N-acyl-{4-[(4-aryl-phenyl)sulfonylmethyl]piperidine} compounds and their therapeutic use

1. A compound of the following formula:

or a pharmaceutically acceptable salt thereof;

wherein:

—X═ is independently —CH═ or —N═;

“m” is independently 0, 1, 2, or 3 ;

each —R A is independently —F, —Cl, —R AC , —R AF , or —CN;

—R AC is independently saturated linear or branched C 1-3 alkyl;

—R AF is independently saturated linear or branched C 1-3 fluoroalkyl;

“n” is independently 0, 1, or 2;

each —R B is independently —F, —Cl, —R BC , —R BF , or —CN;

—R BC is independently saturated linear or branched C 1-3 alkyl;

—R BF is independently saturated linear or branched C 1-3 fluoroalkyl;

—R 1 is independently —H or —R 1X ;

—R 1X is independently —F, —R 1C , or —R 1F ;

—R 1C is independently saturated linear or branched C 1-3 alkyl;

—R 1F is independently saturated linear or branched C 1-3 fluoroalkyl;

—R 2 is independently —H or —R 2X ;

—R 2X is independently —F, —R 2C , or —R 2F ;

—R 2C is independently saturated linear or branched C 1-3 alkyl;

—R 2F is independently saturated linear or branched C 1-3 fluoroalkyl;

or —R 1 and —R 2 , taken together with the carbon atom to which they are attached, form saturated C3-6cycloalkyl;

—R 3 is independently —H or —R 3X ;

—R 3X is independently —R 3C or —R 3F ;

—R 3C is independently saturated linear or branched C 1-3 alkyl;

—R 3F is independently saturated linear or branched C 1-3 fluoroalkyl;

—R 4 is independently —R 4C , —R 4CC , or —N(R 4N1 ) (R 4N2 );

—R 4C is independently saturated linear or branched C 1-6 alkyl;

—R 4CC is independently saturated C 3-6 cycloalkyl;

—R 4N1 is independently —H or —R 4N1C ;

—R 4N1C is independently saturated linear or branched C 1-4 alkyl;

—R 4N2 is independently —H or —R 4N2C ; and

—R 4N2C is independently saturated linear or branched C 1-4 alkyl,

or —N(R 4N1 )(R 4N2 ) is independently azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl,

or morpholinyl, and is optionally substituted with one or more saturated linear or branched C 1-4 alkyl groups.

2. The compound according to claim 1 , wherein —X═ is —CH═.

3. The compound according to claim 1 , wherein “m” is 1 or 2.

4. The compound according to claim 3 , wherein each —R A is independently —F, —Cl, or —CN.

5. The compound according to claim 4 , wherein “n” is independently 1 or 2.

6. The compound according to claim 5 , wherein each —R B is independently —F, —Cl, or —CN.

7. The compound according to claim 4 , wherein “n” is 0.

8. The compound according to claim 1 , wherein the group:

is independently selected from:

wherein each of —R A1 , —R A2 , —R A3 , —R A4 , and —R A5 is independently —F, —Cl, or —CN.

9. The compound according to claim 1 , wherein the group:

is:

wherein each of —R A1 and —R A3 is independently —F, —Cl, or —CN.

10. The compound according to claim 9 , wherein the group:

is:

11. The compound according to claim 9 , wherein the group:

is independently selected from:

wherein each of —R B1 and —R B2 is independently —F, —Cl, or —CN.

12. The compound according to claim 11 , wherein —R 1 is —H.

13. The compound according to claim 12 , wherein —R 2 is —H.

14. The compound according to claim 13 , wherein —R 3 is —H.

15. The compound according to claim 14 , wherein —R 4 is —R 4C .

16. The compound according to claim 15 , wherein —R 4C is saturated linear or branched C 1-4 alkyl.

17. The compound according to claim 15 , wherein —R 4C is —CH 3 or —CH 2 CH 3 .

18. A composition comprising a compound according to claim 1 , and a carrier, diluent, or excipient.

19. A method of preparing a composition comprising the step of mixing a compound according to claim 1 and a carrier or diluent.

20. A method of treatment of a disorder comprising administering to a patient in need of treatment a therapeutically effective amount of a compound according to claim 1 , wherein the treatment is treatment of:

an autoimmune/inflammatory disorder;

cancer; or

a disorder mediated by osteoclasts.

21. The method according to claim 20 , wherein the treatment is treatment of:

inflammatory arthritis; rheumatoid arthritis; psoriatic arthritis; ankylosing spondylitis; spondyloarthritis; reactive arthritis; infectious arthritis; systemic lupus erythematosus; scleroderma; gout; adult-onset Still's disease; juvenile idiopathic arthritis; psoriasis; systemic lupus erythematosus; lupus nephritis; systemic sclerosis; scleroderma; hepatitis; endometriosis; adenomyosis; Sjogren's 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 disease; atopy; allergic rhinitis; atopic dermatitis; anaphylaxis; allergic bronchopulmonary aspergillosis; allergic gastroenteritis; hypersensitivity pneumonitis; an allergy; type I diabetes; rheumatic fever; celiac disease; encephalitis; oophoritis; primary biliary cirrhosis; insulin-resistant diabetes; autoimmune adrenal insufficiency (Addison's disease); acne; acne conglobate; acne fulminans; autoimmune oophoritis; autoimmune orchitis; autoimmune haemolytic anaemia; paroxysmal cold hemoglobinuria; Behçet's disease; autoimmune thrombocytopenia; autoimmune neutropenia; pernicious anaemia; pure red cell anaemia; autoimmune coagulopathy; myasthenia gravis; autoimmune polyneuritis; pemphigus; rheumatic carditis; Goodpasture's syndrome; postcardiotomy syndrome; polymyositis; dermatomyositis; irritable bowel syndrome; pancreatitis; gastritis, lichen planus; delayed type hypersensitivity; chronic pulmonary inflammation; pulmonary alveolitis; pulmonary granuloma; gingival inflammation; endodontic disease; periodontal disease; hypersensitivity pneumonitis; hay fever; anaphylaxis; skin allergy; hives; gout; polycystic kidney disease; cryopyrin-associated periodic syndrome (CAPS); Muckle-Wells 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's) thyroiditis; blistering disorder; vasculitis syndrome; immune-complex mediated vasculitis; bronchitis; cystic fibrosis; pneumonia; pulmonary oedema; pulmonary embolism; sarcoidosis; hypertension; emphysema; respiratory failure; acute respiratory distress syndrome; BENTA disease; or polymyositis.

22. The method according to claim 20 , wherein the treatment is treatment of:

inflammatory arthritis; 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.

23. The method according to claim 20 , wherein the treatment is treatment of:

multiple myeloma; lymphoma; leukaemia; carcinoma; sarcoma;

Hodgkin's lymphoma; non-Hodgkin's lymphoma; lymphocytic lymphoma; granulocytic lymphoma; monocytic lymphoma; diffuse large B-cell lymphoma (DLBCL); mantel cell lymphoma (MCL); follicular cell lymphoma (FL); mucosa-associated lymphoid tissue (MALT) lymphoma; marginal zone lymphoma; T-cell lymphoma; marginal zone lymphoma; Burkitt's lymphoma;

chronic lymphocytic leukemia (CLL); acute myeloid leukemia (AML); acute lymphocytic leukemia (ALL); lymphoblastic T-cell leukemia; chronic myelogenous leukemia (CML); hairy-cell leukemia; acute lymphoblastic T-cell leukemia; acute eosinophilic leukemia; immunoblastic large-cell leukemia; megakaryoblastic leukemia; acute megakaryocytic leukemia; promyelocytic leukemia; erythroleukemia; plasmacytoma;

colon cancer; breast cancer; ovarian cancer; lung cancer; small cell lung carcinoma; non-small cell lung carcinoma; prostate cancer; cancer of the oral cavity or pharynx; cancer of the lip, tongue, mouth, larynx, pharynx, salivary gland, or buccal mucosa; esophageal cancer; stomach cancer; small intestine cancer; large intestine cancer; rectal cancer; liver passage cancer; biliary passage cancer; pancreatic cancer; bone cancer; connective tissue cancer; skin cancer; cervical cancer; uterine cancer; corpus cancer; endometrial cancer; vulval cancer; vaginal cancer; testicular cancer; bladder cancer; kidney cancer; ureter cancer; urethral cancer; urachus cancer; eye cancer; glioma; spinal cord cancer; central nervous system cancer; peripheral nervous system cancer; meningeal cancer; thyroid cancer; adrenocarcinoma; astrocytoma; acoustic neuroma; anaplastic astrocytoma; basal cell carcinoma; blastoglioma; choriocarcinoma; chordoma; craniopharyngioma; cutaneous melanoma; cystadenocarcinoma; embryonal carcinoma; ependymoma; epithelial carcinoma; gastric cancer; genitourinary tract cancer; glioblastoma multiforme; head and neck cancer; hemangioblastoma; hepatocellular carcinoma; renal cell carcinoma (RCC); hepatoma; large cell carcinoma; medullary thyroid carcinoma; medulloblastoma; meningioma mesothelioma; myeloma; neuroblastoma; oligodendroglioma; epithelial ovarian cancer; papillary carcinoma; papillary adenocarcinoma; paraganglioma; parathyroid tumour; pheochromocytoma; pinealoma; plasmacytoma; retinoblastoma; sebaceous gland carcinoma; seminoma; melanoma; squamous cell carcinoma; sweat gland carcinoma; synovioma; thyroid cancer; uveal melanoma; Wilm's tumour;

Askin's tumour; sarcoma botryoides; chondrosarcoma; endotheliosarcoma; Ewing's sarcoma; Malignant hemagioendothelioma; malignant Schwannoma; osteosarcoma; gastrointestinal stromal tumour (GIST); myxosarcoma; alveolar soft part sarcoma; angiosarcoma; cystosarcoma phyllodes; dermatofibrosarcoma; desmoid tumour; desmoplastic small round cell tumour; extraskeletal chondrosarcoma; osteosarcoma; fibrosarcoma; hemagiopericytoma; hemangiosarcoma; Kaposi's sarcoma; leiomyosarcoma; liposarcoma; lyphangiosarcoma; lymphangioendotheliosarcoma; lymphosarcoma; malignant peripheral nerve sheath tumour; neurofibrosarcoma; plexiform fibrohistiocytic tumour; rhabdomyosarcoma; or synovial sarcoma.

24. A compound of one of following formulae, or a pharmaceutically acceptable salt thereof:

25. A compound of the following formula, or a pharmaceutically acceptable salt thereof: