Quinoline derivatives as inhibitors of AXL / MER RTK and CSF1R

Abstract

The present invention relates to quinoline derivatives as inhibitors of Axl / Mer RTK (receptor tyrosine kinase) and CSF1R (colony stimulating factor 1 receptor). These compounds are suitable for treating disorders associated with, associated with, caused by or induced by Axl / Mer RTK and CSF1R, particularly their hyperfunction. The compounds are suitable for treating hyperproliferative disorders, such as cancer, particularly immunosuppressive cancers (e.g., those with innate immune immunosuppression in the tumor microenvironment (TME)), refractory cancers and cancer metastasis. They can also be used to treat inflammatory diseases and / or neurodegenerative diseases.

Description

Technical Field

[0001] The present invention relates to quinoline derivatives as inhibitors of Axl / Mer RTK (receptor tyrosine kinase) and CSF1R (colony stimulating factor 1 receptor). These compounds are suitable for treating disorders associated with, associated with, caused by or induced by Axl / Mer RTK and CSF1R, particularly their hyperfunction. The compounds are suitable for treating hyperproliferative disorders such as cancer, particularly immunosuppressive cancers (e.g., those with innate immune immunosuppression in the tumor microenvironment (TME)), refractory cancers and cancer metastasis. They can also be used to treat inflammatory diseases and / or neurodegenerative diseases. Background Art

[0002] Axl / Mer receptor tyrosine kinase (Axl / Mer RTK) is a member of the TAM (tyrosine, Axl, Mer) receptor tyrosine kinase. They are characterized by an extracellular domain consisting of two immunoglobulin-like domains followed by two type 3 fibronectin-like domains. The activation of the Axl / Mer occurs through its cognate protein ligands, which are growth arrest-specific protein 6 (Gas6) and protein S (Pros1), respectively.

[0003] Axl / Mer RTKs are known to regulate cell growth, differentiation and survival, but in recent years, Axl / Mer RTKs have become promising targets for cancer immunotherapy and are known to be regulators of immune homeostasis. These receptors, under the guidance of their cognate ligands Gas6 and Pros1, ensure the resolution of inflammation by inhibiting the activation of innate cells and restoring tissue function by promoting tissue repair and clearing apoptotic cells under normal circumstances (Paolino M et al., Cancers (Basel). 2016 Oct 21; 8(10) pii: E97).

[0004] However, in the tumor microenvironment (TME), activation of Axl / Mer receptors can lead to immune escape through Axl / Mer RTK-driven phagocytosis of apoptotic cells, negative regulation of immune responses, and subsequent inhibition of T cell activation (Zagórska A et al., Nat Immunol. 2014 October; 15(10): 920-8). In addition, Axl / Mer RTK plays a role in regulating the cytokine environment of tumors to limit effective CD8+ T cell recruitment and polarize macrophages to the M2 anti-inflammatory state, which plays an important role in enhancing tumor progression (Akalu YT et al., Immunol Rev. 2017 March; 276(1): 165-177). In addition, inhibition of the TLR pathway by Axl / Mer RTK in DCs triggers the suppression of CD8+ cytotoxic T cell populations, which can improve anti-tumor immunity. In addition, activation of the TAM family has been reported to downregulate TLR signaling-mediated inflammatory responses by increasing the expression of SOCS 1 and 3.

[0005] It has also been reported that the Axl / Mer receptor negatively regulates the activation of NK cells by regulating Cbl / b and inhibits the production of IFNγ cytokines by activated NK cells. Therefore, inhibition of the Axl / Mer receptor may be used as a new immunotherapy for various cancer patients by inducing a host immune response against tumor cell invasion (Davra V et al., Cancers (Basel). 2016 November 29; 8(12). pii: E107).

[0006] Colony stimulating factor 1 receptor (CSF1R) is also a cell surface homodimeric type III receptor tyrosine kinase of macrophages and other cells of the myeloid lineage, which is encoded by the c-fms proto-oncogene. Activation of CSF1R occurs through binding by its ligands CSF1 and IL-34 (Hume DA et al., Blood. 2012 Feb 23; 119(8): 1810-20).

[0007] CSF1R is known to regulate the differentiation of myeloid progenitor cells into heterogeneous populations of monocytes, macrophages, dendritic cells (DCs) and bone-resorbing osteoclasts. In addition, activated CSF1R promotes the survival, proliferation, differentiation and chemotaxis of differentiated macrophages (Geissmann F et al., Science. 2010 Feb 5; 327(5966): 656-61).

[0008] Based on the role of CSF1R in immune cells, various different approaches targeting CSF1R or its ligands are being developed for immunotherapy and cancer and are currently in the clinical stage. Summary of the invention

[0009] The object of the present invention is to provide compounds and / or pharmaceutically acceptable salts thereof which can be used as pharmaceutically active agents, in particular for the treatment of cell proliferative diseases such as cancer, but also for the treatment of inflammatory diseases and / or neurodegenerative diseases, as well as compositions comprising at least one such compound and / or a pharmaceutically acceptable salt thereof as a pharmaceutically active ingredient.

[0010] In a first aspect, the present invention relates to a compound having the general formula I:

[0011]

[0012] in

[0013] X 1 Independently selected from CR at each occurrence 3 and N;

[0014] X 2 Independently selected from CR at each occurrence 4 and N;

[0015] n is independently selected at each occurrence from 0, 1, and 2;

[0016] A is independently selected at each occurrence from any structure depicted in the following group W;

[0017]

[0018] Group W

[0019] R 1 is independently selected at each occurrence from hydrogen; C1-C6 alkyl; 5 and NR 5 R 6 C1-C6 alkyl substituted by one or both of: C3-C10 cycloalkyl; C1-C4 haloalkyl; -(C=O)R 5 A group consisting of; any one of which is optionally substituted;

[0020] R 2 In each occurrence, it is independently selected from C1-C6 alkyl; C3-C10 cycloalkyl; C1-C4 haloalkyl; -NR 7 R 8 ;-OR 8 A group consisting of; any one of which is optionally substituted;

[0021] R 3 and R 4 is independently selected at each occurrence from hydrogen; halogen such as Cl or F; C1-C3 alkyl; OR 5 ; A group consisting of C1-C4 haloalkyl; any one of which is optionally substituted;

[0022] R 5 and R 6 is independently selected at each occurrence from the group consisting of hydrogen; C1-C6 alkyl; C3-C10 cycloalkyl; C1-C4 haloalkyl, any of which is optionally substituted;

[0023] R 7 is independently selected at each occurrence from hydrogen; C1-C6 alkyl; 5 and NR 5 R 6 A group consisting of a C1-C6 alkyl group substituted by one or both of: C3-C10 cycloalkyl group; C1-C4 haloalkyl group; any one of which is optionally substituted;

[0024] R 8 independently selected at each occurrence from hydrogen; -CH(CH3)2; -C(CH3)3; C3-C10 cycloalkyl; C3-C10 heterocycloalkyl; C1-C4 haloalkyl; 5 and NR 5 R 6 The group consisting of C1-C6 alkyl substituted by one or both of C3-C10 cycloalkyl, C3-C10 heterocycloalkyl and C1-C4 haloalkyl; any of which is optionally substituted;

[0025] Z 1 independently selected at each occurrence from hydrogen; C1-C6 alkyl; 5 and NR 5 R 6 C1-C6 alkyl substituted by one or both of: C3-C10 cycloalkyl; halogen, OR 7 and NR 9 R 10 C3-C10 cycloalkyl substituted by one or more of: C3-C10 heterocycloalkyl; C3-C10 heterocycloalkyl substituted by one or more of halogen, C1-C6 alkyl, C3-C10 cycloalkyl and C1-C4 haloalkyl; C1-C4 haloalkyl;

[0026] R 9 and R 10 is independently selected at each occurrence from the group consisting of hydrogen; C1-C6 alkyl; C3-C10 cycloalkyl; C1-C4 haloalkyl; any of which is optionally substituted;

[0027] R 11 and R 12is independently selected at each occurrence from the group consisting of C1-C6 alkyl; C3-C10 cycloalkyl; C3-C10 heterocycloalkyl; C1-C4 haloalkyl; any of which is optionally substituted;

[0028] and pharmaceutically acceptable salts thereof.

[0029] In one embodiment, the compounds according to the present invention have the general formula II:

[0030]

[0031] in

[0032] R 1 , R 2 , R 3 , R 4 , R 11 , R 12 , Z 1 , X 1 , X 2 and n is as defined above;

[0033] and pharmaceutically acceptable salts thereof.

[0034] In one embodiment, the compounds according to the present invention have the general formula III:

[0035]

[0036] in

[0037] R 1 , R 2 , R 3 , R 4 , Z 1 , X 1 , X 2 and n is as defined above;

[0038] and pharmaceutically acceptable salts thereof,

[0039] Preferably,

[0040] R 3 and R 4 is independently selected at each occurrence from the group consisting of hydrogen; halogen such as Cl or F; C1-C3 alkyl, which is optionally substituted;

[0041] R 8 independently selected at each occurrence from hydrogen; -CH(CH3)2; -C(CH3)3; C3-C10 cycloalkyl; C1-C4 haloalkyl; 5 and NR 5 R 6C1-C6 alkyl substituted by one or both of: C3-C10 cycloalkyl and C1-C4 haloalkyl; any of which is optionally substituted; and

[0042] Z 1 is independently selected at each occurrence from hydrogen; C1-C6 alkyl; 5 and NR 5 R 6 C1-C6 alkyl substituted by one or both of: C3-C10 cycloalkyl; halogen, OR 7 and NR 9 R 10 C3-C10 cycloalkyl substituted by one or more of: C3-C10 heterocycloalkyl; C3-C10 heterocycloalkyl substituted by one or more of halogen, C1-C6 alkyl, C3-C10 cycloalkyl and C1-C4 haloalkyl; the group consisting of C1-C4 haloalkyl; and pharmaceutically acceptable salts thereof.

[0043] In one embodiment, the compounds according to the present invention have the general formula IV:

[0044]

[0045] in

[0046] R 1 , R 2 , R 3 , R 4 , Z 1 , X 2 and n are as defined above; and pharmaceutically acceptable salts thereof.

[0047] In one embodiment, the compounds according to the present invention have the general formula V:

[0048]

[0049] in

[0050] R 1 , R 2 , R 3 , R 4 , Z 1 and n are as defined above; and pharmaceutically acceptable salts thereof;

[0051] Preferably,

[0052] R 3 and R 4 It is hydrogen;

[0053] and pharmaceutically acceptable salts thereof.

[0054] In one embodiment, n=0 or 1, and Z 1 is selected from C1-C6 alkyl, in particular methyl, ethyl, propyl or isopropyl; C3-C10 cycloalkyl, in particular C3 cycloalkyl; C3-C10 heterocycloalkyl; 5 and NR 5 R 6 C1-C6 alkyl substituted by one or both of the following: and pharmaceutically acceptable salts thereof.

[0055] In one embodiment, R 2 Yes OR 8 , and R 8 Selected from -CH(CH3)2; -C(CH3)3; C1-C4 haloalkyl; C1-C6 alkyl substituted by one or both of C3-C10 cycloalkyl, C3-C10 heterocycloalkyl and C1-C4 haloalkyl; or C1-C6 alkyl substituted by one of C1-C4 haloalkyl, in particular trifluoromethyl, difluoromethyl, fluoromethyl, trifluoroethyl, difluoroethyl, fluoroethyl, trifluoropropyl, difluoropropyl, fluoropropyl, trifluoroisopropyl, difluoroisopropyl and fluoroisopropyl; and pharmaceutically acceptable salts thereof.

[0056] In one embodiment, n=0 or 1, and Z 1 is selected from C1-C6 alkyl, in particular methyl, ethyl, propyl or isopropyl; C3-C10 cycloalkyl, in particular C3 cycloalkyl; C3-C10 heterocycloalkyl; 5 and NR 5 R 6 C1-C6 alkyl substituted by one or both of 5 and R 6 is independently selected at each occurrence from hydrogen; C1-C6 alkyl; C3-C10 cycloalkyl; C1-C4 haloalkyl; any of which is optionally substituted;

[0057] and

[0058] R 2 Yes OR 8 , and R 8 Selected from -CH(CH3)2; -C(CH3)3; C1-C4 haloalkyl; C1-C6 alkyl substituted by one or both of C3-C10 cycloalkyl, C3-C10 heterocycloalkyl and C1-C4 haloalkyl; or C1-C6 alkyl substituted by one of C1-C4 haloalkyl, in particular trifluoromethyl, difluoromethyl, fluoromethyl, trifluoroethyl, difluoroethyl, fluoroethyl, trifluoropropyl, difluoropropyl, fluoropropyl, trifluoroisopropyl, difluoroisopropyl and fluoroisopropyl;

[0059] and pharmaceutically acceptable salts thereof.

[0060] In one embodiment, R 2 Yes OR 8 , and R 8 selected from C1-C4 haloalkyl, in particular one of trifluoromethyl, difluoromethyl, fluoromethyl, trifluoroethyl, difluoroethyl, fluoroethyl, trifluoropropyl, difluoropropyl, fluoropropyl, trifluoroisopropyl, difluoroisopropyl and fluoroisopropyl; or C1-C6 alkyl substituted by one of trifluoromethyl, difluoromethyl, fluoromethyl, trifluoroethyl, difluoroethyl, fluoroethyl, trifluoropropyl, difluoropropyl, fluoropropyl, trifluoroisopropyl, difluoroisopropyl and fluoroisopropyl.

[0061] In one embodiment, n=0 or 1, and Z 1 Selected from methyl, ethyl, propyl, isopropyl, C3 cycloalkyl, C4 cycloalkyl and C5 cycloalkyl.

[0062] In one embodiment, n=0 or 1; Z 1 is selected from the group consisting of methyl, ethyl, propyl, isopropyl, C3 cycloalkyl, C4 cycloalkyl and C5 cycloalkyl; and

[0063] R 2 Yes OR 8 ; and R 8 selected from C1-C4 haloalkyl, in particular one of trifluoromethyl, difluoromethyl, fluoromethyl, trifluoroethyl, difluoroethyl, fluoroethyl, trifluoropropyl, difluoropropyl, fluoropropyl, trifluoroisopropyl, difluoroisopropyl and fluoroisopropyl; or C1-C6 alkyl substituted by one of trifluoromethyl, difluoromethyl, fluoromethyl, trifluoroethyl, difluoroethyl, fluoroethyl, trifluoropropyl, difluoropropyl, fluoropropyl, trifluoroisopropyl, difluoroisopropyl and fluoroisopropyl.

[0064] In one embodiment, the compound according to the present invention has one of the structures shown below:

[0065]

[0066]

[0067]

[0068]

[0069]

[0070]

[0071]

[0072]

[0073]

[0074]

[0075]

[0076]

[0077]

[0078]

[0079] In another aspect, the present invention relates to a composition comprising at least one compound according to the present invention and at least one pharmaceutically acceptable carrier, excipient and / or diluent.

[0080] In one embodiment, the composition according to the present invention further comprises at least one other pharmaceutically active agent.

[0081] In another aspect, the invention relates to a compound according to the invention or a composition according to the invention for use as a pharmaceutically active agent, preferably in a method for the treatment of a disorder.

[0082] On the other hand, the present invention relates to a compound according to the present invention or a composition according to the present invention for use in the treatment of disorders associated with, associated with, caused by or induced by Axl / Mer and CSF1R receptor tyrosine kinases, in particular disorders associated with, associated with or caused by Axl / Mer and CSF1R (colony stimulating factor 1 receptor), preferably disorders associated with, associated with or caused by hyperfunction of said Axl / Mer and hyperfunction of said CSF1R.

[0083] In one embodiment, the disorder is selected from a hyperproliferative disorder, an inflammatory disorder, and a neurodegenerative disorder.

[0084] In one embodiment, the hyperproliferative disorder is a cancer, preferably a cancer selected from the group consisting of adenocarcinoma, acoustic neuroma, acute lymphoblastic leukemia, acute myeloid leukemia, adrenocortical carcinoma, AIDS-related cancers, AIDS-related lymphomas, anal cancer, appendix cancer, astrocytoma, atypical teratoid / rhabdoid tumors, ampullary carcinoma, basal cell tumor, bile duct cancer, bladder cancer, bone cancer, osteosarcoma and malignant fibrous histiocytoma, brain stem glioma, brain tumor, atypical teratoid / rhabdoid tumor of the central nervous system, craniopharyngioma, ependymoma, ependymoma, medulloblastoma, medullary epithelioma, moderately differentiated pineal parenchymal tumor, supratentorial primitive neuroectodermal tumor and pineoblastoma, brain and spinal cord tumors. tumors, breast cancer, urachal tumors, Burkitt lymphoma, carcinoid tumors, choroidal melanoma, gastrointestinal cancer, central nervous system lymphoma, cervical cancer, uterine corpus cancer, chordoma, chronic lymphocytic leukemia, chronic myeloid leukemia, chronic myeloproliferative disorder, colon cancer, colorectal cancer, cutaneous T-cell lymphoma, desmoid tumor, mycosis fungoides, endometrial cancer, esophageal cancer, esthesia neuroblastoma, tumors of the Ewing sarcoma family, extracranial germ cell tumors, extragonadal germ cell tumors, extrahepatic bile duct cancer, ear tumors, intraocular melanoma, retinoblastoma, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors, gastrointestinal stromal cell tumors, gynecological tumors, ovarian germ cell tumors, gestational trophoblastic tumors, gliomas, gallbladder cancer , hairy cell leukemia, head and neck cancer, heart cancer, hepatocellular carcinoma, histiocytosis, hypopharyngeal cancer, blood cancers, islet cell tumors (endocrine pancreas), renal cell carcinoma, kidney cancer, Langerhans cell histiocytosis, laryngeal cancer, leukemia, lip and oral cancer, liver cancer, lung cancer, non-small cell lung cancer, small intestine tumors, small cell lung cancer, Hodgkin lymphoma, non-Hodgkin lymphoma, primary central nervous system lymphoma, macroglobulinemia, malignant fibrous histiocytoma and osteosarcoma of bone, melanoma, Merkel cell carcinoma, mesothelioma, primary occult metastatic squamous neck cancer, spinalioms, multiple endocrine neoplasms syndrome, myelodysplastic syndrome, myelodysplastic / myeloproliferative neoplasms, myeloid leukemia, multiple Myeloma, Myeloproliferative disorders, Nasal and paranasal sinus cancer, Nasopharyngeal cancer, Neuroblastoma, Oral cancer, Oropharyngeal cancer, Osteosarcoma and malignant fibrous histiocytoma of bone, Ovarian cancer, Ovarian epithelial cancer, Ovarian low malignant potential tumors, Oligodendroglioma, Plasma cell tumors, Pancreatic cancer, Papilloma, Parathyroid cancer, Penile cancer, Pharyngeal cancer, Pituitary tumors, Plasma cell neoplasms / multiple myeloma, Pleuropulmonary blastoma, Prostate cancer, Rectal cancer, Renal cell carcinoma, Transitional cell carcinoma, Respiratory tract cancer, Rhabdomyosarcoma, Salivary gland cancer, Sarcoma, Skin testicular cancer, Ewing's sarcoma, Kaposi's sarcoma, Uterine sarcoma, Non-melanoma skin cancer, Melanoma skin cancer, Skin cancer, Small intestine cancer, Soft tissue sarcoma, Squamous cell carcinoma, Squamous neck cancer, Gastric cancer, Soft tissue tumors,Testicular cancer, Laryngeal cancer, Thymoma and thymic cancer, Thyroid cancer, Transitional cell cancer of the renal pelvis and ureter, Trophoblastic tumors, Testicular cancer, Cancers during pregnancy, Urinary tract tumors, Ureteral and renal pelvis cancer, Urethra cancer, Urothelial cancer, Uterine cancer, Vaginal cancer, Vulvar cancer, Waldenstrom's macroglobulinemia and Wilms' tumor, Cancers that cause fluid accumulation in the body's potential spaces, pleural effusions, pericardial effusions, peritoneal effusions also known as ascites, Giant cell tumors (GCT), GCT of bone, Pigmented villonodular synovitis (PVNS), Tenosynovial giant cell tumor (TGCT), TGCT of the tendon sheath (TGCT-TS). ,

[0085] In one embodiment, the inflammatory disorder is selected from osteoarthritis, inflammatory bowel syndrome, transplant rejection, systemic lupus erythematosus, ulcerative colitis, Crohn's disease, chronic obstructive pulmonary disease, emphysema, Kawasaki disease, hemophagocytic syndrome (macrophage activation syndrome), multicentric reticulohistiocytosis, atherosclerosis, primary progressive multiple sclerosis, type I diabetes, type II diabetes, insulin resistance, hyperglycemia, obesity, lipolysis, eosinophilia, osteoporosis, increased risk of fracture, Paget's disease, hypercalcemia, infection-mediated osteolysis (e.g., osteomyelitis), periprosthetic or wear debris-mediated osteolysis, endometriosis, inflammatory pain, chronic pain, and bone pain.

[0086] In one embodiment, the neurodegenerative disorder is selected from Binswanger dementia, holoprosencephaly, microcephaly, cerebral palsy, congenital hydrocephalus, ascites, progressive supranuclear palsy, glaucoma, Wilson's disease, Alzheimer's disease and other dementias, Parkinson's disease (PD) and PD-related disorders, multi-infarct dementia, frontotemporal dementia, pseudodementia, prion disease, motor neuron disease, Huntington's disease, spinocerebellar ataxia and spinal muscular atrophy.

[0087] In one embodiment, the use is in combination with another pharmaceutically active drug or therapy, particularly radiotherapy, chemotherapeutic agents, targeted drugs and immune checkpoint inhibitor drugs.

[0088] In another aspect, the present invention relates to a method for treating a disease selected from a hyperproliferative disorder, an inflammatory disorder and / or a neurodegenerative disorder, the method comprising administering to a patient in need thereof a compound according to the present invention or a composition according to the present invention.

[0089] The present invention also relates to the use of a compound or composition according to the present invention as defined above for the manufacture of a medicament for the treatment of a disease associated with, associated with, caused by, or induced by Axl / Mer and CSF1R. The present invention also relates to a method for treating a disease associated with, associated with, caused by, and / or induced by Axl / Mer and CSF1R, the method comprising administering a compound according to the present invention to a patient in need thereof. In one embodiment, the disease associated with, associated with, caused by, and / or induced by Axl / Mer and CSF1R is selected from a hyperproliferative disorder, an inflammatory disorder, and a neurodegenerative disorder, all of which are further defined above.

[0090] Without wishing to be bound by any theory, the inventors believe that the compounds of the present invention are highly effective inhibitors of Axl / Mer and CSF1R and are therefore suitable for treating disorders associated with, associated with, or caused by Axl / Mer and CSF1R, particularly their hyperfunction, thereby having an effect on one or more of cell survival, proliferation, autophagy, vascular smooth muscle homeostasis, migration, adhesion, angiogenesis, platelet aggregation, thrombus stabilization, erythropoiesis, oligodendrocyte survival, osteoclast function, innate immunity, inflammation, phagocytosis of apoptotic cells, and / or natural killer cell differentiation.

[0091] The compounds of the invention are capable of inhibiting cell proliferation and are therefore suitable for treating and / or preventing Axl / Mer and CSF1R induced hyperproliferative disorders, in particular disorders selected from cancer, in particular immunosuppressive cancers and refractory cancers and primary tumor metastasis. In a preferred embodiment of the invention, the Axl / Mer and CSF1R induced disorder is associated with overexpression and / or overactivity of Axl / Mer and CSF1R, for example an increased degree of autophosphorylation compared to normal tissue. The hyperproliferative disorder may be a cancer, preferably a cancer selected from breast cancer, colon cancer, prostate cancer, lung cancer, gastric cancer, ovarian cancer, endometrial cancer, renal cancer, hepatocellular carcinoma, thyroid cancer, uterine cancer, esophageal cancer, squamous cell carcinoma, leukemia, osteosarcoma, melanoma, glioblastoma and neuroblastoma. In a particularly preferred embodiment, the disorder is selected from breast cancer, glioblastoma, renal cancer, non-small cell lung cancer (NSCLC) and melanoma.

[0092] In a particularly preferred embodiment, the disorder is selected from breast cancer, glioblastoma, renal cancer, non-small cell lung cancer (NSCLC) and melanoma. Examples of disorders associated with, associated with, caused by and / or induced by hyperfunction of Axl / Mer and CSF1R are acute lymphoblastic leukemia, acute myeloid leukemia, adrenocortical carcinoma, AIDS-related cancers, AIDS-related lymphomas, anal cancer, appendix cancer, astrocytoma, atypical teratoid / rhabdoid tumors, basal cell tumors, bile duct cancer, bladder cancer, bone cancer, osteosarcoma and malignant fibrous histiocytoma, brain stem glioma, brain tumor, atypical teratoid / rhabdoid tumor of the central nervous system, astrocytoma, craniopharyngioma, ependymoma, ependymoma, medulloblastoma, medullary epithelioma, moderately differentiated pineal parenchymal tumor, supratentorial primitive neuroectoderma, glioma of the brain ... Germ layer tumors and pineoblastoma, brain and spinal cord tumors, breast cancer, bronchial tumors, Burkitt lymphoma, carcinoid tumors, gastrointestinal cancer, central nervous system (CNS) lymphoma, cervical cancer, chordoma, chronic lymphocytic leukemia, chronic myeloid leukemia, chronic myeloproliferative disorder, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, mycosis fungoides, Sezary syndrome, endometrial cancer, ependymoma, ependymoma, esophageal cancer, sensorineuroblastoma, tumors of the Ewing sarcoma family, extracranial germ cell tumors, extragonadal germ cell tumors, extrahepatic bile duct cancer, intraocular melanoma, retinoblastoma, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors, gastrointestinal stromal cell tumors, extracranial germ cell tumors, extragonadal germ cell tumors, ovarian germ cell tumors, gestational trophoblastic tumors, gliomas, hairy cell leukemia, head and neck cancer, heart cancer, hepatocellular (liver) cancer, histiocytosis, Hodgkin lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumor (endocrine pancreas), Kaposi sarcoma, renal cell carcinoma, kidney cancer, Langerhans cell histiocytosis, laryngeal cancer, acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, leukemia, lip and oral cancer, liver cancer, lung cancer, non-small cell lung cancer, small cell lung cancer, AIDS-related lymphoma, Burkitt lymphoma, cutaneous T-cell Lymphoma, Hodgkin's lymphoma, Non-Hodgkin's lymphoma, Primary central nervous system lymphoma, Macroglobulinemia, Malignant fibrous histiocytoma and osteosarcoma of bone, Medulloblastoma, Medullary epithelioma, Melanoma, Intraocular melanoma, Merkel cell carcinoma, Mesothelioma, Primary occult metastatic squamous neck cancer, Oral cancer, Multiple endocrine neoplasms syndrome, Multiple myeloma / plasma cell neoplasms, Myelodysplastic syndrome, Myelodysplastic / myeloproliferative neoplasms, Myeloid leukemia, Myeloid leukemia, Myeloma (multiple), Myeloproliferative disorders, Nasal and paranasal sinus cancer, Nasopharyngeal carcinoma, Neuroblastoma, Non-Hodgkin's lymphoma, Non-small cell lung cancer, Oral cancer, Oral cancer, Oropharyngeal cancer,Osteosarcoma and malignant fibrous histiocytoma of bone, ovarian cancer, ovarian epithelial cancer, ovarian germ cell tumor, ovarian low malignant potential tumor, pancreatic cancer, papilloma, parathyroid cancer, penile cancer, pharyngeal cancer, pinealoblastoma and supratentorial primitive neuroectodermal tumor, pituitary tumor, plasma cell neoplasm / multiple myeloma, pleuropulmonary blastoma, pregnancy and breast cancer, prostate cancer, colorectal cancer, renal cell (kidney) cancer, transitional cell carcinoma, respiratory cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, Ewing's sarcoma, Kaposi's Western sarcoma, uterine sarcoma, non-melanoma skin cancer, melanoma skin cancer, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, squamous neck cancer, gastric cancer, supratentorial primitive neuroectodermal tumor, T-cell lymphoma, testicular cancer, laryngeal cancer, thymoma and thymic carcinoma, thyroid cancer, transitional cell carcinoma of the renal pelvis and ureter, trophoblastic tumor, cancer of pregnancy, cancer of the ureter and renal pelvis, transitional cell carcinoma, urethral cancer, uterine cancer, endometrial cancer, uterine sarcoma, vaginal cancer, vulvar cancer, Waldenstrom's macroglobulinemia and Wilms' tumor.

[0093] The compounds of the present invention are highly effective inhibitors of Axl / Mer and CSF1R. The compounds of the present invention are suitable for use as pharmaceutically active agents, which are suitable for treating disorders associated with, associated with, or caused by Axl / Mer and CSF1R, particularly their hyperfunction. Therefore, the compounds of the present invention are suitable for treating disorders induced by Axl / Mer and CSF1R.

[0094] Without wishing to be bound by any theory, the inventors believe that CSF1, a chemokine, appears to be a promising target for inhibiting the contribution of TAMs to tumor development. CSF1 is a potent chemoattractant and is considered to be the most important growth factor regulating the differentiation of monocytes into macrophages. Therefore, the inventors believe that inhibiting CSF1R signaling in tumor-promoting TAMs represents an attractive strategy to eliminate or repolarize these cells and may be a new immunotherapy for cancer patients.

[0095] Again without wishing to be bound by any theory, the inventors believe that blockade of CSF1 / CSF1R not only reduces the number of TAMs, but also reprograms the remaining TAMs to support antigen presentation and T cell activation within the tumor microenvironment. This in turn leads to reduced immunosuppression and increased interferon response, thereby limiting tumor progression (Zhu Y et al., Cancer Res. 2014 Sep 15; 74(18):5057-69).

[0096] In summary, dual inhibition of CSF1R and Axl / Mer RTK is expected to provide a powerful anti-cancer effect through immunomodulation by using different signaling pathways of immune cells. The present invention provides compounds with dual inhibitory ability to CSF1R and Axl / Mer RTK. They can then be used as pharmaceutical active agents, especially for cancer therapy through immune system modulation.

[0097] When used herein, the term "optionally substituted" means that a hydrogen atom or several such hydrogen atoms present and attached to a member atom within a group may be replaced by a suitable group, for example, a halogen including fluorine, chlorine, C1-C3 alkyl, C1-C3 haloalkyl such as CH2F, CHF2, CF3, CH2CF3, methylhydroxy, hydroxy, COOMe, C(O)H, COOH, alkoxy, in particular C1-C3 alkoxy such as OMe or OCF3.

[0098] In one embodiment, the present invention also relates to pharmaceutically acceptable salts of the compounds according to the present invention.

[0099] The present invention also relates to a combination of a compound according to the invention together with another anticancer agent.

[0100] The combination of the compound according to the present invention and another anticancer agent has a better anticancer effect. For example, the combination with other anticancer agents may restore the sensitivity of the cell line that has become resistant to other anticancer agents, and also has synergistic effect with the combination of other immune checkpoint inhibitors and radiotherapy. The example of the medicament that the compound according to the present invention can be combined with is cytotoxic drugs (actinomycin, all-trans retinoic acid, azacitidine, azathioprine, bleomycin, bortezomib, carboplatin, capecitabine, cisplatin, chlorambucil, cyclophosphamide, cytarabine, daunorubicin, docetaxel, doxifluridine, doxorubicin, epirubicin, epothilone, etoposide, fluorouracil, gemcitabine, hydroxyurea, idarubicin, imatinib, irinotecan, nitrogen mustard, mercaptopurine , methotrexate, mitoxantrone, oxaliplatin, paclitaxel, pemetrexed, teniposide, thioguanine, topotecan, valrubicin, vemurafenib, vinblastine, vincristine, vindesine, vinorelbine), targeted drugs (bevacizumab, rituximab, ipilimumab, bortezomib, imatinib, seliciclib, ado-trastuzumab, afatinib, aldesleukin, axitinib, belinstat, bevacizumab, bortezomib, bosutinib, brentuximab Antirestatins, cabozantinib, canakinumab, carfilzomib, ceritinib, cetuximab, crizotinib, dabrafenib, dasatinib, erlotinib, everolimus, gefitinib, ibrutinib, ibrutinib, idelalisib, imatinib, lapatinib, lenvatinib, nilotinib, obinutuzumab, ofatumumab, olaparib, palbociclib, panitumumab, panobinostat, pazopanib, pertuzumab, ponatinib, ramucirumab, regorafenib, rituximab monoclonal antibody, romidepsin, ruxolitinib, siprolimab, sirolimus-T, sorafenib, temsirolimus, tocilizumab, tofacitinib, tositumomab, trametinib, trastuzumab, vandetanib, vemurafenib, vismodegib, vorinostat, ziv-aflibercept), immune checkpoint inhibitor drugs (ipilimumab, nivolumab, pembrolizumab, atezolizumab, avelumab, bevacizumab, tremelimumab).

[0101] Other combinations may also or instead include several compounds according to the invention together. These combinations are also contemplated and encompassed by the combinations according to the invention.

[0102] The term "alkyl" refers to a monovalent straight, branched or cyclic chain saturated aliphatic hydrocarbon group having a number of carbon atoms within a specified range. Thus, for example, "C1-C6 alkyl" refers to hexylalkyl and pentylalkyl isomers and any of n-butyl, isobutyl, sec-butyl and tert-butyl, n-propyl and isopropyl, cyclopropyl, ethyl and methyl.

[0103] The term "alkenyl" refers to a monovalent straight or branched aliphatic hydrocarbon radical containing one carbon-carbon double bond and having a number of carbon atoms within the specified range. Thus, for example, "C2-C6 alkenyl" refers to all hexenyl and pentenyl isomers as well as 1-butenyl, 2-butenyl, 3-butenyl, isobutenyl, 1-propenyl, 2-propenyl and vinyl.

[0104] Unless otherwise limited, the term "cycloalkyl" alone or in combination with any other term refers to a cyclic hydrocarbon group having 3 to 8 carbon atoms, such as optionally substituted or unsubstituted. Thus, for example, "C3-C8 cycloalkyl" refers to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

[0105] The term "haloalkyl" refers to an alkyl group as defined herein that is substituted with at least one halogen. Examples of straight or branched "haloalkyl" groups that can be used in the present invention include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, and tert-butyl groups that are independently substituted with one or more halogens. The term "haloalkyl" should be interpreted as including substituents such as -CHF2, -CF3, -CH2-CH2-F, -CH2-CF3, etc. More specifically, the term "C1-C4 haloalkyl" is meant to include, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, fluoropropyl, difluoropropyl, trifluoropropyl, fluoroisopropyl, difluoroisopropyl, trifluoroisopropyl, fluorobutyl, difluorobutyl, trifluorobutyl, wherein "butyl" includes all butyl isomers, i.e., n-butyl, isobutyl, sec-butyl and tert-butyl, and alkyl groups of any of the foregoing substituted with chlorine, as well as C1-C4 alkyl groups in which more than one hydrogen is replaced by halogen (F, Cl, Br and / or I).

[0106] The term "heteroalkyl" refers to an alkyl group in which one or more carbon atoms are replaced by a heteroatom such as O, N or S. For example, if the carbon atom of the alkyl group attached to the parent molecule is replaced by a heteroatom (e.g., O, N or S), the resulting heteroalkyl group is an alkoxy group (e.g., -OCH3, etc.), an amine (e.g., -NHCH3, -N(CH3)2, etc.), or a sulfanyl group (e.g., -SCH3, etc.), respectively. If the non-terminal carbon atom of the alkyl group not attached to the parent molecule is replaced by a heteroatom (e.g., O, N or S), the resulting heteroalkyl group is an alkyl ether (e.g., -CH2CH2-O-CH3, etc.), an alkyl amine (e.g., -CH2NHCH3, -CH2N(CH3)2, etc.), or an alkyl sulfide (e.g., -CH2-S-CH3), respectively.

[0107] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0108] As used herein, the term "phenyl" means an optionally substituted or unsubstituted phenyl group.

[0109] As used herein, the term "benzyl" means an optionally substituted or unsubstituted benzyl group.

[0110] The term "heteroaryl" refers to (i) optionally substituted 5- and 6-membered heteroaromatic rings, and (ii) optionally substituted 9- and 10-membered bicyclic fused ring systems in which at least one ring is aromatic, wherein the heteroaromatic ring or the bicyclic fused ring system contains 1 to 4 heteroatoms independently selected from N, O and S, wherein each N is optionally in the form of an oxide, and each S in a ring that is not aromatic is optionally S(O) or S(O)2. Suitable 5- and 6-membered heteroaromatic rings include, for example, pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thienyl, furanyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl and thiadiazolyl. Suitable 9- and 10-membered heterobicyclic fused ring systems include, for example, benzofuranyl, indolyl, indazolyl, naphthyridinyl, isobenzofuranyl, benzopiperidinyl, benzisoxazolyl, benzoxazolyl, chromenyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, isoindolyl, benzodioxolyl, benzofuranyl, imidazo[1,2-a]pyridinyl, benzotriazolyl, dihydroindolinyl, dihydroisoindolyl, indazolyl, indolinyl, isoindolyl, quinoxalinyl, quinazolinyl, 2,3-dihydrobenzofuranyl, and 2,3-dihydrobenzo-1,4-dioxanyl.

[0111] The term "heterocyclyl" or "heterocycloalkyl", especially "C3-C 10"heterocycloalkyl" refers to (i) an optionally substituted 3- to 10-membered saturated or unsaturated but non-aromatic monocyclic ring containing at least one carbon atom and 1 to 4 heteroatoms, (ii) an optionally substituted bicyclic ring system containing 1 to 6 heteroatoms, and (iii) an optionally substituted tricyclic ring system, wherein each ring in (ii) or (iii) is independently fused to or bridged with another one or more rings, and each ring is saturated or unsaturated but non-aromatic, and wherein each heteroatom in (i), (ii) and (iii) is independently selected from N, O and S, wherein each N is optionally in the form of an oxide, and each S is optionally oxidized to S(O) or S(O)2. Suitable 3 - to 10-membered saturated heterocycloalkanes include, for example, azetidinyl, piperidinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, pyrrolidinyl, imidazolidinyl, piperazinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrazolidinyl, hexahydropyrimidinyl, thiazinyl, thioazepanyl, azepanyl, diazepanyl, tetrahydropyranyl, tetrahydrothiopyranyl, dioxane and azocyclooctyl. Suitable unsaturated heterocycles include heterocycles corresponding to the saturated heterocycles listed in the previous sentence and in which single bonds are replaced by double bonds. It should be understood that the specific rings and ring systems suitable for use in the present invention are not limited to those listed in this paragraph and the preceding paragraphs. These rings and ring systems are merely representative.

[0112] Pharmaceutical composition

[0113] Pharmaceutically acceptable salt

[0114] Examples of pharmaceutically acceptable addition salts include, but are not limited to, nontoxic inorganic and organic acid addition salts such as acetate derived from acetic acid, aconitate derived from aconitic acid, ascorbate derived from ascorbic acid, benzenesulfonate derived from benzenesulfonic acid, benzoate derived from benzoic acid, cinnamate derived from cinnamic acid, citrate derived from citric acid, pamoate derived from pamoic acid, heptanoate derived from heptanoic acid, formate derived from formic acid, fumarate derived from fumaric acid, glutamate derived from glutamic acid, glycolate derived from glycolic acid, hydrochloride derived from hydrochloric acid, hydrobromide derived from hydrobromic acid, The salts may be formed by procedures well known and described in the art.

[0115] Other acids, such as oxalic acid, which might not be considered pharmaceutically acceptable, may be employed in the preparation of salts useful as intermediates in obtaining the chemical compounds of the invention and their pharmaceutically acceptable acid addition salts.

[0116] In another embodiment, the compounds of the invention are used according to the invention in their corresponding free base form.

[0117] The metal salts of the chemical compounds of the present invention include alkali metal salts such as sodium salts of the chemical compounds of the present invention containing a carboxyl group.

[0118] The chemical compounds of the invention may be provided in unsolvated form or in solvated form with pharmaceutically acceptable solvents such as water, ethanol, etc. The solvated forms may also include hydrate forms, such as monohydrate, dihydrate, hemihydrate, trihydrate, tetrahydrate, etc. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the present invention.

[0119] Administration and dosage form

[0120] The production and administration of the medicament containing the compound of the present invention, its active metabolite, isomer or salt according to the present invention can be carried out according to known pharmaceutical methods.

[0121] Although the compounds of the invention that can be used in therapy according to the invention can be administered in the form of the original chemical compound, it is preferred that the active ingredient is introduced into a pharmaceutical composition, optionally in the form of a physiologically acceptable salt, together with one or more adjuvants, excipients, carriers, buffers, diluents and / or other customary pharmaceutical excipients. These salts of the compounds of the invention may be anhydrous or solvated.

[0122] In a preferred embodiment, the present invention provides a medicament comprising a compound or a pharmaceutically acceptable salt or derivative thereof that can be used according to the present invention, and one or more pharmaceutically acceptable carriers therefor and optionally other therapeutic and / or prophylactic ingredients. The carrier must be "acceptable" in the sense of being compatible with the other ingredients of the dosage form and not deleterious to the recipient thereof.

[0123] The medicine of the present invention can be suitable for oral, rectal, bronchial, nasal, local, buccal, sublingual, transdermal, vaginal or parenteral (including skin, subcutaneous, intramuscular, intraperitoneal, intravenous, intraarterial, intracerebral, intraocular injection or infusion) medicine for administration, or take the form suitable for administration by suction or insufflation including powder and liquid aerosol administration or medicine administered by sustained release system. The suitable example of sustained release system includes the semipermeable matrix of the solid hydrophobic polymer containing the compound of the present invention, and the matrix can take the form of shaped articles such as film or microcapsule.

[0124] Therefore, the compounds that can be used according to the present invention can be placed in pharmaceutical forms and unit dosage forms thereof together with conventional adjuvants, carriers or diluents. These forms include solids, especially tablets, filled capsules, powders and pellets, and liquids, especially aqueous or non-aqueous solutions, suspensions, emulsions, elixirs and capsules filled with them, all of which are used for oral administration, suppositories for rectal administration and sterile injection solutions for parenteral use. Such drugs and unit dosage forms thereof can contain conventional ingredients in conventional proportions, with or without additional active compounds or principles, and such unit dosage forms can contain any suitable effective amount of the active ingredient commensurate with the daily dosage range to be used.

[0125] The compounds that can be used according to the invention can be administered in a wide variety of oral and parenteral dosage forms. It will be apparent to those skilled in the art that the following dosage forms may contain a compound that can be used according to the invention or a pharmaceutically acceptable salt of a compound that can be used according to the invention as an active ingredient.

[0126] For preparing medicaments from the compounds that can be used according to the invention, pharmaceutically acceptable carriers can be solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories and dispersible granules. A solid carrier can be one or more substances which may also act as a diluent, flavoring agent, solubilizer, lubricant, suspending agent, binder, preservative, tablet disintegrating agent or encapsulating material.

[0127] In powders, the carrier is a finely divided solid with which the finely divided active ingredient is mixed. In tablets, the active ingredient is mixed with a carrier having the necessary binding capacity in suitable proportions and compressed into the desired shape and size. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low melting waxes, cocoa butter, and the like. The term "preparation" is intended to include dosage forms of the active compound with an encapsulating material as a carrier providing a capsule in which the active ingredient, with or without a carrier, is surrounded by the carrier and thereby associated with it. Likewise, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid forms suitable for oral administration.

[0128] In order to prepare suppositories, first low melting point wax such as a mixture of fatty acid glycerides or cocoa butter is melted, and for example, active ingredient is evenly dispersed therein by stirring. The molten homogeneous mixture is then poured in a convenient size mold, allowing it to cool and therefore solidify. Compositions suitable for vaginal administration can exist as pessaries, tampons, creams, gels, pastes, foams or sprays, which also contain suitable carriers as known in the art except the active ingredient. Liquid preparations include solutions, suspensions and emulsions, such as water or water-propylene glycol solutions. For example, parenteral injection liquid preparations can be formulated into a solution in an aqueous polyethylene glycol solution.

[0129] Therefore, the chemical compound according to the present invention can be formulated for parenteral administration (e.g., by injection, such as bolus injection or continuous infusion), and can be present in ampoules, prefilled syringes, small volume infusions, or in multi-dose containers with added preservatives in the form of unit doses. The composition can take the form of a suspension, solution, or emulsion such as in an oily or aqueous medium, and can contain preparatons such as suspending agents, stabilizers, and / or dispersants. Alternatively, the active ingredient can take the form of a powder obtained by aseptic separation of sterile solids or by freeze drying from a solution, for reconstitution with a suitable medium such as sterile pyrogen-free water before use.

[0130] Aqueous solutions suitable for oral use can be prepared by dissolving the active ingredient in water and adding suitable colorants, flavoring agents, stabilizers and thickeners as desired. Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active ingredient in water with a viscous material such as a natural or synthetic gum, resin, methylcellulose, sodium carboxymethylcellulose or other well-known suspending agents.

[0131] Also included are solid form preparations that are intended to be converted into liquid form preparations for oral administration just before use. These liquid forms include solutions, suspensions, and emulsions. These preparations, in addition to the active ingredient, may also contain coloring agents, flavoring agents, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, etc.

[0132] In one embodiment of the invention, the drug is administered topically or systemically or by a combination of both routes.

[0133] For administration, in one embodiment, the compounds of the present invention can be administered in a dosage form containing 0.001% to 70% by weight of the compound, preferably 0.01% to 70% by weight of the compound, even more preferably 0.1% to 70% by weight of the compound. In one embodiment, the suitable amount of the compound administered is in the range of 0.01 mg / kg body weight to 1 g / kg body weight.

[0134] Compositions suitable for administration also include lozenges comprising the active agent in a flavored base, usually sucrose and acacia or tragacanth; lozenges comprising the active ingredient in a shaped base such as gelatin and glycerin or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.

[0135] The solution or suspension is directly applied to the nasal cavity by conventional means, for example, using a dropper, a pipette or a spray. The composition can be provided in a single dose or multiple dose form. In the latter case of a dropper or a pipette, this can be achieved by administering the solution or suspension of a predetermined volume suitable for the patient. In the case of a spray, this can be achieved, for example, by a metered atomizing spray pump.

[0136] Administration to the respiratory tract can also be achieved using an aerosol formulation in which the active ingredient is provided in a pressurized package with a suitable propellant such as a chlorofluorocarbon (CFC) such as dichlorodifluoromethane, trichloromonofluoromethane or dichlorotetrafluoroethane, carbon dioxide or other suitable gas. The aerosol can also conveniently contain a surfactant such as lecithin. The dosage of the drug can be controlled by equipping a metering valve.

[0137] Alternatively, the active ingredient may be provided in the form of a dry powder, for example a powder mixture of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethylcellulose and polyvinylpyrrolidone (PVP). Conveniently, the powder carrier will form a gel in the nasal cavity. The powder composition may be presented in unit dosage form, for example in capsules or cartridges of, for example, gelatin or blister packs from which the powder can be administered using an inhaler.

[0138] In compositions intended for administration to the respiratory tract, including intranasal compositions, the compound will typically have a small particle size, for example of the order of 5 microns or less. Such a particle size may be obtained by means known in the art, for example by micronization.

[0139] When desired, compositions adapted to give sustained-release of the active ingredient may be used.

[0140] The pharmaceutical preparation is preferably in unit dosage form. In this form, the preparation is subdivided into unit doses containing appropriate amounts of the active ingredient. The unit dosage form can be a packaged preparation containing discrete quantities of the preparation, such as packaged tablets, capsules, and powders in vials or ampoules. In addition, the unit dosage form can also be a capsule, tablet, cachet, or lozenge itself, or it can be any of these dosage forms in a packaged form in appropriate quantities. Preferred compositions are tablets or capsules for oral administration and liquids for intravenous administration and continuous infusion.

[0141] Further details of techniques for formulation and administration may be found in the latest edition of Remington's Pharmaceutical Sciences (Maack Publishing Co. Easton, Pa.).

[0142] The present invention is further illustrated by the following figures, tables and examples, which are provided to illustrate the present invention and not to limit it.

[0143] surface

[0144] Referring now to the figures and tables,

[0145] Table 1 shows activity data for selected compounds of the invention in Axl, Mer and CSF1R binding assays. Inhibition is expressed as Kd using the following symbols: A = Kd less than 0.1 uM; B = Kd greater than 0.1 uM but less than 0.5 uM; C = Kd greater than 0.5 uM. "nd" = not determined.

[0146] Table 2 shows the activity data of the CSF1R binding assay for selected compounds of the invention. Inhibition is expressed as a percentage number as a percentage of inhibition ("Percent (%)"), and the inhibition numbers are divided into different categories ("Range") using the following additional symbols: A = ≥ 80% inhibition; 80% inhibition > B ≥ 50% inhibition; 50% inhibition > C.

[0147] Table 3 shows the activity data of selected compounds of the invention in the cellular Axl Elisa assay (H1299). Inhibition is expressed as IC using the following symbols: 50 :A=IC 50 Less than 0.5uM; B = IC 50 Greater than or equal to 0.5uM but less than 1.0uM; C = IC 50 Greater than or equal to 1.0uM.

[0148] Table 4 shows the activity data of selected compounds of the invention in the cellular CSF1R Elisa assay (THP-1). Inhibition is expressed as IC using the following symbols: 50 :A=IC 50 Less than 0.5uM; B = IC 50 Greater than or equal to 0.5uM but less than 1.0uM; C = IC 50 Greater than or equal to 1.0uM.

[0149] Table 5 shows the CSF1R activity data in the cellular M-NFS-60 viability assay; CSF1R inhibition is expressed as IC using the following notation: 50 :A:IC 50 <1.0μM; B: 1.0μM≤IC 50 <10μM; C:IC 50 ≥10μM.

[0150] Table 6 shows the data for Axl, Mer and CSF1R activity in the cell BaF3 viability assay; inhibition is expressed as IC using the following symbols 50 :A:IC 50 <1.0μM; B: 1.0μM≤IC 50 <10μM; C:IC 50 ≥10μM.

[0151] Table 7 shows comparative data for selected compounds of the invention (marked with double asterisks **) compared to selected compounds of WO2016 / 166250 (marked with a single asterisk *) in terms of binding activity (Axl and Mer) and cellular activity (Axl H1299 Elisa assay).

[0152] Table 8 summarizes the structures and corresponding characteristics of compounds 1-179.

[0153] Figure 1 and 2 Comparative data of compound 4 of the present invention (annotated with two asterisks ** and diamonds) compared to compound 27 of WO2016 / 166250 (annotated with a single asterisk * and open squares) in the mouse models EMT-6 and MV4-11 are shown; EMT-6 measures triple inhibition of Axl, Mer and CSF1R. MV4-11 measures inhibition of Axl. Example

[0154] The invention will now be further described with reference to the following examples, which are intended to illustrate but not to limit the scope of the invention.

[0155] Example 1 Kinase Binding Assay for Axl and Mer

[0156] Binding Assay Principle

[0157] Eu kinase binding assays were performed at Life Technologies using the manufacturer's instructions for each indicated kinase.

[0158] In brief, the principle behind this assay is based on the binding and displacement of an Alexa Fluor 647 labeled tracer to the kinase of interest. Binding of the tracer to the kinase is detected using an EU labeled anti-tag antibody. Simultaneous binding of both the tracer and the antibody to the kinase generates a FRET signal. Binding of an inhibitor to the kinase competes with binding of the tracer, resulting in a loss of the FRET signal.

[0159] Binding assay protocol for AXL and Mer

[0160] A given compound was diluted in DMSO to make a stock compound solution. The stock compound solution was diluted in DMSO in 8 steps. Each diluted compound solution in DMSO was diluted in a kinase buffer. Four working solutions were then prepared. First, the tracer working solution consisted of tracer 236 and a kinase buffer. Secondly, the Axl, Mer, Tyro3 or Me / anti-GST-AB working solution contained one of the kinases Axl and Mer or anti-GST-AB (=anti-glutathione-S-transferase antibody) in the kinase buffer. Third, an anti-GST-AB working solution was made using anti-GST-AB and kinase buffer. Finally, in the DMSO working solution, DMSO was added to the kinase buffer to a final concentration of 3%. Each of the four working solutions was added separately to the assay plate and then incubated at room temperature for 1 h. After incubation, EnVision (Perkin Elmer) was used to measure the FRET signal of the assay plate using the program LanthaHTRF assay. Data evaluation was performed in the Quattro Workflow software. Kd (equilibrium dissociation constant) values ​​were calculated relative to vehicle (DMSO) control wells.

[0161] Table 1 summarizes the results obtained for the AXL and Mer kinase binding assays.

[0162] Example 2: Kinase Binding Assay for CSF1R

[0163] Binding Assay Principle

[0164] KINOMEscan TM It is a competitive binding assay based on quantitatively measuring the ability of a compound to compete with an immobilized ligand for the active site. The assay is performed by combining three components: a kinase with a DNA tag; an immobilized ligand; and a test compound. The ability of the test compound to compete with the immobilized ligand is measured by quantitative PCR of the DNA tag.

[0165] Binding assay protocol for CSF1R

[0166] E. coli was grown to logarithmic phase, infected with T7 phage and incubated at 32°C with shaking until lysis. The lysate was centrifuged and filtered to remove cell debris. The remaining kinases were produced in HEK-293 cells and subsequently tagged with DNA for qPCR detection. Streptavidin-coated magnetic beads were treated with biotinylated small molecule ligands at room temperature for 30 minutes to produce affinity resins for kinase assays. The beads with ligands were blocked with excess biotin and washed with blocking buffer (SeaBlock (Pierce), 1% BSA, 0.05% Tween 20, 1mM DTT) to remove unbound ligands and reduce nonspecific binding. The binding reaction was assembled by combining kinases, affinity beads with ligands and test compounds in 1x binding buffer (20% SeaBlock, 0.17X PBS, 0.05% Tween 20, 6mM DTT). Test compounds were prepared as 111X stocks in 100% DMSO. Kd was determined using 11 points of 3-fold compound serial dilutions and three DMSO control points. All compounds used for Kd measurements were distributed into 100% DMSO by acoustic transfer (non-contact distribution). The compounds were then directly diluted in the assay so that the final concentration of DMSO was 0.9%. In the case of % inhibition, the test compounds were prepared as 40X stocks in 100% DMSO and directly diluted in the assay. All reactions were carried out in polypropylene 384-well plates. The final volume of each reaction was 0.02 ml. The assay plate was incubated at room temperature with shaking for 1 hour, and the affinity beads were washed with washing buffer (1x PBS, 0.05% Tween 20). The beads were then resuspended in elution buffer (1x PBS, 0.05% Tween 20, 0.5 μM non-biotinylated affinity ligand) and incubated at room temperature with shaking for 30 minutes. The kinase concentration in the eluate was measured by qPCR.

[0167] The CSF1R kinase binding activity results are shown in Table 1 (K d ) and 2 (% inhibition at 0.1 uM concentration of the test compound).

[0168] Data analysis

[0169] The binding constant (Kd) was calculated using the Hill equation using a standard dose response curve:

[0170]

[0171] The Hill slope was set to -1.

[0172] The curves were fitted using a nonlinear least squares fit using the Levenberg-Marquardt algorithm.

[0173] The % inhibition of binding was calculated as follows:

[0174]

[0175] Negative control = DMSO (100% control)

[0176] Positive control = control compound (0% control)

[0177] Example 3: Cellular Axl Inhibition Assay

[0178] Axl Cell Assay Principle

[0179] Axl is expressed in several malignant cancer cells, especially H1299 cells, which endogenously express Axl. When induced with the Axl ligand Ga6, an increase in Axl phosphorylation (p-Axl) was observed.

[0180] Enzyme-linked immunosorbent assay (ELISA) using H1299 cells

[0181] The H1299 cells should reach 40-80% confluence in the cell culture flask. The cells were then washed with DPBS and treated with trypsin. After centrifugation, the cell pellet was resuspended with pre-warmed culture medium (RPMI1640, 10% FBS) and the cells were separated by pipetting up and down 6 times with a 10 ml serological pipette. The cell suspension was diluted to a final concentration of 1.25×10 5cells / ml. Then add 80μl / well of cell suspension to the plate. Incubate the cell plate at 37°C / 5% CO2 overnight. Dissolve the compound to 10mM with DMSO and keep in a nitrogen cabinet. Prepare a compound reservoir plate, starting with a concentration of 0.50mM (5μl+95μl DMSO) for the reference compound and 1.5mM (6μl+34μl DMSO) for the test compound; then prepare 3-fold serial dilutions (10 doses) of the compound. Then dilute the compound with culture medium in the middle plate (2μl compound + 198μl culture medium). Transfer 20μl of the diluted compound from the middle plate to the cell-coated plate. Incubate the cell plate at 37°C / 5% CO2 for 24h. Add 25μl of human Gas6 (1000ng / ml) to a 96-well plate; the final concentration of human Gas6 is 200ng / ml. Incubate the plate at 37°C / 5% CO2 for 1h. Remove the culture medium and wash the cells once with 300ul / well of ice-cold 1X PBS. Then remove the PBS and add 100μl / well of ice-cold 1X cell lysis buffer to the 96-well plate. Shake the plate at 4°C for 40min. Then store the plate at -20°C. After the microwell strips reach room temperature, break off the required number of microwells. Place the microwells in the strip rack. Unused microwells must be resealed immediately and stored at 4°C. Add 60μl of cell lysate to the appropriate wells. Seal with tape and press tightly on top of the microwells. Incubate the plate at 37°C for 2h. Gently remove the tape and wash the wells 5 times with 1X wash buffer, 300μl per well each time. Add 100μl of reconstituted detection antibody (green) to each well. Seal with tape and incubate the plate at 37°C for 1h. Repeat the washing procedure. Add 100 μl of reconstructed HRP-coupled secondary antibody to each well. Seal with tape and incubate the plate at 37°C for 30 min. Repeat the washing procedure. Add 100 μl of TMB substrate to each well. Seal with tape and incubate the plate at 37°C for 15 min. Add 100 μl of stop solution to each well. Shake gently for a few seconds. Read the absorbance at 450 nm within 30 min after adding the stop solution. Calculations and formulas: Using XL Fit software, the following calculations and formulas were used for data analysis: Curve fitting was made using a sigmoidal dose response model (fit model 205). The data are reported in Table 3 (shown further below).

[0182] Example 4: Cellular CSF1R inhibition assay

[0183] CSF1R Cell Assay Principle

[0184] The normal proto-oncogene c-fms encodes a macrophage growth factor (M-CSF, also known as CSF1) receptor, which is involved in the growth, survival and differentiation of the monocyte-macrophage lineage. THP-1 cells serve as a model for human monocytes. It was confirmed that when induced by the CSF1R ligand CSF1, an increase in CSF1R phosphorylation (p-CSF1R) can be observed. M-NFS-60 cells are a mouse myeloid cell line that shows CSF1-dependent proliferation, i.e., it requires CSF1 for its growth.

[0185] Enzyme-linked immunosorbent assay (ELISA) using THP-1 cells

[0186] THP-1 cells should be grown at 5 × 10 5 Up to 1×10 6 The cell culture flask was maintained at a density of 2×10 cells / ml. After centrifugation, the supernatant was aspirated. The cell pellet was resuspended in pre-warmed growth medium (RPMI1640, 10% FBS, 0.05 mM 2-mercaptoethanol) and the cells were separated by pipetting up and down 6 times with a 10 ml serological pipette. The cell suspension must be diluted with pre-warmed growth medium to a final concentration of 2×10 cells / ml per 80 μl. 5Cells. Add 80 μl cell suspension to all wells of the plate. The cell plate is incubated at 37°C / 5% CO2. The compound is dissolved in 100% DMSO to make a 10mM storage solution (aliquots are stored in a nitrogen cabinet). The 10mM compound solution is diluted twice in 100% DMSO to obtain a 5mM solution (10 μl+10 μl DMSO), and then 3 times of serial dilutions (10 μl+20 μl DMSO) of 10 doses are made. For reference compounds, the 10mM compound solution is diluted 20 times in 100% DMSO to obtain a 0.5mM solution (2 μl+38 μl DMSO), and then 3 times of serial dilutions (10 μl+20 μl DMSO) of 10 doses are made. The 2 μl diluted compound is transferred to 198 μl culture medium to obtain a solution where the highest point concentration is 50 μM for the compound and 5 μM for the reference compound. Then 20 μl of cpd solution was transferred to the assay plate (two wells). The plate was incubated at 37°C / 5% CO2 for 24h. The final concentration of DMSO in all wells was 0.2%. Human M-CSF was reconstituted in sterile water at 50 μg / ml. (Aliquots were stored at -80°C). Human M-CSF was diluted to 50 ng / ml with fresh culture medium 1:1000. After 24h of compound treatment, 25 μl of diluted human M-CSF (50 ng / ml) was transferred to the cell plate according to the plate map. The final concentration of human M-CSF in all wells was 10 ng / ml. The plate was incubated at 37°C / 5% CO2 for 5min. At the beginning, a suitable amount of complete lysis buffer (100 μL / well) was prepared and stored on ice. After 5min of human M-CSF stimulation, the plate was washed once with 300 μL of ice-cold PBS. Then 100 μl of lysis buffer was added to each well. Shake the plate at 4°C for 40 min. The plate can now be stored at -20°C. After the microwell strips have been equilibrated at room temperature, break off the required number of microwells. Place the microwells in the strip rack. Unused microwells must be resealed immediately and stored at 4°C. Add 90 μl of cell lysate to the appropriate wells. Seal with tape and press firmly on top of the microwells. Incubate the plate at 37°C for 2 h. Gently remove the tape and wash the wells 4 times with 1X wash buffer, 200 μl per well each time. Add 100 μl of reconstituted detection antibody (green) to each well. Seal with tape and incubate the plate at 37°C for 1 h. Repeat the washing procedure. Add 100 μl of reconstituted HRP-conjugated secondary antibody to each well. Seal with tape and incubate the plate at 37°C for 30 min. Repeat the washing procedure. Add 100 μl of TMB substrate to each well. Seal with tape and incubate the plate at 37°C for 10 min or at 25°C for 30 min.Calculations and formulas: The following calculations and formulas were used for data analysis using XL Fit software: Curve fits were made using a sigmoidal dose response model (Fit Model 205). The data are reported in Table 4 (shown further below).

[0187] Cell Titer-Glo (CTG) Assay Using M-NFS-60 Cells

[0188] M-NFS-60 cells were cultured in RPMI-1640 medium containing 10% FBS, 0.05 mM 2-mercaptoethanol, penicillin (100 U / ml) / streptomycin (100 mg / ml) and supplemented with 62 ng / ml recombinant human M-CSF at 37°C / 5% CO2. Aliquots of the cells were seeded in 96-well plates (2×10 5 Cells were added to 100 μl / well) and then incubated at 37°C / 5% CO2 for 1 h. Compounds were dissolved in 100% DMSO to make a 10 mM stock solution (aliquots were stored in a nitrogen cabinet). The 10 mM compound solution was diluted twice in 100% DMSO to obtain a 5 mM solution (10 μl + 10 μl DMSO), and then 10 doses of 3-fold serial dilutions were made (10 μl + 20 μl DMSO). For reference compounds, the 10 mM compound solution was diluted 20 times in 100% DMSO to obtain a 0.5 mM solution (2 μl + 38 μl DMSO), and then 8 doses of 3-fold serial dilutions were made (10 μl + 20 μl DMSO). The 96-well plate was equilibrated at room temperature for 30 min. 50 μl was added to each well. Reagent, and mix on orbital shaker for 2min to induce cell lysis. The 96-well plate is incubated at room temperature for 10min to stabilize the luminescent signal. Luminescence is measured at 700nm by EnVison plate reader. Calculation and formula: Using XL Fit software, the following calculation and formula are used for data analysis: curve fitting is made using S-shaped dose response model (fit model 205). Data are reported in Table 5 (further shown below).

[0189] Example 5: Cellular Axl, Mer and CSF1R Inhibition Measured by BaF3 Viability Assay

[0190] Principle of the BaF3 cell-based assay

[0191] In this system, IL-3 dependent Ba / F3 cells are modified to express activated recombinant kinases (in the present case Axl, Mer and CSF1R). After removal of IL-3, the survival and proliferation of the modified cells are dependent on the activity of the recombinant kinases. Inhibition of these kinases by the test compounds reduces the survival and proliferation of the cells.

[0192] BaF3 cell-based assay protocol

[0193] Cell lines are maintained in a growth medium (GM) consisting of RPMI 1640 supplemented with 10% FBS. Cells in the logarithmic growth phase are harvested, and 5,000 cells are distributed in 50 μl GM in each well of a 384-well plate. 2 ng / ml IL-3 is further supplemented to the parental cells (or experimental assays when specified) to support cell growth and survival. 50 nanoliters of reference standards or experimental compounds (in duplicate) indicated are added to suitable wells, and cells are cultured at 37°C / 5% CO2 for 48 h. Survival rate is determined by adding 10 μl Cell Titer Glo and measuring luminescence, which is reported as relative light units (RLU) measured in counts per second. Using GraphPad Prism software, the following calculations and formulas are used for data analysis: Curve fitting is made using a dose response curve-inhibition. Data are reported in Table 6 (further shown below).

[0194] Example 6: Comparison of selected compounds of the present invention with selected compounds of WO 2016 / 166250 in terms of binding activity Comparison of Axl and Mer and cell activity

[0195] Table 7 shows the superiority of compounds 4, 10, 16 and 92 of the present invention (marked with **) compared with structurally similar compounds 27, 64, 22 and 48 (marked with *) of WO 2016 / 166250, respectively, in terms of their binding activity to Axl and Mer and their cell activity in the H1299 Elisa assay. The data are extracted from Tables 1, 2, and 3 and are further reported in Table 7 below.

[0196] Example 7: EMT-6 and MV4-11 mouse models

[0197] a) EMT-6 mouse model

[0198] Homologous model

[0199] It has also been shown that Axl / Mer is constitutively and inducibly expressed on a variety of immune cells, particularly dendritic cells (DC) and macrophages, which act as negative feedback to balance proinflammatory signaling. In the case of CSF1R, it mediates tumorigenesis in the tumor immune microenvironment and is expressed on myeloid cell tumor-associated macrophages (TAMs); the increase in serum CSF1, the increase in the number of TAMs in tumors and the high expression of tissue CSF1 and / or CSF1R are associated with poor prognosis in patients with various cancers. Mouse syngeneic tumor models are widely used tools to prove the activity of new anticancer immunotherapy. EMT-6 syngeneic models contain significantly more myeloid cells, and also contain a higher percentage of TAMs. Therefore, EMT-6 is a suitable model for studying the efficacy of immuno-oncology drugs by changes in target immune cells.

[0200] Treatment regimen for the EMT-6 syngeneic tumor model

[0201] BALB / c mice (6–8-week-old female, Beijing Vital River Laboratory Animal Technology Co., Ltd.) were inoculated with EMT-6 tumor cells (1×10 6 ) subcutaneously for tumorigenesis. For the study, treatment began on day 6 after tumor inoculation, and mice were orally dosed daily with each test compound or vehicle. Tumor volume was measured every three days using a digital caliper and calculated using the following formula: V = 0.5a × b 2 , wherein a and b are respectively the long and short diameters of the tumor in mm.Weight was measured every three days.All procedures related to animal operation, care and treatment in the study were carried out in accordance with the guidelines approved by the Animal Care and Use Committee (Institutional Animal Care and Use Committee) (IACUC) of WuXi AppTec, and followed the guidance of the Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC) of laboratory animal care.During daily monitoring, the tumor growth and treatment of animals were checked every day for any effects on normal behavior such as activity, food and water consumption (only by observation), weight gain / reduction (weight measured 3 times a week), eye / hair loss of luster, and any other abnormal effects stated in the scheme.Death and observed clinical signs were recorded on the basis of the number of animals in each subgroup. Figure 1exemplarily reports data for compound 4 of the present invention compared to the structurally similar compound 27 of WO 2016 / 166250 and demonstrates that the compounds according to the present invention delay tumor growth to a significantly greater extent compared to other compounds or the medium.

[0202] b) MV4-11 mouse model

[0203] Xenograft Models

[0204] High expression of Axl or Gas6 in patients with acute myeloid leukemia (AML) is associated with poor survival outcomes. AML cells induce the expression and secretion of the Axl ligand Gas6 by bone marrow-derived stromal cells (BMDSCs). Gas6 in turn mediates the proliferation, survival, and chemoresistance of AML cells expressing Axl. This Gas6 / Axl paracrine axis between AML cells and BMDSCs establishes a chemoprotective tumor cell niche that can be eliminated by Axl-targeted approaches. The Axl / Gas6 axis promotes proliferation and chemoresistance of leukemic cells.

[0205] Treatment regimen for MV4-11 xenograft tumor model

[0206] BALB / c nude mice (6–8-week-old female, Shanghai SIPPR / BK Laboratory Animal Co., LTD.) were inoculated with MV4-11 tumor cells (1×10 7 ) subcutaneously for tumorigenesis. For the study, treatment began on day 10 after tumor inoculation, and mice were orally dosed daily with each test compound or vehicle. Tumor volume was measured every three days using a digital caliper and calculated using the following formula: V = 0.5a × b 2, wherein a and b are respectively the long and short diameters of the tumor in mm.Weight was measured every three days.All procedures related to animal operation, care and treatment in the study were carried out in accordance with the guidelines approved by the Animal Care and Use Committee (Institutional Animal Care and Use Committee) (IACUC) of WuXi AppTec, and followed the guidance of the Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC) of laboratory animal care.During daily monitoring, the tumor growth and treatment of animals were checked every day for any effects on normal behavior such as activity, food and water consumption (only by observation), weight gain / reduction (weight measured 3 times a week), eye / hair loss of luster, and any other abnormal effects stated in the scheme.Death and observed clinical signs were recorded on the basis of the number of animals in each subgroup. Figure 2 exemplarily reports data for compound 4 of the present invention compared to the structurally similar compound 27 of WO 2016 / 166250 and demonstrates that the compounds according to the present invention delay tumor growth to a significantly greater extent compared to other compounds or the medium.

[0207] The data for EMT-6 and MV4-11 are shown in Figure 1 (EMT-6 syngeneic model efficacy study) and 2 (MV4-11 xenograft model efficacy study).

[0208] Example 8: Derivatization of the dimethoxyquinoline universal skeleton

[0209] The proposed compounds were derivatized according to the methods outlined below (Schemes 1-21). The resulting derivatives were examined for kinase binding, cellular activity, and in vivo activity using the assays described above (Examples 1-7), and the results are summarized in Tables 1-7 and Figure 1 and 2 The synthesized compounds 1-179 are shown in Table 8 below.

[0210] Scheme 1 - General Synthetic Route I

[0211]

[0212] General synthesis procedure of C1

[0213] A method for preparing the compound of C1 is shown in Scheme 1. The reaction of A1 and B1 is carried out in DMF in the presence of HATU (O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate), TEA to give C1. Alternatively, the reaction of A1 and B1 is carried out in pyridine in the presence of EDCI (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide) to give C1.

[0214] Scheme 2 - General synthesis of compound 4

[0215]

[0216] A3 General Synthesis Procedure

[0217] Compound A2 (20.0 g, 53.1 mmol) was slowly added to HCl (3 M, 180 mL) at 10 ° C, then the mixture was cooled to 0 ° C, and a solution of NaNO (11.8 g, 55.8 mmol) in water (50 mL) was added, and the mixture became a brown solution (solution A). Solution A was added dropwise to a mixture of 4-chloro-3-keto-butyric acid ethyl ester (28.2 g, 170 mmol) and NaOAc (66.1 g, 812 mmol) in H O (2000 mL) / EtOH (500 mL) at 0-5 ° C. The mixture was then stirred at 10 ° C for 1 hour. A yellow powder was precipitated from the reaction mixture. This phenomenon indicates that the reaction proceeds, and LCMS shows a desired MS value of 80%. The mixture was filtered, the filter cake was washed with water (500 mL) and dried under high vacuum, giving 35.0 g of compound A3 as a yellow powder (yield: 72.2%).

[0218] A4 General Synthesis Procedure

[0219] To a solution of compound A3 (35.0 g, 117.17 mmol) in anhydrous EtOH (300 mL) was added KOAc (23.0 g, 234 mmol). The mixture was heated and refluxed at 78.3 °C for 6 hours. The reaction mixture was a yellow solution. LCMS showed a desired MS value of 86.7%. The mixture was cooled to room temperature. Most of the EtOH was removed under reduced pressure and the residue was partitioned between EtOAc (800 mL) and H2O (800 mL). The aqueous phase was extracted with EtOAc (800 mL). The combined organic extracts were washed with brine (900 mL x 2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give 27.0 g of compound A4 as a yellow powder (yield: 87.9%).

[0220] A5 General Synthesis Procedure

[0221] At 0 ℃, NaH (3.05g, 76.3mmol, 60% dispersion in mineral oil) was added to a solution of compound A4 (10.0g, 38.1mmol) in DMF (100mL), then the mixture was stirred at 20 ℃ for 30 minutes, then CF3CH2OTf (17.7g, 76.3mmol) was added to the mixture, and the reaction mixture was warmed to 60 ℃ for 2.5 hours. LCMS showed that the reaction was complete. The mixture was cooled to room temperature, diluted with water (1000mL), extracted with EtOAc (1000mL x 3). The combined extracts were washed with brine (1500mL x 2), dried over anhydrous Na2SO4 and filtered, then concentrated under reduced pressure to give 46.0g (crude, containing a small amount of DMF) as compound A5 of yellow jelly.

[0222] General synthesis procedure of A6

[0223] To a mixture of compound A5 (40.0 g, 116 mmol) in MeCN (400 mL) was added CAN (191 g, 349 mmol) in H2O (200 mL) at 0°C, then the mixture was allowed to warm to 20°C and stirred at 20°C for 17 hours. TLC (PE / EtOAc=1 / 2) showed that the reaction was complete. The mixture was extracted with EtOAc (500 mL x 3), the combined extracts were washed with saturated aqueous NaHCO3 (800 mL x 3), the organic phase was dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by Combi flash (PE / EtOAc=4 / 1 to 2 / 1) to give 7.60 g (yield: 27.5%) of compound A6 as a yellow solid.

[0224] A7's general synthesis procedure

[0225] Cs2CO3 (31.3 g, 96.1 mmol) was added to a solution of compound A6 (9.15 g, 38.4 mmol) and D1-2 (7.18 g, 42.3 mmol) in MeCN (100 mL). The reaction was stirred at 25 ° C for 17 hours to give a yellow suspension. LCMS showed that the reaction was complete. The reaction mixture was filtered. The filter cake was washed with EtOAc (300 mL). The filtrate was distributed with EtOAc (300 mL) and water (400 mL). The organic phase was washed with brine (400 mL x 2) and dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a crude residue. The residue was purified by Combi flash (PE / EtOAc=1:0 to 3:1) to give 4.3 g of the unwanted isomer as a yellow oil (yield: 40%) (less polar) and 4.9 g of compound A7 as a yellow gum (yield: 46%) (more polar).

[0226] A8's general synthesis procedure

[0227] To a solution of compound A7 (4.9 g, 17.5 mmol) in MeOH (33 mL) was added NaOH (2.10 g, 52.5 mmol) in H2O (8 mL). The reaction was stirred at 20 °C for 2 hours to give a yellow solution. TLC showed that the reaction was complete. Most of the MeOH was removed under reduced pressure. The reaction mixture was adjusted to pH = 4 using HCl aqueous solution (1 M). The mixture was extracted with DCM (110 mL x 3). The organic layer was washed with brine (150 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give 4.41 g of compound A8 as a yellow gum (yield: 100%).

[0228] 4 General synthesis procedure

[0229] Compound B1-1 (5.30 g, 17.8 mmol) was added to a solution of compound A8 (4.41 g, 17.5 mmol) and EDCI (5.03 g, 26.2 mmol) in pyridine (40 mL). The reaction was stirred at 25 ° C for 17 hours to give a yellow solution. LCMS showed that the starting material was not completely consumed. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was distributed between DCM (400 mL) and H2O (300 mL). The organic layer was washed with H2O (200 mL x 2), brine (200 mL x 2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a yellow jelly. The crude product was purified by Combi Flash (EtOAc: PE = 0: 1 to 1: 0), and the eluent was concentrated under reduced pressure to give an off-white jelly. The product was dissolved in MeCN (30 mL) and H2O (33 mL) and freeze-dried to give 5.23 g of compound 7 as a white powder (yield: 55%, purity: 98.5%).

[0230] Scheme 3 - General synthesis of compound 1

[0231]

[0232] A9's general synthesis procedure

[0233] To a mixture of compound A6 (1.00 g, 4.20 mmol), Cs2CO3 (3.42 g, 10.5 mmol) in DMF (10 mL) was added D1-2 (524 mg, 3.36 mmol). The mixture was stirred at 15 ° C for 2 hours to give a yellow mixture. LCMS showed that the reaction was complete. The mixture was distributed between EtOAc (50 mL) and H2O (50 mL). The aqueous phase was extracted with EtOAc (50 mL). The combined organic extracts were washed with brine (50 mL x 2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a crude product as a yellow oil. The residue was purified by Combi flash (PE: EA = 1: 0 to 3: 1) to give A9 (240 mg, 21.5% yield, more polar, desired product) as a yellow gum. LCMS (Rt = 1.080 min) showed the desired MS value.

[0234] A10 General Synthesis Procedure

[0235] To a mixture of A9 (240 mg, 0.902 mmol) in DCM (3 mL) was added 1,3-dibromo-5,5-dimethyl-imidazolidine-2,4-dione (155 mg, 0.541 mmol). The mixture was stirred at 15 ° C for 12 hours, LCMS showed that the starting material remained, and Br2 (200 uL) was added and stirred at 15 ° C for 12 hours to give a yellow mixture. TLC showed that the reaction was complete. The mixture was distributed between DCM (50 mL) and saturated sodium bicarbonate (30 mL), dried over anhydrous Na2SO4 and filtered, and then concentrated under reduced pressure to give A10 (300 mg, 96.4% yield) as a yellow powder. LCMS (Rt = 1.243 min) showed the desired MS value.

[0236] A11's general synthesis program

[0237] To a mixture of A10 (300 mg, 0.869 mmol), Cs2CO3 (708 mg, 2.17 mmol) in dioxane (3 mL) and H2O (1 mL) was added 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborane (327 mg, 2.61 mmol), Pd(dppf)Cl2.CH2Cl2 (71 mg, 0.0869 mmol). The reaction mixture was stirred at 80 ° C for 12 hours under N2 atmosphere to give a black mixture. LCMS (Rt=1.186 min) showed that the reaction was complete. The mixture was cooled to room temperature and distributed between DCM (30 mL) and water (20 mL). The aqueous phase was extracted with DCM (30 mL). The combined organic extracts were washed with brine (50 mL x 2), concentrated under reduced pressure to give the crude product as brown oil, which was purified by Combi flash (PE / EA = 1 / 0 to 3 / 1) to give A11 (53 mg, 21.8% yield) as yellow oil.

[0238] A12's general synthesis program

[0239] To a mixture of A11 (50 mg, 0.178 mmol) in EtOH (1 mL) was added a solution of NaOH (7.14 mg, 0.178 mmol) in H2O (1 mL). The mixture was stirred at 15 °C for 2 hours to give a brown suspension. TLC showed that the reaction was complete. The mixture was concentrated under reduced pressure to remove EtOH. The aqueous phase was diluted with water (30 mL), acidified to pH = 4-5 with HCl (3 M) and freeze-dried to give A12 (46 mg, crude) as a yellow jelly, which was used in the next step.

[0240] General synthesis procedure of 1

[0241] To a mixture of A12 (45 mg, 178 mmol), HATU (92.5 mg, 0.243 mmol) in DMF (1 mL) was added B1-1 (48.2 mg, 0.162 mmol), TEA (45 uL) under N2 atmosphere. The mixture was stirred at 60 ° C for 12 hours to give a yellow mixture. LCMS showed that the reaction was complete. The mixture was cooled to room temperature and poured into water (10 mL). A yellow solid precipitated from the mixture. The mixture was filtered and the filter cake was washed with water (5 mL) to give a crude product as a brown solid, which was purified by preparative TLC (DCM / MeOH=10 / 1) and freeze-dried to give 1 (42.9 mg, 49.3% yield, 99.1% purity) as a yellow powder.

[0242] Scheme 4 - General synthesis of compound 3

[0243]

[0244] A13's general synthesis procedure

[0245] First batch:

[0246] To a solution of A6 (200 mg, 0.840 mmol), D1-3 (216 mg, 2.52 mmol), pyridine (79.7 mg, 1.01 mmol) and DMAP (308 mg, 2.52 mmol) in dioxane (5 mL) was added Cu(OAc)2 (229 mg, 1.26 mmol), and the mixture was stirred in air at 100° C. for 17 hours. Crude LCMS (Rt: 1.490 min, 1.636 min) showed the reaction was complete.

[0247] Second batch:

[0248] To a solution of A6 (500 mg, 2.10 mmol), D1-3 (541 mg, 6.30 mmol), pyridine (199 mg, 2.52 mmol) and DMAP (770 mg, 6.30 mmol) in dioxane (10 mL) was added Cu(OAc)2 (572 mg, 3.15 mmol), and the mixture was stirred in air at 100° C. for 17 hours. Crude LCMS and TLC (PE / EtOAc=3 / 1) showed the reaction was complete.

[0249] The mixture of each batch was combined and poured into water (100 mL), extracted with EA (50 mL x 3), the combined extracts were washed with aqueous NH3.H2O (50 mL x 3, 14%) and brine (100 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by Combi flash to give 510 mg of A13 as a yellow gum (total yield: 20%) and 320 mg of A13-1 as a white powder.

[0250] A14's general synthesis procedure

[0251] First batch:

[0252] To a solution of A13 (100 mg, 0.359 mmol, 1 eq) in DCM (5 mL) was added Br2 (57 mg, 0.36 mmol, 1 eq) and the mixture was stirred at 15 °C for 17 hours to give a brown solution. Crude LCMS (RT: 0.977 min) showed that the reaction was not complete, then additional Br2 (104 mg) was added to the above mixture and the resulting mixture was stirred at 15 °C for 24 hours to give a brown solution. TLC (PE / EtOAc=3 / 1) showed that the reaction was complete. Second batch:

[0253] To a solution of A13 (410 mg, 1.47 mmol) in DCM (5 mL) was added Br2 (236 mg, 1.47 mmol), and the mixture was stirred at 15° C. for 17 hours to give a brown solution. TLC (plate 1, PE / EtOAc=3 / 1) showed that the reaction was not complete, then Br2 (500 mg) was added to the above mixture, and the mixture was stirred at 30° C. for 1 hour, and TLC (plate 2, PE / EtOAc=3 / 1) showed that the reaction was complete.

[0254] The mixture of two combined batches was poured into DCM (50 mL) and washed with saturated aqueous NaHCO3 (50 mL x 3), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give a residue, which was purified by Combiflash (PE / EtOAc=10 / 1 to 2 / 1) to give 450 mg (yield: 86%) of A14 as a white powder.

[0255] A15 general synthesis procedure

[0256] To a solution of A14 (450 mg, 1.26 mmol), E1 (1.37 g, 3.78 mmol) and LiCl (53 mg, 1.3 mmol) in DMF (5 mL) was added Pd(dppf)Cl2 (184 mg, 0.252 mmol), the mixture was purged with N2 three times and stirred at 100°C for 17 hours to give a brown suspension. Crude LCMS (Rt: 1.233 min) and TLC (PE / EtOAc=3 / 1) showed that the reaction was complete, and then the mixture was treated with HCl (10 mL, 1 M) to give a brown suspension, TLC (PE / EtOAc=3 / 1) and LCMS showed that the reaction was complete. The pH value of the mixture was adjusted to 8 with saturated aqueous NaHCO, extracted with EtOAc (30 mL x 3), the combined extracts were washed with brine (50 mL), dried over anhydrous NaSO, filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by Combi flash (PE / EtOAc=10 / 1) to give 100 mg (yield: 26%) of A15 as a yellow powder.

[0257] A16 general synthesis procedure

[0258] To a solution of A15 (100 mg, 0.327 mmol) in EtOH (3 mL) was added NaOH (26 mg, 0.65 mmol) in H2O (1 mL), and the mixture was stirred at 15 °C for 3 hours to give a yellow powder. TLC (EtOAc) showed that the reaction was complete. The pH value of the mixture was adjusted to 5, and the mixture was concentrated under reduced pressure to give a residue, which was dried in vacuo. The crude compound was then treated with aqueous NaOH (1 M, 20 mL) to form a Na salt, then extracted with EtOAc (10 mL x2) to remove impurities, the pH value of the aqueous phase was adjusted to 5 with aqueous HCl (3 M), extracted with DCM (30 mL x 3), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give 60 mg (yield: 63%) of A16 as a white powder.

[0259] 3 General synthesis procedure

[0260] To a solution of A16 (60 mg, 0.21 mmol), B1-1 (61 mg, 0.21 mmol) and TEA (104 mg, 1.03 mmol) in DMF (1 mL) was added HATU (156 mg, 0.411 mmol) and the mixture was stirred at 15 °C for 17 hours to give a suspension. Crude LCMS and HPLC showed that the reaction proceeded well. The mixture was filtered and the filter cake was washed with MeCN (2 mL) to give the product (about 60 mg, HNMR: contains DMF (7%)). The product was freeze-dried to give 36 mg (yield: 31%) of 3 as a white powder.

[0261] Scheme 5 - General synthesis of compound 6

[0262]

[0263] A17 General Synthesis Procedure

[0264] A mixture of A4 (10.0 g, 38.0 mmol) and Cs2CO3 (24.8 g, 76.3 mmol) in DMF (20 mL) was stirred at 25 ° C for 30 minutes. E2 (9.38 g, 76.3 mmol, 7.2 mL) was added to the obtained mixture. The mixture was stirred at 25 ° C for 16 hours to form a brown mixture. LCMS showed that the reaction was complete. The mixture was distributed between EtOAc (200 mL) and H2O (200 mL). The aqueous phase was extracted with EtOAc (200 mL x 2). The combined organic extracts were washed with brine (500 mL x 2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give A17 (10.50 g, yield: 90.5%) as a brown solid.

[0265] A18 general synthesis procedure

[0266] A solution of A17 (10.5 g, 34.5 mmol) in MeCN (100 mL) was added at 0 ° C. A solution of CAN (56.7 g, 104 mmol) in H2O (100 mL). The mixture was stirred at 25 ° C for 16 hours to form a brown solution. LCMS showed that the reaction was complete. EtOAc (500 mL) and saturated NaHCO3 (500 mL) were added to the mixture. The mixture was filtered. The filtrate was separated. The aqueous phase was extracted with EtOAc (500 mL x 2). The combined organic extracts were washed with brine (800 mL x 2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue, which was purified by Combi flash (PE / EtOAc=1 / 0 to 4 / 1) to give A18 (2.40 g, yield: 22.2%, LCMS: 63.2%) as a dark yellow oil.

[0267] A19 general synthesis procedure

[0268] To a mixture of A18 (1.00 g, 5.04 mmol) and CsCO (3.29 g, 10.1 mmol) in DMF (10 mL) was added D1-2 (944 mg, 6.05 mmol, 0.48 mL). The mixture was stirred at 20 ° C for 4 hours to form a brown mixture. LCMS showed that the reaction was complete. The mixture was cooled to room temperature. The mixture was distributed between EtOAc (30 mL) and H2O (30 mL). The aqueous phase was extracted with EtOAc (30 mL x 2). The combined organic extracts were washed with brine (80 mL x 3), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue, which was purified by Combi flash (eluent: PE / EtOAc=3 / 1) to give A19 (300 mg, yield: 26.4% more polar) and A19-1 (450 mg, yield: 39.4%, less polar) as yellow oils.

[0269] General synthesis procedure of A20

[0270] To a mixture of A19 (300 mg, 1.33 mmol) in EtOH (8 mL) and H2O (4 mL) was added NaOH (159 mg, 3.98 mmol). The mixture was stirred at 15 ° C for 2 hours. LCMS showed that compound 2 remained. The mixture was stirred for 1 hour to form a yellow solution. TLC (eluent: EtOAc) showed that the reaction was complete. Most of the EtOH was removed under reduced pressure. The aqueous solution was diluted with H2O (5 mL) and adjusted to pH=3-4 with HCl (2M, aqueous), then extracted with DCM (10 mL x 3). The organic extract was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give A20 (230 mg, yield: 87.5%) as a yellow jelly.

[0271] 6 General synthesis procedure

[0272] To a mixture of A20 (240 mg, 1.21 mmol) and B1-1 (300 mg, 1.01 mmol) in DMF (6 mL) was added HATU (575 mg, 1.51 mmol) and TEA (306 mg, 3.03 mmol, 0.42 mL). The mixture was stirred at 15 ° C for 17 hours. LCMS showed that the reaction was not completed. The mixture was warmed to 60 ° C and continued to stir for 3 hours. LCMS showed that the reaction was not completed. The mixture was continued to stir at 60 ° C for 17 hours to form a brown mixture. LCMS showed that the reaction was complete. The mixture was distributed between EtOAc (20 mL) and H2O (20 mL). The aqueous phase was extracted with EtOAc (20 mL x 2). The combined organic extracts were washed with brine (50 mL x 3), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue which was purified by Combi flash (eluent: PE / EtOAc=1 / to 7 / 3) and freeze dried to give an impure product. The impure product was further purified by preparative TLC (eluent: PE / EtOAc=1 / 9) to give 50 mg of product which was still found to contain impurities from LCMS. H NMR showed pure. The sample was then further purified by preparative HPLC (0.05% NH4HCO3). Most of the MeCN was removed by freeze drying to give 6 (25.4 mg, yield: 5.3%, LCMS: 100%) as a white powder.

[0273] Scheme 6 - General synthesis of compound 15

[0274]

[0275] General synthesis procedure of A21

[0276] To a mixture of A4 (25 g, 95.3 mmol) in DMF (150 mL) was added Cs2CO3 (77.7 g, 238 mmol), E3 (25 g, 185 mmol, 18.8 mL). The mixture was stirred at 25°C for 17 hours to give a brown mixture. LCMS showed that the reaction was not complete, and new 10 g of E3 was added to the above mixture and the mixture was stirred at 25°C for 3 hours. LCMS (Rt = 1.622 min) showed that the reaction was complete. The mixture was filtered, the filter cake was washed with EtOAc (500 mL), the filtrate was washed with water (400 mL), the aqueous phase was extracted with EtOAc (150 mL x 2), the combined extracts were washed with water (500 mL x 3), brine (500 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give A21 (18 g, 40.9 mmol) as a brown oil. The crude product was used in the next step without purification.

[0277] General synthesis procedure of A22

[0278] To a mixture of A21 (18 g, 56.9 mmol) in MeCN (150 mL) was added ACN (93.6 g, 170 mmol, 85.1 mL) in H2O (150 mL) at 0-5°C. The mixture was stirred at 25°C for 17 hours to give a brown mixture. LCMS (Rt = 1.244 min) showed that the reaction was complete. The mixture was partitioned between EtOAc (300 mL) and water (300 mL), the aqueous phase was extracted with EtOAc (150 mL x 2), the combined extracts were washed with saturated NaHCO3 (500 mL x 3), brine (500 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a crude product, which was purified by Combi flash (PE / EA = 10: 1 to 2: 1) to give A22 (1.4 g, crude) as a brown gum.

[0279] General synthesis procedure of A23

[0280] To a solution of A22 (1.2 g, 5.71 mmol), D1-1 (1.46 g, 8.56 mmol) in DMF (15 mL) was added CsCO (3.72 g, 11.4 mmol). The reaction was stirred at 20 ° C for 17 hours under N atmosphere to give a yellow suspension. LCMS (Rt = 1.526 min) showed that the reaction was complete. The reaction mixture was distributed between EtOAc (300 mL) and H O (500 mL). The separated aqueous phase was extracted with EtOAc (100 mL). The combined organic layer was washed with H O (200 mL x 2), brine (100 mL), dried over anhydrous Na SO, filtered and concentrated under reduced pressure to give a residue. The residue was purified by Combi flash (petroleum ether / ethyl acetate = 1 / 0 to 3 / 1) to give 310 mg (yield: 19.4%, purity: 90%, more polar) of A23 as a yellow-brown oil and 430 mg (yield: 29.8%, purity: 99.7%, less polar) of A23-1 as a yellow oil.

[0281] A24's general synthesis procedure

[0282] To a solution of A23 (310 mg, 1.23 mmol) in MeOH (3 mL) was added a solution of NaOH (147 mg, 3.69 mmol) in H2O (4 mL). The reaction was stirred at 20 ° C for 2 hours to give a yellow solution. TLC showed that the reaction was complete. The reaction mixture was adjusted to pH = 5 with HCl aqueous solution (1 M). The mixture was extracted with EtOAc (100 mL x 2). The organic layer was washed with brine (60 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give 300 mg (crude) of A24 as a yellow oil.

[0283] General synthesis procedure of A25

[0284] To a solution of A24 (150 mg, 0.669 mmol), B1-1 (199 mg, 0.669 mmol) in pyridine (3 mL) was added EDCI (192 mg, 1.00 mmol) under N2 atmosphere. The reaction was stirred at 20°C for 17 hours under N2 atmosphere to give a yellow mixture. LCMS (Rt = 1.459 min) showed that the reaction was complete. The reaction mixture was partitioned between EtOAc (100 mL) and water (100 mL). The aqueous phase was extracted with EtOAc (60 mL x 3). The combined extracts were washed with 0.5 M NaOH aqueous solution (70 mL), H2O (70 mL), 0.5 M HCl aqueous solution (70 mL), H2O (70 mL), brine (60 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give 170 mg (yield: 50.5%) of A25 as a yellow gum.

[0285] 15 General synthesis procedures

[0286] To a solution of A25 (170 mg, 0.338 mmol) in THF (3 mL) was added NMO (79 mg, 0.675 mmol), OsO (26 mg, 0.101 mmol) in H2O (2 mL). The reaction was stirred at 20 ° C for 17 hours to give a yellow mixture. LCMS showed that the reaction was complete. A solution of Na2SO3 (400 mg) in H2O (4 mL) was added to the reaction mixture and stirred at 25 ° C for 20 minutes. After filtration, the filtrate was distributed between EtOAc (100 mL) and H2O (20 mL). The aqueous layer was extracted with EtOAc (50 mL x 2). The combined organic layers were washed with H2O (40 mL x 2), brine (40 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. After purification by preparative HPLC (0.01% NH 4 HCO 3 ), the eluate was freeze-dried to give 47.9 mg (yield: 26.4%, purity: 100%) of 15 as a white powder.

[0287] Scheme 7 - General synthesis of compounds 17 and 19

[0288]

[0289] General synthesis procedure of A26

[0290] To a solution of A6 (0.4 g, 1.68 mmol, 1 eq) in CH3CN (20 mL) was added Cs2CO3 (821 mg, 2.52 mmol, 1.5 eq) and D1-4 (186 mg, 2.02 mmol, 1.2 eq). The resulting mixture was stirred at 15 ° C for 16 hours to give a yellow suspension. LCMS and TLC (PE / EtOAc=1 / 1) showed that the reaction was complete. The reaction mixture was quenched by adding H2O (50 mL) and extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine (10 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE / EtOAc=1 / 1) to give A26 (184 mg, 37.2% yield) as a white solid.

[0291] General synthesis procedure of A27

[0292] To a solution of A26 (184 mg, 0.625 mmol, 1 eq) in MeOH (12 mL) and H2O (2 mL) was added NaOH (75 mg, 1.88 mmol, 3 eq). The resulting mixture was stirred at 15 °C for 2 hours to give a yellow solution. LCMS showed that the reaction was complete. The reaction mixture was concentrated under reduced pressure to give a residue, which was then diluted with H2O (10 mL) and extracted with EtOAc (10 mL). The aqueous layer was adjusted to pH = 4 with 0.5 M HCl (5 mL) and then concentrated under reduced pressure to give A27 (300 mg, crude, containing a lot of NaCl salts) as a white solid. The product was used directly in the next step without further purification.

[0293] General synthesis procedure for 19

[0294] A27 (158 mg, 0.592 mmol, 1.1 eq) and EDCI (155 mg, 0.807 mmol, 1.5 eq) were added to a solution of B1-1 (160 mg, 0.538 mmol, 1 eq) in pyridine (3 mL). The resulting mixture was stirred at 15 ° C for 16 hours to give a yellow solution. LCMS showed that the reaction was complete and the desired product was formed. The reaction mixture was concentrated under reduced pressure to give a residue. H2O (20 mL) was added to the residue and extracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine (10 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiO2, PE / EtOAc=0 / 1) to give 19 (185 mg, 63% yield) as a white solid.

[0295] General synthesis procedure for 17

[0296] To a solution of 19 (185 mg, 0.339 mmol, 1 eq) in MeOH (5 mL) was added NaBH (25.7 mg, 0.678 mmol, 2 eq), the mixture obtained was stirred at 0 ° C for 1 hour to give a colorless solution. LCMS showed that the reaction was complete. The reaction mixture was quenched by adding H2O (1 mL) and concentrated under reduced pressure to give a residue. The residue was then diluted with H2O (20 mL) and extracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine (10 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was dissolved in CH3CN (2 mL) and H2O (5 mL), then freeze-dried to give the product. HNMR and HPLC showed that the product contained impurities, and the impure product was further purified by preparative HPLC (column: Waters Xbridge 150*255 mobile phase: [water (0.05% ammonium hydroxide v / v)-ACN]; B%: 40%-75%, 7 min). The fractions were concentrated and freeze-dried to give 17 (89.9 mg, 48.4% yield, 100% purity) as a white solid.

[0297] Scheme 8 - General synthesis of compound 63

[0298]

[0299] General synthesis procedure of A28

[0300] A mixture of D1-5 (2.55 g, 10.1 mmol, 564 uL, 1.20 eq), A6 (2.00 g, 8.40 mmol, 1.00 eq) and Cs2CO3 (5.47 g, 16.80 mmol, 2.00 eq) in dioxane (17.0 mL) was heated to 100°C for 12 h. LCMS (A28: RT = 1.24 min) showed that compound A6 was completely consumed and a major peak with the desired m / z was detected. The mixture was concentrated and the filtrate was concentrated. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 3 / 1 to 1 / 1) (TLC: petroleum ether / ethyl acetate = 1 / 1, A28: Rf = 0.35). A28 (1.8 g, 4.55 mmol, 54.2% yield) was obtained as a yellow solid.

[0301] General synthesis procedure of A29

[0302] To a solution of compound A28 (1.80 g, 4.55 mmol, 1 eq) in MeOH (12.6 mL) was added dropwise a solution of NaOH (364 mg, 9.11 mmol, 2.0 eq) in H2O (3.60 mL) at 15-25°C. The mixture was stirred at 15-25°C for 12 h. TLC (petroleum ether / ethyl acetate=1 / 1, A28: Rf=0.35, A29: Rf=0.01) showed that compound A28 was completely consumed. The mixture was concentrated. The pH value of the residue was adjusted to 5-6 with 4M HCl (15.0 mL). The mixture was extracted with a solution of DCM and IPA (3 / 1, 20 mL x 4). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated. Compound A29 (1.39 g, 3.78 mmol, 83.1% yield) was obtained as a yellow solid.

[0303] General synthesis procedure of A30

[0304] To a solution of compound A29 (200 mg, 544 umol, 1.00 eq) and compound B1-1 (165 mg, 555 umol, 1.02 eq) in pyridine (5 V) was added EDCI (156 mg, 816 umol, 1.50 eq). The mixture was stirred at 15-25 ° C for 12 h under N2. LCMS (A30: RT = 1.04 min) showed that compound A29 was completely consumed and a main peak with the desired m / z was detected. The reaction mixture was concentrated. Compound A30 (200 mg, 309 umol, 56.8% yield) was obtained as a brown oil.

[0305] General synthesis procedure for 63

[0306] A solution of formula A30 (1.00 eq) in HCl / MeOH (50 mL) was stirred at 15 ° C for 2 h. LCMS showed that compound A30 was completely consumed and a main peak with the desired m / z was detected. The mixture was concentrated under reduced pressure to give a residue. The crude product was purified by reverse phase HPLC (0.1% HCl conditions) (HPLC). Compound 63 (168 mg, 92.4% yield, 99.2% purity) was obtained as a yellow solid.

[0307] Scheme 9 - General synthesis of compound 23

[0308]

[0309] A32 General Synthesis Procedure

[0310] To a mixture of A31 (10 g, 63.7 mmol, 1 eq) in EtOH (150 mL) was slowly added SOCl2 (8.33 g, 70.0 mmol, 5.08 mL, 1.1 eq) at 20 ° C (rt), and the resulting mixture was stirred at 20 ° C for 48 hours to give a colorless solution. The reaction was not detected by TLC or LCMS because it was a common reaction. The mixture was directly concentrated and then re-evaporated with 100 mL of toluene to give A32 (12.4 g, crude product) as a white solid.

[0311] A33 General Synthesis Procedure

[0312] To a mixture of compound A32 (12.4 g, 66.9 mmol, 1 eq) and K2CO3 (23.1 g, 167 mmol, 2.5 eq) in MeCN (120 mL) was added condition D1-1 (28.5 g, 167 mmol, 16.4 mL, 2.5 eq), and the resulting mixture was heated to 60-70 ° C for 16 hours to obtain a white mixture. TLC showed two new spots. The mixture was distributed between EtOAc (100 mL) and H2O (100 mL). The aqueous phase was extracted with EtOAc (100 mL x 2). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a crude product. The crude product was purified by Combi Flash (PE / EtOAc=1 / 0 to 4 / 1 to 3 / 1 to obtain compound A33 (9.5 g, 62.4% yield) as a yellow oil.

[0313] A34 General Synthesis Procedure

[0314] To a solution of A33 (2 g, 8.8 mmol, 1 eq) in MeOH (20 mL) was added wet Pd / C (200 mg, 10% purity) under N2 atmosphere. The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred at 15 °C for 3 hours under H2 (15 psi) to give a black suspension. LCMS showed that the reaction was complete. The reaction mixture was filtered on a celite pad and the filtrate was concentrated to give A34 (1.55 g, 88.8% yield, 99.4% purity) as a yellow oil.

[0315] General synthesis procedure of A35

[0316] To a solution of A34 (200 mg, 1.01 mmol, 1 eq) in CH3CN (10 mL) was added 2,2,2-trifluoroethyl trifluoromethanesulfonate (353 mg, 1.52 mmol, 1.5 eq), K2CO3 (308 mg, 2.23 mmol, 2.2 eq) and Et3N (154 mg, 1.52 mmol, 0.2 mL, 1.5 eq). The resulting mixture was heated and stirred at 90 ° C (oil bath) for 4 hours to give a yellow suspension. LCMS showed that the reaction was complete, and TLC (PE: EtOAc = 3: 1) showed that part of the starting material remained, forming a new spot. The reaction mixture was quenched by adding H2O (30 mL) and extracted with EtOAc (30 mL x 2). The combined organic layers were washed with brine (10 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO 2 , PE:EtOAc=3:1) to give compound A35 (110 mg, 38.9% yield) as a white solid.

[0317] A36 General Synthesis Procedure

[0318] To a solution of A35 (110 mg, 0.394 mmol, 1 eq) in MeOH (8 mL) and H2O (2 mL) was added NaOH (78.8 mg, 1.97 mmol, 5 eq). The resulting mixture was stirred at 15 °C for 2 hours to give a colorless solution. LCMS showed that the reaction was complete. The reaction mixture was adjusted to pH ~ 4 with 0.5 M HCl and stirred for 30 min, then concentrated under reduced pressure to give A36 (121 mg, crude) as a white solid.

[0319] General synthesis procedure for 23

[0320] To a solution of B1-1 (95 mg, 0.32 mmol, 1 eq) and A36 (88.3 mg, 0.35 mmol, 1.1 eq) in pyridine (2 mL) was added EDCI (92 mg, 0.48 mmol, 1.5 eq). The resulting mixture was stirred at 15 ° C for 16 hours to give a yellow suspension. LCMS showed that most of the starting materials were consumed and formed the desired product. The reaction mixture was concentrated under reduced pressure to give a residue, then diluted with H2O (20 mL), extracted with EtOAc (20 mL x 2). The combined organic layer was washed with saline (10 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE:EtOAc=1:1) to give the product, which was dissolved in CH3CN (2 mL) and H2O (3 mL) and freeze-dried to give 23 (56.5 mg, 33.3% yield, 100% purity) as a white powder.

[0321] Scheme 10 - General synthesis of compound 34

[0322]

[0323] A37 General Synthesis Procedure

[0324] To a mixture of A32 (5.45 g, 29.4 mmol, 1 eq) and 3,4-dihydro-2H-pyran (7.43 g, 88.3 mmol, 8.07 mL, 3 eq) in THF (40 mL) was added TsOH (507 mg, 2.94 mmol, 0.1 eq). The resulting mixture was stirred at 80 ° C for 16 hours to give a yellow solution. TLC (PE / EtOAc=3 / 1) showed that the reaction was complete. The reaction mixture was quenched with H2O (100 mL) and extracted with EtOAc (50 mL x 2). The organic layer was washed with brine (20 mL x 3), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (SiO2, PE / EtOAc=3:1) to give 7.01 g (yield: 88.4%) of A37 as a yellow oil.

[0325] General synthesis procedure of A38

[0326] To a solution of A37 (7.01 g, 26.0 mmol, 1 eq) in MeOH (70 mL) under N2 was added wet Pd / C (1.5 g, 10% purity, 50% in water). The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred at 25°C under H2 (15 psi) for 16 hours to give a black suspension. TLC (PE / EtOAc=2 / 1) showed that the reaction was complete. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated to give 5.84 g (yield: 93.7%) of A38 as a purple oil.

[0327] General synthesis procedure of A39

[0328] To a mixture of A38 (4.20 g, 17.6 mmol, 1 eq) in DCE (25 mL) was added tetrahydropyran-4-carbaldehyde (2.20 g, 19.3 mmol, 1.1 eq), NaBH(OAc)3 (9.30 g, 43.9 mmol, 2.5 eq) and HOAc (1.05 g, 17.6 mmol, 1.0 mL, 1 eq). The resulting mixture was stirred at 25°C for 17 hours to give a purple suspension. TLC (PE / EtOAc=2 / 1) showed that the reaction was complete. The mixture was concentrated under reduced pressure to give 5.53 g (crude) of A39 as a purple oil.

[0329] General synthesis procedure of A40

[0330] To a solution of A39 (5.53 g, 16.4 mmol, 1 eq) in MeOH (50 mL) was added polyoxymethylene (2.46 g, 16.39 mmol), HOAc (984 mg, 16.4 mmol, 937 uL, 1 eq) and NaBH3CN (1.03 g, 16.4 mmol, 1 eq). The resulting mixture was stirred at 25 ° C for 72 hours to give a light red solution. TLC (PE / EtOAc=1 / 1) showed that the reaction was complete. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was dissolved in EtOAc (50 mL). Saturated Na2CO3 (40 mL) was added to the solution. The aqueous layer was extracted with EtOAc (20 mL). The combined organic layers were washed with brine (15 mL x2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give 5.38 g (crude) of A40 as a brown oil.

[0331] General synthesis procedure of A41

[0332] To a solution of A40 (5.38 g, 15.3 mmol, 1 eq) in DCM (90 mL) was added TFA (46.2 g, 405 mmol, 30 mL, 26.5 eq). The resulting mixture was stirred at 25 ° C for 16 hours to give a brown mixture. TLC (PE / EtOAc=1 / 1) showed that the starting material was still remaining. LCMS (Rt=0.665 min) showed 83% of the desired compound MS. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc (50 mL). Saturated Na2CO3 (100 mL) was added to the solution. The aqueous phase was extracted with EtOAc (30 mL). The combined organic layers were washed with brine (20 mL x 3), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by Combi flash (PE / EtOAc=1 / 1) to give 1.98 g (yield: 48.4%) of A41 as brown gum.

[0333] General synthesis procedure of A42

[0334] To a solution of A41 (520 mg, 1.95 mmol, 1 eq) and D1-1 (827 mg, 4.86 mmol, 475 uL, 2.5 eq) in MeCN (10 mL) was added KCO (672 mg, 4.86 mmol, 2.5 eq) at 25 ° C, and the mixture was then stirred at 60 ° C for 16 hours to give an off-white suspension. TLC (PE / EtOAc=1 / 1) showed two new spots. LCMS (Rt=0.711 min) showed that the reaction was complete. The mixture was concentrated in vacuo, and the residue was quenched with water (30 mL). The resulting solution was extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (10 mL x 2), dried over anhydrous NaSO, filtered and concentrated in vacuo to give a residue. The residue was purified by Combi flash (PE / EtOAc = 3 / 1 to 2 / 1 to 1 / 1) to give 280 mg (yield: 46.5%) of A42 as a yellow oil.

[0335] General synthesis procedure of A43

[0336] To a solution of A42 (280 mg, 0.905 mmol, 1 eq) in MeOH (4 mL) was added NaOH (3 M, 603 uL, 2 eq) in H2O (0.6 mL), and the mixture was stirred at 20 °C for 18 hours to give a colorless mixture. TLC (PE / EtOAc=1 / 1) showed a new spot. LCMS (Rt=0.518 min) showed that the reaction was complete. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was quenched by adding H2O (10 mL) and then extracted with EtOAc (20 mL). 2N hydrochloric acid was then added to the aqueous phase to adjust pH=1 by aq.HCl. The aqueous phase was extracted with DCM (10 mL x 8). The combined organic layers were washed with brine (10 mL x 3), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give 90 mg (crude) of A43 as a light yellow solid. LCMS shows a purity of 81%. From LCMS it is seen that the aqueous phase still contains product. Toluene (10 mL x 5) is then added to the aqueous phase. The aqueous phase is concentrated under reduced pressure to give 130 mg (crude, containing NaCl salt) of A43 as a white solid. LCMS shows a desired MS value of 98%.

[0337] General synthesis procedure for 34

[0338] To a solution of A43 (130 mg, 0.457 mmol, 3 eq) and B1-1 (45 mg, 0.15 mmol, 1 eq) in pyridine (1.5 mL) was added EDCI (44 mg, 0.23 mmol, 1.5 eq). The resulting mixture was stirred at 20 ° C for 16 hours to give a yellow mixture. TLC (EtOAc) showed a new spot. LCMS showed 4.9% of the desired compound MS. The mixture was continued to be stirred at 20 ° C for 8 hours. Then additional EDCI (44 mg, 0.23 mmol, 1.5 eq) was added. The mixture was stirred at 20 ° C for 48 hours. LCMS (Rt = 0.773 min) showed 7.2% of the desired compound MS. The mixture was distributed between DCM (50 mL) and water (30 mL). The aqueous phase was extracted with DCM (20 mL x 3). The combined extracts were washed with saturated brine (10 mL x 2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC [(PE / EtOAc=1 / 1) / (DCM / MeOH=10 / 1)=1 / 1] to give 34 (3.7 mg, yield: 4.2%, purity: 97.5%) as a white powder.

[0339] Scheme 11 - General synthesis of compound 35

[0340]

[0341] General synthesis procedure of B3

[0342] A suspension of Na (2.66 g, 116 mmol, 3 eq) in MeOH (40 mL) was stirred at 25 ° C for 30 min. Then B2 (10 g, 38.6 mmol, 1 eq) was added to the above mixture. The reaction was stirred at 80 ° C for 17 hours to give a yellow suspension. TLC showed that the starting material was not completely consumed. The mixture was cooled to room temperature. The pH of the mixture was adjusted to 1-2 by HCl aqueous solution (4 M) and extracted with EtOAc (200 mL x 2). The combined extracts were washed with brine (200 mL x 2), dried over anhydrous Na2SO4 and filtered, and then concentrated under reduced pressure to give B3 (8.3 g, yield: 79%) as a yellow oil.

[0343] General synthesis procedure of B4

[0344] Under N2, add Pd2(dba)3(599mg, 0.655mmol, 0.025eq), BINAP(1.22g, 1.96mmol, 0.075eq) and t-BuONa(3.52g, 36.7mmol, 1.4eq) to a solution of B3(7.1g, 26.2mmol, 1eq) and benzophenone imine(5.7g, 31.4mmol, 1.2eq) in toluene(150mL).The mixture obtained is heated and stirred at 90 ℃ for 12 hours, giving a red solution.TLC shows the formation of the desired product.By adding H2O(150mL) the reaction mixture is quenched, and extracted with EtOAc(150mL x 2).The organic layer merged is washed with saline (50mL x 2), at Na2SO4 upper drying, filtered and concentrated under reduced pressure, giving a residue. The residue was purified by column chromatography (SiO 2 , PE / EtOAc=20:1) to give 6 g of crude product, which was triturated with PE / EtOAc=40 mL / 2 mL to give 4.65 g of B4 as a light yellow solid.

[0345] General synthesis procedure of B5

[0346] A solution of B4 (5.4 g, 14.5 mmol, 1 eq) in HCl / MeOH (4 M) (20 mL) was stirred at 20 ° C for 30 min to give a white suspension. LCMS showed that the reaction was complete. The reaction mixture was concentrated under reduced pressure to give a residue. Then it was diluted with H2O (50 mL) and alkalized to pH = ~ 9 with saturated NaHCO3 solution and extracted with EtOAc (50 mL). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE / EtOAc = 3 / 1) to give B5 (2.5 g, yield: 83%) as a yellow oil.

[0347] General synthesis procedure of B6

[0348] A mixture of 2,2-dimethyl-1,3-dioxane-4,6-dione (1.83 g, 12.7 mmol, 1.05 eq) and diethoxymethoxyethane (1.97 g, 13.3 mmol, 1.1 eq) was heated at 50 ° C and stirred for 1.5 hours. Then a solution of B5 (2.5 g, 12.1 mmol, 1 eq) in MeOH (10 mL) was added to the mixture. The mixture was stirred at 50 ° C for 1 hour to give a yellow suspension. The mixture was cooled to room temperature and EtOH (20 mL) was added. The resulting mixture was stirred at 0 ° C for 30 min. White powder was observed. The mixture was filtered. The filter cake was washed with EtOH (20 mL) and dried under high vacuum to give 1.3 g of white solid, but LCMS and H NMR showed that it was not the desired product. The filtrate was extracted with EtOAc (50 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column (PE / EtOAc=3 / 1) to give B6 (550 mg, crude) as a yellow solid. H NMR showed a mixture of the desired compound and B5.

[0349] General synthesis procedure of B7

[0350] Under N2, a solution of B6 (550 mg, 1.00 mmol, 1 eq) in Dowtherm A (4 mL) was heated and stirred at 210 ° C for 1 hour to give a brown solution. TLC showed that the reaction was complete. The reaction was cooled to room temperature, quenched by adding H2O (20 mL) and extracted with EtOAc (20 mL x 2). The combined organic layer was washed with saline (10 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, DCM: MeOH = 10: 1) to give B7 (30 mg, yield: 11%, purity: 98%) as a yellow solid.

[0351] General synthesis procedure of B8

[0352] Cs2CO3 (56.6 mg, 0.174 mmol, 1.5 eq) was added to a solution of B7 (30 mg, 0.116 mmol, 1 eq) and 1,2-difluoro-4-nitrobenzene (18.4 mg, 0.116 mmol, 1 eq) in DMF (1 mL). The resulting mixture was heated and stirred at 40 ° C for 2 hrs to give a red solution. LCMS showed that the reaction was complete. The reaction was quenched by adding H2O (20 mL) and extracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine (10 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (PE: EtOAc = 1: 1) to give B8 (30 mg, yield: 65%) as a yellow solid.

[0353] General synthesis procedure of B1-2

[0354] Pd / C (wet) (20 mg, 10% purity) in 50% water was added to a solution of B8 (30 mg, 0.075 mmol, 1 eq) in EtOH (5 mL) under N2. The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred at 20 ° C for 12 hours under H2 (15 psi) to give a black suspension. LCMS and TLC showed that a portion of the starting material remained and a new spot was formed. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by preparative TLC (PE: EtOAc = 1: 1) to give B1-2 (20 mg, yield: 72%, purity: 100%) as an off-white solid.

[0355] General synthesis procedure of A44

[0356] D1-1 (3.07 g, 18 mmol, 2.5 eq) was added to a suspension of A18 (1.43 g, 7.21 mmol, 1 eq) and K2CO3 (2.49 g, 18 mmol, 2.5 eq) in MeCN (143 mL) at 25 °C. The reaction was stirred at 60 °C for 17 hours to give a yellow suspension. LCMS showed that the reaction was complete. The reaction mixture was combined with the test reaction from 100 mg of A18 and then arranged. The reaction mixture was distributed between EtOAc (200 mL) and H2O (200 mL). The organic layer was washed with brine (200 mL x 2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a black oil. The crude product was purified by Combi Flash (EtOAc: PE = 0: 1 to 1: 4) to give A44 (0.8 g, yield: 43%, purity: 95%) as a yellow oil.

[0357] General synthesis procedure of A45

[0358] To a solution of A44 (0.8 g, 3.33 mmol, 1 eq) in MeOH (10 mL) was added NaOH (400 mg, 9.99 mmol, 3 eq) in H2O (3 mL). The reaction was stirred at 25 °C for 1.5 hours to give a yellow solution. LCMS showed that the starting material was not completely consumed. The reaction was stirred at 25 °C for 17 hours to give a yellow solution. LCMS showed that the starting material was completely consumed. The reaction was adjusted to pH = 4 and extracted with EtOAc (200 mL). The organic layer was washed with brine (150 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give A45 (710 mg, crude) as a yellow oil.

[0359] General synthesis procedure for 35

[0360] To a solution of B1-2 (20 mg, 1 eq) and A45 (17.3 mg, 0.081 mmol, 1.5 eq) in pyridine (0.5 mL) was added EDCI (15.6 mg, 0.081 mmol, 1.5 eq). The resulting mixture was stirred at 20 °C for 12 hrs to give a yellow solution. LCMS showed that the reaction was complete. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Waters Xbridge 150*50 10u; mobile phase: [water (0.05% ammonium hydroxide v / v)-ACN]; B%: 55%-85%, 7.8 min), then concentrated and freeze-dried to give 35 (11.8 mg, yield: 38%, purity: 100%) as a white powder.

[0361] Scheme 12 - General Synthesis of Compound 44

[0362]

[0363] General synthesis procedure of A46

[0364] A mixture of D1-6 (831.50 mg, 5.04 mmol, 1.20 eq), A6 (1.00 g, 4.20 mmol, 1.00 eq) and Cs2CO3 (2.74 g, 8.40 mmol, 2.00 eq) in dioxane (8.5 mL) was heated to 80°C for 12 h. TLC (petroleum ether / ethyl acetate = 1 / 1, A6: Rf = 0.42, A46: Rf = 0.36) showed that A6 was consumed. The mixture was concentrated, and the filtrate was concentrated. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 3 / 1 to 1 / 1) (TLC: petroleum ether / ethyl acetate = 1 / 1, A46: Rf = 0.36). A46 (0.82 g, 2.54 mmol, 60.60% yield) was obtained as a yellow oil.

[0365] General synthesis procedure of A47

[0366] To a solution of A46 (0.82 g, 2.54 mmol, 1.00 eq) in MeOH (5.7 mL) was added dropwise a solution of NaOH (305 mg, 7.63 mmol, 3.00 eq) in H2O (1.64 mL) at 15-25°C. The mixture was stirred at 15-25°C for 5 h. TLC (petroleum ether / ethyl acetate=1 / 1, A46: Rf=0.34, A47: Rf=0.01) showed that A46 was completely consumed. The mixture was concentrated. The pH value of the residue was adjusted to 5-6 with 4M HCl (15.0 mL). The mixture was extracted with a solution of DCM and IPA (3 / 1, 20 mL x4). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated. A47 (0.68 g, 2.31 mmol, 90.83% yield) was obtained as a yellow oil.

[0367] General synthesis procedure for 44

[0368] To a solution of A47 (0.15 g, 510 umol, 1.00 eq) in pyridine (5 mL) was added EDCI (147 mg, 765 umol, 1.50 eq) and stirred for 15 min. To the mixture was added B1-1 (155 mg, 520 umol, 1.02 eq). The mixture was stirred at 25° C. for 12 h. LC-MS (44: RT=0.84 min) showed that A47 was completely consumed and a major peak with the desired mass was detected. HPLC (ET24988-44-P1A, compound 44: RT=2.55 min) showed that a major peak was detected. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by reverse phase HPLC (0.1% HCl condition). 44 (0.08 g, 134 umol, 26.3% yield, 96.2% purity) was obtained as a yellow solid.

[0369] Scheme 13 - General Synthesis of Compound 120

[0370]

[0371] General synthesis procedure of D1-8

[0372] Mg (67.1g, 2.76mol, 10eq) and I2 (701mg, 2.76mmol, 0.01eq) in THF (350mL) suspension was slowly added 1,2-dibromoethane (259g, 1.38mol, 5.0eq) in THF (1L) at a rate such that the internal temperature was maintained between 40-55°C. After the addition, a solution of D1-7 (50g, 276mmol, 1eq) in THF (375mL) was added dropwise. The reaction mixture was kept at 40-55°C for 16h. TLC (petroleum ether / ethyl acetate=2 / 1, D1-8: Rf=0.27) showed that D1-7 was completely consumed and many new spots were formed. The reaction was slowly quenched with saturated NH4Cl (3L) at 0°C. The mixture is extracted and the aqueous phase is extracted with DCM / i-PrOH (v / v=10 / 1, 2.5 L and 1 L). The combined organic layer is dried over Na2SO4, filtered and concentrated. The residue is purified by column chromatography (SiO2, petroleum ether / ethyl acetate=10 / 1 to 3 / 1). D1-8 (14 g, 137 mmol, 49.6% yield) is obtained as a yellow oil, which is used in the next step without further purification.

[0373] General synthetic procedure of D1-9

[0374] To a solution of D1-8 (7 g, 68.5 mmol, 1.0 eq) and TEA (20.8 g, 206 mmol, 3.0 eq) in DCM (60 mL) was slowly added dropwise MsCl (15.7 g, 137.1 mmol, 2.0 eq) at 0°C for 0.5 h. The mixture was stirred at 25°C for 3 h. TLC (petroleum ether / ethyl acetate=2 / 1, PMA, D1-8: Rf=0.27) showed that D1-8 was completely consumed. The reaction mixture was quenched by adding aqueous NH4Cl (5 mL) and extracted with CH2Cl2 (30 mL, 15 mL). The organic phases were combined, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=20 / to 1 / 1). D1-9 (11.5 g, crude product) was obtained as a red oil, which was used in the next step without further purification.

[0375] General synthesis procedure of A48

[0376] To a solution of D1-9 (21.3 g, 89.43 mmol, 1.0 eq) and Cs2CO3 (87.42 g, 268.30 mmol, 3.0 eq) in dioxane (150 mL) was added A6 (20.95 g, 116.26 mmol, 1.3 eq) at 15°C. The mixture was stirred at 40°C for 3 h. TLC (petroleum ether / ethyl acetate=1 / 1, A47: Rf=0.3) showed that D1-9 was completely consumed. Water (5 mL) was added to the reaction mixture and extracted with EtOAc (5 mL). The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=20 / 1 to 3 / 1). A48 (15.2 g, crude product) was obtained as a red oil and used in the next step without further purification.

[0377] General synthesis procedure of A49

[0378] To a solution of A48 (15.5 g, 48.1 mmol, 1.0 eq) in MeOH (30 mL) and H2O (30 mL) was added LiOH.H2O (6.05 g, 144 mmol, 3 eq) at 15°C. The mixture was stirred at 15°C for 3 h. TLC (petroleum ether / ethyl acetate=1 / 1, A47: Rf=0.3) showed that A47 was completely consumed. The reaction mixture was concentrated to remove MeOH. The pH value was adjusted to 2-3 with HCl solution (1 M, 18 mL). The mixture was extracted with DCM (100 mL). The organic phase was dried over Na2SO4. The mixture was filtered, and the filtrate was concentrated to give the product. A49 (14 g, 47.6 mmol, 98.9% yield) was obtained as a light red solid, which was used in the next step without further purification.

[0379] 120 General Synthesis Procedure

[0380] To a solution of A49 (200 mg, 679 umol, 1 eq) in DCM (2 mL) was added B1-3 (243 mg, 815 umol, 1.2 eq) and DIPEA (175 mg, 1.36 mmol, 2.0 eq) at 25°C. T3P (648 mg, 1.02 mmol, 50% purity in EtOAc solution, 1.5 eq) was added to the mixture at 15°C. The mixture was stirred at 25°C for 16 h. LCMS (120: RT = 1.01 min) showed that 12.9% of 120 was detected. The mixture was washed with water (2 mL). The organic phase was concentrated to give a residue. The residue was purified by preparative HPLC (column: Waters Xbridge Prep OBD C18 150*40mm*10um; mobile phase: [water (10mM NH4HCO3)-ACN]; B%: 30%-50%, 8min), to obtain 120 (40mg, 68.7umol, 10.1% yield, 98.6% purity) as an off-white solid.

[0381] Scheme 14 - General Synthesis of Compound 115

[0382]

[0383] General synthesis procedure of B10

[0384] A mixture of B9 (500 mg, 2.24 mmol, 1 eq) and 3-fluoro-4-nitrophenol (703 mg, 4.47 mmol, 2 eq) in chlorobenzene (10 mL) was stirred at 131 ° C for 12 hours to give an off-white suspension. LCMS (Rt = 1.045-1.107 min) showed ~ 25% of 545-1 and ~ 75% of the desired MS value. The reaction mixture was filtered, the filter cake was washed with toluene (10 mL) and dried under vacuum to give the crude compound. The crude compound was alkalized with 10% aq. NaOH, and the suspension was stirred at room temperature for 1 hour. The mixture was filtered and the filter cake was dried in high vacuum to give B10 (300 mg, 37.6% yield, 96.5% purity) as a yellow solid.

[0385] General synthetic procedure for B1-4

[0386] To a mixture of B10 (300 mg, 0.871 mmol, 1 eq) and NH4Cl (466 mg, 8.71 mmol, 10 eq) in EtOH (10 mL) was added Zn (570 mg, 8.71 mmol, 10 eq). The reaction mixture was stirred at 20°C for 12 hours to give a black mixture. LCMS (Rt = 0.997 min) showed that the reaction was complete. The mixture was filtered and the filtrate was concentrated under reduced pressure to give B1-4 (270 mg, 99% yield) as a yellow solid. The crude product was used in the next step without further purification.

[0387] General synthesis procedure for 115

[0388] To a solution of compound A49 (1.00 eq) and B1-4 (1.02 eq) in pyridine (5 V) was added EDCI (1.50 eq) under N2 at 15-25°C. The mixture was stirred at 15-25°C for 12 h under N2. LCMS showed that A49 was completely consumed and a major peak with the desired m / z was detected. The mixture was concentrated under reduced pressure to give a residue. The crude product was purified by reverse phase HPLC. 115 (128 mg, 60.7% yield, 95.6% purity) was obtained as a white solid.

[0389] Scheme 15 - General Synthesis of Compound 53

[0390]

[0391] General synthesis procedure of A50

[0392] A mixture of compound A6 (3.00 g, 12.6 mmol, 1.00 eq), D1-10 (2.78 g, 15.1 mmol, 1.74 mL, 1.20 eq) and Cs2CO3 (8.21 g, 25.2 mmol, 2.00 eq) in dioxane (45 mL) was heated to 30°C for 60 h. LCMS (A49: RT = 1.16 min) showed that A6 was completely consumed and the desired MS was detected. The mixture was filtered and the filtrate was concentrated. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 3 / 1 to 1 / 1) (TLC: petroleum ether / ethyl acetate = 1 / 1, A49: Rf = 0.50). A50 (2.5 g, 8.50 mmol, 67.4% yield) was obtained as a yellow solid.

[0393] General synthesis procedure of A51

[0394] To a solution of A49 (2.5 g, 8.50 mmol, 1 eq) in MeOH (17.5 mL) and H2O (5 mL) was added NaOH (1.02 g, 25.5 mmol, 3 eq). The mixture was stirred at 25°C for 4 hr. TLC (petroleum ether / ethyl acetate=3 / 1, A49: Rf=0.30, A50: Rf=0.00) showed that A49 was completely consumed, and a major new spot with greater polarity was detected. Ethyl acetate (20 mL) and H2O (10 mL) were added to the reaction mixture and stirred at 15-25°C for 10 min. The mixture was separated. The pH value of the aqueous layer was adjusted to 5-6 with 4M HCl (10.0 mL). The mixture was extracted with a solution of DCM and IPA (3 / 1, 30 mL x 4). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated. A51 (2 g, 7.51 mmol, 88.4% yield) was obtained as a light yellow oil.

[0395] General synthesis procedure of B12

[0396] To a mixture of B11 (1 g, 4.87 mmol, 1 eq) and 1,2-difluoro-4-nitrobenzene (1.55 g, 9.75 mmol, 1.08 mL, 2 eq) in DMSO (10 mL) was added Cs2CO3 (3.18 g, 9.75 mmol, 2 eq). The reaction mixture was stirred at 50 ° C for 12 hours to give a brown mixture. LCMS showed that the reaction was complete. The mixture was allowed to warm to 20 ° C, diluted with EtOAc (100 mL), washed with water (50 mL x 3) and brine (80 mL), dried over anhydrous Na2SO4, filtered and concentrated to give a crude compound. The crude compound was purified by flash silica gel chromatography ( 20g Silica gel flash column, eluent 10%-50%-100% ethyl acetate / petroleum ether gradient @30 mL / min) afforded B12 (1 g, 59% yield, 98.9% purity) as a yellow solid.

[0397] General synthesis procedure of B1-5

[0398] To a mixture of B12 (1 g, 2.90 mmol, 1 eq) in MeOH (20 mL) under N2 was added Pd / C (200 mg, 10% purity, 50% H2O). The suspension was degassed under vacuum and purged with H2 twice. The mixture was stirred at 20°C under H2 (15 psi) for 12 hours to give a black mixture. LCMS showed that the reaction was complete. The mixture was filtered and the filtrate was concentrated under reduced pressure to give B1-5 (560 mg, 61.3% yield) as an off-white solid. The product was used in the next step without further purification.

[0399] General synthesis procedure for 53

[0400] To a solution of A50 (1.00 eq) and B1-5 (1.02 eq) in pyridine (7 V) was added EDCI (1.50 eq) at 15-25 °C under N2. The mixture was stirred at 15-25 °C for 12 h under N2. LCMS showed that A51 was completely consumed and a major peak with the desired m / z was detected. The mixture was concentrated under reduced pressure to give a residue. The crude product was purified by reverse phase HPLC. 53 (199 mg, 61.7% yield, 98.3% purity) was obtained as a yellow solid.

[0401] Scheme 16 - General Synthesis of Compound 58

[0402]

[0403] General synthesis procedure of B13

[0404] Cs2CO3 (1.59 g, 4.87 mmol, 2 eq) was added to a mixture of B11 (500 mg, 2.44 mmol, 1 eq) and 1-fluoro-2-methyl-4-nitrobenzene (756 mg, 4.87 mmol, 2 eq) in DMSO (5 mL). The reaction mixture was stirred at 50 ° C for 12 hours to give a black mixture. LCMS showed that the reaction was complete. The mixture was diluted with EtOAc (100 mL), washed with water (30 mL x 3) and brine (30 mL), and concentrated under reduced pressure to give a crude compound. The crude compound was purified by rapid silica gel chromatography ( 12g Silica gel flash column, eluent 5-70% ethyl acetate / petroleum ether gradient @30 mL / min) afforded B13 (190 mg, 22.4% yield, 98% purity) as a yellow solid.

[0405] General synthetic procedure of B1-6

[0406] To a mixture of B13 (190 mg, 558.28 umol, 1 eq) in MeOH (10 mL) was added Pd / C (38 mg, 10% purity, 50% H2O) under N2. The suspension was degassed under vacuum and purged twice with H2. The mixture was stirred at 20°C under H2 (15 psi) for 12 hours to give a black mixture. LCMS (Rt = 0.670 min) showed that the reaction was complete. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give B1-6 (150 mg, crude) as a yellow oil. The crude compound was used in the next step without further purification.

[0407] General synthesis procedure for 58

[0408] To a solution of A51 (1.00 eq) and B1-6 (1.02 eq) in pyridine (7V) was added EDCI (1.50 eq) at 15-25°C under N2. The mixture was stirred at 15-25°C for 12 h under N2. LCMS showed that A51 was completely consumed and a major peak with the desired m / z was detected. The mixture was concentrated under reduced pressure to give a residue. The crude product was purified by reverse phase HPLC. 58 (168 mg, 52.4% yield, 98.2% purity) was obtained as a white solid.

[0409] Scheme 17 - General Synthesis of Compound 176

[0410]

[0411] General synthesis procedure of A53

[0412] Na (339.38 mg, 14.76 mmol, 349.88 uL, 1.1 eq) was added to EtOH (25 mL), and after Na hours, diethyl malonate (3.01 g, 18.79 mmol, 2.84 mL, 1.4 eq) was added to the above mixture, and the mixture was stirred at 100 ° C for 30 min. A solution of A52 (2.00 g, 13.42 mmol, 1.50 mL, 1 eq) in EtOH (10 mL) was added dropwise to the reaction mixture over 10 min, and then the mixture was stirred for 17 hr. TLC showed that a major new spot with lower polarity was detected. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with water (50 mL) and extracted with EtOAc (50 mL*2). The combined organic layer was washed with HCl (1N) (25 mL*2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (eluent: 0-2% ethyl acetate / petroleum ether gradient) to give 2.6 g (yield: 84.87%) of A53 as a colorless oil.

[0413] A54 General Synthesis Procedure

[0414] To a solution of A53 (2.6 g, 11.39 mmol, 1 eq) in H2O (10 mL) and EtOH (10 mL) was added KOH (2.56 g, 45.56 mmol, 4 eq), and the mixture was stirred at 15°C for 1.5 hr. TLC showed that the reaction was complete. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with water (20 mL), and the pH was adjusted to 3-5 with HCl (1 N), and then it was extracted with EtOAc (20 mL*3). The combined organic layers were washed with NaCl aqueous solution (20 mL*3), dried over Na2SO4, filtered and concentrated under reduced pressure to give 1.7 g (yield: 86.69%) of A54 as a white solid.

[0415] General synthesis procedure of A55

[0416] A solution of A54 (1.7 g, 9.87 mmol, 1 eq) in NMP (2 mL) was stirred at 110°C for 2 hr. TLC indicated that starting material remained, and a major new spot with lower polarity was detected. The mixture was then heated to 120°C for 17 hr, and TLC indicated that starting material still remained. The reaction mixture was diluted with water (30 mL), and it was extracted with EtOAc (30 mL*2). The combined organic layers were washed with aqueous NaCl solution (30 mL*2), dried over Na2SO4, filtered and concentrated under reduced pressure to give 1.01 g (yield: 79.81%) of A55 as a white solid.

[0417] General synthesis procedure of A56

[0418] To a solution of A55 (1.01 g, 7.88 mmol, 1 eq) and 2,2-dimethyl-1,3-dioxane-4,6-dione (1.25 g, 8.67 mmol, 1.1 eq) in DCM (15 mL) was added DMAP (1.44 g, 11.82 mmol, 1.5 eq), and after the mixture was cooled to 0°C, EDCI (2.11 g, 11.03 mmol, 1.4 eq) was added. The mixture was stirred at 15°C for 17 hr. TLC indicated that the reaction was complete, and a major new spot with lower polarity was detected. The mixture was treated with 50 ml of water, and the mixture was extracted with EtOAc (50 mL×2). The combined organic layers were washed with 1N HCl (20 mL×2), dried over magnesium sulfate and concentrated under reduced pressure to give 1.9 g (yield: 94.82%) of A56 as a yellow oil.

[0419] General synthesis procedure of A57

[0420] A solution of A56 (1.9 g, 7.47 mmol, 1 eq) in EtOH (40 mL) was stirred at 80° C. for 4 hr. TLC indicated that the reaction was complete. The reaction mixture was concentrated under reduced pressure to give 1.47 g (yield: 99.23%) of A57 as a yellow oil.

[0421] General synthesis procedure of A58

[0422] A solution of NaNO2 (767.36 mg, 11.12 mmol, 1.5 eq) in H2O (12 mL) was added dropwise to a solution of A57 (1.47 g, 7.41 mmol, 1 eq) in CH3COOH (4 mL) and H2O (12 mL) at 0°C. The stirred mixture was maintained at 0°C for 2 h and then at 15°C for 2.5 h. Water (10 mL) was then added and the mixture was stirred for 17 hr. TLC indicated that the reaction was complete. The reaction mixture was diluted with water (10 mL) and it was extracted with EtOAc (30 mL*2). The combined organic layers were washed with sat.aq.NaHCO3 (15 mL*2), brine (15 mL*2), dried over Na2SO4, filtered and concentrated under reduced pressure to give 1.42 g (yield: 84.27%) of A58 as a yellow oil.

[0423] General synthesis procedure of A59

[0424] To a solution of A58 (3.1 g, 13.64 mmol, 1 eq) in EtOH (50 mL) was added wet Pd / C (0.4 g) and conc. HCl (227.82 mg, 6.25 mmol, 223.36 uL). The suspension was degassed and purged with H2 3 times. The mixture was stirred at 40 °C for 17 hr under H2 (15 Psi). TLC indicated that the reaction was complete. The suspension was filtered through a celite pad and the pad was washed with EtOH (10 mL×3). The combined filtrate was concentrated to dryness to give 3.3 g (yield: 96.87%, HCl) of A59 as a white solid.

[0425] General synthesis procedure of A60

[0426] To a solution of A59 (1.00 g, 4.00 mmol, 1 eq, HCl) in DCM (5 mL) was added TEA (1.22 g, 12.01 mmol, 1.67 mL, 3 eq), followed by dropwise addition of 4,4,4-trifluorobutyryl chloride (1.29 g, 8.01 mmol, 2 eq) at 0 °C. After addition, the mixture was stirred at 20 °C for 1 hr to give a yellow mixture. TLC indicated that the reaction was complete. The reaction mixture was diluted with water (50 mL) and it was extracted with EtOAc (50 mL*2). The combined organic layers were washed with sat.aq.NaHCO3 (20 mL*2), NaCl (20 mL*2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (eluent: 0-20% ethyl acetate / petroleum ether) to afford 0.32 g (yield: 23.69%) of A60 as a yellow oil.

[0427] General synthesis procedure of A61

[0428] To a solution of A60 (0.32 g, 948.62 umol, 1 eq) in DCM (10 mL) was added PPh3 (497.62 mg, 1.90 mmol, 2 eq), I2 (481.53 mg, 1.90 mmol, 382.17 uL, 2 eq) and TEA (383.96 mg, 3.79 mmol, 528.15 uL, 4 eq). The mixture was stirred at 20 ° C for 2 hr. TLC showed that the reaction was complete. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (10 mL * 3). The combined organic layer was washed with NaCl aqueous solution (10 mL * 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica chromatography (silica flash column, eluent: 0-20% ethyl acetate / petroleum ether gradient) to afford 0.22 g (yield: 72.63%) of A61 as a yellow oil.

[0429] General synthesis procedure of A62

[0430] To a solution of compound A61 (0.29 g, 908.18 umol, 1 eq) in THF (8 mL) and H2O (2 mL) was added LiOH.H2O (57.17 mg, 1.36 mmol, 1.5 eq), and the mixture was stirred at 20 °C for 17 hr to give a yellow mixture. The mixture was then stirred at 50 °C for 6 hr. LCMS showed that the reaction was complete. The residue was diluted with water (20 mL) and then freeze-dried to give 0.325 g (crude) of A62 as a white solid.

[0431] General synthesis procedure for 176

[0432] To a solution of A62 (0.15 g, crude) in pyridine (2 mL) was added B1-1 (153.11 mg, 514.99 umol, 1 eq) and EDCI (148.09 mg, 772.49 umol, 1.5 eq). The mixture was stirred at 15 ° C for 17 hr to give a yellow mixture. LCMS showed that 7% of the desired product was detected. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (10 mL * 3). The combined organic layers were washed with NaCl aqueous solution (10 mL * 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (DCM: MeOH = 20: 1) to give 5 mg (yield: 1.46%) of 176 as a white solid.

[0433] Scheme 18 - General Synthesis of Compound 178

[0434]

[0435] A64 general synthesis program

[0436] To a mixture of A63 (2 g, 9.17 mmol, 1 eq) in DMF (20 mL) at 0 ° C., Cs2CO3 (7.47 g, 22.9 mmol, 2.5 eq) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (4.26 g, 18.3 mmol, 2 eq) were added and the mixture was stirred at 15 ° C. for 1 hour to give a pale mixture. LCMS showed that the desired product was observed. The mixture was poured into ice water (30 mL). The aqueous phase was extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with brine (50 mL x 5), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product. The crude product was purified by Combi Flash (PE / EtOAc=1 / 0 to 3 / 1) to give A63 (1.49 g, 42.5% yield) as a white solid.

[0437] General synthesis procedure of A65

[0438] To a mixture of A64 (1.49 g, 3.90 mmol, 1 eq) and D1-3 (1.00 g, 11.70 mmol, 3 eq) in H o (2 mL) and toluene (20 mL) was added K pO (2.07 g, 9.75 mmol, 2.5 eq), PCy (109 mg, 390 umol, 126 uL, 0.1 eq) and Pd (OAc) (87.5 mg, 390 umol, 0.1 eq), and the mixture was stirred at 80 ° C for 5 hours under N protection to give a yellow mixture. LCMS showed that the desired product was observed. The mixture was distributed between EtOAc (15 mL) and water (10 mL). The aqueous phase was extracted with EtOAc (10 mL x 2). The combined organic extracts were washed with brine (10 mL), dried over Na sO, filtered and concentrated under reduced pressure to give a crude product. The crude product was purified by Combi Flash (PE / EtOAc = 1 / 0 to 5 / 1 to 3 / 1) to afford A65 (150 mg, 11.2% yield) as a yellow solid.

[0439] General synthesis procedure of A66

[0440] To the mixture of A65 (150mg, 437umol, 1eq) in THF (2mL) and H2O (1mL) was added LiOH.H2O (36.6mg, 874umol, 2eq), and the mixture was stirred at 15°C for 1 hour to give a yellow mixture. LCMS showed that the reactant was consumed. The mixture was acidified to pH=4-5 with 1N HCl, and then it was distributed between DCM (15mL) and water (10mL). The aqueous phase was extracted with DCM (10mL x 2). The combined organic extracts were washed with brine (10mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain A66 (70mg, 61.3% yield) as a yellow jelly.

[0441] General synthesis procedure for 178

[0442] To a mixture of A66 (70 mg, 268 umol, 1 eq) and B1-1 (71.7 mg, 241 umol, 0.9 eq) in pyridine (2 mL) was added EDCI (102 mg, 535 umol, 2 eq), and the mixture was stirred at 15 ° C for 16 hours to give a yellow mixture. LCMS showed that the reaction was complete. The mixture was concentrated under reduced pressure to give a crude product. The crude product was purified by preparative HPLC (Waters Xbridge BEH C18 100*25mm*5um; mobile phase: [water (0.05% ammonium hydroxide v / v)-ACN]; B%: 45%-75%, 9.5 min) to give 178 (35.1 mg, 24.2% yield) as a white powder.

[0443] Scheme 19 - General Synthesis of Compound 179

[0444]

[0445] General synthesis procedure of A68

[0446] CsCO (12.4 g, 37.9 mmol, 1.5 eq) was added to a suspension of A67 (4 g, 25.3 mmol, 1 eq) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (6.46 g, 27.8 mmol, 1.1 eq) in DMF (30 mL). The reaction was stirred at 60-70 ° C for 16 hours to give a light yellow suspension. TLC showed that the reaction was complete. The mixture was distributed between water (100 mL) and EtOAc (100 mL). The organic layer was washed with brine (100 mL x 3), dried over anhydrous NaSO, filtered and concentrated under reduced pressure to give A68 (6.1 g, crude) as a white powder.

[0447] General synthesis procedure of A69

[0448] Under N2, LDA (2M, 2.29mL, 1.1eq) was added to a solution of A68 (1g, 4.16mmol, 1eq) in THF (5mL) at -78°C. The reaction mixture was stirred for 5min, and a solution of I2 (1.16g, 4.58mmol, 1.1eq) in THF (5mL) was added. The reaction was stirred for 30min at -78°C, then warmed to 20°C for 17 hours, giving a yellow mixture. LCMS showed that most of the starting material was still remaining. The mixture was quenched with water (5mL), and 1N HCl (1mL) was added. The mixture was distributed between EtOAc (80mL) and H2O (80mL). The organic layer was washed with saturated brine (80mL x3), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by Combiflash (PE / EtOAc = 1 / 0 to 10 / 1) to give A69 (70 mg, 4.6% yield) as a yellow gum.

[0449] A 70 General synthesis procedures

[0450] To a solution of A69 (170 mg, 0.464 mmol, 1 eq) in THF (3 mL) was added LiOH (22 mg, 0.928 mmol, 2 eq) in H2O (1 mL). The reaction was stirred at 20°C for 1.5 hours to give a yellow mixture. LCMS showed that the starting material was not completely consumed. LiOH (20 mg) was added. The reaction was stirred at 20°C for 17 hours to give a yellow mixture. LCMS showed that the starting material was not completely consumed. LiOH (20 mg) was added. The reaction was stirred at 40°C for 5 hours to give a yellow mixture. TLC showed that the reaction was complete. The reaction was adjusted to pH=4 with 1N HCl at 0-10°C and extracted with DCM (30 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give A70 (130 mg, 79.5% yield) as a yellow gum.

[0451] General synthesis procedure of C3

[0452] To a mixture of A70 (120 mg, 0.341 mmol, 1 eq) and B1-1 (101 mg, 0.341 mmol, 1 eq) in pyridine (2 mL) was added EDCI (131 mg, 0.682 mmol, 2 eq). The reaction was stirred at 20 ° C for 17 hours to give a yellow mixture. LCMS showed that the reaction was complete. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was distributed between EtOAc (20 mL) and H2O (20 mL). The aqueous layer was extracted with EtOAc (20 mL x 2). The combined organic layer was washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a yellow jelly. The crude product was purified by preparative TLC (first EtOAc / PE=1 / 3, then DCM / MeOH=30:1) to give C3 (150 mg, 69.7% yield, 100% purity) as an off-white powder.

[0453] General synthesis procedure for 179

[0454] To a mixture of C3 (130 mg, 0.206 mmol, 1 eq), D1-3 (28 mg, 0.329 mmol, 1.6 eq), P(cy)3 (8 mg, 0.021 mmol, 0.1 eq) and K3PO4 (153 mg, 0.721 mmol, 3.5 eq) in toluene (2 mL) and H2O (0.2 mL) was added Pd(OAc)2 (5 mg, 0.021 mmol, 0.1 eq). The reaction was stirred at 100°C for 2 hours under N2 to give a yellow mixture. LCMS showed that the starting material was not completely consumed. The reaction was stirred at 100°C for 2 hours under N2 to give a yellow mixture. LCMS showed that the starting material was not completely consumed. Cyclopropylboronic acid (30 mg) and K3PO4 (150 mg) were added to the reaction mixture. The reaction was stirred at 100°C for 1 hour under N2 to give a yellow mixture. LCMS showed that the starting material was not completely consumed. The mixture was distributed between EtOAc (30mL) and H2O (30mL). The aqueous layer was extracted with EtOAc (20mL x 2). The combined organic layer was washed with brine (20mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by preparative TLC (DCM / MeOH=40 / 1) to give a yellow jelly. LCMS showed impurity. The yellow jelly was purified by preparative HPLC (column: Waters Xbridge C18150*50mm*10um; mobile phase: [water (0.04% NH3H2O+10mM NH4HCO3)-ACN]; B%: 50%-80%, 11min). LCMS showed impurity. The eluent was concentrated under reduced pressure to give a yellow oil. The oil was purified by preparative TLC (EtOAc / PE=1 / 2) to give a yellow jelly. LCMS showed impure. The yellow gum was purified by preparative HPLC (column: Welch Xtimate C18 100*25mm*3um; mobile phase: [water (0.05% ammonium hydroxide v / v)-ACN]; B%: 64%-64%, 12min). The eluent was concentrated under reduced pressure to give a residue. The residue was partitioned between MeCN (5 mL) and H2O (5 mL) and freeze-dried to give 179 (12.2 mg, 10.9% yield, 100% purity) as a white powder.

[0455] Scheme 20-General Synthetic Route II

[0456]

[0457] General synthesis procedure of A71

[0458] To a solution of A6 (10 g, 42.0 mmol, 1 eq) and 3,4-dihydro-2H-pyran (10.6 g, 126 mmol, 11.5 mL, 3 eq) in THF (100 mL) was added p-TsOH (723 mg, 4.20 mmol, 0.1 eq). The resulting mixture was stirred at 80 ° C for 3 hrs to give a yellow solution. TLC (PE: EtOAc = 3: 1) showed that the reaction was complete. The reaction mixture was concentrated under reduced pressure to give a residue. It was then diluted with H2O (100 mL) and extracted with EtOAc (100 mL x 2). The combined organic layers were washed with brine (60 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO 2 , PE:EtOAc=3:1) to give A71 (13 g, 94.6% yield, 98.5% purity) as a yellow oil.

[0459] General synthesis procedure of A72

[0460] To a solution of A71 (13 g, 40.3 mmol, 1 eq) in MeOH (60 mL) and THF (60 mL) was added NaOH (3 M, 40.3 mL, 3 eq). The resulting mixture was heated and stirred at 60 ° C for 1 hr to give a red solution. LCMS showed that the reaction was complete. The reaction mixture was concentrated under reduced pressure to give a residue. It was then diluted with H2O (50 mL) and extracted with EtOAc (100 mL x 2). The aqueous layer was adjusted to pH ~ 5 and extracted with DCM (100 mL x 2), washed with brine (30 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give A72 (9.9 g, 83.4% yield, 100% purity) as a yellow solid.

[0461] General synthesis procedure of C4

[0462] To a mixture of compound A72 (8.28 g, 28.2 mmol, 1.5 eq), compound B1-1 (5.58 g, 18.8 mmol, 1 eq) in pyridine (15 mL) was added EDCI (7.20 g, 37.5 mmol, 2 eq). The reaction was stirred at 20 ° C for 17 hours to give a yellow mixture. LCMS showed that the starting material was not completely consumed. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was distributed between EtOAc (200 mL) and H2O (200 mL). The organic layer was washed with H2O (200 mL x 2), brine (200 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a yellow gum. The crude product was purified by Combi Flash (EtOAc / PE=0 / 1 to 7 / 2) to give C4 (6.29 g, yield: 57%, purity: 98%) as a yellow gum.

[0463] 16 General synthesis procedures

[0464] To a solution of C4 (6.29 g, 11 mmol, 1 eq) in DCM (20 mL) at 0 ° C was added TFA (10 mL, 135 mmol, 12.3 eq). The reaction was stirred at 20 ° C for 17 hours to give a yellow solution. LCMS showed that the starting material was not completely consumed. The mixture was concentrated under reduced pressure to give a residue. The residue was dissolved in THF (20 mL). HCl (2M, 11 mL, 2 eq) was added. The reaction was stirred at 20 ° C for 2 hours to give a yellow solution. LCMS showed that the starting material was not completely consumed. HCl (2M, 11 mL, 2 eq) was added. The reaction was stirred at 20 ° C for 2 hours to give a yellow solution. TLC showed that the starting material was not completely consumed. THF (25 mL) and HCl (2M, 25 mL) were added. The reaction was stirred at 50 ° C for 17 hours to give a yellow solution. LCMS showed that the starting material was not completely consumed. The reaction was stirred at 55 ° C for 1.5 hours to give a yellow solution. The 1-(2-nitro-1-yl)-2-nitropropene was added to 4-nitropropene (2-nitropropene) and 4-nitropropene (2-nitropropene) (3-nitropropene).LCMS shows that the starting material is not completely consumed.After filtration, the filter cake is washed with H2O (10mL x 2), distributed between NaHCO3 (300mL), DCM (300mL), MeOH (50mL).The aqueous layer is extracted with DCM (300mL).The combined organic layer is dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a yellow powder.The crude product is ground with EtOAc / PE (1 / 1, 40mL) to give 16 (4.26g, yield: 79%, purity: 100%) as a white powder.

[0465] General synthesis procedure of C2

[0466] The method for preparing compounds of C2 is shown in Scheme 8. The reaction of 16 and D1 is carried out in the presence of Cs2CO3 in a solvent such as DMF or MeCN to give C2. In addition, many D1 alkyl reagents are commercially available.

[0467] Scheme 21 - General synthesis of compound 29

[0468]

[0469] CsCO (20 mg, 0.613 mmol, 1.5 eq) was added to a solution of 16 (20 mg, 0.409 mmol, 1 eq) and D1-11 (2.37 mg, 0.409 mmol, 2.86 uL, 1 eq) in CHCN (2 mL). The resulting mixture was stirred at 20 ° C for 16 hours to give a yellow solution. TLC (PE: EtOAc = 0: 1) showed that the remaining starting material was very little and the desired product was formed. The reaction mixture was quenched by adding H2O (5 mL) and extracted with EtOAc (5 mL). The combined organic layer was washed with brine (3 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by TLC (PE:EtOAc=0:1), then dissolved in CH3CN (1 mL) and H2O (1 mL), and freeze-dried to give 29 (14 mg, 62.6% yield, 100% purity) as a white powder.

[0470] References

[0471] The Role of TAM Family Receptors in Immune Cell Function: Implications for Cancer Therapy, Paolino M, Penninger JM., Cancers (Basel). 2016 Oct 21;8(10).pii:E97.

[0472] Diversification of TAM receptor tyrosine kinase function, Zagórska A, Través PG, Lew ED, Dransfield I, Lemke G., Nat Immunol. 2014 Oct;15(10):920-8.

[0473] TAM receptor tyrosine kinases as emerging targets of innate immune checkpoint blockade for cancer therapy, Akalu YT, Rothlin CV, Ghosh S., Immunol Rev. 2017 Mar; 276(1): 165-177.

[0474] Ligand Activation of TAM Family Receptors-Implications for Tumor Biology and Therapeutic Response, Davra V, Kimani SG, Calianese D, Birge RB., Cancers (Basel). 2016 Nov 29;8(12).pii:E107.

[0475] Development of monocytes, macrophages, and dendritic cells, Geissmann F, Manz mg, Jung S, Sieweke MH, Merad M, Ley K., Science. 2010 Feb 5; 327(5966): 656-61.

[0476] CSF1 / CSF1R blockade reprograms tumor-infiltrating macrophages and improves response to T-cell checkpoint immunotherapy in pancreatic cancer models. Zhu Y, Knolhoff BL, Meyer MA, Nywening TM, West BL, Luo J, Wang-Gillam A, Goedegebuure SP, Linehan DC, DeNardo DG., Cancer Res. 2014 Sep 15;74(18):5057-69.

[0477] The present invention is now further exemplified by Tables 1-7, which show the activity data of selected compounds in the binding assays of Examples 1-2 (Tables 1-2), in the cell ELISA assays of Examples 3-4 (Tables 3 and 4), in the cell viability assays of Examples 4 and 5 (Tables 5 and 6), and in Examples 6-7 (Table 7) and Example 8 (Table 8). Figure 1 and 2 ); and the structures of compounds 1-179 include 1 The H-NMR data are shown in Table 8.

[0478]

[0479]

[0480]

[0481]

[0482]

[0483]

[0484]

[0485]

[0486]

[0487]

[0488]

[0489]

[0490]

[0491]

[0492]

[0493]

[0494]

[0495]

[0496]

[0497]

[0498]

[0499]

[0500]

[0501]

[0502]

[0503]

[0504]

[0505]

[0506]

[0507]

[0508]

[0509]

[0510]

[0511]

[0512]

[0513]

[0514]

[0515]

[0516]

[0517]

[0518]

[0519] *: Compound of WO2016 / 166250

[0520] **: Compound of the present invention

[0521]

[0522]

[0523]

[0524]

[0525]

[0526]

[0527]

[0528]

[0529]

[0530]

[0531]

[0532]

[0533]

[0534]

[0535]

[0536]

[0537]

[0538]

[0539]

[0540]

[0541]

[0542]

[0543]

[0544]

[0545]

[0546]

[0547]

[0548]

[0549]

[0550]

Claims

1. A compound having the general formula I: in X 1 Independently selected from CR at each occurrence 3 and N; X 2 Independently selected from CR at each occurrence 4 and N; n is independently selected from 0 and 1 at each occurrence; A is independently selected at each occurrence from any structure depicted in the following group W; Group W R 1 is independently selected at each occurrence from hydrogen; C1-C6 alkyl; 5 and NR 5 R 6 C1-C6 alkyl substituted by one or both of: C3-C10 cycloalkyl; C1-C4 haloalkyl; -(C=O)R 5 The group composed of; R 2 is - OR 8 ; R 3 and R 4 is independently selected at each occurrence from hydrogen; halogen; C1-C3 alkyl; OR 5 ; A group consisting of C1-C4 haloalkyl; R 5 and R 6 is independently selected at each occurrence from the group consisting of hydrogen; C1-C6 alkyl; C3-C10 cycloalkyl; C1-C4 haloalkyl; R 8 independently selected at each occurrence from -CH(CH3)2; -C(CH3)3; C1-C4 haloalkyl; C1-C6 alkyl substituted by one or both of cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, C3-C10 heterocycloalkyl and C1-C4 haloalkyl; and C1-C6 alkyl substituted by C1-C4 haloalkyl; Z 1 is independently selected at each occurrence from hydrogen; C1-C6 alkyl; 5 and NR 5 R 6 The group consisting of C1-C6 alkyl substituted by one or both of: C3-C10 cycloalkyl; and C3-C10 heterocycloalkyl; R 11 and R 12 is independently selected at each occurrence from the group consisting of C1-C6 alkyl; C3-C10 cycloalkyl; C3-C10 heterocycloalkyl; C1-C4 haloalkyl; and pharmaceutically acceptable salts thereof.

2. The compound according to claim 1, which has the general formula II: in R 1 , R 2 , R 3 , R 4 , R 11 , R 12 , Z 1 , X 1 , X 2 and n as defined in claim 1; and pharmaceutically acceptable salts thereof.

3. The compound according to claim 1, which has the general formula III: in R 1 , R 2 , R 3 , R 4 , Z 1 , X 1 , X 2 and n as defined in claim 1; and pharmaceutically acceptable salts thereof.

4. The compound according to claim 3, wherein R 3 and R 4 is independently selected at each occurrence from the group consisting of hydrogen; halogen; C1-C3 alkyl; R 8 is independently selected at each occurrence from the group consisting of -CH(CH3)2; -C(CH3)3; C1-C4 haloalkyl; and C1-C6 alkyl substituted with one or both of cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and C1-C4 haloalkyl; and Z 1 is independently selected at each occurrence from hydrogen; C1-C6 alkyl; 5 and NR 5 R 6 The group consisting of C1-C6 alkyl substituted by one or both of: C3-C10 cycloalkyl; and C3-C10 heterocycloalkyl; and pharmaceutically acceptable salts thereof.

5. The compound according to claim 1, which has the general formula IV: in R 1 , R 2 , R 3 , R 4 , Z 1 , X 2 and n as defined in claim 1; and pharmaceutically acceptable salts thereof.

6. The compound according to claim 1, which has the general formula V: in R 1 , R 2 , R 3 , R 4 , Z 1 and n as defined in claim 1; and pharmaceutically acceptable salts thereof.

7. The compound according to claim 6, wherein R 3 and R 4 is hydrogen; and pharmaceutically acceptable salts thereof.

8. The compound according to claim 1, wherein n=0 or 1, and Z 1 Selected from C1-C6 alkyl; C3-C10 cycloalkyl; C3-C10 heterocycloalkyl; OR 5 and NR 5 R 6 C1-C6 alkyl substituted by one or both of: and pharmaceutically acceptable salts thereof.

9. The compound according to claim 8, wherein Z 1 Selected from methyl, ethyl, propyl, isopropyl or C3 cycloalkyl.

10. The compound according to claim 1, wherein R 2 Yes OR 8 , and R 8 Selected from -CH(CH3)2; -C(CH3)3; C1-C4 haloalkyl; C1-C6 alkyl substituted by one or both of cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, C3-C10 heterocycloalkyl and C1-C4 haloalkyl; or C1-C6 alkyl substituted by one of trifluoromethyl, difluoromethyl, fluoromethyl, trifluoroethyl, difluoroethyl, fluoroethyl, trifluoropropyl, difluoropropyl, fluoropropyl, trifluoroisopropyl, difluoroisopropyl and fluoroisopropyl; and pharmaceutically acceptable salts thereof.

11. The compound according to any one of claims 8 to 10, wherein n = 0 or 1, and Z 1 is selected from methyl, ethyl, propyl or isopropyl; C3 cycloalkyl; C3-C10 heterocycloalkyl; 5 and NR 5 R 6 C1-C6 alkyl substituted by one or both of 5 and R 6 is independently selected at each occurrence from hydrogen; C1-C6 alkyl; C3-C10 cycloalkyl; C1-C4 haloalkyl; and R 2 Yes OR 8 , and R 8 Selected from -CH(CH3)2; -C(CH3)3; C1-C4 haloalkyl; C1-C6 alkyl substituted by one or both of cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, C3-C10 heterocycloalkyl and C1-C4 haloalkyl; or C1-C6 alkyl substituted by one of trifluoromethyl, difluoromethyl, fluoromethyl, trifluoroethyl, difluoroethyl, fluoroethyl, trifluoropropyl, difluoropropyl, fluoropropyl, trifluoroisopropyl, difluoroisopropyl and fluoroisopropyl; and pharmaceutically acceptable salts thereof.

12. The compound according to claim 1, wherein R 2 Yes OR 8 , and R 8 Selected from C1-C4 haloalkyl; or C1-C6 alkyl substituted by C1-C4 haloalkyl.

13. The compound according to claim 12, wherein R 8 One selected from trifluoromethyl, difluoromethyl, fluoromethyl, trifluoroethyl, difluoroethyl, fluoroethyl, trifluoropropyl, difluoropropyl, fluoropropyl, trifluoroisopropyl, difluoroisopropyl and fluoroisopropyl; or C1-C6 alkyl substituted by one of trifluoromethyl, difluoromethyl, fluoromethyl, trifluoroethyl, difluoroethyl, fluoroethyl, trifluoropropyl, difluoropropyl, fluoropropyl, trifluoroisopropyl, difluoroisopropyl and fluoroisopropyl.

14. The compound according to claim 1, wherein n = 0 or 1, and Z 1 Selected from methyl, ethyl, propyl, isopropyl, C3 cycloalkyl, C4 cycloalkyl and C5 cycloalkyl.

15. A compound according to any one of claims 12 to 14, wherein n = 0 or 1; Z 1 is selected from the group consisting of methyl, ethyl, propyl, isopropyl, C3 cycloalkyl, C4 cycloalkyl and C5 cycloalkyl; and R 2 Yes OR 8 ; and R 8 Selected from C1-C4 haloalkyl; or C1-C6 alkyl substituted by C1-C4 haloalkyl.

16. The compound according to claim 15, wherein R 8 One selected from trifluoromethyl, difluoromethyl, fluoromethyl, trifluoroethyl, difluoroethyl, fluoroethyl, trifluoropropyl, difluoropropyl, fluoropropyl, trifluoroisopropyl, difluoroisopropyl and fluoroisopropyl; or C1-C6 alkyl substituted by one of trifluoromethyl, difluoromethyl, fluoromethyl, trifluoroethyl, difluoroethyl, fluoroethyl, trifluoropropyl, difluoropropyl, fluoropropyl, trifluoroisopropyl, difluoroisopropyl and fluoroisopropyl.

17. The compound according to claim 1, having one of the structures shown below: 。 18. A composition comprising at least one compound according to any one of claims 1 to 17 and at least one pharmaceutically acceptable carrier, excipient and / or diluent.

19. The composition of claim 18, further comprising at least one other pharmaceutically active agent.

20. Use of a compound according to any one of claims 1-17 or a composition according to any one of claims 18-19 for the preparation of a medicament for treating a disorder associated with, associated with, caused by or induced by Axl / Mer and CSF1R receptor tyrosine kinases.

21. The use according to claim 20, wherein the disorder is a disorder associated with, associated with or caused by Axl / Mer and CSF1R.

22. The use according to claim 20, wherein the disorder is a disorder associated with, accompanied by, or caused by hyperfunction of the Axl / Mer and the CSF1R.

23. The use according to any one of claims 20 to 22, wherein the disorder is selected from a hyperproliferative disorder, an inflammatory disorder and a neurodegenerative disorder.

24. The use according to claim 23, wherein the hyperproliferative disorder is cancer.

25. The use according to claim 24, wherein the cancer is selected from the group consisting of adenocarcinoma, gynecological tumors, hematological tumors, sarcomas.

26. The use according to claim 24, wherein the cancer is selected from the group consisting of bone cancer, brain tumors, gastrointestinal cancer, myeloproliferative disorders, respiratory cancers, urinary tract tumors.

27. The use according to claim 24, wherein the cancer is selected from soft tissue tumors, squamous cell carcinoma.

28. The use according to claim 24, wherein the cancer is selected from AIDS-related cancers.

29. The use according to claim 24, wherein the cancer is selected from head and neck cancer.

30. The use according to claim 24, wherein the cancer is selected from brain and spinal cord tumors.

31. The use according to claim 24, wherein the cancer is selected from astrocytoma.

32. The use according to claim 24, wherein the cancer is selected from central nervous system lymphoma.

33. The use according to claim 24, wherein the cancer is selected from atypical teratoid / rhabdoid tumors of the central nervous system.

34. The use according to claim 24, wherein the cancer is selected from atypical teratoid / rhabdoid tumors.

35. The use according to claim 24, wherein the cancer is selected from cancers of pregnancy.

36. The use according to claim 24, wherein the cancer is selected from trophoblastic tumors.

37. The use according to claim 24, wherein the cancer is selected from gestational trophoblastic tumor.

38. The use according to claim 24, wherein the cancer is selected from urethral cancer.

39. The method of claim 24, wherein the cancer is selected from the group consisting of: acoustic neuroma, adrenocortical carcinoma, anal cancer, appendix cancer, basal cell tumor, bile duct cancer, bladder cancer, osteosarcoma, brain stem glioma, medullary epithelioma, breast cancer, urachal tumor, Burkitt lymphoma, carcinoid tumor, choroidal melanoma, chordoma, colon cancer, cutaneous T-cell lymphoma, desmoid tumor, mycosis fungoides, extracranial germ cell tumor, extragonadal germ cell tumor, ear tumor, intraocular melanoma, retinoblastoma, gallbladder cancer, gastric cancer, ovarian germ cell tumor, glioma, heart cancer, histiocytosis, renal cancer, Langerhans cell histiocytosis, leukemia, lip and oral cavity cancer, liver cancer, lung cancer, Hodgkin lymphoma, macroglobulinemia, melanoma, Merkel cell carcinoma, mesothelioma, spinalioms, multiple endocrine neoplasia syndrome, myelodysplastic syndrome, nasal and paranasal sinus cancer, neuroblastoma, ovarian cancer, oligodendroglioma, plasmacytoma, pancreatic cancer, papilloma, parathyroid cancer, penile cancer, pituitary tumors, prostate cancer, rectal cancer, transitional cell carcinoma, rhabdomyosarcoma, cutaneous testicular cancer, Kaposi's sarcoma, skin cancer, small intestine cancer, soft tissue sarcoma, testicular cancer, thymoma and thymic cancer, thyroid cancer, uterine cancer, vaginal cancer, Waldenstrom's macroglobulinemia and Wilms' tumor, giant cell tumor, pigmented villonodular synovitis.

40. The use according to claim 24, wherein the cancer is selected from craniopharyngioma.

41. The use according to claim 24, wherein the cancer is selected from ependymoma.

42. The use according to claim 24, wherein the cancer is selected from ependymoma.

43. The use according to claim 24, wherein the cancer is selected from medulloblastoma.

44. The use according to claim 24, wherein the cancer is selected from moderately differentiated pineal parenchymal tumors.

45. The use according to claim 24, wherein the cancer is selected from esthesia neuroblastoma.

46. ​​The use according to claim 24, wherein the cancer is selected from tumors of the Ewing's sarcoma family.

47. The use according to claim 24, wherein the cancer is selected from chronic myeloproliferative disorders.

48. The use according to claim 24, wherein the cancer is selected from multiple myeloma.

49. The use according to claim 24, wherein the cancer is selected from supratentorial primitive neuroectodermal tumors and pineoblastoma.

50. The use according to claim 24, wherein the cancer is selected from gastrointestinal carcinoid tumors.

51. The use according to claim 24, wherein the cancer is selected from gastrointestinal stromal tumors.

52. Use according to claim 24, wherein the cancer is selected from colorectal cancer, small intestine tumors.

53. The use according to claim 24, wherein the cancer is selected from nasopharyngeal carcinoma.

54. The use according to claim 24, wherein the cancer is selected from oropharyngeal cancer.

55. The use according to claim 24, wherein the cancer is selected from hypopharyngeal cancer.

56. The use according to claim 24, wherein the cancer is selected from pharyngeal cancer.

57. The use according to claim 24, wherein the cancer is selected from laryngeal cancer.

58. The use according to claim 24, wherein the cancer is selected from salivary gland cancer.

59. The use according to claim 24, wherein the cancer is selected from squamous neck cancer.

60. The use according to claim 24, wherein the cancer is selected from primary occult metastatic squamous neck cancer.

61. The use according to claim 24, wherein the cancer is selected from pleuropulmonary blastoma.

62. The use according to claim 24, wherein the cancer is selected from esophageal cancer.

63. The use according to claim 24, wherein the cancer is selected from extrahepatic bile duct carcinoma.

64. The use according to claim 24, wherein the cancer is selected from cancers that cause accumulation of fluid in potential spaces of the body, pleural effusion, pericardial effusion, peritoneal effusion also known as ascites.

65. The use according to claim 24, wherein the cancer is selected from pancreatic islet cell tumors.

66. The use according to claim 24, wherein the cancer is selected from ampullary carcinoma.

67. The use according to claim 24, wherein the cancer is selected from cervical cancer.

68. The use according to claim 24, wherein the cancer is selected from uterine corpus cancer.

69. The use according to claim 24, wherein the cancer is selected from endometrial cancer.

70. The use according to claim 24, wherein the cancer is selected from uterine sarcoma.

71. The use according to claim 24, wherein the cancer is selected from vulvar cancer.

72. The use according to claim 24, wherein the cancer is selected from ureteral cancer.

73. The use according to claim 24, wherein the cancer is selected from renal pelvic cancer.

74. The use according to claim 24, wherein the cancer is selected from urothelial carcinoma.

75. The method of claim 24, wherein the cancer is selected from the group consisting of acute lymphoblastic leukemia, acute myeloid leukemia, malignant fibrous histiocytoma, chronic lymphocytic leukemia, chronic myeloid leukemia, gastrointestinal stromal cell tumor, hairy cell leukemia, hepatocellular carcinoma, renal cell carcinoma, non-small cell lung cancer, small cell lung cancer, non-Hodgkin lymphoma, primary central nervous system lymphoma, oral cancer, ovarian epithelial cancer, ovarian low malignant potential tumor, plasma cell neoplasm, Ewing's sarcoma, non-melanoma skin cancer, melanoma skin cancer, transitional cell carcinoma of the renal pelvis and ureter.

76. The use according to claim 24, wherein the cancer is selected from AIDS-related lymphoma.

77. The use according to claim 24, wherein the cancer is selected from giant cell tumor of bone and giant cell tumor of tendon sheath.

78. The use according to claim 24, wherein the cancer is TGCT of the tendon sheath.

79. The use according to claim 23, wherein the inflammatory disorder is selected from osteoarthritis, inflammatory bowel syndrome, transplant rejection, systemic lupus erythematosus, chronic obstructive pulmonary disease, emphysema, Kawasaki disease, hemophagocytic syndrome, atherosclerosis, primary progressive multiple sclerosis, type I diabetes, type II diabetes, insulin resistance, hyperglycemia, obesity, eosinophilia, osteoporosis, Paget's disease, hypercalcemia, infection-mediated osteolysis, periprosthetic or wear debris-mediated osteolysis, endometriosis, inflammatory pain, chronic pain and bone pain.

80. The use according to claim 23, wherein the inflammatory disorder is selected from ulcerative colitis and multicentric reticulohistiocytosis.

81. The use according to claim 23, wherein the inflammatory disorder is selected from Crohn's disease.

82. The use according to claim 23, wherein the inflammatory disorder is selected from macrophage activation syndrome and osteomyelitis.

83. The method of claim 23, wherein the neurodegenerative disorder is selected from the group consisting of Binswanger dementia, holoprosencephaly, microcephaly, cerebral palsy, congenital hydrocephalus, ascites, progressive supranuclear palsy, glaucoma, Wilson's disease, Alzheimer's disease, Parkinson's disease, multi-infarct dementia, frontotemporal dementia, pseudodementia, prion disease, motor neuron disease, Huntington's disease, spinocerebellar ataxia, and spinal muscular atrophy.

84. The use according to claim 23, wherein the neurodegenerative disorder is selected from Parkinson's disease-related disorders.

85. Use of a compound according to any one of claims 1-17 or a composition according to any one of claims 18-19 in combination with another pharmaceutically active agent in the preparation of a medicament for treating a disorder associated with, associated with, caused by or induced by Axl / Mer and CSF1R receptor tyrosine kinases.

86. The use according to claim 85, wherein the another pharmaceutically active drug is selected from a chemotherapeutic agent, a targeted drug, an immune checkpoint inhibitor drug and an anti-cancer agent.

Images