Modulators of mas-related g-protein receptor x4 and related products and methods

Abstract

or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein n, x, A, Q1, Q2, Z, R, R1, R2, R3, R4 and R5 are as defined herein. Pharmaceutical compositions containing such compounds, as well as to compounds themselves, are also provided.

1 . A method for modulating a Mas-Related G-Protein Receptor (MRGPR) X4 by contacting the MRGPRX4 with an effective amount of a compound having the structure of Formula (I): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein:
 n is 0 or 1; 
 x is 0, 1 or 2; 
 A is aryl or heteroaryl; 
 Q 1  and Q 2  are both CR 10 , or one of Q 1  or Q 2  is CR 10  and the other is N; 
 Z is —O—, —S—, —N(R 11 )—, —CH 2 — or —C≡C—; 
 each R 10  is H or alkyl; 
 R is —(CH 2 ) m C(═O)OR 12 , —(CH 2 ) m NHR 13 , —(C═O)NR 14 R 15 , —CH 2 OH, —CN, haloalkyl, carbocycle, heterocycle, or a carboxylic acid isostere; 
 m is 0 or 1; 
 R 11 , R 12  and R 13  are the same or different and individually H or alkyl; 
 R 14  is H and R 15  is H, —SO 2 CH 3 , carbocycle, heterocyle, or alkyl substituted with 0, 1, 2 or 3 substituents selected from —OH, —CN, —NR′R″, C(═O)OH, C(═O)NR′R″, —SO 2 OH, alkoxy, carbocycle, or heterocycle, wherein R′ and R″ are individually H or alkyl, or 
 R 14  and R 15  are taken together with the nitrogen atom to which they are attached to form heterocycle; 
 R 1  is H or alkyl; 
 R 2  is halo, cyano, amino, alkyl, alkoxy, carbocycle or heterocycle; 
 R 3 , R 4  and R 5  are the same or different and either absent or, when present, cyano, nitro, halogen, alkyl, haloalkyl, cyanoalkyl, alkoxy, haloalkoxy, —(C═O)alkyl, —(C═O)NHalkyl, carbocycle, heterocycle, —O-carbocycle or —O-heterocycle, or any two R and R 2  taken together with the atoms to which they are attached form heterocycle; 
 any two R 3 , R 4 , R 5  and R 10 , taken together with the atoms to which they are attached form carbocycle or heterocycle; 
 and wherein each occurrence of carbocycle or heterocycle is substituted with 0, 1, 2 or 3 substituents individually selected from halogen, hydroxyl, oxo, halo, alkyl, haloalkyl, alkoxy, haloalkoxy, carbocycle, or heterocycle. 
 
     
     
         2 . A method for treating an MRGPR X4 dependent condition by administering to a subject in need thereof an effective amount of a compound having the structure of Formula (I): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein:
 n is 0 or 1; 
 x is 0, 1 or 2; 
 A is aryl or heteroaryl; 
 Q 1  and Q 2  are both CR 10 , or one of Q 1  or Q 2  is CR 10  and the other is N; 
 Z is —O—, —S—, —N(R 11 )—, —CH 2 — or —C≡C—; 
 each R 10  is H or alkyl; 
 R is —(CH 2 ) m C(═O)OR 12 , —(CH 2 ) m NHR 13 , —(C═O)NR 14 R 15 , —CH 2 OH, —CN, haloalkyl, carbocycle, heterocycle, or a carboxylic acid isostere; 
 m is 0 or 1; 
 R 11 , R 12  and R 13  are the same or different and individually H or alkyl; 
 R 14  is H and R 15  is H, —SO 2 CH 3 , carbocycle, heterocyle, or alkyl substituted with 0, 1, 2 or 3 substituents selected from —OH, —CN, —NR′R″, C(═O)OH, C(═O)NR′R″, —SO 2 OH, alkoxy, carbocycle, or heterocycle, wherein R′ and R″ are individually H or alkyl, or 
 R 14  and R 15  are taken together with the nitrogen atom to which they are attached to form heterocycle; 
 R 1  is H or alkyl; 
 R 2  is halo, cyano, amino, alkyl, alkoxy, carbocycle or heterocycle; 
 R 3 , R 4  and R 5  are the same or different and either absent or, when present, cyano, nitro, halogen, alkyl, haloalkyl, cyanoalkyl, alkoxy, haloalkoxy, —(C═O)alkyl, —(C═O)NHalkyl, carbocycle, heterocycle, —O-carbocycle or —O-heterocycle, or any two R and R 2  taken together with the atoms to which they are attached form heterocycle; 
 any two R 3 , R 4 , R 5  and R 10 , taken together with the atoms to which they are attached form carbocycle or heterocycle; 
 and wherein each occurrence of carbocycle or heterocycle is substituted with 0, 1, 2 or 3 substituents individually selected from halogen, hydroxyl, oxo, halo, alkyl, haloalkyl, alkoxy, haloalkoxy, carbocycle, or heterocycle. 
 
     
     
         3 . The method of  claim 2 , wherein the MRGPR X4 dependent condition is a condition that is caused by the activation of MRGPR X4 by a bile acid or analog thereof. 
     
     
         4 . The method of  claim 2  wherein the MRGPR X4 dependent condition is an itch associated condition, a pain associated condition, or an autoimmune disorder. 
     
     
         5 . The method of  claim 4  wherein the itch associated condition is chronic itch, cholestatic pruritus, contact dermatitis, allergic blepharitis, anemia, atopic dermatitis, bullous pemphigoid, candidiasis, chicken pox, cholestasis, end-stage renal failure, hemodialysis, contact dermatitis, dermatitis herpetiformis, diabetes, drug allergy, dry skin, dyshidrotic dermatitis, ectopic eczema, eczema, erythrasma, folliculitis, fungal skin infection, hemorrhoids, herpes, HIV infection, Hodgkin's disease, hyperthyroidism, iron deficiency anemia, kidney disease, leukemia, liver disease, lymphoma, malignancy, multiple myeloma, neurodermatitis, onchocerciasis, Paget's disease, pediculosis, polycythemia  rubra  vera, pruritus ani, pseudorabies, psoriasis, rectal prolapse, scabies, schistosomiasis, scleroderma, severe stress, stasia dermatitis, swimmer's itch, thyroid disease, tinea cruris, uremic pruritus, or urticaria. 
     
     
         6 . The method of  claim 5  wherein the itch associated condition is cholestatic pruritus, uremic pruritus, atopic dermatitis, dry skin, psoriasis, contact dermatitis, or eczema. 
     
     
         7 . The method of  claim 5 , wherein the itch associated condition is a liver disease, wherein the liver disease is primary biliary cholangitis, primary sclerosing cholangitis, Alagille syndrome, Progressive familial intrahepatic cholestasis, Intrahepatic cholestasis of pregnancy, nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), biliary atresia, chronic B hepatitis, drug-chronic viral hepatitis, induced liver injury (DILI), liver fibrosis, cholestatic liver disease, or alcoholic liver disease. 
     
     
         8 . The method of  claim 2 , further comprises administering to the subject a pharmaceutically effective amount of a second therapeutic agent. 
     
     
         9 . The method of  claim 8 , wherein the MRGPR X4 dependent condition is a liver disease and the second therapeutic agent is ursodeoxycholic acid (UDCA), norUrsodeoxycholic acid, cholestyramine, stanozolol, naltrexone, rifampicin, Alisol B 23-acetate (AB23A), curcumin, dihydroartemisinin, fenofibrate, bezafibrate, metronidazole, methotrexate, colchicine, metformin, betaine, glucagon, naltrexone, a farnesoid X-receptor (FXR) agonist, a peroxisome proliferator-activated receptor (PPAR) agonist, a thyroid hormone receptor beta (TRβ) agonist, or any combination thereof. 
     
     
         10 . The method of  claim 9 , wherein the FXR agonist is obeticholic acid, Turofexorate isopropyl (WAY-362450), 3-(2,6-dichlorophenyl)-4-(3′-carboxy-2-chlorostilben-4-yl)oxymethyl-5-isopropylisoxazole (GW4064), PX20606 (PX-102), PX-101, INT-767, INT-787, TERN-101, altenusin, tropifexor (LJN452), nidufexor, turofexorate isopropyl, fexaramine, silymarin, silybin, hedragonic acid, cafestol, Cilofexor (GS-9674 or Px-104), EDP-305, BAR704, BAR502, EYP-001, RDX-023, AGN-242266, HPG-1860, MET-409, AGN-242256, EP-024297, IOT-022, M-480, INV-33, RDX023-02, or any combination thereof. 
     
     
         11 . The method of  claim 9 , wherein the PPAR agonist is a PPAR-alpha agonist, a PPAR-gamma agonist, a PPAR-delta agonist, a PPAR-alpha/gamma dual agonist, a PPAR alpha/delta dual agonist, a PPAR gamma/delta dual agonist, or PPAR alpha/gamma/delta pan agonist, optionally wherein:
 the PPAR alpha agonist is fenofibrate, ciprofibrate, pemafibrate, gemfibrozil, clofibrate, binifibrate, clinofibrate, clofibric acid, nicofibrate, pirifibrate, plafibride, ronifibrate, theofibrate, tocofibrate, or SRI 0171;   the PPAR gamma agonist is rosiglitazone, pioglitazone, deuterium-stabilized R-pioglitazone, efatutazone, ATx08-001, OMS-405, CHS-131, THR-0921, SER-150-DN, KDT-501, GED-0507-34-Levo, CLC-3001, or ALL-4;   the PPAR delta agonist is GW501516 (endurabol or ({4-[({4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy} acetic acid)), MBX8025 (seladelpar or {2-methyl-4-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethylsylfanyl]-phenoxy}-acetic acid), GW0742 ([4-[[[2-[3-fluoro-4-(trifluoromethyl)phenyl]-4-methyl-5-thiazolyl]methyl]thio]-2-methyl phenoxy] acetic acid), L165041, HPP-593, or NCP-1046;   the PPAR alpha/gamma agonist is saroglitazar, aleglitazar, muraglitazar, tesaglitazar, or DSP-8658;   the PPAR alpha/delta agonist is elafibranor or T913659;   the PPAR gamma/delta agonist is a conjugated linoleic acid (CLA) or T3D-959; and   the PPAR alpha/gamma/delta agonist is IVA337 (lanifibranor), TTA (tetradecylthioacetic acid), bavachinin, GW4148, GW9135, bezafibrate, lobeglitazone, 2-(4-(5,6-methylenedioxybenzo[d]thiazol-2-yl)-2-methylphenoxy)-2-methylpropanoic acid (MHY2013), or CS038.   
     
     
         12 . The method of  claim 9 , wherein the TRO agonist is sobetirome, eprotirome, GC-24, MGL-3196, MGL-3745, VK-2809, KB141 [3,5-dichloro-4-(4-hydroxy-3-isopropylphenoxy) phenylacetic acid], MB07811 (2R,4S)-4-(3-chlorophenyl)-2-[(3,5-dimethyl-4-(4′-hydroxy-3′-isopropylbenzyl)phenoxy)methyl]-2-oxido-[1,3,2]-dioxaphosphonane), or any combination thereof. 
     
     
         13 . The method of  claim 4  wherein the pain associated condition is acute pain, advanced prostate cancer, AIDS-related pain, ankylosing spondylitis, arachnoiditis, arthritis, arthrofibrosis, ataxic cerebral palsy, autoimmune atrophic gastritis, avascular necrosis, back pain, Behcet's disease (syndrome), burning mouth syndrome, bursitis, cancer pain, carpal tunnel, cauda equina syndrome, central pain syndrome, cerebral palsy, cervical stenosis, Charcot-Marie-Tooth (CMT) disease, chronic fatigue syndrome (CFS), chronic functional abdominal pain (CFAP), chronic pain, chronic pancreatitis, collapsed lung (pneumothorax), complex regional pain syndrome (RSD), corneal neuropathic pain, Crohn's disease, degenerative disc disease, Dercum's disease, dermatomyositis, diabetic peripheral neuropathy (DPN), dystonia, Ehlers-Danlos syndrome (EDS), endometriosis, eosinophilia-myalgia syndrome (EMS), erythromelalgia, fibromyalgia, gout, headaches, herniated disc, hydrocephalus, intercostal neuraligia, interstitial cystitis, irritable bowel syndrome (IBS), juvenile dermatositis, knee injury, leg pain, loin pain-haematuria syndrome, lupus, lyme disease, medullary sponge kidney (MSK), meralgia paresthetica, mesothelioma, migraine, musculoskeletal pain, myofascial pain, myositis, neck pain, neuropathic pain, occipital neuralgia, osteoarthritis, Paget's disease, Parsonage Turner syndrome, pelvic pain, peripheral neuropathy, phantom limb pain, pinched nerve, polycystic kidney disease, polymyalgia rhuematica, polymyositis, porphyria, post herniorraphy pain syndrome, post mastectomy pain syndrome, post stroke pain, post thorocotomy pain syndrome, postherpetic neuralgia (Shingles), post-polio syndrome, primary lateral sclerosis, psoriatic arthritis, pudendal neuralgia, radiculopathy, Raynaud's disease, rheumatoid arthritis (RA), sacroiliac joint dysfunction, sarcoidosi, Scheuemann's kyphosis disease, sciatica, Scoliosis, shingles (Herpes Zoster), Sjogren's syndrome, spasmodic torticollis, sphincter of oddi dysfunction, spinal cerebellum ataxia (SCA ataxia), spinal cord injury, spinal stenosis, syringomyelia, tarlov cysts, transverse myelitis, trigeminal neuralgia, neuropathic pain, ulcerative colitis, vascular pain or vulvodynia. 
     
     
         14 . The method of  claim 4  wherein the autoimmune disorder is chronic inflammation, multiple sclerosis, Steven Johnson's syndrome, appendicitis, bursitis, colitis, cystitis, dermatitis, phlebitis, reflex sympathetic dystrophy/complex regional pain syndrome (rsd/crps), rhinitis, tendonitis, tonsillitis, acne vulgaris, reactive airway disorder, asthma, airway infection, autoinflammatory disease, celiac disease, chronic prostatitis, diverticulitis, glomerulonephritis, hidradenitis suppurativa, hypersensitivities, intestinal disorder, epithelial intestinal disorder, inflammatory bowel disease, irritable bowel syndrome, colitis, interstitial cystitis, otitis, pelvic inflammatory disease, endometrial pain, reperfusion injury, rheumatic fever, rheumatoid arthritis, sarcoidosis, transplant rejection, or vasculitis. 
     
     
         15 . The method of any one of  claims 1 - 14 , wherein the compound has the structure of a compound listed Table A or B, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof. 
     
     
         16 . A pharmaceutical composition comprising a compound having the structure of Formula (I), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, and a pharmaceutically acceptable excipient: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein:
 n is 0 or 1; 
 x is 0, 1 or 2; 
 A is aryl or heteroaryl; 
 Q 1  and Q 2  are both CR 10 , or one of Q 1  or Q 2  is CR 10  and the other is N; 
 Z is —O—, —S—, —N(R 11 )—, —CH 2 — or —C≡C—; 
 each R 10  is H or alkyl; 
 R is —(CH 2 ) m C(═O)OR 12 , —(CH 2 ) m NHR 13 , —(C═O)NR 14 R 15 , —CH 2 OH, —CN, haloalkyl, carbocycle, heterocycle, or a carboxylic acid isostere; 
 m is 0 or 1; 
 R 11 , R 12  and R 13  are the same or different and individually H or alkyl; 
 R 14  is H and R 15  is H, —SO 2 CH 3 , carbocycle, heterocyle, or alkyl substituted with 0, 1, 2 or 3 substituents selected from —OH, —CN, —NR′R″, C(═O)OH, C(═O)NR′R″, —SO 2 OH, alkoxy, carbocycle, or heterocycle, wherein R′ and R″ are individually H or alkyl, or 
 R 14  and R 15  are taken together with the nitrogen atom to which they are attached to form heterocycle; 
 R 1  is H or alkyl; 
 R 2  is halo, cyano, amino, alkyl, alkoxy, carbocycle or heterocycle; 
 R 3 , R 4  and R 5  are the same or different and either absent or, when present, cyano, nitro, halogen, alkyl, haloalkyl, cyanoalkyl, alkoxy, haloalkoxy, —(C═O)alkyl, —(C═O)NHalkyl, carbocycle, heterocycle, —O-carbocycle or —O-heterocycle, or 
 any two R and R 2  taken together with the atoms to which they are attached form heterocycle; 
 any two R 3 , R 4 , R 5  and R 10 , taken together with the atoms to which they are attached form carbocycle or heterocycle; 
 and wherein each occurrence of carbocycle or heterocycle is substituted with 0, 1, 2 or 3 substituents individually selected from halogen, hydroxyl, oxo, halo, alkyl, haloalkyl, alkoxy, haloalkoxy, carbocycle, or heterocycle. 
 
     
     
         17 . The pharmaceutical composition of  claim 16 , further comprising a second therapeutic agent. 
     
     
         18 . The pharmaceutical composition of  claim 17 , wherein the second therapeutic agent is ursodeoxycholic acid (UDCA), norUrsodeoxycholic acid, cholestyramine, stanozolol, naltrexone, rifampicin, Alisol B 23-acetate (AB23A), curcumin, dihydroartemisinin, fenofibrate, bezafibrate, metronidazole, methotrexate, colchicine, metformin, betaine, glucagon, naltrexone, a farnesoid X-receptor (FXR) agonist, a peroxisome proliferator-activated receptor (PPAR) agonist, a thyroid hormone receptor beta (TRβ) agonist, or any combination thereof. 
     
     
         19 . The pharmaceutical composition of  claim 18 , wherein:
 (a) the FXR agonist is obeticholic acid, Turofexorate isopropyl (WAY-362450), 3-(2,6-dichlorophenyl)-4-(3′-carboxy-2-chlorostilbene-4-yl)oxymethyl-5-isopropylisoxazole (GW4064), PX20606 (PX-102), PX-101, INT-767, INT-787, TERN-101, altenusin, tropifexor (LJN452), nidufexor, turofexorate isopropyl, fexaramine, silymarin, silybin, hedragonic acid, cafestol, Cilofexor (GS-9674 or Px-104), EDP-305, BAR704, BAR502, EYP-001, RDX-023, AGN-242266, HPG-1860, MET-409, AGN-242256, EP-024297, IOT-022, M-480, INV-33, RDX023-02, or any combination thereof,   (b) the PPAR agonist is a PPAR-alpha agonist, a PPAR-gamma agonist, a PPAR-delta agonist, a PPAR-alpha/gamma dual agonist, a PPAR alpha/delta dual agonist, a PPAR gamma/delta dual agonist, or PPAR alpha/gamma/delta pan agonist, optionally wherein:   the PPAR alpha agonist is fenofibrate, ciprofibrate, pemafibrate, gemfibrozil, clofibrate, binifibrate, clinofibrate, clofibric acid, nicofibrate, pirifibrate, plafibride, ronifibrate, theofibrate, tocofibrate, or SRI 0171;   the PPAR gamma agonist is rosiglitazone, pioglitazone, deuterium-stabilized R-pioglitazone, efatutazone, ATx08-001, OMS-405, CHS-131, THR-0921, SER-150-DN, KDT-501, GED-0507-34-Levo, CLC-3001, or ALL-4;   the PPAR delta agonist is GW501516 (endurabol or {4-[({4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy} acetic acid)), MBX8025 (seladelpar or {2-methyl-4-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethylsylfanyl]-phenoxy}-acetic acid), GW0742 ([4-[[[2-[3-fluoro-4-(trifluoromethyl)phenyl]-4-methyl-5-thiazolyl]methyl]thio]-2-methyl phenoxy] acetic acid), L165041, HPP-593, or NCP-1046;   the PPAR alpha/gamma agonist is saroglitazar, aleglitazar, muraglitazar, tesaglitazar, or DSP-8658;   the PPAR alpha/delta agonist is elafibranor or T913659;   the PPAR gamma/delta agonist is a conjugated linoleic acid (CLA) or T3D-959; and   the PPAR alpha/gamma/delta agonist is IVA337 (lanifibranor), TTA (tetradecylthioacetic acid), bavachinin, GW4148, GW9135, bezafibrate, lobeglitazone, 2-(4-(5,6-methylenedioxybenzo[d]thiazol-2-yl)-2-methylphenoxy)-2-methylpropanoic acid (MHY2013), or CS038; or   (c) the TRO agonist is sobetirome, eprotirome, GC-24, MGL-3196, MGL-3745, VK-2809, KB141 [3,5-dichloro-4-(4-hydroxy-3-isopropylphenoxy) phenylacetic acid], MB07811 (2R,4S)-4-(3-chlorophenyl)-2-[(3,5-dimethyl-4-(4′-hydroxy-3′-isopropylbenzyl)phenoxy)methyl]-2-oxido-[1,3,2]-dioxaphosphonane), or any combination thereof.   
     
     
         20 . A compound having one of the following structures, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof. 
       
         
           
                 
                 
                 
               
                     
                     
                 
                     
                   Cpd No. 
                   Structure 
                 
                     
                     
                 
                     
                    1-55 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                     
                 
                     
                    1-78 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                     
                 
                     
                    5-1 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                     
                 
                     
                    4-10 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                     
                 
                     
                    1-65 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                     
                 
                     
                    4-11 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                     
                 
                     
                    1-58 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                     
                 
                     
                    1-56 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                     
                 
                     
                    9-1 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                     
                 
                     
                    1-82 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                     
                 
                     
                    1-85 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                     
                 
                     
                    1-29 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                     
                 
                     
                    1-101 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                     
                 
                     
                    2-3 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                     
                 
                     
                    1-103 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                     
                 
                     
                    1-112 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                     
                 
                     
                    4-7 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                     
                 
                     
                   11-1 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                     
                 
             
                
                
                
               
               
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         21 . A compound having one of the structures listed in Table A, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof. 
     
     
         22 . A compound having one of the structures listed in Table B, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof. 
     
     
         23 . The method of  claim 5  wherein the itch associated condition is kidney disease. 
     
     
         24 . The method of  claim 23  wherein kidney disease is end-stage renal failure. 
     
     
         25 . The method of  claim 23  wherein kidney disease is medullary sponge kidney (MSK). 
     
     
         26 . The method of  claim 23  wherein kidney disease is polycystic kidney disease. 
     
     
         27 . The method of  claim 4  wherein the MRGPR X4 dependent condition is an itch associated condition. 
     
     
         28 . The method of  claim 27  wherein the itch associated condition is associated with a metabolite of heme. 
     
     
         29 . The method of  claim 27  wherein the metabolite of heme is bilirubin. 
     
     
         30 . The method of  claim 27  wherein the metabolite of heme is biliverdin. 
     
     
         31 . The method of  claim 27  wherein the metabolite of heme is urobilin. 
     
     
         32 . The method of  claim 27  wherein the metabolite of heme is urobilinogen. 
     
     
         33 . The method of  claim 27  wherein the metabolite of heme is stercobilin.