JP7011638B2 - Tetrahydropyranylamino-pyrrolopyrimidinone and how to use it - Google Patents

Description

Field of Application This application is a mutant BTK useful in the treatment of diseases or disorders related to BTK kinase, including immune disorders, cancer, cardiovascular disease, viral infections, inflammation, metabolic / endocrine dysfunction, and neuropathy. With respect to inhibitors of Bruton's tyrosine kinase (BTK), including. Specifically, the present application relates to compounds and compositions thereof that inhibit BTK, methods for treating diseases or disorders associated with BTK, and methods for synthesizing these compounds.

background
BTK is a member of the Tec family of tyrosine kinases and plays an important role in premature B cell development and regulation of mature B cell activation and survival. (Hunter, Cell, 1987 50, 823-829 (Non-Patent Document 1)). BTK functions downstream of multiple receptors, such as growth factors, B cell antigens, chemokines, and congenital immunoreceptors, and cell proliferation, survival, differentiation, motility, angiogenesis, cytokine production, and antigens. Initiate several cellular processes, including presentation.

BTK-deficient mouse models have shown the role that BTK plays in allergic disorders and / or autoimmune and / or inflammatory diseases. For example, deficiency of BTK in a standard mouse preclinical model of systemic lupus erythematosus (SLE) has been shown to result in a marked improvement in disease progression. In addition, BTK-deficient mice can be resistant to the development of collagen-induced arthritis and are less susceptible to Staphylococcus-induced arthritis. Due to the role of BTK in B cell activation, BTK inhibitors may also be useful as inhibitors of B cell-mediated pathogenic activity (such as autoantibody production). Expression of BTK in osteoclasts, mast cells and monocytes has been shown to be important for the function of these cells. For example, impaired IgE-mediated mast cell activation and reduced TNF-α production by activated monocytes have been associated with BTK deficiency in mice and humans. Therefore, BTK inhibition is an allergic disorder such as SLE, rheumatoid arthritis, polycystitis, idiopathic thrombocytopenic purpura (ITP), severe myasthenia, allergic rhinitis, and asthma and / or autoimmune and / Alternatively, it may be useful in the treatment of inflammatory diseases (DiPaolo et. Al., Nature Chem. Biol. 2011, 7 (1): 41-50 (Non-Patent Document 2); Liu et. Al., Jour. Pharmacol. and Exp. Ther. 2011, 338 (1): 154-163 (Non-Patent Document 3)).

In addition, the role of BTK in apoptosis demonstrates the usefulness of inhibiting BTK activity for the treatment of cancer, B-cell lymphoma, leukemia, and other hematological malignancies. In addition, given the role of BTK in osteoclast function, inhibition of BTK activity may be useful in the treatment of bone disorders such as osteoporosis.

Therefore, inhibition of BTK by small molecule inhibitors has the potential to treat immune disorders, cancer, cardiovascular disease, viral infections, inflammation, metabolic / endocrine dysfunction, and neuropathy. Therefore, there is a considerable need for strong small molecule inhibitors of BTK.

Hunter, Cell, 1987 50, 823-829 DiPaolo et. Al., Nature Chem. Biol. 2011, 7 (1): 41-50 Liu et. Al., Jour. Pharmacol. And Exp. Ther. 2011, 338 (1): 154-163

または薬学的に許容されるその塩、その互変異性体、プロドラッグ、溶媒和物、代謝産物、多形体、類似体もしくは誘導体に関する。本明細書において用いられる場合、「式(I)の化合物」および「化合物(I)」という表現は、同じ化合物を指し、互換的に用いることができる。 Summary The first aspect of this application is the compound of formula (I):

Or with respect to the pharmaceutically acceptable salt thereof, its homozygous form, a prodrug, a solvate, a metabolite, a polymorph, an analog or a derivative thereof. As used herein, the terms "compound of formula (I)" and "compound (I)" refer to the same compound and can be used interchangeably.

Another aspect of the present application is a compound of formula (I) or a pharmaceutically acceptable salt thereof, a prodrug, a solvate, a metabolite, a polymorph, an analog or derivative, and a pharmaceutical. Containing a pharmaceutical composition comprising an acceptable diluent, excipient or carrier.

Another aspect of the application relates to methods of treating BTK-mediated disorders. The method comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, a mutant, a prodrug, a solvate, for patients in need of treatment for a disease or disorder associated with the regulation of BTK kinase. , Includes the step of administering a therapeutically effective amount of a metabolite, polymorph, analog or derivative.

Another aspect of the application relates to methods of treating BTK-mediated disorders. The method comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, a mutant, a prodrug, a solvate, for patients in need of treatment for a disease or disorder associated with the regulation of BTK kinase. , A step of administering a therapeutically effective amount of a pharmaceutical composition comprising a metabolite, a polymorph, an analog or derivative, and a pharmaceutically acceptable diluent, excipient or carrier.

Another aspect of the application relates to methods of treating cell proliferation disorders. The method comprises the need for the compound of formula (I) or a pharmaceutically acceptable salt thereof, a prodrug, a solvate, a metabolite, a polymorph, an analog or a derivative thereof. Includes the step of administering a therapeutically effective amount.

Another aspect of the application relates to methods of treating cell proliferation disorders. The method comprises the need for a compound of formula (I) or a pharmaceutically acceptable salt thereof, a prodrug, a solvent, a metabolite, a polymorph, an analog or a derivative thereof. And the step of administering a therapeutically effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable diluent, excipient or carrier.

Another aspect of this application relates to methods of treating cancer. The method comprises the need for the compound of formula (I) or a pharmaceutically acceptable salt thereof, a prodrug, a solvate, a metabolite, a polymorph, an analog or a derivative thereof. Includes the step of administering a therapeutically effective amount.

Another aspect of this application relates to methods of treating cancer. The method comprises the need for a compound of formula (I) or a pharmaceutically acceptable salt thereof, a prodrug, a solvent, a metabolite, a polymorph, an analog or a derivative thereof. And the step of administering a therapeutically effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable diluent, excipient or carrier.

Another aspect of the application relates to a method of regulating (eg, inhibiting) BTK. The method comprises the need for the compound of formula (I) or a pharmaceutically acceptable salt thereof, a prodrug, a solvate, a metabolite, a polymorph, an analog or a derivative thereof. Includes the step of administering a therapeutically effective amount.

Another aspect of the application relates to a method of regulating (eg, inhibiting) BTK. The method comprises the need for a compound of formula (I) or a pharmaceutically acceptable salt thereof, a prodrug, a solvent, a metabolite, a polymorph, an analog or a derivative thereof. And the step of administering a therapeutically effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable diluent, excipient or carrier.

Another aspect of the application is a compound of formula (I) for use in BTK-mediated disorders, cell proliferation disorders, or methods of treating cancer or regulating (eg, inhibiting) BTK. With respect to its pharmaceutically acceptable salts, tautomers, prodrugs, solvates, metabolites, polymorphs, analogs or derivatives thereof. A compound of formula (I), or a pharmaceutically acceptable salt thereof, a mutant, a prodrug, a solvate, a metabolite, a polymorph, an analog or a derivative thereof, is therapeutically effective in a patient in need thereof. Administered in dose.

Another aspect of the present application is a compound of formula (I) or for use in a method of treating a BTK-mediated disorder, cell proliferation disorder, or cancer or in a method of regulating (eg, inhibiting) BTK. A pharmacy containing a pharmaceutically acceptable salt thereof, a mutant, a prodrug, a solvate, a metabolite, a polymorph, an analog or a derivative, and a pharmaceutically acceptable diluent, excipient or carrier. With respect to the composition. The composition is administered in a therapeutically effective amount to the patient in need thereof.

Another aspect of the present application is a compound of formula (I) or in the manufacture of a drug for treating BTK-mediated disorders, cell proliferation disorders, or cancers or for regulating (eg, inhibiting) BTK. With respect to the use of pharmaceutically acceptable salts thereof, metavariants, prodrugs, solvates, metabolites, polymorphs, analogs or derivatives thereof. A compound of formula (I), or a pharmaceutically acceptable salt thereof, a mutant, a prodrug, a solvate, a metabolite, a polymorph, an analog or a derivative thereof, is therapeutically effective in a patient in need thereof. Administered in dose.

Another aspect of the present application is a compound of formula (I) or in the manufacture of a drug for treating a BTK-mediated disorder, cell proliferation disorder, or cancer or for regulating (eg, inhibiting) BTK. A pharmacy containing a pharmaceutically acceptable salt thereof, a metavariant, a prodrug, a solvent, a metabolite, a polymorph, an analog or a derivative, and a pharmaceutically acceptable diluent, excipient or carrier. With respect to the use of the composition. The composition is administered in a therapeutically effective amount to the patient in need thereof.

This application is a method for treating a disease or disorder related to the regulation of BTK kinase, including, but not limited to, immune disorders, cancers, cardiovascular diseases, viral infections, inflammation, metabolic / endocrine dysfunction, and neuropathy. And a compound of formula (I), or a pharmaceutically acceptable salt thereof, a mutant, a prodrug, a solvent, a metabolite thereof, in a patient suffering from at least one of the diseases or disorders. , A method further comprising the step of administering a polymorph, analog or derivative.

This application is a therapeutic agent in the treatment of diseases such as immune disorders, cancer, cardiovascular diseases, viral infections, inflammation, metabolic / endocrine dysfunction, neuropathy and other diseases associated with the regulation of BTK kinase. Provides an inhibitor of.

または薬学的に許容されるその塩、その互変異性体、プロドラッグ、溶媒和物、代謝産物、多形体、類似体もしくは誘導体。
[本発明1002]
本発明1001の化合物または薬学的に許容されるその塩、その互変異性体、プロドラッグ、溶媒和物、代謝産物、多形体、類似体もしくは誘導体、および薬学的に許容される希釈剤、賦形剤または担体を含む薬学的組成物。
[本発明1003]
その必要がある患者に、治療的有効量の本発明1001の化合物または薬学的に許容されるその塩、互変異性体、プロドラッグ、溶媒和物、代謝産物、多形体、類似体もしくは誘導体、あるいは本発明1002の薬学的組成物を投与する段階を含む、BTK介在性障害を処置する方法。
[本発明1004]
BTK介在性障害が免疫障害、がん、心血管疾患、ウイルス感染、炎症、代謝/内分泌機能障害および神経障害から選択される、本発明1003の方法。
[本発明1005]
がんが、乳がん、卵巣がん、子宮頸がん、前立腺がん、精巣がん、尿生殖器がん、食道がん、喉頭がん、神経膠芽腫、神経芽細胞腫、胃がん、皮膚がん、角化棘細胞腫、肺がん、類表皮がん、大細胞がん、非小細胞肺がん(NSCLC)、小細胞がん、肺腺がん、骨がん、結腸がん、腺腫、膵臓がん、腺がん、甲状腺がん、濾胞がん、未分化がん、乳頭がん、精上皮腫、黒色腫、肉腫、膀胱がん、肝がんおよび胆道がん、腎臓がん、膵臓がん、骨髄障害、リンパ腫、毛様細胞、口腔がん、上咽頭がん、咽頭がん、口唇がん、舌がん、口のがん、小腸がん、結腸直腸がん、大腸がん、直腸がん、脳および中枢神経系のがん、ホジキン白血病、気管支がん、甲状腺がん、肝臓および肝内胆管のがん、肝細胞がん、胃がん、神経膠腫/神経膠芽腫、子宮内膜がん、黒色腫、腎臓および腎盂のがん、膀胱がん、子宮体がん、子宮頸がん、多発性骨髄腫、急性骨髄性白血病、慢性骨髄性白血病、リンパ性白血病、慢性リンパ性白血病(CLL)、骨髄性白血病、口腔および咽頭のがん、非ホジキンリンパ腫、黒色腫、ならびに結腸絨毛腺腫から選択される、本発明1004の方法。
[本発明1006]
障害が、関節リウマチ、全身および局所炎症、関節炎、免疫抑制に関連する炎症、臓器移植拒絶反応、アレルギー、潰瘍性大腸炎、クローン病、皮膚炎、喘息、全身性エリテマトーデス、シェーグレン症候群、多発性硬化症、強皮症/全身性硬化症、特発性血小板減少性紫斑病(ITP)、抗好中球細胞質抗体(ANCA)関連血管炎、慢性閉塞性肺疾患(COPD)、または乾癬である、本発明1004の方法。
[本発明1007]
その必要がある患者に、有効量の本発明1001の化合物または薬学的に許容されるその塩、互変異性体、プロドラッグ、溶媒和物、代謝産物、多形体、類似体もしくは誘導体、あるいは本発明1002の薬学的組成物を投与する段階を含む、BTKを調節する方法。
[本発明1008]
BTK介在性障害を処置する方法またはBTKを調節する方法に使用するための、本発明1001の化合物または薬学的に許容されるその塩、互変異性体、プロドラッグ、溶媒和物、代謝産物、多形体、類似体もしくは誘導体、あるいは本発明1002の薬学的組成物。
[本発明1009]
BTK介在性障害が、免疫障害、がん、心血管疾患、ウイルス感染、炎症、代謝/内分泌機能障害および神経障害から選択される、本発明1008の化合物または組成物。
[本発明1010]
がんが、乳がん、卵巣がん、子宮頸がん、前立腺がん、精巣がん、尿生殖器がん、食道がん、喉頭がん、神経膠芽腫、神経芽細胞腫、胃がん、皮膚がん、角化棘細胞腫、肺がん、類表皮がん、大細胞がん、非小細胞肺がん(NSCLC)、小細胞がん、肺腺がん、骨がん、結腸がん、腺腫、膵臓がん、腺がん、甲状腺がん、濾胞がん、未分化がん、乳頭がん、精上皮腫、黒色腫、肉腫、膀胱がん、肝がんおよび胆道がん、腎臓がん、膵臓がん、骨髄障害、リンパ腫、毛様細胞、口腔がん、上咽頭がん、咽頭がん、口唇がん、舌がん、口のがん、小腸がん、結腸直腸がん、大腸がん、直腸がん、脳および中枢神経系のがん、ホジキン白血病、気管支がん、甲状腺がん、肝臓および肝内胆管のがん、肝細胞がん、胃がん、神経膠腫/神経膠芽腫、子宮内膜がん、黒色腫、腎臓および腎盂のがん、膀胱がん、子宮体がん、子宮頸がん、多発性骨髄腫、急性骨髄性白血病、慢性骨髄性白血病、リンパ性白血病、慢性リンパ性白血病(CLL)、骨髄性白血病、口腔および咽頭のがん、非ホジキンリンパ腫、黒色腫、ならびに結腸絨毛腺腫から選択される、本発明1009の化合物または組成物。
[本発明1011]
障害が、関節リウマチ、全身および局所炎症、関節炎、免疫抑制に関連する炎症、臓器移植拒絶反応、アレルギー、潰瘍性大腸炎、クローン病、皮膚炎、喘息、全身性エリテマトーデス、シェーグレン症候群、多発性硬化症、強皮症/全身性硬化症、特発性血小板減少性紫斑病(ITP)、抗好中球細胞質抗体(ANCA)関連血管炎、慢性閉塞性肺疾患(COPD)、または乾癬である、本発明1009の化合物または組成物。
[本発明1012]
BTK介在性障害を処置するためまたはBTKを調節するための薬物の製造における、本発明1001の化合物または薬学的に許容されるその塩、互変異性体、プロドラッグ、溶媒和物、代謝産物、多形体、類似体もしくは誘導体、あるいは本発明1002の薬学的組成物の使用。
[本発明1013]
BTK介在性疾患または障害が、免疫障害、がん、心血管疾患、ウイルス感染、炎症、代謝/内分泌機能障害および神経障害から選択される、本発明1012の使用。
[本発明1014]
がんが、乳がん、卵巣がん、子宮頸がん、前立腺がん、精巣がん、尿生殖器がん、食道がん、喉頭がん、神経膠芽腫、神経芽細胞腫、胃がん、皮膚がん、角化棘細胞腫、肺がん、類表皮がん、大細胞がん、非小細胞肺がん(NSCLC)、小細胞がん、肺腺がん、骨がん、結腸がん、腺腫、膵臓がん、腺がん、甲状腺がん、濾胞がん、未分化がん、乳頭がん、精上皮腫、黒色腫、肉腫、膀胱がん、肝がんおよび胆道がん、腎臓がん、膵臓がん、骨髄障害、リンパ腫、毛様細胞、口腔がん、上咽頭がん、咽頭がん、口唇がん、舌がん、口のがん、小腸がん、結腸直腸がん、大腸がん、直腸がん、脳および中枢神経系のがん、ホジキン白血病、気管支がん、甲状腺がん、肝臓および肝内胆管のがん、肝細胞がん、胃がん、神経膠腫/神経膠芽腫、子宮内膜がん、黒色腫、腎臓および腎盂のがん、膀胱がん、子宮体がん、子宮頸がん、多発性骨髄腫、急性骨髄性白血病、慢性骨髄性白血病、リンパ性白血病、慢性リンパ性白血病(CLL)、骨髄性白血病、口腔および咽頭のがん、非ホジキンリンパ腫、黒色腫、ならびに結腸絨毛腺腫から選択される、本発明1013の使用。
[本発明1015]
障害が、関節リウマチ、全身および局所炎症、関節炎、免疫抑制に関連する炎症、臓器移植拒絶反応、アレルギー、潰瘍性大腸炎、クローン病、皮膚炎、喘息、全身性エリテマトーデス、シェーグレン症候群、多発性硬化症、強皮症/全身性硬化症、特発性血小板減少性紫斑病(ITP)、抗好中球細胞質抗体(ANCA)関連血管炎、慢性閉塞性肺疾患(COPD)、または乾癬である、本発明1013の使用。 The present application further provides compounds and compositions having an improved efficacy and safety profile compared to known BTK inhibitors. The application also has a novel mechanism of action on BTK kinase in the treatment of various types of diseases including immune disorders, cancer, cardiovascular disease, viral infections, inflammation, metabolic / endocrine dysfunction, and neuropathy. Provide the agent. Finally, this application provides the medical community with novel pharmacological strategies for the treatment of diseases and disorders associated with BTK kinase.
[Invention 1001]
Compound of formula (I):

Or the pharmaceutically acceptable salt thereof, its homozygous form, prodrug, solvate, metabolite, polymorph, analog or derivative thereof.
[Invention 1002]
Compounds of the invention 1001 or pharmaceutically acceptable salts thereof, their homozygous forms, prodrugs, solvates, metabolites, polymorphs, analogs or derivatives, and pharmaceutically acceptable diluents. A pharmaceutical composition comprising a form or carrier.
[Invention 1003]
A therapeutically effective amount of a compound of the invention 1001 or a pharmaceutically acceptable salt thereof, a metabolite, a prodrug, a solvate, a metabolite, a polymorph, an analog or a derivative thereof, for the patient in need thereof. Alternatively, a method of treating a BTK-mediated disorder comprising the step of administering the pharmaceutical composition of the present invention 1002.
[Invention 1004]
The method of the invention 1003, wherein the BTK-mediated disorder is selected from immune disorders, cancer, cardiovascular disease, viral infections, inflammation, metabolic / endocrine dysfunction and neuropathy.
[Invention 1005]
Cancers include breast cancer, ovarian cancer, cervical cancer, prostate cancer, testis cancer, urogenital cancer, esophageal cancer, laryngeal cancer, glioblastoma, neuroblastoma, gastric cancer, and skin. , Keratinized spinal cell tumor, lung cancer, epidermoid cancer, large cell cancer, non-small cell lung cancer (NSCLC), small cell cancer, lung adenocarcinoma, bone cancer, colon cancer, adenomas, pancreas Cancer, adenocarcinoma, thyroid cancer, follicular cancer, undifferentiated cancer, papillary cancer, sperm epithelioma, melanoma, sarcoma, bladder cancer, liver cancer and biliary tract cancer, kidney cancer, pancreas Cancer, bone marrow disorder, lymphoma, hairy cells, oral cancer, nasopharyngeal cancer, pharyngeal cancer, lip cancer, tongue cancer, mouth cancer, small bowel cancer, colon-rectal cancer, colon cancer, Rectal cancer, brain and central nervous system cancer, Hodgkin leukemia, bronchial cancer, thyroid cancer, liver and intrahepatic bile duct cancer, hepatocellular carcinoma, gastric cancer, glioma / glioblastoma, uterus Endometrial cancer, melanoma, kidney and renal pelvis cancer, bladder cancer, uterine body cancer, cervical cancer, multiple myeloma, acute myeloid leukemia, chronic myeloid leukemia, lymphocytic leukemia, chronic lymph The method of the present invention 1004, which is selected from sex leukemia (CLL), myeloid leukemia, cancer of the oral cavity and pharynx, non-hodgkin lymphoma, melanoma, and colon choriocarcinoma.
[Invention 1006]
Disorders include rheumatoid arthritis, systemic and local inflammation, arthritis, inflammation associated with immunosuppression, organ transplant rejection, allergies, ulcerative colitis, Crohn's disease, dermatitis, asthma, systemic lupus erythematosus, Sjogren's syndrome, multiple sclerosis Disease, scleroderma / systemic sclerosis, idiopathic thrombocytopenic purpura (ITP), antineutrophil cytoplasmic antibody (ANCA) -related arthritis, chronic obstructive pulmonary disease (COPD), or psoriasis, book The method of invention 1004.
[Invention 1007]
For patients in need thereof, an effective amount of the compound of the present invention 1001 or a pharmaceutically acceptable salt thereof, a prodrug, a solvate, a metabolite, a polymorph, an analog or a derivative thereof, or a book thereof. A method of regulating BTK, comprising the step of administering the pharmaceutical composition of invention 1002.
[Invention 1008]
Compounds of the invention 1001 or pharmaceutically acceptable salts thereof, prodrugs, solvates, metabolites, for use in methods of treating or regulating BTK-mediated disorders. Polymorphs, analogs or derivatives, or pharmaceutical compositions of the present invention 1002.
[Invention 1009]
The compound or composition of the invention 1008, wherein the BTK-mediated disorder is selected from immune disorders, cancer, cardiovascular disease, viral infections, inflammation, metabolic / endocrine dysfunction and neuropathy.
[Invention 1010]
Cancers include breast cancer, ovarian cancer, cervical cancer, prostate cancer, testis cancer, urogenital cancer, esophageal cancer, laryngeal cancer, glioblastoma, neuroblastoma, gastric cancer, and skin. , Keratinized spinal cell tumor, lung cancer, epidermoid cancer, large cell cancer, non-small cell lung cancer (NSCLC), small cell cancer, lung adenocarcinoma, bone cancer, colon cancer, adenomas, pancreas Cancer, adenocarcinoma, thyroid cancer, follicular cancer, undifferentiated cancer, papillary cancer, sperm epithelioma, melanoma, sarcoma, bladder cancer, liver cancer and biliary tract cancer, kidney cancer, pancreas Cancer, bone marrow disorder, lymphoma, hairy cells, oral cancer, nasopharyngeal cancer, pharyngeal cancer, lip cancer, tongue cancer, mouth cancer, small bowel cancer, colon-rectal cancer, colon cancer, Rectal cancer, brain and central nervous system cancer, Hodgkin leukemia, bronchial cancer, thyroid cancer, liver and intrahepatic bile duct cancer, hepatocellular carcinoma, gastric cancer, glioma / glioblastoma, uterus Endometrial cancer, melanoma, kidney and renal pelvis cancer, bladder cancer, uterine body cancer, cervical cancer, multiple myeloma, acute myeloid leukemia, chronic myeloid leukemia, lymphocytic leukemia, chronic lymph A compound or composition of the invention 1009 selected from sex leukemia (CLL), myeloid leukemia, oral and pharyngeal cancer, non-Hodgkin's lymphoma, melanoma, and colon villous adenomas.
[Invention 1011]
Disorders include rheumatoid arthritis, systemic and local inflammation, arthritis, inflammation associated with immunosuppression, organ transplant rejection, allergies, ulcerative colitis, Crohn's disease, dermatitis, asthma, systemic lupus erythematosus, Sjogren's syndrome, multiple sclerosis Disease, scleroderma / systemic sclerosis, idiopathic thrombocytopenic purpura (ITP), antineutrophil cytoplasmic antibody (ANCA) -related arthritis, chronic obstructive pulmonary disease (COPD), or psoriasis, book The compound or composition of invention 1009.
[Invention 1012]
Compounds of the invention 1001 or pharmaceutically acceptable salts thereof, prodrugs, solvates, metabolites, in the manufacture of drugs to treat or regulate BTK-mediated disorders. Use of polyforms, analogs or derivatives, or pharmaceutical compositions of the present invention 1002.
[Invention 1013]
Use of the present invention 1012, wherein the BTK-mediated disease or disorder is selected from immune disorders, cancer, cardiovascular disease, viral infections, inflammation, metabolic / endocrine dysfunction and neuropathy.
[Invention 1014]
Cancers include breast cancer, ovarian cancer, cervical cancer, prostate cancer, testis cancer, urogenital cancer, esophageal cancer, laryngeal cancer, glioblastoma, neuroblastoma, gastric cancer, and skin. , Keratinized spinal cell tumor, lung cancer, epidermoid cancer, large cell cancer, non-small cell lung cancer (NSCLC), small cell cancer, lung adenocarcinoma, bone cancer, colon cancer, adenomas, pancreas Cancer, adenocarcinoma, thyroid cancer, follicular cancer, undifferentiated cancer, papillary cancer, sperm epithelioma, melanoma, sarcoma, bladder cancer, liver cancer and biliary tract cancer, kidney cancer, pancreas Cancer, bone marrow disorder, lymphoma, hairy cells, oral cancer, nasopharyngeal cancer, pharyngeal cancer, lip cancer, tongue cancer, mouth cancer, small bowel cancer, colon-rectal cancer, colon cancer, Rectal cancer, brain and central nervous system cancer, Hodgkin leukemia, bronchial cancer, thyroid cancer, liver and intrahepatic bile duct cancer, hepatocellular carcinoma, gastric cancer, glioma / glioblastoma, uterus Endometrial cancer, melanoma, kidney and renal pelvis cancer, bladder cancer, uterine body cancer, cervical cancer, multiple myeloma, acute myeloid leukemia, chronic myeloid leukemia, lymphocytic leukemia, chronic lymph Use of the present invention 1013, selected from sex leukemia (CLL), myeloid leukemia, oral and pharyngeal cancer, non-Hodgkin's lymphoma, melanoma, and colon villous adenomas.
[Invention 1015]
Disorders include rheumatoid arthritis, systemic and local inflammation, arthritis, inflammation associated with immunosuppression, organ transplant rejection, allergies, ulcerative colitis, Crohn's disease, dermatitis, asthma, systemic lupus erythematosus, Sjogren's syndrome, multiple sclerosis Disease, scleroderma / systemic sclerosis, idiopathic thrombocytopenic purpura (ITP), antineutrophil cytoplasmic antibody (ANCA) -related arthritis, chronic obstructive pulmonary disease (COPD), or psoriasis, book Use of invention 1013.

Detailed Description The present application relates to compounds and compositions capable of regulating Bruton's tyrosine kinase (BTK) activity. The present application is for a compound of formula (I) or a pharmaceutically acceptable salt thereof, a prodrug, a solvate, a metabolite, a polymorph, an analog or a derivative thereof for a patient in need thereof. It features a method of treating, preventing or ameliorating a disease or disorder involving BTK by the step of administering a therapeutically effective amount. The methods of this application can be used in the treatment of various BTK-mediated diseases and disorders depending on the step of inhibiting the activity of BTK kinase. Inhibition of BTK provides treatment, prevention or amelioration of diseases including, but not limited to, immune disorders, cancers, cardiovascular diseases, viral infections, inflammation, metabolic / endocrine dysfunction, and neuropathy.

および薬学的に許容されるその塩、その互変異性体、プロドラッグ、溶媒和物、代謝産物、多形体、類似体または誘導体。 In the first aspect of this application, the compound of formula (I) is described:

And its pharmaceutically acceptable salts, their tautomers, prodrugs, solvates, metabolites, polymorphs, analogs or derivatives.

In one embodiment, the compound of formula (I) is a pharmaceutically acceptable salt. In another embodiment, the compound of formula (I) is a hydrate. In yet another embodiment, the compound of formula (I) is a solvate.

Details of this application are given in the accompanying description below. Methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present application, but exemplary methods and materials are described below. Other features, objectives, and advantages of this application will become apparent from the description and from the claims. To the extent of this specification and the appended claims, the singular also includes the plural, unless expressly specified otherwise in the context. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. All patents and publications cited herein are incorporated herein by reference in their entirety.

Definitions The articles "one (a)" and "one (an)" are used in this application to refer to one or more (ie, at least one) grammatical objects of an article. As an example, "an element" means one element or more than one element.

The term "and / or" is used in this application to mean "and" or "or" unless otherwise indicated.

The application also comprises a pharmaceutical composition comprising an effective amount of a compound of formula (I) and a pharmaceutically acceptable carrier.

As used in this application, the term "carrier" includes carriers, excipients, and diluents to transport or transport a drug from one organ or part of the body to another organ or part of the body of interest. Means a material, composition or medium involved, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material.

The compound of formula (I) can form a salt, which is also within the scope of this application. References to compounds in the formulas herein are understood to include references to their salts, unless otherwise indicated.

Typical "pharmaceutically acceptable salts" include, for example, water-soluble and water-insoluble salts, such as acetates, amsonates (4,4-diaminostylben-2,2-disulfonates), and the like. Benzenesulfonate, benzonate, hydrogen carbonate, hydrogen sulfate, hydrogen tartrate, borate, bromide salt, butyrate, calcium salt, calcium edetate, cansylate, carbonate, chloride Salts, citrates, clavulariate, dihydrochlorides, edetates, edicates, estolates, esylates, fumerates, fiunarates, gluceptates , Gluconate, Glutamate, Glycolyl alsanate, Hexafluorophosphate, Hexylresorcinate, Hydrabamine salt, Hydrobromide, Hydroxate, Hydroxynaphthoate, Iodine salt, Isothionate , Lactate, lactobionate, laurate, magnesium salt, malate, maleate, mandelate, mesylate, methyl bromide, methyl nitrate, methyl sulfate, mutinate, napsilic acid Salts, nitrates, N-methylglucamine ammonium salts, 3-hydroxy-2-naphthoate, oleate, oxalate, palmitate, pamoate (1,1-methene-bis-2-hydroxy- 3-naphthoate, einbonate), pantothenate, phosphate / diphosphate, picrate, polygalacturonate, propionate, p-toluenesulfonate, salicylate, Includes stearate, basic acetate, succinate, sulfate, sulfosalicylate, suramate, tannate, tartrate, theocrate, tosylate, triethiodide and valerate.

The compounds of this application, including, for example, pharmaceutically acceptable salts of the compounds, metavariants, prodrugs and polymorphs, are present in solvate or non-solvate form with other solvent molecules. Can be done.

"Solvate" means a solvent addition form comprising either a stoichiometric or non-stoichiometric solvent. Some compounds or salts have a tendency to trap a constant molar ratio of solvent molecules in a crystalline solid phase, thereby forming a solvate. If the solvent is water, the solvate formed is a hydrate; if the solvent is alcohol, the solvate formed is a solvate alcohol. Hydrate is formed by the combination of one or more molecules of water with one molecule of substance, where the water retains its molecular state as H ₂ O.

All stereoisomers of the compound (eg, geometric isomers, optical isomers, etc.) (including salts of the compounds, aerosols, esters and prodrugs and salts of the prodrugs, neutrals and esters. ), For example due to asymmetric carbons on various substituents, including enantiomers (which may be present even in the absence of asymmetric carbons), rotational isomers, atropisomers and diastereomers. It is intended that what may be done is within the scope of the present application, as well as the positional isomers (eg, 4-pyridyl and 3-pyridyl). For example, if the compound of formula (I) incorporates a double bond or fused ring, both cis and trans forms, and mixtures are included within the scope of this application. The individual character isomers of the compounds of this application may be substantially free of, for example, other isomers, or, for example, as racemates, or with all other or other selected character isomers. May be mixed. The chiral center of this application can have the S or R configuration defined by the IUPAC 1974 Recommendation. The use of terms such as "salt," "solvent," "ester," and "prodrug" refers to enantiomers, stereoisomers, racemates, tautomers, and positional isomers of the compounds of the invention. , Racemic or prodrug salts, solvates, esters and prodrugs are intended to be applied equally.

The term "isomer" refers to a compound having the same composition and molecular weight, but with different physical and / or chemical properties. Structural differences can be in the composition (geometric isomers) or the ability to rotate the plane of polarization (stereoisomers). With respect to stereoisomers, the compounds of formula (I) have one or more asymmetric carbon atoms and can exist as racemates, racemic mixtures, or as individual mirror image isomers or diastereomers.

In the present specification, the structural formulas of compounds represent specific isomers for convenience in some cases, but the present application applies to geometric isomers, optical isomers based on asymmetric carbons, and steric isomers. Includes all isomers, such as body, metamutables, etc.

By "isomer" is meant a compound having the same molecular formula, but in a different order of bonding of the atoms or in a different arrangement of the atoms in space. Isomers with different atomic arrangements in space are called "stereoisomers". Stereoisomers that are not mirror images of each other are referred to as "diastereomers", and stereoisomers that are mirror images that cannot be superimposed on each other are referred to as "enantiomers" or sometimes optical isomers. Mixtures containing equal amounts of chiral individual enantiomers are referred to as "racemic mixtures".

The compounds of this application contain asymmetric or chiral centers and can therefore be present in different stereoisomers. Mixtures thereof, including all stereoisomers and racemic mixtures of the compounds of this application, are intended to form part of this application. In addition, the present application includes all geometric and positional isomers. For example, if the compounds of this application incorporate double bonds or fused rings, both cis and trans forms, and mixtures are included within the scope of this application. Each compound disclosed herein comprises all enantiomers consistent with the general structure of the compound. The compound can be racemic or enantiomerically pure, or any other form with respect to stereochemistry. Assay results may reflect data collected for racemates, enantiomerically pure forms, or any other form with respect to stereochemistry.

Carbon atoms attached to four non-identical substituents are called "chiral centers".

By "chiral isomer" is meant a compound having at least one chiral center. Compounds with two or more chiral centers can exist as individual diastereomers or as a mixture of diastereomers referred to as "diastereomeric mixtures". If one chiral center is present, the stereoisomer can be characterized by the absolute configuration (R or S) of that chiral center. Absolute configuration refers to the configuration of substituents bonded to the chiral center in space. Substituents attached to the target chiral center are Cahn, Ingold and Prelog ordering rules (Cahn et al., Angew. Chem. Inter. Edit. 1966, 5, 385; errata 511; Cahn et al., Angew. Chem. 1966, 78, 413; Cahn and Ingold, J. Chem. Soc. 1951 (London), 612; Cahn et al., Experientia 1956, 12, 81; Cahn, J. Chem. Educ. 1964, 41, 116 ).

By "geometric isomer" is meant a diastereomer whose presence results from obstruction of rotation around the double bond. These configurations are named according to the Cahn-Ingold-Prelog rule by the prefix cis and trans, or Z and E, which indicate that the group is on the same or opposite side of the double bond in the molecule. Will be done.

In another aspect of the present application, the compound of formula (I) is an enantiomer. In some embodiments, the compound is an (S) -enantiomer. In another embodiment, the compound is an (R) -enantiomer. In yet another embodiment, the compound of formula (I) can be a (+) or (-) enantiomer. The compound may contain more than one stereocenter.

In another aspect of the present application, the compound of formula (I) is a diastereomer. In some embodiments, the compound is a syn diastereomer. In another embodiment, the compound is an anti diastereomer.

The diastereomeric mixture can be separated into its individual diastereomers based on its physicochemical differences by methods well known to those of skill in the art, such as by chromatography and / or fractional crystallization. The enantiomers convert the enantiomer mixture into a diastereomeric mixture by reaction with a suitable optically active compound (eg, a chiral auxiliary group such as chiral alcohol or Mosher's acidified) to separate the diastereomers. And can be separated by converting (eg, hydrolyzing) individual diastereomers to the corresponding pure enantiomers. Enantiomers can also be separated by the use of chiral HPLC columns.

It is possible that the compounds of this application may exist in different tautomeric forms, all of which are included within the scope of this application. Also included in this application are, for example, all keto-enol and imine-enamine forms of the compound.

A "tautomer" is one of two or more structural isomers that exist in equilibrium and is easily converted from one isomer to another. This conversion results in the formal transfer of hydrogen atoms with the switching of adjacent conjugated double bonds. The tautomer exists as a mixture of tautomer sets in solution. In the solid form, one tautomer is usually predominant. In a solution capable of tautomerism, the chemical equilibrium of the tautomer is reached. The exact ratio of tautomers depends on several factors, including temperature, solvent and pH. The concept of tautomers that can be tautomerized by tautomerization is called tautomerism.

Of the various types of tautomerization possible, two are commonly observed. In keto-enol tautomerism, simultaneous shift of electron and hydrogen atom occurs. Ring-to-chain tautomerization is such that the aldehyde group (-CHO) in a sugar chain molecule reacts with one of the hydroxy groups (-OH) in the same molecule, as indicated by glucose. As a result of giving the shape).

Common tautomeric pairs include ketone-enol, amide-nitrile, lactam-lactim, amide-imidic acid tautomerism in heterocyclic rings (eg, in nucleobases such as guanine, thymine and cytosine). Amine-enamine and enamine-imine. A pair of (pyrrolopyrimidinyl) methanone- (pyrrolopyrimidinyl) methanol tautomer is included in this application.

The present application is a compound of formula (I) or a pharmaceutically acceptable salt thereof, the same of which is useful for treating diseases and disorders related to the regulation of BTK kinase, which can inhibit BTK. Concerning prodrugs, solvates, metabolites, polymorphs, analogs or derivatives. The present application applies to compounds of formula (I), or pharmaceutically acceptable salts thereof, their metabolites, prodrugs, solvates, metabolites, polymorphs, similarities that are useful in inhibiting BTK. Further related to the body or derivatives. In some embodiments, the BTK is a wild-type BTK. In another embodiment, the BTK is a mutant BTK.

Another aspect of the present application relates to a compound of formula (I) that inhibits the kinase activity of a variant BTK, such as a drug resistance variant BTK with a drug resistance variant (eg, C481S variant). In some embodiments, the patient or subject does not respond to a BTK inhibitor or relapses after BTK inhibitor treatment due to a mutation in the BTK kinase that interferes with target inhibition (eg, the C481S mutation). In one embodiment, the BTK mutation is a C481S mutation.

In some embodiments, the present application is ibrutinib, GDC-0834, RN486, CGI-560, CGI-1746, HM-71224, CC-292, ONO-4059, CNX-774, and in inhibition of BTK activity. Provided are compounds of formula (I) that are more potent than one or more known BTK inhibitors, including but not limited to LFM-A13. For example, the compound is an inhibition of BTK activity from ibrutinib, GDC-0834, RN486, CGI-560, CGI-1746, HM-71224, CC-292, ONO-4059, CNX-774, and / or LFM-A13. Can also be at least about 2x, 3x, 5x, 10x, 25x, 50x or about 100x stronger (eg, as measured by an IC ₅₀ ).

In some embodiments, the application is an inhibition of the activity of BTK, including one or more mutations described herein, eg, C481S, in ibrutinib, GDC-0834, RN486, CGI-560, CGI-. More potent than one or more known BTK inhibitors, including but not limited to 1746, HM-71224, CC-292, ONO-4059, CNX-774, and LFM-A13, formula (I). Compounds are provided. For example, the compound is an inhibition of the activity of BTK, including one or more mutations described herein, ibrutinib, GDC-0834, RN486, CGI-560, CGI-1746, HM-71224, CC-292. , ONO-4059, CNX-774, and / or at least about 2x, 3x, 5x, 10x, 25x, 50x or about 100x stronger than LFM-A13 (eg, measured by IC ₅₀ ). If) can be. Drug-resistant BTK variants can have, but are not limited to, drug resistance mutations, including C481S mutations.

The efficacy of the inhibitor can be determined by the IC ₅₀ value. Compounds with lower _IC50 values are more potent inhibitors than compounds with higher _IC50 values when measured under substantially similar conditions.

The compounds of this application are converted to N-oxides by treating them with an oxidizing agent (eg, 3-chloroperoxybenzoic acid (m-CPBA) and / or hydrogen peroxide) to obtain the other compounds of this application. be able to. Therefore, all nitrogen-containing compounds shown and claimed are the compounds as shown and their N-oxide derivatives (which are N → O or N ^{+ -O-} , if allowed by valence and structure). Can be represented) and is considered to include both. Furthermore, in another example, the nitrogen in the compounds of this application can be converted to an N-hydroxy compound or an N-alkoxy compound. For example, N-hydroxy compounds can be prepared by oxidation of the parent amide with an oxidizing agent such as m-CPBA. All nitrogen-containing compounds shown and claimed are also compounds as shown and their N-hydroxy derivatives (ie, N-OH) and N-alkoxy derivatives (ie, if allowed by valence and structure). , N-OR, in the equation R is substituted or unsubstituted C ₁ to C ₆ alkyl, C ₁ to C ₆ alkenyl, C ₁ to C ₆ alkynyl, 3- to 14-membered carbocycle or 3- to 14-membered heterocycle. ) And both are considered to be exhaustive.

As used in this application, the term "prodrug" means a compound that can be converted in vivo to the disclosed compound by metabolic means (eg, by hydrolysis).

Since prodrugs are known to enhance a number of desirable properties of a pharmaceutical (eg, solubility, bioavailability, production, etc.), a compound of formula (I), or a pharmaceutically acceptable salt thereof. , Mutual variants, solvates, metabolites, polymorphs, analogs or derivatives can be delivered in prodrug form. Accordingly, the present application delivers prodrugs of compounds of formula (I), or pharmaceutically acceptable salts thereof, tautomers, solvates, metabolites, polymorphs, analogs or derivatives thereof. It is intended to cover the methods and the compositions containing them. The "prodrug" is intended to include any covalently bound carrier that releases the active parent drug of the present application in vivo when such a prodrug is administered to a mammalian subject. Prodrugs are prepared by modifying the functional groups present in the compound so that the modification is cleaved into the parent compound, either by routine operation or in vivo. The prodrug is an application in which a hydroxyl group or an amino group is attached to any group that is cleaved to form a free hydroxyl group or a free amino group, respectively, when the prodrug of the present application is administered to a mammalian subject. Compounds are included. Examples of prodrugs include compounds of each of the formulas described herein or pharmaceutically acceptable salts thereof, metavariants, prodrugs, solvates, metabolites, polymorphs, analogs or Examples include, but are not limited to, acetates, formates and benzoate derivatives of alcohol and amine functional groups in the derivatives.

The terms "crystal polymorph", "polymorph" or "crystal morphology" can be used to crystallize a compound (or a salt or admixture thereof) in different crystal packed arrangements, all of which have the same elemental composition. Means structure. Different crystal morphologies usually have different X-ray diffraction patterns, infrared spectra, melting points, density hardness, crystal shape, optical and electrical properties, stability and solubility. Recrystallization solvent, crystallization rate, storage temperature and other factors can predominate one crystal morphology. Crystal polymorphs of compounds can be prepared by crystallization under different conditions.

As used herein, the term "analog" is structurally similar to another compound, but in composition (by atom replacement of one atom with a different element or of a particular functional group). Refers to slightly different compounds in presence or by replacement of one functional group with another. Thus, an analog is a compound that is similar or equivalent in function and appearance, but similar or unequal in structure or origin to the reference compound.

The application also includes isotope-labeled compounds, which include atoms in which one or more atoms have an atomic mass or mass number that is different from the atomic mass or mass number most commonly found in nature. Apart from the fact that they are replaced, they are identical to those listed in each of the equations described herein. Examples of isotopes that can be incorporated into the compounds of this application include isotopes of hydrogen, carbon, nitrogen and fluorine, such as ³ H, ¹¹ C, ¹⁴ C, ² H and ¹⁸ F.

Compounds of formula (I), including the isotopes described above and / or other isotopes of other atoms, or pharmaceutically acceptable salts thereof, metavariants, prodrugs, solvates, metabolites, poly. The features, analogs or derivatives are within the scope of this application. Isotope-labeled compounds of this application, such as those incorporating radioisotopes such as ³ H, ¹⁴ C, are useful in drug and / or substrate tissue distribution assays. Tritiumization, ie ³ H and carbon-14, i.e. ¹⁴ C isotopes, are useful for ease of preparation and detectability. The ¹¹ C and ¹⁸ F isotopes are useful in PET (positron emission tomography). PET is useful in brain imaging. ^In addition, substitution with deuterium, a heavier isotope, such as 2H, provides certain therapeutic benefits resulting from greater metabolic stability, such as increased in vivo half-life or reduced dose requirements. It can, and therefore may be preferred in some circumstances, isotope-labeled compounds of formula (I), or pharmaceutically acceptable salts thereof, metamutants, prodrugs, admixtures, metabolites. , Polyforms, analogs or derivatives are generally disclosed in the schemes described herein and / or in examples by using readily available isotope labeling reagents instead of non-isotope labeling reagents. It can be prepared by performing the procedure. In one embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof, a metavariant, a prodrug, a solvate, a metabolite, a polymorph, an analog or a derivative is isotope labeled. do not have.

The present application relates to compounds that are regulators of BTK. In one embodiment, the compounds of this application are inhibitors of BTK.

As used in this application, the terms "dosing," "dosing," or "dosing" refer to the disclosed compound or a pharmaceutically acceptable salt or composition of the disclosed compound to be administered directly to the subject. Or the administration of a prodrug, derivative or analog of a compound or a pharmaceutically acceptable salt or composition of a compound to a subject, thereby forming an equal amount of active compound in the subject's body. be able to.

A "patient" or "subject" is a mammal, such as a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate, such as a monkey, chimpanzee, baboon or rhesus monkey.

An "effective amount" or "therapeutically effective amount" when used in the context of a compound or pharmaceutical composition is an amount effective in treating or preventing a disease in a subject as described herein.

The term "treat" with respect to a subject refers to ameliorating at least one symptom of the subject's disorder. Treatment involves healing, ameliorating, or at least partially improving the disorder.

The compounds of this application, or pharmaceutically acceptable salts thereof, metavariants, prodrugs, solvates, metabolites, polymorphs, analogs or derivatives thereof are also used to prevent diseases, conditions or disorders. Can be used. As used herein, "preventing" or "preventing" describes reducing or eliminating the onset of symptoms or complications of a disease, condition or disorder.

The term "disorder" is used herein to mean the term disease, condition, or illness, unless otherwise indicated, and is used interchangeably with them.

As used herein, the term "BTK-mediated" disease or disorder means any disease or other adverse condition in which BTK or a variant thereof is known to play a role. Accordingly, another aspect of the present application relates to treating or alleviating the severity of one or more diseases in which BTK or variants thereof are known to play a role. Specifically, the present application applies to a compound of formula (I), or a pharmaceutically acceptable salt thereof, a metabolite, a prodrug, a solvent, a metabolite, a polymorph, for a patient in need thereof. It relates to a method of treating or alleviating the severity of a disease or condition selected from proliferative or autoimmune disorders, comprising the step of administering an analog or derivative, or a composition according to the present application.

As used herein, the term "cell proliferation disorder" refers to an undesirable condition in which unregulated or abnormal proliferation of cells, or both, may or may not be cancerous. Or a condition that can cause disease. The exemplary cell proliferation disorders of the present application include various conditions in which cell division is not regulated. Exemplary cell proliferative disorders include neoplasms, benign tumors, malignant tumors, precancerous conditions, in situ tumors, encapsulating tumors, metastatic tumors, liquid tumors, solid tumors, immunological tumors, and hematology. Tumors, cancers, cancers, leukemias, lymphomas, sarcomas, and rapidly dividing cells include, but are not limited to. The term "rapidly dividing cell", as used herein, is arbitrary, dividing at a rate greater than or greater than that predicted or observed between adjacent or adjacent cells within the same tissue. Is defined as a cell. Cell proliferation disorders include precancerous or precancerous conditions. Cell proliferation disorders include cancer. Preferably, the methods provided herein are used to treat or alleviate the symptoms of cancer. The term "cancer" includes solid tumors, as well as hematological tumors and / or malignant diseases. A "precancer cell" or "precancerous cell" is a cell that exhibits a precancerous or precancerous cell proliferative disorder. A "cancer cell" or "cancerous cell" is a cell that exhibits a cell proliferation disorder that is a cancer. Any reproducible means of measurement can be used to identify cancer cells or precancerous cells. Cancer cells or precancerous cells can be identified by histological or malignancy classification of tissue samples (eg, biopsy samples). Cancer cells or precancerous cells can be identified by the use of appropriate molecular markers.

Exemplary non-cancerous conditions or disorders include rheumatoid arthritis; inflammation; autoimmune disease; lymphoproliferative condition; tip giant disease; rheumatic spondylitis; osteoarthritis; gout, other arthritis conditions; septicemia; Septic shock; Endotoxic shock; Gram-negative sepsis; Toxic shock syndrome; Asthma; Adult respiratory promotion syndrome; Chronic obstructive pulmonary disease; Chronic lung inflammation; Inflammatory bowel disease; Crohn's disease; Psoriasis; Eczema; Pancreatic fibrosis; Liver fibrosis; Acute and chronic rectal disease; Hypersensitivity bowel syndrome; pyresis; Restenosis; Cerebral malaria; Stroke and ischemic injury; Neurotrauma; Alzheimer's disease; Huntington's disease; Parkinson's disease Acute and chronic pain; Allergic rhinitis; Allergic conjunctivitis; Chronic heart failure; Acute coronary pulse syndrome; Vicious fluid; Malaria; Leprosy; Leishmania disease; Lime disease; Reiter syndrome; Luminous sacitis; Tendonitis; Tennosylitis; Hernia-like, ruptured, or prolapsed intervertebral disc syndrome; Marble bone disease; Thrombosis; Restenosis; Skeletal pneumonia; Pulmonary muscle overgrowth; Bone resorption disease, eg Osteoporosis; Hosted transplant reaction; Multiple sclerosis; Wolves; Fibromyalgia; AIDS and other viral diseases such as herpes zoster, simple herpes I or II, influenza virus and cytomegalovirus; and true diabetes However, it is not limited to these.

Exemplary cancers include adrenocortical cancer, AIDS-related cancer, AIDS-related lymphoma, anal cancer, anal rectal cancer, anal duct cancer, worm drop cancer, and cerebral stellate cell tumor in childhood. , Childhood cerebral stellate cell tumor, basal cell cancer, skin cancer (non-black tumor), bile duct cancer, extrahepatic total bile duct cancer, intrahepatic total bile duct cancer, bladder cancer, Urinary bladder cancer, bone and joint cancer, osteosarcoma and malignant fibrous histiocytoma, brain cancer, brain tumor, brain stem glioma, cerebral stellate cell tumor, cerebral stellate cell tumor / malignant Stellate cell tumor, ventricular lining cell tumor, medullary cell tumor, tent upper undifferentiated ectodermal tumor, tract and hypothalamic glioma, breast cancer, bronchial adenomas / cartinoids, cancers, gastrointestinal, Nervous system cancer, nervous system lymphoma, central nervous system cancer, central nervous system lymphoma, cervical cancer, childhood cancer, chronic lymphocytic leukemia, chronic myeloid leukemia, chronic myeloproliferative disorder, colon cancer , Colon-rectal cancer, cutaneous T-cell lymphoma, lymphoid neoplasm, mycobacterial sarcoma, Seziary syndrome, endometrial cancer, esophageal cancer, extracranial reproductive cell tumor, extrahepatic reproductive cell tumor, liver External total bile duct cancer, eye cancer, intraocular melanoma, retinal blastoma, bile sac cancer, gastric (stomach) cancer, gastrointestinal cancer, gastrointestinal stromal tumor (GIST), reproduction Cellular tumor, ovarian germ cell tumor, gestational chorionic villous tumor glioma, head and neck cancer, hepatocellular (liver) cancer, Hodgkin lymphoma, hypopharyngeal cancer, intraocular melanoma, eye cancer, Langerhans islet cell Tumor (endocrine pancreas), capage sarcoma, kidney cancer, rectal cancer, kidney cancer, pharyngeal cancer, acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia , Lip and oral cancer, liver cancer, lung cancer, non-small cell lung cancer, small cell lung cancer, AIDS-related lymphoma, non-hodgkin lymphoma, central nervous system primary lymphoma, Waldenstraem macroglobulinemia, medullary blast Tumors, melanomas, intraocular (eye) melanomas, Mercell cell carcinomas, malignant mesothelomas, mesencema, metastatic squamous cervical cancers, oral cancers, tongue cancers, multiple endocrines Tumor syndrome, fungal cystoma, myelopathy syndrome, myelopathy / myeloid proliferative disorder, chronic myeloid leukemia, acute myeloid leukemia, multiple myeloma, chronic myeloproliferative disorder, nasopharyngeal cancer, neuroblast Cell tumor, mouth cancer, oral cancer, oropharyngeal cancer, ovarian cancer, ovarian epithelial cancer, borderline malignant ovarian tumor, pancreas Visceral cancer, islet cell pancreatic cancer, sinus and nasal cancer, parathyroid cancer, penis cancer, pharyngeal cancer, brown cell tumor, pine fruit blastoma and tent upper undifferentiated neuroendoblast. Tumor, pituitary tumor, plasmacell neoplasm / multiple myeloma, pleural lung blastoma, prostate cancer, rectal cancer, renal disc and urinary tract, transitional cell cancer, retinal blastoma, transverse myoma , Salivary adenocarcinoma, Ewing family sarcoma tumor, Capage sarcoma, soft tissue sarcoma, uterine cancer, uterine sarcoma, skin cancer (non-black tumor), skin cancer (black tumor), Mercel cell skin cancer, small intestine Cancer, soft tissue sarcoma, squamous epithelial cancer, gastric cancer, tent upper undifferentiated neuroextradermal tumor, testis cancer, throat cancer, thoracic adenomas, thoracic adenomas and thoracic adenocarcinomas, thyroid cancer, renal disc and urinary tract And other urinary migrating cell cancers, gestational villous tumors, urinary tract cancers, endometrial uterine cancers, uterine sarcoma, uterine body cancers, vaginal cancers, genital cancers, and Wilms tumors. , Not limited to these.

Methods for Preparing Compounds The compounds of this application can be produced by a variety of methods, including standard chemistry. A suitable synthetic route is drawn in the scheme shown below.

The compound of formula (I) can be prepared by a method known in the art of organic synthesis, which is partially represented by the following synthesis scheme. In the schemes below, it is well understood that sensitive or reactive protecting groups are utilized as needed according to general principles or chemistry. Protecting groups are operated according to standard methods of organic synthesis (T. W. Greene and P. G. M. Wuts, "Protective Groups in Organic Synthesis", Third edition, Wiley, New York 1999). These groups are removed at a convenient stage of compound synthesis using methods readily apparent to those of skill in the art. The selection process, as well as the reaction conditions and their order of execution, must be consistent with the preparation of the compounds of this application.

One of ordinary skill in the art will recognize whether the stereocenter is present in the compound of formula (I). Accordingly, the present application includes both possible stereoisomers (unless specified in synthesis) and includes not only racemic compounds but also individual enantiomers and / or diastereomers. If the compound is desired as a single enantiomer or diastereomer, it can be obtained by stereospecific synthesis or by division of the final product or any convenient intermediate. The division of the final product, intermediate, or starting material can be influenced by any suitable method known in the art. See, for example, "Stereochemistry of Organic Compounds" by E. L. Eliel, S. H. Wilen and L. N. Mander (Wiley-lnterscience, 1994).

The compounds described herein may be made from commercially available starting materials or synthesized using known organic, inorganic and / or enzymatic processes.

The compounds of this application can be prepared by several methods well known to those skilled in the art of organic synthesis. As an example, the compounds of this application can be synthesized using the following methods, along with synthetic methods known in the field of synthetic organic chemistry, or variations thereof as understood by those of skill in the art. Preferred methods include, but are not limited to, those described below. The compounds of this application (ie, compounds of formula (I)) can be synthesized by following the steps outlined in General Scheme 1, which includes the order in which the intermediates 2-a-2-h are assembled. Starting materials are commercially available or produced by known procedures in the reported literature or as illustrated.

中間体2-a、2-b、2-c、2-d、2-e、2-f、2-gおよび2-hを用いることにより式(I)の化合物を調製する一般的な方法が一般的スキーム1に概説されている。溶媒、例えばN,N-ジメチルホルムアミド(DMF)中で強塩基、例えば水素化ナトリウム(NaH)を用いて2-クロロ-4-フルオロベンゾニトリル2-aにフェノール2-bを求核付加して、2-cを得る。高温で溶媒、例えばエタノール中、塩基、例えば水酸化カリウム(KOH)を用いて2-cを加水分解して、カルボン酸2-dを得る。溶媒、例えばN,N-ジメチルホルムアミド(DMF)中、塩基、例えば炭酸カリウム(K₂CO₃)または炭酸セシウム(Cs₂CO₃)を用いヨウ化メチルで2-dをエステル化して2-eを得る。溶媒、例えばテトラヒドロフラン(THF)中、強塩基、例えばn-ブチルリチウム(n-BuLi)を用い2-eで中間体2-fをアシル化して2-gを得る。塩基、例えばN,N-ジイソプロピルエチルアミン(DIPEA)を用いて、および任意で溶媒、例えばN,N-ジメチルホルムアミド(DMF)中でアミン2-hを塩化アリール2-gに求核付加して、式(I)の化合物を得る。 General scheme 1

Common methods for preparing compounds of formula (I) by using intermediates 2-a, 2-b, 2-c, 2-d, 2-e, 2-f, 2-g and 2-h. Is outlined in General Scheme 1. Nucleophilic addition of phenol2-b to 2-chloro-4-fluorobenzonitrile 2-a using a strong base, such as sodium hydride (NaH), in a solvent such as N, N-dimethylformamide (DMF). , 2-c. Hydrolyze 2-c with a solvent, such as ethanol, at elevated temperature, using a base, such as potassium hydroxide (KOH), to give the carboxylic acid 2-d. 2-d is esterified with methyl iodide using a base such as potassium carbonate (K ₂ CO ₃ ) or cesium carbonate (Cs ₂ CO ₃ ) in a solvent such as N, N-dimethylformamide (DMF) to 2-e. To get. The intermediate 2-f is acylated with 2-e in a solvent such as tetrahydrofuran (THF) with a strong base such as n-butyllithium (n-BuLi) to give 2-g. Nucleophilic addition of amine 2-h to aryl 2-g chloride with a base such as N, N-diisopropylethylamine (DIPEA) and optionally in a solvent such as N, N-dimethylformamide (DMF). Obtain the compound of formula (I).

Mixtures of enantiomers, diastereomers and cis / trans isomers obtained from the above process are simply chromatographed by chiral salt technique, normal phase, reverse phase or chromatography with a chiral column, depending on the nature of the separation. It can be separated into one component.

Biological assay
BTK kinase activity assay
Test inhibitors and controls are prepared in solvent (ie DMSO) and added to each well of the reaction plate. Full-length active BTK is diluted in assay buffer and added to each well. After preincubation, the kinase reaction is initiated by the addition of an activated mixture diluted in assay buffer containing biotinylated PLCγ2 peptide and ATP. The plate is incubated and the reaction is stopped in the dark by the addition of a stop / detection mixture prepared in assay buffer. Incubate the assay plate in the dark and read the plate with a plate reader.

BTK C481S Kinase Activity Assay Test Inhibitors and controls are prepared in solvent (ie, DMSO) at the desired final concentration and added to each well of the reaction plate. Full length BTKC481S is diluted in assay buffer and added to each well in a certain volume. After preincubation, the kinase reaction is initiated by the addition of an activated mixture diluted in assay buffer containing biotinylated PLCγ2 peptide and ATP. The plate is incubated and the reaction is stopped in the dark by the addition of a stop / detection mixture prepared in assay buffer. Incubate the assay plate in the dark and read the plate with a plate reader.

Antiproliferative assay Cell survival is determined by the MTS assay. Briefly, cells (ie, TMD-8 cells or Rec-1 cells) are plated in 96-well plates, cultured in complete growth medium, and then treated with different drugs and drug combinations. After adding MTS / PMS and incubating, cell viability is evaluated using a microplate reader. Standardize the data to raw controls and analyze in Microsoft Excel.

Methods of Using Compounds Another aspect of the application relates to methods of treating, preventing, inhibiting or eliminating diseases or disorders associated with the regulation of BTK (eg, inhibition of BTK). The method comprises an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, a metabolite, a prodrug, a solvent for patients in need of treatment for a disease or disorder associated with the regulation of BTK. It comprises the step of administering a pharmaceutical composition of a Japanese product, a metabolite, a polymorph, an analog or a derivative, or a compound of formula (I). In one embodiment, the BTK-mediated disorder is selected from immune disorders, cancer, cardiovascular disease, viral infections, inflammation, metabolic / endocrine dysfunction and neuropathy. In some embodiments, the method comprises an anti-inflammatory agent, an immunomodulatory agent, a chemotherapeutic agent, a neuronutrient factor, an agent for treating cardiovascular disease, an agent for treating liver disease, an antiviral agent, blood. Further comprising administering additional therapeutic agents selected from agents for treating disorders, agents for treating diabetes, and agents for treating immunodeficiency disorders. In some embodiments, the BTK is a wild-type BTK. In another embodiment, the BTK is a variant BTK (eg, BTK C481S variant).

Another aspect of the application is a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, a mutant, a prodrug, a solvent, a metabolite, in the patient in need thereof. It relates to a method of treating, preventing, inhibiting or eliminating a cell proliferative disorder, comprising administering a pharmaceutical composition of a polymorph, analog or derivative, or compound of formula (I). In one embodiment, the cell proliferation disorder is cancer. In some embodiments, the method comprises an anti-inflammatory agent, an immunomodulatory agent, a chemotherapeutic agent, a neuronutrient factor, an agent for treating cardiovascular disease, an agent for treating liver disease, an antiviral agent, blood. Further comprising administering additional therapeutic agents selected from agents for treating disorders, agents for treating diabetes, and agents for treating immunodeficiency disorders.

Another aspect of the application is a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, a mutant, a prodrug, a solvent, a metabolite, in the patient in need thereof. It relates to a method of regulating BTK, comprising the step of administering a pharmaceutical composition of a polymorph, analog or derivative, or compound of formula (I). In one embodiment, regulating BTK is inhibiting BTK. In some embodiments, the BTK is a wild-type BTK. In another embodiment, the BTK is a variant BTK (eg, BTK C481S variant).

Another aspect of the present application is a compound of formula (I) or a pharmaceutically acceptable salt thereof, a metabolite, a prodrug, a solvate, for use in a method of treating a BTK-mediated disorder. With respect to metabolites, polymorphs, analogs or derivatives. In one embodiment, the disease or disorder is selected from immune disorders, cancer, cardiovascular disease, viral infections, inflammation, metabolic / endocrine dysfunction and neuropathy. In some embodiments, the method comprises an anti-inflammatory agent, an immunomodulatory agent, a chemotherapeutic agent, a neuronutrient factor, an agent for treating cardiovascular disease, an agent for treating liver disease, an antiviral agent, blood. Further comprising administering additional therapeutic agents selected from agents for treating disorders, agents for treating diabetes, and agents for treating immunodeficiency disorders. In some embodiments, the BTK is a wild-type BTK. In another embodiment, the BTK is a variant BTK (eg, BTK C481S variant).

In another aspect, the present application is a compound of formula (I) or a pharmaceutically acceptable salt thereof, a metabolite, a prodrug, a solvate for use in a method of treating a BTK-mediated disorder. , Metabolites, polymorphs, analogs or derivatives relating to pharmaceutical compositions. In one embodiment, the disease or disorder is selected from immune disorders, cancer, cardiovascular disease, viral infections, inflammation, metabolic / endocrine dysfunction and neuropathy. In some embodiments, the method comprises an anti-inflammatory agent, an immunomodulatory agent, a chemotherapeutic agent, a neuronutrient factor, an agent for treating cardiovascular disease, an agent for treating liver disease, an antiviral agent, blood. Further comprising administering additional therapeutic agents selected from agents for treating disorders, agents for treating diabetes, and agents for treating immunodeficiency disorders. In some embodiments, the BTK is a wild-type BTK. In another embodiment, the BTK is a variant BTK (eg, BTK C481S variant).

Another aspect of the present application is a compound of formula (I) or a pharmaceutically acceptable salt thereof, tautomer, prodrug for use in a method of treating, preventing, inhibiting or eliminating a cell proliferation disorder. For drugs, solvates, metabolites, polymorphs, analogs or derivatives. In one embodiment, the cell proliferation disorder is cancer.

In another aspect, the present application is a compound of formula (I) or a pharmaceutically acceptable salt thereof, a polymorph, for use in a method of treating, preventing, inhibiting or eliminating a cell proliferation disorder. With respect to pharmaceutical compositions of prodrugs, solvates, metabolites, polymorphs, analogs or derivatives. In one embodiment, the cell proliferation disorder is cancer.

Another aspect of the present application is a compound of formula (I) or a pharmaceutically acceptable salt thereof, a metabolite, a prodrug, a solvate, a metabolite, a polymorphate for use in the regulation of BTK. , Similars or derivatives. In one embodiment, regulating BTK is inhibiting BTK. In some embodiments, the BTK is a wild-type BTK. In another embodiment, the BTK is a variant BTK (eg, BTK C481S variant).

In another aspect, the application applies to a compound of formula (I) or a pharmaceutically acceptable salt thereof, a mutant, a prodrug, a solvate, a metabolite, many, for use in the regulation of BTK. With respect to pharmaceutical compositions of forms, analogs or derivatives. In one embodiment, regulating BTK is inhibiting BTK. In some embodiments, the BTK is a wild-type BTK. In another embodiment, the BTK is a variant BTK (eg, BTK C481S variant).

Another aspect of the present application is a compound of formula (I) or a pharmaceutically acceptable salt thereof, a metabolite, a prodrug, a solvate in the manufacture of a drug for treating a BTK-mediated disease or disorder. Concerning the use of substances, metabolites, polymorphs, analogs or derivatives. In one embodiment, the disease or disorder is selected from immune disorders, cancer, cardiovascular disease, viral infections, inflammation, metabolic / endocrine dysfunction and neuropathy. In some embodiments, the treatment is an anti-inflammatory agent, an immunomodulatory agent, a chemotherapeutic agent, a neurotrophic factor, an agent for treating cardiovascular disease, an agent for treating liver disease, an antiviral agent, a blood disorder. Further comprises the step of administering an additional therapeutic agent selected from agents for treating the disease, agents for treating diabetes, and agents for treating immunodeficiency disorders. In some embodiments, the BTK is a wild-type BTK. In another embodiment, the BTK is a variant BTK (eg, BTK C481S variant).

In another aspect, the application applies to a compound of formula (I) or a pharmaceutically acceptable salt thereof, a metabolite, a prodrug, a solvent in the manufacture of a drug for treating a BTK-mediated disease or disorder. Concerning the use of pharmaceutical compositions of Japanese products, metabolites, polymorphs, analogs or derivatives. In one embodiment, the disease or disorder is selected from immune disorders, cancer, cardiovascular disease, viral infections, inflammation, metabolic / endocrine dysfunction and neuropathy. In some embodiments, the treatment is an anti-inflammatory agent, an immunomodulatory agent, a chemotherapeutic agent, a neurotrophic factor, an agent for treating cardiovascular disease, an agent for treating liver disease, an antiviral agent, a blood disorder. Further comprises the step of administering an additional therapeutic agent selected from agents for treating the disease, agents for treating diabetes, and agents for treating immunodeficiency disorders. In some embodiments, the BTK is a wild-type BTK. In another embodiment, the BTK is a variant BTK (eg, BTK C481S variant).

Another aspect of the present application is a compound of formula (I) or a pharmaceutically acceptable salt thereof, a metabolite, a prodrug in the manufacture of a drug for treating, preventing, inhibiting or eliminating a cell proliferation disorder. Concerning the use of drugs, solvates, metabolites, polymorphs, analogs or derivatives. In one embodiment, the cell proliferation disorder is cancer.

In another aspect, the present application is a compound of formula (I) or a pharmaceutically acceptable salt thereof, a metabolite, in the manufacture of a drug for treating, preventing, inhibiting or eliminating a cell proliferation disorder. Concerning the use of pharmaceutical compositions of prodrugs, solvates, metabolites, polymorphs, analogs or derivatives. In one embodiment, the cell proliferation disorder is cancer.

Another aspect of the present application is a compound of formula (I) or a pharmaceutically acceptable salt thereof, a mutant, a prodrug, a solvate, a metabolite, in the manufacture of a drug for regulating BTK. Concerning the use of polymorphs, analogs or derivatives. In one embodiment, regulating BTK is inhibiting BTK. In some embodiments, the BTK is a wild-type BTK. In another embodiment, the BTK is a variant BTK (eg, BTK C481S variant).

In another aspect, the application applies to a compound of formula (I) or a pharmaceutically acceptable salt thereof, a mutant, a prodrug, a solvate, a metabolite in the manufacture of a drug for regulating BTK. , Polymorphs, analogs or derivatives relating to the use of pharmaceutical compositions. In one embodiment, regulating BTK is inhibiting BTK. In some embodiments, the BTK is a wild-type BTK. In another embodiment, the BTK is a variant BTK (eg, BTK C481S variant).

In some aspects of the methods and uses described herein, the cancer is breast cancer, ovarian cancer, cervical cancer, prostate cancer, testicular cancer, genitourinary cancer, esophageal cancer, laryngeal cancer. Cancer, glioblastoma, neuroblastoma, gastric cancer, skin cancer, keratinized spinal cell tumor, lung cancer, epidermoid cancer, large cell cancer, non-small cell lung cancer (NSCLC), small cell cancer, Lung adenocarcinoma, bone cancer, colon cancer, adenomas, pancreatic cancer, adenocarcinoma, thyroid cancer, follicular cancer, undifferentiated cancer, papillary cancer, sperm epithelioma, melanoma, sarcoma, bladder Cancer, liver cancer and biliary tract cancer, kidney cancer, pancreatic cancer, bone marrow disorder, lymphoma, hairy cells, oral cancer, nasopharyngeal cancer, pharyngeal cancer, lip cancer, tongue cancer, mouth Cancer, small bowel cancer, colon-rectal cancer, colon cancer, rectal cancer, brain and central nervous system cancer, Hodgkin leukemia, bronchial cancer, thyroid cancer, liver and intrahepatic bile duct cancer, Hepatic cell cancer, gastric cancer, glioma / glioma, endometrial cancer, melanoma, kidney and renal pelvis cancer, bladder cancer, uterine body cancer, cervical cancer, multiple myeloma , Acute myeloid leukemia, chronic myeloid leukemia, lymphocytic leukemia, chronic lymphocytic leukemia (CLL), myeloid leukemia, oral and pharyngeal cancer, non-Hodgkin lymphoma, melanoma, and colon villous adenomas.

In any aspect of the present application, the cancer can be any cancer in any organ, eg, the cancer is glioma, thyroid cancer, breast cancer, small cell lung cancer, non-small cell lung cancer,. Gastric cancer, colon cancer, gastrointestinal stromal cancer, pancreatic cancer, bile duct cancer, CNS cancer, ovarian cancer, endometrial cancer, prostate cancer, kidney cancer, undifferentiated large cell lymphoma, leukemia , Multiple myeloma, mesotheloma and melanoma, and combinations thereof.

In some aspects of the methods and uses described herein, the disease or disorder is an immune disorder. In one embodiment, the immune disorder is rheumatoid arthritis.

In some aspects of the methods and uses described herein, the disease or disorder is systemic and local inflammation, arthritis, inflammation associated with immunosuppression, organ transplant rejection, allergies, ulcerative colitis, Crohn's disease, Dermatitis, asthma, systemic lupus erythematosus, Sjogren's syndrome, multiple sclerosis, scleroderma / systemic sclerosis, idiopathic thrombocytopenic purpura (ITP), antineutrophil cytoplasmic antibody (ANCA) -related vasculitis, Chronic obstructive pulmonary disease (COPD), psoriasis.

In one embodiment, a method of treating a disease or disorder associated with BTK regulation, including immune disorders, cancer, cardiovascular disease, viral infections, inflammation, metabolic / endocrine dysfunction and neuropathy, is the disease or disorder. Including the step of administering the compound of formula (I) to a patient suffering from at least one of the above.

The disclosed compounds of this application can be administered in an amount effective to treat or prevent the disorder and / or prevent its occurrence in the subject.

The compounds of this application can be administered in therapeutically effective amounts in one or more therapeutic agents (combination of drugs) or modality, eg combination therapy with non-drug therapy. For example, synergies can occur with other antiproliferative, anticancer, immunomodulatory or anti-inflammatory substances. In some embodiments, the compound of formula (I) is an anti-inflammatory agent, an immunomodulator, a chemotherapeutic agent, a neurotrophic factor, an agent for treating cardiovascular disease, an agent for treating liver disease, an anti-virus. It is administered in combination with additional therapeutic agents selected from viral agents, agents for treating blood disorders, agents for treating diabetes, and agents for treating immunodeficiency disorders. When the compounds of this application are administered in conjunction with other treatments, the dose of the co-administered compound will, of course, be treated according to the particular drug utilized, depending on the type of co-drug utilized. It will change depending on the condition to be done.

Combination therapies include other biologically active ingredients (but not limited to antivirals, immunomodulators, chemotherapeutic agents, neuronutrient factors, agents for treating cardiovascular disease, liver). Agents for treating diseases, antivirals, agents for treating blood disorders, agents for treating diabetes, and agents for treating immunodeficiency disorders) and non-pharmacological therapies (limited) However, this includes administration of the compound in combination with (such as surgery or radiotherapy). For example, the compounds of this application can be used in combination with other pharmaceutically active compounds, preferably compounds capable of enhancing the effects of the compounds of this application. The compounds of this application can be administered simultaneously (as a single preparation or separate preparations) or sequentially to other drug therapies or treatment modality. In general, combination therapy envisions the administration of two or more drugs during a single cycle or treatment process.

Pharmaceutical Compositions The application also applies in combination with at least one pharmaceutically acceptable excipient or carrier to a compound of formula (I), or a pharmaceutically acceptable salt thereof, a polymorph, a pro. Provided are pharmaceutical compositions comprising drugs, solvates, metabolites, polymorphs, analogs or derivatives.

A "pharmaceutical composition" is a formulation in a form suitable for administration to a subject that contains a compound of the present application. In one embodiment, the pharmaceutical composition is in bulk form or unit dose form. The unit dose form is any of a variety of forms, including, for example, a single pump of capsules, IV bags, tablets, aerosol inhalers or vials. Of the active ingredient in a unit dose composition (eg, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, a metavariant, a prodrug, a solvate, a metabolite, a polymorph, an analog or a derivative thereof). The amount of pharmaceutical product) is an effective amount and varies depending on the specific treatment involved. One of ordinary skill in the art will appreciate that it is sometimes necessary to make routine changes to the dosage, depending on the patient's age and condition. The dosage will also depend on the route of administration. Various routes have been engineered, including oral, lung, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalation, cheek, sublingual, intrapleural, intrasheath, intranasal, etc. To. Dosage forms for topical or transdermal administration of the compounds of this application include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. In one embodiment, the active ingredient is mixed with a pharmaceutically acceptable carrier under sterile conditions and mixed with any preservative, buffer or propellant required.

As used herein, the phrase "pharmaceutically acceptable" is within reasonable medical judgment without excessive toxicity, irritation, allergic response, or other problems or complications. Refers to a compound, material, composition, carrier, and / or dosage form suitable for use in contact with human and animal tissues, which meets a reasonable benefit / risk ratio.

"Pharmaceutically acceptable excipients" are generally safe, non-toxic, and biologically and otherwise not desirable in the preparation of pharmaceutical compositions. Means useful excipients, including those acceptable for veterinary and human pharmaceutical applications. "Pharmaceutically acceptable excipients" as used herein and in the appended claims are one such excipient and two or more such excipients. Including both.

The pharmaceutical compositions of this application are formulated to suit their intended route of administration. Examples of routes of administration include parenteral, eg, intravenous, intradermal, subcutaneous, oral (eg, inhalation), transdermal (local) and transmucosal administration. Solutions or suspensions used for parenteral, intradermal or subcutaneous applications can contain the following components: water for injection, aqueous saline, non-volatile oils, polyethylene glycol, glycerin, propylene glycol or other. Sterilized diluents such as synthetic solvents; Antibacterial agents such as benzyl alcohol or methylparaben; Antioxidants such as ascorbic acid or sodium chloride; Chelating agents such as ethylenediamine tetraacetic acid; Acetates, citrates or phosphates Buffer solutions such as salts, and agents for adjusting tension, such as sodium chloride or dextrose. The pH can be adjusted with an acid or base, such as hydrochloric acid or sodium hydroxide. Parenteral preparations can be contained in ampoules, disposable syringes or multidose vials made from glass or plastic.

The compounds or pharmaceutical compositions of this application can be administered to a subject by many of the well known methods currently used for chemotherapeutic treatment. For example, in the treatment of cancer, the compounds of this application may be injected directly into the tumor, injected into the bloodstream or body cavity, or taken orally, or patched through the skin. The dose selected should be sufficient to build an effective treatment, but not high enough to cause unacceptable side effects. The condition of the disease (eg, cancer, precancer, etc.) and the health of the patient should preferably be closely monitored during and over a reasonable period of time after treatment.

The term "therapeutic effective amount" as used herein refers to the amount of agent for treating, alleviating or preventing an identified disease or condition, or for exhibiting a detectable therapeutic or inhibitory effect. Point to. The effect can be detected by any assay method known in the art. The correct effective amount for a subject will depend on the subject's weight, size and health status; the nature and extent of the condition; and the therapeutic or combination of therapeutic agents selected for administration. The therapeutically effective amount for a given situation can be determined by routine experimentation within the skill and judgment of the clinician. In one embodiment, the disease or disorder is selected from immune disorders, cancer, cardiovascular disease, viral infections, inflammation, metabolic / endocrine dysfunction, and neuropathy. In another embodiment, the disease or condition being treated is cancer. In another embodiment, the disease or condition being treated is a cell proliferation disorder.

For any compound, a therapeutically effective amount can first be estimated, eg, in a cell culture assay or animal model of neoplastic cells, usually either rat, mouse, rabbit, dog or pig. Animal models can also be used to determine appropriate concentration ranges and routes of administration. Such information can then be used to determine doses and routes useful for administration in humans. Therapeutic / prophylactic efficacy and toxicity are relative to standard pharmaceutical procedures in cell cultures or laboratory animals, such as ED ₅₀ (therapeutically effective dose in 50% of the population) and LD ₅₀ (50% of the population). (Fatal dose). The dose ratio of toxicity to therapeutic effect is the therapeutic index, which can be expressed as the ratio LD ₅₀ / ED ₅₀ . Pharmaceutical compositions that exhibit a large therapeutic index are preferred. Dosages may vary within this range depending on the dosage form used, patient susceptibility, and route of administration.

Dosages and doses are adjusted to provide sufficient levels of active agent or to maintain the desired effect. Factors that could be considered include the severity of the disease state, the subject's general health, the subject's age, weight and gender, diet, frequency and frequency of administration, drug combination, response susceptibility, and tolerance / response to treatment. included. The long-acting pharmaceutical composition may be administered once every 3-4 days, weekly or every 2 weeks, depending on the half-life and clearance rate of the particular formulation.

Pharmaceutical compositions containing the active compound of the present application (ie, the compound of formula (I)) are in a generally known manner, eg, conventional mixing, dissolution, granulation, sugar preparation, wet grinding, etc. It can be produced by the process of emulsification, encapsulation, capture, or lyophilization. The pharmaceutical composition is conventional with one or more pharmaceutically acceptable carriers containing excipients and / or auxiliary ingredients that facilitate the processing of the active compound into a pharmaceutically usable preparation. Can be prescribed in the form. Of course, the appropriate formulation will depend on the route of administration chosen.

Suitable pharmaceutical compositions for injectable applications include sterile aqueous solutions (if water soluble) or sterile dispersions and sterile powders for the immediate preparation of injectable sterile solutions or sterile dispersions. For intravenous administration, suitable carriers include saline, bacteriostatic saline, Cremophor EL ™ (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS). In all cases, the composition should be sterile and should be fluid enough to be easily injected. It must be stable under manufacturing and storage conditions, which must be protected against the contaminants of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, a polyol (eg, glycerol, propylene glycol, liquid polyethylene glycol, etc.), and a suitable mixture thereof. Its proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Protection from the action of microorganisms can be achieved with various antibacterial and antifungal agents such as parabens, chlorobutanol, phenols, ascorbic acid, thimerosal and the like. In many cases, it may be preferable to include isotonic agents, such as sugars, polyhydric alcohols such as mannitol, sorbitol, sodium chloride in the composition. Sustained absorption of the injectable composition can be achieved by including in the composition an agent that delays absorption, such as aluminum monostearate and gelatin.

Injectable sterile solutions are prepared by incorporating the required amount of active compound in a suitable solvent, optionally with one or a combination of the components listed above, followed by filtration sterilization. be able to. Generally, dispersions are prepared by incorporating the active compound into a sterile medium containing a basic dispersion medium and other components required from those listed above. For sterile powders for the preparation of injectable sterile solutions, the methods of preparation are vacuum drying and freezing resulting from the solution which is pre-sterilized and filtered with powder of any additional ingredients desired in addition to the active ingredient. It is a drying method.

Oral compositions generally include an inert diluent or an edible pharmaceutically acceptable carrier. They can be encapsulated in gelatin capsules or compressed into tablets. For therapeutic oral administration, the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules. Oral compositions can also be prepared using a liquid carrier for use as a mouthwash, in which case the compounds in the liquid carrier are orally applied, swished, and swallowed or swallowed. Will be done. A pharmaceutically compatible binder and / or auxiliary substance can be included as part of the composition. The tablets, pills, capsules, troches, etc. can contain compounds of any or similar properties of the following ingredients: excipients such as microcrystalline cellulose, tragacant rubber or gelatin; starch or lactose. Disintegrants such as excipients, arginic acid, Primogel, or corn starch; lubricants such as magnesium stearate or Sterotes; flow promoters such as colloidal silicon dioxide; sweeteners such as sucrose or saccharin; or Fragrance additives such as peppermint, methyl salicylate, or orange flavor.

For administration by inhalation, the compound is delivered in the form of an aerosol spray from a suitable propellant, eg, a pressurized container or dispenser containing a gas such as carbon dioxide, or a sprayer.

Systemic administration can also be by transmucosal or percutaneous means. For transmucosal or transdermal administration, a penetrant suitable for the permeation barrier is used in the formulation. Such penetrants are generally known in the art and include, for example, surfactants, bile salts, and fusidic acid derivatives for transmucosal administration. Transmucosal administration can be achieved by the use of nasal sprays or suppositories. For transdermal administration, the active compound is formulated in an ointment, plaster, gel, or cream as is generally known in the art.

The active compound can be prepared with a pharmaceutically acceptable carrier capable of protecting the compound from rapid removal from the body, such as controlled release formulations, including implants and microencapsulated delivery systems. Biodegradable and biocompatible polymers such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid can be used. Methods of preparation of such formulations will be apparent to those of skill in the art. The material is also commercially available from Alza and Nova Pharmaceuticals. Liposomal suspensions (including liposomes that target infected cells with monoclonal antibodies to viral antigens) can also be used as pharmaceutically acceptable carriers. These can be prepared by methods known to those of skill in the art, for example, as described in US Pat. No. 4,522,811.

For ease of administration and dosage uniformity, it is particularly advantageous to formulate oral or parenteral compositions in dosage unit form. Dosage unit form, as used herein, refers to physically discontinuous units suitable as a single dose for the subject to be treated, each unit producing the desired therapeutic effect. Contains the calculated amount of active compound in relation to the required pharmaceutical carrier. The specifications of the dosage unit form of the present application are determined and depend directly on the unique characteristics of the active compound and the particular therapeutic effect desired to be achieved.

In therapeutic applications, the dosage of the pharmaceutical composition used in this application is, among other factors, the agent, the age, weight, and clinical condition of the recipient patient, among other factors that affect the dose selected. And it depends on the experience and judgment of the doctor or practitioner who gives the treatment. In general, the dose should be sufficient to result in slowing of tumor growth, preferably regression, and preferably complete regression of the cancer. Dosages can range from about 0.01 mg / kg / day to about 5000 mg / kg / day. An effective amount of a drug is an amount that results in an objectively identifiable improvement that is noticed by a physician or other authorized observer. For example, tumor regression in a patient can be measured in relation to tumor diameter. A decrease in tumor diameter indicates regression. Retraction is also indicated by the fact that the tumor does not recur after stopping treatment. As used herein, the term "dose-effective mode" refers to the amount of active compound to produce the desired biological effect in a subject or cell.

The pharmaceutical composition can be included in a container, pack or dispenser with instructions for administration.

As used herein, "pharmaceutically acceptable salt" refers to a derivative of a compound of the present application in which the parent compound has been modified by producing its acid or basic salt. Examples of pharmaceutically acceptable salts include amines, mineral or organic acid salts of basic residues such as alkalis, or organic salts of acidic residues such as carboxylic acids. Not limited to. Pharmaceutically acceptable salts include, for example, conventional non-toxic or quaternary ammonium salts of the parent compound formed from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, bicarbonate, carbonic acid, citric acid, edetic acid, ethandisulfone. Acids, 1,2-ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, glycolyarsanilic acid, hexylresorcinic acid, hydrabamic acid, hydrobromic acid, hydrochloric acid, Hydroiodic acid, hydroxymaleic acid, hydroxynaphthoic acid, isetioic acid, lactic acid, lactobionic acid, lauryl sulfate, maleic acid, malic acid, mandelic acid, methanesulfonic acid, napsylic acid, nitrate, oxalic acid, pamoic acid , Pantothenic acid, phenylacetic acid, phosphoric acid, polygalacturonic acid, propionic acid, salicylic acid, stearic acid, subacetic acid, succinic acid, sulfamic acid, sulfanic acid, sulfuric acid, tannic acid, tartaric acid, toluenesulfonic acid, and generally Includes, but is not limited to, salts derived from inorganic and organic acids selected from existing amic acids such as glycine, alanine, phenylalanine, arginine and the like.

Other examples of pharmaceutically acceptable salts include hexanoic acid, cyclopentanepropionic acid, pyruvate, malonic acid, 3- (4-hydroxybenzoyl) benzoic acid, silicic acid, 4-chlorobenzenesulfonic acid, 2 -Naphthalene sulfonic acid, 4-toluene sulfonic acid, Drosophila sulfonic acid, 4-methylbicyclo- [2.2.2] -octa-2-en-1-carboxylic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butyl Examples include acetic acid and muconic acid. The application also applies when the acidic protons present in the parent compound are replaced by metal ions such as alkali metal ions, alkaline earth metal ions, or aluminum ions; or ethanolamine, diethanolamine, triethanolamine, tromethamine, N-. Includes salts formed either when coordinating with organic bases such as methylglucamine.

It should be understood that all references to pharmaceutically acceptable salts include the solvent-added form (solvate) or crystalline form (polymorph) of the same salt as defined herein.

The compounds of this application can also be prepared as esters, eg, pharmaceutically acceptable esters. For example, a carboxylic acid functional group in a compound can be converted to its corresponding ester, such as a methyl ester, ethyl ester or other ester. Also, the alcohol group in the compound can be converted to its corresponding ester, such as an acetate ester, a propionic acid ester or another ester.

The compounds of this application can also be prepared as prodrugs, eg, pharmaceutically acceptable prodrugs. The terms "pro-drug" and "prodrug" are used interchangeably herein to refer to any compound that releases an active parent drug in vivo. Since prodrugs are known to enhance a number of desired properties of the drug (eg, solubility, bioavailability, production, etc.), the compounds of this application are delivered in the form of prodrugs. Can be done. Accordingly, this application is intended to cover prodrugs of the compounds claimed in the present application, methods of delivering them, and compositions containing them. A "prodrug" is intended to include any covalently bound carrier that releases the active parent drug of the present application in vivo when such a prodrug is administered to a subject. Prodrugs in this application are prepared by modifying the functional groups present in the compound in a manner such that the modification is cleaved to the parent compound, either by conventional procedure or in vivo. The prodrug may cleave a hydroxy group, an amino group, a sulfhydryl group, a carboxy group or a carbonyl group in vivo to form a free hydroxyl group, a free amino group, a free sulfhydryl group, a free carboxy group or a free carbonyl group, respectively. Includes compounds of this application attached to any group.

Examples of prodrugs include esters of hydroxy functional groups (eg, acetate, dialkylaminoacetates, formates, phosphates, sulfates and benzoic acid derivatives) and carbamate (eg, N, N-dimethylaminocarbonyl) of the compounds of this application. , Esters of carboxyl functional groups (eg, ethyl esters, morpholinoethanol esters), N-acyl derivatives of amino functional groups (eg, N-acetyl), N-Mannich bases, Schiff bases and enaminones, ketone functional groups and aldehyde functional groups. Examples include, but are not limited to, oxime, acetal, ketal and enol esters, but but not limited to these, see Bundegaard, H., Design of Prodrugs, p1-92, Elsevier, New York-Oxford (1985).

Compounds, or pharmaceutically acceptable salts thereof, metavariants, prodrugs, solvates, metabolites, polymorphs, analogs, or derivatives can be oral, nasal, transdermal, lung, inhalation, cheek. , Sublingual, intraperitoneal, subcutaneous, intramuscular, intravenous, rectal, intrapleural, intrasheath and parenteral. In one embodiment, the compound or a pharmaceutically acceptable salt thereof, a homozygous, a prodrug, a solvate, a metabolite, a polymorph, an analog or a derivative thereof is administered orally. Those of skill in the art will recognize the benefits of a particular route of administration.

Dosing regimens that utilize compounds include the patient's type, species, age, weight, gender and medical condition; the severity of the condition being treated; the route of administration; the patient's renal and hepatic function; and the specific compound to be adopted. Alternatively, it is selected by a variety of factors, including its pharmaceutically acceptable salts, metavariants, prodrugs, solvates, metabolites, polymorphs, analogs or derivatives. A normally skilled physician or veterinarian can easily determine and prescribe the effective amount of drug required to prevent the condition, counter the condition, or stop the progression of the condition. ..

Techniques for the formulation and administration of the disclosed compounds of this application can be found in Remington: the Science and Practice of Pharmacy, 19th edition, ^Mack Publishing Co., Easton, PA (1995). In one embodiment, the compounds described herein and their pharmaceutically acceptable salts, metavariants, prodrugs, solvates, metabolites, polymorphs, analogs or derivatives are pharmaceutical. Used in preparation in combination with a pharmaceutically acceptable carrier or diluent. Suitable pharmaceutically acceptable carriers include inert solid bulking agents or diluents, and sterile aqueous or organic solutions. The compounds or pharmaceutically acceptable salts, prodrugs, solvates, metabolites, polymorphs, analogs or derivatives thereof are within the scope described herein in such pharmaceutical compositions. It will be present in sufficient amount to provide the desired dose.

All percentages and ratios used herein are by weight, unless otherwise indicated. Other features and advantages of this application are evident from the various examples. The examples provided illustrate various ingredients and methodologies that are useful in practicing this application. The examples do not limit the claimed application. Based on this application, one of ordinary skill in the art can identify and adopt other components and methodologies useful in practicing this application.

The present application will be further described by the following examples and synthetic schemes, which should not be construed as limiting the scope or intent of the present application to the particular procedures described herein. It should be understood that these examples are provided to illustrate certain embodiments and are not intended to limit the scope of this application. It should be further understood that various other aspects, modifications, and equivalents that may be suggested to those skilled in the art can be used without departing from the spirit of the claims of this application and / or the attachment. be.

Analytical Methods, Materials, and Measuring Means Unless otherwise noted, reagents and solvents were used as received from commercial suppliers. Proton nuclear magnetic resonance (NMR) spectra were obtained at 400 MHz on either a Bruker or Varian spectrometer. The spectrum is shown in ppm (δ) and the coupling constant J is reported in Hertz. Tetramethylsilane (TMS) was used as the internal standard. Mass spectra were collected using a Waters ZQ Single Quad mass spectrometer (ion trap ESI). Purity and low resolution mass spectrometric data are measured using a Waters Acquity i-class ultra-high performance liquid chromatography (UPLC) system equipped with an Acquity Photo Diode Array Detector, an Acquity Evaporative Light Scattering Detector (ELSD) and a Waters ZQ Mass Spectrometer. Was done. Data were acquired using Waters MassLynx 4.1 software and the purity was characterized by UV wavelength 220 nm, ELSD and ESI. Column: Acquity UPLC BEH C18 1.7 μm 2.1 × 50 mm; Flow rate 0.6 mL / min; Solvent A (95/5 / 0.1 10 mM ammonium formate / acetonitrile / formic acid), Solvent B (95/5 / 0.09 acetonitrile / water / formic acid) ); Gradient: Holds 5-100% B from 0 to 2 minutes, 100% B from 2.2 minutes, then 5% B from 2.21 minutes.

The abbreviations used in the following examples and elsewhere herein are:
DCM Dichloromethane
DIEA N, N-diisopropylethylamine
DIPEA N, N-diisopropylethylamine
DMF N, N-dimethylformamide
DMSO dimethyl sulfoxide
DTT Dithiothreitol
EDTA ethylenediaminetetraacetic acid
EGTA ethylene glycol tetraacetic acid
Et ₂ O Diethyl Ether
EtOAc Ethyl acetate
EtOH ethanol
LCMS Liquid Chromatography-Mass Spectrometry
MeOH Methanol
MS mass spectrometry
NMR nuclear magnetic resonance
ppm per million

段階1: 2-クロロ-4-フェノキシベンゾニトリル(中間体2-B)
DMF (30 mL)に溶解したフェノール(3.66 g, 39 mmol)を、ガス発生が止むまで少量ずつ、油中に分散したNaH 60% (1.56 g, 39 mmol)で処理した。反応混合物を室温で10分間撹拌し、次いで2-クロロ-4-フルオロベンゾニトリル(2-A, 5.0 g, 32.5 mmol)を添加した。混合物を、完了まで(LCMS)室温で3時間撹拌した。揮発性物質を真空除去し、粗生成物をDCM/水に分配した。有機相を分離し、飽和塩水溶液で洗浄し、Na₂SO₄で乾燥させた。濃縮して灰白色固体7.5 gを得た。

Example 1: 2-Chloro-4-phenoxybenzoate (Intermediate 2-D)

Step 1: 2-Chloro-4-phenoxybenzonitrile (Intermediate 2-B)
Phenol (3.66 g, 39 mmol) dissolved in DMF (30 mL) was treated in small portions with 60% NaH (1.56 g, 39 mmol) dispersed in oil until gas generation stopped. The reaction mixture was stirred at room temperature for 10 minutes, then 2-chloro-4-fluorobenzonitrile (2-A, 5.0 g, 32.5 mmol) was added. The mixture was stirred at room temperature (LCMS) for 3 hours until completion. Volatiles were evacuated and the crude product was dispensed into DCM / water. The organic phase was separated, washed with saturated aqueous salt solution and dried over Na ₂ SO ₄ . Concentration gave 7.5 g of a grayish white solid.

Stage 2: 2-Chloro-4-phenoxybenzoic acid (intermediate 2-C)
2-Chloro-4-phenoxybenzonitrile (2-B, 7.0 g, 30.6 mmol), potassium hydroxide 5M (100 mL) and EtOH (20 mL) under reflux for 6 hours (until the starting material is consumed) Stirred. The mixture was cooled to room temperature and the mixture was slowly acidified with concentrated HCl. The precipitate was filtered off and dried to give a beige solid (2-C, 7.15 g, 94%).

Stage 3: Methyl 2-chloro-4-phenoxybenzoate (intermediate 2-D)
2-Chloro-4-phenoxybenzoic acid (2-C, 5.0 g, 20.2 mmol) was dissolved in DMF (50 mL) and solid K ₂ CO ₃ (4.15 g, 30.1 mmol) was added. The reaction mixture was cooled to 0 ° C. and methyl iodide (1.4 mL, 22.2 mmol) was added dropwise. The mixture was allowed to warm to room temperature over 1 hour. All starting material was consumed within that period. The mixture was diluted with water and extracted with Et ₂ O. Drying and concentrating in vacuo gave a yellow oil (2-D, 4.15 g, 79%), which was used without further purification.

段階1: 5-ブロモ-4-クロロ-7H-ピロロ[2,3-d]ピリミジン(中間体2-F)
温度を25～30℃前後に維持しながら、DCM (800 mL)に溶解した4-クロロ-7H-ピロロ[2,3-d]ピリミジン(2-E, 20.0 g, 130.7 mmol)をN-ブロモスクシンイミド(26.7 g, 149.8 mmol)で少しずつ処理した。反応混合物を室温で終夜撹拌した。水を添加し(500 mL)、相を分離した。有機相をNa₂SO₄で乾燥させ、ろ過し、真空で濃縮した。粗生成物をEt₂O中で粉砕して、ろ過後に5-ブロモ-4-クロロ-7H-ピロロ[2,3-d]ピリミジンを白色固体(2-F, 22.43 g, 74%)として得た。融点: 242～244℃;

Example 2: (2-Chloro-4-phenoxyphenyl) (4-(((3R, 6S) -6- (hydroxymethyl) tetrahydro-2H-pyran-3-yl) amino) -7H-pyrrolo [2, 3-d] Pyrimidine-5-yl) Metanone (Compound (I))

Step 1: 5-bromo-4-chloro-7H-pyrrolo [2,3-d] pyrimidine (intermediate 2-F)
4-Chloro-7H-pyrrolo [2,3-d] pyrimidine (2-E, 20.0 g, 130.7 mmol) dissolved in DCM (800 mL) was added to N-bromo while maintaining the temperature at around 25 to 30 ° C. It was treated little by little with succinimide (26.7 g, 149.8 mmol). The reaction mixture was stirred at room temperature overnight. Water was added (500 mL) and the phases were separated. The organic phase was dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude product is ground in Et ₂ O to give 5-bromo-4-chloro-7H-pyrrolo [2,3-d] pyrimidine as a white solid (2-F, 22.43 g, 74%) after filtration. rice field. Melting point: 242 to 244 ° C;

Step 2: (2-Chloro-4-phenoxyphenyl) (4-chloro-7H-pyrrolo [2,3-d] pyrimidine-5-yl) methanone (intermediate 2-G)
5-Bromo-4-chloro-7H-pyrrolo [2,3-d] pyrimidin (2-F, 6.90 g, 29.7 mmol) in THF (200 mL) in a stirred solution under an inert atmosphere at -78 ° C n- BuLi (2.69 M, 23.2 mL, 62.3 mmol in hexanes) was added dropwise. The reaction mixture was held at -78 ° C for 1 hour, followed by a solution of methyl 2-chloro-4-phenoxybenzoate (2-D, 8.19 g, 31.2 mmol) in THF (80 mL) precooled (up to -78 ° C). Added. The reaction mixture was stirred at −78 ° C. for 1 hour, then the reaction was stopped by the addition of HCl 1N (65 mL). The mixture was warmed to room temperature and then extracted with EtOAc (3 x 100 mL). The combined extracts were washed with brine, dried over Na ₂ SO ₄ , and concentrated in vacuo. The crude product was purified by column chromatography (SiO ₂ , hexane / EtOAc) and (2-chloro-4-phenoxyphenyl) (4-chloro-7H-pyrrolo [2,3-d] pyrimidine-5-yl). Metanone was obtained as a white solid (2-G, 4.73 g, 41%).

Step 3: (2-Chloro-4-phenoxyphenyl) (4-(((3R, 6S) -6- (hydroxymethyl) tetrahydro-2H-pyran-3-yl) amino) -7H-pyrrolo [2,3] -d] Pyrimidine-5-yl) Metanon (I)
(2-Chloro-4-phenoxyphenyl) (4-chloro-7H-pyrrolo [2,3-d] pyrimidine-5-yl) methanone (2-G, 200 mg, 0.52 mmol), ((2S, 5R)) A mixture of -5-aminotetrahydro-2H-pyran-2-yl) methanol (72 mg, 0.54 mmol) and DIPEA (272 μL, 1.56 mmol) was stirred at 160 ° C. for 1 hour under microwave irradiation. Volatile substances are removed in vacuum and the residue is purified by column chromatography (NH ₂ -SiO ₂ , DCM / MeOH) with (2-chloro-4-phenoxyphenyl) (4-(((3R, 6S)-). 6- (Hydroxymethyl) Tetrahydro-2H-Pyran-3-yl) Amino) -7H-Pyrrolo [2,3-d] Pyrimidine-5-yl) Metanone as a grayish white solid ((I), 175 mg, 70%) Got as.

Example 3: BTK Kinase Activity Assay Prepare test inhibitors and controls (CGI-1746, GDC-0834, PCI-32765, dasatinib, and R-406) in 10% DMSO at 10-fold the desired final concentration. And added to each well of the reaction plate (Corning 96-well semi-regional solid colorless non-bonded surface plate) in a volume of 2.5 μl. Full-length active BTK assay buffer (50 mM Tris, pH 8.0, 0.02 mg / ml BSA, 10 mM MgCl ₂ , 1 mM EGTA, 10% glycerol, 0.2 mM Na ₃ VO ₄ , 1 mM DTT, 0.1 mM β-glyceroline Dilute in acid, and 0.2 mM NaF) and added to each well in a volume of 17.5 μl towards a final concentration in 25 μl of 0.08 nM reaction. After 30 minutes of preincubation at room temperature, the kinase reaction was initiated by the addition of 5 μl of the activation mixture diluted in assay buffer containing biotinylated PLCγ2 peptide and ATP towards a final concentration of 150 nM biotinylated PLCγ2 and 180 μM ATP. did. The plates were incubated at room temperature for 60 minutes. The reaction was stopped in the dark by the addition of 10 μl of stop / detection mixture prepared in assay buffer containing EDTA and AlphaScreen ™ streptavidin donor and anti-pTYR100 acceptor beads. Final concentrations were both 10 mM EDTA and 500 ng / well AlphaScreen ™ donor and acceptor beads. The assay plates were incubated at room temperature for 60 minutes in the dark and the plates were read with a Perkin Elmer Envision Multilabel plate reader (excitation wavelength: 640 nm, emission wavelength: 570 nm). The results are shown in Table 1.

Example 4: BTK C481S Kinase Activity Assay Test Inhibitors and controls (staurosporine) were prepared in 10% DMSO at 10 times the desired final concentration and reaction plates (Corning 96-well semi-regional solid colorless). Each well of the unbound surface plate) was added in a volume of 2.5 μl. Full-length BTKC481S in assay buffer (50 mM Tris, pH 8.0, 0.02 mg / ml BSA, 10 mM MgCl ₂ , 1 mM EGTA, 10% glycerol, 1 mM DTT, 1 mM β-glycerophosphate, and 1 mM NaF). Dilute with, and added to each well in a volume of 17.5 μl towards a final concentration in 25 μl of 10 nM reaction. After 30 minutes of preincubation at room temperature, the kinase reaction was initiated by the addition of 5 μl of the activation mixture diluted in assay buffer containing biotinylated PLCγ2 peptide and ATP towards the final concentration of 125 nM biotinylated PLCγ2 and 60 μM ATP. did. The plates were incubated at room temperature for 60 minutes. The reaction was stopped in the dark by the addition of 10 μl of stop / detection mixture prepared in assay buffer containing EDTA, staurosporine and AlphaScreen ™ streptavidin donor and anti-pTYR100 acceptor beads. Final concentrations were both 15 mM EDTA, 1 μM staurosporine and 500 ng / well AlphaScreen ™ (Amplified Luminescent Proximity Homogeneous Assay) technology donors and acceptor beads. The assay plates were incubated at room temperature for 60 minutes in the dark and the plates were read with a Perkin Elmer Envision Multilabel plate reader (excitation wavelength: 640 nm, emission wavelength: 570 nm). The results are shown in Table 1.

Example 5: Antiproliferative Assay Cell survival was determined by the MTS assay. Briefly, cells (ie, TMD-8 cells or Rec-1 cells) are plated in 96-well plates with 2,000-10,000 cells per well, cultured for 24 hours in complete growth medium, and then varied. Treated with drug and drug combination for 72 hours. After adding MTS / PMS and incubating for 4 hours, cell viability was evaluated using a microplate reader (absorbance at 490 nm). Data were standardized for raw controls and analyzed in Microsoft Excel. The results are shown in Table 1.

(Table 1) Biological activity of compound (I)

Equivalents One of ordinary skill in the art will be able to recognize or establish a number of equivalents for the particular embodiments specifically described herein using only routine experimentation. Such equivalents are intended to be included in the following claims.

Claims (16)

Compound of formula (I):

Or a pharmaceutical composition comprising a pharmaceutically acceptable salt, tautomer, or solvate thereof for treating cancer in a subject in need thereof.
The cancer is a variant BTK-mediated cancer, wherein the variant BTK comprises a drug resistance mutation .
The pharmaceutical composition. The pharmaceutical composition according to claim 1 , wherein the drug resistance mutation is a mutation in amino acid 481. The pharmaceutical composition according to claim 1 , wherein the drug resistance mutation is C481S. Compound of formula (I):

Or a pharmaceutical composition comprising a pharmaceutically acceptable salt, tautomer, or solvate thereof for treating cancer in a subject in need thereof.
The cancer is a mutant BTK-mediated cancer and is resistant to BTK inhibitors.
The pharmaceutical composition. The pharmaceutical composition according to claim 4 , wherein the BTK inhibitor is ibrutinib. Cancers are breast cancer, ovarian cancer, cervical cancer, prostate cancer, testis cancer, esophageal cancer, laryngeal cancer, stomach cancer, skin cancer, lung cancer, bone cancer, pancreatic cancer, colon cancer , Thyroid cancer, biliary tract cancer, hairy cells, oral cancer, nasopharyngeal cancer, lip cancer, tongue cancer, mouth cancer, colon cancer, small bowel cancer, colon rectal cancer, rectal cancer Cancer of the brain and central nervous system, bronchial cancer, liver cancer, intrahepatic bile duct cancer, bladder cancer, uterine body cancer, kidney cancer, renal pelvis cancer, oral cancer, pharynx Cancer, glioblastoma, neuroblastoma, keratinized spinous cell tumor, epidermal cancer, large cell cancer, non-small cell lung cancer (NSCLC), small cell cancer, lung adenocarcinoma, adenocarcinoma, Adenocarcinoma, follicular cancer, undifferentiated cancer, papillary cancer, sperm epithelioma, melanoma, sarcoma, bladder cancer, liver cancer, kidney cancer, myelopathy, lymphoma, Hodgkin leukemia, hepatocellular carcinoma , Glycria, endometrial cancer, multiple myeloma, acute myeloid leukemia, chronic myeloid leukemia, lymphocytic leukemia, chronic lymphocytic leukemia (CLL), myeloid leukemia, non-Hodgkin's lymphoma, and colon villous adenoma The pharmaceutical composition according to claim 1 or 4 , which is selected from. The pharmaceutical composition according to claim 1 or 4, wherein the cancer is chronic lymphocytic leukemia. The pharmaceutical composition according to claim 1 or 4 , wherein the cancer is lymphoma. The pharmaceutical composition according to claim 8 , wherein the lymphoma is a non-Hodgkin lymphoma. The pharmaceutical composition according to claim 8 , wherein the lymphoma is a B-cell lymphoma. The pharmaceutical composition according to claim 8 , wherein the lymphoma is undifferentiated large cell lymphoma, central nervous system (CNS) lymphoma, or Waldenstrem macroglobulinemia. The pharmaceutical composition according to claim 1 or 4, wherein the cancer is bone marrow disorder or myeloid leukemia. The pharmaceutical composition according to claim 1 or 4, wherein the cancer is acute myeloid leukemia. The pharmaceutical composition according to claim 1 or 4, wherein the cancer is multiple myeloma. The pharmaceutical composition according to claim 1 or 4, wherein the cancer is lymphocytic leukemia. The pharmaceutical composition according to claim 1 or 4, wherein the cancer is a sarcoma or a brain tumor.