated in vacuo and the residue was dissolved in ethanol (10 mL). Adding 3-bromo-4-fluoro-N²Pyridin-2-yl-benzene-1, 2-diamine (0.96g,3.4mmol), the reaction was heated at 75 ℃ for 16 h. The reaction mixture was concentrated in vacuo, the residue was dissolved in water and the product was extracted with EtOAc (3X 20 mL). The combined organic extracts were washed with brine and dried (MgSO) ₄) And concentrated in vacuo. The residue obtained is treated by flash chromatography (SiO)₂Eluting with 0-100% EtOAc in cyclohexane) to give the title compound as a white solid (832mg, 56%). LCMS (method C) R_T=3.39min,[M+H]+=435+437。

[ (S) -1- (7-bromo-6-fluoro-1-pyridin-2-yl-1H-benzimidazol-2-yl) ethyl ] - [9- (tetrahydro-pyran-2-yl) -9H-purin-6-yl ] -amine

Reacting [ (S) -1- (7-bromo-6-fluoro-1-pyridin-2-yl-1H-benzimidazol-2-yl) ethyl]Di (tert-butyl) carbamate (220mg,0.66mmol) dissolved in hydrochloric acidTo an alkane solution (15mL,4M), the reaction was stirred at RT for 1 h. The reaction mixture was concentrated in vacuo, then the residue was dissolved in IPA, and 6-chloro-9- (tetrahydro-pyran-2-yl) -9H-purine (203mg,0.85mmol) and DIPEA (168. mu.L, 0.99mmol) were added. The reaction mixture was heated at 90 ℃ for 16h and then concentrated in vacuo. The residue obtained is treated by flash chromatography (SiO)₂Eluting with 0-100% methanol in EtOAc) to give the title compound as a white solid (267mg, 76%). LCMS (method C) R_T=3.01min,[M+H]+=537+538。

[ (S) -1- (7-cyclopropyl-6-fluoro-1-pyridin-2-yl-1H-benzimidazol-2-yl) ethyl ] - [9- (tetrahydro-pyran-2-yl) -9H-purin-6-yl ] amine

To [ (S) -1- (7-bromo-6-fluoro-1-pyridin-2-yl-1H-benzimidazol-2-yl) ethyl]- [9- (tetrahydro-pyran-2-yl) -9H-purin-6-yl ]Amine (267mg,0.49mmol) in bisTo a solution in alkane (10mL) and water (0.5mL) were added cyclopropylboronic acid (64mg,0.75mmol), cesium carbonate (242mg,0.75mmol) and tetrakis (triphenylphosphine) palladium (0) (57mg,0.05mmol), and the reaction mixture was degassed by bubbling argon through the mixture while sonicating. The reaction mixture was heated at reflux for 16 h. The reaction mixture was diluted with water and extracted with EtOAc (3X 20 mL). The combined organic extracts were washed with brine and dried (MgSO)₄) And concentrated in vacuo. The resulting residue was treated with preparative HPLC (C18Phenomenex column, 10-90% MeCN in water with 0.1% formic acid, 25min gradient) to give the title compound as a white solid (59mg, 24%). LCMS (method C) R_T=2.98min,[M+H]+=499。

(3-fluoro-2-methyl-6-nitro-phenyl) -pyridin-2-ylamine

Potassium tert-butoxide (2.59g,23.1mmol) was added to a solution of 2-aminopyridine (1.14g,12.1mmol) in THF (30mL) at 0 deg.C and the reaction mixture was stirred at 0 deg.C for 20 min. 1, 3-difluoro-2-methyl-4-nitrobenzene (2g,11.6mmol) was added as a solution in THF (10mL) and the reaction mixture was stirred at 0 deg.C for 30 min. The reaction mixture was diluted with water and the product was extracted with EtOAc (3X 40 mL). The combined organic extracts were washed with brine and dried (MgSO) ₄) And concentrated in vacuo. The residue obtained is treated by flash chromatography (SiO)₂Eluting with 0-100% EtOAc in cyclohexane) to give the title compound as a yellow solid (2g, 70%).¹HNMR400MHzδ(CDCl₃):8.53(1H,br s),8.19(1H,ddd,J=5.1,1.9,0.8Hz),8.02(1H,dd,J=9.2,5.7Hz),7.57(1H,ddd,J=8.2,7.3,1.9Hz),6.94(1H,dd,J=9.1,8.2Hz),6.86(1H,ddd,J=7.3,5.1,1.0Hz),6.69(1H,dt,J=8.3,0.9Hz),2.06(3H,d,J=2.8Hz)。

4-fluoro-3-methyl-N²-pyridin-2-yl-benzene-1, 2-diamine

To a solution of (3-fluoro-2-methyl-6-nitro-phenyl) -pyridin-2-yl-amine (2g,8.1mmol) in EtOAc (25mL) was added palladium on carbon (200mg,10% by weight) and the reaction mixture was stirred at RT for 16h under a hydrogen atmosphere. The reaction mixture was filtered and the filtrate was concentrated in vacuo to give the title compound as a white solid (1.7g, 100%).¹H NMR400MHzδ(CDCl₃):8.19-8.11(1H,m),7.42(1H,ddd,J=8.8,7.1,2.0Hz),6.86(1H,t,J=8.9Hz),6.69(1H,dd,J=6.9,5.1Hz),6.61(1H,dd,J=8.8,5.4Hz),6.16(1H,d,J=8.3Hz),6.07(1H,br s),3.76(2H,br s),2.10(3H,d,J=1.9Hz)。

[ (S) -1- (6-fluoro-7-methyl-1-pyridin-2-yl-1H-benzimidazol-2-yl) ethyl ] -carbamic acid tert-butyl ester

To a suspension of tert-butyl ((S) -1-carbamoylethyl) carbamate (1.52g,8.1mmol) in DCM (15mL) was added triethyloxytetrafluoroborate (1.63g,8.6mmol) and the reaction mixture was stirred at RT for 2h, during which time the solid dissolved. The reaction mixture was concentrated in vacuo and the residue was dissolved in ethanol (15 mL). Adding 4-fluoro-3-methyl-N²Pyridin-2-yl-benzene-1, 2-diamine (1.0g,5.1mmol), the reaction was heated at 75 ℃ for 16 h. The reaction mixture was concentrated in vacuo, the residue dissolved in water and extracted with EtOAc (3X 20mL) And (3) obtaining the product. The combined organic extracts were washed with brine and dried (MgSO)₄) And concentrated in vacuo. The residue obtained is treated by flash chromatography (SiO)₂Eluting with 0-100% EtOAc in cyclohexane) to give the title compound as a white solid (1.29g, 76%). LCMS (method C) R_T=3.22min,[M+H]+=371。

(S) -1- (6-fluoro-7-methyl-1-pyridin-2-yl-1H-benzimidazol-2-yl) ethylamine dihydrochloride

Reacting [ (S) -1- (6-fluoro-7-methyl-1-pyridin-2-yl-1H-benzimidazol-2-yl) ethyl]Tert-butyl carbamate (1.29g,3.5mmol) was dissolved in dioxane solution of hydrochloric acid (15mL,4M) and the reaction was stirred at RT for 1 h. The reaction mixture was concentrated in vacuo to give the title compound as an off-white solid (1.17g, 100%). LCMS (method C) R_T=1.88min,[M+H]+=271。

6-fluoro-3-nitro-2- (pyridin-2-ylamino) benzonitrile

Potassium tert-butoxide (2.44g,21.6mmol) was added to a solution of 2-aminopyridine (1.07g,11.4mmol) in THF (40mL) at 0 deg.C and the reaction mixture was stirred at 0 deg.C for 20 min. The resulting mixture was added via cannula to a solution of 3-amino-2, 6-difluorobenzonitrile (2g,0.8mmol) in THF (10mL) at-78 deg.C and the reaction mixture was stirred at-78 deg.C for 15 min. The reaction mixture was diluted with water and the product was extracted with EtOAc (3X 40 mL). The combined organic extracts were washed with brine and dried (MgSO) ₄) And concentrated in vacuo. The residue obtained is treated by flash chromatography (SiO)₂Eluting with 0-100% EtOAc in cyclohexane) to give the title compound as a yellow solid (1.3g, 46%).¹H NMR400MHzδ(CDCl₃):9.28(1H,d,J=16.6Hz),9.16-9.11(1H,m),7.92(1H,dd,J=8.6,5.3Hz),7.57(1H,ddd,J=8.9,6.5,1.8Hz),7.34(1H,ddd,J=9.0,1.3,0.8Hz),6.94(1H,dd,J=11.8,8.8Hz),6.84(1H,dd,J=7.7,6.5,1.5Hz)。

3-amino-6-fluoro-2- (pyridin-2-ylamino) benzonitrile

6-fluoro-3-nitro-2- (pyridin-2-ylamino) benzonitrile (1.3g,5.0mmol), iron powder (1.12g,20.1mmol) and ammonium chloride (1.55g,30.2mmol) in methanol (20mL) and water (7mL) were heated at 90 ℃ for 3 h. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was dissolved in water and extracted with EtOAc (3X 40 mL). The combined organic extracts were washed with brine and dried (MgSO)₄) And concentrated in vacuo to give the title compound as a yellow solid (620mg, 54%).¹HNMR400MHzδ(CDCl₃):9.05(1H,ddd,J=7.5,1.1,0.8Hz),9.00-8.89(1H,m),7.34(1H,ddd,J=9.1,6.2,1.7Hz),7.23-7.19(1H,m),6.83(1H,s),6.80(1H,d,J=2.8Hz),6.65(1H,ddd,J=7.6,6.4,1.4Hz),4.53(2H,br s)。

[ (S) -1- (7-cyano-6-fluoro-1-pyridin-2-yl-1H-benzimidazol-2-yl) ethyl ] carbamic acid tert-butyl ester

To a suspension of tert-butyl ((S) -1-carbamoylethyl) carbamate (820mg,4.4mmol) in DCM (7mL) was added triethyloxyTetrafluoroborate (877mg,4.6mmol) and the reaction mixture was stirred at RT for 2h during which time the solid dissolved. The reaction mixture was concentrated in vacuo and the residue was dissolved in ethanol (7)mL). 3-amino-6-fluoro-2- (pyridin-2-ylamino) benzonitrile (620mg,2.7mmol) was added and the reaction was heated at 75 ℃ for 16 h. The reaction mixture was concentrated in vacuo, the residue was dissolved in water and the product was extracted with EtOAc (3X 20 mL). The combined organic extracts were washed with brine and dried (MgSO) ₄) And concentrated in vacuo. The residue obtained is treated by flash chromatography (SiO)₂Eluting with 0-100% EtOAc in cyclohexane) to give the title compound as a white solid (563mg, 54%). LCMS (method C) R_T=3.20min,[M+H]+=382。

2- ((S) -1-aminoethyl) -5-fluoro-3-pyridin-2-yl-3H-benzimidazole-4-carbonitrile dihydrochloride

Reacting [ (S) -1- (7-cyano-6-fluoro-1-pyridin-2-yl-1H-benzimidazol-2-yl) ethyl]Di (tert-butyl) carbamate (563mg,1.47mmol) dissolved in hydrochloric acidTo an alkane solution (10mL,4M), the reaction was stirred at RT for 1 h. The reaction mixture was concentrated in vacuo to give the title compound as an off-white solid (523mg, 100%). LCMS (method C) R_T=1.75min,[M+H]+=282。

2- ((S) -1-aminoethyl) -5-fluoro-3-phenyl-3H-benzimidazole-4-carboxylic acid methyl ester dihydrochloride

To a solution of methyl 3-amino-6-fluoro-2-phenylaminobenzoate (1g,3.8mmol), Boc-ala-OH (727mg,3.8mmol) and HOAT (522mg,3.8mmol) in DCM (20mL) was added N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride (810mg,4.2mmol) at 0 deg.C and the reaction mixture was stirred at 0 deg.C for 2h. The reaction mixture was diluted with water and extracted with DCM (3 × 10 mL). The combined organic fractions were washed with brine and dried (MgSO)₄) And concentrated in vacuo. Dissolving the residue in HCl II In an alkane solution (20mL,4M), the reaction mixture was heated at 75 ℃ for 45 min. The reaction mixture was concentrated in vacuo to give the title product as a dark purple solid (1.48g, 100%). LCMS (method C) R_T=1.95min,[M+H]+=314。

5-fluoro-3-phenyl-2- { (S) -1- [9- (tetrahydro-pyran-2-yl) -9H-purin-6-ylamino ] ethyl } -3H-benzimidazole-4-carboxylic acid methyl ester

To a solution of 2- ((S) -1-aminoethyl) -5-fluoro-3-phenyl-3H-benzimidazole-4-carboxylic acid methyl ester dihydrochloride (1.4g,3.8mmol) in IPA (20mL) was added 6-chloro-9- (tetrahydro-pyran-2-yl) -9H-purine (1.18mg,4.94mmol) and DIPEA (2.6mL,15.2mmol) and the reaction mixture was heated at 90 ℃ for 16H. The reaction mixture was concentrated in vacuo and the resulting residue was treated with flash chromatography (SiO)₂Eluting with 0-10% methanol in EtOAc) to give the title compound as a white solid (1.34g, 67%). LCMS (method C) R_T=3.11min,[M+H]+=516。

5-fluoro-3-phenyl-2- { (S) -1- [9- (tetrahydro-pyran-2-yl) -9H-purin-6-ylamino ] ethyl } -3H-benzimidazole-4-carboxylic acid

To 5-fluoro-3-phenyl-2- { (S) -1- [9- (tetrahydro-pyran-2-yl) -9H-purin-6-ylamino]Ethyl } -3H-benzimidazole-4-carboxylic acid methyl ester (1.34g,2.66mmol) in methanol (40mL) and water (4mL)To the solution was added lithium hydroxide monohydrate (0.l66g,15.9mmol) and the reaction mixture was heated at 80 ℃ for 16 h. The reaction mixture was concentrated in vacuo to remove methanol, and the resulting aqueous solution was acidified to ph-4 by addition of HCl (1M), resulting in formation of a precipitate. The product was collected by filtration and dried in vacuo to give the title compound as an off-white solid (564mg, 43%). LCMS (method C) R _T=2.44min,[M+H]+=502。

(2, 3-difluoro-6-nitro-phenyl) -phenylamine

To a solution of aniline (1.6g,16.9mmol) in THF (40mL) at-78 deg.C was added LiHMDS (34mL,1M,33.9mmol) and the reaction mixture was stirred at-78 deg.C for 10 min. This solution was added via cannula to a solution of 2,3, 4-trifluoronitrobenzene (3g,16.9mmol) in THF (10mL) at-78 deg.C and the dark purple reaction mixture was stirred for 30min at-78 deg.C. The reaction mixture was diluted with water and extracted with EtOAc (3X 30 mL). The combined organic fractions were washed with brine and dried (MgSO)₄) Concentrated in vacuo to give the title compound as a dark orange solid (4.2)_g,100%)。¹H NMR400MHzδ(CDCl₃):8.95(1H,br s),8.00(1H,ddd,J=9.7,5.4,2.3Hz),7.31-7.25(2H,m),7.13-7.08(1H,m),7.04-6.99(2H,m),6.75-6.67(1H,m)。

3, 4-difluoro-N²-phenyl-1, 2-diamines

(2, 3-difluoro-6-nitro-phenyl) -phenylamine (4.2g,16.9mmol), iron powder (3.8g,67.6mmol) and ammonium chloride (5.2g,101.4mmol) in methanol (60mL) and water (15mL) were heated at 90 ℃ for 3 h. The reaction mixture was filtered and the filtrate was concentrated in vacuo. Dissolving the residue inWater and extracted with EtOAc (3 × 40 mL). The combined organic extracts were washed with brine and dried (MgSO)₄) And concentrated in vacuo to give the title compound as a red solid (3.7g, 100%).¹H NMR400MHzδ(CDCl₃):7.25-7.16(2H,m),6.94-6.82(2H,m),6.70-6.64(2H,m),6.47(1H,ddd,J=12.0,6.1,3.0Hz),5.23(1H,br s),3.71(2H,br s)。

(R) -1- (6, 7-difluoro-1-phenyl-1H-benzimidazol-2-yl) -2-methoxyethylamine dihydrochloride

To 3, 4-difluoro-N²To a solution of-phenyl-1, 2-diamine (400mg,1.8mmol), Boc-ser (OMe) -OH (800mg,2.0mmol), HOAT (340mg,2.0mmol) and N-methylmorpholine (500. mu.L, 4.0mmol) in DCM (5mL) was added N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride (480mg,2.0mmol) and the reaction mixture was stirred at RT for 16 h. The reaction mixture was diluted with water and extracted with DCM (3 × 10 mL). The combined organic fractions were washed with brine and dried (MgSO)₄) And concentrated in vacuo. Dissolving the residue in HCl IIIn an alkane solution (10mL,4M), the reaction mixture was heated at 80 ℃ for 4 h. The reaction mixture was concentrated in vacuo and the resulting residue was dissolved in EtOAc (10 mL). The solution was saturated with NaHCO₃The aqueous solution was washed and the product was extracted with EtOAc (3X 10 mL). The combined organic extracts were washed with brine and dried (MgSO)₄) Concentrated in vacuo and the residue obtained is subjected to flash chromatography (SiO)₂Eluting with 0-10% methanol in DCM) to give the title compound as an off-white solid (207mg, 38%). LCMS (method C) R_T=2.27min,[M+H]+=304。

[ (R) -1- (6, 7-difluoro-1-phenyl-1H-benzimidazol-2-yl) -2-methoxyethyl ] - [9- (tetrahydro-pyran-2-yl) -9H-purin-6-yl ] amine

To a solution of (R) -1- (6, 7-difluoro-1-phenyl-1H-benzimidazol-2-yl) -2-methoxyethylamine dihydrochloride (0.20g,0.68mmol) in 2-butanol (5mL) was added 6-chloro-9- (tetrahydro-pyran-2-yl) -9H-purine (0.195mg,0.81mmol) and DIPEA (233 μ L,1.36mmol) and the reaction mixture was heated at 90 ℃ for 16H. The reaction mixture was concentrated in vacuo and the resulting residue was treated with flash chromatography (SiO) ₂Eluting with 0-10% methanol in EtOAc) to give the title compound as an off-white solid (290mg, 84%). LCMS (method C) R_T=3.48min,[M+H]+=506。

2-bromo-4-nitro-3-phenylaminophenol

To a solution of (2-bromo-3-fluoro-6-nitrophenyl) phenylamine (1.5g,4.8mmol) in bisTo a solution in alkane (20mL) and water (10mL) were added tris (dibenzylideneacetone) dipalladium (0) (88mg,0.96mmol), 2-di-tert-butylphosphino-2 ',4',6' -triisopropylbiphenyl (164mg,0.39mmol), and potassium hydroxide (812mg,14.4 mmol). The reaction mixture was degassed by bubbling argon through the mixture while sonicating. The reaction mixture was heated at 90 ℃ for 3h, then diluted with water and acidified to-pH 3 by addition of HCl (1N). The mixture was extracted with EtOAc (3X 20 mL). The combined organic fractions were washed with brine and dried (MgSO)₄) The residue is concentrated in vacuo and the residue is treated by flash chromatography (SiO)₂Eluting with 0-100% EtOAc in cyclohexane) to give the title compound as a yellow solid (879mg, 59%).¹H NMR400MHzδ(CDCl₃):8.85(1H,br s),8.18(1H,d,J=12.6Hz),7.31-7.24(2H,m),7.10-7.03(1H,m),6.92-6.86(2H,m),6.80(1H,d,J=12.6Hz)。

(2-bromo-3-methoxy-6-nitro-phenyl) -phenylamine

To a solution of 2-bromo-4-nitro-3-phenylaminophenol (450mg,1.45mmol) in acetone were added methyl iodide (0.34mL,5.44mmol) and potassium carbonate (751mg,5.44mmol) and the reaction mixture was heated at 40 ℃ for 16 h. The mixture was diluted with water and extracted with EtOAc (3X 20 mL). The combined organic fractions were washed with brine and dried (MgSO) ₄) Concentration in vacuo afforded the title compound as a yellow oil (470mg, 100%).¹H NMR400MHzδ(CDCl₃):8.36(1H,br s),8.19(1H,d,J=9.6Hz),7.28-7.22(2H,m),7.05-7.00(1H,m),6.89-6.84(2H,m),6.69(1H,d,J=9.7Hz),4.01(3H,s)。

3-bromo-4-methoxy-N²-phenyl-1, 2-diamines

To a solution of (2-bromo-3-methoxy-6-nitro-phenyl) -phenylamine (470mg,1.81mmol) in EtOAc (15mL) was added palladium on carbon (100mg,10% by weight) and the reaction mixture was stirred at RT for 16h under a hydrogen atmosphere. The reaction mixture was filtered and the filtrate was concentrated in vacuo to give the title compound as a yellow solid (426mg, 100%).¹H NMR400MHzδ(CDCl₃):7.24-7.17(2H,m),6.89-6.83(1H,m),6.74-6.72(1H,m),6.68-6.63(2H,m),5.48(1H,br s),3.85(3H,s)。

(S) -1- (7-bromo-6-methoxy-1-phenyl-1H-benzimidazol-2-yl) ethylamine dihydrochloride

To 3-bromo-4-methoxy-N at 0 deg.C²To a solution of-phenyl-benzene-1, 2-diamine (421mg,1.8mmol), Boc-ala-OH (343mg,1.8mmol) and HOAT (247mg,1.8mmol) in DCM (10mL) was added N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride (383mg,1.99mmol) and the reaction mixture was stirred at 0 ℃ for 1 h. The reaction mixture was diluted with water and extracted with DCM (3 × 10 mL). The combined organic fractions were washed with brine and dried (MgSO)₄) And concentrated in vacuo. Dissolving the residue in HCl IIAlkane solution (10mL,4M) and the reaction mixture was heated at 75 ℃ for 1 h. The reaction mixture was concentrated in vacuo to give the title product as a dark purple solid (758mg, 100%). LCMS (method C) R _T=2.15min,[M+H]+=346&348。

[ (S) -1- (7-bromo-6-methoxy-1-phenyl-1H-benzimidazol-2-yl) ethyl ] - [9- (tetrahydro-pyran-2-yl) -9H-purin-6-yl ] amine

To a solution of (S) -1- (7-bromo-6-methoxy-1-phenyl-1H-benzimidazol-2-yl) ethylamine dihydrochloride (0.75g,1.8mmol) in IPA (10mL) was added 6-chloro-9- (tetrahydro-pyran-2-yl) -9H-purine (0.56mg,2.34mmol) and DIPEA (1.2mL,7.2mmol) and the reaction mixture was heated at 90 ℃ for 16H. The reaction mixture was concentrated in vacuo and the resulting residue was treated with flash chromatography (SiO)₂Eluting with 0-10% methanol in EtOAc) to give the title compound as a white solid (453mg, 44%). LCMS (method C) R_T=3.22min,[M+H]+=548&550。

(3-Oxocyclobutyl) carbamic acid tert-butyl ester

To 3-oxocyclobutanecarboxylic acid (10g,87.64mmol) in CH with vigorous stirring₂Cl₂(60mL) to the solution SOCl₂(19mL,262.92 mmol). The resulting mixture was refluxed for 1.5 h. After cooling, the solvent was evaporated under reduced pressure. The residue was dissolved in DCE (2X 30mL) and evaporated to remove HCl and SOCl₂. The crude product was dissolved in acetone (25mL) and the resulting solution was added dropwise over 30min to pre-cooled (at 0 ℃ C.) NaN₃(11.48g,177.03mmol) in H₂O (30 mL). The mixture was stirred at 0 ℃ for 1h, then ice (80g) was added and the product was taken up in Et ₂O extraction (4X 75mL), drying (MgSO₄) And concentrated to 120mL under reduced pressure. The resulting solution was added to toluene (100mL) and the mixture was heated at 90 ℃. After distilling off the residual ether, the mixture was stirred at 90 ℃ for 30min until the N production ceased₂. Tert-butanol (27.68mL) was then added and the mixture was heated at 90 ℃ for 16 h. The reaction mixture was cooled to room temperature and the solvent was removed in vacuo to give the title compound as a pale red shiny solid (14.35g, 88.5%).¹H NMR(CDCl₃400 MHz). delta.4.9 (1H, br, NH),4.35-4.17(1H, m),3.46-3.31(2H, m),3.11-2.96(2H, m),1.45(9H, s). (NMR Spectrum No. 328453)

(cis-3-Hydroxycyclobutyl) carbamic acid tert-butyl ester

Tert-butyl (3-oxocyclobutyl) carbamate (10g,54.05mmol) was dissolved in dry THF (100mL) under an argon atmosphere and the solution was cooled to-78 ℃. Dropwise adding over 1h(1M THF solution, 81.1mL,81.1 mmol). The mixture was kept at-78 ℃ for 1H and NaOH (3.3g) was added dropwise over 30min in H₂Solution in O (36mL) then 30% H dropwise over 2H₂O₂Aqueous solution (30 mL). A dark yellow precipitate was observed. The resulting mixture was warmed to room temperature, then diluted with EtOAc (250mL) and 10% Na₂SO₃The aqueous solution (100mL) and brine (50mL) were washed and dried (MgSO ₄). The solvent was evaporated in vacuo to yield a yellow oil which solidified upon standing. The product was triturated with cyclohexane (50mL) to give the title compound as a yellow solid (7.2g (72%).¹H NMR(CDCl₃,400MHz):δ4.62(1H,br,NH),4.08-3.95(1H,m),3.74-3.54(1H,m),2.83-2.69(2H,m),2.43(1H,br,d,J=3.69Hz),1.86-1.72(2H,m),1.46(9H,s)。

(cis-3-Benzyloxycyclobutyl) carbamic acid tert-butyl ester

Tert-butyl (cis-3-hydroxycyclobutyl) carbamate (2.0g,10.7mmol) was dissolved in dry THF (50mL) under a nitrogen atmosphere and the solution was cooled to 0 ℃. To this clear solution was added sodium hydride (60% dispersion in oil, 0.428g,10.7mmol) in portions (H generation was observed)₂). The mixture was stirred at rt for 30min, then benzyl bromide (1.91mL,16.04mmol) was added dropwise and the resulting yellow suspension was stirred at rt for 16 h. Reacting with saturated NH₄Aqueous Cl (20mL) was quenched and washed with saturated NaHCO₃Partition between aqueous solution (40mL) and DCM (60 mL). The combined organic fractions were washed with brine (20mL) and dried (MgSO)₄) And concentrated in vacuo. The resulting residue was purified by column chromatography (gradient eluted with 0-50% EtOAc in cyclohexane) to give the title compound as a white solid (2.40g, 81%).¹H NMR(CDCl₃,400MHz):δ7.41-7.22(5H,m),4.66(1H,br,NH),4.42(2H,s),3.83-3.65(2H,m),2.79-2.61(2H,m),1.86-1.72(2H,m),1.46(9H,s)。

Cis-3-benzyloxy-cyclobutylamine

To a solution of tert-butyl (cis-3-benzyloxycyclobutyl) carbamate (2.40g,8.67mmol) in DCM (20mL) was added TFA (4mL) and the mixture was stirred at RT for 3 h. Volatiles were removed under vacuum and the resulting residue was dissolved in DCM and loaded onto SCX-2(20 g). The column was washed with DCM, then MeOH, then 2M NH ₃Washed with MeOH solution. The relevant fractions were concentrated in vacuo to give the title compound as a yellow oil (1.48g, 95%).¹H NMR(CDCl₃,400MHz):δ7.36-7.30(5H,m),4.40(2H,s),3.73-3.61(1H,m),3.06-2.93(1H,m),2.72-2.58(2H,m),1.74-1.61(2H,m),1.47(2H,s,br)。

N²- (cis-3-benzyloxycyclobutyl) -4-fluorobenzene-1, 2-diamine

To a solution of 2, 4-difluoro-1-nitrobenzene (0.92mL,8.36mmol) in CH₃To a solution in CN (60mL) were added cis-3-benzyloxycyclobutylamine (1.48g,8.36mmol) and DIPEA (1.46mL,8.36 mmol). The reaction mixture was stirred at RT for 18h, then concentrated in vacuo to give the title compound as a yellow oil (3.2g, quantitative yield). To a solution of the product thus obtained (1.6g,5.03mmol) in MeOH (20mL) were added iron powder (1.13g,20.12mmol), NH₄Cl (1.56g,30.18mmol) and H₂O (8mL), the reaction mixture was stirred at 90 ℃ for 2h under a nitrogen atmosphere. The resulting dark green mixture was usedPad filtration and vacuum concentration of the filtrate afforded a dark brown solid. The crude material was partitioned between EtOAc (50mL) and water (30 mL). The aqueous layer was extracted with EtOAc (2X 30 mL). The combined organic fractions were washed with brine (20mL) and dried (MgSO)₄) And concentrated in vacuo to give the title compound as a dark brown gum (1.13g, 78%).¹H NMR(CDCl₃300MHz delta 7.25-7.30(5H, m),6.6(1H, dd, J =14.0,2.8Hz),6.35-6.26(1H, m),6.26-6.18(1H, m),4.43(2H, s),3.95-3.83(1H, m),3.50-3.37(1H, m),2.90-2.78(2H, m),1.92-1.79(2H, m). 328138 for NMR. LCMS (method B) R _T2.87min[M+H]⁺287。

[ (S) -1- [1- (cis-3-benzyloxycyclobutyl) -6-fluoro-1H-benzimidazol-2-yl ] ethyl ] carbamic acid tert-butyl ester

Will N²A solution of- (cis-3-benzyloxycyclobutyl) -4-fluorobenzene-1, 2-diamine (1.13g,3.95mmol), (S) -2-tert-butoxycarbonylaminopropionic acid (0.83g,4.35mmol) and HOAt (0.59g,4.35mmol) in DCM (20mL) was cooled to 0 ℃ under a nitrogen atmosphere. To this mixture was added N- (3-dimethylaminopropyl) -N-ethylcarbodiimide hydrochloride (0.83g,4.35mmol) in portions and the reaction mixture was stirred at RT for 1 h. The reaction mixture was warmed to RT and then partitioned between DCM and 10% aqueous citric acid. The organic fraction was washed with brine (20mL) and dried (MgSO)₄) Concentrated in vacuo and the resulting dark brown residue purified by column chromatography (Si-PCC gradient eluted with 0-40% EtOAc in cyclohexane) to give the title compound as a yellow gum which solidified upon standing (1.93g, 93%).¹H NMR(CDCl₃400MHz δ 7.46(1H, s, br),7.36-7.30(5H, m),7.11(1H, q, J =14.8Hz,2.5Hz),6.37(1H, dt, J =19.5Hz,2.8Hz),6.25(1H, dd, J =14Hz,2.82Hz),4.94(1H, d, J =5.83Hz),4.43(2H, s),4.23-4.07(1H, m),3.93-3.81(1H, m),3.47-3.35(1H, m),2.88-2.75(1H, m),2.03-1,85(1H, m),1.45(3H, d, J =2.46Hz),1.43(9H, s). LCMS (method B) R _T3.88min[M+H]⁺458. 110183151. Will thus be obtainedThe compound (1g,2.19mmol) was dissolved in AcOH (15mL) and heated at 70 ℃ for 18 h. After cooling to RT, the volatiles were evaporated under reduced pressure and the residue was taken up in DCM (40mL) and saturated NaHCO₃The solutions (20mL) were partitioned between. The organic fraction was washed with brine (20mL) and dried (MgSO)₄) And concentrated in vacuo. The resulting dark yellow residue was purified by column chromatography (Si-PCC gradient eluted with 0-50% EtOAc in cyclohexane) to give the title compound as a pale red gum (570mg, 60%). LCMS (method B) R_T3.61min[M+H]⁺440.0。¹H NMR(CDCl₃,400MHz):δ7.70-7.60(2H,m),7.44-7.37(5H,m),7.05-6.96(1H,m),5.38-5.26(1H,m),5.20-5.05(1H,m),4.82-4.68(1H,m),4.55(2H,s),4.10-3.97(1H,m),3.02-2.77(4H,m),1.47(3H,d,J=2.44Hz),1.44(9H,s)。

(S) -1- [1- (cis-3-benzyloxycyclobutyl) -6-fluoro-1H-benzimidazol-2-yl ] ethylamine

To [ (S) -1- [1- (cis-3-benzyloxycyclobutyl) -6-fluoro-1H-benzimidazol-2-yl]Ethyl radical]To a solution of tert-butyl carbamate (570mg,1.3mmol) in DCM (10mL) was added TFA (4mL) and the mixture was stirred at RT for 1 h. Volatiles were removed under vacuum and the resulting residue was dissolved in DCM and loaded onto SCX-2(20 g). The column was washed with DCM, then MeOH, then 2M NH₃Washed with MeOH solution. The relevant fractions were concentrated in vacuo to give the title compound as a yellow gum (320mg, 73%). LCMS (method J) R _T1.97min[M+H]⁺340。¹H NMR(CDCl₃,400MHz):δ7.69-7.55(2H,m),7.44-7.24(5H,m),7.0(1H,dt,J=11.8,2.5Hz),4.81-4.66(1H,m),4.53(2H,s),4.32-4.21(1H,m),4.08-3.95(1H,m),3.02-2.75(4H,m),1.90(2H,s,br),1.50(3H,d,J=7.0Hz)-NMR:328174

[ (S) -1- [1- (cis-3-benzyloxycyclobutyl) -6-fluoro-1H-benzimidazol-2-yl ] ethyl ] - (9H-purin-6-yl) -amine

Reacting (S) -1- [1- (cis-3-benzyloxy-cyclobutyl) -6-fluoro-1H-benzimidazol-2-yl]A mixture of ethylamine (310mg,0.91mmol), 6-chloro-9- (tetrahydropyran-2-yl) -9H-purine (219mg,0.91mmol) and DIPEA (0.81mL,4.57mmol) in IPA (5mL) was heated at 90 deg.C in a sealed vial for 16H. After cooling to RT, the reaction mixture was concentrated in vacuo, dissolved in DCM and loaded into DCMSCX-2 column, washed with DCM, MeOH, and then with 2MNH₃Washing with MeOH. The product containing fractions were combined and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC,0-10%2M NH)₃Gradient eluent in DCM/MeOH) to give the title compound as a glassy white solid (320mg, 76%). LCMS (method B) R_T2.76min[M+H]⁺458。¹H NMR(CDCl₃,400MHz):δ8.48(1H,s),7.95(1H,s),7.71-7.58(2H,m),7.42-7.35(5H,m),7.07-6.90(2H,m),5.95(1H,s,br),4.97-4.80(m,1H),4.52(2H,s),4.05-3.92(1H,m),3.01-2.86(2H,m),2.81-2.64(1H,m),1.75(3H,d,J=6.85Hz)。

Trans-4-nitrobenzoic acid 3-tert-butoxycarbonylaminocyclobutyl ester

To a solution of tert-butyl (cis-3-hydroxycyclobutyl) carbamate (2g,10.7mmol) and p-nitrobenzoic acid (1.97g,11.8mmol) in dry THF (40mL) was added triphenylphosphine (4.20g,16.05mol) and DEAD (3.17mL,20.0mmol) successively at 0 ℃. The resulting mixture was stirred at rt (rt) overnight. The resulting dark red solution was concentrated in vacuo and the residue was purified by column chromatography (Si-PCC, with Gradient elution with 0-50% EtOAc in cyclohexane) gave the title compound as a pale yellow solid (4.2g, quantitative yield).¹H NMR(CDCl₃):δ8.29(2H,dd,J=8.9Hz),δ8.20(2H,dd,J=8.9Hz),5.42-5.31(1H,m),4.7(1H,s,br),4.37-4.26(1H,m),2.71-2.57(2H,m),2.53-2.36(2H,m),1.45(9H,s)。

(trans-3-Hydroxycyclobutyl) carbamic acid tert-butyl ester

To K₂CO₃(1.26g,9.06mmol)、H₂To a mixture of O (8.5mL) and methanol (40mL) was added trans-4-nitrobenzoic acid 3-tert- (butoxycarbonylamino) cyclobutyl ester (2.0g,5.97 mmol). The resulting mixture was refluxed at 70 ℃ for 1 h. The reaction mixture was cooled to RT, filtered, and the filtrate was concentrated in vacuo to give the title compound as a pale yellow solid (0.95g, 82%).¹H NMR(CDCl₃)δ4.67(1H,s,br),4.55-4.40(1H,m),2.38-2.14(4H,m),1.82(1H,s,br),1.43(9H,s)。

(trans-3-benzyloxycyclobutyl) carbamic acid tert-butyl ester

Under a nitrogen atmosphere, tert-butyl (trans-3-hydroxycyclobutyl) carbamate (0.93g,4.97mmol) was dissolved in dry THF (20mL) and the solution was cooled to 0 ℃. To this clear solution was added sodium hydride (60% dispersion in oil, 0.2g,4.97mmol) in portions (H generation was observed)₂). The mixture was stirred at RT for 30min, then benzyl bromide (0.88mL,7.45mmol) was added dropwise and the resulting dark brown suspension was stirred at RT for 16 h. The reaction mixture was washed with saturated NH₄Aqueous Cl (20mL) was quenched and washed with saturated NaHCO₃Partition between aqueous solution (40mL) and DCM (60 mL). Will be combinedThe organic fraction of (A) was washed with brine (20mL) and dried (MgSO) ₄) And concentrated in vacuo. The resulting residue was purified by column chromatography (gradient eluted with 0-50% EtOAc in cyclohexane) to give the title compound as an off-white solid (0.99g, 72%).¹H NMR(CDCl₃,400MHz):δ7.35-7.31(5H,m),4.65(1H,br,NH),4.40(2H,s),4.24-4.12(2H,m),2.50-2.35(2H,m),2.18-2.06(2H,m),1.43(9H,s)。

Trans-3-benzyloxy-cyclobutylamine

To a solution of tert-butyl (trans-3-benzyloxycyclobutyl) carbamate (0.99g,3.56mmol) in DCM (10mL) was added TFA (2mL) and the mixture was stirred at RT for 3 h. Volatiles were removed under vacuum and the resulting residue was dissolved in DCM and loaded onto a SCX-2(20g) column. The column was washed with DCM, then MeOH, then 2M NH₃Washed with MeOH solution. The relevant fractions were concentrated in vacuo to give the title compound as a yellow oil (0.6g, quantitative yield).¹H NMR(CDCl₃,400MHz):δ7.36-7.31(5H,m),4.40(2H,s),4.29-4.20(1H,m),3.75-3.65(1H,m),2.39-2.26(2H,m),2.02-1.90(2H,m),1.49(2H,s,br)。

N²- (trans-3-benzyloxycyclobutyl) -4-fluorobenzene-1, 2-diamine

To a solution of 2, 4-difluoro-1-nitrobenzene (0.37mL,3.39mmol) in CH₃To a solution in CN (10mL) was added trans-3-benzyloxycyclobutylamine (0.6g,3.39mmol) and DIPEA (0.6mL,3.39 mmol). The reaction mixture was stirred at RT for 18h, then concentrated in vacuo to afford the compound as a yellow oil (1.2g, quantitative yield). To the product thus obtained (1.2g,3.77mmol) in MeOH (20mL) was added iron powder (0.85g,15.08mmol) and NH ₄Cl (1.17g,22.62mmol) and H₂O (8mL), the reaction mixture was stirred at 90 ℃ under a nitrogen atmosphere for 2 h. The resulting dark green mixture was usedThe pad was filtered and the filtrate was concentrated in vacuo. The resulting residue was partitioned between EtOAc (50mL) and water (30 mL). The aqueous layer was extracted with EtOAc (2X 30mL), and the combined organic fractions were washed with brine (20mL) and dried (MgSO)₄) And concentrated in vacuo to give the title compound as a dark yellow gum (0.73g, 68%).¹H NMR(CDCl₃,300MHz):δ7.37-7.32(5H,m),6.63(1H,q,J=14.0Hz,2.8Hz),6.40(1H,dt,J=19.6Hz,2.7Hz),6.20(1H,dd,J=13.6Hz,2.7Hz),4.44(2H,s),4.35-4.24(1H,m),4.01-3.92(1H,m),2.55-2.42(2H,m),2.25-2.13(2H,m)。

[ (S) -1- [1- (trans-3-benzyloxycyclobutyl) -6-fluoro-1H-benzimidazol-2-yl ] ethyl ] carbamic acid tert-butyl ester

Will N²A mixture of- (trans-3-benzyloxycyclobutyl) -4-fluoro-benzene-1, 2-diamine (1.73g,2.55mmol), (S) -2-tert-butoxycarbonylaminopropionic acid (0.54g,2.81mmol) and HOAt (0.38g,2.81mmol) in DCM (20mL) was cooled to 0 ℃ under a nitrogen atmosphere. To this mixture was added N- (3-dimethylaminopropyl) -N-ethylcarbodiimide hydrochloride (0.54g,2.81mmol) in portions and the reaction mixture was stirred at RT for 1 h. The reaction mixture was warmed to RT and then partitioned between DCM (30mL) and 10% aqueous citric acid (20 mL). The organic layer was washed with brine (20mL) and dried (MgSO)₄) And concentrated in vacuo, and the resulting residue purified by column chromatography (Si-PCC, gradient eluted with 0-50% EtOAc in cyclohexane) to give the title compound as an off-white gum which solidified upon standing (0.88g, 75%). 328289 for NMR. LCMS (method B) R _T3.85min[M+H]⁺458。

The compound thus obtained (0.88g,1.93mmol) was dissolved in AcOH (10mL) and heated at 70 ℃ for 18 h. After cooling to RT, the volatiles were evaporated in vacuo and the residue was taken up in DCM (40mL) and saturated NaHCO₃The aqueous solution (20mL) was partitioned. The organic fraction was washed with brine (20mL) and dried (MgSO)₄) And then concentrated in vacuo. The resulting dark brown residue was purified by column chromatography (Si-PCC, gradient eluted with 0-50% EtOAc in cyclohexane) to give the title compound as a dark yellow oil (0.46g, 55%). LCMS (method B) R_T3.63min[M+H]⁺440

(S) -1- [1- (trans-3-benzyloxycyclobutyl) -6-fluoro-1H-benzimidazol-2-yl ] ethylamine

To [ (S) -1- [1- (trans-3-benzyloxycyclobutyl) -6-fluoro-1H-benzimidazol-2-yl]Ethyl radical]To a solution of tert-butyl carbamate (0.46g,1.05mmol) in DCM (10mL) was added TFA (4mL) and the mixture was stirred at RT for 1 h. The volatiles were removed in vacuo and the resulting pale red gummy residue was dissolved in DCM and loaded onto a column of SCX-2(20 g). The column was washed with DCM, then MeOH, then 2M NH₃Washed with MeOH solution. The relevant fractions were concentrated in vacuo to give the title compound as a yellow gum (0.28g, 80%). LCMS (method B) R _T2.17min[M+H]⁺340

[ (S) -1- [1- (trans-3-benzyloxycyclobutyl) -6-fluoro-1H-benzimidazol-2-yl ] ethyl ] - (9H-purin-6-yl) amine

Reacting (S) -1- [1- (trans-3-benzyloxy cyclobutyl) -6-fluoro-1H-benzimidazole-2-yl]A mixture of ethylamine (210mg,0.62mmol), 6-chloro-9- (tetrahydropyran-2-yl) -9H-purine (148mg,0.62mmol) and DIPEA (0.55mL,3.09mmol) in IPA (5mL) was heated at 90 deg.C in a sealed vial for 16H. After cooling to RT, the reaction mixture was concentrated in vacuo, dissolved in DCM and loaded into DCMSCX-2 column, washed with DCM, MeOH, and then with 2MNH₃Washing with MeOH. The product containing fractions were combined and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC with 0-5%2M NH)₃Gradient MeOH in DCM) to give the title compound as a colorless glassy solid (120mg, 43%). LCMS (method J) R_T2.72min[M+H]⁺458

4-amino-6- [ (S) -1- [1- (trans-3-benzyloxycyclobutyl) -6-fluoro-1H-benzimidazol-2-yl ] ethylamino ] -pyrimidine-5-carbonitrile

Reacting (S) -1- [1- (trans-3-benzyloxy-cyclobutyl) -6-fluoro-1H-benzimidazol-2-yl]A mixture of ethylamine (67mg,0.20mmol), 4-amino-6-chloropyrimidine-5-carbonitrile (31mg,0.20mmol), and DIPEA (0.18mL,0.99mmol) in IPA (3mL) was heated at 90 deg.C for 16h in a sealed vial. After cooling to RT, the reaction mixture was concentrated in vacuo, dissolved in DCM and loaded into DCM SCX-2 column, washed with DCM, then with MeOH, then with 2MNH₃Washing with MeOH. The product containing fractions were combined and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC with 0-5%2M NH)₃Gradient elution in DCM/MeOH) gave the title compound as a colorless glassy solid (60mg, 67%). LCMS (method B) R_T3.09min[M+H]⁺458

(cis-3-methoxycyclobutyl) carbamic acid tert-butyl ester

Tert-butyl (cis-3-hydroxycyclobutyl) carbamate (0.8g,4.3mmol) was dissolved in dry THF (25mL) under a nitrogen atmosphere and the solution was cooled to 0 ℃. To this clear solution was added sodium hydride (60% dispersion in oil, 0.17g,4.3mmol) in portions (H generation was observed)₂). The mixture was stirred at RT for 30 min. Methyl iodide (0.40mL,1.5mmol) was then added dropwise and the resulting yellow suspension was stirred at RT for 16 h. The reaction mixture was washed with saturated NH₄Quenched with aqueous Cl (20mL) and saturated NaHCO₃Partition between aqueous solution (40mL) and DCM (60 mL). The combined organic fractions were washed with brine (20mL) and dried (MgSO)₄) And concentrated in vacuo. The resulting residue was purified by column chromatography (gradient elution of 0-70% EtOAc in cyclohexane) to give the title compound as a white solid (0.58g, 66%). ¹H NMR(CDCl₃,300MHz):δ4.66(1H,br,NH),3.71-3.62(1H,m),3.61-3.50(1H,m),2.71(3H,s),2.76-1.62(2H,m),1.78-1.62(2H,m),1.41(9H,s)。

Cis-3-methoxycyclobutylamine

To a solution of tert-butyl (cis-3-methoxycyclobutyl) carbamate (580mg,2.8mmol) in DCM (20mL) was added TFA (10mL) and the mixture was stirred at RT for 2 h. Volatile materials were removed under vacuum and the resulting residue was loaded ontoSCX-2 column. The column was washed with MeOH, then 2M NH₃Washing with MeOH. The basic fractions were combined and concentrated in vacuo to give the titleThe title compound was a yellow oil (170mg, 58%).¹H NMR(CDCl₃,300MHz):δ3.53-3.48(1H,m),3.06-2.93(1H,m),2.71-2.58(2H,m),1.64-1.52(2H,m),1.51(2H,s,br)。

4-fluoro-N²- (cis-3-methoxycyclobutyl) benzene-1, 2-diamine

To a solution of 2, 4-difluoro-1-nitrobenzene (0.18mL,1.6mmol) in CH₃To a solution in CN (3mL) were added cis-3-methoxycyclobutylamine (0.17g,1.6mmol) and DIPEA (0.28mL,1.6 mmol). The reaction mixture was stirred at RT for 18h, then concentrated in vacuo. The resulting residue was used in the next step without any further purification (0.39g, quantitative yield). To a solution of the product thus obtained (1.6mmol) in EtOAc (15mL) was added Pd/C (350mg) and the reaction mixture was stirred under a hydrogen atmosphere at RT for 18 h. Mixing the suspension withPad filtration and concentration of the filtrate in vacuo afforded the title compound as a dark oil (0.453g, quantitative yield).¹H NMR(CDCl₃,300MHz):δ6.67-6.06(1H,m),6.35-6.17(2H,m),3.75-3.63(1H,m),3.61-3.25(3H,br s),3.22(3H,s),3.12-2.93(1H,m),2.90-2.78(2H,m),1.85-1.60(2H,m)。

{ (S) -1- [ 6-fluoro-1- (cis-3-methoxycyclobutyl) 1H-benzimidazol-2-yl ] ethyl } carbamic acid tert-butyl ester

Reacting 4-fluoro-N²- (cis-3-methoxycyclobutyl) benzene-1, 2-diamine (0.34g,1.6mmol), (S) -2-tert-butoxycarbonylaminopropionic acid (0.33g,1.8mmol) and HOAt (0.24g,1.8mmol) in DCM (8mL)The mixture was cooled to 0 ℃ under a nitrogen atmosphere. To this mixture was added N- (3-dimethylaminopropyl) -N-ethylcarbodiimide hydrochloride (0.35g,1.8mmol) portionwise and the mixture was stirred at RT for 1 h. The reaction mixture was warmed to RT and then quenched in DCM (30mL) and saturated NaHCO₃The aqueous solution (20mL) was partitioned. The organic fraction was washed with brine (20mL) and dried (MgSO)₄) And concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC gradient eluted with 0-50% EtOAc in cyclohexane) to afford compound as a pink oil (0.348g, 57%). The compound thus obtained was dissolved in AcOH (8mL) and heated at 70 ℃ for 18 h. After cooling to RT, the volatiles were evaporated in vacuo and the residue was taken up in DCM (40mL) and saturated NaHCO₃The aqueous solution (20mL) was partitioned. The organic fraction was washed with brine (20mL) and dried (MgSO)₄) And then concentrated in vacuo. The resulting dark brown residue was purified by column chromatography (Si-PCC, gradient eluted with 0-50% EtOAc in cyclohexane) to give the title compound as a yellow oil (0.222g, 38%). LCMS (method B) R _T2.86min[M+H]⁺364.03

(S) -1- [ 6-fluoro-1- (cis-3-methoxycyclobutyl) -1H-benzimidazol-2-yl ] ethylamine

To { (S) -1- [ 6-fluoro-1- (cis-3-methoxycyclobutyl) 1H-benzimidazol-2-yl]Ethyl } carbamic acid tert-butyl ester (0.22g,0.61mmol) in DCM (5mL) was added TFA (3mL) and the mixture was stirred at RT for 1.5 h. Volatile materials were removed under vacuum and the resulting residue was loaded ontoSCX-2 column. The column was washed with MeOH, then 2MNH₃Washing with MeOH. The basic fractions were combined and concentrated in vacuo. The crude material was used in the next step without further purification. Yellow oil (quantitative yield). LCMS (method B) R_T1.72min[M+H]⁺263.90。

(trans-3-methoxycyclobutyl) carbamic acid tert-butyl ester

Tert-butyl (trans-3-hydroxycyclobutyl) carbamate (1.18g,6.3mmol) was dissolved in dry THF (25mL) under a nitrogen atmosphere and the solution was cooled to 0 ℃. To this clear solution was added sodium hydride (60% dispersion in oil, 0.25g,6.3mmol) in portions (H generation was observed)₂). The reaction mixture was stirred at RT for 30 min. Methyl iodide (0.40mL,1.5mmol) was then added and the resulting yellow suspension was stirred at RT for 16 h. The reaction mixture was washed with saturated NH₄Quenched with aqueous Cl (20mL) and saturated NaHCO ₃Partition between aqueous solution (40mL) and DCM (60 mL). The combined organic fractions were washed with brine (20mL) and dried (MgSO)₄) Filtered and concentrated in vacuo. The resulting residue was purified by column chromatography (gradient elution of 0-70% EtOAc in cyclohexane) to give the title compound as a yellow oil (1.05g, 82%).¹H NMR(CDCl₃,300MHz):δ4.65(1H,br s),4.22-4.10(1H,m),4.00-3.92(1H,m),2.40-2.28(2H,m),2.18-2.12(2H,m),1.43(9H,s)。

Trans-3-methoxycyclobutylamine

To a solution of tert-butyl (trans-3-methoxycyclobutyl) carbamate (1.05g,5.1mmol) in DCM (30mL) was added TFA (15mL) and the mixture was stirred at RT for 2 h. Volatile materials were removed under vacuum and the resulting residue was loaded ontoSCX-2 column.The column was washed with MeOH, then 2M NH₃Washing with MeOH. The basic fractions were combined and concentrated in vacuo to give the title compound as a yellow oil (511mg, 96%).¹H NMR(CDCl₃,300MHz):δ7.42(2H,br s),4.30-4.09(2H,m),3.78(1H,d,J=10.3Hz),3.12(3H,s),1.43-1.15(3H,m)。

4-fluoro-N²- (trans-3-methoxycyclobutyl) benzene-1, 2-diamine

To a solution of 2, 4-difluoro-1-nitrobenzene (0.2mL,1.7mmol) in CH₃To a solution in CN (3mL) was added trans-3-methoxycyclobutylamine (0.18g,1.7mmol) and DIPEA (0.3mL,1.7 mmol). The reaction mixture was stirred at RT for 18h, then concentrated in vacuo. The resulting residue was used in the next step without further purification (0.41g, quantitative yield). To a solution of the product thus obtained (1.7mmol) in EtOAc (15mL) was added Pd/C (350mg) and the reaction mixture was stirred at RT for 18h under a hydrogen atmosphere. Mixing the suspension with Pad filtration and concentration of the filtrate in vacuo afforded the title compound as a dark oil (0.36g, quantitative yield).¹H NMR(CDCl₃,300MHz):δ6.68-6.59(1H,m),6.33(1H,dt,J=19.6Hz,2.7Hz),6.18(1H,dd,J=13.6Hz,2.7Hz),4.00-3.90(1H,m),3.76-3.63(1H,m),3.53(3H,brs),3.27(3H,s),2.49-2.37(2H,m),2.36-2.12(2H,m)。

{ (S) -1- [ 6-fluoro-1- (trans-3-methoxycyclobutyl) 1H-benzimidazol-2-yl ] ethyl } carbamic acid tert-butyl ester

Reacting 4-fluoro-N²(trans-3-methoxycyclo ringA solution of butyl) benzene-1, 2-diamine (0.36g,1.7mmol), (S) -2-tert-butoxycarbonylaminopropionic acid (0.35g,1.9mmol) and HOAt (0.26g,1.9mmol) in DCM (8mL) was cooled to 0 ℃ under a nitrogen atmosphere. To this mixture was added N- (3-dimethylaminopropyl) -N-ethylcarbodiimide hydrochloride (0.36g,1.9mmol) portionwise and the mixture was stirred at RT for 1 h. The reaction mixture was warmed to RT and then quenched in DCM (30mL) and saturated NaHCO₃The aqueous solution (20mL) was partitioned. The organic fraction was washed with brine (20mL) and dried (MgSO)₄) And concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC gradient eluted with 0-50% EtOAc in cyclohexane) to afford compound as a pink solid (0.188g, 29%). The compound thus obtained was dissolved in AcOH (8mL) and heated at 70 ℃ for 18 h. After cooling to RT, the volatiles were evaporated in vacuo and the residue was taken up in DCM (40mL) and saturated NaHCO₃The aqueous solution (20mL) was partitioned. The organic fraction was washed with brine (20mL) and dried (MgSO) ₄) And concentrated in vacuo. The resulting dark brown residue was purified by column chromatography (Si-PCC, gradient eluted with 0-50% EtOAc in cyclohexane) to give the title compound as a yellow oil (0.125g, 20%). LCMS (method B) R_T2.84min[M+H]⁺364.05

(S) -1- [ 6-fluoro-1- (cis-3-methoxycyclobutyl) -1H-benzimidazol-2-yl ] ethylamine

To { (S) -1- [ 6-fluoro-1- (trans-3-methoxycyclobutyl) 1H-benzimidazol-2-yl]Ethyl } carbamic acid tert-butyl ester (0.125g,0.34mmol) in DCM (3mL) was added TFA (2mL) and the mixture was stirred at RT for 1.5 h. Volatile materials were removed under vacuum and the resulting residue was loaded ontoSCX-2 column. The column was washed with MeOH, then 2MNH₃Washing with MeOH. The basic fractions were combined and concentrated in vacuo.The crude material was used in the next step without further purification. Yellow oil (85mg, 95%). LCMS (method J) R_T1.60min[M+H]⁺264.23。610116410

(5-fluoro-2-nitrophenyl) -pyridin-4-yl-amine

Potassium tert-butoxide (898mg,8.0mmol) was added to a stirred solution of 4-aminopyridine (376mg,4.00mmol) in anhydrous THF (5mL) at 0 deg.C under a nitrogen atmosphere. After stirring at 0 ℃ for 15min, 2, 4-difluoro-1-nitrobenzene (0.44mL,4.0mmol) in anhydrous THF (5mL) was added and stirring continued at 0 ℃ for 1 h. The reaction mixture was poured onto saturated NH ₄Aqueous Cl solution (50 mL). The aqueous phase was extracted with EtOAc (× 2), the combined organic fractions were washed with brine and dried (Na)₂SO₄) And concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient eluted with 0-10% MeOH in DCM) to give the title compound as a yellow solid (557mg, 60%). LCMS (method C) R_T1.26min[M+H]⁺234.12

4-fluoro-N²-pyridin-4-yl-benzene-1, 2-diamine

To a mixture of (5-fluoro-2-nitro-phenyl) -pyridin-4-yl-amine (375mg,1.61mmol) in 3:1 MeOH/water mixture (40mL) was added NH₄Cl (516mg,9.65mmol) and iron powder (359mg,6.43mmol) and the reaction mixture was heated at 80 ℃ for 2 h. After cooling to RT, the solid was usedThe pad was filtered off and washed with additional MeOH. The filtrate was concentrated in vacuo and the residue obtained was washed with waterDCM and saturated NaHCO₃The aqueous solution was partitioned. The organic fraction was dried and concentrated in vacuo to give the title compound as a dark beige solid (215mg, 66%). LCMS (method C) R_T1.32min[M+H]⁺204.09

[1- (6-fluoro-1-pyridin-4-yl-1H-benzimidazol-2-yl) ethyl ] carbamic acid tert-butyl ester

To a suspension of (S) -Boc-alaninamide (385mg,2.05mmol) in DCM (5mL) under a nitrogen atmosphere was added triethyloxy in one portionTetrafluoroborate (389mg,2.05 mmol). The resulting mixture was stirred at RT for 1 h. Volatiles were removed under reduced pressure and the resulting residue was added 4-fluoro-N in anhydrous EtOH (5mL) ²-pyridin-4-yl-benzene-1, 2-diamine (208mg,1.02mmol) and the mixture was stirred at 80 ℃ for 16 h. Volatiles were removed under reduced pressure and the resulting residue was taken up in DCM and saturated NaHCO₃The aqueous solution was partitioned. The organic fraction was dried, concentrated in vacuo and the resulting residue was purified by column chromatography (Si-PCC, gradient elution with 0-10% MeOH in EtOAc) to give the title compound as a pale yellow oil (210mg, 58%). LCMS (method C) R_T2.84min[M+H]⁺357.15

1- (6-fluoro-1-pyridin-4-yl-1H-benzimidazol-2-yl) ethylamine

Reacting [1- (6-fluoro-1-pyridin-4-yl-1H-benzimidazol-2-yl) ethyl]A mixture of tert-butyl carbamate (210mg,0.59mmol) in DCM (2mL) and TFA (1mL) was stirred at RT for 2 h. Loading the reaction mixture intoSCX-2 column, which was washed with MeOH, then 2M NH₃Washing with MeOH. The basic fractions were combined and concentrated in vacuo to give the title compound (120mg,79%) as a yellow solid. LCMS (method C) R_T1.63min[M+H]⁺257.15。

(5-fluoro-2-nitrophenyl) - (5-fluoropyridin-3-yl) amine

LiHMDS (1.0M THF solution, 10.0mL,10.0mmol) was added dropwise to a stirred solution of 3-amino-5-fluoropyridine (588mg,5.26mmol) in anhydrous THF (10mL) at-78 deg.C under a nitrogen atmosphere. After 20min, 2, 4-difluoro-1-nitrobenzene (0.55mL,5.0mmol) was added and stirring continued at-78 ℃ for 1 h. The reaction mixture was poured onto saturated NH ₄Aqueous Cl solution (50 mL). The aqueous phase was extracted with EtOAc (× 2), the combined organic fractions were washed with brine and dried (Na)₂SO₄) And concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient elution of 0-100% EtOAc in DCM) to give the title compound as an orange solid (428mg, 34%). LCMS (method C) R_T3.27min[M+H]⁺252.16

An alternative procedure was to add potassium tert-butoxide (28.1g,0.25mol) in two portions to a stirred solution of 3-amino-5-fluoropyridine (14.0g,0.125mol) in anhydrous THF (400mL) at 0 deg.C under a nitrogen atmosphere. After stirring at 0 ℃ for 45min, the resulting dark purple solution was transferred at 0 ℃ via cannula to a stirred solution of 2, 4-difluoro-1-nitrobenzene (13.8mL,0.125mol) in anhydrous THF (100mL) over 20 min. The resulting mixture was stirred for another 45min and then poured into NH at RT₄Cl solution (1:1 saturated solution: H₂O, 1L). The resulting yellow precipitate was filtered off, washed with water and dried under vacuum at 50 ℃ to give the title compound,as an orange solid (18.2 g). The filtrate was partially evaporated to remove some of the reaction solvent, the resulting precipitate was filtered off and then triturated with EtOAc to give another 3.5g (21.7 g total, 69%) of the title compound LCMS (method C): R _T3.18min[M+H]⁺252.13

4-fluoro-N²- (5-fluoropyridin-3-yl) benzene-1, 2-diamine

A mixture of (5-fluoro-2-nitro-phenyl) - (5-fluoropyridin-3-yl) amine (425mg,1.69mmol) in EtOAc (30mL) was degassed with a stream of nitrogen, then 10% Pd/C (50mg) was added and stirred at RT for 19h under a hydrogen atmosphere. The mixture was filtered and the filtrate was concentrated in vacuo to give the title compound as a brown solid (395mg, quantitative yield). LCMS (method C) R_T2.24min[M+H]⁺222.07

(S) -1- [ 6-fluoro-1- (5-fluoropyridin-3-yl) -1H-benzimidazol-2-yl ] ethylamine

To a suspension of (S) -Boc-alaninamide (337mg,1.79mmol) in DCM (5mL) under a nitrogen atmosphere was added triethyloxy in one portionTetrafluoroborate (340mg,1.79 mmol). The resulting mixture was stirred at RT for 1 h. Volatiles were removed under reduced pressure and the resulting residue was added 4-fluoro-N in anhydrous EtOH (5mL)²- (5-Fluoropyridin-3-yl) -benzene-1, 2-diamine (198mg,0.895mmol) and the mixture was stirred at 80 ℃ for 18 h. Volatiles were removed in vacuo and the resulting residue was taken up in DCM and saturated NaHCO₃The aqueous solution was partitioned. The organic fraction is dried, concentrated in vacuo and the residue obtained is taken up inTo DCM (2mL) was added TFA (1 mL). After stirring for 1h at RT, the reaction mixture is diluted with MeOH and loaded onto SCX-2 column. The column was washed with MeOH, then 2M NH₃Washing with MeOH. The basic fractions were combined and concentrated in vacuo and the resulting residue was purified by column chromatography (Si-PCC, gradient elution with 0-20% MeOH in DCM) to give the title compound as a colorless oil (52mg, 21% yield over two steps). LCMS (method C) R_T1.76min[M+H]⁺275.20

{ (S) -1- [ 6-fluoro-1- (5-fluoropyridin-3-yl) -1H-benzimidazol-2-yl ] ethyl } carbamic acid tert-butyl ester

To a suspension of (S) -Boc-alaninamide (17.4g,92.5mmol) in DCM (180mL, molecular sieves dried) under nitrogen atmosphere was added triethyloxy-chloride in one portionTetrafluoroborate (16.0g,84.1 mmol). The resulting mixture was stirred at RT for 2 h. Volatiles were removed under vacuum and the resulting residue was taken up in anhydrous EtOH (200mL) and 4-fluoro-N was added²- (5-Fluoropyridin-3-yl) -benzene-1, 2-diamine (6.20g,28.0 mmol). After stirring the reaction mixture at 60 ℃ for 2h, the solvent was removed in vacuo and the resulting residue was taken up in DCM and NaHCO₃The aqueous solution was partitioned. The layers were separated and the aqueous fraction was extracted with DCM. The combined organic fractions were dried (Na)₂SO₄) And concentrated in vacuo. The resulting residue was purified by column chromatography (120g of Si-PCC, gradient eluted with 0-70% EtOAc in DCM) to give the title compound as a green solid (10.1g, 96%). LCMS (method C) R _T3.23min[M+H]⁺375.18。

2-cyclopropylamino-6-fluoro-3-nitrobenzoic acid

To a solution of 2, 6-difluoro-3-nitrobenzoic acid (1.0g,4.92mmol) in IMS (5mL) and water (5mL) was added Et₃N (1.23mL,8.86mmol) and cyclopropylamine (360. mu.L, 5.17 mmol). The reaction mixture was stirred at RT for 28 h. The pH of the solution was adjusted to 1 by addition of 1M aqueous HCl. A precipitate formed and the solid was collected by filtration and washed with water to give the title compound (841mg,71%) as a yellow solid.¹H NMR(CDCl₃,400MHz):δ8.78(1H,s),8.28(1H,dd,J=9.45,5.85Hz),6.49(1H,m),2.84(1H,m),0.85(2H,m),0.68(2H,m)

2-Cyclopropylamino-6-fluoro-3-nitrobenzoic acid methyl ester

Trimethylsilyldiazomethane (2M in hexane, 2.6mL,5.21mmol) was added dropwise to a solution of 2-cyclopropylamino-6-fluoro-3-nitrobenzoic acid (836mg,3.48mmol) in MeOH (4mL) and DCM (16mL) at 0 deg.C. The solution was stirred for 15min, then the volatiles were removed under reduced pressure to give the title compound (867mg, 98%). LCMS (method C) R_T3.50min[M+H]⁺255.10

3-amino-2-cyclopropylamino-6-fluorobenzoic acid methyl ester

A mixture of methyl 2-cyclopropylamino-6-fluoro-3-nitrobenzoate (865mg,3.40mmol) in EtOAc (25mL) was degassed with a stream of nitrogen, then 10% Pd/C (116mg) was added and hydrogen at RTStirred under atmosphere for 20 h. The suspension was filtered and the filtrate was concentrated in vacuo to give the title compound as a dark yellow oil (756mg, 99%). LCMS (method C) R _T2.29min[M+H]⁺225.18。

2- ((S) -1-tert-Butoxycarbonylaminoethyl) -3-cyclopropyl-5-fluoro-3H-benzimidazole-4-carboxylic acid methyl ester

A mixture of methyl 3-amino-2-cyclopropylamino-6-fluorobenzoate (756mg,3.37mmol), (S) -2-tert-butoxycarbonylaminopropionic acid (702mg,3.71mmol), HOAt (505mg,3.71mmol) and N- (3-dimethylaminopropyl) -N-ethylcarbodiimide hydrochloride (711mg,3.71mmol) in DCM (20mL) was stirred at 0 ℃ for 1 h. The reaction mixture was washed with DCM and saturated NaHCO₃The aqueous solution was partitioned. The organic fraction was dried and concentrated in vacuo. The resulting residue was taken up in AcOH (20mL) and heated at 70 ℃ for 21 h. After cooling to RT, the volatiles were evaporated in vacuo and the residue was taken up in EtOAc and saturated NaHCO₃The aqueous solution was partitioned. The aqueous phase was extracted with EtOAc and the combined organic fractions were washed with brine and dried (Na)₂SO₄) And concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient elution with 0-50% EtOAc in DCM) to afford the title compound (700mg, 55% yield in two steps). LCMS (method C) R_T3.27min[M+H]⁺378.18

3-cyclopropyl-5-fluoro-2- { (S) -1- [9- (tetrahydropyran-2-yl) -9H-purin-6-ylamino ] ethyl } -3H-benzimidazole-4-carboxylic acid methyl ester

To methyl 2- ((S) -1-tert-butoxycarbonylaminoethyl) -3-cyclopropyl-5-fluoro-3H-benzimidazole-4-carboxylate (698mg,1.85 mmo) l) to a solution in DCM (3mL) was added TFA (3mL) and the reaction mixture was stirred at RT for 2 h. Loading the crude mixture intoSCX-2 column, which was washed with MeOH, then 2M NH₃Washing with MeOH. The basic fractions were combined and concentrated in vacuo to give methyl 2- ((S) -1-aminoethyl) -3-cyclopropyl-5-fluoro-3H-benzimidazole-4-carboxylate as a yellow oil. The resulting residue was treated with 6-chloro-9- (tetrahydropyran-2-yl) -9H-purine (486mg,2.03mmol) and DIPEA (970. mu.L, 5.55mmol) in n-butanol (3 mL). The reaction mixture was heated in a sealed vial at 100 ℃ for 20 h. After cooling to RT, the volatiles were removed under reduced pressure and the resulting residue was purified by column chromatography (Si-PCC, gradient elution of 0-10% MeOH in EtOAc) to give the title compound (780mg, 88% yield over two steps). LCMS (method C) R_T2.91min[M+H]⁺480.22。

3-cyclopropyl-5-fluoro-2- { (S) -1- [9- (tetrahydropyran-2-yl) -9H-purin-6-ylamino ] ethyl } -3H-benzimidazole-4-carboxylic acid

Coupling 3-cyclopropyl-5-fluoro-2- { (S) -1- [9- (tetrahydropyran-2-yl) -9H-purin-6-ylamino]Ethyl } -3H-benzimidazole-4-carboxylic acid methyl ester (607mg,1.27mmol) and LiOH. H₂A solution of O (266mg,6.33mmol) in MeOH (20mL) and water (2mL) was heated at 80 deg.C for 22 h. Addition of additional LiOH. H ₂O (266mg) and the mixture was heated at 80 ℃ for 5 h. After cooling to RT, the pH of the mixture was adjusted to 4 by addition of 1M aqueous HCl. The organic solvent was removed under reduced pressure and the aqueous phase was extracted with EtOAc. The organic fraction was washed with brine and dried (Na)₂SO₄) And concentrated in vacuo. The residue was purified by column chromatography (Si-PCC with 0-20%2M NH)₃Gradient MeOH in DCM) to give the title compound (127mg, 21% yield in two steps) as a white solid. LCMS (method)C):R_T2.17min[M+H]⁺466.22。

(5-fluoro-2-nitrophenyl) - (3-fluoropyridin-2-yl) amine

LiHMDS (1.0M THF solution, 4.0mL,4.0mmol) was added dropwise to a stirred solution of 2-amino-3-fluoropyridine (224mg,2.0mmol) in anhydrous THF (5mL) at-78 deg.C under a nitrogen atmosphere. After stirring at-78 ℃ for 15min, a solution of 2, 4-difluoro-1-nitrobenzene (0.22mL,2.0mmol) in THF (5mL) was added and stirring continued at-78 ℃ for 1 h. The mixture was slowly warmed to 0 ℃ and stirring was continued for 1 h. The crude solution was poured into saturated NH₄Aqueous Cl solution (50 mL). The aqueous phase was extracted with EtOAc (× 3), the combined organic fractions were washed with water then brine, dried (Na)₂SO₄) And concentrated in vacuo. The resulting residue was purified by column chromatography (gradient elution of Si-PCC,0-100% DCM in cyclohexane) to give the title compound as an orange solid (93mg, 19%). LCMS (method C) R _T3.97min[M+H]⁺252.10。

4-fluoro-N²- (3-fluoropyridin-2-yl) benzene-1, 2-diamine

A mixture of (5-fluoro-2-nitro-phenyl) - (3-fluoropyridin-2-yl) amine (93mg,0.370mmol) in EtOAc (10mL) was degassed with a stream of nitrogen, then 10% Pd/C (10mg) was added and stirred at RT for 3h under a hydrogen atmosphere. The mixture was then filtered through a phase separator and the filtrate was concentrated in vacuo to give the title compound as a brown solid (81mg, 99%). LCMS (method C) R_T1.70min[M+H]⁺222.18。

{1- [ 6-fluoro-1- (3-fluoropyridin-2-yl) -1H-benzimidazol-2-yl ] ethyl } carbamic acid tert-butyl ester

Reacting 4-fluoro-N²A mixture of (3-fluoropyridin-2-yl) benzene-1, 2-diamine (81mg,0.37mmol), (S) -2-tert-butoxycarbonylaminopropionic acid (76mg,0.40mmol), HOAt (55mg,0.40mmol) and N- (3-dimethylaminopropyl) -N-ethylcarbodiimide hydrochloride (77mg,0.40mmol) in DCM (5mL) was stirred at 0 ℃ for 2 h. The reaction mixture was washed with DCM and saturated NaHCO₃The aqueous solution was partitioned. The organic layer was dried and concentrated in vacuo. The resulting residue was taken up in AcOH (5mL) and heated at 70 ℃ for 24 h. After cooling to RT, the volatiles were removed in vacuo and the resulting residue was taken up in EtOAc and saturated NaHCO₃The aqueous solution was partitioned. The organic fraction was washed with water, then brine, then dried (Na) ₂SO₄) And concentrated in vacuo. The resulting oil was purified by column chromatography (Si-PCC, gradient elution with 0-10% MeOH in EtOAc) to give the title compound as an orange oil (84mg, 61%). LCMS (method C) R_T3.28min[M+H]⁺375.22

Benzyl- (5-fluoro-2-nitrophenyl) amine

2, 4-difluoro-1-nitrobenzene (2.00g,12.57mmol) was dissolved in acetonitrile (20mL) and DIPEA (2.2mL,12.57mmol) was added, followed by dropwise addition of benzylamine (1.35g,12.57 mmol). The reaction mixture was stirred at RT under nitrogen atmosphere overnight. The mixture was concentrated in vacuo to give the title compound as a yellow oil which solidified upon standing (3.8g, 100%). The crude material was used in the next step without purification.¹H NMR(CDCl₃,400MHz):δ8.55(1H,s),8.25(1H,dd,J=9.46,6.08Hz),7.43-7.29(5H,m),6.47(1H,dd,J=11.35,2.60Hz),6.39(1H,ddd,J=9.46,7.28,2.61Hz),4.51(2H,d,J=5.60Hz)

N²-benzoyl-4-fluoro-benzene-1, 2-diamine

A mixture of benzyl- (5-fluoro-2-nitrophenyl) amine (3.8g,15.2mmol), iron powder (3.42g,60.8mmol) and ammonium chloride (4.7g,91.2mmol) in methanol (40mL) and water (10mL) was heated to 90 ℃ for 2h under a nitrogen atmosphere. The resulting mixture was diluted with methanol (20mL) and washed with waterAnd (5) filtering. Will be provided withWash with DCM, methanol and EtOAc (4 ×) and concentrate the filtrate in vacuo. The residue was partitioned between water (25mL) and EtOAc (40mL), and the aqueous layer was extracted with EtOAc (2X 30 mL). The combined organic fractions were washed with brine (25mL) and dried (MgSO) ₄) Filtration and concentration in vacuo afforded the title compound as a dark brown gum (2.17g, 66%). The crude material was used in the next step without purification.¹H NMR(CDCl₃,400MHz):δ7.41-7.25(5H,m),6.67-6.59(1H,m),6.40-6.28(2H,m),4.28(2H,s)

[ (S) -1- (2-benzylamino-4-fluorophenylcarbamoyl) ethyl ] carbamic acid tert-butyl ester

Will N²-benzyl-4-fluoro-benzene-1, 2-diamine (1.2g,5.55mmol) was dissolved in DCM (20mL) and (S) -2-tert-butoxycarbonylaminopropionic acid (1.14g,6.0mmol) and HOAt (0.82g,6.0mmol) were added. The reaction mixture was cooled to 0 ℃ and N- (3-dimethylaminopropyl) -N' -ethylcarbo-xide was addedDiimine (1.15g,6.0 mmol). The resulting dark brown mixture was stirred at 0 ℃ for 1 h. The mixture was brought to RT and diluted with DCM (20mL) and washed with 10% aqueous citric acid. The organic fraction was washed with brine (20mL) and dried (MgSO)₄) Filtered and concentrated in vacuo. The residue was purified by column chromatography (silica gel, gradient eluted with 0-50% EtOAc in cyclohexane) to give the title compound as a dark yellow gum which solidified upon standing (1.7g, 79%). LCMS (method B) R_T3.67min[M+H]⁺388.1

[ (S) -1- (1-benzyl-6-fluoro-1H-benzimidazol-2-yl) ethyl ] carbamic acid tert-butyl ester

Reacting [ (S) -1- (2-benzylamino-4-fluorophenylcarbamoyl) ethyl]Tert-butyl carbamate (1.7g,4.39mmol) was dissolved in acetic acid (15mL) and heated at 70 ℃ overnight under a nitrogen atmosphere. The reaction mixture was then heated at 80 ℃ for 6 h. The resulting mixture was then cooled to RT and concentrated in vacuo. The residue was purified by column chromatography (silica gel, gradient eluted with 0-50% EtOAc in cyclohexane) to give the title compound as an off-white solid (0.88g, 55%). ¹H NMR(CDCl₃,400MHz):δ7.68(1H,dd,J=8.81,4.79Hz),7.34-7.26(3H,m),7.08-6.95(3H,m),6.90(1H,dd,J=8.69,2.43Hz),5.43(2H,d,J=5.40Hz),5.18-5.06(1H,m),1.53(3H,d,J=6.73Hz),1.37(9H,s)。

(S) -1- (1-benzyl-6-fluoro-1H-benzimidazol-2-yl) ethylamine

Reacting [ (S) -1- (1-benzyl-6-fluoro-1H-benzimidazol-2-yl) ethyl]Tert-butyl carbamate (0.88g,2.39mmol) was dissolved in DCM (10mL) and TFA (4mL) was added dropwise. The light green mixture was placed under nitrogenStir under atmosphere at RT for 1 h. The resulting mixture was concentrated in vacuo and the residue was passed throughSCX-2 column with DCM, MeOH, then 2M NH₃Was eluted with MeOH to give the title compound as a pale red gum (0.60g, 93%).¹H NMR(CDCl₃,400MHz):δ7.69(1H,dd,J=8.81,4.80Hz),7.37-7.28(3H,m),7.09-7.95(3H,m),6.89(1H,dd,J=8.75,2.44Hz),5.54-5.34(2H,m),4.26(1H,q,J=6.67Hz),1.54(3H,d,J=6.61Hz)

(5-fluoro-2-nitrophenyl) isopropylamine

2, 4-difluoro-1-nitrobenzene (2.00g,12.57mmol) was dissolved in acetonitrile (20mL) and DIPEA (2.2mL,12.57mmol) was added followed by isopropylamine (1.07mL,12.57 mmol). The bright yellow mixture was stirred at RT overnight. The resulting mixture was concentrated in vacuo and the residue was purified by column chromatography (silica gel, gradient eluted with 0-5% EtOAc in cyclohexane) to give the title compound as a yellow gum (2.1g, 99%). Contaminated with some unreacted 2, 4-difluoro-1-nitrobenzene, but was used in the next step without any further purification.¹H NMR(CDCl₃,400MHz):δ8.20(1H,dd,J=9.53,6.21Hz),6.48(1H,dd,J=11.71,2.63Hz),6.33(1H,m),3.80-3.64(1H,m),1.33(6H,d,J=6.36Hz)

4-fluoro-N²-isopropylbenzene-1, 2-diamine

(5-fluoro-2-nitrophenyl) isopropylamine (2.1g,12.6mmol) was dissolved in EtOAc (60mL), the flask was evacuated and flushed with nitrogen, then 10% Pd/C (0.21g) was added . The mixture was stirred under hydrogen atmosphere overnight. An additional 10% Pd/C (0.21g) was added and the mixture was stirred under an atmosphere of hydrogen for a further 3 h. An additional 10% Pd/C (0.21g) was added and the mixture was stirred under an atmosphere of hydrogen for an additional 2 h. The resulting mixture was used under a nitrogen atmosphereFiltration and concentration of the filtrate in vacuo gave the title compound as a dark red oil (1.5g, 88%).¹H NMR(CDCl₃,400MHz):δ6.62(1H,dd,J=8.34,5.72Hz),6.36(1H,dd,J=11.17,2.77Hz),6.28(1H,td,J=8.43,2.75Hz),3.61-3.47(1H,m),1.24(6H,d,J=6.27Hz)

[ (S) -1- (6-fluoro-1-isopropyl-1H-benzimidazol-2-yl) ethyl ] carbamic acid tert-butyl ester

Reacting 4-fluoro-N²-cumene-1, 2-diamine (0.7g,5.07mmol) was dissolved in DCM (10mL) and (S) -2-tert-butoxycarbonylaminopropionic acid (1.06g,5.58mmol) was added. To the resulting dark red solution was added HOAt (0.76g,5.58mmol), followed by N-methylmorpholine (1.23mL,11.15mmol) and N- (3-dimethylaminopropyl) -N' ethylcarbodiimide (1.07g,5.58 mmol). The resulting blue/black solution was stirred under nitrogen at RT overnight. The mixture was diluted with DCM (40mL) and saturated NaHCO₃Aqueous solution (20mL) and brine (20 mL). The organic fraction was dried (MgSO)₄) Filtered and concentrated in vacuo to give a dark red oil. It was purified by column chromatography (silica gel, gradient eluted with 0-20% EtOAc in DCM) to give a red oil which solidified on standing. It was dissolved in acetic acid (20mL) and heated at 70 ℃ overnight. The resulting mixture was then cooled to RT and concentrated in vacuo to give the title compound as a dark red gum (1.0g, 88%). The material was used in the next step without any purification. LCMS (method B) R _T2.78min[M+H]⁺322.2

(S) -1- (6-fluoro-1-isopropyl-1H-benzimidazol-2-yl) ethylamine

Reacting [ (S) -1- (6-fluoro-1-isopropyl-1H-benzimidazol-2-yl) ethyl]Tert-butyl carbamate (1.0g,3.11mmol) was dissolved in DCM (10mL) and TFA (5mL) was added. The reaction mixture was stirred at RT for 30 min. The resulting mixture was concentrated in vacuo and the residue was dissolved in DCM (40mL) and saturated NaHCO₃The aqueous solution (20mL) was stirred vigorously for 10 minutes. The layers were separated and the organic fraction was washed with brine (20mL) and dried (MgSO)₄) Filtered and concentrated in vacuo to give the title compound (0.5g, 72%).¹H NMR(CDCl₃,400MHz):δ7.65(1H,dd,J=8.83,5.01Hz),7.20(1H,dd,J=9.40,2.46Hz),6.97(1H,ddd,J=9.58,8.80,2.43Hz),4.92-4.82(1H,m),4.37-4.28(1H,q,J=6.68Hz),1.64(6H,d,J=6.98Hz),1.58(3H,d,J=6.65Hz)。

(5-fluoro-2-nitrophenyl) - (4-fluorophenyl) amine

Under a nitrogen atmosphere, 4-fluoroaniline (1.47g,13.19mmol) was dissolved in THF (20mL) and cooled to-70 ℃. A solution of 1M LiHMDS in THF (25.14mL,25.14mmol) was added dropwise and the mixture was stirred at-70 ℃ for 15 minutes under a nitrogen atmosphere. To the mixture was added dropwise a solution of 2, 4-difluoronitrobenzene (2.0g,12.57mmol) in THF (10mL) at-70 deg.C, and the resulting violet solution was stirred at-70 deg.C for 30 min. The reaction mixture was washed with saturated NH₄Aqueous Cl was quenched and extracted into EtOAc (3X 50 mL). The combined organic fractions were dried (MgSO)₄) Filtered and concentrated in vacuo. The residue was purified by column chromatography (silica gel, gradient elution with 0-100% DCM in cyclohexane) to give the title compound as Orange solid (2.94g, 100%).¹H NMR(CDCl₃,400MHz):δ9.53(1H,s),8.27(1H,dd,J=9.48,5.98Hz),7.29-7.22(2H,m),7.20-7.11(2H,m),6.64(1H,dd,J=11.26,2.65Hz),6.48(1H,ddd,J=9.47,7.12,2.65Hz)

4-fluoro-N²- (4-fluorophenyl) benzene-1, 2-diamine

(5-fluoro-2-nitrophenyl) - (4-fluorophenyl) amine (2.94g,11.76mmol) was dissolved in EtOAc (120mL), and the flask was evacuated and flushed with nitrogen. 10% Pd/C (0.29g) was added and the reaction mixture was stirred at RT overnight under a hydrogen atmosphere. Mixing the obtained mixture withFiltration and concentration of the filtrate in vacuo gave the title compound as an orange oil (2.67g, 91%).¹H NMR(CDCl₃,400MHz):δ7.01-6.92(2H,m),6.87-6.68(4H,m),6.61(1H,td,J=8.35,2.79Hz),5.24(1H,s),3.46(2H,s)

{ (S) -1- [ 6-fluoro-1- (4-fluorophenyl) -1H-benzimidazol-2-yl ] ethyl } carbamic acid tert-butyl ester

Reacting 4-fluoro-N²- (4-fluorophenyl) benzene-1, 2-diamine (0.7g,3.18mmol) was dissolved in DCM (10mL) and (S) -2-tert-butoxycarbonylaminopropionic acid (0.68g,3.55mmol) was added. To the resulting solution was added HOAt (0.49g,3.55mmol), followed by N-methylmorpholine (0.85mL,7.69mmol), followed by N- (3-dimethylaminopropyl) -N' ethylcarbodiimide (0.69g,3.55 mmol). The resulting dark yellow solution was stirred at RT overnight. Additional (S) -2-tert-butoxycarbonylaminopropionic acid (0.38g,2.00mmol), HOAt (0.24g,1.76mmol), N-methylMorpholine (0.40mL,3.64mmol) and N- (3-dimethylaminopropyl) -N' ethylcarbodiimide (0.34g,1.78mmol), and the reaction mixture was stirred at RT for 2 h. The mixture was diluted with DCM and then saturated NaHCO ₃Aqueous solution (20mL) and brine (20 mL). The organic fraction was dried (MgSO)₄) Filtered and concentrated in vacuo to give a dark red oil. It was purified by column chromatography (SiO)₂Gradient elution with 0-10% EtOAc in DCM) gave an off-white solid (1.25 g). It was dissolved in acetic acid (20mL) and heated to 70 ℃ for 48 h. The resulting mixture was then cooled to RT and concentrated in vacuo. The residue was dissolved in DCM (40mL) and saturated NaHCO was used₃Aqueous solution (20mL) and brine (20 mL). The organic fraction was dried (MgSO)₄) Filtered and concentrated in vacuo. The resulting dark red oil was purified by column chromatography (SiO)₂Gradient elution with 0-20% EtOAc in DCM) to give the title compound as a yellow gum (0.8g, 68%). LCMS (method J) R_T3.55min[M+H]⁺374.1

(S) -1- [ 6-fluoro-1- (4-fluorophenyl) -1H-benzimidazol-2-yl ] ethylamine

Reacting { (S) -1- [ 6-fluoro-1- (4-fluorophenyl) -1H-benzimidazol-2-yl]Tert-butyl ethyl } carbamate (0.8g,2.14mmol) was dissolved in DCM (10mL) and TFA (5mL) was added. The reaction mixture was stirred at RT for 1 h. The resulting mixture was concentrated in vacuo to give a dark green gum. It was dissolved in DCM (40mL) and saturated NaHCO₃The aqueous solution (20mL) was stirred vigorously for 10 minutes. The layers were separated and the organic fraction was dried (MgSO ₄) Filtered and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 10% MeOH in DCM) to give the title compound (0.33g, 57%). LCMS (method C) R_T1.86min[M+H]⁺274.2

(5-fluoro-2-nitrophenyl) - (3-fluorophenyl) amine

A solution of 3-fluorophenyl amine (1.47g,13.19mmol) in dry THF (20mL) was cooled to-70 ℃. 1M LiHMDS in THF (25.14mL,25.14mmol) was added dropwise over 10 minutes to give a dark yellow solution. To this yellow solution was added dropwise a solution of 2, 4-difluoronitrobenzene (2.00g,12.57mmol) in anhydrous THF (10mL) to give a purple solution. The reaction mixture was stirred at-70 ℃ for 15 minutes and then allowed to reach RT. Then with saturated NH₄Aqueous Cl (25mL) was quenched and extracted into EtOAc (3X 50 mL). The combined organic fractions were washed with brine (25mL) and dried (MgSO)₄) Filtered and concentrated in vacuo to give a dark red solid. It was purified by column chromatography (SiO)₂Gradient elution of 0-100% DCM in cyclohexane) gave the title compound as an orange solid (2.79g, 89%).¹H NMR(CDCl₃,400MHz):δ9.61(1H,s),8.28(1H,dd,J=9.48,5.96Hz),7.45-7.37(1H,m),7.11-6.94(3H,m),6.88(1H,dd,J=11.16,2.64Hz),6.58-6.49(1H,m)

4-fluoro-N²- (3-fluorophenyl) benzene-1, 2-diamine

(5-fluoro-2-nitrophenyl) - (3-fluorophenyl) amine (2.79g,11.16mmol) was dissolved in EtOAc (110mL), and the flask was evacuated and flushed with nitrogen. 10% Pd/C (0.3g) was added and the reaction mixture was stirred under a hydrogen atmosphere at RT overnight. An additional 10% Pd/C (0.3g) was added and the reaction mixture was stirred under an atmosphere of hydrogen for an additional 2 h. Mixing the obtained mixture with Filtration and concentration of the filtrate in vacuo gave the title compound as a brown oil which solidified upon standing (2.57g, 100%).¹H NMR(CDCl₃,400MHz):δ7.17(1H,td,J=8.16,6.58Hz),6.94-6.87(1H,m),6.76-6.70(2H,m),6.62-6.47(3H,m),5.35(1H,s),3.54(2H,s)

{ (S) -1- [ 4-fluoro-2- (3-fluorophenylamino) phenylcarbamoyl ] ethyl } carbamic acid tert-butyl ester and { (S) -1- [ 6-fluoro-1- (3-fluorophenyl) -1H-benzimidazol-2-yl ] ethyl } carbamic acid tert-butyl ester

Reacting 4-fluoro-N²- (3-fluorophenyl) benzene-1, 2-diamine (0.7g,3.18mmol) was dissolved in DCM (10mL) under a nitrogen atmosphere and (S) -2-tert-butoxycarbonylaminopropionic acid (0.68g,3.55mmol) was added. To the resulting solution was added HOAt (0.49g,3.55mmol), followed by N-methylmorpholine (0.85mL,7.69mmol) and N- (3-dimethylaminopropyl) -N' ethylcarbodiimide (0.69g,3.55 mmol). The resulting dark yellow solution was stirred at RT (room temperature) under nitrogen atmosphere overnight. The reaction mixture was diluted with DCM and saturated NaHCO₃Aqueous solution (20mL) and brine (20 mL). The organic fraction was dried (MgSO)₄) Filtered and concentrated in vacuo. The residue was purified by column chromatography (silica gel, gradient eluted with 0-10% EtOAc in DCM) to afford an off-white solid (1.2 g). It was dissolved in acetic acid (15mL) and heated to 70 ℃ overnight. The resulting mixture was then cooled to RT and concentrated in vacuo. The residue was dissolved in DCM and saturated NaHCO ₃Aqueous solution (20mL) and brine (20 mL). The organic fraction was dried (MgSO)₄) Filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO)₂Gradient elution with 0-20% EtOAc in DCM) gave two title compounds as off-white solids (0.78 g and 0.15g, respectively).

{ (S) -1- [ 4-fluoro-2- (3-fluorophenylamino) phenylcarbamoyl]Ethyl } carbamic acid tert-butyl ester:¹H NMR(CDCl₃,400MHz):δ8.05(1H,s),7.45(1H,dd,J=8.83,5.91Hz),7.23-7.14(1H,m),7.04(1H,dd,J=10.32,2.82Hz),6.78-6.57(4H,m),6.38(1H,s),4.95-4.86(1H,m),4.27-4.17(1H,m),1.46-1.39(12H,m)

{ (S) -1- [ 6-fluoro-1- (3-fluorophenyl) -1H-benzimidazol-2-yl]Ethyl } carbamic acid tert-butyl ester:¹H NMR(CDCl₃,400MHz):δ7.69(1H,dd,J=8.83,4.74Hz),7.62-7.53(1H,m),7.30-7.21(2H,m),7.17(1H,d,J=8.97Hz),7.04(1H,ddd,J=9.56,8.82,2.48Hz),6.81(1H,dd,J=8.52,2.48Hz),5.48-5.39(1H,m),5.03-4.89(1H,m),1.44(3H,d,J=6.89Hz),1.40(9H,s)

(S) -1- [ 6-fluoro-1- (3-fluorophenyl) -1H-benzimidazol-2-yl ] ethylamine

Process 1 reacting { (S) -1- [ 4-fluoro-2- (3-fluorophenylamino) phenylcarbamoyl]Ethyl } carbamic acid tert-butyl ester (0.5g,1.28mmol) dissolved in 4M HClAlkane solution (10mL) and the reaction mixture was heated to 70 ℃ for 2 h. The resulting mixture was then cooled to RT and concentrated in vacuo. The residue was dissolved in DCM (40mL) and saturated NaHCO was used₃Aqueous solution (20mL) and brine (20 mL). The organic layer was dried (MgSO₄) Filtration and concentration in vacuo afforded the title compound as a yellow gum (0.38g, 100%).

Method 2 reacting { (S) -1- [ 6-fluoro-1- (3-fluorophenyl) -1H-benzimidazol-2-yl]Ethyl } carbamic acid tert-butyl ester (0.14g,0.38mmol) was dissolved in DCM (6mL) and TFA (3mL) was added dropwise. The reaction mixture was stirred at RT for 1 h. The resulting mixture was concentrated in vacuo. The residue was dissolved in DCM (40mL) and saturated NaHCO ₃The aqueous solution (20mL) was stirred vigorously for 10 minutes. The organic fraction was separated and dried (MgSO)₄) Filtered and concentrated in vacuo to give the title compound (80mg, 80%).¹H NMR(CDCl₃,400MHz):δ7.72(1H,dd,J=8.79,4.74Hz),7.64-7.55(1H,m),7.33-7.16(3H,m),7.05(1H,td,J=9.15,2.48Hz),6.83(1H,d,J=8.47Hz),4.16(1H,s),1.71(2H,s),1.50(3H,d,J=6.52Hz)

(5-fluoro-2-nitrophenyl) - (2-fluorophenyl) amine

A solution of 2-fluorophenyl amine (1.47g,13.19mmol) in dry THF (20mL) was cooled to-70 ℃. 1M LiHMDS in THF (25.14mL,25.14mmol) was added dropwise over 10min to give a dark yellow solution. To the yellow solution was added dropwise a solution of 2, 4-difluoronitrobenzene (2.00g,12.57mmol) in anhydrous THF (10mL) to give a purple solution. It was stirred at-70 ℃ for 15 minutes and then allowed to reach RT. Then with saturated NH₄Aqueous Cl (25mL) was quenched and extracted into EtOAc (3X 50 mL). The combined organic fractions were washed with brine (25mL) and dried (MgSO)₄) Filtered and concentrated in vacuo to give an orange solid. This was purified by column chromatography (silica gel, gradient elution with 0-100% DCM in cyclohexane) to give the title compound as a yellow solid (3.04g, 97%).¹H NMR(CDCl₃,400MHz):δ9.36(1H,s),8.20(1H,dd,J=9.45,5.94Hz),7.34-7.26(1H,m),7.24-7.10(3H,m),6.56(1H,dt,J=11.09,2.07Hz),6.45(1H,ddd,J=9.44,7.13,2.63Hz)

4-fluoro-N²- (2-fluorophenyl) benzene-1, 2-diamine

(5-fluoro-2-nitrophenyl) - (2-fluorophenyl) amine (3.04g,12.16mmol) was dissolved in EtOAc (120mL), and the flask was evacuated and flushed with nitrogen. 10% Pd/C (0.3g) was added and the reaction mixture was stirred under a hydrogen atmosphere at RT overnight. An additional 10% Pd/C (0.3g) was added and the reaction mixture was stirred under an atmosphere of hydrogen for an additional 2 h. Mixing the obtained mixture with Filtration and concentration of the filtrate in vacuo gave the title compound as a dark yellow oil which solidified upon standing (2.89g, 95%).¹H NMR(CDCl₃,400MHz):δ7.05-6.87(2H,m),6.83-6.68(3H,m),6.68-6.59(2H,m),5.36(1H,s),3.49(2H,s)

{ (S) -1- [ 4-fluoro-2- (2-fluorophenylamino) phenylcarbamoyl ] ethyl } carbamic acid tert-butyl ester

Reacting 4-fluoro-N²- (2-fluorophenyl) benzene-1, 2-diamine (0.7g,3.18mmol) was dissolved in DCM (10mL) under a nitrogen atmosphere and (S) -2-tert-butoxycarbonylaminopropionic acid (0.68g,3.55mmol) was added. To the resulting solution was added HOAt (0.49g,3.55mmol), followed by N-methylmorpholine (0.85mL,7.69mmol) and N- (3-dimethylaminopropyl) -N' ethylcarbodiimide (0.69g,3.55 mmol). The resulting dark yellow solution was stirred under nitrogen at RT overnight. Additional (S) -2-tert-butoxycarbonylaminopropionic acid (0.34g,1.78mmol), HOAt (0.24g,1.78mmol), N-methylmorpholine (0.40mL,3.64mmol) and N- (3-dimethylaminopropyl) -N' ethylcarbodiimide (0.34g,1.78mmol) were added and the reaction stirred at RT for an additional 2 h. The reaction mixture was diluted with DCM and saturated NaHCO₃Aqueous solution (20mL) and brine (20 mL). The organic fraction was dried (MgSO)₄) Filtered and concentrated in vacuo. The residual dark red oil was purified by column chromatography (SiO)₂Gradient elution with 0-10% EtOAc in DCM) gave an off-white solid (1.04 g). It was dissolved in acetic acid (15mL) and heated to 70 ℃ for 48 h. The resulting mixture was cooled to RT and concentrated in vacuo. The residual pink oil was dissolved in DCM and saturated NaHCO ₃Aqueous solution (20mL) and brine (20 mL). The organic fraction was dried (MgSO)₄) Filtered and concentrated in vacuo. The residue was purified by column chromatography (silica gel, gradient eluted with 0-20% EtOAc in DCM) to afford the title compoundProduct (0.7g, 59%). LCMS (method J) R_T3.62min[M+H]⁺392.1

(S) -1- [ 6-fluoro-1- (2-fluorophenyl) -1H-benzimidazol-2-yl ] ethylamine

Reacting { (S) -1- [ 4-fluoro-2- (2-fluorophenylamino) phenylcarbamoyl]Tert-butyl ethyl } carbamate (0.7g,1.80mmol) was dissolved in 4M HCl in dioxane (10mL) and the reaction mixture was heated to 70 ℃ for 5 h. The resulting mixture was concentrated in vacuo, the residue dissolved in DCM (40mL) and saturated NaHCO₃Aqueous solution (20mL) and brine (20 mL). The organic fraction was dried (MgSO)₄) Filtered and concentrated in vacuo to give a red gum. This was purified by column chromatography (silica gel, gradient eluted with 0-10% MeOH in DCM) to give the title compound (0.22g, 46%). LCMS (method C) R_T1.74min[M+H]⁺274.3

(5-fluoro-2-nitrophenyl) - (3-methoxyphenyl) amine

A solution of 3-methoxyphenylamine (1.58g,12.82mmol) in dry THF (20mL) was cooled to-70 ℃. A1M solution of LiHMDS in THF (25.14mL,25.14mmol) was added dropwise over 10 minutes. This was stirred at-70 ℃ for 15 minutes, then a solution of 2, 4-difluoronitrobenzene (2.00g,12.57mmol) in anhydrous THF (10mL) was added dropwise. The dark yellow solution was then brought to RT and saturated NH was used ₄And (4) quenching by using a Cl aqueous solution. It was extracted into EtOAc (3 ×), the combined organic fractions were washed with brine (20mL), dried (MgSO)₄) Filtration and concentration in vacuo afforded the title compound as a dark yellow gum which solidified upon standing (3.35g, 100%).¹H NMR(CDCl₃,400MHz):δ9.60(1H,s),8.25(1H,dd,J=9.48,5.99Hz),7.34(1H,t,J=8.00Hz),6.90-6.77(4H,m),6.47(1H,ddd,J=9.47,7.11,2.64Hz),3.83(3H,s)

4-fluoro-N²- (3-methoxyphenyl) benzene-1, 2-diamine

(5-fluoro-2-nitrophenyl) - (3-methoxyphenyl) amine (3.35g,12.7mmol) was dissolved in EtOAc (50mL), and the flask was evacuated and flushed with nitrogen. 10% Pd/C (0.35g) was added and the reaction mixture was stirred under a hydrogen atmosphere at RT overnight. An additional 10% Pd/C (0.35g) was added and the reaction mixture was stirred under an atmosphere of hydrogen for an additional 1 h. Mixing the obtained mixture withFiltration and concentration of the filtrate in vacuo afforded the title compound as a red gum (2.97g, 100%).¹H NMR(CDCl₃,400MHz):δ7.15(1H,t,J=8.08Hz),6.91(1H,dd,J=9.89,2.72Hz),6.76-6.62(2H,m),6.49-6.37(3H,m),5.29(1H,s),3.77(3H,s),3.52(2H,s)

(S) -1- [ 6-fluoro-1- (3-methoxyphenyl) -1H-benzimidazol-2-yl ] ethylamine

Reacting 4-fluoro-N²- (3-methoxyphenyl) benzene-1, 2-diamine (0.7g,2.99mmol) was dissolved in DCM (10mL) under a nitrogen atmosphere and (S) -2-tert-butoxycarbonylaminopropionic acid (0.63g,3.29mmol) and HOAt (0.45g,3.29mmol) were added. The mixture was cooled to 0 ℃ and N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide (0.63g,3.29mmol) was added portionwise. The reaction mixture was stirred at 0 ℃ for 1h and then brought to RT. It was then diluted with DCM (40mL) and washed with 10% citric acid and brine (20 mL). The organic fraction was dried (MgSO)₄) Filtered and concentrated in vacuo. The residue was dissolved in acetic acid (10mL) and heated at 70 ℃ overnight. The resulting mixture was cooled to RT and concentrated in vacuo to give a dark brown gum. It was purified by column chromatography (SiO)₂Gradient elution with 0-5% MeOH in DCM) gave boc-protected title compound as a red gum which solidified upon standing (0.78g, 68%). It was dissolved in DCM (10mL) and TFA (3mL) was added. The reaction mixture was stirred at RT for 1 h. The resulting mixture was concentrated in vacuo and the residue was dissolved in DCM (40mL) and saturated NaHCO₃The aqueous solution was stirred vigorously for 10 minutes. The layers were separated and the organic fraction was washed with brine (20mL) and dried (MgSO)₄) Filtration and concentration in vacuo afforded the title compound as a red gum (0.4g, 70%). LCMS (method B) R_T1.90min[M+H]⁺286.0

{ (S) -1- [ 6-fluoro-1- (3-methoxyphenyl) -1H-benzimidazol-2-yl ] ethyl } -9H-purin-6-yl) amine

Reacting (S) -1- [ 6-fluoro-1- (3-methoxyphenyl) -1H-benzimidazol-2-yl]Ethyl amine (0.4g,1.4mmol) was dissolved in n-butanol (5mL) and 6-chloro-9- (tetrahydropyran-2-yl) -9H-purine (0.335g,1.4mmol) and DIPEA (1.24mL,7.01mmol) were added. The reaction mixture was heated at 100 ℃ overnight. The resulting mixture was then cooled to RT and concentrated in vacuo. The residue is passed downwards SCX-2 column with DCM, MeOH and 2M NH₃Eluted with MeOH to give a light red solid. It was purified by column chromatography (SiO)₂Gradient elution with 0-15% MeOH in DCM) to give the title compound plus (S) -N- [ 4-fluoro-2- (3-methoxyphenylamino) phenyl]-2- (9H-purin-6-ylamino) propionamide. The mixture was redissolved in acetic acid (3mL) and incubated at 100 deg.CHeating for 5 h. The resulting mixture was then cooled to RT and concentrated in vacuo. The residue was purified by column chromatography (silica gel, with 0-7% [2M NH ]₃In MeOH (E) solution]Gradient elution of DCM) to give the title compound as an off-white solid (36%). LCMS (method J) R_T2.55min[M+H]⁺404.2

Cyclohexyl- (5-fluoro-2-nitrophenyl) amine

2, 4-difluoronitrobenzene (2.00g,12.57mmol) was dissolved in acetonitrile (20mL) and cyclohexylamine (1.25g,12.57mmol) and DIPEA (2.2mL,12.57mmol) were added. The reaction mixture was stirred at RT overnight. The resulting mixture was concentrated in vacuo to give a bright yellow gum. This was purified by column chromatography (silica gel, gradient eluted with 0-10% EtOAc in cyclohexane) to afford the title compound as a bright yellow oil (2.4g, 92%).¹H NMR(CDCl₃,400MHz):δ8.20(1H,dd,J=9.50,6.22Hz),6.49(1H,dd,J=11.75,2.62Hz),6.31(1H,ddd,J=9.51,7.26,2.61Hz),3.47-3.33(1H,m),2.11-1.98(2H,m),1.85-1.77(2H,m),1.72-1.60(1H,m),1.48-1.26(5H,m)

N²-cyclohexyl-4-fluorobenzene-1, 2-diamine

(cyclohexyl- (5-fluoro-2-nitrophenyl) amine (2.4g,10.0mmol) was dissolved in EtOAc (40mL), the flask was evacuated and flushed with nitrogen, 10% Pd/C (0.24g) was added and the reaction mixture was stirred under hydrogen at RT overnight, the resulting mixture was used Filtration and concentration of the filtrate in vacuo afforded the title compound as a dark red oil (1.9g, 9)2%)。¹H NMR(CDCl₃,400MHz):δ6.61(1H,dd,J=8.35,5.74Hz),6.35(1H,dd,J=11.23,2.77Hz),6.27(1H,td,J=8.43,2.76Hz),3.23-3.11(1H,m),2.11-2.00(2H,m),1.83-1.72(2H,m),1.70-1.60(1H,m),1.47-1.12(5H,m)

[ (S) -1- [ 1-cyclohexyl-6-fluoro-1H-benzimidazol-2-yl) ethyl ] carbamic acid tert-butyl ester

Will N²-cyclohexyl-4-fluorobenzene-1, 2-diamine (0.7g,3.36mmol) was dissolved in DCM (10mL) and (S) -2-tert-butoxycarbonylaminopropionic acid (0.70g,3.70mmol) and HOAt (0.51g,3.70mmol) were added. The dark green solution was cooled to 0 ℃ and N- (3-dimethylaminopropyl) -N' ethylcarbodiimide (0.71g,3.70mmol) was added portionwise over 5 minutes. The reaction mixture was stirred at 0 ℃ for 1 h. The resulting mixture was brought to RT and then diluted with DCM (20mL) and washed with citric acid (20mL) and brine (20 mL). The organic fraction was dried (MgSO)₄) Filtered and concentrated in vacuo to give a pale red gum (1.36 g). It was dissolved in acetic acid (10mL) and heated at 80 ℃ overnight. The resulting mixture was then cooled to RT and concentrated in vacuo. The residue was dissolved in DCM (40mL) and saturated NaHCO was used₃Aqueous solution (20mL) and brine (20 mL). The organic fraction was dried (MgSO)₄) Filtered and concentrated in vacuo to give a dark red gum. This was purified by column chromatography (silica gel, gradient eluted with 0-50% EtOAc in cyclohexane) to give the title compound as a yellow gum (0.55g, 43%). LCMS (method B) R _T3.22min[M+H]⁺362.1

(S) -1- (1-cyclohexyl-6-fluoro-1H-benzimidazol-2-yl) ethylamine

Reacting [ (S) -1- [ 1-cyclohexyl-6-fluoro-1H-benzimidazol-2-yl) ethyl]Tert-butyl carbamate (0.55g,1.52mmol) was dissolved in DCM (10mL) and TFA (4mL) was added. The reaction mixture was stirred at RT for 30 min. The resulting mixture was concentrated in vacuo, the residue dissolved in DCM (40mL) and reacted with saturated NaHCO₃The aqueous solution was stirred vigorously for 10 minutes. The layers were separated and the organic fraction was washed with brine (20mL) and dried (MgSO)₄) Filtration and concentration in vacuo afforded the title compound as a dark yellow gum which solidified upon standing (0.41g, 100%).¹H NMR(CDCl₃,400MHz):δ7.63(1H,s),7.22(1H,s),7.01-6.89(1H,m),4.43-4.21(2H,m),2.29-2.09(2H,m),2.06-1.66(5H,m),1.57(3H,s),1.51-1.23(3H,m)

3-bromo-N²-cyclopropyl-4-fluorobenzene-1, 2-diamine

To a solution of 2-bromo-1, 3-difluoro-4-nitrobenzene (1.19g,5.0mmol) in MeCN (10mL) was added DIPEA (1.74mL,10.0mmol) and cyclopropylamine (360. mu.L, 5.17 mmol). The reaction mixture was stirred at RT for 4 h. Volatiles were removed under reduced pressure and the resulting residue was partitioned between DCM and water. The organic fraction was dried, concentrated in vacuo, and the resulting residue was taken up in a 3:1 mixture of MeOH: water (40 mL). Addition of NH₄Cl (1.53g,28.6mmol) and iron powder (1.06g,4.76mmol), the reaction mixture was heated at 80 ℃ for 3 h. After cooling to RT, the mixture was used The pad was filtered and washed with additional MeOH. The filtrate was concentrated in vacuo and the resulting residue was taken up in DCM and NaHCO₃The aqueous solution was partitioned. The organic fraction was dried and concentrated in vacuo and the resulting residue was purified by column chromatography (Si-PCC gradient eluted with 0-5% MeOH in EtOAc) to give the title compound as a brown oil (759mg, 62% over two steps). LCMS (method C) R_T2.97min[M+H]⁺245.02

[ (S) -1- (3-bromo-2-cyclopropylamino-4-fluorophenylcarbamoyl) ethyl ] carbamic acid tert-butyl ester

Reacting 3-bromo-N²A mixture of-cyclopropyl-4-fluorobenzene-1, 2-diamine (759mg,3.10mmol), (S) -2-tert-butoxycarbonylaminopropionic acid (644mg,3.41mmol), HOAt (464mg,3.41mmol) and N- (3-dimethylaminopropyl) -N-ethylcarbodiimide hydrochloride (654mg,3.41mmol) in DCM (20mL) was stirred at 0 deg.C for 1 h. The reaction mixture was then washed with DCM and saturated NaHCO₃The solutions were partitioned. The organic fraction was dried and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient eluted with 0-50% EtOAc in cyclohexane) to give the title compound (1.05g,81%) as a pale beige solid. LCMS (method C) R_T3.66min[M+H]⁺416.05

[ (S) -1- (7-bromo-1-cyclopropyl-6-fluoro-1H-benzimidazol-2-yl) ethyl ] carbamic acid tert-butyl ester

Reacting [ (S) -1- (3-bromo-2-cyclopropylamino-4-fluoro-phenylcarbamoyl) ethyl]Tert-butyl carbamate (1.05g,2.52mmol) was taken up in AcOH (12mL) and heated at 70 ℃ for 16 h. After cooling to RT, the volatiles were evaporated in vacuo and the residue was taken up in EtOAc and saturated NaHCO₃The solutions were partitioned. The aqueous phase was further extracted with EtOAc and the combined organic fractions were washed with brine and dried (Na)₂SO₄) And concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC gradient eluted with 0-50% EtOAc in cyclohexane) to give the title compound (771mg,77%) as a yellow oil. LCMS (method C):R_T3.65min[M+H]⁺398.09。

(S) -1- (7-bromo-1-cyclopropyl-6-fluoro-1H-benzimidazol-2-yl) ethylamine

TFA (1mL) was added to [ (S) -1- (7-bromo-1-cyclopropyl-6-fluoro-1H-benzimidazol-2-yl) ethyl]Tert-butyl carbamate (133mg,0.33mmol) in DCM (3 mL). After stirring for 2h at RT, the reaction mixture is diluted with MeOH and loaded ontoSCX-2 column. The column was washed with MeOH, then 2M NH₃Washing with MeOH. The basic fractions were combined and concentrated in vacuo to give the title compound as a colorless oil (87mg, 87%). LCMS (method C) R_T1.99min[M+H]⁺298.10

{ (S) -1- [ 1-cyclopropyl-6-fluoro-7- (morpholine-4-carbonyl) -1H-benzimidazol-2-yl ] ethyl } carbamic acid tert-butyl ester

Methyl 2- ((S) -1-tert-butoxycarbonylaminoethyl) -3-cyclopropyl-5-fluoro-3H-benzimidazole-4-carboxylate (441mg,1.17mmol) and LiOH. H₂A solution of O (196mg,4.67mmol) in MeOH (20mL) and water (2mL) was heated at 90 deg.C for 4 h. Addition of additional LiOH. H₂O (196mg), and the mixture was heated at 90 ℃ for 48 h. After cooling to RT, the organic solvent was removed in vacuo and the reaction mixture was washed with 1M HCl_{(aqueous solution)}The pH of the mixture was adjusted to 3. The aqueous phase was extracted with EtOAc (× 3), the combined organic fractions were washed with brine and dried (Na)₂SO₄) And concentrated in vacuo. The residue (349mg), HATU (401mg,1.06mmol), morpholine (125. mu.L, 1)44mmol) and DIPEA (335. mu.L, 1.92mmol) in DCM (10mL) were stirred at RT for 1 h. The reaction mixture was washed with DCM and saturated NaHCO₃The solutions were partitioned. The organic layer was dried and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient eluted with 0-100% EtOAc in cyclohexane) to give the title compound (380mg, 75% yield over two steps) as a pale yellow oil. LCMS (method C) R_T2.64min[M+H]⁺433.25

[2- ((S) -1-aminoethyl) -3-cyclopropyl-5-fluoro-3H-benzimidazol-4-yl ] -morpholin-4-yl-methanone

TFA (1mL) was added to stirred { (S) -1- [ 1-cyclopropyl-6-fluoro-7- (morpholine-4-carbonyl) -1H-benzimidazol-2-yl ]Ethyl } carbamic acid tert-butyl ester (380mg,0.88mmol) in DCM (3 mL). After stirring for 2h at RT, the reaction mixture is diluted with MeOH and loaded ontoSCX-2 column. The column was washed with MeOH, then 2MNH₃Washing with MeOH. The basic fractions were combined and concentrated in vacuo to give the title compound as a pale yellow oil (214mg, 73%). LCMS (method B) R_T1.62 and 1.70min [ M + H ]]⁺333.12

(5-fluoro-2-nitro-phenyl) (1-methyl-1H-pyrazol-3-yl) amine

Potassium tert-butoxide (898mg,8.0mmol) was added to a stirred solution of 1-methyl-1H-pyrazol-3-ylamine (0.35mL4.00mmol) in anhydrous THF (5mL) at 0 deg.C under a nitrogen atmosphere. After 15min, 2, 4-difluoro in anhydrous THF (5mL) was added1-Nitrobenzene (0.44mL,4.0mmol) and stirring was continued at 0 deg.C for 1 h. The reaction mixture was poured onto NH₄Cl solution (50 mL). The aqueous phase was extracted with EtOAc (× 2), the combined organic fractions were washed with brine and dried (Na)₂SO₄) And concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient eluted with 0-100% EtOAc in cyclohexane) to give the title compound as a dark red solid (386mg, 41%). LCMS (method C) R_T3.29min[M+H]⁺237.08

4-fluoro-N²- (1-methyl-1H-pyrazol-3-yl) -benzene-1, 2-diamine

A mixture of (5-fluoro-2-nitro-phenyl) - (1-methyl-1H-pyrazol-3-yl) amine (386mg,1.63mmol) in EtOAc (10mL) was degassed with a stream of nitrogen, then 10% Pd/C (50mg) was added and stirred at RT for 24H under a hydrogen atmosphere. The mixture was filtered and the filtrate was concentrated in vacuo to give the title compound as a grey oil (350mg, quantitative yield). LCMS (method C) R_T1.63min[M+H]⁺207.17

{ (S) -1- [ 6-fluoro-1- (1-methyl-1H-pyrazol-3-yl) -1H-benzimidazol-2-yl ] ethyl } carbamic acid tert-butyl ester

To a suspension of (S) -Boc-alaninamide (614mg,3.27mmol) in DCM (5mL) under a nitrogen atmosphere was added triethyloxy in one portionTetrafluoroborate (621mg,3.27 mmol). The resulting mixture was stirred at RT for 1 h. Volatiles were removed under vacuum and the resulting residue was added 4-fluoro-N in anhydrous EtOH (5mL)²- (1-methyl-1H-pyrazol-3-yl) -benzene-1, 2-diamine (350mg,1.70mmol) and the mixture was stirred at 80 ℃ for 2H. Volatiles were removed under vacuum and the resulting residue was taken up in DCM and NaHCO₃The aqueous solution was partitioned. The organic fraction was dried, concentrated in vacuo, and the resulting residue was purified by column chromatography (Si-PCC, gradient elution of 0-50% EtOAc in DCM) to give the title compound as a violet oil (187mg, 31%). LCMS (method B) R _T3.18min[M+H]⁺360.05

(2-bromo-6-nitrophenyl) phenylamine

A solution of 1-bromo-2-fluoro-3-nitrobenzene (5g,22.7mmol) and aniline (4.2mL,45mmol) in DMSO (10mL,2M) was evacuated in a sealed flask and purged with argon. The mixture was heated at 100 ℃ for 12 h. Subjecting the cooled mixture to KHSO₄(saturated aqueous solution, 100mL) and brine, dried (Na)₂SO₄) And concentrated to give the product (2-bromo-6-nitrophenyl) phenylamine as a bright orange solid (6.5g, quantitative yield).¹H NMR(400MHz,CDCl₃):δ7.96(1H,dd,J=8.5,1.7Hz),7.86(1H,br s),7.75(1H,dd,J=8.2,1.5Hz),7.16-7.22(2H,m),6.90-6.99(2H,m),6.77(2H,m)。

3-bromo-N²-phenyl-1, 2-diamines

(2-bromo-6-nitrophenyl) phenylamine (6.5g,22.7mmol) was dissolved in EtOAc (100mL) under nitrogen and SnCl was added₂.H₂O (25 g). The resulting mixture was heated at reflux for 5 h. The cooled reaction mixture was washed with NaHCO₃(saturated aqueous, 100mL) diluted and additional NaHCO was added₃Until boilingThe part stops. Mixing the mixture withFiltration to remove insoluble inorganic materials. The EtOAc layer was separated, washed with brine and dried (Na)₂SO₄) And concentrated in vacuo. The residue was purified by chromatography (Si-PCC,0-50% EtOAc in cyclohexane) to afford the product as a yellow crystalline solid (4.41g, 77%). 1H NMR (300MHz, CDCl)₃):δ7.24-7.17(2H,m),7.01(1H,dd,J=8.0,1.5Hz),6.94(1H,d,J=7.9Hz),6.85(1H,dt,J=7.4,1.0Hz),6.72(1H,dd,J=7.9,1.5Hz),6.67-6.61(2H,m),5.36(1H,br s),3.97(2H,br s)

[ (S) -1- (3-bromo-2-phenylamino (phenylcarbamoyl)) ethyl ] carbamic acid tert-butyl ester

Reacting 3-bromo-N²-phenyl-benzene-1, 2-diamine (2.46g,9mmol), (S) - (2-tert-butoxycarbonylamino) propionic acid (1.7g,9mmol) and HOAt (1.43g,10.8mmol) were suspended in DCM (50mL) and the resulting mixture was cooled at 0 ℃. The reaction mixture was stirred under nitrogen for 1h, at which time all solid material dissolved. N- (3-dimethylaminopropyl) -N-ethylcarbodiimide hydrochloride (2.57g,13.3mmol) was added to the solution and stirring was continued for 1 h. Citric acid (saturated aqueous solution, 50mL) was added to the reaction mixture, resulting in the precipitation of a white solid. The mixture was diluted with water until the solid dissolved. The resulting solution was extracted with additional DCM. The DCM extract was washed with brine and dried (Na)₂SO₄) And concentrated in vacuo to give the product as a white foam (3.9g, quantitative yield). LCMS (method B) R_T3.90min;m/z[M+H]⁺434/436

(S) -1- (7-bromo-1-phenyl-1H-benzimidazol-2-yl) ethylamine dihydrochloride

Reacting [ (S) -1- (3-bromo-2-phenylamino (phenylcarbamoyl)) ethyl]Tert-butyl carbamate (3.9g,9mmol) was dissolved in HCl (25mL,2M bisAlkane solution). Heating the resulting brown solution to 60 ℃ for 6 h; during this time boiling was observed and a white solid precipitated. The white solid was isolated by filtration, washed with EtOAc and diethyl ether to give the product as a white solid (2.7g, 77%). LCMS (method B) R _T2.22min;m/z[M+H]⁺316/318

[ (S) -1- (7-bromo-1-phenyl-1H-benzimidazol-2-yl) ethyl ] [9- (tetrahydropyran-2-yl) -9H-purin-6-yl ] amine

(S) -1- (7-bromo-1-phenyl-1H-benzimidazol-2-yl) ethylamine dihydrochloride (1g,2.5mmol), 6-chloro-9- (tetrahydropyran-2-yl) -9H-purine (0.736g,3.1mmol), and DIPEA (2.26mL,13mmol) in IPA (4mL) was heated in a sealed tube for 4H. The cooled reaction mixture was concentrated in vacuo; the residue was dissolved in EtOAc and the resulting solution was washed with water, brine and dried (Na)₂SO₄) And concentrated in vacuo. The residue was purified on silica (Si-PCC,0-10% MeOH in DCM) to give the product as a white solid (870mg, 67%). LCMS (method B) R_T3.48min;m/z[M+H]⁺518/520

2-amino-4-chloro-6-methylpyrimidine-5-carbonitrile

Step i) 4-chloro-5-iodo-6-methylpyrimidin-2-ylamine

4-chloro-6-methylpyrimidin-2-ylamine (5g,0.04mol) was suspended in acetonitrile (50mL) and methanol (50mL) and N-iodosuccinimide (12g,0.05mol,1.5equiv.) was added to the resulting mixture. The mixture was heated to 60 ℃ for 3h under nitrogen atmosphere. A solid precipitated out of the resulting brown mixture, which was isolated by filtration and washed with cyclohexane to give 6g,65% of a white crystalline solid. Additional product (. about.2.5 g) was present in the mother liquor. LCMS m/e270 ³⁵Cl/272³⁷Cl(M⁺+1);

Step ii) 2-amino-4-chloro-6-methylpyrimidine-5-carbonitrile

A mixture of 4-chloro-5-iodo-6-methylpyrimidin-2-ylamine (1.35g,5.0mmol), zinc cyanide (288mg,2.45mmol) and tetrakis (triphenylphosphine) palladium (290mg,5mol%) in DMF (20mL) was purged with argon and heated by microwave irradiation at 140 ℃ for 15 min. After cooling to RT, the residue was partitioned between EtOAc and water. The aqueous phase was further extracted with EtOAc and the combined organic fractions were washed with brine and dried (Na)₂SO₄) And concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient elution with 0-30% EtOAc in DCM) and then further purified by column chromatography (Si-PCC, gradient elution with 0-7% MeOH in DCM) to give the title compound (40mg,5%) as a pale yellow solid. LCMS (method C) R_T2.23min[M+H]⁺169.00。¹HNMR(DMSO-d₆,400MHz):δ8.11(2H,br s),2.42(3H,s)

(5-fluoro-2-nitrophenyl) pyrimidin-4-ylamine

At 0 deg.CTo 4-aminopyrimidine (1.0g,10.52mmol) in THF (40ml) was added potassium tert-butoxide (2.46g,22mmol) under nitrogen. After stirring for 5min, 2, 4-difluoronitrobenzene (1.672g,10.52mmol) was added dropwise. The reaction was stirred at 0 ℃ for 1h, then at 20 ℃ for 1h, then quenched with 5% citric acid to give a pH of 5. The mixture was extracted with EtOAc (150mL) and dried (Na) ₂SO₄) And evaporated to give an orange gum. This was purified by column chromatography (Si-PCC, gradient eluted with 0-5% MeOH in DCM) to give the title compound as a yellow solid (0.31g, 12%). LCMS (method B) R_T=2.16min,[M+H]⁺=234.91

4-fluoro-N²-pyrimidin-4-ylphenyl-1, 2-diamine

(5-fluoro-2-nitrophenyl) pyrimidin-4-ylamine (0.31g,1.32mmol) was hydrogenated in IMS at RT and pressure for 3.5h using Pd-C (30mg) as a catalyst. The catalyst was removed by filtration through Celite. The filtrate was concentrated in vacuo to give the title compound as an orange solid (0.249g, 92%). LCMS (method J) R_T=0.56min,[M+H]⁺=205.16

{ (S) -1- [ 4-fluoro-2- (pyrimidin-4-ylamino) phenylcarbamoyl ] ethyl } carbamic acid tert-butyl ester

4-fluoro-N in DCM at 0 ℃ under nitrogen²To pyrimidin-4-ylphenyl-1, 2-diamine (0.247g,1.21mmol), Boc-alanine (0.24g,1.27mmol) and HOAT (0.165g,1.21mmol) was added N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride (0.244g,1.27 mmol). The reaction was stirred and allowed to warm to RT overnight. The mixture was diluted with DCM (20mL) and washed with 0.5M NaHCO₃(20mL)And (6) washing. The organic extracts were dried (Na)₂SO₄) Concentrated in vacuo and purified by column chromatography (Si-PCC with 0-8% (9:1MeOH/.880 NH)₃) Gradient elution with DCM). The product containing fractions were evaporated to give the title compound (0.272g,60%) LCMS (method J): R _T=1.93min,[M+H]⁺=376.20

(S) -N- [ 4-fluoro-2- (pyrimidin-4-ylamino) phenyl ] -2- [9- (tetrahydropyran-2-yl) -9H-purin-6-ylamino ] propionamide

Reacting { (S) -1- [ 4-fluoro-2- (pyrimidin-4-ylamino) phenylcarbamoyl]Ethyl } carbamic acid tert-butyl ester (0.27g,0.72mmol) bis with 4M HClThe alkane solution (10mL) was treated at 20 ℃ for 45 min. The solvent was removed by evaporation under reduced pressure to give a solid (0.29 g). 0.145g of the solid was treated in a sealed tube with 6-chloro-9- (tetrahydropyran-2-yl) -9H-purine (103mg,0.43mmol) and DIPEA (0.25mL),1.44mmol) in IPA (1.5mL) at 80 deg.C under argon for 16H. The reaction mixture was diluted with EtOAc (20mL) and washed with water (5 mL). The aqueous layer was extracted with EtOAc (10 mL). The combined organic extracts were dried (Na)₂SO₄) Concentrated in vacuo and purified by column chromatography (Si-PCC, gradient eluted with 0-10% (9:1MeOH/.880NH3) in DCM) to give the title compound as an orange gum (88mg, 51%). LCMS (method B) R_T1.99min[M+H]⁺478.13

(S) -N- [ 4-fluoro-2- (pyrimidin-4-ylamino) phenyl ] -2- (9H-purin-6-ylamino) thiopropionamide

Reacting (S) -N- [ 4-fluoro-2- (pyrimidin-4-ylamino) phenyl]-2- [9- (tetrahydro-pyran-2-yl) -9H-purin-6-ylamino]Propionamide (88mg,0.18mmol) and Lawesson's reagent (298mg,0.74mmol) were heated at reflux under nitrogen in THF (4mL) for 16 h. Additional Lawesson's reagent (150mg,0.37mmol) was added and the reaction refluxed for an additional 24 h. The reaction mixture was cooled, diluted with EtOAc (30mL), and extracted with 1M HCl (2X 5 mL). Extracting the aqueous extract with Na ₂CO₃Basified and extracted with EtOAc (2X 20 mL). The combined organic extracts were dried (Na)₂SO₄) Concentrated in vacuo and purified by column chromatography (Si-PCC, gradient eluted with 0-10% (9:1MeOH/.880NH3) in DCM) to give the title compound as a colorless gum (9mg, 12%). LCMS (method B) R_T1.88min[M+H]⁺410.09

(5-fluoro-2-nitro-phenyl) -pyrazin-2-yl-amine RDP2963-165-02

LiHMDS (1.0M tetrahydrofuran solution, 27.4ml,27.4mmol) was added to a solution of aminopyrazine (1.43g,15.0mmol) in tetrahydrofuran (50.0ml) at-5 ℃. The reaction was stirred for 15 min, then 2, 4-difluoronitrobenzene (1.50ml,13.7mmol) was added and the reaction stirred for an additional 45 min. The reaction was quenched with water, then poured into sodium bicarbonate (dilute aqueous solution), and the aqueous layer extracted with EtOAc (× 3). The combined organic fractions were washed with brine and dried (Na)₂SO₄) And concentrated in vacuo. The product is purified by chromatography (SiO)₂0-70% EtOAc/cyclohexane) to give the title compound (918mg, 29%).¹H NMR(CDCl₃,400MHz):δ10.7(1H,br s),8.84(1H,dd,J12.3,2.8Hz),8.37(1H,d,J1.7Hz),8.34(1H,dd,J9.4,5.7Hz),8.29(1H,dd,J2.8,1.6Hz),8.23(1H,d,J2.7Hz),6.75(1H,ddd,J9.6,6.8,2.7Hz)。

4-fluoro-N²-pyrazin-2-yl-benzene-1, 2-diamines

(5-fluoro-2-nitrophenyl) pyrazin-2-yl-amine (415mg,1.77mmol) in IMS (15.0ml) was added to palladium on charcoal (10 wt%, 45.0mg) and stirred under a hydrogen atmosphere overnight. Subjecting the reaction mixture to Filter and concentrate the filtrate in vacuo. The product is purified by chromatography (SiO)₂0-10%2M ammonia-methanol/DCM) to give the title compound (160mg,0.78mmol, 44%).¹HNMR(MeOD,400MHz):δ8.04(2H,m),7.83(1H,m),7.21(1H,dd,J9.9,2.8Hz),6.84(1H,dd,J8.7,5.6Hz),6.74(1H,ddd,J8.9,8.2,2.9Hz)。

{ (S) -1- [ 4-fluoro-2- (pyrazin-2-ylamino) -phenylcarbamoyl ] -ethyl } -carbamic acid tert-butyl ester

N- (tert-Butoxycarbonyl) -L-alanine (150mg,0.78mmol), N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride (165mg,0.86mmol) and HOAt (106mg,0.78mmol) were added to 4-fluoro-N in DCM (10.0ml) and DMF (1.00ml) at 0 deg.C²-pyrazin-2-yl-benzene-1, 2-diamine (160mg,0.78 mmol). The reaction was stirred for 3h, then poured into water and the aqueous layer extracted with DCM (× 3). The combined organic fractions were washed with brine and dried (Na)₂SO₄) And concentrated in vacuo. The product is purified by chromatography (SiO)₂0-10% methanol/DCM) to give the title compound (144mg,0.38mmol, 50%). LCMS R_T3.02min[M+H]⁺376.2。¹H NMR(CDCl₃,400MHz):δ8.36(1H,s),8.12(1H,dd,J2.8,1.5Hz),8.03(1H,br s),8.02(1H,d,J2.7Hz),7.92(1H,br s),7.62(1H,br s),7.28(1H,m),6.77(1H,td,J8.4,2.9Hz),4.97(1H,br s),4.20(1H,m),1.49(3H,d,J7.2Hz),1.45(9H,s)。

(S) -2-amino-N- [ 4-fluoro-2- (pyrazin-2-ylamino) -phenyl ] -propionamide hydrochloride

Reacting { (S) -1- [ 4-fluoro-2- (pyrazin-2-ylamino) phenylcarbamoyl]Ethyl } carbamic acid tert-butyl ester (144mg,0.38mmol) suspended in hydrochloric acid (4.0M of 1, 4-bisAlkane solution, 5.0ml) and heated at 60 ℃ for 20 minutes, then concentrated in vacuo to give the title compound (118mg,0.38mmol, 99%). ¹H NMR(MeOD,400MHz):δ8.20(2H,m),7.96(1H,d,J2.7Hz),7.59(1H,dd,J10.1,2.7Hz),7.53(1H,dd,J9.2,5.9Hz),6.96(1H,td,J8.3,2.9Hz),4.10(3H,m),1.49(3H,d,J7.0Hz)。

(S) -N- [ 4-fluoro-2- (pyrazin-2-ylamino) -phenyl ] -2- [9- (tetrahydropyran-2-yl) -9H-purin-6-ylamino ] propionamide

Triethylamine (211. mu.l, 1.52mol) was added to (S) -2-amino-N- [ 4-fluoro-2- (pyrazin-2-ylamino) phenyl in IPA (5.0ml)]Propionamide hydrochloride (118mg,0.38mmol) and 6-chloro-9- (tetrahydro-2-pyranyl) purine (109mg,0.45mol) and heated at 80 ℃ overnight. The reaction was poured into water and the aqueous layer was extracted into EtOAc (× 3). The combined organic fractions were washed with brine and dried (Na)₂SO₄) And concentrated in vacuo. The product is purified by chromatography (SiO)₂0-10%2M ammonia-methanol/DCM) to give the title compound as a 1:1 diastereomeric mixture (100mg,0.21mmol, 55%). LCMS (method C) R_T2.55min[M+H]⁺478.2。¹H NMR(MeOD,400MHz):δ8.26(2H,m),7.84(2H,m),7.58(2H,m),7.32(1H,ddd,J11.9,10.1,2.8Hz),6.92(1H,ddd,J8.9,8.1,2.9Hz),5.70(1H,m),4.16(1H,m),4.80(1H,m),3.80(1H,m),2.18(3H,m),1.80(2H,m),1.61(4H,m)。

(5-fluoro-2-nitrophenyl) -pyrimidin-2-yl-amines

LiHMDS (1.0M in tetrahydrofuran, 27.4ml,27.4mmol) was added to 2-aminopyrimidine (1.43g,15.0mmol) in tetrahydrofuran (50.0ml) and stirred for 10min, 2, 4-difluoronitrobenzene (1.50ml,13.7mmol) was added and the reaction stirred for a further 15 min. The reaction mixture was quenched with water, then poured into sodium bicarbonate (dilute aqueous solution), and the aqueous layer was extracted with EtOAc (× 3). The combined organic fractions were washed with brine and dried (Na) ₂SO₄) And concentrated in vacuo. The product is purified by chromatography (SiO)₂0-100% EtOAc/cyclohexane) to give the title compound (800mg,3.42mmol, 25%).¹H NMR(CDCl₃,400MHz):δ8.94(1H,dd,J12.3,2.4Hz),8.62(2H,d,J4.8Hz),8.36(1H,dd,J9.4,6.1Hz),7.08(1H,t,J4.8Hz),6.88(1H,ddd,J9.6,7.2,2.8Hz)。

4-fluoro-N²-pyrimidin-2-yl-benzene-1, 2-diamines

(5-fluoro-2-nitrophenyl) pyrimidin-2-yl-amine (336mg,1.43mmol) in IMS (25.0ml) was added to palladium on charcoal (10 wt%, 35.0mg) and stirred under a hydrogen atmosphere overnight. Mixing the mixture withFilter and concentrate the filtrate in vacuo. The product is purified by chromatography (SiO)₂0-10% methanol/DCM) to give the title compound (215mg,1.05mmol, 74%).¹H NMR(MeOD,400MHz):δ8.37(2H,d,J4.9Hz),7.29(1H,dd,J10.4,2.9Hz),6.84(1H,dd,J8.8,5.6Hz),6.77(1H,t,J4.9Hz),6.72(1H,ddd,J8.6,8.1,2.9Hz)。

{ (S) -1- [ 4-fluoro-2- (pyrimidin-2-ylamino) phenylcarbamoyl ] ethyl } carbamic acid tert-butyl ester

N- (tert-Butoxycarbonyl) -L-alanine (199mg,1.05mmol), N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride (222mg,1.15mmol) and HOAt (143mg,1.05mmol) were added to 4-fluoro-N in DCM (8.0ml) and DMF (800. mu.l) at 0 deg.C²Pyrimidin-2-yl-benzene-1, 2-diamine (215mg,1.05 mmol). The reaction was stirred for 2h, then poured into water and the aqueous layer extracted with DCM (× 3). The combined organic fractions were washed with brine and dried (Na)₂SO₄) And concentrated in vacuo. The product is purified by chromatography (SiO)₂0-10% methanol/DCM) to give the title compound (350mg,0.93mmol, 89%). LCMS R _T2.98min[M+H]⁺376.1。¹H NMR(CDCl₃,300MHz):δ8.48(1H,br s),8.42(2H,d,J4.9Hz),7.69(1H,br s),7.50(2H,m),6.84(1H,td,J8.5,2.9Hz),6.76(1H,t,J4.9Hz),5.01(1H,br s),4.28(1H,qn,J7.6Hz),1.44(9H,s),1.43(3H,d,J7.4Hz)。

(S) -2-amino-N- [ 4-fluoro-2- (pyrimidin-2-ylamino) phenyl ] propanamide hydrochloride

Reacting { (S) -1- [ 4-fluoro-2- (pyrimidin-2-ylamino) phenylcarbamoyl]Ethyl } carbamic acid tert-butyl ester (350mg,0.93mmol) dissolved in hydrochloric acid (4.0M1, 4-bisAlkane solution) and stirred for 1 h. The reaction was concentrated in vacuo to give the title compound (289mg,0.93mmol, 99%).¹H NMR(MeOD,400MHz):δ8.69(2H,d,J5.3Hz),7.62(1H,d,J9.3Hz),7.60(1H,dd,J8.7,2.7Hz),7.19(1H,9.0,7.9,2.9Hz),7.19(1H,t,J5.3Hz),4.21(1H,q,J7.2Hz),1.58(3H,d,J7.2Hz)。

(S) -N- [ 4-fluoro-2- (pyrimidin-2-ylamino) phenyl ] -2- [9- (tetrahydropyran-2-yl) -9H-purin-6-ylamino ] propionamide

Triethylamine (518. mu.l, 3.72mol) was added to (S) -2-amino-N- [ 4-fluoro-2- (pyrimidin-2-ylamino) phenyl ] in IPA (5.0ml)]Propionamide hydrochloride 161b (289mg,0.93mmol) and 6-chloro-9- (tetrahydropyran-2-yl) purine (265mg,1.10mol) and heated to 80 ℃ overnight. The reaction was poured into water and the aqueous layer was extracted into EtOAc (× 3). The combined organic fractions were washed with brine and dried (Na)₂SO₄) And concentrated in vacuo. The product is purified by chromatography (SiO)₂0-10%2M ammonia-methanol/DCM) to give the title compound as a 1:1 diastereomeric mixture (236mg,0.50mmol, 53%). LCMS R_T2.63min[M+H]⁺478.2。

(5-fluoro-2-nitrophenyl) pyridin-3-ylamine

Potassium tert-butoxide (4.48g,40mmol) was slowly added to a solution of 3-aminopyridine (1.88g,20mmol) in anhydrous THF (40mL) at 0 deg.C. To the purple solution was added 2-4-difluoronitrobenzene (2.2mL,20mmol) in anhydrous THF (40mL) dropwise and stirred at 0 ℃ for 1 h. The reaction mixture was poured into saturated ammonium chloride (200mL) and extracted with EtOAc (2X 200 mL). The combined organic fractions were washed with brine (200mL) and dried (Na) ₂SO₄) And concentrated in vacuo. The dark orange solid was purified by column chromatography (Si-PPC, eluting with a gradient of 0-50% EtOAc in DCM) to give the title compound as a bright orange solid (2.21g, 47%). LCMS (method C) R_T2.39min[M+H]⁺234。¹H NMR(CDCl₃,400MHz):δ9.58(1H,bs),8.61(1H,d,J=2.5Hz),8.54(1H,dd,J=5.0,1.5Hz),8.29(1H,dd,J=9.5,6.0Hz),7.65-7.62(1H,m),7.40(1H,ddd,J=8.0,5.0,1.0Hz),6.73(1H,dd,J=11.0,2.5Hz),6.55(1H,ddd,J=9.5,7.0,2.5Hz)。

4-fluoro-N²-pyridin-3-yl-benzene-1, 2-diamine

In N₂Next, a solution of (5-fluoro-2-nitrophenyl) pyridin-3-ylamine (2.21g,9.5mmol) in EtOAc (65mL) was added to a slurry of palladium on carbon (10% by weight, 220mg) in EtOAc (10 mL). The reaction mixture was stirred at RT under hydrogen atmosphere for 16 h. Mixing the mixture withFiltration and concentration of the filtrate in vacuo afforded the title compound as a white solid which turned red upon standing (1.83mg, 95%). LCMS (method B) R_T0.81min[M+H]⁺204。¹H NMR(CDCl₃,400MHz):δ8.23(1H,dd,J=3.0,1.0Hz),8.13(1H,dd,J=4.51.5Hz),7.15(1H,ddd,J=8.0,4.5,0.5Hz),7.10(1H,ddd,J=8.5,2.5,1.5Hz),6.85(1H,dd,J=9.5,2.5Hz),6.76-6.68(2H,m),5.50(1H,bs),3.56(2H,bs)。

[ (S) -1- (6-fluoro-1-pyridin-3-yl-1H-benzimidazol-2-yl) ethyl ] carbamic acid tert-butyl ester

A triethyl oxy groupA solution of tetrafluoroborate (561mg,3.0mmol) in DCM (4mL) was added to a slurry of (S) -2-methylaminopropionamide (561mg, 3.15mmol) in DCM (6mL) and stirred at RT for 1.5 h. The reaction mixture was concentrated in vacuo and 4-fluoro-N in EtOH (6mL) was added²Pyridin-3-yl-benzene-1, 2-diamine (200mg,0.98mmol) and heated at 60 ℃ for 2.5 h. The reaction mixture was cooled to RT and concentrated in vacuo. The resulting residue was taken up in DCM (25mL) and saturated NaHCO was used ₃(25mL) washing. The aqueous material was further extracted with DCM (2X 25 mL). The combined organic fractions were dried (Na)₂SO₄) And concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PPC, eluting with a gradient of 10-50% EtOAc in DCM) to give the title compound as an orange oil (292mg, 83%). LCMS (method C) R_T2.96min[M+H]⁺357。¹H NMR(CDCl₃,400MHz):δ8.80(1H,dd,J=5.0,1.5Hz),8.72(1H,d,J=2.5Hz),7.84-7.83(1H,m),7.70(1H,dd,J=9.0,4.5Hz),7.57(1H,ddd,8.0,5.0,1.0Hz),7.05(1H,ddd,J=9.5,9.0,2.5Hz),6.76(1H,dd,J=8.5,2.5Hz),5.43(1H,d,7.0Hz),4.89(1H,dq,J=7.0,7.0Hz),1.46(3H,d,J=7.0Hz),1.38(9H,s)。

(S) -1- (6-fluoro-1-pyridin-3-yl-1H-benzimidazol-2-yl) ethylamine

Reacting [ (S) -1- (6-fluoro-1-pyridin-3-yl-1H-benzimidazol-2-yl) ethyl]A solution of tert-butyl carbamate (292mg,0.82mmol) in TFA (4mL) and DCM (12mL) was stirred at RT for 1 h. Loading the reaction mixture intoSCX-2 column. The column was washed with MeOH, then 2M NH₃Washing with MeOH. The basic fractions were combined and concentrated in vacuo. The residue was purified by column chromatography (Si-PPC, using 0-10%2M NH)₃MeOH (E) inDCM solution gradient elution) to give the title compound as a pale yellow oil (141mg, 67%). Marfey test 76% de. LCMS (method C) R_T1.34min[M+H]⁺257。¹H NMR(CDCl₃,400MHz):δ8.80(1H,dd,J=5.0,1.5Hz),8.73-8.72(1H,m),7.81(1H,ddd,J=8.0,2.5,1.5Hz),7.71(1H,ddd,J=9.0,4.5,0.5Hz),7.56(1H,ddd,J=8.0,5.0,1.0Hz),7.04(1H,ddd,J=9.5,9.0,2.5Hz),6.75(1H,ddd,J=8.5,2.5,0.5Hz),4.08(1H,q,6.5Hz),1.87(2H,bs),1.48(3H,d,J=6.5Hz)。

(3, 5-difluorophenyl) - (5-fluoro-2-nitrophenyl) amine

Potassium tert-butoxide (4.45g,40mmol) was slowly added to a solution of 3, 5-difluoroaniline (2.56g,20mmol) in anhydrous THF (40mL) at 0 deg.C. To the purple solution was added 2-4-difluoronitrobenzene (2.2mL,20mmol) in anhydrous THF (40mL) dropwise and stirred at 0 ℃ for 1 h. The reaction mixture was poured into saturated ammonium chloride (150mL) and extracted with EtOAc (2X 100 mL). The combined organic fractions were washed with brine (200mL) and dried (Na) ₂SO₄) And concentrated in vacuo. The dark orange solid was purified by column chromatography (Si-PPC, gradient eluted with 0-10% EtOAc in cyclohexane) to give the title compound as a brown solid (4.1, 61%). LCMS (method B) R_T4.04min[M-H]⁺267。¹H NMR(CDCl₃,400MHz):δ9.56(1H,bs),8.28(1H,dd,J=9.5,6.0Hz),6.96(1H,dd,J=11.0,2.5Hz),6.86-6.79(2H,m),6.73-6.67(1H,m),6.60(1H,ddd,J=9.5,7.0,2.5Hz)。

N²- (3, 5-difluorophenyl) -4-fluorobenzene-1, 2-diamine

Under nitrogen, (3, 5-difluorophenyl) - (5-fluoro-2-nitro) was addedA solution of phenylphenyl) amine (2.0g,7.5mmol) in EtOAc (65mL) was added to a slurry of palladium on carbon (10% wt, 200mg) in EtOAc (10 mL). The reaction mixture was stirred at RT under hydrogen atmosphere for 4 h. Mixing the mixture withFilter and concentrate the filtrate in vacuo. The resulting residue was purified by column chromatography (Si-PPC, eluting with a gradient of 0-30% EtOAc/cyclohexane) to give the title compound as a white solid which turned red on standing (1.07g, 60%). LCMS (method C) R_T3.40min[M+H]⁺239。¹H NMR(CDCl₃,400MHz):δ6.90-6.87(1H,m),6.81-6.73(2H,m),6.31-6.23(3H,m),5.42(1H,bs),3.58(2H,bs)。

{ (S) -1- [1- (3, 5-difluorophenyl) -6-fluoro-1H-benzimidazol-2-yl ] ethyl } carbamic acid tert-butyl ester

A triethyl oxy groupA solution of tetrafluoroborate (1.2g,6.3mmol) in DCM (10mL) was added to a slurry of (S) -2-methylaminopropionamide (1.26g,6.7mmol) in DCM (10mL) and stirred at RT for 1.5 h. The reaction solution was concentrated in vacuo and N in EtOH (12mL) was added²- (3, 5-difluorophenyl) -4-fluorobenzene-1, 2-diamine (500mg,2.1mmol) and heated at 60 ℃ for 4.5 h. The reaction mixture was cooled to RT and concentrated in vacuo. The resulting residue was taken up in DCM25mL) and saturated NaHCO ₃(25mL) washing. The aqueous material was further extracted with DCM (2X 25 mL). The combined organic fractions were dried (Na)₂SO₄) And concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PPC, eluting with a gradient of 0-50% EtOAc/cyclohexane) to give the title compound as a pale yellow oil (668mg, 81%). LCMS (method C) R_T3.70min[M+H]⁺392。¹H NMR(CDCl₃,400MHz):δ7.70(1H,dd,J=9.0,5.0Hz),7.08-7.00(4H,m),6.84(1H,dd,J=8.5,2.5Hz),5.36(1H,d,J=7.0Hz),4.98(1H,dq,J=7.0,7.0Hz),1.48(3H,d,J=7.0Hz),1.40(9H,s)。

(S) -1- [1- (3, 5-difluorophenyl) -6-fluoro-1H-benzimidazol-2-yl ] ethylamine

Reacting { (S) -1- [1- (3, 5-difluorophenyl) -6-fluoro-1H-benzimidazol-2-yl]A solution of tert-butyl ethyl } carbamate (668mg,1.7mmol) in TFA (4mL) and DCM (12mL) was stirred at RT for 1 h. Loading the reaction solution intoSCX-2 column. The column was washed with MeOH, then 2M NH₃Washing with MeOH. The basic fractions were combined and concentrated in vacuo to give the title compound as a pale yellow oil (497mg, 99%). Marfey test 97% de. LCMS (method C) R_T1.96min[M+H]⁺292。¹H NMR(CDCl₃,400MHz):δ7.70(1H,dd,J=9.0,5.0Hz),7.08-7.00(2H,m),6.97-6.93(2H,m),6.80(1H,dd,J=8.0,2.5Hz),6.19(2H,bs),4.51(1H,q,7.0Hz),1.55(3H,d,J=7.0Hz)。

{ (S) -1- [1- (3, 5-difluorophenyl) -6-fluoro-1H-benzimidazol-2-yl ] -ethyl } - [9- (tetrahydropyran-2-yl) -9H-purin-6-yl ] amine

Reacting (S) -1- [1- (3, 5-difluorophenyl) -6-fluoro-1H-benzimidazol-2-yl]A mixture of ethylamine (206mg,0.71mmol), 6-chloro-9- (tetrahydropyran-2-yl) -9H-purine (169mg,0.71mmol) and DIPEA (0.37mL,2.1mmol) in IPA (1.4mL) was heated in a sealed tube at 90 deg.C for 20H. After cooling to RT, the volatiles were removed under vacuum and the residue was dried The residue was purified by column chromatography (Si-PPC, using 0-10%2M NH)₃Gradient eluted in MeOH/DCM) to give the title compound as a colorless glass (141mg, 40%). LCMS (method C) R_T3.38min[M+H]⁺494。¹H NMR(CDCl₃,400MHz):δ8.29-8.28(1H,m),7.97-7.96(1H,m),7.72-7.68(1H,m),7.10-7.01(3H,m),6.97-6.91(1H,m),6.86-6.82(1H,m),6.37(1H,bs),5.79-5.67(2H,m),4.18-4.13(1H,m),3.80-3.73(1H,m),2.11-1.97(3H,m),1.80-1.63(6H,m)。

(3-fluoro-6-nitro-2-pyridin-2-yl-phenyl) - (2-methoxyethyl) amine

A mixture of 2- (2-chloro-6-fluoro-3-nitrophenyl) pyridine (618mg,2.6mmol), 2-methoxyethylamine (0.23mL,2.6mmol) and DIPEA (0.48mL,2.7mmol) in MeCN (5mL) was stirred at 0 ℃ for 1.5 h. After warming to RT, the volatiles were removed under vacuum. The resulting residue was purified by column chromatography (Si-PPC, eluting with a 0-70% EtOAc/cyclohexane gradient) to give the title compound as a yellow oil (414mg, 54%). LCMS (method C) R_T2.95min[M+H]⁺292。¹H NMR(CDCl₃,400MHz):δ8.73(1H,ddd,J=5.0,2.0,1.0Hz),8.47(1H,bs),8.26(1H,dd,J=9.5,6.0Hz),7.79(1H,ddd,8.0,8.0,2.0Hz),7.45-7.43(1H,m),7.32(1H,ddd,J=7.5,5.0,1.0Hz),6.52(1H,dd,9.5,8.0Hz),3.29-3.26(2H,m),3.28(3H,s),2.63-2.60(2H,m)

4-fluoro-N²- (2-methoxyethyl) -3-pyridin-2-yl-benzene-1, 2-diamine

A solution of (3-fluoro-6-nitro-2-pyridin-2-yl-phenyl) - (2-methoxyethyl) amine (414mg,1.4mmol) in EtOAc (5mL) was added under nitrogenPalladium on carbon (10% by weight, 41mg) in EtOAc (5 mL). The reaction mixture was stirred at RT under hydrogen atmosphere for 4 h. Mixing the mixture withFiltration and concentration of the filtrate in vacuo gave the title compound as a yellow oil (382mg, 99%). LCMS (method C) R_T1.92min[M+H]⁺262。¹H NMR(CDCl₃,400MHz):δ8.72(1H,ddd,J=5.0,2.0,1.0Hz),7.77,(1H,ddd,J=8.0,8.0,2.0Hz),7.60-7.56(1H,m),7.26(1H,ddd,J=7.5,5.0,1.0Hz),6.73-6.66(2H,m),5.67(1h,bs),3.86(2H,bs),3.18-3.16(2H,m),3.01(3H,s),2.96-2.93(2H,m)

{ (S) -1- [ 4-fluoro-2- (2-methoxyethylamino) -3-pyridin-2-yl-phenylcarbamoyl ] -ethyl } -carbamic acid tert-butyl ester

At 0 ℃ to 4-fluoro-N²To a solution of- (2-methoxyethyl) -3-pyridin-2-yl-benzene-1, 2-diamine (371mg,4.42mmol), L-Boc-ala-OH (296mg,1.56mmol) and HOAt (213mg,1.56mmol) in DCM (5mL) was added N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride (299mg,1.56mmol) portionwise and the reaction mixture was stirred at 0 ℃ for 1 h. The reaction mixture was diluted with DCM (20mL) and washed with citric acid solution (10% by weight, 20 mL). The aqueous material was further extracted with DCM (3X 20 mL). The combined organic fractions were dried (Na)₂SO₄) And concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PPC, gradient eluted with 25-75% EtOAc/cyclohexane) to give the title compound as a white solid (373mg, 61%). LCMS (method C) R_T2.80min[M+H]⁺433。¹H NMR(CDCl₃,400MHz):δ8.89(1H,bs),8.71(1H,ddd,J=5.0,2.0,1.0Hz),8.29(1H,dd,J=9.0,6.0Hz),7.80(1H,ddd,J=8.0,8.0,2.0Hz),7.63-7.60(1H,m),7.29(1H,ddd,J=7.5,5.0,1.5Hz),6.88(1H,dd,10.0,10.0Hz),5.74(1H,bs),5.32(1H,bs),4.44-4.34(1H,m),3.27(2H,t,5.0Hz),3.24(3H,s),2.85-2.79(2H,m),1.47(3H,d,J=7.0Hz),1.46(9H,s)。

{ (S) -1- [ 6-fluoro-1- (2-methoxyethyl) -7-pyridin-2-yl-1H-benzimidazol-2-yl ] ethyl } carbamic acid tert-butyl ester

Reacting { (S) -1- [ 4-fluoro-2- (2-methoxyethylamino) -3-pyridin-2-yl-phenylcarbamoyl]A solution of tert-butyl ethyl carbamate (368mg,0.85mmol) in AcOH (5mL) was heated in a sealed tube at 70 ℃ for 16 h. After cooling to RT, the volatiles were removed in vacuo and the resulting residue was taken up in DCM (15mL) and washed with saturated NaHCO ₃(30mL) washed. The aqueous material was further extracted with DCM (2X 15 mL). The combined organic fractions were washed with brine (15mL) and dried (Na)₂SO₄) And concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PPC, eluting with a gradient of 20-75% EtOAc/cyclohexane) to give the title compound as a white solid (239mg, 68%). LCMS (method C) R_T2.92min[M+H]⁺415。¹H NMR(CDCl₃,400MHz):δ7.84(1H,ddd,J=7.5,7.5,2.0Hz),7.71(1H,dd,J=9.0,5.0Hz),7.59-7.56(1H,m),7.38(1H,ddd,J=7.5,5.0,1.5Hz),7.09(1H,dd,J=10.5,9.0Hz),5.29-5.19(2H,m),4.33-4.26(1H,m),3.91(1H,ddd,J=15.0,4.0,4.0Hz),3.14-3.08(2H,m),3.07(1H,s),1.60(3H,d,J=6.5Hz),1.41(9H,s)

(S) -1- [ 6-fluoro-1- (2-methoxyethyl) -7-pyridin-2-yl-1H-benzimidazol-2-yl ] ethylamine

Reacting { (S) -1- [ 6-fluoro-1- (2-methoxyethyl) -7-pyridin-2-yl-1H-benzimidazol-2-yl]Ethyl } carbamic acid tert-butyl ester (231mg,0.56mmol) in TFA (2mL) and DCM (6mL)The solution was stirred at RT for 45 min. Loading the reaction mixture intoSCX-2 column. The column was washed with MeOH, then 2M NH₃Washing with MeOH. The basic fractions were combined and concentrated in vacuo to give the title compound as a pale yellow oil (179mg, 99%). Marfey test:>and (3) 99% of de. LCMS (method C) R_T1.76min[M+H]⁺315。¹H NMR(CDCl₃,400MHz):δ8.75(1H,ddd,J=5.0,2.0,1.0Hz),7.84(1H,ddd,J=7.5,7.5,2.0Hz),7.73(1H,dd,J=9.0,5.0Hz),7.60-7.57(1H,m),7.38(1H,ddd,J=7.5,5.0,1.0Hz),7.09(1H,dd,J=10.0,9.0Hz),4.33(1H,q,J=6.5Hz),4.12(1H,ddd,J=15.5,5.5,4.5Hz),4.02(1H,ddd,J=15.5,7.0,5.0Hz),3.12-3.01(2H,m),3.06(3H,m),2.00(2H,bs),1.59(3H,d,J=6.5Hz)。

(2-bromo-6-nitrophenyl) methylamine

A mixture of 1-bromo-2-fluoro-3-nitrobenzene (3.96g,18mmol), 2M methylamine in MeOH (18mL,36mmol) and DIPEA (3.3mL,19mmol) was stirred at RT for 3 h. The reaction mixture was concentrated in vacuo. The resulting residue was taken up in DCM (100mL) and saturated NaHCO was used ₃(100mL) washing. The aqueous layer was further extracted with DCM (100 mL). The combined organic fractions were washed with brine (50mL) and Na₂SO₄Dried and concentrated in vacuo to give the title compound as a bright orange oil (4.16g, 99%). LCMS (method C) R_T3.39min[M+H]⁺231 (for)⁷⁹Br)。¹H NMR(CDCl₃,400MHz):δ7.86(1H,dd,J=8.5,1.5Hz),7.67(1H,dd,J=8.0,1.5Hz),6.67(1H,dd,J=8.5,8.0Hz),3.13(1H,bs),3.01(3H,d,J=5.5Hz)。

3-bromo-N²-methylbenzene-1, 2-diamine

Adding (2-bromo-6-nitrophenyl) methylamine (4.16g,18mmol), ammonium chloride (5.6g,108mmol) and iron powder (4.09g,72mmol) in H₂A mixture of O (32mL) and MeOH (80mL) was stirred vigorously at 90 deg.C for 5 h. After cooling to RT, the reaction mixture was usedFiltration, washing with MeOH/DCM and concentration of the filtrate in vacuo. The resulting residue was taken up in EtOAc (75mL) with H₂O (75mL) wash. The aqueous material was further extracted with EtOAc (2X 75 mL). The combined organic fractions were washed with brine (50mL) and dried (Na)₂SO₄) And concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PPC, eluting with a gradient of 10-75% EtOAc/cyclohexane) to give the title compound as a red oil (1.46g, 40%). LCMS (method C) R_T1.79min[M+H]⁺211 (for)⁷⁹Br)。¹H NMR(CDCl₃,400MHz):δ6.92(1H,dd,J=8.0,1.5Hz),6.75(1H,dd,8.0,8.0Hz),6.64(1H,dd,J=8.0,1.5Hz),4.02(2H,bs),3.25(1H,bs),2.68(3H,s)。

[ (S) -1- (7-bromo-1-methyl-1H-benzimidazol-2-yl) ethyl ] carbamic acid tert-butyl ester

At 0 ℃ to 3-bromo-N²To a solution of-methylbenzene-1, 2-diamine (1.46g,7.3mmol), L-Boc-ala-OH (1.51g,8.0mmol) and HOAt (1.09g,8.0mmol) in DCM (25mL) was added N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride (1.53g,8.0mmol) in portions and the reaction mixture was stirred at 0 ℃ for 1 h. The reaction mixture was diluted with DCM (20mL) and washed with citric acid solution (10% by weight, 20 mL). The aqueous material was further extracted with DCM (3X 20 mL). The combined organic fractions were dried (Na) ₂SO₄) Is true ofAnd (4) concentrating in air. The resulting residue was purified by column chromatography (Si-PPC, eluting with a gradient of 25-75% EtOAc/cyclohexane) to give a mixture of two amide regioisomers (regioisomers) and the cycloadduct. The mixture was dissolved in AcOH (20mL) and heated in a sealed tube at 70 ℃ for 16 h. After cooling to RT, the volatiles were removed in vacuo and the resulting residue was taken up in DCM (30mL) and washed with saturated NaHCO₃(60mL) washing. The aqueous material was further extracted with DCM (2X 30 mL). The combined organic fractions were washed with brine (30mL) and dried (Na)₂SO₄) And concentrated in vacuo to give the title compound as a red oil (1.8g, 70%). LCMS (method C) R_T3.14min[M+H]⁺354 (to⁷⁹Br)。¹H NMR(CDCl₃,400MHz):δ7.64(1H,d,J=8.0Hz),7.38(1H,d,J=7.5Hz),7.08(1H,dd,J=8.0Hz),5.48(1H,d,J=8.5Hz,5.16(1H,dq,J=8.5,7.0Hz),4.12(3H,m),1.61(3H,d,J=7.0Hz),1.45(9H,s)。

(S) -1- (7-bromo-1-methyl-1H-benzimidazol-2-yl) ethylamine

Reacting [ (S) -1- (7-bromo-1-methyl-1H-benzimidazol-2-yl) ethyl]A solution of tert-butyl carbamate (1.8g,5.1mmol) in TFA (7.5mL) and DCM (22.5mL) was stirred at RT for 45 min. Loading the reaction solution intoSCX-2 column. The column was washed with MeOH, then 2M NH₃Washing with MeOH. The basic fractions were combined and concentrated in vacuo to give the title compound as a pale red solid (1.3g, 99%). Marfey test 98% de. LCMS (method C) R _T1.49min[M+H]⁺415 (for⁷⁹Br)。

{ (S) -1- [ 6-fluoro-1- (5-fluoropyridin-3-yl) -1H-benzimidazol-2-yl ] propyl } carbamic acid tert-butyl ester

To a suspension of tert-butyl ((S) -1-carbamoylpropyl) carbamate (250mg,1.24mmol) in DCM (5mL) was added triethyloxyTetrafluoroborate (228mg,1.20mmol) and the reaction mixture was stirred at RT under argon for 1.5 h. The reaction mixture was concentrated in vacuo and the residue was dissolved in ethanol (3 mL). Adding 4-fluoro-N²- (5-Fluoropyridin-3-yl) benzene-1, 2-diamine (88mg,0.40mmol), and the reaction mixture was heated at 60 ℃ for 20 min. The reaction mixture was concentrated in vacuo and the residue was taken up in DCM and saturated NaHCO₃Are distributed among the devices. The organic fraction was washed with brine and dried (Na)₂SO₄) And concentrated in vacuo. The resulting residue was flash chromatographed (Si-PPC, gradient eluted with 0-50% EtOAc in cyclohexane) to give the title compound as a white foam (128mg, 82%). LCMS (method J) R_T=3.42min,[M+H]⁺=389。

(S) -1- [ 6-fluoro-1- (5-fluoropyridin-3-yl) -1H-benzimidazol-2-yl ] propylamine

TFA (0.12mL,1.58mmol) was added to { (S) -1- [ 6-fluoro-1- (5-fluoropyridin-3-yl) -1H-benzimidazol-2-yl]Propyl } carbamic acid tert-butyl ester (123mg,0.33mmol) in DCM (2mL) and the reaction stirred at RT for 18 h. The reaction mixture was concentrated in vacuo and passed through 2g SCX-2 column with 2M NH₃MeOH elution. The basic fraction was concentrated in vacuo to give the title compound as a brown oil (92mg, quantitative yield). LCMS (method J) R_T=1.86min,[M+H]⁺=289。

{ (S) -1- [ 6-fluoro-1- (5-fluoropyridin-3-yl) -1H-benzimidazol-2-yl ] propyl } - [9- (tetrahydropyran-2-yl) -9H-purin-6-yl ] amine

Reacting (S) -1- [ 6-fluoro-1- (5-fluoropyridin-3-yl) -1H-benzimidazol-2-yl]A mixture of propylamine (70mg,0.24mmol), 6-chloro-9- (tetrahydropyran-2-yl) -9H-purine (57mg,0.24mmol) and DIPEA (84. mu.L, 0.48mmol) in IPA (3mL) was heated at 90 deg.C for 24H. After cooling to RT, the volatiles were removed in vacuo and the resulting residue was purified by column chromatography (Si-PPC, gradient eluted with 0-7% MeOH in DCM) to give the title compound as a light brown oil (96mg, 82%). LCMS (method J) R_T=3.03min,[M+H]⁺=491。

[ (S) -1- (6-fluoro-1-phenyl-1H-benzimidazol-2-yl) propyl ] carbamic acid tert-butyl ester

To a suspension of tert-butyl ((S) -1-carbamoylpropyl) carbamate (300mg,1.48mmol) in DCM (5mL) was added triethyloxyTetrafluoroborate (273mg,1.43mmol) and the reaction mixture was stirred at RT under argon for 1.5 h. The reaction mixture was concentrated in vacuo and the resulting residue was dissolved in ethanol (3 mL). Adding 4-fluoro-N ²-phenyl-benzene-1, 2-diamine (97mg,0.48mmol), and the reaction was heated at 70 ℃ for 1 h. The reaction mixture was concentrated in vacuo and the resulting residue was taken up in DCM and saturated NaHCO₃Are distributed among the devices. The organic fraction was washed with brine and dried (Na)₂SO₄) And concentrated in vacuo. The resulting residue was flash chromatographed (Si-PPC, gradient elution with 0-20% EtOAc in cyclohexane) to give the title compound as a pink foam (96mg, 54%). LCMS (method J) R_T=3.70min,[M+H]⁺=370。

(S) -1- (6-fluoro-1-phenyl-1H-benzimidazol-2-yl) propylamine

TFA (0.50mL,6.73mmol) was added to [ (S) -1- (6-fluoro-1-phenyl-1H-benzimidazol-2-yl) propyl ] acetate]To a solution of tert-butyl carbamate (92mg,0.25mmol) in DCM (2mL) the reaction was stirred at RT for 1.5 h. The reaction mixture was concentrated in vacuo and passed through 2gSCX-2 column with 2M NH₃MeOH elution. The basic fraction was concentrated in vacuo to give the title compound (57mg,85%) as a red oil. LCMS (method J) R_T=2.08min,[M+H]⁺=270。

[ (S) -1- (6-fluoro-1-phenyl-1H-benzimidazol-2-yl) propyl ] - [9- (tetrahydropyran-2-yl) -9H-purin-6-yl ] amine

A mixture of (S) -1- (6-fluoro-1-phenyl-1H-benzimidazol-2-yl) propylamine (55mg,0.20mmol), 6-chloro-9- (tetrahydropyran-2-yl) -9H-purine (49mg,0.20mmol) and DIPEA (105. mu.L, 0.60mmol) in IPA (0.5mL) was heated at 90 deg.C for 24H. After cooling to RT, the volatiles were removed in vacuo and the resulting residue was purified by column chromatography (Si-PPC, gradient eluted with 0-5% MeOH in DCM) to give the title compound as a light brown oil (84mg, 89%). LCMS (method J) R _T=3.30min,[M+H]⁺=471。

2-amino-4-chloropyrimidine-5-carbonitrile

To a stirred solution of 2, 4-dichloropyrimidine-5-carbonitrile (500mg,2.87mmol) in MeOH (5mL) was added 2M NH₃MeOH (5 mL). After stirring for 20min, the resulting precipitate was filtered and washed with MeOH to give the title compound as a white solid (173mg, 39%). LCMS (method C) R_T1.91min[M+H]⁺155.1。¹H NMR(DMSO-d₆,400MHz):δ8.68(1H,s),8.23(2H,br s)

(2-bromo-3-fluoro-6-nitrophenyl) methylamine

Methylamine (2M in THF, 19mL,38.1mmol) was added to a solution of 2-bromo-1, 3-difluoro-4-nitrobenzene (4.53g,19mmol) and DIPEA (6.8mL,38.1mmol) in THF (70mL) and the resulting mixture was stirred at 60 ℃ for 3 h. The reaction mixture is concentrated in vacuo and the residue is purified by chromatography over (SiO)₂0-80% DCM in cyclohexane) to give the title compound as an orange/yellow solid (4.32g, 91%). LCMS (method C) R_T3.46min[M+H]⁺249.0,251.0。

3-bromo-4-fluoro-N²-methylbenzene-1, 2-diamine

Ammonium chloride (6.24g,117mmol) and iron powder (4.34g,77.7mmol) were added to stirred (2-bromo-3-fluoro-6-nitro-compound)Phenyl) methylamine (4.84g,19.4mmol) in a mixture of 3:1 methanol/water (320mL) and the resulting mixture heated at reflux for 24 h. The solid material was removed by filtration and the filtrate was concentrated to about 1/3 volumes. The mixture was partitioned between DCM (3 ×) and water, and the combined DCM extracts were dried (Na) ₂SO₄) And concentrated in vacuo. The residue obtained is purified by chromatography (SiO)₂Eluting with 0-5% methanol in DCM) to give the title compound as an oil (1.99g, 47%). LCMS (method C) R_T2.37min[M+H]⁺219.0,221.0

[ (S) -1- (3-bromo-2, 4-difluorophenylcarbamoyl) ethyl ] carbamic acid tert-butyl ester

N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride (1.54g,8.13mmol) was added to stirred 3-bromo-4-fluoro-N at 0 ℃ under nitrogen²A mixture of-methylbenzene-1, 2-diamine (1.78g,8.13mmol), (S) -2-tert-butoxycarbonylamino) propionic acid (1.54g,8.13mmol) and HOAt (1.11g,8.13mmol) in DCM was stirred for a further 16 h. The reaction mixture was washed with DCM and saturated NaHCO₃The aqueous solution was partitioned. The combined DCM extracts were dried (Na)₂SO₄) And concentrated in vacuo. The residue is purified by chromatography (SiO)₂0-3% (2M ammonia in methanol) in DCM) to give the title compound as an off-white solid (2.91g, 92%). LCMS (method C) R_T3.33min[M+H]⁺390.1,392.1

[ (S) -1- (7-bromo-6-fluoro-1-methyl-1H-benzimidazol-2-yl) ethyl ] carbamic acid tert-butyl ester

Reacting [ (S) -1- (3-bromo-2, 4-di)Fluorophenyl carbamoyl) ethyl]A solution of tert-butyl carbamate (2.91g,7.46mmol) in acetic acid (50mL) was stirred at 75 ℃ under nitrogen for 1 h. Separating [ (S) -1- (3-bromo-2, 4-difluorophenylcarbamoyl) ethyl ]A solution of tert-butyl carbamate (0.36g,0.91mmol) in acetic acid (10mL) was stirred at 75 ℃ under nitrogen for 2 h. The reactions were combined, then concentrated in vacuo and the residue was taken up in DCM and saturated NaHCO₃The aqueous solution was partitioned. The combined DCM extracts were dried (Na)₂SO₄) And concentrated in vacuo to give the title compound as a white solid (3.03g, 97%). LCMS (method C) R_T3.41min[M+H]⁺372.1,374.1。

(S) -1- (7-bromo-6-fluoro-1-methyl-1H-benzimidazol-2-yl) ethylamine

TFA (40mL) was added to [ (S) -1- (7-bromo-6-fluoro-1-methyl-1H-benzimidazol-2-yl) ethyl]A solution of tert-butyl carbamate (3.02g,8.11mmol) in DCM (20mL) was stirred for 15 min. The reaction mixture was concentrated in vacuo and the residue was taken up in DCM and saturated NaHCO₃The aqueous solution was partitioned. The combined DCM extracts were dried (Na)₂SO₄) And concentrated in vacuo to give the title compound as a white solid (2.04g, 92%). LCMS (method C) R_T1.83min[M+H]⁺271.9,273.9

4-amino-6- [ (S) -1- (7-bromo-6-fluoro-1-methyl-1H-benzimidazol-2-yl) ethylamino ] pyrimidine-5-carbonitrile

4-amino-6-chloropyrimidine-5-carbonitrile (0.88g,5.71mmol) was added to (S) -1- (7-bromo-6-fluoro-1-methyl-1H-benzimidazol-2-yl) ethylamine (1.11g,4.08mmol) and DIPEA (2.6mL,14.7 mmol)) In IPA (30mL) and the resulting mixture was stirred at 85 deg.C for 16 h. The reaction mixture was poured into water and the precipitated solid was removed by filtration. The solid was washed with water and dried to give the title compound as an off-white solid (1.61g, 100%). LCMS (method C) R _T2.68min[M+H]⁺390.1,392.1

(5-fluoro-2-nitro-phenyl) - (1-methyl-1H-pyrazol-4-yl) -amine

Potassium tert-butoxide (1.16g,10.3mmol) was added to a solution of 1-methyl-1H-pyrazol-4-ylamine (0.50g,5.15mmol) in THF (10mL) at 0 deg.C under nitrogen and the resulting mixture was stirred for 15 min. 2, 4-difluoro-1-nitrobenzene (0.98g,6.18mmol) in THF (5mL) was added and stirring was continued for 1 h. The reaction mixture was poured into saturated aqueous ammonium chloride and extracted with EtOAc (× 3). The combined EtOAc extracts were dried (Na)₂SO₄) And concentrated in vacuo. The residue obtained is purified by chromatography (SiO)₂0-2% methanol in DCM) to give the title compound as a red gummy solid (0.19g, 16%). LCMS (method B) R_T3.12min[M+H]⁺236.9

4-fluoro-N²- (1-methyl-1H-pyrazol-4-yl) -benzene-1, 2-diamine,

a mixture of (5-fluoro-2-nitrophenyl) - (1-methyl-1H-pyrazol-4-yl) amine (102mg,0.43mmol) and 10% palladium on carbon (25mg) in EtOAc (10mL) was stirred under a hydrogen atmosphere, atmospheric pressure, and at 20 ℃ for 6H. A mixture of the isolated (5-fluoro-2-nitrophenyl) - (1-methyl-1H-pyrazol-4-yl) amine (0.19g,0.80mmol) and 10% palladium on carbon (50mg) in EtOAc (10mL) under a hydrogen atmosphere, atmospheric pressure and 20Stirring at deg.C for 5 h. The catalyst was removed by filtration, and the filtrates were combined and concentrated in vacuo. The residue obtained is purified by chromatography (SiO) ₂0-8% (2M ammonia in methanol) in DCM) to give the title compound as a brown oil (0.188g, 74%). LCMS (method C) R_T1.61min[M+H]⁺207.1

{ (S) -1- [ 6-fluoro-1- (1-methyl-1H-pyrazol-4-yl) -1H-benzimidazol-2-yl ] -ethyl } -carbamic acid tert-butyl ester

At 20 ℃ under nitrogen, the triethyl oxideTetrafluoroborate (0.35g,1.86mmol) was added to a solution of tert-butyl ((S) -1-carbamoylethyl) carbamate (0.41g,2.22mmol) in DCM (10mL) and the resulting mixture was stirred for 3h, then concentrated in vacuo. The residue was dissolved in ethanol (10mL) and 4-fluoro-N was added²- (1-methyl-1H-pyrazol-4-yl) -benzene-1, 2-diamine (0.183g,0.89 mmol). The resulting solution was stirred under nitrogen at reflux for 16 h. The reaction mixture was concentrated in vacuo and the residue was taken up in DCM (. times.3) and saturated NaHCO₃The aqueous solution was partitioned. The combined DCM extracts were dried (Na)₂SO₄) And concentrated in vacuo. The residue obtained is purified by chromatography (SiO)₂0-5% (2M ammonia in methanol) in DCM) to give the title compound as a brown oil (0.274g, 86%). LCMS (method C) R_T2.77min[M+H]⁺360.2。

(S) -1- [ 6-fluoro-1- (1-methyl-1H-pyrazol-4-yl) -1H-benzimidazol-2-yl ] ethylamine

TFA (10mL) was added to { (S) -1- [ 6-fluoro-1- (1-methyl-1H-pyrazol-4-yl) -1H-benzimidazol-2-yl ]Ethyl } carbamic acid tert-butyl ester (0.268g,0.75mmol) in DCM (5mL) and stirred for 15 min. The reaction mixture was concentrated in vacuo and the residue was taken up in DCM (. times.3) and saturated NaHCO₃The aqueous solution was partitioned. The combined DCM extracts were dried (Na)₂SO₄) And concentrated in vacuo. The residue obtained is purified by chromatography (SiO)₂0-10% (2M ammonia in methanol) in DCM) to give the title compound as an oil (0.113g, 59%). LCMS (method C) R_T1.72min[M+H]⁺260.1

(5-fluoro-2-nitrophenyl) - (2-methyl-2H-pyrazol-3-yl) amine

Potassium tert-butoxide (1.16g,10.3mmol) was added to a solution of 2-methyl-2H-pyrazol-3-ylamine (0.50g,5.15mmol) in THF (10mL) at 0 deg.C under nitrogen and the resulting mixture was stirred for 15 min. 2, 4-difluoro-1-nitrobenzene (0.98g,6.18mmol) in THF (5mL) was added and stirring continued for 2 h. The reaction mixture was poured into saturated aqueous ammonium chloride and extracted with EtOAc (× 3). The combined EtOAc extracts were dried (Na)₂SO₄) And concentrated in vacuo. The residue obtained is purified by chromatography (SiO)₂0-2% methanol in DCM) to give the title compound as a yellow/brown crystalline solid (0.98g, 80%). LCMS (method C) R_T2.98min[M+H]⁺237.0

4-fluoro-N²- (2-methyl-2H-pyrazol-3-yl) benzene-1, 2-diamine,

Reacting (5-fluoro-2-nitrophenyl) - (2-methyl-2H-pyridine)A mixture of oxazol-3-yl) -amine (0.96g,4.06mmol) and 10% palladium on carbon (0.20g) in EtOAc (40mL) was stirred under hydrogen atmosphere at atmospheric pressure and 20 ℃ for 5 h. The catalyst was removed by filtration and the filtrate was concentrated in vacuo to give the title compound as a white solid (0.63g, 88%). LCMS (method C) R_T1.88min[M+H]⁺207.0

{ (S) -1- [ 6-fluoro-1- (2-methyl-2H-pyrazol-3-yl) -1H-benzimidazol-2-yl ] -ethyl } -carbamic acid tert-butyl ester

At 20 ℃ under nitrogen, the triethyl oxideTetrafluoroborate (1.06g,5.60mmol) was added to a solution of tert-butyl ((S) -1-carbamoylethyl) carbamate (1.26g,6.67mmol) in DCM (20mL) and the resulting mixture was stirred for 3h, then concentrated in vacuo. The resulting residue was dissolved in ethanol (20mL) and 4-fluoro-N was added²- (2-methyl-2H-pyrazol-3-yl) -benzene-1, 2-diamine (0.55g,2.67mmol), the reaction mixture was stirred under nitrogen at reflux for 16H. The reaction mixture was concentrated in vacuo and the residue was taken up in DCM (. times.3) and saturated NaHCO₃The aqueous solution was partitioned. The combined DCM extracts were dried (Na)₂SO₄) And concentrated in vacuo. The residue obtained is purified by chromatography (SiO)₂0-5% (2M ammonia in methanol) in DCM) to give the title compound as a yellow oil (1.25g, 100%). LCMS (method C) R _T3.08min[M+H]⁺360.2。310091751

(S) -1- [ 6-fluoro-1- (2-methyl-2H-pyrazol-3-yl) -1H-benzimidazol-2-yl ] -ethylamine

TFA (20mL) was added to { (S) -1- [ 6-fluoro-1- (2-methyl-2H-pyrazol-3-yl) -1H-benzimidazol-2-yl]-Ethyl } carbamic acid tert-butyl ester (0.96g,2.67mmol) in DCM (10mL) and stirred for 15 min. The reaction mixture was concentrated in vacuo and the residue was taken up in DCM (. times.3) and saturated NaHCO₃The aqueous solution was partitioned. The combined DCM extracts were dried (Na)₂SO₄) And concentrated in vacuo. The residue obtained is purified by chromatography (SiO)₂0-10% (2M ammonia in methanol) in DCM) to give the title compound as a colourless oil (0.69g, 51%). LCMS (method C) R_T1.55,1.72min[M+H]⁺260.1。

[2- ((S) -1-aminoethyl) -5-fluoro-3-phenyl-3H-benzimidazol-4-yl ] morpholin-4-yl-methanone dihydrochloride

To a solution of 2- ((S) -1-tert-butoxycarbonylaminoethyl) -5-fluoro-3-phenyl-3H-benzimidazole-4-carboxylic acid (279mg,0.69mmol) and morpholine (244. mu.L, 2.80mmol) in DCM (5mL) was added HATU (398mg,1.05mmol) and the reaction was stirred at RT for 1H. The reaction mixture was washed with saturated NaHCO₃The aqueous solution was diluted and extracted with DCM (3X 10 mL). The combined organic fractions were washed with brine and dried (MgSO)₄) And concentrated in vacuo to give the product as a yellow oil. LCMS (method C) R _T=3.01min,[M+H]+ = 469. The product was dissolved in a dioxane solution of HCl (4N,10mL) and the reaction mixture was stirred at RT for 30 min. The reaction mixture was concentrated in vacuo to afford the product as an off-white solid. LCMS (method C) R_T=0.27min,[M+H]+=369。

1, 3-difluoro-4-nitro-2-vinylbenzene

2-bromo-1, 3-difluoro-4-nitrobenzene (0.20g,0.84mmol), tributylvinylstannane (0.27mL,0.924mmol) and Pd (PPh)₃)₄(48.6mg,0.042mmol) in bisThe solution in alkane (4mL) was heated with microwave radiation at 150 ℃ for 1 h. The cooled reaction mixture was concentrated in vacuo and the resulting residue was purified by column chromatography (Si-PCC, eluent 2-10% EtOAc in cyclohexane) to give the title compound as a light orange oil (0.119g, 77%).¹H NMR(CDCl₃,300MHz):8.01-7.93(1H,m),7.03(1H,dt,J=9.2,1.9Hz),6.71(1H,dd,J=18.0,12.0Hz),6.15(1H,d,J=18.0Hz),5.77(1H,d,J=12.0Hz)

Allyl- (3-fluoro-6-nitro-2-vinylphenyl) amine

To a solution of 1, 3-difluoro-4-nitro-2-vinylbenzene (115mg,0.621mmol) in DMF (3mL) was added allylamine (0.0513mL,0.683mmol) and potassium carbonate (0.173g,1.24 mmol). The reaction mixture was stirred at RT for 2h, then partitioned between water and EtOAc. The aqueous phase was extracted with EtOAc, the combined organic layers were washed with water, then brine, and then dried (Na)₂SO₄) And concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC with 1-5% EtOAc in cyclohexane as eluent) to afford the title compound as a yellow oil (109.6mg, 79%). ¹H NMR(CDCl₃,300MHz):8.08(1H,dd J=9.4,5.8Hz),7.64(1H,bs),6.57(1H,t,J=9.3Hz),6.51(1H,dd,J=18.0,11.6Hz),5.81(1H,tdd,J=17.1,10.2,5.5Hz),5.72(1H,ddd,J=18.0,2.5,1.6Hz),5.65(1H,ddd,J=11.6,1.5,0.9Hz),5.26(1H,dq,J=17.1,1.5Hz),5.17(1H,dq,J=10.2,1.4Hz),3.98(2H,ddt,J=6.3,5.5,1.6Hz)

5-fluoro-8-nitro-1, 2-dihydroquinoline

To a solution of allyl- (3-fluoro-6-nitro-2-vinylphenyl) amine (109mg,0.49mmol) in DCM (10mL) was added Grubbs' catalyst (second generation, benzylidene [1, 3-bis (2,4, 6-trimethylphenyl) -2-imidazolidinylidene)]Dichloro (tricyclohexylphosphine) ruthenium) (8.5mg,0.01 mmol). The reaction mixture was stirred at RT for 16h then purified by column chromatography (Si-PCC, eluent DCM) to give the title compound as a red solid (83.6mg, 88%).¹H NMR(CDCl₃,300MHz):8.17(1H,bs),7.88(1H,dd,J=9.6,6.0Hz),6.52(1H,dt,J=10.3,2.2Hz),6.22(1H,dd,J=9.7,8.3Hz),5.77-5.71(1H,m),4.55-4.52(2H,m)

5-fluoro-1, 2,3, 4-tetrahydroquinolin-8-ylamine

To a solution of 5-fluoro-8-nitro-1, 2-dihydroquinoline (83.6mg,0.43mmol) in EtOAc (10mL) was added a slurry of 10% Pd/C (28mg) in IMS (3mL) and the reaction mixture was stirred at RT for 22h under a hydrogen atmosphere. Then the suspension is appliedPad filtration and concentration of the filtrate in vacuo afforded a mixture of the title compound and 5-fluoroquinolin-8-ylamine as a purple oil (70.4mg, 99%).¹H NMR(CDCl₃300MHz) (Signal of title Compound) 6.46(1H, dd, J =8.5,5.5Hz),6.28(1H, dd, J =9.2,8.5Hz),3.31-3.28(2H, m),3.24(3H, bs),2.72(2H, t, J =6.5Hz),1.94-1.86(2H, m)

[ (S) -1- (5-fluoro-1, 2,3, 4-tetrahydroquinolin-8-ylcarbamoyl) ethyl ] carbamic acid tert-butyl ester

To an ice-cooled mixture of 5-fluoro-1, 2,3, 4-tetrahydroquinolin-8-ylamine and 5-fluoroquinolin-8-ylamine from the previous step (70.4mg,0.424mmol), (S) -2-tert-butoxycarbonylaminopropionic acid (88.3mg,0.466mmol) and HOAt (57.7mg,0.424mmol) in DCM (6mL) was added EDCI HCl (97.7mg,0.51 mmol). The reaction mixture was stirred in an ice bath for 2h, then diluted with DCM and taken over Na ₂CO₃Aqueous solution, then washed with water. The organic layer was dried (Na)₂SO₄) And then concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC gradient eluted with 20-50% EtOAc in cyclohexane) to give the title compound as a purple gum (105mg, 73%). LCMS (method B) R_T3.35min[M+H]⁺338。

[ (S) -1- (7-fluoro-5, 6-dihydro-4H-imidazo [4,5,1-ij ] quinolin-2-yl) ethyl ] carbamic acid tert-butyl ester

Reacting [ (S) -1- (5-fluoro-1, 2,3, 4-tetrahydroquinolin-8-ylcarbamoyl) ethyl]A solution of tert-butyl carbamate (15mg,0.044mmol) in AcOH (1mL) was stirred at 100 ℃ for 2h, then concentrated in vacuo. The other part of [ (S) -1- (5-fluoro-1, 2,3, 4-tetrahydroquinolin-8-ylcarbamoyl) ethyl]Tert-butyl carbamate (90mg,0.267mmol) was stirred in AcOH (5mL) at 100 ℃ for 1h, then concentrated in vacuo. The combined residues were purified by column chromatography (Si-PCC gradient eluted with 30-60% EtOAc in cyclohexane) to give the title compound as a colourless gum (78mg, 79%). LCMS (method J) R_T2.19min[M+H]⁺320

(S) -1- (7-fluoro-5, 6-dihydro-4H-imidazo [4,5,1-ij ] quinolin-2-yl) ethylamine

To ice-cooled [ (S) -1- (7-fluoro-5, 6-dihydro-4H-imidazo [4,5,1-ij ]]Quinolin-2-yl) ethyl]To a solution of tert-butyl carbamate (78mg,0.244mmol) in DCM (4mL) was added TFA (1.3mL) and the mixture was stirred at RT for 1.5 h. Toluene was added and the volatiles were removed under reduced pressure and the resulting residue was dissolved in MeOH and loaded onto SCX-2 column. The column was washed with MeOH, 0.5M NH₃The product eluted with MeOH. The product containing fractions were combined and concentrated in vacuo to give the title compound as a colourless gum (49.5mg, 93%). LCMS (method B) R_T1.78min[M+H]⁺220

But-3-enyl- (3-fluoro-6-nitro-2-vinylphenyl) amine

To an ice-cooled solution of 1, 3-difluoro-4-nitro-2-vinylbenzene (389mg,2.1mmol) in DMF (8mL) were added 3-butenylamine hydrochloride (248mg,2.31mmol) and potassium carbonate (0.87g,6.3 mmol). The reaction mixture was stirred at RT for 2h, then partitioned between water and EtOAc. The aqueous phase was extracted with EtOAc, the combined organic layers were washed with water, then brine, and then dried (Na)₂SO₄) And concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, eluent 2-4% EtOAc in cyclohexane) to give the title compound as an orange oil (327.6mg, 66%). LCMS (method B) R_T4.27min[M+H]⁺237

6-fluoro-9-nitro-2, 3-dihydro-1H-benzo [ b]Aza derivatives

To a solution of but-3-enyl- (3-fluoro-6-nitro-2-vinylphenyl) amine (327.6mg,1.386mmol) in DCM (30mL) was added Grubbs' catalyst (second generation, benzylidene [1, 3-bis (2,4, 6-trimethylphenyl) -2-imidazolidinylidene]Dichloro (tricyclohexylphosphine) ruthenium) (47mg,0.055 mmol). The reaction mixture was stirred at RT for 16h, then another portion of Grubbs catalyst (47mg,0.055mmol) was added and stirring continued for an additional 64 h. The reaction mixture was concentrated in vacuo and then purified by column chromatography (Si-PCC with 2-6% EtOAc in cyclohexane as eluent). The recovered starting material (145mg) was dissolved in DCM (20mL) and Grubbs second generation catalyst (30mg,0.035mmol) was added. The reaction mixture was heated at reflux for 6h and then placed at RT for 16 h. The reaction mixture was concentrated in vacuo, combined with the product from the primary purification and purified by column chromatography (Si-PCC, eluent 2-8% EtOAc in cyclohexane) to give the title compound as a red solid (225.4mg, 78%). ¹H NMR(CDCl₃,300MHz):8.90(1H,bs),8.09(1H,dd,J=9.4,6.0Hz),6.67(1H,dt,J=12.3,1.8Hz),6.47(1H,t,J=9.6Hz),6.16(1H,dt,J=12.3,4.7Hz),3.52(2H,q,J=4.9Hz),2.65(2H,dq,J=4.8,1.8Hz)

6-fluoro-2, 3,4, 5-tetrahydro-1H-benzo [ b]Aza derivatives-9-Amines

To 6-fluoro-9-nitro-2, 3-dihydro-1H-benzo [ b]Aza derivatives(225.4mg,1.0826mmol) in EtOAc (15mL)A slurry of 10% Pd/C (50mg) in IMS (4mL) was added and the reaction mixture was stirred at RT for 20h under a hydrogen atmosphere. Then the suspension is appliedPad filtration and concentration of the filtrate in vacuo gave the title compound as a violet oil (197mg, quantitative yield). LCMS (method J) R_T1.69min[M+H]⁺181\

[ (S) -1- (6-fluoro-2, 3,4, 5-tetrahydro-1H-benzo [ b ]]Aza derivatives-9-ylcarbamoyl) ethyl]Carbamic acid tert-butyl ester

To ice-cooled 6-fluoro-2, 3,4, 5-tetrahydro-1H-benzo [ b]Aza derivatives-9-Amines = (195mg,1.0826mmol), (S) -2-tert-butoxycarbonylaminopropionic acid (225mg,1.19mmol) and HOAt (147mg,1.083mmol) to a mixture in DCM (10mL) EDCI HCl (249mg,1.3mmol) was added. The reaction mixture was stirred in an ice bath for 2h, then diluted with DCM and taken over Na₂CO₃Aqueous solution, then washed with water. The organic layer was dried (Na)₂SO₄) And then concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC gradient eluted with 20-50% EtOAc in cyclohexane) to give the title compound as a pink gum (270.6mg, 71%). LCMS (method J) R _T3.26min[M+H]⁺352

[ (S) -1- (5-fluoro-6, 7,8, 9-tetrahydro-2, 9 a-diazabenzo [ cd)]-1-yl) ethyl]Carbamic acid tert-butyl ester

Mixing [ (S) -1- (6-fluoro-2, 3,4, 5-tetrahydro-1H-benzo [ b ]]Aza derivatives-9-ylcarbamoyl) ethyl]A solution of tert-butyl carbamate (270mg,0.768mmol) in AcOH (4mL) was stirred at 80 ℃ for 1h, then concentrated in vacuo. The residue was purified by column chromatography (Si-PCC gradient eluted with 30-60% EtOAc in cyclohexane) to give the title compound as a pale pink gum (252.6 m)_g99%). LCMS (method B) R_T2.63min[M+H]⁺334

(S) -1- (5-fluoro-6, 7,8, 9-tetrahydro-2, 9 a-diazabenzo [ cd]-1-yl) ethylamine

To ice-cooled [ (S) -1- (5-fluoro-6, 7,8, 9-tetrahydro-2, 9 a-diazabenzo [ cd)]-1-yl) ethyl]To a solution of tert-butyl carbamate (252.6mg,0.7576mmol) in DCM (8mL) was added TFA (2mL) and the mixture was stirred at RT for 1.5 h. Toluene was added and the volatiles were removed under reduced pressure and the resulting residue was dissolved in MeOH and loaded ontoSCX-2 column. The column was washed with MeOH, 0.5M NH₃The product eluted with MeOH. The product-containing fractions were combined and concentrated in vacuo to give the title compound as a pale pink solid (144.5 mg)82%). LCMS (method J) R_T1.93min[M+H]⁺234

2- (1-methylallyl) isoindole-1, 3-dione

To a suspension of potassium phthalimide (7.08g,38.2mmol) in DMF (60mL) was added potassium carbonate (1.06g,7.6mmol) and 3-chloro-1-butene (5.0mL,49.7 mmol). The mixture was heated at reflux in a 135 ℃ bath for 4 h. The cooled reaction mixture was concentrated in vacuo and water (65mL) was added over 5 minutes at 40 ℃ with rapid stirring. The resulting suspension was cooled in an ice bath, then the solid was collected by filtration, washed with water (2 × 7mL), then ethanol/water (45:55,14mL) and dried under vacuum at 50 ℃ for 16h to give the title compound as an off-white (buff) solid (5.0g, 65%).¹H NMR((CD₃)₂SO,300MHz):7.87-7.83(4H,m),6.12(1H,ddd,J=17.3,10.5,5.7Hz),5.17(1H,dt,J=17.3,1.4Hz),5.13(1H,dt,J=10.4,1.4Hz),4.88-4.78(1H,m),1.51(3H,d,J=7.1Hz)

Ethanol solution of 1-methyl allyl amine

2-aminoethanol (3.2mL) was added to a solution of 2- (1-methylallyl) isoindole-1, 3-dione (2.5g,12.4mmol) in EtOH (5.2 mL). The mixture was stirred at 35 ℃ for 3h and then subjected to short path distillation. The mixture of 1-methylallylamine and EtOH was collected by distillation (bp65-70 ℃) and used directly in the next step.¹H NMR(CDCl₃300MHz) (Signal of title compound) 5.86(1H, ddd, J =17.2,10.3,6.1Hz),5.10(1H, dt, J =17.2,1.4Hz),4.97(1H, dt, J =10.3,1.4Hz),3.52-3.43(1H, m),1.17(3H, d, J =6.6Hz)

(3-fluoro-6-nitro-2-vinylphenyl) - (1-methylallyl) amine

To a solution of 1, 3-difluoro-4-nitro-2-vinylbenzene (150mg,0.81mmol) in DMF (3mL) was added a mixture of 1-methylallylamine in ethanol (0.4 mL). Potassium carbonate (0.224g,1.62mmol) was added and the mixture was stirred at RT for 1 h. An additional portion of 1-methylallylamine in ethanol (0.3mL) was added and stirring was continued for 1h, then the reaction mixture was partitioned between water and EtOAc. The aqueous phase was extracted with EtOAc, the combined organic layers were washed with water, then brine, and then dried (Na)₂SO₄) And concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, eluent 2-6% EtOAc in cyclohexane) to give the title compound as a yellow oil (134mg, 70%).¹H NMR(CDCl₃,300MHz):8.06(1H,dd J=9.4,5.7Hz),7.23(1H,bs),6.62(1H,t,J=9.3Hz),6.48(1H,dd,J=18.0,11.6Hz),5.81-5.62(2H,m),5.64(1H,dt,J=11.6,1.3Hz),5.12-5.00(2H,m),4.38-4.25(1H,m),1.27(3H,d,J=6.6Hz)

5-fluoro-2-methyl-8-nitro-1, 2-dihydroquinoline

To a solution of (3-fluoro-6-nitro-2-vinylphenyl) - (1-methylallyl) amine (134mg,0.567mmol) in DCM (10mL) was added Grubbs' catalyst (second generation, benzylidene [1, 3-bis (2,4, 6-trimethylphenyl) -2-imidazolidinylidene]Dichloro (tricyclohexylphosphine) ruthenium) (9.6mg,0.011 mmol). The reaction mixture was stirred at RT for 64h then purified by column chromatography (Si-PCC, eluent 1-4% EtOAc in cyclohexane) to afford recovered starting material (56mg) and the title compound (62.8 mg). Dissolving the recovered starting material Dissolve in DCM (10mL) and add Grubbs' catalyst (second generation, benzylidene [1, 3-bis (2,4, 6-trimethylphenyl) -2-imidazolidinylidene]Dichloro (tricyclohexylphosphine) ruthenium) (12 mg). The reaction mixture was stirred at 45 ℃ for 16h, then purified by column chromatography (Si-PCC, DCM). The combined products were further purified by column chromatography (Si-PCC, eluent 1.5-4% EtOAc in cyclohexane) to give the title compound as a red solid (76.8mg, 65%).¹H NMR(CDCl₃,300MHz):8.26(1H,bs),7.92(1H,dd,J=9.6,6.0Hz),6.53(1H,dd,J=10.2,1.7Hz),6.24(1H,dd,J=9.7,8.4Hz),5.70-5.65(1H,m),4.72-4.63(1H,m),1.43(3H,J=6.6Hz)

5-fluoro-2-methyl-1, 2,3, 4-tetrahydroquinolin-8-ylamine

A suspension of 10% Pd/C (30mg) in a mixture of IMS (3mL) and EtOAc (5mL) was stirred under a hydrogen atmosphere for 15min, then a solution of 5-fluoro-2-methyl-8-nitro-1, 2-dihydroquinoline (76.8mg,0.369mmol) in EtOAc (15mL) was added. The reaction mixture was stirred at RT under hydrogen atmosphere for 20 h. Then the suspension is appliedPad filtration and concentration of the filtrate in vacuo afforded a mixture of the title compound and 5-fluoro-2-methylquinolin-8-ylamine as a purple oil. LCMS (method J) R_T1.90min(28%)[M+H]⁺181 and 2.26min (42%) [ M + H]⁺177

[ (S) -1- (5-fluoro-2-methyl-1, 2,3, 4-tetrahydroquinolin-8-ylcarbamoyl) ethyl ] carbamic acid tert-butyl ester

To 5-fluoro-2-methyl-1, 2,3, 4-tetrakis-methyl-1 obtained from the previous stepTo a mixture of hydroquinolin-8-ylamine and 5-fluoro-2-methylquinolin-8-ylamine (0.369mmol) in DCM (10mL) were added (S) -2-tert-butoxycarbonylaminopropionic acid (76.8mg,0.405mmol) and HOAt (56mg,0.41 mmol). The mixture was cooled in an ice bath and EDCI HCl (85mg,0.44mmol) was added. The reaction mixture was stirred in an ice bath for 2h, then diluted with DCM and taken over Na ₂CO₃Aqueous solution, then washed with water. The organic layer was dried (Na)₂SO₄) And then concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC gradient eluted with 20-50% EtOAc in cyclohexane) to give the title compound as a colorless solid (63.6mg,49%,2 steps). LCMS (method J) R_T3.40min[M+H]⁺352

[ (S) -1- (7-fluoro-4-methyl-5, 6-dihydro-4H-imidazo [4,5,1-ij ] quinolin-2-yl) ethyl ] carbamic acid tert-butyl ester

Reacting [ (S) -1- (5-fluoro-2-methyl-1, 2,3, 4-tetrahydroquinolin-8-ylcarbamoyl) ethyl]A solution of tert-butyl carbamate (63.6mg,0.181mmol) in AcOH (5mL) was stirred at 80 ℃ for 2.5h, then concentrated in vacuo. The residue was purified by column chromatography (Si-PCC gradient eluted with 20-50% EtOAc in cyclohexane) to give the title compound as a colorless gum (24.2mg,40%) LCMS (method B): R_T2.45min[M+H]⁺334

(S) -1- (7-fluoro-4-methyl-5, 6-dihydro-4H-imidazo [4,5,1-ij ] quinolin-2-yl) ethylamine

To ice-cold [ (S) -1- (7-fluoro-4-methyl-5, 6-dihydro-4H-imidazo [4,5,1-ij ]]Quinolin-2-yl) ethyl]To a solution of tert-butyl carbamate (24.2mg,0.0726mmol) in DCM (4mL) was addedTFA (0.8mL) and the mixture was stirred at RT for 16 h. Toluene was added and the volatiles were removed under reduced pressure and the resulting residue was dissolved in MeOH and loaded onto SCX-2 column. The column was washed with MeOH, 0.5M NH₃The product eluted with MeOH. The product containing fractions were combined and concentrated in vacuo to give the title compound as a colourless gum (15.8mg, 93%). LCMS (method B) R_T1.98min[M+H]⁺234

2, 6-difluoro-3-nitrophenol

A solution of 1, 3-difluoro-2-methoxy-4-nitrobenzene (0.50g,2.644mmol) in 33% HBr in AcOH (4mL) was heated at 100 ℃ for 1h with microwave radiation. The cooled reaction mixture was diluted with toluene and concentrated in vacuo. The residue was washed with NaHCO₃Partitioned between aqueous and EtOAc. The aqueous phase was acidified with 1M HCl and extracted twice with DCM. The combined DCM extracts were washed with water and dried (Na)₂SO₄) And concentrated in vacuo to give the title compound as an off-white solid (0.29g, 63%).¹H NMR(CDCl₃,300MHz):7.70(1H,ddd,J=9.5,7.8,5.4Hz),7.06(1H,ddd,J=9.4,9.0,2.2Hz),5.61(1H,bs)

[2- (2, 6-difluoro-3-nitrophenoxy) ethyl ] carbamic acid tert-butyl ester

To a solution of 2, 6-difluoro-3-nitrophenol (248mg,1.416mmol) and triphenylphosphine (558mg,2.127mmol) in THF (10mL) was added a solution of tert-butyl (2-hydroxyethyl) carbamate (274mg,1.70mmol) in THF (2 mL). Mixing the mixture in iceThe bath was cooled and a solution of diethyl azodicarboxylate (372mg,2.127mmol) in THF (2mL) was added over 5 min. After 5min, the reaction was taken out of the ice bath, stirred at RT for 2h, then concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, eluent 30-40% EtOAc in cyclohexane) to give the title compound as a colorless gum (483mg, quantitative yield). ¹H NMR(CDCl₃,300MHz):7.84(1H,ddd,J=9.5,7.8,5.3Hz),7.05(1H,dt,J=9.9,2.2Hz),5.05(1H,bs),4.26(2H,t,J=5.0Hz),3.52(2H,q,J=5.4Hz),1.45(9H,s)

8-fluoro-5-nitro-3, 4-dihydro-2H-benzo [1, 4%]Oxazines

To ice-cold [2- (2, 6-difluoro-3-nitrophenoxy) ethyl]To a solution of tert-butyl carbamate (450mg,1.416mmol) in DCM (20mL) was added TFA (4 mL). The reaction mixture was stirred at RT for 2.5h, then toluene was added and volatiles were removed under reduced pressure. The resulting residue was dissolved in acetonitrile (10mL) and 2M Na was added₂CO₃(10mL) and the mixture was stirred at RT for 1 h. The reaction mixture was partitioned between EtOAc and brine and the organic phase was dried (Na)₂SO₄) And concentrated in vacuo. The residue was purified by column chromatography (Si-PCC, eluent 10-30% EtOAc in cyclohexane) to give the title compound as an orange solid (250mg, 89%).¹H NMR(CDCl₃,300MHz):7.94(1H,bs),7.78(1H,dd,J=9.7,5.4Hz),6.45(1H,t,J=9.5Hz),4.31(2H,t,J=4.6Hz),3.70-3.66(2H,m)

8-fluoro-3, 4-dihydro-2H-benzo [1,4 ]]Oxazin-5-ylamine

To 8-fluoro-5-nitro-3, 4-dihydro-2H-benzo [1,4 ]]To a solution of oxazine (290mg,1.463mmol) in EtOAc (15mL) was added a 10% Pd/C (50mg) slurry in IMS (2mL) and the reaction mixture was stirred at RT for 18h under a hydrogen atmosphere. Then the suspension is appliedPad filtration and concentration of the filtrate in vacuo afforded the title compound as a purple oil (243mg, 99%).

[ (S) -1- (8-fluoro-3, 4-dihydro-2H-benzo [1,4 ]]Oxazin-5-ylcarbamoyl) ethyl]Carbamic acid tert-butyl ester

Ice-cooled 8-fluoro-3, 4-dihydro-2H-benzo [1,4 ]]To a mixture of oxazin-5-ylamine (243mg,1.445mmol), (S) -2-tert-butoxycarbonylaminopropionic acid (305mg,1.61mmol), and HOAt (200mg,1.463mmol) in DCM (15mL) was added EDCI HCl (337mg,1.76 mmol). The reaction mixture was stirred in an ice bath for 90min, then diluted with DCM and taken over Na₂CO₃Aqueous solution, then washed with water. The organic layer was dried (Na)₂SO₄) And then concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient eluted with 50-70% EtOAc in cyclohexane) to give the title compound as a pale yellow foam (440mg, 89%). LCMS (Square)Method B) R_T3.02min[M+H]⁺340

[1- (6-fluoro-3, 4-dihydro-5-oxa-1, 2 a-diaza-acenaphthen-2-yl) ethyl ] carbamic acid tert-butyl ester

Mixing [ (S) -1- (8-fluoro-3, 4-dihydro-2H-benzo [1,4 ]]Oxazin-5-ylcarbamoyl) ethyl]A solution of tert-butyl carbamate (440mg,1.297mmol) in AcOH (15mL) was stirred sequentially at 80 ℃ for 1h, at 100 ℃ for 5h, and then at 85 ℃ for 16 h. The reaction mixture was concentrated in vacuo with toluene to give the title compound and N- [1- (6-fluoro-3, 4-dihydro-5-oxa-1, 2 a-diaza-acenaphthen-2-yl) ethyl]Mixtures of acetamides. LCMS (method B) R_T1.72min[M+H]⁺264&2.51min[M+H]⁺322

1- (6-fluoro-3, 4-dihydro-5-oxa-1, 2 a-diaza-acenaphthen-2-yl) ethylamine

To ice-cooled [1- (6-fluoro-3, 4-dihydro-5-oxa-1, 2 a-diaza-acenaphthen-2-yl) ethyl group from the previous step]Carbamic acid tert-butyl ester and N- [1- (6-fluoro-3, 4-dihydro-5-oxa-1, 2 a-diaza-acenaphthen-2-yl) ethyl ester]A mixture of acetamide in DCM (15mL) was added TFA (3mL) and the mixture was stirred at RT for 2 h. Toluene was added and the volatiles were removed under reduced pressure and the resulting residue was dissolved in MeOH and loaded ontoSCX-2 column. The column was washed with MeOH, 0.5MNH₃The product eluted with MeOH. Will containFractions of product were combined and concentrated in vacuo. Purification by column chromatography (Si-PCC with 2-8%2M NH)₃Gradient MeOH in DCM) to give the title compound as a pale brown gum (185.6mg,65%,2 steps). LCMS (method B) R_T1.54min[M+H]⁺222

[1- (6-fluoro-3, 4-dihydro-5-oxa-1, 2 a-diazacenaphthen-2-yl) ethyl ] - [9- (tetrahydropyran-2-yl) -9H-purin-6-yl ] amine

A mixture of 1- (6-fluoro-3, 4-dihydro-5-oxa-1, 2 a-diazacenaphthen-2-yl) ethylamine (85mg,0.38mmol), 6-chloro-9- (tetrahydropyran-2-yl) -9H-purine (92mg,0.38mmol) and DIPEA (132 μ L,0.76mmol) in IPA (1mL) was heated at 100 deg.C for 18H. After cooling to RT, the volatiles were removed in vacuo and the resulting residue was purified by column chromatography (Si-PPC, gradient eluted with 0-5% MeOH in DCM) to give the title compound as a light yellow oil (132mg, 82%). LCMS (method J) R _T=2.22min,[M+H]⁺=424

[3- (2, 6-difluoro-3-nitrophenoxy) propyl ] carbamic acid tert-butyl ester

To a solution of 2, 6-difluoro-3-nitrophenol (170mg,0.971mmol) and triphenylphosphine (383mg,1.46mmol) in THF (8mL) was added a solution of tert-butyl (3-hydroxypropyl) carbamate (204mg,1.165mmol) in THF (1 mL). The mixture was cooled in an ice bath and a solution of diethyl azodicarboxylate (255mg,1.46mmol) in THF (1mL) was added. The reaction was stirred at RT for 30min and then concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC with 25-40% EtOAc in cyclohexane as eluent) to give the title compound as a colorless gum (296mg, 9)2%)。¹H NMR(CDCl₃300MHz) 7.81(1H, ddd, J =9.4,7.8,5.3Hz),7.04(1H, dt, J =9.4,2.2Hz),4.77(1H, bs),4.27(2H, t, J =6.0Hz),3.37(2H, q, J =6.4Hz),2.00(2H, quintuple, J =6.3Hz),1.45(9H, s)

4-fluoro-1-nitro-6, 7,8, 9-tetrahydro-5-oxa-9-azabenzocycloheptene

To ice-cold [3- (2, 6-difluoro-3-nitrophenoxy) propyl]To a solution of tert-butyl carbamate (296mg,0.8907mmol) in DCM (15mL) was added TFA (3 mL). The reaction mixture was stirred at RT for 2h, then toluene was added and volatiles were removed under reduced pressure. The resulting residue was dissolved in acetonitrile (6mL) and 2M Na was added ₂CO₃(6mL) and the mixture was stirred at RT for 1.5 h. The reaction mixture was partitioned between EtOAc and brine and the organic phase was dried (Na)₂SO₄) And concentrated in vacuo. The residue was purified by column chromatography (Si-PCC, eluent 10-20% EtOAc in cyclohexane) to give the title compound as a red solid (158.4mg, 84%).¹H NMR(CDCl₃,300MHz):8.08(1H,bs),7.87(1H,dd,J=9.6,5.6Hz),6.44(1H,dd,J=9.8,8.7Hz),4.40(2H,t,J=6.6Hz),3.78-3.73(2H,m),2.29-2.20(2H,m)

4-fluoro-6, 7,8, 9-tetrahydro-5-oxa-9-azabenzocyclohepten-1-ylamine

To a solution of 4-fluoro-1-nitro-6, 7,8, 9-tetrahydro-5-oxa-9-azabenzocycloheptene (158mg,0.746mmol) in EtOAc (10mL) was added a 10% Pd/C (30mg) slurry in IMS (1mL) and the reaction mixture was stirred at RT for 18h under a hydrogen atmosphere. Then the suspension is appliedPad filtration and concentration of the filtrate in vacuo afforded the title compound as a brown solid (131.5mg, 97%).¹H NMR(CDCl₃,300MHz):6.46(1H,dd,J=10.2,8.6Hz),6.35(1H,dd,J=8.7,5.1Hz),4.25(2H,t,J=5.8Hz),3.36-3.32(5H,bs&m),2.06(2H, quintuple, J =5.8Hz)

[ (S) -1- (5-fluoro-8, 9-dihydro-7H-6-oxa-2, 9 a-diazabenzo [ c, d)]-1-yl) ethyl]Carbamic acid tert-butyl ester

To a suspension of tert-butyl ((S) -1-carbamoylethyl) carbamate (413mg,2.19mmol) in DCM (5mL) was added triethyloxyTetrafluoroborate (405mg,2.13mmol) and the reaction mixture was stirred under argon at RT for 1.5 h. The reaction mixture was concentrated in vacuo and the residue was dissolved in ethanol (3 mL). 4-fluoro-6, 7,8, 9-tetrahydro-5-oxa-9-azabenzocyclohepten-1-ylamine (129mg,0.71mmol) was added and the reaction was heated at 70 ℃ for 45 min. The reaction mixture was concentrated in vacuo and the residue was taken up in DCM and saturated NaHCO ₃Are distributed among the devices. The organic phase was washed with brine and dried (Na)₂SO₄) And concentrated in vacuo. The resulting residue was chromatographed using flash chromatography (Si-PPC, gradient eluted with 0-30% DCM in cyclohexane) to give the title compound as a white foam (154mg, 65%).¹H NMR(CDCl₃,300MHz):δ7.25(1H,dd,J=8.7,3.9Hz),7.05(1H,dd,J=11.6,8.7Hz),5.34-5.29(1H,m),5.18-5.08(1H,m),4.48-4.44(2H,m),4.38-4.20(2H,m),2.50-2.43(2H,m),1.63(3H,d,J=6.7Hz),1.44(9H,s)。¹H NMR(DMSO,400MHz):δ8.03(1H,s),7.66(1H,d,J=7.2Hz),7.26(2H,br s),7.14(1H,dd,J=8.6,4.0Hz),7.02(1H,dd,J=11.9,8.6Hz),5.62(1H,dq,J=7.2,6.7Hz),4.41(1H,ddd,J=12.1,4.6,3.7Hz),4.33(1H,ddd,J=12.1,9.2,4.4Hz),4.24-4.12(2H,m),2.34-2.28(2H,m),1.55(3H,d,J=6.7Hz)

(S) -1- (5-fluoro-8, 9-dihydro-7H-6-oxa-2, 9 a-diazabenzo [ c, d)]-1-yl) ethylamine

TFA (0.50mL,6.73mmol) was added to [ (S) -1- (5-fluoro-8, 9-dihydro-7H-6-oxa-2, 9 a-diazabenzo [ c, d ]]-1-yl) ethyl]To a solution of tert-butyl carbamate (151mg,0.45mmol) in DCM (2mL) the reaction was stirred at RT for 30 min. The crude reaction mixture was passed through 2gSCX-2 column with 2M NH₃MeOH elution. The basic fraction was concentrated in vacuo to give the title compound as a beige solid (104mg, 98%). LCMS (method B) R_T=1.74min,[M+H]⁺=236

(S, R) -and (S, S) -O-methylmandelic acid amides with dr of 1.3:98.7 and 98.8:1.2, respectively, as determined by LCMS (method K): r_T3.68 and 3.64min [ M + H ]]⁺384.2

[ (S) -1- (5-fluoro-8, 9-dihydro-7H-6-oxa-2, 9 a-diazabenzo [ c, d)]-1-yl) ethyl]- [9- (tetrahydropyran-2-yl) -9H-purin-6-yl]Amines as pesticides

Reacting (S) -1- (5-fluoro-8, 9-dihydro-7H-6-oxa-2, 9 a-diazabenzo [ c, d]A mixture of-1-yl) ethylamine (64mg,0.27mmol), 6-chloro-9- (tetrahydropyran-2-yl) -9H-purine (65mg,0.27mmol) and DIPEA (94. mu.L, 0.54mmol) in IPA (0.5mL) was heated at 100 deg.C for 24H. After cooling to RT, the volatiles were removed in vacuo and the resulting residue was purified by column chromatography (Si-PPC, gradient eluted with 0-5% MeOH in DCM) to give the title compound as a light yellow oil (86mg, 73%). LCMS (method J) R _T=2.33min,[M+H]⁺=438。

[ (S) -2- (2, 6-difluoro-3-nitrophenoxy) -1-methylethyl ] carbamic acid tert-butyl ester

Diethyl azodicarboxylate (349 μ L,2.22mmol) in THF (1mL) was slowly added to a solution of 2, 6-difluoro-3-nitrophenol (260mg,1.48mmol), ((S) -2-hydroxy-1-methylethyl) carbamic acid tert-butyl ester (312mg,1.78mmol), and triphenylphosphine (582mg,2.22mmol) in THF (10mL) at 0 deg.C. The solution was stirred at 0 ℃ for 30min and then concentrated in vacuo. The residue was purified by flash column chromatography (Si-PPC, gradient eluted with 0-30% EtOAc in cyclohexane) to give the title compound as a pale yellow oil (340mg, 69%).¹H NMR(CDCl₃,300MHz):δ7.82(1H,ddd,J=13.0,9.5,5.3Hz),7.04(1H,app.td,J=9.4,2.1Hz),4.75(1H,br s),4.24-4.12(2H,m),4.00(1H,br s),1.44(9H,s),1.34(3H,d,J=6.9Hz)

(S) -8-fluoro-3-methyl-5-nitro-3, 4-dihydro-2H-benzo [1, 4-]Oxazines

TFA (3mL) was added to [ (S) -2- (2, 6-difluoro-3-nitrophenoxy) -1-methylethyl]Tert-butyl carbamate (340mg,1.02mmol) in DCM (15mL) and the mixture was stirred at rt for 90 min. PhMe (25mL) was added and the solution was concentrated in vacuo. The resulting residue was taken up in MeCN (7 mL); 2M Na was added₂CO₃Aqueous solution (7mL) and the mixture stirred vigorously at rt for another 90 min. EtOAc (25mL) and brine (25mL) were added and the phases separated. The aqueous layer was extracted with EtOAc (2X 25mL) and the combined organics were dried (Na) ₂SO₄) And concentrated in vacuo. The crude reaction mixture was purified by flash chromatography (Si-PPC, gradient elution with 0-20% EtOAc in cyclohexane) to afford the title compound as a bright yellow solid (183mg, 84%).¹H NMR(CDCl₃,300MHz):δ7.85(1H,br s),7.78(1H,dd,J=9.8,5.5Hz),6.45(1H,app.t,J=9.8Hz),4.36-4.28(1H,m),3.84-3.77(2H,m),1.35(3H,d,J=6.2Hz)

(S) -8-fluoro-3-methyl-3, 4-dihydro-2H-benzo [1, 4-]Oxazin-5-ylamine

Reacting (S) -8-fluoro-3-methyl-5-nitro-3, 4-dihydro-2H-benzo [1,4 ]]Suspension of oxazine (183mg,0.86mmol) and 10% Pd/C (37mg) in EtOAc (12mL) and IMS (1.2mL) in H₂Stirred under balloon for 16 h. The reaction mixture was filtered over celite and the filtrate was concentrated in vacuo to give the title compound,as a pale yellow oil (160mg, quantitative yield).¹H NMR(CDCl₃,300MHz):δ6.35(1H,dd,J=10.8,8.6Hz),6.14(1H,dd,J=8.6,4.6Hz),4.19(1H,dd,J=10.5,2.9Hz),3.64(1H,dd,J=10.5,8.4Hz),3.43(1H,dqd,J=8.4,6.5,2.9Hz),3.10(3H,br s),1.17(3H,d,J=6.5Hz)

[ (S) -1- ((S) -6-fluoro-3-methyl-3, 4-dihydro-5-oxa-1, 2 a-diazacenaphthen-2-yl) ethyl ] carbamic acid tert-butyl ester

Reacting (S) -8-fluoro-3-methyl-3, 4-dihydro-2H-benzo [1,4 ]]Oxazin-5-ylamine (160mg,0.86mmol) was added to a solution of (S) -2-tert-butoxycarbonylaminopropionimidate (propionimid acid) ethyl ester (570mg,2.64mmol) in EtOH (10mL) and the reaction was heated at 75 ℃ for 60 min. The reaction mixture was concentrated in vacuo and the residue was taken up in DCM and saturated NaHCO₃Are distributed among the devices. The organic phase was washed with brine and dried (Na)₂SO₄) And concentrated in vacuo. The resulting residue was chromatographed using flash chromatography (Si-PPC, gradient eluted with 0-40% DCM in cyclohexane) to give the title compound as an off-white foam (220mg, 76%). LCMS (method J) R _T=2.50min,[M+H]⁺=336。

(S) -1- ((S) -6-fluoro-3-methyl-3, 4-dihydro-5-oxa-1, 2 a-diazacenaphthen-2-yl) ethylamine

TFA (1.00mL) was added to [ (S) -1- ((S) -6-fluoro-3-methyl-3, 4-dihydro-5-oxa-1, 2 a-diazacenaphthen-2-yl) ethyl]To a solution of tert-butyl carbamate (220mg,0.66mmol) in DCM (4mL) the reaction was stirred at RTAnd (5) 60 min. The crude reaction mixture was passed through 2gSCX-2 column with 2M NH₃MeOH elution. The basic fraction was concentrated in vacuo to give the title compound (149mg,96%) as a light brown oil. LCMS (method J) R_T=0.32min,[M+H]⁺=236。

[ (S) -1- ((S) -6-fluoro-3-methyl-3, 4-dihydro-5-oxa-1, 2 a-diazacenaphthen-2-yl) ethyl ] [9- (tetrahydropyran-2-yl) -9H-purin-6-yl ] amine

A mixture of (S) -1- ((S) -6-fluoro-3-methyl-3, 4-dihydro-5-oxa-1, 2 a-diazacenaphthen-2-yl) ethylamine (69mg,0.29mmol), 6-chloro-9- (tetrahydropyran-2-yl) -9H-purine (70mg,0.29mmol) and DIPEA (101. mu.L, 0.58mmol) in IPA (1mL) was heated at 100 deg.C for 18H. After cooling to RT, the volatiles were removed under vacuum and the resulting residue was purified by column chromatography (Si-PPC with 0-6%2M NH₃Gradient MeOH in DCM) to give the title compound as a light brown oil (117mg, 92%). LCMS (method J) R _T=2.50min,[M+H]⁺=438

[ (R) -2- (2, 6-difluoro-3-nitrophenoxy) -1-methylethyl ] carbamic acid tert-butyl ester

Diethyl azodicarboxylate (328. mu.L, 2.09mmol) in THF (1mL) was slowly added to a solution of 2, 6-difluoro-3-nitrophenol (243mg,1.39mmol), ((R) -tert-butyl 2-hydroxy-1-methyl-ethyl) carbamate (292mg,1.67mmol), and triphenylphosphine (547mg,2.09mmol) in THF (10mL) at 0 ℃. The solution was stirred at 0 ℃ for 30min, thenAnd (4) concentrating in vacuum. The residue was purified by flash chromatography (Si-PPC, gradient eluted with 0-30% EtOAc in cyclohexane) to give the title compound as a pale yellow oil (333mg, 72%).¹H NMR(CDCl₃,300MHz):δ7.82(1H,ddd,J=13.0,9.4,5.3Hz),7.04(1H,app.td,J=9.4,2.2Hz),4.76(1H,br s),4.23-4.12(2H,m),4.07-3.95(1H,m),1.44(9H,s),1.34(3H,d,J=6.8Hz)

(R) -8-fluoro-3-methyl-5-nitro-3, 4-dihydro-2H-benzo [1, 4-]Oxazines

TFA (3mL) was added to [ (R) -2- (2, 6-difluoro-3-nitrophenoxy) -1-methylethyl]Tert-butyl carbamate (333mg,1.00mmol) in DCM (15mL) and the mixture was stirred at rt for 90 min. PhMe (25mL) was added and the solution was concentrated in vacuo. The resulting residue was taken up in MeCN (7 mL); 2M Na was added₂CO₃Aqueous solution (7mL) and the mixture stirred vigorously at rt for another 90 min. EtOAc (25mL) and brine (25mL) were added and the phases separated. The aqueous layer was extracted with EtOAc (2X 25mL) and the combined organics were dried (Na) ₂SO₄) And concentrated in vacuo. The crude reaction mixture was purified by flash chromatography (Si-PPC, gradient eluted with 0-20% EtOAc in cyclohexane) to afford the title compound as a bright yellow solid (184mg, 87%).¹H NMR(CDCl₃,300MHz):δ7.84(1H,br s),7.79(1H,dd,J=9.8,5.6Hz),6.45(1H,app.t,J=9.8Hz),4.36-4.28(1H,m),3.84-3.76(2H,m),1.35(3H,d,J=6.3Hz)

(R) -8-fluoro-3-methyl-3, 4-dihydro-2H-benzo [1, 4-]Oxazin-5-ylamine

Reacting (R) -8-fluoro-3-methyl-5-nitro-3, 4-dihydro-2H-benzo [1,4 ]]Suspension of oxazine (183mg,0.86mmol) and 10% Pd/C (37mg) in EtOAc (12mL) and IMS (1.2mL) in H₂Stirred under balloon for 16 h. The reaction mixture was filtered over celite and the filtrate was concentrated in vacuo to give the title compound as a pale yellow oil (162mg, quantitative yield).¹H NMR(CDCl₃,300MHz):δ6.36(1H,dd,J=10.6,8.6Hz),6.14(1H,dd,J=8.6,4.6Hz),4.19(1H,dd,J=10.4,2.7Hz),3.65(1H,dd,J=10.4,8.0Hz),3.44(1H,dqd,J=8.0,6.5,2.7Hz),3.13(3H,br s),1.17(3H,d,J=6.5Hz)

[ (S) -1- ((R) -6-fluoro-3-methyl-3, 4-dihydro-5-oxa-1, 2 a-diazacenaphthen-2-yl) ethyl ] carbamic acid tert-butyl ester

Reacting (R) -8-fluoro-3-methyl-3, 4-dihydro-2H-benzo [1,4 ]]Oxazin-5-ylamine (162mg,0.86mmol) was added to a solution of ethyl (S) -2-tert-butoxycarbonylaminopropionimidate (570mg,2.64mmol) in EtOH (10mL) and the reaction was heated at 75 ℃ for 60 min. The reaction mixture was concentrated in vacuo and the residue was taken up in DCM and saturated NaHCO₃Are distributed among the devices. The organic phase was washed with brine and dried (Na)₂SO₄) And concentrated in vacuo. The resulting residue was chromatographed using flash chromatography (Si-PPC, gradient eluted with 0-40% DCM in cyclohexane) to afford the title compound as an off-white foam (188mg, 65%). LCMS (method J) R _T=2.42min,[M+H]⁺=336。

(S) -1- ((R) -6-fluoro-3-methyl-3, 4-dihydro-5-oxa-1, 2 a-diazacenaphthen-2-yl) ethylamine

TFA (1.00mL) was added to [ (S) -1- ((R) -6-fluoro-3-methyl-3, 4-dihydro-5-oxa-1, 2 a-diazacenaphthen-2-yl) ethyl]Tert-butyl carbamate (188mg,0.56mmol) in DCM (4mL) and the reaction stirred at RT for 60 min. The crude reaction mixture was passed through 2gSCX-2 column with 2M NH₃MeOH elution. The basic fraction was concentrated in vacuo to give the title compound (130mg,99%) as a light oil. LCMS (method B) R_T=1.82min,[M+H]⁺=236。

[ (S) -1- ((R) -6-fluoro-3-methyl-3, 4-dihydro-5-oxa-1, 2 a-diazacenaphthen-2-yl) ethyl ] [9- (tetrahydropyran-2-yl) -9H-purin-6-yl ] amine

A mixture of (S) -1- ((R) -6-fluoro-3-methyl-3, 4-dihydro-5-oxa-1, 2 a-diazacenaphthen-2-yl) ethylamine (68mg,0.29mmol), 6-chloro-9- (tetrahydropyran-2-yl) -9H-purine (70mg,0.29mmol) and DIPEA (101. mu.L, 0.58mmol) in IPA (1mL) was heated at 100 deg.C for 18H. After cooling to RT, the volatiles were removed under vacuum and the resulting residue was purified by column chromatography (Si-PPC with 0-6%2M NH₃Gradient MeOH in DCM) to give the title compound as a light brown oil (93mg, 73%). LCMS (method J) R_T=2.39min,[M+H]⁺=438。

1, 3-difluoro-2-methoxy-4-nitrobenzene

To a solution of trifluoroacetic anhydride (26.2mL,0.19mol) in DCM (100mL) was added hydrogen peroxide (50% solution in water, 12.9mL,0.17mol) dropwise at 0 deg.C and the reaction mixture was stirred at 0 deg.C for 1.5 h. 2, 4-difluoro-3-methoxyphenylamine (3g,18.9mmol) was added as a solution in DCM (20mL) and the reaction mixture was stirred at RT for 3 h. The reaction mixture was diluted with brine and extracted with DCM (3 × 30 mL). The combined organic fractions were washed with saturated NaHCO₃Washed with aqueous solution and dried (MgSO)₄) And concentrated in vacuo. The residue obtained is treated by flash chromatography (SiO)₂With 0-100% Et₂O in cyclohexane) to give the title compound as a colorless solid (2.03g, 57%).¹H NMR400MHzδ(CDCl₃):7.83-7.76(1H,m),7.03(1H,td,J=9.4,2.5Hz),4.08(3H,t,J=1.1Hz)。

(3-fluoro-2-methoxy-6-nitrophenyl) phenylamine

A solution of 1, 3-difluoro-2-methoxy-4-nitrobenzene (1g,5.29mmol) and aniline (0.53mL,5.82mmol) in DMSO (10mL) was heated at 100 ℃ for 4 h. The reaction mixture was diluted with water and the product was extracted with EtOAc (3X 15 mL). The combined organic extracts were washed with brine and dried (MgSO)₄) And concentrated in vacuo. The residue obtained is treated by flash chromatography (SiO)₂Using 0-50% Et₂O in cyclohexane) to give the title compound as an off-white solid (1.05g, 76%). ¹H NMR400MHzδ(CDCl₃):8.82(1H,br s),7.96(1H,dd,J=9.5,5.3Hz),7.32-7.26(2H,m),7.12-7.07(1H,m),7.02-6.98(2H,m),6.74(1H,t,J=9.5Hz),3.53(3H,d,J=1.1Hz)。

4-fluoro-3-methoxy-N²-phenyl-1, 2-diamines

To a solution of (3-fluoro-2-methoxy-6-nitrophenyl) phenylamine (322mg,1.2mmol) in EtOAc (5mL) was added palladium on carbon (30mg,10% by weight) and the reaction mixture was stirred at RT for 4 hours under a hydrogen atmosphere. The reaction mixture was filtered and the filtrate was concentrated in vacuo to give the title compound as a white solid which darkened to red upon standing (284mg, 100%).¹H NMR400MHzδ(CDCl₃):7.24-7.18(2H,m),6.88-6.78(2H,m),6.71-6.66(2H,m),6.43(1H,dd,J=9.0,4.5Hz),5.50(1H,br s),3.77(3H,d,J=1.7Hz),3.64(2H,br s)。

[ (S) -1- (6-fluoro-7-methoxy-1-phenyl-1H-benzimidazol-2-yl) ethyl ] -carbamic acid tert-butyl ester

To a suspension of tert-butyl ((S) -1-carbamoylethyl) carbamate (779mg,4.1mmol) in DCM (5mL) was added triethyloxyTetrafluoroborate (671mg,3.5mmol) and the reaction mixture was stirred at RT for 2 hours during which time the solid dissolved. The reaction mixture was concentrated in vacuo and the residue was dissolved in ethanol (5 mL). Adding 4-fluoro-3-methoxy-N²-phenyl-1, 2-diamine (283mg,1.2mmol), and the reaction was heated at 70 ℃ for 1.5 h. The reaction mixture was concentrated in vacuo, the residue was dissolved in water and the product was extracted with EtOAc (3X 20 mL). The combined organic extracts were washed with brine and dried (MgSO)₄) And concentrated in vacuo. The residue obtained is treated by flash chromatography (SiO) ₂Eluting with 0-100% EtOAc in cyclohexane) to give the title compound as a white solid (349mg, 74%). LCMS (method C) R_T=3.52min,[M+H]+=386。

(S) -1- (6-fluoro-7-methoxy-1-phenyl-1H-benzimidazol-2-yl) ethylamine dihydrochloride

Reacting [ (S) -1- (6-fluoro-7-methoxy-1-phenyl-1H-benzimidazol-2-yl) ethyl]Tert-butyl carbamate (349mg,0.91mmol) was dissolved in methanol (1mL) and a dioxane solution of hydrochloric acid (3mL,4M) and the reaction was stirred at RT for 1 h. The reaction mixture was concentrated in vacuo to give the title compound as an off-white solid (321mg, 100%). LCMS (method C) R_T=2.02min,[M+H]+=286。

(2, 6-difluoro-3-nitrophenyl) acetonitrile

To a solution of (2, 6-difluorophenyl) acetonitrile (5g,32.7mmol) in concentrated sulfuric acid (15mL) at-78 deg.C was added dropwise a solution of nitric acid (65%,2.25mL,32.7mmol) in concentrated sulfuric acid (5 mL). Upon complete addition, the reaction mixture was poured onto ice and the precipitate formed was collected by filtration, washed with water and dried in vacuo to give the title product as a white solid (6.4g, 100%).¹H NMR400MHzδ(CDCl₃):8.24-8.16(1H,m),7.17(1H,ddd,J=9.6,7.8,1.9Hz),3.84(2H,t,J=1.2Hz)。

(6-fluoro-3-nitro-2-phenylaminophenyl) acetonitrile

The reaction mixture was stirred with (2, 6-difluoro-3-nitrophenyl) acetonitrile (4g,20.1mmol) and anilineA solution of (1.83mL,20.1mmol) in DMSO (20mL) was heated at 100 ℃ for 16 h. The reaction mixture was diluted with water (100mL) and extracted with EtOAc (3X 20 mL). The combined organic extracts were washed with brine and dried (MgSO) ₄) And concentrated in vacuo. The residue obtained is treated by flash chromatography (SiO)₂Eluting with 0-100% EtOAc in cyclohexane) to give the title compound as a brown oil (959mg, 18%).¹H NMR400MHzδ(CDCl₃):8.27(1H,dd,J=9.4,5.9Hz),7.38-7.32(2H,m),7.17-7.12(1H,m),6.98-6.90(3H,m),3.44(2H,d,J=1.7Hz)。

(3-amino-6-fluoro-2-phenylaminophenyl) acetonitrile

(6-fluoro-3-nitro-2-phenylaminophenyl) acetonitrile (463mg,1.70mmol), iron powder (194mg,3.41mmol) and ammonium chloride (263mg,5.12mmol) were heated in methanol (10mL) and water (3mL) at 90 ℃ for 1 h. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was dissolved in water and extracted with EtOAc (3X 20 mL). The combined organic extracts were washed with brine and dried (MgSO)₄) And concentrated in vacuo. The residue obtained is treated by flash chromatography (SiO)₂Eluting with 0-100% EtOAc in cyclohexane) to give the title compound as a brown solid (228mg, 55%).¹H NMR400MHzδ(CDCl₃):7.23-7.17(2H,m),6.95(1H,t,J=8.9Hz),6.83(1H,tt,J=7.4,1.0Hz),6.77(1H,dd,J=8.9,5.5Hz),6.61-6.56(2H,m),5.12(1H,br s),3.79(2H,br s),3.59(2H,d,J=1.2Hz)。

[2- ((S) -1-aminoethyl) -5-fluoro-3-phenyl-3H-benzimidazol-4-yl ] acetonitrile dihydrochloride

To ((S) -1-carbamoylethyl) aminoTo a suspension of tert-butyl formate (435mg,2.31mmol) in DCM (5mL) was added triethyl oxideTetrafluoroborate (369mg,1.94mmol) and the reaction mixture was stirred at RT for 2 hours, during which time the solid dissolved. The reaction mixture was concentrated in vacuo and the residue was dissolved in ethanol (5 mL). (3-amino-6-fluoro-2-phenylaminophenyl) acetonitrile (223mg,0.92mmol) was added and the reaction was heated at 70 ℃ for 1 h. The reaction mixture was concentrated in vacuo, the residue was dissolved in water and the product was extracted with EtOAc (3 × 20 mL). The combined organic extracts were washed with brine and dried (MgSO) ₄) And concentrated in vacuo. The residue obtained is treated by flash chromatography (SiO)₂Eluted with 0-100% EtOAc in cyclohexane) LCMS (method C): RT =3.36min, [ M + H ]]+ = 395. Dissolving the product in HCl IITo an alkane solution (4N,10mL), the reaction was stirred at RT for 1 h. The reaction mixture was concentrated in vacuo to give the title product as an off-white solid (227mg, 67%). LCMS (method C) R_T=1.88min,[M+H]+=295。

6-fluoro-2- (5-fluoropyridin-3-ylamino) -3-nitrobenzonitrile

To a solution of 5-fluoropyridin-3-ylamine (1.22g,10.9mmol) in THF (30mL) at 0 deg.C was added potassium tert-butoxide (2.43g,21.7mmol) and the reaction mixture was stirred at 0 deg.C for 10 min. This solution was added via cannula to a solution of 2, 6-difluoro-3-nitrobenzonitrile (2g,10.9mmol) in THF (20mL) at-78 deg.C and the dark purple reaction mixture was stirred at-78 deg.C for 10 min. The reaction mixture was diluted with water and extracted with EtOAc (3X 30 mL). The combined organic fractions were washed with brine and dried (MgSO)₄) And (4) concentrating in vacuum. The residue obtained is treated by flash chromatography (SiO)₂Eluted with 0-100% EtOAc in cyclohexane). The resulting solid was triturated with pentane to give the title compound as an orange solid (1.73g, 58%).¹H NMR400MHzδ(CDCl₃):9.73(1H,br s),8.53(1H,dd,J=9.5,5.7Hz),8.47(1H,d,J=2.5Hz),8.43-8.40(1H,m),7.33(1H,dt,J=8.8,2.2Hz),6.83(1H,dd,J=9.5,7.3Hz)。

3-amino-6-fluoro-2- (5-fluoropyridin-3-ylamino) benzonitrile

(6-fluoro-2- (5-fluoropyridin-3-ylamino) -3-nitrobenzonitrile (1.73g,6.26mmol), iron powder (712mg,12.5mmol) and ammonium chloride (966mg,18.8mmol) were heated in methanol (40mL) and water (12mL) at 90 ℃ for 1 h. the reaction mixture was filtered and the filtrate concentrated in vacuo, the residue was dissolved in water and extracted with EtOAc (3X 20 mL). the combined organic extracts were washed with brine, dried (MgSO)₄) And concentrated in vacuo. The residue obtained is treated by flash chromatography (SiO)₂Eluting with 0-100% EtOAc in cyclohexane) to give the title compound as a brown solid (948mg, 61%).¹H NMR400MHzδ(CDCl₃):8.05(1H,d,J=2.4Hz),8.03-7.99(1H,m),7.01(1H,d,J=2.1Hz),6.99(1H,s),6.59(1H,dt,J=10.2,2.4Hz),5.78(1H,br s),3.84(2H,br s)。

{ (S) -1- [ 7-cyano-6-fluoro-1- (5-fluoropyridin-3-yl) -1H-benzimidazol-2-yl ] -ethyl } carbamic acid tert-butyl ester

To a suspension of tert-butyl ((S) -1-carbamoyl-ethyl) carbamate (1.81g,9.63mmol) in DCM (20mL) was added triethyloxyTetrafluoroborate (1.54g,8.08mmol) and the reaction mixture was stirred at RT for 2 hours during which time the solid dissolved. The reaction mixture was concentrated in vacuo and the residue was dissolved in ethanol (20 mL). 3-amino-6-fluoro-2- (5-fluoropyridin-3-ylamino) benzonitrile (948mg,3.86mmol) was added and the reaction was heated at 70 ℃ for 1 h. The reaction mixture was concentrated in vacuo, the residue was dissolved in water and the product was extracted with EtOAc (3X 20 mL). The combined organic extracts were washed with brine and dried (MgSO) ₄) And concentrated in vacuo. The residue obtained is treated by flash chromatography (SiO)₂Eluting with 0-100% EtOAc in cyclohexane) to give the title compound as an off-white solid. LCMS (method C) R_T=3.20min,[M+H-^tBu]+=344,100%,[M+H]+=400,10%。

2, 6-difluorobenzyl acetate

Acetyl chloride (1.13mL,15.8mmol) was added dropwise to a solution of 2, 6-difluorobenzyl alcohol (1.76g,12.2mmol) and triethylamine (3.43mL,24.4mmol) in DCM (20mL) at 0 deg.C. The reaction mixture was stirred at 0 ℃ for 30 min. The reaction mixture was diluted with water and extracted with DCM (3 × 20 mL). The combined organic fractions were washed with brine and dried (MgSO)₄) And concentrated in vacuo. The residue obtained is treated by flash chromatography (SiO)₂Eluting with 0-100% EtOAc in cyclohexane) to give the title compound as a colorless oil (1.72g, 76%).¹H NMR400MHzδ(CDCl₃):7.37-7.28(1H,m),6.96-6.88(2H,m),5.20(2H,s),2.08(3H,s)。

2, 6-difluoro-3-nitrobenzyl acetate

At 0 deg.C, adding 2, 6-di-acetic acidFluorobenzyl ester (8g,42.9mmol) was added dropwise to fuming nitric acid (50mL) and the reaction mixture was stirred at 0 deg.C for 30 min. The reaction mixture was poured onto ice and the product was extracted with DCM (3 × 30 mL). The combined organic fractions were washed with saturated NaHCO₃The aqueous solution was then washed with brine and dried (MgSO)₄) And concentrated in vacuo to give the title compound as a yellow oil (8.69g, 87%). ¹H NMR300MHzδ(CDCl₃):8.21-8.12(1H,m),7.09(1H,ddd,J=9.6,7.9,1.9Hz),5.24(2H,t,J=1.5Hz),2.10(3H,s)。

Acetic acid 6-fluoro-3-nitro-2-phenylaminobenzyl ester

A solution of 2, 6-difluoro-3-nitrobenzyl acetate (3g,12.9mmol) and aniline (1.5mL,16.9mmol) in DMSO (10mL) was heated at 100 ℃ for 16 h. The reaction mixture was diluted with water and extracted with EtOAc (3X 15 mL). The combined organic fractions were washed with brine and dried (MgSO)₄) And concentrated in vacuo. The residue obtained is treated by flash chromatography (SiO)₂Eluting with 0-100% EtOAc in cyclohexane) to give the title compound as a brown oil (3.2g, 81%).¹H NMR400MHzδ(CDCl₃):8.21(1H,dd,J=9.4,5.9Hz),7.30-7.24(2H,m),7.10-7.04(1H,m),6.97-6.92(2H,m),6.83(1H,dd,J=9.3,8.4),4.93(2H,d,J=2.0Hz),1.94(3H,s)

Acetic acid 3-amino-6-fluoro-2-phenylaminobenzyl ester

To a solution of 6-fluoro-3-nitro-2-phenylaminobenzyl acetate (3.2g,10.5mmol) in EtOAc (50mL) was added palladium on carbon (600mg,10% by weight) and the reaction mixture was stirred at RT under a hydrogen atmosphere for 16 h. The reaction mixture was filtered and concentrated under vacuumAnd (4) liquid. The residue obtained is treated by flash chromatography (SiO)₂Eluting with 0-100% DCM in cyclohexane) to give the title compound as a brown solid (2.3mg, 80%).¹H NMR400MHzδ(CDCl₃):7.22-7.15(2H,m),6.86(1H,t,J=8.9Hz),6.81(1H,tt,J=7.4,1.0Hz),6.78-6.71(1H,m),6.63-6.58(2H,m),6.43(1H,br s),5.10(2H,d,J=1.9Hz),3.72(2H,br s),1.99(3H,s)。

Acetic acid 2- ((S) -1-tert-butoxycarbonylaminoethyl) -5-fluoro-3-phenyl-3H-benzimidazol-4-ylmethyl ester

To a suspension of tert-butyl (S) -1-carbamoylethyl) carbamate (3.94g,20.9mmol) in DCM (20mL) was added triethyloxy Tetrafluoroborate (3.35)_g17.6mmol) and the reaction mixture was stirred at RT for 2 hours, during which time the solid dissolved. The reaction mixture was concentrated in vacuo and the residue was dissolved in ethanol (20 mL). 3-amino-6-fluoro-2-phenylaminobenzyl acetate (2.3g,8.38mmol) was added and the reaction was heated at 75 ℃ for 1 h. The reaction mixture was concentrated in vacuo, the residue was dissolved in water and the product was extracted with EtOAc (3 × 20 mL). The combined organic extracts were washed with brine and dried (MgSO)₄) And concentrated in vacuo. The residue obtained is treated by flash chromatography (SiO)₂Eluting with 0-100% EtOAc in cyclohexane) to give the title compound as an off-white solid. LCMS (method C) R_T=3.37min,[M+H-^tBu]+=372,100%,[M+H]+=428,40%。

[2- ((S) -1-aminoethyl) -5-fluoro-3-phenyl-3H-benzimidazol-4-yl ] -methanol dihydrochloride

To a solution of acetic acid 2- ((S) -1-tert-butoxycarbonylaminoethyl) -5-fluoro-3-phenyl-3H-benzimidazol-4-ylmethyl ester (190mg,0.44mmol) in methanol (2mL) was added a dioxane solution of HCl (4N,5mL) and the reaction was stirred at RT for 2H. The reaction mixture was concentrated in vacuo to give the title compound as a beige solid (159mg, 100%). LCMS (method C) R_T=1.61min,[M+H]+=372。

4-amino-6- [ (S) -1- [1- (cis-3-benzyloxycyclobutyl) -6-fluoro-1H-benzimidazol-2-yl ] ethylamino ] -pyrimidine-5-carbonitrile

Reacting (S) -1- [1- (cis-3-benzyloxy-cyclobutyl) -6-fluoro-1H-benzimidazol-2-yl]A mixture of ethylamine (50mg,0.15mmol), 4-amino-6-chloropyrimidine-5-carbonitrile (23mg,0.15mmol), and DIPEA (0.13mL,0.74mmol) in IPA (3mL) was heated at 90 deg.C for 16h in a sealed vial. After cooling to RT, the reaction mixture was concentrated in vacuo, dissolved in DCM and loaded into DCMSCX-2 column, which is washed with DCM, then with MeOH, then with 2M NH₃Washing with MeOH. The product containing fractions were combined and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC with 0-5%2M NH)₃Gradient MeOH in DCM) to give the title compound as a colorless glassy solid (50mg, 75%). LCMS (method B) R_T3.11min[M+H]⁺458。110185004

2- (2, 6-difluoro-3-nitrophenyl) pyridine

Will be located at two2-Tributylstannylpyridine (4.24g,12mmol), 2-bromo-1, 3-difluoro-4-nitrobenzene (2.5g,10mmol) and Pd (PPh) in an alkane (20mL)₃)₄(605mg,0.5mmol) was placed in a microwave vial. The sealed vial was evacuated and purged with argon (x 3). The resulting mixture was heated under microwave irradiation at 150 ℃ for 1.5 h. The cooled mixture was evaporated, the residue suspended in DCM and the resulting mixture filtered to remove insoluble material. The filtrate was concentrated in vacuo and the resulting residue was purified by chromatography (Si-PPC, eluting with a 0-50% EtOAc/cyclohexane gradient) to give the title compound as a bright orange solid (0.8g, 33%). ¹H NMR(CDCl₃,400MHz):δ8.79(1H,ddd,J=6.5,2.4,1.3Hz),8.18(1H,ddd,J=12.4,10.8,7.4Hz),7.86(1H,td,J=10.4,2.4Hz),7.51(1H,dquin,J=10.5,1.6Hz),7.41(1H,ddd,J=10.2,6.5,1.5Hz),7.16(1H,ddd,J=13.3,10.8,2.5Hz)

(3-fluoro-6-nitro-2-pyridin-2-yl-phenyl) isopropylamine

A mixture of 2- (2, 6-difluoro-3-nitrophenyl) pyridine (0.85g,3.6mmol), isopropylamine (0.31mL,3.6mmol) and DIPEA (0.63mL,3.6mmol) in acetonitrile (10mL) was stirred at RT overnight. The mixture was concentrated in vacuo and the resulting residue was purified by chromatography (Si-PPC, eluting with a 0-50% EtOAc/cyclohexane gradient) to give the title compound as a yellow oil (0.49g, 50%).¹H NMR(CDCl₃,400MHz):δ8.76(1H,ddd,J=6.5,3.7,2.4Hz),8.26(1H,dd,J=12.7,8.1Hz),7.86(1H,br s),7.81(1H,td,J=10.4,2.5Hz),7.46(1H,dq,J=10.5,1.5Hz),7.34(1H,ddd,J=10.2,6.5,1.6Hz),6.57(1H,dd,J=12.7,10.8Hz),2.70-2.54(1H,m),0.93(6H,d,J=8.4Hz)

4-fluoro-N²-isopropyl-3-pyridin-2-yl-benzene-1, 2-diAmines as pesticides

(3-fluoro-6-nitro-2-pyridin-2-yl-phenyl) isopropylamine (0.49g,1.79mmol) was dissolved in EtOAc (10 mL). The flask was evacuated and charged with N₂And (5) purifying. Pd/C (10%) was added and the mixture was brought to atmospheric pressure under H₂The hydrogenation is carried out under an atmosphere. The mixture was stirred overnight. The flask was evacuated and charged with N₂And (5) purifying. The catalyst was removed by filtration and the filtrate was concentrated in vacuo and the resulting residue was purified by chromatography (Si-PPC, eluting with a 0-50% EtOAc/cyclohexane gradient) to give the title compound as a yellow oil (0.47g, 99%).¹H NMR(CDCl₃,400MHz):δ8.71(1H,ddd,J=6.6,2.4,1.3Hz),7.78(1H,ddd,J=10.6,10.2,2.5Hz),7.57(1H,ddt,J=10.6,5.2,1.4Hz),7.26(1H,ddd,J=10.0,6.6,1.6Hz),6.76-6.66(2H,m),5.34(1H,br s),3.80(2H,br s),3.19(1H,sept,J=8.5Hz),7.63(6H,d,J=8.5Hz)

(S) -1- (4-fluoro-2-isopropylamino-3-pyridin-2-yl-phenylcarbamoyl) ethyl ] carbamic acid tert-butyl ester

Reacting 4-fluoro-N²A solution of-isopropyl-3-pyridin-2-yl-benzene-1, 2-diamine (0.47g,1.91mmol), Boc-alanine (0.4g,2.1mmol), HOAt (0.29g,2.1mmol) in DCM (15mL) was cooled to 0 ℃. EDC (0.40g,2.1mmol) was added portionwise and the resulting mixture was stirred for 1 h. The mixture was diluted with DCM (20mL), the organic layer was washed with citric acid, brine, dried (MgSO) ₄) And evaporated. The resulting residue was purified by chromatography (Si-PPC, eluting with a gradient of 0-50% EtOAc in cyclohexane) to give the title compound as a colorless oil (0.7g, 88%). LCMS (method K) R_T3.10min[M+H]⁺417

[ (S) -1- (6-fluoro-1-isopropyl-7-pyridin-2-yl-1H-benzimidazol-2-yl) ethyl ] carbamic acid tert-butyl ester

Reacting (S) -1- (4-fluoro-2-isopropylamino-3-pyridin-2-yl-phenylcarbamoyl) ethyl]Tert-butyl carbamate (0.7g) was dissolved in AcOH (10mL) and the resulting solution was heated at 70 ℃ overnight. The cooled mixture was evaporated, the residue was dissolved in DCM and the organic layer was washed with NaHCO₃Washed with brine and dried (MgSO)₄) And evaporated to give the title compound as a yellow solid (0.6g, 89%).¹H NMR(CDCl₃,400MHz):δ8.78(1H,ddd,J=6.5,2.4,1.2Hz),7.87(1H,td,J=10.3,2.4Hz),7.70(1H,dd J=11.8,6.4Hz),7.56(1H,dq,J=10.4,1.5Hz),7.41(1H,ddd,J=10.2,6.6,1.6Hz),7.09(1H,dd,J=13.4,11.8Hz),6.45(1H,d,J=12.6Hz),5.38-5.26(1H,m),4.02(1H,sept,J=9.2Hz),1.59(3H,d,J=9.1Hz),1.48-1.35(15H,m)

(S) -1- (6-fluoro-1-isopropyl-7-pyridin-2-yl-1H-benzimidazol-2-yl) ethylamine

Reacting [ (S) -1- (6-fluoro-1-isopropyl-7-pyridin-2-yl-1H-benzimidazol-2-yl) ethyl]Tert-butyl carbamate (0.6g,1.5mmol) was dissolved in 20% TFA in DCM (10 mL). The resulting solution was stirred for 1h, then the mixture was passed through an SCX column. The column was washed with DCM and MeOH to remove non-basic impurities, then 2M NH₃MeOH to elute the product. The product fractions were concentrated to give a yellow solid (0.34g, 76%). ¹H NMR(CDCl₃,400MHz):δ8.77(1H,d,J=6.1Hz),7.85(1H,td,J=10.5,2.4Hz),7.69(1H,dd,J=11.4,6.4Hz),7.57(1H,d,J=10.8Hz),7.38(1H,dd,J=9.8,6.9Hz),7.07(1H,dd,J=13.7,11.6Hz),4.35(1H,q,J=8.7Hz),4.03(1H,sept,J=9.3Hz),1.60(3H,d,J=8.8Hz),1.40-1.29(6H,m)

(3-fluoro-6-nitro-2-pyridin-2-yl-phenyl) methylamine

A mixture of 2- (2, 6-difluoro-3-nitrophenyl) pyridine (1.0g,4.2mmol), methylamine (2.24mL,4.24mmol,2M in THF), and DIPEA (0.75mL,4.2mmol) in acetonitrile (10mL) was stirred at RT overnight. The mixture was concentrated in vacuo and the resulting residue was purified by chromatography (Si-PPC, eluting with a 0-40% EtOAc/cyclohexane gradient) to give the title compound as a yellow solid (0.89g, 84%).¹H NMR(CDCl₃,400MHz):δ8.74(1H,ddd,5.0,2.1,1.0Hz)8.46(1H,br s)8.27(1H,dd,9.5,6.2Hz),7.80(1H,td,7.8,2.1Hz),7.47(1H,dq,4.0,1.2Hz),7.34(1H,dd,9.5,8.2Hz),2.36(3H,d,5.3Hz)

4-fluoro-N²-methyl-3-pyridin-2-yl-benzene-1, 2-diamine

(3-fluoro-6-nitro-2-pyridin-2-yl-phenyl) methylamine (0.89g,3.59mmol) was dissolved in EtOAc (15 mL). The flask was evacuated and charged with N₂And (5) purifying. Pd/C (180mg,10%) was added and the mixture was brought to atmospheric pressure with H₂And (4) hydrogenation. The mixture was stirred overnight. The flask was evacuated and charged with N₂And (5) purifying. The catalyst was removed by filtration, the filtrate was concentrated in vacuo and the resulting residue was purified by chromatography (Si-PPC, eluting with a 0-50% EtOAc/cyclohexane gradient) to give the title compound as a yellow oil (0.75g, 96%).¹H NMR(CDCl₃,400MHz):δ8.70(1H,ddd,5.0,1.9,1.0Hz),7.78(1H,td,7.8,1.9Hz),7.59(1H,ddt,7.9,3.6,1.1Hz),7.27(1H,ddd,7.6,4.9,1.2Hz),6.72(1H,d,1.1),6.70(1H,s),5.10(1H,s),3.82(2H,s),2.44(3H,s)

[ (S) -1- (6-fluoro-1-methyl-7-pyridin-2-yl-1H-benzimidazol-2-yl) ethyl ] carbamic acid tert-butyl ester

Reacting 4-fluoro-N²A solution of-methyl-3-pyridin-2-yl-benzene-1, 2-diamine (0.75g,3.44mmol), Boc-Ala (0.72g,3.78mmol), HOAt (0.52g,3.78mmol) in DCM (10mL) was cooled to 0 ℃. EDC (0.73g,3.78mmol) was added portionwise and the resulting mixture was stirred for 1 h. The mixture was diluted with DCM (20mL), the organic layer was washed with citric acid, brine, dried (MgSO) ₄) And evaporated. The resulting residue was purified by chromatography (Si-PPC, eluting with a gradient of 0-50% EtOAc/cyclohexane) to give the title compound as a white solid (0.3g, 24%). LCMS (method J) R_T2.42min[M+H]⁺371

(S) -1- (6-fluoro-1-methyl-7-pyridin-2-yl-1H-benzimidazol-2-yl) ethylamine

Reacting [ (S) -1- (6-fluoro-1-methyl-7-pyridin-2-yl-1H-benzimidazol-2-yl) ethyl]Tert-butyl carbamate (0.3g,0.81mmol) was dissolved in 20% TFA in DCM (10 mL). The resulting solution was stirred for 1h, then the mixture was passed through an SCX column. Wash column with DCM, MeOH, 2M NH₃MeOH to elute the product. The product fractions were concentrated to give a yellow solid (0.2g, 92%). LCMS (method J) R_T1.39min[M+H]⁺271

Ethyl- (3-fluoro-6-nitro-2-pyridin-2-yl-phenyl) amine

2- (2, 6-difluoro-3-nitrophenyl) pyridine (1.00g,4.29mmol), ethylamine (2.24mL,4.29mmol), then DIPEA (0.75mL,4.29mmol) were added to acetonitrile (10mL) and the resulting mixture was stirred at 20 ℃ under a nitrogen atmosphere for 40 hours. The mixture was concentrated in vacuo and the residue was purified by silica gel chromatography (Si-PPC, eluting with a 0-50% EtOAc/cyclohexane gradient) to give the title compound as a yellow oil (1.00g, 90%).¹H NMR(CDCl₃)δ:8.73(1H,ddd,J=6.6,2.4,1.3Hz),8.28(1H,dd,J=12.6,8.1Hz),7.80(1H,td,J=10.3,2.4Hz),7.45(1H,dq,J=10.4,1.6Hz),7.33(1H,ddd,J=10.1,6.5,1.6Hz),6.51(1H,dd,J=12.7,10.9Hz),2.54-2.44(2H,m),1.03(3H,t,J=9.6Hz)

N²-ethyl-4-fluoro-3-pyridin-2-yl-benzene-1, 2-diamine

A mixture of ethyl- (3-fluoro-6-nitro-2-pyridin-2-yl-phenyl) amine (1.00g,3.82mmol) and 10% palladium on carbon (0.10g) in ethyl acetate (15mL) was stirred under an atmosphere of hydrogen, atmospheric pressure and at 20 ℃ for 3 days. The catalyst was removed by filtration and the resulting solution was concentrated in vacuo. The residue was purified by silica gel chromatography (Si-PPC, eluting with a 0-100% EtOAc/cyclohexane gradient) to give the title compound as a yellow oil (0.61g, 69%).¹H NMR(CDCl₃)δ:8.71(1H,ddd,J=6.6,2.5,1.3Hz),7.78(1H,ddd,J=10.5,10.1,2.5Hz),7.58(1H,ddt,J=10.6,5.0,1.4Hz),7.27(1H,ddd,J=10.0,6.5,1.6Hz),6.76-6.66(2H,m),5.24(1H,br s),3.82(2H,br s),2.76(2H,t,J=9.5Hz),0.82(3H,t,J=9.5Hz)

[ (S) -1- (1-Ethyl-6-fluoro-7-pyridin-2-yl-1H-benzimidazol-2-yl) ethyl ] carbamic acid tert-butyl ester

Will N²-Ethyl-4-fluoro-3-pyridin-2-yl-benzene-1, 2-diamine (0.61g,2,63mmol) was dissolved in DCM (10mL) and then (S) - (2-tert-butoxycarbonylamino) propionic acid (0.55g,2.89mmol) and 1-hydroxy-7-azabenzotriazole (0.40g,2.89mmol) were added. The mixture was cooled to 0 ℃ and EDCI (1.54g,8.13mmol) was added and the resulting mixture was stirred at 0 ℃ for 1 hour under a nitrogen atmosphere. The mixture was diluted with DCM (40mL), the solution was washed with 10% aqueous citric acid and then brine. The organic solution was dried (MgSO₄) And concentrated in vacuo. The residue was purified by silica gel chromatography (Si-PPC, eluting with a 0-50% EtOAc/cyclohexane gradient) to give the title compound as a yellow oil (0.65g, 65%). LCMS (method J) R _T1.88min[M+H]⁺385.3

(S) -1- (1-ethyl-6-fluoro-7-pyridin-2-yl-1H-benzimidazol-2-yl) ethylamine,

reacting [ (S) -1- (1-ethyl-6-fluoro-7-pyridin-2-yl-1H-benzimidazol-2-yl) ethyl]Tert-butyl carbamate (0.65g,1.7mmol) was added to a solution of 20% TFA in DCM (10mL) and the resulting solution was stirred at 20 ℃ for 1 h. The reaction mixture was concentrated in vacuo and the residue was loaded intoSCX-2 column, wash it with MeOH, 2M NH₃The product was eluted with MeOH and then concentrated in vacuo to give the title compound as a pale yellow gum (0.42g, 88%). LCMS (method B) R_T1.65min[M+H]⁺285.1

(3-Cyanocyclobutyl) carbamic acid tert-butyl ester

Sodium cyanide (0.29g,5.9mmol) was added to a solution of methanesulfonic acid (3-tert-butoxycarbonylamino) cyclobutyl ester (1.05g,3.9mmol) in DMF (5mL) and the resulting mixture was stirred at 85 ℃ under nitrogen for 24 h. Additional sodium cyanide (0.38g,7.8mmol) was added and the mixture was stirred at 85 ℃ under nitrogen for 24 hours. The cooled reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water (2 ×) and brine, then concentrated in vacuo. The residue was purified by silica gel chromatography (Si-PPC; 0-50% elution with ethyl acetate in cyclohexane) to give the title compound as a white solid (0.45g,72%)

3-aminocyclobutanecarbonitrile

Tert-butyl (3-cyanocyclobutyl) carbamate (0.45g,2.3mmol) was added to a solution of 20% TFA in DCM (5mL) and the resulting solution was stirred at 20 ℃ for 1 h. The reaction mixture was concentrated in vacuo and the residue was loaded intoSCX-2 column, which was washed with DCM and MeOH, then 2M NH₃The product was eluted with MeOH and then concentrated in vacuo to give the title compound as a light yellow oil (0.238g, 100%).¹H NMR(CDCl₃)δ:3.79-3.93(1H,m),2.94-3.07(1H,m),2.55-2.69(2H,m),2.04-2.18(2H,m),1.42-1.57(2H,br s)

3- (5-fluoro-2-nitrophenylamino) cyclobutanecarbonitrile

2, 4-difluoro-1-nitrobenzene (0.38g,2.4 mmol)) 3-aminocyclobutanecarbonitrile (0.23g,2.4mmol), then DIPEA (0.425mL,2.4mmol) was added to acetonitrile (10mL) and the resulting mixture was stirred at 20 ℃ under a nitrogen atmosphere for 16 h. The mixture was concentrated in vacuo and the residue was purified by silica gel chromatography (Si-PPC; 0-50% elution with ethyl acetate in cyclohexane) to give the title compound as a yellow solid (0.38g, 68%).¹H NMR(CDCl₃)δ:8.23(1H,dd,J=9.2,5.8Hz),8.20(1H,br s),6.41-6.49(1H,m),6.29(1H,dd,J=11.0,2.7Hz),4.30-4.43(1H,m),3.20-3.31(1H,m),2.87-2.98(2H,m),2.42-2.55(2H,m)

3- (2-amino-5-fluorophenylamino) cyclobutanecarbonitrile

A mixture of 3- (5-fluoro-2-nitrophenylamino) cyclobutanecarbonitrile (0.38g,1.61mmol), iron powder (0.36g,6.44mmol), and ammonium chloride (0.50g,9.66mmol) in methanol (10mL) and water (4mL) was stirred at 90 ℃ for 2 hours. After cooling, the solid material was filtered off and the solution was concentrated in vacuo. The residue was partitioned between ethyl acetate (3X) and water, then the combined organic layers were washed with brine, dried (Na) ₂SO₄) And concentrated in vacuo to give the title compound as a dark green gum (0.26g, 79%). LCMS (method B) R_T1.75min[M+H]⁺206.0

{ (S) -1- [2- (3-Cyanocyclobutylamino) -4-fluorophenylcarbamoyl ] ethyl } carbamic acid tert-butyl ester

3- (2-amino-5-fluorophenylamino) cyclobutanecarbonitrile (0.0.26g,1.27mmol) was dissolved in DCM (10mL), followed by addition of (S) - (2-tert-butoxycarbonylamino) propionic acid (0.265g,1.39mmol) and 1-hydroxy-7-azabenzotriazole (0.19g,1.39 m)mol). The mixture was cooled to 0 ℃ and EDCI (0.267g,1.39mmol) was added and the resulting mixture was stirred at 0 ℃ for 1 hour under a nitrogen atmosphere. The mixture was diluted with DCM (20mL), washed with 10% aqueous citric acid and then brine. The organic solution was dried (MgSO₄) And concentrated in vacuo. The residue was purified by silica gel chromatography (Si-PPC; 0-60% elution with ethyl acetate in cyclohexane) to give the title compound as a yellow gum (0.31g, 66%).¹H NMR(CDCl₃)δ:7.46(1H,br s),7.05(1H,dd,J=8.8,6.0Hz),6.36-6.45(1H,m),6.20(1H,dd,J=11.0,2.7Hz),4.89-5.01(1H,m),4.14-4.25(1H,m),3.10-3.24(1H,m),2.71-2.86(2H,m),2.32-2.48(2H,m),1.46(9H,s)

{ (S) -1- [1- (3-cyanocyclobutyl) -6-fluoro-1H-benzimidazol-2-yl ] ethyl } carbamic acid tert-butyl ester

Reacting { (S) -1- [2- (3-cyanocyclobutylamino) -4-fluorophenylcarbamoyl]A solution of tert-butyl-ethyl } carbamate (0.31g,0.83mmol) in acetic acid (5mL) was stirred at 70 ℃ for 16 h, then at 80 ℃ for 8 h. The mixture was concentrated in vacuo and the residue was dissolved in DCM and then saturated NaHCO ₃Washed with aqueous solution and brine, dried (Na)₂SO₄) And concentrated in vacuo. The residue was purified by chromatography (Si-PPC; 0-100% in ethyl acetate in cyclohexane) to give the title compound as a colourless gum (0.21g, 73%). LCMS (method J) R_T2.87min[M+H]⁺358.0

3- [2- ((S) -1-aminoethyl) -6-fluorobenzoimidazol-1-yl ] cyclobutanecarbonitrile

Reacting { (S) -1- [1- (3-cyano)Cyclobutyl) -6-fluoro-1H-benzimidazol-2-yl]Tert-butyl ethyl } carbamate (0.21g,0.586mmol) was added to a solution of 20% TFA in DCM (7mL) and the resulting solution was stirred at 20 ℃ for 1 h. The reaction mixture was concentrated in vacuo and the residue was loaded intoSCX-2 column, which was washed with DCM and MeOH, then 2M NH₃The product was eluted with MeOH and concentrated in vacuo to give the title compound as a colourless solid (0.076g, 51%). LCMS (method J) R_T1.52min[M+H]⁺259

[ (4-fluoro-2-phenylaminophenylcarbamoyl) methyl ] carbamic acid tert-butyl ester

To a mixture of 4-fluoro-2-phenylaminoaniline (3.0g,14.85mmol), tert-butoxycarbonylglycine (2.4g,15mmol) and HOAt (0.68g,5mmol) in DCM (20mL) and DMF (1mL) at 0 deg.C was added EDCI (2.88g,15 mmol). The mixture was stirred at 0 ℃ for 1 h. Adding saturated NaHCO to the reaction mixture ₃Aqueous solution (20mL), Na₂CO₃Saturated aqueous solution (10mL) and water (10 mL). The mixture was extracted with DCM (2X 20mL) and the combined organic layers were dried (Na)₂SO₄) And concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient eluted with 0-8% MeOH in DCM) to give the title compound as a brown gum (4.79g, 89%).¹H NMRδ(ppm)(CHCl₃-d):7.95(1H,s),7.50(1H,dd,J=8.83,5.91Hz),7.32-7.22(2H,m),6.98-6.97(4H,m),6.68(1H,dt,J=8.6,2.7Hz),6.05(1H,s),5.06(1H,s),3.89(2H,d,J=5.92Hz),1.42(9H,s)

(6-fluoro-1-phenyl-1H-benzimidazol-2-ylmethyl) -carbamic acid tert-butyl ester

Reacting [ (4-fluoro-2-phenylaminophenylcarbamoyl) methyl]Tert-butyl carbamate (0.37g,1.03mmol) was taken up in AcOH (10mL) and heated at 70 ℃ for 16 h. After cooling to RT, the volatiles were removed under reduced pressure, the resulting residue was partitioned between EtOAc and water and the mixture was taken over Na₂CO₃Alkalizing. The organic layer was dried (Na)₂SO₄) And concentrated in vacuo. The resulting oil was purified by column chromatography (Si-PCC gradient eluted with 0-60% EtOAc in cyclohexane) to afford the title compound as a white foam (0.265g, 75%). LCMS (method B) R_T3.35min[M+H]⁺342.03

(6-fluoro-1-phenyl-1H-benzimidazol-2-yl) methylamine hydrochloride

Tert-butyl (6-fluoro-1-phenyl-1H-benzimidazol-2-ylmethyl) carbamate (0.265g,0.77mmol) was treated with 4M HCl in dioxane (5mL) at room temperature for 45 min. The reaction was evaporated to dryness and the residue was triturated with ether to give the title product as a white solid (226mg, ca. 100%). LCMS (method B) R _T2.06min[M+H]⁺241.98

(6-fluoro-1-phenyl-1H-benzimidazol-2-ylmethyl) [9- (tetrahydropyran-2-yl) -9H-purin-6-yl ] amine

(6-fluoro-1-phenyl-1H-benzimidazol-2-yl) methylamine hydrochloride (0.113g,0.4mmol), 6-chloro-9- (tetrahydropyran-2-yl) -9H-purine (0.19g,0.8mmol), triethylamine (0.28mL,2mmol) in isopropanol (2mL) was heated to 80 ℃ in a sealed tube for 6H.The reaction mixture was partitioned between DCM and water and the organic layer was dried (Na)₂SO₄) And concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient eluted with 0-3.5% MeOH in DCM) to give the title compound as a colorless gum (0.125g, 70%). LCMS (method B) R_T2.99min[M+H]⁺444.19。

4-chloro-2-methylnicotinonitrile

To 4-methoxy-2-methylnicotinonitrile (Tet6222,2006) (100mg,0.67mmol) in phosphorus oxychloride (2mL) was added phosphorus pentachloride (156mg,0.75 mmol). The mixture was heated to reflux under nitrogen for 15 h. The reaction was quenched with ice, stirred for 10min, then with NaHCO₃Neutralized and extracted with EtOAc. The combined organic extracts were dried (Na)₂SO₄) Evaporated to dryness and purified by column chromatography (Si-PCC, gradient eluted with 0-50% EtOAc in cyclohexane). The product-containing fractions were evaporated to give the title compound as a pale pink solid (35 m) _g,34%)。¹H NMRδ(ppm)(CDCl₃-d):8.56(1H,d,J=5.46Hz),7.32(2H,d,J=5.46Hz),2.81(3H,s)。

A compound of formula I

Example 101N- (1- (3-phenylbenzo [ b ]]Thien-2-yl) ethyl) -9H-purin-6-amine 101

1- (3-Phenylbenzo [ b ] from example 23]A mixture of thiophen-2-yl) ethylamine (160mg,0.63mmol), 6-chloro-9H-purine (98mg,0.63mmol) and DIPEA (0.16mL,0.95mmol) in n-butanol (1.3mL) was stirred in a sealed vial at 120 ℃ for 3 days. After cooling to RT, the crude reaction mixture is loadedOn SCX-2, wash it with MeOH, 2M NH₃The product eluted with MeOH. The product containing fractions were combined, concentrated in vacuo, and the resulting residue was purified by column chromatography (Si-PCC, gradient eluted with 0-6% MeOH in DCM) followed by trituration with EtOAc to give 101(105mg, 45%). LCMS R_T4.33min[M+H]⁺372.1。¹H NMR(DMSO,400MHz):δ8.21(1H,s),8.16-8.10(2H,m),7.92-7.86(1H,m),7.66-7.54(4H,m),7.50-7.44(1H,m),7.37-7.26(3H,m),5.76(1H,s),1.50(3H,d,J=6.94Hz)

Example 102N- (1- (1-phenyl-1H-benzo [ d ]]Imidazol-2-yl) ethyl) -9H-purin-6-amine 102

1- (1-phenyl-1H-benzimidazol-2-yl) ethylamine (211mg,0.89mmol) from example 4 and 6-chloro-9H-purine (137mg,0.89mmol) were placed in a sealed tube with n-butanol (1.7mL) and the solution was heated to 120 ℃ for 48H. The cooled suspension was washed with MeOH/CHCl₃Diluting, and loading the obtained solutionSCX-2 column. The column was washed with MeOH, 2M NH₃The product eluted with MeOH. The product was further purified by column chromatography (Si-PCC, gradient eluted with 0-6% MeOH in DCM) followed by trituration with EtOAc to give racemic 102 as a cream solid (190mg, 60%). LCMS R _T2.99min[M+H]⁺356.2。¹H NMR(DMSO,400MHz):δ8.18-8.07(2H,m),7.94-7.85(1H,m),7.71-7.45(7H,m),7.27-7.17(2H,m),7.11-7.06(1H,m),5.52(1H,br),1.57(3H,d,J=6.83Hz)

Example 103N- (1- (3-phenylbenzofuran-2-yl) ethyl) -9H-purin-6-amine 103

A mixture of 1- (3-phenylbenzofuran-2-yl) ethylamine, example 24(0.706mmol), 6-chloro-9H-purine (213mg,1.38mmol) and DIPEA (0.24mL,1.38mmol) in n-butanol (5mL) was heated at 100 ℃ for 18H. After cooling to RT, the volatiles were removed under reduced pressure and the resulting residue was purified by column chromatography (Si-PCC, gradient eluted with 0-5% MeOH in DCM) followed by trituration with water MeOH to give 103 as an off-white solid (107mg, two steps)Yield 43%). LCMS R_T4.15min[M+H]⁺356.1。¹H NMR(DMSO,400MHz):δ8.21-7.95(3H,m),7.73-7.60(3H,m),7.58-7.49(3H,m),7.46-7.23(3H,m),5.84(1H,s),1.67(3H,d,J=6.99Hz)

Example 104(S) -N- (1- (1-phenyl-1H-benzo [ d ]]Imidazol-2-yl) ethyl) -9H-purine_-6_-Amine 104

Racemic N- (1- (1-phenyl-1H-benzo [ d ] imidazol-2-yl) ethyl) -9H-purin-6-amine 102 was subjected to chiral HPLC separation to give 104.

Example 105(R) -N- (1- (1-phenyl-1H-benzo [ d ]]Imidazol-2-yl) ethyl) -9H-purine_-6_-Amine 105

Racemic N- (1- (1-phenyl-1H-benzo [ d ] imidazol-2-yl) ethyl) -9H-purin-6-amine 102 was subjected to chiral HPLC separation to give 105.

Example 1069- ((1-phenyl-1H-benzo [ d)]Imidazol-2-yl) methyl) -9H-purin-6-amine 106

To a mixture of 9H-purin-6-ylamine (61mg,0.454mmol) in DMF (1mL) was added NaH (60% in mineral oil, 18mg,0.454mmol) and the suspension was stirred at RT under a nitrogen atmosphere for 10 min. 2-bromomethyl-1-phenyl-1H-benzimidazole from example 5 (0.454mmol) in DMF (3mL) was then added and the reaction mixture was stirred at RT for 1H. Loading the crude reaction mixture into SCX-2 column, wash it with MeOH, 2M NH₃The product eluted with MeOH. The product containing fractions were combined and concentrated under reduced pressure. The resulting residue was purified by column chromatography (Si-PCC, gradient eluted with 0-10% MeOH in DCM), then triturated with ether and purified by preparative HPLC (Phenomenex Gemini 5. mu. m C18, 20-98% with 0.1% HCO)₂Acetonitrile/water gradient elution of H). Crystallization from EtOAc/MeOH afforded 106 as a white solid (10mg, 6%). LCMS R_T3.47min[M+H]⁺342.1。¹H NMR(CDCl₃,400MHz):δ8.21(1H,s),7.87(1H,s),7.84(1H,d,J=8.01Hz),7.48-7.43(3H,m),7.36-7.20(4H,m),7.12(1H,d,J=8.03Hz),5.57(2H,s),5.50(2H,br)

Alternatively, 2-chloromethyl-1-phenyl-1H-benzimidazole (140mg,0.57mmol), 9H-purin-6-ylamine (78mg,0.57mmol), and Cs₂CO₃A mixture of (200mg,0.57mmol) and sodium iodide (85mg,0.25mmol) in DMF (1mL) was heated in a sealed tube under microwave irradiation at 80 ℃ for 18 h. The mixture was diluted with water (80mL), with EtOAc and then CHCl₃And (4) extracting. The combined organic layers were dried (Na)₂SO₄) And concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, ISCO column, gradient eluted 0-8% MeOH in DCM) followed by crystallization from EtOAc: MeOH to afford 106(60mg, 31%). LCMS R_T2.99min[M+H]⁺342.0。¹H NMR(CDCl₃,400MHz):δ8.21(1H,s),7.87(1H,s),7.84(1H,d,J=8.01Hz),7.48-7.43(3H,m),7.36-7.20(4H,m),7.12(1H,d,J=8.03Hz),5.57(2H,s),5.50(2H,br)

Example 107N- (1- (1-ethyl-1H-benzo [ d ]]Imidazol-2-yl) ethyl) -9H-purin-6-amine 107

A mixture of 1- (1-ethyl-1H-1, 3-benzooxadiazol-2-yl) ethan-1-amine dihydrochloride (346mg,1.32mmol), 6-chloro-9H-purine (204mg,1.32mmol) and DIPEA (904. mu.L, 5.28mmol) in n-butanol (2.5mL) was stirred in a sealed tube at 120 ℃ for 3H. After cooling to RT, the crude reaction mixture is loaded SCX-2 column, wash it with MeOH, 2M NH₃The product eluted with MeOH. The product containing fractions were combined and concentrated under reduced pressure. The resulting residue was purified by column chromatography (Si-PCC,0-10%2M NH)₃Gradient eluent in DCM/MeOH), triturated with EtOAc/ether mixture, filtered and washed with additional ether to give racemic 107 as a pale pink solid (182mg, 45%). LCMS R_T2.18min[M+H]⁺308.1。¹H NMR(CDCl₃,400MHz):δ8.51(1H,s),7.95(1H,s),7.76(1H,d,J=7.17Hz),7.39-7.34(1H,m),7.31-7.15(3H,m),6.03(1H,br),4.51-4.39(1H,m),4.37-4.26(1H,m),1.97-1.80(4H,m),1.43(3H,t,J=7.21Hz)

Example 108(S) -N- (1- (4-methyl-1-phenyl-1H-benzo [ d)]Imidazol-2-yl) ethyl) -9H-purin-6-amine 108

A mixture of (S) -1- (4-methyl-1-phenyl-1H-benzimidazol-2-yl) ethylamine from example 3 (100mg,0.398mmol), 6-chloro-9H-purine (68mg,0.438mmol) and DIPEA (83. mu.L, 0.478mmol) in n-butanol (1mL) was stirred in a sealed vial at 100 ℃ for 20H. After cooling to RT, the mixture was partitioned between DCM and water. The organic layer was then separated, dried and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC,0-10%2 MNH)₃Gradient eluent in DCM/MeOH) then sonicated in cyclohexane to afford 108 as an off-white solid (56mg,38%) LCMS: R_T3.17min[M+H]⁺370.1。¹HNMR(DMSO,400MHz):δ8.13(1H,bs),8.08(1H,s),7.96-7.85(1H,m),7.67-7.44(5H,m),7.12-6.99(2H,m),6.86(1H,d,J=7.80Hz),5.49(1H,br),2.56(3H,s),1.57(3H,d,J=6.86Hz)

Example 109(R) -N- (1- (4-methyl-1-phenyl-1H-benzo [ d)]Imidazol-2-yl) ethyl) -9H-purin-6-amine 109

A mixture of (R) -1- (4-methyl-1-phenyl-1H-benzimidazol-2-yl) ethylamine (100mg,0.398mmol), 6-chloro-9H-purine (68mg,0.438mmol) and DIPEA (83. mu.L, 0.478mmol) from example 2 in n-butanol (1mL) was stirred in a sealed vial at 100 ℃ for 20H. After cooling to RT, the mixture was partitioned between DCM and water. The organic layer was then separated, dried and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC,0-10%2 MNH)₃Gradient eluent in DCM/MeOH) then sonicated in cyclohexane to give 109 as a brown solid (62mg,42%) LCMS: R_T3.17min[M+H]⁺370.1。¹HNMR(DMSO,400MHz):δ8.18-8.06(2H,m),7.95-7.86(1H,m),7.66-7.45(5H,m),7.11-7.00(2H,m),6.86(1H,d,J=7.81Hz),5.49(1H,br),2.56(3H,s),1.57(3H,d,J=6.84Hz)

Example 110(S) -N- (1- (7-methyl-1-phenyl-1H-benzo [ d)]Imidazol-2-yl) ethyl) -9H-purin-6-amine 110

A mixture of (S) -1- (7-methyl-1-phenyl-1H-benzimidazol-2-yl) ethylamine from example 1 (100mg,0.398mmol), 6-chloro-9H-purine (65mg,0.418mmol) and DIPEA (77. mu.L, 0.438mmol) in n-butanol (2mL) was stirred under microwave irradiation at 140 ℃ for 1H. The volatiles were removed under reduced pressure and the residue was partitioned between DCM and water. The organic phase is then separated off, dried and concentrated in vacuo. The crude product was purified by column chromatography (Si-PCC with 0-10%2 MNH)₃Gradient eluent in DCM/MeOH) then triturated with IMS to give 110 as a white solid (6.2mg,4%) LCMS: R _T3.08min[M+H]⁺370.1。¹H NMR(DMSO,400MHz):δ8.12(1H,bs),8.07(1H,s),7.83-7.75(1H,m),7.64-7.37(7H,m),7.09(1H,t,J=7.67Hz),6.92(1H,d,J=7.29Hz),5.25(1H,br),1.81(3H,s),1.54(3H,d,J=6.84Hz)

Example 1114-amino-8- ((1-phenyl-1H-benzo [ d)]Imidazol-2-yl) methyl) pyrido [2,3-d]Pyrimidin-5 (8H) -ones 111

4-amino-8H-pyrido [2,3-d]Pyrimidin-5-one (35mg,0.214mmol), 2-chloromethyl-1-phenyl-1H-benzimidazole (52mg,0.214mmol), Cs₂CO₃A mixture of (105mg,0.321mmol) and potassium iodide (4mg,0.021mmol) in DMF (1mL) was stirred in a sealed tube at 130 ℃ for 3 h. Volatiles were removed under reduced pressure and the residue was suspended in DCM and filtered. The filtrate was purified by column chromatography (Si-PCC with 0-10%2M NH)₃Gradient eluent in DCM/MeOH) and the resulting material was triturated with ether to give 111 as a pale yellow solid (28mg, 36%). LCMS R_T3.47min[M+H]⁺369.1。¹H NMR(CDCl₃,400MHz):δ9.76(1H,bs),8.07(1H,s),7.82-7.77(1H,m),7.65(1H,d,J=7.97Hz),7.50-7.44(3H,m),7.34-7.23(4H,m),7.14-7.09(1H,m),6.28(1H,d,J=7.97),5.86-5.78(1H,m),5.63(2H,s)

Example 112(S)-4-(2- (1- (9H-purin-6-ylamino) ethyl) -1H-benzo [ d]Imidazol-1-yl) piperidine-1-carboxylic acid tert-butyl ester 112

4- [2- ((S) -1-aminoethyl) benzimidazol-1-yl from example 6]A mixture of piperidine-1-carboxylic acid tert-butyl ester (202mg), 6-chloro-9H-purine (91mg,0.586mmol) and DIPEA (0.2mL,1.17mmol) in n-butanol (1mL) was stirred in a sealed tube at 120 ℃ for 3H. After cooling to RT, the crude reaction mixture was partitioned between EtOAc and water. The organic layer was washed with brine and then dried (Na) ₂SO₄) And concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC,0-10%2M NH)₃Gradient eluent in DCM/MeOH) then triturated with ether to give 112 as a light brown solid (113mg, 38% yield in two steps). LCMS R_T3.24min[M+H]⁺463.2。¹H NMR(CDCl₃,400MHz):δ8.54(1H,s),7.98(1H,s),7.78(1H,d,J=7.55Hz),7.49(1H,d,J=7.36Hz),7.28-7.07(3H,m),6.13(1H,br),4.89-4.78(1H,m),4.47-4.04(2H,m),2.97-2.78(1H,m),2.60-2.26(3H,m),1.99-1.62(6H,m),1.49(9H,s)

Example 113(S) -N- (1- (1- (piperidin-4-yl) -1H-benzo [ d)]Imidazol-2-yl) ethyl) -9H-purin-6-amine 113

To 4- {2- [ (S) -1- (9H-purin-6-ylamino) ethyl]To a solution of tert-butyl benzimidazol-1-yl } piperidine-1-carboxylate 112(101mg,0.218mmol) in DCM (3mL) was added TFA (1mL) and the mixture was stirred at RT for 2 h. Loading the reaction mixture intoSCX-2 column, wash it with MeOH, 2M NH₃The product eluted with MeOH. The product containing fractions were combined and concentrated under reduced pressure. The residue was purified by column chromatography (Si-PCC with 0-20%2 MNH)₃Gradient MeOH in DCM) to give 113 as a white solid (68mg, 86%). LCMS R_T1.65min[M+H]⁺363.1。¹H NMR(CDCl₃,400MHz):δ8.34(1H,s),7.88(1H,s),7.75-7.65(3H,m),7.27-7.19(3H,m),6.01(1H,br),4.80-4.70(1H,m),3.39-3.38(1H,m),3.37-3.30(1H,m),3.19-3.09(1H,m),2.89-2.38(3H,m)1.99-1.70(6H,m)

Example 114(S) -N- (1- (3-phenyl-3H-imidazo [4, 5-b)]Pyridin-2-yl) ethyl) -9H-purin-6-amine 114

(S) -1- (3-phenyl-3H-imidazo [4,5-b ] from example 10]A mixture of pyridin-2-yl) ethylamine from (270mg,1.13mmol), 6-chloro-9H-purine (250mg,1.59mmol) and DIPEA (0.36mL,2.04mmol) in n-butanol (1.5mL) was stirred in a sealed tube at 120 ℃ for 48H. After cooling to RT, the crude reaction mixture was taken up in DCM and saturated NaHCO ₃The solutions were partitioned. The aqueous phase was further extracted with DCM (× 3), the combined organic layers were washed with brine and then dried (Na)₂SO₄) And concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC,0-10%2M NH)₃Gradient eluent in DCM/MeOH), then triturated with ether, then treated with preparative HPLC (Phenomenex Gemini5 μm C18, gradient elution 60 min: 20-98% with 0.1% HCO₂H acetonitrile/water) to yield 114 as an off-white solid (32mg, 8%). LCMS R_T2.64min[M+H]⁺357.0。¹H NMR(DMSO,400MHz):δ8.23(1H,dd,J=4.76,1.48Hz),8.18-7.97(4H,m),7.67-7.41(5H,m),7.29(1H,dd,J=7.99,4.76Hz),1.57(3H,d,J=6.83Hz)

Example 115(S) -1- (4- (2- (1- (9H-purin-6-ylamino) ethyl) -1H-benzo [ d]Imidazol-1-yl) piperidin-1-yl) ethanone 115

To a stirred [ (S) -1- (1-piperidin-4-yl-1H-benzimidazol-2-yl) ethyl radical]To a suspension of- (9H-purin-6-yl) amine 113(46mg,0.127mmol) and DIPEA (26. mu.L, 0.152mmol) in dry THF (3mL) and dry DCM (1mL) was added acetyl chloride (9. mu.L, 0.127 mmol). Stirring was continued at RT for 3h, then the volatiles were removed under reduced pressure and the resulting residue partitioned between EtOAc and water. The aqueous layer was further washed with DCM, then the organic layer was washed with brine and dried (Na)₂SO₄) And concentrated in vacuo. The resulting residues were combined and purified by preparative HPLC (Phenomenex Gemini 5. mu. m C18, 20min gradient: 5-70% with 0.1% HCO ₂H acetonitrile/water)Then is loaded toSCX-2 column. The column was washed with MeOH, 2MNH₃The product eluted with MeOH. The product containing fractions were combined and concentrated under reduced pressure to give 115 as a white solid (10mg, 19%). LCMS R_T2.13min[M+H]⁺405.1。¹H NMR(CDCl₃400 MHz. delta.8.35 (1H, s),7.88(1H, s),7.78-7.70(1H, m),7.49-7.42(1H, m),7.28-7.20(3H, m),6.05(1H, s),4.98-4.82(1.5H, m),4.71-4.61(0.5H, m),4.09-3.99(0.5H, m),3.90-3.78(0.5H, m),3.42-3.37(0.5H, m),3.32-3.18(0.5H, m),2.88-2.37(1H, m),2.20-2.10(4H, m),2.06-1.96(1H, m),1.90-1.69(5H, m). Splitting of signals due to the presence of rotamers

Example 116N- (1- (3-phenyl-1H-indol-2-yl) ethyl) -9H-purin-6-amine 116

{1- [ 3-phenyl-1- (toluene-4-sulfonyl) -1H-indol-2-yl ] -from example 21]A mixture of ethyl } - (9H-purin-6-yl) amine (200mg,0.393mmol) and 2M KOH (0.8mL) in MeOH (4mL) was stirred at 70 ℃ for 72H. Volatiles were removed under reduced pressure and the resulting residue was diluted with water. The pH of the solution was adjusted to 1 by addition of 1M HCl and then by addition of saturated NaHCO₃The solution was adjusted to pH 8. The aqueous layer was extracted with EtOAc (. times.3) and the combined organic layers were dried (Na)₂SO₄) And concentrated in vacuo. The resulting residue was purified by preparative HPLC (Phenomenex Gemini 5. mu. m C18 with 10-98% of 0.1% HCO ₂Acetonitrile/water gradient of H) followed by column chromatography purification (Si-PCC,0-10%2M NH₃Gradient eluent in DCM/MeOH) to give 116 as a white solid (83mg, 60%). LCMS R_T3.98min[M+H]⁺355.0。¹H NMR(DMSO,400MHz):δ11.29(1H,s),8.21-8.09(2H,m),7.71-7.55(3H,m),7.52-7.42(5H,m),7.32(1H,t,J=7.39Hz),7.13(1H,t,J=7.93Hz),7.02(1H,t,J=7.93Hz),5.96(1H,s),1.62(3H,d,J=6.93Hz)

Example 117(S) -N- (1- (5-methyl-1-phenyl-1H-benzo [ d)]Imidazol-2-yl) ethyl) -9H-purin-6-amine 117

A mixture of (S) -1- (5-methyl-1-phenyl-1H-benzimidazol-2-yl) ethylamine from example 14 (100mg,0.398mmol), 6-chloro-9H-purine (74mg,0.478mmol) and DIPEA (0.347mL,1.99mmol) in n-butanol (2mL) was stirred in a sealed vial at 120 ℃ for 20H. After cooling to RT, the volatiles were removed under reduced pressure and the resulting residue was purified by column chromatography (Si-PCC gradient eluted with 0-20% MeOH in EtOAc) followed by trituration with acetonitrile to give 117 as an off-white solid (54mg, 37%). LCMS R_T3.11min[M+H]⁺370.1。¹H NMR(DMSO,400MHz):δ12.90(1H,bs),8.20-8.00(2H,m),7.84(1H,s),7.69-7.39(6H,m),7.07-6.89(2H,m),5.49(1H,bs),2.39(3H,s),1.53(3H,d,J=6.79Hz)

Example 118(S) -N- (1- (6-methyl-1-phenyl-1H-benzo [ d)]Imidazol-2-yl) ethyl) -9H-purin-6-amine 118

(S) -1- (6-methyl-1-phenyl-1H-benzimidazol-2-yl) ethylamine from example 13 (100mg,0.398mmol), 6-chloro-9H-purine (65mg,0.418mmol) and DIPEA (0.347mL,1.99mmol) in dioxaneThe mixture in alkane (3mL) was stirred in a sealed vial at 100 ℃ for 20 h. After cooling to RT, the volatiles were removed under reduced pressure and the resulting residue was purified by column chromatography (Si-PCC gradient eluted with 0-20% MeOH in EtOAc) followed by crystallization from acetonitrile to give 118 as a white solid (35mg, 24%). LCMS R _T3.15min[M+H]⁺370.1。¹H NMR(DMSO,400MHz):δ8.17-8.07(2H,m),7.88-7.78(1H,m),7.64-7.45(6H,m),7.06(1H,d,J=8.26Hz),6.86(1H,s),5.50(1H,br),2.35(3H,s),1.54(3H,d,J=6.82Hz)

Example 119(S) -N- (1- (1-phenyl-1H-benzo [ d ]]Imidazol-2-yl) propyl) -9H-purine_-6_-Amine 119

(S) -1- (1-phenyl-1H-benzimidazol-2-yl) propylamine from example 12 (100mg,0.398mmol), 6-chloro-9H-purine (65mg,0.418mmol) and DIPEA (0.348mL,2.0mmol) were added to a solutionThe mixture in dioxane (3mL) was stirred at 100 ℃ for 24 h. After cooling to RT, the volatiles were removed under reduced pressure and the resulting residue was purified by column chromatography (Si-PCC gradient eluted with 0-20% MeOH in EtOAc) followed by crystallization from acetonitrile to give 119 as a white solid (50mg, 34%). LCMS R_T3.23min[M+H]⁺370.0。¹H NMR(DMSO,400MHz):δ8.21-8.07(2H,m),7.86-7.49(7H,m),7.28-7.17(2H,m),7.08(1H,d,J=7.68Hz),5.42(1H,br),2.08-1.90(2H,m),0.83(3H,t,J=7.32Hz)

Example 120(S) -N- (1- (4-chloro-1-phenyl-1H-benzo [ d)]Imidazol-2-yl) ethyl) -9H-purin-6-amine 120

A mixture of (S) -1- (4-chloro-1-phenyl-1H-benzimidazol-2-yl) ethylamine (250mg,0.92mmol), 6-chloro-9H-purine (200mg,1.29mmol) and DIPEA (0.29mL,1.66mmol) from example 9 in n-butanol (2mL) was stirred in a sealed tube at 120 ℃ for 16H. Additional 6-chloro-9H-purine (100mg,0.64mmol) and DIPEA (0.14mL,0.802mmol) were added and stirring continued at 120 ℃ for 24H. After cooling to RT, the crude reaction mixture was partitioned between DCM and water. The aqueous phase was further extracted with DCM (× 3), then the combined organic layers were washed with brine and dried (Na) ₂SO₄) And concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC with 0-8%2M NH)₃Gradient elution in DCM/MeOH), followed by purification by preparative HPLC (Phenomenex Gemini5 μm C18, 60min gradient: 20-98% with 0.1% HCO₂H acetonitrile/water) to yield 120(66mg, 42%). LCMS R_T3.69min[M+H]⁺390.0。¹H NMR(CDCl₃,400MHz):δ12.90(1H,bs),8.28-7.90(3H,m),7.71-7.41(5H,m),7.32(1H,d,J=7.75Hz),7.19(1H,t,J=7.90Hz),7.03(1H,d,J=8.10Hz),5.46(1H,br),1.67-1.53(3H,m)

Example 121(S) -1- (4- (2- (1- (9H-purin-6-ylamino) ethyl) -1H-benzo [ d]Imidazol-1-yl) piperidin-1-yl) -2-hydroxy-2-methylpropan-1-one 121

To a stirred [ (S) -1- (1-piperidin-4-yl-1H-benzimidazol-2-yl) ethyl radical]- (9H-purin-6-yl) amine 113(97mg,0.268 mmo)L) to a solution in DMF (5mL) was added 2-hydroxy-2-methylpropanoic acid (31mg,0.294mmol), DIPEA (230. mu.L, 1.34mmol) and HATU (153mg,0.401 mmol). Stirring was continued at RT for 18h, then the crude reaction mixture was taken up in EtOAc and saturated NaHCO₃The solutions were partitioned. The organic layer was washed with brine and then dried (Na)₂SO₄) And concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC,0-10%2M NH)₃Gradient eluent in DCM/MeOH) to give 121 as a pale beige solid (33mg, 31%). LCMS R_T2.28min[M+H]⁺449.1。¹H NMR(CDCl₃,400MHz):δ8.51(1H,s),7.98(1H,s),7.79(1H,d,J=7.80Hz),7.36-6.99(4H,m),5.32(1H,bs),5.02-4.88(2H,m),4.78(1H,bs),4.59-4.49(1H,br),2.64-2.44(2H,m),2.37-2.22(1H,m),2.05(1H,d,J=12.70Hz),2.95-1.49(11H,m)

Example 122(S) -2- (1- (9H-purin-6-ylamino) ethyl) -1-phenyl-1H-benzo [ d]Imidazole-6-carbonitrile 122

A mixture of 2- ((S) -1-aminoethyl) -3-phenyl-3H-benzimidazole-5-carbonitrile from example 11 (370mg,1.4mmol), 6-chloro-9H-purine (217mg,1.4mmol), and DIPEA (0.36mL,2.1mmol) in n-butanol (2.8mL) was stirred in a sealed tube at 120 ℃ for 6H. After cooling to RT, the crude reaction mixture is loaded SCX-2 column, wash it with MeOH, 2M NH₃The product eluted with MeOH. The product containing fractions were combined and concentrated under reduced pressure. The residue was purified by column chromatography (Si-PCC with 0-10%2 MNH)₃Gradient of EtOAc/MeOH followed by 0-10%2M NH₃Gradient eluent in DCM/MeOH) to give 122 as a white solid (200mg, 37%). LCMS R_T3.29min[M+H]⁺381.1。¹H NMR(DMSO,400MHz):δ8.21-7.97(3H,m),7.84(1H,d,J=8.35Hz),7.72-7.46(7H,m),5.49(1H,br),1.59(3H,d,J=6.87Hz)

Example 123(S) -N- (1- (6-fluoro-1-phenyl-1H-benzo [ d)]Imidazol-2-yl) ethyl) -9H-purine-6-Amines 123

A mixture of (S) -1- (6-fluoro-1-phenyl-1H-benzimidazol-2-yl) ethylamine (861mg,3.37mmol), 6-chloro-9H-purine (521mg,3.37mmol) and DIPEA (1.73mL,10.12mmol) from example 8 in n-butanol (3.5mL) was stirred in a sealed tube at 100 ℃ for 18H. After cooling to RT, the volatile substances were removed under reduced pressure and the residue obtained was loadedSCX-2 column, wash it with MeOH, 2M NH₃The product eluted with MeOH. The product containing fractions were combined and concentrated under reduced pressure. The product thus obtained was further purified by column chromatography (Si-PCC with 0-20%2M NH)₃EtOAc/MeOH in EtOAc) followed by sonication in EtOAc. The suspension was concentrated in vacuo and the solid was triturated with ether to give 123 as a white/pink solid (136mg, 11%). LCMS R _T3.38min[M+H]⁺374.0。¹H NMR(DMSO,400MHz):δ8.20-8.03(2H,m),7.91(1H,bs),7.73-7.44(6H,m),7.09(1H,t,J=9.72Hz),6.85(1H,d,J=8.92Hz),5.50(1H,bs),1.55(3H,d,J=6.82Hz)

Or [ (S) -1- (6-fluoro-1-phenyl-1H-benzimidazol-2-yl) ethyl]- [9- (tetrahydropyran-2-yl) -9H-purin-6-yl]The amine (30g,65.6mmol) was dissolved in EtOAc (200mL), HCl (1M MeOH solution, 210mL) was added dropwise and the resulting solution was stirred for 2 h. The solvent was removed in vacuo and the resulting solid recrystallized from hot EtOAc/EtOH to give 123 as a white crystalline solid (11g, 45%). Crystallization from the mother liquor yields additional product.¹H NMR(MeOD-d₄,400MHz):δ8.60(1H,s),8.53(1H,s),7.8(1H,dd,J9.8,4.2Hz),7.67(5H,br s),7.42(1H,td,J9.2,2.3Hz),7.14(1H,dd,J7.1,2.4Hz),5.67(1H,m),1.87(3H,d,J6.9Hz)

Example 124(S) -N- (1- (7-fluoro-1-phenyl-1H-benzo [ d)]Imidazol-2-yl) ethyl) -9H-purin-6-amine 124

(S) -1- (7-fluoro-1-phenyl-1H-benzimidazol-2-yl) ethylamine from example 7 (367mg,1.44mmol), 6-chloro-9H-purine (222mg,1.44mmol) and DIPEA (0.74mL, 4)31mmol) in n-butanol (3.5mL) was stirred in a sealed tube at 100 ℃ for 48 h. After cooling to RT, the volatile substances were removed under reduced pressure and the residue obtained was loadedSCX-2 column, wash it with MeOH, 2M NH₃The product eluted with MeOH. The product containing fractions were combined and concentrated under reduced pressure. The product thus obtained was further purified by column chromatography (Si-PCC with 0-20%2M NH)₃Gradient of EtOAc/MeOH) followed by (Si-PCC,0-10%2M NH)₃Gradient elution in DCM/MeOH) followed by sonication in MeOH. The suspension was then diluted with ether and the solid collected by filtration to give 124 as a white solid (103mg, 19%). LCMS R _T3.40min[M+H]⁺374.0。¹H NMR(DMSO,400MHz):δ8.17-8.04(2H,m),7.98-7.86(1H,br),7.75-7.35(6H,m),7.19(1H,td,J=8.09,4.87Hz),7.02(1H,dd,J=11.60,8.02Hz),5.37(1H,bs),1.56(3H,d,J=6.86Hz)

Example 125(S) -1- (4- (2- (1- (9H-purin-6-ylamino) ethyl) -1H-benzo [ d]Imidazol-1-yl) piperidin-1-yl) -2- (dimethylamino) ethanone 125

To [ (S) -1- (1-piperidin-4-yl-1H-benzimidazol-2-yl) ethyl]To a solution of- (9H-purin-6-yl) amine 113(97mg,0.268mmol), dimethylaminoacetic acid (30mg,0.294mmol) and DIPEA (230. mu.L, 1.34mmol) in DMF (5mL) was added HATU (153mg,0.401mmol) and the mixture was stirred at RT for 1H. Loading the crude reaction mixture intoSCX-2 column, wash it with MeOH, 2M NH₃The product eluted with MeOH. The product containing fractions were combined and then concentrated in vacuo and purified by column chromatography (Si-PCC with 0-20%2 MNH)₃Gradient MeOH in DCM) was triturated with ether. The product thus obtained was further purified by preparative HPLC (Phenomenex Gemini 5. mu. m C18, 20min gradient: 5-60% with 0.1% NH)₄Acetonitrile/water of OH) toSCX-2. The column was washed with MeOH, 2M NH₃The product eluted with MeOH. The basic fractions were then combined and concentrated in vacuo to give 125 as a white solid (40mg, 33%). LCMS R_T1.67min[M+H]⁺448.1。¹H NMR(CDCl₃And MeOD,400MHz): δ 8.45(1H, s),7.94(1H, s),7.77(1H, d, J =7.62Hz),7.41(1H, d, J =7.73Hz),7.26-7.17(3H, m),6.10(1H, s),4.99-4.81(1.5H, m),4.64-4.53(0.5H, m),4.38-4.27(0.5H, m),4.21-4.08(0.5H, m),3.32-3.01(2H, m),2.87-2.16(10H, m),2.05-1.27(6H, m). Due to the presence of rotamers, the signal is cleaved.

Example 126(S) -3- (4- (2- (1- (9H-purin-6-ylamino) ethyl) -1H-benzo [ d]Imidazol-1-yl) piperidin-1-yl) propionitrile 126

Reacting [ (S) -1- (1-piperidin-4-yl-1H-benzimidazol-2-yl) ethyl]A mixture of (9H-purin-6-yl) amine 113(75mg,0.207mmol) and acrylonitrile (75. mu.L, 1.14mmol) in IMS (3mL) was stirred in a sealed tube at 70 ℃ for 3H. After cooling to RT, the crude reaction mixture is loadedSCX-2 column, wash it with MeOH, 2M NH₃The product eluted with MeOH. The product containing fractions were combined, concentrated in vacuo, and purified by column chromatography (Si-PCC,0-10%2M NH)₃Gradient eluent in DCM/MeOH), then purified by preparative HPLC (Phenomenex Gemini5 μm C18, 20min gradient: 5-60% with 0.1% NH₄Acetonitrile/water of OH) and finally loaded toOn SCX-2, wash it with MeOH, 2MNH₃The product eluted with MeOH. The ammonia fractions were combined and concentrated in vacuo to give 126 as a white solid (28mg, 33%). LCMS R_T1.67min[M+H]⁺416.1。¹H NMR(CDCl₃,400MHz):δ8.52(1H,s),7.96(1H,s),7.80-7.73(1H,m),7.65-7.59(1H,m),7.26-7.08(3H,m),5.29(1H,bs),4.69-4.57(1H,m),3.09(1H,bd,J=11.28Hz),2.90(1H,d,J=11.11Hz),2.76-2.60(3H,m),2.37-2.25(3H,m),2.30-2.30(1H,m),1.98-1.66(7H,m)

Example 127(S) -N- (1- (1- (tetrahydro-2H-pyran-4-yl) -1H-benzo [ d)]Imidazol-2-yl) ethyl) -9H-purin-6-amine 127

(S) -1- [1- (tetrahydropyran-4-yl) -1H-benzimidazol-2-yl radical from example 17]A mixture of ethylamine (195mg,0.796mmol), 6-chloro-9- (tetrahydropyran-2-yl) -9H-purine (266mg,1.11mmol) and DIPEA (0.25mL,1.43mmol) in n-butanol (2mL) was stirred in a sealed vial at 120 ℃ for 3 days. After cooling to RT, the volatile substances were removed under reduced pressure and the residue obtained was loaded On SCX-2, wash it with MeOH, 2MNH₃The product eluted with MeOH. The product containing fractions were combined, concentrated in vacuo and the resulting residue was purified by column chromatography (Si-PCC,0-10%2M NH)₃Gradient elution with MeOH in DCM) then trituration with a mixture of EtOAc and MeOH afforded 127 as an off-white solid (148mg, 51%). LCMS R_T2.29min[M+H]⁺364.0。¹H NMR(DMSO,400MHz):δ12.93(1H,bs),8.30-7.81(3H,m),7.61-7.59(2H,m),7.17-7.03(2H,m),5.96(1H,bs),4.81-4.63(1H,m),3.94(1H,d,J=11.07Hz),3.74(1H,d,J=11.25Hz),3.35(1H,bs),2.84(1H,bs),2.47-2.35(1H,m),2.30-2.17(1H,m),1.75(1H,bd),1.64(3H,d,J=6.71Hz),1.50(1H,bs)

Example 128N- ((1S) -1- (1- (tetrahydro-2H-pyran-3-yl) -1H-benzo [ d)]Imidazol-2-yl) ethyl) -9H-purin-6-amine 128

(S) -1- [1- (tetrahydropyran-3-yl) -1H-benzimidazol-2-yl radical from example 18]A mixture of ethylamine (295mg,1.20mmol), 6-chloro-9- (tetrahydropyran-2-yl) -9H-purine (400mg,1.68mmol) and DIPEA (0.38mL,2.16mmol) in n-butanol (2mL) was stirred in a sealed vial at 100 ℃ for 16H. After cooling to RT, the volatile substances were removed under reduced pressure and the residue obtained was loadedOn SCX-2, wash it with MeOH, 2M NH₃The product eluted with MeOH. The product containing fractions were combined and concentrated in vacuo. For the second repetitionPurification of SCX-2 followed by column chromatography of the resulting residue (Si-PCC,0-10%2 MNH)₃Gradient elution in DCM/MeOH) gave 128 as a white solid (310mg, 71%). LCMS R _T2.42 and 2.46min [ M + H ]]⁺364.0。¹H NMR (DMSO,400MHz) < delta > 8.38-7.88(3H, m),7.80(1H, t, J =8.38Hz),7.65-7.54(1H, m),7.21-7.09(2H, m),5.95(1H, br),4.71-4.57(1H, m),4.14-4.04(1H, m),4.00-3.86(1H, m),3.83-3.71(1H, m),3.55-3.43(1H, m),3.16(0.5H, d, J =4.68Hz),2.56-2.43(0.5H, m),2.36-2.23(0.5H, m),2.02(0.5H, br),1.83-1.72(4H, m),1.56 (0.68 bH, b), 1.08 (1H, m), 1.13.08 (1H, m). Due to the presence of rotamers/tautomers, the signal is cleaved.

Example 129(S) -N- (1- (1- (1- (oxetan-3-yl) piperidin-4-yl) -1H-benzo [ d]Imidazol-2-yl) ethyl) -9H-purin-6-amine 129

To (S) -N- (1- (1- (piperidin-4-yl) -1H-benzo [ d ] from example 113]Imidazol-2-yl) ethyl) -9H-purin-6-amine (99mg,0.273mmol) to a mixture in anhydrous DCE (10mL) was added oxetan-3-one (32. mu.L, 0.546mmol) followed by AcOH (16. mu.L, 0.273mmol) and(angstrom) powdered molecular sieve (0.1 g). After stirring for 4h, sodium triacetoxyborohydride (116mg,0.546mmol) was added and stirring was continued for 48 h. Loading the crude reaction mixture intoOn SCX-2, wash it with MeOH, 2M NH₃The product eluted with MeOH. The product-containing fractions are combined, concentrated in vacuo, and the residue obtained is purified by column chromatography Conversion of (Si-PCC,0-10%2M NH₃Gradient elution in DCM/MeOH), then trituration with ether and MeOH afforded 129 as a white solid (50mg, 44%). LCMS R_T1.61min[M+H]⁺419.1。¹H NMR(DMSO,400MHz,80℃):δ8.25(1H,s),8.05(1H,s),7.65-7.59(2H,m),7.44(1H,bs),7.20-7.13(2H,m),6.16-6.04(1H,m),4.63-4.39(6H,m),3.50-3.42(1H,m),2.93-2.85(1H,bd,J=10.45Hz),2.76-2.69(1H,bd,J=10.45Hz),2.40-2.28(1H,m),2.04-1.93(1H,t,J=11.60Hz),1.90-1.81(1H,m),1.76-1.53(6H,m)

Example 130(S) -4- (2- (1- (9H-purin-6-ylamino) ethyl) -1H-benzo [ d]Imidazol-1-yl) -N-isopropylpiperidine-1-carboxamide 130

To [ (S) -1- ((R) -1-piperidin-3-yl-1H-benzimidazol-2-yl) ethyl obtained in example 16]To a mixture of- (9H-purin-6-yl) amine (88mg,0.243mmol) in dry DCM (5mL) was added 2-isocyanato (isocyanato) propane (31 μ L,0.316mmol) and the reaction mixture was stirred at RT for 3H. The crude reaction mixture was partitioned between DCM and water, then the organic layer was washed with brine and dried (Na)₂SO₄) And concentrated in vacuo. The resulting residue was purified by preparative HPLC (Phenomenex Gemini 5. mu. m C18, 20min gradient: 5-70 with 0.1% HCO₂H acetonitrile/water), then withSCX-2 purification. The column was washed with MeOH, 2MNH₃The product eluted with MeOH. The product containing fractions were combined and concentrated in vacuo to afford 130 as a white solid (26mg, 24%). LCMS R_T2.48min[M+H]⁺448.1。¹H NMR (DMSO plus TFA,400MHz): delta 8.72(1H, s),8.56(1H, s),7.98-7.91(1H, m),7.79-7.73(1H, m),7.58-7.52(2H, m),6.11(1H, bs),5.13-5.02(1H, m),4.19(2H, t, J =14.33Hz),3.87-3.76(1H, m),2.88(1H, t, J =12.16Hz),2.74-2.64(1H, m),2.44-2.23(4H, m),2.08-1.91(3H, m),1.86(3H, d, J =6.95Hz),1.09(6H, d, J = 7.82)

Example 131(S) -N- (1- (1- (1-isopropylpiperidin-4-yl) -1H-benzo [ d)]Imidazol-2-yl) ethyl) -9H-purin-6-amine 131

To (S) -N- (1- (1- (piperidin-4-yl) -1H-benzo [ d ] from example 113]Imidazol-2-yl) ethyl) -9H-purin-6-amine (81mg,0.223mmol) to a mixture of anhydrous DCM (2mL) was added acetone (49. mu.L, 0.67mmol) followed by AcOH (1 drop). After stirring for 5min, sodium triacetoxyborohydride (71mg,0.335mmol) was added and stirring continued for 19 h. Loading the crude reaction mixture intoOn SCX-2, wash it with MeOH, 2M NH₃The product eluted with MeOH. The product containing fractions were combined, concentrated in vacuo and the resulting residue was purified by preparative HPLC (Phenomenex Gemini5 μm C18, 20min gradient: 5-40% acetonitrile/water with 0.1% NH4 OH) followed bySCX-2 purification. The column was washed with MeOH, 2M NH₃The product eluted with MeOH. The product containing fractions were combined and concentrated in vacuo to afford 131 as a pale yellow solid (22mg, 24%). LCMS R_T1.68min[M+H]⁺405.1。¹H NMR (DMSO plus TFA,400MHz): delta 8.82(1H, bs),8.57(1H, s),8.22(1H, d, J =8.16Hz),7.77(1H, d, J =7.78Hz),7.64-7.52(2H, m),5.97(1H, bs),5.49-5.35(1H, br),3.79-3.58(3H, m),3.43-3.24(2H, m),3.00-2.78(2H, m),2.68-2.48(3H, m),2.38(1H, bd, J =16.58Hz),1.89(3H, d, J =6.93Hz),1.36(6H, dd, J =6.61,2.47Hz)

Example 132N- ((S) -1- (1- ((R) -1-isopropylpiperidin-3-yl) -1H-benzo [ d)]Imidazol-2-yl) ethyl) -9H-purin-6-amine 132

To [ (S) -1- ((R) -1-piperidin-3-yl-1H-benzimidazol-2-yl) ethyl obtained in example 16]To a mixture of (9H-purin-6-yl) amine (150mg,0.414mmol) in anhydrous DCM (3mL) was added acetone (90. mu.L, 1.24mmol) followed by AcOH (1 drop). After stirring for 5min, sodium triacetoxyborohydride (132mg,0.621mmol) was added and stirring continued for 22 h. The mixture was then treated with NaOH (1N,2mL) and then stirred vigorously for 10 min. Removing the volatile materials under vacuum and removing the residueThe material was purified by column chromatography (Si-PCC with 0-15%2M NH)₃Gradient MeOH in DCM) to give 132(58mg, 35%). LCMS R_T1.91min[M+H]⁺405.1。¹H NMR(DMSO,400MHz):δ12.97(1H,s),8.33-8.06(2H,m),7.96(1H,br),7.72(1H,d,J=7.33Hz),7.62(1H,d,J=7.14Hz),7.24-7.07(2H,m),5.93(1H,s),4.66-4.52(1H,m),3.00-2.83(2H,m),2.81-2.65(2H,m),2.23(1H,t,J=11.59Hz),2.15-2.01(1H,m),1.84-1.57(5H,m),1.26-1.07(1H,m),0.96(6H,d,J=6.51Hz)

Example 1332- ((R) -3- (2- ((S) -1- (9H-purin-6-ylamino) ethyl) -1H-benzo [ d]Imidazol-1-yl) piperidin-1-yl) acetamide 133

The [ (S) -1- ((R) -1-piperidin-3-yl-1H-benzimidazol-2-yl) ethyl radical from example 16]A mixture of (9H-purin-6-yl) amine (150mg,0.414mmol), 2-bromo-acetamide (57mg,0.414mmol) and DIPEA (215. mu.L, 1.24mmol) in IMS (2mL) was stirred in a sealed vial at 70 ℃ for 20H. After cooling to RT, the volatiles were removed under reduced pressure and the resulting residue was purified by column chromatography (Si-PCC with 0-15%2M NH) ₃Gradient elution in DCM/MeOH). The product containing fractions were concentrated in vacuo and the resulting residue triturated with MeOH to give 133(59mg, 34%). LCMS R_T1.80min[M+H]⁺420.1。¹H NMR(DMSO,400MHz):δ8.25(1H,s),8.14(1H,s),8.01-7.90(1H,m),7.74-7.66(1H,m),7.63-7.55(1H,m),7.28-7.03(4H,m),5.95(1H,bs),4.75(1H,br),3.04-2.86(4H,m),2.74(1H,bd,J=11.16Hz),2.24(1H,bt,J=11.70Hz),1.80-1.55(5H,m),1.35-1.19(1H,m)

Example 1341- ((R) -3- (2- ((S) -1- (9H-purin-6-ylamino) ethyl) -1H-benzo [ d]Imidazol-1-yl) piperidin-1-yl) -2- (dimethylamino) ethanone 134

The [ (S) -1- ((R) -1-piperidin-3-yl-1H-benzimidazol-2-yl) ethyl radical from example 16]- (9H-purin-6-yl) amine (150mg,0.414mmol), dimethylaminoacetic acid (47mg,0.455mmol), HOAt (62mg,0.455mmol), N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride (87 μ L,0.455mmol), and a mixture of 4-methylmorpholine (0.10mL,0.911mmol) in anhydrous DCM (4mL) inStir at RT for 20 h. The volatiles were removed under vacuum and the resulting residue was purified by column chromatography (Si-PCC with 0-15%2M NH)₃Gradient elution in DCM/MeOH) then trituration with ether afforded 134(55mg, 30%). LCMS R_T1.79min[M+H]⁺448.1。¹H NMR (DMSO,400MHz) < delta > 8.23-7.93(3H, m),7.90-7.78(1H, m),7.68-7.58(1H, m),7.21-7.12(2H, m),4.80-4.69(1H, br),4.53-4.30(1H, m),4.22(0.6H, bd, J =12.25Hz),4.03(0.4H, bd, J =12.25Hz),3.85(0.6H, t, J =12.08Hz),3.44-3.26(1.4H, t, J =12.08Hz),3.21-3.10(1H, m),2.99(0.4H, bd, J =13.04Hz),2.90-2.64(1.6H, m),2.44-2.26(1H, m), 2.11-2.25H, 1.25 Hz), 1.11-4H, m (1H, m), 1.85H, m). Due to the presence of rotamers, the signal is cleaved.

Example 1351- ((R) -3- (2- ((S) -1- (9H-purin-6-ylamino) ethyl) -1H-benzo [ d]Imidazol-1-yl) piperidin-1-yl) -2-hydroxy-2-methylpropan-1-one 135

The [ (S) -1- ((R) -1-piperidin-3-yl-1H-benzimidazol-2-yl) ethyl radical from example 16]A mixture of- (9H-purin-6-yl) amine (150mg,0.414mmol), 2-hydroxy-2-methylpropanoic acid (47mg,0.455mmol), HOAt (62mg,0.455mmol), N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride (87 μ L,0.455mmol), and 4-methylmorpholine (0.10mL,0.911mmol) in dry DCM (4mL) was stirred at RT for 20H. The volatiles were removed under vacuum and the resulting residue was purified by column chromatography (Si-PCC with 0-15%2M NH)₃Gradient MeOH in DCM) then triturated with ether to give 135(65mg, 35%). LCMS R_T2.44min[M+H]⁺449.1。¹H NMR(DMSO,400MHz):δ8.24-7.90(3H,m),7.88-7.81(1H,m),7.67-7.56(1H,m),7.23-7.07(2H,m),5.90(1H,s),5.51(1H,s),5.30-3.76(4H,br),2.45-2.28(1H,m),1.93-1.61(5H,m),1.48-1.27(6H,m),1.20-1.08(1H,m)

Example 136(S) -N- (1- (4-fluoro-1-phenyl-1H-benzo [ d)]Imidazol-2-yl) ethyl) -9H-purin-6-amine 136

(S) -1- (4-fluoro-1-phenyl-1H-benzimidazol-2-yl) ethylamine from example 15 (0.407mmol), 6-chloro-9- (tetrahydropyran-2-yl) -9H-purine (1)22mg,0.509mmol) and DIPEA (0.444mL,2.55mmol) in n-butanol (3mL) were stirred in a sealed vial at 100 ℃ for 20 h. After cooling to RT, the volatiles were removed under reduced pressure and the resulting residue was purified by column chromatography (Si-PCC, gradient elution with 0-10% MeOH in EtOAc). The product containing fractions were concentrated in vacuo, and the resulting residue was dissolved in EtOAc (10mL) and stirred with 2N HCl (10mL) for 15 min. Volatiles were removed under reduced pressure and the residue was dissolved in MeOH (2mL) and triturated with ether to give 136 as a beige powder (126mg, 78%). LCMS R _T3.47min[M+H]⁺374.0。¹H NMR(DMSO,400MHz):δ10.03(1H,s),8.66(1H,s),8.55(1H,s),7.68-7.38(5H,m),7.28-7.21(1H,m),7.13(1H,dd,J=10.91,7.98Hz),6.94(1H,dd,J=8.11,0.82Hz),5.68-5.59(1H,m),1.72(3H,d,J=6.85Hz)

Example 137(S) -2- (1- (9H-purin-6-ylamino) ethyl) -1-phenyl-1H-benzo [ d]Imidazole-6-carboxamides 137

To (S) -2- (1- (9H-purin-6-ylamino) ethyl) -1-phenyl-1H-benzo [ d]To a solution of imidazole-6-carbonitrile 122(70mg,0.18mmol) in DMSO (2mL) was added potassium carbonate (10mg,0.07mmol) followed by hydrogen peroxide (30%,0.2 mL). After stirring for 1h, additional potassium carbonate in water (10mg,0.07mmol) and 90.2mL hydrogen peroxide were added and stirring was continued for 1 h. The solution was then diluted with water (30mL) and EtOAc was added. A precipitate formed which was filtered off to give 137 as a white solid (47mg, 64%). LCMS R_T2.41min[M+H]⁺399.1。¹H NMR(DMSO,400MHz):δ8.20-8.07(2H,m),8.03-7.92(2H,m),7.81(1H,d,J=9.19Hz),7.76-7.50(6H,m),7.24(1H,s),5.51(1H,bs),1.58(3H,d,J=6.84Hz)

Example 138(S) -N- (1- (7-chloro-1-phenyl-1H-benzo [ d)]Imidazol-2-yl) ethyl) -9H-purin-6-amine 138

A mixture of (S) -1- (7-chloro-1-phenyl-1H-benzimidazol-2-yl) ethylamine (482mg,1.77mmol), 6-chloro-9- (tetrahydropyran-2-yl) -9H-purine (466mg,1.95mmol), and DIPEA (0.91mL,5.32mmol) from example 19 in IMS (3.5mL) was stirred in a sealed vial at 90 ℃ for 48H. In thatAfter cooling to RT, the volatile substances are removed under reduced pressure and the residue obtained is loadedOn SCX-2, it is washed with MeOH and then with 2M NH₃Washing with MeOH. The product containing fractions (basic and methanolic) were combined and concentrated in vacuo. For the second time The SCX-2 purification was repeated and the residue obtained was purified by column chromatography (Si-PCC with 0-10%2M NH)₃Gradient elution in DCM/MeOH). The basic fractions were combined, concentrated in vacuo, and the residue refluxed in MeOH. After cooling to RT, the solid was filtered off and washed with EtOAc to give 138 as a white solid (379mg, 55%). LCMS R_T3.65min[M+H]⁺390.0。¹H NMR(DMSO,400MHz):δ8.20-8.06(2H,m),7.94(1H,s),7.69-7.36(6H,m),7.24-7.19(2H,m),5.26(1H,bs),1.10(3H,d,J=7.00Hz)

Example 1397- ((1-phenyl-1H-benzo [ d)]Imidazol-2-yl) methyl) -7H-pyrrolo [2,3-d]Pyrimidin-4-amine 139

Step 1: 4-chloro-7- (1-phenyl-1H-benzimidazol-2-ylmethyl) -7H-pyrrolo [2,3-d ] pyrimidine

Reacting 4-chloro-7H-pyrrolo [2,3-d]Pyrimidine (0.62g,4.1mmol), 2- (chloromethyl) -1-phenyl-1H-benzo [ d]Imidazole (1.0g,4.1mmol) and K₂CO₃A mixture of (0.6g,4.3mmol) in DMSO (20mL) was stirred at room temperature overnight. The mixture was then added to H₂O (50mL), extracted with EtOAc (20 mL. times.3). The combined organic layers were concentrated in vacuo to give 4-chloro-7- (1-phenyl-1H-benzoimidazol-2-ylmethyl) -7H-pyrrolo [2,3-d]Pyrimidine (1.2g, yield 80%) as a brown solid.

Step 2, adding 4-Chloro-7- (1-phenyl-1H-benzimidazol-2-ylmethyl) -7H-pyrrolo [2,3-d]-pyrimidine (1.0g,2.7mmol) in NH₄A solution in OH (5mL) and MeOH (10mL) was stirred in a sealed tube at 90 deg.C overnight. The mixture was then concentrated in vacuo. The residue was purified by P-TLC to give 139(0.2g, 22% yield) as a white solid. LCMS (ESI), M + H ⁺=339.14。1HNMR(400MHz,CDCl₃)δ5.505(s,1H),6.503(s,1H),6.936(s,2H),7.031(s,1H),7.205-7.209(q,J=1.6Hz,1H),7.219-7.228(m,2H),7.490-7.540(m,5H),7.555-7.559(d,J=1.6Hz,1H),7.910(s,1H)

Example 1405-iodo-7- ((1-phenyl-1H-benzo [ d)]Imidazol-2-yl) methyl) -7H-pyrrolo [2,3-d]Pyrimidin-4-amine 140

Step 1 4-chloro-5-iodo-7H-pyrrolo [2,3-d ] pyrimidine

Reacting 4-chloro-7H-pyrrolo [2,3-d]A mixture of pyrimidine (3.0g,20mmol) and NIS (4.9g,20.1mmol) in DMF (100mL) was stirred in the dark at room temperature overnight. The mixture was then concentrated in vacuo. The residue was taken up in 10% Na₂SO₃Treating and filtering to obtain 4-chloro-5-iodo-7H-pyrrolo [2,3-d]Pyrimidine (4.0g, yield 72%) as a yellow solid.

Step 2-4-chloro-5-iodo-7- (1-phenyl-1H-benzimidazol-2-ylmethyl) -7H-pyrrolo [2,3-d ] pyrimidine

4-chloro-5-iodo-7H-pyrrolo [2,3-d]Pyrimidine (1.15g,4.1mmol), 1- (1-phenyl-1H-benzo [ d ] from example 4]Imidazol-2-yl) ethylamine (1.0g,4.1mol) and K₂CO₃A mixture of (0.6g,4.3mmol) in DMSO (20mL) was stirred at room temperature overnight. Then adding the mixtureTo H₂In O (50mL), with CH₂Cl₂Extraction (20 mL. times.3). The combined organic layers were concentrated in vacuo to give 4-chloro-5-iodo-7- (1-phenyl-1H-benzoimidazol-2-ylmethyl) -7H-pyrrolo [2,3-d]Pyrimidine (1.7g, 85% yield) as a brown solid.

Step 3, 4-chloro-5-iodo-7- (1-phenyl-1H-benzoimidazol-2-ylmethyl) -7H-pyrrolo [2,3-d ]Pyrimidine (1.0g,2mmol) in NH₄A solution in OH (5mL) and MeOH (10mL) was stirred in a sealed tube at 90 deg.C overnight. The mixture was then filtered. The precipitate was purified by P-TLC to give 140(0.4g, yield 42%) as a white solid. LCMS (ESI), M + H⁺=465.041HNMR(400MHz,DMSO)δ5.518(s,2H),6.574(s,2H),7.128(s,2H),7.210-7.232(m,2H),7.343(s,1H),7.521-7.622(m,6H),7.968(s,1H)

Example 1413-iodo-1- ((1-phenyl-1H-benzo [ d)]Imidazol-2-yl) methyl) -1H-pyrazolo [3,4-d]Pyrimidin-4-amine 141

Step 1 3-iodo-1H-pyrazolo [3,4-d ] pyrimidin-4-ylamine

Reacting 1H-pyrazolo [3,4-d]A mixture of pyrimidin-4-ylamine (5.0g,37mmol) and NIS (10.7g,45mmol) in DMF (100mL) was stirred at 70 ℃ overnight. The mixture was then cooled to room temperature and filtered to give 3-iodo-1H-pyrazolo [3,4-d]Pyrimidin-4-ylamine (4.1g) as a white solid. The filtrate was concentrated and the residue was taken up with 10% Na₂SO₃And processing and filtering to obtain another batch. (5.1g, total yield 96%)

Step 2, 3-iodo-1H-pyrazolo [3,4-d]Pyrimidin-4-ylamine (11.0g,41.1mmol), 2- (chloromethyl) -1-phenyl-1H-benzo [ d]Imidazole (10.0g,41.4mmol) and K₂CO₃A mixture of (6.0g,43.4mmol) in DMSO (60mL) was stirred at room temperature overnight. The mixture was then added to H₂O (100mL) and extracted with EtOAc (100 mL. times.3). The combined organic matterThe layers were concentrated in vacuo and the residue was purified by silica gel column chromatography (PE: EtOAc =2:1) to give 141(10.0g, 52% yield) as a yellow solid. LCMS (ESI), M + H ⁺=466.04。1HNMR(400MHz,CDCl₃)δ5.783(s,2H),5.785(s,2H),7.068-7.090(q,J=0.8Hz,1H),7.088-7.307(m,3H),7.362-7.422(m,4H),7.800-7.822(d,J=0.8Hz,1H),8.219-8.221(d,J=1.2Hz,2H)

Example 1423-methyl-1- ((1-phenyl-1H-benzo [ d)]Imidazol-2-yl) methyl) -1H-pyrazolo [3,4-d]Pyrimidin-4-amine 142

Step 1:2- (1-ethoxy-ethylene) -malononitrile

Malononitrile (5.0g,76mmol), (EtO)₃CCH₃(14.8g,91mmol) and CH₃The mixture of COOH (1mL) was stirred at 80 ℃ for 45 min. The mixture was then cooled to room temperature and filtered to give 2- (1-ethoxy-ethylene) -malononitrile (8.9g, yield 86%) as a yellow solid.

Step 2-5-amino-3-methyl-1H-pyrazole-4-carbonitrile

To hydrazine H at 0 deg.C₂NNH₂(3.7g,74mmol) to a solution in EtOH (5mL) was added 2- (1-ethoxy-ethylene) -malononitrile (5.0g,37mmol) in one portion. The mixture was then heated to 80 ℃ for 1.5 hours. The mixture was then cooled to room temperature and H was added₂O, cooled with an ice/water bath and filtered to give 5-amino-3-methyl-1H-pyrazole-4-carbonitrile (2.3g, yield 51%) as a yellow solid.

Step 3-3-methyl-1H-pyrazolo [3,4-d ] pyrimidin-4-ylamine

A solution of 5-amino-3-methyl-1H-pyrazole-4-carbonitrile (1.5g,12.3mmol) in formamide (6mL) was stirred at 210 ℃ for 45 min. After cooling to room temperature, the mixture was poured into water (5mL), filtered and washed with water to give 3-methyl-1H-pyrazolo [3,4-d ] pyrimidin-4-ylamine (1.2g, 65% yield) as a gray solid.

Step 4, reacting 3-methyl-1H-pyrazolo [3,4-d]Pyrimidin-4-ylamine (1.2g,8mmol), (2.0g,8mmol) and K₂CO₃A mixture of (1.16g,8.4mmol) in DMSO (40mL) was stirred at 50 ℃ for 3 hours. The mixture was then cooled to room temperature and H was added₂O (50mL), extracted with EtOAc (40 mL. times.3). The combined organic layers were concentrated in vacuo. The residue was purified by P-TLC to give 142(0.8g, yield 28%) as a yellow solid. LCMS (ESI), M + H⁺=354.15。1HNMR(400MHz,CDCl₃)δ2.443(s,3H),5.532(s,2H),5.646(s,2H),7.017-7.037(d,J=8Hz,1H),7.153-7.205(m,4H),7.239-7.258(m,3H),7.720-7.739(d,J=7.6Hz,1H),8.129(s,1H)

Example 143(S) -N- (1- (1-phenyl-1H-benzo [ d ]]Imidazol-2-yl) ethyl) thieno [2,3-d]Pyrimidin-4-amine 143

To a 10-mL sealed tube was placed (1S) -1- (1-phenyl-1H-1, 3-benzodiazol-2-yl) ethan-1-amine (300mg,1.26mmol,1.00equiv), 4-chlorothieno [2,3-d ] from example 4]Pyrimidine (250mg,1.47mmol,1.16equiv), N-ethyl-N-isopropylpropan-2-amine (322mg), and BuOH (5 mL). The resulting solution was stirred at 120 ℃ overnight and concentrated under vacuum. The residue was applied to a silica gel column, eluting with ethyl acetate/petroleum ether (0:100-80:20) to give 260mg (55%) of 143 as a pale yellow solid. LC-MS (ES, M/z):372[ M + H]⁺。1H-NMR(300MHz,CD₃OD,ppm):δ8.19(s,1H),7.70(d,1H),7.68-7.08(m,10H),5.74-5.67(m,1H),1.73(d,3H)

Example 144(S)-5-methyl-N- (1- (1-phenyl-1H-benzo [ d ]]Imidazol-2-yl) ethyl) -7H-pyrrolo [2,3-d]Pyrimidin-4-amine 144

Into a 10-mL sealed test tube was placed (S) -1- (1-phenyl-1H-benzo [ d ] from example 4]Imidazol-2-yl) ethylamine (300mg,1.26mmol,1.00equiv), 4-chloro-5-methyl-7H-pyrrolo [2,3-d]Pyrimidine (250mg,1.49mmol,1.18equiv), N-ethyl-N-isopropylpropan-2-amine (322mg,2.50mmol,1.97equiv) and BuOH (5 mL). The resulting solution was stirred at 120 ℃ overnight and concentrated in vacuo. The residue was applied to a silica gel column, eluting with ethyl acetate/hexane (0:100-80:20) to give 270mg (58%) of 144 as a white solid. LC-MS (ES, M/z):369[ M + H]⁺。H-NMR(300MHz,CD₃OD,ppm):δ7.98(s,1H),7.70-7.53(m,6H),7.33-7.23(m,2H),7.14-7.11(m,1H),6.83(d,1H),5.68-5.61(m,1H),2.49(d,3H),1.67(d,3H)

Example 145(S) -N4- (1- (1-phenyl-1H-benzo [ d)]Imidazol-2-yl) ethyl) pyrimidine-2, 4-diamine 145

A25-mL round bottom flask was charged with a solution of (S) -1- (1-phenyl-1H-benzo [ d ] imidazol-2-yl) ethylamine from example 4 (238mg,1.00mmol,1.00equiv) in ethanol (8mL) and 4-chloropyrimidin-2-amine (130mg,0.99mmol,0.98equiv, 98%). The resulting solution was stirred at 100 ℃ overnight and concentrated under vacuum. The crude product was applied to a C18 column (water/acetonitrile) to yield 150mg (44%)145 as a white solid. LC-MS (ES, M/z) < delta > 331[ M + H ] + H-NMR (300MHz, CD3OD, ppm) < delta > 7.83(d,1H),7.57(M,8H),6.11(q,1H),5.61(q,1H),1.67(d,3H)

Example 146(S) -N4- (1- (1-phenyl-1H-benzo [ d)]Imidazol-2-yl) ethyl) pyrimidine-4, 6-diamine 146

(S) -1- (1-phenyl-1H-benzo [ d ] from example 4]Imidazol-2-yl) ethylamine (321.6mg,1.36mmol,1.00equiv) in dioxaneA solution in an alkane (10mL) and 6-chloropyrimidin-4-amine hydrochloride (456.3mg,2.71mmol,2.00equiv,98%) were stirred in an oil bath at 130 deg.C overnight. Mixing the obtained mixture inConcentrate under vacuum. The residue was applied to a C18 column eluting with acetonitrile/water (0-40%) to give 298.6mg (60%) of 146 hydrochloride salt as yellow crystals. LC-MS (ES, M/z): delta 331[ M + H]+H-NMR:(400MHz,CD3OD,ppm)δ:8.15(s,1H),7.87-7.58(m,8H),7.38-7.36(m,1H),5.88(br s,1H),5.41-5.36(q,1H),1.747-1.73(d,3H)

Example 147(S) -N- (1- (1-phenyl-1H-benzo [ d ]]Imidazol-2-yl) ethyl) -5H-pyrrolo [3,2-d]Pyrimidin-4-amine 147

Into a 25-mL round bottom flask was placed (S) -1- (1-phenyl-1H-benzo [ d ] from example 4]Solution of imidazol-2-yl) ethylamine (238mg,1.00mmol,1.00equiv) in n-BuOH (8mL), 4-chloro-5H-pyrrolo [3,2-d ] from example 20]Pyrimidine (155mg,0.99mmol,0.99equiv,98%) and N-ethyl-N-isopropylpropan-2-amine (400mg,3.03mmol,3.02equiv, 98%). The resulting solution was stirred at 130 ℃ overnight and concentrated under vacuum. The residue was purified by application to a C18 column, eluting with water/acetonitrile (95:5-20:80), to give 150mg (41%)147 as a light yellow solid. LC-MS (ES, M/z):355[ M + H ]⁺。1H-NMR(300MHz,CD₃OD,ppm):δ8.49(s,1H),7.85-7.48(m,9H),7.32-7.30(m,1H),6.63(d,1H),5.81-5.74(m,1H),1.89(d,3H)

Example 148(S) -N- (1- (1-phenyl-1H-benzo [ d ]]Imidazol-2-yl) ethyl) -7H-pyrrolo [2,3-d]Pyrimidin-4-amine 148

Into a 25-mL round bottom flask was placed (S) -1- (1-phenyl-1H-benzo [ d ] from example 4]Solution of imidazol-2-yl) ethylamine (238mg,1.00mmol,1.00equiv) in n-BuOH (5mL), 4-chloro-7H-pyrrolo [2,3-d]Pyrimidine (153mg,1.00mmol,1.00equiv) and N-ethyl-N-isopropylpropan-2-amine (0.5 mL). The resulting solution was stirred at 130 ℃ overnight and concentrated under vacuum. The crude product was purified by application to a C18 column (water/acetonitrile) to yield 150mg (41%)148 as a white solid. LC-MS (ES, M/z):355[ M + H]⁺。H-NMR(300MHz,CD₃OD,ppm):δ7.97(s,1H),7.69(d,1H),7.48(m,5H),7.25(m,2H),7.11(m,2H),6.58(d,1H),5.65(q,1H),1.71(d,3H)

Example 149(S) -N6- (1- (1-phenyl-1H-benzo [ d)]Imidazol-2-yl) ethyl) -9H-purine-2, 6-diamine 149

Into a 25-mL round bottom flask was placed (S) -1- (1-phenyl-1H-benzo [ d ] from example 4]A solution of imidazol-2-yl) ethylamine (238mg,1.00mmol,1.00equiv) in N-BuOH (8mL), 6-chloro-9H-purin-2-amine (155mg,0.91mmol,0.91equiv,98%) and N-ethyl-N-isopropylpropan-2-amine (390mg,2.96mmol,2.95equiv, 98%). The resulting solution was stirred at 130 ℃ overnight and concentrated under vacuum. The residue was eluted on a C18 column (water/acetonitrile) to yield 0.150g (40%)149 as a white solid. LC-MS (ES, M/z):371[ M + H ]⁺。H-NMR(300MHz,CD₃OD,ppm):δ7.71(d,2H),7.51(s,5H),7.29(m,2H),7.10(d,1H),5.67(s,1H),1.69(d,3H)

Example 1502- ((R) -3- (2- ((S) -1- (9H-purin-6-ylamino) ethyl) -1H-benzo [ d]Imidazol-1-yl) piperidin-1-yl) ethanol 150

The [ (S) -1- ((R) -1-piperidin-3-yl-1H-benzimidazol-2-yl) ethyl radical from example 16]A mixture of (9H-purin-6-yl) amine (150mg,0.414mmol), 2-bromoethanol (30 μ L,0.414mmol) and DIPEA (215 μ L,1.24mmol) in IMS (2mL) was stirred in a sealed vial at 70 deg.C for 20H. After cooling to RT, the volatiles were removed under reduced pressure and the resulting residue was purified by column chromatography (Si-PCC with 0-15%2M NH)₃Gradient elution in DCM/MeOH), followed by sonication in cyclohexane for HPLC purification (Phenomenex Gemini5 μmC18, 20min gradient: 5-50% with 0.1% NH₄Acetonitrile/water of OH). The product containing fractions were concentrated in vacuo to afford 150 as a white solid (8mg, 5%). LCMS R_T1.72min[M+H]⁺407.1。¹H NMR(DMSO,400MHz):8.30-8.07(2H,m),7.95(1H,bs),7.73-7.68(1H,m),7.63-7.58(1H,m),7.20-7.11(2H,m),5.93(1H,bs),4.68-4.57(1H,m),4.36(1H,bs),3.48(2H,bs),3.03-2.97(1H,m),2.89-2.77(2H,m),2.52-2.39(3H,m),2.14-2.98(2H,m),1.74-1.66(4H,m),1.61-1.53(1H,m),1.24-1.10(1H,m)

Example 1512- ((R) -3- (2- ((S) -1- (9H-purin-6-ylamino) ethyl) -1H-benzo [ d]Imidazole-1-yl)Piperidin-1-yl) -N, N-dimethylacetamide 151

The [ (S) -1- ((R) -1-piperidin-3-yl-1H-benzimidazol-2-yl) ethyl radical from example 16]A mixture of (9H-purin-6-yl) amine (150mg,0.414mmol), 2-chloro-N, N-dimethylacetamide (43 μ L,0.414mmol) and DIPEA (215 μ L,1.24mmol) in IMS (2mL) was stirred in a sealed vial at 70 ℃ for 20H. After cooling to RT, the volatiles were removed under reduced pressure and the resulting residue was purified by column chromatography (Si-PCC with 0-15%2M NH) ₃Gradient elution in DCM/MeOH) followed by HPLC purification (Phenomenex Gemini5 μm C18, 20min gradient: 5-50% with 0.1% NH₄Acetonitrile/water of OH). The product containing fractions were concentrated in vacuo to afford 151 as a white solid (8mg, 4%). LCMS R_T1.87min[M+H]⁺448.1。¹HNMR(DMSO,400MHz):δ8.24(1H,s),8.10(1H,s),7.95(1H,bs),7.73-7.68(1H,m),7.65-7.58(1H,m),7.21-7.12(2H,m),4.66-4.55(1H,m),3.22(2H,s),3.06-2.88(6H,m),2.80(3H,s),2.75-2.68(1H,m),2.21(1H,t,J=11.73Hz),2.10-1.96(1H,m),1.77-1.6494H,m),1.55(1H,bd,J=13.18Hz),1.13-0.98(1H,m)

Example 1523- (4-amino-1- ((1-phenyl-1H-benzo [ d)]Imidazol-2-yl) methyl) -1H-pyrazolo [3,4-d]Pyrimidin-3-yl) prop-2-yn-1-ol 152

Reacting 3-iodo-1- ((1-phenyl-1H-benzo [ d)]Imidazol-2-yl) methyl) -1H-pyrazolo [3,4-d]Pyrimidin-4-amine 141(1.5g,3.2mmol), prop-2-yn-1-ol (0.4g,6.4mmol), CuI (0.2g,0.64mmol), and Pd (PPh)₃)₂Cl₂(0.25g,0.32mmol) in Et₂The mixture in NH (30mL) was stirred at 25 ℃ for 2 h. The mixture was then added to H₂In O (50mL), with CH₂Cl₂(30 mL. times.3). The combined organic layers were concentrated in vacuo. The residue is treated with CH₂Cl₂Work-up and filtration gave 152(400mg, 32% yield) as a yellow solid. LCMS (ESI), M + H⁺=394.15。1HNMR(400MHz,DMSO)δ4.322-4.337(d,J=6Hz,2H),5.395-5.425(t,J=6Hz,1H),5.710(s,2H),5.735(s,2H),7.090-7.107(d,J=6.8Hz,1H),7.223-7.249(m,2H),7.414-7.491(s,5H),7.643-7.663(d,J=8Hz,1H),8.092(s,1H)

Example 1533- (4-amino-1- ((1-phenyl-1H-benzo [ d)]Imidazol-2-yl) methyl) -1H-pyrazolo [3,4-d]Pyrimidin-3-yl) -5-fluorophenol 153

Reacting 3-iodo-1- ((1-phenyl-1H-benzo [ d)]Imidazol-2-yl) methyl) -1H-pyrazolo [3,4-d]Pyrimidin-4-amine 141(1.0g,2.14mmol), 3-fluoro-5-hydroxyphenylboronic acid (0.4g,2.56mmol), Pd (dppf) Cl ₂(0.2g) and CsF (0.65g,4.3mmol) in DME (20mL) and H₂The mixture in O (2mL) was refluxed overnight. The mixture was then cooled to room temperature and H was added₂O (50mL), extracted with EtOAc (20 mL. times.3). The combined organic layers were washed with brine, washed with Na₂SO₄Dried and then concentrated in vacuo. The residue is treated with CH₂Cl₂Work-up and filtration gave 153(300mg, 31% yield) as a grey solid. LCMS (ESI), M + H⁺=450.16。1HNMR(400MHz,DMSO)δ5.795(s,2H),6.606-6.633(d,J=10.8Hz,1H),6.720-6.724(d,J=8.8Hz,1H),6.800(s,2H),7.065-7.083(d,J=7.2Hz,1H),7.213-7.260(m,2H),7.400(s,5H),7.657-7.676(d,J=7.6Hz,1H),8.119(s,1H),10.139(s,1H)

Example 1543- (1H-indol-3-yl) -1- ((1-phenyl-1H-benzo [ d)]Imidazol-2-yl) methyl) -1H-pyrazolo [3,4-d]Pyrimidin-4-amine 154

To 1- (1-phenyl-1H-benzimidazol-2-ylmethyl) -3- [1- (toluene-4-sulfonyl) -1H-indol-3-yl]-1H-pyrazolo [3,4-d]To a solution of pyrimidin-4-ylamine in EtOH (20mL) was added NaOH (2M,20 mL). After stirring at room temperature overnight, the mixture was concentrated in vacuo. Adding H to the residue₂Using CH in combination with O₂Cl₂And (4) extracting. The combined organic layers were evaporated and the residue was purified by P-HPLC to give 154(500mg, yield 51%) as a white solid. LCMS (ESI), M + H⁺=455.18。1HNMR(400MHz,DMSO)δ5.891(s,2H),7.033-7.068(t,J=7Hz,1H),7.111-7.186(m,2H),7.233-7.284(m,2H),7.458-7.513(m,6H),7.622-7.642(d,J=8Hz,1H),7.682-7.703(d,J=1.8Hz,1H),7.724-7.731(d,J=2.8Hz,1H),8.367(s,1H),11.639-11.644(d,J=2Hz,1H)

Example 1554- (4-amino-1- ((1-phenyl-1H-benzo [ d)]Imidazol-2-yl) methyl) -1H-pyrazolo [3,4-d]Pyrimidin-3-yl) -2-fluorophenol 155

Reacting 3-iodo-1- ((1-phenyl-1H-benzo [ d)]Imidazol-2-yl) methyl) -1H-pyrazolo [3,4-d ]Pyrimidin-4-amine 141(1.5g,3.2mmol), 3-fluoro-4-hydroxyphenylboronic acid (0.6g,3.8mmol), Pd (dppf) Cl₂(0.3g) and CsF (1.0g,6.4mmol) in DME (30mL) and H₂The mixture in O (3mL) was refluxed overnight. The mixture was then cooled to room temperature and H was added₂O (50mL), extracted with EtOAc (30 mL. times.3). The combined organic layers were washed with brine and concentrated in vacuo. The residue is treated with CH₂Cl₂Work-up and filtration gave 155(500mg, 34% yield) as a white solid. LCMS (ESI), M + H⁺=450.16。1HNMR(400MHz,DMSO)δ5.875(s,2H),7.046-7.120(m,2H),7.175-7.200(d,J=1.6Hz,1H),7.242-7.307(m,3H),7.432-7.472(m,5H),7.687-7.708(d,J=1.2Hz,1H),8.335(s,1H)

Example 156N- (6- (4-amino-1- ((1-phenyl-1H-benzo [ d)]Imidazol-2-yl) methyl) -1H-pyrazolo [3,4-d]Pyrimidin-3-yl) benzo [ d]Thiazol-2-yl) acetamide 156

Step 1 preparation of n- (6-bromo-benzothiazol-2-yl) -acetamide

The reaction mixture was washed with 6-bromo-benzothiazol-2-ylamine (3.0g,13mmol), Ac₂O (1.6g,16.5mmol) and DMAP (2.4g,19.5mmol) in CH₂Cl₂The mixture in (50mL) was stirred at room temperature for 1 hour. The mixture was then washed with HCl (2M), saturated Na₂CO₃Then washed with brine and Na₂SO₄And (5) drying. Evaporation of CH₂Cl₂Phase to give n- (6-bromo-benzothia)Oxazol-2-yl) -acetamide (2.5g, 71% yield) as a white solid.

Step 2 n- [6- (4,4,5, 5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -benzothiazol-2-yl ] -acetamide

N- (6-bromo-benzothiazol-2-yl) -acetamide (1.35g,5mmol), 4,4,4',4',5,5,5',5' -octamethyl-2, 2' -bis (1,3, 2-dioxaborolane) (2.51g,10mmol), Pd (dppf) Cl ₂(0.25g,0.3mmol) and potassium acetate CH₃COOK (2.45g,25mmol) in DMSO (20mL) at 80 deg.C under N₂Stirred for 2 hours. The mixture was then cooled to room temperature and H was added₂O (100mL), extracted with EtOAc (40 mL. times.3). The combined organic layers were concentrated in vacuo. The residue was purified by silica gel column chromatography (PE: EtOAc =3:1) to give n- [6- (4,4,5, 5-tetramethyl- [1,3, 2)]Dioxaborolan-2-yl) -benzothiazol-2-yl]Acetamide (1.2g, yield 75%) as a yellow solid.

Step 3, mixing n- [6- (4,4,5, 5-tetramethyl- [1,3,2 ]]Dioxaborolan-2-yl) -benzothiazol-2-yl]-acetamide (1.0g,3.3mmol), 2- (chloromethyl) -1-phenyl-1H-benzo [ d]Imidazole (1.4g,3.0mmol), Pd (dppf) Cl₂(0.5g) and CsF (0.91g,6.0mmol) in DME (20mL) and H₂Mixture in O (2mL) in N₂Reflux overnight. The mixture was then cooled to room temperature and H was added₂O (50mL), extracted with EtOAc (20 mL. times.3). The combined organic layers were washed with brine, washed with Na₂SO₄Dried and concentrated in vacuo. The residue was purified by P-TLC to give 156(400mg, yield 25%) as a brown solid.

Example 1571- ((1-phenyl)-1H-benzo [ d]Imidazol-2-yl) methyl) -1H-pyrazolo [3,4-d]Pyrimidin-6-amine 157

Step 1-4-chloro-1H-pyrazolo [3,4-d ] pyrimidin-6-ylamine

To 2-amino-4, 6-dichloro-pyrimidine-5-carbaldehyde (1.0g,5.2mmol) and Et₃N (0.63g,6.2mmol) in THF (20mL) and H₂To the mixture in O (2mL) was added hydrazine H₂NNH₂(10g,0.2 mol). The mixture was then stirred at room temperature for 1.5 hours. The mixture was then concentrated in vacuo. Adding H to the residue₂O and filtering to obtain 4-chloro-1H-pyrazolo [3,4-d]Pyrimidin-6-ylamine (0.8g, 91% yield) as a yellow solid.

Step 2-4-chloro-1- (1-phenyl-1H-benzimidazol-2-ylmethyl) -1H-pyrazolo [3,4-d ] pyrimidin-6-ylamine

Reacting 4-chloro-1H-pyrazolo [3,4-d]Pyrimidin-6-ylamine (1.0g,5.9mmol), 2- (chloromethyl) -1-phenyl-1H-benzo [ d]Imidazole (1.4g,5.9mmol) and K₂CO₃A mixture of (0.86g,6.2mmol) in DMSO (20mL) was stirred at room temperature overnight. Then adding H to the mixture₂O (50mL) with CH₂Cl₂Extraction (20 mL. times.3). The combined organic layers were concentrated in vacuo to give 4-chloro-1- (1-phenyl-1H-benzoimidazol-2-ylmethyl) -1H-pyrazolo [3,4-d]Pyrimidin-6-ylamine (1.5g, 68% yield) as an orange solid.

Step 3, reacting 4-chloro-1- (1-phenyl-1H-benzimidazol-2-ylmethyl) -1H-pyrazolo [3,4-d]A solution of pyrimidin-6-ylamine (1.5g,4mmol) and Pd/C (0.3g) in MeOH was reacted with H₂40psi were stirred together at 50 deg.C overnight. The mixture was filtered and the filtrate was concentrated in vacuo. Removing residues The residue was purified by P-TLC to give 157(200mg, yield 15%) as a white solid. LCMS (ESI), M + H⁺=340.14。1HNMR(400MHz,DMSO)δ5.0374(s,2H),5.597(s,2H),7.015(s,1H),7.152-7.211(m,5H),7.309-7.327(m,3H),7.746(s,2H),8.567(s,1H)

Example 158(S) -8-methyl-N- (1- (1-phenyl-1H-benzo [ d)]Imidazol-2-yl) ethyl) -9H-purin-6-amine 158

Step 1 6-chloro-8-methyl-9H-purine

A solution of N- (4-amino-6-oxo-1, 6-dihydropyrimidin-5-yl) acetamide (330mg,1.92mmol,1.00equiv,98%) in phosphorus oxychloride (5mL) was refluxed overnight. The resulting mixture was concentrated under vacuum. The residue was redissolved in 10mL ethyl acetate and washed with 10mL saturated aqueous sodium bicarbonate, 1X 10mL water, and 1X 10mL brine. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo to give 20mg (6%) of 6-chloro-8-methyl-9H-purine as a yellow solid.

Step 2A solution of (1S) -1- (1-phenyl-1H-1, 3-benzodiazol-2-yl) ethan-1-amine (150mg,0.62mmol,1.00equiv,98%), 6-chloro-8-methyl-9H-purine (150mg,0.87mmol,1.41equiv) and ethylbis (propan-2-yl) amine (0.3mL,98%) from example 4 in butan-1-ol (6mL) was stirred at 130 ℃ overnight. The resulting mixture was concentrated under vacuum. The residue was purified on a C18 column, eluting with water/acetonitrile to give 75mg (30%) of 158 as a white solid. LC-MS (ES, M/z)370[ M + H ] +. H-NMR (300MHz, CD3OD, ppm) delta 8.04(s,1H),7.69(d,1H),7.55(m,5H),7.30(m,2H),7.11(d,1H),5.63(s,1H),2.55(s,3H),1.71(d,3H)

Example 159(S) -1-methyl-N- (1- (1-phenyl-1H-benzo [ d)]Imidazol-2-yl) ethyl) -1H-pyrazolo [4,3-d]Pyrimidin-5-amines 159

Step 1N- (2-chloro-4-methylpyrimidin-5-yl) acetamide

A solution of 2-chloro-4-methylpyrimidin-5-amine (10g,68.26mmol,1.00equiv,98%) and acetic anhydride (14.3g,137.27mmol,2.01equiv,98%) in acetic acid (50mL) was stirred at room temperature for 2 h. The resulting mixture was concentrated in vacuo to give 11g (82%) of N- (2-chloro-4-methylpyrimidin-5-yl) acetamide as an off-white solid.

Step 2 1- [ 5-chloro-1H-pyrazolo [4,3-d ] pyrimidin-1-yl ] ethan-1-one

A solution of N- (2-chloro-4-methylpyrimidin-5-yl) acetamide (9g,46.06mmol,1.00equiv,95%), potassium acetate (3.3g,32.95mmol,0.72equiv,98%), acetic anhydride (17.27g,165.78mmol,3.60equiv) and isoamyl nitrite (13.6g,116.24mmol,2.52equiv,98%) in chloroform (180mL) was refluxed overnight. The resulting mixture was washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo to give 7g (73%) of 1- [ 5-chloro-1H-pyrazolo [4,3-d ] pyrimidin-1-yl ] ethan-1-one as a white solid.

Step 3 5-chloro-1H-pyrazolo [4,3-d ] pyrimidine

Hydrochloric acid (70mL,8%) was added dropwise to a solution of 1- [ 5-chloro-1H-pyrazolo [4,3-d ] pyrimidin-1-yl ] ethan-1-one (7g,33.83mmol,1.00equiv,95%) in tetrahydrofuran (70mL) at 50 ℃. The resulting solution was refluxed for 30min and then extracted with 2X 100mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated in vacuo to give 2.5g (45%) of 5-chloro-1H-pyrazolo [4,3-d ] pyrimidine as a white solid.

Step 4 5-chloro-1-methyl-1H-pyrazolo [4,3-d ] pyrimidine

Potassium tert-butoxide (1.68g,14.67mmol,1.14equiv) was added to a solution of 5-chloro-1H-pyrazolo [4,3-d ] pyrimidine (2.1g,12.91mmol,1.00equiv,95%) in tetrahydrofuran (50mL) at 0 ℃. After stirring the reaction mixture at 0 ℃ for 30min, methyl iodide (3g,20.71mmol,1.60equiv,98%) was added dropwise at 0 ℃. The resulting solution was stirred at room temperature for 4.5h, then concentrated under vacuum. The residue was loaded onto a silica gel column and eluted with dichloromethane/ethyl acetate (10/1) to give 300mg (14%) of 5-chloro-1-methyl-1H-pyrazolo [4,3-d ] pyrimidine as a white solid.

Step 5 (S) -1- (1-phenyl-1H-benzo [ d ] from example 4]Imidazol-2-yl) ethylamine (200mg,0.83mmol,1.00equiv,98%), 5-chloro-1-methyl-1H-pyrazolo [4, 3-d)]A solution of pyrimidine (180mg,1.07mmol,1.29equiv) and methyl bis (propan-2-yl) amine (0.3mL,98%) in n-butanol (8mL) was stirred at 130 ℃ for 96 h. The resulting mixture was concentrated in vacuo and the residue was purified on a C18 column, eluting with water/acetonitrile to give 110mg (31%)159 as a pale yellow solid. LC-MS (ES, M/z)370[ M + H]⁺,221,115。H-NMR:(CD₃OD,300Hz,ppm)δ8.86(s,1H),7.70(s,1H),7.65-7.54(m,6H),7.61(d,2H),7.09(s,1H),5.30(m,1H),4.04(s,3H),1.64(d,3H)

Example 160(S) -N- (1- (6-fluoro-1-phenyl-1H-benzo [ d)]Imidazol-2-yl) propyl) -7H-purin-6-amine 160

A mixture of (S) -1- (6-fluoro-1-phenyl-1H-benzimidazol-2-yl) propylamine from example 28 (42mg,0.16mmol), 6-chloro-9- (tetrahydropyran-2-yl) -9H-purine (37mg,0.16mmol) and DIPEA (0.14mL,0.8mmol) in n-butanol (1mL) was stirred in a sealed vial at 90 ℃ for 16H. After cooling toAfter RT, the crude reaction mixture is loadedOn SCX-2, it is washed with MeOH and then with 2M NH₃Washing with MeOH. The basic fractions were combined and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC,0-10%2 MNH)₃Gradient MeOH in DCM) to give 160 as a white solid (13mg, 21%). LCMS R_T3.61min[M+H]⁺388.1。¹H NMR(DMSO,400MHz):δ8.22-8.03(2H,m),7.80(1H,s),7.71-7.43(6H,m),7.09(1H,t,J=9.42Hz),6.85(1H,d,J=8.93Hz),5.38(1H,s),2.08-1.88(2H,m),0.83(3H,t,J=7.34Hz)

Example 161(S) -N- (1- (5-fluoro-1-phenyl-1H-benzo [ d)]Imidazol-2-yl) ethyl) -7H-purin-6-amine 161

A mixture of (S) -1- (5-fluoro-1-phenyl-1H-benzimidazol-2-yl) ethylamine (379mg,1.4mmol), 6-chloro-9- (tetrahydropyran-2-yl) -9H-purine (340mg,1.4mmol), and DIPEA (1.2mL,7.0mmol) in n-butanol (7mL) from example 29 was stirred in a sealed vial at 90 ℃ for 18H. After cooling to RT, the volatile substances were removed under reduced pressure and the residue obtained was loadedOn SCX-2, it is washed with MeOH and then with 2M NH₃Washing with MeOH. The basic fractions were combined and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC,0-10%2M NH) ₃Gradient elution in DCM/MeOH) gave 161(65mg, 12%). LCMS R_T3.34min[M+H]⁺374.1。¹H NMR(DMSO,400MHz):δ8.19-8.00(2H,m),7.92(1H,s),7.67-7.41(6H,m),7.06(2H,d,J=7.13Hz),5.47(1H,s),1.56(3H,d,J=6.83Hz)

Example 1629- ((3-phenyl-1H-indol-2-yl) methyl) -9H-purin-6-amine 162

9- [ 3-phenyl-1- (toluene-4-sulfonyl) -1H-indol-2-ylmethyl from example 22]-9H-purin-6-ylamine (330mg,0.667mmol) and 2M KOHA mixture (1.3mL) in MeOH (20mL) was stirred at 70 ℃ for 5 h. Volatiles were removed under reduced pressure and the resulting residue was diluted with water. The pH of the solution was adjusted to 1 by addition of 1M HCl and then by addition of saturated NaHCO₃The solution was adjusted to pH 8. The aqueous layer was extracted with EtOAc (. times.3) and the combined organic layers were dried (Na)₂SO₄) And concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient eluted with 0-9% MeOH in DCM) to give 162 as a white solid (102mg, 45%). LCMS R_T3.79min[M+H]⁺341.2。¹H NMR(DMSO,400MHz):δ11.31(1H,s),8.16(1H,s),8.02(1H,s),7.64-7.59(2H,m),7.57(1H,d,J=7.96Hz),7.50(2H,t,J=7.96Hz),7.43-7.33(2H,m),7.24(2H,s),7.16(1H,t,J=7.50Hz),7.07(1H,t,J=7.50Hz),5.59(2H,s)

Example 1639- ((3-Phenylbenzofuran-2-yl) methyl) -9H-purin-6-amine 163

To a mixture of NaH (60% in mineral oil, 18mg,0.43mmol) in DMF (5mL) at 0 deg.C was added 9H-purin-6-ylamine (54mg,0.397 mmol). After stirring at 0 ℃ for 5min, a solution of 3-phenylbenzofuran-2-ylmethyl methanesulfonate from example 25 (100mg,0.331mmol) in DMF (1mL) was added dropwise, the mixture was slowly warmed to RT and stirred at RT for 2.5 h. The reaction mixture was then quenched by the addition of water and diluted with DCM. The organic layer was dried (Na) ₂SO₄) And concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient elution with 0-10% MeOH in EtOAc) triturated with EtOAc with cyclohexane to afford 163 as an off-white solid (33mg, 29%). LCMS R_T3.85min[M+H]⁺342.1。¹H NMR(DMSO,400MHz):δ8.21(1H,s),8.11(1H,s),7.79-7.74(2H,m),7.63-7.53(4H,m),7.50-7.44(1H,m),7.38-7.27(2H,m),7.23(2H,s),5.65(2H,s)

Example 1641- ((3-Phenylbenzo [ b ]]Thien-2-yl) methyl) -1H-pyrazolo [3,4-d]Pyrimidin-4-amines 164

NaH (60% in mineral oil, 13mg,0.314mmol) was added to 1H-pyrazolo [3,4-d ] in one portion at RT]Pyrimidin-4-ylamine (42mg,0.314mmol) inIn a mixture in DMF (5 mL). After stirring for 5min, methanesulfonic acid 3-phenylbenzo [ b ] from example 26 was added dropwise]A solution of thien-2-ylmethyl ester (100mg,0.314mmol) in DMF (1mL) was stirred at RT for a further 30 min. The reaction mixture was then quenched by the addition of water and diluted with EtOAc. The aqueous phase was further extracted with EtOAc (2X 100mL) and the combined organic layers were washed with brine and then dried (Na)₂SO₄) And concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient elution with 0-10% MeOH in EtOAc) and triturated with MeOH with water to give 164 as an off-white solid (17mg, 15%). LCMS R_T4.13min[M+H]⁺358.1。¹H NMR(DMSO,400MHz):δ8.23(1H,s),8.16(1H,s),7.95-7.90(1H,m),7.70-7.59(4H,m),7.56-7.49(2H,m),7.42-7.35(2H,m),5.72(2H,s)

Example 165N- ((3-phenylbenzo [ b ]]Thien-2-yl) methyl) -9H-purin-6-amine 165

The C- (3-phenylbenzo [ b ] from example 26 ]A mixture of thiophen-2-yl) methylamine (230mg,0.961mmol), 6-chloro-9H-purine (278mg,1.80mmol) and DIPEA (0.34mL,1.92mmol) in n-butanol (10mL) was heated at 100 ℃ for 20H. After cooling to RT, the volatiles were removed under reduced pressure and the resulting residue was purified by column chromatography (Si-PCC, gradient eluted with 0-10% MeOH in DCM) followed by sonication in ether. Further purification by column chromatography (Si-PCC, gradient eluted with 0-5% MeOH in DCM) afforded 165 as a white solid (132mg, 38%). LCMS R_T4.22min[M+H]⁺358.1。¹H NMR(DMSO,400MHz):δ12.96(1H,s),8.40(1H,s),8.23(1H,s),8.14(1H,s),7.94-7.85(1H,m),7.63-7.54(4H,m),7.51-7.43(2H,m),7.38-7.29(2H,m),4.94(2H,s)

Example 1669- ((3-Phenylbenzo [ b ]]Thien-2-yl) methyl) -9H-purin-6-amine 166

NaH (60% in mineral oil, 15mg,0.377mmol) was added in one portion to a mixture of 9H-purin-6-ylamine (47mg,0.345mmol) in DMF (3mL) at RT. After stirring for 5min, methanesulfonic acid 3-phenylbenzo [ b ] from example 26 was added dropwise]Thien-2-ylmethylA solution of the base ester (100mg,0.314mmol) in DMF (2mL) was stirred at RT for a further 30 min. The reaction mixture was then quenched by the addition of water to form a solid. The precipitate was collected by filtration and purified by column chromatography (Si-PCC, gradient eluted with 0-10% MeOH in EtOAc) triturated with ether to give 166 as a white solid (52mg, 46%). LCMS R _T3.99min[M+H]⁺358.1。¹H NMR(DMSO,400MHz):δ8.15(1H,s),8.06(1H,s),7.98-7.92(1H,m),7.64-7.59(4H,m),7.57-7.46(2H,m),7.42-7.37(2H,m),7.27(2H,s),5.63(2H,s)

Example 1679- ((3-o-tolylbenzo [ b)]Thien-2-yl) methyl) -9H-purin-6-amine 167

NaH (60% in mineral oil, 16mg,0.39mmol) was added in one portion to a solution of 9H-purin-6-ylamine (49mg,0.36mmol) in DMF (5mL) at RT. After stirring for 5min, methanesulfonic acid 3-o-tolylbenzo [ b ] from example 27 was added dropwise]A solution of thien-2-ylmethyl ester (100mg,0.30mmol) in DMF (1mL) was stirred at RT for a further 19 h. The reaction mixture was then quenched by the addition of water to form a solid. The precipitate was collected by filtration and purified by column chromatography (Si-PCC gradient eluted with 0-10% MeOH in EtOAc) to give 167 as a white solid (75mg, 67%). LCMS R_T4.13min[M+H]⁺372.1。¹H NMR(DMSO,400MHz):δ8.11(1H,s),7.96-7.88(2H,m),7.45-7.30(6H,m),7.23(2H,s),7.12-7.07(1H,m),5.46(1H,d,J=16.2Hz),5.38(1H,d,J=16.2Hz),1.99(3H,s)

Example 168(9H-purin-6-yl) - [1- (3-o-tolyl-3H-imidazo [4,5-b ]]Pyridin-2-yl) -ethyl]Amine 168

Reacting (S) -1- (3-o-tolyl-3H-imidazo [4, 5-b)]A mixture of pyridin-2-yl) ethylamine (330mg,1.31mmol), 6-chloro-9- (tetrahydropyran-2-yl) -9H-purine (430mg,1.83mmol) and DIPEA (0.41mL,2.35mmol) in n-butanol (2mL) was heated at 90 ℃ for 16H in a sealed vial. After cooling to RT, the crude reaction mixture is loadedSCX-2 column and MeOH, then 2M NH ₃Washing with MeOH. The product containing fractions were combined and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC with 0-10%2M NH)₃Gradient MeOH in DCM) to give 168 as a white solid (155mg, 32%). LCMS (method K) R_T2.70 and 2.83min [ M + H ]]⁺371.1。¹H NMR(DMSO-d₆400 MHz). delta.12.89 (1H, s),8.30-7.86(4H, m),7.69-7.08(5H, m),5.47(1H, s),1.96(3H, s),1.68(1.5H, d, J =6.77Hz),1.50(1.5H, d, J =6.84 Hz). Due to the presence of rotamers/tautomers, the signal is cleaved.

Example 169[ (S) -1- (3-phenyl-3H-imidazo [4, 5-b)]Pyridin-2-yl) -propyl]- (9H-purin-6-yl) -amine 169

Reacting (S) -1- (3-phenyl-3H-imidazo [4, 5-b)]A mixture of pyridin-2-yl) propylamine (430mg,1.70mmol), 6-chloro-9- (tetrahydropyran-2-yl) -9H-purine (560mg,2.39mmol) and DIPEA (0.54mL,3.07mmol) in n-butanol (3mL) was heated at 90 ℃ for 16H in a sealed vial. After cooling to RT, the crude reaction mixture is loadedSCX-2 column, washing with MeOH, then 2M NH₃Washing with MeOH. The basic fractions were combined and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC with 0-8%2M NH)₃Gradient elution in DCM/MeOH) afforded 169 as a white solid (136mg, 22%). LCMS (method K) R _T2.89min[M+H]⁺371.1。¹H NMR(DMSO-d₆,400MHz):δ12.91(1H,s),8.30-7.70(5H,m),7.68-7.21(6H,m),5.42(1H,s),2.01(2H,bs),1.01-0.71(3H,m)。

Example 1703- {2- [ (S) -1- (9H-purin-6-ylamino) -ethyl]-benzimidazol-1-yl } -benzonitrile 170

Reacting 3- [2- ((S) -1-aminoethyl) benzimidazol-1-yl]A mixture of benzonitrile (54mg,0.21mmol), 6-chloro-9- (tetrahydropyran-2-yl) -9H-purine (69mg,0.29mmol) and DIPEA (65. mu.L, 0.37mmol) in n-butanol (0.5mL) in 9Heat at 0 ℃ for 16h in a sealed vial. After cooling to RT, the crude reaction mixture is loadedSCX-2 column, washing with MeOH, then 2M NH₃Washing with MeOH. The basic fractions were combined and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC with 0-10%2M NH)₃Gradient elution in DCM/MeOH) followed by preparative HPLC purification (Phenomenex Gemini5 μm C18 with 20-98% of 0.1% HCO)₂Acetonitrile/water gradient of H) to give 170 as a white solid (29 m)_g37%). LCMS (method K) R_T3.03min[M+H]⁺381.0。¹H NMR(DMSO-d₆,400MHz):δ12.90(1H,s),8.25-7.49(8H,m),7.32-7.17(2H,m),7.09(1H,d,J=7.84Hz),5.60(1H,s),1.64(3H,d,J=6.81Hz)

Example 171[1- (6-fluoro-1-phenyl-1H-benzimidazol-2-yl) -2-methoxy-ethyl]- (7H-purin-6-yl) -amine 171

A mixture of (R) -1- (6-fluoro-1-phenyl-1H-benzimidazol-2-yl) -2-methoxyethylamine (110mg,0.39mmol), 6-chloro-9- (tetrahydropyran-2-yl) -9H-purine (93mg,0.39mmol) and DIPEA (340 μ L,1.9mmol) in n-butanol (2.5mL) was heated at 90 ℃ for 18H in a sealed vial. After cooling to RT, the volatile substances were removed under reduced pressure and the residue obtained was loaded SCX-2 column, washing with MeOH, then 2M NH₃Washing with MeOH. The product containing fractions were combined and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC with 0-10%2M NH)₃Gradient elution in DCM/MeOH) afforded 171 as a white solid (51 m)_g32%). LCMS (method B) R_T3.52min[M+H]⁺404.0。¹H NMR(DMSO-d₆400 MHz). delta.8.25-8.01 (2H, m),7.87(1H, s),7.77-7.47(6H, m),7.15-7.05(1H, m),6.87(1H, dd, J =8.93,2.37Hz),5.64(1H, s),3.84(2H, d, J =6.60Hz),3.14(3H, s). Due to the presence of rotamers/tautomersSignal splitting.

Example 1722- (6-fluoro-1-phenyl-1H-benzimidazol-2-yl) -2- (7H-purin-6-ylamino) -ethanol 172

To [ (R) -2-benzyloxy-1- (6-fluoro-1-phenyl-1H-benzimidazol-2-yl) ethyl at 0 ℃ under a nitrogen atmosphere]To a solution of (7H-purin-6-yl) amine (124mg,0.26mmol) in anhydrous DCM (3mL) was added boron tribromide (1.0M in DCM, 0.3mL,0.26mmol) dropwise. The reaction mixture was slowly warmed to RT and stirred at RT for 1 h. Addition of additional BBr₃(0.3mL) and stirring was continued for 1 h. MeOH was then added and volatiles were removed under reduced pressure. The resulting residue was purified by column chromatography (Si-PCC with 0-10%2M NH)₃Gradient elution in DCM/MeOH) gave 172(60mg, 59%). LCMS (method K) R _T3.11min[M+H]⁺390.0。¹HNMR(DMSO-d₆400 MHz). delta.12.93 (0.8H, s),12.17(0.2H, s),8.27-8.01(2H, m),7.74-7.43(6H, m),7.16-7.01(1H, m),6.93-6.79(1H, m),5.56-5.31(1H, m),5.21-5.02(1H, m),3.95-3.74(2H, m). Signal cleavage due to the presence of rotamers/tautomers

Example 173[ (S) -1- (6-chloro-1-phenyl-1H-benzimidazol-2-yl) -ethyl]- (9H-purin-6-yl) -amine 173

A mixture of (S) -1- (6-chloro-1-phenyl-1H-benzimidazol-2-yl) ethylamine (796mg,2.93mmol), 6-chloro-9- (tetrahydropyran-2-yl) -9H-purine (769mg,3.22mmol) and DIPEA (1.50mL,8.79mmol) in n-butanol (6mL) was heated at 100 ℃ for 17H in a sealed vial. After cooling to RT, the volatile substances were removed under reduced pressure and the residue obtained was loadedSCX-2 column, washing with MeOH, then 2M NH₃Washing with MeOH. The basic fractions were combined and concentrated in vacuo. The resulting residue was triturated with hot MeOH to give 173 as an off-white solid (334mg, 29%). LCMS (method K) R_T3.73min[M+H]⁺390.0。¹H NMR(DMSO-d₆,400MHz):δ12.85(1H,s),8.18-8.04(2H,m),7.94(1H,s),7.71-7.45(6H,m),7.26(1H,dd,J=8.57,2.01Hz),7.05(1H,d,J=1.97Hz),5.48(1H,s),1.56(3H,d,J=6.84Hz)

Example 1744- { 6-fluoro-2- [ (S) -1- (9H-purin-6-ylamino) -ethyl]-benzimidazol-1-yl } -cyclohexanecarbonitrile 174

Reacting 4- [2- ((S) -1-aminoethyl) -6-fluorobenzoimidazol-1-yl]A mixture of cyclohexanecarbonitrile (100mg,0.35mmol), 6-chloro-9- (tetrahydropyran-2-yl) -9H-purine (91mg,0.38mmol) and DIPEA (0.10mL,0.72mmol) in n-butanol (0.7mL) was heated at 105 ℃ for 48H. After cooling to RT, the crude reaction mixture was taken up with 4N HCl bis Treated with an alkane solution (0.5mL) and stirred at RT for 1 h. Loading the crude mixture intoSCX-2 column, washing with MeOH, then 2M NH₃Washing with MeOH. The basic fractions were combined, concentrated in vacuo, and the resulting residue was purified by column chromatography (Si-PCC, gradient eluted with 0-8% MeOH in DCM), then triturated with hot EtOAc and purified by preparative HPLC (Phenomenex Gemini5 μm C18, 0-40% HCl with 0.1% HCO)₂Acetonitrile/water gradient elution of H) to give 174 as a white solid (26 m)_g18%). LCMS (method K) R_T2.93min[M+H]⁺405.1。¹H NMR(DMSO-d₆400MHz delta 12.45(1H, s),8.34-7.94(3H, m),7.71-7.56(2H, m),7.05-6.96(1H, m),5.96(1H, bs),4.62-4.59(1H, m),3.09-2.95(1H, m),2.38-2.25(1H, m),2.21-2.07(2H, m),1.93(1H, bd, J =12.75Hz),1.84(1H, bd, J =12.00Hz),1.73-1.65(5H, m),1.02(1H, bs). Due to the presence of rotamers/tautomers, are broad signals

Example 175(1R,2R) -1- (6-fluoro-1-phenyl-1H-benzimidazol-2-yl) -1- (7H-purin-6-ylamino) -propan-2-ol 175

To the mixture of [ (1R,2R) -2-benzyloxy-1- (6-fluoro-1-phenyl-1H-benzimidazole-2-Yl) propyl group]To a solution of (7H-purin-6-yl) amine (128mg,0.26mmol) in anhydrous DCM (3mL) was added boron tribromide (1.0M in DCM, 0.5mL,0.5mmol) dropwise. The reaction mixture was slowly warmed to RT and stirred at RT for 1.5 h. MeOH was added and volatiles were removed under reduced pressure. The resulting residue was purified by column chromatography (Si-PCC,0-10%2M NH) ₃Gradient MeOH in DCM) to give 175(25mg, 24%). LCMS (method K) R_T3.30min[M+H]⁺404.1。¹H NMR(DMSO-d₆400MHz delta 12.99(1H, s),8.32-8.06(2H, m),7.83-7.48(6H, m),7.28-7.03(2H, m),6.88(1H, dd, J =8.94,2.49Hz),5.18(1H, s),4.20-4.02(2H, m),1.08-0.93(3H, m). Due to the presence of rotamers/tautomers, the signal is cleaved.

Example 176[1- (6-fluoro-1-pyridin-3-yl-1H-benzimidazol-2-yl) -ethyl]- (9H-purin-6-yl) -amine 176

A mixture of (S) -1- (6-fluoro-1-pyridin-3-yl-1H-benzimidazol-2-yl) ethylamine (81mg,0.32mmol), 6-chloro-9- (tetrahydropyran-2-yl) -9H-purine (83mg,0.35mmol) and DIPEA (162. mu.L, 0.95mmol) in n-butanol (1mL) was heated at 90 ℃ for 65H in a sealed vial. After cooling to RT, the volatile substances were removed under reduced pressure and the residue obtained was loadedSCX-2 column, add MeOH and then 2M NH₃MeOH wash (three replicates with SCX column). The product containing fractions were combined and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient eluted with 0-10% MeOH in DCM) then triturated with MeOH to give 176 as an off-white solid (47mg, 40%). LCMS (method K) R_T2.75min[M+H]⁺375.0。¹H NMR(DMSO-d₆,400MHz):δ12.65(1H,s),8.79(1H,d,J=2.46Hz),8.61(1H,s),8.15-7.91(4H,m),7.71(1H,dd,J=8.80,4.84Hz),7.55-7.46(1H,m),7.11(1H,td,J=9.33,2.43Hz),6.93(1H,dd,J=8.91,2.44Hz),5.49(1H,s),1.62(3H,d,J=6.83Hz)

Example 177(9H-purin-6-yl) - [ (S) -1- (3-m-tolyl-3H-imidazole Azolo [4,5-b ] s]Pyridin-2-yl) -ethyl]-amine 177

Reacting (S) -1- (3-m-tolyl-3H-imidazo [4, 5-b)]A mixture of pyridin-2-yl) ethylamine (420mg,1.66mmol), 6-chloro-9- (tetrahydropyran-2-yl) -9H-purine (550mg,2.33mmol) and DIPEA (0.52mL,3.00mmol) in n-butanol (3mL) was heated at 90 ℃ for 16H in a sealed vial. After cooling to RT, the crude reaction mixture is loadedSCX-2 column, washing with MeOH, then 2M NH₃Washing with MeOH. The basic fractions were combined and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC with 0-10%2M NH)₃Gradient MeOH in DCM) gave 177 as a white solid (190mg, 31%). LCMS (method K) R_T2.84min[M+H]⁺371.0。¹H NMR(DMSO-d₆400 MHz). delta.12.90 (1H, s),8.33-7.77(5H, m),7.45-7.14(5H, m),5.56(1H, br),2.25(3H, s),1.58(3H, d, J =6.81 Hz). Due to the presence of rotamers/tautomers, a broad signal.

Example 178[ (S) -1- (7-bromo-6-fluoro-1-phenyl-1H-benzimidazol-2-yl) -ethyl]- (9H-purin-6-yl) -amine 178

Reacting 4N HClAn alkane solution (0.5mL) was added to [ (S) -1- (7-bromo-6-fluoro-1-phenyl-1H-benzimidazol-2-yl) ethyl]- [9- (tetrahydropyran-2-yl) -9H-purin-6-yl]A solution of amine (128mg,0.24mmol) in MeOH (3mL) and the mixture was stirred at RT for 30 min. Volatiles were removed under vacuum and the resulting residue was purified by HPLC (Phenomenex Gemini5 μm C18, 25min gradient: 10-90 with 0.1% HCO ₂H acetonitrile/water) to yield 178(88mg, 81%). LCMS (method K) R_T3.82min[M+H]⁺451.9/453.8。¹H NMR(DMSO-d₆,400MHz):δ8.19-7.86(3H,m),7.70(1H,dd,J=8.75,4.59Hz),7.64-7.33(5H,m),7.26(1H,t,J=9.22Hz),5.22(1H,s),1.56(3H,d,J=6.87Hz)

Example 179[1- (7-chloro-6-fluoro-1-phenyl-1H-benzimidazol-2-yl) -ethyl]- (9H-purin-6-yl) -amine 179

A solution of 4N HCl in dioxane (0.5mL) was added to [ (S) -1- (7-chloro-6-fluoro-1-phenyl-1H-benzimidazol-2-yl) ethyl]- [9- (tetrahydropyran-2-yl) -9H-purin-6-yl]A solution of amine (166mg,0.34mmol) in MeOH (5mL) and the mixture stirred at RT for 1 h. Volatiles were removed under vacuum and the resulting residue was purified by HPLC (Phenomenex Gemini5 μm C18, 25min gradient: 10-90% with 0.1% HCO₂H acetonitrile/water) to yield 179(96mg, 69%). LCMS (method K) R_T3.80min[M+H]⁺408.0/409.9/411.08。¹H NMR(DMSO-d₆,400MHz):δ8.22-7.83(3H,m),7.69-7.34(6H,m),7.33-7.24(1H,t,J=9.50Hz),5.25(1H,s),1.56(3H,d,J=6.88Hz)

Example 181[ (S) -1- (6-fluoro-1-phenyl-1H-benzimidazol-2-yl) -ethyl]-methyl- (9H-purin-6-yl) -amine 181

Reacting [ (S) -1- (6-fluoro-1-phenyl-1H-benzimidazol-2-yl) ethyl]A mixture of methylamine (102mg,0.38mmol), 6-chloro-9- (tetrahydropyran-2-yl) -9H-purine (91mg,0.38mmol) and DIPEA (0.33mL,1.9mmol) in n-butanol (2mL) was heated at 90 ℃ for 18H in a sealed vial. After cooling to RT, the volatile substances were removed under reduced pressure and the residue obtained was loadedSCX-2 column. The column was washed with MeOH, then 2M NH₃Washing with MeOH. The basic fractions were combined, concentrated in vacuo and the residue purified by column chromatography (Si-PCC with 0-10%2M NH) ₃Gradient elution in DCM/MeOH) gave 181(123mg, 84%). LCMS (method K) R_T3.39min[M+H]⁺388.1。¹H NMR(DMSO-d₆,400MHz,80℃):δ7.99(1H,s),7.90(1H,s),7.75(1H,dd,J=8.81,4.87Hz),7.30-7.22(2H,m),7.17-6.95(5H,m),6.73(1H,dd,J=8.93,2.53Hz),3.12(3H,br s),1.71(3H,d,J=6.76Hz)

Example 182[1- (6-fluoro-1-pyridin-2-yl-1H-benzimidazol-2-yl) -ethyl]- (9H-purin-6-yl) -amine 182

Reacting (S) -N- [ 4-fluoro-2- (pyridin-2-ylamino) phenyl]A mixture of-2- (9H-purin-6-ylamino) propionamide (130mg,0.332mmol) in AcOH (1mL) was heated at 80 ℃ for 2H. A second portion of (S) -N- [ 4-fluoro-2- (pyridin-2-ylamino) phenyl]-2- (9H-purin-6-ylamino) propionamide (136mg,0.347mmol) was heated in AcOH (5mL) at 100 ℃ for 2H. The two crude reaction mixtures were combined and the volatiles were removed under vacuum. The resulting residue was washed with EtOAc and saturated NaHCO₃The aqueous solution was partitioned. The organic layer was washed with water, then brine, then dried (Na)₂SO₄) And concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient eluted with 0-10% MeOH in DCM) then triturated in MeOH/ether to give 182 as an off-white solid (66mg, 26%). LCMS (method K) R_T2.94min[M+H]⁺375.0。¹H NMR(DMSO-d₆,400MHz):δ12.89(1H,br s),8.61(1H,br s),8.20-7.80(4H,m),7.79-7.67(2H,m),7.52-7.43(1H,m),7.20-7.08(2H,m),5.86(1H,br s),1.63(3H,d,J=6.82Hz)

Example 183[ (S) -1- (6-fluoro-7-methyl-1-phenyl-1H-benzimidazol-2-yl) -ethyl]- (9H-purin-6-yl) -amine 183

A mixture of (S) -1- (6-fluoro-7-methyl-1-phenyl-1H-benzimidazol-2-yl) ethylamine dihydrochloride (330mg,1.23mmol), 6-chloro-9- (tetrahydropyran-2-yl) -9H-purine (351mg,1.47mmol) and DIPEA (320. mu.L, 2.45mmol) in n-butanol (6mL) was heated at 90 ℃ for 18H in a sealed vial. After cooling to RT, the volatiles were removed under reduced pressure and the resulting residue was purified by column chromatography (Si-PCC gradient elution with 0-10% MeOH in EtOAc). The compound thus obtained was dissolved in MeOH (5mL) and 4N HCl The solution in alkane solution (1ml) was stirred at RT for 1h, then the volatiles were removed under reduced pressure. The resulting residue was washed with EtOAc and saturated NaHCO₃Partitioning between solutions. A white solid precipitated out and was collected by filtration to give 183(333mg, 70%). LCMS (method K) R_T3.46min[M+H]⁺388.1。¹HNMR(DMSO-d₆,400MHz):δ12.55(1H,s),8.06-8.00(2H,m),7.71-7.39(7H,m),7.05(1H,dd,J=10.58,8.77Hz),5.30(1H,br s),1.70(3H,d,J=1.84Hz),1.53(3H,d,J=6.84Hz)

Example 185{ (S) -1- [ 6-fluoro-1- (3-fluoro-phenyl) -1H-benzimidazol-2-yl]-ethyl } - (9H-purin-6-yl) -amine 185

Reacting (S) -1- [ 6-fluoro-1- (3-fluorophenyl) -1H-benzimidazol-2-yl]Ethylamine (0.45g,1.64mmol) was dissolved in n-butanol (10mL) and 6-chloro-9- (tetrahydropyran-2-yl) -9H-purine (0.39g,1.64mmol) and DIPEA (1.45mL,8.24mmol) were added. The reaction mixture was heated at 90 ℃ overnight. The resulting mixture was then cooled to RT and concentrated in vacuo. Passing the residue throughSCX-2 column with DCM, MeOH and 2M NH₃Eluted with MeOH to give crude product. This material was purified by column chromatography (silica gel, gradient eluted with 0-7.5% MeOH in DCM) to afford 185 as an off-white solid (100mg, 20%). LCMS (method K) R_T3.52min[M+H]⁺392.0¹H NMR(DMSO-d₆,400MHz):δ8.09(1H,s),8.05(1H,s),7.91(1H,s),7.68(1H,dd,J=8.80,4.85Hz),7.58-7.47(2H,m),7.42(1H,d,J=7.91Hz),7.32-7.23(1H,m),7.09(1H,td,J=9.32,2.48Hz),6.92(1H,dd,J=8.93,2.50Hz),5.63-5.47(1H,m),1.58(3H,d,J=6.82Hz)

Example 186{1- [ 6-fluoro-1- (4-fluoro-phenyl) -1H-benzimidazol-2-yl]-ethyl } - (9H-purin-6-yl) -amine 186

Reacting (S) -1- [ 6-fluoro-1- (4-fluorophenyl) -1H-benzimidazol-2-yl]Ethyl amine (0.33g,1.21mmol) was dissolved in n-butanol (10mL) and 6-chloro-9- (tetrahydropyran-2-yl) -9H-purine (0.29g,1.21mmol) and DIPEA (1.05mL,6.04mmol) were added. The reaction mixture was heated to 100 ℃ overnight. Additional DIPEA (0.53mL,3.02mmol) was added and the reaction mixture was heated at 100 ℃ for 2 h. Then the The resulting mixture was cooled to RT and then concentrated in vacuo. Passing the residue throughSCX-2 column with DCM, MeOH, then 2M NH₃Eluted with MeOH to give a yellow gum. It was purified by column chromatography (silica gel, gradient eluted with 0-10% MeOH in DCM) to give 186 as an off-white solid (0.13g, 32%). LCMS (method K) R_T3.50min[M+H]⁺392.1¹H NMR(DMSO-d₆,400MHz):δ8.11(1H,s),8.07(1H,s),7.92(1H,s),7.71-7.62(3H,m),7.38-7.28(2H,m),7.13-7.06(1H,m),6.87(1H,dd,J=8.92,2.50Hz),5.49(1H,s),1.58(3H,d,J=6.85Hz)

Example 187(S) -3- (6-fluoro-1-phenyl-1H-benzimidazol-2-yl) -3- (9H-purin-6-ylamino) -propan-1-ol 187

To [ (S) -3-benzyloxy-1- (6-fluoro-1-phenyl-1H-benzimidazol-2-yl) propyl group at 0 ℃ under a nitrogen atmosphere]To a solution of (9H-purin-6-yl) amine (296mg,0.6mmol) in anhydrous DCM (6mL) was added boron tribromide (1.0M in DCM, 1.2mL,1.2mmol) dropwise. The reaction mixture was stirred at 0 ℃ for 1 h. MeOH was then added and volatiles were removed under reduced pressure. The resulting residue was purified by column chromatography (Si-PCC with 0-10%2M NH)₃Gradient elution in DCM/MeOH) afforded 187(160mg, 66%). LCMS (method K) R_T3.10min[M+H]⁺404.1¹H NMR(DMSO-d₆400 MHz). delta.12.55 (1H, s),8.28-7.83(3H, m),7.81-7.44(6H, m),7.16-7.01(1m),6.91-6.79(1H, m),5.56(1H, br s),4.60(1H, br s),3.57-3.38(2H, m),2.23-2.00(2H, m). Due to the presence of rotamers/tautomers, the signal is cleaved.

Example 188[ (R) -1- (6-fluoro-7-methyl-1-phenyl-1H-benzimidazol-2-yl) -2-methoxy-ethyl]- (9H-purin-6-yl) -amine 188

(R) -1- (6-fluoro-7-methyl-1-phenyl-1H-benzimidazol-2-yl) -2-methoxyethylamine (270mg,0.9mmol), 6-chloro-9- (tetrahydropyran-2-yl) -9H-purine (258mg,1.08mmol) and DIPEA (308. mu.L, 1.8mmol)The mixture in n-butanol (5mL) was heated in a sealed vial at 90 ℃ for 18 h. After cooling to RT, the volatiles were removed under reduced pressure and the resulting residue was purified by column chromatography (Si-PCC gradient eluted with 0-10% MeOH in EtOAc) to give [ (R) -1- (6-fluoro-7-methyl-1-phenyl-1H-benzoimidazol-2-yl) -2-methoxyethyl ] (R) -1]- [9- (tetrahydropyran-2-yl) -9H-purin-6-yl]Amine LCMS (method C) R_T3.38min[M+H]⁺502.2。

The compound thus obtained was dissolved in MeOH (5mL) and 4N HClThe solution in alkane solution (2ml) was stirred at RT for 30min, then the volatiles were removed under reduced pressure. The resulting residue was washed with EtOAc and saturated NaHCO₃The solutions were partitioned. The aqueous phase was further extracted with EtOAc, and the combined organic fractions were washed with brine and dried (MgSO)₄) And concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC gradient eluted with 0-10% MeOH in EtOAc) followed by trituration with hot EtOAc to afford 188(183mg, 49% over two). LCMS (method K) R _T3.64min[M+H]⁺418.1。¹H NMR(DMSO-d₆,400MHz):δ12.50(1H,s),8.27-8.01(2H,m),7.92-7.36(7H,m),7.07(1H,dd,J=10.56,8.79Hz),5.44(1H,br s),3.83(2H,d,J=6.49Hz),3.16(3H,s),1.71(3H,s)

Example 1895-fluoro-3-phenyl-2- [1- (9H-purin-6-ylamino) -ethyl]-3H-benzimidazole-4-carbonitrile 189

A mixture of 3-amino-6-fluoro-2-phenylaminobenzonitrile (960mg,4.22mmol), (S) -2-tert-butoxycarbonylaminopropionic acid (879mg,4.6mmol), HOAt (633mg,4.6mmol), 4-methylmorpholine (1.02mL,9.29mmol) and N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride (892mg,4.6mmol) in DCM (5mL) was stirred at RT for 1 h. The reaction mixture was diluted with water and extracted with DCM (× 3). The combined organic fractions were washed with brine and then dried (MgSO)₄) And concentrated in vacuo. A solution of the resulting residue in AcOH (5mL) was heated at 70 ℃ for 18h and then concentrated under reduced pressure. Subjecting the residue toThe residue was washed with EtOAc and saturated NaHCO₃The aqueous solution was partitioned. The aqueous phase was extracted with EtOAc (× 3), the combined organic fractions were washed with brine and dried (MgSO)₄) And concentrated in vacuo. The residue obtained is dissolved in 4N HCl bisAlkane solution (5mL) and stirred at RT for 1 h. The volatiles were removed under reduced pressure to give 2- ((S) -1-aminoethyl) -5-fluoro-3-phenyl-3H-benzimidazole-4-carbonitrile hydrochloride as a brown solid, which was used in the next step without further purification.

A portion of the compound thus obtained (250mg,0.89mmol) was treated with 6-chloro-9- (tetrahydropyran-2-yl) -9H-purine (255mg,1.07mmol) and DIPEA (609. mu.L, 3.57mmol) in n-butanol (5mL) and heated in a sealed vial at 90 ℃ for 18H. After cooling to RT, the volatiles were removed under reduced pressure and the resulting residue was purified by column chromatography (Si-PCC gradient elution with 0-10% MeOH in EtOAc). The relevant fractions were combined and concentrated under reduced pressure. The resulting residue was dissolved in MeOH (5mL) and treated with 4N HCl in dioxane (1 mL). The reaction mixture was stirred at RT for 1h, then the volatiles were removed under reduced pressure. The resulting residue was purified by reverse phase HPLC (Phenomenex Gemini 5. mu. m C18, 20min gradient: 10-90% with 0.1% HCO₂H acetonitrile/water) to yield 189(58mg, 16%). LCMS (method K) R_T3.30min[M+H]⁺399.0。¹H NMR(DMSO-d₆,400MHz):δ12.88(1H,br s),8.18-7.80(4H,m),7.72-7.39(5H,m),7.36(1H,t,J=9.62Hz),5.31(1H,br s),1.58(3H,d,J=6.89Hz)

Example 190[1- (6, 7-difluoro-1-phenyl-1H-benzimidazol-2-yl) -2-methoxy-ethyl]- (9H-purin-6-yl) -amine 190

To [ (R) -1- (6, 7-difluoro-1-phenyl-1H-benzimidazol-2-yl) -2-methoxyethyl]- [9- (tetrahydro-pyran-2-yl) -9H-purin-6-yl]To a solution of amine (290mg,0.57mmol) in methanol (5mL) was added HCl bisAlkane solution (0.5mL,4M) and the reaction was stirred at RT for 30 min. The reaction mixture was concentrated in vacuo and the resulting residue was dissolved in EtOAc (10 mL). The solution was saturated with NaHCO ₃The aqueous solution was washed and the product was extracted with EtOAc (3X 10 mL). The combined organic extracts were washed with brine and dried (MgSO)₄) And concentrated in vacuo. The resulting residue was triturated with ether, collected by filtration and dried in vacuo to give 190 as a white solid (111mg, 46%).¹H NMR400MHz(DMSO-d₆) Delta 8.13-7.98(2H, m),7.89(1H, br s),7.74-7.58(2H, m),7.59-7.39(4H, m),7.29-7.14(1H, m),5.47(1H, br s),3.87-3.77(2H, m),3.11(3H, s). LCMS (method K) R_T=3.72min,[M+H]+=422

Example 191{ (S) -1- [3- (3-chloro-phenyl) -3H-imidazo [4,5-b { (S) -3]Pyridin-2-yl]-ethyl } - (9H-purin-6-yl) -amine 191

To { (S) -1- [3- (3-chlorophenyl) -3H-imidazo [4,5-b { (S) -3]Pyridin-2-yl]Ethyl } carbamic acid tert-butyl ester (35mg,0.09mmol) in DCM (1mL) TFA (1mL) was added and the mixture was stirred at RT for 3 h. Loading the crude mixture intoSCX-2 column, washing with MeOH, then 2M NH₃Washing with MeOH. The basic fractions were combined and concentrated in vacuo to give (S) -1- [3- (3-chlorophenyl) -3H-imidazo [4, 5-b)]Pyridin-2-yl]Ethylamine as an orange oil (23 mg).

A mixture of the compound thus obtained (23mg), 6-chloro-9- (tetrahydropyran-2-yl) -9H-purine (21mg,0.09mmol) and DIPEA (45. mu.L, 0.25mmol) in n-butanol (0.5mL) was heated at 100 ℃ for 18H in a sealed vial. After cooling to RT, the crude mixture is loaded SCX-2 column, washing with MeOH, then 2M NH₃Washing with MeOH. The basic fractions were combined, concentrated in vacuo and the residue purified by column chromatography (Si-PCC in 0-10% MeOH in DCM)Gradient elution) to give 191 as a pink/red solid (18mg, 49% yield over two steps). LCMS (method K) R_T2.97min[M+H]⁺391.0。¹HNMR(DMSO-d₆,400MHz):δ8.26(1H,dd,J=4.77,1.47Hz),8.14-7.95(4H,m),7.71(1H,brs),7.58-7.53(1H，m)，7.49-7.41(2H，m)，7.33(lH，dd，J＝7.99，4.78Hz)，5.62(1H，brs)，1.63(3H，d，J＝6.82Hz)

Example 192{ (S) -1- [3- (4-chloro-phenyl) -3H-imidazo [4,5-b { (S) -3]Pyridin-2-yl]-ethyl } - (9H-purin-6-yl) -amine 192

To { (S) -1- [3- (4-chlorophenyl) -3H-imidazo [4,5-b { (S) -3]Pyridin-2-yl]Tert-butyl ethyl carbamate (99mg,0.27mmol) in DCM (1mL) was added TFA (1mL) and the reaction mixture was stirred at RT for 3 h. Loading the crude mixture intoSCX-2 column, washing with MeOH, then 2M NH₃Washing with MeOH. The basic fractions were combined and concentrated in vacuo to give (S) -1- [3- (4-chlorophenyl) -3H-imidazo [4, 5-b)]Pyridin-2-yl]Ethylamine as an orange oil (71 mg).

A mixture of the compound thus obtained (71mg), 6-chloro-9- (tetrahydropyran-2-yl) -9H-purine (65mg,0.27mmol) and DIPEA (135. mu.L, 0.78mmol) in n-butanol (1mL) was heated at 100 ℃ for 18H in a sealed vial. After cooling to RT, the crude mixture is loadedSCX-2 column, washing with MeOH, then 2M NH ₃Washing with MeOH. The basic fractions were combined, concentrated in vacuo, and the resulting residue was purified by column chromatography (Si-PCC, gradient eluted with 0-10% MeOH in DCM) to give 192 as a pink/red solid (29mg, 28% over two steps). LCMS (method K) R_T3.03min[M+H]⁺391.0。¹HNMR(DMSO-d₆,400MHz):δ8.25(1H,dd,J=4.77,1.47Hz),8.16-7.94(4H,m),7.67-7.60(2H,m),7.58-7.49(2H,m),7.31(1H,dd,J=7.99,4.77Hz),5.55(1H,brs),161(3H,d,J=6.85Hz

Example 195{1- [ 6-fluoro-1- (2-fluoro-phenyl) -1H-benzimidazol-2-yl]-ethyl } - (9H-purin-6-yl) -amine 195

Reacting (S) -1- [ 6-fluoro-1- (2-fluorophenyl) -1H-benzimidazol-2-yl]Ethyl amine (0.22g,0.81mmol) was dissolved in n-butanol (5mL) and 6-chloro-9- (tetrahydropyran-2-yl) -9H-purine (0.193g,0.81mmol) and DIPEA (0.70mL,4.03mmol) were added. The reaction mixture was heated at 100 ℃ overnight. The resulting mixture was then cooled to RT and then concentrated in vacuo. Passing the residue throughSCX-2 column with DCM, MeOH and 2M NH₃Eluted with MeOH to give a pale yellow gum. This was purified by column chromatography (silica gel, gradient eluted with 0-5% MeOH in DCM) to give 195 as an off-white solid (209mg, 67%). LCMS (method K) R_T3.34/3.52min[M+H]⁺392.0¹H NMR(DMSO-d₆400 MHz). delta.8.16-7.79 (3H, m),7.77-7.64(2H, m),7.58-7.21(3H, m),7.16-7.09(1H, m),6.92-6.83(1H, m),5.63-5.38(1H, m),1.69(1.5H, d, J =6.85Hz),1.58(1.5H, d, J =6.86 Hz). The NMR signal indicated it to be a mixture of rotamers.

Example 196[ 2-methyl-1- (3-phenyl-3H-imidazo [4,5-b ]]Pyridin-2-yl) -propyl]- (9H-purin-6-yl) -amine 196

A solution of (S) -3-methyl-N- (2-phenylaminopyridin-3-yl) -2- (9H-purin-6-ylamino) butanamide (821mg,2.0mmol) in AcOH (10mL) was heated at 100 deg.C for 2H. After cooling to RT, the volatiles were removed under reduced pressure and the resulting residue was taken up in DCM and saturated NaHCO₃The aqueous solution was partitioned. The aqueous phase was extracted with DCM and the combined organic fractions were dried (MgSO)₄) And concentrated in vacuo. The residue was purified by column chromatography (Si-PCC with 0-10%2 MNH)₃Gradient MeOH in DCM) to give 196 as a light brown solid (365mg, 46%). LCMS (method K) R_T3.18min[M+H]⁺385.1。¹H NMR(DMSO-d₆,400MHz) δ 8.29-7.99(4H, m),7.78-7.42(6H, m),7.31(1H, dd, J =8.01,4.75Hz),5.40(1H, br s),2.45-2.34(1H, m),0.95(3H, d, J =6.69Hz),0.81(3H, br d, J =6.59 Hz). Due to the presence of rotamers/tautomers, the signal is cleaved.

Example 1975-fluoro-3-phenyl-2- [1- (9H-purin-6-ylamino) -ethyl]-3H-benzimidazole-4-carboxylic acid methyl ester 197

Reacting 5-fluoro-3-phenyl-2- { (S) -1- [9- (tetrahydropyran-2-yl) -9H-purin-6-ylamino]A solution of methyl ethyl } -3H-benzimidazole-4-carboxylate (50mg,0.097mmol) in MeOH (2mL) and 4N HCl in dioxane (0.5mL) was stirred at RT for 30min, then the volatiles were removed under reduced pressure. The resulting residue was dissolved in a minimum amount of MeOH and EtOAc. A solid precipitated upon standing and was collected by filtration to give 197(21mg, 46%). LCMS (method K) R _T3.28min[M+H]⁺432.1。¹HNMR(DMSO-d₆,400MHz):δ12.65(1H,s),9.92(1H,brs),8.61(1H,s),8.50(1H,s),7.89(1H,dd,J=8.90,4.75Hz),7.59-7.48(2H,m),7.45-7.30(3H,m),7.25(1H,dd,J=10.49,8.90Hz),5.51-5.40(1H，m)，3.0g(3H，s)，1.65(3H，d，J＝6.84Hz)

Example 198[1- (7-cyclopropyl-6-fluoro-1-phenyl-1H-benzimidazol-2-yl) -ethyl]- (9H-purin-6-yl) -amine 198

To [ (S) -1- (7-cyclopropyl-6-fluoro-1-phenyl-1H-benzimidazol-2-yl) ethyl]- [9- (tetrahydropyran-2-yl) -9H-purin-6-yl]To a mixture of amine (20mg,0.04mmol) in MeOH (2mL) was added 4N HCl bisAlkane solution (0.25mL) and the reaction mixture was stirred at RT for 30 min. Volatiles were removed under reduced pressure and the resulting residue was purified by reverse phase HPLC (Phenomenex Gemini5 μm C18, 20min gradient: 10-90% with 0.1% HCO₂H acetonitrile/water) to yield 198(8mg, 48%). LCMS (method K) R_T3.74 and 3.81min [ M + H]⁺414.1。

¹HNMR(DMSO-d₆,400MHz):δ12.89(1H,brs),8.19-7.97(2H,m),7.90-7.30(7H,m),7.04-6.95(1H,dd,J=11.67,8.76Hz),5.29(1H,brs),1.52(3H,d,J=6.81Hz),128-1.18(1H,m),0.43-0.29(2H,m),0.25-0.08(2H,m)

Example 199[1- (1-phenyl-1H-imidazo [4,5-b ]]Pyridin-2-yl) -ethyl]- (9H-purin-6-yl) -amine 199

Reacting (S) -1- (1-phenyl-1H-imidazo [4, 5-b)]A mixture of pyridin-2-yl) ethylamine (330mg,1.38mmol), 6-chloro-9- (tetrahydropyran-2-yl) -9H-purine (460mg,1.94mmol) and DIPEA (440. mu.L, 2.49mmol) in n-butanol (2mL) was heated at 90 ℃ for 16H in a sealed vial. After cooling to RT, the volatile substances were removed under reduced pressure and the residue obtained was loadedSCX-2 column, washing with MeOH, then 2M NH₃Washing with MeOH. The product containing fractions were combined and concentrated in vacuo. The residue was purified by column chromatography (Si-PCC with 0-15%2M NH) ₃Gradient elution in DCM/MeOH), followed by crystallization with EtOAc and MeOH afforded 199 as a white solid (178mg, 36%). LCMS (method K) R_T2.72min[M+H]⁺357.0。

¹HNMR(DMSO-d₆,400MHz):δ8.42(１H,dd,J=4.73，1.53Hz)，8.20-7.94(3H，m)，7.68(2H，d，J＝7.55Hz)，7.63-7.48(4H，m)，7.23(1H，dd，J=8.06,4.74Hz),5.51(1H,brs),1.60(3H,d,J=6.85Hz)

Example 200[ 2-ethoxy-1- (6-fluoro-1-phenyl-1H-benzimidazol-2-yl) -ethyl]- (9H-purin-6-yl) -amine 200

A mixture of (R) -2-ethoxy-1- (6-fluoro-1-phenyl-1H-benzimidazol-2-yl) ethylamine (510mg,1.7mmol), 6-chloro-9- (tetrahydropyran-2-yl) -9H-purine (410mg,1.7mmol) and DIPEA (1.5mL,8.5mmol) in n-butanol (6mL) was heated at 90 ℃ for 18H in a sealed vial. After cooling to RT, the volatile substances were removed under reduced pressure and the residue obtained was loadedSCX-2 column. The column was washed with MeOH, then 2M NH₃Washing with MeOH. The basic fractions were combined, concentrated in vacuo and the residue purified by column chromatography (Si-PCC with 0-10%2 MNH)₃Gradient elution in DCM/MeOH) gave 200 as a white solid (158mg, 22%). LCMS (method K) R_T3.80min[M+H]⁺418.1。

¹HNMR(DMSO-d₆,400MHz):δ12.60(1H,s),δ8.22-8.05(2H,m),7.87(1H,brs),7.75-7.49(6H,m),7.11(1H,td,J=9.32,2.48Hz),6.89(1H,dd,J=8.92,2.50Hz),5.63(1H,brs),3.88(2H,brd,J=6.76Hz),3.40-3.33(2H,m),1.01-0.91(3H,m)

Example 201[ (S) -1- (1-cyclohexyl-6-fluoro-1H-benzimidazol-2-yl) -ethyl]- (9H-purin-6-yl) -amine 201

(S) -1- (1-cyclohexyl-6-fluoro-1H-benzimidazol-2-yl) ethylamine (0.41g,1.56mmol) was dissolved in n-butanol (5mL) and 6-chloro-9- (tetrahydropyran-2-yl) -9H-purine (0.374g,1.56mmol) and DIPEA (1.38mL,7.82mmol) were added. The reaction mixture was heated to 100 ℃ overnight. The resulting mixture was then cooled to RT and concentrated in vacuo. Passing the residue through SCX-2 column with DCM, MeOH and 2M NH₃Eluted with MeOH to give crude product. This was purified by column chromatography (silica gel, gradient eluted with 0-10% MeOH in DCM) to give 201 as a pale yellow gum which solidified upon standing (204mg, 35%). LCMS (method K) R_T3.31min[M+H]⁺380.1¹HNMR(DMSO-d₆,400MHz):δ8.30(1H,s),8.15(1H,s),8.04(1H,s),7.66-7.54(2H,m),7.02(1H,td,J=9.29,2.34Hz),6.00(1H,s),4.51-4.37(1H,m),2.27-2.13(1H,m),2.07-1.95(1H,m),1.88-1.75(2H,m),1.70(3H,d,J=6.70Hz),1.64-1.44(3H,m),1.39-1.26(2H,m),0.75-0.57(1H,m)

Example 202{ 5-fluoro-3-phenyl-2- [1- (9H-purin-6-ylamino) -ethyl]-3H-Benzimidazol-4-yl } - (4-methyl-piperazin-1-yl) -methanone 202

Reacting 5-fluoro-3-phenyl-2- { (S) -1- [9- (tetrahydropyran-2-yl) -9H-purin-6-ylamino]A mixture of ethyl } -3H-benzimidazole-4-carboxylic acid (100mg,0.2mmol), HATU (91mg,0.24mmol), 1-methylpiperazine (33. mu.L, 0.3mmol) and DIPEA (69. mu.L, 0.4mmol) in DCM (2mL) was stirred at RT for 1H. The crude mixture was diluted with water and extracted with DCM. The aqueous phase was further extracted with DCM and the combined organic fractions were dried (MgSO)₄) And concentrated in vacuo. The resulting residue was dissolved in MeOH (1mL) and 4N HCl in bisTo an alkane solution (0.25mL), the mixture was stirred at RT for 30 min. The volatiles were removed under reduced pressure and the resulting residue was purified by HPLC (Waters C18Xbridge,20min gradient: 10-90% with 0.1% NH)₄Acetonitrile/water of OH) to yield 202(59mg, 59%). LCMS (method K) R_T2.02min[M+H]⁺500.1。¹HNMR(DMSO-d₆+TFA-D,400MHz,80℃):δ12.45(１H,s),8.52(１H,brs),8.44(１H,d,J=6.07Hz),7.85-7.80(１H,m),7.56-7.27(5H,m),7.24-7.17(１H,m),5.67(１H,brs),3.76-3.52(１H,m),3.49-3.37(１H,m),3.34-2.87(7H,m),2.81(3H,s),171-1.64(3H,m)

Example 203 { 5-fluoro-3-phenyl-2- [1- (9H-purin-6-ylamino) -ethyl]-3H-benzimidazol-4-yl } -morpholin-4-yl-methanone 203

Reacting 5-fluoro-3-phenyl-2- { (S) -1- [9- (tetrahydropyran-2-yl) -9H-purin-6-ylamino]A mixture of ethyl } -3H-benzimidazole-4-carboxylic acid (100mg,0.2mmol), HATU (91mg,0.24mmol), morpholine (26. mu.L, 0.3mmol) and DIPEA (69. mu.L, 0.4mmol) in DCM (2mL) was stirred at RT for 1H. The crude mixture was diluted with water and extracted with DCM. The aqueous phase was further extracted with DCM and the combined organic fractions were dried (MgSO)₄) And concentrated in vacuo. The resulting residue was dissolved in MeOH (2mL) and 4N HCl in bisIn an alkane solution (0.25mL), theThe mixture was stirred at RT for 30 min. The volatiles were removed under reduced pressure and the resulting residue was purified by HPLC (Waters C18Xbridge,20min gradient: 10-90% with 0.1% NH)₄Acetonitrile/water of OH) to yield 203(69mg, 71%). LCMS (method K) R_T2.64 and 2.67min [ M + H ]]⁺487.1。

¹HNMR(DMSO-d₆+TFA-D,400MHz,80℃):δ8.52(1H,brs),8.46(1H,d,J=6.25Hz),7.83-7.75(1H,m),7.57-7.43(5H,m),7.32-7.15(2H,m),5.66(1H,brs),3.50-3.24(5H,m),3.15-3.05(1H,m),3.04-2.95(1H,m),2.70-2.58(1H,m),1.74-1.65(3H,m)

Example 2045-fluoro-3-phenyl-2- [1- (9H-purin-6-ylamino) -ethyl]-3H-benzimidazole-4-carboxylic acid dimethylamide 204

Reacting 5-fluoro-3-phenyl-2- { (S) -1- [9- (tetrahydropyran-2-yl) -9H-purin-6-ylamino]A mixture of ethyl } -3H-benzimidazole-4-carboxylic acid (100mg,0.2mmol), HATU (91mg,0.24mmol), dimethylamine (2M in THF, 0.2mL,0.4mmol), and DIPEA (69. mu.L, 0.4mmol) in DCM (2mL) was stirred at RT for 1H. The crude mixture was diluted with water and extracted with DCM. The aqueous phase was further extracted with DCM and the combined organic fractions were dried (MgSO) ₄) And concentrated in vacuo. The resulting residue was dissolved in MeOH (2mL) and 4N HCl in bisTo an alkane solution (0.25mL), the mixture was stirred at RT for 30 min. The volatiles were removed under reduced pressure and the resulting residue was purified by HPLC (Waters C18Xbridge,20min gradient: 10-90% with 0.1% NH)₄Acetonitrile/water of OH) to yield 204(60mg, 68%). LCMS (method K) R_T2.58 and 2.71min [ M + H ]]⁺445.1。¹H NMR

(DMSO-d₆,400MHz,80℃):δ12.45(1H,s),8.04(1H,d,J=4.86),8.00(1H,s),7.69(1H,dd,J=8.83,4.88Hz),7.52-7.25(6H,m),7.12-7.05(1H,m),5.58-5.39(1H,m),2.64(1.5H,s),2.58(1.5H，s)，2.34(3H，d，J＝431Hz)，1.56(3H，t，J＝6.63Hz)

Example 205[1- (6-fluoro-1-pyridin-3-yl-1H-benzimidazol-2-yl) -propyl]- (9H-purin-6-yl) -amine 205

A mixture of (S) -1- (6-fluoro-1-pyridin-3-yl-1H-benzimidazol-2-yl) propylamine (243mg,0.90mmol), 6-chloro-9- (tetrahydropyran-2-yl) -9H-purine (210mg,0.90mmol) and DIPEA (780 μ L,4.5mmol) in n-butanol (3mL) was heated at 100 ℃ for 18H in a sealed vial. After cooling to RT, the volatile substances were removed under reduced pressure and the residue obtained was loadedSCX-2 column, washing with MeOH, then 2M NH₃Washing with MeOH. The product containing fractions were combined and concentrated in vacuo. The residue was purified by column chromatography (Si-PCC with 0-10%2 MNH)₃Gradient elution in DCM/MeOH) gave 205(145mg, 42%). LCMS (method K) R_T2.96min[M+H]⁺389.1。¹H NMR

(DMSO-d₆,400MHz):δ12.65(1H,s),8.81(1H,d,J=2.47Hz),8.67(1H,brs),8.21-8.01(3H,m),7.91(1H,brs),7.73(1H,dd,J=8.81,4.84Hz),7.56(1H,brs),7.18-7.08(1H,m),6.95(1H,dd,J=8.88,2.48Hz),5.35(1H,brs),2.19-2.01(2H,m),0.90(3H,t,J=7.32Hz)

Example 206[1- (6-fluoro-1-pyridin-3-yl-1H-benzimidazol-2-yl) -2-methyl-propyl ]- (9H-purin-6-yl) -amine 206

A mixture of (S) -1- (6-fluoro-1-pyridin-3-yl-1H-benzimidazol-2-yl) -2-methylpropylamine (135mg,0.48mmol), 6-chloro-9- (tetrahydropyran-2-yl) -9H-purine (110mg,0.48mmol), and DIPEA (0.4mL,2.4mmol) in n-butanol (2mL) was heated at 100 ℃ for 18H in a sealed vial. After cooling to RT, the volatile substances were removed under reduced pressure and the residue obtained was loadedSCX-2 column. The column was washed with MeOH, then 2M NH₃Washing with MeOH. The basic fractions are combined, concentrated in vacuo and the residue obtained is purified by column chromatography(Si-PCC with 0-10%2M NH₃Gradient elution in DCM/MeOH) gave 206(75mg, 39%). LCMS (method K) R_T3.19min[M+H]⁺403.0。

¹HNMR(DMSO-d₆,400MHz):δ12.85(1H,s),8.86-8.59(2H,m),8.18-7.88(3H,m),7.79-7.47(3H,m),7.11(1H,td,J=9.31,2.48Hz),6.93(1H,brd,J=8.83Hz),5.21(1H,brs),0.99-0.90(4H,m),0.85(3H,brs)

Example 207{1- [ 6-fluoro-1- (6-methoxy-pyridin-3-yl) -1H-benzimidazol-2-yl]-ethyl } - (9H-purin-6-yl) -amine 207

Reacting { (S) -1- [ 6-fluoro-1- (6-methoxypyridin-3-yl) -1H-benzimidazol-2-yl]A mixture of tert-butyl ethyl } carbamate (52mg,0.14mmol) in DCM (3mL) and TFA (1mL) was stirred at RT for 2 h. Loading the crude reaction mixture intoSCX-2 column, washing with MeOH, then 2M NH₃Washing with MeOH. The basic fractions were combined and concentrated in vacuo to give (S) -1- [ 6-fluoro-1- (6-methoxypyridin-3-yl) -1H-benzimidazol-2-yl ]Ethylamine as a pink oil (37mg, 96%). LCMS (method C) R_T1.98min[M+H]⁺287.2。

A mixture of the compound thus obtained (37mg,0.13mmol), 6-chloro-9- (tetrahydropyran-2-yl) -9H-purine (32mg,0.14mmol) and DIPEA (66. mu.L, 0.39mmol) in n-butanol (0.5mL) was heated at 100 ℃ for 18H in a sealed vial. After cooling to RT, the crude mixture was diluted with MeOH and loaded intoSCX-2 column. The column was washed with MeOH, then 2M NH₃Washing with MeOH. The basic fractions were combined, concentrated in vacuo and the residue purified on a second SCX-2 column. The basic fractions were combined, concentrated in vacuo and the resulting residue was purified by column chromatography (Si-PCC, gradient eluted with 0-10% MeOH in DCM) to give 207 as a pale yellow solid (29mg, 55%). L isCMS (method K) R_T3.24min[M+H]⁺405.0。

¹HNMR

(DMSO-d₆,400MHz):δ12.88(1H,brs),8.33(1H,s),8.20-7.78(4H,m),7.72-7.63(1H,m),7.09(1H，t，J＝9.41Hz)，6.98-6.72(2H，m)，5.50(1H，brs)，3.86(3H，s)，1.62(3H，d，J＝6.85Hz)

Example 208{1- [ 6-fluoro-1- (5-fluoro-pyridin-2-yl) -1H-benzimidazol-2-yl]-ethyl } - (9H-purin-6-yl) -amine 208

Reacting { (S) -1- [ 6-fluoro-1- (5-fluoropyridin-2-yl) -1H-benzimidazol-2-yl]A mixture of tert-butyl ethyl } carbamate (33mg,0.09mmol) in DCM (1mL) and TFA (0.5mL) was stirred at RT for 2 h. Loading the crude reaction mixture intoSCX-2 column, washing with MeOH, then 2M NH₃Washing with MeOH. Combining the basic fractions and concentrating in vacuo to give (S) -1- [ 6-fluoro-1- (5-fluoropyridin-2-yl) -1H-benzimidazol-2-yl ]Ethylamine as a yellow oil (19mg, 79%). LCMS (method C) R_T0.27 and 1.84min [ M + H ]]⁺275.2。

A mixture of the compound thus obtained (19mg,0.07mmol), 6-chloro-9- (tetrahydropyran-2-yl) -9H-purine (17mg,0.07mmol) and DIPEA (36. mu.L, 0.21mmol) in n-butanol (0.5mL) was heated at 100 ℃ for 18H in a sealed vial. After cooling to RT, the crude mixture was diluted with MeOH and loaded intoSCX-2 column. The column was washed with MeOH, then 2M NH₃Washing with MeOH. The basic fractions were combined, concentrated in vacuo and the residue purified over a second SCX-2 column. The basic fractions were combined, concentrated in vacuo, and the resulting residue was purified by column chromatography (Si-PCC, gradient eluted with 0-10% MeOH in DCM) to give 208 as a pale yellow solid (24mg, 88%). LCMS (method K) R_T3.22min[M+H]⁺393.0。

¹HNMR

(DMSO-d₆,400MHz):δ12.35(1H,s),8.55(1H,brs),8.07(1H,brs),8.00(1H,s),7.95-7.75(3H,m),7.73-7.65(1H,m),7.15-7.10(2H,m),5.79(1H,brs),1.63(3H,d,J=6.84Hz)

Example 210[1- (6-fluoro-1-pyridin-2-yl-1H-benzimidazol-2-yl) -ethyl]- (9H-purin-6-yl) -amine 210

A mixture of (S) -1- (6-fluoro-1-pyridin-2-yl-1H-benzimidazol-2-yl) ethylamine (764mg,3.0mmol), 6-chloro-9- (tetrahydropyran-2-yl) -9H-purine (710mg,3.0mmol), and DIPEA (2.6mL,15mmol) in IPA (8mL) was heated at 90 deg.C for 16H. After cooling to RT, the volatile substances were removed under reduced pressure and the residue obtained was loaded SCX-2 column. The column was washed with MeOH, then 2M NH₃Washing with MeOH. The basic fractions were combined, concentrated in vacuo, and the resulting residue was purified by column chromatography (Si-PCC with 0-10%2M NH)₃EtOAc in MeOH gradient elution) afforded 210 as a white solid (700mg, 63%). LCMS (method K) R_T2.94min[M+H]⁺375.0。

¹HNMR(DMSO-d₆,400MHz):δ12.89(1H,brs),8.61(1H,brs),8.20-7.80(4H,m),7.79-7.67(2H,m),7.52-7.43(1H，m)，7.20-7.08(2H，m)，5.86(1H，brs)，1.63(3H，d，J＝6.82Hz)

Example 2283- { 6-fluoro-2- [1- (9H-purin-6-ylamino) -ethyl]-benzimidazol-1-yl } -phenol 228

Reacting { (S) -1- [ 6-fluoro-1- (3-methoxyphenyl) -1H-benzimidazol-2-yl]Ethyl } -9H-purin-6-yl) amine (0.215g,0.53mmol) was suspended in DCM (8mL) and cooled to 0 deg.C under a nitrogen atmosphere. Boron tribromide (1M in DCM) (1.06mL,1.06mmol) was added dropwise to bring the reaction mixture to RT, then stirred for 1 h. The mixture was cooled again to 0Additional boron tribromide solution (1.06mL,1.06mmol) was added and the reaction mixture was stirred at RT for 3 h. The reaction mixture was again cooled to 0 ℃ and additional boron tribromide solution (1.06mL,1.06mmol) was added. The reaction mixture was stirred at RT overnight. The off-white suspension was quenched with MeOH (5mL) to give a clear solution. It is concentrated in vacuo and the residue is purified by column chromatography (silica gel, with 0-15% [2MNH ]₃In MeOH (E) solution]Gradient elution of DCM) to give an insoluble off-white solid. It was suspended in water and filtered through a nylon membrane. The resulting solid was dried under vacuum at 50 ℃ overnight to give 228(153mg, 79%). LCMS (method K) R _T2.95min[M+H]⁺390.0

¹HNMR(DMSO-d₆,400MHz):δ8.17-8.05(2H,m),7.86(1H,s),7.65(1H,dd,J=8.79,4.84Hz),7.39-7.29(1H,m),7.12-6.84(5H,m),5.51(1H,s),1.53(3H,d,J=6.84Hz)

Example 236[1- (1-phenyl-1H-imidazo [4,5-c ]]Pyridin-2-yl) -ethyl]- (9H-purin-6-yl) -amine 236

1- (1-phenyl-1H-imidazo [4, 5-c)]A mixture of pyridin-2-yl) ethylamine (184mg,0.77mmol), 6-chloro-9- (tetrahydropyran-2-yl) -9H-purine (256mg,1.08mmol) and DIPEA (0.25mL,1.39mmol) in 1-butanol (2mL) was stirred at 90 ℃ for 16H in a sealed microwave tube. Loading the resulting mixture intoSCX-2 column, washed with MeOH. With 2MNH₃The product was eluted with MeOH and then concentrated in vacuo. The residue obtained is purified by chromatography (SiO)₂0-10% (2M ammonia in methanol) in DCM), followed by purification by preparative HPLC (Phenomenex Gemini5 μ M C18, 60min gradient: 20-98% with 0.1% HCO₂H acetonitrile/water) to yield 236 as a white solid (0.017g, 6%). LCMS (method K) R_t2.04min,[M+H]⁺357。

¹HNMR(DMSO-d₆):δ12.89(1H,s),8.94(1H,s),8.30(1H,d,J=5.54Hz),8.09-8.00(2H，m)，7.65-7.50(5H，m)，7.12(1H，d，J＝5.57Hz)，5.53(1H，s)，1.58(4H，d，J＝7.36Hz)

Example 237[1- (3-phenyl-3H-imidazo [4,5-c ]]Pyridin-2-yl) -ethyl]- (9H-purin-6-yl) -amine 237

1- (3-phenyl-3H-imidazo [4, 5-c)]A mixture of pyridin-2-yl) ethylamine (254mg,1.07mmol), 6-chloro-9- (tetrahydropyran-2-yl) -9H-purine (0.35g,1.49mmol) and DIPEA (0.34mL,1.92mmol) in 1-butanol (3mL) was stirred at 90 ℃ for 16H in a sealed tube. The resulting mixture was concentrated in vacuo and the residue was purified by chromatography (SiO) ₂0-10% (2M ammonia in methanol) in DCM). The product was dissolved in methanol and HCl/bisAlkane (4M,1.3mL,5.35mmol) and stirred for 20 min. Loading the mixture intoSCX-2 column, washing with MeOH, 2M NH₃The product was eluted with MeOH and then concentrated in vacuo. The residue obtained is purified by chromatography (SiO)₂0-15% (2M ammonia in methanol) in DCM) to give a waxy solid which was triturated with EtOAc/ether to give 237 as a brown solid (0.056g, 15%). LCMS (method K) R_t1.98min,[M+H]⁺357。

¹HNMR(DMSO-d₆):δ13.10-12.60(1H,bs),8.43(1H,s),8.37(1H,d,J=5.53Hz)，8.13(1H，s)，8.07(1H，s)，7.70-7.68(3H，m)，7.61-7.5O(3H，m)，5.49(lH，m)，1.59(3H,d,J=6.87Hz)

Example 238{1- [ 6-fluoro-1- (3-fluoro-pyridin-2-yl) -1H-benzimidazol-2-yl]-ethyl } - (9H-purin-6-yl) -amine 238

Reacting {1- [ 6-fluoro-1- (3-fluoropyridin-2-yl) -1H-benzimidazol-2-yl]A mixture of ethyl } -carbamic acid tert-butyl ester (84mg,0.22mmol) in DCM (1mL) and TFA (1mL) was stirred at RT for 2 h. Mixing the reactionObject is loaded toSCX-2 column, washing with MeOH, then 2M NH₃Washing with MeOH. The basic fractions were combined and concentrated in vacuo to give a dark orange oil. A mixture of the residue, 6-chloro-9- (tetrahydropyran-2-yl) -9H-purine (53mg,0.22mmol) and DIPEA (110 μ L,0.63mmol) in n-butanol (0.5mL) was heated at 100 ℃ for 16H in a sealed vial. After cooling to RT, the reaction mixture was diluted with MeOH and loaded into SCX-2 column. The column was washed with MeOH, then 2M NH₃Washing with MeOH. The basic fractions were combined, concentrated in vacuo, and the resulting residue was purified by column chromatography (Si-PCC, gradient eluted with 0-10% MeOH in DCM), followed by reverse phase HPLC (Phenomenex Gemini 5. mu. m C18, 5-60% with 0.1% NH)₄Acetonitrile/water gradient of OH) to give 238 as a white solid (14mg, 16%). LCMS (method K) R_T3.09min[M+H]⁺393.01。

¹HNMR(DMSO-d₆,400MHz):δ8.40(1H,s),8.07-7.81(4H,m)，7.73(1H，dd，J＝8.86，4.85Hz)，7.56(1H，s)，7.18-7.04(2H，m)，5.68(1H，s)，1.70(3H，d，J=6.75Hz)

Example 243[1- (6-fluoro-1-pyrazin-2-yl-1H-benzimidazol-2-yl) -ethyl]- (7H-purin-6-yl) -amine 243

Reacting (S) -N- [ 4-fluoro-2- (pyrazin-2-ylamino) phenyl]-2- [9- (tetrahydropyran-2-yl) -9H-purin-6-ylamino]Propionamide (100mg,0.21mmol) was dissolved in acetic acid (6.0ml) and heated to 80 ℃ overnight. The reaction was cooled, neutralized with sodium hydroxide (1.0M aqueous solution), and the aqueous layer was extracted with EtOAc (× 3). The combined organic fractions were washed with brine, dried over sodium sulfate and concentrated in vacuo. The product is purified by chromatography (SiO)₂0-10% methanol in DCM) to give 243(30.0mg, 39%). LCMS (method C) R_T2.85min[M+H]⁺376.0。

^lHNMR(MeOD，400MHz)：δ8.94(1H，s)，8.60(2H，m)，7.98(2H,s),7.67(1H,dd,J=8.7,4.6Hz),7.10(2H,m),5.83(1H,brs),1.81(3H,d,J=7.0Hz)

Example 2445-fluoro-3-phenyl-2- [ (S) -1- (9H-purin-6-ylamino) -propyl]-3H-benzimidazole-4-carbonitrile 244

A mixture of 2- ((S) -1-amino-propyl) -5-fluoro-3-phenyl-3H-benzimidazole-4-carbonitrile (0.260g,0.88mmol), 6-chloro-9- (tetrahydropyran-2-yl) -9H-purine (0.290g,1.24mmol), and DIPEA (0.28mL,1.59m mol) in IPA (2mL) was stirred at 90 deg.C in a sealed tube for 16H. The resulting mixture was concentrated in vacuo and the residue was purified by chromatography (SiO) ₂0-10% (2M ammonia in methanol) in DCM). The product was dissolved in methanol and HCl/bisAlkane (4M,1.1mL,0.00450mol) and stirred for 20 min. Loading the mixture intoSCX-2 column, washing with MeOH, 2M NH₃The product was eluted with MeOH and then concentrated in vacuo. The residue obtained is purified by chromatography (SiO)₂0-10% (2M ammonia in methanol) in DCM) to give 244 as a white solid (0.205g, 57%). LCMS (method K) R_t3.51min,[M+H]⁺413。

¹HNMR(DMSO-d₆):δ13.20-

12.50(1H,bs),9.60(1H,s),8.00(1H,s)，7.71(1H,m),7.60(2H,s),7.51-7.49(3H,m),7.11-7.08(1H，m)，6.86(1H，m)，5.64(1H，m)，2.10(3H，s)，1.5O(3H，d，J＝6.81Hz)

Example 2464-amino-6- [ (S) -1- (6-fluoro-1-phenyl-1H-benzimidazol-2-yl) -ethylamino]-pyrimidine-5-carbonitrile 246

Reacting (S) -1- (6-fluoro-1-phenyl)-1H-benzimidazol-2-yl) ethylamine dihydrochloride (328mg,1.00mmol) was placed in a sealed tube with 4-amino-6-chloropyrimidine-5-carbonitrile (154.5mg,1.00mol), DIPEA (0.7mL,4.00mol) and IPA (1 mL). The tube was flushed with argon, sealed and the contents heated at 90 ℃ for 16 h. The cooled mixture was evaporated and then diluted with EtOAc and water. The organic layer was washed with brine and dried (MgSO)₄) And evaporated. The crude residue was chromatographed on silica (Si-PCC,1-80% EtOAc in DCM). The product containing fractions were pooled and evaporated to almost dryness. The residue was triturated in ether to give 246 as a creamy solid (240mg, 65%). 1H NMR (CDCl) ₃400MHz δ 8.01(1H, s),7.69(1H, dd, J =8.8,4.7Hz),7.59-7.49(3H, m),7.43-7.36(2H, m),7.02(1H, td, J =9.2,1.1Hz),6.77(1H, dd, J =8.6,2.4Hz),6.18(1H, d, J =7.5Hz),5.52(1H, quin, J =7.2Hz),5.30(2H, br s),1.54(3H, d, J =6.9 Hz). LCMS (method K) R_T3.80min[M+H]⁺374

Example 247[ (S) -1- (6-fluoro-1-pyridin-2-yl-1H-benzimidazol-2-yl) -propyl]- (9H-purin-6-yl) -amine 247

A mixture of (S) -1- (6-fluoro-1-pyridin-2-yl-1H-benzimidazol-2-yl) propylamine (348mg,1.3mmol), 6-chloro-9- (tetrahydropyran-2-yl) -9H-purine (310mg,1.3mmol) and DIPEA (1.1mL,6.4mmol) in IPA (4mL) was heated at 90 deg.C for 72H. After cooling to RT, the volatile substances were removed under reduced pressure and the residue obtained was loadedSCX-2 column. The column was washed with MeOH, then 2M NH₃Washing with MeOH. The basic fractions were combined, concentrated in vacuo, and the resulting residue was purified by column chromatography (Si-PCC with 0-5%2M NH)₃Gradient elution in DCM/MeOH) gave 247 as a white solid (320mg, 63%). LCMS (method K) R_T3.17min[M+H]⁺389.1。

¹HNMR(DMSO-d₆,400MHz)：

δ12.85(1H,brs),8.65(1H,s),8.15-8.03(2H,m),7.99(1H,s),7.84-7.76(2H,m),7.71(1H,dd,J=8.75,4.90Hz),7.55-7.48(1H,m),7.20-7.08(2H,m),5.73(1H,s),2.15-2.06(1H,m),205-1.951Hm)0.90(3HtJ=730Hz)

Example 2562- ((R) -3- { 6-fluoro-2- [ (S) -1- (9H-purin-6-ylamino) -ethyl]-benzimidazol-1-yl } -piperidin-1-yl) -ethanol 256

2- [ (R) -3- (5-fluoro-2- { (S) -2- [9- (tetrahydropyran-2-yl) -9H-purin-6-ylamino) 2, 2-dimethylpropionic acid ]Propionylamino phenylamino) piperidin-1-yl]A solution of ethyl ester (213mg,0.35mmol) in 6M aqueous HCl (10mL) was refluxed for 40 min. After cooling to RT, the volatiles were removed under reduced pressure and the resulting residue was purified by column chromatography (C)₁₈Gradient eluted with 2-35% MeOH in 0.5% TFA/H2O) and then in twoAlkane/water (1:1) toSCX-2 column. Use the column twoAlkane/water (1:1) and then with bisAlkane wash with 10%880NH₃2 ofAlkane solution, then with 2M NH₃The product eluted with MeOH. Further purification by column chromatography (Si-PCC with 3-21%2M NH)₃Gradient elution in DCM/MeOH) gave 256 as a pale yellow solid (40mg, 27%). LCMS (method K) R_T1.94min[M+H]⁺425.1。

¹HNMR(CD₃OD，400MHz)：δ8.30(1H，s)，8.08(1H，s)，7.59(1H，dd，J＝8.9，5.0Hz)，7.49(1H，dd，J＝9.5，2.3Hz)，7.01(1H，dt，J＝9.2，2.4Hz)，6.03(1H，bs)，3.67(2H,t,J=5.8Hz),3.13-3.09(1H,m),2.98-2.92(2H,m),2.69-2.55(2H,m),2.28-2.14(2H,m),1.93-1.88(1H,m),1.82(3H,d,J=7.0Hz),1.77-1.74(1H,m),1.51-1.41(1H,m)

Example 258N- [ (S) -1- (6-fluoro-1-phenyl-1H-benzimidazol-2-yl) -ethyl]-6-methyl- [1,3,5]Triazine-2, 4-diamine 258

Mixing (S) -1- (6-fluoro-1-phenyl-1H-benzimidazol-2-yl) ethylamine dihydrochloride (100mg,0.31mmol) and 4-chloro-6-methyl- [1,3,5]A mixture of triazin-2-ylamine (48.4mg,0.34mmol) and DIPEA (0.26mL,1.52mmol) in n-butanol (2mL) was stirred in a sealed vial at 90 deg.C for 16 h. After cooling to RT, the volatiles were removed under reduced pressure and the resulting residue was purified by column chromatography (C)₁₈With 20-45% MeOH in 0.5% TFA/H ₂Gradient elution of solution in O) and then loaded intoSCX-2 column. The column was washed with MeOH, 0.5M NH₃The product was eluted with MeOH to give 258 as a white solid (94.2mg, 85%). LCMS (method K) R_T3.04min[M+H]⁺364.1。¹H NMR(DMSO-d₆400MHz,80 ℃): delta 7.65(1H, dd, J =8.7,4.8Hz),7.61-7.57(2H, m),7.55-7.51(3H, m),7.04(1H, ddd, J =9.8,8.7,2.5Hz),6.91(1H, bs),6.77(1H, dd, J =9.0,2.5Hz),6.13(2H, bs),5.26(1H, quintuple, J =7.3Hz),2.02(3H, s),1.44(3H, d, J =6.9Hz)

Example 2592- ((R) -3- { 6-fluoro-2- [ (S) -1- (9H-purin-6-ylamino) -propyl]-benzimidazol-1-yl } -piperidin-1-yl) -ethanol 259

2- [ (R) -3- (5-fluoro-2- { (S) -2- [9- (tetrahydropyran-2-yl) -9H-purin-6-ylamino) 2, 2-dimethylpropionic acid]Butyrylamino phenylamino) piperidin-1-yl]A solution of ethyl ester (258mg,0.41mmol) in 6M aqueous HCl (3mL) was refluxed for 40 min. After cooling to RT, the volatiles were removed under reduced pressure and the resulting residue was purified by column chromatography (C)₁₈With 2-30% MeOH in 0.5% TFA/H₂Gradient elution in O) followed by a second stepAlkane/water (1:1) toSCX-2 column. Use the column twoAlkane/water (1:1) and then with bisAlkane wash with 10%880NH₃2 ofAlkane solution, then with 2M NH₃The product eluted with MeOH. Further purification by column chromatography (Si-PCC with 3-21%2M NH) ₃Gradient elution in DCM/MeOH) afforded a colorless solid. The preparation was repeated in the same ratio and combined to yield 44.4mg259 (12%). LCMS (method K) R_T2.07min[M+H]⁺439.1。

¹HNMR(CD₃OD，400NHz)：δ8.28(1H，s)，8.09(1H，s)，7.59(1H，dd，J=8.9，5.OHz)，7.50(1H，dd，J＝9.6，23Hz)，7.00(1H，dt，J＝9.2，2.3Hz)，5.84(1H，bs)，5.04-4.94(1H，m)，3.68(2H,t,J=5.8Hz),3.12-3.08(1H,m),3.00-2.93(2H,m),2.71-2.57(2H,m),2.33-2.16(4H,m),1.89-1.86(1H,m),1.82-1.77(1H,m),1.62-1.51(1H,m),1.09(3H,t,J=7.4Hz)

Example 260{ (S) -1- [ 6-fluoro-1- (5-fluoro-pyridin-3-yl) -1H-benzimidazol-2-yl]-ethyl } - (9H-purin-6-yl) -amine 260

Reacting (S) -1- [ 6-fluoro-1- (5-fluoropyridin-3-yl) -1H-benzimidazol-2-yl]A mixture of ethylamine (46mg,0.17mmol), 6-chloro-9- (tetrahydropyran-2-yl) -9H-purine (44mg,0.18mmol) and DIPEA (86 μ L,0.50mmol) in n-butanol (1mL) was heated at 90 ℃ for 60H in a sealed vial. After cooling to RT, the resulting mixture was diluted with MeOH and loaded intoSCX-2 column. The column was washed with MeOH, then 2M NH₃Washing with MeOH. The basic fractions were combined, concentrated in vacuo, and the resulting residue was purified by column chromatography (Si-PCC, gradient eluted with 0-10% MeOH in DCM) to give 260 as a pale yellow solid (48mg, 73%).

LCMS (method K) R_T3.04min[M+H]⁺393.02。

¹HNMR(DMSO-d₆,400MHz)：

δ8.63(1H,s),8.56(1H,s),8.14-8.05(2H,m),8.03-7.93(2H,m),7.72(1H,dd,J=8.80,4.85Hz)，7.12(1H，ddd，J＝9.86，8.79，2.51Hz)，7.05(1H，dd，J＝8.96，2.48Hz)，5.60(1H，s)，1.65(3H，d，J＝6.80Hz)

Example 261[ (S) -1- (6-fluoro-1-pyrimidin-2-yl-1H-benzimidazol-2-yl) -ethyl]- (7H-purin-6-yl) -amine 261

2, 4-bis (4-methoxyphenyl) -2, 4-dithio-1, 3,2, 4-dithiadiphosphetane (369mg,0.91mmol) was added to (S) -N- [ 4-fluoro-2- (pyrimidin-2-ylamino) phenyl ] in tetrahydrofuran (5.0ml) ]-2- [9- (tetrahydropyran-2-yl) -9H-purin-6-ylamino]Propionamide (109mg,0.23mmol) and heated to 80 ℃ overnight. The reaction mixture was cooled and concentrated in vacuo. The residue was taken up in EtOAc/1M hydrochloric acid (aq) and the aqueous layer was extracted three times with EtOAc. The aqueous layer was neutralized with sodium hydroxide (1M aq) and extracted with EtOAc (. times.3). The neutral organic fraction was washed with brine and dried (Na)₂SO₄) And concentrated in vacuo. The product is purified by chromatography (SiO)₂0-20% methanol in DCM) to give 261(35mg, 41%). LCMS R_T3.08min[M+H]⁺376.0。¹H NMR

(CDCl₃,400MHz):δ8.90(2H,d,J=4.9Hz),8.02(2H,s),7.97(1H,dd,J=9.8,2.7Hz),7.60(lH，dd，J＝8.7，5.OHz)，7.42(lH，t，J＝4.8Hz)，7.08(1H，td，79.0，2.6Hz)，6.52(1H，brs)，1.83(3H，d，76.8Hz)

Example 262N- {6- [ (S) -1- (6-fluoro-1-phenyl-1H-benzimidazol-2-yl) -ethylamino]-9H-purin-2-yl } -acetamide 262

A mixture of (S) -1- (6-fluoro-1-phenyl-1H-benzimidazol-2-yl) ethylamine dihydrochloride (0.22g,0.68mmol), N- (6-chloro-9H-purin-2-yl) acetamide (0.20g,0.95mmol), and DIPEA (0.60mL,3.38mmol) in IPA (2mL) was stirred at 85 deg.C in a sealed tube for 16H. The resulting mixture was diluted with DCM/methanol and concentrated in vacuo onto silica gel, and the residue was purified by chromatography (SiO)₂0-15% (2M ammonia in methanol) in DCM), followed by purification by preparative HPLC (Phenomenex Gemini5 μ M C18, 60min gradient: 20-98% with 0.1% HCO ₂H acetonitrile/water) to yield 262 as a white solid (0.067g, 23%). LCMS (method K) R_t3.14min,[M+H]⁺431。

¹HNMR(DMSO-d₆):δ13.20-12.50(1H,bs),9.60(1H,s),8.00(1H,s),7.71(1H,m),7.60(2H,s),7.51-7.49(3H,m),7.11-7.08(1H,m),6.86(1H,m)，5.64(1H，m)，2.10(3H，s)，1.5O(3H，d，J＝6.81Hz)

Example 267N- [ (S) -1- (6-fluoro-1-phenyl-1H-benzimidazol-2-yl) -ethyl]-[1,3,5]Triazine-2, 4-diamine 267

To 6-chloro-N- [ (S) -1- (6-fluoro-1-phenyl-1H-benzimidazol-2-yl) ethyl]-[1,3,5]To a solution of triazine-2, 4-diamine (100mg,0.26mmol) in EtOAc (10mL) was added a slurry of 10% Pd/C (40mg) in IMS (5mL) and the reaction mixture was stirred at RT under a hydrogen atmosphere for 18 h. Then the suspension is appliedThe pad was filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (C)₁₈With 20-55% MeOH in 0.5% TFA/H₂Gradient elution of solution in O) and then loaded intoSCX-2 column. The column was washed with MeOH, 0.5M NH₃The product was eluted with MeOH to give 267 as a colorless foam (42.3g, 46%). LCMS (method K) R_T3.14min[M+H]⁺350.0。

¹HNMR

(DMSO-d₆400MHz,80 ℃): δ 7.87(1H, s),7.66(1H, dd, J =8.8,4.9Hz),7.60-7.56(2H, m),7.54-7.49(3H, m), 7.08(1H, bs), 7.04(1H, ddd, J ═ 9.8, 8.7, 2.5Hz), 6.77(1H, dd, J ═ 9.0, 2.5Hz), 6.28(2H, bs), 5.23(1H, quintuple, J ═ 7.1Hz), 1.45(3H, d, J ═ 6.9Hz)

Example 2696-chloro-N- [ (S) -1- (6-fluoro-1-phenyl-1H-benzimidazol-2-yl) -ethyl]-[1,3,5]Triazine-2, 4-diamine 269

To ice-cooled (S) -1- (6-fluoro-1-phenyl-1H-benzimidazol-2-yl) ethylamine dihydrochloride (226mg,0.69mmol), 4, 6-dichloro- [1,3,5 ]To a mixture of triazin-2-ylamine (125mg,0.76mmol) and IPA (5mL) was added DIPEA (0.59mL,3.45 mmol). The reaction mixture was stirred at RT (RT) for 64 h. The solvent was removed under reduced pressure and the resulting residue was washed with EtOAc and Na₂CO₃The aqueous solution was partitioned. The aqueous phase was extracted with EtOAc, the combined organic fractions were washed with water and then brine, then dried (Na)₂SO₄) And concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, eluent EtOAc) to give the title compound as a colorless foam (quantitative yield). A portion (50mg) was further purified by column chromatography (Si-PCC with EtOAc as eluent) to give 269 as a colorless foam (31.8mg) after evaporation from acetone. LCMS (method K) R_T4.06min[M+H]⁺384.0/385.9。

¹HNMR(DMSO-d₆,400MHz,80℃):δ

7.69(lH, bs), 7.66(1H, dd, J-8.8, 4.9Hz), 7.60-7.50(5H, m), 7.07-7.02(lH, m), 6.78(2H, bs), 6.77(1H, dd, J-8.9, 2.4Hz), 5.21(1H, quintuple, J-7.1 Hz), 1.46(3H, d, J-6.9 Hz)

Example 270[ (R) -1- (6-fluoro-1-pyridin-2-yl-1H-benzimidazol-2-yl) -2-methoxy-ethyl]- (9H-purin-6-yl) -amine 270

A mixture of (R) -1- (6-fluoro-1-pyridin-2-yl-1H-benzimidazol-2-yl) -2-methoxyethylamine (69mg,0.24mmol), 6-chloro-9- (tetrahydropyran-2-yl) -9H-purine (56mg,0.24mmol), and DIPEA (0.21mL,1.2mmol) in IPA (1mL) was heated at 90 deg.C for 16H. After cooling to RT, the volatile substances were removed under reduced pressure and the residue obtained was loaded SCX-2 column. The column was washed with MeOH, then 2M NH₃Washing with MeOH. The basic fractions were combined, concentrated in vacuo and the residue purified by column chromatography (Si-PCC with 0-7.5%2 MNH)₃Gradient MeOH in DCM) to give 270 as a white solid (48mg, 49%). LCMS (method K) R_T3.07min[M+H]⁺405.0。

¹HNMR(DMSO-d₆,400MHz):δ12.80(1H,brs)，8.65(1H,s)，8.16-8.04(2H,m),7.98(1H,s),7.87-7.81(1H,m),7.79(1H,d，J=8.01Hz),7.72(1H,dd,J=8.82,4.90Hz)，7.56-7.49(1H,m),7.21-7.10(2H,m),6.05(1H,s),3.90(2H,d,J=6.25Hz),3.20(3H,s)

Example 2714-amino-6- [ (R) -1- (6-fluoro-1-pyridin-2-yl-1H-benzimidazol-2-yl) -2-methoxy-ethylamino]-pyrimidine-5-carbonitrile 271

A mixture of (R) -1- (6-fluoro-1-pyridin-2-yl-1H-benzimidazol-2-yl) -2-methoxyethylamine (69mg,0.24mmol), 4-amino-6-chloropyrimidine-5-carbonitrile (37mg,0.24mmol) and DIPEA (0.21mL,1.2mmol) in IPA (1mL) was heated at 90 deg.C for 16H. After cooling to RT, the volatile substances were removed under reduced pressure and the residue obtained was loadedSCX-2 column. The column was washed with MeOH, then 2M NH₃Washing with MeOH. The basic fractions were combined and concentrated in vacuoAnd the resulting residue was purified by column chromatography (Si-PCC, gradient eluted with 0-20% DCM in EtOAc) to give 271 as a yellow solid (78mg, 80%). LCMS (method K) R_T3.52min[M+H]⁺405.0。

¹HNMR

(DMSO-d₆,400MHz):δ8.68-8.64(1H,m),8.11(1H,td,J=7.76,1.94Hz),7.84(1H,s),7.79-7.73(2H,m),7.66(1H,d,J=7.94Hz),7.56(1H,ddd,J=7.52,4.87,0.98Hz),7.30-7.13(4H,m),6.03-5.95(1H,m),3.83(2H,d,J=6.59Hz),3.19(3H,s)

Example 272[1- (7-bromo-6-methoxy-1-phenyl-1H-benzimidazol-2-yl) -ethyl]- (9H-purin-6-yl) -amine 272

Reacting [ (S) -1- (7-bromo-6-methoxy-1-phenyl-1H-benzimidazol-2-yl) ethyl ]- [9- (tetrahydro-pyran-2-yl) -9H-purin-6-yl]The amine (453mg,0.83mmol) was dissolved in HCl in methanol (5mL,2.5M) and the reaction was stirred at RT for 2 h. The reaction mixture was concentrated in vacuo and the resulting residue was treated with preparative HPLC (C18Phenomenex column, 10-90% MeCN in water with 0.1% formic acid, 20min gradient) to give 272 as a white solid (70mg, 18%).¹H NMR400MHzδ(DMSO-d₆) 8.08(1H, br s),8.02(1H, s),7.84(1H, br s),7.59(1H, d, J =8.6Hz),7.55-7.26(5H, m),7.05(1H, d, J =9.0Hz),5.15(1H, br s),3.79(3H, s),1.49(3H, d, J =6.6 Hz). LCMS (method K) R_T=3.53min,[M+H]⁺=464+466

Example 273{ 5-fluoro-3-phenyl-2- [ (S) -1- (9H-purin-6-ylamino) -ethyl]-3H-benzimidazol-4-yl } -morpholin-4-yl-methanone 273

To 5-fluoro-3-phenyl-2- { (S) -1- [9- (tetrahydro-pyran-2-yl) -9H-purin-6-ylamino]To a solution of ethyl } -3H-benzimidazole-4-carboxylic acid (200mg,0.39mmol) and morpholine (42. mu.L, 0.48mmol) in DCM (10mL) was added HATU (197mg,0.52mmol) and the reaction was stirred at RT for 1H. The reaction mixture was diluted with water and extracted with DCM (3 × 10 mL). The combined organic fractions were washed with brine and dried (MgSO)₄) Concentrating under vacuum, and filtering the obtained residueFlash chromatography (SiO)₂Eluted with 0-10% methanol in EtOAc) LCMS (method C): R _T=2.60min,[M+H]And + = 571. The product was dissolved in HCl in methanol (5mL,2.5M) and the reaction was stirred at RT for 2 h. The reaction mixture was concentrated in vacuo and the resulting residue was loaded onto a SCX2 column, washed with methanol and then eluted with ammonia in methanol (2M). The eluate was concentrated in vacuo and the residue was purified by HPLC (C18,10-90% MeCN in H₂Solution in O, 0.1% formic acid, 20min gradient) to give 273 as a white solid (107mg,55%)

¹HNMR(DMSO-d₆+

TFA-D,400MHz,80℃):δ8.52(1H,brs),8.46(1H,d,J=6.25Hz),7.83-7.75(1H,m),7.57-7.43(5H,m),7.32-7.15(2H,m),5.66(1H,brs),3.50-3.24(5H,m),3.15-3.05(1H,m),3.04-2.95(1H,m),2.70-2.58(1H,m),1.74-1.65(3H,m)

LCMS (method K) R_T=2.63min,[M+H]+=487,R_T=2.66min,[M+H]+=487

Example 274[ (S) -1- (7-cyclopropyl-6-fluoro-1-pyridin-2-yl-1H-benzimidazol-2-yl) -ethyl]- (9H-purin-6-yl) -amine 274

Reacting [ (S) -1- (7-cyclopropyl-6-fluoro-1-pyridin-2-yl-1H-benzimidazol-2-yl) ethyl]- [9- (tetrahydro-pyran-2-yl) -9H-purin-6-yl]The amine (59mg,0.12mmol) was dissolved in HCl in methanol (5mL,2.5M) and the reaction was stirred at RT for 30 min. The reaction mixture was concentrated in vacuo and the resulting residue was treated with preparative HPLC (C18Phenomenex column, 5-80% MeCN in water with 0.1% formic acid, 20min gradient) to give 274 as a white solid (28mg, 57%).¹H NMR400MHz(DMSO-d₆) Δ 12.83(1H, br s),8.50(1H, br s),8.22-7.58(7H, m),7.00(1H, dd, J =11.3,9.4Hz),5.66-5.20(1H, m),1.52(3H, d, J =6.6Hz),1.32-1.21(1H, m),0.37-0.20(2H, m),1.89-0.07(1H, m),0.03-0.00(1H, m), LCMS (method K): R _T=3.27min,[M+H]+=415

Example 2754-amino-6- [ (S) -1- (6-fluoro-1-pyridin-2-yl-1H-benzimidazol-2-yl) -ethylamino]-pyrimidine-5-carbonitrile 275

A mixture of (S) -1- (6-fluoro-1-pyridin-2-yl-1H-benzimidazol-2-yl) ethylamine (281mg,1.1mmol), 4-amino-6-chloropyrimidine-5-carbonitrile (170mg,1.1mmol) and DIPEA (1mL,5.5mmol) in IPA (2mL) was heated at 90 deg.C for 16H. After cooling to RT, the volatile substances were removed under reduced pressure and the residue obtained was loadedSCX-2 column. The column was washed with MeOH, then 2M NH₃Washing with MeOH. The basic fractions were combined, concentrated in vacuo and the resulting residue was purified by column chromatography (Si-PCC, gradient eluted with 0-20% DCM in EtOAc) to give 275 as a white solid (295mg, 72%). LCMS (method K) R_T3.37min[M+H]⁺375.0。

¹HNMR(DMSO-d₆,400MHz):δ

8.60(1H,ddd,J=4.88,1.91,0.81Hz),8.06(1H,td,J=7.75,1.94Hz),7.86(1H,s),7.78-7.68(3H,m),7.50(1H,ddd,J=7.52,4.87,0.98Hz),7.21-7.11(4H,m),5.87-5.78(1H,m),1.53(3H,d,J=6.83Hz)

Example 2774-amino-6- { (S) -1- [ 6-fluoro-1- (5-fluoro-pyridin-3-yl) -1H-benzimidazol-2-yl]-ethylamino } -pyrimidine-5-carbonitrile 277

Reacting { (S) -1- [ 6-fluoro-1- (5-fluoropyridin-3-yl) -1H-benzimidazol-2-yl]A mixture of tert-butyl ethyl } carbamate (165mg,0.44mmol) in DCM (3mL) and TFA (1mL) was stirred at RT for 2 h. Loading the reaction mixture intoSCX-2 column, washing with MeOH, then 2M NH₃Washing with MeOH. The basic fractions were combined and concentrated in vacuo to give a yellow oil. A mixture of the residue, 4-amino-6-chloropyrimidine-5-carbonitrile (68mg,0.44mmol) and DIPEA (230. mu.L, 1.32mmol) in IPA (1mL) was heated at 90 deg.C for 16h in a sealed vial. After cooling to RT, the crude mixture was diluted with MeOH and loaded into SCX-2 column. The column was washed with MeOH, then 2M NH₃Washing with MeOH. The basic fractions were combined, concentrated in vacuo, and the resulting residue was purified by column chromatography (Si-PCC, gradient eluted with 0-100% EtOAc in cyclohexane) followed by EtOAc/cyclohexane/Et₂Trituration with O afforded 277 as an off-white solid (73mg, 42% over 2 steps).¹H NMR(DMSO-d₆400 MHz). delta.8.66 (1H, d, J =2.64Hz),8.62(1H, s),8.11-8.03(1H, m),7.83(1H, s),7.78-7.73(2H, m),7.26-7.04(4H, m),5.64-5.54(1H, m),1.58(3H, d, J =6.77 Hz). LCMS (method K) R_T3.40min[M+H]⁺393

Or to { (S) -1- [ 6-fluoro-1- (5-fluoropyridin-3-yl) -1H-benzimidazol-2-yl]Ethyl } carbamic acid tert-butyl ester (10.1g,27.0mmol) in MeOH (40mL) was added 4MHCl in dioxane (100 mL). After stirring the resulting solution at RT for 1h, the mixture was evaporated to dryness to give a dark green solid (13.7 g). To the solid suspension was added 4-amino-6-chloropyrimidine-5-carbonitrile (4.17g,27.0mmol) and DIPEA (23mL,134.9mmol), and the resulting mixture was heated at 90 ℃ for 17 h. After cooling to RT, the crude mixture was concentrated in vacuo to remove most of the solvent. The resulting residue was washed with EtOAc and H₂And (4) distributing among the O. The layers were separated and the aqueous layer was extracted with additional EtOAc. The combined organic fractions were washed with water, brine and dried (Na) ₂SO₄) And concentrated in vacuo. The resulting residue was taken up in DCM/EtOAc and purified by column chromatography (120gSi-PCC gradient eluted with 50-100% EtOAc in cyclohexane) to give the title compound as a yellow solid (3.3 g). The impure fraction was purified by chromatography (Si-PCC gradient eluted with 50-100% EtOAc in cyclohexane) to yield an additional 2.4g of material (5.0 g total, 47%). The product (4g) was taken up in MeOH (. about.30 mL) and stirred under reflux. To this suspension was added several portions of EtOAc until no solids remained (-30 mL addition). The hot solution was filtered and the resulting solution was then allowed to cool to ambient temperature, precipitating a crystalline material. After standing overnight, the crystalline material is filtered off, washed with a little MeOH and washed withVacuum drying at 45 ℃ for 3 days gave 277 as a light champagne solid (1.65 g).¹H NMR(DMSO-d₆400 MHz). delta.8.66 (1H, d, J =2.64Hz),8.62(1H, s),8.11-8.03(1H, m),7.83(1H, s),7.78-7.73(2H, m),7.26-7.04(4H, m),5.64-5.54(1H, m),1.58(3H, d, J =6.77 Hz). LCMS (method K) R_T3.39min[M+H]⁺393.1

Example 2782- ((S) -3- { 6-fluoro-2- [ (S) -1- (9H-purin-6-ylamino) -ethyl]-benzimidazol-1-yl } -piperidin-1-yl) -ethanol 278

2- [ (S) -3- (5-fluoro-2- { (S) -2- [9- (tetrahydropyran-2-yl) -9H-purin-6-ylamino 2, 2-dimethylpropanoic acid ]Propionylamino phenylamino) piperidin-1-yl]A solution of ethyl ester (583mg,0.95mmol) in 6M aqueous HCl (20mL) was refluxed for 30 min. After cooling to RT, the volatile substances were removed under reduced pressure and the residue obtained was taken up in twoAlkane/water (1:1) toSCX-2 column. Use the column twoAlkane/water (1:1) and then with bisAlkane wash with 10%880NH₃2 ofThe product was eluted with an alkane solution. The fractions containing the product were purified by column chromatography (C)₁₈With 2-40% MeOH in 0.5% TFA/H₂Gradient elution in O) followed by a second stepLoaded in an alkane toSCX-2 columnThe above. Use the column twoAlkane wash, then 10%880NH₃2 ofThe product was eluted with an alkane solution. Further purification by column chromatography (Si-PCC with 3-21%2M NH)₃Gradient elution in DCM/MeOH) gave 278 as a colorless solid (85.8mg, 21%). LCMS (method K) R_T2.05min[M+H]⁺425.1。

¹HNMR(CD₃OD，400

MHz):δ8.29(1H,s),8.09(1H,s),7.58(1H,dd,J=9.0,5.0Hz),7.50(1H,dd,J=9.6,2.3Hz),7.00(1H,dt,J=9.3,2.3Hz),5.97(1H,bs),4.80-4.71(1H,m),3.41-3.39(2H,m),3.15-3.10(1H,m),2.92(1H,bd,J=11.3Hz),2.81(1H,t,J=11.OHz),2.53-2.21(4H,m),2.01-1.97(1H,m),1.92-1.86(1H,m),1.80(3H,d,J=6.9Hz),1.78-1.70(1H,m)

Example 2793-phenyl-2- [ (S) -1- (9H-purin-6-ylamino) -ethyl]-3H-benzimidazole-4-carbonitrile 279

Reacting [ (S) -1- (7-bromo-1-phenyl-1H-benzimidazol-2-yl) ethyl][9- (tetrahydropyran-2-yl) -9H-purin-6-yl]Amine (300mg,0.58mmol) was dissolved in DMF (1mL) in a microwave vial and zinc cyanide (68mg,0.58mmol) and Pd (PPh) were added₃)₄(67mg,0.058 mmol). The vial was sealed, evacuated and purged with argon (× 3). The vial was heated at 150 ℃ for 15min with microwave radiation. The resulting colorless solution was poured onto a mixture of EtOAc and water. A white solid precipitated, which was dispersed between the 2 phases. The solid was isolated by filtration, dissolved in DCM and purified with NaHCO ₃The resulting solution was washed (saturated aqueous solution). The DCM fraction was passed through a PTFE column. DCM was removed under vacuum and the residue was passed through an SCX column. The column was washed with MeOH, 2M NH₃MeOH to elute the product. The product fractions were combined, evaporated and the residue was purified by chromatography (Si-PCC) with 0-8% M_eOH in DCM. Will be provided withThe product fractions were concentrated in vacuo to afford a white solid. It was triturated in ether, filtered and dried in vacuo to give 279 as a white solid (160mg, 73%).

1HNMR(DMSO-d₆，400MHz)δ：8.09(1H，brs)，8.03(1H，s)，7.98(2H，d，J＝8.2Hz)，7.66-7.59(3H，m)，7.56-7.37(4H，m)，7.33(1H，t，J＝7.9Hz)，5.35-5.21(1H，m)，1.54(3H，d，J＝6.9Hz)

LCMS (method K) R_T3.07min;m/z381[M+H]⁺

Example 280(R) -2- (6-fluoro-1-pyridin-2-yl-1H-benzimidazol-2-yl) -2- (9H-purin-6-ylamino) -ethanol 280

To a mixture of [ (R) -2-benzyloxy-1- (6-fluoro-1-pyridin-2-yl-1H-benzimidazol-2-yl) ethyl at 0 ℃ under a nitrogen atmosphere]To a solution of (7H-purin-6-yl) amine (336mg,0.7mmol) in anhydrous DCM (8mL) was added boron tribromide (1.0M in DCM, 2.6mL,2.6mmol) dropwise. The reaction mixture was stirred at 0 ℃ for 1 h. MeOH was added and volatiles were removed under reduced pressure. The resulting residue was purified by column chromatography (Si-PCC, gradient eluted with 0-10% MeOH in DCM) to give 280 as a white solid (225mg, 82%). LCMS (method K) R_T2.72min[M+H]⁺391.0。

¹HNMR(DMSO-d₆,400MHz):δ12.90(1H,brs),8.68(1H,s),8.20-8.08(2H,m),8.03(1H,s),7.85(1H,d,J=7.87Hz),7.71(1H,dd,J=8.80,4.89Hz),7.57(1H,t,J=6.07Hz),7.30-7.06(3H,m),5.84(1H,s),5.11(1H,s),4.01-3.82(2H,m)

Example 2854-amino-6- ((S) -1- { 6-fluoro-1- [ (S) -1- (2-hydroxy-ethyl) -piperidin-3-yl ]-1H-benzimidazol-2-yl } -ethylamino) -pyrimidine-5-carbonitrile 285

Reacting 2- { (S) -3- [2- ((S) -1-aminoethyl) -6-fluorobenzoimidazol-1-yl]A mixture of piperidin-1-yl } ethanol (35.6mg,0.12mmol), 4-amino-6-chloropyrimidine-5-carbonitrile (18mg,0.12mmol), and DIPEA (40. mu.L, 0.23mmol) in IPA (1mL) was stirred at 90 deg.C for 3 h. After cooling to RT, the volatiles were removed under reduced pressureThe residue obtained is purified by column chromatography (Si-PCC with 2-10%2M NH)₃Gradient MeOH in DCM) to give 285 as a colorless solid (17mg, 35%). LCMS (method K) R_T2.24min[M+H]⁺425.1。

¹HNMR

(CD₃OD，400MHz)：δ8.06(1H，s)，7.58(1H，dd，J＝8.9，5.OHz)，7.49(1H，dd，J＝9.6，2.4Hz)，7.01(1H，dt，J＝9.2，2.4Hz)，5.84(1H，q，J＝6.9Hz)，4.70-4.61(1H，m)，3.63(2H，t，J＝6.0Hz),3.17-3.12(1H,m),3.01-2.96(1H,m),2.83(1H,t,J=11.OHz),2.66-2.54(2H,m),2.39-2.24(2H,m),1.99-1.88(2H,m),1.86-1.77(1H,m),1.70(3H,d,J=6.9Hz)

Example 286N- [ (S) -1- (6-fluoro-1-phenyl-1H-benzimidazol-2-yl) -ethyl]-[1,3,5]Triazine-2, 4, 6-triamine 286

To 6-chloro-N- [ (S) -1- (6-fluoro-1-phenyl-1H-benzimidazol-2-yl) ethyl]-[1,3,5]Triazine-2, 4-diamine (100mg,0.26mmol) in bis880NH was added to a solution in alkane (1mL)₃(4 mL). The reaction mixture was heated at 100 ℃ with microwave radiation for 1 h. After cooling to RT, the reaction mixture was evaporated and purified by column chromatography (Si-PCC with 2-12%2M NH₃Gradient elution in DCM/MeOH) gave 286 as a pink foam (72.9mg, 77%). LCMS (method K) R_T2.89min[M+H]⁺365.0。

¹HNMR(DMSO-d₆400MHz,80 ℃): δ 7.67-7.60(3H, m), 7.57-7.51(3H, m), 7.05(1H, ddd, J ═ 10.1, 8.8, 2.6Hz), 6.78(1H, dd, J ═ 9.0, 2.5Hz), 6.31(1H, bd, J ═ 7.5Hz), 5.61(4H, bs), 5.22(1H, quintuple, J ═ 7.lHz), 1.40(3H, d, J ═ 6.9Hz)

Example 288[ (S) -1- (6-fluoro-7-methyl-1-pyridin-2-yl-1H-benzimidazol-2-yl) -ethyl]- (9H-purin-6-yl) -amine 288

To a solution of (S) -1- (6-fluoro-7-methyl-1-pyridin-2-yl-1H-benzimidazol-2-yl) ethylamine dihydrochloride (300mg,0.87mmol) in IPA (10mL) was added 6-chloro-9- (tetrahydropyran-2-yl) -9H-purine (271mg,1.14mmol) and DIPEA (448 μ L,2.62mmol) and the reaction mixture was heated at 90 ℃ for 16H. The reaction mixture was concentrated in vacuo and the resulting residue was treated with flash chromatography (SiO)₂Eluted with 0-10% methanol in EtOAc). LCMS (method C) R_T=2.81min,[M+H]And + = 473. The product was dissolved in HCl in methanol (5mL,2.5M) and the reaction was stirred at RT for 30 min. The reaction mixture was concentrated in vacuo and the resulting residue was loaded onto a SCX2 column, washed with methanol and then eluted with ammonia in methanol (2M). The eluate was concentrated in vacuo and the residue triturated with ether to give 288 as a white solid (174mg,51%)¹HNMR400MHzδ(DMSO-d₆80 ℃):8.55-8.49(1H, m),8.01(1H, s),7.89(1H, td, J =7.7,1.9Hz),7.65(1H, d, J =7.6Hz),7.49(1H, dd, J =8.7,4.7Hz),7.46(1H, ddd, J =7.6,4.9,0.9Hz),7.17(1H, br s),7.02(1H, dd, J =10.6,9.0Hz),5.57(1H, br s),1.66(3H, s),1.55(3H, d, J =6.8 Hz). LCMS (method K) R _T=3.01min,[M+H]+=389

Example 2894-amino-6- [ (S) -1- (6-fluoro-7-methyl-1-pyridin-2-yl-1H-benzimidazol-2-yl) -ethylamino]-pyrimidine-5-carbonitrile 289

To a solution of (S) -1- (6-fluoro-7-methyl-1-pyridin-2-yl-1H-benzimidazol-2-yl) ethylamine dihydrochloride (300mg,0.87mmol) in IPA (10mL) was added 4-amino-6-chloropyrimidine-5-carbonitrile (135mg,0.87mmol) and DIPEA (448. mu.L, 2.62mmol) and the reaction mixture was heated at 90 deg.C for 16H. The reaction mixture was concentrated in vacuo and the resulting residue was treated with flash chromatography (SiO)₂Eluted with 0-10% methanol in EtOAc). The product was triturated with ether and then purified by HPLC (C18,10-90% MeCN in H₂O solution, 0.1% formic acid, 20min gradient) to give 289 as a white solid (164mg, 48%).

¹HNMR400MHzδ(DMSO-d₆):8.55(1H,brs),8.00-7.91(1H,m),7.81-7.73(1H,m),7.70-7.60(1H，m)，7.53(1H，dd，J＝8.7，4.6H2)，7.55-7.45(1H，m)，7.21-7.09(1H，m)，7.06(1H,dd,J=10.3,8.7Hz),5.65-5.13(１H,m),1.63(3H,s),1.46(3H,d,J=6.7Hz).

LCMS (method K) R_T=3.40min,[M+H]+=389

Example 2905-fluoro-2- [ (S) -1- (9H-purin-6-ylamino) -ethyl]-3-pyridin-2-yl-3H-benzimidazole-4-carbonitrile 290

To a solution of 2- ((S) -1-aminoethyl) -5-fluoro-3-pyridin-2-yl-3H-benzimidazole-4-carbonitrile dihydrochloride (250mg,0.71mmol) in IPA (7mL) was added 6-chloro-9- (tetrahydro-pyran-2-yl) -9H-purine (220mg,0.92mmol) and DIPEA (361 μ L,2.1mmol) and the reaction mixture was heated at 90 ℃ for 16H. The reaction mixture was concentrated in vacuo and the resulting residue was treated with flash chromatography (SiO) ₂Eluted with 0-10% methanol in EtOAc). LCMS (method C) R_T=2.86min,[M+H]And + = 484. The product was dissolved in HCl in methanol (5mL,2.5M) and the reaction was stirred at RT for 2 h. The reaction mixture was concentrated in vacuo and the resulting residue was loaded onto a SCX2 column, washed with methanol and then eluted with ammonia in methanol (2M). The eluate was concentrated in vacuo and the residue triturated with ether to give 290 as a white solid (174mg,51%)¹H NMR400MHz(DMSO-d₆) δ 12.57(1H, br s),8.53-8.50(1H, m),8.04(1H, dd, J =9.0,4.72Hz),8.00(1H, s),7.96-7.88(1H, m),7.74(1H, d, J =8.0Hz),7.47(1H, dd, J =7.2,4.9Hz),7.43-7.34(1H, m),7.30(1H, dd, J =10.3,9.2Hz),5.71(1H, br s),1.62(3H, d, J =7.0 Hz). LCMS (method K) R_T=2.88min,[M+H]+=400

Example 292[ (S) -1- (7-bromo-1-phenyl-1H-benzimidazol-2-yl) -ethyl]- (9H-purin-6-yl) -amine 292

Reacting [ (S) -1- (7-bromo-1-phenyl-1H-benzimidazol-2-yl) ethyl][9- (tetrahydropyran-2-yl) -9H-purin-6-yl]The amine (60mg,0.12mmol) was dissolved in HCl (1mL,1M MeOH) and the resulting solution was stirred for 15 min. The solvent was removed in vacuo and the residue was crystallized from hot IPA to give 292 as white crystals (53mg, 98%). 1H NMR (DMSOd)₆,400MHz):δ864-8.47(2H, m),7.82-7.76(2H, m),7.74-7.50(5H, m),7.44(1H, t, J =8.1Hz),5.53-5.41(1H, m),1.84(3H, d, J =7.0 Hz). LCMS (method K) R _T3.69min;m/z[M+H]⁺434/436

Example 293(9H-purin-6-yl) - [ (S) -1- (3-pyridin-2-yl-3H-imidazo [4, 5-b)]Pyridin-2-yl) -ethyl]-amines 293

Reacting (S) -1- (3-pyridin-2-yl-3H-imidazo [4, 5-b)]A mixture of pyridin-2-yl) ethylamine (0.134g,0.56mmol), 6-chloro-9- (tetrahydropyran-2-yl) -9H-purine (0.186g,0.78mmol) and DIPEA (0.18mL,1.01mmol) in IPA (2mL) was stirred at 90 deg.C in a sealed tube for 16H. The resulting mixture was concentrated in vacuo and the residue was purified by chromatography (SiO)₂0-10% (2M ammonia in methanol) in DCM). The product was dissolved in methanol and HCl/bisAlkane (4M,1.0mL,4.00mol) and stirred for 30 min. Loading the resulting mixture intoSCX-2 column, washing with MeOH, 2M NH₃The product was eluted with MeOH, then concentrated in vacuo to afford 293 as a white solid (0.160g, 80%). LCMS (method K) R_t2.28min,[M+H]⁺358。

¹HNMR(DMSO-d₆)：δ13.20-12.70(lH，bs)，8.59(lHs),8.31(1H,m),8.13(2H,m),8.03(2H,tm),7.81-7.81(1H,m),7.47(1H,s),7.36(1H,m),5.99(1H，m)，1.67(3H，d，J＝6.82Hz)

Example 2964-amino-6- [1- (6-fluoro-1-pyridin-4-yl-1H-benzimidazol-2-yl) -ethylamino]-pyrimidine-5-carbonitrile 296

A mixture of 1- (6-fluoro-1-pyridin-4-yl-1H-benzimidazol-2-yl) ethylamine (55mg,0.22mmol), 4-amino-6-chloropyrimidine-5-carbonitrile (33mg,0.22mmol) and DIPEA (115 μ L,0.64mmol) in IPA (1mL) was heated at 90 deg.C in a sealed vial for 16H. After cooling to the temperature of the reaction mixture at RT, The crude mixture was diluted with MeOH and loaded ontoSCX-2 column. The column was washed with MeOH, then 2M NH₃Washing with MeOH. The basic fractions were combined, concentrated in vacuo, and the resulting residue was purified by column chromatography (Si-PCC, gradient eluted with 0-10% MeOH in EtOAc) followed by reverse phase HPLC (Phenomenex Gemini 5. mu. m C18, 5-60% with 0.1% NH)₄Gradient of OH in acetonitrile/water) to give 296 as a pale beige solid (21mg, 26%). LCMS (method K) R_T3.00min[M+H]⁺375.06。

¹HNMR

(DMSO-d₆,400MHz):δ8.75-8.71(2H,m),7.88(1H,s),7.79-7.72(2H,m),7.65-7.60(2H,m),7.24-7.12(3H,m),7.06(1H,dd,J=8.98,2.49Hz),5.65-7.56(1H,m),1.57(3H,d,J=6.77H2)

Example 3024-amino-6- [1- (3-phenyl-3H-imidazo [4,5-b ]]Pyridin-2-yl) -ethylamino]-pyrimidine-5-carbonitrile 302

Reacting (S) -1- (3-phenyl-3H-imidazo [4, 5-b)]A mixture of pyridin-2-yl) ethylamine (0.194g,0.81mmol), 4-amino-6-chloropyrimidine-5-carbonitrile (0.176g,1.14mmol) and DIPEA (0.26mL,1.47mol) in IPA (2mL) was stirred at 90 deg.C in a sealed tube for 16 h. The resulting mixture was concentrated in vacuo and the residue was purified by chromatography (SiO)₂0-10% MeOH in EtOAc) to give 302 as a white solid (0.190g, 66%). LCMS (method K) R_t3.01min[M+H]⁺357。

¹HNMR(DMSO-d₆):δ8.25(１H,dd,J=4.76,1.48Hz),8.12(1H,dd,J=7.98,1.48Hz),7.87(1H,s),7.72(1H,d,J=7.21Hz),7.53-7.52(4H,m),7.32(1H,dd,J=7.99,4.77Hz),7.19(2H，s)，5.51(lH，m，J＝6.98Hz)，1.52(3H，d，J＝6.84Hz)

Example 303[1- (6-fluoro-1-pyridin-4-yl-1H-benzimidazol-2-yl) -ethyl]- (9H-purin-6-yl) -amine 303

A mixture of 1- (6-fluoro-1-pyridin-4-yl-1H-benzimidazol-2-yl) ethylamine (60mg,0.23mmol), 6-chloro-9- (tetrahydropyran-2-yl) -9H-purine (59mg,0.25mmol) and DIPEA (125 μ L,0.70mmol) in n-butanol (0.5mL) was heated at 100 ℃ in a sealed vial for 23H. After cooling to RT, the resulting mixture was diluted with MeOH and loaded into SCX-2 column. The column was washed with MeOH, then 2M NH₃Washing with MeOH. The basic fractions were combined, concentrated in vacuo and the residue purified by column chromatography (Si-PCC with 0-10%2 MNH)₃Gradient elution in DCM/MeOH) followed by purification by reverse phase HPLC (phenomenex gemini5 μm C18, 5-60% with 0.1% NH)₄Acetonitrile/water gradient of OH) to give 303 as a pale orange solid (12mg, 14%). LCMS (method K) R_T2.70min[M+H]⁺375.05。¹HNMR(DMSO-d₆,400MHz):δ12.90(1H,s),8.72-8.66(2H,m),8.09-8.01(2H,m),7.73-7.67(3H,m),7.19-701(2H,m),568-5.11(1H,m),1.62(3H,d,J=7.26Hz)

Example 304(S) -3- (6-fluoro-1-pyridin-2-yl-1H-benzimidazol-2-yl) -3- (9H-purin-6-ylamino) -propan-1-ol 304

To [ (S) -3-benzyloxy-1- (6-fluoro-1-pyridin-2-yl-1H-benzimidazol-2-yl) propyl at 0 ℃ under a nitrogen atmosphere]To a solution of (7H-purin-6-yl) amine (465mg,0.8mmol) in anhydrous DCM (8mL) was added boron tribromide (1.0M in DCM, 2.4mL,2.4mmol) dropwise. The reaction mixture was stirred at 0 ℃ for 1 h. MeOH was added and volatiles were removed under reduced pressure. The resulting residue was purified by column chromatography (Si-PCC, gradient eluted with 0-15% MeOH in DCM) to afford 304 as a white solid (143mg, 44%). LCMS (method K) R_T2.73min[M+H]⁺404.9。

¹HNMR(DMSO-d₆,400MHz):δ9.56-9.48(1H,m),8.65-8.57(2H，m)，8.49(1H，s)，8.11(1H，td，J＝7.74，1.90Hz)，7.83-7.74(2H，m)，7.56(1H，t，J＝6.09Hz),7.28-7.16(2H,m),6.07-5.97(1H,m),3.59-3.45(2H,m),2.39-2.29(1H,m),2.24-2.12(lH，m)

Example 3055-fluoro-3-phenyl-2- [ (S) -1- (9H-purin-6-ylamino) -ethyl]-3H-benzimidazole-4-carboxylic acid (2-methoxy-ethyl) -amide 305

To 5-fluoro-3-phenyl-2- { (S) -1- [9- (tetrahydropyran-2-yl) -9H-purin-6-ylamino]To a solution of ethyl } -3H-benzimidazole-4-carboxylic acid (180mg,0.36mmol) and 2-methoxyethanol amine (40mg,0.54mmol) in DCM (10mL) was added HATU (177mg,0.47mmol) and the reaction was stirred at RT for 2H. The reaction mixture was diluted with water and extracted with DCM (3 × 10 mL). The combined organic fractions were washed with brine and dried (MgSO)₄) Concentrated in vacuo and the residue obtained is subjected to flash chromatography (SiO)₂Eluted with 0-10% methanol in EtOAc) LCMS (method C): R_T=2.51min,[M+H]+ = 559. The product was dissolved in HCl in methanol (5mL,2.5M) and the reaction was stirred at RT for 10 min. The reaction mixture was concentrated in vacuo and the resulting residue was purified by HPLC (C18, 10-90% MeCN in H with 0.1% formic acid₂O solution, 20min gradient) to yield 305 as a white solid (65mg, 38%).

¹HNMR400MHz(DMSO-d₆):δ8.29(1H,t,J=5.3Hz),8.08

(1H,brs),8.02(1H,s),84(1H,brs),7.64(1H,dd,J=8.8,4.9Hz),7.50-7.29(5H,m),7.07(1H,t，J＝9.4Hz)，5.22(1H，s)，3.13(3H，s)，3.03(2H，t，J＝6.2Hz)，2.63(2H，q，J＝8.8Hz)，1.47(3H,d,J=6.9Hz)

LCMS (method K) R_T=2.50min,[M+H]+=475

Example 310(S) -N6- (1- (6-fluoro-1-phenyl-1H-benzo [ d)]Imidazol-2-yl) ethyl) -9H-purine-2, 6-diamine 310

A mixture of (S) -1- (6-fluoro-1-phenyl-1H-benzimidazol-2-yl) ethylamine.2 HCl (195mg,0.59mmol), 6-chloro-9H-purin-2-ylamine (106mg,0.62mmol) and DIPEA (415. mu.L, 2.38mmol) in n-butanol (1mL) was placed in a sealed vial at 100 ℃ Heating for 24 h. After cooling to RT, the reaction mixture was diluted with MeOH and loaded intoSCX-2 column. The column was washed with MeOH, then 2M NH₃Washing with MeOH. The basic fractions were combined, concentrated in vacuo, and the resulting residue was purified by column chromatography (Si-PCC,0-10%2M NH)₃Gradient elution in DCM/MeOH) followed by purification by reverse phase HPLC (Phenomenex Gemini5 μmC18 with 5-60% NH 0.1% >)₄Acetonitrile/water gradient of OH) to give 310 as a white solid (52mg, 23%). LCMS (method K) R_T2.89min[M+H]⁺389.02。

¹HNMR(CDC1₃,400MHz):δ7.67(1H,dd,J=8.67,4.59Hz),7.62-7.38(5H,m),7.20(1H,s),7.00(1H,td,J=9.19,2.45Hz),6.79(1H,dd,J=8.61,2.46Hz),5.65(1H,s),4.92(1H,s),1.64(3H，d，J＝6.94Hz)

Example 3113-phenyl-2- [ (S) -1- (9H-purin-6-ylamino) -ethyl]-3H-benzimidazole-4-carboxylic acid amide 311

Reacting 3-phenyl-2- [ (S) -1- (9H-purin-6-ylamino) ethyl]-3H-benzimidazole-4-carbonitrile (70mg,0.18mmol) was dissolved in DMSO (2mL) and K was added to the solution₂CO₃(10mg) solution in water (0.1 mL). Dropwise addition of H₂O₂(0.2mL,30% aqueous solution), the resulting solution was stirred for 2 h. Very slow hydrolysis was observed to occur with LCMS. The solution was mixed with another aliquot of H₂O₂(2X 0.2mL) were heated together at 60 ℃ for 2 days. The cooled mixture was poured onto water. The resulting aqueous solution was passed through an SCX column, which was washed with water and MeOH, and 2M NH₃MeOH to elute the product. The product fractions were combined, evaporated and the residue purified by chromatography (Si-PCC,0-10%2M NH) ₃Methanol solution in DCM). The product fractions were concentrated in vacuo to afford a white solid. It was triturated in ether, filtered and dried in vacuo to give 311 as a white solid (35mg, 50%). 1H NMR (DMSO-d6, 400MHz). delta.8.18-8.00 (2H, m),7.87-7.77(1H, m),7.66(1H, d, J =7.4Hz),7.55-7.27(6H, m),7.23-7.13(2H, m),6.95(1H, s),5.38-5.18(1H, m),1.46(3H, d, J =6.7 Hz). LCMS (method K) R_T1.99min;m/z399[M+H]⁺

Example 313[ (S) -1- (6-fluoro-1-pyridin-2-yl-1H-benzimidazol-2-yl) -ethyl]- (2-trifluoromethyl-9H-purin-6-yl) -amine 313

A mixture of (S) -1- (6-fluoro-1-pyridin-2-yl-1H-benzimidazol-2-yl) ethylamine (0.055g,0.22mmol), 6-chloro-2-trifluoromethyl-9H-purine (0.040g,0.18mmol) and DIPEA (0.096mL,5.39mol) in IPA (1mL) was stirred at 80 deg.C in a sealed tube for 16H. The resulting mixture was concentrated in vacuo and the residue was purified by chromatography (SiO)₂0-15% (2M ammonia in methanol) in DCM), followed by purification by preparative HPLC (Phenomenex Gemini5 μ M C18, 60min gradient: 20-98% with 0.1% HCO₂H acetonitrile/water) to yield 313 as a white solid (0.042g, 23%). LCMS (method K) R_t4.11min,[M+H]⁺443。

¹HNMR(DMSO-d₆)δ:13.20-12.70(1H,bs),

8.59(2H,m),8.32(1H,s),7.97(1H,m),7.74-7.67(2H,m),7.43(1H,s),7.16-7.13(2H,m),5.86(1H，m)，1.69(3H，d，J＝6.82Hz)

Example 3154- [ (S) -1- (6-fluoro-1-pyridin-2-yl-1H-benzimidazol-2-yl) -ethylamino ]-pyrimidine-5-carbonitrile 315

(S) -1- (6-fluoro-1-pyridin-2-yl-1H-benzimidazol-2-yl) ethylamine (256mg,0.54mmol), 4-chloropyrimidine-5-carbonitrile (139mg,0.51mmol), DIPEA (0.2mL,1.14mmol) and IPA (1mL) were placed in a sealed tube and the mixture was heated at 60 ℃ for 1H. The cooled brown mixture was concentrated in vacuo. The residue was partitioned between DCM and water and the DCM extract was isolated by passage through a PTFE column. The DCM extract was concentrated in vacuo and the residue was purified on silica (Si-PPC,1-100% EtOAc in DCM). The product fractions were concentrated in vacuo to afford 315 as a yellow foam (100mg, 52%). 1H NMR (CDCl)₃,400MHz):δ8.76(1H,dd,J=4.6,1.8Hz) 8.57(1H, s),8.41(1H, s),8.02(1H, td, J =7.8,1.9Hz),7.79-7.69(2H, m),7.55(1H, d, J =8.0Hz),7.47(1H, ddd, J =7.5,4.9,0.8Hz),7.09-7.02(2H, m),6.11-6.03(1H, m),1.49(3H, d, J =7.0 Hz). LCMS (method K) R_T3.74min[M+H]⁺360

Example 3164- [ (S) -1- (6-fluoro-1-phenyl-1H-benzimidazol-2-yl) -ethylamino]-pyrimidine-5-carbonitrile 316

(S) -1- (6-fluoro-1-phenyl-1H-benzimidazol-2-yl) ethylamine dihydrochloride (366mg,1.10mmol), 4-chloropyrimidine-5-carbonitrile (155mg,1.10mmol), DIPEA (0.77mL,4.4mmol) and IPA (1mL) were placed in a sealed tube and the reaction mixture was heated at 90 deg.C for 2H. The cooled brown mixture was concentrated in vacuo. The residue was dispersed between DCM and water and the DCM extract was separated via passage through a PTFE column. The DCM extract was concentrated in vacuo and the residue was purified on silica (Si-PPC,1-8% MeOH in DCM). The product fractions were concentrated in vacuo to give a brown foam. The foam was further purified by chromatography (Si-PCC,1-100% EtOAc in DCM) to afford 316 as a yellow solid (274mg, 70%). 1H NMR (CDCl) ₃400 MHz). delta.8.40 (1H, s),8.19(1H, d, J =6.2Hz),7.72(1H, dd, J =8.8,4.8Hz),7.60-7.54(3H, m),7.27(1H, br s),7.04(1H, td, J =9.2,2.5Hz),6.73(1H, dd, J =8.5,2.4Hz),6.35(1H, d, J =6.1Hz),5.52(1H, d, J =7.4Hz),4.91(1H, quin, J =6.9Hz),1.62(3H, d, J =6.8 Hz). LCMS (method K) R_T4.20min[M+H]⁺359

Example 317[ (S) -1- (6-fluoro-1-phenyl-1H-benzimidazol-2-yl) -ethyl]-pyrido [3,2-d]Pyrimidin-4-yl-amines 317

(S) -1- (6-fluoro-1-phenyl-1H-benzimidazol-2-yl) ethylamine dihydrochloride (0.082g,0.25mmol), 4-chloropyrido [3,2-d ] in IPA (1mL)]Pyrimidine (j.med Chem,1833,1996) (0.035g,0.21mmol) and DIPEA (0.174mL,1.0mmol) were heated to 70 ℃ in a sealed tube under argon for 1 h. The reaction mixture was cooled, diluted with EtOAc (20mL) and washed with water (2 mL). The aqueous layer was extracted with EtOAc (10 mL). The combined organic extracts were dried (Na)₂SO₄) Evaporated to dryness and purified by column chromatography (Si-PCC, using0-8%(9:1MeOH/.880NH₃) Gradient elution with DCM). The product containing fractions were evaporated and freeze dried to give 317 as an off-white solid (15mg, 18%). LCMS (method C) R_T3.55min[M+H]⁺385.05。

¹HNMRδ(ppm)(DMSO-d₆):8.83(1H,dd,J=4.24,1.57Hz),863(1H,

d,J=7.55Hz),8.40(1H,s),8.11(1H,dd,J=8.46,1.57Hz),7.84(1H,dd,J=8.47,4.24Hz),7.74(1H，dd，J＝8.81，4.85Hz)，7.59(2H，d，J＝7.53Hz)，7.50-7.5O(3H，m)，7.12(lH，ddd，J＝9.87，8.81，2.53Hz)，6.86(1H，dd，J＝8.92，2.5lHz)，5.59(1H，dq，J＝7.09Hz)，1.59(3H，d，J=6.81Hz)

Example 3184-amino-6- { (S) -1- [ 6-fluoro-7- (morpholine-4-carbonyl) -1-phenyl-1H-benzimidazol-2-yl]-ethylamino } -pyrimidine-5-carbonitrile 318

To [2- ((S) -1-aminoethyl) -5-fluoro-3-phenyl-3H-benzimidazol-4-yl]To a solution of morpholin-4-ylmethanone dihydrochloride (300mg,0.69mmol) in IPA (5mL) was added 4-amino-6-chloropyrimidine-5-carbonitrile (108mg,0.69mmol) and DIPEA (353. mu.L, 2.07mmol) and the reaction mixture was heated at 90 ℃ for 16 h. The reaction mixture was concentrated in vacuo and the resulting residue was treated with flash chromatography (SiO)₂Eluted with 0-4% methanol in EtOAc). The product was triturated with ether. The resulting solid was purified by preparative HPLC (C18Phenomenex column, 10-90% MeCN in water with 0.1% formic acid, 20min gradient) to give the title compound as a white solid (140mg, 42%).

¹HNMR400MHzδ

(DMSO-d₆) (mixture of rotamers) 7.80(0.5H, s), 7.76(0.5H, s), 7.73(1H, dd, J ═ 8.8, 4.8Hz), 7.67(0.5H, d, J ═ 7.5Hz), 7.54(0.5H, d, J ═ 7.2Hz), 7.50-731(5H, m), 7.19-7.07(3H, m), 5.28(0.5H, quin, J =7.1Hz),5.21(0.5H, quin, J =7.0Hz),3.48-3.35(1H, m),3.34-3.18(4H, m),3.10-2.87(2H, m),2.56-2.47 (1H, m),1.47-1.40(3H, m),

LCMS (method K) R_T=2.96min,[M+H]+=487,R_T=3.00min,[M+H]+ =487 (mixture of rotamers)

Example 321[ (S) -1- (6-fluoro-1-phenyl-1H-benzimidazol-2-yl) -ethyl]Imidazo [2, 1-f) ][1,2,4]Triazin-4-yl-amines 321

(S) -1- (6-fluoro-1-phenyl-1H-benzimidazol-2-yl) ethylamine dihydrochloride (0.106g,0.32mmol), 4-chloroimidazo [2,1-f ] in isopropanol (2mL)][1,2,4]Triazine (WO2010/014930) (0.050g,0.32mmol) and diisopropylethylamine (0.222mL,1.28mmol) were heated to 60 ℃ in a sealed test tube for 0.5 h. The reaction mixture was cooled, diluted with EtOAc (20mL) and washed with water (2 mL). The organic extracts were dried (Na)₂SO₄) Evaporated to dryness and purified by column chromatography (Si-PCC with 0-10% (9:1MeOH/.880 NH)₃) Gradient elution with DCM). The product containing fractions were evaporated and freeze dried to give 321 as a pale pink solid (94mg, 78%). LCMS (method C) R_T4.31min[M+H]⁺374.01。

¹HNMRδ(ppm)(DMSO-d)

9.15(lH，d，J＝7.24Hz)，8.02(lH，d，J＝l.09Hz)，7.95(lH，s)，7.71(lH，dd，J＝8.81，4.85Hz),7.57-7.54(3H,m),7.48-7.39(3H,m),7.10(1H,td,J=9.33,2.51Hz),6.83(1H,dd,J=8.91，2.52Hz)，5.57(1H，dq，J＝7.0OHz)，1.61(3H，d，J＝6.88Hz)

Example 322[ (S) -1- (6-fluoro-1-pyridin-2-yl-1H-benzimidazol-2-yl) -ethyl]Imidazo [2, 1-f)][1,2,4]Triazin-4-yl-amines 322

(S) -1- (6-fluoro-1-pyridin-2-yl-1H-benzimidazol-2-yl) ethylamine (0.066g,0.26mmol), 4-chloroimidazo [2,1-f ] in isopropanol (2mL)][1,2,4]Triazine (WO2010/014930) (0.040g,0.26mmol) and diisopropylethylamine (0.090mL,0.52mmol) were heated to 60 ℃ in a sealed test tube for 0.5 h. The reaction mixture was cooled, diluted with EtOAc (20mL) and washed with water (2 mL). The organic extracts were dried (Na) ₂SO₄) Evaporated to dryness and purified by column chromatography (Si-PCC with 0-10% (9:1MeOH/.880 NH)₃) Gradient elution with DCM). The product containing fractions were evaporated and freeze dried to give 322 as a white solid (62mg, 63%). LCMS (method C) R_T3.78min[M+H]⁺375.04。

¹HNMRδ(ppm)(DMSO-d):9.13

(1H,d,J=7.61Hz),8.57(1H,dd,J=4.90,1.81Hz),8.01-7.98(2H,m),7.93(1H,s),7.74-7.73(2H，m)，7.55(1H，d，J＝1.12Hz)，7.44-7.44(1H，m)，7.15-7.15(2H，m)，5.92(1H，dq，J=7.11Hz),1.65(3H,d,J=6.87Hz)

Example 3235-chloro-4- [ (S) -1- (6-fluoro-1-phenyl-1H-benzimidazol-2-yl) -ethylamino]-2-methyl-2H-pyridazin-3-one 323

(S) -1- (6-fluoro-1-phenyl-1H-benzimidazol-2-yl) ethylamine dihydrochloride (1.0g,3.05mmol), 4, 5-dichloro-2-methyl-2H-pyridazin-3-one (J.Org.Chem2473-76,46,1981) (0.546g,3.05mmol) and diisopropylethylamine (2.1mL,12.8mmol) in isopropanol (5mL) were heated to reflux for 4.25H and then heated at 75 ℃ for 20H. The reaction mixture was cooled, diluted with EtOAc (20mL), and washed with 1M sodium carbonate (10 mL). The organic extracts were dried (Na)₂SO₄) Evaporated to dryness and purified by column chromatography (Si-PCC, gradient eluted with 0-10% MeOH in DCM followed by 20-100% EtOAc in DCM). The fractions containing the less polar product were evaporated and freeze dried to give 323 as a yellow solid (78mg, 6.4%). LCMS (method C) R_T4.80min[M+H]⁺398.00。

¹HNMRδ(ppm)(DMSO-d):7.77(1H,dd,J=8.82,

4.85Hz)，7.56-7.55(6H，m)，7.14(1H，ddd，J＝9.9，8.9，2.5OHz)，6.89(lH，dd，J＝8.91，2.51Hz)，6.61(1H，d，J＝9.09Hz)，5.94(1H，t，J＝7.66Hz)，3.56(3H，s)，1.5l(3H，d，J＝6.65Hz)

Example 3264-[(S) -1- (6-fluoro-1-phenyl-1H-benzimidazol-2-yl) -ethylamino]-2-methyl-2H-pyridazin-3-one 326

5-chloro-4- [ (S) -1- (6-fluoro-1-phenyl-1H-benzimidazol-2-yl) ethylamino in ethyl acetate (5mL) and saturated aqueous sodium bicarbonate solution (1mL)]-2-methyl-2H-pyridazin-3-one (0.06g,0.15mmol) was hydrogenated with 10% palladium on carbon (20mg) at room temperature and atmospheric pressure for 3H. The reaction mixture was filtered, evaporated to dryness and purified by column chromatography (Si-PCC, gradient eluted with 50-100% EtOAc in DCM). The product containing fractions were evaporated and freeze dried to yield 326 as a white solid (30mg, 55%). LCMS (method C) R_T4.0min[M+H]⁺364.09。

¹HNMRδ(ppm)(DMSO-d):7.76(1H,dd,J=8.83，4.84Hz)，7.58-7.56(5H，m)，7.44(1H，d，J＝4.98Hz)，7.13(1H，ddd，J＝9.9，8.9，2.5Hz)，6.85(1H，dd，J＝8.90，2.47Hz)，6.74(1H，d，J＝7.91Hz)，5.90(1H，d，J＝5.04Hz)，4.81(1H，dg,J=7.12Hz),3.59(3H,s),1.49(3H,d,J=6.65Hz)

Example 3275-fluoro-3-phenyl-2- [1- (9H-purin-6-ylamino) -ethyl]-3H-benzimidazol-4-ol 327

In a sealed tube, [ (S) -1- (7-bromo-6-fluoro-1-phenyl-1H-benzimidazol-2-yl) ethyl was filtered by bubbling argon through the solution]- [9- (tetrahydropyran-2-yl) -9H-purin-6-yl]Amines (300mg,0.56mmol), tris (dibenzylideneacetone) dipalladium (0) (10mg, 11. mu. mol), 2-di-tert-butylphosphino-2 ',4',6' -triisopropylbiphenyl (19mg, 45. mu. mol), potassium hydroxide (94mg,1.6mmol) in bisA solution in alkane (3mL) and water (2mL) was degassed and then microwaved at 150 ℃ for 30 min. Another portion of tris (dibenzylideneacetone) dipalladium (0) (30mg, 33. mu. mol), 2-di-tert-butylphosphino-2 ',4',6' -triisopropylbiphenyl (57mg, 135. mu. mol) was added, and the mixture was heated with a microwave at 180 ℃ for 1 hour. The reaction mixture was diluted with water and extracted with EtOAc (3X 10 mL). The combined organic fractions were washed with brine and dried (MgSO) ₄) And (4) concentrating in vacuum. The product was purified by preparative HPLC (C18phenomonix column, 10-90% MeCN in water with 0.1% formic acid, 20min gradient). The product was dissolved in HCl in methanol (1.25M,3mL) and the reaction mixture was stirred at RT for 10min, then concentrated in vacuo. The product was purified by preparative HPLC (C18phenomonix column, 10-90% MeCN in water with 0.1% formic acid, 20min gradient) to give 327 as a white solid (15mg, 7%).

1HNMR400MHz

δ(d₆-DMSO):9.53-9.38(1H,m),8.10-7.99(2H,m),7.82-7.69(1H,m),7.62-7.27(5H,m),7.10-6.93(2H,m),5.37-5.17(1H,m),1.43(3H,d,J=7.0Hz),

LCMS (method K) R_T=2.55min,[M+H]+=390

Example 3282-amino-4- [ (S) -1- (6-fluoro-1-phenyl-1H-benzimidazol-2-yl) -ethylamino]-6-methyl-pyrimidine-5-carbonitrile 328

(S) -1- (6-fluoro-1-phenyl-1H-benzimidazol-2-yl) ethylamine dihydrochloride (200mg,0.6mmol), 2-amino-4-chloro-6-methylpyrimidine-5-carbonitrile (102mg,0.6mmol), DIPEA (0.4mL,2.29mmol) and IPA (1mL) were placed in a sealed tube and the mixture was heated at 90 deg.C for 12H. The cooled brown mixture was concentrated in vacuo. The residue was dispersed between DCM and water and the DCM extract was separated via passage through a PTFE column. The DCM extract was concentrated in vacuo and the residue was purified on silica (Si-PPC1-5% MeOH in DCM). The product fractions were concentrated in vacuo to give a yellow foam. The foam was crystallized from EtOAc in cyclohexane to give 328 as a pale yellow solid (25mg, 11%).

1HNMR(CDC1₃,400MHz):δ7.70(1H,dd,J=8.8,4.8Hz),7.59-7.49(3H,m),7.38-7.33(2H，m)，7.02(1H，td，J＝9.2，2.6Hz)，6.77(1H，dd，J＝8.5，2.4Hz)，6.00(1H，d，J＝8.0Hz)，5.49(1H,quin,J=7.3Hz),4.89(2H,brs),2.33(3H,s),1.57(3H,d,J=6.9Hz)

LCMS (method K) R_T3.43min[M+H]⁺388

Example 3302- [ (S) -1- (6-amino-5-cyano-pyrimidin-4-ylamino) -ethyl]-5-fluoro-3-phenyl-3H-benzimidazole-4-carbonitrile 330

To a solution of 2- ((S) -1-aminoethyl) -5-fluoro-3-phenyl-3H-benzimidazole-4-carbonitrile dihydrochloride (110mg,0.29mmol) in IPA (3mL) was added 4-amino-6-chloropyrimidine-5-carbonitrile (45mg,0.29mmol) and DIPEA (148. mu.L, 0.87mmol), and the reaction mixture was heated at 90 ℃ for 16H. The reaction mixture was concentrated in vacuo and the resulting residue was purified by preparative HPLC (C18Phenomenex column, 10-90% MeCN in water with 0.1% formic acid, 20min gradient) to give 330 as a white solid (65mg, 56%).¹H NMR400MHzδ(d₆DMSO) 8.08(1H, dd, J =8.9,4.9Hz),7.78(1H, s),7.70(1H, d, J =7.2Hz),7.62-7.56(1H, m),7.55-7.43(4H, m),7.33(1H, dd, J =10.4,9.0Hz),7.15(2H, br s),5.28(1H, quin, J =6.9Hz),1.48(3H, d, J =6.9Hz), LCMS (method K): R)_T=3.73min,[M+H]+=399

Example 332[ (S) -1- (6-fluoro-1-pyrimidin-4-yl-1H-benzimidazol-2-yl) -ethyl]- (9H-purin-6-yl) -amine 332

Reacting (S) -N- [ 4-fluoro-2- (pyrimidin-4-ylamino) phenyl]-2- (9H-purin-6-ylamino) thiopropionamide (9mg,0.02mmol) in toluene under nitrogen at reflux for 15H. The reaction mixture was purified by column chromatography (Si-PCC with 0-10% (9:1MeOH/.880 NH) ₃) Gradient elution with DCM). The product containing fractions were evaporated and freeze dried to give 332 as a colourless solid (7mg, 85%). LCMS (method C) R_T2.82min[M+H]⁺376.02

¹HNMR(DMSO-d₆)δ：12.8(1H，bs)，9.20(lH，s)，8.95(lH，d，J＝5.4lHz)，8.01-7.89(4H，m),7.73(1H,dd,J=8.81,4.94Hz),7.46(1H,dd,J=9.30,2.50Hz),7.18(1H,td,J=9.27,2.48Hz)，6.03(1H，bs)，1.71(3H，d，J＝6.78Hz)

Example 3332-amino-4- [ (S) -1- (6-fluoro-1-pyridin-2-yl-1H-benzimidazol-2-yl) -ethylamino]-6-methyl-pyrimidine-5-carbonitrile 333

(S) -1- (6-fluoro-1-pyridin-2-yl-1H-benzimidazol-2-yl) ethylamine (217mg,0.85mmol), 2-amino-4-chloro-6-methylpyrimidine-5-carbonitrile (142mg,0.85mmol), DIPEA (0.6mL,3.4mmol) and IPA (1mL) were placed in a sealed tube and the mixture was heated at 70 ℃ for 12H. The cooled brown mixture was concentrated in vacuo. The residue was dispersed between DCM and water and the DCM extract was isolated by passage through a PTFE column. The DCM extract was concentrated in vacuo and the residue was purified on silica (Si-PPC,50-100% EtOAc in cyclohexane). The product fractions were concentrated in vacuo to afford a red solid. The solid was crystallized from EtOAc in cyclohexane to give 333 as a light orange solid (40mg, 12%).

1HNMR(CDC1₃,400MHz):δ8.79-8.75(1H,m),7.99(1H,td,J=7.7,1.8Hz),7.70(1H,dd,J=9.4，4.8Hz)，7.51-7.43(2H，m)，7.11(1H，d，J＝8.2Hz)，7.07-7.0O(2H，m)，5.94-5.85(1H，m)，5.03(2H，brs)，2.32(3H，s)，1.49(3H，d，J＝7.0Hz).

LCMS (method K) R_T3.09min[M+H]⁺389.1

Example 338[ (S) -1- (6-fluoro-7-methoxy-1-phenyl-1H-benzimidazol-2-yl) -ethyl]- (9H-purin-6-yl) -amine 338

To a solution of (S) -1- (6-fluoro-7-methoxy-1-phenyl-1H-benzimidazol-2-yl) ethylamine dihydrochloride (0.16g,0.44mmol) in IPA (3mL) was added 6-chloro-9- (tetrahydropyran-2-yl) -9H-purine (139mg,0.58mmol) and DIPEA (229. mu.L, 1.34mmol), and the reaction mixture was heated at 90 ℃ for 72 hours. The reaction mixture was concentrated in vacuo and the resulting residue was treated with flash chromatography (SiO) ₂Eluting with 0-10% methanol in EtOAc) to give a white solid, LCMS (method C): R_T=3.13min,[M+H]And + = 488. The solid was dissolved in HCl in methanol (1.25M,5mL) and the reaction mixture was stirred at RT for 10 min. The reaction mixture was concentrated in vacuo and the resulting residue was treated with preparative HPLC (C18phenomonix column, 10-90% MeCN in water 0.1% formic acid, 20min gradient) to give 338 as a white solid (113mg, 63%).

¹HNMR400MHzδ(d₆-DMSO):8.10-8.00(2H,m),7.89-

7.75(1H，m)，7.66-7.29(7H，m)，7.13-7.02(1H，m)，538-5.17(1H，m)，3.33(3H，5)，1.48(3H，d，J=6.8Hz),

LCMS (method K) R_T=3.40min,[M+H]+=404

Example 3394-amino-6- [ (S) -1- (6-fluoro-7-methoxy-1-phenyl-1H-benzimidazol-2-yl) -ethylamino]-pyrimidine-5-carbonitrile 339

To a solution of (S) -1- (6-fluoro-7-methoxy-1-phenyl-1H-benzimidazol-2-yl) ethylamine dihydrochloride (160mg,0.44mmol) in IPA (3mL) was added 4-amino-6-chloropyrimidine-5-carbonitrile (72mg,0.47mmol) and DIPEA (229. mu.L, 1.34mmol), and the reaction mixture was heated at 90 ℃ for 72 hours. The reaction mixture was concentrated in vacuo and the resulting residue was purified by preparative HPLC (C18Phenomenex column, 10-90% MeCN in water 0.1% formic acid, 20min gradient) to give 339 as a white solid (119mg, 66%).

¹HNMR400MHzδ(d₆-

DMSO):7.80(1H,s),7.58(1H,d,J=7.3Hz),7.55-7.47(2H,m),7.47-7.40(3H,m),7.39(1H,dd，J＝8.8，4.0Hz)，7.14(2H，brs)，7.10(1H，dd，J＝12.2，8.8Hz)，5.24(1H，quin，J＝6.9Hz)，3.32(3H，d，J＝0.7Hz)，1.43(3H，d，J＝6.8Hz)，

LCMS (method K) R_T=3.86min,[M+H]+=404

Example 3404- [ (S) -1- (6-fluoro-1-phenyl-1H-benzimidazol-2-yl) -ethylamino]-2-methyl-nicotinonitrile 340

(S) -1- (6-fluoro-1-phenyl-1H-benzimidazol-2-yl) ethylamine dihydrochloride (0.083g,0.25mmol), 4-chloro-2-methylnicotinonitrile (0.035g,0.23mmol) and diisopropylethylamine (0.160mL,0.92mmol) were heated in isopropanol (1mL) in a sealed tube under argon to 80 ℃ for 2H and then at 75 ℃And 86 h. The reaction mixture was cooled, diluted with EtOAc (20mL) and washed with water (10 mL). The organic extracts were dried (Na)₂SO₄) Evaporated to dryness and purified by column chromatography (Si-PCC with 0-8% (9:1MeOH/.880 NH)₃) Gradient elution with DCM). The product containing fractions were evaporated and freeze dried to give 340 as a light brown solid (21mg, 24%). LCMS (method C) R_T3.11min[M+H]⁺372.08。

¹HNMRδ(ppm

DMSO-d6):7.98(1H,d,J=6.15Hz),7.77(1H,dd,J=8.82,4.86Hz),7.52-7.50(5H,m),7.12-7.11(2H，m)，6.85(1H，dd，J＝8.91，2.51Hz)，6.40(1H，d，J＝6.24Hz)，5.11(1H，dq，J=7.04Hz),2.41(3H,s),1.56(3H,d,J=6.64Hz)

Example 3416-amino-5-chloro-4- [ (S) -1- (6-fluoro-1-phenyl-1H-benzimidazol-2-yl) -ethylamino]-2-methyl-2H-pyridazin-3-one 341

(S) -1- (6-fluoro-1-phenyl-1H-benzimidazol-2-yl) ethylamine dihydrochloride (1.0g,3.05mmol), 6-amino-4, 5-dichloro-2-methyl-2H-pyridazin-3-one (J.het Chem,5-1037,2000) (0.59g,3.05mmol), and diisopropylethylamine (2.1mL,12.8mmol) in butanol (5mL) was heated to 115 ℃ under argon in a sealed tube for 19H. The reaction mixture was cooled, diluted with EtOAc (50mL) and washed with water (20 mL). The organic extracts were dried (Na) ₂SO₄) Evaporated to dryness and purified by column chromatography (Si-PCC with 1-8% (9:1MeOH/.880 NH)₃) Gradient eluted with DCM then 20-100% EtOAc in cyclohexane). Fractions containing less polar product were evaporated and freeze dried to give 341 as a yellow solid (167mg, 13%). LCMS (method C) R_T4.01min[M+H]⁺313.02。

¹HNMRδ(ppmDMSO-d6)：

7.76(1H，dd，J＝8.81，４.85Hz)，7.56-7.40(5H，m)，7.13(1H，ddd，Ｊ＝9.85，８.80，2.53Hz)，6.88(1H,dd,J=8.91,2.51Hz),5.70(1H,d,J=9.37Hz),5.61-5.60(1H,m),5.52(2H,s),3.37(3H，s)，1.59(3H，d，J=6.56Hz)

Example 3446-amino-4- [ (S) -1- (6-fluoro-1-phenyl-1H-benzimidazol-2-yl) -ethylamino]-2-methyl-2H-pyridazin-3-one 344

6-amino-5-chloro-4- [ (S) -1- (6-fluoro-1-phenyl-1H-benzimidazol-2-yl) ethylamino in ethyl acetate (10mL) and saturated aqueous sodium bicarbonate solution (1mL)]-2-methyl-2H-pyridazin-3-one (0.13g,0.315mmol) was hydrogenated with 10% palladium on carbon (40mg) at room temperature and atmospheric pressure for 24H. The reaction mixture was filtered, evaporated to dryness and purified by column chromatography (Si-PCC, gradient eluted with 0-5% (9:1MeOH/.880NH3) in DCM). The product containing fractions were evaporated and freeze dried to give 344 as a white solid (77mg, 64%). LCMS (method C) R_T3.57min[M+H]⁺379.05。

^１HＮＭＲδ(ppm DMSO-d6)；

7.76(1H，dd，J＝8.82，4.84Hz)，7.63-7.62(5H，m)，7.14(1H，ddd，J＝9.9，8.9，2.5Hz)，6.87(1H,dd,J=8.88,2.51Hz),6.47(1H,d,J=7.48Hz),5.44(1H,s),5.18(2H,s),4.62(1H,dq,J＝6.95Hz)，3.40(3H，s)，1.41(3H，d，J＝6.63Hz)

Example 3454-amino-6- [ (S) -1- (7-cyanomethyl-6-fluoro-1-phenyl-1H-benzimidazol-2-yl) -ethylamino]-pyrimidine-5-carbonitrile 345

To [2- ((S) -1-aminoethyl) -5-fluoro-3-phenyl-3H-benzimidazol-4-yl ]To a solution of acetonitrile dihydrochloride (100mg,0.27mmol) in IPA (2mL) was added 4-amino-6-chloropyrimidine-5-carbonitrile (44mg,0.28mmol) and DIPEA (139. mu.L, 0.82mmol) and the reaction mixture was heated at 90 deg.C for 16 h. The reaction mixture was concentrated in vacuo and the resulting residue was purified by preparative HPLC (C18Phenomenex column, 10-90% MeCN in water 0.1% formic acid, 20min gradient) to give 345 as a white solid (119mg, 66%).¹H NMR400MHzδ(d₆-DMSO):7.73(1H,dd,J=8.8,4.8Hz),7.67(1H,d,J=7.2Hz),7.63-7.58(1H,m),7.56-7.45(4H,m),7.18(1H,dd,J=10.6,8.8Hz),7.14(2H,br s),5.22(1H,quinJ =5.2Hz),3.38-3.21(2H, m),1.47(3H, d, J =6.8Hz), LCMS (method K): R_T=3.56min,[M+H]+=413

Example 3465-fluoro-3- (5-fluoro-pyridin-3-yl) -2- [ (S) -1- (9H-purin-6-ylamino) -ethyl]-3H-benzimidazole-4-carbonitrile 346

Reacting { (S) -1- [ 7-cyano-6-fluoro-1- (5-fluoropyridin-3-yl) -1H-benzimidazol-2-yl]Di-tert-butyl-ethyl } carbamate (215mg,0.54mmol) dissolved in HClAlkane solution (4N,5mL) and the reaction mixture was stirred at RT for 1 hour. The mixture was concentrated in vacuo and the residue was dissolved in IPA (5 mL). 6-chloro-9- (tetrahydropyran-2-yl) -9H-purine (167mg,0.70mmol) and DIPEA (275. mu.L, 1.61mmol) were added and the reaction mixture was heated at 90 ℃ for 16H. The reaction mixture was concentrated in vacuo and the residue obtained was treated with flash chromatography (SiO)₂Eluting with 0-10% methanol in EtOAc) to give an off-white solid LCMS (method C): R) _T=2.89min,[M+H]And + = 502. The solid was dissolved in HCl in methanol (1.25M,5mL) and the reaction mixture was stirred at RT for 10 min. The reaction mixture was concentrated in vacuo and the resulting residue was treated with preparative HPLC (C18Phenomenex column, 0.1% formic acid in 10-90% MeCN water, 20min gradient) to give 346 as a white solid (66mg, 29%).

^１ＨNMR300MHzδ(d₆-DMSO):12.91(1H,brs),8.89-8.46(2H,m),8.44-7.85(5H,m),7.42(1H,t,J=9.6Hz),5.65-5.37(1H,m),1.67(3H,t,J=6.8Hz),

LCMS (method K) R_T=3.03min,[M+H]+=418

Example 3472- [ (S) -1- (6-amino-5-cyano-pyrimidin-4-ylamino) -ethyl]-5-fluoro-3- (5-fluoro-pyridin-3-yl) -3H-benzimidazole-4-carbonitrile 347

Reacting { (S) -1- [ 7-cyano-6-fluoro-1- (5-fluoropyridin-3-yl) -1H-benzimidazol-2-yl]Di-tert-butyl-ethyl } carbamate (215mg,0.54mmol) dissolved in HClAlkane solution (4N,5mL) and the reaction mixture was stirred at RT for 1 hour. The mixture was concentrated in vacuo, the residue dissolved in IPA (5mL), 4-amino-6-chloropyrimidine-5-carbonitrile (87mg,0.56mmol) and DIPEA (275 uL, 1.61mmol) added, and the reaction mixture heated at 90 deg.C for 16 h. The reaction mixture was concentrated in vacuo and the resulting residue was purified by preparative HPLC (C18Phenomenex column, 10-90% MeCN in water 0.1% formic acid, 20min gradient) to give 347 as a white solid (76mg, 34%).

^１ＨNMR300MHzδ(d₆-DMSO):8.83-8.63(2H,m),

8.38-8.00(2H,m),7.87-7.74(2H,m),7.43(1H,t,J=9.6Hz),7.25(2H,brs),5.58-5.43(1H,m),1.65-1.54(3H,m)

LCMS (method K) R_T=3.35min,[M+H]+=418

Example 348 4-amino-6- [ (S) -1- (6-fluoro-1-pyridin-3-yl-1H-benzimidazol-2-yl) -ethylamino]-pyrimidine-5-carbonitrile 348

A mixture of (S) -1- (6-fluoro-1-pyridin-3-yl-1H-benzimidazol-2-yl) ethylamine (80mg,0.31mmol), 4-amino-6-chloropyrimidine-5-carbonitrile (51mg,0.33mmol), and DIPEA (0.16mL,0.93mmol) in IPA (0.7mL) was heated in a sealed tube at 90 deg.C for 16H. After cooling to RT, the volatile substances were removed under reduced pressure and the residue obtained was loadedSCX-2 column. The column was washed with MeOH, then 2M NH₃Washing with MeOH. The basic fractions were combined, concentrated in vacuo and the residue purified by column chromatography (Si-PPC, using 0-10%2M NH)₃MeOH/DCM) to give a light yellow oil. The residue was taken up in EtOAc and the product triturated with cyclohexane. The solid was filtered off to give 348 as an off-white solid (31mg, 26%). LCMS (method K) R_T3.04min[M+H]⁺3.75。

¹HNMR(DMSO-d₆,400MHz):δ8.73(1H,d,J=2.5Hz),8.64(1H,dd,J=5.0，1.5Hz)，8.01-7.98，(1H，m)，7.81(lH，s)，7.76-7.73(2H，m)，7.55(1H，ddd，J＝8.0，5.0，1.0Hz)，7.18(2H，bs)，7.12(1H，ddd，Ｊ＝10.0，9.0，2.5Hz)，6.93(1H，dd，Ｊ＝7.0，2.5Hz)，7.481(1H，dq，7.0，7.0Hz)，1.55(3H，d，J＝7.0Hz)

Example 3494-amino-6- { (S) -1- [1- (3, 5-difluoro-phenyl) -6-fluoro-1H-benzimidazol-2-yl]-ethylamino } -pyrimidine-5-carbonitrile 349

Reacting (S) -1- [1- (3, 5-difluorophenyl) -6-fluoro-1H-benzimidazol-2-yl]A mixture of ethylamine (245mg,0.84mmol), 4-amino-6-chloropyrimidine-5-carbonitrile (137mg,0.88mmol), and DIPEA (0.44mL,2.5mmol) in IPA (1.7mL) was heated in a sealed tube at 90 deg.C for 16 h. After cooling to RT, the volatile substances were removed under reduced pressure and the residue obtained was loaded SCX-2 column. The column was washed with MeOH, then 2M NH₃Washing with MeOH. The basic fractions were combined, concentrated in vacuo and the resulting residue was purified by column chromatography (Si-PPC, eluted with a gradient of 25-75% EtOAc in cyclohexane) to give a colorless oil. The residue was taken up in EtOAc and the product triturated with cyclohexane. The solid was filtered off to give 349 as a white solid (134mg, 39%). LCMS (method K) R_T4.10min[M+H]⁺410。

¹HNMR(DMSO-d₆，400MHz)：δ7.87(1H，s)，7.76-7.7.(2H，m)，7.36-7.31(3H，m)，7.18(2H，bs)，7.13(1H，ddd，J＝10.0，8.5，2.5Hz)，7.05(1H，dd，J＝9.0，2.5Hz)，5.64(1H，dq，J＝7.0，7.0Hz)，1.56(3H，d，J＝7.0Hz)

Example 3504-amino-6- { (S) -1- [ 6-fluoro-1- (5-fluoro-pyridin-3-yl) -1H-benzimidazol-2-yl]-propylamino } -pyrimidine-5-carbonitrile 350

Reacting (S) -1- [ 6-fluoro-1- (5-fluoropyridin-3-yl) -1H-benzimidazol-2-yl]A mixture of propylamine (88mg,0.32mmol), 4-amino-6-chloro-5-cyanopyrimidine (49mg,0.32mmol) and DIPEA (0.11mL,0.64mmol) in IPA (1mL) was heated at 90 deg.C for 5.5 h. After cooling to RT, the volatiles were removed under vacuum and the resulting residue was purified by column chromatography (Si-PPC with 0-5%2M NH₃EtOAc in MeOH gradient elution) to give 350 as a pale yellow solid (83mg, 64%). LCMS (method K) R_T3.67min[M+H]⁺407.0。

¹HNMR(CDCl_3，

400MHz)：δ8.68(1H，d，J＝2.7Hz)，8.60(1H，brs)，8.01(1H，s)，7.70(1H，dd，J＝9.0，4.9Hz)，7.67(1H，brs)，7.06(1H，app.td，J＝9.2，2.4Hz)，6.79(lH，dd，J＝8.3，2.4Hz)，6.00(1H，d，J＝8.0Hz)，5.40(2H，s)，5.31(1H，dt，J＝8.0，7.3Hz)，2.05(1H，dqd，J＝14.7，7.4，7.3Hz)，1.97(1H，dqd，J＝14.7，7.4，7.3Hz)，0.86(3H，t，J＝7.4Hz)

Example 3534-amino-6- [ (S) -1- (6-fluoro-7-hydroxymethyl-1-phenyl-1H-benzimidazol-2-yl) -ethylamino]-pyrimidine-5-carbonitrile 353

To a solution of [2- ((S) -1-aminoethyl) -5-fluoro-3-phenyl-3H-benzimidazol-4-yl ] methanol dihydrochloride (159mg,0.45mmol) in IPA (5mL) was added 4-amino-6-chloropyrimidine-5-carbonitrile (69mg,0.45mmol) and DIPEA (228. mu.L, 1.33mmol), and the reaction mixture was heated at 80 ℃ for 16H. The reaction mixture was concentrated in vacuo and the resulting residue was purified by preparative HPLC (C18Phenomenex column, 10-90% MeCN in water 0.1% formic acid, 20min gradient) to give 353 as a white solid (87mg, 49%).

¹HNMR400MHz

δ(d₆-DMSO):7.78(1H,s),7.65-7.56(2H,m),7.55-7.38(5H,m),7.16(2H,brs),7.05(1H,dd,J＝10.6，8.8Hz)，5.15(1H，quin，J＝6.9Hz)，4.51(1H，t，J＝5.0Hz)，3.97(2H，d，J＝5.0Hz)，1.43(3H，d，J＝6.9Hz)

Example 3584-amino-6- [ (S) -1- (6-fluoro-1-phenyl-1H-benzimidazol-2-yl) -propylamino]-pyrimidine-5-carbonitrile 358

A mixture of (S) -1- (6-fluoro-1-phenyl-1H-benzimidazol-2-yl) propylamine (62mg,0.23mmol), 4-amino-6-chloro-5-cyanopyrimidine (36mg,0.23mmol) and DIPEA (0.08mL,0.46mmol) in IPA (2mL) was heated at 90 deg.C for 6H. After cooling to RT, the volatiles were removed in vacuo and the resulting residue was purified by column chromatography (Si-PPC with 0-5%2MNH₃EtOAc in MeOH gradient elution) to give 358 as a white solid (70mg, 79%). LCMS (method K) R_T4.10min[M+H]⁺388.1。

¹HNMR(DMSO-d₆，400MHz)：δ7.81(lH，s)，7.68

(1H，dd，J＝8.8，4.9Hz)，7.56-7.44(6H，m)，7.16(2H，brs)，7.07(1H，ddd，J＝9.8，8.8，2.5)，6.79(1H，dd，J＝8.9，2.5)，5.29(1H，dt，J＝7.7，6.2)，1.97(1H，dqd，J＝14.9，7.5，6.2)，1.87(1H，dqd，J＝14.9，7.5，6.2)，0.75(3H，t，J＝7.5)

Example 359{ (S) -1- [ 6-fluoro-1- (5-fluoro-pyridin-3-yl) -1H-benzimidazol-2-yl]-propyl } - (9H-purin-6-yl) -amine 359

HCl (0.25mL4M two)Alkyl solution) to { (S) -1- [ 6-fluoro-1- (5-fluoropyridin-3-yl) -1H-benzimidazol-2-yl]Propyl } - [9- (tetrahydropyran-2-yl) -9H-purin-6-yl]Amine (96mg,0.20mmol) in MeOH (1mL) and the reaction mixture stirred at RT for 10 min. The crude reaction mixture was passed through 2gSCX-2 column with 2M NH₃MeOH elution. The basic fraction was concentrated in vacuo to give 359(76mg,94%) as a white solid. LCMS (method K) R_T3.23min[M+H]⁺407.1。

¹HNMR(CD₃0D,400MHz):δ8.59(1H，s)，8.51(1H，s)，8.05(1H，s)，8.03(1H，brs)，7.95(1H，d，J＝8.4Hz)，7.65(1H，dd，J＝8.8，4.6Hz)，7.07(1H，ddd，J＝9.7，8.8，2.6Hz)，6.88(1H，dd，J＝8.6，2.6Hz)，5.54-5.42(1H，m)，2.26(1H，dqd，J＝14.9，7.5，6.4Hz)，2.12(1H，dqd，J＝14.9，7.5，6.4Hz)，1.01(3H，t，J＝7.5Hz)

Example 360[ (S) -1- (6-fluoro-1-phenyl-1H-benzimidazol-2-yl) -propyl ]- (7H-purin-6-yl) -amine 360

HCl (0.22mL4M two)Alkyl solution) was added to [ (S) -1- (6-fluoro-1-phenyl-1H-benzimidazol-2-yl) propyl ] acetate]- [9- (tetrahydropyran-2-yl) -9H-purin-6-yl]Amine (82mg,0.17mmol) in MeOH (2mL) and the reaction stirred at RT for 10 min. The reaction mixture was passed through 2gSCX-2 column with 2M NH₃MeOH elution. The basic fraction was concentrated in vacuo to afford 360 as a white solid (65mg, quantitative yield). LCMS (method K) R_T3.58min[M+H]⁺388.1。

¹HNMR(CD₃0D,400MHz):δ8.06(1H,s),8.04(1H,brs),7.61(lH，dd，J＝8.8，4.6Hz)，7.57-7.43(5H，m)，7.02(lH，ddd，J＝9.6，8.8，2.7Hz)，6.76(1H，dd，J＝8.7，2.7Hz)，5.44(1H，brs)，2·14(1H，dqd，J＝14.8，7.4，6.5Hz)，2.05(1H，dqd，J＝14.8，7.4，6.5Hz)，0.950H，t，J＝7.4Hz)

Example 361{ (S) -1- [1- (3, 5-difluoro-phenyl) -6-fluoro-1H-benzimidazol-2-yl]-ethyl } - (9H-purin-6-yl) -amine 361

Reacting { (S) -1- [1- (3, 5-difluorophenyl) -6-fluoro-1H-benzimidazoleAzol-2-yl]Ethyl } - [9- (tetrahydropyran-2-yl) -9H-purin-6-yl]Di (amine) (137mg,0.28mmol) in 4M HClThe solution in alkane solution (10mL) was stirred at RT for 1 h. The reaction mixture was concentrated in vacuo, diluted with MeOH and loaded ontoSCX-2 column. The column was washed with MeOH, then 2M NH₃Washing with MeOH. The basic fractions were combined and concentrated in vacuo. The residue obtained is purified by column chromatography (Si-PPC, 2.5-10%2M NH)₃Gradient eluted in MeOH/DCM) to give 361 as a white solid (48mg, 42%). LCMS (method K) R_T3.65min[M+H]⁺410。

¹HNMR(CDC1₃,400MHz):δ12.87(1H,bs),8.09-7.94(3H,m),7.70(1H,dd,J=9.0，5.0Hz)，7.40-7.38(2H，m)，7.27-7.23(1H，m)，7.11(1H，ddd，J＝10.0，10.0，2.5Hz)，7.05-7.02(1H，m)，5.71-5.61(lH，m)，1.63(3H，d，J＝7.OHz)

Example 3622-amino-4- [ (S) -1- (6-fluoro-1-phenyl-1H-benzimidazol-2-yl) -ethylamino ]-pyrimidine-5-carbonitrile 362

A mixture of (S) -1- (6-fluoro-1-phenyl-1H-benzimidazol-2-yl) ethylamine.2 HCl (85mg,0.259mmol), 2-amino-4-chloropyrimidine-5-carbonitrile (40mg,0.26mmol), and DIPEA (222 μ L,1.29mmol) in IPA (0.75mL) was heated at 90 deg.C in a sealed vial for 21H. After cooling to RT, the crude mixture was diluted with MeOH and loaded intoSCX-2 column. The column was washed with MeOH, then 2M NH₃Washing with MeOH. The basic fractions were combined, concentrated in vacuo, and the resulting residue was purified by column chromatography (Si-PCC, gradient elution of 0-100% EtOAc in DCM), followed by EtOAc/Et₂Trituration with O/cyclohexane afforded 362 as a white solid (61mg, 63%). LCMS (method K) R_T3.47min[M+H]⁺374.02。

¹HNMR(DMSO-d₆,400MHz):δ8.08(1H,s),7.74(1H,dd,J=8.80，4.85H2)，7.68(1H，d，J＝7.49H2)，7.58-7.52(5H，m)，7.16-6.70(4H，m)，5.51(1H，m)，1.47(3H，d，J＝6.8OHz)

Example 3632-amino-4- { (S) -1- [ 6-fluoro-1- (5-fluoro-pyridin-3-yl) -1H-benzimidazol-2-yl]-ethylamino } -pyrimidine-5-carbonitrile 363

Reacting (S) -1- [ 6-fluoro-1- (5-fluoropyridin-3-yl) -1H-benzimidazol-2-yl]A mixture of ethylamine.2 HCl (118mg,0.34mmol), 2-amino-4-chloropyrimidine-5-carbonitrile (40mg,0.26mmol) and DIPEA (222 uL, 1.29mmol) in IPA (0.75mL) was heated at 90 deg.C in a sealed vial for 18 h. After cooling to RT, the reaction mixture was diluted with MeOH and loaded intoSCX-2 column. The column was washed with MeOH, then 2M NH ₃Washing with MeOH. The basic fractions were combined, concentrated in vacuo, and the resulting residue was purified by column chromatography (Si-PCC, gradient elution with 0-100% EtOAc in DCM), followed by reverse phase HPLC purification (Phenomenex Gemini5 μmC18, with 5-75% of 0.1% NH)₄Acetonitrile/water gradient of OH) to give 363 as a white solid (58mg, 57%). LCMS (method K) R_T3.10min[M+H]⁺392.97。

¹HNMR(DMSO-d₆,400MHz):δ8.66(1H,d,J=2.64Hz),8.62(1H,s),8.o6(1H,s),8.03(1H，d，J＝9.27Hz)，7.76-7.75(2H，m)，7.15(1H，ddd，J＝9.85，8.79，2.51Hz)，7.08(1H，dd，J＝8.96，2.50Hz)，7.05-6.60(2H，m)，5.56(1H，m)，1.55(3H，d，J＝6.75Hz)

Example 3642-amino-4- { (S) -1- [ 6-fluoro-1- (5-fluoro-pyridin-3-yl) -1H-benzimidazol-2-yl]-ethylamino } -6-methyl-pyrimidine-5-carbonitrile 364

Reacting (S) -1- [ 6-fluoro-1- (5-fluoropyridin-3-yl) -1H-benzimidazole-2-yl]A mixture of ethylamine.2 HCl (165mg,0.48mmol), 2-amino-4-chloro-6-methylpyrimidine-5-carbonitrile (60mg,0.36mmol), and DIPEA (315. mu.L, 1.82mmol) in IPA (1mL) was heated at 90 deg.C in a sealed vial for 18 h. After cooling to RT, the reaction mixture was diluted with MeOH and loaded intoSCX-2 column. The column was washed with MeOH, then 2M NH₃Washing with MeOH. The basic fractions were combined, concentrated in vacuo, and the resulting residue was purified by column chromatography (Si-PCC, gradient eluted with 0-100% EtOAc in cyclohexane) followed by reverse phase HPLC (Phenomenex Gemini5 μm C18, 5-75% with 0.1% NH)₄Acetonitrile/water gradient of OH) to afford 364 as a white solid (21mg, 15%). LCMS (method K) R _T3.04min[M+H]⁺407.04。

¹HNMR(DMSO-d₆，400MHZ)：δ8.66(1H，d，J＝2.64Hz)，8.61(1H，d，J＝

1.63Hz)，8.02(lH，d，J＝9.22Hz)，7.77(1H，dd，J＝8.80，4.84Hz)，7.55(lH，d，J＝7.75Hz)，7.15(1H,ddd,J=9.84,8.79,2.50Hz)]7.07(1H,dd,J=8.96,2.48Hz),7.05-6.58(2H,m),5.53(1H，m)，2.18(3H，s)，1.54(3H，d，J＝6.75Hz)

Example 3652-amino-4- [1- (3-phenyl-3H-imidazo [4,5-b ]]Pyridin-2-yl) -ethylamino]-pyrimidine-5-carbonitrile 365

1- (3-phenyl-3H-imidazo [4, 5-b)]A mixture of pyridin-2-yl) ethylamine (68mg,0.29mmol), 2-amino-4-chloropyrimidine-5-carbonitrile (44mg,0.29mmol) and DIPEA (147. mu.L, 0.86mmol) in IPA (1mL) was heated at 90 deg.C in a sealed vial for 18 h. After cooling to RT, the reaction mixture was diluted with MeOH and loaded intoSCX-2 column. The column was washed with MeOH, then 2M NH₃Washing with MeOH. The basic fractions are combined, concentrated in vacuo and the residue obtained is subjected to column chromatographyPurification (Si-PCC, gradient eluted 50-100% EtOAc in cyclohexane) followed by trituration with EtOAc provided 365 as an off-white solid (47mg, 46%). LCMS (method K) R_T2.58min[M+H]⁺357.09。

¹HNMR

(DMSO-d₆,400MHz):δ8.25(1H,dd,J=4.76,1.48Hz),8.14(1H,dd,J=7.98,1.47Hz),8.09(1H,s),7.72(1H,d,J=7.41Hz),7.55-7.43(5H,m),7.32(1H,dd,J=7.99,4.77Hz),7.16-6.68(2H,m),5.55(1H,m),1.49(3H,d，J=6.81Hz)

Example 3662-amino-4-methyl-6- [1- (3-phenyl-3H-imidazo [4,5-b ]]Pyridin-2-yl) -ethylamino]-pyrimidine-5-carbonitrile 366

1- (3-phenyl-3H-imidazo [4, 5-b)]A mixture of pyridin-2-yl) ethylamine (66mg,0.28mmol), 2-amino-4-chloro-6-methylpyrimidine-5-carbonitrile (38mg,0.23mmol), and DIPEA (142. mu.L, 0.831mmol) in IPA (1mL) was heated at 90 deg.C in a sealed vial for 18 h. After cooling to RT, the reaction mixture was diluted with MeOH and loaded into SCX-2 column. The column was washed with MeOH, then 2M NH₃Washing with MeOH. The basic fractions were combined, concentrated in vacuo, and the resulting residue was purified by column chromatography (Si-PCC, gradient eluted with 50-100% EtOAc in cyclohexane) followed by trituration with EtOAc to afford 366 as an off-white solid (41mg, 40%). LCMS (method K) R_T2.54min[M+H]⁺371.10。

¹HNMR(DMSO-d₆,400MHz):δ8.25(1H,dd,J=4.77,1.47Hz),8.14(1H,dd,J=7.98,147Hz),7.55-7.44(6H,m),7.33(1H,m),7.12-661(2H,m),5.52(1H,m),2.21(3H,s),1.47(3H，d，J＝6.8lHz)

Example 3672-amino-4- [ (S) -1- (6-fluoro-1-pyridin-2-yl-1H-benzimidazol-2-yl) -ethylamino]-pyrimidine-5-carbonitrile 367

Reacting (S) -1- (6-fluoro-1-pyridine-2-)A mixture of 1H-benzimidazol-2-yl) ethylamine 2HCl (164mg,0.50mmol), 2-amino-4-chloropyrimidine-5-carbonitrile (77mg,0.50mmol) and DIPEA (427 μ L,2.49mmol) in IPA (1mL) was heated at 90 deg.C for 17H in a sealed vial. After cooling to RT, the reaction mixture was diluted with MeOH and loaded intoSCX-2 column. The column was washed with MeOH, then 2M NH₃Washing with MeOH. The basic fractions were combined, concentrated in vacuo, and the resulting residue was purified by column chromatography (Si-PCC gradient eluted with 0-100% EtOAc in cyclohexane) followed by Et₂Trituration with O afforded 367 as a white solid (72mg, 39%). LCMS (method K) R_T3.06min[M+H]⁺375.00。

¹HNMR(DMSO-d₆,400MHz):δ8.59(1H,m),8.06(2H,m),7.77(2H,m),7.68(1H,d,J=7.41Hz),7.48(1H,m),7.19-6.80(4H,m),5.85(1H,m),1.52(3H,d,J=6.81Hz

Example 3682- [ (S) -1- (2-amino-5-cyano-6-methyl-pyrimidin-4-ylamino) -ethyl ]-5-fluoro-3-pyridin-2-yl-3H-benzimidazole-4-carbonitrile 368

A mixture of 2- ((S) -1-aminoethyl) -5-fluoro-3-pyridin-2-yl-3H-benzimidazole-4-carbonitrile (0.085g,0.240mmol), 2-amino-4-chloro-6-methylpyrimidine-5-carbonitrile (0.057g,0.335mmol), and DIPEA (0.17mL,0.960mmol) in IPA (1.5mL) was stirred at 80 deg.C in a sealed microwave tube for 16H. After cooling, the mixture was concentrated in vacuo and the residue was purified by chromatography (Si-PPC, with 0-8%2M NH)₃Gradient elution in DCM/MeOH) gave 368 as an off-white solid (0.064g, 64%). LCMS (method K) R_T2.87min[M+H]⁺414.1。

¹HNMR(DMSO,400MHz):δ8.76-8.74(1H,d),8.02-7.97(1H,t),7.96-7.92(1H,m),7.58-7.54(1H,m),7.47-7.44(1H,d),7.15-7.10(1H,t),6.06-6.02(1H,d),5.42-5.35(1H,m),5.15-5.11(2H,s),2.32(3H,s),1.61-1.59(3H,d)

Example 3714-amino-6- ((6-fluoro-1-phenyl-1H-benzo [ d)]Imidazol-2-yl) methylamino) pyrimidine-5-carbonitrile 371

(6-fluoro-1-phenyl-1H-benzimidazol-2-yl) methylamine hydrochloride (0.113g,0.4mmol), 4-amino-6-chloropyrimidine-5-carbonitrile (0.123g,0.8mmol), triethylamine (0.28mL,2mmol) were heated in isopropanol (2mL) in a sealed tube to 80 ℃ for 2H. After cooling, the pink solid was removed by filtration and washed with isopropanol (0.5 mL). The material was purified by column chromatography (Si-PCC gradient eluted with 0-4% MeOH in DCM). The product containing fractions were evaporated to give a white solid. It was triturated with ether and dried to give 371 as a white solid (70mg, 69%). LCMS (method C) R _T3.54min[M+H]⁺360.02。

¹HNMRδ(ppm)(DMSO-d):7.87(1H,s),7.69(1H,t,J=5.2Hz),765(１H,dd,J=8.80，4.87H2)，7.64-7.46(5H，m)，7.22(2H，5)，7.06(1H，ddd，J＝9.86，8.79，2.53H2)，6.87(1H，dd，J＝8.97，2.51Hz)，4.62(2H，d，J＝537Hz)

Example 3729- [ (6-fluoro-1-phenyl-benzimidazol-2-yl) methyl]Purine-2-amines 372

To a stirred mixture of 9H-purin-2-ylamine (93mg,0.69mmol) in DMF (1mL) under an atmosphere of RT and nitrogen was added NaH (60% in mineral oil, 23mg,0.69 mmol). After 5min, 2-chloromethyl-6-fluoro-1-phenyl-1H-benzimidazole (150mg,0.575mmol) in DMF (1mL) was added. Stirring was continued at RT for 18 h. Loading the crude reaction mixture intoSCX-2 column, washing with MeOH, then 2M NH₃Washing with MeOH. The basic fractions were combined, concentrated in vacuo, and the resulting residue was purified by column chromatography (Si-PCC,0-10%2M NH)₃Gradient MeOH in DCM) to give 372 as a white solid (96mg, 47%). LCMS (method K) R_T3.17min[M+H]⁺360.0。

¹HNMR(DMSO-d₆,

400MHz):δ8.56(1H,s),8.00(1H,s),7.70-7.57(6H,m),7.16-7.07(1H,m),6.97(1H,dd,J=8.93,2.50Hz),6.43(2H,s),5.48(2H,s)

Example 373N- [ (1S) -1- (1-cyclobutyl-6-fluoro-benzimidazol-2-yl) ethyl]-9H-purin-6-amine 373

A mixture of (S) -1- (1-cyclobutyl-6-fluoro-1H-benzimidazol-2-yl) ethylamine (251mg,1.1mmol), 6-chloro-9- (tetrahydropyran-2-yl) -9H-purine (260mg,1.1mmol) and DIPEA (1.0mL,5.5mmol) in n-butanol (4mL) was heated at 100 ℃ for 18H. After cooling to RT, the volatile substances were removed under reduced pressure and the residue obtained was loadedSCX-2 column. The column was washed with MeOH, then 2M NH ₃Washing with MeOH. The basic fractions were combined, concentrated in vacuo and the residue purified by column chromatography (Si-PCC with 0-10%2M NH)₃Gradient elution in DCM/MeOH) gave 373 as a white solid (140mg, 36%). LCMS (method K) R_T2.93min[M+H]⁺352.1

¹HNMR(DMSO-d₆,

400MHz):δ12.97(1H,br),8.33-7.76(3H,m),7.69-7.53(2H,m),7.09-6.98(1H,m),5.87(1H,brs),5.27-5.14(1H,m),2.93-2.72(2H,m),2.44(1H,brs),2.23(1H,brs),2.02-1.89(1H,m),1.82-1.61(4H,m)

Example 374N- [ (1S) -1- (1-cyclopropyl-6-fluoro-benzimidazol-2-yl) ethyl]-9H-purin-6-amine 374

A mixture of (S) -1- (1-cyclopropyl-6-fluoro-1H-benzimidazol-2-yl) ethylamine (166mg,0.76mmol), 6-chloro-9- (tetrahydropyran-2-yl) -9H-purine (180mg,0.76mmol) and DIPEA (0.7mL,3.8mmol) in n-butanol (3mL) was heated at 100 ℃ for 18H. After cooling to RT, the volatile substances were removed under reduced pressure and the residue obtained was loadedSCX-2 column. The column was washed with MeOH, then 2M NH₃Washing with MeOH. The basic fractions were combined, concentrated in vacuo and the residue purified by column chromatography (Si-PCC,0-10%2M NH)₃Gradient elution in DCM/MeOH) gave 374 as a white solid (125mg, 49%). LCMS (method K) R_T2.72min[M+H]⁺338.1。

¹HNMR(DMSO-d₆,400

MHz):δ8.23-8.09(2H,m),7.90(1H,brs),7.56(1H,dd,J=8.77,4.94Hz),7.37(1H,dd,J=9.27，2.53Hz)，7.05-6.97(1H，m)，5.94(1H，brs)，3.43-3.36(1H，m)，1.69(3H，d，J＝6.80Hz),133-1.00(4H,m)

Example 3769- [ (6-fluoro-1-phenyl-benzimidazol-2-yl) methyl]Purin-6-amine 376

Sodium hydride, NaH (60% in mineral oil, 23mg,0.69mmol) was added to a suspension of 9H-purin-6-ylamine (93mg,0.69mmol) in DMF (1mL) under a nitrogen atmosphere. The reaction mixture was stirred for 15min, then 2-chloromethyl-6-fluoro-1-phenyl-1H-benzimidazole (148mg,0.57mmol) in DMF (1mL) was added. After stirring for 30min at RT, the temperature was raised to 70 ℃ and stirring was continued for 3 h. Volatiles were removed under reduced pressure and the resulting residue was partitioned between DCM and water. The aqueous phase was extracted with DCM (× 3) and the combined organic fractions were dried (Na) ₂SO₄) And concentrated in vacuo. The residue was purified by column chromatography (Si-PCC with 0-10%2 NNH)₃DCM gradient/MeOH) to give 9- (6-fluoro-1-phenyl-1H-benzimidazol-2-ylmethyl) -9H-purin-6-ylamine which is still impure.

Impure 9- (6-fluoro-1-phenyl-1H-benzimidazol-2-ylmethyl) -9H-purin-6-ylamine was purified by reverse phase HPLC (Phenomenex Gemini 5. mu. m C18, with 20-98% HCO 0.1%)₂H in an acetonitrile/water gradient) to afford pure 376 as a white solid (45mg, 22%). LCMS (method K) R_T3.18min[M+H]⁺360.0。¹HNMR(DMSO-d₆，400MHz)：δ8.06(1H，s)，8.04（1H，s)7.68-7.55(6H,m)，7.21(2H,brs),7.15-7.08(1H,m),6.97(1H,dd,J=8.98,2.55Hz),5.58(2H,s)

Example 3773- [ 6-fluoro-2- [1- (9H-purin-6-ylamino) ethyl]Benzimidazol-1-yl]Azetidine-1-carboxylic acid tert-butyl ester 377

Reacting 3- [2- ((S) -1-aminoethyl) -6-fluorobenzoimidazol-1-yl]A mixture of azetidine-1-carboxylic acid tert-butyl ester (354mg,1.05mmol), 6-chloro-9- (tetrahydropyran-2-yl) -9H-purine (278mg,1.16mmol) and DIPEA (0.41mL,3.18mmol) in n-butanol (1.4mL) was heated at 90 ℃ for 16H in a sealed vial. After cooling to RT, the volatile substances were removed under reduced pressure and the residue obtained was loadedSCX-2 column, washing with MeOH, then 2MNH₃Washing with MeOH. The basic fractions were combined, concentrated in vacuo, and the resulting residue was purified by column chromatography (Si-PCC, gradient eluted with 0-5% MeOH in DCM) to give 377 as a white solid (214mg, 71%). LCMS (method K) R _T3.59min[M+H]⁺453.1。

¹HNMR(DMSO-d₆,400MHz):δ12.43(1H,s),8.23(1H,brs),8.14(1H,brs),7.96(1H,d,J=7.67Hz),7.68(1H,dd,J=8.83,5.02Hz),7.36(1H,dd,J=9.41,2.45Hz),7.11(1H,td,J=9.29,2.36Hz),5.79(1H,brs)，5.70-5.60(1H,m),4.48-4.34(2H,m),4.31-4.19(2H,m),1.65(3H,d,J=6.67Hz),1.44(9H,s)

Example 378N- [1- [1- (azetidin-3-yl) -6-fluoro-benzimidazol-2-yl]Ethyl radical]-9H-purin-6-amine 378

To 3- { 6-fluoro-2- [ (S) -1- (9H-purin-6-ylamino) ethyl at 0 deg.C]A solution of tert-butyl benzimidazol-1-yl } azetidine-1-carboxylate (214mg,0.47mmol) in DCM (5mL) was added TFA (1.7mL) dropwise. The mixture was stirred at 0 ℃ for 20min and then slowly warmed to RT. Stirring was continued at RT for 1.5 h. Removing volatile substances under reduced pressure, and loading the obtained residue onSCX-2 column, washing with MeOH, then 2M NH₃Washing with MeOH. The basic fractions were combined and concentrated in vacuo to afford 378 as a white solid (160mg, 96%). LCMS (method K) R_T1.73min[M+H]⁺353.0。

¹HNMR(DMSO-d₆,400MHz):δ8.25(１H,brs),8.17-8.07(2H,m),7.95(1H,brs),7.64(1H,dd,J=8.82,5.08Hz),7.08(1H,td,J=9.27,2.42Hz),5.80(1H,brs),5.63-5.53(1H,m),4.14-4.06(1H，m)，4.01(2H，d，J＝7.2OHz)，3.93-3.74(2H，m)，1.63(3H，d，J＝6.71Hz)

Example 379N- [1- (6-fluoro-1-isopropyl-benzimidazol-2-yl) ethyl]-9H-purin-6-amine 379

(S) -1- (6-fluoro-1-isopropyl-1H-benzimidazol-2-yl) ethylamine (0.5g,2.26mmol) was dissolved in n-butanol (5mL) and 6-chloro-9- (tetrahydropyran-2-yl) -9H-purine (0.54g,2.26mmol) and DIPEA (2mL,11.3mmol) were added. The resulting dark red solution was heated to 100 ℃ overnight. The mixture was cooled to RT and concentrated in vacuo. The residue was purified by column chromatography (silica gel, gradient elution with 0-10% MeOH in DCM) to give 379 as a light red solid (207mg, 27%). LCMS (method K) R _T2.68min[M+H]⁺340.1

¹HNMR(DMSO-d₆,400MHz):δ8.24(1H,s),8.15(1H,s),8.00-7.90(1H,m),7.64-7.55(2H,m),7.02(1H,td,J=9.31,2.40Hz),5.96-5.77(1H,m),4.98-4.85(1H,m),1.67(3H,d,J=6.7lHz)，1.57(3H，d，J＝6.91Hz)，1.46(3H，d，J＝6.78Hz)

Example 380N- [ (1S) -1- [ 6-fluoro-1- (1-isopropylazetidin-3-yl) benzimidazol-2-yl]Ethyl radical]-9H-purin-6-amine 380

To [ (S) -1- (1-azetidin-3-yl-6-fluoro-1H-benzimidazol-2-yl) ethyl]To a solution of- (9H-purin-6-yl) amine (80mg,0.23mmol) in DCM (1.5mL) was added acetone (50. mu.L, 0.68mmol) and AcOH (26. mu.L, 0.45mmol), followed by MeOH (4 drops). In thatAfter stirring at 0 ℃ for 10min, NaBH (OAc) was added in two portions₃(96mg,0.45mmol) and the mixture was warmed to RT. Stirring was continued at RT for 3h, then the reaction mixture was taken up in DCM and saturated NaHCO₃The aqueous solution was partitioned. The aqueous phase was further extracted with DCM and the combined organic fractions were washed with water then brine and dried (Na)₂SO₄) And concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient eluted with 0-5% MeOH in DCM) to afford 380 as a white solid (61mg, 68%). LCMS (method K) R_T1.99min[M+H]⁺395.1。

¹HNMR(DMSO-d₆,400MHz):δ12.25(1H,s),8.23

(1H,brs),8.13(1H,s),8.07(1H,dd,J=10.04,2.53Hz),7.92(1H,brd,J=7.36Hz),7.62(1H,dd,J=8.81,5.10Hz),7.05(1H,td,J=9.25,2.46Hz),5.74(1H,brs),5.28-5.18(1H,m),371(1H,t,J=7.92Hz),3.64-3.49(3H,m),2.51-2.44(1H,m),1.62(3H,d,J=6.69Hz),0.92-0.87(6H,dd,J=6.14,4.75Hz)

Example 3812- (dimethylamino) -1- [3- [ 6-fluoro-2- [1- (9H-purin-6-ylamino) ethyl]Benzimidazol-1-yl]Azetidin-1-yl]Ethanone 381

Reacting [ (S) -1- (1-azetidin-3-yl-6-fluoro-1H-benzimidazol-2-yl) ethyl]A mixture of- (9H-purin-6-yl) amine (75mg,0.21mmol), dimethylaminoacetic acid (25mg.0.23mmol), 4-methylmorpholine (70 μ L,0.64mmol) and HATU (93mg,0.24mmol) in DMF (2mL) was stirred at RT for 4H. The crude mixture was purified in EtOAc and saturated NaHCO ₃The aqueous solution was partitioned. The aqueous phase was further extracted with EtOAc, the combined organic fractions were washed with water, then brine, and dried (MgSO)₄) And concentrated in vacuo. The residue obtained is purified by column chromatography (Si-PCC with 0-10%2N NH)₃Gradient elution in DCM/MeOH) followed by purification by reverse phase HPLC (Phenomenex Gemini5 μm C18 with 5-60% NH 0.1%)₄Acetonitrile/water gradient of OH) to yield 381 as a white solid (20mg, 22%). LCMS (method K) R_T1.86min[M+H]⁺438.1。

¹HNMR(DMSO-d₆,400MHz):δ8.30-7.92(3H，m)，7.71-7.63(1H，m)，7.45-734(1H，m)，7.11(lH，t，J＝9.36Hz)，5.93-5.58(2H，m)，4.82-4.69(1H,m),4.67-4.56(1H,m),4.49-4.34(1H,m),4.25-4.26(1H,m),3.14(1H,d,J=14.18Hz),2.89(1H,dd,J=14.18,3.84Hz)，2.23(3H,s),2.22(3H,s),1.67(3H,d,J=6.66Hz)

Example 3825- [ 6-fluoro-2- [1- (9H-purin-6-ylamino) ethyl]Benzimidazol-1-yl]-1H-pyridin-2-one 382

Reacting (S) -N- [ 4-fluoro-2- (6-fluoropyridin-3-ylamino) phenyl]A mixture of-2- (9H-purin-6-ylamino) propionamide (255mg,0.62mmol) in AcOH (10mL) was heated at 100 ℃ for 24H. After cooling to RT, the volatiles were removed under reduced pressure and the residue was taken up in EtOAc and saturated NaHCO₃The aqueous solution was partitioned. The aqueous phase was extracted with EtOAc, the combined organic fractions were washed with water and then brine, dried (Na)₂SO₄) And concentrated in vacuo. The residue was purified by column chromatography (Si-PCC with 0-20%2M NH)₃Gradient MeOH in DCM) to give 382 as a pink solid (38mg, 16%). LCMS (method K) R_T2.40min[M+H]⁺391.0。

¹HNMR(DMSO-d₆+TFA-D，

400MHz,80℃):δ8.588.49(2H,m),7.82(1H,d,J=2.96Hz),7.75(１H，dd,J=8.81,4.70Hz),7.51(1H,dd,J=9.59,2.99Hz),7.21-7.07(2H,m),6.40(1H,d,J=9.60Hz),5.86(1H,brd),1.79(3H,d,J=6.82Hz)

Example 383 2- [3- [ 6-fluoro-2- [1- (9H-purin-6-ylamino) ethyl]Benzimidazol-1-yl]Azetidin-1-yl]Ethanol 383

To [ (S) -1- (1-azetidin-3-yl-6-fluoro-1H-benzimidazol-2-yl) ethyl]To a solution of (9H-purin-6-yl) amine (200mg,0.57mmol) in DCE (7mL) was added (tert-butyldimethylsilyloxy) acetaldehyde (132. mu.L, 0.62mmol) and AcOH (39. mu.L, 0.68mmol), followed by MeOH (4 drops). Stirring at 0 deg.C for 10min, adding N in two partsaBH(OAc)₃(168mg,0.79mmol) and the mixture was warmed to RT. Stirring was continued at RT for 18h, then the reaction mixture was taken up in DCM and saturated NaHCO₃The aqueous solution was partitioned. The aqueous phase was extracted with DCM and the combined organic fractions were washed with water and then brine and dried (Na)₂SO₄) And concentrated in vacuo. The residue obtained is purified by column chromatography (Si-PCC with 0-10%2N NH)₃Gradient elution in DCM/MeOH) to give [ (S) -1- (1- {1- [2- (tert-butyldimethylsilyloxy) ethyl ]]Azetidin-3-yl } -6-fluoro-1H-benzimidazol-2-yl) ethyl]- (9H-purin-6-yl) amine (211mg, 73%).

A solution of the thus obtained material (211mg) in tetra-n-butylammonium fluoride (1M in THF, 0.38mL,0.38mmol) was stirred at RT for 4 h. The volatiles were removed under reduced pressure and the resulting residue was purified by column chromatography (Si-PCC with 0-15%2N NH) ₃Gradient elution in DCM/MeOH), followed by purification by reverse phase HPLC (Phenomenex Gemini5 μm C18, 30min gradient: 5-60% with 0.1% NH₄Acetonitrile/water of OH) to give 383 as a white solid (118mg, 72%). LCMS (method K) R_T1.78min[M+H]⁺397.0。

¹HNMR(DMSO-d₆，400

MHz):δ8.25(1H，brs)，8.17-8.11(2H，m)，7.93(1H，d，J=7.85Hz)，7.63(1H，dd，J=8.81，5.10Hz),7.07(1H,td,J=9.25，2.46Hz),5.76(1H,brs),5.40-5.31(1H,m),4.48(1H,brs),3.80-3.71(2H,m),3.69-3.55(2H,m),3.46-3.39(2H,brm),2.64(2H,t,J=5.88Hz),1.63(3H，d，J＝6.6gHz)

Example 3863-cyclopropyl-5-fluoro-2- [ (1S) -1- (9H-purin-6-ylamino) ethyl]Benzimidazole-4-carboxylic acid methyl ester 386

Coupling 3-cyclopropyl-5-fluoro-2- { (S) -1- [9- (tetrahydro-pyran-2-yl) -9H-purin-6-ylamino]A solution of methyl ethyl } -3H-benzimidazole-4-carboxylate (178mg,0.37mmol) in DCM was loadedSCX-2 column, wash it with MeOH, then 2M NH₃Washing with MeOH. The basic fractions were combined, concentrated in vacuo and the residue purified over a second SCX-2 column. The basic fractions were combined, concentrated in vacuo and the resulting residue was purified by column chromatography (Si-PCC, gradient eluted with 0-10% MeOH in DCM) to give 386 as a white solid (36mg, 25%). LCMS (method K) R_T3.03min[M+H]⁺396.04。

¹HNMR(DMSO-d₆,400MHz):δ8.25-8.11(2H,m),8.03(1H,s),7.73(1H,dd,J=8.81,4.72Hz),7.13(1H,t,J=9.78Hz),5.98(1H,s),3.94(3H，s),1.68(3H,d,J=6.74Hz),1.17-0.84(4H,m)

Example 389[ 3-cyclopropyl-5-fluoro-2- [ (1S) -1- (9H-purin-6-ylamino) ethyl ] methyl]Benzimidazol-4-yl]-morpholino-methanone 389

Coupling 3-cyclopropyl-5-fluoro-2- { (S) -1- [9- (tetrahydropyran-2-yl) -9H-purin-6-ylamino]A mixture of ethyl } -3H-benzimidazole-4-carboxylic acid (64mg,0.14mmol), HATU (63mg,0.17mmol), morpholine (18. mu.L, 0.216mmol) and DIPEA (47. mu.L, 0.28mmol) in DCM (2mL) was stirred at RT for 1H. Loading the crude mixture into SCX-2 column, which was washed with MeOH, then 2M NH₃Washing with MeOH. The basic fractions were combined, concentrated in vacuo, and the resulting residue was purified by column chromatography (Si-PCC, gradient eluted with 0-10% MeOH in DCM) to give 389 as a white solid (46mg, 75%). LCMS (method K) R_T2.49 and 2.53min [ M + H]⁺451.05。

¹HNMR(DMSO-d₆,400MHz):δ8.24-7.83(3H,m),

7.697.60(1H,m)，7.10(1H,t,J=9.53Hz),6.07-5.84(1H,m),3.90-3.83(1H,m),3.80-3.72(1H,m),3.69-3.59(2H,m),3.59-3.50(2H,m),3.41-3.35(2H,m),3.28-3.20(1H,m),1.72-1.63(3H,m),1.26-0.85(4H,m)

Example 3903- [ 6-fluoro-2- [ (1S) -1- (9H-purin-6-ylamino) ethyl]Benzimidazol-1-yl]Cyclobutanol 390

A mixture of [ (S) -1- [1- (3-benzyloxycyclobutyl) -6-fluoro-1H-benzimidazol-2-yl ] ethyl ] - (9H-purin-6-yl) amine (0.13g,0.29mmol) in DCM (5mL) was cooled to 0 ℃. To this mixture was added boron tribromide (2.1mL,1.43mmol) dropwise and the resulting mixture was stirred at RT for 2 h. The reaction mixture was quenched with MeOH (2mL) and concentrated in vacuo. The resulting yellow solid was purified by column chromatography (Si-PCC, gradient eluted with 0-10% MeOH in DCM) to give 390 as an off-white glassy solid (50mg, 50%).

¹HNMR(DMSO-d₆)：

δ8.98(1H,s)，8.55-8.37(2H，m)，7.93(1H，d，J=9.74Hz)，7.69(1H，dd，J=8.92，4.99Hz)，721(1H,t,J=9.90Hz),5.89(1H,s),4.86-4.75(1H,m),4.05-3.95(1H,m),2.97-2.62(4H,m)，1.70(3H，d，J＝6.75Hz)

Example 3913- [ 6-fluoro-2- [ (1S) -1- (9H-purin-6-ylamino) ethyl]Benzimidazol-1-yl]Cyclobutanol 391

Mixing [ (S) -1- [1- (cis-3-benzyloxy cyclobutyl) -6-fluoro-1H-benzimidazol-2-yl]Ethyl radical]A mixture of- (9H-purin-6-yl) amine (0.12g,0.26mmol) in DCM (5mL) was cooled to 0 ℃. To the mixture was added boron tribromide (1M in DCM, 0.53mL,0.53mmol) dropwise and the resulting mixture was stirred at RT for 2 h. The reaction mixture was quenched with MeOH (2mL) and concentrated in vacuo. The resulting yellow solid was purified by column chromatography (Si-PCC, gradient eluted with 0-10% MeOH in DCM) to give 391 as an off-white glassy solid (50mg, 50%). LCMS (method K) R _T2.21min[M+H]⁺368.3。

¹HNMR(DMSO-d₆):δ12.8(1H,brs),

821(1H,s),8.09(1H,s),7.78-7.89(1H,m),7.47-7.61(2H,m),6.957.04(1H,m)，5.78(１H,brs)，5.43(1H，qn，J＝8.82Hz)，5.111H，d，J＝4.2Hz)，4.41-4.50(1H，m)，2.86-3.04(2H，m)，2.26-2.38(1H,m),2.08-2.20(1H,m),1.59(1H,d,J=6.7Hz)

Example 3924-amino-6- [ [ (1S) -1- [ 6-fluoro-1- (3-hydroxycyclobutyl) benzimidazol-2-yl]Ethyl radical]Amino group]Pyrimidine-5-carbonitrile 392

Reacting 4-amino-6- [ (S) -1- [1- (trans-3-benzyloxycyclobutyl) -6-fluoro-1H-benzimidazol-2-yl]Ethylamino group]Pyrimidine-5-carbonitrile (0.06g,0.13mmol) was cooled to 0 ℃ in DCM (5 mL). To the mixture was added boron tribromide (1M in DCM, 0.26mL,0.23mmol) dropwise and the resulting mixture was stirred at RT for 2 h. The reaction mixture was quenched with MeOH (2mL) and concentrated in vacuo. The resulting yellow solid was purified by column chromatography (Si-PCC, gradient eluted with 0-10% MeOH in DCM) to give 392 as a colorless glassy solid (75mg, quantitative yield). LCMS (method K) R_T2.41min[M+H]⁺368.3。

¹HMR(DMSO-

d₆):δ8.17(1H,d,J=6.44Hz),8.07(1H,s),7.92(1H,d,J=9.28Hz),7.81(1H,dd,J=8.98，4.77Hz)，7.59(2H，s)，7.41(1H，t，J＝9.27Hz)，5.83-5.75(1H，m)，5.49-5.39(1H，m)，4.59-4.53(1H,m),3.16-2.97(2H,m),2.46-2.28(2H,m),1.67(3H,d,J=6.81Hz

Example 393N- [ (1S) -1- (1-benzyl-6-fluoro-benzimidazol-2-yl) ethyl]-9H-purin-6-amine 393

A mixture of (S) -1- (1-benzyl-6-fluoro-1H-benzimidazol-2-yl) ethylamine (322mg,1.20mmol), 6-chloro-9- (tetrahydropyran-2-yl) -9H-purine (286mg,1.20mmol) and DIPEA (1.07mL,5.98mmol) in IPA (5mL) was heated in a sealed vial at 90 deg.C overnight. The resulting mixture was then cooled to RT and then concentrated in vacuo. Passing the residue throughSCX-2 column, eluting with DCM, MeOH and 2M NH₃Eluted with MeOH to give a pale red gum. It is purified by column chromatography (silica gel, with 0-10% [2M NH ] ₃In MeOH (E) solution]Was eluted with a gradient of DCM solution) to give 393,as a white solid (140mg, 31%). LCMS (method K) R_T3.21min[M+H]⁺388.1

¹HNMR(DMSO-d₆,400MHz):88.20(1H,s),8.13(1H,s),8.04-7.93(1H,s),7.63(1H,dd,J=8.80,4.92Hz),7.35-7.17(4H,m),7.16-7.1O(2H,m),7.03(1H,ddd,J=9.91，8.78，2.52Hz)，5.93-5.75(1H，m)，5.61(2H，s)，1.59(3H，d，J＝6.77Hz)

Example 3944-amino-6- [ [ (1S) -1- (1-benzyl-6-fluoro-benzimidazol-2-yl) ethyl]Amino group]Pyrimidine-5-carbonitrile 394

A mixture of (S) -1- (1-benzyl-6-fluoro-1H-benzimidazol-2-yl) ethylamine (320mg,1.19mmol), 4-amino-6-chloropyrimidine-5-carbonitrile (184mg,1.19mmol), and DIPEA (1.06mL,5.95mmol) in IPA (5mL) was heated at 90 deg.C overnight in a sealed vial. The resulting mixture was then cooled to RT and then concentrated in vacuo. The residue was purified by column chromatography (silica gel, with 0-10% [2M NH ]₃In MeOH (E) solution]Gradient elution of DCM) to give 394 as a white solid (164mg, 36%). LCMS (method K) R_T3.58min[M+H]⁺388.1

¹HNMR(DMSO-d₆,

400MHz):δ7.94(1H,s),7.69(1H,d,J=7.9Hz),7.61(1H,dd,J=8.9,4.5Hz)，7.13-7.28(5H，m)，6.95-7.05(3H，m)，5.65(1H，qn，J＝7.9Hz)，5.46(2H，q，J＝9.91，5.5Hz)，3.12(1H，d，J=5.5Hz),1.49(3H,d,J=6.77Hz)

Example 3954-amino-6- [ [ (1S) -1- (7-bromo-1-cyclopropyl-6-fluoro-benzimidazol-2-yl) ethyl]Amino group]Pyrimidine-5-carbonitrile 395

A mixture of (S) -1- (7-bromo-1-cyclopropyl-6-fluoro-1H-benzimidazol-2-yl) ethylamine (80mg,0.27mmol), 4-amino-6-chloropyrimidine-5-carbonitrile (41mg,0.27mmol) and DIPEA (140 μ L,0.80mmol) in IPA (1mL) was heated at 90 deg.C in a sealed vial for 16H. After cooling to RT, the reaction mixture was diluted with MeOH and loaded into SCX-2 column. The column was washed with MeOH, then 2M NH₃Washing with MeOH. The basic fractions were combined, concentrated in vacuo, and the resulting residue was purified by column chromatography (Si-PCC, gradient elution with 0-100% EtOAc in cyclohexane) to give 395 as a white solid (86mg, 77%). LCMS (method K) R_T4.10min[M+H]⁺415.95。

¹HNMR(CDCl₃，400MHz):δ8.20(1H，s)，

7.56(1H,dd,J=8.73,4.57Hz),7.10-7.04(1H,m),6.27(1H,d,J=7.81Hz),6.06-5.98(1H,m),5.32(2H,s),3.52-3.46(1H,m),1.68(3H,d,J=6.75Hz),1.45-1.33(3H,m),120-1.14(1H，m)

Example 396N- [ (1S) -1- [ 6-fluoro-1- (3-methoxycyclobutyl) benzimidazol-2-yl]Ethyl radical]-9H-purin-6-amine 396

To (S) -1- [ 6-fluoro-1- (cis-3-methoxycyclobutyl) -1H-benzimidazol-2-yl]To a solution of ethylamine (160mg,0.61mmol) in IPA (1.5mL) was added 6-chloro-9- (tetrahydropyran-2-yl) -9H-purine (150mg,0.61mmol) and DIPEA (0.53mL,3.1mmol) and the reaction mixture was heated at 90 deg.C for 16H. After cooling to RT, the volatile substances were removed under reduced pressure and the residue obtained was loadedSCX-2 column. The column was washed with MeOH, then 2M NH₃Washing with MeOH. The basic fractions were combined, concentrated in vacuo and the resulting residue was purified by column chromatography (Si-PCC, gradient eluted with 0-5% MeOH in DCM) to give 396 as a white solid (120mg, 52%).

¹HNMRδ(DMSO-d₆):8.24(1H,

s),8.14(1H,s),7.90(1H,d,J=7.84Hz),7.63(1H,dd,J=8.82,5.11Hz),7.54(1H,dd,J=9.80，2.47Hz)，7.11-7.02(1H，m)，5.84(1H，s)，4.99-4.89(1H，m)，3.81-3.72(1H，m)，3.23(3H，s)，2.96-2.59(4H，m)，1.64(3H，d，J＝6.70Hz)

Example 397N- [ (1S) -1- [ 6-fluoro-1- (3-methoxycyclobutyl) benzimidazol-2-yl]Ethyl radical]-9H-purin-6-amine 397

To (S) -1- [ 6-fluoro-1- (trans-3-methoxycyclobutyl) -1H-benzimidazol-2-yl ]To a solution of ethylamine (79mg,0.3mmol) in IPA (1mL) was added 6-chloro-9- (tetrahydropyran-2-yl) -9H-purine (72mg,0.3mmol) and DIPEA (0.26mL,1.5mmol) and the reaction mixture was heated at 90 deg.C for 16H. After cooling to RT, the volatile substances were removed under reduced pressure and the residue obtained was loadedSCX-2 column. The column was washed with MeOH, then 2M NH₃Washing with MeOH. The basic fractions were combined, concentrated in vacuo and the resulting residue was purified by column chromatography (Si-PCC, gradient eluted with 0-5% MeOH in DCM) to afford 397(37mg,32%) as a white solid.

^１HNMRδ(DMSO-d₆):12.82(1H，s)，8.25

(1H,s),8.14(1H,s),7.92(1H,s),7.67-7.57(2H,m),7.05(1H,td,J=9.30,2.38Hz),586(lH，5)，544-533(1H，m)，4.17(1H，t，J=6.72Hz)，3.12(3H，s)，3.07-2.96(1H，m)，2.88-2.86(1H,m),2.56-2.45(1H,m),2.27-2.18(1H,m),1.65(3H,d,J=6.69Hz)

Example 398(S) -N- (1- (7-fluoro-5, 6-dihydro-4H-imidazo [4,5, 1-ij)]Quinolin-2-yl) ethyl) -9H-purin-6-amine 398

Mixing (S) -1- (7-fluoro-5, 6-dihydro-4H-imidazo [4,5, 1-ij)]A mixture of quinolin-2-yl) ethylamine (48.5mg,0.221mmol), 6-chloro-9- (tetrahydropyran-2-yl) -9H-purine (52.9mg,0.221mmol) and DIPEA (0.113mL,0.663mmol) in n-butanol (1mL) was stirred in a sealed vial at 90 ℃ for 16H. After cooling to RT, the volatiles were removed under reduced pressure. The residue was dissolved in MeOH (3mL), and the resulting solution was cooled in an ice bath. A solution of HCl in isopropanol (1.25M,2mL) was added and the mixture was stirred at 0 ℃ for 1h, then concentrated under reduced pressure. Will be provided with The residue was dissolved in MeOH and loaded intoSCX-2 column. The column was washed with MeOH, 0.5M NH₃The product was eluted with MeOH and further purified by column chromatography (Si-PCC with 2-14%2M NH)₃Gradient MeOH in DCM) to give 398 as a white solid (43.4mg, 58%). LCMS (method J) R_T4.80min[M+H]⁺338.2。

¹HNMR((CD₃)₂SO,400MHz):12.81(１H,bs),8.23(１H,s),8.15(１H,s),7.76(1H，d，J＝7.Hz)，7.37(dd，J8.8，4.2Hz)，6.92(1H，dd，J＝10.5，8.8Hz)，5.80(17H，bs)，4.29-4.16(2H，m)，2.87(2H，t，J＝6.1Hz)，2.16-2.05(2H，m)，1.68(3H，d，J＝6.8Hz)

Example 3993- [ 6-fluoro-2- [ (1S) -1- (9H-purin-6-ylamino) ethyl]Benzimidazol-1-yl]Cyclobutanecarbonitrile 399

Reacting 3- [2- ((S) -1-aminoethyl) -6-fluorobenzoimidazol-1-yl]Cyclobutanecarbonitrile (0.075g,0.29mmol), 6-chloro-9- (tetrahydropyran-2-yl) -9H-purine (0.070g,0.29mmol) and DIPEA (0.26mL,1.45mmol) were stirred in 2-propanol (5mL) at 90 ℃ in a sealed microwave tube for 16H. After cooling, the reaction mixture was concentrated in vacuo and the residue was loadedSCX-2 column, which was washed with DCM and MeOH, then 2M NH₃The product was eluted with MeOH and then concentrated in vacuo. The residue was purified by chromatography on silica gel eluting with 100% DCM-10% methanol in DCM to give 399 as a solid (0.035g, 32%). LCMS (method K) R_T2.76min[M+H]⁺376.0。

¹HNMR(MeOD-d₄)δ：8.33(1H，brs)，

8.05(1H,brs),7.53-7.61(2H,m),6.97-7.04(1H,m),6.02(1H,brs),5.76-5.87(1H,m),3.38-3.49(2H,m),3.21-3.30(2H,m),2.76-2.88(1H,m),2.37-2.47(1H,m),1.76(3H,d,J=6.1Hz)

Example 400[ 3-cyclopropyl-5-fluoro-2- [ (1S) -1- (thiazolo [5,4-d ]]Pyrimidin-7-ylamino) ethyl]Benzimidazol-4-yl]Morpholino-methanone 400

Reacting [2- ((S) -1-aminoethyl) -3-cyclopropyl-5-fluoro-3H-benzimidazol-4 yl ]-morpholin-4-yl-methanone (108mg,0.33mmol), 7-chloro-thiazolo [5,4-d]A mixture of pyrimidine (61mg,0.36mmol) and DIPEA (170. mu.L, 0.98mmol) in IPA (1mL) was heated at 90 deg.C in a sealed vial for 17 h. After cooling to RT, the reaction mixture was diluted with MeOH and loaded intoSCX-2 column. The column was washed with MeOH, then 2M NH₃Washing with MeOH. The basic fractions were combined, concentrated in vacuo, and the resulting residue was purified by column chromatography (Si-PCC, gradient eluted with 0-10% MeOH in DCM) to give 400 as a pale yellow solid (110mg, 39%). LCMS (method K) R_T3.16min[M+H]⁺468.02。

¹HNMR(CDCl₃，

400MHz):δ8.82(0.7H,s),8.77(0.3H,s),8.54(0.3H,s),8.52(0.7H,s),7.73-7.65(1H,m),7.17(0.7H,d,J=8.02Hz),7.05-6.95(1H,m),6.67(0.3H,d,J=8.45Hz),6.31-6.23(0.3H,m),6.14-6.04(0.7H,m),4.23-4.14(1H,m),3.93-3.72(4H,m),3.68-3.51(2H,m),3.47-3.33(2H,m),1.84(1H,d,J=6.77Hz),1.75(2H,d,J=6.76Hz),1.54-1.46(0.7H,m),141-129(1H,m),120-1.10(0.3H,m),1.03-0.93(1H,m),0.86-0.71(1H,m)

Example 4014-amino-6- [ [ (1S) -1- [ 1-cyclopropyl-6-fluoro-7- (morpholine-4-carbonyl) benzimidazol-2-yl]Ethyl radical]Amino group]Pyrimidine-5-carbonitrile 401

Reacting [2- ((S) -1-aminoethyl) -3-cyclopropyl-5-fluoro-3H-benzimidazol-4 yl]A mixture of-morpholin-4-yl-methanone (106mg,0.32mmol), 4-amino-6-chloropyrimidine-5-carbonitrile (54mg,0.35mmol) and DIPEA (170. mu.L, 0.98mmol) in IPA (1mL) at 90 deg.C in a sealed vialHeating for 17 h. After cooling to RT, the reaction mixture was diluted with MeOH and loaded intoSCX-2 column. The column was washed with MeOH, then 2M NH₃Washing with MeOH. The basic fractions were combined, concentrated in vacuo, and the resulting residue was purified by column chromatography (Si-PCC, gradient 0-10% MeOH in EtOAc) followed by trituration with EtOAc to give 401 as a white solid (60mg, 31%). LCMS (method K) R _T2.81min[M+H]⁺451.06。

¹HNMR(CDC1₃,400MHz):δ8.18(1H,s),7.71-7.65(1H,m),7.05-6.97(1H,m),6.47-6.40(0.7H,m),6.15-6.05(0.3H,m),5.98-5.88(1H,m),5.38-5.31(2H,m),422-4.14(1H,m),3.93-3.72(4H,m),3.69-3.52(2H,m),3.44-3.33(2H,m),1.73(1H,d,J=6.78Hz)，1.65(2H，d，J＝6.76Hz)，1.43-1.24(2H，m)，1.11-0.93(1H，m)，0.86-0.69(1H，m)

Example 4024-amino-6- [ [ (1S) -1- [ 6-fluoro-1- (1-methylpyrazol-3-yl) benzimidazol-2-yl]Ethyl radical]Amino group]Pyrimidine-5-carbonitrile 402

TFA (1mL) was added to stirred { (S) -1- [ 6-fluoro-1- (1-methyl-1H-pyrazol-3-yl) -1H-benzimidazol-2-yl]Ethyl } carbamic acid tert-butyl ester (126mg,0.35mmol) in DCM (3 mL). After stirring for 3h at RT, the reaction mixture is diluted with MeOH and loaded ontoSCX-2 column. The column was washed with MeOH, then 2MNH₃Washing with MeOH. The basic fractions were combined and concentrated in vacuo to give a brown oil. A mixture of the high residue, 4-amino-6-chloropyrimidine-5-carbonitrile (60mg,0.39mmol) and DIPEA (205. mu.L, 1.17mmol) in IPA (1mL) was heated at 90 deg.C for 16h in a sealed vial. After cooling to RT, the crude mixture was diluted with MeOH and loaded intoSCX-2 column. Will postWashed with MeOH, then 2M NH₃Washing with MeOH. The basic fractions were combined, concentrated in vacuo, and the resulting residue was purified by column chromatography (Si-PCC, gradient elution with 0-10% MeOH in EtOAc) followed by trituration with EtOAc to give 402 as a white solid (71mg, 54% over 2 steps). LCMS (method K) R_T3.27min[M+H]⁺378.04。

¹HNMR(DMSO-d₆,400MHz):δ7.97(1H,s),7.91(1H,d,J=2.31Hz),7.73(1H,dd,J=8.66,4.85Hz),7.61(1H,d,J=7.64Hz),7.25(2H,s),7.17-7.08(2H,m),6.54(1H，d，J＝231Hz)，5.77-5.67(1H，m)，3.89(3H，s)，1.52(3H，d，J＝6.87Hz)

Example 403N- [ (1S) -1- [ 6-fluoro-1- (1-methylpyrazol-3-yl) benzimidazol-2-yl ]Ethyl radical]-9H-purin-6-amine 403

TFA (1mL) was added to stirred { (S) -1- [ 6-fluoro-1- (1-methyl-1H-pyrazol-3-yl) -1H-benzimidazol-2-yl]Ethyl } carbamic acid tert-butyl ester (187mg,0.52mmol) in DCM (3 mL). After stirring for 3h at RT, the reaction mixture is diluted with MeOH and loaded ontoSCX-2 column. The column was washed with MeOH, then 2MNH₃Washing with MeOH. The basic fractions were combined and concentrated in vacuo to give a brown oil. A mixture of the residue, 6-chloro-9- (tetrahydropyran-2-yl) -9H-purine (126mg,0.53mmol) and DIPEA (280. mu.L, 1.59mmol) in IPA (1mL) was heated at 90 deg.C for 24H in a sealed vial. After cooling to RT, the reaction mixture was diluted with MeOH and loaded intoSCX-2 column. The column was washed with MeOH, then 2M NH₃Washing with MeOH. The basic fractions were combined, concentrated in vacuo, and the resulting residue was purified by column chromatography (Si-PCC, gradient eluted with 0-10% MeOH in DCM) and triturated with EtOAc to give 403 as a light brown solid (98mg, 50% over 2 steps). LCMS (method K) R_T2.84min[M+H]⁺378.03。

¹HNMR(DMSO-d₆,400MHz):δ8.21-8.11(2H，m),7.94-7.81(2H,m),7.75-7.66(1H,m),7.19-7.08(2H,m),6.61(1H,d,J=2.29Hz),5.89-5.73(１H,m),3.89(3H,s),1.61(3H，d，J＝6.84Hz)

Example 4044-amino-6- [ [ (1S) -1- [ 6-fluoro-1- (3-hydroxycyclobutyl) benzimidazol-2-yl]Ethyl radical]Amino group]Pyrimidine-5-carbonitrile 404

A mixture of 4-amino-6- { (S) -1- [1- (3-benzyloxycyclobutyl) -6-fluoro-1H-benzimidazol-2-yl ] ethylamino } pyrimidine-5-carbonitrile (0.05g,0.11mmol) in DCM (3mL) was cooled to 0 ℃. To this mixture was added boron tribromide (0.22mL,0.22mmol) dropwise and the resulting mixture was stirred at RT for 2 h. The reaction mixture was quenched with MeOH (2mL) and concentrated in vacuo. The resulting yellow solid was purified by column chromatography (Si-PCC, gradient eluted with 0-10% MeOH in DCM) to afford 404 as an off-white glassy solid (50mg, 99%).

¹HNMR(DMSO-d₆):δ7.97-8.09(3H,m),7,74(1H,dd,J=7.75,4.8Hz),7.50(2H,brs),7.26-7.36(1H,m),5.67(1H,qn,J=6.7Hz),4.70(1H,qn,J=8.5Hz),3.96(1H,m)]2.72-2.91(2H，m)，2.55-2.72(2H，m)，1.6(3H，d，7.2Hz).

LCMS (method K) R_T2.36min[M+H]⁺368

Example 405[ (S) -1- (5-fluoro-6, 7,8, 9-tetrahydro-2, 9 a-diazabenzo [ cd)]-1-yl) ethyl]- (9H-purin-6-yl) amine 405

Reacting (S) -1- (5-fluoro-6, 7,8, 9-tetrahydro-2, 9 a-diazabenzo [ cd]-1-yl) ethylamine (70mg,0.30mmol), 6-chloro-9- (tetrahydropyran-2-yl) -9H-purine (71.8mg,0.30mmol) and DIPEA (0.153mL,0.90mmol) in n-butanol (1.5mL)The mixture of (a) was stirred in a sealed vial at 90 ℃ for 16 h. After cooling to RT, the volatiles were removed under reduced pressure. The residue was dissolved in MeOH (5mL) and cooled in an ice bath. A solution of HCl in isopropanol (1.25M,3mL) was added and the mixture was stirred at 0 ℃ for 1.5h, then concentrated under reduced pressure. The residue was dissolved in MeOH and loaded intoSCX-2 column. The column was washed with MeOH, 0.5M NH₃The product was eluted with MeOH and further purified by column chromatography (Si-PCC with 2-12%2 MNH)₃Gradient elution in DCM/MeOH) gave 405 as a white solid (72.8mg, 69%). LCMS (method K) R_T2.68min[M+H]⁺352.0。

¹HNMR

((cD₃)₂SO,400MHz):12.93(1H,bs),8.24(1H,s),8.15(1H,s),7.89(1H,d,J=7.9Hz),7.43(1H，dd，J＝8.7，4.8Hz)，6.99(lH，dd，J＝l0.8，8.8Hz)，5.83(1H，bs)，431-4.29(2H，m),3.04-301(2H,m),2.08-1.94(4H,m),1.66(3H,d,J=6.7Hz)

Example 4064-amino-6- [ (S) -1- (5-fluoro-6, 7,8, 9-tetrahydro-2, 9 a-diazabenzo [ cd)]-1-yl) ethylamino]Pyrimidine-5-carbonitrile 406

Reacting (S) -1- (5-fluoro-6, 7,8, 9-tetrahydro-2, 9 a-diazabenzo [ cd]A mixture of-1-yl) ethylamine (70mg,0.30mmol), 4-amino-6-chloropyrimidine-5-carbonitrile (46.4mg,0.30mmol) and DIPEA (102. mu.L, 0.60mmol) in isopropanol (1.5mL) was stirred at 90 ℃ for 3 h. After cooling to RT, the volatiles were removed under reduced pressure and the resulting residue was purified by column chromatography (Si-PCC with 2-7%2M NH) ₃Gradient elution in DCM/MeOH). Crystallization from MeOH (5mL) gave 406 as a white solid (43.2mg, 41%). LCMS (method K) R_T2.91min[M+H]⁺352.1。

¹HNMR((CD₃)₂SO,400MHz):8.07(1H,s),7.69(1

H, d, J ═ 7.5Hz), 7.45(lH, dd, J ═ 8.8, 4.8Hz), 7.31(2H, bs), 7.00(lH, dd, J ═ l0.8, 8.7Hz), 5.67(1H, quintuple, J ═ 6.gHz), 4.25-4.14(2H, m), 3.05-3.O1(2H, m), 2.08-1.93(4H, m), 1.58(3H, d, J =6.7Hz)

Example 407[ (S) -1- (7-fluoro-4-methyl-5, 6-dihydro-4H-imidazo [4,5, 1-ij)]Quinolin-2-yl) ethyl]- (9H-purin-6-yl) amine 407

Mixing (S) -1- (7-fluoro-4-methyl-5, 6-dihydro-4H-imidazo [4,5, 1-ij)]A mixture of quinolin-2-yl) ethylamine (15.8mg,0.0677mmol), 6-chloro-9- (tetrahydropyran-2-yl) -9H-purine (17.8mg,0.0745mmol) and DIPEA (0.0346mL,0.20mmol) in n-butanol (0.5mL) was stirred in a sealed vial at 90 ℃ for 16H. After cooling to RT, the volatiles were removed under reduced pressure. The residue was dissolved in MeOH (1.5mL) and cooled in an ice bath. A solution of HCl in isopropanol (1.25M,1mL) was added and the mixture was stirred at 0 ℃ for 90min and then concentrated under reduced pressure. The residue was dissolved in MeOH and loaded intoSCX-2 column. The column was washed with MeOH, 0.5M NH₃The product was eluted with MeOH and further purified by column chromatography (Si-PCC with 2-12%2M NH) ₃Gradient elution in DCM/MeOH) gave 407 as a white solid (8mg, 34%). Analytical data showed that the product was a mixture of diastereomers (ratio 1:1) which could be separated. LCMS (method K) R_T2.59&2.62min[M+H]⁺352。

¹HNMR(CD₃0D,400MHz):8.25&8.24(1H,2s),8.10&8.08(1H,2s),7.39-735(1H，m)，6.96-6.91(1H，m)，5.93&5.82(1H，2bs)，5.26-5.21&4.93-4.87(1H，2m)，3.09-3.03(1H，m)，2.97-2.88(1H，m)，2.27-2.21(1H，m)，2.15-2.03(1H，m)，1.83&1.78(3H，2d,J=6.9Hz),1.45&1.41(3H,2d,J=6.7Hz)

Example 4084-amino-6- [ [ (1S) -1- [ 6-fluoro-1-isopropyl-7- (2-pyridinyl) benzimidazol-2-yl]Ethyl radical]Amino group]Pyrimidine-5-carbonitrile 408

(S) -1- (6-fluoro-1-isopropyl-7-pyridin-2-yl-1H-benzimidazol-2-yl) ethylamine (0.166g,0.56mmol), 4-amino-6-chloropyrimidine-5-carbonitrile (86mg,0.56mmol) and DIPEA (497. mu.L, 2.78mmol) in IPA (5mL) were added and the reaction mixture was heated at 90 deg.C for 16H. The reaction mixture was concentrated in vacuo and the resulting residue was purified by flash chromatography (SiO)₂Eluting with 0-10% methanol in DCM) to give 408 as a white solid (140mg, 61%). LCMS (method K) R_T3.28min[M+H]⁺417。

¹HNMR(DMSO-d₆，40OMHz)：δ

8.70(lH，ddd，J＝4.8，1.7，0.8Hz)，7.99(lH，s)，7.93(1H，td，J＝7.8，1.8Hz)，7.67(1H，dd，J＝8.8，4.9Hz)，7.61(lH，d，J＝7.6Hz)，7.48(1H，ddd，J＝7.6，4.8，1.2Hz)，7.29(3H，brs)，7.12(1H,dd,J=10.3,8.8Hz),5.64(1H,sept,J=7.1Hz),4.01-3.89(1H,m),1.55(3H,d,J=6.6Hz),1.27-1.11(6H,m)

Example 409N- [ (1S) -1- [ 6-fluoro-1-isopropyl-7- (2-pyridyl) benzimidazol-2-yl]Ethyl radical]-9H-purin-6-amine 409

(S) -1- (6-fluoro-1-isopropyl-7-pyridin-2-yl-1H-benzimidazol-2-yl) ethylamine (0.18g,0.6mmol), 6-chloro-9- (tetrahydropyran-2-yl) -9H-purine (145mg,0.60mmol) and DIPEA (543. mu.L, 3.0mmol) were added and the reaction mixture was heated at 90 ℃ for 16H. The reaction mixture was loaded onto an SCX column to remove THP groups. The column was washed with MeOH, 2M NH ₃MeOH to elute the product. The product fractions were collected, concentrated in vacuo and the residue obtained was treated with flash chromatography (SiO)₂Eluting with 0-10% methanol in DCM) to give 409 as a white solid (23mg, 10%). LCMS (method K) R_T2.94min[M+H]⁺417。

¹HNMR(DMSO-d₆,400MHz):δ12.69(1H,brs),869

(1H，d，J＝4.4Hz)，8.17(1H，brs)，8.13(1H，s)，7.93(1H，td，J＝7.8，1.8Hz)，7.66(1H，dd，J＝8.8，5.0Hz)，7.64(1H，brs)，7.62(lH，d，J＝7.8Hz)，7.47(1H，ddd，J＝7.7，4.9，1.1Hz)，7.11(lH，dd，J=10.2，8.9Hz)，5.90-5.78(lH，m)，4.11-3.87(lH，m)，1.62(3H，d，J=6.6Hz)，1.35-1.15(6H，m)

Example 4104-amino-6- [ [ (1S) -1- [ 1-ethyl-6-fluoro-7- (2-pyridinyl) benzimidazol-2-yl]Ethyl radical]Amino group]Pyrimidine-5-carbonitrile 410

A mixture of (S) -1- (1-ethyl-6-fluoro-7-pyridin-2-yl-1H-benzimidazol-2-yl) ethylamine (0.203g,0.715mmol), 4-amino-6-chloropyrimidine-5-carbonitrile (0.11g,0.715mmol), and DIPEA (0.65mL,3.58mmol) in IPA (5mL) was stirred at 80 deg.C in a sealed microwave tube for 16H. After cooling, the mixture was concentrated in vacuo and the residue was chromatographed (Si-PPC, gradient eluted with 0-5% MeOH in DCM) to give 410 as a solid (0.095g, 33%). LCMS (method K) R_T3.03min[M+H]⁺403。

¹HNMR(DMSO-d₆,400MHz):δ8.71-8.67(1H,m)，7.96(1H，s)，7.92(1H，td，J＝7.8，1.9Hz)，7.73(1H，d，J＝7.7Hz)，7.70-7.62(2H，m)，7.47(1H，ddd，J＝7.7，5.0，1.1Hz)，7.25(2H，brs)，7.12(1H，dd，J＝l0.4，8.8Hz)，5.60(1H，quin，J=7.2Hz),3.80-3.67(2H,m),1.55(3H,d,J=6.8Hz),0.69(3H,t,J=7.１Hz)

Example 4114-amino-6- [ [ (1S) -1- [ 6-fluoro-1-methyl-7- (2-pyridinyl) benzimidazol-2-yl]Ethyl radical]Amino group]Pyrimidine-5-carbonitrile 411

(S) -1- (6-fluoro-1-methyl-7-pyridin-2-yl-1H-benzimidazol-2-yl) ethylamine (0.093g,0.35mmol), 4-amino-6-chloropyrimidine-5-carbonitrile (53mg,0.35mmol) and DIPEA (313. mu.L, 1.72mmol) in IPA (5mL) were added The reaction mixture was heated at 90 ℃ for 16 h. The reaction mixture was concentrated in vacuo and the resulting residue was purified by flash chromatography (Si-PPC, gradient eluted with 0-10% methanol in DCM) to give 411 as a white solid (95mg, 72%). LCMS (method K) R_T2.76min[M+H]⁺389。

¹H)NMR(DMSO-d₆，400MHz)：δ8.70

(lH，ddd，J＝4.8，1.7，0.9Hz)，7.98(1H，s)，7.91(lH，td，J＝7.8，1.8Hz)，7.71-7.64(2H，m)，7.60(lH，dq，J＝7.7，0.9Hz)，7.46(1H，ddd，J＝7.6，4.9，1.OHz)，7.26(2H，brs)，7.11(lH，dd，J=10.5,8.8Hz),5.59(1H,quin,J=7.3HZ),3.09(3H,s),1.53(3H,d,J=6.8Hz)

Example 412N- [ (1S) -1- [ 1-ethyl-6-fluoro-7- (2-pyridyl) benzimidazol-2-yl]Ethyl radical]-9H-purin-6-amine 412

A mixture of (S) -1- (1-ethyl-6-fluoro-7-pyridin-2-yl-1H-benzimidazol-2-yl) ethylamine (0.203g,0.715mmol), 6-chloro-9- (tetrahydropyran-2-yl) -9H-purine (145mg,0.60mmol) and DIPEA (543. mu.L, 3.0mmol) was added and the reaction mixture was heated at 90 ℃ for 16H. The reaction mixture was loaded onto an SCX column to remove THP groups. The column was washed with MeOH, 2M NH₃MeOH to elute the product. The product fractions were collected, concentrated in vacuo, and the resulting residue was flash chromatographed (Si-PPC, gradient eluted with 0-7% MeOH in DCM) to give 412 as a white solid (75mg, 25%). LCMS (method K) R_T2.76min[M+H]⁺403。

¹HNMR(DMSO,400MHz):δ12.83(1H,

brs)，8.68(1H，d，J＝4.8Hz)，8.12(2H，d，J＝14.3Hz)，7.95(1H，brs)，7.91(1H，td，J＝7.7，1.7Hz)，7.68-7.62(2H，m)，7.46(1H，d，J＝7.2，5.0Hz)，7.11(lH，dd，J＝10.4，9.0Hz)，5.78-5.67(1H，m)，3.91-3.71(2H，m)，1.63(3H，d，J＝6.8Hz)，0.71(3H，t，J＝6.9Hz)

Example 413N- [ (1S) -1- [ 6-fluoro-1-methyl-7- (2-pyridinyl) benzimidazol-2-yl]Ethyl radical]-9H-purin-6-amine 413

A mixture of (S) -1- (6-fluoro-1-methyl-7-pyridin-2-yl-1H-benzimidazol-2-yl) ethylamine (100mg,0.37mmol), 6-chloro-9- (tetrahydropyran-2-yl) -9H-purine (88mg,0.37mmol) and DIPEA (340. mu.L, 1.85mmol) in IPA (5mL) was added and the reaction mixture was heated at 90 deg.C for 16H. The reaction mixture was loaded onto an SCX column to remove THP groups. The column was washed with MeOH, 2M NH ₃MeOH to elute the product. The product fractions were collected, concentrated in vacuo, and the resulting residue was flash chromatographed (Si-PPC, gradient eluted with 0-5% MeOH in DCM) to give 413 as a white solid (67mg, 47%). LCMS (method K) R_T2.53min[M+H]⁺389。

¹HNMR(DMSO-d₆，40OMHz）：δ

12.7(1H，brs)，8.68(1H，ddd，J＝4.8，1.7，0.8Hz)，8.13(2H，d，J＝21.9Hz)，7.91(lH，brs)，7.90(lH，td，J＝7.8，1.8Hz)，7.65(lH，dd，J＝8.8，4.8Hz)，7.60(lH，tq，J＝7.7，1.lHz)，7.44(lH，ddd，J＝7.5，4.8，1.lHz)，7.10(lH，dd，J＝l0.4，8.8Hz)，5.82-5.67(1H，m)，3.15(3H，s)，1.61(6H，d，J＝6.7Hz)

Example 4144-amino-6- [ [ (1S) -1- [ 1-cyclopropyl-6-fluoro-7- (3-pyridinyl) benzimidazol-2-yl]Ethyl radical]Amino group]Pyrimidine-5-carbonitrile 414

Reacting 4-amino-6- [ (S) -1- (7-bromo-1-cyclopropyl-6-fluoro-1H-benzimidazol-2-yl) ethylamino]Pyrimidine-5-carbonitrile (68mg,0.16mmol), pyridine-3-boronic acid (26mg,0.21mmol), tetrakis (triphenylphosphine) palladium (19mg,10mol%) and cesium carbonate (106mg,0.33mol) in bisAlkane (3mL) and H₂The mixture in O (1.5mL) was purged with argon and then heated with microwave radiation at 140 ℃ for 30 min. After cooling to RT, the reaction mixture was diluted with MeOH and loaded intoSCX-2 column. The column was washed with MeOH, then 2M NH₃Washing with MeOH. The basic fractions were combined, concentrated in vacuo, and the resulting residue was purified by column chromatography (Si-PCC, gradient elution with 0-10% MeOH in EtOAc) followed by reverse phase HPLC (Phenomenex Gemini5 μmC18, 10-90% with 0.1% NH)₄Acetonitrile/water gradient of OH) to give 414 as a white solid (29mg, 43%). LCMS (method K) R _T2.80min[M+H]⁺415.06。

^lHNMR(CDCl₃400MHz)：δ8.74(1H，s)，8.66(1H，dd，J＝4.86，1.69Hz)，8.17(1H，s)，7.86(1H，s)，7.70(lH，dd，J＝8.79，4.66Hz)，7.43(1H，dd，J＝7.83，4.85Hz)，7.13(1H，dd，J＝l0.24，8.78Hz)，6.45-6.14(1H，brm)，5.97(1H，m)，5.36(2H，s)，2.95(lH，m)，1.70(3H，d，J＝6.73Hz)，1.02-0.09(4H，m)

Example 4154-amino-6- [ [ (1S) -1- (1-cyclopropyl-6-fluoro-7-phenyl-benzimidazol-2-yl) ethyl]Amino group]Pyrimidine-5-carbonitrile 415

Reacting 4-amino-6- [ (S) -1- (7-bromo-1-cyclopropyl-6-fluoro-1H-benzimidazol-2-yl) ethylamino]Pyrimidine-5-carbonitrile (68mg,0.16mmol), phenylboronic acid (26mg,0.21mmol), tetrakis (triphenylphosphine) palladium (19mg,10mol%) and cesium carbonate (106mg,0.33mol) in bisAlkane (3mL) and H₂The mixture in O (1.5mL) was purged with argon and then heated with microwave radiation at 140 ℃ for 30 min. After cooling to RT, the reaction mixture was diluted with MeOH and loaded intoSCX-2 column. The column was washed with MeOH, then 2M NH₃Washing with MeOH. The basic fractions were combined, concentrated in vacuo, and the resulting residue was purified by column chromatography (Si-PCC, gradient elution with 0-100% EtOAc in DCM), followed by EtOAc/cyclohexane was recrystallized to yield 415 as a white solid (10mg, 15%). LCMS (method K) R_T4.08min[M+H]⁺414.08。

¹HNMR(CDCl₃40OMHz)：δ

8.17(1H,s),7.65(1H,dd,J=8.89,4.63Hz),7.43-7.42(5H,m),7.09(1H,dd,J=10.20,8.76Hz),6.35(1H,d,J=7.83Hz),5.96(1H,m),5.32(2H,s),2.89-2.83(1H,m),1.69(3H,d,J=6.74Hz)，0.79(lH，m)，0.61(lH，m)，0.47(1H，m)，0.23(1H，m)

Example 4164-amino-6- [ [ (1S) -1- [ 6-fluoro-1- (2-methylpyrazol-3-yl) benzimidazol-2-yl]Ethyl radical]Amino group]Pyrimidine-5-carbonitrile 416

Reacting (S) -1- [ 6-fluoro-1- (2-methyl-2H-pyrazol-3-yl) -1H-benzimidazol-2-yl]A mixture of ethylamine (0.093g,0.359mmol), 4-amino-6-chloropyrimidine-5-carbonitrile (0.078g,0.502mmol) and DIPEA (0.12mL,0.646mmol) in IPA (2mL) was stirred at 80 deg.C in a sealed microwave tube for 16 h. After cooling, the mixture is loaded SCX-2 column, wash it with MeOH, 2M NH₃The product was eluted with MeOH and then concentrated in vacuo. The residue was chromatographed on silica gel eluting with 100% DCM-8% (2M ammonia in methanol) in DCM to give 416 as a white solid (0.107g, 79%). LCMS (method K) R_T3.16,3.28min[M+H]⁺378.0。¹HNMR(DMSO-d₆，400MHz)：δ7.92-

7.87(1H，s)，7.87-7.84(1H,m),7.75-7.75(1H,m),7.60-7.54(1H,m),7.30-7.19(3H,m),6.96(1H,m),6.61-6.44(1H,m),5.47-5.38(1H,m),3.59-3.53(3H,m),3.17(OH,d,J=5.25Hz)，1.58-1.5l(3H，m)

Due to the presence of rotamers/tautomers, the signal is cleaved.

Example 417N- [ (1S) -1- [ 6-fluoro-1- (2-methylpyrazol-3-yl) benzimidazol-2-yl]Ethyl radical]-9H-purin-6-amine 417

Reacting (S) -1- [ 6-fluoro-1- (2-methyl-2H-pyrazol-3-yl) -1H-benzimidazol-2-yl]A mixture of ethylamine (0.093g,0.36mmol), 6-chloro-9- (tetrahydropyran-2-yl) -9H-purine (0.119g,0.50mmol) and DIPEA (0.12mL,0.65mmol) in IPA (2mL) was stirred at 80 deg.C in a sealed tube for 16H. After cooling, the reaction mixture is concentrated in vacuo and the residue is purified by chromatography (SiO)₂0-8% (2M ammonia in methanol) in DCM). The product was dissolved in methanol (4mL) and HCl/bisAlkane (4M,0.6mL,2.4mmol) and then stirred for 30 min. The resulting mixture was concentrated in vacuo and the residue was loaded ontoSCX-2 column, washed with MeOH. With 2M NH₃The product was eluted with MeOH and then concentrated in vacuo to give 417 as a white solid (0.078g, 58%). LCMS (method K) R _T2.79,2.95min[M+H]⁺378.0。

¹HNMR(DMSO-d₆,400MHz):δ12.91-12.00(1H,m),830-781(3H,m)，7.78-7.71(1H，m)，7.50(1H，5)，7.23-7.03(1H，m)，7.03-6.92(1H，m)，6.69-6.51(1H，m)，5.60-5.22(1H,m),3.62-3.55(3H,m),1.65-1.54(3H,m)

Due to the presence of rotamers/tautomers, the signal is cleaved.

Example 4184-amino-6- [ [ (1S) -1- [ 6-fluoro-1- (1-methylpyrazol-4-yl) benzimidazol-2-yl]Ethyl radical]Amino group]Pyrimidine-5-carbonitrile 418

Reacting (S) -1- [ 6-fluoro-1- (1-methyl-1H-pyrazol-4-yl) -1H-benzimidazol-2-yl]A mixture of ethylamine (0.055g,0.21mmol), 4-amino-6-chloropyrimidine-5-carbonitrile (0.046g,0.30mmol) and DIPEA (0.07mL,0.38mmol) in IPA (1.5mL) was stirred at 80 deg.C in a sealed tube for 16 h. After cooling, the reaction mixture is concentrated in vacuo and the residue is purified by chromatography (SiO)₂,0-10%(2M ammonia in methanol) in DCM) to give 418 as a white solid (0.060g, 75%). LCMS (method K) R_T2.94min[M+H]⁺378.0。

¹HNMR(DMSO-d₆,

400MHz):δ8.12(1H,s),7.96(1H,s),7.70-7.60(3H,m),7.25(2H,s),7.09(1H,m),6.96(1H，m)，5.46(1H，m)，3.88(3H，s)，1.51(3H，d，J＝6.85Hz)

Example 419N- [ (1S) -1- [ 6-fluoro-1- (1-methylpyrazol-4-yl) benzimidazol-2-yl]Ethyl radical]-9H-purin-6-amine 419

Reacting (S) -1- [ 6-fluoro-1- (1-methyl-1H-pyrazol-4-yl) -1H-benzimidazol-2-yl]A mixture of ethylamine (0.055g,0.21mmol), 6-chloro-9- (tetrahydropyran-2-yl) -9H-purine (0.070g,0.30mmol) and DIPEA (0.07mL,0.38mmol) in IPA (1.5mL) was stirred at 80 deg.C in a sealed tube for 16H. After cooling, the reaction mixture is concentrated in vacuo and the residue is purified by chromatography (SiO) ₂0-10% (2M ammonia in methanol) in DCM). The product was dissolved in methanol (4mL) and HCl/bisAlkane (4M,0.5mL,2.0mmol) and then stirred for 15 min. The resulting mixture was concentrated in vacuo and the residue was loaded ontoSCX-2 column, washing with MeOH, then 2M NH₃The product was eluted with MeOH and concentrated in vacuo to afford 419 as a white solid (0.050g, 63%). LCMS (method K) R_T2.65min[M+H]⁺378.0。

¹HNMR(DMSO-d₆,400MHz):δ12.90(１H,s),8.22-8.03(3H,m),

789-781(1H,m),7.76(1H,s),7.66-7.62(1H,m),7.09-7.05(1H,m),700-691(1H,m),5.61-5.42(1H,m),3.86(3H,s),1.57(3H,d,J=6.84Hz)

Example 4204-amino-6- [ [ (1S) -1- [ 6-fluoro-1- (2-methoxyethyl) -7- (2-pyridinyl) benzimidazol-2-yl]Ethyl radical]Amino group]Pyrimidine-5-carbonitrile 420

Reacting (S) -1- [ 6-fluoro-1- (2-methoxyethyl) -7-pyridin-2-yl-1H-benzimidazol-2-yl]A mixture of ethylamine (167mg,0.53mmol), 4-amino-6-chloropyrimidine-5-carbonitrile (86mg,0.56mmol), and DIPEA (0.28mL,1.6mmol) in IPA (1mL) was heated at 90 deg.C for 16 h. After cooling to RT, the volatile substances were removed under reduced pressure and the residue obtained was loadedSCX-2 column. The column was washed with MeOH, then 2M NH₃Washing with MeOH. The basic fractions were combined, concentrated in vacuo and the residue purified by column chromatography (Si-PPC, using 0-10%2 MNH)₃MeOH in DCM) afforded 420 as a white solid (146mg, 63%). LCMS (method K) R_T3.15min[M+H]⁺433。

¹HNMR(DMSO-d₆，400MHz)：δ8.73(1H，ddd，J＝5.0，2.0，1.0Hz)，8.03(1H，s)，

7.97(1H，ddd，J＝7.5，7.5，2.0Hz)，7.74(1H，dd，J＝9.0，5.0Hz)，7.70-7.66(2H，m)，7·51(1H，ddd，J＝7.5，5.0，1.0Hz)，7.30(2H，bs)，7.18(1H，dd，J＝10.5，9.0)，5.69(1H，dq，J＝6.5，6.5Hz)，4.14-4.07(1H，m)，3.82(1H，ddd，J＝15.0，5.0，5.0Hz)，3.07-2.99(2H，m)，2.93(1H，s)，1.59(3H，d，J＝6.5Hz)

Example 421 4-amino-6- [ [ (1S) -1- (7-bromo-1-methyl-benzimidazol-2-yl) ethyl]Amino group]Pyrimidine-5-carbonitrile 421

A mixture of (S) -1- (7-bromo-1-methyl-1H-benzimidazol-2-yl) ethylamine (1g,3.9mmol), 4-amino-6-chloropyrimidine-5-carbonitrile (0.64g,4.1mmol) and DIPEA (2.1mL,4.1mmol) in IPA (7.8mL) was heated at 90 deg.C for 16H. After cooling to RT, the reaction mixture was filtered and the solid was washed with MeOH and DCM to give 421 as a cream solid (1.05g, 72%).

LCMS (method K) R_T3.27min[M+H]⁺372 (to)⁷⁹Br)

¹HNMR(DMSO-d₆,400MHz)：

δ8.07(1H，s)，7.79(lH，d，J＝7.5Hz)，7.63(1H，d，J＝8.OHz)，7.41(lH，d，J＝4.OHz)，7.32(2H，bs)，7.11(lH，dd，J＝8.0，8.OHz)，5.70(lH，dq，J＝7.5，7.OHz)，4.0l(3H，s)，1.6O(3H，d，J=7.0Hz)

Example 4224-amino-6- [ [ (1S) -1- [7- (3-cyanophenyl) -1-methyl-benzimidazol-2-yl]Ethyl radical]Amino group]Pyrimidine-5-carbonitrile 422

Reacting 4-amino-6- [ (S) -1- (7-bromo-1-methyl-1H-benzimidazol-2-yl) ethylamino]Pyrimidine-5-carbonitrile (100mg,0.27mmol), 3-cyanophenylboronic acid (51mg,0.35mmol), Pd (PPh)₃)₄(31mg,0.03mmol) and Cs₂CO₃(175mg,0.54mmol) in dioxane (3mL) and H₂The mixture in O (1.5mL) was heated with microwave radiation at 140 ℃ for 30 min. Loading the reaction solution intoSCX-2 column. The column was washed with MeOH, then with 2M NH₃Washed with MeOH solution. The basic fractions were combined and concentrated in vacuo. The residue was purified by column chromatography (Si-PPC, using 0-10%2M NH)₃Gradient MeOH in DCM) to give 422 as a white solid (41mg, 39%). LCMS (method K) R _T3.08min[M+H]⁺395。

¹HNMR(DMSO-d₆,400MHz):δ8.03(1H,s),7.97(1H,s),7.94-7.91(1H,m)，7.82-7.80(1H，m)，7.72-7.66(3H，m)，7.32(2H，bs)，7.26(1H，dd，J=8.0，7.5Hz)，7.07(1H，dd，J＝7.5，1.OHz)，5.65(lH，dq，J＝7.0，7.OHz)，3.29(3H，s)，1.60(3H，d，J＝7.OHz)

Example 4234-amino-6- [ [ (1S) -1- [7- (4-cyanophenyl) group) -1-methyl-benzimidazol-2-yl]Ethyl radical]Amino group]Pyrimidine-5-carbonitrile 423

Reacting 4-amino-6- [ (S) -1- (7-bromo-1-methyl-1H-benzimidazol-2-yl) ethylamino]Pyrimidine-5-carbonitrile (100mg,0.27mmol), 4-cyanophenylboronic acid (51mg,0.35mmol), Pd (PPh)₃)₄(31mg,0.03mmol) and Cs₂CO₃(175mg,0.54mmol) in bisAlkane (3mL) and H₂The mixture in O (1.5mL) was heated with microwave radiation at 140 ℃ for 30 min. Loading the reaction solution intoSCX-2 column. The column was washed with MeOH, then with 2M NH₃Washed with MeOH solution. The basic fractions were combined and concentrated in vacuo. The resulting residue was dissolved in DCM and the fine precipitate was filtered off and washed with DCM. The filtrate was concentrated in vacuo and purified by column chromatography (Si-PPC, using 0-10%2M NH)₃Gradient MeOH/DCM) to give 423 as a white solid (36mg, 34%). LCMS (method K) R_T2.30min[M+H]⁺395。

¹HNMR(DMSO-d₆，40OMHz)：δ8.04(1H，s)，7.96-7.94(2H，m)，7.72-7.67(4H，m)，7.32(2H，bs)，7.27，(lH，dd，J＝8.0，7.5Hz)，7.07(1H，dd，J＝7.5，1.0Hz)，5.66(1H，dq，J＝7.0，7.OHz)，3.28(3H，s)，1.60(3H，d，J＝7.OHz)

Example 4244-amino-6- [ [ (1S) -1- (6-fluoro-1-methyl-7-phenyl-benzimidazol-2-yl) ethyl]Amino group]Pyrimidine-5-carbonitrile 424

Reacting 4-amino-6- [ (S) -1- (7-bromo-6-fluoro-1-methyl-1H-benzimidazol-2-yl) ethylamino]Pyrimidine-5-carbonitrile, (0.10g,0.26mmol), phenylboronic acid (0.041g,0.33mmol), tetrakis (triphenylphosphine) palladium (0) (0.015g,0.013mmol), and a mixture of cesium carbonate (0.17g,0.51mmol) in dioxane (3mL) and water (1.5mL) were placed in a sealed tube and degassed with nitrogen for 5min, then heated with microwave radiation at 140 ℃ for 30min A clock. Loading the resulting mixture intoSCX-2 column, washing with MeOH, then 2M NH₃The product eluted with MeOH. Then concentrated in vacuo. The residue obtained is purified by chromatography (SiO)₂0-7% (2M ammonia in methanol) in DCM), followed by purification by preparative HPLC (Phenomenex Gemini5 μ M C18, 78min gradient: 20-98% with 0.1% HCO₂Acetonitrile/water of H). The relevant fractions were concentrated to about 1/3 volumes in DCM (3X) and saturated NaHCO₃The aqueous solution was partitioned. The combined DCM extracts were dried (Na)₂SO₄) And concentrated in vacuo to give 424 as a white solid (0.058g, 58%). LCMS (method K) R_T3.55min[M+H]⁺388.0。

¹HNMR(DMSO-d₆,400MHz):δ8.03(1H,s),

7.66-7.62(2H,m),7.52-7.41(5H,m),7.30(2H,s),7.13(1H,m),5.61(1H,m),3.15(3H,s),1.57(3H，d，J＝6.72Hz)

Example 4254-amino-6- [ [ (1S) -1- [ 6-fluoro-1-methyl-7- (3-pyridinyl) benzimidazol-2-yl]Ethyl radical]Amino group]Pyrimidine-5-carbonitrile 425

Reacting 4-amino-6- [ (S) -1- (7-bromo-6-fluoro-1-methyl-1H-benzimidazol-2-yl) ethylamino]-pyrimidine-5-carbonitrile, (0.10g,0.26mmol), 3-pyridylboronic acid (0.041g,0.33mmol), tetrakis (triphenylphosphine) palladium (0) (0.015g,0.013mmol) and cesium carbonate (0.17g,0.51mmol) in bis (bromosuccinimide) solutionA mixture of alkane (3mL) and water (1.5mL) was placed in a sealed tube and degassed with nitrogen for 5min, then heated with microwave radiation at 140 ℃ for 30 min. Loading the resulting mixture intoSCX-2 column, then MeOH, 2M NH ₃The product was eluted with MeOH and concentrated in vacuo. Coloring the obtained residue with colorPurification by chromatography (SiO)₂0-10% (2M ammonia in methanol) in DCM), followed by preparative HPLC purification (Phenomenex Gemini5 μ M C18, 78min gradient elution: 20-98 with 0.1% HCO₂H acetonitrile/water) to yield 425 as a white solid (0.066g, 66%). LCMS (method K) R_T2.50min[M+H]⁺389.1。

¹HNMR(DMSO-d₆,400MHz):δ8.72-8.64(2H,m),8.22-8.03(1H,m),7.97-7.90(1H,m),7.75-7.65(2H,m),7.57-7.53(1H,m),7.30(2H,s),7.21-7.17(1H，m)，5.63(1H，m)，3.19-3.17(3H，m)，1.58(3H，d，J＝6.72Hz)

Example 4264-amino-6- [ [ (1S) -1- [ 6-fluoro-7- (1H-indazol-4-yl) -1-methyl-benzimidazol-2-yl]Ethyl radical]Amino group]Pyrimidine-5-carbonitrile 426

Reacting 4-amino-6- [ (S) -1- (7-bromo-6-fluoro-1-methyl-1H-benzimidazol-2-yl) ethylamino]Pyrimidine-5-carbonitrile, (0.10g,0.26mmol), 1H-indazole-4-boronic acid (0.054g,0.33mmol), tetrakis (triphenylphosphine) palladium (0) (0.015g,0.013mmol), and cesium carbonate (0.17g,0.51mmol) in dioxaneA mixture of alkane (3mL) and water (1.5mL) was placed in a sealed tube and degassed with nitrogen for 5 minutes, then heated with microwave radiation at 140 ℃ for 30 min. 1H-indazole-4-boronic acid (0.054g,0.33mmol) and tetrakis (triphenylphosphine) palladium (0) (0.015g,0.01mmol) were added and the resulting mixture was heated with microwave radiation at 140 ℃ for 30 min. Loading the resulting mixture intoSCX-2 column, then MeOH, 2M NH₃The product was eluted with MeOH and concentrated in vacuo. The residue was purified by preparative HPLC (Phenomenex Gemini 5. mu. m C18, 78min gradient: 20-98% with 0.1% HCO ₂H acetonitrile/water) to give 426 as a white solid (0.044g, 40%). LCMS (method K) R_T2.82,2.99min[M+H]⁺428.1。

¹HNMR(DMSO-d₆,400MHz):δ13.30(1H,s),8.23-7.98(1H,m),7.77-7.60(4H,m),7.51-7.48(1H,m),7.367.24(2H,m),7.23-7.08(2H,m),5.59-5.54(1H,m)_i3.00(3H,d,J=8.05Hz)，1.57(3H，dd，J＝6.69，1.65Hz).

Due to the presence of rotamers/tautomers, the signal is cleaved.

Example 4274-amino-6- [ [ (1S) -1- [ 6-fluoro-1-methyl-7- (1-methylpyrazol-4-yl) benzimidazol-2-yl]Ethyl radical]Amino group]Pyrimidine-5-carbonitrile 427

Reacting 4-amino-6- [ (S) -1- (7-bromo-6-fluoro-1-methyl-1H-benzimidazol-2-yl) ethylamino]-pyrimidine-5-carbonitrile (0.10g,0.26mmol), 1-methyl-4- (4,4,5, 5-tetramethyl- [1,3,2 ]]Dioxaborolan-2-yl) -1H-pyrazole (0.069g,0.33mmol), tetrakis (triphenylphosphine) palladium (0) (0.015g,0.01mmol) and cesium carbonate (0.17g,0.51mmol) in dioxaneA mixture of alkane (3mL) and water (1.5mL) was placed in a sealed tube, degassed with nitrogen for 5 minutes, and then heated with microwave radiation at 140 ℃ for 30 minutes. Loading the resulting mixture intoSCX-2 column, then MeOH, 2M NH₃The product was eluted with MeOH and concentrated in vacuo. The residue obtained is purified by chromatography (SiO)₂0-10% (2M ammonia in methanol) in DCM), followed by purification by preparative HPLC (Phenomenex Gemini5 μ M C18, 78min gradient: 20-98% with 0.1% HCO₂H acetonitrile/water) to yield 427 as a white solid (0.081g, 81%). LCMS (method K) R _T2.50min[M+H]⁺392.1。

¹HNMR(DMSO-d₆,400MHz):δ8.24(1H,s),7.92(1H,s),7.67-7.59(2H,m)，7.3I(2H，s)，7.12-7.08(1H，m)，5.64(1H，m)，3.93(3H，s)，3.17(3H，s)，1.58(3H，d，J=6.74H2)

Example 4284-amino group-6- [ [ (1S) -1- [ 6-fluoro-1-methyl-7- (1H-pyrazol-4-yl) benzimidazol-2-yl]Ethyl radical]Amino group]Pyrimidine-5-carbonitrile 428

Reacting 4-amino-6- [ (S) -1- (7-bromo-6-fluoro-1-methyl-1H-benzimidazol-2-yl) ethylamino]-pyrimidine-5-carbonitrile (0.10g,0.26mmol), 4- (4,4,5, 5-tetramethyl- [1,3, 2)]Dioxaborolan-2-yl) -1H-pyrazole (0.065g,0.33mmol), tetrakis (triphenylphosphine) palladium (0) (0.015g,0.01mmol) and cesium carbonate (0.17g,0.51mmol) in dioxaneA mixture of alkane (3mL) and water (1.5mL) was placed in a sealed tube and degassed with nitrogen for 5 minutes, then heated with microwave radiation at 140 ℃ for 40 minutes. Adding 4- (4,4,5, 5-tetramethyl- [1,3,2 ]]Dioxaborolan-2-yl) -1H-pyrazole (0.10g,0.52mmol) and tetrakis (triphenylphosphine) palladium (0) (0.015g,0.01mmol), and the resulting mixture was heated with microwave radiation at 140 ℃ for 80 minutes. Loading the resulting mixture intoSCX-2 column, then MeOH, 2M NH₃The product was eluted with MeOH and then concentrated in vacuo. The residue is purified by chromatography (SiO)₂0-10% (2M ammonia in methanol) in DCM), followed by purification by preparative HPLC (Phenomenex Gemini5 μ M C18, 78min gradient: 20-98% with 0.1% HCO₂H acetonitrile/water) to give 428 as a white solid (0.019g, 20%). LCMS (method K) R _T2.23min[M+H]⁺378.0。

¹HNMR(DMSO-d₆,400MHz):δ13.10(1H,s),8.28(1H,s),8.04(1H,s),7.83(1H,s),7.66-7.64(1H,m),7.60(1H,dd,J=8.74,4.77Hz),7.31(2H,s),7.12-7.06(1H,m),5.66-5.61(1H,m),3.66(3H,s),1.57(3H,d,J=6.73Hz)

Example 4294-amino-6- [ [ (1S) -1- [ 6-fluoro-1-methyl-7- (4-pyridinyl) benzimidazol-2-yl]Ethyl radical]Amino group]Pyrimidine-5-carbonitrile 429

4-amino-6- [ (S) -1- (7-bromo-6-fluoro-1-methyl-1H-benzimidazole-2-Yl) ethylamino]Pyrimidine-5-carbonitrile (0.10g,0.26mmol), 4-pyridylboronic acid (0.041g,0.33mmol), tetrakis (triphenylphosphine) palladium (0) (0.015g,0.01mmol) and cesium carbonate (0.17g,0.51mmol) in dioxaneA mixture of alkane (3mL) and water (1.5mL) was placed in a sealed tube and degassed with nitrogen for 5 minutes, then heated with microwave radiation at 140 ℃ for 40 minutes. Loading the resulting mixture intoSCX-2 column, then MeOH, 2M NH₃The product was eluted with MeOH and then concentrated in vacuo. The residue is purified by chromatography over (SiO)₂Eluted with 0-10% (2M ammonia in methanol) in DCM) and then purified by preparative HPLC (Phenomenex Gemini5 μ M C18, 78min gradient: 20-98% with 0.1% HCO₂Acetonitrile/water of H). The relevant fractions were concentrated to about 1/3 volumes, then in DCM (3X) and saturated NaHCO₃The aqueous solution was partitioned. The combined DCM extracts were dried (Na)₂SO₄) And concentrated in vacuo to give 429 as a white solid (0.066g, 66%). LCMS (method K) R_T2.32min[M+H]⁺389.1。

¹HNMR(DMSO-d₆,400MHz):δ8.72

(2H,d,J=5.05Hz),8.03(1H,s),7.71-7.70(2H,m),7.53(2H,d,J=13.97Hz),7.31(2H,s),7.18(1H,dd,J=10.45,8.79Hz),5.64(1H,m),3.21(3H,s),1.58(3H,d,J=6.74Hz)

Example 430N- [ (1S) -1- (7-bromo-6-fluoro-1-methyl-benzimidazol-2-yl) ethyl ]-9H-purin-6-amine 430

A mixture of (S) -1- (7-bromo-6-fluoro-1-methyl-1H-benzimidazol-2-yl) ethylamine (0.50g,1.84mmol), 6-chloro-9- (tetrahydropyran-2-yl) -9H-purine (0.61g,2.57mmol), and DIPEA (0.60mL,3.31mmol) in IPA (7mL) was stirred at 85 deg.C in a sealed tube for 21H. After cooling, the mixture was partitioned between DCM (3X) and saturated NaHCO₃Between aqueous solutionsAnd (6) distributing. The combined DCM extracts were dried (Na)₂SO₄) Concentrated in vacuo and the residue purified by chromatography (SiO)₂0-5% (2M ammonia in methanol) in DCM). The product was dissolved in methanol (15mL) and HCl/bisAlkane (4M,2.0mL,8.0mmol) and then stirred for 10 min. The reaction mixture was concentrated in vacuo and the residue was loaded ontoSCX-2 column, wash it with MeOH, 2M NH₃The product was eluted with MeOH and then concentrated in vacuo to give 430 as a white solid (0.45g, 63%). LCMS (method K) R_T3.12min[M+H]⁺390.0。

¹HNMR(DMSO-d₆，40OMHz)：δ12.99(lH，s)，8.27-

7.97(3H,m),7.62(1H,dd,J=8.72,4.66Hz),7.23-7.16(1H,m),5.76(1H,m),4.09(3H,s),1.67(3H，d，J＝6.76Hz).

Due to the presence of tautomers, the signal is cleaved.

Example 431N- [ (1S) -1- (6-fluoro-1-methyl-7-phenyl-benzimidazol-2-yl) ethyl]-9H-purin-6-amine 431

Reacting [ (S) -1- (7-bromo-6-fluoro-1-methyl-1H-benzimidazol-2-yl) ethyl]A mixture of (9H-purin-6-yl) amine (0.10g,0.26mmol), phenylboronic acid (0.041g,0.33mmol), tetrakis (triphenylphosphine) palladium (0) (0.015g,0.01mmol), and cesium carbonate (0.17g,0.51mmol) in dioxane (3mL) and water (1.5mL) was placed in a sealed tube, degassed with nitrogen for 5 minutes, and then heated with microwave radiation at 140 ℃ for 45 minutes. Loading the resulting mixture into SCX-2 column, then MeOH, 2M NH₃The product was eluted with MeOH and concentrated in vacuo. The residue is purified by chromatography (SiO)₂0-10% (2M ammonia in methanol) in DCM), followed by purification by preparative HPLC (Phenomenex Gemini5 μ M C18, 78min gradient: 20-98% with 0.1% HCO₂Acetonitrile/water of H). The relevant fractions were concentrated to about 1/3 volumes in DCM (3X) and saturated NaHCO₃The aqueous solution was partitioned. The combined DCM extracts were dried (Na)₂SO₄) And concentrated in vacuo to afford 431 as a white solid (0.075g, 76%). LCMS (method K) R_T3.21min[M+H]⁺388.0。

¹HNMR(DMSO-d₆,400MHz):δ12.98(1H,s)，

826-8.11(2H,m)，7.93-7.86(1H,m),7.64(1H,dd,J=8.82，4.74Hz),7.54-7.39(5H,m),7.157.08(1H,m)，5.82-5.71(1H,m),321(3H,s),1.65(3H,d,J=6.74Hz)

Due to the presence of tautomers, the signal is cleaved.

Example 4324-amino-6- [ [ (1S) -1- [7- (3, 6-dihydro-2H-pyran-4-yl) -6-fluoro-1-methyl-benzimidazol-2-yl]Ethyl radical]Amino group]Pyrimidine-5-carbonitrile 432

Reacting 4-amino-6- [ (S) -1- (7-bromo-6-fluoro-1-methyl-1H-benzimidazol-2-yl) ethylamino]Pyrimidine-5-carbonitrile (122mg,0.31mmol), 4- (4,4,5, 5-tetramethyl- [1,3, 2)]Dioxaborolan-2-yl) -3, 6-dihydro-2H-pyran (85mg,0.41mmol), tetrakis (triphenylphosphine) palladium (36mg,10mol%) and cesium carbonate (204mg,0.63mol) in dioxaneAlkane (3mL) and H₂The mixture in O (1.5mL) was purged with argon and then heated with microwave radiation at 140 ℃ for 30 min. After cooling to RT, the reaction mixture was diluted with MeOH and loaded SCX-2 column. The column was washed with MeOH, then 2M NH₃Washing with MeOH. The basic fractions were combined, concentrated in vacuo, and the resulting residue was purified by column chromatography (Si-PCC, gradient elution with 0-100% EtOAc in DCM)Then purified by reverse phase HPLC (Phenomenex Gemini5 μm C18 with 0.1% NH at 5-75%₄Acetonitrile/water gradient of OH) to give 432 as a white solid (19mg, 15%). LCMS (method K) R_T2.79min[M+H]⁺394.16。

¹HNMR(DMSO-d₆,400MHz):δ8.07(1H,s),7.69(1H,m),

7.55(1H,dd,J=8.76,4.82Hz),7.30(2H,brs),7.04(1H,dd,J=10.42,8.75Hz),5.87(1Hbrs),5.70(1H,m),4.24(2H,s),3.86(2H,m),3.73(3H,s),2.45-2.23(2H,m),1.58(3H,d,J=6.72Hz)

Example 433N- [ (1S) -1- [ 6-fluoro-1-methyl-7- (4-pyridinyl) benzimidazol-2-yl]Ethyl radical]-9H-purin-6-amine 433

Reacting [ (S) -1- (7-bromo-6-fluoro-1-methyl-1H-benzimidazol-2-yl) ethyl]- (9H-purin-6-yl) amine (0.10g,0.26mmol), 4-pyridylboronic acid (0.041g,0.33mmol), tetrakis (triphenylphosphine) palladium (0) (0.015g,0.01mmol) and cesium carbonate (0.17g,0.51mmol) in dioxaneA mixture of alkane (3mL) and water (1.5mL) was placed in a sealed tube and degassed with nitrogen for 5 minutes, then heated with microwave radiation at 140 ℃ for 45 minutes. Loading the resulting mixture intoSCX-2 column, then MeOH, 2M NH₃The product was eluted with MeOH and concentrated in vacuo. The residue is purified by chromatography (SiO)₂0-10% (2M ammonia in methanol) in DCM), followed by purification by preparative HPLC (Phenomenex Gemini5 μ M C18, 78min gradient: 20-98% with 0.1% HCO ₂Acetonitrile/water of H) to yield 433 as a white solid (0.019g, 20%). LCMS (method K) R_T2.10min[M+H]⁺389.1。

¹HNMR(DMSO-d₆,400MHz):δ12.70(1H,s),8.70(2H,s),8.25-8.13(2H,m),7.95(1H,d),771(1H,dd,J=8.80,4.80Hz),7.53(2H,d,J=17.59Hz),7.17(1H,dd,J=10.45,8.79Hz),5.85-5.73(1H,m),3.30(3H,s),1.66(3H,d,J=6.75Hz).

Due to the presence of tautomers, the signal is cleaved.

Example 4344-amino-6- [1- (6-fluoro-3, 4-dihydro-5-oxa-1, 2 a-diazacenaphthen-2-yl) ethylamino]Pyrimidine-5-carbonitrile 434

A mixture of 1- (6-fluoro-3, 4-dihydro-5-oxa-1, 2 a-diazacenaphthen-2-yl) ethylamine (108mg,0.49mmol), 4-amino-6-chloro-5-cyanopyrimidine (75mg,0.49mmol) and DIPEA (171. mu.L, 0.98mmol) in IPA (1mL) was heated at 100 deg.C for 18 h. After cooling to RT, the volatiles were removed in vacuo and the resulting residue was taken up in MeOH and acidified with TFA, at which time the solution became homogeneous. The reaction mixture was passed through 2gSCX-2 column with 2MNH₃MeOH elution. The basic fraction was concentrated in vacuo and the resulting brown residue was purified by column chromatography (Si-PPC, using 0-8%2M NH)₃Gradient elution in DCM/MeOH) gave 434 as a pale yellow solid (125mg, 75%). LCMS (method K) R_T2.49min[M+H]⁺340.1。

¹HNMR(DMSO，400MHz)：δ8.02(1H，s),7.74(1H,d,J=7.4Hz),7.27(2H,brs),7.09(1H,dd,J=8.7,3.3Hz),6.95(1H,dd,J=12.3,8.8Hz),5.60(1H,dg,J=7.4,6.8Hz),4.50-4.41(2H,m),4.36-4.27(2H,m),1.58(3H,d，J＝6.8Hz)

Example 435[1- (6-fluoro-3, 4-dihydro-5-oxa-1, 2 a-diazacenaphthen-2-yl) ethyl]- (9H-purin-6-yl) amine 435

Hydrogen chloride, HCl (384. mu.L of 4M bis)Alkane solution) was added to [1- (6-fluoro-3, 4-dihydro-5-oxa-1, 2 a-diazacenaphthen-2-yl) ethyl ] ethyl ]- [9- (tetrahydropyran-2-yl) -9H-purin-6-yl]To a solution of amine (130mg,0.31mmol) in MeOH (1mL) was addedIt should be stirred at RT for 20 min. The crude reaction mixture was passed through 2gSCX-2 column with 2M NH₃MeOH elution. The basic fraction was concentrated in vacuo to give 435(92mg,87%) as a pale yellow solid. LCMS (method K) R_T2.28min[M+H]⁺340.0。

¹HNMR(CD₃OD，

40OMHz)：δ8.22(lH，s)，8.06(1H，s)，7.06(1H，dd，J＝8.9，3.lHz)，6.91(lH，dd，J＝12.0，8.9Hz)，5.78(1H，brs)，4.63-4.38(4H，m)，1.79(3H，d，J＝7.0Hz)

Example 4364-amino-6- [ (S) -1- (5-fluoro-8, 9-dihydro-7H-6-oxa-2, 9 a-diazabenzo [ c, d)]-1-yl) ethylamino]Pyrimidine-5-carbonitrile 436

Reacting (S) -1- (5-fluoro-8, 9-dihydro-7H-6-oxa-2, 9 a-diazabenzo [ c, d]A mixture of-1-yl) ethylamine (51mg,0.22mmol), 4-amino-6-chloro-5-cyanopyrimidine (34mg,0.22mmol) and DIPEA (77. mu.L, 0.98mmol) in IPA (0.5mL) was heated at 100 deg.C for 24 h. After cooling to RT, the volatiles were removed in vacuo and the resulting residue was taken up in MeOH and acidified with TFA, at which time the solution became homogeneous. The reaction mixture was passed through 2gSCX-2 column with 2M NH₃MeOH elution. The basic fraction was concentrated in vacuo and the resulting brown residue was purified by column chromatography (Si-PPC, using 0-8%2M NH)₃Gradient MeOH in DCM) to give 436 as a white solid (58mg, 75%). LCMS (method K) R_T2.63min[M+H]⁺354.0

Example 437[ (S) -1- (5-fluoro-8, 9-dihydro-7H-6-oxa-2, 9 a-diazabenzo [ c, d) ]-1-yl) ethyl]- (9H-purin-6-yl) amine 437

HCl (250. mu.L of 4M bis)Alkane solution) was added to [ (S) -1- (5-fluoro-8, 9-dihydro-7H-6-oxa-2, 9 a-diazabenzo [ c, d)]-1-yl) ethyl]- [9- (tetrahydropyran-2-yl) -9H-purin-6-yl]Amine (86mg,0.20mmol) in MeOH (1mL) and the reaction stirred at RT for 10 min. The crude reaction mixture was passed through 2gSCX-2 column with 2MNH₃MeOH elution. The basic fraction was concentrated in vacuo to give 437(65mg,92%) as a white solid. LCMS (method K) R_T2.40min[M+H]⁺354.0。

¹HNMR(DMSO,400MHz):δ12.93(1H,s),8.19(1H,brs),8.08(1H,s),7.92-7.7.80(1H,m)，7.11(1H，dd，J＝8.6，3.9Hz)，7.01(1H，dd，J＝11.7，8.6Hz)，5.79(1H，brs)，4.42-4.26(4H,m),2.34-2.27(2H,m),1.63(3H,d,J=6.6Hz)

Example 4384-amino-6- [ (S) -1- ((R) -6-fluoro-3-methyl-3, 4-dihydro-5-oxa-1, 2 a-diazacenaphthen-2-yl) ethylamino]Pyrimidine-5-carbonitrile 438

A mixture of (S) -1- ((R) -6-fluoro-3-methyl-3, 4-dihydro-5-oxa-1, 2 a-diazacenaphthen-2-yl) ethylamine (62mg,0.26mmol), 4-amino-6-chloro-5-cyanopyrimidine (41mg,0.26mmol) and DIPEA (91. mu.L, 0.52mmol) in IPA (1mL) was heated at 100 deg.C for 18 h. After cooling to RT, the volatiles were removed in vacuo and the resulting brown residue was purified by column chromatography (Si-PP)C, with 0-8%2M NH₃Gradient MeOH in DCM) to give 438 as a white solid (77mg, 84%). LCMS (method K) R_T2.74min[M+H]⁺354.1。

¹HNMR(DMSO，40OMHz)：δ

7.98(1H，s)，7.07(1H，dd，J＝8.6，3.OHz)，6.93(1H，dd，J＝12.1，8.6Hz)，5.77(1H，q，J＝7.0Hz)，4.84-4.81(1H，m)，4.46(1H，dd，J＝l1.4，1.3Hz)，4.22(lH，dd，J＝l1.4，2.2Hz)，1.67(3H，d，J＝7.OHz)，1.47(3H，d，J＝6.6Hz)

Example 439[ (S) -1- ((R) -6-fluoro-3-methyl-3, 4-dihydro-5-oxa-1, 2 a-diazacenaphthen-2-yl) ethyl ](9H-purin-6-yl) amine 439

HCl (260. mu.L of two of 4M)Alkane solution) was added to [ (S) -1- ((R) -6-fluoro-3-methyl-3, 4-dihydro-5-oxa-1, 2 a-diazacenaphthen-2-yl) ethyl][9- (tetrahydropyran-2-yl) -9H-purin-6-yl]Amine (93mg,0.21mmol) in MeOH (1mL) and the reaction stirred at RT for 30 min. The crude reaction mixture was passed through 2gSCX-2 column with 2M NH₃MeOH elution. The basic fraction was concentrated in vacuo to give 439(71mg,96%) as a white solid. LCMS (method K) R_T2.50min[M+H]⁺354.0。

¹HNMR(CD₃OD，400

MHz):δ8.21(1H，s)，8.07(1H，s)，7.07(1H，dd，J＝8.8，3.1Hz)，6.93(1H，dd，J＝11.9，8.8Hz)，5.89(1H，brs)，4.88(1H，qdd，J＝6.6，2.3，1.6Hz)，4.45(1H，dd，J＝11.8，1.6Hz)，4.22(lH，dd，J＝l1.8，2.3Hz)，1.76(3H，d，J＝7.OHz)，1.44(3H，d，J＝6.6Hz)

Examples4404-amino-6- [ (S) -1- ((S) -6-fluoro-3-methyl-3, 4-dihydro-5-oxa-1, 2 a-diazacenaphthen-2-yl) ethylamino]Pyrimidine-5-carbonitrile 440

A mixture of (S) -1- ((S) -6-fluoro-3-methyl-3, 4-dihydro-5-oxa-1, 2 a-diazacenaphthen-2-yl) ethylamine (86mg,0.36mmol), 4-amino-6-chloro-5-cyanopyrimidine (56mg,0.36mmol) and DIPEA (125. mu.L, 0.92mmol) in IPA (1mL) was heated at 100 deg.C for 18 h. After cooling to RT, the volatiles were removed in vacuo and the resulting brown residue was purified by column chromatography (Si-PPC, using 0-5%2M NH)₃Gradient MeOH in DCM) to give 440 as a white solid (100mg, 79%). LCMS (method K) R_T2.86min[M+H]⁺354.1。

¹HNMR(DMSO，40OMHz）：δ

801(1H,s),7.08(1H,dd,J=8.8,3.1Hz),6.94(1H,dd,J=12.3,8.8Hz),5.67(1H,q,J=7.OHz)，5.04(1H，qdd，J＝6.6，2.6，1.7Hz)，4.47(1H，dd，J＝l1.9，1.7Hz)，4.20(lH，dd，J＝11.9，2.6Hz)，1.71(3H，d，J＝7.OHz)，1.45(3H，d，J＝6.6Hz)

Example 441[ (S) -1- ((S) -6-fluoro-3-methyl-3, 4-dihydro-5-oxa-1, 2 a-diazacenaphthen-2-yl) ethyl ](9H-purin-6-yl) amine 441

HCl (340. mu.L of 4M bis)Alkane solution) was added to [ (S) -1- ((S) -6-fluoro-3-methyl-3, 4-dihydro-5-oxa-1, 2 a-diazacenaphthen-2-yl) ethyl][9- (tetrahydropyran-2-yl) -9H-purin-6-yl]Amine (117mg,0.27mmol) in MeOH (1mL) and the reaction stirred at RT for 30 min. The crude reaction mixture was passed through 2gSCX-2 column with 2MNH₃MeOH elution. The basic fraction was concentrated in vacuo to give 441(88mg,92%) as an off-white solid. LCMS (method K) R_T2.61min[M+H]⁺354.0。

¹HNMR(CD₃0D,400MHz):δ8.23(1H,s),8.05(1H,s),7.08(1H,dd,J=8.8,3.1Hz)，6.93(1H，dd，J＝12.1，8.8Hz)，5.77(1H，brs)，5.19(lH，qdd，J＝6.7，2.6，1.8Hz)，4.48(lH，dd，J＝l1.5，1.8Hz)，4.20(lH，dd，J＝11.5，2.6Hz)，1.80(3H，d，J＝7.OHz)，1.47(3H，d，J＝6.7Hz)

Example 4424-amino-6- [ (S) -1- (1-cyclopropyl-6-fluoro-7-pyridin-2-yl-1H-benzimidazol-2-yl) ethylamino]-pyrimidine-5-carbonitrile 442

Reacting 4-amino-6- [ (S) -1- (7-bromo-1-cyclopropyl-6-fluoro-1H-benzimidazol-2-yl) ethylamino]Pyrimidine-5-carbonitrile (70mg,0.17mmol), 2- (tributylstannyl) pyridine (0.06mL,0.19mmol), tetrakis (triphenylphosphine) palladium (19mg,10mol%) and copper (I) thiophene-2-carboxylate (6mg,20mol%) in bisThe mixture in the alkane (1mL) was purged with argon and then heated in a microwave reactor (Biotage) at 150 ℃ for 20 min. After cooling to RT, the reaction mixture was diluted with MeOH and loaded intoSCX-2 column. The column was washed with MeOH, then 2M NH₃Washing with MeOH. The basic fractions were combined, concentrated in vacuo and the resulting residue was purified by column chromatography (Si-PCC gradient eluted with 0-10% MeOH in EtOAc) to give 442 as a pale yellow solid (17mg, 24%). LCMS (method K) R _T3.05min[M+H]⁺415.07。

¹HNMR(DMSO-d₆,400MHz):δ8.72(1H,ddd,J=4.87，1.81，0.94Hz)，8.02(1H，s)，7.94(1H，td，J＝7.71，1.84Hz)，7.73-7.66(3H，m)，7.45(1H,ddd,J=7.59,4.87,1.16Hz),7.30(2H,s),7.16(1H,dd,J=10.65,8.75Hz),5.84-5.75(1H,m),3.02-2.95(1H,m),1.61(3H,d,J=6.76Hz),1.25-1.20(1H,m),0.79-0.69(1H,m),0.52-0.43(1H,m),0.41-0.28(1H,m)

Example 443(6-fluoro-1-phenyl-1H-benzimidazol-2-ylmethyl) - (9H-purin-6-yl) amine 443

(6-fluoro-1-phenyl-1H-benzimidazol-2-ylmethyl) [9- (tetrahydropyran-2-yl) -9H-purin-6-yl ] in MeOH (2mL)]Di-reaction of amine (0.125g,0.28mmol) with 4M HClAlkane solution (0.35 mL). After 15min at 20 ℃ the reaction was poured onto a 10g SCX column eluting first with methanol and then with 1:1MeOH/2M NH₃The isopropanol solution of (3) was eluted. The product containing fractions were evaporated to give a white solid. It was triturated with ether and dried to give 443 as a white solid (86mg, 85%). LCMS (method C) R_T3.16min[M+H]⁺360.02。

¹HNMRδ

(ppm)(DMSOd₆):12.9(1H,s)，8.11(2H，s),7.92(1H,s),7.66-7.60(6H,m),7.09(1H,td,J=9.31，2.45Hz)，6.93(1H，dd，J＝8.96，2.5OHz)，4.8(2H，bs)

Example 901PI3K isoform inhibition assay (p110alpha, beta, gamma, delta: alpha, beta, gamma, delta)

PI3K enzyme activity was measured by measuring the amount of phosphatidylinositol 3,4, 5-phosphate (PIP3) formed as a product from the substrate 4,5 phosphatidylinositol 4, 5-phosphate (PIP2) by fluorescence polarization displacement assay (fluorescence polarization displacement spectrometry). Measuring fluorescence PIP₃Reduction of fluorescence polarization of the probe, since its product catalyzed by PI 3K-is by PIP₃-displacement in the binding protein GRP-1 assay. In the presence of 10mM Tris (pH7.5), 50mM NaCl, 4mM MgCl₂5% Glycerol, 25. mu.M ATP, 10. mu.M PIP ₂(Echelon Biosciences), 0.05%3- [ (3-cholamido (cholamido) propyl) dimethylammonium]The assay was performed in 384-well black proximates in the presence of-1-propanesulfonic acid, 1mM dithiothreitol, and 2% DMSO. By adding 40ng/mL p110 α/p85 α, 300ng/mL p110 β/p85 α, 40ng/mL p110 γ or 40ng/mLp110 δ/p85 α (U/mL p110 β/p85 α) to the wellspstate Group, Millipore; Dundee, UK) and 10. mu.M PIP₂(Echelon Biosciences) to initiate the kinase reaction. At the time point (typically 30 minutes) that produced a change in fluorescence polarization fixation consistent with the initial rate conditions, by adding 12.5mM EDTA, 100nM GRP-1 detector and 5nM tetramethyl rhodamine-labeled PIP₃(TAMRA-PIP₃Echelon Biosciences) to stop the reaction. After incubation for 60 minutes at room temperature to equilibrate the labeled and unlabeled PIP3 binding, the parallel and perpendicular components of the fluorescence emission of each sample were measured at an excitation wavelength of 530nm and an emission wavelength of 590nm using an Envision fluorescence plate reader (PerkinElmer Life and nucleic acids; Wellesley, MA) with rhodamine filters. The assay can detect PIP at 0.1-2.0. mu.M₃And (3) obtaining the product. IC was obtained by fitting dose-dependent inhibition data to a 4-parameter equation using Assay Explorer software (MDL, San Ramon, Calif.) ₅₀The value is obtained.

Alternatively, inhibition of PI3K was determined in a radioactive assay with purified recombinant enzyme and ATP at a concentration of 1 uM. Serial dilutions of compounds of formula I were performed in 100% DMSO. The kinase reaction was incubated at room temperature for 1h and stopped by adding PBS. IC was then determined using sigmoidal dose-response curve fitting (variable slope)₅₀The value is obtained.

The same approach can be used to build IC for p110 α (alpha) PI3K binding₅₀The value is obtained.

Recombinant PI3K p110 isoforms α, β and δ can be prepared and purified from an overexpressed recombinant PI3K heterodimeric complex consisting of a p110 catalytic subunit and a p85 regulatory subunit according TO US2008/0275067 using BAC-TO-BAC. Four class I PI 3-kinases were cloned into baculovirus vectors as follows:

p110 δ: FLAG of human p110. delta. was purified by standard recombinant DNA techniques^TMSubcloning of the version of marker (EastmanKodak Co., US4703004; US4782137; US4851341) (Chantry et al, J.biol.chem. (1997)272:19236-41) into the insect cell expression vector pFastbacHTb (Life)Technologies, Gaithersburg, Md.) in the BamH1-Xba1 site, thereby allowing the clone to be located in the His-tagged frame with the vector.

p110 α: similar to the method described above for p110 δ, FLAG for p110 α is used^TMThe tagged version (Volinia et al (1994) Genomics,24(3):427-77) was subcloned into the BamH1-HindIII site of pFastbachtb (Life technologies) so that the clone was in frame with the His tag of the vector.

p 110. beta.: human MARATHON primers according to the manufacturer's protocol^TMThe p110 β (see Hu et al (1993) mol. cell. biol.,13:7677-88) clone was amplified from the Ready spleen cDNA library (Clontech, Palo Alto Calif.).

P110 delta binding IC for selected compounds in Table 1₅₀Values and delta/alpha selectivities include:

example 902Collagen-induced arthritis efficacy test

Mice were tested for the efficacy of the compound of formula I PI3K delta inhibitors to inhibit the induction and/or progression of collagen-induced arthritis. DBA1/J male mice (Jackson Labs;5-6 weeks old) were acclimatized for one week, then injected intradermally into the caudal root with 0.1mL of bovine type II collagen (100mg) emulsion and an equal volume of complete Freund's adjuvant (200mg of Mycobacterium tuberculosis). Three weeks later, the mice were additionally injected with 0.1mL of bovine type II collagen (100mg) emulsion and an equal volume of incomplete Freund's adjuvant at the tail root. Dosing generally begins as soon as the animal shows signs of arthritis or a clinical score of 1-2.

Arthritis was assessed 2-3 times per week for each paw of all mice using a visual scoring system. At the end of the experiment, clinical scores were obtained to assess the edema intensity of the four paws. Each paw was assigned a score of 0 to 4. When no signs of inflammation (swelling and redness) were observed in any of the facet joints (endophalangeal, metacarpophalangeal, metatarsophalangeal) or the greater joints (wrist/carpal, ankle/tarsal), the animals scored 0. Animals scored 1 when very mild to mild inflammation (swelling and/or redness of the paw or one of the toes) was observed, 2 for moderate edema (swelling of two or more joints), 3 for severe edema (severe swelling of the paw with more than two joints affected) and 4 when very severe edema (severe arthritis of all paws and toes) was present. The arthritis index of each mouse was evaluated by adding up the four scores of each paw (maximum score of 16). Plasma and serum samples were taken 1 hour post-dose (orbital blood) and 24 hours post-dose (cardiac puncture). The samples were stored at-20 ℃ until analysis. At the end, the hindpaw was cut at the distal tibia next to the tarsal joint. The left and right hind paws were each placed in a histological cassette and fixed in 10% formalin. The jaws are sent to the histology department door for further operation.

Materials: bovine type II collagen, immune grade, 2mg/ml (5 ml/vial) in 0.05M acetic acid (solution), stored at-20 ℃ from Chondrex, LLC, Seattle, WA. Complete adjuvant H37Ra, 6X 10 ml/box, containing 1mg/ml M.tuberculosis. For laboratory use in animal immunization studies, stored at +4 ℃ and obtained from Difco Laboratories, Detroit, Michigan48232-7058 USA. Incomplete adjuvant H37Ra, 6X 10 ml/box for laboratory use in animal immunization studies, stored at +4 ℃ from Difco Laboratories.

Example 903CD69 Whole blood assay

Human blood was obtained from healthy volunteers with the following limitations: it is not taken after 1 week, and does not smoke. Blood (approximately 20ml to test 8 compounds) was collected by venipuncture into vacutainers (Vacutainer tube) with sodium heparin.

Cynomolgus monkey blood was obtained politely from LAT group of monkeys that had not been previously dosed with chemicals or after the elution period of chemical dosing. Additional cynomolgus monkey blood may be collected during pharmacokinetic or toxicology studies. Blood (25-30 ml for the first monkey used in the experiment, or 3-4ml from monkeys in studies requiring repeated blood draws) was collected by venipuncture into evacuated blood collection tubes with heparin sodium.

For the nine-point dose-response curve, a 1000 or 2000 μ M solution of the compound of formula I in PBS (20X) was diluted by a three-fold serial dilution in 10% DMSO in PBS. Aliquots of 5.5. mu.l of each compound were added in duplicate to 2ml 96-well plates; control and non-irritant wells were prepared by adding 5.5. mu.l of 10% DMSO in PBS. Human whole blood-HWB (100. mu.l) was added to each well. After mixing, the plates were incubated at 37 ℃ with 5% CO₂Incubate for 30 minutes at 100% humidity. Goat F (ab') 2 anti-human IgM (10. mu.l of a 500. mu.g/ml solution to a final concentration of 50. mu.g/ml) was added to each well (except for the non-irritant wells) with mixing and the plates were incubated for a further 20 hours. At the end of the 20 hour incubation, the sample was incubated with fluorescently labeled antibody at 37 ℃ with 5% CO₂Incubate for 30 minutes at 100% humidity. Induced controls, which were unstained, and singly stained were included to compensate for both the regulatory and initial voltage background. The sample was then lysed with PharmingenLyse according to the manufacturer's instructions. The samples were then transferred to 96-well plates suitable for running on the AMS96 well system of the BD Calibur FACs machine. Data were collected and mean fluorescence intensity values were obtained using Cell Quest software. The results were first analyzed using FACS analysis software (Flow Jo). IC50 for test compounds was defined as the concentration that reduced the percentage of CD69 cells positive (which was also CD20 positive stimulated with anti-IgM) by 50% (mean of 8 control wells after subtraction of the mean of 8 wells with no stimulus background). With Xlfit version3, equation 201 calculates the IC50 value by ActivityBase.

IC50 values for selected compounds of table 1 in the CD69 whole blood assay include:

compound number	IC50 (micromolar)
		114	0.0834
123	0.0291
		124	0.0671
138	0.0876
		160	0.179

The foregoing description is only exemplary of the principles of the invention. Further, since numerous modifications and changes will readily occur to those skilled in the art, it is not desired to limit the invention to the exact construction and process illustrated and described. Accordingly, all suitable modifications and equivalents are deemed to fall within the scope of the invention as defined in the appended claims.

The words "comprise", "comprising" or "comprises", when used in this specification and the appended claims, are intended to specify the presence of stated features, integers, components or steps, but they do not preclude the presence or addition of one or more other features, integers, components, steps or groups thereof.

Claims (41)

1. A compound selected from formula I:

and stereoisomers, geometric isomers, tautomers and pharmaceutically acceptable salts thereof, wherein:

Z¹is CR¹Or N;

Z²is CR²Or N;

Z³is CR³Or N;

Z⁴is CR⁴Or N;

wherein Z¹、Z²、Z³And Z⁴None, one or both are N;

wherein (i) X¹Is NR¹⁰And X²Is N, (ii) X¹Is S and X²Is CR¹¹，(iii)X¹Is O and X²Is CR¹¹Or (iv) X¹Is NR¹⁰And X²Is CR¹¹；

Or at X¹Z in the case of N¹And X¹Form optionally substituted by one or more R¹²A group-substituted 5-, 6-or 7-membered heteroaryl or heterocyclyl ring;

R⁵and R⁶Independently selected from H, C₁-C₁₂Alkyl radical, C₂-C₈Alkenyl and C₂-C₈Alkynyl, wherein alkyl, alkenyl and alkynyl are optionally substituted with one or more groups independently selected from: F. cl, Br, I, -CN, -CO₂H、-COCH₃、-COC(CH₃)₃、-CO₂CH₃、-CONH₂、-CONHCH₃、-CON(CH₃)₂、-NO₂、-NH₂、-NHCH₃、-N(CH₃)₂、-NHCOCH₃、-NHS(O)₂CH₃、-N(CH₃)C(CH₃)₂CONH₂、-N(CH₃)CH₂CH₂S(O)₂CH₃、=O、-OH、-OCH₃、-OCH₂CH₃、-OCH(CH₃)₂、-S(O)₂N(CH₃)₂、-SCH₃and-S (O)₂CH₃；

Or R⁵And R⁶Form optionally substituted by one or more R¹²A group-substituted 5-or 6-membered heteroaryl or heterocyclyl ring;

R¹、R²、R³、R⁴and R¹²Independently selected from H, F, Cl, Br、I、-CH₃、-CH₂CH₃、-C(CH₃)₃、-CH₂OH、-CH₂CH₂OH、-C(CH₃)₂OH、-CH₂OCH₃、-CN、-CF₃、-CO₂H、-COCH₃、-COC(CH₃)₃、-CO₂CH₃、-CONH₂、-CONHCH₃、-CON(CH₃)₂、-CONHCH₂CH₂OCH₃、-CON(CH₂CH₂)₂O、-CON(CH₂CH₂)₂N(CH₃)、-C(CH₃)₂CONH₂、-NO₂、-NH₂、-NHCH₃、-N(CH₃)₂、-NHCOCH₃、-NHS(O)₂CH₃、-N(CH₃)C(CH₃)₂CONH₂、-N(CH₃)CH₂CH₂S(O)₂CH₃、=O、-OH、-OCH₃、-OCF₃、-S(O)₂N(CH₃)₂、-SCH₃and-S (O)₂CH₃(ii) a Or

R¹、R²、R³、R⁴And R¹²Independently selected from heterocyclyl having 3 to 20 ring atoms or heteroaryl having 5 to 20 ring atoms, optionally substituted with one or more groups selected from: F. cl, Br, I, -CH₃、-CH₂CH₃、-C(CH₃)₃、-CH₂OH、-CH₂CH₂OH、-C(CH₃)₂OH、-CH₂OCH₃、-CN、-CF₃、-CO₂H、-COCH₃、-COC(CH₃)₃、-CO₂CH₃、-CONH₂、-CONHCH₃、-CON(CH₃)₂、-CONHCH₂CH₂OCH₃、-CON(CH₂CH₂)₂O、-CON(CH₂CH₂)₂N(CH₃)、-C(CH₃)₂CONH₂、-NO₂、-NH₂、-NHCH₃、-N(CH₃)₂、-NHCOCH₃、-NHS(O)₂CH₃、-N(CH₃)C(CH₃)₂CONH₂、-N(CH₃)CH₂CH₂S(O)₂CH₃、=O、-OH、-OCH₃、-OCF₃、-S(O)₂N(CH₃)₂、-SCH₃、-S(O)₂CH₃；

Y is a heterocyclyl having 3 to 20 ring atoms or a heteroaryl having 5 to 20 ring atoms, optionally substituted with one or more groups selected from: F. cl, Br, I, -CH ₃、-CH₂CH₃、-C(CH₃)₃、-CH₂OH、-CH₂CH₂OH、-C(CH₃)₂OH、-CH₂OCH₃、-CN、-CF₃、-CO₂H、-COCH₃、-COC(CH₃)₃、-CO₂CH₃、-CONH₂、-CONHCH₃、-CON(CH₃)₂、-CONHCH₂CH₂OCH₃、-CON(CH₂CH₂)₂O、-CON(CH₂CH₂)₂N(CH₃)、-C(CH₃)₂CONH₂、-NO₂、-NH₂、-NHCH₃、-N(CH₃)₂、-NHCOCH₃、-NHS(O)₂CH₃、-N(CH₃)C(CH₃)₂CONH₂、-N(CH₃)CH₂CH₂S(O)₂CH₃、=O、-OH、-OCH₃、-OCF₃、-S(O)₂N(CH₃)₂、-SCH₃、-S(O)₂CH₃Optionally substituted with-NHCOCH₃Substituted benzo [ d ]]Thiazol-2-yl, cyclopropyl, cyclobutyl, 1-dioxo-thiopyran-4-yl, indolyl, oxetanyl, morpholino and optionally substituted by F, Cl, Br, I, -OH, -CN or-CH₃Substituted phenyl;

or R⁶And Y is optionally substituted with one or more R¹²A group-substituted 5-or 6-membered heteroaryl or heterocyclyl ring;

R¹⁰is H, C₁-C₁₂Alkyl radical, C₂-C₈Alkenyl radical, C₂-C₈Alkynyl, C₆-C₂₀Aryl radical, C₃-C₁₂Carbocyclyl, heterocyclyl having 3 to 20 ring atoms, heteroaryl having 5 to 20 ring atoms, - (C)₁-C₁₂Alkylene group) - (C₃-C₁₂Carbocyclyl), - (C)₁-C₁₂Alkylene) - (heterocyclic group having 3-20 ring atoms), - (C)₁-C₁₂Alkylene) -C (= O) - (heterocyclic group having 3 to 20 ring atoms), - (C₁-C₁₂Alkylene group) - (C₆-C₂₀Aryl), - (C)₆-C₂₀Aryl) - (heteroaryl with 5-20 ring atoms), -C₆-C₂₀Aryl) - (heterocyclic radical having 3-20 ring atoms) and- (C)₁-C₁₂Alkylene) - (heteroaryl having 5-20 ring atoms), wherein alkyl, alkenyl, alkynyl, alkylene, carbocyclyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one or more groups independently selected from: F. cl, Br, I, -CH₃、-CH₂CH₃、-CH(CH₃)₂、-C(CH₃)₃、-CH₂OH、-CH₂CH₂OH、-C(CH₃)₂OH、-CH₂OCH₃、-CN、-CH₂CH₂CN、-CH₂F、-CHF₂、-CH₂CONH₂、-CF₃、-CO₂H、-COCH₃、-COC(CH₃)₂OH、-COCH₂N(CH₃)₂、-COC(CH₃)₃、-CO₂CH₃、-CO₂C(CH₃)₃、-CONH₂、-CONHCH₃、-CON(CH₃)₂、-C(CH₃)₂CONH₂、-NO₂、-NH₂、-NHCH₃、-N(CH₃)₂、-NHCOCH₃、-NHS(O)₂CH₃、-N(CH₃)C(CH₃)₂CONH₂、-N(CH₃)CH₂CH₂S(O)₂CH₃、=O、-OH、-OCH₃、-S(O)₂N(CH₃)₂、-SCH₃、-S(O)₂CH₃Cyclopropyl, cyclobutyl, oxetanyl, morpholino and 1, 1-dioxo-thiopyran-4-yl; and is

R¹¹Is H, F, Cl, Br, I, CN, -N (R)⁵)₂、-OR⁵、C₁-C₁₂Alkyl radical, C₂-C₈Alkenyl radical, C₂-C₈Alkynyl, C₆-C₂₀Aryl radical, C₃-C₁₂Carbocyclyl, heterocyclyl having 3 to 20 ring atoms, heteroaryl having 5 to 20 ring atoms, - (C)₁-C₁₂Alkylene group) - (C₃-C₁₂Carbocyclyl), - (C)₁-C₁₂Alkylene) - (heterocyclic group having 3-20 ring atoms), - (C)₁-C₁₂Alkylene) -C (= O) - (heterocyclic group having 3 to 20 ring atoms), - (C₁-C₁₂Alkylene group) - (C₆-C₂₀Aryl) and- (C)₁-C₁₂Alkylene) - (heteroaryl having 5-20 ring atoms), wherein alkyl, alkenyl, alkynyl, alkylene, carbocyclyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one or more groups independently selected from: F. cl, Br, I, -CH₃、-CH₂CH₃、-C(CH₃)₃、-CH₂OH、-CH₂CH₂OH、-C(CH₃)₂OH、-CH₂OCH₃、-CN、-CH₂F、-CHF₂、-CF₃、-CO₂H、-COCH₃、-COC(CH₃)₃、-CO₂CH₃、-CONH₂、-CONHCH₃、-CON(CH₃)₂、-C(CH₃)₂CONH₂、-NO₂、-NH₂、-NHCH₃、-N(CH₃)₂、-NHCOCH₃、-NHS(O)₂CH₃、-N(CH₃)C(CH₃)₂CONH₂、-N(CH₃)CH₂CH₂S(O)₂CH₃、=O、-OH、-OCH₃、-S(O)₂N(CH₃)₂、-SCH₃、-S(O)₂CH₃Cyclopropyl, cyclobutyl, oxetanyl, morpholino and 1, 1-dioxo-thiopyran-4-yl.

2. The compound of claim 1, wherein Y has the structure:

wherein the wavy line represents the attachment site;

R⁷、R⁸and R⁹Independently selected from H, F, Cl, Br, I, -CH₃、-CH₂CH₃、-C(CH₃)₃、-CH₂OH、-CH₂CH₂OH、-C(CH₃)₂OH、-CH₂OCH₃、-CN、-CF₃、-CO₂H、-COCH₃、-COC(CH₃)₃、-CO₂CH₃、-CONH₂、-CONHCH₃、-CON(CH₃)₂、-CONHCH₂CH₂OCH₃、-CON(CH₂CH₂)₂O、-CON(CH₂CH₂)₂N(CH₃)、-C(CH₃)₂CONH₂、-NO₂、-NH₂、-NHCH₃、-N(CH₃)₂、-NHCOCH₃、-NHS(O)₂CH₃、-N(CH₃)C(CH₃)₂CONH₂、-N(CH₃)CH₂CH₂S(O)₂CH₃、=O、-OH、-OCH₃、-OCF₃、-S(O)₂N(CH₃)₂、-SCH₃、-S(O)₂CH₃Cyclopropyl, cyclobutyl, oxetanyl, morpholino and 1, 1-dioxo-thiopyran-4-yl;

or: (iv) r⁶And R⁹Or (v) R⁸And R⁹Form optionally substituted by one or more R¹²5-or 6-membered with a substituentHeteroaryl or heterocyclyl rings.

3. The compound of claim 1 or 2 selected from formula Ia:

4. The compound of claim 1 or 2 selected from formula Ib:

5. the compound of claim 1 or 2 selected from formula Ic:

6. the compound of claim 1 or 2 selected from formula Id:

7. the compound of any one of claims 1 to 6, wherein Z¹Is CR¹；Z²Is CR²；Z³Is CR³(ii) a And Z is⁴Is CR⁴。

8. The compound of any one of claims 1 to 7, wherein R¹、R²、R³And R⁴Independently selected from H, F, Cl, -CH₃and-CN.

9. The compound of any one of claims 1 to 8, wherein R¹、R²、R³And R⁴One or more of which is F or Cl.

10. The compound of any one of claims 1 to 7, wherein R¹Is optionally substituted cyclopropyl, cyclobutyl, 1-dioxo-thiopyran-4-yl, indazolyl, oxetanyl, morpholino, phenyl, pyranyl, pyrazolyl or pyridyl.

11. The compound of any one of claims 1 to 10, wherein R⁵is-CH₃And R is⁶Is H.

12. The compound of any one of claims 1 to 11, wherein R⁷Is H.

13. A compound according to any one of claims 1 and 7 to 12 wherein Y is [1,3,5] triazine, pyridyl or pyridazinone.

14. The compound of any one of claims 1 to 10 and 12 to 13, wherein R⁵And R⁶Form optionally substituted by one or more R ¹²A group-substituted 5-or 6-membered heteroaryl or heterocyclyl ring.

15. A compound according to any one of claims 2 to 6, wherein R⁶And R⁹Form optionally substituted by one or more R¹²A group-substituted 5-or 6-membered heteroaryl or heterocyclyl ring.

16. The compound of claim 15, wherein R⁶And R⁹Forming an imidazolyl, piperidonyl, pyrrolidinyl or pyrazolyl ring.

17. A compound according to any one of claims 2 to 6, wherein R⁸And R⁹Form optionally substituted by one or more R¹²A group-substituted 5-or 6-membered heteroaryl or heterocyclyl ring.

18. The compound of claim 17, wherein R⁸And R⁹Forming an imidazolyl, piperidonyl, pyrrolidinyl or pyrazolyl ring.

19. The compound of claim 1, wherein X¹Is N and Z¹Is C, X¹And Z¹Form optionally substituted by one or more R¹²A group-substituted 5-, 6-or 7-membered heteroaryl or heterocyclyl ring.

20. The compound of any one of claims 1 to 18, wherein R¹⁰Is optionally substituted with one or more substituents selected from F, Cl and CH₃Phenyl substituted with the group of (1).

21. The compound of any one of claims 1 to 18, wherein R¹⁰Is an optionally substituted heterocyclic group having 3 to 20 ring atoms.

22. The compound of any one of claims 1 to 21, selected from:

N- (1- (3-phenylbenzo [ b ] thiophen-2-yl) ethyl) -9H-purin-6-amine,

n- (1- (1-phenyl-1H-benzo [ d ] imidazol-2-yl) ethyl) -9H-purin-6-amine,

n- (1- (3-phenylbenzofuran-2-yl) ethyl) -9H-purin-6-amine,

(S) -N- (1- (1-phenyl-1H-benzo [ d ] imidazol-2-yl) ethyl) -9H-purin-6-amine,

(R) -N- (1- (1-phenyl-1H-benzo [ d ] imidazol-2-yl) ethyl) -9H-purin-6-amine,

9- ((1-phenyl-1H-benzo [ d ] imidazol-2-yl) methyl) -9H-purin-6-amine,

n- (1- (1-ethyl-1H-benzo [ d ] imidazol-2-yl) ethyl) -9H-purin-6-amine,

(S) -N- (1- (4-methyl-1-phenyl-1H-benzo [ d ] imidazol-2-yl) ethyl) -9H-purin-6-amine,

(R) -N- (1- (4-methyl-1-phenyl-1H-benzo [ d ] imidazol-2-yl) ethyl) -9H-purin-6-amine,

(S) -N- (1- (7-methyl-1-phenyl-1H-benzo [ d ] imidazol-2-yl) ethyl) -9H-purin-6-amine,

4-amino-8- ((1-phenyl-1H-benzo [ d ] imidazol-2-yl) methyl) pyrido [2,3-d ] pyrimidin-5 (8H) -one,

(S) -4- (2- (1- (9H-purin-6-ylamino) ethyl) -1H-benzo [ d ] imidazol-1-yl) piperidine-1-carboxylic acid tert-butyl ester,

(S) -N- (1- (1- (piperidin-4-yl) -1H-benzo [ d ] imidazol-2-yl) ethyl) -9H-purin-6-amine,

(S) -N- (1- (3-phenyl-3H-imidazo [4,5-b ] pyridin-2-yl) ethyl) -9H-purin-6-amine,

(S) -1- (4- (2- (1- (9H-purin-6-ylamino) ethyl) -1H-benzo [ d ] imidazol-1-yl) piperidin-1-yl) ethanone,

n- (1- (3-phenyl-1H-indol-2-yl) ethyl) -9H-purin-6-amine,

(S) -N- (1- (5-methyl-1-phenyl-1H-benzo [ d ] imidazol-2-yl) ethyl) -9H-purin-6-amine,

(S) -N- (1- (6-methyl-1-phenyl-1H-benzo [ d ] imidazol-2-yl) ethyl) -9H-purin-6-amine,

(S) -N- (1- (1-phenyl-1H-benzo [ d ] imidazol-2-yl) propyl) -9H-purin-6-amine,

(S) -N- (1- (4-chloro-1-phenyl-1H-benzo [ d ] imidazol-2-yl) ethyl) -9H-purin-6-amine,

(S) -1- (4- (2- (1- (9H-purin-6-ylamino) ethyl) -1H-benzo [ d ] imidazol-1-yl) piperidin-1-yl) -2-hydroxy-2-methylpropan-1-one,

(S) -2- (1- (9H-purin-6-ylamino) ethyl) -1-phenyl-1H-benzo [ d ] imidazole-6-carbonitrile,

(S) -N- (1- (6-fluoro-1-phenyl-1H-benzo [ d ] imidazol-2-yl) ethyl) -9H-purin-6-amine,

(S) -N- (1- (7-fluoro-1-phenyl-1H-benzo [ d ] imidazol-2-yl) ethyl) -9H-purin-6-amine,

(S) -1- (4- (2- (1- (9H-purin-6-ylamino) ethyl) -1H-benzo [ d ] imidazol-1-yl) piperidin-1-yl) -2- (dimethylamino) ethanone,

(S) -3- (4- (2- (1- (9H-purin-6-ylamino) ethyl) -1H-benzo [ d ] imidazol-1-yl) piperidin-1-yl) propionitrile,

(S) -N- (1- (1- (tetrahydro-2H-pyran-4-yl) -1H-benzo [ d ] imidazol-2-yl) ethyl) -9H-purin-6-amine,

N- ((1S) -1- (1- (tetrahydro-2H-pyran-3-yl) -1H-benzo [ d ] imidazol-2-yl) ethyl) -9H-purin-6-amine,

(S) -N- (1- (1- (1- (oxetan-3-yl) piperidin-4-yl) -1H-benzo [ d ] imidazol-2-yl) ethyl) -9H-purin-6-amine,

(S) -4- (2- (1- (9H-purin-6-ylamino) ethyl) -1H-benzo [ d ] imidazol-1-yl) -N-isopropylpiperidine-1-carboxamide,

(S) -N- (1- (1- (1-isopropylpiperidin-4-yl) -1H-benzo [ d ] imidazol-2-yl) ethyl) -9H-purin-6-amine,

n- ((S) -1- (1- ((R) -1-isopropylpiperidin-3-yl) -1H-benzo [ d ] imidazol-2-yl) ethyl) -9H-purin-6-amine,

2- ((R) -3- (2- ((S) -1- (9H-purin-6-ylamino) ethyl) -1H-benzo [ d ] imidazol-1-yl) piperidin-1-yl) acetamide,

1- ((R) -3- (2- ((S) -1- (9H-purin-6-ylamino) ethyl) -1H-benzo [ d ] imidazol-1-yl) piperidin-1-yl) -2- (dimethylamino) ethanone,

1- ((R) -3- (2- ((S) -1- (9H-purin-6-ylamino) ethyl) -1H-benzo [ d ] imidazol-1-yl) piperidin-1-yl) -2-hydroxy-2-methylpropan-1-one,

(S) -N- (1- (4-fluoro-1-phenyl-1H-benzo [ d ] imidazol-2-yl) ethyl) -9H-purin-6-amine,

(S) -2- (1- (9H-purin-6-ylamino) ethyl) -1-phenyl-1H-benzo [ d ] imidazole-6-carboxamide,

(S) -N- (1- (7-chloro-1-phenyl-1H-benzo [ d ] imidazol-2-yl) ethyl) -9H-purin-6-amine,

7- ((1-phenyl-1H-benzo [ d ] imidazol-2-yl) methyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-amine,

5-iodo-7- ((1-phenyl-1H-benzo [ d ] imidazol-2-yl) methyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-amine,

3-iodo-1- ((1-phenyl-1H-benzo [ d ] imidazol-2-yl) methyl) -1H-pyrazolo [3,4-d ] pyrimidin-4-amine,

3-methyl-1- ((1-phenyl-1H-benzo [ d ] imidazol-2-yl) methyl) -1H-pyrazolo [3,4-d ] pyrimidin-4-amine,

(S) -N- (1- (1-phenyl-1H-benzo [ d ] imidazol-2-yl) ethyl) thieno [2,3-d ] pyrimidin-4-amine,

(S) -5-methyl-N- (1- (1-phenyl-1H-benzo [ d ] imidazol-2-yl) ethyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-amine,

(S) -N4- (1- (1-phenyl-1H-benzo [ d ] imidazol-2-yl) ethyl) pyrimidine-2, 4-diamine,

(S) -N4- (1- (1-phenyl-1H-benzo [ d ] imidazol-2-yl) ethyl) pyrimidine-4, 6-diamine,

(S) -N- (1- (1-phenyl-1H-benzo [ d ] imidazol-2-yl) ethyl) -5H-pyrrolo [3,2-d ] pyrimidin-4-amine,

(S) -N- (1- (1-phenyl-1H-benzo [ d ] imidazol-2-yl) ethyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-amine,

(S) -N6- (1- (1-phenyl-1H-benzo [ d ] imidazol-2-yl) ethyl) -9H-purine-2, 6-diamine,

2- ((R) -3- (2- ((S) -1- (9H-purin-6-ylamino) ethyl) -1H-benzo [ d ] imidazol-1-yl) piperidin-1-yl) ethanol,

2- ((R) -3- (2- ((S) -1- (9H-purin-6-ylamino) ethyl) -1H-benzo [ d ] imidazol-1-yl) piperidin-1-yl) -N, N-dimethylacetamide,

3- (4-amino-1- ((1-phenyl-1H-benzo [ d ] imidazol-2-yl) methyl) -1H-pyrazolo [3,4-d ] pyrimidin-3-yl) prop-2-yn-1-ol,

3- (4-amino-1- ((1-phenyl-1H-benzo [ d ] imidazol-2-yl) methyl) -1H-pyrazolo [3,4-d ] pyrimidin-3-yl) -5-fluorophenol,

3- (1H-indol-3-yl) -1- ((1-phenyl-1H-benzo [ d ] imidazol-2-yl) methyl) -1H-pyrazolo [3,4-d ] pyrimidin-4-amine,

4- (4-amino-1- ((1-phenyl-1H-benzo [ d ] imidazol-2-yl) methyl) -1H-pyrazolo [3,4-d ] pyrimidin-3-yl) -2-fluorophenol,

n- (6- (4-amino-1- ((1-phenyl-1H-benzo [ d ] imidazol-2-yl) methyl) -1H-pyrazolo [3,4-d ] pyrimidin-3-yl) benzo [ d ] thiazol-2-yl) acetamide,

1- ((1-phenyl-1H-benzo [ d ] imidazol-2-yl) methyl) -1H-pyrazolo [3,4-d ] pyrimidin-6-amine,

(S) -8-methyl-N- (1- (1-phenyl-1H-benzo [ d ] imidazol-2-yl) ethyl) -9H-purin-6-amine,

(S) -1-methyl-N- (1- (1-phenyl-1H-benzo [ d ] imidazol-2-yl) ethyl) -1H-pyrazolo [4,3-d ] pyrimidin-5-amine,

(S) -N- (1- (6-fluoro-1-phenyl-1H-benzo [ d ] imidazol-2-yl) propyl) -7H-purin-6-amine,

(S) -N- (1- (5-fluoro-1-phenyl-1H-benzo [ d ] imidazol-2-yl) ethyl) -7H-purin-6-amine,

9- ((3-phenyl-1H-indol-2-yl) methyl) -9H-purin-6-amine,

9- ((3-phenylbenzofuran-2-yl) methyl) -9H-purin-6-amine,

1- ((3-phenylbenzo [ b ] thiophen-2-yl) methyl) -1H-pyrazolo [3,4-d ] pyrimidin-4-amine,

n- ((3-phenylbenzo [ b ] thiophen-2-yl) methyl) -9H-purin-6-amine,

9- ((3-phenylbenzo [ b ] thiophen-2-yl) methyl) -9H-purin-6-amine, and

9- ((3-o-tolylbenzo [ b ] thiophen-2-yl) methyl) -9H-purin-6-amine.

23. The compound of any one of claims 1 to 21, selected from:

(9H-purin-6-yl) - [1- (3-o-tolyl-3H-imidazo [4,5-b ] pyridin-2-yl) -ethyl ] -amine,

[ (S) -1- (3-phenyl-3H-imidazo [4,5-b ] pyridin-2-yl) -propyl ] - (9H-purin-6-yl) -amine,

3- {2- [ (S) -1- (9H-purin-6-ylamino) -ethyl ] -benzimidazol-1-yl } -benzonitrile,

[1- (6-fluoro-1-phenyl-1H-benzimidazol-2-yl) -2-methoxy-ethyl ] - (7H-purin-6-yl) -amine,

2- (6-fluoro-1-phenyl-1H-benzimidazol-2-yl) -2- (7H-purin-6-ylamino) -ethanol,

[ (S) -1- (6-chloro-1-phenyl-1H-benzimidazol-2-yl) -ethyl ] - (9H-purin-6-yl) -amine,

4- { 6-fluoro-2- [ (S) -1- (9H-purin-6-ylamino) -ethyl ] -benzimidazol-1-yl } -cyclohexanecarbonitrile,

(1R,2R) -1- (6-fluoro-1-phenyl-1H-benzimidazol-2-yl) -1- (7H-purin-6-ylamino) -propan-2-ol,

[1- (6-fluoro-1-pyridin-3-yl-1H-benzimidazol-2-yl) -ethyl ] - (9H-purin-6-yl) -amine,

(9H-purin-6-yl) - [ (S) -1- (3-m-tolyl-3H-imidazo [4,5-b ] pyridin-2-yl) -ethyl ] -amine,

[ (S) -1- (7-bromo-6-fluoro-1-phenyl-1H-benzimidazol-2-yl) -ethyl ] - (9H-purin-6-yl) -amine,

[1- (7-chloro-6-fluoro-1-phenyl-1H-benzimidazol-2-yl) -ethyl ] - (9H-purin-6-yl) -amine,

n-4- [ (S) -1- (3-m-tolyl-3H-imidazo [4,5-b ] pyridin-2-yl) -ethyl ] -1H-pyrazolo [3,4-d ] pyrimidine-4, 6-diamine,

[ (S) -1- (6-fluoro-1-phenyl-1H-benzimidazol-2-yl) -ethyl ] -methyl- (9H-purin-6-yl) -amine,

[1- (6-fluoro-1-pyridin-2-yl-1H-benzimidazol-2-yl) -ethyl ] - (9H-purin-6-yl) -amine,

[ (S) -1- (6-fluoro-7-methyl-1-phenyl-1H-benzimidazol-2-yl) -ethyl ] - (9H-purin-6-yl) -amine,

6- [ (S) -2- (3-phenyl-3H-imidazo [4,5-b ] pyridin-2-yl) -pyrrolidin-1-yl ] -9H-purine,

{ (S) -1- [ 6-fluoro-1- (3-fluoro-phenyl) -1H-benzimidazol-2-yl ] -ethyl } - (9H-purin-6-yl) -amine,

{1- [ 6-fluoro-1- (4-fluoro-phenyl) -1H-benzimidazol-2-yl ] -ethyl } - (9H-purin-6-yl) -amine,

(S) -3- (6-fluoro-1-phenyl-1H-benzimidazol-2-yl) -3- (9H-purin-6-ylamino) -propan-1-ol,

[ (R) -1- (6-fluoro-7-methyl-1-phenyl-1H-benzimidazol-2-yl) -2-methoxy-ethyl ] - (9H-purin-6-yl) -amine,

5-fluoro-3-phenyl-2- [1- (9H-purin-6-ylamino) -ethyl ] -3H-benzimidazole-4-carbonitrile,

[1- (6, 7-difluoro-1-phenyl-1H-benzimidazol-2-yl) -2-methoxy-ethyl ] - (9H-purin-6-yl) -amine,

{ (S) -1- [3- (3-chloro-phenyl) -3H-imidazo [4,5-b ] pyridin-2-yl ] -ethyl } - (9H-purin-6-yl) -amine,

{ (S) -1- [3- (4-chloro-phenyl) -3H-imidazo [4,5-b ] pyridin-2-yl ] -ethyl } - (9H-purin-6-yl) -amine,

[1- (7-bromo-1-phenyl-1H-benzimidazol-2-yl) -ethyl ] - (9H-purin-6-yl) -amine,

[1- (6-fluoro-1-phenyl-1H-benzimidazol-2-yl) -ethyl ] - (9H-purin-6-yl) -amine,

{1- [ 6-fluoro-1- (2-fluoro-phenyl) -1H-benzimidazol-2-yl ] -ethyl } - (9H-purin-6-yl) -amine,

[ 2-methyl-1- (3-phenyl-3H-imidazo [4,5-b ] pyridin-2-yl) -propyl ] - (9H-purin-6-yl) -amine,

5-fluoro-3-phenyl-2- [1- (9H-purin-6-ylamino) -ethyl ] -3H-benzimidazole-4-carboxylic acid methyl ester,

[1- (7-cyclopropyl-6-fluoro-1-phenyl-1H-benzimidazol-2-yl) -ethyl ] - (9H-purin-6-yl) -amine,

[1- (1-phenyl-1H-imidazo [4,5-b ] pyridin-2-yl) -ethyl ] - (9H-purin-6-yl) -amine,

[ 2-ethoxy-1- (6-fluoro-1-phenyl-1H-benzimidazol-2-yl) -ethyl ] - (9H-purin-6-yl) -amine,

[ (S) -1- (1-cyclohexyl-6-fluoro-1H-benzimidazol-2-yl) -ethyl ] - (9H-purin-6-yl) -amine,

{ 5-fluoro-3-phenyl-2- [1- (9H-purin-6-ylamino) -ethyl ] -3H-benzimidazol-4-yl } - (4-methyl-piperazin-1-yl) -methanone,

{ 5-fluoro-3-phenyl-2- [1- (9H-purin-6-ylamino) -ethyl ] -3H-benzimidazol-4-yl } -morpholin-4-yl-methanone,

5-fluoro-3-phenyl-2- [1- (9H-purin-6-ylamino) -ethyl ] -3H-benzimidazole-4-carboxylic acid dimethylamide,

[1- (6-fluoro-1-pyridin-3-yl-1H-benzimidazol-2-yl) -propyl ] - (9H-purin-6-yl) -amine,

[1- (6-fluoro-1-pyridin-3-yl-1H-benzimidazol-2-yl) -2-methyl-propyl ] - (9H-purin-6-yl) -amine,

{1- [ 6-fluoro-1- (6-methoxy-pyridin-3-yl) -1H-benzimidazol-2-yl ] -ethyl } - (9H-purin-6-yl) -amine,

{1- [ 6-fluoro-1- (5-fluoro-pyridin-2-yl) -1H-benzimidazol-2-yl ] -ethyl } - (9H-purin-6-yl) -amine,

[1- (6-fluoro-1-pyridin-2-yl-1H-benzimidazol-2-yl) -ethyl ] - (9H-purin-6-yl) -amine,

[1- (6-fluoro-1-pyridin-2-yl-1H-benzimidazol-2-yl) -ethyl ] - (9H-purin-6-yl) -amine,

[1- (6-fluoro-1-phenyl-1H-benzimidazol-2-yl) -propyl ] - (7H-purin-6-yl) -amine,

[1- (6-fluoro-1-phenyl-1H-benzimidazol-2-yl) -propyl ] - (7H-purin-6-yl) -amine,

[1- (6-fluoro-1-phenyl-1H-benzimidazol-2-yl) -2-methoxy-ethyl ] - (7H-purin-6-yl) -amine,

[1- (6-fluoro-1-phenyl-1H-benzimidazol-2-yl) -2-methoxy-ethyl ] - (7H-purin-6-yl) -amine,

[1- (6, 7-difluoro-1-phenyl-1H-benzimidazol-2-yl) -2-methoxy-ethyl ] - (9H-purin-6-yl) -amine,

[1- (6, 7-difluoro-1-phenyl-1H-benzimidazol-2-yl) -2-methoxy-ethyl ] - (9H-purin-6-yl) -amine,

5-fluoro-3-phenyl-2- [1- (9H-purin-6-ylamino) -ethyl ] -3H-benzimidazole-4-carbonitrile,

5-fluoro-3-phenyl-2- [1- (9H-purin-6-ylamino) -ethyl ] -3H-benzimidazole-4-carbonitrile,

[1- (6-fluoro-1-pyridin-3-yl-1H-benzimidazol-2-yl) -ethyl ] - (9H-purin-6-yl) -amine,

[1- (6-fluoro-1-pyridin-3-yl-1H-benzimidazol-2-yl) -ethyl ] - (9H-purin-6-yl) -amine,

{1- [ 6-fluoro-1- (4-fluoro-phenyl) -1H-benzimidazol-2-yl ] -ethyl } - (9H-purin-6-yl) -amine,

{1- [ 6-fluoro-1- (4-fluoro-phenyl) -1H-benzimidazol-2-yl ] -ethyl } - (9H-purin-6-yl) -amine,

2- (6-fluoro-1-phenyl-1H-benzimidazol-2-yl) -2- (7H-purin-6-ylamino) -ethanol,

2- (6-fluoro-1-phenyl-1H-benzimidazol-2-yl) -2- (7H-purin-6-ylamino) -ethanol,

{1- [ 6-fluoro-1- (3-methoxy-phenyl) -1H-benzimidazol-2-yl ] -ethyl } - (9H-purin-6-yl) -amine,

{1- [1- (4-bromo-phenyl) -6-fluoro-1H-benzimidazol-2-yl ] -ethyl } - (9H-purin-6-yl) -amine,

4- { 6-fluoro-2- [1- (9H-purin-6-ylamino) -ethyl ] -benzimidazol-1-yl } -benzonitrile,

3- { 6-fluoro-2- [1- (9H-purin-6-ylamino) -ethyl ] -benzimidazol-1-yl } -phenol,

{1- [ 6-fluoro-1- (5-fluoro-pyridin-3-yl) -1H-benzimidazol-2-yl ] -ethyl } - (9H-purin-6-yl) -amine,

[ (R) -1- (6-fluoro-1-phenyl-1H-benzimidazol-2-yl) -ethyl ] - (9H-purin-6-yl) -amine,

[1- (4, 6-difluoro-1-phenyl-1H-benzimidazol-2-yl) -ethyl ] - (9H-purin-6-yl) -amine,

[1- (6-fluoro-1-pyridin-3-yl-1H-benzimidazol-2-yl) -2-methyl-propyl ] - (9H-purin-6-yl) -amine,

{1- [ 6-fluoro-1- (6-methoxy-pyridin-3-yl) -1H-benzimidazol-2-yl ] -ethyl } - (9H-purin-6-yl) -amine,

[1- (6-fluoro-1-pyridin-3-yl-1H-benzimidazol-2-yl) -2-methyl-propyl ] - (9H-purin-6-yl) -amine,

{1- [ 6-fluoro-1- (6-methoxy-pyridin-3-yl) -1H-benzimidazol-2-yl ] -ethyl } - (9H-purin-6-yl) -amine,

[1- (1-phenyl-1H-imidazo [4,5-c ] pyridin-2-yl) -ethyl ] - (9H-purin-6-yl) -amine,

[1- (3-phenyl-3H-imidazo [4,5-c ] pyridin-2-yl) -ethyl ] - (9H-purin-6-yl) -amine,

{1- [ 6-fluoro-1- (3-fluoro-pyridin-2-yl) -1H-benzimidazol-2-yl ] -ethyl } - (9H-purin-6-yl) -amine,

[1- (6-fluoro-1-pyridin-3-yl-1H-benzimidazol-2-yl) -propyl ] - (9H-purin-6-yl) -amine,

{1- [ 6-fluoro-1- (5-fluoro-pyridin-2-yl) -1H-benzimidazol-2-yl ] -ethyl } - (9H-purin-6-yl) -amine,

{1- [ 6-fluoro-1- (5-fluoro-pyridin-2-yl) -1H-benzimidazol-2-yl ] -ethyl } - (9H-purin-6-yl) -amine,

[1- (6-fluoro-1-pyridin-3-yl-1H-benzimidazol-2-yl) -propyl ] - (9H-purin-6-yl) -amine,

[1- (6-fluoro-1-pyrazin-2-yl-1H-benzimidazol-2-yl) -ethyl ] - (7H-purin-6-yl) -amine,

5-fluoro-3-phenyl-2- [ (S) -1- (9H-purin-6-ylamino) -propyl ] -3H-benzimidazole-4-carbonitrile,

[1- (6-fluoro-1-pyrimidin-2-yl-1H-benzimidazol-2-yl) -ethyl ] - (7H-purin-6-yl) -amine,

4-amino-6- [ (S) -1- (6-fluoro-1-phenyl-1H-benzimidazol-2-yl) -ethylamino ] -pyrimidine-5-carbonitrile,

[ (S) -1- (6-fluoro-1-pyridin-2-yl-1H-benzimidazol-2-yl) -propyl ] - (9H-purin-6-yl) -amine,

4- { 6-fluoro-2- [1- (9H-purin-6-ylamino) -ethyl ] -benzimidazol-1-yl } -benzonitrile,

{1- [ 6-fluoro-1- (3-methoxy-phenyl) -1H-benzimidazol-2-yl ] -ethyl } - (9H-purin-6-yl) -amine,

3- { 6-fluoro-2- [1- (9H-purin-6-ylamino) -ethyl ] -benzimidazol-1-yl } -phenol,

{1- [ 6-fluoro-1- (3-methoxy-phenyl) -1H-benzimidazol-2-yl ] -ethyl } - (9H-purin-6-yl) -amine,

3- { 6-fluoro-2- [1- (9H-purin-6-ylamino) -ethyl ] -benzimidazol-1-yl } -phenol,

4- { 6-fluoro-2- [1- (9H-purin-6-ylamino) -ethyl ] -benzimidazol-1-yl } -benzonitrile,

5-fluoro-N4- [1- (6-fluoro-1-phenyl-1H-benzoimidazol-2-yl) -ethyl ] -pyrimidine-2, 4-diamine,

[1- (6-fluoro-1-phenyl-1H-benzimidazol-2-yl) -ethyl ] -thiazolin-4-yl-amine,

2- ((R) -3- { 6-fluoro-2- [ (S) -1- (9H-purin-6-ylamino) -ethyl ] -benzimidazol-1-yl } -piperidin-1-yl) -ethanol,

2- ((R) -3- { 6-fluoro-2- [ (R) -1- (9H-purin-6-ylamino) -ethyl ] -benzimidazol-1-yl } -piperidin-1-yl) -ethanol,

n- [ (S) -1- (6-fluoro-1-phenyl-1H-benzimidazol-2-yl) -ethyl ] -6-methyl- [1,3,5] triazine-2, 4-diamine,

2- ((R) -3- { 6-fluoro-2- [ (S) -1- (9H-purin-6-ylamino) -propyl ] -benzimidazol-1-yl } -piperidin-1-yl) -ethanol,

{ (S) -1- [ 6-fluoro-1- (5-fluoro-pyridin-3-yl) -1H-benzimidazol-2-yl ] -ethyl } - (9H-purin-6-yl) -amine,

[ (S) -1- (6-fluoro-1-pyrimidin-2-yl-1H-benzimidazol-2-yl) -ethyl ] - (7H-purin-6-yl) -amine,

n- {6- [ (S) -1- (6-fluoro-1-phenyl-1H-benzimidazol-2-yl) -ethylamino ] -9H-purin-2-yl } -acetamide,

{1- [ 6-fluoro-1- (5-fluoro-pyridin-3-yl) -1H-benzimidazol-2-yl ] -ethyl } - (9H-purin-6-yl) -amine,

{1- [ 6-fluoro-1- (5-fluoro-pyridin-3-yl) -1H-benzimidazol-2-yl ] -ethyl } - (9H-purin-6-yl) -amine,

{1- [ 6-fluoro-1- (6-methylamino-pyridin-2-yl) -1H-benzimidazol-2-yl ] -ethyl } - (9H-purin-6-yl) -amine,

n- [1- (6-fluoro-1-phenyl-1H-benzimidazol-2-yl) -ethyl ] -pyrimidine-4, 6-diamine,

n- [ (S) -1- (6-fluoro-1-phenyl-1H-benzimidazol-2-yl) -ethyl ] - [1,3,5] triazine-2, 4-diamine,

n- [ (S) -1- (6-fluoro-1-phenyl-1H-benzimidazol-2-yl) -ethyl ] -N ', N' -dimethyl- [1,3,5] triazine-2, 4, 6-triamine,

6-chloro-N- [ (S) -1- (6-fluoro-1-phenyl-1H-benzimidazol-2-yl) -ethyl ] - [1,3,5] triazine-2, 4-diamine,

[ (R) -1- (6-fluoro-1-pyridin-2-yl-1H-benzimidazol-2-yl) -2-methoxy-ethyl ] - (9H-purin-6-yl) -amine,

4-amino-6- [ (R) -1- (6-fluoro-1-pyridin-2-yl-1H-benzimidazol-2-yl) -2-methoxy-ethylamino ] -pyrimidine-5-carbonitrile,

[1- (7-bromo-6-methoxy-1-phenyl-1H-benzimidazol-2-yl) -ethyl ] - (9H-purin-6-yl) -amine,

{ 5-fluoro-3-phenyl-2- [ (S) -1- (9H-purin-6-ylamino) -ethyl ] -3H-benzimidazol-4-yl } -morpholin-4-yl-methanone,

[ (S) -1- (7-cyclopropyl-6-fluoro-1-pyridin-2-yl-1H-benzimidazol-2-yl) -ethyl ] - (9H-purin-6-yl) -amine,

4-amino-6- [ (S) -1- (6-fluoro-1-pyridin-2-yl-1H-benzimidazol-2-yl) -ethylamino ] -pyrimidine-5-carbonitrile,

N- [ (S) -1- (6-fluoro-1-phenyl-1H-benzimidazol-2-yl) -ethyl ] -6-methoxy- [1,3,5] triazine-2, 4-diamine,

4-amino-6- { (S) -1- [ 6-fluoro-1- (5-fluoro-pyridin-3-yl) -1H-benzimidazol-2-yl ] -ethylamino } -pyrimidine-5-carbonitrile,

2- ((S) -3- { 6-fluoro-2- [ (S) -1- (9H-purin-6-ylamino) -ethyl ] -benzimidazol-1-yl } -piperidin-1-yl) -ethanol,

3-phenyl-2- [ (S) -1- (9H-purin-6-ylamino) -ethyl ] -3H-benzimidazole-4-carbonitrile,

(R) -2- (6-fluoro-1-pyridin-2-yl-1H-benzimidazol-2-yl) -2- (9H-purin-6-ylamino) -ethanol,

5-fluoro-2- [ (S) -1- (9H-purin-6-ylamino) -ethyl ] -3-pyridin-3-yl-3H-benzimidazole-4-carbonitrile,

[1- (6-fluoro-1-phenyl-1H-benzimidazol-2-yl) -ethyl ] -thiazolo [5,4-d ] pyrimidin-7-yl-amine,

[1- (6-fluoro-1-pyrimidin-2-yl-1H-benzimidazol-2-yl) -ethyl ] - (7H-purin-6-yl) -amine,

[1- (6-fluoro-1-pyrimidin-2-yl-1H-benzimidazol-2-yl) -ethyl ] - (7H-purin-6-yl) -amine,

4-amino-6- ((S) -1- { 6-fluoro-1- [ (S) -1- (2-hydroxy-ethyl) -piperidin-3-yl ] -1H-benzimidazol-2-yl } -ethylamino) -pyrimidine-5-carbonitrile,

n- [ (S) -1- (6-fluoro-1-phenyl-1H-benzimidazol-2-yl) -ethyl ] - [1,3,5] triazine-2, 4, 6-triamine,

4-amino-6- [ (S) -1- (6-fluoro-1-phenyl-1H-benzimidazol-2-yl) -ethylamino ] - [1,3,5] triazin-2-ol,

[ (S) -1- (6-fluoro-7-methyl-1-pyridin-2-yl-1H-benzimidazol-2-yl) -ethyl ] - (9H-purin-6-yl) -amine,

4-amino-6- [ (S) -1- (6-fluoro-7-methyl-1-pyridin-2-yl-1H-benzimidazol-2-yl) -ethylamino ] -pyrimidine-5-carbonitrile,

5-fluoro-2- [ (S) -1- (9H-purin-6-ylamino) -ethyl ] -3-pyridin-2-yl-3H-benzimidazole-4-carbonitrile,

2- [ (S) -1- (6-amino-5-cyano-pyrimidin-4-ylamino) -ethyl ] -5-fluoro-3-pyridin-2-yl-3H-benzimidazole-4-carbonitrile,

[ (S) -1- (7-bromo-1-phenyl-1H-benzimidazol-2-yl) -ethyl ] - (9H-purin-6-yl) -amine,

(9H-purin-6-yl) - [ (S) -1- (3-pyridin-2-yl-3H-imidazo [4,5-b ] pyridin-2-yl) -ethyl ] -amine,

[ (S) -1- (7-cyclopropyl-6-fluoro-1-pyridin-3-yl-1H-benzimidazol-2-yl) -ethyl ] - (9H-purin-6-yl) -amine,

{1- [ 6-fluoro-1- (6-methyl-pyridin-2-yl) -1H-benzimidazol-2-yl ] -ethyl } - (9H-purin-6-yl) -amine,

4-amino-6- [1- (6-fluoro-1-pyridin-4-yl-1H-benzimidazol-2-yl) -ethylamino ] -pyrimidine-5-carbonitrile, [ (S) -1- (7-cyclopropyl-1-pyridin-3-yl-1H-benzimidazol-2-yl) -ethyl ] - (9H-purin-6-yl) -amine,

(9H-purin-6-yl) - [ (S) -1- (1-pyridin-3-yl-1H-benzimidazol-2-yl) -ethyl ] -amine,

4-amino-6- [ (S) -1- (7-cyclopropyl-1-pyridin-3-yl-1H-benzimidazol-2-yl) -ethylamino ] -pyrimidine-5-carbonitrile,

4-amino-6- [ (S) -1- (1-pyridin-3-yl-1H-benzimidazol-2-yl) -ethylamino ] -pyrimidine-5-carbonitrile,

4-amino-6- [ (S) -1- (7-bromo-6-fluoro-1-pyridin-3-yl-1H-benzimidazol-2-yl) -ethylamino ] -pyrimidine-5-carbonitrile,

4-amino-6- [1- (3-phenyl-3H-imidazo [4,5-b ] pyridin-2-yl) -ethylamino ] -pyrimidine-5-carbonitrile,

[1- (6-fluoro-1-pyridin-4-yl-1H-benzimidazol-2-yl) -ethyl ] - (9H-purin-6-yl) -amine,

(S) -3- (6-fluoro-1-pyridin-2-yl-1H-benzimidazol-2-yl) -3- (9H-purin-6-ylamino) -propan-1-ol,

5-fluoro-3-phenyl-2- [ (S) -1- (9H-purin-6-ylamino) -ethyl ] -3H-benzimidazole-4-carboxylic acid (2-methoxy-ethyl) -amide,

4-amino-6- [ (S) -1- (7-cyclopropyl-6-fluoro-1-pyridin-3-yl-1H-benzimidazol-2-yl) -ethylamino ] -pyrimidine-5-carbonitrile,

[ (R) -1- (6-fluoro-1-pyridin-3-yl-1H-benzimidazol-2-yl) -ethyl ] - (9H-purin-6-yl) -amine,

[ (S) -1- (6-fluoro-1-pyridin-3-yl-1H-benzimidazol-2-yl) -ethyl ] - (9H-purin-6-yl) -amine,

[ (R) -1- (3-phenyl-3H-imidazo [4,5-b ] pyridin-2-yl) -ethyl ] - (9H-purin-6-yl) -amine,

(S) -N6- (1- (6-fluoro-1-phenyl-1H-benzo [ d ] imidazol-2-yl) ethyl) -9H-purine-2, 6-diamine,

3-phenyl-2- [ (S) -1- (9H-purin-6-ylamino) -ethyl ] -3H-benzimidazole-4-carboxylic acid amide,

4- [ (S) -1- (6-fluoro-1-phenyl-1H-benzimidazol-2-yl) -ethylamino ] -nicotinonitrile,

[ (S) -1- (6-fluoro-1-pyridin-2-yl-1H-benzimidazol-2-yl) -ethyl ] - (2-trifluoromethyl-9H-purin-6-yl) -amine,

2-chloro-4- [ (S) -1- (6-fluoro-1-phenyl-1H-benzimidazol-2-yl) -ethylamino ] -pyrimidine-5-carbonitrile,

4- [ (S) -1- (6-fluoro-1-pyridin-2-yl-1H-benzimidazol-2-yl) -ethylamino ] -pyrimidine-5-carbonitrile,

4- [ (S) -1- (6-fluoro-1-phenyl-1H-benzimidazol-2-yl) -ethylamino ] -pyrimidine-5-carbonitrile,

[ (S) -1- (6-fluoro-1-phenyl-1H-benzimidazol-2-yl) -ethyl ] -pyrido [3,2-d ] pyrimidin-4-yl-amine,

4-amino-6- { (S) -1- [ 6-fluoro-7- (morpholine-4-carbonyl) -1-phenyl-1H-benzoimidazol-2-yl ] -ethylamino } -pyrimidine-5-carbonitrile,

4- [ (S) -1- (6-fluoro-1-pyridin-2-yl-1H-benzimidazol-2-yl) -ethylamino ] -nicotinonitrile,

[ (S) -1- (1-benzo [1,3] dioxol-5-yl-6-fluoro-1H-benzimidazol-2-yl) -ethyl ] - (9H-purin-6-yl) -amine,

[ (S) -1- (6-fluoro-1-phenyl-1H-benzimidazol-2-yl) -ethyl ] -imidazo [2,1-f ] [1,2,4] triazin-4-yl-amine,

[ (S) -1- (6-fluoro-1-pyridin-2-yl-1H-benzimidazol-2-yl) -ethyl ] -imidazo [2,1-f ] [1,2,4] triazin-4-yl-amine,

5-chloro-4- [ (S) -1- (6-fluoro-1-phenyl-1H-benzimidazol-2-yl) -ethylamino ] -2-methyl-2H-pyridazin-3-one,

4-chloro-5- [ (S) -1- (6-fluoro-1-phenyl-1H-benzimidazol-2-yl) -ethylamino ] -2-methyl-2H-pyridazin-3-one,

5- [ (S) -1- (6-fluoro-1-phenyl-1H-benzimidazol-2-yl) -ethylamino ] -2-methyl-2H-pyridazin-3-one,

4- [ (S) -1- (6-fluoro-1-phenyl-1H-benzimidazol-2-yl) -ethylamino ] -2-methyl-2H-pyridazin-3-one,

5-fluoro-3-phenyl-2- [1- (9H-purin-6-ylamino) -ethyl ] -3H-benzimidazol-4-ol,

2-amino-4- [ (S) -1- (6-fluoro-1-phenyl-1H-benzimidazol-2-yl) -ethylamino ] -6-methyl-pyrimidine-5-carbonitrile,

{ (S) -1- [ 6-fluoro-1- (3-morpholin-4-yl-phenyl) -1H-benzimidazol-2-yl ] -ethyl } - (9H-purin-6-yl) -amine,

2- [ (S) -1- (6-amino-5-cyano-pyrimidin-4-ylamino) -ethyl ] -5-fluoro-3-phenyl-3H-benzimidazole-4-carbonitrile,

4-amino-6- { (R) -1- [ 6-fluoro-1- (5-fluoro-pyridin-3-yl) -1H-benzimidazol-2-yl ] -ethylamino } -pyrimidine-5-carbonitrile,

[ (S) -1- (6-fluoro-1-pyrimidin-4-yl-1H-benzimidazol-2-yl) -ethyl ] - (9H-purin-6-yl) -amine,

2-amino-4- [ (S) -1- (6-fluoro-1-pyridin-2-yl-1H-benzimidazol-2-yl) -ethylamino ] -6-methyl-pyrimidine-5-carbonitrile,

[ (R) -1- (6-fluoro-1-pyridin-2-yl-1H-benzimidazol-2-yl) -ethyl ] - (9H-purin-6-yl) -amine,

4-amino-6- [ (R) -1- (6-fluoro-1-pyridin-2-yl-1H-benzimidazol-2-yl) -ethylamino ] -pyrimidine-5-carbonitrile,

4-amino-6- [ (R) -1- (3-phenyl-3H-imidazo [4,5-b ] pyridin-2-yl) -ethylamino ] -pyrimidine-5-carbonitrile,

4-amino-6- [ (S) -1- (3-phenyl-3H-imidazo [4,5-b ] pyridin-2-yl) -ethylamino ] -pyrimidine-5-carbonitrile,

[ (S) -1- (6-fluoro-7-methoxy-1-phenyl-1H-benzimidazol-2-yl) -ethyl ] - (9H-purin-6-yl) -amine,

4-amino-6- [ (S) -1- (6-fluoro-7-methoxy-1-phenyl-1H-benzimidazol-2-yl) -ethylamino ] -pyrimidine-5-carbonitrile,

4- [ (S) -1- (6-fluoro-1-phenyl-1H-benzimidazol-2-yl) -ethylamino ] -2-methyl-nicotinonitrile,

6-amino-5-chloro-4- [ (S) -1- (6-fluoro-1-phenyl-1H-benzimidazol-2-yl) -ethylamino ] -2-methyl-2H-pyridazin-3-one,

6-amino-4-chloro-5- [ (S) -1- (6-fluoro-1-phenyl-1H-benzimidazol-2-yl) -ethylamino ] -2-methyl-2H-pyridazin-3-one,

4-amino-6- [ (R) -1- (6-fluoro-1-phenyl-1H-benzimidazol-2-yl) -ethylamino ] -pyrimidine-5-carbonitrile,

6-amino-4- [ (S) -1- (6-fluoro-1-phenyl-1H-benzimidazol-2-yl) -ethylamino ] -2-methyl-2H-pyridazin-3-one,

4-amino-6- [ (S) -1- (7-cyanomethyl-6-fluoro-1-phenyl-1H-benzimidazol-2-yl) -ethylamino ] -pyrimidine-5-carbonitrile,

5-fluoro-3- (5-fluoro-pyridin-3-yl) -2- [ (S) -1- (9H-purin-6-ylamino) -ethyl ] -3H-benzimidazole-4-carbonitrile,

2- [ (S) -1- (6-amino-5-cyano-pyrimidin-4-ylamino) -ethyl ] -5-fluoro-3- (5-fluoro-pyridin-3-yl) -3H-benzimidazole-4-carbonitrile,

4-amino-6- [ (S) -1- (6-fluoro-1-pyridin-3-yl-1H-benzimidazol-2-yl) -ethylamino ] -pyrimidine-5-carbonitrile,

4-amino-6- { (S) -1- [1- (3, 5-difluoro-phenyl) -6-fluoro-1H-benzimidazol-2-yl ] -ethylamino } -pyrimidine-5-carbonitrile,

4-amino-6- { (S) -1- [ 6-fluoro-1- (5-fluoro-pyridin-3-yl) -1H-benzimidazol-2-yl ] -propylamino } -pyrimidine-5-carbonitrile,

[ (S) -1- (6-fluoro-1-phenyl-1H-benzimidazol-2-yl) -ethyl ] -pyrazolo [1,5-a ] [1,3,5] triazin-4-yl-amine,

[ (S) -1- (6-fluoro-1-phenyl-1H-benzimidazol-2-yl) -ethyl ] - (3H-imidazo [4,5-b ] pyridin-7-yl) -amine,

4-amino-6- [ (S) -1- (6-fluoro-7-hydroxymethyl-1-phenyl-1H-benzimidazol-2-yl) -ethylamino ] -pyrimidine-5-carbonitrile,

4-amino-6- [ (S) -1- (6-fluoro-1-pyridin-4-yl-1H-benzimidazol-2-yl) -ethylamino ] -pyrimidine-5-carbonitrile,

4-amino-6- [ (R) -1- (6-fluoro-1-pyridin-4-yl-1H-benzimidazol-2-yl) -ethylamino ] -pyrimidine-5-carbonitrile,

[ (R) -1- (6-fluoro-1-pyridin-4-yl-1H-benzimidazol-2-yl) -ethyl ] - (9H-purin-6-yl) -amine,

[ (S) -1- (6-fluoro-1-pyridin-4-yl-1H-benzimidazol-2-yl) -ethyl ] - (9H-purin-6-yl) -amine,

4-amino-6- [ (S) -1- (6-fluoro-1-phenyl-1H-benzimidazol-2-yl) -propylamino ] -pyrimidine-5-carbonitrile,

{ (S) -1- [ 6-fluoro-1- (5-fluoro-pyridin-3-yl) -1H-benzimidazol-2-yl ] -propyl } - (9H-purin-6-yl) -amine,

[ (S) -1- (6-fluoro-1-phenyl-1H-benzimidazol-2-yl) -propyl ] - (7H-purin-6-yl) -amine,

{ (S) -1- [1- (3, 5-difluoro-phenyl) -6-fluoro-1H-benzimidazol-2-yl ] -ethyl } - (9H-purin-6-yl) -amine,

2-amino-4- [ (S) -1- (6-fluoro-1-phenyl-1H-benzimidazol-2-yl) -ethylamino ] -pyrimidine-5-carbonitrile,

2-amino-4- { (S) -1- [ 6-fluoro-1- (5-fluoro-pyridin-3-yl) -1H-benzimidazol-2-yl ] -ethylamino } -pyrimidine-5-carbonitrile,

2-amino-4- { (S) -1- [ 6-fluoro-1- (5-fluoro-pyridin-3-yl) -1H-benzimidazol-2-yl ] -ethylamino } -6-methyl-pyrimidine-5-carbonitrile,

2-amino-4- [1- (3-phenyl-3H-imidazo [4,5-b ] pyridin-2-yl) -ethylamino ] -pyrimidine-5-carbonitrile,

2-amino-4-methyl-6- [1- (3-phenyl-3H-imidazo [4,5-b ] pyridin-2-yl) -ethylamino ] -pyrimidine-5-carbonitrile,

2-amino-4- [ (S) -1- (6-fluoro-1-pyridin-2-yl-1H-benzimidazol-2-yl) -ethylamino ] -pyrimidine-5-carbonitrile,

2- [ (S) -1- (2-amino-5-cyano-6-methyl-pyrimidin-4-ylamino) -ethyl ] -5-fluoro-3-pyridin-2-yl-3H-benzimidazole-4-carbonitrile,

4-amino-6- [ (R) -1- (6-fluoro-1-pyridin-2-yl-1H-benzimidazol-2-yl) -2-hydroxy-ethylamino ] -pyrimidine-5-carbonitrile,

4-amino-6- [ (S) -1- (6-fluoro-1-pyridin-2-yl-1H-benzimidazol-2-yl) -ethylamino ] -2-hydroxy-pyrimidine-5-carbonitrile, and

4-amino-6- ((6-fluoro-1-phenyl-1H-benzo [ d ] imidazol-2-yl) methylamino) pyrimidine-5-carbonitrile.

24. The compound of any one of claims 1 to 21, selected from:

9- [ (6-fluoro-1-phenyl-benzimidazol-2-yl) methyl ] purin-2-amine,

n- [ (1S) -1- (1-cyclobutyl-6-fluoro-benzimidazol-2-yl) ethyl ] -9H-purin-6-amine,

n- [ (1S) -1- (1-cyclopropyl-6-fluoro-benzimidazol-2-yl) ethyl ] -9H-purin-6-amine,

3- [ (6-fluoro-1-phenyl-benzimidazol-2-yl) methyl ] purin-6-amine,

9- [ (6-fluoro-1-phenyl-benzimidazol-2-yl) methyl ] purin-6-amine,

3- [ 6-fluoro-2- [1- (9H-purin-6-ylamino) ethyl ] benzimidazol-1-yl ] azetidine-1-carboxylic acid tert-butyl ester,

n- [1- [1- (azetidin-3-yl) -6-fluoro-benzimidazol-2-yl ] ethyl ] -9H-purin-6-amine,

n- [1- (6-fluoro-1-isopropyl-benzimidazol-2-yl) ethyl ] -9H-purin-6-amine,

N- [ (1S) -1- [ 6-fluoro-1- (1-isopropylazetidin-3-yl) benzimidazol-2-yl ] ethyl ] -9H-purin-6-amine,

2- (dimethylamino) -1- [3- [ 6-fluoro-2- [1- (9H-purin-6-ylamino) ethyl ] benzimidazol-1-yl ] azetidin-1-yl ] ethanone,

5- [ 6-fluoro-2- [1- (9H-purin-6-ylamino) ethyl ] benzimidazol-1-yl ] -1H-pyridin-2-one,

2- [3- [ 6-fluoro-2- [1- (9H-purin-6-ylamino) ethyl ] benzimidazol-1-yl ] azetidin-1-yl ] ethanol,

3- [ 6-fluoro-2- [1- (9H-purin-6-ylamino) ethyl ] benzimidazol-1-yl ] phenol,

n- [1- (6-fluoro-1-pyrazin-2-yl-benzimidazol-2-yl) ethyl ] -7H-purin-6-amine,

3-cyclopropyl-5-fluoro-2- [ (1S) -1- (9H-purin-6-ylamino) ethyl ] benzimidazole-4-carboxylic acid methyl ester,

3- [ 6-fluoro-2- [1- (9H-purin-6-ylamino) ethyl ] benzimidazol-1-yl ] phenol,

3- [ 6-fluoro-2- [1- (9H-purin-6-ylamino) ethyl ] benzimidazol-1-yl ] phenol,

[ 3-cyclopropyl-5-fluoro-2- [ (1S) -1- (9H-purin-6-ylamino) ethyl ] benzimidazol-4-yl ] -morpholino-methanone,

3- [ 6-fluoro-2- [ (1S) -1- (9H-purin-6-ylamino) ethyl ] benzimidazol-1-yl ] cyclobutanol,

3- [ 6-fluoro-2- [ (1S) -1- (9H-purin-6-ylamino) ethyl ] benzimidazol-1-yl ] cyclobutanol,

4-amino-6- [ [ (1S) -1- [ 6-fluoro-1- (3-hydroxycyclobutyl) benzimidazol-2-yl ] ethyl ] amino ] pyrimidine-5-carbonitrile,

n- [ (1S) -1- (1-benzyl-6-fluoro-benzimidazol-2-yl) ethyl ] -9H-purin-6-amine,

4-amino-6- [ [ (1S) -1- (1-benzyl-6-fluoro-benzimidazol-2-yl) ethyl ] amino ] pyrimidine-5-carbonitrile,

4-amino-6- [ [ (1S) -1- (7-bromo-1-cyclopropyl-6-fluoro-benzimidazol-2-yl) ethyl ] amino ] pyrimidine-5-carbonitrile,

n- [ (1S) -1- [ 6-fluoro-1- (3-methoxycyclobutyl) benzimidazol-2-yl ] ethyl ] -9H-purin-6-amine,

n- [ (1S) -1- [ 6-fluoro-1- (3-methoxycyclobutyl) benzimidazol-2-yl ] ethyl ] -9H-purin-6-amine,

(S) -N- (1- (7-fluoro-5, 6-dihydro-4H-imidazo [4,5,1-ij ] quinolin-2-yl) ethyl) -9H-purin-6-amine,

3- [ 6-fluoro-2- [ (1S) -1- (9H-purin-6-ylamino) ethyl ] benzimidazol-1-yl ] cyclobutanecarbonitrile,

[ 3-cyclopropyl-5-fluoro-2- [ (1S) -1- (thiazolo [5,4-d ] pyrimidin-7-ylamino) ethyl ] benzimidazol-4-yl ] -morpholino-methanone,

4-amino-6- [ [ (1S) -1- [ 1-cyclopropyl-6-fluoro-7- (morpholine-4-carbonyl) benzimidazol-2-yl ] ethyl ] amino ] pyrimidine-5-carbonitrile,

4-amino-6- [ [ (1S) -1- [ 6-fluoro-1- (1-methylpyrazol-3-yl) benzimidazol-2-yl ] ethyl ] amino ] pyrimidine-5-carbonitrile,

N- [ (1S) -1- [ 6-fluoro-1- (1-methylpyrazol-3-yl) benzimidazol-2-yl ] ethyl ] -9H-purin-6-amine,

4-amino-6- [ [ (1S) -1- [ 6-fluoro-1- (3-hydroxycyclobutyl) benzimidazol-2-yl ] ethyl ] amino ] pyrimidine-5-carbonitrile,

[ (S) -1- (5-fluoro-6, 7,8, 9-tetrahydro-2, 9 a-diazabenzo [ cd)]-1-yl) ethyl]- (9H-purin-6-yl) amine,

4-amino-6- [ (S) -1- (5-fluoro-6, 7,8, 9-tetrahydro-2, 9 a-diazabenzo [ cd)]-1-yl) ethylamino](ii) a pyrimidine-5-carbonitrile,

[ (S) -1- (7-fluoro-4-methyl-5, 6-dihydro-4H-imidazo [4,5,1-ij ] quinolin-2-yl) ethyl ] - (9H-purin-6-yl) amine,

4-amino-6- [ [ (1S) -1- [ 6-fluoro-1-isopropyl-7- (2-pyridyl) benzimidazol-2-yl ] ethyl ] amino ] pyrimidine-5-carbonitrile,

n- [ (1S) -1- [ 6-fluoro-1-isopropyl-7- (2-pyridyl) benzimidazol-2-yl ] ethyl ] -9H-purin-6-amine, 4-amino-6- [ [ (1S) -1- [ 1-ethyl-6-fluoro-7- (2-pyridyl) benzimidazol-2-yl ] ethyl ] amino ] pyrimidine-5-carbonitrile,

4-amino-6- [ [ (1S) -1- [ 6-fluoro-1-methyl-7- (2-pyridyl) benzimidazol-2-yl ] ethyl ] amino ] pyrimidine-5-carbonitrile,

n- [ (1S) -1- [ 1-ethyl-6-fluoro-7- (2-pyridyl) benzimidazol-2-yl ] ethyl ] -9H-purin-6-amine,

n- [ (1S) -1- [ 6-fluoro-1-methyl-7- (2-pyridyl) benzimidazol-2-yl ] ethyl ] -9H-purin-6-amine,

4-amino-6- [ [ (1S) -1- [ 1-cyclopropyl-6-fluoro-7- (3-pyridinyl) benzimidazol-2-yl ] ethyl ] amino ] pyrimidine-5-carbonitrile,

4-amino-6- [ [ (1S) -1- (1-cyclopropyl-6-fluoro-7-phenyl-benzimidazol-2-yl) ethyl ] amino ] pyrimidine-5-carbonitrile,

4-amino-6- [ [ (1S) -1- [ 6-fluoro-1- (2-methylpyrazol-3-yl) benzimidazol-2-yl ] ethyl ] amino ] pyrimidine-5-carbonitrile,

n- [ (1S) -1- [ 6-fluoro-1- (2-methylpyrazol-3-yl) benzimidazol-2-yl ] ethyl ] -9H-purin-6-amine,

4-amino-6- [ [ (1S) -1- [ 6-fluoro-1- (1-methylpyrazol-4-yl) benzimidazol-2-yl ] ethyl ] amino ] pyrimidine-5-carbonitrile,

n- [ (1S) -1- [ 6-fluoro-1- (1-methylpyrazol-4-yl) benzimidazol-2-yl ] ethyl ] -9H-purin-6-amine,

4-amino-6- [ [ (1S) -1- [ 6-fluoro-1- (2-methoxyethyl) -7- (2-pyridinyl) benzimidazol-2-yl ] ethyl ] amino ] pyrimidine-5-carbonitrile,

4-amino-6- [ [ (1S) -1- (7-bromo-1-methyl-benzimidazol-2-yl) ethyl ] amino ] pyrimidine-5-carbonitrile,

4-amino-6- [ [ (1S) -1- [7- (3-cyanophenyl) -1-methyl-benzimidazol-2-yl ] ethyl ] amino ] pyrimidine-5-carbonitrile,

4-amino-6- [ [ (1S) -1- [7- (4-cyanophenyl) -1-methyl-benzimidazol-2-yl ] ethyl ] amino ] pyrimidine-5-carbonitrile,

4-amino-6- [ [ (1S) -1- (6-fluoro-1-methyl-7-phenyl-benzimidazol-2-yl) ethyl ] amino ] pyrimidine-5-carbonitrile,

4-amino-6- [ [ (1S) -1- [ 6-fluoro-1-methyl-7- (3-pyridinyl) benzimidazol-2-yl ] ethyl ] amino ] pyrimidine-5-carbonitrile,

4-amino-6- [ [ (1S) -1- [ 6-fluoro-7- (1H-indazol-4-yl) -1-methyl-benzimidazol-2-yl ] ethyl ] amino ] pyrimidine-5-carbonitrile,

4-amino-6- [ [ (1S) -1- [ 6-fluoro-1-methyl-7- (1-methylpyrazol-4-yl) benzimidazol-2-yl ] ethyl ] amino ] pyrimidine-5-carbonitrile,

4-amino-6- [ [ (1S) -1- [ 6-fluoro-1-methyl-7- (1H-pyrazol-4-yl) benzimidazol-2-yl ] ethyl ] amino ] pyrimidine-5-carbonitrile,

4-amino-6- [ [ (1S) -1- [ 6-fluoro-1-methyl-7- (4-pyridinyl) benzimidazol-2-yl ] ethyl ] amino ] pyrimidine-5-carbonitrile,

n- [ (1S) -1- (7-bromo-6-fluoro-1-methyl-benzimidazol-2-yl) ethyl ] -9H-purin-6-amine,

n- [ (1S) -1- (6-fluoro-1-methyl-7-phenyl-benzimidazol-2-yl) ethyl ] -9H-purin-6-amine,

4-amino-6- [ [ (1S) -1- [7- (3, 6-dihydro-2H-pyran-4-yl) -6-fluoro-1-methyl-benzimidazol-2-yl ] ethyl ] amino ] pyrimidine-5-carbonitrile,

n- [ (1S) -1- [ 6-fluoro-1-methyl-7- (4-pyridyl) benzimidazol-2-yl ] ethyl ] -9H-purin-6-amine,

4-amino-6- [1- (6-fluoro-3, 4-dihydro-5-oxa-1, 2 a-diazacenaphthen-2-yl) ethylamino ] pyrimidine-5-carbonitrile,

[1- (6-fluoro-3, 4-dihydro-5-oxa-1, 2 a-diazacenaphthen-2-yl) ethyl ] - (9H-purin-6-yl) amine,

4-amino-6- [ (S) -1- (5-fluoro-8, 9-dihydro-7H-6-oxa-2, 9 a-diazabenzo [ c, d)]-1-yl) ethylamino](ii) a pyrimidine-5-carbonitrile,

[ (S) -1- (5-fluoro-8, 9-dihydro-7H-6-oxa-2, 9 a-diazabenzo [ c, d)]-1-yl) ethyl]- (9H-purin-6-yl) amine,

4-amino-6- [ (S) -1- ((R) -6-fluoro-3-methyl-3, 4-dihydro-5-oxa-1, 2 a-diazacenaphthen-2-yl) ethylamino ] pyrimidine-5-carbonitrile,

[ (S) -1- ((R) -6-fluoro-3-methyl-3, 4-dihydro-5-oxa-1, 2 a-diazacenaphthen-2-yl) ethyl ] (9H-purin-6-yl) amine,

4-amino-6- [ (S) -1- ((S) -6-fluoro-3-methyl-3, 4-dihydro-5-oxa-1, 2 a-diazacenaphthen-2-yl) ethylamino ] pyrimidine-5-carbonitrile,

[ (S) -1- ((S) -6-fluoro-3-methyl-3, 4-dihydro-5-oxa-1, 2 a-diazacenaphthen-2-yl) ethyl ] (9H-purin-6-yl) amine,

4-amino-6- [ (S) -1- (1-cyclopropyl-6-fluoro-7-pyridin-2-yl-1H-benzimidazol-2-yl) ethylamino ] -pyrimidine-5-carbonitrile, and

(6-fluoro-1-phenyl-1H-benzimidazol-2-ylmethyl) - (9H-purin-6-yl) amine.

25. A compound selected from formula I:

and stereoisomers, geometric isomers, tautomers and pharmaceutically acceptable salts thereof, wherein:

Z¹is CR¹Or N;

Z²is CR²Or N;

Z³is CR³Or N;

Z⁴is CR⁴Or N;

wherein Z¹、Z²、Z³And Z ⁴None, one or both are N;

wherein (i) X¹Is NR¹⁰And X²Is N, (ii) X¹Is S and X²Is CR¹¹，(iii)X¹Is O and X²Is CR¹¹Or (iv) X¹Is NR¹⁰And X²Is CR¹¹；

R⁵And R⁶Independently selected from H, C₁-C₁₂Alkyl radical, C₂-C₈Alkenyl and C₂-C₈Alkynyl, wherein alkyl, alkenyl and alkynyl are optionally substituted with one or more groups independently selected from: F. cl, Br, I, -CN, -CO₂H、-COCH₃、-COC(CH₃)₃、-CO₂CH₃、-CONH₂、-CONHCH₃、-CON(CH₃)₂、-NO₂、-NH₂、-NHCH₃、-N(CH₃)₂、-NHCOCH₃、-NHS(O)₂CH₃、-N(CH₃)C(CH₃)₂CONH₂、-N(CH₃)CH₂CH₂S(O)₂CH₃、=O、-OH、-OCH₃、-OCH₂CH₃、-OCH(CH₃)₂、-S(O)₂N(CH₃)₂、-SCH₃and-S (O)₂CH₃；

R¹、R²、R³、R⁴、R⁷、R⁸、R⁹And R¹²Independently selected from H, F, Cl, Br, I, -CH₃、-CH₂CH₃、-C(CH₃)₃、-CH₂OH、-CH₂CH₂OH、-C(CH₃)₂OH、-CH₂OCH₃、-CN、-CF₃、-CO₂H、-COCH₃、-COC(CH₃)₃、-CO₂CH₃、-CONH₂、-CONHCH₃、-CON(CH₃)₂、-C(CH₃)₂CONH₂、-NO₂、-NH₂、-NHCH₃、-N(CH₃)₂、-NHCOCH₃、-NHS(O)₂CH₃、-N(CH₃)C(CH₃)₂CONH₂、-N(CH₃)CH₂CH₂S(O)₂CH₃、=O、-OH、-OCH₃、-OCF₃、-S(O)₂N(CH₃)₂、-SCH₃、-S(O)₂CH₃Cyclopropyl, cyclobutyl, oxetanyl, morpholino and 1, 1-dioxo-thiopyran-4-yl;

or R⁶And R⁹Or R⁸And R⁹Form optionally substituted by one or more R¹²A group-substituted 5-or 6-membered heteroaryl or heterocyclyl ring;

R¹⁰is H, C₁-C₁₂Alkyl radical, C₂-C₈Alkenyl radical, C₂-C₈Alkynyl, C₆-C₂₀Aryl radical, C₃-C₁₂Carbocyclyl, C₂-C₂₀Heterocyclic group, C₁-C₂₀Heteroaryl, - (C)₁-C₁₂Alkylene group) - (C₃-C₁₂Carbocyclyl), - (C)₁-C₁₂Alkylene group) - (C₂-C₂₀Heterocyclyl), - (C)₁-C₁₂Alkylene) -C (= O) - (C)₂-C₂₀Heterocyclyl), - (C)₁-C₁₂Alkylene group) - (C₆-C₂₀Aryl), - (C)₆-C₂₀Aryl group) - (C₁-C₂₀Heteroaryl), - (C)₆-C₂₀Aryl group) - (C₂-C₂₀Heterocyclyl) and- (C)₁-C₁₂Alkylene group) - (C₁-C₂₀Heteroaryl), wherein alkyl, alkenyl, alkynyl, alkylene, carbocyclyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one or more groups independently selected from: F. cl, Br, I, -CH ₃、-CH₂CH₃、-C(CH₃)₃、-CH₂OH、-CH₂CH₂OH、-C(CH₃)₂OH、-CH₂OCH₃、-CN、-CH₂F、-CHF₂、-CF₃、-CO₂H、-COCH₃、-COC(CH₃)₃、-CO₂CH₃、-CONH₂、-CONHCH₃、-CON(CH₃)₂、-C(CH₃)₂CONH₂、-NO₂、-NH₂、-NHCH₃、-N(CH₃)₂、-NHCOCH₃、-NHS(O)₂CH₃、-N(CH₃)C(CH₃)₂CONH₂、-N(CH₃)CH₂CH₂S(O)₂CH₃、=O、-OH、-OCH₃、-S(O)₂N(CH₃)₂、-SCH₃、-S(O)₂CH₃Cyclopropyl, cyclobutyl, oxetanyl, morpholino and 1, 1-dioxo-thiopyran-4-yl; and is

R¹¹Is H, F, Cl, Br, I, CN, -N (R)⁵)₂、-OR⁵、C₁-C₁₂Alkyl radical, C₂-C₈Alkenyl radical, C₂-C₈Alkynyl, C₆-C₂₀Aryl radical, C₃-C₁₂Carbocyclyl, C₂-C₂₀Heterocyclic group, C₁-C₂₀Heteroaryl, - (C)₁-C₁₂Alkylene group) - (C₃-C₁₂Carbocyclyl), - (C)₁-C₁₂Alkylene group) - (C₂-C₂₀Heterocyclyl), - (C)₁-C₁₂Alkylene) -C (= O) - (C)₂-C₂₀Heterocyclyl), - (C)₁-C₁₂Alkylene radical)-(C₆-C₂₀Aryl) and- (C)₁-C₁₂Alkylene group) - (C₁-C₂₀Heteroaryl), wherein alkyl, alkenyl, alkynyl, alkylene, carbocyclyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one or more groups independently selected from: F. cl, Br, I, -CH₃、-CH₂CH₃、-C(CH₃)₃、-CH₂OH、-CH₂CH₂OH、-C(CH₃)₂OH、-CH₂OCH₃、-CN、-CH₂F、-CHF₂、-CF₃、-CO₂H、-COCH₃、-COC(CH₃)₃、-CO₂CH₃、-CONH₂、-CONHCH₃、-CON(CH₃)₂、-C(CH₃)₂CONH₂、-NO₂、-NH₂、-NHCH₃、-N(CH₃)₂、-NHCOCH₃、-NHS(O)₂CH₃、-N(CH₃)C(CH₃)₂CONH₂、-N(CH₃)CH₂CH₂S(O)₂CH₃、=O、-OH、-OCH₃、-S(O)₂N(CH₃)₂、-SCH₃、-S(O)₂CH₃Cyclopropyl, cyclobutyl, oxetanyl, morpholino and 1, 1-dioxo-thiopyran-4-yl.

26. A pharmaceutical composition comprising a compound of any one of claims 1 to 25 and a pharmaceutically acceptable carrier, glidant, diluent, or excipient.

27. The pharmaceutical composition of claim 26, further comprising a chemotherapeutic agent.

28. A process for preparing a pharmaceutical composition comprising combining a compound of any one of claims 1 to 25 with a pharmaceutically acceptable carrier.

29. A method of treating a disease or disorder, the method comprising administering to a patient having a disease or disorder selected from cancer, immune disorders, cardiovascular disease, viral infection, inflammation, metabolism/endocrine function disorders, and neurological disorders, and mediated by the p110 δ isoform of PI3 kinase, a therapeutically effective amount of a compound according to any one of claims 1 to 25.

30. The method of claim 29, wherein the disease or disorder is an immune disorder.

31. The method of claim 29, wherein the disease or disorder is systemic and local inflammation, arthritis, inflammation associated with immune suppression, organ transplant rejection, allergies, ulcerative colitis, crohn's disease, dermatitis, asthma, systemic lupus erythematosus, sjogren's syndrome, multiple sclerosis, scleroderma/systemic sclerosis, Idiopathic Thrombocytopenic Purpura (ITP), anti-neutrophil cytoplasmic antibody (ANCA) vasculitis, Chronic Obstructive Pulmonary Disease (COPD), psoriasis.

32. The method of claim 29, wherein the disease or disorder is a cancer selected from the group consisting of breast cancer, ovarian cancer, cervical cancer, prostate cancer, testicular cancer, genitourinary tract cancer, esophageal cancer, laryngeal cancer, glioblastoma, neuroblastoma, gastric cancer, skin cancer, keratoacanthoma, lung cancer, epidermoid carcinoma, large cell carcinoma, non-small cell lung cancer (NSCLC), small cell carcinoma, lung adenocarcinoma, bone cancer, colon cancer, adenoma, pancreatic cancer, adenoma, thyroid cancer, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, sarcoma, bladder cancer, liver cancer, and biliary tract cancer, kidney cancer, pancreatic cancer, myeloid disorders, lymphoma, hairy cell carcinoma, buccal cavity cancer, nasopharyngeal cancer, pharyngeal cancer, lip cancer, tongue cancer, mouth cancer, small bowel cancer, colon-rectal cancer, large bowel cancer, rectal cancer, cancers of the brain and central nervous system, cancer of the colon, cancer of the kidney, pancreas, bone marrow, lymphoma, hairy cell, buccal cavity, nasopharyngeal carcinoma, pharyngeal, Hodgkin's disease, leukemia, bronchial carcinoma, thyroid carcinoma, cancer of the liver and intrahepatic bile ducts, hepatocellular carcinoma, gastric carcinoma, glioma/glioblastoma, endometrial carcinoma, melanoma, renal and renal pelvis cancers, bladder cancer, uterine corpus carcinoma, cervical cancer, multiple myeloma, acute myelogenous leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, lymphocytic leukemia, myeloid leukemia, oral and pharyngeal cancers, non-hodgkin's lymphoma, melanoma, or villous colon adenoma.

33. The method of claim 29, wherein the disease or disorder is a hematopoietic malignancy selected from the group consisting of leukemia, non-hodgkin's lymphoma, diffuse large hematopoietic lymphoma, follicular lymphoma, mantle cell lymphoma, Chronic Lymphocytic Leukemia (CLL), multiple myeloma, Acute Myeloid Leukemia (AML), and myeloid leukemia (MCL).

34. The method of claim 29, further comprising administering an additional therapeutic agent selected from the group consisting of chemotherapeutic agents, anti-inflammatory agents, immunomodulatory agents, neurotropic factors, agents for treating cardiovascular disease, agents for treating liver disease, antiviral agents, agents for treating blood disorders, agents for treating diabetes, and agents for treating immunodeficiency disorders.

35. A kit for treating a disorder mediated by the p110 δ isoform of PI3 kinase, comprising:

a) a first pharmaceutical composition of claim 26; and

b) instructions for use.

36. A compound according to any one of claims 1 to 25 for use as a medicament.

37. Use of a compound according to any one of claims 1 to 25 for the treatment of a disease or disorder selected from cancer, immune disorders, cardiovascular disease, viral infection, inflammation, metabolism/endocrine function disorders and neurological disorders, and mediated by the p110 δ isoform of PI3 kinase.

38. A compound according to any one of claims 1 to 25 for use in the treatment of a disease or disorder selected from cancer, immune disorders, cardiovascular disease, viral infection, inflammation, metabolism/endocrine function disorders and neurological disorders, and mediated by the p110 δ isoform of PI3 kinase.

39. Use of a compound according to any one of claims 1 to 25 in the manufacture of a medicament.

40. The use of claim 39, wherein the medicament is for the treatment of cancer, immune disorders, cardiovascular disease, viral infection, inflammation, metabolism/endocrine function disorders, and neurological disorders.

41. The invention as hereinbefore described.