BOEHM MARCUS (US)
HUANG LIMING (US)
MARTINBOROUGH ESTHER (US)
SAINZ MARCOS (US)
SELFRIDGE BRANDON (US)
YEAGER ADAM (US)
US201162631234P |
LIT ET AL.: "Salt Selection for Basic Drugs", INT. J. PHARM., vol. 33, 1986, pages 201 - 217
"Remington: The Science and Practice of Pharmacy", 2005, LIPPENCOTT WILLIAMS & WILKINS
CLAIMS 1. A compound having structure (I): a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof, wherein: R1 is cycloalkyl, aryl, heterocyclyl, -(CH2)nQ, -CHQR, or -CQ(R)2, wherein R1 is optionallybstituted with one or more Rq1; Q is C1-6 alkyl, aryl, cycloalkyl, heterocyclyl, -CH2C(O)OR, -C(O)OR, -C(O)NHR, trihalomethyl,halomethyl, -CN, -N(R)2, -N(R)C(O)R, -N(R)C(O)OR, or -N(R)S(O)2R, wherein Q is optionallybstituted with one or more Rq2; Rq1 and Rq2 are independently H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl,teroaryl, heterocyclyl, -OR, -O(CH2)nR, haloalkoxy, -C(O)OR, -C(O)R, -OC(O)R, halo, haloalkyl, -CN, -R)2, -N(R)C(=NH)N(R)2, -N(R)C(O)R, -N(R)S(O)2R, S(O)2R, -C(H)Q’R, or -(CH2)nQ’ where Q’ is selected m C1-6 alkyl, aryl, cycloalkyl, heterocyclyl, OR’, -C(O)OR’, -OC(O)R’, haloalkyl, -CN, -N(R’)2, -R’)C(O)R’, and -N(R’)S(O)2R’; D is N or CRd; W is N or CRw; Z is N or CRz; each R is independently H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -C(O)NHR’, amino, -(CH2)nR’, o, aryl, cycloalkyl, heteroaryl or heterocyclyl, or two R groups taken together with the atom to ich they are attached form a carbocyle or heterocycle; R’ is H, C1-6 alkyl, haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl, orterocyclyl; Rd is H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -CN, halo, -C(O)R, aryl, cycloalkyl, heteroaryl, orterocyclyl; Rw is H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -CN, halo, -C(O)R, aryl, cycloalkyl, heteroaryl, orterocyclyl; Rz is H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -CN, halo, -C(O)R, aryl, cycloalkyl, heteroaryl, orterocyclyl; each n is independently 0, 1, 2, 3, 4 or 5; when D is CRd,, W is CRw, and Z is CRz, then R2 is H, C1-6 alkyl, C2-6 alkenyl, cycloalkyl, -OR, -O)OR, -OC(O)R, halo, -CF3, -CF2H, -C(F)H2, C(F)2R, -C(F)(R)2, -N(R)2, -N(R)C(O)R, -N(R)S(O)2R, orO)2R; or when at least one of D, W or Z is N, then R2 is C1-6 alkyl, C2-6 alkenyl, cycloalkyl, -OR, -C(O)OR,C(O)R, halo, -CF3, -CF2H, -C(F)H2, C(F)2R, -C(F)(R)2, -N(R)2, -N(R)C(O)R, -N(R)S(O)2R, or S(O)2R; each R3 is independently H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl,terocyclyl, -OR, -C(O)OR, -OC(O)R, halo, haloalkyl, -CN, -N(R)2, -N(R)C(O)R, -N(R)S(O)2R, or S(O)2R; with the provisos that: when D is CRd, then W and Z cannot both be N; when D and Z are both N, then R2 cannot be dimethylamino; and when D is CH, Z is CH and W is CRw, then Rw is not cyano or piperidine. 2. The compound of claim 1, wherein the compound has one of the followinguctures (Ia) or (Ia’): a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof. 3. The compound of claim 1, wherein the compound has one of the followinguctures (Ib), (Ic), (Id), (Ie), (If) or (Ig): (Ig) a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof. 4. The compound of any one of claims 1-3, wherein R1 is aryl, -(CH2)nQ, -CHQR, or - (R)2, wherein R1 is optionally substituted with one or more Rq1; Q is aryl, -CH2C(O)OR, -C(O)OR, -C(O)NHR, haloalkyl, -CN, -N(R)2, -N(R)C(O)R, -N(R)C(O)OR, or(R)S(O)2R, wherein Q is optionally substituted with one or more Rq2. 5. The compound of claim 4, wherein R1 is phenyl. 6. The compound of any one of claims 4-5, wherein the aryl is unsubstituted. 7. The compound of any one of claim 4-5, wherein the aryl is substituted with one orore Rq1. 8. The compound of claim 7, wherein Rq1 is H, -OR, -N(R)2, -N(R)S(O)2R, -CN, -N(R)C(O)R,(H)Q’R, heterocyclyl, or halo. 9. The compound of any one of claims 1-3, wherein R1 is heterocyclyl, -(CH2)nQ, -CHQR, -CQ(R)2, wherein R1 is optionally substituted with one or more Rq1; Q is heterocyclyl, -CH2C(O)OR, -C(O)OR, -C(O)NHR, haloalkyl, -CN, -N(R)2, -N(R)C(O)R, -R)C(O)OR, or -N(R)S(O)2R, wherein Q is optionally substituted with one or more Rq2. 10. The compound of claim 9, wherein the heterocyclyl is unsubstituted. 11. The compound of claim 10, wherein the heterocyclyl is substituted with one or more . 12. The compound of claim 11, wherein Rq1 is H, C1-6 alkyl, -N(R)2, or cycloalkyl. 13. The compound of any one of claims 1-3, wherein R1 is -(CH2)nQ; Q is -N(R)2, -N(R)C(O)R, -N(R)C(O)OR, or -N(R)S(O)2R, wherein Q is optionally substituted withe or more Rq2. 14. The compound of claim 13, wherein n is 0 and Q is N(R)2. 15. The compound of any one of claims 1-3, wherein R1 is -CQ(R)2; Q is - trihalomethyl, -CN, -N(R)2, -N(R)C(O)R, -N(R)C(O)OR, or -N(R)S(O)2R, wherein Q istionally substituted with one or more Rq2. 16. The compound of claim 15, wherein Q is trihalomethyl. 17. The compound of any one of claims 1-16, wherein each R3 is H. 18. The compound of any one of claims 1-17, wherein D is CRd, W is CRw and Z is CRz anderein each Rd, Rw and Rz are independently C1-6 alkyl, H, -CN, halo, or -C(O)R. 19. The compound of any one of claims 1-18, wherein D is N, W is CRw and Z is CRz anderein R2 is –CF3, C1-6 alkyl, -N(R)2, cycloalkyl, -C(O)OR, or halo. 20. The compound of claim 19, wherein R2 is –CF3. 21. The compound of claim 19, wherein R2 is C1-6 alkyl. 22. The compound of claim 19, wherein R2 is -N(R)2. 23. The compound of claim 19, wherein R2 is cycloalkyl. 24. The compound of claim 19, wherein R2 is -C(O)OR. 25. The compound of claim 19, wherein R2 is halo. 26. The compound of any one of claims 1-17, wherein at least two of D, W and Z is N,d wherein R2 is C1-6 alkyl, –OR, or -N(R)2. 27. A compound selected from any one of the compounds listed in Table 1, or aarmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof. 28. A pharmaceutical composition comprising the compound of any one of claims 1-27, a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof and at least onearmaceutically acceptable excipient. 29. A method of modulating a Mas-Related G-Protein Receptor (MRGPR) X2 or aRGPRX2 ortholog by contacting MRGPRX2 or MRGPRX2 ortholog with an effective amount of thearmaceutical composition of claim 28. 30. A method of treating a MRGPRX2 or a MRGPRX2 ortholog dependent condition byministering to a subject in need thereof an effective amount of the pharmaceutical composition ofim 28. 31. The method of claim 30, wherein the MRGPRX2 or the MRGPRX2 ortholog dependentndition is a pseudo-allergic reaction, an itch associated condition, a pain associated condition, or anlammatory or autoimmune disorder. 32. The method of claim 31, wherein the itch associated condition is chronic itch; contactrmatitis; Allergic blepharitis; Anemia; Atopic dermatitis; Bullous pemphigoid; Candidiasis; Chickenx; end-stage renal failure; hemodialysis; Chronic urticaria; Contact dermatitis, Atopic Dermatitis;rmatitis herpetiformis; Diabetes; Drug allergy, Dry skin; Dyshidrotic dermatitis; Ectopic eczema;sinophilic fasciitis; Epidermolysis bullosa; Erythrasma; Food allergy; Folliculitis; Fungal skin infection;morrhoids; Herpes; HIV infection; Hodgkin's disease; Hyperthyroidism; Iodinated contrast dyeergy; Iron deficiency anemia; Kidney disease; Leukemia, porphyrias; Lymphoma; Malignancy; astocystosis; Multiple myeloma; Neurodermatitis; Onchocerciasis; Paget's disease; Pediculosis; lycythemia rubra vera; Prurigo nodularis; Lichen Planus; Lichen Sclerosis; Pruritus ani; Pseudorabies; oriasis; Rectal prolapse; Sarcoidosis granulomas; Scabies; Schistosomiasis; Scleroderma, Severe ess, Stasia dermatitis; Swimmer's itch; Thyroid disease; Tinea cruris; Rosacea; Cutaneousmyloidosis; Scleroderma; Acne; wound healing; burn healing; ocular itch; or Urticaria. 33. The method of claim 32, wherein the itch associated condition is urticaria, pruritus, opic dermatitis, dry skin, psoriasis, contact dermatitis, or eczema. 34. The method of claim 31, wherein the pain associated condition is Acute Pain, vanced Prostate Cancer, AIDS-Related Pain, Ankylosing Spondylitis, Arachnoiditis, Arthritis, throfibrosis, Ataxic Cerebral Palsy, Autoimmune Atrophic Gastritis, Avascular Necrosis, Back Pain, hcet’s Disease (Syndrome), Burning Mouth Syndrome, Bursitis, Cancer Pain, Carpal Tunnel, Cauda uina Syndrome, Central Pain Syndrome, Cerebral Palsy, Cervical Stenosis, Charcot-Marie-Tooth MT) Disease, Chronic Fatigue Syndrome (CFS), Chronic Functional Abdominal Pain (CFAP), Chronic n, Chronic Pancreatitis, Chronic Pelvic Pain Syndrome, Collapsed Lung (Pneumothorax), Complex gional Pain Syndrome (RSD), Corneal Neuropathic Pain, Crohn’s Disease, Degenerative Disc Disease, ntal Pain, Dercum’s Disease, Dermatomyositis, Diabetic Peripheral Neuropathy (DPN), Dystonia, lers-Danlos Syndrome (EDS), Endometriosis, Eosinophilia-Myalgia Syndrome (EMS), ythromelalgia, Fibromyalgia, Gout, Headaches, Herniated disc, Hydrocephalus, Intercostal uraligia, Interstitial Cystitis, Irritable Bowel syndrome (IBS), Juvenile Dermatositis ermatomyositis), Knee Injury, Leg Pain, Loin Pain-Haematuria Syndrome, Lupus, Lyme Disease, edullary Sponge Kidney (MSK), Meralgia Paresthetica, Mesothelioma, Migraine, Musculoskeletal n, Myofascial Pain, Myositis, Neck Pain, Neuropathic Pain, Occipital Neuralgia, Osteoarthritis, get’s Disease, Parsonage Turner Syndrome, Pelvic Pain, Periodontitis Pain, Peripheral Neuropathy, antom Limb Pain, Pinched Nerve, Polycystic Kidney Disease, Polymyalgia Rhuematica, Polymyositis, rphyria, Post Herniorraphy Pain Syndrome, Post Mastectomy, Postoperative Pain, Pain Syndrome, st Stroke Pain, Post Thorocotomy Pain Syndrome, Postherpetic Neuralgia (Shingles), Post-Polio ndrome, Primary Lateral Sclerosis, Psoriatic Arthritis, Pudendal Neuralgia, Radiculopathy, Raynaud’s ease, Rheumatoid Arthritis (RA), Sacroiliac Joint Dysfunction, Sarcoidosi, Scheuemann’s Kyphosis ease, Sciatica, Scoliosis, Shingles (Herpes Zoster), Sjogren’s Syndrome, Spasmodic Torticollis, hincter of Oddi Dysfunction, Spinal Cerebellum Ataxia (SCA Ataxia), Spinal Cord Injury, Spinalenosis, Syringomyelia, Tarlov Cysts, Transverse Myelitis, Trigeminal Neuralgia, Neuropathic Pain,cerative Colitis, Vascular Pain or Vulvodynia 35. The method of claim 31, wherein the inflammatory or autoimmune disorder isronic inflammation, mast cell activation syndrome, Multiple Sclerosis, Steven Johnson’s Syndrome,xic Epidermal Necrolysis, appendicitis, bursitis, cutaneous lupus, colitis, cystitis, dermatitis,lebitis, reflex sympathetic dystrophy/complex regional pain syndrome (rsd/crps), rhinitis,ndonitis, tonsillitis, acne vulgaris, sinusitis, rosacea, psoriasis, graft-versus-host disease, reactiveway disorder, asthma, airway infection, autoinflammatory disease, celiac disease, chronicostatitis, diverticulitis, glomerulonephritis, hidradenitis suppurativa, hypersensitivities, intestinal order, epithelial intestinal disorder, inflammatory bowel disease, irritable bowel syndrome,ohn’s Disease, ulcerative colitis, lupus erythematous, interstitial cystitis, otitis, pelvic inflammatory ease, endometrial pain, reperfusion injury, rheumatic fever, rheumatoid arthritis, sarcoidosis, nsplant rejection, psoriasis, lung inflammation, chronic obstructive pulmonary disease,rdiovascular disease, or vasculitis. |
or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof. In one embodiment R 1 is aryl, -(CH 2 ) n Q, -CHQR, or -CQ(R) 2 , wherein R 1 is optionally substituted with one or more R q1 ; Q is aryl, -CH 2 C(O)OR, -C(O)OR, -C(O)NHR, haloalkyl, -CN, -N(R) 2 , -N(R)C(O)R, - N(R)C(O)OR, or -N(R)S(O) 2 R, wherein Q is optionally substituted with one or more R q2 . In a specific embodiment, R 1 is phenyl. In some embodiments, the aryl is unsubstituted. In yet other embodiments, the aryl is substituted with one or more R q1 . In some other embodiments, R q1 is H, -OR, -N(R) 2 , -N(R)S(O) 2 R, -CN, -N(R)C(O)R, –C(H)Q’R, heterocyclyl, or halo. In one embodiment, R 1 is heterocyclyl, -(CH2)nQ, -CHQR, or -CQ(R) 2 , wherein R 1 is optionally substituted with one or more R q1 ; Q is heterocyclyl, -CH2C(O)OR, -C(O)OR, -C(O)NHR, haloalkyl, -CN, -N(R) 2 , -N(R)C(O)R, - N(R)C(O)OR, or -N(R)S(O) 2 R, wherein Q is optionally substituted with one or more R q2 . In some embodiments, the heterocyclyl is unsubstituted. In one embodiment, the heterocyclyl is substituted with one or more R q1 . In some other embodiments, R q1 is H, C 1-6 alkyl, -N(R) 2 , or cycloalkyl. In one embodiment, R 1 is -(CH 2 ) n Q; Q is -N(R) 2 , -N(R)C(O)R, -N(R)C(O)OR, or -N(R)S(O) 2 R, wherein Q is optionally substituted with one or more R q2 . In a specific embodiment, n is 0 and Q is N(R) 2 . In yet other embodiments, R 1 is -CQ(R) 2 ; Q is - trihalomethyl, -CN, -N(R) 2 , -N(R)C(O)R, -N(R)C(O)OR, or -N(R)S(O) 2 R, wherein Q is optionally substituted with one or more R q2 . In a specific embodiment, Q is trihalomethyl. In one embodiment, each R 3 is H. In another embodiment, D is CR d , W is CR w and Z is CR z and wherein each R d , R w and R z are independently C 1-6 alkyl, H, -CN, halo, or -C(O)R. In some embodiments, D is N, W is CR w and Z is CR z and wherein R 2 is –CF 3 , C 1-6 alkyl, - N(R) 2 , cycloalkyl, -C(O)OR, or halo. In a specific embodiment, R 2 is –CF 3 . In another embodiment, R 2 is C 1-6 alkyl. In yet another embodiment, R 2 is -N(R) 2 . In some other embodiments, R 2 is cycloalkyl. In yet another embodiment, R 2 is -C(O)OR. In one embodiment, R 2 is halo. In some other embodiments, at least two of D, W and Z is N, and wherein R 2 is C 1-6 alkyl, –OR, or -N(R) 2 . In one embodiment, a compound is selected from any one of the compounds listed in Table I, or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof. Table I. Representative compounds having Structure (I) Cpd Cpd Structure Structure No. No. 4-21 4-28 4-22 4-29 4-23 4-30 4-24 4-31 4-25 4-32 4-26 4-33 4-27 Representative compounds of structure (I), as well as structures (Ia), (Ia’), (Ib), (Ic), (Id), (Ie), (If) or (Ig) as applicable, include, but not limited to, any one of the compounds listed below in their IUPAC names as well as a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof. N-[(1R,3S)-3-{[2,6-bis(trifluoromethyl)pyridin-4-yl]amino}cy clohexyl]-4- methoxybenzamide; N-[(1R,3S)-3-{[2,6-bis(trifluoromethyl)pyridin-4-yl]amino}cy clohexyl]benzamide; N-[(1s,4s)-4-{[2,6-bis(trifluoromethyl)pyridin-4-yl]amino}cy clohexyl]benzamide; 4-methoxy-N-[(1s,4s)-4-{[4-cyano-3- (trifluoromethyl)phenyl]amino}cyclohexyl]benzamide; 4-methoxy-N-[(1R,3S)-3-{[2-(trifluoromethyl)-5H,6H,7H-cyclop enta[d]pyrimidin-4- yl]amino}cyclohexyl]benzamide; N-[(1s,4s)-4-{[2-(dimethylamino)-6-(trifluoromethyl)pyrimidi n-4- yl]amino}cyclohexyl]benzamide; 4-fluoro-N-[(1s,4s)-4-{[2-(pyrrolidin-1-yl)-6-(trifluorometh yl)pyrimidin-4- yl]amino}cyclohexyl]benzamide; 4-fluoro-N-[(1s,4s)-4-{[2-(dimethylamino)-6-(trifluoromethyl )pyrimidin-4- yl]amino}cyclohexyl]benzamide; 4-fluoro-N-[(1s,4s)-4-{[6-methoxy-2-(trifluoromethyl)pyrimid in-4- yl]amino}cyclohexyl]benzamide; 4-(dimethylamino)-N-[(1s,4s)-4-{[2,6-bis(trifluoromethyl)pyr idin-4- yl]amino}cyclohexyl]benzamide; 3-methyl-N-[(1s,4s)-4-{[2,6-bis(trifluoromethyl)pyridin-4-yl ]amino}cyclohexyl]furan-2- carboxamide; 3-cyano-N-[(1s,4s)-4-{[2,6-bis(trifluoromethyl)pyridin-4- yl]amino}cyclohexyl]benzamide; 4-fluoro-N-[(1s,4s)-4-{[2,6-bis(trifluoromethyl)pyridin-4- yl]amino}cyclohexyl]benzamide; 4-fluoro-N-[(1s,4s)-4-{[2-(trifluoromethyl)-5,6,7,8-tetrahyd roquinazolin-4- yl]amino}cyclohexyl]benzamide; N-[(1s,4s)-4-{[4-cyano-3-(trifluoromethyl)phenyl]amino}cyclo hexyl]-1H-indole-4- carboxamide; 4-(dimethylamino)-2-fluoro-N-[(1s,4s)-4-{[4-cyano-3- (trifluoromethyl)phenyl]amino}cyclohexyl]benzamide; 4-(propane-2-sulfonamido)-N-[(1s,4s)-4-{[4-cyano-3- (trifluoromethyl)phenyl]amino}cyclohexyl]benzamide; 2-amino-N-[(1s,4s)-4-{[4-cyano-3-(trifluoromethyl)phenyl]ami no}cyclohexyl]-1,3- thiazole-4-carboxamide; 3-(dimethylamino)-N-[(1s,4s)-4-{[4-cyano-3- (trifluoromethyl)phenyl]amino}cyclohexyl]benzamide; 1-methyl-N-[(1s,4s)-4-{[4-cyano-3-(trifluoromethyl)phenyl]am ino}cyclohexyl]-1H- pyrazole-5-carboxamide; 4-(N-methylmethanesulfonamido)-N-[(1s,4s)-4-{[4-cyano-3- (trifluoromethyl)phenyl]amino}cyclohexyl]benzamide; N-[(1s,4s)-4-{[4-cyano-3-(trifluoromethyl)phenyl]amino}cyclo hexyl]-1H-indole-3- carboxamide; N-[(1s,4s)-4-{[4-cyano-3-(trifluoromethyl)phenyl]amino}cyclo hexyl]imidazo[1,2- a]pyridine-6-carboxamide; 4-(dimethylamino)-N-[(1s,4s)-4-{[4-cyano-3- (trifluoromethyl)phenyl]amino}cyclohexyl]benzamide; 4-fluoro-N-[(1s,4s)-4-{[4-cyano-3- (trifluoromethyl)phenyl]amino}cyclohexyl]benzamide; 3-methoxy-N-[(1s,4s)-4-{[4-cyano-3- (trifluoromethyl)phenyl]amino}cyclohexyl]benzamide; N-[(1s,4s)-4-{[4-cyano-3-(trifluoromethyl)phenyl]amino}cyclo hexyl]-1,3-benzothiazole- 7-carboxamide; 4-(morpholin-4-yl)-N-[(1s,4s)-4-{[4-cyano-3- (trifluoromethyl)phenyl]amino}cyclohexyl]benzamide; N-[(1R,3S)-3-{[3,5-bis(trifluoromethyl)phenyl]amino}cyclohex yl]-4- methoxybenzamide; 4-fluoro-N-[(1s,4s)-4-{[3,5-bis(trifluoromethyl)phenyl]amino }cyclohexyl]benzamide; 4-fluoro-N-[(1s,4s)-4-{[2-chloro-6-(trifluoromethyl)pyridin- 4- yl]amino}cyclohexyl]benzamide; 4-fluoro-N-[(1s,4s)-4-{[2-cyclopropyl-6-(trifluoromethyl)pyr idin-4- yl]amino}cyclohexyl]benzamide; 4-methoxy-N-[(1s,4s)-4-({2-[(3-methylphenyl)amino]-6-(triflu oromethyl)pyridin-4- yl}amino)cyclohexyl]benzamide; 4-fluoro-N-[(1s,4s)-4-{[2-(phenylamino)-6-(trifluoromethyl)p yrimidin-4- yl]amino}cyclohexyl]benzamide; 4-(dimethylamino)-N-[(1s,4s)-4-({2-[ethyl(methyl)amino]-6-(t rifluoromethyl)pyrimidin- 4-yl}amino)cyclohexyl]benzamide; 4-methoxy-N-[(1s,4s)-4-{[2-(ethylamino)-6-(trifluoromethyl)p yrimidin-4- yl]amino}cyclohexyl]benzamide; 4-(dimethylamino)-N-[(1s,4s)-4-{[2-(dimethylamino)-6-(triflu oromethyl)pyridin-4- yl]amino}cyclohexyl]benzamide; 4-methoxy-N-[(1s,4s)-4-{[4-fluoro-3- (trifluoromethyl)phenyl]amino}cyclohexyl]benzamide; 3-(dimethylamino)-N-[(1s,4s)-4-{[2,6-bis(trifluoromethyl)pyr idin-4- yl]amino}cyclohexyl]benzamide; 4-methoxy-N-[(1s,4s)-4-{[2-(dimethylamino)-6-(trifluoromethy l)pyrimidin-4- yl]amino}cyclohexyl]benzamide; 4-methoxy-N-[(1s,4s)-4-({2-[methyl(propan-2-yl)amino]-6-(tri fluoromethyl)pyrimidin- 4-yl}amino)cyclohexyl]benzamide; 4-methoxy-N-[(1s,4s)-4-{[2,6-bis(trifluoromethyl)pyridin-4- yl]amino}cyclohexyl]benzamide; 4-(dimethylamino)-N-[(1s,4s)-4-{[2-(dimethylamino)-6-(triflu oromethyl)pyrimidin-4- yl]amino}cyclohexyl]benzamide; 3-cyano-N-[(1s,4s)-4-{[2-(dimethylamino)-6-(trifluoromethyl) pyrimidin-4- yl]amino}cyclohexyl]benzamide; 6-methyl-N-[(1s,4s)-4-{[2,6-bis(trifluoromethyl)pyridin-4-yl ]amino}cyclohexyl]-1H-1,3- benzodiazole-5-carboxamide; 2,3-dioxo-N-[(1s,4s)-4-{[2,6-bis(trifluoromethyl)pyridin-4-y l]amino}cyclohexyl]-2,3- dihydro-1H-indole-7-carboxamide; 1-ethyl-N-[(1s,4s)-4-{[2,6-bis(trifluoromethyl)pyridin-4-yl] amino}cyclohexyl]-1H- pyrazole-5-carboxamide; 4-cyano-N-[(1s,4s)-4-{[2,6-bis(trifluoromethyl)pyridin-4- yl]amino}cyclohexyl]benzamide; 4-chloro-N-[(1s,4s)-4-{[2,6-bis(trifluoromethyl)pyridin-4- yl]amino}cyclohexyl]benzamide; 1-methyl-N-[(1s,4s)-4-{[2,6-bis(trifluoromethyl)pyridin-4-yl ]amino}cyclohexyl]-1,2,3,4- tetrahydroquinoline-7-carboxamide; 3-(2-methylpropanamido)-N-[(1s,4s)-4-{[2,6-bis(trifluorometh yl)pyridin-4- yl]amino}cyclohexyl]benzamide; 3-(1-cyanoethyl)-N-[(1s,4s)-4-{[2,6-bis(trifluoromethyl)pyri din-4- yl]amino}cyclohexyl]benzamide; 3-methanesulfonamido-N-[(1s,4s)-4-{[2,6-bis(trifluoromethyl) pyridin-4- yl]amino}cyclohexyl]benzamide; N-[(1s,4s)-4-{[2,6-bis(trifluoromethyl)pyridin-4-yl]amino}cy clohexyl]-1,3- benzothiazole-7-carboxamide; N-[(1s,4s)-4-{[2,6-bis(trifluoromethyl)pyridin-4-yl]amino}cy clohexyl]-1H-indole-4- carboxamide; 3-acetamido-N-[(1s,4s)-4-{[2,6-bis(trifluoromethyl)pyridin-4 - yl]amino}cyclohexyl]benzamide; 4-(methylamino)-N-[(1s,4s)-4-{[2,6-bis(trifluoromethyl)pyrid in-4- yl]amino}cyclohexyl]benzamide; 3-[(methylcarbamoyl)amino]-N-[(1s,4s)-4-{[2,6-bis(trifluorom ethyl)pyridin-4- yl]amino}cyclohexyl]benzamide; N-[(1s,4s)-4-{[2,6-bis(trifluoromethyl)pyridin-4-yl]amino}cy clohexyl]-1H-pyrrole-1- carboxamide; 3-methoxy-N-[(1s,4s)-4-{[2,6-bis(trifluoromethyl)pyridin-4- yl]amino}cyclohexyl]benzamide; 1-methyl-N-[(1s,4s)-4-{[2,6-bis(trifluoromethyl)pyridin-4-yl ]amino}cyclohexyl]-1,2,3,4- tetrahydroquinoline-5-carboxamide; 4-carbamimidamido-N-[(1s,4s)-4-{[2,6-bis(trifluoromethyl)pyr idin-4- yl]amino}cyclohexyl]benzamide; 1-methyl-N-[(1s,4s)-4-{[2,6-bis(trifluoromethyl)pyridin-4-yl ]amino}cyclohexyl]-1,2,3,4- tetrahydroquinoline-6-carboxamide; N-[(1s,4s)-4-{[2,6-bis(trifluoromethyl)pyridin-4-yl]amino}cy clohexyl]-1H-indole-3- carboxamide; 4-(N-methylmethanesulfonamido)-N-[(1s,4s)-4-{[2,6-bis(triflu oromethyl)pyridin-4- yl]amino}cyclohexyl]benzamide; 4-(3,5-dimethyl-1H-pyrazol-1-yl)-N-[(1s,4s)-4-{[2,6-bis(trif luoromethyl)pyridin-4- yl]amino}cyclohexyl]benzamide; 4-(1H-imidazol-1-yl)-N-[(1s,4s)-4-{[2,6-bis(trifluoromethyl) pyridin-4- yl]amino}cyclohexyl]benzamide; 1-methyl-N-[(1s,4s)-4-{[2,6-bis(trifluoromethyl)pyridin-4-yl ]amino}cyclohexyl]-1,2,3,4- tetrahydroquinoline-8-carboxamide; 2-amino-N-[(1s,4s)-4-{[2,6-bis(trifluoromethyl)pyridin-4-yl] amino}cyclohexyl]-1,3- thiazole-4-carboxamide; 3-hydroxy-N-[(1s,4s)-4-{[2,6-bis(trifluoromethyl)pyridin-4- yl]amino}cyclohexyl]benzamide; 3,3-dimethyl-1-[(1s,4s)-4-{[2,6-bis(trifluoromethyl)pyridin- 4-yl]amino}cyclohexyl]urea; N-[(1s,4s)-4-{[2,6-bis(trifluoromethyl)pyridin-4-yl]amino}cy clohexyl]-4-(1H-1,2,3,4- tetrazol-1-yl)benzamide; 4-(1H-pyrazol-1-yl)-N-[(1s,4s)-4-{[2,6-bis(trifluoromethyl)p yridin-4- yl]amino}cyclohexyl]benzamide; 2,4-dichloro-N-[(1s,4s)-4-{[2,6-bis(trifluoromethyl)pyridin- 4- yl]amino}cyclohexyl]benzamide; 4-(3-methyl-5-oxo-4,5-dihydro-1H-pyrazol-1-yl)-N-[(1s,4s)-4- {[2,6- bis(trifluoromethyl)pyridin-4-yl]amino}cyclohexyl]benzamide; 2-methyl-N-[(1s,4s)-4-{[2,6-bis(trifluoromethyl)pyridin-4-yl ]amino}cyclohexyl]-1,2,3,4- tetrahydroisoquinoline-5-carboxamide; N-[(1s,4s)-4-{[2,6-bis(trifluoromethyl)pyridin-4-yl]amino}cy clohexyl]-1H-1,3- benzodiazole-2-carboxamide; 4-methyl-N-[(1s,4s)-4-{[2,6-bis(trifluoromethyl)pyridin-4- yl]amino}cyclohexyl]piperazine-1-carboxamide; N-[(1s,4s)-4-{[2,6-bis(trifluoromethyl)pyridin-4-yl]amino}cy clohexyl]-4,5,6,7- tetrahydro-1H-indole-2-carboxamide; 4-(1,1-dioxo-1λ⁶-thiomorpholin-4-yl)-N-[(1s,4s)-4-{[2,6-b is(trifluoromethyl)pyridin-4- yl]amino}cyclohexyl]benzamide; N-[(1s,4s)-4-{[2,6-bis(trifluoromethyl)pyridin-4-yl]amino}cy clohexyl]imidazo[1,2- a]pyridine-6-carboxamide; 1-methyl-N-[(1s,4s)-4-{[2,6-bis(trifluoromethyl)pyridin-4- yl]amino}cyclohexyl]pyrrolidine-3-carboxamide; 4-(pyrrolidin-1-yl)-N-[(1s,4s)-4-{[2,6-bis(trifluoromethyl)p yridin-4- yl]amino}cyclohexyl]benzamide; N-[(1s,4s)-4-{[2,6-bis(trifluoromethyl)pyridin-4-yl]amino}cy clohexyl]-5,6,7,8- tetrahydronaphthalene-2-carboxamide; 4-methoxy-N-[(1s,4s)-4-{[2-(difluoromethyl)-6-(trifluorometh yl)pyridin-4- yl]amino}cyclohexyl]benzamide; N-[(1s,4s)-4-{[4-cyano-3-(trifluoromethyl)phenyl]amino}cyclo hexyl]-5- (trifluoromethyl)-1H-pyrazole-4-carboxamide; N-[(1s,4s)-4-{[4-cyano-3-(trifluoromethyl)phenyl]amino}cyclo hexyl]-1-(2,2,2- trifluoroethyl)-1H-pyrazole-4-carboxamide; N-[(1s,4s)-4-{[4-cyano-3-methyl-5- (trifluoromethyl)phenyl]amino}cyclohexyl]imidazo[1,2-a]pyrid ine-6-carboxamide; 5-chloro-N-[(1s,4s)-4-{[4-cyano-3-(trifluoromethyl)phenyl]am ino}cyclohexyl]-1H- pyrazole-4-carboxamide; 5-cyclopropyl-N-[(1s,4s)-4-{[4-cyano-3-(trifluoromethyl)phen yl]amino}cyclohexyl]-1H- pyrazole-4-carboxamide; 4-(methylamino)-N-[(1s,4s)-4-{[4-cyano-3- (trifluoromethyl)phenyl]amino}cyclohexyl]benzamide; 4-acetamido-N-[(1s,4s)-4-{[4-cyano-3- (trifluoromethyl)phenyl]amino}cyclohexyl]benzamide; N-[(1s,4s)-4-{[4-cyano-3-(trifluoromethyl)phenyl]amino}cyclo hexyl]-1H-indazole-7- carboxamide; N-[(1s,4s)-4-{[4-cyano-3-(trifluoromethyl)phenyl]amino}cyclo hexyl]-1H-indazole-4- carboxamide; 4-(4-methyl-1H-imidazol-1-yl)-N-[(1s,4s)-4-{[4-cyano-3- (trifluoromethyl)phenyl]amino}cyclohexyl]benzamide; N-[(1s,4s)-4-{[4-cyano-3-(trifluoromethyl)phenyl]amino}cyclo hexyl]-1H-pyrrolo[2,3- b]pyridine-4-carboxamide; 4-[(2,2-difluoroethyl)amino]-N-[(1s,4s)-4-{[4-cyano-3- (trifluoromethyl)phenyl]amino}cyclohexyl]benzamide; 4-[(2,2-difluoroethyl)(methyl)amino]-N-[(1s,4s)-4-{[4-cyano- 3- (trifluoromethyl)phenyl]amino}cyclohexyl]benzamide; 2-[(propan-2-yl)amino]-N-[(1s,4s)-4-{[4-cyano-3- (trifluoromethyl)phenyl]amino}cyclohexyl]pyridine-4-carboxam ide; 5-cyano-N-[(1s,4s)-4-{[4-cyano-3-(trifluoromethyl)phenyl]ami no}cyclohexyl]-1H- pyrazole-4-carboxamide; N-[(1s,4s)-4-{[4-cyano-3-(trifluoromethyl)phenyl]amino}cyclo hexyl]-1H-pyrrolo[2,3- b]pyridine-3-carboxamide; N-[(1s,4s)-4-{[4-cyano-3-(trifluoromethyl)phenyl]amino}cyclo hexyl]-1H-pyrazolo[4,3- b]pyridine-7-carboxamide; N-[(1s,4s)-4-{[4-cyano-3-(trifluoromethyl)phenyl]amino}cyclo hexyl]-1H-pyrazolo[3,4- b]pyridine-4-carboxamide; 2-methyl-N-[(1s,4s)-4-{[4-cyano-3-(trifluoromethyl)phenyl]am ino}cyclohexyl]-1H- pyrrolo[2,3-b]pyridine-4-carboxamide; 1-methyl-N-[(1s,4s)-4-{[4-cyano-3-(trifluoromethyl)phenyl]am ino}cyclohexyl]-1H- pyrrolo[2,3-b]pyridine-4-carboxamide; 4-methyl-N-[(1s,4s)-4-{[4-cyano-3-(trifluoromethyl)phenyl]am ino}cyclohexyl]-1H- indole-3-carboxamide; N-[(1s,4s)-4-{[4-cyano-3-(trifluoromethyl)phenyl]amino}cyclo hexyl]-1H-pyrrolo[3,2- c]pyridine-3-carboxamide; N-[(1s,4s)-4-{[4-cyano-3-(trifluoromethyl)phenyl]amino}cyclo hexyl]-1H-pyrrolo[2,3- c]pyridine-3-carboxamide; N1-methyl-N4-[(1s,4s)-4-{[4-cyano-3- (trifluoromethyl)phenyl]amino}cyclohexyl]benzene-1,4-dicarbo xamide; 2-(methylamino)-N-[(1s,4s)-4-{[4-cyano-3- (trifluoromethyl)phenyl]amino}cyclohexyl]pyridine-4-carboxam ide; 2,6-dimethyl-N-[(1s,4s)-4-{[4-cyano-3-methyl-5- (trifluoromethyl)phenyl]amino}cyclohexyl]pyridine-4-carboxam ide; 2-[(propan-2-yl)amino]-N-[(1s,4s)-4-{[4-cyano-3-methyl-5- (trifluoromethyl)phenyl]amino}cyclohexyl]pyridine-4-carboxam ide; 4-(methylamino)-N-[(1s,4s)-4-{[4-cyano-3-methyl-5- (trifluoromethyl)phenyl]amino}cyclohexyl]benzamide; 2-(methylamino)-N-[(1s,4s)-4-{[4-cyano-3-methyl-5- (trifluoromethyl)phenyl]amino}cyclohexyl]pyridine-4-carboxam ide; N-[(1s,4s)-4-{[4-cyano-3-methyl-5-(trifluoromethyl)phenyl]am ino}cyclohexyl]-1-(2,2,2- trifluoroethyl)-1H-pyrazole-4-carboxamide; 1-ethyl-N-[(1s,4s)-4-{[4-cyano-3-methyl-5-(trifluoromethyl)p henyl]amino}cyclohexyl]- 1H-pyrazole-5-carboxamide; 4-[(2,2-difluoroethyl)(methyl)amino]-N-[(1s,4s)-4-{[4-cyano- 3-methyl-5- (trifluoromethyl)phenyl]amino}cyclohexyl]benzamide; N-((1s,4s)-4-((4-cyano-3-(trifluoromethyl)phenyl)amino)cyclo hexyl)-1-(2,2,2- trifluoroethyl)-1H-pyrazole-4-carboxamide; 4-[(2,2-difluoroethyl)amino]-N-[(1s,4s)-4-{[4-cyano-3-methyl -5- (trifluoromethyl)phenyl]amino}cyclohexyl]benzamide; and N-[(1s,4s)-4-{[4-cyano-3-methyl-5- (trifluoromethyl)phenyl]amino}cyclohexyl]imidazo[1,5-a]pyrid ine-6-carboxamide. Pharmaceutical Compositions In certain embodiments, the invention provides a pharmaceutical composition comprising a compound of structure (I) or any of the structures (Ia), (Ia’), (Ib), (Ic), (Id), (Ie), (If) or (Ig), or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof, together with at least one pharmaceutically acceptable carrier, diluent, or excipient. For example, the active compound will usually be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier which can be in the form of an ampoule, capsule, sachet, paper, or other container. When the active compound is mixed with a carrier, or when the carrier serves as a diluent, it can be solid, semi-solid, or liquid material that acts as a vehicle, excipient, or medium for the active compound. The active compound can be adsorbed on a granular solid carrier, for example contained in a sachet. Some examples of suitable carriers are water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatin, lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugar, cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid, or lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, polyoxyethylene, hydroxymethylcellulose, and polyvinylpyrrolidone. Similarly, the carrier or diluent can include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax. As used herein, the term “pharmaceutical composition” refers to a composition containing one or more of the compounds described herein, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof, formulated with a pharmaceutically acceptable carrier, which can also include other additives, and manufactured or sold with the approval of a governmental regulatory agency as part of a therapeutic regimen for the treatment of disease in a mammal. Pharmaceutical compositions can be formulated, for example, for oral administration in unit dosage form (e.g., a tablet, capsule, caplet, gelcap, or syrup); for topical administration (e.g., as a cream, gel, lotion, or ointment); for intravenous administration (e.g., as a sterile solution free of particulate emboli and in a solvent system suitable for intravenous use); for administration to a pediatric subject (e.g., solution, syrup, suspension, elixir, powder for reconstitution as suspension or solution, dispersible/effervescent tablet, chewable tablet, lollipop, freezer pops, troches, oral thin strips, orally disintegrating tablet, orally disintegrating strip, and sprinkle oral powder or granules); or in any other formulation described herein. Conventional procedures and ingredients for the selection and preparation of suitable formulations are described, for example, in Remington: The Science and Practice of Pharmacy, 21st Ed., Gennaro, Ed., Lippencott Williams & Wilkins (2005) and in The United States Pharmacopeia: The National Formulary (USP 36 NF31), published in 2013. In some embodiments, the pharmaceutical composition comprising a compound of structure (I) or any of the structures (Ia), (Ia’), (Ib), (Ic), (Id), (Ie), (If) or (Ig), or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof, with at least one pharmaceutically acceptable carrier, diluent, or excipient further comprises a second therapeutic agent. In one embodiment, the second therapeutic agent is an antihistamine, such as an H1 receptor antagonist or an H2 receptor antagonist. In one embodiment, the second therapeutic agent is an H1 receptor antagonist antihistamine, such as levocetirizine, loratadine, fexofenadine, cetirizine, desloratadine, olopatadine, diphenhydramine, cyproheptadine or hydroxyzine pamoate. In one embodiment, the second therapeutic agent is a H2 receptor antagonist, such as cimetidine, nizatidine, ranitidine or famotidine. In one embodiment, the second therapeutic agent is a leukotriene receptor antagonist or leukotriene synthesis inhibitor, such as montelukast, zafirlukast, pranlukast, or 5-lipoxygenase inhibitor (e.g., zileuton, hypericum perforatum). In one embodiment, the second therapeutic agent is an immunomodulatory agent such as Omalizumab or immunoglobulin therapy. In one embodiment, the second therapeutic agent is a corticosteroid, such as hydrocortisone, cortisone, ethamethasoneb, triamcinolone, prednisone, prednisolone, or fludrocortisone. In one embodiment, the second therapeutic agent is a tricylic antidepressant that can relieve itch such as doxepin, amitriptyline or nortriptyline. In one embodiment, the second therapeutic agent is an anti-inflammatory drug such as dapsone, sulfasalazine, hydroxycholoroquine or colchicine. In one embodiment, the second therapeutic agent is an immunosuppressant such as cyclosporine, methotrexate, mycophenolic acid or tacromilus. In one embodiment, the second therapeutic agent is an H1 receptor antagonist antihistamine, such as levocetirizine, loratadine, fexofenadine, cetirizine, desloratadine, olopatadine, diphenhydramine, cyproheptadine or hydroxyzine pamoate. In one embodiment, the second therapeutic agent is a H2 receptor antagonist, such as cimetidine, nizatidine, ranitidine or famotidine. In one embodiment, the second therapeutic agent is a leukotriene receptor antagonist or leukotriene synthesis inhibitor, such as montelukast, zafirlukast, pranlukast, or 5-lipoxygenase inhibitor (e.g., zileuton, hypericum perforatum). In one embodiment, the second therapeutic agent is an immunomodulatory agent such as Omalizumab or immunoglobulin therapy. In one embodiment, the second therapeutic agent is a corticosteroid, such as hydrocortisone, cortisone, ethamethasoneb, triamcinolone, prednisone, prednisolone, or fludrocortisone. In one embodiment, the second therapeutic agent is a tricylic antidepressant that can relieve itch such as doxepin, amitriptyline or nortriptyline. In one embodiment, the second therapeutic agent is an anti-inflammatory drug such as dapsone, sulfasalazine, hydroxycholoroquine or colchicine. In one embodiment, the second therapeutic agent is an immunosuppressant such as cyclosporine, methotrexate, mycophenolic acid or tacromilus. As used herein, the term “pharmaceutically acceptable carrier” refers to any ingredient other than the disclosed compounds, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof (e.g., a carrier capable of suspending or dissolving the active compound) and having the properties of being nontoxic and non-inflammatory in a patient. Excipients may include, for example: antiadherents, antioxidants, binders, coatings, compression aids, disintegrants, dyes (colors), emollients, emulsifiers, fillers (diluents), film formers or coatings, flavors, fragrances, glidants (flow enhancers), lubricants, preservatives, printing inks, sorbents, suspending or dispersing agents, sweeteners, or waters of hydration. Exemplary excipients include, but are not limited to: butylated hydroxytoluene (BHT), calcium carbonate, calcium phosphate (dibasic), calcium stearate, croscarmellose, crosslinked polyvinyl pyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methyl paraben, microcrystalline cellulose, polyethylene glycol, polyvinyl pyrrolidone, povidone, pregelatinized starch, propyl paraben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethyl cellulose, sodium citrate, sodium starch glycolate, sorbitol, starch (corn), stearic acid, stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, and xylitol. The formulations can be mixed with auxiliary agents which do not deleteriously react with the active compounds. Such additives can include wetting agents, emulsifying and suspending agents, salt for influencing osmotic pressure, buffers and/or coloring substances, preserving agents, sweetening agents, or flavoring agents. The compositions can also be sterilized if desired. The route of administration can be any route which effectively transports the active compound of the invention to the appropriate or desired site of action, such as oral, nasal, pulmonary, buccal, subdermal, intradermal, transdermal, or parenteral, including intravenous, subcutaneous and/or intramuscular. In one embodiment, the route of administration is oral. In another embodiment, the route of administration is topical. Dosage forms can be administered once a day, or more than once a day, such as twice or thrice daily. Alternatively, dosage forms can be administered less frequently than daily, such as every other day, or weekly, if found to be advisable by a prescribing physician or drug’s prescribing information. Dosing regimens include, for example, dose titration to the extent necessary or useful for the indication to be treated, thus allowing the patient’s body to adapt to the treatment, to minimize or avoid unwanted side effects associated with the treatment, and/or to maximize the therapeutic effect of the present compounds. Other dosage forms include delayed or controlled-release forms. Suitable dosage regimens and/or forms include those set out, for example, in the latest edition of the Physicians' Desk Reference, incorporated herein by reference. Proper dosages for pediatric patients can be determined using known methods, including weight, age, body surface area, and models such as Simcyp® Pediatric Simulation modeling (CERTARA, Princeton, N.J.) which can be used to establish a pharmacokinetic approach for dosing that takes into account patient age, ontogeny of the clearance pathways to eliminate a compound of any one of formulas (Ia) through (1f), and body surface area (BSA). In one embodiment, the dosage form is formulated to provide a pediatric dose from about 30% to about 100% of an adult dose, or about 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% of an adult dose. In one embodiment, the invention provides an oral pharmaceutical composition comprising structure (I) or any of the structures (Ia), (Ia’), (Ib), (Ic), (Id), (Ie), (If) or (Ig), or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof, together with at least one pharmaceutically acceptable oral carrier, diluent, or excipient. In another embodiment, the invention provides a topical pharmaceutical composition comprising a compound of structure (I) or any of the structures (Ia), (Ia’), (Ib), (Ic), (Id), (Ie), (If) or (Ig), or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof, together with at least one pharmaceutically acceptable topical carrier, diluent, or excipient. For example, the oral pharmaceutical composition is provided to treat cholestatic pruritus, wherein the dosage regimen is, for example, once a day. In one embodiment, the topical pharmaceutical composition is provided to treat atopic dermatitis. In another embodiment, there are provided methods of making a composition of a compound described herein including formulating a compound of the invention with a pharmaceutically acceptable carrier or diluent. In some embodiments, the pharmaceutically acceptable carrier or diluent is suitable for oral administration. In some such embodiments, the methods can further include the step of formulating the composition into a tablet or capsule. In other embodiments, the pharmaceutically acceptable carrier or diluent is suitable for parenteral administration. In some such embodiments, the methods further include the step of lyophilizing the composition to form a lyophilized preparation. In some embodiments, the composition is formulated into a pediatric dosage form suitable for treating a pediatric subject. In certain embodiments, the invention provides a compound having structure (I) or any of the structures (Ia), (Ia’), (Ib), (Ic), (Id), (Ie), (If) or (Ig), or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof. Such compounds can be synthesized using standard synthetic techniques known to those skilled in the art. For example, compounds of the present invention can be synthesized using appropriately modified synthetic procedures set forth in the following Examples and Reaction Schemes. To this end, the reactions, processes, and synthetic methods described herein are not limited to the specific conditions described in the following experimental section, but rather are intended as a guide to one with suitable skill in this field. For example, reactions may be carried out in any suitable solvent, or other reagents to perform the transformation[s] necessary. Generally, suitable solvents are protic or aprotic solvents which are substantially non-reactive with the reactants, the intermediates or products at the temperatures at which the reactions are carried out (i.e., temperatures which may range from the freezing to boiling temperatures). A given reaction may be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction, suitable solvents for a particular work-up following the reaction may be employed. All reagents, for which the synthesis is not described in the experimental part, are either commercially available, or are known compounds or may be formed from known compounds by known methods by a person skilled in the art. The compounds and intermediates produced according to the methods of the invention may require purification. Purification of organic compounds is well known to a person skilled in the art and there may be several ways of purifying the same compound. In some cases, no purification may be necessary. In some cases, the compounds may be purified by crystallization. In some cases, impurities may be stirred out using a suitable solvent. In some cases, the compounds may be purified by chromatography, particularly flash column chromatography, using purpose-made or prepacked silica gel cartridges and eluents such as gradients of solvents such as heptane, ether, ethyl acetate, acetonitrile, ethanol and the like. In some cases, the compounds may be purified by preparative HPLC using methods as described. Purification methods as described herein may provide compounds of the present invention which possess a sufficiently basic or acidic functionality in the form of a salt, such as, in the case of a compound of the present invention which is sufficiently basic, a trifluoroacetate or formate salt, or, in the case of a compound of the present invention which is sufficiently acidic, an ammonium salt. A salt of this type can either be transformed into its free base or free acid form, respectively, by various methods known to a person skilled in the art or be used as salts in subsequent biological assays. It is to be understood that the specific form of a compound of the present invention as isolated and as described herein is not necessarily the only form in which said compound can be applied to a biological assay in order to quantify the specific biological activity. Chemical names were generated using the ChemDraw naming software (Version 17.0.0.206) by PerkinElmer Informatics, Inc. In some cases, generally accepted names of commercially available reagents were used in place of names generated by the naming software. EXAMPLES General Methods 1H NMR (400 MHz) spectra were obtained in solution of deuterochloroform (CDCl 3 ), deuteromethanol (CD3OD) or dimethyl sulfoxide – D6 (DMSO). HPLC retention times, purities, and mass spectra (LCMS) were obtained using one of the following methods: Method 1: Agilent 1260 Infinity II System equipped with an Agilent Poroshell 120 EC-18, 2.7 μm, 4.6 x 100 mm column at 30 °C, using H2O with 0.1% formic acid as the mobile phase A, and MeCN with 0.1% formic acid as the mobile phase B. An ESI detector in positive mode was used. The gradient was 5-95% mobile phase B over 12 min then held at 95% for 1.8 min, then return to 10% mobile phase B over 0.2 min. The flow rate was 1 mL/min. Method 2: Agilent 1290 Infinity II System equipped with an Agilent Poroshell 120 EC-18, 1.9 μm, 2.1 x 50 mm column at 35 °C, using H2O with 0.1% formic acid as the mobile phase A, and MeCN with 0.1% formic acid as the mobile phase B. An ESI detector in positive mode was used. The gradient was 20-95% mobile phase B over 0.8 min then held at 95% for 0.7 mins, then return to 20% mobile phase B over 0.7 min. The flow rate was 0.7 mL/min. Method 3: Agilent 1260 Infinity II System equipped with an Agilent Poroshell 120 EC-18, 2.7 μm, 4.6 x 100 mm column at 30 °C, using H2O with 0.1% formic acid as the mobile phase A, and MeCN with 0.1% formic acid as the mobile phase B. An ESI detector in positive mode was used. The gradient was 5-95% mobile phase B over 5 min then held at 95% for 1.8 min, then return to 20% mobile phase B over 0.2 min. The flow rate was 1 mL/min. Method 4: Agilent 1200 System equipped with a Kinetex C18 50 x 2.1mm (5um particles), using H2O with 0.037% Trifluoroacetic Acid as the mobile phase A, and MeCN with 0.018% Trifluoroacetic Acid as the mobile phase B. An ESI detector in positive mode was used. The gradient was 5% B at 0.00min and 5-90% B at 0.00-0.80 min, 90-95% B at 0.80-0.12 min, and then 95-5%B in 0.01min, hold on 5% B for 0.34min, the flow rate was 1.5 ml/min.^ Method 5: Shimadzu SCL-10A system equipped with Agilent Eclipse XDB-C18, 5 uM, 4.6 x 150 mm column and PE Sciex API 150 EX, using water with 0.1% trifluoroacetic acid as the mobile phase A, and methanol with 0.1% trifluoroacetic acid as the mobile phase B. The gradient was 5-95% mobile phase B over 12 min then held at 95% mobile phase B for 3 min, then return to 5% mobile phase B for 1 min. The flow rate was 1 mL/min. Method 6: Shimadzu LCMS-2020 System equipped with an Kinetex EVO C182.1 x 30mm, (5um particles), using H2O with 0.0375% Trifluoroacetic Acid as the mobile phase A, and MeCN with 0.01875% Trifluoroacetic Acid as the mobile phase B. An ESI detector in positive mode was used. The gradient was 5% B at 0.00min and 5-95% B at 0.00-0.80 min, 95-95% B at 0.80-1.2 min, and then 95-5%B in 0.01min, hold on 5% B for 0.34min, the flow rate was 1.5 ml/min. The pyridine, dichloromethane (DCM), tetrahydrofuran (THF), and toluene used in the procedures were from Aldrich Sure-Seal bottles kept under nitrogen (N2). Other solvents were used as is. All reactions were stirred magnetically, and temperatures are external reaction temperatures. Chromatographies were typically carried out using a Combiflash Rf flash purification system (Teledyne Isco) equipped with Redisep (Teledyne Isco) Rf Gold Normal- Phase silica gel (SiO 2 ) columns or by using a similar system. Preparative HPLC purifications were typically performed using one of the following systems: 1) Waters System equipped with a Waters 2489 uv/vis detector, an Aquity QDA detector, a Waters xBridge Prep C185 μm OBD, 30 x 150 mm column, and eluting with various gradients of H2O/ MeCN (0.1% formic acid) at a 30 mL/min flow rate, 2) Teledyne Isco ACCQPrep® HP150 UV system equipped with a Waters xBridge Prep C185 μm OBD, 30 x 150 mm column, and eluting with various gradients of H2O/ MeCN (0.1% formic acid) at a 42.5 mL/min flow rate, or 3) column: Phenomenex Synergi C18150 x 30 mm- 4μm; mobile phase: [H2O (0.225%formic acid)-MeCN];B%: 55%-85%,12min) and were typically concentrated using a Genevac EZ-2. The following additional abbreviations are used: ethyl acetate (EA), triethylamine (TEA), water (H2O, sodium chloride (NaCl), Hydrochloridric acid (HCl), methanol (MeOH), dimethyl sulfoxide (DMSO), silica gel (SiO2), diisobutylaluminium hydride (DIBAL), trifluoroacetic acid (TFA), 4-dimethylaminopyridine (DMAP), diphenylphosphoryl azide (DPPA), benzoyl peroxide (BPO), 1,1'-bis(diphenylphosphino)ferrocene (dppf), bis(pinacolato)diboron (B2pin2), tetrahydrofuran (THF), 1,4-diazabicyclo[2.2.2]octane bis(sulfur dioxide) adduct (DABSO), hexafluorophosphate azabenzotriazole tetramethyl uronium (HATU), hydroxybenzotriazole (HOBt), N-methyl morpholine (NMM), N-Bromosuccinimide (NBS), diisopropylethyl amine (DIPEA or DIEA), diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), 2-[2- (dicyclohexylphosphino)phenyl]-N-methylindole (CM-Phos), triflic acid (TfOH), l-ethyl-3-(3- dimethylaminopropyl) carbodiimide hydrochloride (EDC), isopropanol (IPA), dimethylformamide (DMF), dimethyl acetamide (DMA), dichloromethane (DCM), 1,2- dichloroethane (DCE), acetonitrile (MeCN or ACN), 1,1’-thiocarbonyldiimidazole (TCDI), petroleum ether (PE), not determined (ND), retention time (RT), molecular weight (mw), room temperature (rt), hour (hr), and not applicable (N/A).
EXAMPLE 1 Scheme 1 Reagents: i. R1COCl, DIPEA, solvent (DCM); ii. HCl, solvent (1,4-dioxane); iii. R2X, Base (DIPEA), solvent (DMSO), heat SYNTHESIS OF EXAMPLE 1 Step 1-1. Synthesis of tert-butyl ((1S,3R)-3-(4-methoxybenzamido)cyclohexyl)carbamate To a stirring solution of an ice-cold solution of (1S,3R)-3-Amino-1-(Boc- amino)cyclohexane (1.142 g, 1.0 eq., 5.329 mmol) in DCM (30 mL) was added with DIPEA (1.377 g, 1.9 mL, 2.0 eq., 10.66 mmol), followed by slow addition of 4-methoxybenzoyl chloride (954.5 mg, 758 µL, 1.05 eq., 5.595 mmol). The resulting mixture was stirred at room temperature. After stirring for 18 hours, the reaction mixture was filtered, and the filter cake was washed with DCM and dried under high vacuum to yield tert-butyl ((1S,3R)-3-(4- methoxybenzamido)cyclohexyl)carbamate (1.659 g, 4.761 mmol, 89.35 % yield). LCMS-ESI (m/z) calculated: 348.44; found 349.2 [M+H] + , RT = 4.239 min (Method 3). 1H NMR (400 MHz, DMSO-d6) δ 8.09 (d, J = 7.9 Hz, 1H), 7.82 (d, J = 8.4 Hz, 2H), 6.97 (d, J = 8.4 Hz, 2H), 6.83 (d, J = 8.1 Hz, 1H), 3.80 (s, 3H), 3.79 – 3.71 (m, 1H), 3.31 – 3.22 (m, 1H), 1.93 (d, J = 12.0 Hz, 1H), 1.77 – 1.68 (m, 3H), 1.38 (s, 9H), 1.31 – 1.17 (m, 3H), 1.11 – 1.01 (m, 1H). Step 1-2. Synthesis of N-((1R,3S)-3-aminocyclohexyl)-4-methoxybenzamide.HCl Methoxybenzamido)cyclohexyl)carbamate (1.654 g, 1 eq., 4.747 mmol) in EtOH (40 mL) was added 1.25M hydrogen chloride in 1,4-dioxane (1.731 g, 37.97 mL, 1.25 molar, 10 eq., 47.47 mmol). The resulting mixture was stirred at 50 °C for 17 hours. The reaction mixture was directly concentrated to yield a white solid, which was further dried under high vacuum to yield N-((1R,3S)-3-aminocyclohexyl)-4-methoxybenzamide hydrochloride (1.331 g, 4.674 mmol, 98.46 % yield), which was used without further purification in the next step. LCMS-ESI (m/z) calculated: 248.44; found 249.2 [M+H] + , RT = 1.665 min (Method 3). 1H NMR (400 MHz, DMSO-d6) δ 8.26 (d, J = 7.9 Hz, 1H), 8.09 (s, 3H), 7.84 (d, J = 8.4 Hz, 2H), 6.98 (d, J = 8.4 Hz, 2H), 3.91 – 3.81 (m, 1H), 3.80 (s, 3H), 3.13 – 3.05 (m, 1H), 2.12 (d, J = 11.6 Hz, 1H), 1.91 (d, J = 12.0 Hz, 1H), 1.78 (d, J = 12.0 Hz, 2H), 1.44 – 1.21 (m, 4H).
Step 1-3. Synthesis of N-((1R,3S)-3-((2,6-bis(trifluoromethyl)pyridin-4-yl)amino)cy clohexyl)-4- methoxybenzamide (Example 1) To a solution of 4-chloro-2,6-bis(trifluoromethyl)pyridine (53 mg, 1 eq., 0.21 mmol) and N-((1R,3S)-3-aminocyclohexyl)-4-methoxybenzamide hydrochloride (60 mg, 1 eq., 0.21 mmol) in DMSO (2 mL) was added DIPEA (0.11 g, 0.15 mL, 4 eq., 0.84 mmol). The vial was capped and the resulting solution was stirred at 130 °C. After stirring for 16 hours, the reaction mixture was cooled to room temperature, filtered. The filtrate was purified by prep-HPLC to yield N-((1R,3S)-3-((2,6-bis(trifluoromethyl)pyridin-4-yl)amino)cy clohexyl)-4- methoxybenzamide (46 mg, 100 µmol, 48 % yield). LCMS-ESI (m/z) calculated: 461.41; found 462.2 [M+H] + , RT = 9.559 min (Method 1). 1H NMR (400 MHz, DMSO-d6) δ 8.13 (d, J = 8.0 Hz, 1H), 7.82 (d, J = 8.4 Hz, 2H), 7.63 (d, J = 8.3 Hz, 1H), 7.16 (s, 2H), 6.97 (d, J = 8.4 Hz, 2H), 4.03 – 3.93 (m, 1H), 3.80 (s, 3H), 3.77 – 3.68 (m, 1H), 2.10 – 2.03 (m, 1H), 1.94 – 1.82 (m, 2H), 1.77 (d, J = 12.3 Hz, 1H), 1.48 (q, J = 13.1 Hz, 1H), 1.36 – 1.21 (m, 2H), 1.15 – 1.04 (m, 1H).
EXAMPLE 2 SYNTHESIS OF EXAMPLE 2 Step 1-1. Synthesis of tert-butyl ((1S,3R)-3-benzamidocyclohexyl)carbamate To an ice-cold solution of (1S,3R)-3-amino-1-(Boc-amino)cyclohexane (1.238 g, 1 eq., 5.777 mmol) in DCM (30 mL) was added DIPEA (1.493 g, 2.0 mL, 2 eq., 11.55 mmol), followed by addition of benzoyl chloride (852.6 mg, 704.1 µL, 1.05 eq., 6.066 mmol). The resulting mixture was allowed to stir at room temperature for 1 hour. The reaction mixture was filtered, and the filter cake was washed with DCM and dried under vacuum to yield tert-butyl ((1S,3R)- 3-benzamidocyclohexyl)carbamate (1.575 g, 4.946 mmol, 86 % yield). It was used as is in the next step. LCMS-ESI (m/z) calculated: 318.30; found 319.2 [M+H] + , RT = 4.237 min (Method 3). 1H NMR (400 MHz, DMSO-d6) δ 8.26 (d, J = 7.9 Hz, 1H), 7.83 (d, J = 7.5 Hz, 2H), 7.53 – 7.42 (m, 3H), 6.84 (d, J = 8.0 Hz, 1H), 3.84 – 3.74 (m, 1H), 3.31 – 3.23 (m, 1H), 1.95 (d, J = 12.0 Hz, 1H), 1.79 – 1.68 (m, 3H), 1.38 (s, 9H), 1.31 – 1.17 (m, 3H), 1.11 – 1.02 (m, 1H). Step 1-2. Synthesis of N-((1R,3S)-3-aminocyclohexyl)benzamide hydrochloride To a stirred suspension of tert-butyl ((1S,3R)-3-benzamidocyclohexyl)carbamate (1.570 g, 1 eq., 4.931 mmol) in 1,4-dioxane (35 mL) was added 4M hydrogen chloride in 1,4-dioxane (10 eq., 49.31 mmol). The resulting mixture was stirred at 50 °C for 19 hours. The reaction mixture was concentrated, dried under vacuum to yield N-((1R,3S)-3- aminocyclohexyl)benzamide hydrochloride (1.201 g, 4.714 mmol, 96 % yield). LCMS-ESI (m/z) calculated: 218.30; found 219.2 [M+H] + , RT = 0.261 min (Method 2). 1H NMR (400 MHz, DMSO-d6) δ 8.42 (d, J = 7.9 Hz, 1H), 8.11 (s, 3H), 7.85 (d, J = 7.5 Hz, 2H), 7.55 – 7.41 (m, 3H), 3.93 – 3.80 (m, 1H), 3.18 – 3.04 (m, 1H), 2.14 (d, J = 11.8 Hz, 1H), 1.92 (d, J = 12.0 Hz, 1H), 1.79 (d, J = 11.4 Hz, 2H), 1.48 – 1.20 (m, 4H). Step 1-3. Synthesis of N-((1R,3S)-3-((2,6-bis(trifluoromethyl)pyridin-4- yl)amino)cyclohexyl)benzamide (Example 2) To a solution of 4-chloro-2,6-bis(trifluoromethyl)pyridine (59 mg, 1 eq., 0.24 mmol) and N-((1R,3S)-3-aminocyclohexyl)benzamide hydrochloride (60 mg, 1 eq., 0.24 mmol) in DMSO (2 mL) was added DIPEA (0.12 g, 0.16 mL, 4 eq., 0.94 mmol). The vial was capped and the resulting solution was stirred at 130 °C. After stirring for 22 hours, the reaction mixture was cooled to room temperature, filtered. The filtrate was purified by prep-HPLC to yield N-((1R,3S)-3-((2,6-bis(trifluoromethyl)pyridin-4-yl)amino)cy clohexyl) benzamide (2.5 mg, 5.8 µmol, 2.5 % yield). LCMS-ESI (m/z) calculated: 431.38; found 432.2 [M+H] + , RT = 9.535 min (Method 1). EXAMPLE 3 SYNTHESIS OF EXAMPLE 3 Step 1-1. Synthesis of tert-butyl ((1S,4S)-4-benzamidocyclohexyl)carbamate To an ice-cold solution of 1-N-Boc-cis-1,4-cyclohexyldiamine (500 mg, 1 eq., 2.33 mmol) in DCM (6 mL) was added DIPEA (603 mg, 0.81 mL, 2 eq., 4.67 mmol), followed by slow addition of benzoyl chloride (344 mg, 284 µL, 1.05 eq., 2.45 mmol). The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure and the residue purified by flash column chromatography (0-80% EtOAc/hexanes) to yield tert-butyl ((1S,4S)-4-benzamidocyclohexyl)carbamate (703 mg, 2.21 mmol, 95 % yield). LCMS-ESI (m/z) calculated: 318.19; found 319.1 [M+H] + , RT = 4.191 min (Method 3) 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.02 (d, J = 6.8 Hz, 1H), 7.83 (d, J = 7.6 Hz, 2H), 7.53 – 7.42 (m, 3H), 6.58 (s, 1H), 3.84 – 3.77 (m, 1H), 3.45 – 3.38 (m, 1H), 1.77 – 1.67 (m, 4H), 1.59 – 1.48 (m, 4H), 1.39 (s, 9H). Step 1-2. Synthesis of N-((1s,4s)-4-aminocyclohexyl)benzamide hydrochloride To a solution of tert-butyl ((1S,4S)-4-benzamidocyclohexyl)carbamate (699 mg, 1 eq., 2.20 mmol) in 1,4-Dioxane (5 mL) was added 4M hydrogen chloride in 1,4-dioxane (800 mg, 5.49 mL, 4.00 molar, 10 eq., 22.0 mmol). The resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was filtered, and the filter cake was washed with diethyl ether and dried under high vacuum to yield N-((1S,4S)-4-aminocyclohexyl)benzamide hydrochloride (517 mg, 2.03 mmol, 92 % yield). It was used as is in the following step. LCMS-ESI (m/z) calculated: 218.14; found 219.2 [M+H] + , RT = 1.294 min (Method 3) 1H NMR (400 MHz, DMSO-d6) δ 8.39 (s, 1H), 8.19 – 7.97 (m, 4H), 7.86 (d, J = 7.6 Hz, 2H), 7.55 – 7.42 (m, 3H), 3.93 – 3.84 (m, 1H), 3.17 – 3.06 (m, 1H), 1.96 – 1.87 (m, 2H), 1.85 – 1.71 (m, 4H), 1.66 – 1.56 (m, 2H). Step 1-3. Synthesis of N-((1S,4S)-4-((2,6-bis(trifluoromethyl)pyridin-4-yl)amino)cy clohexyl) benzamide (Example 3) To a solution of 4-chloro-2,6-bis(trifluoromethyl)pyridine (59 mg, 1 eq., 0.24 mmol) and N-((1S,4S)-4-aminocyclohexyl)benzamide hydrochloride (60 mg, 1 eq., 0.24 mmol) in DMSO (2 mL) was added DIPEA (0.12 g, 0.16 mL, 4 eq., 0.94 mmol). The vial was capped and the resulting solution was heated at 130 °C. After stirring for 18 hours, the reaction mixture was cooled to room temperature and filtered. The filtrate was purified by prep-HPLC to yield N-((1S,4S)-4-((2,6-bis(trifluoromethyl)pyridin-4-yl)amino) cyclohexyl)benzamide (45.6 mg, 106 µmol, 45 % yield). LCMS-ESI (m/z) calculated: 431.00; found 432.2 [M+H] + , RT = 9.524 min (Method 1) 1H NMR (400 MHz, DMSO-d 6 ) δ 8.21 (d, J = 6.5 Hz, 1H), 7.84 (d, J = 7.5 Hz, 2H), 7.61 (d, J = 6.9 Hz, 1H), 7.54 – 7.42 (m, 3H), 7.19 (s, 2H), 3.94 – 3.84 (m, 1H), 3.78 – 3.70 (m, 1H), 1.82 – 1.66 (m, 8H). EXAMPLE 4 S YNTHESIS OF EXAMPLE 4 4-fluoro-2-(trifluoromethyl)benzonitrile (12 mg, 63.46 umol, 1.05 eq.), N-((1S,4S)-(4- aminocyclohexyl)-4-methoxy-benzamide (15 mg, 60.41 umol, 1 eq.), K 2 CO 3 (25.05 mg, 181.22 umol, 3 eq.) were dissolved in ACN (1 mL) and heated to 80 °C for 12 hours. The mixture was cooled down to room temperature, filtered and the filtrate was concentrated in vacuo. The residue was purified by prep-HPLC to yield N-[4-[4-cyano-3-(trifluoromethyl)anilino]cyclohexyl]- 4-methoxy-benzamide (2.0 mg, 4.79 umol, 8% yield). 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.65 (d, J=8.93 Hz, 2 H) 7.48 - 7.51 (m, 1 H) 6.85 - 6.88 (m, 2 H) 6.78 - 6.80 (m, 1 H) 6.61 - 6.64 (m, 1 H) 5.88 - 5.94 (m, 1 H) 4.04 - 4.11 (m, 1 H) 3.78 - 3.80 (m, 3 H) 3.54 - 3.61 (m, 1 H) 1.81 - 1.90 (m, 4 H) 1.61 - 1.73 (m, 4 H). The compounds listed in Table 1 were made using the procedures of Scheme 1. Table 1
Scheme 2 Reagents: R2X, Base (t-Bu-ONa, TEA, Cs2CO3…), Catalyst (Pd(OAc)2, BINAP), solvent (1,4- dioxane) EXAMPLE 5 SYNTHESIS OF EXAMPLE 5 Synthesis of N-((1S,3R)-3-((3,5-bis(trifluoromethyl)phenyl)amino)cyclohex yl)-4- methoxybenzamide A mixture of 3,5-bis(trifluoromethyl)bromobenzene (103 mg, 1 eq., 351 µmol), N- ((1R,3S)-3-aminocyclohexyl)-4-methoxybenzamide.HCl (100 mg, 1 eq., 351 µmol), cesium carbonate (343 mg, 3 eq., 1.05 mmol), palladium(II) acetate (3.94 mg, 0.05 eq., 17.6 µmol), and BINAP (21.9 mg, 0.10 eq., 35.1 µmol) in 1,4-Dioxane (3 mL) was bubbled with nitrogen for 5 minutes. The vial was capped and the resulting yellow mixture was stirred at 100 °C. After stirring for 18 hours, the reaction mixture was cooled to room temperature, filtered. The filtrate was purified by prep-HPLC to yield N-((1S,3R)-3-((3,5- bis(trifluoromethyl)phenyl)amino)cyclohexyl)-4-methoxybenzam ide (36.6 mg, 79.5 µmol, 22.6 % yield). LCMS-ESI (m/z) calculated: 460.42; found 461.2 [M+H] + , RT = 10.799 min (Method 1) 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.12 (d, J = 7.9 Hz, 1H), 7.82 (d, J = 8.4 Hz, 2H), 7.13 (s, 2H), 7.02 – 6.95 (m, 3H), 6.56 (d, J = 8.3 Hz, 1H), 4.00 – 3.90 (m, 1H), 3.80 (s, 3H), 3.61 – 3.50 (m, 1H), 2.13 – 2.06 (m, 1H), 1.93 (d, J = 12.5 Hz, 1H), 1.85 (d, J = 12.2 Hz, 1H), 1.80 – 1.73 (m, 1H), 1.53 – 1.42 (m, 1H), 1.32 – 1.20 (m, 2H), 1.11 – 1.00 (m, 1H). EXAMPLE 6 SYNTHESIS OF EXAMPLE 6 Synthesis of tert-butyl N-((1S,4S)-[4-[(4-fluorobenzoyl)amino]cyclohexyl]carbamate To a mixture of tert-butyl cis-N-(4-aminocyclohexyl)carbamate (1.35 g, 6.31 mmol, 1 eq.) and TEA (1.28 g, 12.61 mmol, 1.76 mL, 2 eq.) in DCM (20 mL) was added 4-fluorobenzoyl chloride (1 g, 6.31 mmol, 757.58 uL, 1 eq.) at 0 °C, then the reaction mixture was stirred at 25 °C for 0.5 hr. The reaction mixture was concentrated to give a residue that was purified by silica on column chromatography (eluent: PE/EtOAc=10:1 to 1:1). Tert-butyl N-[4-[(4- fluorobenzoyl)amino]cyclohexyl]carbamate (2 g, 5.95 mmol, 94% yield) was obtained. Synthesis of cis-N-(4-aminocyclohexyl)-4-fluoro-benzamide.HCl A mixture of tert-butyl N-[4-[(4-fluorobenzoyl)amino]cyclohexyl]carbamate (2 g, 5.95 mmol, 1 eq.) in HCl/EtOAc (4 M, 5 mL, 3.36 eq.) was stirred at 25 °C for 1 hr. The reaction mixture was concentrated to give N-(1S,4S)-(4-aminocyclohexyl)-4-fluoro-benzamide.HCl (1.5 g, 5.50 mmol, 93% yield). It was used as is in the next step directly. LCMS-ESI (m/z) calculated: 236.3; found 237.4 [M+H] + , RT = 0.237 min (Method 4). Synthesis of N-((1S,4S)-4-((3,5-bis(trifluoromethyl)phenyl)amino)cyclohex yl)-4- fluorobenzamide A mixture of 3,5-bis(trifluoromethyl)bromobenzene (107 mg, 1 eq., 367 µmol), N- (1S,4S)-(4-aminocyclohexyl)-4-fluoro-benzamide.HCl (100 mg, 1 eq., 367 µmol), cesium carbonate (358 mg, 3 eq., 1.10 mmol), palladium(II) acetate (4.12 mg, 0.05 eq., 18.3 µmol), and BINAP (22.8 mg, 0.10 eq., 36.7 µmol) in 1,4-Dioxane (3 mL) was bubbled with nitrogen for 5 minutes. The vial was capped and the resulting mixture was stirred at 100 °C. After stirring for 16.5 hours, the reaction mixture was cooled to room temperature, filtered. The filtrate was purified by prep-HPLC to yield N-((1S,4S)-4-((3,5-bis(trifluoromethyl)phenyl)amino)cyclohex yl)- 4-fluorobenzamide (7.8 mg, 17 µmol, 5 % yield). LCMS-ESI (m/z) calculated: 448.385; found 449.2 [M+H] + , RT = 11.396 min (Method 1). 1H NMR (400 MHz, DMSO-d6) δ 8.23 (d, J = 6.7 Hz, 1H), 7.93 (s, 2H), 7.28 (t, J = 8.8 Hz, 2H), 7.14 (s, 2H), 7.02 (s, 1H), 6.60 (d, J = 6.4 Hz, 1H), 3.91 – 3.82 (m, 1H), 3.63 – 3.55 (m, 1H), 1.84 – 1.63 (m, 8H). EXAMPLE 7 SYNTHESIS OF EXAMPLE 7 Synthesis of N-(1S, 4S)-[4-[[2-chloro-6-(trifluoromethyl)-4-pyridyl]amino]cycloh exyl]-4-fluoro- benzamide A mixture of N-(1S, 4S)-(4-aminocyclohexyl)-4-fluoro-benzamide.HCl (177.43 mg, 650.54 umol, 1 eq.), 2-chloro-4-iodo-6-(trifluoromethyl)pyridine (200 mg, 650.54 umol, 1 eq.), DavePhos (25.60 mg, 65.05 umol, 0.1 eq.) and t-BuONa (187.56 mg, 1.95 mmol, 3 eq.) in dioxane (10 mL) was degassed and purged with N2 for 3 times, and then Pd2(dba)3 (29.79 mg, 32.53 umol, 0.05 eq.) was added under N 2 atmosphere. The reaction mixture was stirred at 100 °C for 3 h under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC and lyophilized to give N-(1S,4S)-[4-[[2-chloro- 6-(trifluoromethyl)-4-pyridyl]amino]cyclohexyl]-4-fluoro-ben zamide (19.4 mg, 46.66 umol, 7% yield). LCMS-ESI (m/z) calculated: 415.82; found 416.2 [M+H] + , RT = 0.974 min (Method 6). 1 H NMR (400 MHz, DMSO-d6) δ = 8.22 (br d, J = 6.4 Hz, 1H), 8.00 - 7.85 (m, 2H), 7.38 (br d, J = 7.0 Hz, 1H), 7.28 (t, J = 9.2 Hz, 2H), 7.12 (br d, J = 2.4 Hz, 1H), 7.12 - 6.95 (m, 1H), 6.77 (br s, 1H), 3.87 (br d, J = 1.2 Hz, 1H), 3.63 (br s, 1H), 1.83 - 1.60 (m, 8H). EXAMPLE 8 SYNTHESIS OF EXAMPLE 8 Synthesis of N-(1S, 4S)-[4-[[2-cyclopropyl-6-(trifluoromethyl)-4-pyridyl]amino]c yclohexyl]-4- fluoro-benzamide A mixture of N-(1S, 4S)-[4-[[2-chloro-6-(trifluoromethyl)-4-pyridyl]amino]cycloh exyl]-4- fluoro-benzamide (100 mg, 240.49 umol, 1eq.), cyclopropylboronic acid (61.97 mg, 721.48 umol, 3 eq.), Cs2CO3 (156.71 mg, 480.99 umol, 2 eq.) in dioxane (3 mL) was degassed and purged with N2 for 3 times. Pd(dppf)Cl 2 (17.60 mg, 24.05 umol, 0.1 eq.) was added under N 2 atmosphere. The mixture was stirred at 100 °C for 12 hrs under N2 atmosphere. The reaction mixture was filtered, and the filtrate concentrated to give the residue. The residue was purified by prep-HPLC to give N-(1S, 4S)- [4-[[2-cyclopropyl-6-(trifluoromethyl)-4- pyridyl]amino]cyclohexyl]-4-fluoro-benzamide (8.9 mg, 18.72 umol, 8% yield). LCMS-ESI (m/z) calculated: 421.44; found 422.3 [M+H] + , RT = 0.839 min (Method 4). 1 H NMR (400 MHz, DMSO-d6) δ = 8.51 - 8.38 (m, 1H), 8.24 (d, J = 6.8 Hz, 1H), 7.95 - 7.89 (m,2H), 7.34 - 7.23 (m, 2H), 6.85 - 6.76 (m, 2H), 6.60 (s, 1H), 3.87 (br s, 1H), 3.58 (br d, J = 3.2 Hz,1H), 2.04 - 1.91 (m, 1H), 1.83 - 1.62 (m, 8H), 0.92 - 0.79 (m, 4H). EXAMPLE 9 SYNTHESIS OF EXAMPLE 9 Synthesis of N-(1S,4S)-[4-[[2-chloro-6-(trifluoromethyl)-4-pyridyl]amino] cyclohexyl]-4- methoxy-benzamide To a solution of 2-chloro-4-iodo-6-(trifluoromethyl)pyridine (200 mg, 650.54 umol, 1 eq.) and N-(1S,4S)-(4-aminocyclohexyl)-4-methoxy-benzamide (161.54 mg, 650.54 umol, 1 eq.) in dioxane (5 mL) was added Pd2(dba)3 (59.57 mg, 65.05 umol, 0.1 eq.), Xantphos (75.28 mg, 130.11 umol, 0.2 eq.) and Cs2CO3 (423.91 mg, 1.30 mmol, 2 eq.) . Then mixture was stirred at 80 °C for 12 hrs under N2 atmosphere. The residue was purified by flash silica gel chromatography (petroleum ether:ethyl acetate) to yield N-(1S,4S)-[4-[[2-chloro-6- (trifluoromethyl)-4-pyridyl]amino]cyclohexyl]-4-methoxy-benz amide (90 mg, 121.86 umol, 18.73% yield). LCMS-ESI (m/z) calculated: 427.85; found 428.2 [M+H] + , RT = 0.937 min (Method 4). Synthesis of 4-methoxy-N-[4-[[2-(3-methylanilino)-6-(trifluoromethyl)-4-p yridyl]amino] cyclohexyl]benzamide To a solution of N-[4-[[2-chloro-6-(trifluoromethyl)-4-pyridyl]amino]cyclohex yl]-4- methoxy-benzamide (30 mg, 40.62 umol, 1 eq.) and 3-methylaniline (6.53 mg, 60.93 umol, 6.60 uL, 1.5 eq.) in dioxane (2 mL) was added Cs2CO3 (26.47 mg, 81.24 umol, 2 eq.) and Ruphos Pd G3 (3.40 mg, 4.06 umol, 0.1 eq.). The mixture was stirred at 100 °C for 12 hrs under N2 atmosphere. After return to rt, the mixture was filtrated, and the filtrate was concentrated under vacuum to give a residue. The residue was purified by prep-HPLC to yield 4-methoxy-N-[4-[[2-(3- methylanilino)-6-(trifluoromethyl)-4-pyridyl]amino]cyclohexy l]benzamide (13.3 mg, 25.51 umol, 63% yield). LCMS-ESI (m/z) calculated: 498.55; found 499.3 [M+H] + , RT = 0.932 min (Method 4). The compounds listed in Table 2 were made using the procedures of Scheme 2. Table 2 EXAMPLE 10 SYNTHESIS OF EXAMPLE 10 Synthesis of N-(1S,4S)-[4-[[2-chloro-6-(trifluoromethyl)pyrimidin-4-yl]am ino]cyclohexyl]-4- fluoro-benzamide A mixture of 2,4-dichloro-6-(trifluoromethyl)pyrimidine (0.1 g, 460.88 umol, 100.00 uL, 1 eq.), N-(1S,4S)-(4-aminocyclohexyl)-4-fluoro-benzamide.HCl (125.70 mg, 460.88 umol, 1 eq.) and DIEA (119.13 mg, 921.76 umol, 160.55 uL, 2 eq.) in DMF (1 mL) was stirred at 25 °C for 1 hour. The reaction mixture was diluted with H2O (15 mL) and extracted with EA (25 mL x 3). The combined organic layers were combined and washed with sat.aq NaCl (50 mL x 3), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO2, PE: EA = 1:1) to yield N-(1S,4S)-[4-[[2-chloro-6- (trifluoromethyl)pyrimidin-4-yl]amino]cyclohexyl]-4-fluoro-b enzamide (0.15 g, 359.89 umol, 78% yield). 1H NMR (400 MHz, DMSO-d6) δ = 8.45 (d, J = 6.8 Hz, 1H), 8.25 (d, J = 6.4 Hz, 1H), 7.94 - 7.90 (m, 2H), 7.31 - 7.26 (m, 2H), 6.97 (s, 1H), 3.98 - 3.79 (m, 2H), 1.84 - 1.80 (m, 2H), 1.78 - 1.71(m, 6H). Synthesis of N-(1S,4S)-[4-[[2-anilino-6-(trifluoromethyl)pyrimidin-4-yl]a mino]cyclohexyl]-4- fluoro-benzamide Aniline (11.17 mg, 119.96 umol, 10.95 uL, 1 eq.), N-(1S,4S)-[4-[[2-chloro-6- (trifluoromethyl)pyrimidin-4-yl]amino]cyclohexyl]-4-fluoro-b enzamide (50 mg, 119.96 umol, 1 eq.) and DIEA (77.52 mg, 599.80 umol, 104.47 uL, 5 eq.) were taken up into a microwave tube in NMP (2 mL). The sealed tube was heated at 180 °C for 8 hrs in a microwave. The reaction mixture was filtered. The filtrate was purified by prep-HPLC to yield N-[4-[[2-anilino-6- (trifluoromethyl)pyrimidin-4-yl]amino]cyclohexyl]-4-fluoro-b enzamide (5 mg, 9.62 umol, 8% yield). LCMS-ESI (m/z) calculated: 473.48; found 474.2 [M+H] + , RT = 1.021 min (Method 4). 1H NMR (400 MHz, DMSO-d6) δ = 9.47 (s, 1H), 8.44 (s, 1H), 8.27 (d, J = 6.0 Hz, 1H), 7.95 - 7.91 (m, 2H), 7.77 - 7.71 (m, 3H), 7.31 - 7.23 (m, 4H), 6.94 (t, J = 7.6 Hz, 1H), 6.44 (s, 1H), 4.04 (d, J = 1.2 Hz, 1H), 3.90 (d, J = 1.2 Hz, 1H), 1.90 - 1.84 (m,2H), 1.80 - 1.69 (m, 6H). EXAMPLE 11 SYNTHESIS OF EXAMPLE 11 Synthesis 4-(dimethylamino)-N-(1S,4S)-[4-[[2-[ethyl(methyl)amino]-6- (trifluoromethyl)pyrimidin-4-yl]amino] cyclohexyl]benzamide To the mixture of N-(1S,4S)-[4-[[2-chloro-6-(trifluoromethyl)pyrimidin-4- yl]amino]cyclohexyl]-4-(dimethylamino)benzamide.HCl (50 mg, 113.15 umol, 1 eq.), N- methylethanamine (21.63 mg, 226.31 umol, 31.44 uL, 2 eq., HCl) in NMP (1 mL) was added DIEA (73.12 mg, 565.77 umol, 98.55 uL, 5 eq.) at 25 °C, then the reaction mixture was stirred at 120 °C for 1 hr. The reaction mixture was filtered. The filtrate was purified by prep-HPLC to yield compound 4-(dimethylamino)-N-(1S,4S)-[4-[[2-[ethyl(methyl)amino]-6- (trifluoromethyl)pyrimidin-4-yl]amino]cyclohexyl] benzamide (21 mg, 45.21 umol, 40% yield). LCMS-ESI (m/z) calculated: 464.54; found 465 [M+H] + , RT = 0.968 min (Method 4). 1H NMR (400 MHz, DMSO-d6) δ = 7.80 - 7.76 (m, 1H), 7.73 (d, J = 8.8 Hz, 2H), 7.36 (br d, J = 5.2 Hz, 1H), 6.68 (d, J = 9.0 Hz, 2H), 6.21 (s, 1H), 3.97 (br d, J = 1.2 Hz, 1H), 3.82 (br t, J = 8.4 Hz, 1H), 3.56 (q, J = 7.0 Hz, 2H), 3.02 (s, 3H), 2.95 (s, 6H), 1.88 (br s, 2H), 1.75 - 1.58 (m, 6H), 1.07 (t, J = 7.0 Hz, 3H). EXAMPLE 12 SYNTHESIS OF EXAMPLE 12 Synthesis N-(1S,4S)-[4-[[2-(ethylamino)-6-(trifluoromethyl)pyrimidin-4 -yl]amino]cyclohexyl]-4- methoxy-benzamide A mixture of N-(1S,4S)-[4-[[2-chloro-6-(trifluoromethyl)pyrimidin-4- yl]amino]cyclohexyl]-4-methoxy-benzamide (30 mg, 69.96 umol, 1 eq.), ethanamine (6.31 mg, 139.92 umol, 9.16 uL, 2 eq., HCl) and K2CO3 (48.34 mg, 349.80 umol, 5 eq.) in DMF (1 mL) was stirred at 120 °C for 12 hrs. The reaction mixture was filtered, and the filtrate concentrated to give a residue. The residue was purified by prep-HPLC to give N-(1S,4S)-[4-[[2-(ethylamino)-6- (trifluoromethyl)pyrimidin-4-yl]amino]cyclohexyl]-4-methoxy- benzamide (3 mg, 6.49 umol, 9% yield). LCMS-ESI (m/z) calculated: 437.47; found 438 [M+H] + , RT = 0.868 min (Method 6). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.73 (d, J=8.88 Hz, 2 H) 6.94 (d, J=8.75 Hz, 2 H) 5.99 (s, 2 H) 5.03 - 5.13 (m, 1H) 4.09 - 4.21 (m, 1 H) 3.90 - 4.04 (m, 1 H) 3.86 (s, 3 H) 3.36 - 3.47 (m, 2 H) 1.84 - 1.97 (m, 5 H) 1.63 - 1.75 (m, 3 H) 1.21 (t, J=7.25 Hz, 3 H). The compounds listed in Table 3 were made using the procedures used for Example 12 in the presence of the appropriate amine. Table 3 Scheme 3 Reagents: i. R1X, DIPEA, solvent (DMSO, NMP), heat; ii. HCl, solvent (1,4-dioxane), heat; iii. R2COCl, base (DIEA), solvent (DMF) or R2COOH, peptide coupling reagents EXAMPLE 13 SYNTHESIS OF EXAMPLE 13 Synthesis of tert-butyl ((1S,4S)-4-((3,5-bis(trifluoromethyl)phenyl)amino) cyclohexyl)carbamate A solution of 3,5-bis(trifluoromethyl)fluorobenzene (500 mg, 1 eq., 2.15 mmol) and tert-butyl ((1S,4S)-4-aminocyclohexyl)carbamate (462 mg, 1 eq., 2.15 mmol) and DIPEA (1.11 g, 1.5 mL, 4 eq., 8.62 mmol) in DMSO (8 mL) was stirred at 130 °C. After 24 hours, the reaction mixture was cooled to room temperature, diluted with water and extracted with EtOAc. The organic layers were combined, washed with brine and concentrated under reduced pressure. The residue was dissolved in DCM and purified by flash column chromatography (40g SiO2, 0-80% EtOAc/hexanes) to yield tert-butyl ((1S,4S)-4-((3,5- bis(trifluoromethyl)phenyl)amino)cyclohexyl)carbamate (333 mg, 781 µmol, 36 %). LCMS-ESI (m/z) calculated: 426.40; found 427.1 [M+H] + , RT = 6.335 min (Method 3). 1H NMR (400 MHz, DMSO-d6) δ 7.11 (s, 2H), 6.99 (s, 1H), 6.86 – 6.69 (m, 1H), 6.52 (d, J = 6.8 Hz, 1H), 3.52 – 3.44 (m, 1H), 3.41 – 3.33 (m, 1H), 1.66 – 1.53 (m, 8H), 1.38 (s, 9H). Synthesis of (1S,4S)-N1-(2-(trifluoromethyl)quinolin-4-yl)cyclohexane-1,4 -diamine hydrochloride To a solution containing tert-butyl ((1S,4S)-4-((3,5-bis(trifluoromethyl)phenyl) amino)cyclohexyl)carbamate (329 mg, 1 eq., 804 µmol) in 1,4-Dioxane (5 mL) was added 4M hydrogen chloride in 1,4-dioxane (293 mg, 2.01 mL, 4.00 molar, 10 eq., 8.04 mmol). The resulting mixture was allowed to stir at room temperature for 21 hours. The reaction mixture was filtered, and the filter cake was washed with diethyl ether and dried under high vacuum to yield (1S,4S)-N1-(2-(trifluoromethyl)quinolin-4-yl)cyclohexane-1,4 -diamine hydrochloride (262 mg, 758 µmol, 94 % yield). It was used as is in the next step. LCMS-ESI (m/z) calculated: 326.79; found 327.2 [M+H] + , RT = 3.236 min (Method 3). 1H NMR (400 MHz, DMSO-d6) δ 8.19 – 7.97 (m, 3H), 7.15 (s, 2H), 7.03 (s, 1H), 6.50 (s, 3H), 3.62 – 3.55 (m, 1H), 3.18 – 3.07 (m, 1H), 1.81 – 1.61 (m, 8H). Synthesis of N-((1S,4S)-4-((3,5-bis(trifluoromethyl)phenyl)amino)cyclohex yl)benzamide To a stirred solution of (1S,4S)-N1-(2-(trifluoromethyl)quinolin-4-yl)cyclohexane-1,4 - diamine hydrochloride (75 mg, 1 eq., 0.21 mmol) and DIPEA (0.11 g, 0.14 mL, 4 eq., 0.83 mmol) in DMF (2 mL) was added benzoyl chloride (31 mg, 25 µL, 1.05 eq., 0.22 mmol). The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered and the filtrate purified by prep-HPLC to yield N-((1S,4S)-4-((3,5-bis(trifluoromethyl)phenyl)amino) cyclohexyl)benzamide (21.4 mg, 49.7 µmol, 24 % yield). LCMS-ESI (m/z) calculated: 430.39; found 431.2 [M+H] + , RT = 11.032 min (Method 1). 1H NMR (400 MHz, DMSO-d 6 ) δ 8.20 (d, J = 6.7 Hz, 1H), 7.84 (d, J = 7.5 Hz, 2H), 7.54 – 7.42 (m, 3H), 7.15 (s, 2H), 7.02 (s, 1H), 6.59 (d, J = 6.4 Hz, 1H), 3.93 – 3.83 (m, 1H), 3.63 – 3.56 (m, 1H), 1.81 – 1.64 (m, 8H). EXAMPLE 14 SYNTHESIS OF EXAMPLE 14 Synthesis of N-((1S,4S)-4-((3,5-bis(trifluoromethyl)phenyl)amino)cyclohex yl)-4- methoxybenzamide To a solution of N-((1S,4S)-4-((3,5-bis(trifluoromethyl)phenyl)amino) cyclohexyl)benzamide (75 mg, 1 eq., 0.21 mmol) and DIPEA (0.11 g, 0.14 mL, 4 eq., 0.83 mmol) in DMF (2 mL) was added 4-methoxybenzoyl chloride (37 mg, 29 µL, 1.05 eq., 0.22 mmol). The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered and the filtrate purified by prep-HPLC to yield N-((1S,4S)-4-((3,5- bis(trifluoromethyl)phenyl)amino)cyclohexyl)-4-methoxybenzam ide (24.7 mg, 53.6 µmol, 26 % yield). LCMS-ESI (m/z) calculated: 460.42; found 461.2 [M+H] + , RT = 11.039 min (Method 1). 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.03 (d, J = 6.7 Hz, 1H), 7.84 (d, J = 8.5 Hz, 2H), 7.14 (s, 2H), 7.03 – 6.94 (m, 3H), 6.59 (d, J = 6.4 Hz, 1H), 3.89 – 3.82 (m, 1H), 3.80 (s, 3H), 3.62 – 3.56 (m, 1H), 1.82 – 1.63 (m, 8H). EXAMPLE 15 SYNTHESIS OF EXAMPLE 15 Synthesis of N-(1S,4S)-[4-[[2,6-bis(trifluoromethyl)-4-pyridyl]amino]cycl ohexyl]-3- (dimethylamino)benzamide To a solution of N-4-[2,6-bis(trifluoromethyl)-4-pyridyl]cyclohexane-1,4-diam ine (50 mg, 113.30 umol, 1 eq., TFA) and 3-(dimethylamino)benzoic acid (18.72 mg, 113.30 umol, 1 eq.) in DMF (1.5 mL) was added DIPEA (43.93 mg, 339.91 umol, 59.21 uL, 3 eq.). Then HATU (64.62 mg, 169.96 umol, 1.5 eq.) was added and the mixture was stirred for 2 hrs at 25 °C. The mixture was partitioned between EtOAc (25 mL) and water (25 mL). The aqueous phase was extracted with EtOAc (10mLx2). The combined organic layers were dried over MgSO4 and concentrated under vacuum. The crude product was purified by reversed-phase HPLC to yield N-(1S,4S)-[4- [[2,6-bis(trifluoromethyl)-4-pyridyl]amino] cyclohexyl]-3-(dimethylamino)benzamide (45.37 mg, 95.63 umol, 84% yield). LCMS-ESI (m/z) calculated: 474.4; found 475.1 [M+H] + , RT = 0.589 min (Method 4). 1H NMR (400 MHz, DMSO-d6) δ = 8.10 - 8.04 (m, 1H), 7.64 - 7.58 (m, 1H), 7.29 - 7.18 (m, 2H), 7.14 (br s, 3H), 6.89 - 6.84(m, 1H), 3.91 - 3.83 (m, 1H), 3.78 - 3.72 (m, 1H), 2.94 (s, 6H), 1.73 (br s, 8H). EXAMPLE 16 SYNTHESIS OF EXAMPLE 16 Synthesis of tert-butyl N-(1S,4S)-[4-[[2-chloro-6-(trifluoromethyl)pyrimidin-4- yl]amino]cyclohexyl] carbamate To the mixture of 2,4-dichloro-6-(trifluoromethyl)pyrimidine (1 g, 4.61 mmol, 1.00 mL, 1 eq.), tert-butyl N-(1S,4S)-(4-aminocyclohexyl)carbamate (987.68 mg, 4.61 mmol, 1 eq.) in DMF (20 mL) was added DIEA (1.19 g, 9.22 mmol, 1.61 mL, 2eq.) at 25 °C, then the reaction mixture was stirred at 25 °C for 12 hrs. The reaction mixture was partitioned between ethyl acetate (30 mL) and water (20 mL), extracted with ethyl acetate (30 mL x3). The combined organic layers were washed with brine (20 mLx3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate) to yield tert-butyl N-(1S,4S)-[4-[[2-chloro-6- (trifluoromethyl)pyrimidin-4-yl]amino]cyclohexyl]carbamate (1.62 g, 3.77 mmol, 82% yield). 1H NMR (400 MHz, DMSO-d6) δ = 8.38 (br d, J = 7.2 Hz, 1H), 6.95 (s, 1H), 6.84 (br dd, J = 1.0, 2.6 Hz, 1H), 3.96 - 3.83 (m, 1H), 3.38 (br d, J = 4.0 Hz, 1H), 1.72 - 1.53 (m, 8H), 1.39 (s, 9H). Synthesis of tert-butyl N-(1S,4S)-[4-[[2-(dimethylamino)-6-(trifluoromethyl)pyrimidi n-4- yl]amino] cyclohexyl]carbamate To the mixture of tert-butyl N-(1S,4S)-[4-[[2-chloro-6-(trifluoromethyl)pyrimidin-4- yl]amino]cyclohexyl]carbamate (1 g, 2.53 mmol, 1eq.), N-methylmethanamine (413.07 mg, 5.07 mmol, 464.13 uL, 2 eq., HCl) in DMSO (10 mL) was added DIEA (654.70 mg, 5.07 mmol, 882.34 uL, 2 eq.) at 25 °C, then the reaction mixture was stirred at 120 °C for 1 hr. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (20 mLx3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate) to yield tert-butyl N-(1S,4S)-[4-[[2-(dimethylamino)-6- (trifluoromethyl)pyrimidin-4-yl]amino]cyclohexyl]carbamate (1 g, 2.45 mmol, 97% yield). 1H NMR (400 MHz, DMSO-d6) δ = 7.32 (br d, J = 4.0 Hz, 1H), 6.83 - 6.70 (m, 1H), 6.18 (s, 1H), 3.90 (br d, J = 2.0 Hz, 1H), 3.34 - 3.33 (m, 1H), 3.04 (s, 6H), 1.76 - 1.68 (m, 2H), 1.61 (br dd, J = 3.8, 6.2 Hz, 2H), 1.58 - 1.54 (m, 4H), 1.38 (s, 9H). Synthesis of N-(1S,4S)-4-(4-aminocyclohexyl)-N2,N2-dimethyl-6-(trifluorom ethyl)pyrimidine- 2,4-diamine Tert-butyl N-(1S,4S)-[4-[[2-(dimethylamino)-6-(trifluoromethyl)pyrimidi n-4- yl]amino]cyclohexyl] carbamate (500 mg, 1.24 mmol, 1 eq.) in 4N HCl/EtOAc (10 mL) was stirred at 25 °C for 1 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was diluted with MeOH (20 mL), and Amberlyst A-21, ion exchange resin was added and stirred at 25 °C for 0.5 hr til the pH = 7. The compound was used in the next step without further purification. LCMS-ESI (m/z) calculated: 303.33; found 303.09 [M+H] + , RT = 0.723 min (Method 4). Synthesis of N-(1S,4S)-[4-[[2-(dimethylamino)-6-(trifluoromethyl)pyrimidi n-4- yl]amino]cyclohexyl]-4-methoxy-benzamide (Example 16) To the mixture of N-(1S,4S)-4-(4-aminocyclohexyl)-N2,N2-dimethyl-6- (trifluoromethyl)pyrimidine-2,4-diamine (50 mg, 164.84 umol, 1 eq.), 4-methoxybenzoic acid (25.08 mg, 164.84 umol, 22.68 uL, 1 eq.) in DMF (1 mL) was added DIEA (42.61 mg, 329.68 umol, 57.42 uL, 2 eq.), HATU (68.94 mg, 181.32 umol, 1.1 eq.) at 25 °C, then the reaction mixture was stirred at 25 °C for 1hr. The reaction mixture was filtered. The filtrate was purified by prep-HPLC and lyophilized to yield N-(1S,4S)-[4-[[2-(dimethylamino)-6-(trifluoromethyl)pyrimidi n-4- yl]amino]cyclohexyl]-4-methoxy-benzamide (33.4 mg, 76.35 umol, 46% yield). LCMS-ESI (m/z) calculated: 437.47; found 438.0 [M+H] + , RT = 0.941 min (Method 1). 1H NMR (400 MHz, DMSO-d6) δ = 8.02 (br d, J = 5.9 Hz, 1H), 7.84 (d, J = 8.8 Hz, 2H), 7.37 (br d, J = 4.8 Hz, 1H), 6.97 (d, J =8.8 Hz, 2H), 6.21 (s, 1H), 3.98 (br s, 1H), 3.84 (br s, 1H), 3.80 (s, 3H), 3.06 (s, 6H), 1.89 (br d, J = 4.3 Hz, 2H), 1.75 - 1.62 (m, 6H). EXAMPLE 17 SYNTHESIS OF EXAMPLE 17 Synthesis of methyl 1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carboxylate To a stirring solution of methyl 1H-pyrazole-4-carboxylate (200 mg, 1 eq., 1.59 mmol), 2,2,2- trifluoroethyl trifluoromethanesulfonate (736.17 mg, 2 eq., 3.17 mmol), Cs 2 CO 3 (1.55 g, 3 eq., 4.76 mmol) in ACN (3 mL). Then it was stirred at 60 °C for 12 hours. The mixture was filtered, and filtrate was collected. The crude product was purified by reversed-phase flash and lyophilized to yield methyl 1-(2,2,2-trifluoroethyl)pyrazole-4-carboxylate (114 mg, 542.79 umol, 34.23% yield). LCMS-ESI (m/z) calculated: 208.1; found 209.2 [M+H] + , RT = 0.392 min (Method 4). 1H NMR (400 MHz, DMSO-d6) δ = 8.47 (s, 1H), 8.00 (s, 1H), 5.21 (q, J = 9.2 Hz, 2H), 3.76 (s, 3H). Synthesis of 1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carboxylic acid To a stirring solution of methyl 1-(2,2,2-trifluoroethyl)pyrazole-4-carboxylate (114 mg, 1 eq., 547.71 umol) and LiOH.H 2 O (68.95 mg, 3 eq., 1.64 mmol) in MeOH (1.5 mL) and H 2 O (1.5 mL). The solution was stirred at 50 °C for 1 hour. The mixture was adjusted to pH 7 with 1 M HCl and concentrated in vacuum to yield 1-(2,2,2-trifluoroethyl)pyrazole-4-carboxylic acid (106 mg, crude). The crude product was used for next step without purification. LCMS-ESI (m/z) calculated: 194.1; found 195.2 [M+H] + , RT = 0.322 min (Method 4). Synthesis of tert-butyl ((1s,4s)-4-((4-cyano-3-(trifluoromethyl)phenyl)amino)cyclohe xyl) carbamate To a stirring solution of 4-fluoro-2-(trifluoromethyl)benzonitrile (10 g, 1 eq., 52.88 mmol) and tert-butyl N-(4- aminocyclohexyl)carbamate (11.33 g, 1 eq., 52.88 mmol) in DMF (100 mL) was added K 2 CO 3 (14.62 g, 2 eq., 105.76 mmol). The mixture was stirred at 80 °C for 1 hour. The reaction mixture was filtered and concentrated, then the mixture was poured into Brine (150 mL) and EtOAc (150 mL). The water layer was washed with EtOAc (100 mL X 5), the organic phase was dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography to yield tert-butyl N-[4-[4-cyano-3- (trifluoromethyl)anilino]cyclohexyl]carbamate (13.8 g, 35.99 mmol, 68% yield). LCMS-ESI (m/z) calculated: 383.4; found 384.2 [M+H] + , RT = 0.679 min (Method 4). 1H NMR (400 MHz, DMSO-d6) δ = 7.69 (d, J = 8.6 Hz, 1H), 7.08 (br d, J = 7.3 Hz, 2H), 6.85 (dd, J = 1.8, 8.8 Hz, 1H), 6.79 (br s, 1H), 3.49 (br s, 1H), 3.39 (br d, J = 2.6 Hz, 1H), 1.74 - 1.49 (m, 9H), 1.39 (s, 10H). 4-(((1s,4s)-4-aminocyclohexyl)amino)-2-(trifluoromethyl)benz onitrile To a stirring solution of tert-butyl N-[4-[4-cyano-3-(trifluoromethyl)anilino]cyclohexyl] carbamate (5.5 g, 1 eq., 14.35 mmol) in DCM (48 mL) and TFA (12 mL). The mixture was stirred at 25 °C for 12 hours. The mixture was concentrated and was washed with MTBE (20 ml X 5) to yield 4-[(4-aminocyclohexyl)amino]-2-(trifluoromethyl)benzonitrile (2.6 g, 9.18 mmol, 64% yield). LCMS-ESI (m/z) calculated: 283.2; found 284.0 [M+H] + , RT = 0.457 min (Method 4). Synthesis of N-((1s,4s)-4-((4-cyano-3-(trifluoromethyl)phenyl)amino)cyclo hexyl)-1-(2,2,2- trifluoroethyl)-1H-pyrazole-4-carboxamide (Example 17) To a stirring solution of 5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (31.73 mg, 1 eq., 176.18 umol), 4-[(4- aminocyclohexyl)amino]-2-(trifluoromethyl)benzonitrile (70 mg, 1 eq., 176.18 umol) in DMF (1.5 mL) was added DIPEA (68.31 mg, 3 eq., 528.54 umol) and HATU (100.48 mg, 1.5 eq., 264.27 umol) and stirred for 2 hours at 25 °C. The reaction mixture concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase HPLC:Column and lyophilized to yield N-[4-[4-cyano-3- (trifluoromethyl)anilino]cyclohexyl]-5-(trifluoromethyl)-1H- pyrazole-4-carboxamide (37 mg, 82.58 umol, 47% yield) . LCMS-ESI (m/z) calculated: 445.3; found 446.1 [M+H] + , RT = 0.672 min (Method 4). 1H NMR (400 MHz, DMSO-d6) δ = 14.20 - 12.99 (s, 1H), 8.44 - 8.33 (d, 1H), 7.94 (d, J = 6.8 Hz, 1H), 7.71 (d, J = 8.8 Hz, 1H), 7.18 - 7.06 (m, 2H), 6.87 (dd, J = 1.8, 8.8 Hz, 1H), 3.81 (br d, J = 4.6 Hz, 1H), 3.57 (br s, 1H), 1.81 - 1.56 (m, 8H). The compounds listed in Table 4 were made using the procedures of Scheme 3. Table 4
EXAMPLE 18 Scheme 4 Reagents: i. R1X, Base (t-Bu-ONa, TEA, Cs2CO3…), Catalyst (Pd(OAc)2, BINAP), solvent (1,4- dioxane); ii. Acidic deprotection (HCl, TFA), solvent (1,4-dioxane); iii. R 2 COCl, base (DIEA), solvent (DMF) or R2COOH, peptide coupling reagents SYNTHESIS OF EXAMPLE 18 Synthesis of 4-bromo-2-methyl-6-(trifluoromethyl)benzonitrile To a stirring solution of 4-bromo-1-fluoro-2-(trifluoromethyl)benzene (10.0 g, 1 eq., 41.15 mmol) in THF (100 mL) was added LDA (24.69 mL, 1.2 eq., 2 M) dropwise at -78 °C under N2 atmosphere. After stirring at -78 °C for 0.5 hours, MeI (11.68 g, 2 eq., 82.31 mmol) was added dropwise and the reaction was stirred at -78 °C for 0.5 hour. The reaction solution was quenched by saturated NH 4 Cl aqueous solution (200 mL) and then extracted with ethyl acetate (3 x100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography and the fractions were checked by TLC to yield 5-bromo-2-fluoro-1-methyl-3- (trifluoromethyl)benzene (8.4 g, 32.68 mmol, 72% yield) as colorless oil. 1 H NMR (400 MHz, CHLOROFORM-d) δ = 7.46 (m, 2H), 2.24 (s, 3H). Synthesis of 4-bromo-2-methyl-6-(trifluoromethyl)benzonitrile To a stirring solution of 5-bromo-2-fluoro-1-methyl-3-(trifluoromethyl)benzene (8.4 g, 1.0 eq., 32.68 mmol) in DMSO (100 mL) was added NaCN (1.82 g, 1.14 eq., 37.14 mmol) and stirred for 2 hours at 100°C. The reaction solution was cooled to room temperature and then diluted with water (500 mL), basified to pH=10 by 1M NaOH then extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine (2 x 100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The water phase was quenched by 5% NaClO aqueous solution. The residue was purified by column chromatography and the fractions were checked by TLC to yield 4-bromo-2-methyl-6-(trifluoromethyl)benzonitrile (3.4 g, 12.88 mmol, 39% yield). 1 H NMR (400 MHz, CHLOROFORM-d) δ = 7.77 (s, 1H), 7.74 (s, 1H), 2.64 (s, 3H). Synthesis of tert-butyl ((1s,4s)-4-((4-cyano-3-methyl-5-(trifluoromethyl)phenyl)amin o) cyclohexyl)carbamate To a stirring solution of 4-bromo-2-methyl-6-(trifluoromethyl)benzonitrile (1.5 g, 1 eq., 5.68 mmol) tert-butyl N-(4- aminocyclohexyl)carbamate (1.22 g, 1 eq., 5.68 mmol) in dioxane (20 mL) was added Cs 2 CO 3 (5.55 g, 3 eq., 17.04 mmol), XantPhos Pd G3 (538.75 mg, 0.1 eq., 568.09 umol) and was stirred for 12 hours at 100 °C. The mixture was partitioned between EtOAc (50 mL) and water (50 mL). The aqueous phase was extracted with EtOAc (50 mLX 2). Organic phases were dried over MgSO4 and concentrated under vacuum. The residue was purified by column chromatography to yield tert-butyl N-[4-[4-cyano-3-methyl-5- (trifluoromethyl)anilino]cyclohexyl]carbamate (1.4 g, 3.52 mmol, 43% yield). LCMS-ESI (m/z) calculated: 397.2; found 398.2 [M+H] + , RT = 0.624 min (Method 4). The compounds listed in Table 5 were made using the procedures of Scheme 4 starting from tert-butyl ((1S, 4S)-4-((4-cyano-3-methyl-5-(trifluoromethyl)phenyl)amino) cyclohexyl)carbamate and the appropriate acid or acid chloride. Table 5
EXAMPLE 19 MRGPRX2 ACTIVITY CHO cells stably transfected to express human MRGPRX2 were maintained in an incubator at 37° C with 5% CO2 and grown in F12 (HAM) media with 10% fetal bovine serum (FBS), 1% Glutamax, 1% penicillin /streptomycin, 800 µg/mL Geneticin (G418), and 300 µg/mL Hygromycin B. Cells were plated in a 384-well assay plate at 20,000 cells per well in 12 µL of Opti-MEM and kept in an incubator overnight. On the day of the assay, compounds solubilized at 10 mM in DMSO were added as a 10-point curve (30 uM final top concentration with 1:3 serial dilutions) using a Tecan D300E digital dispenser. Agonists were diluted in assay buffer (final concentrations of 5.7 mM Tris-HCl, 43 mM NaCl, 50 mM LiCl, pH= 8) and 2 µL of the agonist Cortistatin-14 (CPC Scientific, catalog CORT-002) are added to each well. Final concentrations of agonists were 0.3 µM Cortistatin-14. Final concentrations of DMSO were kept consistent across the plate. Plates were incubated in the dark for 1 hr at 37 °C and then for 1 hr at room temperature. IP-1 standards and HTRF detection reagents were added according to the IP-One – Gq Kit purchased from Cisbio (part number 62IPAPEJ) and incubated in the dark for 1 hr at room temperature. The plate was read on a Molecular Devices SpectraMax iD5 plate reader. The HTRF ratio was calculated from the raw data and graphed using GraphPad Prism to calculate an IC50 value for each compound. Activity data for selected MRGPRX2 antagonists (versus 0.3 uM Corstitatin-14 agonist) are displayed in Table 5. The activity ranges are denoted as follows: “+++++” denotes antagonist activity <100 nM; “++++” denotes antagonist activity between 100 and 500 nM; “+++” denotes activity between 501 and 1000 nM; “++” denotes activity between 1001 and 2500 nM; and “+” denotes activity >2500 nM. Table 5
The various embodiments described above can be combined to provide further embodiments. All of the U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications and non-patent publications referred to in this specification and/or listed in the Application Data Sheet are incorporated herein by reference, in their entirety. Aspects of the embodiments can be modified, if necessary, to employ concepts of the various patents, applications and publications to provide yet further embodiments. These and other changes can be made to the embodiments in light of the above- detailed description. In general, in the following claims, the terms used should not be construed to limit the claims to the specific embodiments disclosed in the specification and the claims but should be construed to include all possible embodiments along with the full scope of equivalents to which such claims are entitled. Accordingly, the claims are not limited by the disclosure. This application claims the benefit of priority to U.S. Provisional Application No. 63/123,411, filed December 9, 2020, which application is hereby incorporated by reference in its entirety.