阅读说明：本技术 N-酰基-{4-[(4-芳基-苯基)磺酰基甲基]哌啶}化合物及其治疗用途 (N-acyl- {4- [ (4-aryl-phenyl) sulfonylmethyl ] piperidine } compounds and their therapeutic use ) 是由 利萨·帕特尔 斯蒂芬·艾伦·史密斯 斯蒂芬·保罗·科林伍德 于 2020-04-17 设计创作，主要内容包括：本发明总体上涉及治疗性化合物领域。更具体地,本发明涉及下式的某些N-酰基-{4-[(4-芳基-苯基)磺酰基甲基]哌啶}化合物(在本文中总称为NASMP化合物),其可用于例如治疗病症(例如,疾病),包括例如多发性骨髓瘤、弥漫性大B细胞淋巴瘤、急性骨髓性白血病、嗜酸性粒细胞白血病、胶质母细胞瘤、黑色素瘤、卵巢癌、抗化学疗法性癌症、抗辐射性癌症、炎性关节炎、类风湿性关节炎、银屑病关节炎、银屑病、溃疡性结肠炎、克罗恩氏病、系统性红斑狼疮(SLE)、狼疮性肾炎、哮喘、慢性阻塞性肺病(COPD)、化脓性汗腺炎、自身免疫性肝炎等。本发明还涉及包含此类化合物的药物组合物,以及此类化合物和组合物在例如治疗中的用途。(The present invention relates generally to the field of therapeutic compounds. More particularly, the present invention relates to certain N-acyl- {4- [ (4-aryl-phenyl) sulfonylmethyl groups of the formula]Piperidine compounds (collectively referred to herein asIs a NASMP compound) that can be used, for example, to treat a disorder (e.g., a disease) including, for example, multiple myeloma, diffuse large B-cell lymphoma, acute myelogenous leukemia, eosinophilic leukemia, glioblastoma, melanoma, ovarian cancer, anti-chemotherapy cancer, anti-radiation cancer, inflammatory arthritis, rheumatoid arthritis, psoriatic arthritis, psoriasis, ulcerative colitis, crohn's disease, Systemic Lupus Erythematosus (SLE), lupus nephritis, asthma, Chronic Obstructive Pulmonary Disease (COPD), hidradenitis suppurativa, autoimmune hepatitis, and the like. The invention also relates to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, for example in therapy.)

1. A compound having the formula:

or a pharmaceutically acceptable salt or solvate thereof;

wherein:

-X is independently-CH or-N;

"m" is independently 0, 1, 2 or 3;

each of-R^AIndependently is-F, -Cl, -R^AC、-R^AFor-CN;

-R^ACindependently saturated straight or branched chain C_1-3An alkyl group;

-R^AFindependently saturated straight or branched chain C_1-3A fluoroalkyl group;

"n" is independently 0, 1 or 2;

each of-R^BIndependently is-F, -Cl, -R^BC、-R^BFor-CN;

-R^BCindependently saturated straight or branched chain C_1-3An alkyl group;

-R^BFindependently saturated straight or branched chain C_1-3A fluoroalkyl group;

-R¹independently is-H or-R^1X；

-R^1XIndependently is-F, -R^1Cor-R^1F；

-R^1CIndependently a saturated straight chainOr branched C_1-3An alkyl group;

-R^1Findependently saturated straight or branched chain C_1-3A fluoroalkyl group;

-R²independently is-H or-R^2X；

-R^2XIndependently is-F, -R^2Cor-R ^2F；

-R^2CIndependently saturated straight or branched chain C_1-3An alkyl group;

-R^2Findependently saturated straight or branched chain C_1-3A fluoroalkyl group;

or-R¹and-R²Together with the carbon atom to which they are attached form saturated C_3-6A cycloalkyl group;

-R³independently is-H or-R^3X；

-R^3XIndependently is-R^3Cor-R^3F；

-R^3CIndependently saturated straight or branched chain C_1-3An alkyl group;

-R^3Findependently saturated straight or branched chain C_1-3A fluoroalkyl group;

-R⁴independently is-R^4C、-R^4CCor-N (R)^4N1)(R^4N2)；

-R^4CIndependently saturated straight or branched chain C_1-6An alkyl group;

-R^4CCindependently saturated C_3-6A cycloalkyl group;

-R^4N1independently is-H or-R^4N1C；

-R^4N1CIndependently saturated straight or branched chain C_1-4An alkyl group;

-R^4N2independently is-H or-R^4N2C(ii) a And is

-R^4N2CIndependently saturated straight or branched chain C_1-4An alkyl group;

or-N (R)^4N1)(R^4N2) Independently is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl, and is straight-chain or saturated with one or more groupsBranched chain C_1-4Alkyl is optionally substituted.

2. The compound of claim 1, wherein-X-is-CH.

3. The compound of claim 1, wherein-X-is-N.

4. A compound according to any one of claims 1 to 3, wherein "m" is independently 0, 1 or 2.

5. A compound according to any one of claims 1 to 3, wherein "m" is 1 or 2.

6. A compound according to any one of claims 1 to 5, wherein each-R^AAnd, if present, is independently-F, -Cl or-CN.

7. A compound according to any one of claims 1 to 5, wherein each-R^AAnd if present, is-F.

8. A compound according to any one of claims 1 to 5, wherein each-R^AAnd, if present, is-Cl.

9. A compound according to any one of claims 1 to 8, wherein each-R^ACIf present, is-CH₃。

10. The compound of any one of claims 1 to 9, wherein each-R^AFIf present, is-CF₃。

11. The compound of any one of claims 1 to 10, wherein "n" is independently 1 or 2.

12. The compound of any one of claims 1 to 10, wherein "n" is 0.

13. The compound of any one of claims 1 to 12, wherein each-R^BAnd, if present, is independently-F, -Cl or-CN.

14. The compound of any one of claims 1 to 12, wherein each-R^BAnd if present, is-F.

15. The compound of any one of claims 1 to 12, wherein each-R^BAnd, if present, is-Cl.

16. The compound of any one of claims 1 to 15, wherein each-R ^BCIf present, is-CH₃。

17. The compound of any one of claims 1 to 16, wherein each-R^BFIf present, is-CF₃。

18. The compound of claim 1, wherein the group:

independently selected from:

wherein-R^A1、-R^A2、-R^A3、-R^A4and-R^A5Each of which is independently as para-R^AAs defined.

19. The compound of claim 1, wherein the group:

independently selected from:

wherein-R^A1、-R^A2、-R^A3、-R^A4and-R^A5Each of which is independently as para-R^AAs defined.

20. The compound of claim 1, wherein the group:

independently selected from:

wherein-R^A1、-R^A3and-R^A5Each of which is independently as para-R^AAs defined.

21. The compound of claim 1, wherein the group:

comprises the following steps:

wherein-R^A1and-R^A3Each of which is independently as para-R^AAs defined.

22. The compound of any one of claims 1 and 18 to 21, wherein the group:

independently selected from:

wherein-R^B1and-R^B2Each of which is independently as para-R^BAs defined.

23. The compound of any one of claims 1 and 18 to 21, wherein the group:

independently selected from:

wherein-R^B1and-R^B2Each of which is independently as para-R^BAs defined.

24. The compound of any one of claims 1 and 18 to 21, wherein the group:

comprises the following steps:

25. the compound of any one of claims 1 and 18 to 21, wherein the group:

independently selected from:

wherein-R^B1and-R^B2Each of which is independently as para-R^BAs defined.

26. The compound of any one of claims 1 to 25, wherein-R¹is-R^1X。

27. The compound of any one of claims 1 to 25, wherein-R¹is-H.

28. The compound according to any one of claims 1 to 27, wherein-R^1XIf present, is independently-F, -R^1Cor-R^1F。

29. The compound according to any one of claims 1 to 27, wherein-R^1XAnd if present, is-F.

30. The compound according to any one of claims 1 to 27, wherein-R^1XIf present, is-R^1C。

31. According to claimThe compound of any one of claims 1 to 30, wherein-R^1CIf present, is-CH₃。

32. The compound of any one of claims 1 to 31, wherein-R²is-R^2X。

33. The compound of any one of claims 1 to 31, wherein-R²is-H.

34. The compound of any one of claims 1 to 33, wherein-R ^2XIf present, is independently-F, -R^2Cor-R^2F。

35. The compound of any one of claims 1 to 33, wherein-R^2XAnd if present, is-F.

36. The compound of any one of claims 1 to 33, wherein-R^2XIf present, is-R^2C。

37. The compound of any one of claims 1 to 36, wherein-R^2CIf present, is-CH₃。

38. The compound of any one of claims 1 to 25, wherein-R¹and-R²Together with the carbon atom to which they are attached form saturated C_3-6A cycloalkyl group.

39. The compound of any one of claims 1 to 38, wherein-R³is-R^3X。

40. The compound of any one of claims 1 to 38, wherein-R³is-H.

41. The method according to any one of claims 1 to 40The compound of any one of, wherein-R^3XIf present, is-R^3C。

42. The compound of any one of claims 1 to 41, wherein-R^3CIf present, is-CH₃。

43. A compound according to any one of claims 1 to 42, wherein-R⁴is-R^4C。

44. A compound according to any one of claims 1 to 42, wherein-R⁴is-R^4CC。

45. A compound according to any one of claims 1 to 42, wherein-R ⁴is-N (R)^4N1)(R^4N2)。

46. The compound of any one of claims 1 to 45, wherein-R^4CIf present, is a saturated straight or branched chain C_1-4An alkyl group.

47. The compound of any one of claims 1 to 45, wherein-R^4CIf present, is-CH₃or-CH₂CH₃。

48. The compound of any one of claims 1 to 47, wherein-R^4N1If present, is-R^4N1C。

49. The compound of any one of claims 1 to 47, wherein-R^4N1And if present, is-H.

50. A compound according to any one of claims 1 to 49, wherein-R^4N1CIf present, is a saturated straight or branched chain C_1-3An alkyl group.

51. A compound according to any one of claims 1 to 49, wherein-R^4N1CIf present, is-CH₃or-CH₂CH₃。

52. A compound according to any one of claims 1 to 51, wherein-R^4N2If present, is-R^4N2C。

53. A compound according to any one of claims 1 to 51, wherein-R^4N2And if present, is-H.

54. The compound of any one of claims 1 to 53, wherein-R^4N2CIf present, is a saturated straight or branched chain C_1-3An alkyl group.

55. The compound of any one of claims 1 to 53, wherein-R ^4N2CIf present, is-CH₃or-CH₂CH₃。

56. The compound of any one of claims 1 to 45, wherein-N (R)^4N1)(R^4N2) Independently pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl, if present; and is saturated by one or more linear or branched C_1-4Alkyl is optionally substituted.

57. A compound according to any one of claims 1 to 56, wherein-R¹and-R²And the compound is a compound of the formula:

58. compound according to any one of claims 1 to 56In which-R is¹and-R²And the compound is a compound of the formula:

59. the compound of claim 1, which is a compound of one of the following formulae or a pharmaceutically acceptable salt or solvate thereof:

NASMP-01 to NASMP-21.

60. A composition comprising a compound of any one of claims 1 to 59 and a carrier, diluent or excipient.

61. A method of making a composition comprising the step of mixing a compound of any one of claims 1 to 59 with a carrier or diluent.

62. A compound as claimed in any one of claims 1 to 59 for use in a method of treatment of the human or animal body by therapy.

63. A compound according to any one of claims 1 to 59 for use in a method of treatment of a disorder.

64. Use of a compound of any one of claims 1 to 59 in the manufacture of a medicament for treating a disorder.

65. A method of treating a disorder comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1.

66. A compound for use according to claim 63, use according to claim 64 or method according to claim 65, wherein the treatment is a treatment of:

disorders associated with alterations in cellular metabolism.

67. A compound for use according to claim 63, use according to claim 64 or method according to claim 65, wherein the treatment is a treatment of:

autoimmune/inflammatory disorders; cancer; or a condition mediated by osteoclasts.

68. A compound for use according to claim 63, use according to claim 64 or method according to claim 65, wherein the treatment is a treatment of:

multiple myeloma, diffuse large B-cell lymphoma, acute myeloid leukemia, eosinophilic leukemia, glioblastoma, melanoma, ovarian cancer, anti-chemotherapy cancer, anti-radiation cancer, inflammatory arthritis, rheumatoid arthritis, psoriatic arthritis, psoriasis, ulcerative colitis, crohn's disease, Systemic Lupus Erythematosus (SLE), lupus nephritis, asthma, Chronic Obstructive Pulmonary Disease (COPD).

69. A compound for use according to claim 63, use according to claim 64 or method according to claim 65, wherein the treatment is a treatment of:

autoimmune/inflammatory disorders.

70. A compound for use according to claim 63, use according to claim 64 or method according to claim 65, wherein the treatment is a treatment of:

inflammatory arthritis (including, for example, rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, spondyloarthritis, reactive arthritis, infectious arthritis, systemic lupus erythematosus, scleroderma, gout, adult still's disease, juvenile idiopathic arthritis); psoriasis; systemic lupus erythematosus; lupus nephritis; systemic sclerosis; scleroderma; hepatitis; endometriosis; adenomyosis of the uterus; sicca syndrome; inflammatory bowel disease; ulcerative colitis; crohn's disease; multiple sclerosis; asthma; atherosclerosis; chronic Obstructive Pulmonary Disease (COPD); uveitis; hidradenitis suppurativa; autoimmune hepatitis; pulmonary fibrosis; allergic diseases (including, for example, atopy, allergic rhinitis, atopic dermatitis, anaphylaxis, allergic bronchopulmonary aspergillosis, allergic gastroenteritis, allergic pneumonia); (ii) an allergic reaction; type I diabetes; rheumatic fever; celiac disease; encephalitis; oophoritis; primary biliary cirrhosis; insulin-resistant diabetes; autoimmune adrenal insufficiency (addison's disease); acne; acne conglomerates; fulminant acne; autoimmune oophoritis; autoimmune orchitis; autoimmune hemolytic anemia; paroxysmal cold hemoglobinuria; behcet's disease; autoimmune thrombocytopenia; autoimmune neutropenia; pernicious anemia; pure red cell anemia; autoimmune coagulopathy; myasthenia gravis; autoimmune polyneuritis; pemphigus; rheumatic cardioitis; goodpasture's syndrome; post-cardiotomy syndrome; polymyositis; dermatomyositis; irritable bowel syndrome; pancreatitis; gastritis, lichen planus; delayed type hypersensitivity reactions; chronic pulmonary inflammation; alveolitis; pulmonary granuloma; gingivitis; endodontic disease; periodontal disease; allergic pneumonia; pollinating; (ii) an allergic reaction; skin allergy; urticaria; gout; polycystic kidney disease; coldness-imidacloprid associated periodic syndrome (CAPS); moore-weidi syndrome; guillain-barre syndrome; chronic inflammatory demyelinating polyneuropathy; organ or transplant rejection; chronic allograft rejection; acute or chronic graft versus host disease; dermatitis; atopic dermatomyositis; graves' disease; autoimmune (hashimoto) thyroiditis; blistering disorders; vasculitis syndrome; immune complex-mediated vasculitis; bronchitis; cystic fibrosis; pneumonia; pulmonary edema; pulmonary embolism; sarcoidosis; hypertension; emphysema; respiratory failure; acute respiratory distress syndrome; a BENTA disease; or polymyositis.

71. A compound for use according to claim 63, use according to claim 64 or method according to claim 65, wherein the treatment is a treatment of:

inflammatory arthritis (including, for example, rheumatoid arthritis; psoriatic arthritis; systemic lupus erythematosus; juvenile idiopathic arthritis); psoriasis; lupus nephritis; systemic sclerosis; inflammatory bowel disease; ulcerative colitis; crohn's disease; hidradenitis suppurativa; or multiple sclerosis.

72. A compound for use according to claim 63, use according to claim 64 or method according to claim 65, wherein the treatment is a treatment of:

cancer.

73. A compound for use according to claim 63, use according to claim 64 or method according to claim 65, wherein the treatment is a treatment of:

multiple myeloma; lymphoma; leukemia; cancer; or a sarcoma.

74. A compound for use according to claim 63, use according to claim 64 or method according to claim 65, wherein the treatment is a treatment of:

hodgkin lymphoma; non-hodgkin lymphoma; lymphocytic lymphomas; granulocytic lymphoma; monocytic lymphoma; diffuse large B-cell lymphoma (DLBCL); mantle Cell Lymphoma (MCL); follicular cell lymphoma (FL); mucosa-associated lymphoid tissue (MALT) lymphoma; marginal zone lymphoma; t cell lymphoma; marginal zone lymphoma; or burkitt's lymphoma.

75. A compound for use according to claim 63, use according to claim 64 or method according to claim 65, wherein the treatment is a treatment of:

chronic Lymphocytic Leukemia (CLL); acute Myeloid Leukemia (AML); acute Lymphocytic Leukemia (ALL); lymphocytic T cell leukemia; chronic Myelogenous Leukemia (CML); hairy cell leukemia; acute lymphocytic T cell leukemia; acute eosinophilic leukemia; immunoblastic large cell leukemia; megakaryocytic leukemia; acute megakaryocytic leukemia; promyelocytic leukemia; erythroleukemia; or a plasmacytoma.

76. A compound for use according to claim 63, use according to claim 64 or method according to claim 65, wherein the treatment is a treatment of:

colon cancer; breast cancer; ovarian cancer; lung cancer (including, for example, small cell lung cancer and non-small cell lung cancer); prostate cancer; oral or pharyngeal cancer (including, for example, lip cancer, tongue cancer, mouth cancer, throat cancer, pharyngeal cancer, salivary gland cancer, buccal mucosal cancer); esophageal cancer; gastric cancer; small bowel cancer; large bowel cancer; rectal cancer; liver cancer; biliary tract cancer; pancreatic cancer; bone cancer; connective tissue cancer; skin cancer; cervical cancer; uterine cancer; body cancer; endometrial cancer; vulvar cancer; vaginal cancer; testicular cancer; bladder cancer; kidney cancer; cancer of the ureter; cancer of the urethra; umbilical duct cancer; eye cancer; glioma; spinal cord cancer; central nervous system cancer; cancer of the peripheral nervous system; meningeal cancer; thyroid cancer; adrenal cancer; astrocytoma; acoustic neuroma; anaplastic astrocytoma; basal cell carcinoma; a blast cell glioma; choriocarcinoma; chordoma; craniopharyngioma; cutaneous melanoma; cystic carcinoma; an embryonic carcinoma; ependymoma; epithelial cancer; gastric cancer; genitourinary tract cancer; glioblastoma multiforme; head and neck cancer; hemangioblastoma; hepatocellular carcinoma; renal Cell Carcinoma (RCC); liver cancer; large cell carcinoma; medullary thyroid carcinoma; medulloblastoma; meningioma mesothelioma; a myeloma cell; neuroblastoma; oligodendroglioma; epithelial ovarian cancer; papillary carcinoma; papillary adenocarcinoma; paragangliomas; parathyroid tumors; pheochromocytoma; pineal tumor; a plasmacytoma; retinoblastoma; sebaceous gland cancer; seminoma; melanoma; squamous cell carcinoma; sweat gland cancer; a synovial tumor; thyroid cancer; uveal melanoma; or Wilms' tumor.

77. A compound for use according to claim 63, use according to claim 64 or method according to claim 65, wherein the treatment is a treatment of:

colon cancer; breast cancer; ovarian cancer; lung cancer (including, for example, small cell lung cancer and non-small cell lung cancer); prostate cancer; gastric cancer; pancreatic cancer; bone cancer; skin cancer; cervical cancer; uterine cancer; endometrial cancer; testicular cancer; bladder cancer; kidney cancer; eye cancer; liver cancer; glioma; thyroid cancer; adrenal cancer; astrocytoma; acoustic neuroma; anaplastic astrocytoma; cutaneous melanoma; gastric cancer; glioblastoma multiforme; head and neck cancer; hepatocellular carcinoma; renal Cell Carcinoma (RCC); melanoma; or squamous cell carcinoma.

78. A compound for use according to claim 63, use according to claim 64 or method according to claim 65, wherein the treatment is a treatment of:

colon cancer; breast cancer; ovarian cancer; lung cancer (including, for example, small cell lung cancer and non-small cell lung cancer); prostate cancer; pancreatic cancer; bone cancer; liver cancer; glioblastoma multiforme; head and neck cancer; or melanoma.

79. A compound for use according to claim 63, use according to claim 64 or method according to claim 65, wherein the treatment is a treatment of:

(ii) an askin tumor; botryoid sarcoma; chondrosarcoma; an endothelial sarcoma; ewing's sarcoma; malignant vascular endothelioma; malignant schwannoma; osteosarcoma; gastrointestinal stromal tumors (GIST); myxosarcoma; alveolar soft part sarcoma; angiosarcoma; phyllocystic sarcoma; fibrosarcoma of the skin; desmoid tumors; fibroproliferative small round cell tumors; extraosseous chondrosarcoma; osteosarcoma; fibrosarcoma; vascular endothelial cell tumor; angiosarcoma; kaposi's sarcoma; leiomyosarcoma; liposarcoma; lymphangioleiomyosarcoma; lymphatic endothelial sarcoma; lymphosarcoma; malignant peripheral nerve sheath tumor; neurofibrosarcoma; plexiform fibrohistiocytoma; rhabdomyosarcoma; or synovial sarcoma.

80. A compound for use according to claim 63, use according to claim 64 or method according to claim 65, wherein the treatment is a treatment of:

treatment of refractory cancers (including, for example, anti-chemotherapy cancers and anti-radiotherapy cancers); metastatic cancer; transferring; or recurrent cancer.

81. A compound for use according to claim 63, use according to claim 64 or method according to claim 65, wherein the treatment is a treatment of:

A condition mediated by osteoclasts.

82. A compound for use according to claim 63, use according to claim 64 or method according to claim 65, wherein the treatment is a treatment of:

rheumatoid arthritis; osteoporosis; paget's disease; osteopetrosis; osteoarthritis; ectopic bone formation; bone loss associated with endometriosis; adenomyosis of the uterus; bone neoplasia (including, e.g., as a primary tumor or as a metastasis and including, e.g., bone cancer; osteosarcoma; or an osteoma); cancer-associated bone disorders (including, for example, metastatic bone disease associated with, for example, breast cancer, lung cancer, prostate cancer, or multiple myeloma; changes in bone mineralization and density associated with cancer, including, for example, hypercalcemia associated with cancer); bone metastases (including, for example, osteolytic bone metastases); hypercalcemia (including, for example, hypercalcemia associated with cancer, hypercalcemia resulting from conditions associated with increased bone resorption (including, for example, hypercalcemia resulting from vitamin D poisoning, primary or tertiary hyperparathyroidism, immobilization, or sarcoidosis), or aseptic loosening of prosthetic implants (e.g., artificial joints, such as the knee, hip, etc.).

83. A compound for use according to claim 63, use according to claim 64 or method according to claim 65, wherein the treatment is a treatment of:

rheumatoid arthritis; osteoporosis; bone neoplasia (including, e.g., as a primary tumor or as a metastasis and including, e.g., bone cancer; osteosarcoma; or an osteoma); cancer-related bone disorders (including, for example, metastatic bone disease associated with breast cancer, lung cancer, prostate cancer, or multiple myeloma; changes in bone mineralization and density associated with cancer, including, for example, hypercalcemia associated with cancer); or bone metastases (including, for example, osteolytic bone metastases).

Technical Field

The present invention relates generally to the field of therapeutic compounds. More particularly, the present invention relates to certain N-acyl- {4- [ (4-aryl-phenyl) sulfonylmethyl ] piperidine } compounds (collectively referred to herein as NASMP compounds), which are useful, for example, in the treatment of disorders (e.g., diseases) including, for example, multiple myeloma, diffuse large B-cell lymphoma, acute myelogenous leukemia, eosinophilic leukemia, glioblastoma, melanoma, ovarian cancer, anti-chemotherapy cancer, anti-radiation cancer, inflammatory arthritis, rheumatoid arthritis, psoriatic arthritis, psoriasis, ulcerative colitis, Crohn's disease, Systemic Lupus Erythematosus (SLE), lupus nephritis, asthma, Chronic Obstructive Pulmonary Disease (COPD), hidradenitis suppurativa, autoimmune hepatitis, and the like. The invention also relates to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, for example in therapy.

Background

Numerous publications are cited herein in order to more fully describe and disclose the present invention and the state of the art to which the invention pertains. Each of these publications in its entirety is hereby incorporated by reference into the present disclosure to the same extent as if each individual publication was specifically and individually indicated to be incorporated by reference.

Throughout the specification including the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

It must be noted that, as used in the specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to a "pharmaceutical carrier" includes mixtures of two or more such carriers, and the like.

Ranges are generally expressed herein as from "about" one particular value, and/or to "about" another particular value. When such a range is expressed, another embodiment includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent "about," it will be understood that the particular value forms another embodiment.

This disclosure includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art or relevant to the presently claimed invention, nor is it an admission that any publication specifically or implicitly referenced is prior art.

Cell metabolism

Cellular metabolism is a complex set of biochemical reaction sequences that occur in the cells of an organism to sustain life. Each reaction sequence is called a metabolic pathway, and these pathways act synergistically to provide energy, synthesize new molecules, and break down and remove other molecules within the cell. One key metabolic pathway is known as oxidative phosphorylation, a process by which electrons transfer through carriers known as electron transport complexes to form energy in the form of Adenosine Triphosphate (ATP). Other examples of metabolic pathways include glycolysis (the process by which glucose breaks down to release ATP) and beta oxidation (the process by which fatty acids break down).

Glycolysis occurs in the cytoplasm. Glucose (a substrate for glycolysis) is converted to pyruvate through a series of ten enzyme-catalyzed reactions. This pyruvate is in turn converted to lactate, the final product of glycolysis. ATP is formed directly by phosphate transfer from the substrate to ATP or substrate phosphorylation. Some of the pyruvate enters the tricarboxylic acid (TCA) cycle, while most of the final product lactate is flushed out of the cells. Oxidative phosphorylation occurs in the mitochondria of cells. Glutamine, glucose or fatty acids are the suppliers of the electron transport chain, and ATP is formed by a series of redox reactions with oxygen as the final electron acceptor. A series of redox reactions occur through four complexes of electron transport chains, which then create an electrochemical gradient in the inner mitochondrial membrane. The protons are returned to the mitochondrial matrix by ATP synthase, and this process is coupled with ATP synthesis. A total of 36mol ATP is produced per 1mol glucose.

The metabolic characteristics of certain cell types can vary widely. For example, energy production by cancer cells is abnormally biased towards aerobic glycolysis (a process known as the Warburg effect), and shows increased fatty acid synthesis and increased rates of amino acid glutamine metabolism. Additionally, changes in cancer cell metabolism can make it resistant to treatment, and some studies have shown that chemoresistance is driven at least in part by mitochondrial metabolism and oxidative phosphorylation, while high levels of ATP in cancer cells can lead to increased efflux of chemotherapeutic agents and promote hypoxia-related drug resistance.

Similar to cancer cells, immune cells exhibit metabolic changes depending on their activation state and the stimulation signals they receive. The field of immune metabolism is the study of the interface between immunology and metabolism, as it relates to the management of immune cell function, and their role in chronic inflammatory diseases and cancer, among others.

Chronic inflammatory diseases

Inflammation is a tissue immune response due to physical injury. Acute inflammation is a normal protective response of the body to protect and heal after injury or infection, characterized by heat, swelling and redness of the injured area. However, if inflammation persists for a long period of time, it becomes chronic. Chronic inflammation is a hallmark and contributing factor in a range of disease states including rheumatoid arthritis, inflammatory bowel disease, systemic lupus erythematosus, multiple sclerosis and psoriasis.

The inflammatory process is complex and involves a biological cascade of molecular and cellular signals that alter physiological responses. At the site of injury, the cells release molecular signals such as cytokines and interleukins, causing many changes in the affected area, including vasodilation, increased blood flow, increased vascular permeability, leukocyte (white blood cell) invasion, and fluid exudation containing proteins such as immunoglobulins (antibodies). The inflammatory cascade involves several different types of leukocytes, including granulocytes, monocytes and lymphocytes. However, chronic inflammation is primarily mediated by monocytes and long-lived macrophages; monocytes mature into macrophages once they leave the blood stream and enter the tissue. Macrophages phagocytose and digest microorganisms, foreign invaders, and senescent cells, and macrophages release several different chemical mediators, including tumor necrosis factor-alpha (TNF α), interleukins (e.g., IL-1, IL-6, IL-12, and IL-23), and prostaglandins that sustain inflammatory responses. In the later stages, other cells, including lymphocytes, invade the affected tissue. Recent evidence suggests that many aberrant immune responses occur as a result of an interruption in metabolic processes, and that altering cellular metabolism may enhance or reduce immune responses. Thus, alterations in monocyte, macrophage and lymphocyte metabolism (immune metabolism) are critical to driving the disease.

Thus, there is a common pathological basis for a variety of chronic inflammatory diseases. In addition, the characteristics of chronic inflammation are also observed in other diseases, including cancer and metabolic diseases, such as obesity, atherosclerosis, and diabetes.

One of the most common chronic inflammatory disorders is the disorder Rheumatoid Arthritis (RA), which affects up to 2% of the population worldwide. Although it is a complex disease, there are many physiological, cellular, and biochemical factors associated with the progression of RA that are common in a range of other diseases, including those with autoimmune (e.g., multiple sclerosis), inflammatory (e.g., atherosclerosis and cancer), bone loss (e.g., osteoporosis), and proliferative (e.g., hematologic malignancies) components. This makes the understanding of RA not only important for the study of a wider range of diseases, but also suggests that agents that act by modifying these common processes may have utility beyond RA. The latter is demonstrated by clinical practice, where RA drugs have proven to have broad utility in a variety of other conditions.

Rheumatoid arthritis and related autoimmune/inflammatory diseases

Rheumatoid Arthritis (RA) is an autoimmune disorder characterized by chronic inflammation of the synovial lining of multiple joints with progressive joint degeneration. RA typically affects the joints of the wrist and hand, and may also affect the elbows, shoulders, hips, neck, and knees, resulting in severe pain and disability (see, e.g., Scott et al, 2010). The World Health Organization (WHO) updates estimates of global disease burden in 2010, 2370 million people suffer from RA, with rising incidence due to the association between the disorder and age increase.

As with all autoimmune disorders, the exact cause of RA remains unclear, although possible triggers include decreased self-tolerance, abnormal response to environmental factors, infectious agents, and hormonal stimulation (see, e.g., Klareskog et al, 2006; Firestein et al, 2005). The major features of the disorder are innate and adaptive immune dysregulation in which proinflammatory and anti-inflammatory cytokines are imbalanced, the balance between osteoclast-mediated degradation and osteoblast-mediated deposition in the bone marrow cavity is altered (see, e.g., Kleyer et al, 2014; Jung et al, 2014).

At the cellular level, the progression of RA usually begins with T cells infiltrating the synovial lining of the affected joint; this then results in the activation of monocytes, macrophages and synovial fibroblasts by intercellular contact, and the subsequent release of various cytokines, including tumor necrosis factor-alpha (TNF α) and proinflammatory interleukins such as IL-1, IL-6, IL-12 and IL-23 (see, e.g., Astry et al, 2011). These pro-inflammatory cytokines then help to coordinate several complex signaling cascades, including NF κ B, Interferon Regulatory Factor (IRF), Toll-like receptors (TLRs), and Jak/STAT pathways (see, e.g., malemed et al, 2010), which result in the induction of genes encoding various products that propagate inflammatory responses and also promote tissue destruction. These products include tissue degrading enzymes such as collagenases, Matrix Metalloproteinases (MMPs), cathepsins, and other proinflammatory factors such as selectins, integrins, leukotrienes, prostaglandins, chemokines, and other cytokines (see, e.g., McInnes et al, 2011; Chimenti et al, 2015). In addition, these cells also increase MMP production, leading to degradation of extracellular matrix and loss of articular cartilage (see, e.g., Sun, 2010), a process that also involves a special class of cells called osteoclasts and factors called receptor activators of nuclear factor kappa-B ligand (RANKL) (see, e.g., Takayanagi, 2009).

RANKL is an important factor in osteoclastogenesis, and upregulation of RANKL production leads to increased osteoclast differentiation and ultimately to bone destruction (see, e.g., Long et al, 2012). The inflammatory response of RA results in the accumulation of lymphocytes, dendritic cells and macrophages, all of which operate locally to produce cytokines and other proinflammatory mediators, such as TNF α and IL-6, which further potentiate the effect of RANKL on bone destruction. In addition, the inflammatory cascade leads to synovial cell proliferation (see, e.g., Takayanagi, 2009), which in turn leads to synovial thickening and vascularization to form destructive and aggressive tissues called pannus. The pannus contains osteoclasts that destroy bone and metalloproteinases that are involved in cartilage destruction. Therefore, the RANKL axis is crucial for the progression and pathology of RA as well as the bone immune system (the interaction between the immune system and the bone system), which is the core of the pathology of many different disease states.

Role of immune metabolism in RA

All cells produce Adenosine Triphosphate (ATP), a high-energy molecule that serves as a fuel, and synthesize macromolecules to maintain their basic cellular functions, whether they are active, replicating, or quiescent (see, e.g., Spies et al, 2012). These bioenergy requirements are met by intracellular interrelated metabolic pathways: glycolysis (the first step of glucose breakdown), the tricarboxylic acid cycle (a series of reactions that release stored energy from carbohydrates, fats and proteins), and oxidative phosphorylation (the process of forming ATP by electron transfer). Changes in these pathways drive effector functions of immune cells from lymphocytes to monocytes as well as macrophages and dendritic cells, and can also regulate cell fate.

In chronic inflammatory diseases including RA, activation of the immune system consumes a very large amount of energy (up to 2,000 kJ/day) (see, e.g., Straub et al, 2010). The immune system uses this energy, at least in part, to maintain a chronic inflammatory state in response to environmental signals (see, e.g., procaccii et al, 2012; Nutsch et al, 2011), and thus the interaction between immunology and metabolism plays an important role in the pathophysiology of chronic inflammatory diseases (see, e.g., Perl, 2017; Ganeshan et al, 2014).

Several metabolic changes in cells involved in inflammation are seen in immune cells of RA (see, e.g., Weyand et al, 2017 a). Chronic stimulation and synovial microenvironment alters T cell and macrophage metabolism in RA. For example, T cells from RA patients show reduced expression of 6-phosphofructose 2-kinase/fructose-2, 6-bisphosphatase 3(PFKFB3) (an enzyme involved in ATP production and autophagy) (see, e.g., Yang et al, 2013), while macrophages from RA patients produce higher levels of ATP than cells from healthy individuals (see, e.g., Weyand et al, 2017 b). In addition to direct changes in cells, the hypoxic environment in RA synovium (see, e.g., Fearon et al, 2016) causes chronic mitochondrial hyperpolarization, which is also seen in Systemic Lupus Erythematosus (SLE) and fibroblast-like synoviocytes from RA patients; there is a shift to glycolysis compared to cells from non-inflammatory environments (see, e.g., Garcia-Carbonnel et al, 2016). Therefore, agents that modulate ATP or alter immune cell metabolism have great potential for use in the treatment of chronic inflammatory diseases such as RA, SLE, Inflammatory Bowel Disease (IBD), psoriasis and atherosclerosis.

Cell metabolism and cancer

Cellular energy in the form of ATP is produced by two major pathways: mitochondrial oxidative phosphorylation and cytoplasmic glycolysis. In normal cells, glycolysis is followed by oxidation of pyruvate using the oxidative phosphorylation mechanism of mitochondria, and this is the major pathway for ATP production. However, in cancer cells, glycolysis is up-regulated and lactate is fermented in the cytoplasm of the cell, a process known as the Warburg effect. Thus, reprogrammed metabolism is a hallmark of cancer and contributes to the growth and proliferation of cells under stress conditions.

Mitochondrial metabolism is also important for the production of building blocks required for cancer cell proliferation, and cancer cells also require mitochondrial oxidative metabolism to maintain their redox balance. Most cancer cells display functional mitochondria and are capable of producing ATP via mitochondrial metabolism (see, e.g., Koppenol, 2011). Depending on the cellular environment, mitochondria contribute significantly to the production of cellular Reactive Oxygen Species (ROS) as a natural byproduct of mitochondrial ATP production. The formation of ROS occurs due to incomplete reduction of molecular oxygen, and in cancer cells, ROS have been shown to promote tumor development and progression by inducing oncogenic signals, genetic instability, and DNA mutations (see, e.g., Weinberg et al, 2010). However, cytotoxicity occurs when the production of ROS exceeds the ability of intracellular ROS detoxification systems. Therefore, cancer cells must tightly control their metabolic mechanisms to maintain a balance between ROS generation and clearance.

Thus, alterations in cellular and mitochondrial metabolism are critical to tumor growth and proliferation. Indeed, increased mitochondrial biogenesis and associated oxidative phosphorylation have been demonstrated to promote tumor metastasis (see, e.g., LeBleu et al, 2014), while decreasing oxidative phosphorylation has also been proposed as a means of targeting cancer stem cells (see, e.g., Fiorillo et al, 2016). The data also show that targeting components of the mitochondrial electron transport chain can have anti-cancer effects. For example, inhibition of tumorigenesis by complex I of antidiabetic metformin (see, e.g., Evans et al, 2005; Pollak et al, 2014; Wheaton et al, 2014; Bridges et al, 2014) while novel small electron transport molecule inhibitors also show antitumor activity in cancer xenograft models (see, e.g., Ellinghaus et al, 2013). Thus, altering cellular metabolism is becoming a means to prevent cancer growth and progression as well as to overcome resistance to chemotherapy and prevent metastasis.

Bone immune system and bone disorders

The bone immune system is a term for the combination and related interaction between the immune system and the skeletal system.

Under normal physiological conditions, the skeletal system provides support, movement, protection for vital organs, and provides a mineral reservoir for calcium and phosphate. To achieve and accommodate these functions, bone is in a state of dynamic equilibrium characterized by continuous osteoclast-mediated bone resorption and osteoblast-mediated bone deposition (see, e.g., karsteny et al, 2002). This biological process is known as bone "remodeling" and occurs in a manner that binds to osteoblasts that produce key osteoclast differentiation factors (including RANKL described above) and osteoclasts that promote bone formation by producing osteoblast mediators upon degradation of bone.

Both innate and adaptive immune cells act on osteoclasts and osteoblasts through various cell surface and secretory mediators (see, e.g., Takayanagi, 2009). Activation of the RANKL Receptor (RANK) on osteoclast precursors initiates a series of transcriptional changes that lead to the expression of mechanisms required for osteoclast formation and bone resorption, including attachment to bone, acid secretion, and molecules required for proteolysis. Many transcription factors important for osteoclast differentiation are key regulators of the immune response, such as NF κ B and nuclear factor c1 of activated T cells (NFATc1), and this process is also enhanced by factors involved in inflammation, such as TNF α and IL-6.

In addition to a key role in the progression and pathogenesis of RA, the bone immune system also plays a key role in many other diseases including osteoporosis and other bone disorders and cancer (see, e.g., Dallas et al, 2011).

Osteoporosis is a common disease characterized by decreased bone density, degeneration of bone tissue, and increased risk of fracture. Many factors contribute to the pathogenesis of osteoporosis, including poor diet, lack of exercise, smoking, and excessive alcohol consumption. Osteoporosis also occurs in association with inflammatory diseases such as rheumatoid arthritis, endocrine diseases such as thyrotoxicosis, and certain drug therapies such as glucocorticoid therapy. Indeed, osteoporosis-related brittle fractures represent one of the most important complications that patients with rheumatic diseases (such as RA, systemic lupus erythematosus and ankylosing spondylitis) can develop.

Paget's disease of bone is a common, unexplained condition characterized by increased bone turnover and disturbance of bone remodeling, areas of increased osteoclast and osteoblast activity. Although paget's bone is generally denser than normal bone, the abnormal structure results in mechanical weakening of the bone, resulting in bone deformity and increased susceptibility to pathological fractures.

IL-6, TNF α, and RANKL signals have been shown to play a major role in osteoclast overactivity and subsequent increased bone loss (see, e.g., Tanaka et al, 2003; Roodman, 2006). Monoclonal antibody AMG-162 (which has passed through anti-RANKL: (Amgen), and through increasing evidence that anti-TNF α and anti-IL-6 therapies also prevent bone loss in arthritic diseases, validating the use of drugs that affect these pathways (see, e.g., Ogata et al, 2012; billiau, 2010).

Bone immune system and cancer

Many types of cancer affect bone. Cancer-related bone diseases can manifest as the occurrence of hypercalcemia or the development of osteolytic and/or sclerosing metastases. Increased osteoclastic bone resorption plays a key role in the pathogenesis of both of these disorders. Although almost any cancer can be complicated by bone metastases, the most common sources are multiple myeloma, breast and prostate cancer. The most common tumors associated with hypercalcemia are multiple myeloma, breast cancer and lung cancer.

As mentioned above, RANK/RANKL signaling is critical for osteoclast formation and bone resorption that occurs during skeletal remodeling. While physiological levels of RANK/RANKL signaling stimulate proliferation and cell survival of mammary epithelial cells, abnormal RANK/RANKL signaling in these tissues has recently been shown to affect the occurrence and progression of mammary tumorigenesis, and the use of denosumab (r) has been shownAmgen) blocking RANKL signaling is effective in preventing secondary complications of bone metastasis (such as pathological fractures) and hypercalcemia in breast cancer patients (see, e.g., Steger et al, 2011).

Therapies that block RANK/RANKL signaling may also reduce the ability to promote bone cancer metastasis to bone. It has been demonstrated that the chemotactic response is induced in human epithelial tumor cells and melanoma cells by RANK signalling on their surface, whereas therapeutic treatment of mice with osteoprotegerin (neutralizing RANKL receptor RANK) significantly reduces the tumor burden in bone, but not in other organs, in a mouse model of melanoma metastasis.

In addition to the role of RANKL in cancer, there is increasing evidence that activation of nfkb by molecules such as TNF α may play a major role in the promotion and progression of hematologic malignancies such as myelomas and lymphomas, and solid tumors such as breast, prostate and lung cancers (see, e.g., Baud et al, 2009). There is also an increasing awareness of the role and importance of inflammation and the bone immune system in cancer and in the development of resistance to radiation and chemotherapeutic agents. Furthermore, inflammation has been shown to be actually one of the essential features of cancer (see, e.g., Mantovani, 2009). Therefore, improving the efficacy of anti-cancer treatments by preventing NF κ B activation is a promising strategy to augment existing treatment regimens, and is currently under investigation, most notably for the treatment of multiple myeloma.

Defects in the normal apoptotic pathway are also associated with the development and progression of tumor cell growth and inflammation. Apoptosis (programmed cell death) plays a key role in removing abnormal cells; defects in the signaling cascade, which often lead to their induction, play a key role in tumorigenesis. Radiation therapy and many chemotherapeutic agents act by causing cell damage, which typically induces apoptosis; thus, defects in the pathway also reduce the effectiveness of such agents. The most important effector molecule in the signaling pathway leading to apoptosis is called caspase, which can be triggered by a number of stimuli, including TNF α binding to its receptor. Mutations in the gene encoding caspase are found in many tumor types, including gastric, breast, renal cell and cervical cancers, as well as the common T-cell lymphoblastic and basal cell amelogenesis (see, e.g., philichenkov et al, 2004). Compounds that activate caspases and thus sensitize cells to apoptosis would be very effective as a single agent or as cancer therapy in enhancing the effectiveness of existing cancer chemotherapy and radiation therapy.

Agents for regulating cellular and immune metabolism, preventing inflammation and altering the bone immune system

The present inventors have identified novel compounds, which, for example, modulate cellular and immune metabolism, prevent inflammation and alter the bone immune system, and thus are useful in the treatment of the corresponding disorders as described herein.

Without wishing to be bound by any particular theory, the inventors believe that this effect may have an effect on inflammatory signaling by involving mechanisms that regulate cellular and immune cell metabolism by reducing cellular ATP.

Known compounds

Greig et al, 2010a describes certain biphenyl-4-sulfonic acid amides for the treatment of: inflammation and/or joint destruction and/or bone loss; disorders mediated by excessive and/or inappropriate and/or prolonged activation of the immune system; inflammatory and autoimmune disorders, such as rheumatoid arthritis, psoriasis, psoriatic arthritis, Chronic Obstructive Pulmonary Disease (COPD), atherosclerosis, inflammatory bowel disease and ankylosing spondylitis; disorders associated with bone loss, such as bone loss associated with excessive osteoclast activity in rheumatoid arthritis, osteoporosis, cancer-related bone disease, and paget's disease; and cancers, such as hematologic malignancies and solid tumors. Examples of compounds shown therein include the following:

Patel et al, 2014 and Patel et al, 2016 describe certain substituted N- (4-hydroxy-4-methyl-cyclohexyl) -4-phenyl-benzenesulfonamide and N- (4-hydroxy-4-methyl-cyclohexyl) -4- (2-pyridyl) benzenesulfonamide compounds (e.g., HMC-C-01, shown below) for use in the treatment of: inflammation and/or joint destruction and/or bone loss; disorders mediated by excessive and/or inappropriate and/or prolonged activation of the immune system; inflammatory and autoimmune disorders, such as rheumatoid arthritis; psoriasis; psoriatic arthritis; chronic Obstructive Pulmonary Disease (COPD); asthma; atherosclerosis; inflammatory bowel disease; ankylosing spondylitis; multiple sclerosis; systemic lupus erythematosus; sicca syndrome; disorders associated with bone loss, such as bone loss associated with excessive osteoclast activity in rheumatoid arthritis, osteoporosis, cancer-related bone disease or paget's disease; cancers, such as hematological malignancies, such as multiple myeloma, leukemia or lymphoma, or solid tumor cancers, such as bladder cancer, breast cancer (female and/or male), colon cancer, renal cell carcinoma, kidney cancer, lung cancer, pancreatic cancer, gastric cancer, prostate cancer, brain cancer, skin cancer, thyroid cancer, basal cell ameloblastoma or melanoma; disorders associated with fibrosis, such as Systemic sclerosis or scleroderma; or rare vasculitis, such as Behcet's disease: (disease)。

Riemer et al, 1996, describe certain benzylpiperidine derivatives of the formula which are said to be useful in the treatment of psychotic disorders caused by impairment of the dopamine system.

Duan et al, 2003, describe certain barbituric acid derivatives of the formula which are said to be useful as TACE inhibitors.

Li et al, 2006 describe certain compounds of the formula which are said to be inhibitors of 11-beta hydroxysteroid dehydrogenase type I (11 beta-HSD 1).

Hayashi et al, 2007 describes certain compounds of the formula which are said to be useful as MMP-13 selective inhibitors.

Moore et al, 2008 describes certain compounds of the formula which are said to be useful as modulators of secreted frizzled related protein-1 for the treatment of osteoporosis, arthritis, COPD, and the like.

Fang et al, 2008, describe certain compounds of the formula which are said to be useful in the treatment of metabolic disorders such as diabetes (type I and type II), obesity, and related disorders.

Horiuchi et al, 2009, describe certain compounds of the formula which are said to be useful in the treatment of diabetes.

Rock et al, 2011 describes certain compounds (see table 1, page 8566 therein) which are said to be useful as androgen receptor inhibitors for the treatment of prostate cancer.

Lee et al, 2003, describe certain piperidine derivatives of the formula which are said to be useful as GPR119 agonists.

Bilotta et al, 2014 describe certain compounds of the formula which are said to be useful in the treatment of HCV infection.

Novel compounds with improved properties

In addition to having excellent biological properties, e.g., similar to or superior to related sulfonamide compounds (e.g., as described in Greig et al, 2010a, Patel et al, 2014, and Patel et al, 2016), the NASMP compounds described herein have the additional advantage of forming little or no undesirable sulfonamide metabolites.

For example, as demonstrated by the data provided herein, the related sulfonamide compounds (e.g., reference compound HMC-C-01-a) produce biaryl sulfonamide metabolites (e.g., MET-001) with long half-lives and thus persist in the circulation. Such biaryl sulfonamide metabolites can induce metabolism in rats, complicating rodent toxicity assessments, and in turn may impact the exploitability of the compounds for human use. Thus, compounds with a lower propensity to form biaryl sulfonamide metabolites have greater potential for exploitation by humans.

As demonstrated by the data provided herein, NASMP compounds exhibit a greatly reduced propensity to form biaryl sulfonamide metabolites, and thus have a greatly increased suitability for development for human use, as compared to known sulfonamide compounds.

In addition, the NASMP compounds described herein have other advantageous properties that are the same as, and generally better than, the properties of the related sulfonamide compounds, including, for example, improved metabolism and solubility.

If the drug is to be used clinically, it must have suitable pharmacokinetic characteristics. It must exhibit sufficient absorption to allow administration to a human at a level suitable for acting on the therapeutic target. Solubility is a key factor in driving absorption of compounds from the gastrointestinal tract into the circulation. In addition, the drug must have sufficient distribution and metabolic characteristics to ensure that administration can occur at regular intervals, for example once or twice a day.

The NASMP compounds described herein show good solubility and thus have a good tendency to be absorbed from the gastrointestinal tract.

The NASMP compounds described herein also exhibit significant advantages in their metabolic stability in vitro and reduced propensity to form metabolism-induced biaryl sulfonamide metabolites (e.g., similar to MET-001).

Optimization of drug metabolism and pharmacokinetic properties (absorption, distribution, metabolism, excretion-ADME) is a development hurdle of equal challenge and importance compared to optimization of pharmacodynamic (drug action on the body) and safety (adverse effects) properties. The NASMP compounds described herein offer significant advantages (as compared to known compounds) as oral therapeutics by improving their metabolic and pharmacokinetic properties with little or no loss of potency towards biological targets.

As described herein, the NASMP compounds described herein combine desirable features of agents for treating, for example, autoimmune/inflammatory disorders and cancer.

Disclosure of Invention

One aspect of the present invention relates to certain substituted N-acyl- {4- [ (4-aryl-phenyl) sulfonylmethyl ] piperidine } compounds (collectively referred to herein as NASMP compounds), as described herein.

Another aspect of the invention relates to a composition (e.g., a pharmaceutical composition) comprising a NASMP compound as described herein and a carrier, diluent, or excipient (e.g., a pharmaceutically acceptable carrier, diluent, or excipient).

Another aspect of the invention relates to a method of making a composition (e.g., a pharmaceutical composition) comprising the step of admixing a NASMP compound as described herein and a carrier, diluent, or excipient (e.g., a pharmaceutically acceptable carrier, diluent, or excipient).

Another aspect of the invention relates to a NASMP compound as described herein for use in a method of treatment of the human or animal body by therapy, for example for use in a method of treatment of a condition (e.g., a disease) as described herein.

Another aspect of the invention relates to the use of a NASMP compound as described herein in the manufacture of a medicament for treating, e.g., treating, a condition (e.g., a disease) as described herein.

Another aspect of the invention relates to a method of treating a condition (e.g., disease), e.g., as described herein, comprising administering to a patient in need of treatment a therapeutically effective amount of a NASMP compound as described herein, preferably in the form of a pharmaceutical composition.

Another aspect of the invention relates to a kit comprising (a) a NASMP compound as described herein, preferably as a pharmaceutical composition and provided in a suitable container and/or in a suitable package; and (b) instructions for use, such as written instructions on how to administer the compound.

Another aspect of the invention relates to a NASMP compound obtainable by a synthetic method as described herein or a method comprising a synthetic method as described herein.

Another aspect of the invention relates to a NASMP compound obtained by a synthetic method as described herein or a method comprising a synthetic method as described herein.

Another aspect of the present invention relates to novel intermediates as described herein which are suitable for use in the synthetic processes described herein.

Another aspect of the present invention relates to the use of such novel intermediates as described herein in the synthetic processes described herein.

As will be appreciated by those skilled in the art, features and preferred embodiments of one aspect of the invention will also relate to other aspects of the invention.

Drawings

FIG. 1 is a graph of the mean arthritis index of the compound of the invention NASMP-01-A administered by oral gavage at 10 mg/kg/day (open circles) and control (closed circles) as a function of time (day of administration).

FIG. 2 is a graph of mean arthritis index as a function of time (day of administration) for the reference compound CHMSA-01-A administered by oral gavage at 10 mg/kg/day (open circles) and control (closed circles).

FIG. 3 is a graph of mean arthritis index as a function of time (day of administration) for test reference CHMSA-03-A administered by oral gavage at 10 mg/kg/day (open circles) and control (closed circles).

Figure 4 is a graph of the arthritis index as a function of time (day of administration) for reference compound ABD899 administered with the drug etanercept (triangle) on the market at 10 mg/kg/day (open circles), control (closed circles) and positive control.

FIG. 5 is a graph of the arthritic index of the reference compound HMC-C-01-A as a function of time (day of administration) administered at 10 mg/kg/day (open circles) and control (closed circles).

Detailed Description

Compound (I)

One aspect of the present invention relates to certain substituted N-acyl- {4- [ (4-aryl-phenyl) sulfonylmethyl ] piperidine } compounds, which relate to the following biphenyl and pyridyl-phenyl compounds:

accordingly, one aspect of the present invention is a compound of the formula or a pharmaceutically acceptable salt or solvate thereof, wherein ═ X-, -R —)¹、-R²、-R³、-R⁴、-R^A、-R^BM and N are as defined herein (for convenience, collectively referred to herein as "N-acyl- {4- [ (4-aryl-phenyl) sulfonylmethyl]Piperidine } compounds "and" NASMP compounds "):

piperidine ring

Unless otherwise indicated, all relative orientations of substituents on the piperidine ring and all conformations of the piperidine ring ("chair", "boat", "twisted", etc.) are intended to be encompassed by reference to compounds not specified to a particular orientation and/or conformation.

By linking the nitrogen atom of the piperidine ring to C (═ O) R⁴The bonds of the groups may be rotation-constrained and rotamers may result. Unless otherwise indicated, all such rotamers are intended to be encompassed in reference to compounds not designated as a particular rotamer.

^{1 2}Configuration of-R and carbon to which-R is attached

Note that according to the group-R¹and-R²May be chiral and may therefore be in either the (R) or (S) configuration.

Unless otherwise indicated, all such configurations are intended to be encompassed by reference to compounds not specifying a particular configuration.

A compound of one configuration may be indicated as follows:

compounds of other configurations may be indicated as follows:

other substituents on the piperidine ring

For the avoidance of doubt, it is intended to exclude from R³(which may be-H) and-C (═ O) R⁴In addition, the piperidine ring has no other non-hydrogen substituents.

Conformation of biaryl group

Note that according to the "m" group-R^AThe group "n" R^BAnd X, there may be free rotation about a single bond connecting the two aryl groups.

For the avoidance of doubt, it is intended to encompass all such rotational conformations (i.e. different rotations around a single bond connecting two aryl groups). For example, the following formula is intended to be equivalent and represents the same group:

detailed description of the preferred embodiments

Some embodiments of the invention include the following:

(1) a compound of the formula:

or a pharmaceutically acceptable salt or solvate thereof;

wherein:

-X is independently-CH or-N;

"m" is independently 0, 1, 2 or 3;

Each of-R^AIndependently is-F, -Cl, -R^AC、-R^AFor-CN;

-R^ACindependently saturated straight or branched chain C_1-3An alkyl group;

-R^AFindependently saturated straight or branched chain C_1-3A fluoroalkyl group;

"n" is independently 0, 1 or 2;

each of-R^BIndependently is-F, -Cl, -R^BC、-R^BFor-CN;

-R^BCindependently saturated straight or branched chain C_1-3An alkyl group;

-R^BFindependently saturated straight or branched chain C_1-3A fluoroalkyl group;

-R¹independently is-H or-R^1X；

-R^1XIndependently is-F, -R^1Cor-R^1F；

-R^1CIndependently saturated straight or branched chain C_1-3An alkyl group;

-R^1Findependently saturated straight or branched chain C_1-3A fluoroalkyl group;

-R²independently is-H or-R^2X；

-R^2XIndependently is-F, -R^2Cor-R^2F；

-R^2CIndependently saturated straight or branched chain C_1-3An alkyl group;

-R^2Findependently saturated straight or branched chain C_1-3A fluoroalkyl group;

or-R¹and-R²Together with the carbon atom to which they are attached form saturated C_3-6A cycloalkyl group;

-R³independently is-H or-R^3X；

-R^3XIndependently is-R^3Cor-R^3F；

-R^3CIndependently saturated straight or branched chain C_1-3An alkyl group;

-R^3Findependently saturated straight or branched chain C_1-3A fluoroalkyl group;

-R⁴independently is-R^4C、-R^4CCor-N (R)^4N1)(R^4N2)；

-R^4CIndependently saturated straight or branched chain C_1-6An alkyl group;

-R^4CCindependently saturated C_3-6A cycloalkyl group;

-R^4N1independently is-H or-R^4N1C；

-R^4N1CIndependently saturated straight or branched chain C_1-4An alkyl group;

-R^4N2independently is-H or-R ^4N2C(ii) a And is

-R^4N2CIndependently saturated straight or branched chain C_1-4An alkyl group.

or-N (R)^4N1)(R^4N2) Independently azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl, and optionally saturated with one or more linear or branched C_1-4Alkyl substitution.

Unless otherwise indicated, where a compound having one or more chiral centers and possibly two or more stereoisomers is shown or described, all such stereoisomers are disclosed and encompassed individually (e.g., as separated from one or more other stereoisomers) and as mixtures (e.g., as equimolar or non-equimolar mixtures of two or more stereoisomers). For example, where a compound has one chiral center, each of the (R) and (S) enantiomers is disclosed and encompassed individually (e.g., as separated from the other enantiomer) and as a mixture (e.g., as an equimolar or non-equimolar mixture of the two enantiomers), unless otherwise specified.

For the avoidance of doubt, when-X ═ is-CH ═ and "m" is nonzero, then-X ═ can be-C (R)^A)＝。

The term "saturated straight or branched chain C_1-3Alkyl "means-CH ₃(methyl), -CH₂CH₃(ethyl), -CH₂CH₂CH₃(n-propyl) and-CH (CH)₃)₂(isopropyl group).

The term "saturated straight or branched chain C_1-4Alkyl "additionally includes-CH₂CH₂CH₂CH₃(n-butyl), -CH₂CH(CH₃)₂(isobutyl), -CH (CH)₃)CH₂CH₃(sec-butyl) and-C (CH)₃)₃(tert-butyl).

The term "saturated straight or branched chain C_1-6Alkyl "additionally includes, for example, -CH₂CH₂CH₂CH₂CH₃(n-pentyl), -CH₂CH₂CH(CH₃)₂(isopentyl), -CH₂CH₂CH₂CH₂CH₂CH₃(n-hexyl), -CH₂CH₂CH₂CH(CH₃)₂(isohexyl) and the like.

The term "saturated straight or branched chain C_1-3Fluoroalkyl "means a saturated straight or branched chain C substituted with one or more fluoro groups_1-3An alkyl group. Thus, C_1-3Fluoroalkyl groups include, for example, -CF₃、-CH₂F、-CHF₂、-CH₂CF₃、-CH₂CH₂F, and the like.

The term "saturated C_3-6Cycloalkyl "means cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

Group ═ X-

(2) The compound according to (1), wherein-X-is-CH.

(3) The compound according to (1), wherein-X-is-N.

Index "m"

(4) The compound according to any one of (1) to (3), wherein "m" is independently 0, 1 or 2.

(5) The compound according to any one of (1) to (3), wherein "m" is 1 or 2 or 3.

(6) The compound according to any one of (1) to (3), wherein "m" is 1 or 2.

(7) The compound according to any one of (1) to (3), wherein "m" is 1.

(8) The compound according to any one of (1) to (3), wherein "m" is 2.

(9) The compound according to any one of (1) to (3), wherein "m" is 3.

^Agroup-R

(10) The compound according to any one of (1) to (9), wherein each-R^AAnd, if present, is independently-F, -Cl or-CN.

(11) The compound according to any one of (1) to (9), wherein each-R^AAnd if present, is-F.

(12) The compound according to any one of (1) to (9), wherein each-R^AAnd, if present, is-Cl.

^ACgroup-R

(13) The compound according to any one of (1) to (12), wherein each-R^ACIf present, is-CH₃。

^AFgroup-R

(14) The compound according to any one of (1) to (13), wherein each-R^AFIf present, is-CF₃。

Index "n"

(15) The compound according to any one of (1) to (14), wherein "n" is independently 1 or 2.

(16) The compound according to any one of (1) to (14), wherein "n" is 0.

(17) The compound according to any one of (1) to (14), wherein "n" is 1.

(18) The compound according to any one of (1) to (14), wherein "n" is 2.

^Bgroup-R

(19) The compound according to any one of (1) to (18), wherein each-R ^BAnd, if present, is independently-F, -Cl or-CN.

(20) The compound according to any one of (1) to (18), wherein each-R^BAnd if present, is-F.

(21) The compound according to any one of (1) to (18), wherein each-R^BAnd, if present, is-Cl.

^BCgroup-R

(22) The compound according to any one of (1) to (21), wherein each-R^BCIf present, is-CH₃。

^BFgroup-R

(23) The compound according to any one of (1) to (22), wherein each-R^BFIf present, is-CF₃。

Terminal aryl radical

(24) The compound according to (1), wherein the group:

independently selected from:

wherein-R^A1、-R^A2、-R^A3、-R^A4and-R^A5Each of which is independently as para-R^AAs defined.

(25) The compound according to (1), wherein the group:

independently selected from:

wherein-R^A1、-R^A2、-R^A3、-R^A4and-R^A5Each of which is independently as para-R^AAs defined.

(26) The compound according to (1), wherein the group:

independently selected from:

wherein-R^A1、-R^A3and-R^A5Each of which is independently as para-R^AAs defined.

(27) The compound according to (1), wherein the group:

comprises the following steps:

wherein-R^A1and-R^A3Each of which is independently as para-R^AAs defined.

Linking phenylene radicals

(28) The compound according to any one of (1) and (24) to (27), wherein the group:

Independently selected from:

wherein-R^B1and-R^B2Each of which is independently as para-R^BAs defined.

(29) The compound according to any one of (1) and (24) to (27), wherein the group:

independently selected from:

wherein-R^B1and-R^B2Each of which is independently as para-R^BAs defined.

(30) The compound according to any one of (1) and (24) to (27), wherein the group:

comprises the following steps:

(31) the compound according to any one of (1) and (24) to (27), wherein the group:

independently selected from:

wherein-R^B1and-R^B2Each of which is independently as para-R^BAs defined.

Biaryl radicals

(32) The compound according to (1), wherein the group:

independently selected from:

wherein:

-R^A1、-R^A3and-R^A5Each of which is independently as para-R^ADefining; and is

-R^B2Independently as para-R^BAs defined.

(33) The compound according to (1), wherein the group:

independently selected from:

wherein:

-R^A1and-R^A3Each of which is independently as para-R^ADefining; and is

-R^B2Independently as para-R^BAs defined.

(34) The compound according to (1), wherein the group:

comprises the following steps:

wherein-R^A1and-R^A3Each of which is independently as para-R^AAs defined.

^A1group-R

(35) The compound according to any one of (24) to (34), wherein-R^A1And, if present, are independently-F, -Cl, -R ^A1C、-R^A1For-CN.

(36) The compound according to any one of (24) to (34), wherein-R^A1And, if present, is independently-F, -Cl or-CN.

(37) The compound according to any one of (24) to (34), wherein-R^A1And if present, is-F.

(38) The compound according to any one of (24) to (34), wherein-R^A1And, if present, is-Cl.

(39) The compound according to any one of (24) to (34), wherein-R^A1And if present, is-CN.

(40) The compound according to any one of (24) to (34), wherein-R^A1If present, is-R^A1C。

(41) The compound according to any one of (24) to (34), wherein-R^A1If present, is-R^A1F。

^A1Cgroup-R

(42) The compound according to any one of (24) to (41), wherein-R^A1CIf present, is-CH₃。

^A1Fgroup-R

(43) The compound according to any one of (24) to (42), wherein-R^A1FIf present, is-CF₃。

^A2group-R

(44) The compound according to any one of (24) to (43), wherein-R^A2And, if present, are independently-F, -Cl, -R^A2C、-R^A2For-CN.

(45) The compound according to any one of (24) to (43), wherein-R^A2And, if present, is independently-F, -Cl or-CN.

(46) The compound according to any one of (24) to (43), wherein-R ^A2And if present, is-F.

(47) The compound according to any one of (24) to (43), wherein-R^A2And, if present, is-Cl.

(48) The compound according to any one of (24) to (43), wherein-R^A2And if present, is-CN.

(49) The compound according to any one of (24) to (43), wherein-R^A2If present, is-R^A2C。

(50) The compound according to any one of (24) to (43), wherein-R^A2If present, is-R^A2F。

^A2Cgroup-R

(51) The compound according to any one of (24) to (50), wherein-R^A2CIf present, is-CH₃。

^A2Fgroup-R

(52) The compound according to any one of (24) to (51), wherein-R^A2FIf present, is-CF₃。

^A3group-R

(53) The compound according to any one of (24) to (52), wherein-R^A3And, if present, are independently-F, -Cl, -R^A3C、-R^A3For-CN.

(54) The compound according to any one of (24) to (52), wherein-R^A3And, if present, is independently-F, -Cl or-CN.

(55) The compound according to any one of (24) to (52), wherein-R^A3And if present, is-F.

(56) The compound according to any one of (24) to (52), wherein-R^A3And, if present, is-Cl.

(57) The compound according to any one of (24) to (52), wherein-R ^A3And if present, is-CN.

(58) The compound according to any one of (24) to (52), wherein-R^A3If present, is-R^A3C。

(59) The compound according to any one of (24) to (52), wherein-R^A3If present, is-R^A3F。

^A3Cgroup-R

(60) The compound according to any one of (24) to (59), wherein-R^A3CIf present, is-CH₃。

^A3Fgroup-R

(61) The compound according to any one of (24) to (60), wherein-R^A3FIf present, is-CF₃。

^A4group-R

(62) The compound according to any one of (24) to (61), wherein-R^A4And, if present, are independently-F, -Cl, -R^A4C、-R^A4For-CN.

(63) The compound according to any one of (24) to (61)wherein-R^A4And, if present, is independently-F, -Cl or-CN.

(64) The compound according to any one of (24) to (61), wherein-R^A4And if present, is-F.

(65) The compound according to any one of (24) to (61), wherein-R^A4And, if present, is-Cl.

(66) The compound according to any one of (24) to (61), wherein-R^A4And if present, is-CN.

(67) The compound according to any one of (24) to (61), wherein-R^A4If present, is-R^A4C。

(68) The compound according to any one of (24) to (61), wherein-R ^A4If present, is-R^A4F。

^A4Cgroup-R

(69) The compound according to any one of (24) to (68), wherein-R^A4CIf present, is-CH₃。

^A4Fgroup-R

(70) The compound according to any one of (24) to (69), wherein-R^A4FIf present, is-CF₃。

^A5group-R

(71) The compound according to any one of (24) to (70), wherein-R^A5And, if present, are independently-F, -Cl, -R^A5C、-R^A5For-CN.

(72) The compound according to any one of (24) to (70), wherein-R^A5And, if present, is independently-F, -Cl or-CN.

(73) The compound according to any one of (24) to (70), wherein-R^A5And if present, is-F.

(74) The compound according to any one of (24) to (70), wherein-R^A5And, if present, is-Cl.

(75) The method according to any one of (24) to (70)The compound of (a), wherein-R^A5And if present, is-CN.

(76) The compound according to any one of (24) to (70), wherein-R^A5If present, is-R^A5C。

(77) The compound according to any one of (24) to (70), wherein-R^A5If present, is-R^A5F。

^A5Cgroup-R

(78) The compound according to any one of (24) to (77), wherein-R^A5CIf present, is-CH₃。

^A5Fgroup-R

(79) The compound according to any one of (24) to (78), wherein-R ^A5FIf present, is-CF₃。

^B1group-R

(80) The compound according to any one of (28) to (79), wherein-R^B1And, if present, are independently-F, -Cl, -R^B1C、-R^B1For-CN.

(81) The compound according to any one of (28) to (79), wherein-R^B1And, if present, is independently-F, -Cl or-CN.

(82) The compound according to any one of (28) to (79), wherein-R^B1And if present, is-F.

(83) The compound according to any one of (28) to (79), wherein-R^B1And, if present, is-Cl.

(84) The compound according to any one of (28) to (79), wherein-R^B1And if present, is-CN.

(85) The compound according to any one of (28) to (79), wherein-R^B1If present, is-R^B1C。

(86) The compound according to any one of (28) to (79), wherein-R^B1If present, is-R^B1F。

^B1Cgroup-R

(87) The compound according to any one of (28) to (86), wherein-R^B1CIf present, is-CH₃。

^B1Fgroup-R

(88) The compound according to any one of (28) to (87), wherein-R^B1FIf present, is-CF₃。

^B2group-R

(89) The compound according to any one of (28) to (88), wherein-R^B2And, if present, are independently-F, -Cl, -R^B2C、-R^B2For-CN.

(90) The compound according to any one of (28) to (88), wherein-R^B2And, if present, is independently-F, -Cl or-CN.

(91) The compound according to any one of (28) to (88), wherein-R^B2And if present, is-F.

(92) The compound according to any one of (28) to (88), wherein-R^B2And, if present, is-Cl.

(93) The compound according to any one of (28) to (88), wherein-R^B2And if present, is-CN.

(94) The compound according to any one of (28) to (88), wherein-R^B2If present, is-R^B2C。

(95) The compound according to any one of (28) to (88), wherein-R^B2If present, is-R^B2F。

^B2Cgroup-R

(96) The compound according to any one of (28) to (95), wherein-R^B2CIf present, is-CH₃。

^B2Fgroup-R

(97) The compound according to any one of (28) to (96), wherein-R^B2FIf present, is-CF₃。

¹group-R

(98) The compound according to any one of (1) to (97), wherein-R¹is-R^1X。

(99) The compound according to any one of (1) to (97), wherein-R¹is-H.

^1Xgroup-R

(100) The compound according to any one of (1) to (99), wherein-R^1XIf present, is independently-F, -R^1Cor-R^1F。

(101) The compound according to any one of (1) to (99), wherein-R ^1XAnd if present, is-F.

(102) The compound according to any one of (1) to (99), wherein-R^1XIf present, is-R^1C。

(103) The compound according to any one of (1) to (99), wherein-R^1XIf present, is-R^1F。

^1Cgroup-R

(104) The compound according to any one of (1) to (103), wherein-R^1CIf present, is-CH₃。

^1Fgroup-R

(105) The compound according to any one of (1) to (104), wherein-R^1FIf present, is-CF₃。

²group-R

(106) The compound according to any one of (1) to (105), wherein-R²is-R^2X。

(107) The compound according to any one of (1) to (105), wherein-R²is-H.

^2Xgroup-R

(108) The compound according to any one of (1) to (107), wherein-R^2XIf present, is independently-F, -R^2Cor-R^2F。

(109) The compound according to any one of (1) to (107), wherein-R^2XAnd if present, is-F.

(110) The compound according to any one of (1) to (107), wherein-R^2XIf present, is-R^2C。

(111) The compound according to any one of (1) to (107), wherein-R^2XIf present, is-R^2F。

^2Cgroup-R

(112) The compound according to any one of (1) to (111), wherein-R^2CIf present, is-CH ₃。

^2Fgroup-R

(113) The compound according to any one of (1) to (112), wherein-R^2FIf present, is-CF₃。

^{1 2}The radicals-R and-R together

(114) The compound according to any one of (1) to (97), wherein-R¹and-R²Together with the carbon atom to which they are attached form saturated C_3-6A cycloalkyl group.

(115) The compound according to any one of (1) to (97), wherein-R¹and-R²Together with the carbon atom to which they are attached form a cyclopropyl group.

(116) The compound according to any one of (1) to (97), wherein-R¹and-R²Together with the carbon atom to which they are attached form a cyclobutyl group.

(117) The compound according to any one of (1) to (97), wherein-R¹and-R⁶²Together with the carbon atom to which they are attached form a cyclopentyl group.

(118) The compound according to any one of (1) to (97), wherein-R¹and-R²Together with the carbon atoms to which they are attached form cyclohexyl.

³group-R

(119) The compound according to any one of (1) to (118), wherein-R³is-R^3X。

(120) The compound according to any one of (1) to (118), wherein-R³is-H.

^3Xgroup-R

(121) The compound according to any one of (1) to (120), wherein-R^3XIf present, is-R^3C。

(122) The compound according to any one of (1) to (120), wherein-R ^3XIf present, is-R^3F。

^3Cgroup-R

(123) The compound according to any one of (1) to (122), wherein-R^3CIf present, is-CH₃。

^3Fgroup-R

(124) The compound according to any one of (1) to (123), wherein-R^3FIf present, is-CF₃。

⁴group-R

(125) The compound according to any one of (1) to (124), wherein-R⁴is-R^4C。

(126) The compound according to any one of (1) to (124), wherein-R⁴is-R^4CC。

(127) The compound according to any one of (1) to (124), wherein-R⁴is-N (R)^4N1)(R^4N2)。

^4Cgroup-R

(128) The compound according to any one of (1) to (127), wherein-R^4CIf present, is a saturated straight or branched chain C_1-4An alkyl group.

(129) The method according to any one of (1) to (127)Compound (II) wherein-R^4CIf present, is a saturated straight or branched chain C_1-3An alkyl group.

(130) The compound according to any one of (1) to (127), wherein-R^4CIf present, is-CH₃or-CH₂CH₃。

(131) The compound according to any one of (1) to (127), wherein-R^4CIf present, is-CH₃。

^4CCgroup-R

(132) The compound according to any one of (1) to (131), wherein-R^4CCAnd, if present, cyclopropyl.

(133) The compound according to any one of (1) to (131), wherein-R ^4CCAnd, if present, is cyclobutyl.

(134) The compound according to any one of (1) to (131), wherein-R^4CCAnd, if present, is cyclopentyl.

(135) The compound according to any one of (1) to (131), wherein-R^4CCAnd, if present, cyclohexyl.

^4N1group-R

(136) The compound according to any one of (1) to (135), wherein-R^4N1If present, is-R^4N1C。

(137) The compound according to any one of (1) to (135), wherein-R^4N1And if present, is-H.

^4N1Cgroup-R

(138) The compound according to any one of (1) to (137), wherein-R^4N1CIf present, is a saturated straight or branched chain C_1-3An alkyl group.

(139) The compound according to any one of (1) to (137), wherein-R^4N1CIf present, is-CH₃or-CH₂CH₃。

(140) The compound according to any one of (1) to (137), wherein-R^4N1CIf present, is-CH₃。

^4N2group-R

(141) The compound according to any one of (1) to (140), wherein-R^4N2If present, is-R^4N2C。

(142) The compound according to any one of (1) to (140), wherein-R^4N2And if present, is-H.

^4N2Cgroup-R

(143) The compound according to any one of (1) to (142), wherein-R^4N2CIf present, is a saturated straight or branched chain C _1-3An alkyl group.

(144) The compound according to any one of (1) to (142), wherein-R^4N2CIf present, is-CH₃or-CH₂CH₃。

(145) The compound according to any one of (1) to (142), wherein-R^4N2CIf present, is-CH₃。

^{4N1 4N2}The group-N (R) (when cyclic)

(146) The compound according to any one of (1) to (127), wherein-N (R)^4N1)(R^4N2) Independently pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl, if present; and optionally one or more saturated straight or branched C_1-4Alkyl substitution.

(147) The compound according to any one of (1) to (127), wherein-N (R)^4N1)(R^4N2) And, if present, is independently pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl.

^{1 2}Configuration of-R and carbon to which-R is attached

(148) The compound according to any one of (1) to (147), wherein-R¹and-R²And the compound is a compound of the formula:

(149) the compound according to any one of (1) to (147), wherein-R¹and-R²And the compound is a compound of the formula:

some preferred compounds

(150) The compound according to (1), which is a compound of one of the following formulae or a pharmaceutically acceptable salt or solvate thereof:

Combination of

It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. On the contrary, in the singular for the sake of brevityVarious features of the invention that are described in the context of embodiments may also be provided separately or in any suitable subcombination. With a variable (e.g., ═ X-, m, -R)^A、-R^AC、-R^AF、n、-R^B、-R^BC、-R^BF、-R^A1、-R^A1C、-R^A1F、-R^A2、-R^A2C、-R^A2F、-R^A3、-R^A3C、-R^A3F、-R^A4、-R^A4C、-R^A4F、-R^A5、-R^A5C、-R^A5F、-R^B1、-R^B1C、-R^B1F、-R^B2、-R^B2C、-R^B2F、-R¹、-R^1X、-R^1C、-R^1F、-R²、-R^2X、-R^2C、-R^2F、-R³、-R^3X、-R^3C、-R^3F、-R⁴、-R^4C、-R^4CC、-R^4N1、-R^4N1C、-R^4N2、-R^4N2CEtc.) are specifically encompassed by the present invention and disclosed herein to the same extent as if each and every combination was individually and specifically disclosed herein, such combinations are intended to encompass compounds that are stable compounds (i.e., compounds that can be isolated, characterized, and tested for biological activity). In this context, the skilled person will readily appreciate that certain combinations of groups (e.g. substituents) may result in compounds that may not be readily synthesized and/or chemically unstable. In addition, all subcombinations of the chemical groups listed in the embodiments describing such variables are also specifically encompassed by the present invention and disclosed herein as if each and every such subcombination of chemical groups were individually and specifically disclosed herein.

In substantially purified form

One aspect of the invention relates to a NASMP compound in substantially purified form and/or in substantially contaminant-free form as described herein.

In one embodiment, the substantially purified form is at least 50 wt.%, such as at least 60 wt.%, such as at least 70 wt.%, such as at least 80 wt.%, such as at least 90 wt.%, such as at least 95 wt.%, such as at least 97 wt.%, such as at least 98 wt.%, such as at least 99 wt.%.

Unless otherwise indicated, substantially purified form refers to any stereoisomeric or enantiomeric form of the compound. For example, in one embodiment, substantially purified form refers to a mixture of stereoisomers, i.e., purified relative to other compounds. In one embodiment, a substantially purified form refers to one stereoisomer, e.g., an optically pure stereoisomer. In one embodiment, substantially purified form refers to a mixture of enantiomers. In one embodiment, substantially purified form refers to an equimolar mixture (i.e., racemic mixture, racemate) of the enantiomers. In one embodiment, a substantially purified form refers to one enantiomer, e.g., an optically pure enantiomer.

In one embodiment, the contaminant comprises no more than 50 wt.%, such as no more than 40 wt.%, such as no more than 30 wt.%, such as no more than 20 wt.%, such as no more than 10 wt.%, such as no more than 5 wt.%, such as no more than 3 wt.%, such as no more than 2 wt.%, such as no more than 1 wt.%.

Unless otherwise indicated, contaminants refer to other compounds, i.e., compounds other than stereoisomers or enantiomers. In one embodiment, contaminants refer to other compounds and other stereoisomers. In one embodiment, contaminants refer to other compounds and other enantiomers.

In one embodiment, the substantially purified form is at least 60% optically pure (i.e., 60% of the compound is the desired stereoisomer or enantiomer and 40% is the undesired stereoisomer or enantiomer on a molar basis), for example at least 70% optically pure, for example at least 80% optically pure, for example at least 90% optically pure, for example at least 95% optically pure, for example at least 97% optically pure, for example at least 98% optically pure, for example at least 99% optically pure.

Isomers

Certain compounds may exist in one or more specific geometric, optical, enantiomeric, diastereomeric, epimeric, atropic (atropic), stereoisomeric, tautomeric, conformational or anomeric forms, including but not limited to cis and trans; e-form and Z-form; c-, t-, and r-forms; an inward form and an outward form; r-, S-and meso forms; d-form and L-form; d-form and l-form; the (+) form and the (-) form; keto, enol, and enolate forms; cis and trans forms; syncline and anticline forms; alpha-form and beta-form; an axial form and a flat form; boat, chair, twist, envelope, and half-chair types, and combinations thereof, are hereinafter collectively referred to as "isomers" ("isomeric forms").

References to a class of structures are likely to include the structural isomeric forms within that class (e.g., C)_1-3Alkyl groups include n-propyl and isopropyl; butyl includes n-butyl, isobutyl, sec-butyl and tert-butyl; methoxyphenyl includes o-methoxyphenyl, m-methoxyphenyl, and p-methoxyphenyl). However, references to particular groups or substitution patterns are not intended to include other structures (or constituent isomers) that differ in the connection between atoms rather than in spatial position. For example, mention is made of methoxy-OCH ₃Is not to be construed as referring to the structural isomer hydroxymethyl-CH₂OH。

The above exclusion does not relate to tautomeric forms, such as keto forms, enol forms and enolate forms, such as for example in the following tautomeric pairs: keto/enol (explained below), imine/enamine, amide/imino alcohol, amidine/amidine, nitroso/oxime, thioketone/enethiol, N-nitroso/hydroxyazo and nitro/isonitro. Reference herein to one tautomer is intended to encompass both tautomers.

Note that specifically included in the term "isomer" are compounds having one or more isotopic substitutions. For example, H may be in any isotopic form, including¹H、²H, (D) and³h (T); c may be in any isotopic form, including¹²C、¹³C and¹⁴c; o may be in any isotopic form, including¹⁶O and¹⁸o, and the like.

Unless otherwise indicated, reference to a particular compound includes all such isomeric forms, including mixtures (racemic mixtures) thereof. Methods for preparing (e.g., asymmetric synthesis) and separating (e.g., fractional crystallization and chromatographic means) such isomeric forms are known in the art or are readily obtained by adapting the methods taught or known herein in a known manner.

Salt (salt)

It may be convenient or desirable to prepare, purify, and/or handle a corresponding salt, e.g., a pharmaceutically acceptable salt, of a compound. Examples of Pharmaceutically Acceptable Salts are discussed in Berge et al, 1977, "pharmaceutical Acceptable Salts"J.Pharm.Sci.Volume 66, pages 1-19.

For example, if the compound is anionic or has a functional group that can be anionic (e.g., -COOH can be-COO^-) Then the salt can be formed with the appropriate cation. Examples of suitable inorganic cations include, but are not limited to, alkali metal ions such as Na⁺And K⁺Alkaline earth metal cations such as Ca²⁺And Mg²⁺And other cations such as Al³⁺And ammonium ion (i.e. NH)₄ ⁺). Examples of suitable organic cations include, but are not limited to, substituted ammonium ions (e.g., NH)₃R⁺、NH₂R₂ ⁺、NHR₃ ⁺、NR₄ ⁺) For example, wherein each R is independently a straight or branched chain saturated C_1-18Alkyl radical, C_3-8Cycloalkyl radical, C_3-8cycloalkyl-C_1-6Alkyl and phenyl-C_1-6Alkyl, wherein phenyl is optionally substituted. Some examples of suitable substituted ammonium ions are those derived from: ethylamine, diethylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline, meglumine, and tromethamine, and amino acids such as lysine and arginine. A common example of a quaternary ammonium ion is N (CH) ₃)₄ ⁺。

If the compound is cationic or has a functional group which becomes cationic after protonation (e.g., -NH)₂Can become-NH₃ ⁺) Salts may then be formed with suitable anions.

For example, if the parent structure contains a cationic group (e.g., -NMe)₂ ⁺) Or having functional groups which become cationic after protonation (e.g., -NH)₂Can become-NH₃ ⁺) Salts may then be formed with suitable anions. In the case of quaternary ammonium compounds, a counter anion is generally always present to balance the positive charge. If other than cationic groups (e.g., -NMe)₂ ⁺、-NH₃ ⁺) In addition, compounds which contain groups capable of forming anions (e.g., -COOH) may form internal salts (also known as zwitterions).

Examples of suitable inorganic anions include, but are not limited to, those derived from the following inorganic acids: hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfurous acid, nitric acid, nitrous acid, phosphoric acid, and phosphorous acid.

Examples of suitable organic anions include, but are not limited to, those derived from the following organic acids: 2-acetoxybenzoic acid, acetic acid, trifluoroacetic acid, ascorbic acid, aspartic acid, benzoic acid, camphorsulfonic acid, cinnamic acid, citric acid, edetic acid, 1, 2-ethanedisulfonic acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, hydroxymaleic acid, hydroxynaphthalenecarboxylic acid, hydroxyethanesulfonic acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, methanesulfonic acid, mucic acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, pantothenic acid, phenylacetic acid, benzenesulfonic acid, propionic acid, pyruvic acid, salicylic acid, stearic acid, succinic acid, sulfanilic acid, tartaric acid, toluenesulfonic acid, and valeric acid. Examples of suitable polymeric organic anions include, but are not limited to, those derived from the following polymeric acids: tannic acid, carboxymethyl cellulose.

Particularly useful for quaternary ammonium compounds (e.g., having pendent groups-NMe)₃ ⁺Those of groups) include 1-adamantanesulfonate, benzenesulfonate, bisulfate, bromide, chloride, iodide, methanesulfonate, methylsulfate, 1, 5-naphthalene disulfonate, 4-nitrobenzenesulfonate, formate, tartrate, tosylate, trifluoroacetate, trifluoromethylsulfonate, sulfate. Likewise, if the compound also contains groups capable of forming anions (e.g., -COOH), internal salts may be formed.

Unless otherwise indicated, reference to a particular compound also includes its salt form.

Solvates and hydrates

It may be convenient or desirable to prepare, purify, and/or handle the corresponding solvate of the compound. The term "solvate" as used herein in the conventional sense refers to a complex of a solute (e.g., a compound, a salt of a compound) and a solvent. If the solvent is water, the solvate may conveniently be referred to as a hydrate, e.g. a monohydrate, dihydrate, trihydrate, etc.

Unless otherwise indicated, reference to a particular compound also includes its solvate and hydrate forms.

Chemically protected forms

It may be convenient or desirable to prepare, purify and/or handle the compound in a chemically protected form. The term "chemically protected form" is used herein in the conventional chemical sense and refers to compounds in which one or more reactive functional groups are protected from undesirable chemical reactions under specific conditions (e.g., pH, temperature, radiation, solvent, etc.). In practice, functional groups that would otherwise be reactive under certain conditions are reversibly rendered unreactive using well-known chemical methods. In chemically protected form, one or The plurality of reactive functional groups are in the form of protected or protecting groups (alternatively masked or shielding groups or blocked or end-capping groups). By protecting the reactive functional group, reactions involving other unprotected reactive functional groups can be carried out without affecting the protected group; the protecting group can generally be removed or the masking group can be converted in a subsequent step without substantially affecting the rest of the molecule. See, for example, the following examples,Protective Groups in Organic Synthesis(T.Green and P.Wuts; 4 th edition; John Wiley and Sons, 2006).

A wide variety of such "protection", "blocking" or "masking" methods are widely used and well known in organic synthesis. For example, a compound having two non-equivalently reactive functional groups (both of which are reactive under certain conditions) can be derivatized such that one of the functional groups is "protected" and thus not reactive under certain conditions; so protected, the compounds can be used as reactants effectively having only one reactive functional group. After the desired reaction (involving other functional groups) is complete, the protected group can be "deprotected" to restore it to its original function.

For example, a hydroxy group may be protected as an ether (-OR) OR ester (-OC (═ O) R), for example, as: tert-butyl ether; benzyl, benzhydryl (diphenylmethyl) or trityl (triphenylmethyl) ether; trimethylsilyl or tert-butyldimethylsilyl ether; or acetyl ester (-OC (═ O) CH₃，-OAc)。

Prodrugs

It may be convenient or desirable to prepare, purify, and/or handle the compound in prodrug form. As used herein, the term "prodrug" relates to a compound that produces the desired active compound in vivo. In general, prodrugs are inactive or less active than the desired active compound, but may provide advantageous handling, administration, or metabolic properties.

For example, some prodrugs are esters (e.g., physiologically acceptable metabolically labile esters) of the active compound. During metabolism, the ester group (-C (═ O) OR) is cleaved to yield the active drug. Such esters may be formed, for example, by esterification of any carboxylic acid group (-C (═ O) OH) in the parent compound and, where appropriate, protection of any other reactive groups present in the parent compound, followed by deprotection as required.

In addition, some prodrugs are enzymatically activated to produce an active compound or a compound that produces an active compound upon further chemical reaction (e.g., as in enzyme prodrug therapy for Antibodies (ADEPT), enzyme prodrug therapy for Genes (GDEPT), enzyme prodrug therapy for Lipids (LIDEPT), etc.). For example, the prodrug may be a sugar derivative or other glycoside conjugate, or may be an amino acid ester derivative.

General chemical Synthesis

Described herein are methods for the chemical synthesis of NASMP compounds. These and/or other well known methods may be modified and/or adapted in known ways to provide additional NASMP compounds and/or alternative or improved synthetic methods.

In one method (as shown in scheme A), piperidine-4-methanol is N-acylated or N-carbamylated with, for example, acetic anhydride or acetyl chloride in the presence of a base such as trimethylamine. The N-acylated or N-carbamoyl derivative is then converted to the mesylate salt with methanesulfonyl chloride (MsCl) in the presence of a base such as triethylamine. The mesylate salt is formed from an aromatic thiolate anion using a base such as cesium carbonate (Cs)₂CO₃₎And the sulfide derivatives thus formed are substituted using m-chloroperoxybenzoic acid (m-CPBA) or potassium permanganate (KMnO)₄) Oxidation to the sulfone. Biaryl sulfones are catalyzed by using transition metals such as tetrakis (triphenylphosphine) palladium (0) (Pd (PPh)₃)₄) Coupling the appropriate aromatic borate ester or acid to bromobenzenesulfone.

Scheme A

In a second approach (as shown in scheme B),catalysis of compounds such as bis (triphenylphosphine) palladium (II) dichloride (Pd (PPh) using 4,4,5, 5-tetramethyl-2- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1,3, 2-dioxaborane and transition metals ₃)₂Cl₂) The bromo (mono) phenylsulfone formed in scheme a is converted to the boronic ester. Biaryl sulfones are catalyzed by using transition metals such as tetrakis (triphenylphosphine) palladium (0) (Pd (PPh)₃)₄) Or [1,1' -bis (diphenylphosphino) ferrocene]Palladium (II) dichloride (Pd (dppf) Cl₂) Coupling of a boronic ester with an appropriate aromatic bromide, iodide or triflate.

Scheme B

Where the appropriate aromatic thiol is not readily commercially available, it may be prepared by using a reducing agent such as triphenylphosphine (PPh)₃) Reduction of the corresponding sulfonyl chloride (as shown in scheme C).

Scheme C

Alternatively (as shown in scheme D1), an appropriately substituted aniline can be substituted with sodium nitrite (NaNO)₂) And diazotization with an acid such as hydrochloric acid (HCl). The diazonium salt is then reacted with potassium ethyl xanthate and subsequently hydrolyzed with potassium hydroxide (KOH) to yield the aromatic thiol.

Scheme D1

In the case where one of the substituents is a nitrile group (as shown in scheme D2), the nitrile may be hydrated into a primary amide during hydrolysis by potassium hydroxide. If this is the case, the aromatic thiol containing the primary amide substituent is coupled with the bromide as in schemes A and B, and then treated with a dehydrating agent such as trifluoroacetic anhydride (TFAA) to regenerate the nitrile from the primary amide.

Scheme D2

Biaryl thiols can be obtained as follows (as shown in scheme E): the appropriate biphenyl compounds were prepared from boronic acids and halobenzenes by Suzuki coupling. Using chlorosulfonic acid (ClSO) for biphenyl₃H) Sulfonylation to give the corresponding sulfonic acid. The acid was then reacted with thionyl chloride (SOCl)₂) To give the corresponding arylsulfonyl chloride. With, for example, triphenylphosphine (PPh)₃) Reducing sulfonyl chloride to obtain biaryl mercaptan derivative.

Scheme E

Biaryl thiols can be reacted with N-acylated/N-carbamoylated-O-methanesulfonylated-piperidine-4-methanol derivatives, e.g., as in schemes a and B.

Alternatively (as shown in scheme F), the compound can be in triethylsilane (Et)₃SiH) was treated with trifluoroacetic acid (TFA) to remove the Boc group. The resulting product may then be N-acetylated or N-carbamylated in the presence of a base such as pyridine. The bromomethylpiperidine may be in the presence of a base such as cesium carbonate (Cs)₂CO₃₎With a biaryl thiol and the sulphide thus formed is reacted with, for example, m-chloroperoxybenzoic acid (m-CPBA) or potassium permanganate (KMnO)₄) Oxidizing to obtain the target compound.

Scheme F

N-acylated bromomethylpiperidines may also be used in place of the mesylate salt in schemes A and B.

In an alternative process (as shown in scheme G1), the biaryl thiol can be reacted with N-Boc-4-bromomethylpiperidine or N-Boc-4-methylsulfonyloxymethylpiperidine to give a sulfide, which is oxidized with, for example, m-chloroperbenzoic acid (m-CPBA) to give the biaryl sulfone (Z1).

Scheme G1

In an alternative approach (as shown in scheme G2), biaryls can be constructed by reaction of appropriate monoaryl thiols, oxidation, and coupling with appropriate boronic acid or ester derivatives, as shown in scheme a.

Scheme G2

For compounds with R1 ═ R2 ═ H in biaryl sulfones (Z1), the Boc group can be removed by treatment with trifluoroacetic acid, and the piperidine thus formed can then be N-acylated or N-carbamylated (e.g., as shown in scheme H).

Scheme H

Additionally (as shown in scheme J1), biaryl sulfones (Z1) may be treated with a base such as sodium hexamethyldisilazane (NaHMDS) followed by a fluorinating agent such as N-fluorobenzenesulfonylimide (NFSI) or an alkylating agent such as methyl iodide (MeI), respectively, to give biaryl sulfones where R1 ═ fluorine (Z2-F) or R1 ═ methyl (Z2-Me). The Boc group can then be removed by treatment with trifluoroacetic acid, and the piperidine thus formed can then be N-acylated or N-carbamoylated. Isomers may be separated if desired.

Scheme J1

Additionally (as shown in scheme J2), biaryl sulfones of R1 ═ fluorine (Z2-F) can be subsequently treated with bases such as sodium hexamethyldisilazane (NaHMDS) followed by treatment with fluorinating agents such as N-fluorobenzenesulfonylimide (NFSI) to give compounds of R1 ═ R2 ═ F (Z3-F2). The Boc group can then be removed by treatment with trifluoroacetic acid, and the piperidine thus formed can then be N-acylated or N-carbamoylated.

Scheme J2

In a similar manner (as shown in scheme J3), a biaryl sulfone of R1 ═ alkyl, e.g. methyl (Z2-Me), can be treated with a similar base, followed by treatment with an alkylating agent such as methyl iodide, to give a compound of R1 ═ R2 ═ alkyl, e.g. methyl (Z3-Me 2). The Boc group can then be removed by treatment with trifluoroacetic acid, and the piperidine thus formed can then be N-acylated or N-carbamoylated.

Scheme J3

Additionally, biaryl sulfones (e.g., Z2-F, where R1 ═ fluorine; Z2-Me, where R1 ═ methyl) may be treated with a base such as Lithium Diisopropylamide (LDA), followed by a fluorinating agent such as N-fluorobenzenesulfonylimide (NFSI) or an alkylating agent such as MeI to give biaryl sulfones of R2 ═ fluorine or R2 ═ alkyl (e.g., methyl). Thus, compounds where R1 and R2 are different (e.g., R1 ═ fluoro and R2 ═ methyl; R1 ═ methyl and R2 ═ ethyl; and the like) can be prepared. In the case where R1 is different from R2, the isomers may be separated, if desired.

Alternatively (as shown in scheme J4), in the case of R1 ═ R2, biaryl sulfone (Z1) can be treated with excess sodium hexamethyldisilazane (NaHMDS) and excess alkyl halide or N-fluorobenzenesulfonylimide (NFSI) to directly result in a disubstituted sulfone having R1 ═ R2 ═ alkyl or R1 ═ R2 ═ fluorine. The Boc group can then be removed by treatment with trifluoroacetic acid, and the piperidine thus formed can then be N-acylated or N-carbamoylated.

Scheme J4

In another approach (as shown in scheme K), a base such as potassium carbonate (K) is used₂CO₃) 4-chloromethylpyridine is reacted with an aromatic thiolate anion and the sulfide derivative thus formed is oxidized to the sulfone using m-chloroperbenzoic acid (m-CPBA). In alkali such as cesium carbonate (Cs)₂CO₃) In the presence of a sulfone, the sulfone is reacted with an alkyl derivative having a leaving group at each terminal carbon atom, such as 1-bromo-2-chloroethane. The resulting cycloalkyl derivative is then coupled to a suitable aryl partner, such as an arylboronic acid ester such as tetrakis (triphenylphosphine) palladium (0) using transition metal catalysis, using hydrogen (H)₂) And catalysts such as platinum dioxide (PtO)₂) The pyridine ring is reduced and the reduction product is then N-acylated or N-carbamylated as desired.

Scheme K

These and/or other well known methods may be modified and/or adapted in known ways to facilitate the synthesis of additional compounds described herein. See, for example:

Comprehensive Organic Transformations A Guide to Functional Group Preparations, 2 nd edition (Wiley)2010.ed. R.C.Larock. ISBN: 978-1-118-.

Comprehensive Organic Synthesis, 2 nd edition (Elsevier)2014 Total edition P.Knochel, G.A.Molander. Ebook ISBN:9780080977430 hardcover ISBN: 9780080977423.

Science of Synthesis: Cross Coupling and Heck-Type Reactions, Workbench edition (Thieme)2013.Ed.G.Molander, J.P.Wolfe, Mats Larhed.ISBN 9783131734112.

Greene's Protective Groups in Organic Synthesis, 4 th edition (Wiley)2006.P.G.M.Wuts, T.W.Greene. printing ISBN:9780471697541. Online ISBN: 9780470053485.

e-EROS Encyclopedia of Reagents for Organic Synthesis, (Wiley). Online ISBN:9780470842898.DOI: 10.1002/047084289X.

Organic Reactions:Electrophilic Fluorination with N–F Rea gents,(Wiley)2008.J.Baudoux,D.Cahard.DOI:10.1002/0471264180.or069.02。

Composition comprising a metal oxide and a metal oxide

One aspect of the invention relates to a composition (e.g., a pharmaceutical composition) comprising a NASMP compound as described herein and a carrier, diluent, or excipient (e.g., a pharmaceutically acceptable carrier, diluent, or excipient).

In one embodiment, the composition further comprises one or more (e.g., 1, 2, 3, 4) additional therapeutic agents as described herein.

Another aspect of the invention relates to a method of making a composition (e.g., a pharmaceutical composition) comprising admixing a NASMP compound as described herein and a carrier, diluent, or excipient (e.g., a pharmaceutically acceptable carrier, diluent, or excipient).

Another aspect of the invention relates to a method of making a composition (e.g., a pharmaceutical composition) comprising administering a NASMP compound as described herein; one or more (e.g., 1, 2, 3, 4) additional therapeutic agents as described herein; and a carrier, diluent, or excipient (e.g., a pharmaceutically acceptable carrier, diluent, or excipient).

Use of

The NASMP compounds as described herein can be used, for example, to treat a disorder (e.g., a disease), including, for example, a disorder (e.g., a disease) described herein.

Use in a method of treatment

Another aspect of the invention relates to a NASMP compound as described herein for use in a method of treatment of the human or animal body by therapy, for example for use in a method of treatment of a condition (e.g., a disease) as described herein.

Another aspect of the invention relates to a NASMP compound as described herein in combination with one or more (e.g., 1, 2, 3, 4) additional therapeutic agents as described herein for use in a method of treatment of the human or animal body by therapy, for example for use in a method of treatment of a condition (e.g., a disease) as described herein.

Use in the manufacture of a medicament

Another aspect of the invention relates to the use of a NASMP compound as described herein in the manufacture of a medicament for treating, e.g., treating, a condition (e.g., a disease) as described herein.

In one embodiment, the medicament comprises a NASMP compound.

Another aspect of the invention relates to the use of a NASMP compound as described herein and one or more (e.g., 1, 2, 3, 4) additional therapeutic agents as described herein in the manufacture of a medicament for treating, e.g., treating, a condition (e.g., disease) as described herein.

In one embodiment, the medicament comprises a NASMP compound and one or more (e.g., 1, 2, 3, 4) additional therapeutic agents.

Method of treatment

Another aspect of the invention relates to a method of treating a condition (e.g., disease), e.g., as described herein, comprising administering to a patient in need of treatment a therapeutically effective amount of a NASMP compound as described herein, preferably in the form of a pharmaceutical composition.

Another aspect of the invention relates to a method of treating a condition (e.g., disease), e.g., as described herein, comprising administering to a patient in need of treatment a therapeutically effective amount of a NASMP compound as described herein, preferably in the form of a pharmaceutical composition; and one or more (e.g., 1, 2, 3, 4) additional therapeutic agents as described herein, preferably in the form of a pharmaceutical composition.

Treated disorders-conditions associated with alterations in cellular metabolism

In one embodiment, the treatment is a treatment: disorders associated with alterations in cellular metabolism.

In one embodiment, the treatment is a treatment: disorders of cellular metabolism.

Examples of such disorders include many of the disorders described below, including, for example, autoimmune/inflammatory disorders; cancer; and disorders mediated by osteoclasts.

In one embodiment, the treatment is treatment of multiple myeloma, diffuse large B-cell lymphoma, acute myelogenous leukemia, eosinophilic leukemia, glioblastoma, melanoma, ovarian cancer, anti-chemotherapy cancer, anti-radiation cancer, inflammatory arthritis, rheumatoid arthritis, psoriatic arthritis, psoriasis, ulcerative colitis, crohn's disease, Systemic Lupus Erythematosus (SLE), lupus nephritis, asthma, Chronic Obstructive Pulmonary Disease (COPD).

Treated disorder-autoimmune/inflammatory disorders

In one embodiment, the treatment is a treatment: autoimmune/inflammatory disorders.

In one embodiment, the treatment is a treatment: an autoimmune disorder.

In one embodiment, the treatment is a treatment: an inflammatory disorder.

In one embodiment, the treatment is a treatment: inflammatory arthritis (including, for example, rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, spondyloarthritis, reactive arthritis, infectious arthritis, systemic lupus erythematosus, scleroderma, gout, adult stelesAlzheimer's disease (adult-onset Still's disease); juvenile idiopathic arthritis); psoriasis; systemic lupus erythematosus; lupus nephritis; systemic sclerosis; scleroderma; hepatitis; endometriosis; adenomyosis of the uterus; sicca syndrome; inflammatory bowel disease; ulcerative colitis; crohn's disease; multiple sclerosis; asthma; atherosclerosis; chronic Obstructive Pulmonary Disease (COPD); uveitis; hidradenitis suppurativa; autoimmune hepatitis; pulmonary fibrosis; allergic diseases (including, for example, atopy, allergic rhinitis, atopic dermatitis, anaphylaxis, allergic bronchopulmonary aspergillosis, allergic gastroenteritis, allergic pneumonia); (ii) an allergic reaction; type I diabetes; rheumatic fever; celiac disease; encephalitis; oophoritis; primary biliary cirrhosis; insulin-resistant diabetes; autoimmune adrenal insufficiency (Addison's disease); acne; acne conglomerates; fulminant acne; autoimmune oophoritis; autoimmune orchitis; autoimmune hemolytic anemia; paroxysmal cold hemoglobinuria; behcet's disease (A) disconnect); autoimmune thrombocytopenia; autoimmune neutropenia; pernicious anemia; pure red cell anemia; autoimmune coagulopathy; myasthenia gravis; autoimmune polyneuritis; pemphigus; rheumatic cardioitis; goodpasture's syndrome; post-cardiotomy syndrome; polymyositis; dermatomyositis; irritable bowel syndrome; pancreatitis; gastritis, lichen planus; delayed type hypersensitivity reactions; chronic pulmonary inflammation; alveolitis; pulmonary granuloma; gingivitis; endodontic disease; periodontal disease; allergic pneumonia; pollinating; (ii) an allergic reaction; skin allergy; urticaria; gout; polycystic kidney disease; coldness-imidacloprid associated periodic syndrome (CAPS); Mueller-Weldii Syndrome (Mulkle-Wells Syndrome); Guillain-Barre syndrome (Guillain-Barre syndrome); chronic inflammatory demyelinating polyneuropathy; organ or transplant rejection; chronic allograft rejection; acute or chronic graft versus host disease; dermatitis (dermatitis)(ii) a Atopic dermatomyositis; graves' disease; autoimmune (Hashimoto's) thyroiditis; blistering disorders; vasculitis syndrome; immune complex-mediated vasculitis; bronchitis; cystic fibrosis; pneumonia; pulmonary edema; pulmonary embolism; sarcoidosis; hypertension; emphysema; respiratory failure; acute respiratory distress syndrome; a BENTA disease; or polymyositis.

In one embodiment, the treatment is a treatment: inflammatory arthritis (including, for example, rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, spondyloarthritis, reactive arthritis, infectious arthritis, systemic lupus erythematosus, scleroderma, gout, adult still's disease, juvenile idiopathic arthritis); psoriasis; systemic lupus erythematosus, lupus nephritis; systemic sclerosis; scleroderma; hepatitis; endometriosis; adenomyosis of the uterus; sicca syndrome; inflammatory bowel disease; ulcerative colitis; crohn's disease; hidradenitis suppurativa; autoimmune hepatitis; multiple sclerosis; asthma; atherosclerosis; chronic Obstructive Pulmonary Disease (COPD); uveitis; or pulmonary fibrosis.

In one embodiment, the treatment is a treatment: inflammatory arthritis (including, for example, rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, spondyloarthritis, reactive arthritis, infectious arthritis, systemic lupus erythematosus, scleroderma, gout, adult still's disease, juvenile idiopathic arthritis).

In one embodiment, the treatment is a treatment: psoriasis; psoriatic arthritis; systemic lupus erythematosus; lupus nephritis; systemic sclerosis; scleroderma; hepatitis; endometriosis; adenomyosis of the uterus; sicca syndrome; inflammatory bowel disease; ulcerative colitis; crohn's disease; hidradenitis suppurativa; autoimmune hepatitis; multiple sclerosis; asthma; atherosclerosis; chronic Obstructive Pulmonary Disease (COPD); uveitis; or pulmonary fibrosis.

In one embodiment, the treatment is a treatment: inflammatory arthritis (including, for example, rheumatoid arthritis; psoriatic arthritis; systemic lupus erythematosus; juvenile idiopathic arthritis); psoriasis; lupus nephritis; systemic sclerosis; inflammatory bowel disease; ulcerative colitis; crohn's disease; hidradenitis suppurativa; autoimmune hepatitis; or multiple sclerosis.

In one embodiment, the treatment is a treatment: inflammatory arthritis.

In one embodiment, the treatment is a treatment: rheumatoid arthritis.

In one embodiment, the treatment is a treatment: psoriatic arthritis.

In one embodiment, the treatment is a treatment: systemic lupus erythematosus.

In one embodiment, the treatment is a treatment: juvenile idiopathic arthritis.

In one embodiment, the treatment is a treatment: psoriasis.

In one embodiment, the treatment is a treatment: lupus nephritis.

In one embodiment, the treatment is a treatment: systemic sclerosis.

In one embodiment, the treatment is a treatment: inflammatory bowel disease.

In one embodiment, the treatment is a treatment: ulcerative colitis.

In one embodiment, the treatment is a treatment: crohn's disease.

In one embodiment, the treatment is a treatment: hidradenitis suppurativa.

In one embodiment, the treatment is a treatment: autoimmune hepatitis.

In one embodiment, the treatment is a treatment: multiple sclerosis.

Cancer as the condition of treatment

In one embodiment, the treatment is a treatment: cancer.

In one embodiment, the treatment is a treatment: multiple myeloma; lymphoma; leukemia; cancer; or a sarcoma.

Multiple myeloma:

in one embodiment, the treatment is a treatment: multiple myeloma.

Lymphoma:

in one embodiment, the treatment is a treatment: lymphoma.

In one embodiment, the treatment is a treatment: hodgkin lymphoma; non-hodgkin lymphoma; lymphocytic lymphomas; granulocytic lymphoma; monocytic lymphoma; diffuse large B-cell lymphoma (DLBCL); mantle Cell Lymphoma (MCL); follicular cell lymphoma (FL); mucosa-associated lymphoid tissue (MALT) lymphoma; marginal zone lymphoma; t cell lymphoma; marginal zone lymphoma; or Burkitt's lymphoma.

In one embodiment, the treatment is treatment of lymphocytic lymphoma; granulocytic lymphoma; monocytic lymphoma; or diffuse large B-cell lymphoma (DLBCL).

In one embodiment, the treatment is a treatment: diffuse large B-cell lymphoma (DLBCL).

Leukemia:

in one embodiment, the treatment is a treatment: leukemia is treated with the compound.

In one embodiment, the treatment is a treatment: chronic Lymphocytic Leukemia (CLL); acute Myeloid Leukemia (AML); acute Lymphocytic Leukemia (ALL); lymphocytic T cell leukemia; chronic Myelogenous Leukemia (CML); hairy cell leukemia; acute lymphocytic T cell leukemia; acute eosinophilic leukemia; immunoblastic large cell leukemia; megakaryocytic leukemia; acute megakaryocytic leukemia; promyelocytic leukemia; erythroleukemia; or a plasmacytoma.

In one embodiment, the treatment is a treatment: chronic Lymphocytic Leukemia (CLL); acute Myeloid Leukemia (AML); acute Lymphocytic Leukemia (ALL); lymphocytic T cell leukemia; chronic Myelogenous Leukemia (CML); or acute eosinophilic leukemia.

In one embodiment, the treatment is a treatment: chronic Lymphocytic Leukemia (CLL).

In one embodiment, the treatment is a treatment: acute Myeloid Leukemia (AML).

In one embodiment, the treatment is a treatment: acute Lymphocytic Leukemia (ALL).

In one embodiment, the treatment is a treatment: lymphocytic T cell leukemia.

In one embodiment, the treatment is a treatment: chronic Myelogenous Leukemia (CML).

Cancer:

in one embodiment, the treatment is a treatment: cancer.

In one embodiment, the treatment is a treatment: colon cancer; breast cancer; ovarian cancer; lung cancer (including, for example, small cell lung cancer and non-small cell lung cancer); prostate cancer; oral or pharyngeal cancer (including, for example, lip cancer, tongue cancer, mouth cancer, throat cancer, pharyngeal cancer, salivary gland cancer, buccal mucosal cancer); esophageal cancer; gastric cancer; small bowel cancer; large bowel cancer; rectal cancer; liver cancer; biliary tract cancer; pancreatic cancer; bone cancer; connective tissue cancer; skin cancer; cervical cancer; uterine cancer; body cancer; endometrial cancer; vulvar cancer; vaginal cancer; testicular cancer; bladder cancer; kidney cancer; cancer of the ureter; cancer of the urethra; umbilical duct cancer; eye cancer; glioma; spinal cord cancer; central nervous system cancer; cancer of the peripheral nervous system; meningeal cancer; thyroid cancer; adrenal cancer; astrocytoma; acoustic neuroma; anaplastic astrocytoma; basal cell carcinoma; a blast cell glioma; choriocarcinoma; chordoma; craniopharyngioma; cutaneous melanoma; cystic carcinoma; an embryonic carcinoma; ependymoma; epithelial cancer; gastric cancer; genitourinary tract cancer; glioblastoma multiforme; head and neck cancer; hemangioblastoma; hepatocellular carcinoma; renal Cell Carcinoma (RCC); liver cancer; large cell carcinoma; medullary thyroid carcinoma; medulloblastoma; meningioma mesothelioma; a myeloma cell; neuroblastoma; oligodendroglioma; epithelial ovarian cancer; papillary carcinoma; papillary adenocarcinoma; paragangliomas; parathyroid tumors; pheochromocytoma; pineal tumor; a plasmacytoma; retinoblastoma; sebaceous gland cancer; seminoma; melanoma; squamous cell carcinoma; sweat gland cancer; a synovial tumor; thyroid cancer; uveal melanoma; or Wilms 'tumor (Wilm's tumor).

In one embodiment, the treatment is a treatment: colon cancer; breast cancer; ovarian cancer; lung cancer (including, for example, small cell lung cancer and non-small cell lung cancer); prostate cancer; gastric cancer; pancreatic cancer; bone cancer; skin cancer; cervical cancer; uterine cancer; endometrial cancer; testicular cancer; bladder cancer; kidney cancer; eye cancer; liver cancer; glioma; thyroid cancer; adrenal cancer; astrocytoma; acoustic neuroma; anaplastic astrocytoma; cutaneous melanoma; gastric cancer; glioblastoma multiforme; head and neck cancer; hepatocellular carcinoma; renal Cell Carcinoma (RCC); melanoma; or squamous cell carcinoma.

In one embodiment, the treatment is a treatment: colon cancer; breast cancer; ovarian cancer; lung cancer (including, for example, small cell lung cancer and non-small cell lung cancer); prostate cancer; pancreatic cancer; bone cancer; liver cancer; glioblastoma multiforme; head and neck cancer; or melanoma.

In one embodiment, the treatment is a treatment: melanoma is a tumor.

In one embodiment, the treatment is a treatment: glioblastoma multiforme.

In one embodiment, the treatment is a treatment: breast cancer.

In one embodiment, the treatment is a treatment: prostate cancer.

In one embodiment, the treatment is a treatment: bone cancer.

In one embodiment, the treatment is a treatment: pancreatic cancer.

In one embodiment, the treatment is a treatment: head and neck cancer.

In one embodiment, the treatment is a treatment: lung cancer (including, for example, small cell lung cancer and non-small cell lung cancer).

In one embodiment, the treatment is a treatment: ovarian cancer.

In one embodiment, the treatment is a treatment: liver cancer.

Sarcoma:

in one embodiment, the treatment is a treatment: sarcoma.

In one embodiment, the treatment is a treatment: (iii) astroma (Askin's tomour); botryoid sarcoma; chondrosarcoma; an endothelial sarcoma; ewing's sarcoma; malignant vascular endothelioma; malignant schwannoma; osteosarcoma; gastrointestinal stromal tumors (GIST); myxosarcoma; alveolar soft part sarcoma; angiosarcoma; phyllocystic sarcoma; fibrosarcoma of the skin; desmoid tumors; fibroproliferative small round cell tumors; extraosseous chondrosarcoma; osteosarcoma; fibrosarcoma; vascular endothelial cell tumor; angiosarcoma; kaposi's sarcoma; leiomyosarcoma; liposarcoma; lymphangiosarcoma (lyphangiosarcoma); lymphatic endothelial sarcoma; lymphosarcoma; malignant peripheral nerve sheath tumor; neurofibrosarcoma; plexiform fibrosarcoma (plexiform fibrosiotic turour); rhabdomyosarcoma; or synovial sarcoma.

Treatment of refractory cancer:

in one embodiment, the treatment is a treatment: treatment of refractory cancers (including, for example, anti-chemotherapy cancers and anti-radiotherapy cancers); metastatic cancer; transferring; or recurrent cancer.

In one embodiment, the treatment is a treatment: resistant to chemotherapeutic cancers (including, for example, resistant to chemotherapeutic multiple myeloma, lymphoma, leukemia, carcinoma, and sarcoma).

In one embodiment, the treatment is a treatment: radioresistant cancers (including, for example, radioresistant multiple myeloma, lymphoma, leukemia, carcinoma, and sarcoma).

In one embodiment, the treatment is a treatment: metastatic cancer.

In one embodiment, the treatment is a treatment: and (5) transferring.

In one embodiment, the treatment is a treatment: recurrent cancer.

In one embodiment, the treatment is for: preventing, reducing, or overcoming resistance to radiation therapy or chemotherapy (e.g., due to changes in cellular metabolism); preventing or reducing tumor invasion; preventing or reducing tumor metastasis; improving the effect of antitumor agents; and/or enhancing the action of an immunomodulator.

In one embodiment, the treatment is for: preventing, reducing or overcoming resistance to radiotherapy.

In one embodiment, the treatment is for: preventing, reducing or overcoming resistance to chemotherapy.

In one embodiment, the treatment is for: preventing or reducing tumor invasion or tumor metastasis; improving the effect of antitumor agents; and/or enhancing the action of an immunomodulator.

In one embodiment, the treatment is for: improving the effect of antitumor agents; and/or enhancing the action of an immunomodulator.

In one embodiment, the treatment is for: improving the action of immunomodulator.

Condition for treatment-osteoclast mediated disorder

In one embodiment, the treatment is a treatment: a condition mediated by osteoclasts.

In one embodiment, the treatment is a treatment: rheumatoid arthritis; osteoporosis; paget's disease; osteopetrosis; osteoarthritis; ectopic bone formation; bone loss associated with endometriosis; bone neoplasia (including, e.g., as a primary tumor or as a metastasis and including, e.g., bone cancer; osteosarcoma; or an osteoma); cancer-associated bone disorders (including, for example, metastatic bone disease associated with, for example, breast cancer, lung cancer, prostate cancer, or multiple myeloma; changes in bone mineralization and density associated with cancer, including, for example, hypercalcemia associated with cancer); bone metastases (including, for example, osteolytic bone metastases); hypercalcemia (including, for example, hypercalcemia associated with cancer, hypercalcemia resulting from conditions associated with increased bone resorption (including, for example, hypercalcemia resulting from vitamin D poisoning, primary or tertiary hyperparathyroidism, immobilization, or sarcoidosis), or aseptic loosening of prosthetic implants (e.g., artificial joints, such as the knee, hip, etc.).

In one embodiment, the treatment is a treatment: rheumatoid arthritis; osteoporosis; bone neoplasia (including, e.g., as a primary tumor or as a metastasis and including, e.g., bone cancer; osteosarcoma; or an osteoma); cancer-related bone disorders (including, for example, metastatic bone disease associated with breast cancer, lung cancer, prostate cancer, or multiple myeloma; changes in bone mineralization and density associated with cancer, including, for example, hypercalcemia associated with cancer); or bone metastases (including, for example, osteolytic bone metastases).

In one embodiment, the treatment is a treatment: rheumatoid arthritis.

In one embodiment, the treatment is a treatment: osteoporosis.

In one embodiment, the treatment is a treatment: bone neoplasia (including, e.g., as a primary tumor or as a metastasis and including, e.g., bone cancer; osteosarcoma; or an osteosarcoma).

In one embodiment, the treatment is a treatment: bone cancer; osteosarcoma; or a osteoma.

In one embodiment, the treatment is a treatment: cancer-associated bone disorders (including, for example, metastatic bone disease associated with breast cancer, lung cancer, prostate cancer, or multiple myeloma; changes in bone mineralization and density associated with cancer, including, for example, hypercalcemia associated with cancer).

In one embodiment, the treatment is a treatment: bone metastasis.

Treatment of

The term "treating" as used herein in the context of treating a condition generally refers to both treatment and therapy, whether human or animal (e.g., in veterinary applications), in which some desired therapeutic effect is achieved, e.g., inhibiting the progression of the condition, and includes reducing the rate of progression, stopping the rate of progression, alleviating the symptoms of the condition, ameliorating the condition, and curing the condition. Treatment as a prophylactic measure (i.e., prophylaxis) is also included. For example, the term "treating" encompasses the use of a patient who has not yet developed a disorder but is at risk of developing a disorder.

For example, treatment of inflammation includes preventing inflammation, reducing the occurrence of inflammation, reducing the severity of inflammation, alleviating the symptoms of inflammation, and the like.

As used herein, the term "therapeutically effective amount" refers to an amount of a compound, or a material, composition, or dosage form comprising the compound, that is effective, when administered according to a desired treatment regimen, to produce some desired therapeutic effect commensurate with a reasonable benefit/risk ratio.

Combination therapy

The term "treatment" includes combination treatments and therapies in which two or more treatments or therapies are combined, e.g., sequentially or simultaneously. For example, the compounds described herein may also be used in combination therapy, e.g., in combination with other agents, e.g., anti-inflammatory agents and the like. Examples of treatments and therapies include chemotherapy (administration of active agents including, for example, drugs, antibodies (e.g., as in immunotherapy), prodrugs (e.g., as in photodynamic therapy, GDEPT, ADEPT, etc.), surgery, radiotherapy, photodynamic therapy, gene therapy, and controlled diet.

One aspect of the present invention pertains to a compound as described herein in combination with one or more additional therapeutic agents.

The particular combination will be determined by the physician who will select the dosage using his common general knowledge and dosing regimens known to the skilled practitioner.

The agents (i.e., the compounds described herein, plus one or more other agents) may be administered simultaneously or sequentially, and may be administered in separate different dosage regimens and by different routes. For example, when administered sequentially, the agents can be administered at closely spaced intervals (e.g., for a period of 5-10 minutes) or at longer intervals (e.g., 1, 2, 3, 4, or more hours apart or even longer periods apart when desired), and the precise dosage regimen will be commensurate with the nature of the therapeutic agent(s).

The agents (i.e., the compounds described herein, plus one or more other agents) may be formulated together in a single dosage form, or the individual agents may be formulated separately and provided together in a kit, optionally with instructions for their use.

Other uses

The NASMP compounds described herein may also be used as part of an in vitro assay, for example, to determine whether a candidate host is likely to benefit from treatment with the compound in question.

The NASMP compounds described herein can also be used as standards, for example, in assays to identify other compounds, other anti-inflammatory agents, and the like.

Medicine box

One aspect of the invention relates to a kit comprising (a) a NASMP compound or a composition comprising a NASMP compound as described herein, e.g., preferably provided in a suitable container and/or in a suitable package; and (b) instructions for use, such as written instructions on how to administer the compound or composition.

In one embodiment, the kit further comprises one or more (e.g., 1, 2, 3, 4) additional therapeutic agents as described herein.

The written instructions may also include a list of indications that the active ingredient is suitable for treatment.

Route of administration

The NASMP compound or pharmaceutical composition comprising the NASMP compound may be administered to the subject by any convenient route of administration, whether systemic/peripheral or local (i.e., at the desired site of action).

Routes of administration include oral (e.g., by ingestion); cheek; under the tongue; transdermal (including, for example, via a patch, plaster, etc.); transmucosal (including, for example, through patches, plasters, etc.); intranasally (e.g., by nasal spray, drops, or from a nebulizer or dry powder delivery device); eye (e.g., by eye drops); pulmonary (e.g., by inhalation or insufflation therapy using, for example, aerosols, e.g., through the mouth or nose); rectally (e.g., by suppository or enema); the vagina (e.g., through a pessary); parenterally, e.g., by injection, including subcutaneously, intradermally, intramuscularly, intravenously, intraarterially, intracardially, intrathecally, intraspinally, intracapsularly, subcapsularly, intraorbitally, intraperitoneally, intratracheally, subcutaneously, intraarticularly, subarachnoid, and intrasternally; by implanting the depot or depot, for example subcutaneously or intramuscularly.

In a preferred embodiment, the route of administration is oral (e.g., by ingestion).

In a preferred embodiment, the route of administration is parenteral (e.g., by injection).

Subject/patient

The subject/patient can be a chordate, vertebrate, mammal, placental mammal, marsupial mammal (e.g., kangaroo, koala), rodent (e.g., guinea pig, hamster, rat, mouse), murine (e.g., mouse), lagomorph (e.g., rabbit), avian (e.g., bird), canine (e.g., dog), feline (e.g., cat), equine (e.g., horse), porcine (porcine) (e.g., pig (pig)), ovine (e.g., sheep), bovine (e.g., cow), primate, simian (e.g., monkey or ape), simian (e.g., marmoset, baboon), ape (e.g., gorilla, chimpanzee, orangutan, gibbon), or human. Furthermore, the subject/patient may be any developmental form thereof, e.g., a fetus.

In a preferred embodiment, the subject/patient is a human.

Preparation

Although the NASMP compound can be administered alone, it is preferred that it be present in the form of a pharmaceutical formulation (e.g., composition, formulation, medicament) comprising at least one NASMP compound as described herein, along with one or more other pharmaceutically acceptable ingredients well known to those skilled in the art, including pharmaceutically acceptable carriers, diluents, excipients, adjuvants, fillers, buffers, preservatives, antioxidants, lubricants, stabilizers, solubilizers, surfactants (e.g., wetting agents), masking agents, colorants, flavorants, and sweeteners. The formulation may also contain other active agents, such as other therapeutic or prophylactic agents.

Accordingly, the present invention also provides a pharmaceutical composition as defined herein, and a method of manufacturing a pharmaceutical composition, the method comprising admixing at least one NASMP compound as described herein together with one or more other pharmaceutically acceptable ingredients (e.g., carriers, diluents, excipients, etc.) well known to those skilled in the art. If formulated as discrete units (e.g., tablets, etc.), each unit contains a predetermined amount (dose) of the compound.

As used herein, the term "pharmaceutically acceptable" refers to compounds, ingredients, materials, compositions, dosage forms, and the like, which are, within the scope of sound medical judgment, suitable for use in contact with the tissue of the subject (e.g., human) in question without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. Each carrier, diluent, excipient, etc., must also be "acceptable" in the sense of being compatible with the other ingredients of the formulation.

Suitable carriers, diluents, excipients and the like may be present in standard pharmaceutical readouts such asRemington's Pharmaceutical Sciences18 th edition, Mack Publishing Company, Easton, Pa., 1990; andHandbook of Pharmaceutical Excipients5 th edition, 2005.

The formulations may be prepared by any method well known in the art of pharmacy. Such methods include the step of bringing into association the compound with the carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the compound with carriers (e.g., liquid carriers, finely divided solid carriers, and the like), and then shaping the product as necessary.

The formulations may be prepared to provide rapid or slow release; immediate, delayed, timed or sustained release; or a combination thereof.

The formulations may suitably be in the form of a liquid, solution (e.g. aqueous, non-aqueous), suspension (e.g. aqueous, non-aqueous), emulsion (e.g. oil-in-water, water-in-oil), elixir, syrup, troche, mouthwash, drop, tablet (including, for example, coated tablet), granule, powder, lozenge, pastille, capsule (including, for example, hard and soft gelatin capsules), cachet, pill, ampoule, bolus, suppository, pessary, tincture, gel, paste, ointment, cream, lotion, oil, foam, spray, mist, or aerosol.

The formulations may suitably be provided as patches, plasters, bandages, dressings and the like impregnated with one or more compounds and optionally one or more other pharmaceutically acceptable ingredients, including for example penetration (permeation), permeation (permeation) and absorption promoters. The formulation may also suitably be provided in the form of a depot or depot.

The compounds may be dissolved, suspended, or mixed with one or more other pharmaceutically acceptable ingredients. The compounds may be presented as liposomes or other microparticles designed, for example, to target the compounds to blood components or one or more organs.

Formulations suitable for oral administration (e.g., by ingestion) include liquids, solutions (e.g., aqueous, non-aqueous), suspensions (e.g., aqueous, non-aqueous), emulsions (e.g., oil-in-water, water-in-oil), elixirs, syrups, lozenges, tablets, granules, powders, capsules, cachets, pills, ampoules, boluses.

Formulations suitable for oral administration include mouthwashes, lozenges, pastilles, as well as patches, plasters, reservoirs and depots. Lozenges generally comprise a compound with a flavoring base, usually sucrose and acacia or tragacanth. Pastilles typically comprise an inert base such as gelatin and glycerin or sucrose and acacia. Mouthwashes generally comprise a compound in a suitable liquid carrier.

Formulations suitable for sublingual administration include tablets, lozenges, pastilles, capsules and pills.

Formulations suitable for oral transmucosal administration include liquids, solutions (e.g., aqueous, nonaqueous), suspensions (e.g., aqueous, nonaqueous), emulsions (e.g., oil-in-water, water-in-oil), mouthwashes, lozenges, pastilles, as well as patches, plasters, depots, and depots.

Formulations suitable for parenteral transmucosal administration include liquids, solutions (e.g., aqueous, nonaqueous), suspensions (e.g., aqueous, nonaqueous), emulsions (e.g., oil-in-water, water-in-oil), suppositories, pessaries, gels, pastes, ointments, creams, lotions, oils, and patches, plasters, depots, and depots.

Formulations suitable for transdermal administration include gels, ointments, salves, creams, lotions, and oils, as well as patches, plasters, bandages, dressings, depots, and reservoirs.

Tablets may be made by conventional means, for example compression or moulding, optionally together with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine a compound in a free-flowing form such as a powder or granules, optionally mixed with: one or more binders (e.g., povidone, gelatin, gum arabic, sorbitol, tragacanth, hydroxypropylmethylcellulose); fillers or diluents (e.g., lactose, microcrystalline cellulose, dibasic calcium phosphate); lubricants (e.g., magnesium stearate, talc, silicon dioxide); disintegrants (e.g., sodium starch glycolate, crospovidone, croscarmellose sodium); surface active or dispersing or wetting agents (e.g., sodium lauryl sulfate); preservatives (e.g., methylparaben, propylparaben, sorbic acid); flavors, taste enhancers, and sweeteners. Molded tablets may be prepared by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the compounds therein, using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile. The tablets may optionally be provided with, for example, a release-modifying coating (e.g., an enteric coating) to provide release in parts of the intestinal tract other than the stomach.

Ointments are generally prepared from the compound and either a paraffin or a water-miscible ointment base.

Creams are generally prepared from the compound and an oil-in-water cream base. If desired, the aqueous phase of the cream base may include, for example, at least about 30% weight/weight of a polyol, i.e., an alcohol having two or more hydroxyl groups, such as propylene glycol, 1, 3-butylene glycol, mannitol, sorbitol, glycerol, and polyethylene glycol, and mixtures thereof. Topical formulations may desirably include compounds that enhance absorption or penetration of the compounds through the skin or other affected areas. Examples of such skin permeation enhancers include dimethyl sulfoxide and related analogs.

Emulsions are typically prepared from a compound and an oil phase, which may optionally comprise only emulsifiers (otherwise known as laxatives), or which may comprise a mixture of at least one emulsifier with a fat or oil or with both a fat and an oil. Preferably, a hydrophilic emulsifier is included with a lipophilic emulsifier that acts as a stabilizer. Also preferably oils and fats. In summary, the emulsifiers with or without stabilizers constitute the so-called emulsifying waxes, and the waxes, together with the oils and/or fats, constitute the so-called emulsifying ointment base, which forms the oily dispersed phase of the cream formulation.

Suitable emulsifiers and emulsion stabilizers include Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, monostearyl glyceric acid and sodium lauryl sulfate. The selection of an appropriate oil or fat for the formulation is based on achieving the desired cosmetic properties, as the solubility of the compound in most oils that are useful in pharmaceutical emulsion formulations can be very low. The cream should therefore preferably be a non-greasy, non-staining and washable product having a suitable consistency to avoid leakage from tubes or other containers. Straight or branched chain, mono-or dibasic alkyl esters such as diisoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched chain esters known as Crodamol CAP may be used, the last three being preferred esters. These may be used alone or in combination depending on the desired properties. Alternatively, high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils may be used.

Formulations suitable for intranasal administration in which the carrier is a liquid, including for example in the form of nasal sprays, nasal drops or by aerosol administration or by nebuliser, include aqueous or oily solutions of the active compound.

Formulations suitable for intranasal administration in which the carrier is a solid include, for example, formulations presented as a coarse powder having a particle size, for example, in the range of from about 20 microns to about 500 microns, which are administered in a snuff manner, i.e., by rapid inhalation through the nasal passage from a container of the powder placed in the vicinity of the nose.

Formulations suitable for pulmonary administration (e.g. by inhalation or insufflation therapy) include those in the form of an aerosol spray presentation from pressurized packs with the aid of a suitable propellant, e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.

Formulations suitable for ocular administration include eye drops wherein the compound is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the compound.

Formulations suitable for rectal administration may be presented as a suppository with a suitable base comprising, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols, such as cocoa butter or salicylates; or as a solution or suspension for enema therapy.

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

Formulations suitable for parenteral administration (e.g., by injection) include aqueous or non-aqueous, isotonic, pyrogen-free, sterile liquids (e.g., solutions, suspensions) in which the compound is dissolved, suspended, or otherwise provided (e.g., in liposomes or other microparticles). Such liquids may additionally contain other pharmaceutically acceptable ingredients such as antioxidants, buffers, preservatives, stabilizers, bacteriostats, suspending agents, thickening agents, and solutes that render the formulation isotonic with the blood (or other relevant bodily fluids) of the intended recipient. Examples of excipients include, for example, water, alcohols, polyols, glycerol, vegetable oils, and the like. Examples of suitable isotonic formulations for use in such formulations include sodium chloride injection, ringer's solution, or lactated ringer's injection. Typically, the concentration of the compound in the liquid is from about 1ng/mL to about 10. mu.g/mL, such as from about 10ng/mL to about 1. mu.g/mL. The formulations may be presented in unit-dose or multi-dose sealed containers, for example, ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets.

Dosage form

One skilled in the art will recognize that the appropriate dosage of the NASMP compound and the composition comprising the NASMP compound may vary from patient to patient. Determining the optimal dosage will generally involve balancing the level of therapeutic benefit against any risk or deleterious side effects. The selected dosage level will depend on a variety of factors including the activity of the particular NASMP compound, the route of administration, the time of administration, the rate of excretion of the NASMP compound, the duration of the treatment, the other drugs, compounds and/or materials used in combination, the severity of the condition, and the race, sex, age, weight, condition, general health, and previous medical history of the patient. The amount and route of administration of the NASMP compound will ultimately be at the discretion of the physician, veterinarian, or clinician, but the dosage is generally selected to achieve a local concentration at the site of action that achieves the desired effect without causing substantially harmful or toxic side effects.

Administration can be effected in one dose, continuously or intermittently (e.g., in divided doses at appropriate time intervals) throughout the course of treatment. Methods of determining the most effective mode of administration and dosage are well known to those skilled in the art and will vary with the formulation used for treatment, the purpose of the treatment, the target cell or cells being treated and the subject being treated. Single or multiple administrations can be carried out according to the dose level and mode selected by the treating physician, veterinarian or clinician.

Generally, suitable dosages of the NASMP compound range from about 10 μ g/kg to about 20mg/kg of subject body weight per day (more typically from about 100 μ g/kg to about 10mg/kg of subject body weight). When the compound is a salt, ester, amide, prodrug, or the like, the amount administered is calculated based on the parent compound, and thus the actual weight to be used increases proportionally.

Chemical synthesis

Acronyms and abbreviations

AcCl: acetyl chloride

Ac₂O: acetic anhydride

B₂pin₂: bis (pinacolato) diboron

DCM: methylene dichloride

DMAP: 4-dimethylaminopyridine

DMF: dimethyl formamide

DMSO, DMSO: dimethyl sulfoxide

ESI: electrospray ionization

Et₃N: triethylamine

EtOAc: ethyl acetate

HPLC: high performance liquid chromatography

LCMS: liquid chromatography-mass spectrometry

m-CPBA: meta-chloroperoxybenzoic acid

MeOH: methanol

Ms: methanesulfonic acid salt

m/z: mass to charge ratio

NaHMDS: bis (trimethylsilyl) amide sodium salt

NFSI: n-fluorobenzenesulfonylimides

NMR: nuclear magnetic resonance (Spectrum)

rt: at room temperature

TBAB: tetrabutylammonium bromide

TES: triethylsilane

TFA: trifluoroacetic acid

TFAA: trifluoroacetic anhydride

THF: tetrahydrofuran (THF)

TLC: thin layer chromatography

Analytical HPLC (method A)

Unless otherwise indicated, analytical HPLC characterization of the target compound (i.e., "synthetic compound") was performed on the following system:

Column: x-select CSH C18, 4.6mmx150mm, ID 3.5 μm

Sample introduction amount: 5 μ L

Flow rate: 1mL/min

Solvent: a: 0.1% formic acid in water acetonitrile (95:5)

B: acetonitrile

Gradient (B% increases linearly between 1 and 8 min):

time (min)	A％	B％
			0	95	5
1	95	5
			8	0	100
12	0	100
			14	95	5
18	95	5

Analytical HPLC (method)B)

Analytical HPLC characterization of intermediates 47, 49, 50 and 51 and large scale synthesis of synthetic compound 1 were performed on the following system:

column: acquisty BEH Phenyl, 4.6mmx30mm, ID 1.7 μm

Sample introduction amount: 5 μ L

Flow rate: 2mL/min

Solvent: a: 0.03% aqueous TFA

B: acetonitrile 0.03% TFA

Gradient:

thin Layer Chromatography (TLC)

TLC analysis was performed using pre-coated TLC plates with silica gel 60, in which the fluorescent indicator UV-254 was from Loba Chemie.

Synthesis scheme 1

Intermediate 1

1- (4- (hydroxymethyl) piperidin-1-yl) ethan-1-one

To a solution of piperidin-4-ylcarbinol (25.00g, 217.05mmol) in DCM (250mL) at 0 deg.C were added triethylamine (60.50mL, 434.10mmol) and acetic anhydride (22.56mL, 238.75 mmol). The reaction mixture was warmed to room temperature and stirred for 16 h. By TLC [ mobile phase: 10% methanol in DCM ] the progress of the reaction was monitored. After completion of the reaction, water (250mL) was added to the reaction mixture and the layers were separated. The aqueous layer was extracted with DCM (3 × 250 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure to give the title compound, intermediate 1, as a colorless oil (20.00g, crude). This compound was used in the next step without further purification.

Analyzing data:

¹H NMR(400MHz,DMSO-d₆)δ(ppm):4.48(t,J＝5.2Hz,1H),4.35(dd,J＝11.2,2.0Hz,1H),3.78(d,J＝14.0Hz,1H),3.25(t,J＝5.6Hz,2H),2.97(td,J＝13.2,2.8Hz,1H),2.46(td,J＝12.4,2.4Hz,1H),1.97(s,3H),1.70–1.50(m,3H),1.10–0.85(m,2H)。

intermediate 2

(1-acetylpiperidin-4-yl) methyl methanesulfonate

To a solution of 1- (4- (hydroxymethyl) piperidin-1-yl) ethan-1-one intermediate 1(20.00g, 127.21mmol) in DCM (200mL) at 0 deg.C was added triethylamine (35.39mL, 254.43mmol) and methanesulfonyl chloride (10.83mL, 139.94mmol) dropwise. The reaction mixture was then warmed to room temperature and stirred for 4 h. By TLC [ mobile phase: 10% methanol in DCM ] the progress of the reaction was monitored. After completion of the reaction, the reaction mixture was quenched with water (50mL) and extracted with DCM (3X 200 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure to give the title compound, intermediate 2, as a yellow oil (25.00g, crude). This compound was used in the next step without further purification.

Analyzing data:

LCMS(ESI)m/z＝235.95[M+H]⁺。

intermediate 3

1- (4- (((4-bromophenyl) thio) methyl) piperidin-1-yl) ethan-1-one

To a solution of 4-bromobenzenethiol (2.82g, 14.95mmol) in acetone (50mL) at room temperature under an argon atmosphere was added cesium carbonate (8.85g, 27.18mmol) and the reaction mixture was stirred for 30 min. Then, (1-acetylpiperidin-4-yl) methyl methanesulfonate intermediate 2(3.20g, 13.59mmol) was added to the reaction mixture and the reaction was heated to 60 ℃ under an argon atmosphere for 16 h. By TLC [ mobile phase: 100% Ethyl acetate ]The progress of the reaction was monitored. After completion of the reaction, the reaction mixture was cooled to room temperature, filtered through a celite pad and the filtrate was concentrated to dryness under reduced pressure. The crude product is passed through silica gel column chromatography (Gradient 10-100% ethyl acetate in hexanes to 5% methanol in DCM) to give the title compound, intermediate 3, as a colorless thick oil (3.95g, 80%).

Analyzing data:

¹H NMR(400MHz,CDCl₃)δ(ppm):7.39(d,J＝8.4Hz,2H),7.18(d,J＝8.4Hz,2H),4.61(d,J＝13.2Hz,1H),3.81(d,J＝14.0Hz,1H),3.04–2.95(m,1H),2.90–2.75(m,2H),2.55–2.45(m,1H),2.08(s,3H),1.96–1.80(m,2H),1.80–1.65(m,1H),1.25–1.11(m,2H)。

intermediate 4

1- (4- (((4-bromophenyl) sulfonyl) methyl) piperidin-1-yl) ethan-1-one

To a stirred solution of 1- (4- (((4-bromophenyl) thio) methyl) piperidin-1-yl) ethan-1-one intermediate 3(3.90g, 11.88mmol) in DCM (60mL) was added m-chloroperbenzoic acid (60%) (10.25g, 35.64mmol) portionwise at 0 deg.C. The reaction mixture was warmed to room temperature and stirred for 16 h. By TLC [ mobile phase: 10% methanol in DCM ] the progress of the reaction was monitored. After completion of the reaction, the reaction mixture was quenched with saturated aqueous sodium thiosulfate solution (50 mL). The layers were separated and the organic layer was washed with saturated aqueous sodium bicarbonate (2 × 50 mL). The organic layer was dried over sodium sulfate, filtered and concentrated to dryness under reduced pressure to obtain the title compound intermediate 4 as an off-white solid (4.02g, crude). This compound was used in the next step without further purification.

Analyzing data:

LCMS(ESI):m/z＝361.90[M+H]⁺(⁸¹Br)。

intermediate 5

1- (4- (((4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) sulfonyl) methyl) piperidin-1-yl) ethan-1-one

To a reaction tube was added a solution of 1- (4- (((4-bromophenyl) sulfonyl) methyl) piperidin-1-yl) ethan-1-one intermediate 4(2.00g, 5.55mmol), bis (pinacolato) diboron (1.70g, 6.66mmol) and potassium acetate (1.63g, 16.65mmol) in 1, 4-dioxane (30 mL). The tube was sealed and degassed by purging with nitrogen for 15 min. Bis (triphenylphosphine) palladium (II) dichloride (0.060g, 0.083mmol) was added to the reaction mixture under a nitrogen atmosphere and purging with nitrogen was continued for 5 min. The reaction mixture was heated to 90 ℃ for 4 h. By TLC [ mobile phase: 10% methanol in DCM ] the progress of the reaction was monitored. After completion of the reaction, the reaction mixture was cooled to room temperature and concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography (100-200 mesh, gradient 0-5% methanol in DCM) to give the title compound intermediate 5 as a black solid (1.50g, 66%).

Analyzing data:

LCMS(ESI)m/z＝408.21[M+H]⁺(Borate ester), 326.04[ M + H]⁺(corresponding to boric acid).

Synthesis scheme 2

Synthesis of Compound 1

1- (4- (((2',4' -difluoro- [1,1' -biphenyl ] -4-yl) sulfonyl) methyl) piperidin-1-yl) ethan-1-one

(NASMP-01)

To the reaction tube was added a solution of 1- (4- (((4-bromophenyl) sulfonyl) methyl) piperidin-1-yl) ethan-1-one intermediate 4(0.500g, 1.39mmol), 2- (2, 4-difluorophenyl) -4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan (0.366g, 1.52mmol) and sodium carbonate (0.367g, 3.46mmol) in a mixture of 1, 4-dioxane-water (3:1, 8 mL). The tube was sealed and degassed by purging with argon for 15 min. Tetrakis (triphenylphosphine) palladium (0) (0.160g, 0.139mmol) was added to the reaction mixture under an argon atmosphere and purging with argon was continued for 5 min. The reaction mixture was heated at 90 ℃ for 12 h. By TLC [ mobile phase: 10% methanol in DCM]The progress of the reaction was monitored. After completion of the reaction, the reaction mixture was cooled to room temperature and concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography (230-400 mesh, gradient 0-10% methanol in DCM). The compound is purified by preparative HPLC (mobile phase: 0.5% formic acid in acetonitrile/water mixture; solid phase: C₁₈Silica) to give the title compound as an off-white solid, compound 1(0.220g, 40%).

Analyzing data:

LCMS(ESI)m/z＝394.10[M+H]⁺。

HPLC (see general methods): retention time: 8.03 min; purity: 99.75 percent.

¹H NMR(400MHz,DMSO-d₆)δ(ppm):7.97(d,J＝8.4Hz,2H),7.78(d,J＝7.2Hz,2H),7.63–7.59(m,1H),7.33–7.28(m,1H),7.21–7.17(m,1H),4.19(d,J＝13.2Hz,1H),3.71(d,J＝14.0Hz,1H),3.28(d,J＝6.0Hz,2H),2.98(t,J＝8.4Hz,1H),2.62–2.52(m,1H),2.10–2.02(m,1H),1.93(s,3H),1.87–1.72(m,2H),1.32–1.20(m,1H),1.20–1.07(m,1H)。

Synthesis scheme 3

Synthesis of Compound 2

1- (4- (((3',4' -difluoro- [1,1' -biphenyl ] -4-yl) sulfonyl) methyl) piperidin-1-yl) ethan-1-one

(NASMP-02)

To the reaction tube was added a solution of 1- (4- (((4-bromophenyl) sulfonyl) methyl) piperidin-1-yl) ethan-1-one intermediate 4(0.500g, 1.38mmol), (3, 4-difluorophenyl) boronic acid (0.263g, 1.66mmol) and sodium carbonate (0.367g, 3.46mmol) in a mixture of 1, 4-dioxane: water (3:1, 13 mL). The tube was sealed and degassed by purging with nitrogen for 5min, after which tetrakis (triphenylphosphine) palladium (0) (0.159g, 0.138mmol) was added to the reaction mixture under a nitrogen atmosphere and purging with nitrogen was continued for a further 5 min. The reaction mixture was then heated at 90 ℃ for 16h under a nitrogen atmosphere. By TLC [ mobile phase: 50% ethyl acetate in hexane]The progress of the reaction was monitored. After completion of the reaction, the reaction mixture was cooled to room temperature and filtered through a celite pad. The celite pad was washed with ethyl acetate (2 × 100 mL). The combined organic layers were concentrated to dryness under reduced pressure. The crude product is passed through silica gel column chromatography (Gradient 10-50% ethyl acetate in hexanes). The resulting compound was further purified by stirring with diethyl ether (25mL) and n-pentane (50mL), and the solid was filtered off and dried under reduced pressure to give the title compound (synthetic compound 2) as an off-white solid (0.410g, 76%).

Analyzing data:

LCMS(ESI)m/z＝393.85[M+H]⁺。

HPLC (see general methods): retention time: 8.06 min; purity: 99.22 percent.

¹H NMR(400MHz,DMSO-d₆)δ(ppm):7.98(s,4H),7.97–7.88(m,1H),7.68–7.62(m,1H),7.62–7.54(m,1H),4.21(d,J＝13.2Hz,1H),3.72(d,J＝14.0Hz,1H),3.36(d,J＝6.4Hz,2H),3.00(t,J＝11.6Hz,1H),2.60–2.50(m,1H),2.10–2.00(m,1H),1.94(s,3H),1.84–1.70(m,2H),1.30–1.19(m,1H),1.19–1.05(m,1H)。

Synthesis scheme 4

Synthesis of Compound 3

1- (4- (((2',5' -difluoro- [1,1' -biphenyl ] -4-yl) sulfonyl) methyl) piperidin-1-yl) ethan-1-one

(NASMP-03)

To the reaction tube was added a solution of 1- (4- (((4-bromophenyl) sulfonyl) methyl) piperidin-1-yl) ethan-1-one intermediate 4(0.500g, 1.38mmol), (2, 5-difluorophenyl) boronic acid (0.263g, 1.66mmol) and sodium carbonate (0.367g, 3.46mmol) in a mixture of 1, 4-dioxane: water (3:1, 13 mL). The tube was sealed and degassed by purging with nitrogen for 10min, after which tetrakis (triphenylphosphine) palladium (0) (0.159g, 0.138mmol) was added to the reaction mixture under a nitrogen atmosphere and purging with nitrogen was continued for a further 5 min. The reaction mixture was then heated at 90 ℃ for 16h under a nitrogen atmosphere. By TLC [ mobile phase: 50% ethyl acetate in hexane]The progress of the reaction was monitored. After completion of the reaction, the reaction mixture was cooled to room temperature and filtered through a celite pad. The celite pad was washed with ethyl acetate (2 × 100 mL). The combined organic layers are placed inConcentrating to dryness under reduced pressure. The crude product is passed through silica gel column chromatography (Gradient 10-50% ethyl acetate in hexanes). The obtained compound was further purified by stirring with diethyl ether and n-pentane (50mL), filtered and dried under reduced pressure to give the title compound (synthesized compound 3) as an off-white solid (0.430g, 79%).

Analyzing data:

LCMS(ESI)m/z＝394.05[M+H]⁺。

HPLC (see general methods): retention time: 7.79 min; purity: 99.43 percent.

¹H NMR(400MHz,DMSO-d₆)δ(ppm):8.02(d,J＝8.0Hz,2H),7.87(d,J＝7.2Hz,2H),7.57–7.51(m,1H),7.48–7.41(m,1H),7.40–7.33(m,1H),4.23(d,J＝12.4Hz,1H),3.74(d,J＝13.2Hz,1H),3.38(d,J＝6.0Hz,2H),3.02(t,J＝11.2Hz,1H),2.57(t,J＝12.4Hz,1H),2.14–2.03(m,1H),1.96(s,3H),1.80(dd,J＝13.6&22.8Hz,2H),1.32–1.20(m,1H),1.20–1.06(m,1H)。

Synthesis scheme 5

Synthesis of Compound 4

4'- (((1-acetylpiperidin-4-yl) methyl) sulfonyl) -2-fluoro- [1,1' -biphenyl ] -4-carbonitrile

(NASMP-04)

To a reaction tube was added a solution of 1- (4- (((4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) sulfonyl) methyl) piperidin-1-yl) ethan-1-one intermediate 5(0.750g, 1.84mmol), 4-bromo-3-fluorobenzonitrile (0.405g, 2.03mmol) and sodium carbonate (0.487g, 4.60mmol) in a mixture of 1, 4-dioxane-water (3:1, 13 mL). The tube was sealed and degassed by purging with argon for 10 min. Tetrakis (triphenylphosphine) palladium (0) (0.210g, 0.180mmol) was added to the reaction mixture under an argon atmosphere and purging with argon was continued for 5 min. The reaction mixture was heated at 100 ℃ for 12 h. By TLC [ mobile phase: 10% methanol in DCM ] the progress of the reaction was monitored. After completion of the reaction, the reaction mixture was cooled to room temperature and concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography (230-400 mesh, gradient 0-5% methanol in DCM) to give the title compound (synthetic compound 4) as a white solid (0.210g, 29%).

Analyzing data:

LCMS(ESI)m/z＝401.10[M+H]⁺。

HPLC (see general methods): retention time: 7.63 min; purity: 99.25 percent.

¹H NMR(400MHz,DMSO-d₆)δ(ppm):8.08–8.03(m,3H),7.91–7.81(m,4H),4.23(d,J＝13.2Hz,1H),3.73(d,J＝13.2Hz,1H),3.39(d,J＝6.0Hz,2H),3.06–2.98(m,1H),2.61–2.50(m,1H),2.15–2.04(br m,1H),1.96(s,3H),1.87–1.73(m,2H),1.31–1.20(m,1H),1.20–1.07(m,1H)。

Synthesis scheme 6

Synthesis of Compound 5

4'- (((1-acetylpiperidin-4-yl) methyl) sulfonyl) -2-chloro- [1,1' -biphenyl ] -4-carbonitrile

(NASMP-05)

To a reaction tube were added 1- (4- (((4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) sulfonyl) methyl) piperidin-1-yl) ethan-1-one intermediate 5(0.750g, 1.84mmol), 4-bromo-3-chlorobenzeneNitrile (0.438g, 2.03mmol) and sodium carbonate (0.487g, 4.60mmol) in a 1, 4-dioxane-water (3:1, 13mL) mixture. The tube was sealed and degassed by purging with argon for 15 min. Tetrakis (triphenylphosphine) palladium (0) (0.213g, 0.184mmol) was added to the reaction mixture under an argon atmosphere and purging with argon was continued for 10 min. The reaction mixture was heated at 90 ℃ for 16 h. By TLC [ mobile phase: 10% methanol in DCM]The progress of the reaction was monitored. After completion of the reaction, the reaction mixture was cooled to room temperature and concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography (230-400 mesh, gradient 0-5% methanol in DCM). The product is purified by preparative HPLC (mobile phase: 0.5% formic acid in acetonitrile/water mixture; solid phase: C ₁₈Silica) to give the title compound (synthetic compound 5) as a white solid (0.250g, 32%).

Analyzing data:

LCMS(ESI)m/z＝417.10[M+H]⁺。

HPLC (see general methods): retention time: 8.01 min; purity: 99.52 percent.

¹H NMR(400MHz,DMSO-d₆)δ(ppm):8.24(s,1H),8.03(d,J＝8.0Hz,2H),7.96(d,J＝8.0Hz,1H),7.75(d,J＝8.0Hz,2H),7.68(d,J＝8.0Hz,1H),4.22(d,J＝13.6Hz,1H),3.73(d,J＝13.2Hz,1H),3.38(d,J＝6.0Hz,2H),3.05–2.97(m,1H),2.60–2.50(m,1H),2.16–2.04(br m,1H),1.95(s,3H),1.86–1.70(m,2H),1.32–1.20(m,1H),1.20–1.05(m,1H)。

Synthesis scheme 7

Synthesis of Compound 6

4'- (((1-acetylpiperidin-4-yl) methyl) sulfonyl) -4-chloro- [1,1' -biphenyl ] -2-carbonitrile

(NASMP-06)

To the reaction tube was added a solution of 2-bromo-5-chlorobenzonitrile (0.60g, 2.77mmol), 1- (4- (((4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) sulfonyl) methyl) piperidin-1-yl) ethan-1-one intermediate 5(1.35g, 3.32mmol) and sodium carbonate (0.68g, 6.42mmol) in a mixture of 1, 4-dioxane and water (4:1, 15 mL). The tube was sealed and degassed by purging with argon for 15min, after which tetrakis (triphenylphosphine) palladium (0) (0.32g, 0.27mmol) was added to the reaction mixture under an argon atmosphere, followed by purging with argon for 5 min. The reaction was heated at 90 ℃ for 16 h. By TLC [ mobile phase: 80% ethyl acetate in hexane ] the progress of the reaction was monitored. After completion of the reaction, the mixture was cooled to room temperature, filtered through a celite pad and the celite pad was washed with ethyl acetate (300 mL). The combined filtrates were concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography (230-400 mesh, gradient 50% ethyl acetate in hexane, then 60% ethyl acetate in DCM) to give the compound, which was stirred in ether (25 mL). The solid was filtered, washed with diethyl ether (50mL), pentane (50mL) and dried under reduced pressure to dryness to give the title compound (synthesized compound 6) as an off-white solid (0.61g 53%).

Analyzing data:

LCMS(ESI)m/z＝416.90[M+H]⁺。

HPLC (see general methods): retention time: 7.99 min; purity: 98.11 percent.

¹H NMR(400MHz,DMSO-d₆)δ(ppm):8.23(d,J＝2.0Hz,1H),8.08(d,J＝8.4Hz,2H),7.93(dd,J＝8.4,2.0Hz,1H),7.88(d,J＝8.4Hz,2H),7.72(d,J＝8.8Hz,1H),4.22(d,J＝13.2Hz,1H),3.73(d,J＝13.6Hz,1H),3.41(d,J＝6.0Hz,2H),3.06–2.97(m,1H),2.61–2.52(m,1H),2.15–2.05(m,1H),1.96(s,3H),1.85–1.72(m,2H),1.32–1.06(m,2H)。

Synthesis scheme 8

Combination of Chinese herbs To compound 7

1- (4- (((2' -fluoro-4 ' - (trifluoromethyl) - [1,1' -biphenyl ] -4-yl) sulfonyl) methyl) piperidin-1-yl) ethan-1-one

(NASMP-07)

To the reaction tube was added a solution of 1-bromo-2-fluoro-4- (trifluoromethyl) benzene (0.60g, 2.47mmol), 1- (4- (((4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) sulfonyl) methyl) piperidin-1-yl) ethan-1-one intermediate 5(1.21g, 2.96mmol) and sodium carbonate (0.653g, 6.17mmol) in a mixture of 1, 4-dioxane and water (4:1, 15 mL). The tube was sealed and degassed by purging with argon for 15min, after which tetrakis (triphenylphosphine) palladium (0) (0.29g, 0.25mmol) was added to the reaction mixture, followed by purging with argon for 5 min. The reaction mixture was heated at 90 ℃ for 16 h. By TLC [ mobile phase: 80% ethyl acetate in hexane]The progress of the reaction was monitored. After completion of the reaction, the reaction mixture was filtered through a pad of celite and the pad was washed with ethyl acetate (2 × 150 mL). The combined filtrates were concentrated to dryness under reduced pressure. The crude product is passed through silica gel column chromatography (Gradient 50% ethyl acetate in hexane, then 60% ethyl acetate in DCM) to give the compound, which was stirred in ether (20mL) for 15 min. The solid was filtered off and dried under reduced pressure to give the title compound (synthesized compound 7) as an off-white solid (0.31g, 28%).

Analyzing data:

LCMS(ESI)m/z＝443.90[M+H]⁺。

HPLC (see general methods): retention time: 8.60 min; purity: 99.66 percent.

¹H NMR(400MHz,DMSO-d₆)δ(ppm):8.06(d,J＝8.4Hz,2H),7.92–7.83(m,4H),7.75(d,J＝8.0Hz,1H),4.23(d,J＝13.2Hz,1H),3.74(d,J＝13.6Hz,1H),3.40(d,J＝6.0Hz,2H),3.06–2.98(m,1H),2.61–2.52(m,1H),2.15–2.04(m,1H),1.96(s,3H),1.88–1.73(m,2H),1.32–1.20(m,1H),1.20–1.06(m,1H)。

Synthesis scheme 9

Synthesis of Compound 8

1- (4- (((2',3' -difluoro- [1,1' -biphenyl ] -4-yl) sulfonyl) methyl) piperidin-1-yl) ethan-1-one

(NASMP-08)

To the reaction tube was added a solution of 1-bromo-2, 3-difluorobenzene (0.60g, 3.11mmol), 1- (4- (((4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) sulfonyl) methyl) piperidin-1-yl) ethan-1-one intermediate 5(1.52g, 3.73mmol) and sodium carbonate (0.82g, 7.77mmol) in a mixture of 1, 4-dioxane and water (4:1, 15 mL). The tube was sealed and degassed by purging with argon for 30min, after which tetrakis (triphenylphosphine) palladium (0) (0.36g, 0.31mmol) was added to the reaction mixture and purged again with argon for 5 min. The reaction mixture was then heated at 90 ℃ for 16 h. By TLC [ mobile phase: 100% Ethyl acetate]The progress of the reaction was monitored. After completion of the reaction, the reaction mixture was cooled to room temperature, filtered through a celite pad, the celite pad was washed with ethyl acetate (50mL) and the combined filtrate was concentrated to dryness under reduced pressure. The crude product is passed through silica gel column chromatography (Gradient 0-100% ethyl acetate in hexanes) to give the title compound (synthetic compound 8) as a white solid (0.30g, 25%).

Analyzing data:

LCMS(ESI)m/z＝393.95[M+H]⁺。

HPLC (see general methods): retention time: 7.98 min; purity: 95.43 percent.

¹H NMR(400MHz,DMSO-d₆)δ(ppm):8.01(d,J＝8.0Hz,2H),7.84(d,J＝7.2Hz,2H),7.55-7.47(m,1H),7.43–7.38(m,1H),7.36–7.30(m,1H),4.20(d,J＝13.2Hz,1H),3.70(d,J＝13.2Hz,1H),3.35(d,J＝6.4Hz,2H),3.03–2.95(m,1H),2.57–2.48(m,1H),2.12–2.00(m,1H),1.92(s,3H),1.84–1.70(m,2H),1.29–1.18(m,1H),1.18–1.04(m,1H)。

Synthesis scheme 10

Synthesis of Compound 9

1- (4- (((2',6' -difluoro- [1,1' -biphenyl ] -4-yl) sulfonyl) methyl) piperidin-1-yl) ethan-1-one

(NASMP-09)

To the reaction tube was added a solution of 2-bromo-1, 3-difluorobenzene (0.500g, 2.59mmol), 1- (4- (((4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) sulfonyl) methyl) piperidin-1-yl) ethan-1-one intermediate 5(2.109g, 5.18mmol) and sodium carbonate (0.686g, 6.47mmol) in a mixture of 1, 4-dioxane and water (4:1, 50 mL). The tube was sealed and degassed by purging with argon for 10min, after which tetrakis (triphenylphosphine) palladium (0) (0.299g, 0.259mmol) was added to the reaction mixture under an argon atmosphere and purging with argon was continued for a further 5 min. The reaction mixture was then heated at 90 ℃ for 16h under an argon atmosphere. By TLC [ mobile phase: 5% methanol in DCM ] the progress of the reaction was monitored. After completion of the reaction, the reaction mixture was filtered through a pad of celite and the pad was washed with ethyl acetate (2 × 150 mL). The combined filtrates were concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography (230-400 mesh, gradient 100% DCM, then 20-50% ethyl acetate in DCM). The obtained compound was further purified by stirring in ether (20mL) for 15min, followed by trituration with 10% ethyl acetate in ether (15 mL). The solid was filtered off and dried under reduced pressure to give the title compound (synthesized compound 9) as an off-white solid (0.190g, 19%).

Analyzing data:

LCMS(ESI)m/z＝394.00[M+H]⁺。

HPLC (see general methods): retention time: 7.88 min; purity: 98.49 percent.

¹H NMR(400MHz,DMSO-d₆)δ(ppm):8.04(d,J＝8.0Hz,2H),7.77(d,J＝7.6Hz,2H),7.60–7.50(m,1H),7.29(t,J＝8.4Hz,2H),4.23(d,J＝12.4Hz,1H),3.75(d,J＝13.2Hz,1H),3.39(d,J＝6.4Hz,2H),3.03(t,J＝11.2Hz,1H),2.58(t,J＝11.6Hz,1H),2.17–2.04(m,1H),1.96(s,3H),1.80(dd,J＝12.4&25.2Hz,2H),1.32–1.20(m,1H),1.20–1.06(m,1H)。

Synthesis scheme 11

Intermediate 6

4-bromo-3-fluorobenzenethiol

To a solution of triphenylphosphine (8.63g, 32.91mmol) in DCM (30mL) and DMF (1mL) was added 4-bromo-3-fluorobenzenesulfonyl chloride (3.00g, 10.97mmol) dropwise at room temperature. The reaction was stirred at room temperature for 16 h. By TLC [ mobile phase: 10% ethyl acetate in hexane ] the progress of the reaction was monitored. After completion of the reaction, 1M aqueous HCl (50mL) was added to the reaction mixture and the layers were separated. The organic layer was concentrated to dryness under reduced pressure. The residue was dissolved in 1M aqueous NaOH (50mL) and the mixture was filtered through a pad of celite. The filtrate was washed with diethyl ether (3 × 50mL), neutralized with 1M aqueous HCl (60mL) and extracted with diethyl ether (3 × 50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure to give the title compound, intermediate 6, as a colorless oil (1.41g, crude). This compound was used in the next step without further purification.

Intermediate 7

1- (4- (((4-bromo-3-fluorophenyl) thio) methyl) piperidin-1-yl) ethan-1-one

To a solution of 4-bromo-3-fluorobenzenethiol intermediate 6(1.30g, 6.31mmol) in acetone (40mL) under an argon atmosphere was added cesium carbonate (3.73g, 11.46mmol) at room temperature, and the reaction mixture was stirred for 30 min. To the resulting reaction mixture was added (1-acetylpiperidin-4-yl) methyl methanesulfonate intermediate 2(1.35g, 5.73mmol) at room temperature. The reaction mixture was then heated at 60 ℃ for 16 h. By TLC [ mobile phase: 50% ethyl acetate in hexane ]The progress of the reaction was monitored. After completion of the reaction, the reaction mixture was cooled to room temperature, filtered through a celite pad and the filtrate was concentrated to dryness under reduced pressure. The crude product is passed through silica gel column chromatography (Gradient 10-50% ethyl acetate in hexanes) to give the title compound intermediate 7 as a light yellow thick oil (1.63g, 82%).

Analyzing data:

LCMS(ESI)m/z＝348.05[M+H]⁺(⁸¹Br)。

intermediate 8

1- (4- (((4-bromo-3-fluorophenyl) sulfonyl) methyl) piperidin-1-yl) ethan-1-one

To a solution of 1- (4- (((4-bromo-3-fluorophenyl) thio) methyl) piperidin-1-yl) ethan-1-one intermediate 7(1.60g, 4.62mmol) in DCM (40mL) at 0 deg.C was added m-chloroperbenzoic acid (60%) (3.98g, 13.86mmol) portionwise. The reaction mixture was warmed to room temperature and stirred for 16 h. By TLC [ mobile phase: 5% methanol in DCM ] the progress of the reaction was monitored. After completion of the reaction, the reaction mixture was quenched with saturated aqueous sodium thiosulfate (25mL), the layers were separated, and the organic layer was washed with saturated aqueous sodium bicarbonate (2 × 25 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure to give the title compound intermediate 8(1.63g, crude) as an off-white solid. This compound was used in the next step without further purification.

Analyzing data:

LCMS(ESI)m/z＝377.80[M+H]⁺(⁷⁹Br)。

intermediate 9

1- (4- (((3-fluoro-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) sulfonyl) methyl) piperidin-1-yl) ethan-1-one

To the reaction tube was added a solution of 1- (4- (((4-bromo-3-fluorophenyl) sulfonyl) methyl) piperidin-1-yl) ethan-1-one intermediate 8(1.60g, 4.23mmol), bis (pinacolato) diboron (1.29g, 5.07mmol) and potassium acetate (1.25g, 12.69mmol) in 1, 4-dioxane (25 mL). The tube was sealed and degassed by purging with nitrogen for 15min, after which 1, 1' -bis (diphenylphosphino) ferrocene dichloropalladium (II), DCM complex (0.104g, 0.126mmol) were added to the reaction mixture under a nitrogen atmosphere and purging with nitrogen was continued for a further 5 min. The reaction mixture was then heated to 90 ℃ for 16 h. By TLC [ mobile phase: 5% methanol in DCM ] the progress of the reaction was monitored. After completion of the reaction, the reaction mixture was cooled to room temperature, filtered through a pad of celite and washed with ethyl acetate (75 mL). The combined filtrates were concentrated to dryness under reduced pressure. The obtained residue was stirred in pentane (2 × 25mL), the solvent was decanted and the solid was dried to dryness under reduced pressure to give the title compound intermediate 9(3.01g, crude) as a dark brown solid. This compound was used in the next step without further purification.

Analyzing data:

LCMS(ESI)m/z＝343.90[M+H]⁺(corresponding to boric acid).

Synthesis scheme 12

Synthesis of Compound 10

4' - (((1-acetylpiperidin-4-yl) methyl) sulfonyl) -2' -fluoro- [1,1' -biphenyl ] -4-carbonitrile

(NASMP-10)

To the reaction tube was added a solution of 1- (4- (((4-bromo-3-fluorophenyl) sulfonyl) methyl) piperidin-1-yl) ethan-1-one intermediate 8(1.00g, 2.64mmol), (4-cyanophenyl) boronic acid (0.427g, 2.91mmol) and sodium carbonate (0.700g, 6.61mmol) in a mixture of 1, 4-dioxane-water (3:1, 13 mL). The tube was sealed and degassed by purging with argon for 10 min. Tetrakis (triphenylphosphine) palladium (0) (0.306g, 0.264mmol) was added to the reaction mixture under an argon atmosphere and purging with argon was continued for 10 min. The reaction mixture was heated at 90 ℃ for 12 h. By TLC [ mobile phase: 10% methanol in DCM ] the progress of the reaction was monitored. After completion of the reaction, the reaction mixture was cooled to room temperature and concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography (230-400 mesh, gradient 0-10% methanol in DCM) to give the title compound (synthetic compound 10) as a white solid (0.450g, 43%).

Analyzing data:

LCMS(ESI)m/z＝401.05[M+H]⁺。

HPLC (see general methods): retention time: 7.86 min; purity: 98.37 percent.

¹H NMR(400MHz,DMSO-d₆)δ(ppm):8.01(d,J＝8.4Hz,2H),7.96–7.86(m,3H),7.84(d,J＝7.2Hz,2H),4.23(d,J＝12.8Hz,1H),3.74(d,J＝13.6Hz,1H),3.45(d,J＝6.4Hz,2H),3.07–2.98(m,1H),2.62–2.52(m,1H),2.15–2.04(br m,1H),1.96(s,3H),1.88–1.73(m,2H),1.32–1.20(m,1H),1.20–1.08(m,1H)。

Synthesis scheme 13

Synthesis of Compound 11

1- (4- (((4- (3, 5-difluoropyridin-2-yl) -3-fluorophenyl) sulfonyl) methyl) piperidin-1-yl) ethan-1-one

(NASMP-11)

To the reaction tube was added a solution of 2-bromo-3, 5-difluoropyridine (0.60g, 3.09mmol), 1- (4- (((3-fluoro-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) sulfonyl) methyl) piperidin-1-yl) ethan-1-one intermediate 9(1.45g, 3.40mmol), and sodium carbonate (0.76g, 7.17mmol) in a mixture of 1, 4-dioxane-water (4:1, 15 mL). The tube was sealed and degassed by purging with argon for 15min, after which tetrakis (triphenylphosphine) palladium (0) (0.36g, 0.30mmol) was added to the reaction mixture under an argon atmosphere and purging with argon was continued for a further 5 min. The reaction mixture was heated at 90 ℃ for 16 h. By TLC [ mobile phase: 70% ethyl acetate in hexane]The progress of the reaction was monitored. After completion of the reaction, the reaction mixture was cooled to room temperature, filtered through a pad of celite and the pad was washed with ethyl acetate (2 × 150 mL). The combined organic layers were concentrated to dryness under reduced pressure. Passing the crude product through silica gelColumn chromatography (1)Gradient 50-100% ethyl acetate in hexanes). The compound was triturated with ether (25mL) and the solid was filtered off and dried. The compound is purified by preparative HPLC (mobile phase: 0.5% formic acid in acetonitrile/water mixture; solid phase: C ₁₈Silica) was further purified. The product obtained was dissolved with saturated aqueous sodium bicarbonate (25mL) and extracted with DCM (3 × 50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to give the title compound (synthetic compound 11) as an off-white solid (0.39g, 31%).

Analyzing data:

LCMS(ESI)m/z＝412.90[M+H]⁺。

HPLC (see general methods): retention time: 7.43 min; purity: 97.73 percent.

¹H NMR(400MHz,DMSO-d₆)δ(ppm):8.71(d,J＝2.0Hz,1H),8.19–8.14(m,1H),7.95–7.86(m,3H),4.20(d,J＝13.2Hz,1H),3.71(d,J＝13.6Hz,1H),3.44(d,J＝6.4Hz,2H),3.04–2.92(m,1H),2.60–2.50(m,1H),2.21–2.02(m,1H),1.93(s,3H),1.83–1.70(m,2H),1.30–1.05(m,2H)。

Synthesis scheme 14

Intermediate 10

4-bromo-2- (trifluoromethyl) benzenethiol

To a stirred solution of 4-bromo-2- (trifluoromethyl) benzenesulfonyl chloride (4.00g, 12.36mmol) in toluene (20mL) at 0 deg.C was added dropwise a solution of triphenylphosphine (9.72g, 37.09mmol) in toluene (8 mL). The reaction mixture was stirred at 5 ℃ to 10 ℃ for 45 min. The progress of the reaction was monitored by TLC [ mobile phase, 25% ethyl acetate in hexane ]. After completion of the reaction, the reaction mixture was quenched with water (8mL), the obtained precipitate was filtered and the filtrate was sent to a separatory funnel. Then, 1N aqueous KOH (20mL) was added to the filtrate, three layers were observed, and the upper layer was discarded. The remaining layer was extracted with toluene (2 × 50mL) and the toluene layer was discarded. The aqueous layer was acidified with citric acid to pH about 3 and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine (50mL), dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure to give the title compound intermediate 10(3.00g, crude) as a brown liquid. This compound was used in the next step without further purification.

Intermediate 11

1- (4- (((4-bromo-2- (trifluoromethyl) phenyl) thio) methyl) piperidin-1-yl) ethan-1-one

To a stirred solution of 4-bromo-2- (trifluoromethyl) benzenethiol intermediate 10(3.00g, 11.68mmol) in acetone (20mL) at room temperature was added a solution of cesium carbonate (6.92g, 21.24mmol) and (1-acetylpiperidin-4-yl) methylmethanesulfonate intermediate 2(2.50g, 10.62mmol) in acetone (5 mL). The reaction mixture was then heated at 60 ℃ for 16 h. By TLC [ mobile phase: 70% ethyl acetate in hexane ] the progress of the reaction was monitored. After completion of the reaction, the reaction mixture was cooled to room temperature, filtered through a celite pad and the filtrate was concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography (100-200 gradient 0-70% ethyl acetate in hexane) to give the title compound, intermediate 11, as a yellow oil (3.50g 83%).

Analyzing data:

LCMS(ESI):m/z＝398.15[M+H]⁺(⁸¹Br)。

intermediate 12

1- (4- (((4-bromo-2- (trifluoromethyl) phenyl) sulfonyl) methyl) piperidin-1-yl) ethan-1-one

To a stirred solution of 1- (4- (((4-bromo-2- (trifluoromethyl) phenyl) thio) methyl) piperidin-1-yl) ethan-1-one intermediate 11(3.50g, 8.83mmol) in DCM (35mL) was added m-chloroperbenzoic acid (60%) (4.57g, 26.49mmol) portionwise at 0 ℃. The reaction mixture was warmed to room temperature and stirred for 16 h. By TLC [ mobile phase: 80% ethyl acetate in hexane ] the progress of the reaction was monitored. After completion of the reaction, the reaction mixture was quenched with saturated aqueous sodium thiosulfate solution and the layers were separated. The organic layer was washed with saturated aqueous sodium bicarbonate (2 × 50mL) and brine (50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to give the title compound, intermediate 12, as a yellow oil (3.00 g). This compound was used in the next step without further purification.

Analyzing data:

LCMS(ESI):m/z＝429.85[M+H]⁺(⁸¹Br)。

synthesis of Compound 12

1- (4- (((2',4' -difluoro-3- (trifluoromethyl) - [1,1' -biphenyl ] -4-yl) sulfonyl) methyl) piperidin-1-yl) ethan-1-one

(NASMP-12)

To the reaction tube was added a solution of 1- (4- (((4-bromo-2- (trifluoromethyl) phenyl) sulfonyl) methyl) piperidin-1-yl) ethan-1-one intermediate 12(1.00g, 2.33mmol), 2- (2, 4-difluorophenyl) -4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan (0.67g, 2.80mmol) and sodium carbonate (0.61g, 5.83mmol) in a mixture of 1, 4-dioxane and water (4:1, 15 mL). The tube was sealed and degassed by purging with argon for 15min, after which tetrakis (triphenylphosphine) palladium (0) (0.27g, 0.23mmol) was added to the reaction mixture and purged again with argon for 5 min. The reaction mixture was then heated at 90 ℃ for 16 h. By TLC [ mobile phase: 70% ethyl acetate in hexane ] the progress of the reaction was monitored. After completion of the reaction, the reaction mixture was cooled to room temperature, and filtered through a celite pad, and the celite pad was washed with ethyl acetate (50 mL). The combined filtrates were concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography (230-400 mesh, gradient 0-100% ethyl acetate in hexane) to give the title compound (synthesized compound 12) as a white viscous solid (0.24g, 22%).

Analyzing data:

LCMS(ESI)m/z＝461.90[M+H]⁺。

HPLC (see general methods): retention time: 8.65 min; purity: 98.14 percent.

¹H NMR(400MHz,DMSO-d₆)δ(ppm):8.31(d,J＝8.8Hz,1H),8.15(s,2H),7.83–7.75(m,1H),7.53–7.46(m,1H),7.33–7.27(m,1H),4.26(d,J＝13.2Hz,1H),3.75(d,J＝13.2Hz,1H),3.40(d,J＝6.4Hz,2H),3.10–3.00(m,1H),2.62–2.52(m,1H),2.30–2.20(m,1H),1.96(s,3H),1.90–1.75(m,2H),1.35–1.10(m,2H)。

Synthesis scheme 15

Intermediate 13

2-bromo-5-mercaptobenzamides

5-amino-2-bromoxynil (2.00g, 10.15mmol) was dissolved in concentrated HCl (4mL) and cooled to 0 ℃ in an ice bath. Adding NaNO over a period of 10min₂A solution of (0.728g, 10.55mmol) in water (6mL) was added dropwise to the reaction mixture. The cold diazonium salt solution was then added to a solution of potassium O-ethyl xanthate (3.31g, 20.30mmol) in water (6 mL). Then will beThe reaction mixture was warmed to room temperature and the mixture was heated at 75 ℃ for 3 h. The reaction mixture was cooled to 0 ℃ and saturated NaHCO₃The aqueous solution was basified to pH 8. The mixture was extracted with diethyl ether (3 × 50 mL). The combined organic layers were passed over anhydrous Na₂SO₄Dried, filtered and concentrated to dryness under reduced pressure. The residue was dissolved in methanol (70mL) and freshly ground KOH pellets (2.84g, 50.75mmol) were added. The reaction mixture was heated to reflux under an argon atmosphere for 17 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. Water (40mL) was added to the obtained residue, and the resulting mixture was washed with diethyl ether (50 mL). The aqueous layer was purified by dropwise addition of 3NH ₂SO₄Acidified to pH 1-2 and extracted with DCM (3 × 50 mL). The combined organic layers were washed with water (50mL), dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure to give the title compound intermediate 13 as a yellow oil (1.20g, crude). This compound was used in the next step without further purification.

Analyzing data:

LCMS(ESI)m/z＝233.85[M+H]⁺(⁸¹Br)。

intermediate 14

5- (((1-acetylpiperidin-4-yl) methyl) thio) -2-bromobenzamide

To a stirred solution of 2-bromo-5-mercaptobenzamide intermediate 13(1.10g, 4.74mmol) and (1-acetylpiperidin-4-yl) methylmethanesulfonate intermediate 2(1.12g, 4.74mmol) in acetone (30mL) was added cesium carbonate (1.85g, 5.69mmol) at room temperature. The reaction mixture was heated to reflux for 16 h. By TLC [ mobile phase: 60% ethyl acetate in hexane ] the progress of the reaction was monitored. After completion of the reaction, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in water (60mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (100-200 mesh, gradient 10-50% ethyl acetate in hexane) to give the title compound intermediate 14 as a brown solid (1.55g, 88%).

Analyzing data:

LCMS(ESI)m/z＝370.95[M+H]⁺(⁷⁹Br)。

intermediate 15

5- (((1-acetylpiperidin-4-yl) methyl) thio) -2-bromoxynil

To a stirred solution of 5- (((1-acetylpiperidin-4-yl) methyl) thio) -2-bromobenzamide intermediate 14(1.50g, 4.04mmol) and pyridine (0.652mL, 8.08mmol) in 1, 4-dioxane (30mL) was added TFAA (0.626mL, 4.44mmol) dropwise at 0 ℃. The reaction mixture was warmed to room temperature and stirred for 1.5 h. By TLC [ mobile phase: 50% ethyl acetate in hexane ] the progress of the reaction was monitored. After completion of the reaction, the reaction mixture was quenched with water (60mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (100-200 mesh, gradient 0-50% ethyl acetate in hexane) to give the title compound intermediate 15 as a light yellow thick oil (1.35g, 95%).

Analyzing data:

LCMS(ESI)m/z＝352.95[M+H]⁺(⁷⁹Br)。

intermediate 16

5- (((1-acetylpiperidin-4-yl) methyl) sulfonyl) -2-bromoxynil

To a stirred solution of 5- (((1-acetylpiperidin-4-yl) methyl) thio) -2-bromoxynil intermediate 15(1.30g, 3.69mmol) in DCM (30mL) was added m-chloroperbenzoic acid (55%) (3.47g, 11.07mmol) dropwise at room temperature. The reaction mixture was stirred at room temperature for 16 h. By TLC [ mobile phase: 60% ethyl acetate in hexane ] the progress of the reaction was monitored. After completion of the reaction, the reaction mixture was diluted with DCM (70mL) and washed with saturated aqueous sodium bicarbonate (2 × 50mL) and brine (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography (100-200 mesh, gradient 10-60% ethyl acetate in hexanes) to give the title compound intermediate 16 as a brown thick oil (1.20g, 84%).

Analyzing data:

¹H NMR(400MHz,DMSO-d₆)δ(ppm):8.44(d,J＝2.0Hz,1H),8.15(d,J＝8.0Hz,1H),8.07(dd,J＝8.8,2.4Hz,1H),4.19(d,J＝13.2Hz,1H),3.69(d,J＝13.6Hz,1H),3.41(d,J＝6.8Hz,2H),3.03–2.94(m,1H),2.58–2.48(m,1H),2.08–1.95(m,1H),1.92(s,3H),1.79–1.67(m,2H),1.25–1.01(m,2H)。

synthesis of Compound 13

4- (((1-acetylpiperidin-4-yl) methyl) sulfonyl) -2',4' -difluoro- [1,1' -biphenyl ] -2-carbonitrile

(NASMP-13)

To the reaction tube was added a solution of 5- (((1-acetylpiperidin-4-yl) methyl) sulfonyl) -2-bromoxynil intermediate 16(1.20g, 3.11mmol), 2- (2, 4-difluorophenyl) -4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan (0.897g, 3.73mmol) and sodium carbonate (0.825g, 7.78mmol) in a mixture of 1, 4-dioxane: water (5:1, 24 mL). The tube was sealed and degassed by purging with nitrogen for 15min, after which tetrakis (triphenylphosphine) palladium (0) (0.36g, 0.30mmol) was added under nitrogen atmosphere and purging with nitrogen continued for 5 min. The reaction mixture was heated at 100 ℃ for 16 h. By TLC [ mobile phase: 60% ethyl acetate in hexane ] the progress of the reaction was monitored. After completion of the reaction, the reaction mixture was cooled to room temperature and concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography (100-200 mesh, gradient 10-60% ethyl acetate in hexane) to give the title compound (synthesized compound 13) as a white solid (0.40g, 31%).

Analyzing data:

LCMS(ESI):m/z＝419.04[M+H]⁺。

HPLC (see general methods): retention time: 7.87 min; purity: 98.52 percent.

¹H NMR(400MHz,DMSO-d₆)δ(ppm):8.51(d,J＝1.6Hz,1H),8.26(dd,J＝8.4,1.6Hz,1H),7.88(d,J＝8.0Hz,1H),7.70–7.62(m,1H),7.56–7.48(m,1H),7.34–7.28(m,1H),4.20(d,J＝14.0Hz,1H),3.71(d,J＝13.6Hz,1H),3.47(d,J＝6.8Hz,2H),3.06–2.96(m,1H),2.64–2.52(m,1H),2.16–2.05(m,1H),1.93(s,3H),1.85–1.70(m,2H),1.30–1.19(m,1H),1.17–1.05(m,1H)。

Synthesis scheme 16

Intermediate 17

4- (hydroxymethyl) -N, N-dimethylpiperidine-1-carboxamide

To a stirred solution of piperidin-4-ylmethanol (5.00g, 43.41mmol) in DCM (50mL) was added triethylamine (12.70mL, 91.16mmol) and the reaction mixture was stirred for 15 min. To the reaction mixture was added dimethylcarbamoyl chloride (4.19mL, 45.50mmol) dropwise at 0 ℃. The reaction mixture was warmed to room temperature and stirred for 3 h. By TLC [ mobile phase: 5% methanol in DCM ] the progress of the reaction was monitored. After completion of the reaction, the reaction mixture was quenched by addition of ice water (50mL) and extracted with DCM (2 × 150 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure to give the title compound intermediate 17(5.05g, crude) as a colorless thick oil. This compound was used in the next step without further purification.

Analyzing data:

LCMS(ESI)m/z＝186.95[M+H]⁺。

intermediate 18

(1- (dimethylcarbamoyl) piperidin-4-yl) methylmethanesulfonate

To a stirred solution of 4- (hydroxymethyl) -N, N-dimethylpiperidine-1-carboxamide intermediate 17(5.00g, 26.84mmol) in DCM (50mL) cooled at 0 ℃ was added triethylamine (7.48mL, 53.68mmol) followed by methanesulfonyl chloride (2.28mL, 29.52 mmol). The reaction mixture was then warmed to room temperature and stirred for 16 h. By TLC [ mobile phase: 5% methanol in DCM ] the progress of the reaction was monitored. After completion of the reaction, the reaction mixture was quenched with water (50mL), the layers were separated and the organic layer was washed with water (50mL) and brine (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure to give the title compound intermediate 18(4.54g, crude) as a colorless thick oil. This compound was used in the next step without further purification.

Analyzing data:

LCMS(ESI)m/z＝265.20[M+H]⁺。

intermediate 19

4- (((4-bromophenyl) thio) methyl) -N, N-dimethylpiperidine-1-carboxamide

To a stirred solution of 4-bromobenzenethiol (3.14g, 16.64mmol) in acetone (70mL) under an argon atmosphere was added cesium carbonate (9.85g, 30.26mmol) and the reaction mixture was stirred at room temperature for 30 min. To the resulting mixture was added (1- (dimethylcarbamoyl)Yl) piperidin-4-yl) methyl methanesulfonate intermediate 18(4.00g, 15.13mmol), and the reaction mixture was heated to 60 ℃ for 16 h. By TLC [ mobile phase: 50% ethyl acetate in hexane]The progress of the reaction was monitored. After completion of the reaction, the reaction mixture was filtered through a celite pad and the filtrate was concentrated to dryness under reduced pressure. The crude product is passed through silica gel column chromatography (Gradient 50-100% ethyl acetate in hexanes) to give the title compound, intermediate 19, as a white solid (3.20g, 59%).

Analyzing data:

LCMS(ESI)m/z＝359.05[M+H]⁺(⁸¹Br)。

intermediate 20

4- (((4-bromophenyl) sulfonyl) methyl) -N, N-dimethylpiperidine-1-carboxamide

To a stirred solution of 4- (((4-bromophenyl) thio) methyl) -N, N-dimethylpiperidine-1-carboxamide intermediate 19(3.10g, 8.67mmol) in DCM (50mL) at 0 ℃ was added m-chloroperbenzoic acid (60%) (7.48g, 26.02 mmol). The reaction mixture was then warmed to room temperature and stirred for 16 h. By TLC [ mobile phase: 5% methanol in DCM ] the progress of the reaction was monitored. After completion of the reaction, the reaction mixture was quenched with saturated aqueous sodium thiosulfate (50mL), the layers were separated, and the organic layer was washed with saturated aqueous sodium bicarbonate (2 × 50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure to give the title compound, intermediate 20, as an off-white solid (3.00g, crude). This compound was used in the next step without further purification.

Analyzing data:

LCMS(ESI)m/z＝388.90[M+H]⁺(⁷⁹Br)。

synthesis of Compound 14

4- (((2',4' -difluoro- [1,1' -biphenyl ] -4-yl) sulfonyl) methyl) -N, N-dimethylpiperidine-1-carboxamide

(NASMP-14)

To the reaction tube was added a solution of 4- (((4-bromophenyl) sulfonyl) methyl) -N, N-dimethylpiperidine-1-carboxamide intermediate 20(1.00g, 2.56mmol), 2- (2, 4-difluorophenyl) -4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan (0.678g, 2.82mmol) and sodium carbonate (0.629g, 5.93mmol) in a mixture of 1, 4-dioxane and water (4:1, 15 mL). The tube was sealed and degassed with argon for 15min, after which tetrakis (triphenylphosphine) palladium (0) (0.296g, 0.25mmol) was added under an argon atmosphere and purging with argon was continued for 5 min. The reaction mixture was then heated at 90 ℃ for 16 h. By TLC [ mobile phase: 60% ethyl acetate in hexane]The progress of the reaction was monitored. After completion of the reaction, the reaction mixture was filtered through a pad of celite and the pad was washed with ethyl acetate (2 × 150 mL). The combined filtrates were concentrated to dryness under reduced pressure. The crude product is passed through silica gel column chromatography (Gradient 50-100% ethyl acetate in hexanes) to afford the compound, which was stirred in ether (25mL) for 15 min. The solid was filtered, washed with diethyl ether (15mL) and pentane (15mL) and dried under reduced pressure to give the title compound (syn compound 14) as an off-white solid (0.69g, 64%).

Analyzing data:

LCMS(ESI)m/z＝422.95[M+H]⁺。

HPLC (see general methods): retention time: 8.33 min; purity: 99.26 percent.

¹H NMR(400MHz,DMSO-d₆)δ(ppm):8.01(d,J＝8.0Hz,2H),7.82(d,J＝7.2Hz,2H),7.72–7.58(m,1H),7.48–7.41(m,1H),7.29–7.23(m,1H),3.46(d,J＝13.2Hz,2H),3.36(d,J＝6.4Hz,2H),2.69(s,6H),2.72–2.62(m,2H),2.08–1.94(m,1H),1.77(d,J＝12.0Hz,2H),1.32–1.20(m,2H)。

Synthesis scheme 17

Intermediate 21

1- (4- (hydroxymethyl) piperidin-1-yl) propan-1-one

To a stirred solution of piperidin-4-ylmethanol (5.00g, 43.41mmol) in DCM (60mL) was added triethylamine (7.87mL, 56.43mmol) and DMAP (1.06g, 8.68mmol) and the reaction mixture was cooled to 0 ℃ in an ice bath. Propionyl chloride (4.17mL, 47.75mmol) was then added to the reaction mixture at 0 ℃. The reaction mixture was warmed to room temperature and stirred for 3 h. By TLC [ mobile phase: 10% methanol in DCM ] the progress of the reaction was monitored. After completion of the reaction, the reaction mixture was diluted with water (100mL) and extracted with DCM (3X 50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure to give the title compound, intermediate 21, as a colorless oil (4.25g, crude). This compound was used in the next step without further purification.

Analyzing data:

LCMS(ESI)m/z＝172.00[M+H]⁺。

intermediate 22

(1-Propoylpiperidin-4-yl) methyl methanesulfonate

To a stirred solution of 1- (4- (hydroxymethyl) piperidin-1-yl) propan-1-one intermediate 21(4.20g, 24.53mmol) in DCM (50mL) at 0 deg.C was added triethylamine (4.44mL, 31.88mmol), followed by methanesulfonyl chloride (2.28mL, 29.43 mmol). The reaction mixture was warmed to room temperature and stirred for 1 h. By TLC [ mobile phase: 5% methanol in DCM ] the progress of the reaction was monitored. After completion of the reaction, the reaction mixture was diluted with water (70mL) and extracted with DCM (2 × 60 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure to give the title compound intermediate 22(4.41g, crude) as a brown oil. This compound was used in the next step without further purification.

Analyzing data:

LCMS(ESI)m/z＝250.10[M+H]⁺。

intermediate 23

1- (4- (((4-bromophenyl) thio) methyl) piperidin-1-yl) propan-1-one

To a stirred solution of (1-propionylpiperidin-4-yl) methyl methanesulfonate intermediate 22(4.30g, 17.25mmol) and 4-bromobenzenethiol (3.59g, 18.97mmol) in acetone (60mL) was added cesium carbonate (6.74g, 20.70mmol) at room temperature. The reaction mixture was heated to reflux for 16 h. By TLC [ mobile phase: 60% ethyl acetate in hexane ] the progress of the reaction was monitored. After completion of the reaction, the reaction mixture was cooled to room temperature and concentrated to dryness under reduced pressure. Water (80mL) was added to the obtained residue and the resulting mixture was extracted with ethyl acetate (3 × 60 mL). The combined organic layers were washed with brine (30mL), dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography (100-200 mesh, gradient 10-60% ethyl acetate in hexanes) to afford the title compound intermediate 23 as a viscous yellow oil (4.85g, 82%).

Analyzing data:

LCMS(ESI)m/z＝344.15[M+H]⁺(⁸¹Br)。

intermediate 24

1- (4- (((4-bromophenyl) sulfonyl) methyl) piperidin-1-yl) propan-1-one

To a stirred solution of 1- (4- (((4-bromophenyl) thio) methyl) piperidin-1-yl) propan-1-one intermediate 23(4.80g, 14.02mmol) in DCM (60mL) at 0 ℃ was added m-chloroperbenzoic acid (55%) (13.24g, 42.21mmol) portionwise. The reaction mixture was warmed to room temperature and stirred for 16 h. By TLC [ mobile phase: 80% ethyl acetate in hexane ] the progress of the reaction was monitored. After completion of the reaction, the reaction mixture was diluted with DCM (100mL), washed with saturated aqueous sodium bicarbonate (100mL) and brine (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography (100-200 mesh, gradient 10-80% ethyl acetate in hexanes) to afford the title compound intermediate 24 as a yellow thick oil (4.30g, 82%).

Analyzing data:

LCMS(ESI)m/z＝374.10[M+H]⁺(⁷⁹Br)。

synthesis of Compound 15

1- (4- (((2',4' -difluoro- [1,1' -biphenyl ] -4-yl) sulfonyl) methyl) piperidin-1-yl) propan-1-one

(NASMP-15)

To the reaction tube was added a solution of 1- (4- (((4-bromophenyl) sulfonyl) methyl) piperidin-1-yl) propan-1-one intermediate 24(1.60g, 4.27mmol), 2- (2, 4-difluorophenyl) -4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan (1.23g, 5.13mmol), and sodium carbonate (1.13g, 10.72mmol) in a mixture of 1, 4-dioxane-water (5:1, 30 mL). The tube was sealed and degassed by purging with argon for 15 min. Tetrakis (triphenylphosphine) palladium (0) (0.495g, 0.427mmol) was added to the reaction mixture under an argon atmosphere, then purged with argon for 5 min. The reaction mixture was heated at 100 ℃ for 16 h. By TLC [ mobile phase: 60% ethyl acetate ] the progress of the reaction was monitored. After completion of the reaction, the reaction mixture was cooled to room temperature and concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography (100-200 mesh, gradient 10-70% ethyl acetate in hexane) to give the title compound (synthesized compound 15) as a white solid (0.73g, 42%).

Analyzing data:

LCMS(ESI):m/z＝408.10[M+H]⁺。

HPLC (see general methods): retention time: 8.40 min; purity: 99.03 percent.

¹H NMR(400MHz,DMSO-d₆)δ(ppm):8.01(d,J＝8.4Hz,2H),7.82(dd,J＝7.6,0.8Hz,2H),7.72–7.65(m,1H),7.48–7.46(m,1H),7.29–7.23(m,1H),4.25(d,J＝12.4Hz,1H),3.78(d,J＝14.0Hz,1H),3.36(d,J＝6.4Hz,2H),2.99(t,J＝11.6Hz,1H),2.58(t,J＝13.2Hz,1H),2.27(q,J＝7.6Hz,2H),2.14–2.02(m,1H),1.87–1.73(m,2H),1.30–1.06(m,2H),0.96(t,J＝7.2Hz,3H)。

Synthesis scheme 18

Intermediate 25

1- (4- (hydroxymethyl) -4-methylpiperidin-1-yl) ethan-1-one

To a stirred solution of 4- (hydroxymethyl) -4-methylpiperidine-1-carboxylic acid tert-butyl ester (2.50g, 10.90mmol) in 1, 4-dioxane (25mL) at 0 deg.C was added 4M HCl in 1, 4-dioxane (15 mL). The reaction mixture was warmed to room temperature and stirred for 4 h. By TLC [ mobile phase: 5% methanol in DCM ] the progress of the reaction was monitored. After completion of the reaction, the reaction mixture was concentrated to dryness under reduced pressure to obtain a white solid (1.90g, crude). To a stirred solution of the crude compound in DCM (40mL) was added triethylamine (6.40mL, 45.84mmol) at 0 deg.C, followed by acetic anhydride (1.20mL, 12.61 mmol). The reaction mixture was warmed to room temperature and stirred for 5 h. By TLC [ mobile phase: 5% methanol in DCM ] the progress of the reaction was monitored. After completion of the reaction, the reaction mixture was diluted with water (25mL) and extracted with DCM (3X 25 mL). The combined organic layers were washed with brine (50mL), dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure to give the title compound, intermediate 25, as a yellow oil (1.59g, crude). This compound was used in the next step without further purification.

Analyzing data:

LCMS(ESI)m/z＝171.90[M+H]⁺。

intermediate 26

(1-acetyl-4-methylpiperidin-4-yl) methyl methanesulfonate

To a stirred solution of 1- (4- (hydroxymethyl) -4-methylpiperidin-1-yl) ethan-1-one intermediate 25(1.59g, 9.28mmol) in DCM (15mL) at 0 ℃ was added triethylamine (2.58mL, 18.57mmol) followed by methanesulfonyl chloride (0.79mL, 10.21 mmol). The reaction mixture was warmed to room temperature and stirred for 16 h. By TLC [ mobile phase: 5% methanol in DCM ] the progress of the reaction was monitored. After completion of the reaction, the reaction mixture was diluted with DCM (50mL), washed with water (50mL) and brine (25 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure to give the title compound, intermediate 26, as a yellow oil (1.88g, crude). This compound was used in the next step without further purification.

Analyzing data:

LCMS(ESI)m/z＝250.00[M+H]⁺。

intermediate 27

1- (4- (((4-bromophenyl) thio) methyl) -4-methylpiperidin-1-yl) ethan-1-one

To a stirred solution of (1-acetyl-4-methylpiperidin-4-yl) methyl methanesulfonate intermediate 26(1.88g, 7.54mmol) and 4-bromobenzenethiol (1.56g, 8.29mmol) in acetone (35mL) was added cesium carbonate (4.91g, 15.08mmol) at room temperature. The reaction mixture was then heated at 60 ℃ for 16 h. By TLC [ mobile phase: 70% ethyl acetate in hexane ] the progress of the reaction was monitored. After completion of the reaction, the reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography (100-200 mesh, gradient 0-70% ethyl acetate in hexane) to give the title compound intermediate 27 as a yellow oil (1.00g, 39%).

Analyzing data:

LCMS(ESI)m/z＝343.90[M+H]⁺(⁸¹Br)。

intermediate 28

1- (4- (((4-bromophenyl) sulfonyl) methyl) -4-methylpiperidin-1-yl) ethan-1-one

To a stirred solution of 1- (4- (((4-bromophenyl) thio) methyl) -4-methylpiperidin-1-yl) ethan-1-one intermediate 27(1.00g, 2.92mmol) in DCM (10mL) at 0 ℃ was added m-chloroperbenzoic acid (60%) (2.52g, 8.76mmol) portionwise. The reaction mixture was then warmed to room temperature and stirred for 6 h. By TLC [ mobile phase: 70% ethyl acetate in hexane ] the progress of the reaction was monitored. After completion of the reaction, the reaction was quenched with saturated aqueous sodium thiosulfate (10mL) and stirred until all solids were dissolved. The organic layer was separated, washed with saturated aqueous sodium bicarbonate (2 × 25mL) and brine (25 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure to give the title compound intermediate 28(1.00g, crude) as a yellow oil. This compound was used in the next step without further purification.

Analyzing data:

LCMS(ESI)m/z＝376.05[M+H]⁺(⁸¹Br)。

intermediate 29

1- (4-methyl-4- (((4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) sulfonyl) methyl) piperidin-1-yl) ethan-1-one

To a reaction tube was added a solution of 1- (4- (((4-bromophenyl) sulfonyl) methyl) -4-methylpiperidin-1-yl) ethan-1-one intermediate 28(1.00g, 2.67mmol), bis (pinacolato) diboron (0.814g, 3.20mmol) and potassium acetate (0.786g, 8.01mmol) in 1, 4-dioxane (10 mL). The tube was sealed and degassed by purging with nitrogen for 15min, after which bis (triphenylphosphine) palladium (II) dichloride (0.038g, 0.053mmol) was added to the reaction mixture under a nitrogen atmosphere, followed by purging with nitrogen for a further 5 min. The reaction mixture was heated at 90 ℃ for 16 h. By TLC [ mobile phase: 100% ethyl acetate ] the progress of the reaction was monitored. After completion of the reaction, the reaction mixture was cooled to room temperature, filtered through a celite pad, and the celite pad was washed with ethyl acetate (50 mL). The combined filtrates were concentrated to dryness under reduced pressure. The residue was triturated with pentane (2 × 25mL), the solid was filtered off and dried under reduced pressure to give the title compound intermediate 29 as a brown solid (0.93g, crude). This compound was used in the next step without further purification.

Analyzing data:

LCMS(ESI)m/z＝340.05[M+H]⁺(corresponding to boric acid).

Synthesis of Compound 16

4'- (((1-acetyl-4-methylpiperidin-4-yl) methyl) sulfonyl) -4-chloro- [1,1' -biphenyl ] -2-carbonitrile

(NASMP-16)

To the reaction tube was added a solution of 2-bromo-5-chlorobenzonitrile (0.400g, 1.85mmol), 1- (4-methyl-4- (((4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) sulfonyl) methyl) piperidin-1-yl) ethan-1-one intermediate 29(0.934g, 2.22mmol), and sodium carbonate (0.490g, 4.63mmol) in a mixture of 1, 4-dioxane: water (3:1, 13 mL). The tube was sealed and degassed by purging with argon for 15min, after which tetrakis (triphenylphosphine) palladium (0) (0.213g, 0.184mmol) was added to the reaction mixture under an argon atmosphere, followed by purging with argon for a further 5 min. The reaction mixture was heated at 90 ℃ for 16 h. By TLC [ mobile phase: 100% ethyl acetate ] the progress of the reaction was monitored. After completion of the reaction, the reaction mixture was cooled to room temperature, filtered through a celite pad, and the celite pad was washed with ethyl acetate (50 mL). The combined filtrates were concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography (100-200 mesh, gradient 0-100% ethyl acetate in hexane) to give the title compound (synthesized compound 16) as a white solid (0.50g, 63%).

Analyzing data:

LCMS(ESI):m/z＝431.05[M+H]⁺。

HPLC (see general methods): retention time: 8.26 min; purity: 98.56 percent.

¹H NMR(400MHz,DMSO-d₆)δ(ppm):8.23(d,J＝2.4Hz,1H),8.09(d,J＝8.4Hz,2H),7.93(dd,J＝8.8,2.4Hz,1H),7.86(d,J＝8.0Hz,2H),7.71(d,J＝8.4Hz,1H),3.58–3.42(m,2H),3.50(d,J＝4.0Hz,2H),3.38–3.28(m,2H),1.96(s,3H),1.78–1.70(m,1H),1.66–1.58(m,1H),1.52–1.44(m,1H),1.40–1.32(m,1H),1.26(s,3H)。

Synthesis scheme 19

Intermediate 30

4- (((methylsulfonyl) oxy) methyl) piperidine-1-carboxylic acid tert-butyl ester

To a stirred solution of tert-butyl 4- (hydroxymethyl) piperidine-1-carboxylate (15.0g, 69.67mmol) in DCM (80mL) at 0 deg.C was added triethylamine (19.42mL, 139.34mmol) and stirred at the same temperature for 10 min. Methanesulfonyl chloride (5.93mL, 76.64mmol) was then added dropwise to the reaction at 0 ℃. The reaction was warmed to room temperature and stirred for 24 h. By TLC [ mobile phase: 30% ethyl acetate in hexane ] the progress of the reaction was monitored. After completion of the reaction, the reaction was quenched with water (100mL) and extracted with DCM (3 × 60 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure to give the title compound, intermediate 30(21.0g, crude) as a pale yellow viscous oil. This compound was used in the next step without further purification.

Analyzing data:

¹H NMR(400MHz,DMSO-d₆)δ(ppm):4.06(d,J＝6.4Hz,2H),3.95(br d,J＝11.2Hz,2H),3.17(s,3H),2.70(br s,2H),1.92–1.78(m,1H),1.65(d,J＝12.8Hz,2H),1.39(s,9H),1.14–1.02(m,2H)。

intermediate 31

4- (((4-bromophenyl) thio) methyl) piperidine-1-carboxylic acid tert-butyl ester

To a stirred solution of tert-butyl 4- (((methylsulfonyl) oxy) methyl) piperidine-1-carboxylate intermediate 30(21.0g, 71.57mmol) in acetone (150mL) at room temperature under a nitrogen atmosphere was added 4-bromobenzenethiol (14.88g, 78.73mmol) and cesium carbonate (46.64g, 143.15 mmol). The reaction mixture was heated at 60 ℃ for 16 h. By TLC [ mobile phase: 50% ethyl acetate in hexane ] the progress of the reaction was monitored. After completion of the reaction, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. Water (100mL) was added to the obtained residue and the resulting mixture was extracted with ethyl acetate (3 × 70 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure to give the title compound, intermediate 31(18.0g, crude) as a brown solid. This compound was used in the next step without further purification.

Analyzing data:

LCMS(ESI)m/z＝332.00[M-^tBu+H]⁺(⁸¹Br)。

¹H NMR(400MHz,CDCl₃)δ(ppm):7.43–7.39(m,2H),7.21–7.17(m,2H),4.11(br s,2H),2.83(d,J＝6.8Hz,2H),2.67(m,2H),1.71–1.60(m,1H),1.83(d,J＝13.2Hz,2H),1.47(s,9H),1.24–1.12(m,2H)。

intermediate 32

4- (((4-bromophenyl) sulfonyl) methyl) piperidine-1-carboxylic acid tert-butyl ester

To a stirred solution of tert-butyl 4- (((4-bromophenyl) thio) methyl) piperidine-1-carboxylate intermediate 31(18.0g, 46.58mmol) in DCM (200mL) was added m-chloroperbenzoic acid (60%) (40.2g, 139.76mmol) portionwise over a period of 20min at 0 ℃. The reaction mixture was warmed to room temperature and stirred for 16 h. By TLC [ mobile phase: 40% ethyl acetate in hexane ] the progress of the reaction was monitored. After completion of the reaction, the reaction mixture was diluted with DCM (100mL) and washed with saturated aqueous sodium thiosulfate (100mL) and saturated aqueous sodium bicarbonate (100 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography (100-200 mesh, gradient 0-40% ethyl acetate in hexane) to give the title compound intermediate 32 as a white solid (9.50g, 49%).

Analyzing data:

¹H NMR(400MHz,CDCl₃)δ(ppm):7.82–7.71(m,4H),4.07(br s,2H),3.01(d,J＝6.4Hz,2H),2.75(t,J＝12.4Hz,2H),2.24–2.12(m,1H),1.88(d,J＝11.6Hz,2H),1.46(s,9H),1.33–1.20(m,2H)。

intermediate 33

4- (((2',4' -difluoro- [1,1' -biphenyl ] -4-yl) sulfonyl) methyl) piperidine-1-carboxylic acid tert-butyl ester

To the reaction tube was added a solution of tert-butyl 4- (((4-bromophenyl) sulfonyl) methyl) piperidine-1-carboxylate intermediate 32(2.00g, 4.78mmol), 2- (2, 4-difluorophenyl) -4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolane (1.37g, 5.73mmol), and sodium carbonate (1.51g, 14.34mmol) in a mixture of 1, 4-dioxane: water (5:1, 12 mL). The tube was sealed and degassed by purging with nitrogen for 10min, after which [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (II) (0.349g, 0.478mmol) was added under a nitrogen atmosphere and purging with nitrogen was continued for 10 min. The reaction mixture was heated at 100 ℃ for 16h under a nitrogen atmosphere. By TLC [ mobile phase: 40% ethyl acetate in hexane ] the progress of the reaction was monitored. After completion of the reaction, the reaction mixture was cooled to room temperature and concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography (100-200 mesh, gradient 10-70% ethyl acetate in hexane) to give the title compound intermediate 33(1.80g, 84%) as a brown solid.

Analyzing data:

LCMS(ESI)m/z＝352.05[M-Boc+H]⁺。

intermediate 34 and intermediate 35

4- (1- ((2',4' -difluoro- [1,1' -biphenyl ] -4-yl) sulfonyl) ethyl) piperidine-1-carboxylic acid tert-butyl ester (intermediate 34) and

4- (2- ((2',4' -difluoro- [1,1' -biphenyl ] -4-yl) sulfonyl) propan-2-yl) piperidine-1-carboxylic acid tert-butyl ester (intermediate 35)

To a stirred solution of 4- (((2',4' -difluoro- [1,1' -biphenyl ] -4-yl) sulfonyl) methyl) piperidine-1-carboxylic acid tert-butyl ester intermediate 33(1.00g, 2.21mmol) in THF (100mL) at-78 ℃, NaHMDS (17.72mL, 17.72mmol, 1M in THF) was added dropwise and stirred at the same temperature for 30 min. Methyl iodide (1.10mL, 17.72mmol) was then added dropwise to the reaction mixture at the same temperature. The reaction was allowed to warm to room temperature and stirred for 16 h. By TLC [ mobile phase: 40% ethyl acetate in hexane ] the progress of the reaction was monitored. After completion of the reaction, the reaction was quenched with saturated aqueous ammonium chloride (30mL) and extracted with ethyl acetate (3 × 30 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography (100-200 mesh, gradient 0-40% ethyl acetate in hexane) to afford intermediate 35(0.350g, 33%) as a white solid and compound intermediate 34(0.055g, 5%) as a white solid.

Analyzing data:

intermediate 34:

LCMS(ESI)m/z＝488.15[M+Na]⁺。

intermediate 35:

LCMS(ESI)m/z＝502.60[M+Na]⁺。

¹H NMR(400MHz,DMSO-d₆)δ(ppm):7.91(d,J＝8.0Hz,2H),7.83(d,J＝8.0Hz,2H),7.75–7.67(m,1H),7.49–7.41(m,1H),7.30–7.23(m,1H),4.00(d,J＝10.8Hz,2H),2.76–2.55(m,2H),2.00–1.88(m,3H),1.39(s,9H),1.30–1.18(m,2H),1.18(s,6H)。

synthesis scheme 20

Intermediate 36

4- (1- ((2',4' -difluoro- [1,1' -biphenyl ] -4-yl) sulfonyl) ethyl) piperidine hydrochloride

To a stirred solution of 4- (1- ((2',4' -difluoro- [1,1' -biphenyl ] -4-yl) sulfonyl) ethyl) piperidine-1-carboxylic acid tert-butyl ester intermediate 34(0.055g, 0.118mmol) in 1, 4-dioxane (2mL) at 0 ℃ was added a 4M HCl solution in 1, 4-dioxane (2 mL). The reaction was warmed to room temperature and stirred for 2 h. By TLC [ mobile phase: 60% ethyl acetate in hexane ] the progress of the reaction was monitored. After completion of the reaction, the reaction mixture was concentrated to dryness under reduced pressure to give the title compound intermediate 36(0.045g, crude product) as a brown solid in the form of hydrochloride. This compound was used in the next step without further purification.

Analyzing data:

LCMS(ESI)m/z＝366.10[M+H]⁺(free base).

Synthesis of Compound 17

1- (4- (1- ((2',4' -difluoro- [1,1' -biphenyl ] -4-yl) sulfonyl) ethyl) piperidin-1-yl) ethan-1-one

(NASMP-17)

To a stirred solution of 4- (1- ((2',4' -difluoro- [1,1' -biphenyl ] -4-yl) sulfonyl) ethyl) piperidine hydrochloride intermediate 36(0.045g, 0.112mmol) in DCM (4mL) was added triethylamine (0.039mL, 0.280mmol) at 0 ℃ and stirred for 10 min. Acetic anhydride (0.011mL, 0.112mmol) was then added to the reaction at the same temperature. The reaction was warmed to room temperature and stirred for 2 h. By TLC [ mobile phase: 60% ethyl acetate in hexane ] the progress of the reaction was monitored. After completion of the reaction, the reaction mixture was concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography (100-200 mesh, gradient 10-50% ethyl acetate in hexane) to give the title compound (synthesized compound 17) as a white solid (0.012g, 26%).

Analyzing data:

LCMS(ESI)m/z＝408.05[M+H]⁺。

HPLC (see general methods): retention time: 8.26 min; purity: 96.98 percent.

¹H NMR(400MHz,DMSO-d₆)δ(ppm):7.97(d,J＝8.0Hz,2H),7.82(d,J＝7.6Hz,2H),7.73–7.66(m,1H),7.48–7.42(m,1H),7.26(dt,J＝2.0&8.4Hz,1H),4.42(d, J ═ 12.8Hz,1H),3.83(d, J ═ 13.6Hz,1H), 3.44-3.35 (m,1H), 3.06-2.92 (m,1H), 2.60-2.40 (m, 1H; combined with solvent peak), 2.35-2.25 (m,1H),1.97(d, J ═ 1.2Hz,3H),1.81(t, J ═ 11.6Hz,1H), 1.67-1.55 (m,1H), 1.45-1.30 (m,1H), 1.30-1.15 (m,1H),1.10(d, J ═ 6.8Hz, 3H).

Synthesis scheme 21

Intermediate 37

4- (2- ((2',4' -difluoro- [1,1' -biphenyl ] -4-yl) sulfonyl) propan-2-yl) piperidine hydrochloride

To a stirred solution of tert-butyl 4- (2- ((2',4' -difluoro- [1,1' -biphenyl ] -4-yl) sulfonyl) propan-2-yl) piperidine-1-carboxylate intermediate 35(0.350g, 0.729mmol) in 1, 4-dioxane (2mL) at room temperature was added 4M HCl in 1, 4-dioxane (2mL) and stirred for 3 h. By TLC [ mobile phase: 40% ethyl acetate in hexane ] the progress of the reaction was monitored. After completion of the reaction, the reaction mixture was concentrated to dryness under reduced pressure to give the title compound intermediate 37(0.22g, crude) as a brown solid in the form of a hydrochloride salt. This compound was used in the next step without further purification.

Analyzing data:

LCMS(ESI)m/z＝380.40[M+H]⁺(free base).

Synthesis of Compound 18

1- (4- (2- ((2',4' -difluoro- [1,1' -biphenyl ] -4-yl) sulfonyl) propan-2-yl) piperidin-1-yl) ethan-1-one

(NASMP-18)

To a stirred solution of 4- (2- ((2',4' -difluoro- [1,1' -biphenyl ] -4-yl) sulfonyl) propan-2-yl) piperidine hydrochloride intermediate 37(0.220g, 0.529mmol) in DCM (5mL) was added triethylamine (0.184mL, 1.32mmol) at 0 ℃ and stirred for 10 min. Acetic anhydride (0.050mL, 0.529mmol) was then added to the reaction mixture at the same temperature. The reaction was warmed to room temperature and stirred for 1 h. By TLC [ mobile phase: 60% ethyl acetate in hexane ] the progress of the reaction was monitored. After completion of the reaction, the reaction mixture was concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography (100-200 mesh, gradient 10-60% ethyl acetate in hexane) to give the title compound (synthesized compound 18) as a white solid (0.208g, 93%).

Analyzing data:

LCMS(ESI)m/z＝422.05[M+H]⁺。

HPLC (see general methods): retention time: 8.48 min; purity: 99.53 percent.

¹H NMR(400MHz,DMSO-d₆)δ(ppm):7.92(d,J＝8.4Hz,2H),7.83(d,J＝8.0Hz,2H),7.75–7.67(m,1H),7.49–7.42(m,1H),7.30–7.24(m,1H),4.45(d,J＝12.8Hz,1H),3.87(d,J＝13.2Hz,1H),2.97(t,J＝12.4Hz,1H),2.43(t,J＝12.4Hz,1H),2.08–1.88(m,3H),1.98(s,3H),1.41–1.30(m,1H),1.25–1.12(m,1H),1.18(s,6H)。

Synthesis scheme 22

Intermediate body 38

4- (((2',4' -difluoro- [1,1' -biphenyl ] -4-yl) sulfonyl) difluoromethyl) piperidine-1-carboxylic acid tert-butyl ester

A stirred solution of 4- (((2',4' -difluoro- [1,1' -biphenyl ] -4-yl) sulfonyl) methyl) piperidine-1-carboxylic acid tert-butyl ester intermediate 33(0.800g, 1.77mmol) in anhydrous THF (20mL) was cooled to-78 ℃. Then, at-78 ℃, a solution of N-fluorobenzenesulfonylimide (NFSI) (2.79g, 8.85mmol) in anhydrous THF (5mL) was added followed by a solution of NaHMDS (7.08mL, 14.17mmol, 2M in THF). The reaction mixture was stirred at the same temperature for 1 h. By TLC [ mobile phase: 30% ethyl acetate in hexane ] the progress of the reaction was monitored. After completion of the reaction, the reaction was warmed to room temperature and quenched with saturated aqueous ammonium chloride (10 mL). The mixture was diluted with water (50mL) and extracted with ethyl acetate (3 × 30 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (100-200 mesh, gradient 0-25% ethyl acetate in hexane) to give the title compound intermediate 38 as a white solid (0.665g, 77%).

Analyzing data:

LCMS(ESI)m/z＝432.30[M-^tBu+H]⁺。

¹H NMR(400MHz,CDCl₃)δ(ppm):8.04(d,J＝8.4Hz,2H),7.76(d,J＝7.6Hz,2H),7.50–7.43(m,1H),7.06–6.95(m,2H),4.26(br s,2H),2.85–2.65(m,3H),2.12(d,J＝12.8Hz,2H),1.70–1.55(m,2H),1.48(s,9H)。

intermediate 39

4- (((2',4' -difluoro- [1,1' -biphenyl ] -4-yl) sulfonyl) difluoromethyl) piperidine hydrochloride

To a stirred solution of 4- (((2',4' -difluoro- [1,1' -biphenyl ] -4-yl) sulfonyl) difluoromethyl) piperidine-1-carboxylic acid tert-butyl ester intermediate 38(0.660g, 1.35mmol) in 1, 4-dioxane (20mL) at 0 deg.C was added a 4M HCl solution in 1, 4-dioxane (20 mL). The reaction was warmed to room temperature and stirred overnight. By TLC [ mobile phase: 70% ethyl acetate in hexane ] the progress of the reaction was monitored. After completion of the reaction, the reaction mixture was concentrated to dryness under reduced pressure to give the title compound intermediate 39(0.500g, crude) as a pale yellow gum as a hydrochloride salt. This compound was used in the next step without further purification.

Analyzing data:

LCMS(ESI)m/z＝388.30[M+H]⁺(free base).

Synthesis of Compound 19

1- (4- (((2',4' -difluoro- [1,1' -biphenyl ] -4-yl) sulfonyl) difluoromethyl) piperidin-1-yl) ethan-1-one

(NASMP-19)

To a stirred solution of 4- (((2',4' -difluoro- [1,1' -biphenyl ] -4-yl) sulfonyl) difluoromethyl) piperidine hydrochloride intermediate 39(0.400g, 0.943mmol) in DCM (10mL) was added triethylamine (0.329mL, 2.359mmol) at 0 ℃ and stirred at the same temperature for 10 min. Acetyl chloride (0.081mL, 1.132mmol) was then added to the reaction at 0 ℃. The reaction mixture was warmed to room temperature and stirred for 1 h. By TLC [ mobile phase: 60% ethyl acetate in hexane ] the progress of the reaction was monitored. After completion of the reaction, the reaction was quenched with water (30mL) and extracted with DCM (3X 20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography (100-200 mesh, gradient 0-50% ethyl acetate in hexane) to give (synthetic compound 19) as a white solid (0.205g, 51%).

Analyzing data:

LCMS(ESI)m/z＝430.05[M+H]⁺。

HPLC [ method: column: X-Select CSH C18 (4.6X 150) mm, 5 μ; mobile phase: a-aqueous 0.1% TFA; b-acetonitrile; sample introduction amount: 5.0 mu L; flow rate: 1.2 mL/min; gradient program: time (min)/B concentration: 0.01/5, 1.0/5, 8.0/100, 12.0/100, 14.0/5, 18.0/5; retention time: 8.37 min; purity: 95.96 percent.

¹H NMR(400MHz,CDCl₃)δ(ppm):8.04(d,J＝8.4Hz,2H),7.76(d,J＝7.6Hz,2H),7.50–7.43(m,1H),7.06–6.95(m,2H),4.80(d,J＝13.2Hz,1H),3.96(d,J＝13.2Hz,1H),3.16(t,J＝13.6Hz,1H),2.92–2.75(m,1H),2.62(t,J＝12.0Hz,1H),2.25(d,J＝13.6Hz,1H),2.17–2.10(m,1H),2.14(s,3H),1.74–1.55(m,2H)。

Synthesis scheme 23

Intermediate 40

4- (((3',5' -difluoro- [1,1' -biphenyl ] -4-yl) sulfonyl) methyl) piperidine-1-carboxylic acid tert-butyl ester

To the reaction tube was added a solution of tert-butyl 4- (((4-bromophenyl) sulfonyl) methyl) piperidine-1-carboxylate intermediate 32(1.00g, 2.39mmol), (3, 5-difluorophenyl) boronic acid (0.566g, 3.585mmol) and sodium carbonate (0.633g, 5.975mmol) in a mixture of 1, 4-dioxane: water (3:1, 21 mL). The tube was sealed and degassed by purging with argon for 10min, after which tetrakis (triphenylphosphine) palladium (0) (0.276g, 0.239mmol) was added to the reaction mixture under an argon atmosphere and purging with argon was continued for 5 min. The reaction mixture was then heated at 90 ℃ for 16h under an argon atmosphere. By TLC [ mobile phase: 80% ethyl acetate in hexane]The progress of the reaction was monitored. After the reaction is completed, the reaction solution is preparedThe reaction mixture was cooled to room temperature and filtered through a pad of celite. The celite pad was washed with ethyl acetate (2 × 50 mL). The combined organic layers were concentrated to dryness under reduced pressure. The crude product is passed through silica gel column chromatography ( Gradient 0-80% ethyl acetate in hexanes) to afford the title compound intermediate 40 as a yellow oil (0.650g, 60%).

Analyzing data:

LCMS(ESI)m/z＝351.95[M-Boc+H]⁺。

¹H NMR(400MHz,CDCl₃)δ(ppm):8.01(d,J＝8.4Hz,2H),7.75(d,J＝8.0Hz,2H),7.18–7.10(m,2H),6.92–6.85(m,1H),4.16–4.02(m,2H),3.06(d,J＝6.4Hz,2H),2.76(t,J＝10.8Hz,2H),2.30–2.18(m,1H),1.91(br d,J＝11.2Hz,2H),1.46(s,9H),1.35–1.22(m,2H)。

intermediate 41

4- (((3',5' -difluoro- [1,1' -biphenyl ] -4-yl) sulfonyl) methyl) piperidine hydrochloride

To a stirred solution of 4- (((3',5' -difluoro- [1,1' -biphenyl ] -4-yl) sulfonyl) methyl) piperidine-1-carboxylic acid tert-butyl ester intermediate 40(0.650g, 1.439mmol) in 1, 4-dioxane (1mL) at room temperature was added a 4M HCl solution in 1, 4-dioxane (10mL) and stirred for 4 h. By TLC [ mobile phase: 80% ethyl acetate in hexane ] the progress of the reaction was monitored. After completion of the reaction, the reaction mixture was concentrated to dryness under reduced pressure to obtain the title compound intermediate 41(0.460g, crude) as a white solid in the form of hydrochloride. This compound was used in the next step without further purification.

Analyzing data:

LCMS(ESI)m/z＝352.00[M+H]⁺(free base).

Synthesis of Compound 20

1- (4- (((3',5' -difluoro- [1,1' -biphenyl ] -4-yl) sulfonyl) methyl) piperidin-1-yl) ethan-1-one

(NASMP-20)

To a stirred solution of 4- (((3',5' -difluoro- [1,1' -biphenyl ] -4-yl) sulfonyl) methyl) piperidine hydrochloride intermediate 41(0.460g, 1.185mmol) in DCM (10mL) was added triethylamine (0.495mL, 3.555mmol) at 0 ℃, followed by acetic anhydride (0.144mL, 1.422 mmol). The reaction was then warmed to room temperature and stirred for 16 h. By TLC [ mobile phase: 5% methanol in DCM ] the progress of the reaction was monitored. After completion of the reaction, the reaction mixture was diluted with DCM (50mL), washed with water (2 × 25mL) and brine (2 × 25 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure. The crude product was purified by trituration with diethyl ether (2 × 25mL), the solid was filtered off and dried under reduced pressure to give the title compound (syn compound 20) as an off-white solid (0.310g, 67%).

Analyzing data:

LCMS(ESI)m/z＝394.00[M+H]⁺。

HPLC (see general methods): retention time: 8.12 min; purity: 99.24 percent.

¹H NMR(400MHz,DMSO-d₆)δ(ppm):8.06–7.98(m,4H),7.58(d,J＝6.8Hz,2H),7.38–7.31(m,1H),4.23(d,J＝13.2Hz,1H),3.73(d,J＝13.2Hz,1H),3.38(d,J＝6.4Hz,2H),3.04–2.96(m,1H),2.60–2.50(m,1H),2.10–2.00(m,1H),1.95(s,3H),1.85–1.71(m,2H),1.30–1.19(m,1H),1.19–1.05(m,1H)。

Synthesis scheme 24

Intermediate body 42

4- (((4-bromophenyl) thio) methyl) pyridine

To a stirred solution of 4-bromobenzenethiol (5.00g, 26.44mmol) in DMF (50mL) at room temperature was added 4- (chloromethyl) pyridine hydrochloride (4.33g, 26.44mmol) and potassium carbonate (12.79g, 92.55mmol) temperature and the reaction was stirred for 16 h. By TLC [ mobile phase: 30% ethyl acetate in hexane ] the progress of the reaction was monitored. After completion of the reaction, the reaction mixture was quenched with water (200mL) and extracted with ethyl acetate (4 × 60 mL). The combined organic layers were washed with brine (50mL), dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure to give the title compound, intermediate 42, as a brown solid (6.00g, crude). This compound was used in the next step without further purification.

Analyzing data:

LCMS(ESI)m/z＝281.75[M+H]⁺(⁸¹Br)。

intermediate 43

4- (((4-bromophenyl) sulfonyl) methyl) pyridine

To a stirred solution of 4- (((4-bromophenyl) thio) methyl) pyridine intermediate 42(6.00g, 21.41mmol) in DCM (100mL) cooled at 0 deg.C was added m-chloroperbenzoic acid (60%) (13.55g, 47.11mmol) portionwise over a period of 20 min. The reaction mixture was then warmed to room temperature and stirred for 3 h. By TLC [ mobile phase: 50% ethyl acetate in hexane ] the progress of the reaction was monitored. After completion of the reaction, the reaction mixture was diluted with DCM (100mL) and washed with saturated aqueous sodium thiosulfate (50mL) and saturated aqueous sodium bicarbonate (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography (100-200 mesh, gradient 0-40% ethyl acetate in hexane) to give the title compound intermediate 43 as a white solid (3.30g, 49%).

Analyzing data:

LCMS(ESI)m/z＝313.85[M+H]⁺(⁸¹Br)。

intermediate 44

4- (1- ((4-bromophenyl) sulfonyl) cyclopropyl) pyridine

To a stirred solution of 4- (((4-bromophenyl) sulfonyl) methyl) pyridine intermediate 43(2.00g, 6.41mmol) in DMSO (10mL) at room temperature was added 1-bromo-2-chloroethane (2.76g, 19.22mmol), cesium carbonate (6.26g, 19.22mmol), and tetra-n-butylammonium bromide (0.413g, 1.28mmol), and the reaction was stirred for 3 h. By TLC [ mobile phase: 50% ethyl acetate in hexane ] the progress of the reaction was monitored. After completion of the reaction, the reaction was quenched with water (100mL) and extracted with ethyl acetate (3 × 40 mL). The combined organic layers were washed with water (2 × 40mL), dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography (100-200 mesh, gradient 0-25% ethyl acetate in hexane) to give the title compound intermediate 44(1.50g, 69%) as a white solid.

Analyzing data:

LCMS(ESI)m/z＝339.75[M+H]⁺(⁸¹Br)。

¹H NMR(400MHz,DMSO-d₆)δ(ppm):8.48(d,J＝6.0Hz,2H),7.78(d,J＝8.8Hz,2H),7.45(d,J＝8.4Hz,2H),7.12(d,J＝6.0Hz,2H),1.90–1.84(m,2H),1.47–1.40(m,2H)。

intermediate 45

4- (1- ((2',4' -difluoro- [1,1' -biphenyl ] -4-yl) sulfonyl) cyclopropyl) pyridine

To the reaction tube was added a solution of 4- (1- ((4-bromophenyl) sulfonyl) cyclopropyl) pyridine intermediate 44(1.00g, 2.96mmol), 2- (2, 4-difluorophenyl) -4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolane (0.851g, 3.55mmol), and sodium carbonate (0.783g, 7.39mmol) in a mixture of 1, 4-dioxane: water (10:1, 11 mL). The tube was sealed and degassed by purging with nitrogen for 10min, after which tetrakis (triphenylphosphine) palladium (0) (0.341g, 0.296mmol) was added to the reaction mixture under a nitrogen atmosphere and purging with nitrogen was continued for 5 min. The reaction mixture was then heated at 90 ℃ for 16h under a nitrogen atmosphere. By TLC [ mobile phase: 60% ethyl acetate in hexane ] the progress of the reaction was monitored. After completion of the reaction, the reaction mixture was cooled to room temperature and concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography (100-200 mesh, gradient 0-40% ethyl acetate in hexane) to give the title compound intermediate 45 as a brown solid (0.800g, 73%).

Analyzing data:

LCMS(ESI)m/z＝372.00[M+H]⁺。

¹H NMR(400MHz,DMSO-d₆)δ(ppm):8.47(d,J＝4.8Hz,2H),7.72(d,J＝8.0Hz,2H),7.68(m,1H),7.62(d,J＝8.4Hz,2H),7.48–7.40(m,1H),7.29–7.22(m,1H),7.14(d,J＝5.2Hz,2H),1.93–1.86(m,2H),1.49–1.42(m,2H)。

intermediate 46

4- (1- ((2',4' -difluoro- [1,1' -biphenyl ] -4-yl) sulfonyl) cyclopropyl) piperidine hydrochloride

To the parr reactor was added a solution of 4- (1- ((2',4' -difluoro- [1,1' -biphenyl ] -4-yl) sulfonyl) cyclopropyl) pyridine intermediate 45(0.500g, 1.35mmol) in 1, 4-dioxane (10mL) in 4M HCl. The parr reactor was evacuated and backfilled with nitrogen. Platinum dioxide (50mg, 10% w/w) was added to the reaction mixture under a nitrogen atmosphere. The parr reactor was evacuated and backfilled with hydrogen. The reaction was then stirred at room temperature under a hydrogen atmosphere at 100psi for 16 h. By TLC [ mobile phase: 70% ethyl acetate in hexane ] the progress of the reaction was monitored. The reaction mixture was filtered through a pad of celite and the pad was washed with methanol (100mL) and water (50 mL). The combined filtrates were concentrated to dryness under reduced pressure to give the title compound intermediate 46 as a viscous liquid as the hydrochloride salt (0.410g, crude, 35% pure by LCMS). This compound was used in the next step without further purification.

Analyzing data:

LCMS(ESI)m/z＝378.00[M+H]⁺(free base).

Synthesis of Compound 21

1- (4- (1- ((2',4' -difluoro- [1,1' -biphenyl ] -4-yl) sulfonyl) cyclopropyl) piperidin-1-yl) ethan-1-one

(NASMP-21)

To a stirred solution of 4- (1- ((2',4' -difluoro- [1,1' -biphenyl ] -4-yl) sulfonyl) cyclopropyl) piperidine hydrochloride intermediate 46[0.410g (35% pure), 0.346mmol ] in DCM (5mL) was added triethylamine (0.097mL, 0.691mmol) and stirred for 10min at 0 ℃, after which acetyl chloride (0.030mL, 0.415mmol) was added to the reaction. The reaction was then warmed to room temperature and stirred for 1 h. By TLC [ mobile phase: 80% ethyl acetate in hexane ] the progress of the reaction was monitored. After completion of the reaction, the mixture was concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography (230-400 mesh, gradient 0-60% ethyl acetate in hexane). The product was further triturated with ether (2 × 5mL) at 0 ℃ for 15 min. The solid was filtered off and dried under reduced pressure to give (synthetic compound 21) (0.073g, 50%) as a white solid.

Analyzing data:

LCMS(ESI)m/z＝420.10[M+H]⁺。

HPLC (see general methods): retention time: 8.32 min; purity: 95.11 percent.

¹H NMR(400MHz,DMSO-d₆)δ(ppm):8.00(d,J＝8.4Hz,2H),7.82(d,J＝7.6Hz,2H),7.75–7.67(m,1H),7.48–7.41(m,1H),7.29–7.23(m,1H),4.32(d,J＝12.8Hz,1H),3.72(d,J＝14.0Hz,1H),2.88(t,J＝12.0Hz,1H),2.33(t,J＝10.4Hz,1H),2.13–2.02(m,1H),1.91(s,3H),1.54–1.40(m,2H),1.40(br s,2H),1.08(br s,2H),1.10–0.97(m,1H),0.92–0.80(m,1H)。

Synthesis scheme 25

Intermediate 47

1- [4- (bromomethyl) piperidin-1-yl ] ethanones

At room temperature, to N₂Then, 1- [4- (bromomethyl) piperidin-1-yl ] is added to a 2L flanged flask]-2- (tert-butoxy) ethanone (45g, 0.153mol), DCM (900mL) and triethylsilane (21.6mL, 0.255 mol). The reaction was then cooled to 10 ℃ and TFA (107.1mL, 0.631mol) was added dropwise over 15 minutes at 10-15 ℃. The reaction was warmed to room temperature and stirred for 1h, where HPLC indicated no starting material remained. The reaction mixture was then concentrated in vacuo to give a crude oil. The oil was dissolved in DCM (450mL) and cooled to 0 ℃. Pyridine (39.1mL, 0.483mol) was then added dropwise over 15 minutes at 0-5 deg.C, followed by Ac addition over 15 minutes at 0-5 deg.C ₂O (46.1mL, 0.488 mol). The reaction was stirred at 0-5 ℃ for 30 minutes, where HPLC indicated 2.0% intermediate and 93.8% product. The reaction mixture was washed with 1M HCl (225mL) and the aqueous solution was back-extracted with DCM (225 mL). The organics were combined and washed with water (225mLx2) and 10% brine (225mLx 2). The organics were separated and dried over magnesium sulfate before concentration to give 50.4g of crude product of purity 94.31% by HPLC. Then adding the crude productPurify on silica (2.25kg) in 1% MeOH/DCM eluting with 1-3% MeOH/DCM. The clean fraction by TLC was concentrated in vacuo to give a purity of 98.9% by HPLC and by NMR>95% intermediate 47(29.7g, 88%).

Analyzing data:

¹h NMR (400MHz, chloroform-d) δ (ppm) 4.67-4.61(m,1H),3.87-3.82(m,1H),3.30(dq, J ═ 8.0,12.0Hz,2H),3.05(td, J ═ 4.0,12.0Hz,1H),2.53(td, J ═ 4.0,12.0Hz,1H),2.10(s,3H),1.97-1.80(m,3H),1.28-1.13(m, 2H).

Synthesis scheme 26

Intermediate 48

2',4' -difluoro- [1,1' -biphenyl ] -4-sulfonic acid

To be at N₂A1L flanged flask below was charged with 2, 4-difluorobiphenyl (90g, 0.473mol) and chloroform (509 mL). Chlorosulfonic acid (53.1mL, 0.799mol) was then added dropwise over 5 minutes at-15 ℃. The reaction mixture was then stirred at room temperature for 1h, where HPLC indicated 0.9% starting material and 95.4% product. Then N is added ₂Bubble through the reaction mixture for 15 minutes, then concentrate in vacuo to give a white solid. The solid was then dissolved in EtOAc (422mL) and quenched with water (333 mL). The aqueous solution was then separated (poor separation) and saturated brine (422mL) was added dropwise to the organics over 15 minutes to give a thick white suspension. The solid was separated and washed with EtOAc (90mLx2) before drying at 50 ℃ overnight. This gave a purity of by NMR>95% of intermediate 48(98.8g, crude).

Analyzing data:

¹H NMR(400MHz,DMSO-d₆)δ(ppm):7.69-7.66(m,2H),7.55(dt,J＝6.7,8.9Hz,1H),7.47-7.43(m,2H),7.37-7.30(m,1H),7.19-7.14(m,1H),4.05(br s,1H)。

intermediate 49

2',4' -difluoro- [1,1' -biphenyl ] -4-sulfonyl chloride

To be at N₂2L Flange flask below was charged with 2',4' -difluoro- [1,1' -biphenyl]-4-sulfonic acid intermediate 48(98.8g, 0.366mol), thionyl chloride (766mL, 10.50mol) and DMF (1mL, 12.9 mmol). The reaction mixture was then heated to reflux (79 ℃) for 8h, where HPLC analysis showed 3.4% starting material remaining and 95.0% product. The reaction was cooled to room temperature, then concentrated in vacuo, and then azeotroped with toluene (350mLx 2). The residue was then dissolved in EtOAc and washed with water (500mL) and then 10% brine (500 mL). The organics were separated and dried over magnesium sulfate before concentration in vacuo. This gave a purity of 93.8% by HPLC and by NMR >90% intermediate 49(95.6g, crude).

Analyzing data:

¹h NMR (400MHz, chloroform-d) δ (ppm) 8.11(d, J ═ 8.0Hz,2H),7.76(dd, J ═ 4.0,12.0Hz,2H),7.48(dt, J ═ 4.0,8.0Hz,1H),7.08-6.95(m, 2H).

Intermediate 50

2',4' -difluoro- [1,1' -biphenyl ] -4-thiol

To be at N₂2L Flange flask below was charged with 2',4' -difluoro- [1,1' -biphenyl]-4-sulfonyl chloride intermediate 49(90.0g, 0.312mol) and toluene (900 mL). The reaction mixture was then cooled to 0 ℃ and a solution of triphenylphosphine (245.5g, 0.936mol) in toluene (450mL) was added dropwise over 30 minutes at 0-5 ℃. The reaction mixture was then stirred at room temperature for 1h, where HPLC showed no starting materialThe material remained. The reaction mixture was quenched with 1M HCl (225mL) and then concentrated in vacuo to remove toluene. The remaining aqueous layer was then adjusted to pH 10-11 using 2M potassium hydroxide (450mL) to give a suspension. The solids were removed by filtration and washed with water (900mLx 2). The filtrate was then washed with diethyl ether (900mLx 4). The aqueous solution was then pH adjusted to pH 3-4 using 1M HCl (1L) before extraction with ethyl acetate (900mL +450 mL). The organics were then separated and dried over magnesium sulfate and concentrated in vacuo. This gave intermediate 50(82.0g, crude) in a purity of 93.8% by HPLC and 75% by NMR.

Analyzing data:

¹h NMR (400MHz, chloroform-d) delta (ppm) 7.73-7.66(m,2H),7.58-7.52(m,1H),7.50-7.43(m,2H), 6.97-6.87 (m,2H),3.53(s, 1H).

Intermediate 51

1- [4- ({2',4' -difluoro- [1,1' -biphenyl ] -4-yl } sulfanyl) piperidin-1-yl ] ethanone

To be at N₂Next, 500mL of a 3-necked flask was charged with 2',4' -difluoro- [1,1' -biphenyl]-4-thiol intermediate 50(47.7g, 0.215mol), THF (180mL) and MeOH (120 mL). The reaction mixture was then cooled to 0 ℃ and cesium carbonate (87.7g, 0.269mol) was added portionwise over 15 minutes at 0-5 ℃. Then 1- [4- (bromomethyl) piperidin-1-yl is added dropwise over 10 minutes at 5-10 ℃]Ethanone intermediate 47(29.5g, 0.134mol) in THF (60 mL). The reaction mixture was heated to 60 ℃ for 45 minutes, where HPLC indicated no 1- [4- (bromomethyl) piperidin-1-yl]The ethanone intermediate 47 remained. The reaction mixture was cooled to room temperature and filtered; the solid was washed with THF (150 mL). The filtrate was concentrated in vacuo, and the residue was partitioned between EtOAc (600mL) and water (450 mL). The layers were separated and the aqueous solution was back-extracted with EtOAc (300 mL). The organics were combined and dried over magnesium sulfate before concentration in vacuo. This gave 63.6g of crude product. The crude product was purified on silica (3kg) eluting with 1% MeOH/DCM. The clean fraction was concentrated in vacuo to give a purity of 97.9% by HPLC and by NMR>95% intermediate 51(33.9g, 70%).

Analyzing data:

¹h NMR (400MHz, chloroform-d) delta (ppm) 7.44-7.33(m,5H),6.97-6.86(m,2H),4.66-4.59(m,1H),3.85-3.78(m,1H),3.05-2.96(m,1H),2.95-2.81(m,2H),2.57-2.47(m,1H),2.08(s,3H),2.01-1.86(m,2H),1.85-1.74(m,1H),1.27-1.13(m, 2H).

Synthesis of Compound 1

1- (4- (((2',4' -difluoro- [1,1' -biphenyl ] -4-yl) sulfonyl) methyl) piperidin-1-yl) ethan-1-one

(NASMP-01)

To be at N₂1- [4- ({2',4' -difluoro- [1,1' -biphenyl) was charged into a 1L flanged flask]-4-yl } sulfanyl) piperidin-1-yl]Ethanone intermediate 51(33.5g, 0.093mol) and DCM (400 mL). The reaction mixture was cooled to 0 ℃ and m-CPBA (77%) (45.7g, 0.278mol) was added portionwise over 45 minutes at 0-5 ℃. The reaction mixture was then warmed to room temperature and stirred for 1 h. HPLC showed no starting material remaining. The reaction mixture was filtered and the liquid was charged back into the flask. The liquid was then cooled to 0 ℃ and quenched with saturated sodium bicarbonate (340 mL). The layers were separated and the organics were washed with saturated sodium thiosulfate (340 mL). The organics were then separated and washed with sodium bicarbonate (340mLx2+170mL) and sodium thiosulfate (340mLx2+170 mL). HPLC showed no m-CPBA/chlorobenzoic acid remaining. The organics were then separated, dried over magnesium sulfate and concentrated in vacuo. This gave a purity of 95.8% by HPLC and by NMR >95% (Synthesis of Compound 1) (31.0g, 84%).

Analyzing data:

¹H NMR(400MHz,DMSO-d₆)δ(ppm):8.02(d,J＝8.0Hz,2H),7.82(d,J＝8.0Hz,2H),7.69(td,J＝8.0,12.0Hz,1H),7.48-7.40(m,1H),7.29-7.21(m,1H),4.28-4.20(m,1H),3.78-3.70(m,1H),3.40-3.35(m,2H),3.06-2.96(m,1H),2.57(td,J＝4.0,12.0Hz,1H),2.15-2.03(m,1H),1.95(s,3H),1.88-1.74(m,2H),1.26(ddd,J＝4.0,12.0Hz,1H),1.13(ddd,J＝4.0,12.0Hz,1H)。

biological research

Biological study 1

Monocyte ATP production assay

The in vitro potency of test compounds was determined by incubation with Thp1 human monocytes and subsequent determination of Adenosine Triphosphate (ATP) levels using firefly luciferase.

ATP is present in all metabolically active cells. When cells lose integrity, their ability to synthesize ATP is rapidly lost. Therefore, when cells undergo necrosis or apoptosis, the ATP concentration decreases, and the concentration thereof is generally used as a marker of cell viability or cell proliferation. See, e.g., Kang et al, 2015; jiang et al, 2013. ATP levels can be monitored using a firefly (Photinus pyralis) luciferase-based system (see, e.g., Auld et al, 2009) using commercially available kits. The use is called ATPlite^TMTo measure the effect of a test compound on cell viability in vitro. Such one-step detection systems are Adenosine Triphosphate (ATP) monitoring systems, which are based on the generation of light by the reaction of ATP from cells with added luciferase and D-luciferin, as shown in the following reaction scheme:

the emitted light is proportional to the ATP concentration.

The Thp1 cells were seeded at 112500 cells per well in 125 μ L RPMI-1640 (no glucose) containing 1% FBS in 96-well plates. Test compounds were prepared as 100mM solutions in DMSO. These stock solutions were diluted in DMSO and then 1000-fold in culture medium (RPMI) before being added directly to the wells to give the desired final compound concentration. At 37 deg.C/5% CO₂After 24 hours of incubation, ATPLite was added^TM(Perkin Elmer) was added to each well (1:10 vol/vol, 10 μ L). The plates were then incubated at room temperature for 5 minutes and the emitted light was quantified on a Viewlux at a measurement time of 0.3 seconds and 4x4 pixel mixing (binin).

The average results for each test compound are expressed as a percentage (%) of the average control value reflecting cell viability. The mean values of the test concentrations were then plotted and the data fitted to a 4-parameter IC by using Software from Grafit (Erithacus Software)₅₀Equation to calculate IC₅₀. Each experiment was repeated twice and the data are expressed as the average IC of the two experiments₅₀。

The results are summarized in the following table.

⁽¹⁾Obtained using a 9-point concentration range of 10 μ M to 10nM, where each concentration n is 2 replicates. Data are mean values from 2 independent experiments.

⁽²⁾Obtained using an 8-point concentration range of 100 μ M to 100nM, where each concentration n is 2 replicates. Data are mean values from 2 independent experiments.

The data indicate that many of the NASMP compounds described herein, and in particular the compounds NASMP-01, NASMP-07, NASMP-12 and NASMP-15, showed superior potency in the Thp1 monocyte ATP assay, and no loss of potency, as compared to the reference compounds.

Biological study 2

Human hepatocyte study

The metabolic stability of a test compound was measured by determining the disappearance rate of the compound when incubated in the presence of human hepatocytes, the major source of the most important enzyme involved in drug metabolism (cytochrome P450). Drug stability studies in the presence of primary hepatocytes are considered to be a valuable model that allows for the rapid prediction of drug stability in vivo.

Human hepatocytes were obtained from commercial sources and viability was assessed using trypan blue solution prior to use. Test compounds (final concentration 1 μ M, 0.1% DMSO, 0.9% acetonitrile) or markers (diclofenac or diltiazem, final assay concentration 1 μ M, 0.1% DMSO, 0.9% acetonitrile) were incubated with pooled hepatocytes for 60 minutes, and samples were removed at up to 6 time points and analyzed for the presence/amount of test compounds by LC-MS/MS.

Each compound was incubated for 0, 5, 15, 30, 45 or 60 minutes. The reaction was stopped by adding methanol containing an internal standard (1. mu.M tolbutamide) at the appropriate time point, mixed and left at-20 ℃ for ≥ 1 h to quench and allow the protein to precipitate. All samples were centrifuged (2500Xg, 20 min, 4 ℃). Aliquots were analyzed using LC-MS/MS. The reactions were performed in duplicate at 37 ℃.

The data was processed and the results plotted as ln (concentration) versus time. The elimination rate constant (slope of the regression line, k) was calculated using the following formula, where C (t) is the concentration at time t, and C (0) is the starting concentration:

half-life (t) was calculated using the following formula_1/2)：

Intrinsic clearance (Cl) was calculated using the following formula_int) Wherein [ cell ]]For hepatocyte concentration in the assay:

the data are summarized in the table below.

(NC-not calculated due to high stability)

The data indicate that many of the NASMP compounds described herein exhibit higher metabolic stability than the reference compounds, with NASMP-01, NASMP-02, NASMP-03, NASMP-05, NASMP-06, NASMP-09, NASMP-12, NASMP-15, NASMP-16, NASMP-18, and NASMP-20 exhibiting very good stability.

Biological study 3

Water solubility

Water solubility was measured by equilibration of the compound with fasted state simulated intestinal fluid (FaSSIF) and quantified by spectrophotometry.

The preparation of FaSSIF is as follows:

preparation of a blank FaSSIF: 0.21g of sodium hydroxide (NaOH) granules, 1.97g of sodium dihydrogen phosphate (NaH)₂PO₄.2H₂O) and 3.09g of sodium chloride (NaCl) were dissolved in 400mL of deionized water. The pH was adjusted to 6.5 using 1M hydrochloric acid and further deionized water was added to a final volume of 500 mL.

Preparation of FaSSIF: 0.056g SIF powder (containing sodium taurocholate and lecithin) (Phares AG) was dissolved in 25mL of blank FaSSIF and stirred until the powder was completely dissolved. The solution was allowed to stand for 2 hours, during which time the solution became milky white; it was used within 24 hours. The characteristics of the final solution composition were as follows:

sodium taurocholate: 3mM

Lecithin: 0.75mM

Osmotic pressure: 270. + -. 10mOsmol

pH：6.5

Aqueous solubility was determined by adding a known concentration of test compound (dissolved in DMSO) to FaSSIF followed by incubation for 16 hours. The optical density of the test compound is measured at the end of the incubation period and the solubility is determined using the reference. Briefly, two samples were prepared for each assay: reference sample consisting of a solution in the system (phosphate-free, low absorption buffer) and stock solutions of test compounds diluted in propanol in DMSO; and test samples (prepared in triplicate), consisting of 0.5mL of FaSSIF spiked with 0.2mM test compound. Each sample was incubated at room temperature for 16 hours with constant shaking at 250 rpm. At the end of the incubation period, 0.3mL of each sample was filtered through pION filter plates (pION, Woburn MA), diluted 1:1 with propanol, and UV spectrophotometric using Spectra Max Plus-Version 2.1000(Molecular Devices, Sunnyvale, CA) with μ SOL Explorer solubility determination software (pION, Woburn, MA) at λ_maxScans were performed at (190-400 nM).

FaSSIF solubility was calculated using the following formula:

wherein:

"OD" is the optical density;

"Cr" is the reference concentration (33.4. mu.M); and is

"molecular weight" is used to test compounds (e.g., 381.44 for ABD 735).

The data are summarized in the table below.

⁽¹⁾Two replicates of each study were performed at pH 6.5.

⁽²⁾Two replicates of each study were performed at pH 6.8.

⁽³⁾Three replicates were performed for the compounds HMC-C-01-A and ABD 899.

The data indicate that the NASMP compounds described herein show comparable solubility to the reference compounds, with the compounds NASMP-05, NASMP-06, NASMP-07, NASMP-12, NASMP-15, NASMP-17 and NASMP-21 showing particularly good solubility.

Biological study 4

Metabolite identification

Metabolite formation in humans, rats and dogs was evaluated to determine the propensity of compounds to form biaryl metabolites.

Related sulfonamide compounds (e.g., reference compound HMC-C-01-A) produce long-lasting and long-half-life biaryl sulfonamide metabolites (MET-001). In addition, metabolites act as inducers of rat metabolism, which may complicate the assessment of toxicity in rodents. Thus, the lower the propensity to form biaryl metabolites, the greater the suitability of the compounds for human use.

In vitro studies of drug metabolism are typically performed using liver preparations such as isolated perfused liver, liver slices, liver homogenates, isolated cryopreserved hepatocytes, subcellular liver fractions (S9, cytosol and microsomes), or recombinant metabolic enzymes, particularly CYP enzymes, that are overexpressed on non-expressing cell systems. Cryopreserved hepatocytes contain all enzymes and cofactors required for phase I and phase II drug metabolism, making them excellent in vitro models for assessing drug metabolic stability and metabolite profiles.

Cryopreserved human, rat (Sprague Dawley) and dog (Beagle) hepatocytes were thawed from liquid nitrogen and 2X10 ⁶Seeding Density of cells/mL (>95% survival rate). After incubation at 37 ℃ for 15 minutes, samples were taken for zero (0) minute time point evaluation. Test compounds were then added at a final concentration of 10 μ M and the reaction was initiated by the addition of 250 μ Lkrebs Henseleit buffer (KHB, pH 7.4). Samples were tested at 37 deg.C/5% CO₂Incubate for 5, 15, 30 and 60 minutes.

All samples were analyzed by protein precipitation using 500. mu.L ice cold acetonitrile and by the targeted LC-MS/MS method.

At the completion of the study, the results are expressed as the biaryl metabolite detected at the final time point.

The following table shows the presence or absence of biaryl metabolites in primary hepatocyte incubations for the reference compounds HMC-C-01-A and NASMP-01.

The data indicate that the NASMP compounds described herein show greatly increased suitability for development for human use compared to the reference compound (HMC-C-01-A).

Although the reference compound HMC-C-01-A produced a large amount of the biaryl sulfonamide metabolite (MET-001), compound NASMP-01 did not produce either the biaryl sulfonamide metabolite CMPD-03 or the biaryl sulfonic acid metabolite MET-002.

Biological study 5

hERG ion channel assay

Inhibition of the human Ether-a-go-go related gene (hERG) ion channel mediates repolarized IKr currents in cardiac action potentials, suggesting that it contributes to the coordination of electrical activity in the beating heart. When the ability of hERG to conduct current across cell membranes is inhibited or impaired, a potentially fatal condition known as long QT syndrome can result. This association between hERG and long QT syndrome makes hERG inhibition an important anti-target that must be avoided during drug development.

In stably transfected human embryonic kidney cells (hERG-HEK293), binding assays were used to test the activity of compounds on the hERG ion channel. hERG-HEK293 cells were cultured in MEM medium (Invitrogen) + 10% FBS, glutamine and non-essential amino acids at 37 ℃. To prepare the membranes, cells were homogenized on ice, centrifuged at 650Xg for 10 minutes at +4 ℃ and the resulting supernatant centrifuged at 48000Xg for 10 minutes at +4 ℃. The pellet was resuspended in ice-cold 50mM Tris-HCl buffer, 5mM KCl (pH 8.5) and stored frozen in aliquots until use.

For theBinding assay, membranes were thawed, resuspended in assay buffer (10mM HEPES pH 7.4, 0.1% BSA, 5mM potassium chloride, 0.8mM magnesium chloride, 130mM sodium chloride, 1mM EGTA sodium, 10mM glucose), and combined with³H astemizole (1.5nM) and with or without test compound were incubated at 25 ℃ for 60 min. By passing³Scintillation counting of H astemizole, binding was determined after filtration through a membrane and washing in Tris-HCl buffer.

The degree of binding (%) of a compound to the hERG ion channel was measured³Binding of H astemizole and its displacement by the test compound. Values of 0% indicate no binding and values of 100% indicate complete displacement of the radiolabeled ligand.

The results are summarized in the following table.

⁽¹⁾Test at 25. mu.M.

The data indicate that the NASMP compounds described herein have the cardiac safety profile required for orally active drugs and have a safety advantage over reference compounds such as HMC-C-01-A, where NASMP-01, NASMP-09, NASMP-17, NASMP-18 and NASMP-21 exhibit particularly positive characteristics.

Biological study 6

Human cytochrome P450 inhibition assay

Inhibition of cytochrome P450(CYP450) enzymes is one of the major causes of drug-drug interactions in clinical use and can complicate or terminate the development of new drugs.

The ability of test compounds to inhibit the five most relevant cytochrome P450 enzymes was measured by assaying the activity of the cytochrome P450 enzyme in a recombinant cytochrome preparation (called backosomes) (cytox Ltd, dunde, Scotland UK DD 21 NH) in the presence of a specific probe substrate. Bactosomes is a highly efficient and cost effective source of recombinant CYP450, which has higher specific enzyme activity compared to other sources such as liver microsomes. If the compound inhibits the enzyme activity, the rate of disappearance of the probe substrate is reduced. The following CYP450 isoforms were determined: CYP1a2, CYP2C9, CYP2C19, CYP2D6 and CYP3a 4. The study of the CYP450 inhibitory potential in Bactosomes is considered to be a valuable model that allows for the rapid prediction of possible drug-drug interactions in vivo (see, e.g., Weaver et al, 2003).

Bactosomes were obtained from commercial sources (Cypex, Scotland, UK). Test compounds were incubated with Bactosomes at 6 concentrations. The samples were incubated for 10 min, after which the reaction was terminated and the samples were analyzed for the presence/amount of substrate probes by LC-MS/MS Multiple Reaction Monitoring (MRM).

CYP450 enzymes (final protein: 75pmol/mL for CYP1A 2; 12.5pmol/mL for CYP2C 19; and 25pmol/mL for CYP2C9, 2D6 and 3A 4), 0.1M phosphate buffer pH 7.4, probes and test compounds (final concentrations 50, 15.8, 5, 1.58, 0.5 and 0.158. mu.M; diluted from a 10mM stock solution to give a final DMSO concentration of 1%) were preincubated at 37 ℃ for 5 minutes. The reaction was initiated by adding 20. mu.L of 10mM NADPH in phosphate buffer. The final incubation volume was 200. mu.L. The following control inhibitors were used for each CYP450 inhibition assay: CYP1a 2: alpha-naphthalenones; CYP2C 9: sulfaphenazole; CYP2C 19: tranylcypromine; CYP2D 6: quinidine (quinidine); CYP3a 4: ketoconazole.

Each compound was incubated at 37 ℃ for 10 minutes. The reaction was stopped by adding methanol (final composition 1:1, aqueous solution: methanol). The plates were incubated with shaking, cooled at 20 ℃ for 2 hours, and centrifuged at 3500rpm for 15 minutes at 4 ℃ to precipitate the proteins. The supernatant was then transferred to a vial for analysis using MS/MRM, with the conditions shown in the table below.

IC determination by Linear transformation in Microsoft Excel₅₀The value is obtained.

The data are summarized in the table below.

The data indicate that the NASMP compounds described herein exhibit a reduced potential for drug-drug interactions compared to the reference compound, with compounds NASMP-01 and NASMP-05 exhibiting particularly good characteristics.

Biological study 7

Pharmacokinetic Studies in rodents

Absorption and metabolic stability were studied using in vivo pharmacokinetic analysis.

Test compounds were administered to male Han Wistar rats, 196-329g, orally or intravenously (dose levels of 0.25mg/kg body weight intravenously or 1.25mg/kg body weight orally). Test compounds were formulated in 0.5% carboxymethylcellulose (CMC)/0.1% Tween-80 for administration by the oral route, or in 5% DMSO/10% solutol saline for administration by the intravenous route. For compound HMC-C-01-a, it was formulated for oral administration in water with 2% dimethylacetamide/20% hydroxypropyl- β -cyclodextrin. Animals were free to take food throughout the study except for overnight fasting and until 2 hours post-dose on the day of dosing.

Blood samples were collected from the retroorbital plexus at the following time points and contained 20% K ₂Microtubes of EDTA solution:

oral administration: before administration; 0.25, 0.5, 1, 2, 4, 6, 8, 12 and 24 hours post-dose.

Intravenous administration: before administration; 0.033, 0.1, 0.167, 0.25, 0.5, 1, 2, 4, 6, 8, 12, and 24 hours post-dose.

The blood samples were centrifuged to obtain plasma, which was transferred to a separate container and frozen at-20 ℃.

For analysis, samples were thawed at room temperature and prepared by protein precipitation, with acetonitrile spiked with an internal standard (500ng/mL glipizide) at a 1:4 ratio to plasma. The concentration of the test compound in rat plasma samples was determined using LC-MS/MS, where the conditions are shown in the table below.

Pharmacokinetic parameters of the test compounds were calculated by Phoenix WinNonlin version 8.0 (Certara, CA) using standard non-compartmental methods. Peak plasma concentration (C)_max) And time to peak plasma concentration (T)_max) Are observed values. By using the linear trapezoidal rule until the last measurable concentration (AUC)_last) And thereafter by extrapolating the final elimination phase to infinity (AUC)_inf) To determine the area under the plasma concentration-time curve (AUC). Elimination of phase half-life (t)_1/2) Is calculated as 0.693/k_el. Experimental oral bioavailability (F) was calculated by dividing AUC after oral administration (0-24 hours) by adjusted AUC after intravenous administration (0-8 hours) (i.e., F ═ AUC (p.o.) x dose (i.v.))/AUC (i.v.) x dose (p.o.)) and reported as a percentage (%).

The pharmacokinetic data are summarized in the following table.

⁽¹⁾Compounds were dosed in saline 5% DMSO/10% solutol for administration by oral and intravenous routes.

⁽²⁾Samples were collected at the following times: pre-dose, 0.08, 0.25, 0.5, 1, 2, 4, 8, 23 and 24 hours post-intravenous administration; and 0.25, 0.5, 1, 2, 4, 6, 8, 23 and 24 hours before administration, after oral administration.

⁽³⁾Samples were collected at the following times: pre-dose, 0.03, 0.1, 0.167, 0.25, 0.5, 1, 2, 4, 6, 8 and 24 hours post-intravenous administration.

⁽⁴⁾Administered orally at 5 mg/kg.

⁽⁵⁾Administered orally at 10 mg/kg.

These data indicate that the NASMP compounds described herein have superior oral pharmacokinetic properties comparable to the reference compound. This indicates that these compounds are likely to be suitable for use as oral medicaments.

Biological study 8

Collagen-induced arthritis in mice

Seven to eight weeks old male DBA/1j mice were used for all procedures. Animals were housed in groups of 10 animals and were fed and drunk ad libitum at 21 ℃. + -. 2 ℃ with 12 hour light/dark cycles. Complete Freund's Adjuvant (CFA) was prepared by emulsifying 4mg/mL bovine type II collagen with a suspension of 4mg/mL Mycobacterium tuberculosis (Mycobacterium tuberculosis) H37Ra in Incomplete Freund's Adjuvant (IFA) (0.85mL paraffin oil and 0.15mL mannitol monooleate) at a 1:1 (volume/volume) ratio. All mice were immunized subcutaneously with 200 μ g of bovine type II collagen in CFA. After 21 days, all mice were immunized subcutaneously with 100 μ g of bovine type II collagen in IFA. After 'boost' immunization, mice begin to develop signs and symptoms of arthritis.

For macroscopic assessment of arthritis, each mouse was monitored three times per week for the following signs in each paw and summed to generate an Arthritis Index (AI) (maximum AI for one animal is 16):

0-no visible arthritic effect.

Edema and/or erythema of 1-toe.

Edema and/or erythema of 2-toe.

3-edema and/or erythema over 2 toes.

4-severe arthritis of the entire paw and toe.

Animals were divided into treatment groups with a mean arthritis index of 2.5, and then compound was administered once daily for 14 days: by oral gavage for the test compound, or subcutaneously at a dose of 10mg/kg for the positive control etanercept. After completion of the experiment, the mice were sacrificed.

Data were analyzed by generating an average of the arthritis index in each treatment group. The mean arthritis index was then compared to the arthritis index of control (untreated) animals using the following formula to generate percent disease inhibition.

The data are summarized in the table below.

These data indicate that the NASMP compounds described herein show excellent oral in vivo activity in preventing the progression of established severe arthritis.

***

The foregoing has described the principles, preferred embodiments and modes of operation of the present invention. However, the invention should not be construed as being limited to the particular embodiments discussed. Rather, the above-described embodiments should be regarded as illustrative rather than restrictive. It will be appreciated by those skilled in the art that changes could be made in those embodiments without departing from the scope of the invention.

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