Substituted pyrrolopyridine JAK inhibitors and methods of making and using the same

1. A compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, of Formula (I):

wherein:

R 1 is selected from —CO 2 R 5 , —C 1 -C 5 alkyl-CO 2 R 5 , —C 3 -C 6 -cycloalkyl-CO 2 R 5 , —NHCO 2 R 5 , —N(C 1 -C 5 alkyl)-CO 2 R 5 , —O—CO 2 R 5 , or —C 1 -C 5 alkyl-O—CO 2 R 5 ;

R 2 is selected from H, —C 1 -C 4 alkyl, —C 3 -C 6 cycloalkyl, or —C 1 -C 2 alkyl-C 3 -C 6 cycloalkyl, wherein the alkyl or cycloalkyl groups are optionally substituted with one or more groups selected from halogen, —OH, or —O—C 1 -C 5 alkyl;

n is 0, 1 or 2;

Ring A is substituted at one or more carbons with one, two, or three R 3 substituents wherein each R 3 group is independently selected from H, halogen, —C 1 -C 4 alkyl, —C 3 -C 6 cycloalkyl, —OH, or —O—C 1 -C 5 alkyl wherein each alkyl or cycloalkyl group is optionally substituted with one or more groups selected from: halogen, —OH, —C 1 -C 5 alkylalkoxy, or —O—C 1 -C 5 alkyl;

Two R 3 groups on the same or different carbon atoms of the ring A may be optionally joined to form a spirocyclic or bicyclic ring system with ring A;

R 4 is selected from —C(O)—R 6 , —CH 2 R 6 , —C(O)—CH═CH 2 , —C(O)—C(CH 2 OCH 3 )═CH 2 , —C(O)—CH═CHCH 3 , —C(O)—CH═CHCH 2 NR 7 R 8 , —C(O)—C 1 -C 5 alkyl, or —C(O)—C 3 -C 6 cycloalkyl, wherein the alkyl or cycloalkyl groups may be optionally substituted with one or more groups selected from —OH, halogen, alkyne, or —CN;

R 5 is selected from —C 1 -C 5 alkyl, or —C 3 -C 6 cycloalkyl wherein the alkyl or cycloalkyl groups may be optionally substituted by one or more groups selected from halogen, —OH, or —O—C 1 -C 5 alkyl;

R 6 is selected from —C 1 -C 5 alkyl, —C 3 -C 6 cycloalkyl, —C 1 -C 5 alkyl-C 3 -C 6 cycloalkyl, —NR 7 R 8 , —O-aryl, —O-heteroaryl, or heteroaryl wherein the alkyl, cycloalkyl, or heteroaryl groups can be optionally substituted by one or more groups selected from halogen, —CN, alkyne, —OH, trifluoromethyl, —O—C 1 -C 5 alkyl, or —O—C 3 -C 6 cycloalkyl;

R 7 and R 8 are independently selected from H, —C 1 -C 5 alkyl, —C 1 -C 5 alkoxy, or —C 3 -C 5 cycloalkyl wherein the alkyl groups may be optionally substituted by one or more groups selected from halogen, —OH, or —CN; and

R 7 and R 8 may be optionally joined to form a ring to form a heterocycle or with another heteroatom to form a ring.

2. The compound of claim 1 , or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein:

R 1 is —CO 2 R 5 .

3. The compound of claim 1 , or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein:

R 1 is —C 1 -C 5 -alkyl-CO 2 R 5 .

4. The compound of claim 1 , or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein:

R 1 is —C 3 -C 6 -cycloalkyl-CO 2 R 5 .

5. The compound of claim 1 , or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein:

R 1 is —NHCO 2 R 5 .

6. The compound of claim 1 , or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein:

R 1 is —N(C 1 -C 5 alkyl)-CO 2 R 5 .

7. The compound of claim 1 , or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein:

R 1 is —O—CO 2 R 5 .

8. The compound of claim 1 , or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein:

R 1 is —C 1 -C 5 alkyl-O—CO 2 R 5 .

9. A compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, of Formula (III):

wherein:

R 1000 is selected from —CO 2 R 5000 , —C 1 -C 5 alkyl-CO 2 R 5000 , —C 3 -C 6 -cycloalkyl-CO 2 R 5000 , —NHCO 2 R 5000 , —N(C 1 -C 5 alkyl)-CO 2 R 5000 , —O—CO 2 R 5000 , or —C 1 -C 5 alkyl-O—CO 2 R 5000 ;

R 2000 is selected from H, —C 1 -C 4 alkyl, —C 3 -C 6 cycloalkyl, or —C 1 -C 2 alkyl-C 3 -C 6 cycloalkyl, wherein the alkyl or cycloalkyl groups are optionally substituted with one or more groups selected from halogen, —OH, or —O—C 1 -C 5 alkyl;

n is 0, 1 or 2;

Ring Q is substituted at one or more carbons with one, two, or three R 3000 substituents wherein each R 3000 group is independently selected from H, halogen, —C 1 -C 4 alkyl, —C 3 -C 6 cycloalkyl, —OH, or —O—C 1 -C 5 alkyl wherein each alkyl or cycloalkyl group is optionally substituted with one or more groups selected from: halogen, —OH, —C 1 -C 5 alkylalkoxy, or —O—C 1 -C 5 alkyl;

Two R 3000 groups on the same or different carbon atoms of the ring Q may be optionally joined to form a spirocyclic or bicyclic ring system with ring Q;

R 4000 is selected from —C(O)—R 6000 , —CH 2 R 6000 , —C(O)—CH═CH 2 , —C(O)—C(CH 2 OCH 3 )═CH 2 , —C(O)—CH═CHCH 3 , —C(O)—CH═CHCH 2 NR 7000 R 8000 , —C(O)—C 1 -C 5 alkyl, or —C(O)—C 3 -C 6 cycloalkyl, wherein the alkyl or cycloalkyl groups may be optionally substituted with one or more groups selected from —OH, halogen, alkyne, or —CN;

R 5000 is selected from H, —C 1 -C 5 alkyl, and —C 3 -C 6 cycloalkyl wherein the alkyl or cycloalkyl groups may be optionally substituted by one or more groups selected from halogen, —OH, —C 3 -C 5 cycloalkyl, or —O—C 1 -C 5 alkyl;

R 6000 is selected from —C 1 -C 5 alkyl, —C 3 -C 6 cycloalkyl, —C 1 -C 5 alkyl-C 3 -C 6 cycloalkyl, —NR 7000 R 8000 , —O-aryl, —O-heteroaryl, or heteroaryl wherein the alkyl, cycloalkyl, or heteroaryl groups can be optionally substituted by one or more groups selected from halogen, —CN, alkyne, —OH, trifluoromethyl, —O—C 1 -C 5 alkyl, or —O—C 3 -C 6 cycloalkyl;

R 7000 and R 8000 are independently selected from H, —C 1 -C 5 alkyl, —C 1 -C 5 alkoxy, or —C 3 -C 5 cycloalkyl where the alkyl groups may be optionally substituted by one or more groups selected from halogen, —OH, —CN, or —C 3 -C 5 cycloalkyl;

R 7000 and R 8000 may be optionally joined to form a ring to form a heterocycle or with another heteroatom to form a ring.

10. The compound of claim 1 , wherein the compound is selected from the group consisting of:

11. The compound of claim 9 , wherein the compound is selected from the group consisting of:

12. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 , a pharmaceutically acceptable salt thereof, a derivative thereof, or a combination thereof; and a pharmaceutically acceptable carrier.

13. A method of treating a JAK1- and/or JAK3-mediated disease in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of claim 1 , a derivative thereof, or a combination thereof.

14. The method of claim 13 , further comprising administering another therapeutic agent.

15. The method of claim 13 , wherein said JAK1- and/or JAK3-mediated disease is selected from the group consisting of an autoimmune disorder, broad activation of the immune responses, bacterial infection, viral infection, inflammation, a chronic inflammatory disorder, an acute inflammatory disorder or condition, an auto-inflammatory disorder, a fibrotic disorders, a metabolic disorders, a neoplasm, a cardiovascular disorders, a cerebrovascular disorders, a skin disorder, pruritus, a hair loss disorder, a cancer, autoimmune connective tissue disease, an autoimmune condition, Still's disease, adult-onset Still's disease, Th17-associated inflammation, polychondritis, relapsing polychondritis, myositis, polymyositis, autoimmune myositis, dermatomyositis, juvenile dermatomyositis, myasthenia gravis, Arthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, systemic-onset juvenile rheumatoid arthritis, osteoarthritis, infectious arthritis, inflammatory arthritis, inflammatory bowel disease-associated arthritis, idiopathic arthritis, juvenile idiopathic arthritis, systemic juvenile idiopathic arthritis, psoriatic arthritis, spondylitis/spondyloarthritis/spondyloarthropathy, ankylosing spondylitis, gout, scleroderma, systemic scleroderma, juvenile scleroderma, Reiter's syndrome/reactive arthritis, lyme disease, lupus/systemic lupus erythematosus (SLE), lupus erythematosus, pediatric systemic lupus erythematosus, cutaneous lupus, subacute cutaneous lupus, chronic cutaneous lupus/discoid lupus, chilblain lupus erythematosus, polymyalgia rheumatica, enthesitis, mixed connective tissue disease, enthesopathy, carditis, myocarditis, angiogenesis disorders, myelodysplastic syndrome, atherosclerosis, restenosis, restenosis of an atherosclerotic coronary artery, acute coronary syndrome, myocardial infarction, cardiac-allograft vasculopathy, transplant arteriopathy, vasculitis, large vessel vasculitis, small vessel vasculitis, giant-cell arteritis, polyarteritis nodosa, vasculitis syndromes, Takayasu's arteritis, Wegener's granulomatosis, Behcet's Disease, stimulator of interferon genes (STING) associated vasculopathy with onset in infancy (SAVI), a gastrointestinal disorder, enterocolitis, colitis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, irritable bowel syndrome, enteritis syndrome/spastic colon, celiac disease, acute and chronic pancreatitis, primary biliary cirrhosis, primary sclerosing cholangitis, jaundice, cirrhosis, primary biliary cirrhosis, cirrhosis due to fatty liver disease, alcoholic and nonalcoholic steatosis, esophagitis, gastritis, gastric and duodenal ulcers, peritonitis, Nephropathy, immunologically mediated glomerulonephropathy, autoimmune nephropathy, membranous glomerulopathy, a chronic progressive nephropathy, diabetic kidney disease/diabetic nephropathy, renal fibrosis, renal ischemic/reperfusion injury, HIV associated nephropathy, ureteral obstructive nephropathy, glomerulosclerosis, proteinuria, nephrotic syndrome, polycystic kidney disease, autosomal dominant polycystic kidney disease, glomerulonephritis, chronic kidney disease, diabetic nephropathy, hypertension induced nephropathy, diabetic kidney disease, lupus nephritis, interstitial cystitis periodontitis, gingivitis pulmonary inflammation, sinusitis, pneumonia, bronchitis, asthma, bronchial asthma, Churg-Strauss syndrome, bronchiolitis, bronchiolitis obliterans, chronic obstructive pulmonary disease (COPD), interstitial lung disease, pulmonary fibrosis, idiopathic pulmonary fibrosis, acute lung injury, cystic fibrosis, chronic obstructive pulmonary disease, adult respiratory distress syndrome, acute lung injury, drug-induced lung injury, Meniere's disease, an ocular disorder, ocular inflammation, uveitis, dry eye/keratoconjunctivitis sicca, scleritis, episcleritis, keratitis/keratopathy, choroiditis, retinal vasculitis, optic neuritis, retinopathy, diabetic retinopathy, immune mediated retinopathy, macular degeneration, wet macular degeneration, age related macular degeneration, Mastocytosis, iron deficiency anemia, uremia, hypereosinophilic syndrome (HES), systemic mast cell disease (SMCD), myelodysplastic syndrome, idiopathic thrombocytic pupura, bone resorption diseases, a Neurodegenerative disorder, a neurological/neuromuscular disorders, multiple sclerosis, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), familial ALS, sporadic ALS, Alzheimer's disease, myasthenia gravis, Lambert-Eaton myasthenic syndrome (LEMS), Guillain-Barret syndrome, meningitis, encephalitis, traumatic brain injury, nervous system damage, delusional parasitosis, dysregulation of neuronal processes and sensory perception, stroke/neuronal ischemia, spinal cord injury, peripheral neuropathy, tactile hallucinations, spinal cord injury, psychiatric disease, pain, acute pain, chronic pain, neuropathic pain, fibromyalgia, paresthetica, nerve irritation, peripheral neuropathy, pruritus/itch atopic pruritus, xerotic pruritus, pruritus associated with psoriasis/psoriatic itch/psoriasis-associated itch, acute pruritus, chronic pruritus, idiopathic pruritus, chronic idiopathic itch, biliary itch, hepatobiliary-associated itch, renal associated itch/renal itch, uremic itch, cholestasis, intrahepatic cholestasis of pregnancy, lichen simplex chronicus associated pruritus, lymphoma-associated itch, leukemia-associated itch, prurigo nodularis, atopic dermatitis-associated itch, atopic itch/atopic puritis, bullous itch, brachioradial pruritus, neurogenic itch, neuropathic itch, notalgia paresthetica, pruritic popular eruption of HIV, psychogenic itch, swimmer's itch, pruritus or uremic itch, urticarial itch, a dermatologic disorders, dermatologic drug reactions/drug eruptions, xerosis/dry skin, skin rash, skin sensitization, skin irritation, sunburn, shaving, body louse, head lice/pediculosis, pubic lice, cutaneous larva migrans, scabies, parasitic infection, insect infestation, urticarial/hives, popular uritcaria, insect bites, insect stings, dandruff, fungal infection, herpes, varicella/chicken pox, eosinophilic folliculitis, dermatosis of pregnancy/pruritic urticarial papules and plaques of pregnancy (PUPP), inflammatory dermatoses, neutrophilic dermatoses, histiocytoid neutrophilic dermatosis, bowel-bypass syndrome dermatosis, psoriasis/psoriasis vulgaris, lichen planus, lichen sclerosus, acne, acne vulgaris, comedonal acne, inflammatory acne, nodulo-cystic acne, scarring acne, acne keloidalis nuchae, atopies, allergic contact sensitization, allergic dermatitis, dermatitis, atopic dermatitis/eczema, contact dermatitis, photodermatitis, seborrheic dermatitis, stasis dermatitis, acute febrile neutrophilic dermatosis (Sweet's syndrome), chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature syndrome (CANDLE Syndrome), hidradenitis suppurativa, hives, pyoderma gangrenosum, alopecia, eyebrow alopecia, intranasal hair alopecia, scarring alopecia, central centrifugal cicatricial alopecia, nonscarring alopecia, alopecia areata (AA), patchy AA, alopecia totalis (AT), alopecia universalis (AU), ophiasis pattern alopecia areata, sisaihpo pattern alopecia areata, androgenetic/androgenic alopecia (AGA)/male and female pattern AGA, telogen effluvium, tinea capitis, hypotrichosis, hereditary hypotrichosis simplex, lichen planopilaris, frontal fibrosing alopecia, punctate palmoplantar keratoderma, erythema elevatinum diutinum (EED), neutrophilic eccrine hidradenitis, palisading neutrophilic granulomatous dermatitis, neutrophilic urticarial dermatosis, vitiligo, segmental vitiligo, unisegmental vitiligo, bisegmental vitiligo, multisegmental vitiligo, non-segmental vitiligo, acral, facial, acrofacial vitiligo, centrofacial vitiligo, mucosal vitiligo, confetti vitiligo, trichrome vitiligo, marginal inflammatory vitiligo, quadrichrome vitiligo, blue vitiligo, Koebner phenomenon, vulgaris vitiligo, generalized vitiligo, universal vitiligo, mixed vitiligo/nonsegmental associated with segmental vitiligo, focal vitiligo, solitary mucosal vitiligo, vitiligo with or without leukotricia, bullous diseases, immunobullous diseases, bullous pemphigoid, cicatricial pemphigoid, pemphigus vulgaris, linear IgA disease, gestational pemphigoid, xeroderma pigmentosum, disorders of fibrosis and scarring, fibroids, hepatic fibrosis, low grade scarring, scleroderma, increased fibrosis, keloids, post-surgical scars, wound healing, surgical scarring, radiation induced fibrosis, CNS scarring, alimentary track or gastrointestinal fibrosis, renal fibrosis, hepatic or biliary fibrosis, liver fibrosis, cardiac fibrosis, ophthalmic scarring, fibrosclerosis, scar growth, wound or scab healing, keloid, mediastinal fibrosis, myelofibrosis, retroperitoneal fibrosis/Ormond's disease, progressive massive fibrosis, nephrogenic systemic fibrosis, Sjorgren's syndrome, sarcoidosis, familial Mediterranean fever, Cryopyrin associated periodic syndrome, Muckle-Wells syndrome, familial cold auto-inflammatory syndrome/familial cold uticaria/TNF receptor associated periodic syndrome, neonatal-onset multisystem inflammatory disease, hyperoxia induced inflammation, reperfusion injury, post-surgical trauma, tissue injury, elevated temperature syndrome, diabetes, Type I diabetes, Type II diabetes, diabetes mellitus, Hashimoto's thyroiditis, Graves' disease, Addison's disease, Castleman's disease, hyperparathyroidism, menopause, obesity, steroid-resistance, glucose intolerance, metabolic syndrome, thyroid illness, hypophysitis, systemic immune senescence, autoimmune atrophic gastritis, autoimmune atrophic gastritis of pernicious anemia, autoimmune encephalomyelitis, autoimmune orchitis, Goodpasture's disease, Sjogren's syndrome, autoimmune thrombocytopenia, sympathetic ophthalmia, secondary hematologic manifestations of autoimmune diseases, autoimmune hemolytic syndromes, autoimmune hemolytic anemia, autoimmune and inflammatory hepatitis, autoimmune ovarian failure, autoimmune thrombocytopenia, silicone implant associated autoimmune disease, drug-induced autoimmunity, HIV-related autoimmune syndrome, metal-induced autoimmunity, autoimmune deafness, autoimmune thyroid disorders, allergy and allergic reactions, a Type I hypersensitivity reactions, a Type II hypersensitivity reactions, a Type III hypersensitivity reaction diseases, a Type IV hypersensitivity reaction, acute and chronic infection, sepsis syndrome, sepsis, septic shock, endotoxic shock, exotoxin-induced toxic shock, gram negative sepsis, gram positive sepsis, fungal sepsis, toxic shock syndrome, graft vs. host reaction/graft vs. host disease, allograft rejection, early transplantation rejection, lymphoma, leukemia, multiple myeloma, a solid tumor, teratoma, metastatic cancer, a bone disorders, internal cancer, bone cancer, mouth/pharynx cancer, esophagus cancer, larynx cancer, stomach cancer, intestinal cancer, colon cancer, rectum cancer, lung cancer, liver cancer, pancreas cancer, nerve cancer, brain cancer, head and neck cancer, throat cancer, ovary cancer, uterus cancer, prostate cancer, testis cancer, bladder cancer, kidney cancer, breast cancer, gall bladder cancer, cervix cancer, thyroid cancer, prostate cancer, eye cancer, skin cancer, a fibrotic cancer, fibroma, fibroadenomas, fibrosarcoma, a myeloproliferative disorder, neoplasm, hematopoietic neoplasm, a myeloid neoplasm, a lymphoid neoplasm, myelofibrosis, primary myelofibrosis, polycythemia vera, essential thrombocythemia, acute lymphocytic leukemia, acute and chronic myelogenous leukemia, chronic lymphocytic leukemia, acute lymphoblastic leukemia, chronic myelomonocytic leukemia (CMML), or promyelocytic leukemia, multiple myeloma, a myeloid malignancy myeloid metaplasia with myelofibrosis (MMM), primary myelofibrosis (PMF), idiopathic myelofibrosis (IMF), Hodgkin's disease, cutaneous lymphoma, cutaneous T-cell lymphoma, mycosis fungoides, B-cell lymphoma, T-cell lymphoma, mantle cell lymphoma, hairy cell lymphoma, Burkitt's lymphoma, mast cell tumors, Hodgkin's disease, non-Hodgkin's disease, Kaposi's sarcoma, rhabdomyosarcoma, seminoma, teratocarcinoma, osteosarcoma, thyroid follicular cancer, increased accumulation of exogenous opioids or synthetic opioids, notalgia paraesthetica, obsessive-compulsive disorders, nostalgia associated with obsessive-compulsive disorders, and a combination thereof.

16. The method of claim 14 , wherein the other therapeutic agent is selected from a chemotherapeutic agent, an anti-proliferative agent, an anti-inflammatory agent, an immunomodulatory agent, immunosuppressive agent, a neurotrophic factor, an agent for treating cardiovascular disease, an agent for treating diabetes, an agent for treating immunodeficiency disorders, and a combination thereof.

17. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 9 , a pharmaceutically acceptable salt thereof, a derivative thereof, or a combination thereof and a pharmaceutically acceptable carrier.

18. A method of treating a JAK1- and/or JAK3-mediated disease in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of claim 9 , a derivative thereof, or a combination thereof.

19. The method of claim 18 , further comprising administering another therapeutic agent.

20. The method of claim 18 , wherein said JAK1- and/or JAK3-mediated disease is selected from the group consisting of an autoimmune disorder, broad activation of the immune responses, bacterial infection, viral infection, inflammation, a chronic inflammatory disorder, an acute inflammatory disorder or condition, an auto-inflammatory disorder, a fibrotic disorder, a metabolic disorder, a neoplasm, a cardiovascular disorder, a cerebrovascular disorder, a skin disorder, pruritus, a hair loss disorder, a cancer, autoimmune connective tissue disease, an autoimmune condition, Still's disease, adult-onset Still's disease, Th17-associated inflammation, polychondritis, relapsing polychondritis, myositis, polymyositis, autoimmune myositis, dermatomyositis, juvenile dermatomyositis, myasthenia gravis, Arthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, systemic-onset juvenile rheumatoid arthritis, osteoarthritis, infectious arthritis, inflammatory arthritis, inflammatory bowel disease-associated arthritis, idiopathic arthritis, juvenile idiopathic arthritis, systemic juvenile idiopathic arthritis, psoriatic arthritis, spondylitis/spondyloarthritis/spondyloarthropathy, ankylosing spondylitis, gout, scleroderma, systemic scleroderma, juvenile scleroderma, Reiter's syndrome/reactive arthritis, lyme disease, lupus/systemic lupus erythematosus (SLE), lupus erythematosus, pediatric systemic lupus erythematosus, cutaneous lupus, subacute cutaneous lupus, chronic cutaneous lupus/discoid lupus, chilblain lupus erythematosus, polymyalgia rheumatica, enthesitis, mixed connective tissue disease, enthesopathy, carditis, myocarditis, angiogenesis disorders, myelodysplastic syndrome, atherosclerosis, restenosis, restenosis of an atherosclerotic coronary artery, acute coronary syndrome, myocardial infarction, cardiac-allograft vasculopathy, transplant arteriopathy, vasculitis, large vessel vasculitis, small vessel vasculitis, giant-cell arteritis, polyarteritis nodosa, vasculitis syndromes, Takayasu's arteritis, Wegener's granulomatosis, Behcet's Disease, stimulator of interferon genes (STING) associated vasculopathy with onset in infancy (SAVI), a gastrointestinal disorder, enterocolitis, colitis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, irritable bowel syndrome, enteritis syndrome/spastic colon, celiac disease, acute and chronic pancreatitis, primary biliary cirrhosis, primary sclerosing cholangitis, jaundice, cirrhosis, primary biliary cirrhosis, cirrhosis due to fatty liver disease, alcoholic and nonalcoholic steatosis, esophagitis, gastritis, gastric and duodenal ulcers, peritonitis, Nephropathy, immunologically mediated glomerulonephropathy, autoimmune nephropathy, membranous glomerulopathy, a chronic progressive nephropathy, diabetic kidney disease/diabetic nephropathy, renal fibrosis, renal ischemic/reperfusion injury, HIV associated nephropathy, ureteral obstructive nephropathy, glomerulosclerosis, proteinuria, nephrotic syndrome, polycystic kidney disease, autosomal dominant polycystic kidney disease, glomerulonephritis, chronic kidney disease, diabetic nephropathy, hypertension induced nephropathy, diabetic kidney disease, lupus nephritis, interstitial cystitis, periodontitis, gingivitis, pulmonary inflammation, sinusitis, pneumonia, bronchitis, asthma, bronchial asthma, Churg-Strauss syndrome, bronchiolitis, bronchiolitis obliterans, chronic obstructive pulmonary disease (COPD), interstitial lung disease, pulmonary fibrosis, idiopathic pulmonary fibrosis, acute lung injury, cystic fibrosis, chronic obstructive pulmonary disease, adult respiratory distress syndrome, acute lung injury, drug-induced lung injury, Meniere's disease, an ocular disorder, ocular inflammation, uveitis, dry eye/keratoconjunctivitis sicca, scleritis, episcleritis, keratitis/keratopathy, choroiditis, retinal vasculitis, optic neuritis, retinopathy, diabetic retinopathy, immune mediated retinopathy, macular degeneration, wet macular degeneration, dry age related macular degeneration, Mastocytosis, iron deficiency anemia, uremia, hypereosinophilic syndrome (HES), systemic mast cell disease (SMCD), myelodysplastic syndrome, idiopathic thrombocytic pupura, bone resorption diseases, a Neurodegenerative disorder, a neurological/neuromuscular disorder, multiple sclerosis, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), familial ALS, sporadic ALS, Alzheimer's disease, myasthenia gravis, Lambert-Eaton myasthenic syndrome (LEMS), Guillain-Barret syndrome, meningitis, encephalitis, traumatic brain injury, nervous system damage, delusional parasitosis, dysregulation of neuronal processes and sensory perception, stroke/neuronal ischemia, spinal cord injury, peripheral neuropathy, tactile hallucinations, spinal cord injury, psychiatric disease, pain, acute pain, chronic pain, neuropathic pain, fibromyalgia, paresthetica, nerve irritation, peripheral neuropathy, pruritus/itch atopic pruritus, xerotic pruritus, pruritus associated with psoriasis/psoriatic itch/psoriasis-associated itch, acute pruritus, chronic pruritus, idiopathic pruritus, chronic idiopathic itch, biliary itch, hepatobiliary-associated itch, renal associated itch/renal itch, uremic itch, cholestasis, intrahepatic cholestasis of pregnancy, lichen simplex chronicus associated pruritus, lymphoma-associated itch, leukemia-associated itch, prurigo nodularis, atopic dermatitis-associated itch, atopic itch/atopic puritis, bullous itch, brachioradial pruritus, neurogenic itch, neuropathic itch, notalgia paresthetica, pruritic popular eruption of HIV, psychogenic itch, swimmer's itch, pruritus or uremic itch, urticarial itch, a dermatologic disorder, dermatologic drug reactions/drug eruptions, xerosis/dry skin, skin rash, skin sensitization, skin irritation, sunburn, shaving, body louse, head lice/pediculosis, pubic lice, cutaneous larva migrans, scabies, parasitic infection, insect infestation, urticarial/hives, popular uritcaria, insect bites, insect stings, dandruff, fungal infection, herpes, varicella/chicken pox, eosinophilic folliculitis, dermatosis of pregnancy/pruritic urticarial papules and plaques of pregnancy (PUPP), inflammatory dermatoses, neutrophilic dermatoses, histiocytoid neutrophilic dermatosis, bowel-bypass syndrome dermatosis, psoriasis/psoriasis vulgaris, lichen planus, lichen sclerosus, acne, acne vulgaris, comedonal acne, inflammatory acne, nodulo-cystic acne, scarring acne, acne keloidalis nuchae, atopies, allergic contact sensitization, allergic dermatitis, dermatitis, atopic dermatitis/eczema, contact dermatitis, photodermatitis, seborrheic dermatitis, stasis dermatitis, acute febrile neutrophilic dermatosis (Sweet's syndrome), chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature syndrome (CANDLE Syndrome), hidradenitis suppurativa, hives, pyoderma gangrenosum, alopecia, eyebrow alopecia, intranasal hair alopecia, scarring alopecia, central centrifugal cicatricial alopecia, nonscarring alopecia, alopecia areata (AA), patchy AA, alopecia totalis (AT), alopecia universalis (AU), ophiasis pattern alopecia areata, sisaihpo pattern alopecia areata, androgenetic/androgenic alopecia (AGA)/male and female pattern AGA, telogen effluvium, tinea capitis, hypotrichosis, hereditary hypotrichosis simplex, lichen planopilaris, frontal fibrosing alopecia, punctate palmoplantar keratoderma, erythema elevatinum diutinum (EED), neutrophilic eccrine hidradenitis, palisading neutrophilic granulomatous dermatitis, neutrophilic urticarial dermatosis, vitiligo, segmental vitiligo, unisegmental vitiligo, bisegmental vitiligo, multisegmental vitiligo, non-segmental vitiligo, acral, facial, acrofacial vitiligo, centrofacial vitiligo, mucosal vitiligo, confetti vitiligo, trichrome vitiligo, marginal inflammatory vitiligo, quadrichrome vitiligo, blue vitiligo, Koebner phenomenon, vulgaris vitiligo, generalized vitiligo, universal vitiligo, mixed vitiligo/nonsegmental associated with segmental vitiligo, focal vitiligo, solitary mucosal vitiligo, vitiligo with or without leukotricia, bullous diseases, immunobullous diseases, bullous pemphigoid, cicatricial pemphigoid, pemphigus vulgaris, linear IgA disease, gestational pemphigoid, xeroderma pigmentosum, disorders of fibrosis and scarring, fibroids, hepatic fibrosis, low grade scarring, scleroderma, increased fibrosis, keloids, post-surgical scars, wound healing, surgical scarring, radiation induced fibrosis, CNS scarring, alimentary track or gastrointestinal fibrosis, renal fibrosis, hepatic or biliary fibrosis, liver fibrosis, cardiac fibrosis, ophthalmic scarring, fibrosclerosis, scar growth, wound or scab healing, keloid, mediastinal fibrosis, myelofibrosis, retroperitoneal fibrosis/Ormond's disease, progressive massive fibrosis, nephrogenic systemic fibrosis, Sjorgren's syndrome, sarcoidosis, familial Mediterranean fever, Cryopyrin associated periodic syndrome, Muckle-Wells syndrome, familial cold auto-inflammatory syndrome/familial cold uticaria/TNF receptor associated periodic syndrome, neonatal-onset multisystem inflammatory disease, hyperoxia induced inflammation, reperfusion injury, post-surgical trauma, tissue injury, elevated temperature syndrome, diabetes, Type I diabetes, Type II diabetes, diabetes mellitus, Hashimoto's thyroiditis, Graves' disease, Addison's disease, Castleman's disease, hyperparathyroidism, menopause, obesity, steroid-resistance, glucose intolerance, metabolic syndrome, thyroid illness, hypophysitis, systemic immune senescence, autoimmune atrophic gastritis, autoimmune atrophic gastritis of pernicious anemia, autoimmune encephalomyelitis, autoimmune orchitis, Goodpasture's disease, Sjogren's syndrome, autoimmune thrombocytopenia, sympathetic ophthalmia, secondary hematologic manifestations of autoimmune diseases, autoimmune hemolytic syndromes, autoimmune hemolytic anemia, autoimmune and inflammatory hepatitis, autoimmune ovarian failure, autoimmune thrombocytopenia, silicone implant associated autoimmune disease, drug-induced autoimmunity, HIV-related autoimmune syndromes, metal-induced autoimmunity, autoimmune deafness, autoimmune thyroid disorders, allergy and allergic reactions, a Type I hypersensitivity reactions, a Type II hypersensitivity reactions, a Type III hypersensitivity reaction disease, and a Type IV hypersensitivity reaction, acute and chronic infection, sepsis syndrome, sepsis, septic shock, endotoxic shock, exotoxin-induced toxic shock, gram negative sepsis, gram positive sepsis, fungal sepsis, toxic shock syndrome, graft vs. host reaction/graft vs. host disease, allograft rejection, early transplantation rejection, lymphoma, leukemia, multiple myeloma, a solid tumor, teratoma, metastatic cancer, a bone disorders, internal cancer, bone cancer, mouth/pharynx cancer, esophagus cancer, larynx cancer, stomach cancer, intestinal cancer, colon cancer, rectum cancer, lung cancer, liver cancer, pancreas cancer, nerve cancer, brain cancer, head and neck cancer, throat cancer, ovary cancer, uterus cancer, prostate cancer, testis cancer, bladder cancer, kidney cancer, breast cancer, gall bladder cancer, cervix cancer, thyroid cancer, prostate cancer, eye cancer, skin cancer, a fibrotic cancer, fibroma, fibroadenomas, fibrosarcoma, a myeloproliferative disorder, neoplasm, hematopoietic neoplasm, a myeloid neoplasm, a lymphoid neoplasm, myelofibrosis, primary myelofibrosis, polycythemia vera, essential thrombocythemia, acute lymphocytic leukemia, acute and chronic myelogenous leukemia, chronic lymphocytic leukemia, acute lymphoblastic leukemia, chronic myelomonocytic leukemia (CMML), or promyelocytic leukemia, multiple myeloma, a myeloid malignancy myeloid metaplasia with myelofibrosis (MMM), primary myelofibrosis (PMF), idiopathic myelofibrosis (IMF), Hodgkin's disease, cutaneous lymphoma, cutaneous T-cell lymphoma, mycosis fungoides, B-cell lymphoma, T-cell lymphoma, mantle cell lymphoma, hairy cell lymphoma, Burkitt's lymphoma, mast cell tumors, Hodgkin's disease, non-Hodgkin's disease, Kaposi's sarcoma, rhabdomyosarcoma, seminoma, teratocarcinoma, osteosarcoma, thyroid follicular cancer, increased accumulation of exogenous opioids or synthetic opioids, notalgia paraesthetica, obsessive-compulsive disorders, nostalgia associated with obsessive-compulsive disorders, and a combination thereof.

21. The method of claim 19 , wherein the other therapeutic agent is selected from a chemotherapeutic agent, an anti-proliferative agent, an anti-inflammatory agent, an immunomodulatory agent, immunosuppressive agent, a neurotrophic factor, an agent for treating cardiovascular disease, an agent for treating diabetes, an agent for treating immunodeficiency disorders, and a combination thereof.