Bifunctional compounds for degrading BTK via ubiquitin proteosome pathway
The present invention relates to compounds useful for degrading BTK via a ubiquitin proteolytic pathway. The invention also provides pharmaceutically acceptable compositions comprising said compounds and methods of using the compositions in the treatment of various disease, conditions, or disorders.
1 . A compound of Formula (I)
or a pharmaceutically acceptable salt thereof, wherein
R 1 is —H or —C 1-4 alkyl;
X A is N;
X B is N;
X C is CR 2 ;
R 2 is —H, or
R 1 and R 2 taken together with the atoms to which they are attached form a monocyclic heterocycle fused to ring E;
ring A is phenyl, a 4-6 membered monocyclic heteroaryl group having 1-3 heteroatoms independently selected from N, O, and S, or a 9-10 membered bicyclic heteroaryl having 1-3 heteroatoms independently selected from N, O, and S, wherein ring A is optionally substituted with —Z A —R A ;
Z A is a bond, or an optionally substituted branched or straight C 1-3 aliphatic chain wherein up to two carbon units of Z A are optionally and independently replaced by —C(O)—, —C(S)—, —N(R)—, —C(O)N(R)—, —N(R)C(O)—, —CO 2 —, —OCO—, —O—, —S—, —S(O)—, —S(O) 2 , —S(O) 2 N(R)—, or —N(R)S(O) 2 —;
R A is hydrogen, halo, —OH, —NH 2 , —NO 2 , —CN, —CF 3 , —CH 3 , or —OCH 3 ;
ring B is
L is —X 1 —X 2 —X 3 —X 4 —;
X 1 is —N(R)—C(O)—O—, —N(R)—C(O)—, —C(O)—N(R)—, or 7-12 membered spiro bicyclic heterocycloalkyl ring system having 1-3 heteroatoms independently selected from N, O, or S, wherein the spiro bicyclic heterocycloalkyl ring system is optionally substituted with —OH or oxo;
X 2 is a bond, —(CH 2 ) n —O—, —O—(CH 2 ) n —, —C 1-8 alkyl-, a 7-12 membered spiro bicyclic heterocycloalkyl ring system having 1-3 heteroatoms independently selected from N, O, or S, a 4-6 membered monocyclic heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S, a 6-10 membered fused bicyclic heterocycloalkyl having 1-3 heteroatoms independently selected from N, O, or S, or a 6-9 membered bridged bicyclic heterocycloalkyl having 1-3 heteroatoms independently selected from N, O, or S, wherein the spiro bicyclic heterocycloalkyl ring system is optionally substituted with —OH or oxo;
X 3 is a bond, —O—, —(CH 2 ) n —O—, —C 1-4 alkyl-, or a 4-6 membered heterocycloalkyl ring having 1-2 heteroatoms independently selected from N, O, or S;
X 4 is a bond, —C 1-4 alkyl-, or a 4-6 membered heterocycloalkyl ring having 1-2 heteroatoms independently selected from N, O, or S;
each R is independently —H or —C 1-3 alkyl;
Y is
wherein:
each R 4 is independently halo or C 1-4 alkyl;
each Z B is —C(R B ) 2 — or —C(O)—;
each R B is —H or —C 1-4 alkyl;
each n is independently 1, 2, or 3; and
q is 0, 1, or 2.
2 . The compound or pharmaceutically acceptable salt of claim 1 , wherein the compound of Formula (I) is a compound of Formula (IA)
or a pharmaceutically acceptable salt thereof.
3 . The compound or pharmaceutically acceptable salt of claim 1 , wherein the compound of Formula (I) is a compound of Formula (II)
or a pharmaceutically acceptable salt thereof.
4 . The compound or pharmaceutically acceptable salt of claim 3 , wherein the compound of Formula (II) is a compound of Formula (II-A), (II-B), (II-C), (II-B1), (II-B2), (II-B3), or (II-B4)
wherein
one of X D , X E , X F , and X G is optionally a bond, one of X D , X E , X F , and X G is —CH 2 — or —CH 2 —CH 2 —, one of X D , X E , X F , and X G is —NR 5 —, and the remainder are —CH 2 —; and each R 5 is independently —H or —C 1-4 alkyl optionally substituted with halo;
or a pharmaceutically acceptable salt thereof.
5 . The compound or pharmaceutically acceptable salt of claim 3 , wherein ring A is a 9-10 membered bicyclic heteroaryl having 1-3 heteroatoms independently selected from N, O, and S, wherein ring A is optionally substituted with —Z A —R A , Z A is a bond, or an optionally substituted branched or straight C 1-3 aliphatic chain wherein up to two carbon units of Z A are optionally and independently replaced by —C(O)—, —C(S)—, —N(R)—, —C(O)N(R)—, —N(R)C(O)—, —CO 2 —, —OCO—, —O—, —S—, —S(O)—, —S(O) 2 —, —S(O) 2 N(R)—, or —N(R)S(O) 2 — and R A is hydrogen, halo, —OH, —NH 2 , —NO 2 , —CN, —CF 3 , —CH 3 , or —OCH 3 .
6 . The compound or pharmaceutically acceptable salt of claim 1 , wherein q is 0; and
Y is
7 . The compound or pharmaceutically acceptable salt of claim 1 ,
wherein ring A is
wherein Z A is a bond, —C(O)—, —CO 2 —, —OCO—, —S—, —O—, —S(O)—, or —S(O) 2 —, and R A is hydrogen, halo, —OH, —CF 3 , or —CH 3 .
8 . The compound or pharmaceutically acceptable salt of claim 1 , wherein ring A is
wherein Z A is an optionally substituted branched or straight C 1-3 aliphatic chain, and R A is hydrogen, halo, —OH, —NH 2 , —NO 2 , —CN, —CF 3 , or —OCH 3 .
9 . The compound or pharmaceutically acceptable salt of claim 1 , wherein X 1 is —NH—C(O)— or —N(CH 3 )—C(O)—.
10 . The compound or pharmaceutically acceptable salt of claim 1 , wherein X 2 is —CH 2 —O—, —(CH 2 ) 2 —O—, —(CH 2 ) 3 —O—, —CH 2 —, -n-butyl-, or -n-hexyl-, an 7-12 membered spiro bicyclic heterocycloalkyl ring system having 1-3 heteroatoms independently selected from N, O, or S, wherein the spiro bicyclic heterocycloalkyl ring system is optionally substituted with —OH or oxo.
11 . The compound or pharmaceutically acceptable salt of claim 10 , wherein X 2 is
12 . The compound or pharmaceutically acceptable salt of claim 1 , wherein X 2 is a 4-6 membered monocyclic heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S, 6-10 membered fused bicyclic heterocycloalkyl having 1-3 heteroatoms independently selected from N, O, or S, or a 6-9 membered bridged bicyclic heterocycloalkyl having 1-3 heteroatoms independently selected from N, O, or S.
13 . The compound or pharmaceutically acceptable salt of claim 12 , wherein X 2
wherein X 2 is
14 . The compound or pharmaceutically acceptable salt of claim 1 ,
wherein X 3 is a bond, —CH 2 —O—, —C 1-4 alkyl,
X 4 is a bond, —C 1-4 alkyl-,
and
L is selected from
15 . The compound or pharmaceutically acceptable salt of claim 1 , wherein
(i) ring A is
(ii) L is —X 1 —X 2 —X 3 —X 4 —;
(iii) X 1 is —NH—C(O)—;
(iv) X 2 is a 7-12 membered spiro bicyclic heterocycloalkyl ring system having 1-3 heteroatoms independently selected from N, O, or S, a 4-6 membered monocyclic heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S, or a 6-10 membered fused bicyclic heterocycloalkyl having 1-3 heteroatoms independently selected from N, O, or S, wherein the spiro bicyclic heterocycloalkyl ring system is optionally substituted with —OH or oxo;
(v) X 3 is a bond, a 4-6 membered monocyclic heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S, or a —C 1-4 alkyl-;
(vi) X 4 is a bond, a 4-6 membered heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S, or a —C 1-4 alkyl-; and
(vii) Y is
16 . The compound or pharmaceutically acceptable salt of claim 15 , wherein q is 0;
Y is
ring A is
X 2 is
X 3 is bond, —C 1-4 alkyl-, or
X 4 is bond, —C 1-4 alkyl
and
L is selected from
17 . A compound selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
18 . A pharmaceutical composition comprising a compound or pharmaceutically acceptable salt of a compound of claim 1 or 17 and a pharmaceutically acceptable carrier, vehicle, or adjuvant.
19 . A method of treating a disease or disorder mediated by degrading Bruton's tyrosine kinase, comprising administering to a patient or biological sample a compound or pharmaceutically acceptable salt of a compound of claim 1 or 17 , wherein the disease or disorder is cancer or an autoimmune disease.
20 . The method of claim 19 , wherein the cancer is a hematological cancer selected from myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome, Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma) hairy cell, mantle cell lymphoma, Waldenstrom's macroglobulinemia, marginal zone lymphoma, and follicular lymphoma.
21 . The method of claim 19 , wherein the autoimmune disease is selected from urticarial, graft-versus-host disease, pemphigus vulgaris, achalasia, Addison's disease, Adult Still's disease, agammaglobulinemia, alopecia areata, amyloidosis, ankylosing spondylitis, anti-GBM/anti-TBM nephritis, antiphospholipid syndrome, autoimmune angioedema, autoimmune dysautonomia, autoimmune encephalomyelitis, autoimmune hepatitis, autoimmune inner ear disease (AIED), autoimmune myocarditis, autoimmune oophoritis, autoimmune orchitis, autoimmune pancreatitis, autoimmune retinopathy, axonal and neuronal neuropathy (AMAN), Balo disease, Behcet's disease, benign mucosal pemphigoid, bullous pemphigoid, Castleman disease (CD), Celiac disease, Chagas disease, chronic inflammatory demyelinating polyneuropathy (CIDP), chronic recurrent multifocal osteomyelitis (CRMO), Churg-Strauss Syndrome (CSS) or Eosinophilic Granulomatosis (EGPA), cicatricial pemphigoid, Cogan's syndrome, cold agglutinin disease, congenital heart block, coxsackie myocarditis, CREST syndrome, Crohn's disease, dermatitis herpetiformis, dermatomyositis, Devic's disease (neuromyelitis optica), discoid lupus, Dressler's syndrome, endometriosis, eosinophilic esophagitis (EoE), eosinophilic fasciitis, erythema nodosum, essential mixed cryoglobulinemia, evans syndrome, fibromyalgia, fibrosing alveolitis, giant cell arteritis (temporal arteritis), giant cell myocarditis, glomerulonephritis, goodpasture's syndrome, granulomatosis with polyangiitis, Graves' disease, Guillain-Barre syndrome, Hashimoto's thyroiditis, hemolytic anemia, Henoch-Schonlein purpura (HSP), herpes gestationis or pemphigoid gestationis (PG), hidradenitis suppurativa (HS) (Acne Inversa), hypogammalglobulinemia, IgA nephropathy, IgG4-related sclerosing disease, immune thrombocytopeniaurpura (ITP), inclusion body myositis (IBM), interstitial cystitis (IC), juvenile arthritis, juvenile diabetes (Type 1 diabetes), juvenile myositis (JM), Kawasaki disease, Lambert-Eaton syndrome, leukocytoclastic vasculitis, lichen planus, lichen sclerosus, ligneous conjunctivitis, linear IgA disease (LAD), lupus, lyme disease chronic, Meniere's disease, microscopic polyangiitis (MPA), mixed connective tissue disease (MCTD), Mooren's ulcer, Mucha-Habermann disease, Multifocal Motor Neuropathy (MMN) or MMNCB, multiple sclerosis, myasthenia gravis, myositis, narcolepsy, neonatal lupus, neuromyelitis optica, neutropenia, ocular cicatricial pemphigoid, optic neuritis, palindromic rheumatism (PR), PANDAS, paraneoplastic cerebellar degeneration (PCD), paroxysmal nocturnal hemoglobinuria (PNH), Parry Romberg syndrome, pars planitis (peripheral uveitis), Parsonnage-Tumer syndrome, pemphigus, peripheral neuropathy, perivenous encephalomyelitis, pernicious anemia (PA), POEMS syndrome, polyarteritis nodosa, polyglandular syndromes type I, II, III, polymyalgia rheumatica, polymyositis, postmyocardial infarction syndrome, postpericardiotomy syndrome, primary biliary cirrhosis, primary sclerosing cholangitis, progesterone dermatitis, psoriasis, psoriatic arthritis, pure red cell aplasia (PRC A), pyoderma gangrenosum, Raynaud's phenomenon, reactive Arthritis, reflex sympathetic dystrophy, relapsing polychondritis, restless legs syndrome (RLS), retroperitoneal fibrosis, rheumatic fever, rheumatoid arthritis, sarcoidosis, Schmidt syndrome, scleritis, scleroderma, Sjogren's syndrome, sperm and testicular autoimmunity, stiff person syndrome (SPS), subacute bacterial endocarditis (SBE), Susac's syndrome, sympathetic ophthalmia (SO), Takayasu's arteritis, temporal arteritis (giant cell arteritis), thrombocytopenia purpura (TTP), Tolosa-Hunt syndrome (THS), transverse myelitis, Type 1 diabetes, ulcerative colitis (UC), undifferentiated connective tissue disease (UCTD), uveitis, vasculitis, vitiligo, Vogt-Koyanagi-Harada Disease, and Wegener's granulomatosis (or Granulomatosis with Polyangiitis (GPA)).