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CN-122003422-A - Heterocyclic PAD4 inhibitors

CN122003422ACN 122003422 ACN122003422 ACN 122003422ACN-122003422-A

Abstract

The present disclosure relates generally to compounds of formula I that are PAD4 inhibitors, methods for preparing such compounds, pharmaceutical compositions comprising such compounds, and the use of such compounds in the treatment of diseases or disorders associated with PAD4 enzymatic activity. (I)。

Inventors

  • M. Belema
  • J.A. Bender
  • A. H. Anterobov
  • J.M. Galnon
  • A.X.Wang
  • D. L. Cheney

Assignees

  • 百时美施贵宝公司

Dates

Publication Date
20260508
Application Date
20240719
Priority Date
20230721

Claims (20)

  1. 1. A compound of formula I: (I), Or a pharmaceutically acceptable salt, isomer, solvate, prodrug or tautomer thereof, Wherein: X 1 and X 2 are each independently CR 8 or N; Y is selected from -(CR 9 R 10 ) p -、-O-(CR 9 R 10 ) p -、-(CR 9 R 10 ) p -O-(CH 2 ) m -、-(CR 9 R 10 ) p -O-(CH 2 ) m -O-CH 2 - and- (CR 9 R 10 ) p -O-(CH 2 ) m -O-; R 1 is independently-CH (NHR 7 )-(C 1 -C 3 alkyl) or a 4 to 8 membered heterocycle containing at least one heteroatom selected from N, O or S, wherein the alkyl or heterocycle is optionally substituted with one or more R 11 ; R 2 is independently H or C 1 -C 4 alkyl; R 3 is independently H, halogen or C 1 -C 4 alkyl; R 4 is independently hydrogen, C 1 -C 4 alkyl or C 1 -C 4 haloalkyl; R 5 and R 6 are independently selected from H, halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkyl, heteroaryl, and aryl, wherein the heteroaryl or aryl is optionally substituted with one or more halogen or C 1 -C 6 alkoxy, or R 5 and R 6 together with the atoms in between form a C 3 -C 6 cycloalkyl group or a 4-to 8-membered heterocyclic group, or R 5 、R 6 and R 9 together with the atoms intermediate and adjacent to them form a C 3 -C 6 cycloalkyl, 4-to 8-membered heterocyclyl, heteroaryl or aryl, wherein the cycloalkyl, heterocyclyl, heteroaryl or aryl is optionally substituted with one or more R 12 ; Each R 7 is independently selected from H, C 1 -C 4 alkyl and C 3 -C 4 cycloalkyl; Each R 8 is independently selected from H, halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, and C 1 -C 4 alkoxy; Each R 9 is independently H, halogen, C 1 -C 4 alkyl, or C 3 -C 4 carbocyclyl; each R 10 is independently H, halogen, or C 1 -C 4 alkyl; each R 11 is independently selected from H, halogen, C 1 -C 6 alkyl, and C 1 -C 6 alkoxy; Each R 12 is independently selected from the group consisting of H, halogen, -OH, -NH 2 、-CN、C 1 -C 6 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, C 1 -C 4 haloalkyl and C 3 -C 4 cycloalkyl, 3 to 10 membered heterocyclyl, heteroaryl and C 6 -C 10 aryl; L is a bond or-CH 2 -; m is an integer selected from 1,2 and 3, and P is an integer selected from 2, 3, 4, 5 and 6.
  2. 2. The compound of claim 1, wherein the compound has formula (Ia): (Ia), Wherein X 3 is CH 2 , NH, O, or S, and r is an integer from 1 to 3.
  3. 3. The compound according to claim 1 or 2, wherein the compound is of formula (Ia-1) (Ia-1), formula (Ia-2) (Ia-2), formula (Ia-3) (Ia-3), formula (Ia-4) (Ia-4) or formula (Ia-5) (Ia-5) wherein X 3 is NH, O, or S, and A is C 3 -C 8 cycloalkyl, aryl or heteroaryl.
  4. 4. The compound of claim 1, wherein the compound has formula (Ib): (Ib)。
  5. 5. The compound of claim 1 or 4, wherein the compound has formula (Ib-1): (Ib-1), formula (Ib-2): (Ib-2)、 Formula (Ib-3) (Ib-3)、 Formula (Ib-4) (Ib-4)、 Formula (Ib-5) (Ib-5) or Formula (Ib-6) (Ib-6), Wherein A is C 3 -C 8 cycloalkyl, aryl or heteroaryl.
  6. 6. The compound of claim 1, wherein the compound is of formula (Ic): (Ic)。
  7. 7. The compound of claim 1 or 6, wherein the compound is of formula (Ic-1): (Ic-1)、 formula (Ic-2): (Ic-2) Formula (Ic-3) (Ic-3)、 Formula (Ic-4) (Ic-4), or Formula (Ic-5): (Ic-5), wherein A is C 3 -C 8 cycloalkyl, aryl or heteroaryl.
  8. 8. The compound of claim 1, wherein the compound has formula (Id): (Id)、 Formula (Ie): (Ie), or Formula (If): (If), Wherein A is C 3 -C 8 cycloalkyl, aryl or heteroaryl, and r is an integer from 0 to 2.
  9. 9. The compound of any one of the preceding claims, wherein R 2 is H or C 1 -C 4 alkyl.
  10. 10. The compound of any one of the preceding claims, wherein R 3 is H.
  11. 11. The compound of any one of the preceding claims, wherein R 4 is C 1 -C 4 alkyl.
  12. 12. A compound according to any one of the preceding claims, wherein R 7 is methyl or cyclopropyl.
  13. 13. The compound of any one of the preceding claims, wherein at least one R 11 is selected from H, halogen, fluorine, C 1 -C 6 alkoxy, or C 1 -C 6 alkyl.
  14. 14. The compound of any one of the preceding claims, wherein the compound is selected from the group consisting of: or a pharmaceutically acceptable salt, isomer, solvate, prodrug or tautomer thereof.
  15. 15. A pharmaceutical composition comprising a compound according to any one of claims 1-14 and a pharmaceutically acceptable carrier, adjuvant or vehicle.
  16. 16. A method of inhibiting PAD4 in a subject or biological sample, the method comprising the step of contacting the PAD4 with a compound according to any one of claims 1-14.
  17. 17. A method of treating a PAD 4-mediated disease, disorder, or condition in a subject in need thereof, the method comprising the step of administering to the subject the pharmaceutical composition of claim 15.
  18. 18. The method of claim 17, wherein the PAD 4-mediated disease, disorder or condition is selected from the group consisting of acid-induced lung injury, acne (PAPA), acute lymphoblastic leukemia, acute respiratory distress syndrome, addison's disease, adrenal hyperplasia, adrenocortical insufficiency, aging, aids, alcoholic hepatitis, alcoholic liver disease, allergen-induced asthma, allergic bronchopulmonary, aspergillosis, allergic conjunctivitis, alopecia, alzheimer's disease, amyloidosis, amyotrophic lateral sclerosis, and weight loss, angina, angioedema, anhidrosis ectodermal dysplasia with immunodeficiency, Ankylosing spondylitis, anterior segment inflammation, antiphospholipid syndrome, aphtha stomatitis, appendicitis, arthritis, asthma, atherosclerosis, atopic dermatitis, autoimmune diseases, autoimmune hepatitis, bee sting-induced inflammation, behcet's syndrome, bell palsy, beryllium poisoning, bulaue's syndrome, bone pain, bronchiolitis, burn, bursitis, cancer, cardiac hypertrophy, carpal tunnel syndrome, catabolic disorders, cataracts, cerebral aneurysms, chemical stimulus-induced inflammation, chorioretinitis, chronic heart failure, premature chronic lung disease, chronic lymphocytic leukemia, chronic obstructive pulmonary disease, Colitis, complex regional pain syndrome, connective tissue disease, corneal ulcers, crohn's disease, cold inflammatory-related periodic syndrome, cryptococcosis, cystic fibrosis, interleukin-1-receptor antagonist Deficiency (DIRA), dermatitis endotoxemia, dermatomyositis, diffuse intrinsic bridge brain glioma, endometriosis, endotoxemia, epicondylitis, erythroblastosis, familial amyloidosis polyneuropathy, familial cold urticaria, familial mediterranean fever, fetal growth retardation, glaucoma, glomerular disease, glomerulonephritis, gout, gouty arthritis, graft versus host disease, intestinal tract disease, head injury, headache, hearing loss, heart disease, hemolytic anemia, allergic purpura, hepatitis, hereditary periodic fever syndrome, shingles and herpes simplex, HIV-1, hodgkin's disease, huntington's disease, hyalopathy, hyperammonemia, hypercalcemia, hypercholesteremia, hyperimmune globulin D-type with periodic fever (HIDS), aplastic anemia and other anemias, aplastic anemia, idiopathic thrombocytopenic purpura, pigment disorders, infectious mononucleosis, inflammatory bowel disease, inflammatory lung disease, inflammatory neuropathy, inflammatory pain, insect bite induced inflammation, iritis, iridocyclitis, stimulus-induced inflammation, ischemia/reperfusion, juvenile rheumatoid arthritis, keratitis, kidney disease, kidney injury from parasitic infection, prevention of renal graft rejection, leptospirosis, leukemia, lavender's syndrome, lung injury, lupus nephritis, lymphoma, meningitis, mesothelioma, mixed connective tissue disease, murray-Weber syndrome (urticaria, deafness, amyloidosis), multiple sclerosis, muscle loss, muscle atrophy, myasthenia gravis, myocarditis, mycosis fungoides, myelodysplastic syndrome, Myositis, sinusitis, necrotizing enterocolitis, neonatal Onset Multisystem Inflammatory Disease (NOMID), nephrotic syndrome, neuritis, neuropathological disease, non-allergen-induced asthma, obesity, ocular allergies, optic neuritis, organ transplants, osteoarthritis, otitis media, paget's disease, pain, pancreatitis, parkinson's disease, pemphigus, pericarditis, periodic fever, periodontitis, peritoneal endometriosis, pertussis, pharyngitis and adenosis (PFAPA syndrome), plant-stimulant-induced inflammation, pneumonia, pulmonary inflammation, pneumocystis infection, toxic ivy/urushiol oil-induced inflammation, polyarteritis nodosa, Polychondritis, polycystic kidney disease, polymyositis, psoriasis, psychological stress disorders, lung disease, pulmonary hypertension, pulmonary fibrosis, pyoderma gangrenosum, suppurative aseptic arthritis, kidney disease, retinal disease, rheumatic heart disease, rheumatic diseases, rheumatoid arthritis, sarcoidosis, seborrhea, sepsis, severe pain, sickle cells, sickle cell anemia, silica-induced diseases, sjogren's syndrome, skin diseases, sleep apnea, solid tumors, spinal cord injury, stevens-Johnson syndrome, stroke, subarachnoid hemorrhage, sunburn, temporal arteritis, tenosynovitis, thrombocytopenia, Thyroiditis, tissue transplantation, TNF receptor-related periodic syndrome (trap), toxoplasmosis, transplantation, traumatic brain injury, tuberculosis, type 1 diabetes, type 2 diabetes, ulcerative colitis, urticaria, uveitis, and wegener's granulomatosis.
  19. 19. The method of claim 17, wherein the PAD 4-mediated disease, disorder, or condition is selected from the group consisting of rheumatoid arthritis, vasculitis, systemic lupus erythematosus, ulcerative colitis, cancer, cystic fibrosis, asthma, cutaneous lupus erythematosus, and psoriasis.
  20. 20. The method of claim 19, wherein the PAD 4-mediated disease, disorder, or condition is rheumatoid arthritis.

Description

Heterocyclic PAD4 inhibitors Cross Reference to Related Applications The application claims the benefit and priority of U.S. provisional patent application No. 63/514,934, filed on 7/21/2023, the entire contents of which are hereby incorporated by reference. Technical Field The present disclosure relates generally to substituted heterocyclic compounds, methods of preparing these compounds, pharmaceutical compositions comprising these compounds, and the use of these compounds in the treatment of diseases or disorders associated with PAD4 enzymatic activity. Incorporated by reference sequence listing The present application encompasses sequence listings submitted via EFS-WEB in XML format and hereby incorporated by reference in its entirety. The XML copy created at 2023, 6, 19 was named 055920-606P01US_SeqList_ST26.XML and was 3 kilobytes in size. Background PAD4 (SEQ ID NO: 1) is a member of the peptide acyl arginine deiminase (PAD) enzyme family of enzymes capable of catalyzing the citrullination of arginine to citrulline in peptide sequences. PAD4 is responsible for deiminating or citrullinating a variety of proteins in vitro and in vivo, resulting in a variety of functional responses in a variety of diseases (Jones j.e. et al, curr. Opin. Drug discovery.level., 12 (5), (2009), 616-627). Examples of exemplary diseases or disorders include, in addition to oncologic indications, rheumatoid arthritis, diseases in which neutrophils contribute to pathogenesis (e.g. vasculitis, systemic lupus erythematosus, ulcerative colitis). PAD4 inhibitors also have broader applicability as tools and therapeutics for human diseases and disorders through epigenetic mechanisms. Inhibitors of PAD4 are useful against Rheumatoid Arthritis (RA). RA is an autoimmune disease affecting about 1% of the population (Wegner n. Et al, immunol. Rev., 233 (1), (2010), 34-54). It is characterized by inflammation of the joints, resulting in debilitating damage to bone and cartilage. Although inconsistent, a weak genetic correlation between PAD4 polymorphism and susceptibility to RA has been proposed in many population studies (Kochi y. Et al, ann.rheum. Dis., 70, (2011), 512-515). PAD4 has been detected in synovial tissue (along with the family member PAD 2), where the PAD4 is responsible for deimination of a variety of joint proteins. It is speculated that in RA joints, this process leads to disruption of tolerance to citrullinated substrates (such as fibrinogen, vimentin and collagen) and initiation of immune responses to them. These anti-citrullinated protein antibodies (ACPA) contribute to the pathogenesis of the disease and can also be used as diagnostic tests for RA (e.g., commercially available CCP2 or cyclic citrullinated protein 2 tests). In addition, enhanced citrullination can also provide additional direct contributions to disease pathogenesis by its ability to directly affect several articular and inflammatory mediators (e.g., fibrinogen, antithrombin, and various chemokines). In a smaller subset of RA patients, anti-PAD 4 antibodies may be measured and may be correlated with a more aggressive form of the disease. PAD4 inhibitors may also be used to reduce pathological neutrophil activity in a variety of diseases. Studies have shown that the process of neutrophil extracellular Trap (Trap) (NET) formation, the innate defense mechanism by which neutrophils are able to fix and kill pathogens, is associated with histone citrullination and is absent in PAD4 knockout mice (Neeli i. et al, j. immunol, 180, (2008), 1895-1902 and Li p. et al, j. exp.med., 207 (9), (2010), 1853-1862). thus, PAD4 inhibitors may be useful in diseases in which NET formation in tissues contributes to localized injury and disease pathology. Such diseases include, but are not limited to, small vasculitis (Kessenbrock k et al, nat et al, 15 (6), (2009), 623-625), systemic lupus erythematosus (Hakkim a et al, proc. Natl. Acad. Sci. USA, 107 (21), (2010), 9813-9818 and Villanueva e et al, J. Immunol, 187 (1), (2011), 538-52), ulcerative colitis (Savchenko a et al, pathol. Int., 61 (5), (2011), 290-7), ulcerative colitis, and the like, Cystic fibrosis, asthma (Dworski r et al, j. Allergy clin.immunol., 127 (5), (2011), 1260-6), deep venous thrombosis (Fuchs t et al, proc. Natl. Acad. Sci.USA, 107 (36), (2010), 15880-5), periodontitis (Vitkov l et al, ultrastructural pathol., 34 (1), (2010), 25-30), Sepsis (Clark s.r. et al, nat. Med., 13 (4), (2007), 463-9), appendicitis (Brinkmann v. Et al, science, 303, (2004), 1532-5) and stroke. In addition, there is evidence that NET may contribute to pathology in diseases affecting the skin (e.g., in cutaneous lupus erythematosus (Villanueva e. Et al, j. Immunol., 187 (1), (2011), 538-52) and psoriasis (Lin a.m. et al, j. Immunol., 187 (1), (2011), 490-500)), and thus PAD4 inhibitors may show benefit in solving NET skin diseases when administered by systemic or cutaneous routes. PAD4 inhibitors may affect other funct