WO2025062330A1 - Composés hétérocycliques utilisés en tant qu'agents de dégradation sélectifs de cbp - Google Patents

Composés hétérocycliques utilisés en tant qu'agents de dégradation sélectifs de cbp Download PDF

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WO2025062330A1
WO2025062330A1 PCT/IB2024/059098 IB2024059098W WO2025062330A1 WO 2025062330 A1 WO2025062330 A1 WO 2025062330A1 IB 2024059098 W IB2024059098 W IB 2024059098W WO 2025062330 A1 WO2025062330 A1 WO 2025062330A1
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methyl
piperidin
oxo
dimethyl
dihydroquinolin
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Chandrasekhar ABBINENI
Susanta Samajdar
Krishna Chaitanya TALLURI
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Aurigene Oncology Ltd
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Aurigene Oncology Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring

Definitions

  • HETEROCYCLIC COMPOUNDS AS CBP SELECTIVE DEGRADERS The present application claims priority to and the benefit of Indian Patent Application No. IN 202341063268, filed on September 20, 2023, which application is incorporated herein by reference in their entirety.
  • FIELD OF THE INVENTION The present application is directed to heterocyclic compounds of formula (I) as CBP selective degraders, useful for the treatment of cancer.
  • the disclosure also provides pharmaceutically acceptable compositions comprising compounds of the present application and methods of using said compositions in the treatment of diseases associated with CBP degradation.
  • BACKGROUND OF THE INVENTION CREB binding protein (CBP or CREBBP) and its paralog E1A binding protein (p300) are ubiquitously expressed histone acetyl transferases (HAT).
  • CBP and p300 are multidomain proteins that harbour different functional units imperative for chromatin remodelling and transcription like Bromodomain (BD), Histone acetyl transferase (HAT) domain, KIX domain etc.
  • BD Bromodomain
  • HAT Histone acetyl transferase
  • KIX domain KIX domain
  • CBP selective degraders offer synthetic lethality in p300 mutant, CBP dependent, ER positive and Wnt- ⁇ Catenin aberrated cancers.
  • Selective synthetic lethality in p300 mutant and CBP dependent cancers CBP mutation frequency is reported to be higher in several cancers including skin cancers (27%), small cell lung cancers (8%), lymphoma (8-13%) and bladder cancer (10%) (Attar, N.; Kurdistani, S. K. Cold Spring Harb. Perspect. Med.2017, 7, a026534).
  • M is represented by formula (M-1), (M-2), (M-3) or (M-4): , each Y1 and Z1 is independently N or CH; Y2 is a bond, -C(O)NH-*, -NH-C(O)-*, -O- or -NRY-; wherein the asterisk mark [*] represents the point of attachment with the ring having Y 1 ; each Y3 and Y4 is independently N or C; Z2 is N or C; each Z3 and Z4 is independently C, O or N; wherein at least one of Z2, Z3 and Z 4 is C; G 1 is -CH 2 -, NH, S or O; RM1 is hydrogen or (C1-C4)alkyl; RM2 at each occurrence is independently halo, cyano, (C1-C4)alkyl, halo(C1
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I), a pharmaceutically acceptable salt, a stereoisomer, a tautomer, an N-oxide or an ester thereof and at least one pharmaceutically acceptable carrier or excipient (such as a pharmaceutically acceptable carrier or diluent).
  • the present invention provides a pharmaceutical composition for the treatment of diseases or conditions that are dependent upon degradation of CBP.
  • the present invention relates to preparation of compounds of formula (I).
  • Another aspect of the present invention provides methods of treating CBP-mediated diseases or disorders by administering a therapeutically effective amount of a compound of formula (I) a pharmaceutically acceptable salt or a stereoisomer, to a subject in need thereof.
  • Yet another aspect of the present invention provides methods of treating CBP-mediated diseases or disorders wherein the CBP-mediated disease or disorder is cancer, by administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer, to a subject in need thereof.
  • a compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer to a subject in need thereof.
  • the present invention relates to heterocyclic compounds acting as degraders of CBP and pharmaceutical compositions comprising said compounds.
  • the present invention also relates to a use of said compounds and composition comprising said compounds for the treatment and/ or prevention of diverse array of CBP-mediated diseases or disorders.
  • the present invention provides compounds of formula (I),
  • M is represented by formula (M-1), (M-2), (M-3) or (M-4): , each Y1 and Z1 is independently N or CH; Y2 is a bond, -C(O)NH-*, -NH-C(O)-*, -O- or -NRY-; wherein the asterisk mark [*] represents the point of attachment with the ring having Y 1 ; each Y3 and Y4 is independently N or C; Z2 is N or C; each Z3 and Z4 is independently C, O or N; wherein at least one of Z2, Z3 and Z 4 is C; G 1 is -CH 2 -, NH, S or O; RM1 is hydrogen or (C1-C4)alkyl; RM2 at each occurrence is independently halo, cyano, (C1-C4)alkyl, halo(C1
  • the present invention provides compounds of formula (I) or a pharmaceutically acceptable salt, a stereoisomer, a tautomer, an N-oxide or an ester thereof; wherein M is represented by formula (M-1), (M-2) or (M-3): each Y 1 and Z 1 is independently N or CH; Y 2 is a bond, -C(O)NH- * , -NH-C(O)- * , -O- or -NR Y -; wherein the asterisk mark [*] represents the point of attachment with the ring having Y1; each Y 3 and Y 4 is independently N or C; Z 2 is N or C; each Z 3 and Z 4 is independently C, O or N; wherein at least one of Z 2 , Z 3 and Z4 is C; RM1 is hydrogen or (C1-C4)alkyl; R M2 at each occurrence is independently halo, cyano, (C 1 -C 4 )alkyl or (C 1 -C 4
  • provided herein are compounds of formula (IA), or a pharmaceutically acceptable salt, a stereoisomer, a tautomer, an N-oxide or an ester thereof.
  • compounds of formula or a pharmaceutically acceptable salt, a stereoisomer, a tautomer, an N-oxide or an ester thereof are compounds of formula or a pharmaceutically acceptable salt, a stereoisomer, a tautomer, an N-oxide or an ester thereof.
  • provided herein are compounds of formula (ID), or a pharmaceutically acceptable salt, a stereoisomer, a tautomer, an N-oxide or an ester thereof.
  • compounds of formula (IE) or a pharmaceutically acceptable salt, a stereoisomer, a tautomer, an N-oxide or an ester thereof.
  • compounds of formula (IF) or a pharmaceutically acceptable salt, a stereoisomer, a tautomer, an N-oxide or an ester thereof.
  • asterisk mark [*] represents the point of attachment to the ring containing X 1 ; and represents the points of fusion with Q.
  • Q represents fused 5- to 6-membered heteroaryl ring. In yet another embodiment, Q represents fused benzo ring. In yet another embodiment, Q represents ; wherein represents the points of fusion with the ring containing X2. , wherein represents the point of attachment to the ring containing X 1 . In certain embodiments, wherein represents the point of attachment to the ring containing X 1 . represents the point of attachment to the ring containing X1. In one embodiment, represents represents the point of attachment to the ring containing X 1 . represents the point of attachment to the ring containing X1. In one embodiment, represents wherein represents the point of attachment to the ring containing X 1 .
  • L1 is -O-, -O-(CH2)k-O-* or unsubstituted or substituted 3 to 12-membered heterocycloalkylenyl. In certain embodiments, L 1 is -O-, -O-(CH 2 ) k -O-* or 3 to 12-membered heterocycloalkylenyl.
  • L2 is a bond or unsubstituted or substituted (C1-C6)alkylenyl, wherein one or more methylene units of the alkylenyl is optionally and independently replaced with any combination of -C(O)-, -O-, -N(R5)-, (C2-C6)alkenylenyl, (C2-C6)alkynylenyl or (C3- C6)cycloalkylene; wherein the substituent is independently selected from one or more oxo, halo, cyano, hydroxy or (C 1 -C 4 )alkoxy. .
  • L2 is an unsubstituted or substituted (C1-C6)alkylenyl, wherein one or more methylene units of the alkylenyl is optionally and independently replaced with - C(O)-. In one embodiment, L2 is an unsubstituted or substituted (C1-C6)alkylenyl, wherein one methylene unit of the alkylenyl is replaced with -C(O)-. In some embodiments, *-(C1- C4)alkylenyl-C(O)- or *-C(O)-(C1-C4)alkylenyl-. In some embodiments L2 is , one embodiment, L 2 is -C(O)-.
  • L2 is an unsubstituted or substituted (C1-C6)alkylenyl, wherein one or more methylene units of the alkylenyl is optionally and independently replaced with - O-.
  • L 2 is an unsubstituted or substituted (C 1 -C 6 )alkylenyl, wherein one methylene unit of the alkylenyl is replaced with -O-.
  • L 2 is some embodiments, L2 is -O-.
  • L 2 is an unsubstituted or substituted (C 1 -C 6 )alkylenyl, wherein one or more methylene units of the alkylenyl is optionally and independently replaced with (C2-C6)alkenylenyl.
  • L2 is an unsubstituted or substituted (C1-C6)alkylenyl, wherein two methylene units of the alkylenyl are replaced with (C 2 -C 6 )alkenylenyl.
  • L2 is an unsubstituted or substituted (C1-C6)alkylenyl, wherein one or more methylene units of the alkylenyl is optionally and independently replaced with (C 2 -C 6 )alkynylenyl.
  • L 2 is an unsubstituted or substituted (C 1 -C 6 )alkylenyl, wherein two methylene units of the alkylenyl are replaced with (C2-C6)alkynylenyl. . In some embodiments, .
  • L 2 is an unsubstituted or substituted (C 1 -C 6 )alkylenyl, wherein one or more methylene units of the alkylenyl is optionally and independently replaced with - N(R5)-.
  • L2 is an unsubstituted or substituted (C1-C6)alkylenyl, wherein one methylene unit of the alkylenyl is replaced with -N(R 5 )-.
  • L 2 is -N(R 5 )-.
  • L 2 is -N(R 5 )-, wherein R 5 is hydrogen or (C 1 -C 4 )alkyl.
  • L2 is a bond or unsubstituted or substituted (C1-C6)alkylenyl, wherein one or more methylene units of the alkylenyl is optionally and independently replaced with any combination of -C(O)-, -O- or -N(R 5 )-.
  • L 2 is -C(O)-O-, -O- C(O)-, -C(O)-NH-, -NH-C(O)-, -C(O)-NH-C(O)- or -NH-C(O)-NH-.
  • L2 is a bond, -C(O)-, unsubstituted or substituted (C 1 -C 6 )alkylenyl, (C 2 -C 6 )alkenylenyl, (C 2 -C 6 )alkynylenyl, halo(C 1 -C 4 )alkylenyl, *-(C1-C4)alkylenyl-C(O)- or *-C(O)-(C1-C4)alkylenyl-; wherein the substituent at each occurrence is independently selected from one or more oxo, halo or cyano; wherein the asterisk mark [*] represents the point of attachment with L 1 .
  • L 2 is a bond, -C(O)-, unsubstituted or substituted (C 1 - C6)alkylenyl, (C2-C6)alkynylenyl or *-C(O)-(C1-C4)alkylenyl-; wherein the substituent at each occurrence is independently selected from one or more oxo, halo or cyano; wherein the asterisk mark [*] represents the point of attachment with L 1 .
  • L2 is a bond, -C(O)-, (C1-C6)alkylenyl, (C2-C6)alkynylenyl or *-C(O)-(C1-C4)alkylenyl-; wherein the asterisk mark [*] represents the point of attachment with L 1 .
  • L2 is (C1-C6)alkylenyl.
  • L3 is a bond, unsubstituted or substituted 3 to 12-membered cycloalkylenyl or unsubstituted or substituted 3 to 12-membered heterocycloalkylenyl.
  • L 3 is independently a bond, or unsubstituted or substituted 3 to 12-membered heterocycloalkylenyl.
  • asterisk mark [*] represents point of attachment with ring containing X 1 .
  • mark [*] represents point of attachment with M.
  • L 3 represents , wherein the asterisk mark [*] represents point of attachment with M.
  • L2 is a bond or C1-C6 alkylenyl.
  • L 2 is a bond or C 1 -C 4 alkylenyl.
  • L2 and L3 each are bond.
  • L2 is a bond.
  • L 3 is a bond.
  • L1 is directly attached to L3 when L2 is a bond.
  • L1 is directly attached to M when L2 and L3 are each bond.
  • L 2 is directly attached to M when L 3 is a bond.
  • M is (M-1): .
  • (M-1) represents: represents the point of attachment with L.
  • (M-1) represents: or wherein asterisk mark [*] represents the point of attachment with L.
  • M is (M-2): .
  • (M-2) represents: of attachment with L.
  • (M-2) represents: ; wherein asterisk mark [*] represents the point of attachment with L.
  • M is (M-3): .
  • (M-3) represents: , , ; wherein asterisk mark [*] represents the point of attachment with L.
  • M is (M-4): .
  • (M-4) represents: wherein asterisk mark [*] represents the point of attachment with L.
  • R1 is hydrogen or (C1-C4)alkyl.
  • R 2 is hydrogen or (C 1 -C 4 )alkyl.
  • R 3 at each occurrence is hydrogen, cyano, halo, (C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy or unsubstituted or substituted 5- to 6- membered heteroaryl. In certain embodiments, R 3 at each occurrence, independently, is hydrogen, cyano, halo, (C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy or 5 to 6-membered heteroaryl. In certain embodiments, R4, at each occurrence, independently is hydrogen or unsubstituted or substituted (C 1 -C 4 )alkyl.
  • R 4 at each occurrence, independently is hydrogen or (C 1 - C4)alkyl.
  • the compound is selected from: Comp. IUPAC name No. 4-(7-(1-((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-4- 1 yl)methyl)piperidin-4-yl)-1,3-dimethyl-2-oxo-1,2-dihydroquinolin-5-yl)-1- methyl-1,2,3,4-tetrahydroquinoxaline-6-carbonitrile 4-(7-(1-((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-4- 2 yl)methyl)piperidin-4-yl)-1,3-dimethyl-2-oxo-1,2-dihydroquinolin-5-yl)-1- methyl
  • Method of treatment the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof; for the treatment of diseases or disorders mediated by CBP in a subject.
  • the present invention provides the use of a compound of formula (I), (IA), (IB), (IC), (ID), (IE) and (IF) or a pharmaceutical acceptable salt or a stereoisomer thereof for the degradation of CBP.
  • the present invention provides a method of increasing efficacy of a cancer treatment comprising administering to the individual a therapeutically effective amount of a compound of formula (I) or a pharmaceutical acceptable salt or a stereoisomer thereof.
  • the methods provided herein are useful in treating a CBP-mediated disease or disorder involving fibrosis.
  • the CBP-mediated disease or disorder is a fibrotic disease.
  • fibrotic diseases include pulmonary fibrosis, silicosis, cystic fibrosis, renal fibrosis, liver fibrosis, liver cirrhosis, primary sclerosing cholangitis, primary biliary cirrhosis, endomyocardial fibrosis, mediastinal fibrosis, myelofibrosis, retroperitoneal fibrosis, progressive massive fibrosis, nephrogenic systemic fibrosis, Crohn's disease, keloid, myocardial infarction, systemic sclerosis or arthro fibrosis.
  • the present invention provides a method of treating CBP-mediated disease or disorder comprising administering to the subject in need thereof a therapeutically effective amount of compound of formula (I), (IA), (IB), (IC), (ID), (IE) and (IF) or a pharmaceutical acceptable salt or a stereoisomer thereof.
  • the present invention provides a compound of formula (I), (IA), (IB), (IC), (ID), (IE) and (IF) or a pharmaceutical acceptable salt or a stereoisomer thereof for use in the treatment of CBP-mediated disease or disorder in an individual.
  • the present invention provides a use of compound of formula (I), (IA), (IB), (IC), (ID), (IE) and (IF) or a pharmaceutical acceptable salt or a stereoisomer thereof in the manufacture of a medicament for the treatment of CBP-mediated disease or disorder in an individual.
  • CBP bromodomain-mediated disease or disorder is selected from cancer, fibrosis, inflammation, or an inflammatory disease and disorder.
  • CBP bromodomain-mediated disease or disorder is a fibrotic lung disease selected from pulmonary fibrosis, idiopathic pulmonary fibrosis, fibrotic interstitial lung disease, renal fibrosis, interstitial pneumonia, fibrotic variant of non-specific interstitial pneumonia, cystic fibrosis, lung fibrosis, chronic obstructive pulmonary lung disease (COPD), lung cirrhosis and pulmonary arterial hypertension.
  • CBP bromodomain- mediated disease or disorder is fibrotic interstitial lung disease.
  • CBP bromodomain-mediated disease or disorder is interstitial pneumonia.
  • CBP bromodomain-mediated disease or disorder fibrotic variant of non-specific interstitial pneumonia.
  • CBP bromodomain-mediated disease or disorder is cystic fibrosis. In one embodiment, CBP bromodomain-mediated disease or disorder is lung fibrosis. In one embodiment, CBP bromodomain-mediated disease or disorder is chronic obstructive pulmonary lung disease (COPD). In one embodiment, CBP bromodomain-mediated disease or disorder or pulmonary arterial hypertension. In one embodiment, CBP bromodomain-mediated disease or disorder is cancer.
  • COPD chronic obstructive pulmonary lung disease
  • CBP bromodomain-mediated disease or disorder is cancer selected from acoustic neuroma, acute leukemia, acute myeloid leukemia (AML), acute lymphocytic leukemia, acute myelocytic leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acute T-cell leukemia, basal cell carcinoma, bile duct carcinoma, bladder cancer, brain cancer, breast cancer, bronchogenic carcinoma, cancer of male and female reproductive system, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myelocytic (granulocytic) leukemia, chronic myelogenous leukemia, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B
  • the cancer is lung cancer, breast cancer, pancreatic cancer, colorectal cancer, and/or melanoma.
  • the cancer is lung cancer.
  • the lung cancer is NSCLC i.e., non-small cell lung cancer.
  • the cancer is breast cancer.
  • the caner is melanoma.
  • the present invention provides a method of treating lymphoma, leukemia, or prostate cancer in an individual comprising administering the individual an effective amount of compound of formula (I) or a pharmaceutical acceptable salt, a stereoisomer, a tautomer, an N-oxide or an ester thereof.
  • CBP-mediated diseases or disorders also include an inflammatory diseases, an inflammatory conditions, and autoimmune diseases selected from Addison's disease, acute gout, ankylosing spondylitis, asthma, atherosclerosis, Behcet's disease, bullous skin diseases, chronic obstructive pulmonary disease (COPD), Crohn's disease, dermatitis, eczema, giant cell arteritis, glomerulonephritis, hepatitis, hypophysitis, inflammatory bowel disease, Kawasaki disease, lupus nephritis, multiple sclerosis, myocarditis, myositis, nephritis, organ transplant rejection, osteoarthritis, pancreatitis, pericarditis, Polyarteritis nodosa, pneumonitis, primary biliary cirrhosis, psoriasis, psoriatic arthritis, rheumatoid arthritis, scleritis
  • CBP-mediated disease or disorder is: a) a fibrotic lung disease selected from pulmonary fibrosis, idiopathic pulmonary fibrosis, fibrotic interstitial lung disease, renal fibrosis, interstitial pneumonia, fibrotic variant of non-specific interstitial pneumonia, cystic fibrosis, lung fibrosis, chronic obstructive pulmonary lung disease (COPD), lung cirrhosis and pulmonary arterial hypertension; or b) a cancer selected from acoustic neuroma, acute leukemia, acute myeloid leukemia (AML), acute lymphocytic leukemia, acute myelocytic leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acute T-cell leukemia, basal cell carcinoma, bile duct carcinoma, bladder cancer, brain cancer, breast cancer, bronchogenic pulmonary
  • CBP-mediated diseases or disorders also include AIDS; chronic kidney diseases, including, but are not limited to diabetic nephropathy, hypertensive nephropathy, HIV-associated nephropathy, glomerulonephritis, lupus nephritis, IgA nephropathy, focal segmental glomerulosclerosis, membranous glomerulonephritis, minimal change disease, polycystic kidney disease and tubular interstitial nephritis; acute kidney injury or disease or condition including, but are not limited to ischemia-reperfusion induced, cardiac and major surgery induced, percutaneous coronary intervention induced, radio-contrast agent induced, sepsis induced, pneumonia induced, and drug toxicity induced, obesity, dyslipidemia, hypercholesterolemia, Alzheimer's disease, metabolic syndrome, hepatic steatosis, type II diabetes, insulin resistance and diabetic retinopathy.
  • chronic kidney diseases including, but are not limited to diabetic
  • the compounds of the present disclosure are CBP selective degraders. In some embodiments, the compounds of the present disclosure are CBP selective over p300.
  • optionally substituted alkyl refers to the alkyl that may be substituted as well as the event or circumstance where the alkyl is not substituted.
  • optionally substituted refers to a substituent that may be present as well as the event or circumstance where the substituent is not present.
  • substituted refers to moieties having substituents replacing hydrogen on one or more carbons of the backbone.
  • substitution or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc.
  • substituted is contemplated to include all permissible substituents of organic compounds.
  • the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds.
  • the permissible substituents can be one or more and the same or different for appropriate organic compounds.
  • the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms.
  • Substituents can include any substituents described herein, for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl or an acyl), a thiocarbonyl (such as a thioester, a thioacetate or a thioformate), an alkoxyl, an oxo, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a s
  • alkyl refers to saturated aliphatic groups, including but not limited to C1-C10 straight-chain alkyl groups or C3-C10 branched-chain alkyl groups.
  • the “alkyl” group refers to C1-C6 straight-chain alkyl groups or C3-C6 branched- chain alkyl groups.
  • the “alkyl” group refers to C 1 -C 4 straight-chain alkyl groups or C3-C8 branched-chain alkyl groups.
  • alkyl include, but are not limited to, methyl, ethyl, 1-propyl, 2-propyl, n-butyl, sec-butyl, tert-butyl, 1-pentyl, 2-pentyl, 3-pentyl, neo-pentyl, 1-hexyl, 2-hexyl, 3-hexyl, 1-heptyl, 2-heptyl, 3-heptyl, 4-heptyl, 1-octyl, 2-octyl, 3-octyl and 4-octyl.
  • alkylenyl refers to a divalent alkyl group, wherein the “alkyl” group is as defined above.
  • alkylenyl include, but are not limited to, - CH 2 -, -CH 2 CH 2 -, -CH(CH 3 )CH 2 -, -CH 2 CH 2 CH 2 CH 2 -, -CH(CH 3 )CH 2 CH 2 CH 2 - and - CH2CH(CH3)CH2CH2-.
  • acyl refers to –C(O)-R wherein R is alkyl group as defined above.
  • acyl contains (C 1 -C 6 )alkyl and preferably (C 1 -C 4 )alkyl.
  • exemplary acyl groups include, but not limited to acetyl, propanoyl, 2-methylpropanoyl, t-butylacetyl and butanoyl.
  • ester refers to -C(O)OR, wherein R is alkyl group as defined above.
  • an ester contains (C 1 -C 6 )alkyl and preferably (C 1 -C 4 )alkyl.
  • ester groups include, but not limited to, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, tert-butoxy carbonyl and pentoxycarbonyl.
  • alkenyl refers to an alkyl group having one or more double carbon- carbon bonds. Alkenyl groups include, but are not limited to, ethenyl, propenyl, cyclohexenyl, 1-propenyl, 2-propenyl (allyl), iso-propenyl, 2-methyl-l-propenyl, 1-butenyl, and 2- butenyl.
  • Alkenyl groups may be unsubstituted or substituted by one or more suitable substituents, as defined above.
  • alkenylenyl refers to a divalent “alkenyl” as defined above.
  • An “alkenylenyl” group may be substituted or unsubstituted with one or more substituents as described herein.
  • alkynyl refers to an alkyl group as described above having at least one carbon-carbon triple bond and is intended to include both “unsubstituted alkynyls” and “substituted alkynyls”, the latter of which refers to alkynyl moieties having substituents replacing a hydrogen on one or more carbons of the alkynyl group. Such substituents may occur on one or more carbons that are included or not included in one or more triple bonds. Moreover, such substituents include all those contemplated for alkyl groups, as discussed above, except where stability is prohibitive.
  • alkynyl groups substitution of alkynyl groups by one or more alkyl, carbocyclyl, aryl, heterocyclyl, or heteroaryl groups is contemplated.
  • Alkynylenyl groups may be unsubstituted or substituted by one or more suitable substituents, as defined above.
  • the “alkynyl” group refers to C 2 -C 6 alkynyl.
  • Examples of “alkynyl” includes, but not limited to ethynyl, propynyl, butynyl and pentynyl.
  • alkynylenyl refers to a divalent “alkynyl” as defined above.
  • halo or “halogen” alone or in combination with other term(s) means fluorine, chlorine, bromine or iodine.
  • haloalkyl means alkyl substituted with one or more halogen atoms, wherein the halo and alkyl groups are as defined above.
  • halo is used herein interchangeably with the term “halogen” means F, Cl, Br or I.
  • haloalkyl contains (C1-C6)alkyl and preferably (C1-C4)alkyl.
  • haloalkyl examples include, but not limited to, fluoromethyl, difluoromethyl, chloromethyl, trifluoromethyl and 2,2,2- trifluoroethyl.
  • haloalkylenyl refers to a divalent “haloalkyl” as defined above.
  • hydroxy or “hydroxyl” alone or in combination with other term(s) means –OH.
  • cyano refers to –CN; and the term “cyanoalkyl” refers to alkyl substituted with -CN; wherein the alkyl groups are as defined above.
  • alkoxy alone or in combination with other term(s), refers to the group alkyl-O- or –O-alkyl, where alkyl groups are as defined above.
  • alkoxy- groups include but are not limited to methoxy, ethoxy, n-propoxy, n-butoxy, t-butoxy and the like.
  • An alkoxy group can be unsubstituted or substituted with one or more suitable groups.
  • amino refers to a primary amine (–NH 2 ), secondary amine ( , wherein ‘N’ is substituted with two substituents other than hydrogen) or tertiary amine ( ,wherein ‘N’ is substituted with three substituents other than hydrogen) group.
  • amino refers to –CONH 2 group.
  • cycloalkyl alone or in combination with other term(s) means (C 3 -C 12 ) saturated cyclic hydrocarbon ring.
  • a cycloalkyl may be a single ring, which typically contains from 3 to 7 carbon ring atoms.
  • single ring cycloalkyls include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • a cycloalkyl may alternatively be polycyclic or contain more than one ring.
  • polycyclic cycloalkyls include bridged, fused and spirocyclic carbocyclyls.
  • cycloalkyl refers to (C3-C7)cycloalkyl.
  • the term “cycloalkylenyl” or “cycloalkylene” refers to a divalent cycloalkyl group as defined above.
  • cycloalkylenyl or “cycloalkylene” is typically a divalent cycloalkyl that connects one part of a molecule to another.
  • “carbocycle” or “carbocyclyl” used alone or as part of a larger moiety refer to a radical of a saturated or partially unsaturated cyclic aliphatic monocyclic or bicyclic ring system, as described herein, having the specified number of carbons.
  • Exemplary carbocyclyls have from 3 to 18 carbon atoms, for example 3 to 12 carbon atoms, wherein the aliphatic ring system is optionally substituted as defined and described herein.
  • Bicyclic carbocycles having 7 to 12 atoms can be arranged, for example, as a bicyclo [4,5], [5,5], [5,6], or [6,6] system, and bicyclic carbocycles having 9 or 10 ring atoms can be arranged as a bicyclo [5, 6] or [6, 6] system, or as bridged systems such as bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane and bicyclo[3.2.2]nonane.
  • the aliphatic ring system is optionally substituted as defined and described herein.
  • monocyclic carbocycles include, but are not limited to, cycloalkyls and cycloalkenyls, such as cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, l- cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, and the like.
  • cycloalkyls and cycloalkenyls such as cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-eny
  • Carbocyclyl or “carbocycle,” also includes aliphatic rings that are fused to one or more aromatic or nonaromatic rings, such as decahydronaphthyl, tetrahydronaphthyl, decalin, or bicyclo[2.2.2]octane.
  • the term “combination,” “combined,” and related terms refers to the simultaneous or sequential administration of therapeutic agents in accordance with this invention. For example, a compound of the present invention may be administered with another therapeutic agent simultaneously or sequentially in separate unit dosage forms or together in a single unit dosage form.
  • the present invention provides a single unit dosage form comprising a compound of formula (I), an additional therapeutic agent, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
  • heterocycloalkyl refers to a non-aromatic, saturated or partially saturated, or bridged bicyclic, or spirocyclic, or monocyclic or polycyclic ring system of 3 to 15 member, unless the ring size is specifically mentioned, having at least one heteroatom or hetero-group selected from O, N, NH, -S(O)-, -S(O) 2 and S with the remaining ring atoms being independently selected from the group consisting of carbon, oxygen, nitrogen and sulfur.
  • heterocycloalkyl refers to 5- to 12-membered ring.
  • “heterocycloalkyl” refers to 5- to 6-membered ring selected from the group consisting of imidazolidinyl, pyrrolidinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, 1,4-dioxanyl and N-oxides thereof.
  • heteroaryl refers to an aromatic heterocyclic ring system containing, unless the ring size is specifically mentioned, 5 to 20 ring atoms, suitably 5 to 10 ring atoms, which may be a single ring (monocyclic) or multiple rings (bicyclic, tricyclic or polycyclic) fused together or linked covalently.
  • “heteroaryl” is a 5- to 6-membered ring.
  • the rings may contain from 1 to 4 heteroatoms selected from N, O and S, wherein the N or S atom is optionally oxidized or the N atom is optionally quarternized. Any suitable ring position of the heteroaryl moiety may be covalently linked to the defined chemical structure.
  • heteroaryl examples include, but are not limited to: furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, cinnolinyl, isoxazolyl, thiazolyl, isothiazolyl, 1H-tetrazolyl, oxadiazolyl, triazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzofuranyl, benzothienyl, benzotriazinyl, phthalazinyl, thianthrene, dibenzofuranyl, dibenzothienyl, benzimidazolyl, indolyl, isoindolyl, indazolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalin
  • heteroaryl refers to 5- to 6-membered ring selected from the group consisting of furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, cinnolinyl, isoxazolyl, thiazolyl, isothiazolyl, 1H-tetrazolyl, oxadiazolyl, triazolyl, pyridyl, pyrimidinyl, pyrazinyl and pyridazinyl. More preferably, pyrazolyl, pyridyl, oxazolyl and furanyl.
  • heteroaryls are optionally substituted by one or more aforesaid groups.
  • heteroaryl for e.g., pyridine or pyridyl
  • oxo to form a respective pyridine-N-oxide or pyridyl-N-oxide.
  • aryl is optionally substituted monocyclic, bicyclic or polycyclic aromatic hydrocarbon ring system of about 6 to 14 carbon atoms. In one embodiment, “aryl” refers to C 6 -C 10 aryl group.
  • composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • the amount of the compound of formula (I) or pharmaceutically acceptable salt thereof in the pharmaceutical composition(s) can range from about 1 mg to about 1000 mg or from about 2.5 mg to about 500 mg or from about 5 mg to about 250 mg or in any range falling within the broader range of 1 mg to 1000 mg or higher or lower than the afore mentioned range.
  • stereoisomers refers to any enantiomers, diastereoisomers, or geometrical isomers of the compounds of Formula (I), (IA), (IB), (IC), (ID), (IE) and (IF) wherever they are chiral or when they bear one or more double bonds.
  • Individual stereoisomers of compounds can be prepared synthetically from commercially available starting materials which contain chiral centers or by preparation of mixtures of enantiomeric products followed by separation such as conversion to a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques, direct separation of enantiomers on chiral chromatographic columns, or any other appropriate method known in the art.
  • Starting compounds of particular stereochemistry are either commercially available or can be made and resolved by techniques known in the art.
  • the compounds of the present disclosure may exist as geometric isomers. The present disclosure includes all cis, trans, syn, anti, R and S,
  • Mechanism (E) and Z) isomers as well as the appropriate mixtures thereof.
  • tautomer refers to compounds in which hydrogen atoms are transposed to other parts of the molecules and the chemical bonds between the atoms of the molecules are consequently rearranged.
  • Compounds of the present invention, free form and salts thereof, may exist in multiple tautomeric forms. It is understood that all tautomeric forms, insofar as they may exist, are included within the invention.
  • pyridine or pyridyl can be optionally substituted by oxo to form a respective pyridone or pyridon-yl and may include its tautomeric form such as a respective hydroxy-pyridine or hydroxy-pyridyl, provided said tautomeric form may be obtainable.
  • the term “treat”, “treating” and “treatment” refer to a method of alleviating or abrogating a disease and/or its attendant symptoms.
  • the term “prevent”, “preventing” and “prevention” refer to a method of preventing the onset of a disease and/or its attendant symptoms or barring a subject from acquiring a disease.
  • the term “subject” refers to an animal, preferably a mammal and most preferably a human.
  • terapéuticaally effective amount refers to an amount of a compound of formula (I), a pharmaceutically acceptable salt or a stereoisomer thereof; or a composition comprising the compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer thereof, effective in producing the desired therapeutic or pharmacological response in a particular subject suffering from a disease or disorder mediated by CBP bromodomain.
  • the term “therapeutically effective amount” includes the amount of the compound of formula (I), a pharmaceutically acceptable salt or a stereoisomer thereof, when administered, that elicits a positive modification or alteration in the disease or disorder to be treated or is sufficient to effectively prevent development of or alleviate to some extent, one or more of the symptoms associated with the disease or disorder being treated in a subject.
  • the amount of the compound used for the treatment of a subject is low enough to avoid undue or severe side effects, within the scope of sound medical judgment can also be considered.
  • the therapeutically effective amount of the compound or composition will be varied depending upon factors such as the condition of the subject being treated, the severity of the condition being treated or prevented, the duration of the treatment, the nature of concurrent therapy, the age and physical condition of the end user, the specific compound or composition employed the particular pharmaceutically acceptable carrier utilized.
  • “Pharmaceutically acceptable” means that, which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable and includes that which is acceptable for veterinary as well as human pharmaceutical use.
  • pharmaceutically acceptable excipient/carrier refers to pharmaceutically substances such as a liquid or solid filler, diluent, solvent, or encapsulating material.
  • compositions or formulations are generally safe, non-toxic and neither biologically nor otherwise undesirable, including those which are acceptable for human pharmaceutical use as well as veterinary use. See, e.g., Remington: The Science and Practice of Pharmacy, 23rd Ed. (Academic Press, 2020); Handbook of Pharmaceutical Excipients, 9th ed., Sheskey et al, Eds. (Pharmaceutical Press; 2020); Handbook of Pharmaceutical Additives, 3rd ed.; Ash and Ash Eds. ; Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, 2nd ed.
  • pharmaceutically acceptable salt(s) refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form.
  • pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
  • the pharmaceutically acceptable salts of the present disclosure include non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
  • the pharmaceutically acceptable salts of the present disclosure can be synthesized from the parent compound which contains a basic or acidic moiety by various chemical methods.
  • such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two.
  • the present invention also provides methods for formulating the disclosed compounds as for pharmaceutical administration.
  • the aqueous solution is pyrogen-free or substantially pyrogen-free.
  • the excipients can be chosen, for example, to effect delayed release of an agent or to selectively target one or more cells, tissues organs.
  • the pharmaceutical composition can be in dosage unit form such as tablet, capsule (including sprinkle capsule and gelatin capsule), granule, lyophile for reconstitution, powder, solution, syrup, suppository, injection or the like.
  • the composition can also be present in a transdermal delivery system, e.g., a skin patch.
  • the composition can also be present in a solution suitable for topical administration, such as an eye drop.
  • present invention provides a pharmaceutical composition comprising the compound of formula (I) and a pharmaceutically acceptable salt thereof.
  • Pharmaceutical composition and use thereof The compounds of the present invention may be used as single drug or as a pharmaceutical composition in which the compound is mixed with various pharmacologically acceptable materials.
  • the compounds of the invention are typically administered in the form of a pharmaceutical composition.
  • compositions can be prepared using procedures well known in the pharmaceutical art and comprise at least one compound of this invention.
  • the pharmaceutical composition of the present patent application comprises one or more compounds described herein and one or more pharmaceutically acceptable excipients.
  • the pharmaceutically acceptable excipients are approved by regulatory authorities or are generally regarded as safe for human or animal use.
  • the pharmaceutically acceptable excipients include, but are not limited to, carriers, diluents, glidants and lubricants, preservatives, buffering agents, chelating agents, polymers, gelling agents, viscosifying agents and solvents.
  • the pharmaceutical composition can be administered by oral, parenteral or inhalation routes.
  • parenteral administration examples include administration by injection, percutaneous, transmucosal, trans-nasal and transpulmonary administrations.
  • suitable carriers include, but are not limited to, water, salt solutions, alcohols, polyethylene glycols, peanut oil, olive oil, gelatin, lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugar, amylose, magnesium stearate, talc, agar, pectin, acacia, stearic acid, lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, fatty acid esters and polyoxyethylene.
  • the pharmaceutical composition may also include one or more pharmaceutically acceptable auxiliary agents, wetting agents, suspending agents, preserving agents, buffers, sweetening agents, flavouring agents, colorants or any combination of the foregoing.
  • the pharmaceutical compositions may be in conventional forms, for example, tablets, capsules, solutions, suspensions, injectables or products for topical application. Further, the pharmaceutical composition of the present invention may be formulated so as to provide desired release profile. Administration of the compounds of the invention, in pure form or in an appropriate pharmaceutical composition, can be carried out using any of the accepted routes of administration of pharmaceutical compositions.
  • the route of administration may be any route which effectively transports the active compound of the patent application to the appropriate or desired site of action.
  • Suitable routes of administration include, but are not limited to oral, nasal, buccal, dermal, intradermal, transdermal, parenteral, rectal, subcutaneous, intravenous, intraurethral, intramuscular or topical.
  • Solid oral formulations include, but are not limited to, tablets, capsules (soft or hard gelatin), dragees (containing the active ingredient in powder or pellet form), troches and lozenges.
  • Liquid formulations include, but are not limited to, syrups, emulsions and sterile injectable liquids, such as suspensions or solutions.
  • Topical dosage forms of the compounds include ointments, pastes, creams, lotions, powders, solutions, eye or ear drops, impregnated dressings and may contain appropriate conventional additives such as preservatives, solvents to assist drug penetration.
  • the pharmaceutical compositions of the present patent application may be prepared by conventional techniques known in literature.
  • the present invention provides a pharmaceutical composition comprising a compound of formula (I), (IA), (IB), (IC), (ID), (IE) and (IF) or a pharmaceutically acceptable salt or a stereoisomer thereof and at least one pharmaceutically acceptable carrier or excipient.
  • the present invention provides a composition comprising a compound of the disclosure and an excipient and/or pharmaceutically acceptable carrier for treating diseases or conditions or disorders that are dependent upon CBP signalling pathway.
  • the present invention provides a compound of formula (I), (IA), (IB), (IC), (ID), (IE) and (IF) or a pharmaceutically acceptable salt or a stereoisomer thereof for use as a medicament.
  • the present invention provides a compound of formula (I), (IA), (IB), (IC), (ID), (IE) and (IF) or a pharmaceutically acceptable salt or a stereoisomer thereof for use in the treatment of cancer.
  • the present invention provides a compound of formula (I), (IA), (IB), (IC), (ID), (IE) and (IF) or a pharmaceutically acceptable salt or a stereoisomer thereof for use in degrading the target protein in a subject, wherein the target protein is CBP.
  • the present invention provides a compound of formula (I), (IA), (IB), (IC), (ID), (IE) and (IF) or a pharmaceutically acceptable salt or a stereoisomer thereof for use in the treatment of CBP-mediated disorder.
  • CBP-mediated disease or disorder is: a) a fibrotic lung disease selected from pulmonary fibrosis, idiopathic pulmonary fibrosis, fibrotic interstitial lung disease, renal fibrosis, interstitial pneumonia, fibrotic variant of non-specific interstitial pneumonia, cystic fibrosis, lung fibrosis, chronic obstructive pulmonary lung disease (COPD), lung cirrhosis and pulmonary arterial hypertension; or b) a cancer selected from acoustic neuroma, acute leukemia, acute myeloid leukemia (AML),acute lymphocytic leukemia, acute myelocytic leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acute T-cell leukemia, basal cell carcinoma bile duct carcinoma, bladder cancer, brain cancer, breast cancer, bronchogenic pulmonary
  • the CBP-mediated disease or disorder is: a) a fibrotic lung disease selected from pulmonary fibrosis, idiopathic pulmonary fibrosis, fibrotic interstitial lung disease, renal fibrosis, interstitial pneumonia, fibrotic variant of non- specific interstitial pneumonia, cystic fibrosis, lung fibrosis, chronic obstructive pulmonary lung disease (COPD), lung cirrhosis and pulmonary arterial hypertension; or b) a cancer selected from acoustic neuroma, acute leukemia, acute myeloid leukemia (AML), acute lymphocytic leukemia, acute myelocytic leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acute T-cell leukemia, basal cell carcinoma, bile duct carcinoma, bladder cancer, brain cancer, breast cancer, bronch
  • Suitable doses of the compounds for use in treating the diseases or disorders described herein can be determined by those skilled in the relevant art.
  • Therapeutic doses are generally identified through a dose ranging study in humans based on preliminary evidence derived from the animal studies. Doses must be sufficient to result in a desired therapeutic benefit without causing unwanted side effects. Mode of administration, dosage forms and suitable pharmaceutical excipients can also be well used and adjusted by those skilled in the art. All changes and modifications are envisioned within the scope of the present patent application.
  • the compounds of the present invention can also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds.
  • the present invention also embraces isotopically-labeled variants of the present invention which are identical to those recited herein, but for the fact that one or more atoms of the compound are replaced by an atom having the atomic mass or mass number different from the predominant atomic mass or mass number usually found in nature for the atom. All isotopes of any particular atom or element as specified are contemplated within the scope of the compounds of the invention and their uses.
  • Exemplary isotopes that can be incorporated in to compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, chlorine and iodine, such as 2 H (“D”), 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 32 P, 33 P, 35 S, 18 F, 36 Cl, 123 I and 125 I.
  • Isotopically labeled compounds of the present inventions can generally be prepared by following procedures analogous to those disclosed in the schemes and/or in the examples herein below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
  • EXPERIMENTAL provides methods for the preparation of compound of formula (I) according to the description provided herein using appropriate methods and/or materials. It is to be understood by those skilled in the art that known variations of the conditions and processes of the following procedures can be used to prepare these intermediates and compounds. Moreover, by utilizing the procedures described in detail, one of ordinary skill in the art can prepare additional compounds of the present disclosure. Following general guidelines apply to all experimental procedures described here. Until otherwise stated, experiments are performed under positive pressure of nitrogen, temperature described are the external temperature (i.e. oil bath temperature). Reagents and solvents received from vendors are used as such without any further drying or purification. Molarities mentioned here for reagents in solutions are approximate as it was not verified by a prior titration with a standard.
  • the intermediate GS-1 was reacted with GS-1A in presence of suitable reagents and solvents (Na(OAc) 3 BH, AcOH, DMSO-THF) to afford a compound of formula (I).
  • suitable reagents and solvents Na(OAc) 3 BH, AcOH, DMSO-THF
  • General Scheme-2 Some compounds of the present invention may be generally synthesized utilizing the process outlined in General Scheme-2.
  • the intermediate GS-1 was reacted with GS-1B in the presence of suitable reagents and solvents (DIPEA, DMSO, CS 2 CO 3 , PEPPSI-IHept-Cl) to afford a compound of formula (I).
  • Step-2 Synthesis of 5-(7-cyano-4-methyl-3,4-dihydroquinoxalin-1(2H)-yl)-1,3-dimethyl- 2-oxo-1,2-dihydroquinolin-7-yl trifluoromethanesulfonate
  • a solution of Intermediate 1a (8 g, 22.19 mmol) in DCM (300 mL) was cooled to 0 ° C and added TEA (13.91 mL, 99.80 mmol) followed by dropwise addition of trifluoromethanesulfonic anhydride (15.65 g, 55.49 mmol). The reaction mixture was quenched with water after 4 h.
  • Step-1 Synthesis of tert-butyl 4-(5-(7-cyano-4-methyl-3,4-dihydroquinoxalin-1(2H)-yl)- 1,3-dimethyl-2-oxo-1,2-dihydroquinolin-7-yl)-3,6-dihydropyridine-1(2H)-carboxylate
  • Intermediate I-1 5.1 g, 10.35 mmol
  • tert-butyl 4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (4.80 g, 15.53mmol) in DMF (50 mL), was added potassium carbonate (4.29 g, 31.06 mmol), Pd(dppf)Cl2.DCM (1.26 mg, 1.55mmol) and heated to 80 ° C for 16 h.
  • Step-2 Synthesis of tert-butyl 4-(5-(7-cyano-4-methyl-3,4-dihydroquinoxalin-1(2H)-yl)- 1,3-dimethyl-2-oxo-1,2-dihydroquinolin-7-yl)piperidine-1-carboxylate
  • a solution of the Intermediate 2a (3.1 g, 5.89 mmol), was added PtO 2 (0.40 g, 1.76 mmol) in 2:1 ethyl acetate and ethanol mixture (90 mL) and 1 ml of acetic acid.
  • the reaction mixture was stirred under positive pressure of hydrogen in bladder for 24 h. After completion of the reaction, PtO 2 was filtered off and filtrate concentrated to get the crude compound.
  • Step-3 Synthesis of 4-(1,3-dimethyl-2-oxo-7-(piperidin-4-yl)-1,2-dihydroquinolin-5-yl)- 1-methyl-1,2,3,4-tetrahydroquinoxaline-6-carbonitrile
  • TFA 4 mL
  • Step-3 Synthesis of 4-(7-(9-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)-3,9- diazaspiro[5.5]undecan-3-yl)-1,3-dimethyl-2-oxo-1,2-dihydroquinolin-5-yl)-1-methyl- 1,2,3,4-tetrahydroquinoxaline-6-carbonitrile
  • the compound-22 was prepared using a similar procedure described in the synthesis of Intermediate 6c with appropriate variations in coupling method, reactants, quantities of reagents and solvents, and reaction conditions.
  • Table-2 Inter Comp. media Structure Characterization data No tes used 1H NMR (DMSO-D6, 400MHz): ⁇ 10.77 (s, 1H), 7.67 (s, 1H), 7.31 (s, 1H), 7.08-7.04 (m, 2H), 6.7-6.63 (m, 2H), 6.56 (dd, 1H), 6.44 (dd, H4 1H), 5.96 (s, 1H), 5.64 (d, 1H), & 4.35-4.3 (m, 1H), 3.8-3.65 (m, 66 8H), 3.18 (t, 2H), 3.1-2.95 (m, 7H), 2.75-2.7 (m, 1H), 2.65-2.55 (m, 3H), 2.5-2.45 (m, 4H), 2.2-2.05 (m, 6H), 2.05-1.95 (m,
  • Step-2 Synthesis of 4-(7-(1-(2-(1-(2-fluoro-4-nitrophenyl)piperidin-4-yl)ethyl)piperidin- 4-yl)-1,3-dimethyl-2-oxo-1,2-dihydroquinolin-5-yl)-1-methyl-1,2,3,4- tetrahydroquinoxaline-6-carbonitrile
  • the intermediate 23B was prepared using a similar procedure described in the synthesis of Compound-1 with appropriate variations in coupling method, reactants, quantities of reagents and solvents, and reaction conditions.
  • Step-3 Synthesis of 4-(7-(1-(2-(1-(4-amino-2-fluorophenyl)piperidin-4- yl)ethyl)piperidin-4-yl)-1,3-dimethyl-2-oxo-1,2-dihydroquinolin-5-yl)-1-methyl-1,2,3,4- tetrahydroquinoxaline-6-carbonitrile
  • the Intermediate 23C was prepared using a similar procedure described in the synthesis of Intermediate 6b with appropriate variations in coupling method, reactants, quantities of reagents and solvents, and reaction conditions.
  • Step-4 Synthesis of 4-(7-(1-(2-(1-(4-((2,6-dioxopiperidin-3-yl)amino)-2- fluorophenyl)piperidin-4-yl)ethyl)piperidin-4-yl)-1,3-dimethyl-2-oxo-1,2- dihydroquinolin-5-yl)-1-methyl-1,2,3,4-tetrahydroquinoxaline-6-carbonitrile
  • Compound-23 was prepared using a similar procedure described in the synthesis of Intermediate 6c with appropriate variations in coupling method, reactants, quantities of reagents and solvents, and reaction conditions.
  • Example-4 Synthesis of 4-(7-(1-(2-(1-(4-((2,6-dioxopiperidin-3-yl)amino)-2- fluorophenyl)-4-hydroxypiperidin-4-yl)acetyl)piperidin-4-yl)-1,3-dimethyl-2-oxo-1,2- dihydroquinolin-5-yl)-1-methyl-1,2,3,4-tetrahydroquinoxaline-6-carbonitrile (Compound-24) To a stirred solution of the Intermediate I-13 (0.1 g, 0.264 mmol) in DMF (2 mL), was added HATU (0.151 g, 0.39 mmol), DIPEA (0.102g, 0.79 mmol) and stirred at RT for 15 mins.
  • Table-3 Interm Comp ediates Structure Characterization data .
  • Example-5 Synthesis of 4-(7-(1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)piperidin-4-yl)methyl)piperidin-4-yl)-1,3-dimethyl-2-oxo-1,2-dihydroquinolin-5-yl)-1- methyl-1,2,3,4-tetrahydroquinoxaline-6-carbonitrile (Compound-80) A mixture of Intermediate I-23 (0.12 g, 0.229 mmol) and 2-(2,6-dioxopiperidin-3-yl)-4- fluoroisoindoline-1,3-dione (0.095 g, 0.344 mmol), DIPEA (0.089 g, 0.069 mmol) in DMSO (3 mL) was heated to 80 °C for 16 h.
  • DIPEA 0.089 g, 0.069 mmol
  • Example-6 Synthesis of 4-(7-(1-((1-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5- fluoro-1-methyl-1H-indazol-6-yl)-4-hydroxypiperidin-4-yl)methyl)piperidin-4-yl)-1,3- dimethyl-2-oxo-1,2-dihydroquinolin-5-yl)-1-methyl-1,2,3,4-tetrahydroquinoxaline-6- carbonitrile (Compound-81)
  • a solution of Intermediate I-20 0.1 g, 0.185 mmol
  • 1-(5-fluoro-6-iodo-1-methyl-1H-indazol- 3-yl)dihydropyrimidine-2,4(1H,3H)-dione (0.144 g, 0.34 mol) in DMSO (7 mL) was degassed with N 2 and added Cesium carbonate, PEPPSI IHept-Cl
  • Step-2 Synthesis of 4-(7-(1-((1-(1-(26-dioxopiperidin-3-yl)-1H-indazol-5-yl)piperidin-4- yl)methyl)piperidin-4-yl)-1,3-dimethyl-2-oxo-1,2-dihydroquinolin-5-yl)-1-methyl- 1,2,3,4-tetrahydroquinoxaline-6-carbonitrile
  • Compound-83 was prepared using a similar procedure described in the synthesis of I-19e with appropriate variations in coupling method, reactants, quantities of reagents and solvents, and reaction conditions. The crude compound was purified by prep HPLC.
  • Step-3 Synthesis of 4-(7-(1-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2- fluorophenyl)cyclohexyl)methyl)piperidin-4-yl)-1,3-dimethyl-2-oxo-1,2- dihydroquinolin-5-yl)-1-methyl-1,2,3,4-tetrahydroquinoxaline-6-carbonitrile
  • Compound-84 was prepared using a similar procedure described in the synthesis of Intermediate 6c with appropriate variations in coupling method, reactants, quantities of reagents and solvents, and reaction conditions. The crude compound was purified by preparative HPLC.
  • Preparative HPLC conditions Column name KINETEX C18, dimension 250 x 21.2mm, 5 micron; Flow Rate 15 mL per minute.
  • Mobile phase-A was 0.1% Formic acid in Water and B was Acetonitrile.
  • Gradient program 25% B at 0 min, 35% B at 2 nd min, 40% B at 10 th min. This afforded the pure title compound-84 (0.070 g, 14.8%).
  • Step-1 Synthesis of 4-(7-(1-(2-fluoro-4-nitrophenyl)piperidin-4-yl)-1,3-dimethyl-2-oxo- 1,2-dihydroquinolin-5-yl)-1-methyl-1,2,3,4-tetrahydroquinoxaline-6-carbonitrile
  • Intermediate 85A was prepared using a similar procedure described in the synthesis of Intermediate 6a with appropriate variations in coupling method, reactants, quantities of reagents and solvents, and reaction conditions.
  • Step-2 Synthesis of 4-(7-(1-(4-amino-2-fluorophenyl)piperidin-4-yl)-1,3-dimethyl-2-oxo- 1,2-dihydroquinolin-5-yl)-1-methyl-1,2,3,4-tetrahydroquinoxaline-6-carbonitrile
  • Intermediate 85B was prepared using a similar procedure described in the synthesis of 6b with appropriate variations in coupling method, reactants, quantities of reagents and solvents, and reaction conditions.
  • Step-3 Synthesis of 4-(7-(1-(4-((2,6-dioxopiperidin-3-yl)amino)-2- fluorophenyl)piperidin-4-yl)-1,3-dimethyl-2-oxo-1,2-dihydroquinolin-5-yl)-1-methyl- 1,2,3,4-tetrahydroquinoxaline-6-carbonitrile
  • Compound-85 was prepared using a similar procedure described in the synthesis of Intermediate 6c with appropriate variations in coupling method, reactants, quantities of reagents and solvents, and reaction conditions.
  • Exemplary compounds of the present application were screened by the above- mentioned assay and the results were tabulated.
  • the % degradation values for certain exemplary compounds at 0.2 ⁇ M are compiled in the table-5 below.
  • Table-5 % CBP degradation values of exemplary compounds % CBP % CBP Comp. degradation in Comp. degradation in No. HiBiT assay No.
  • GI50 values were determined. Exemplary compounds of the present application were screened by the above-mentioned assay and the results were tabulated. The GI50 values for certain exemplary compounds are compiled in the table-6 below, wherein “A” refers to an GI 50 value less than 0.05 ⁇ M, “B” refers to an GI 50 value in range of 0.05 ⁇ M to 10 ⁇ M (both inclusive) and “C” refers to an GI 50 value greater than 10 ⁇ M.
  • N 1 A 1, 10, 15, 18, 19, 20, 21, 31, 33, 34, 35, 37, 46, 51, 53, 57, 58, 59, 60, 61, 68, 71, 76, 78, 81 and 83; B 4, 11, 13,14, 16, 24, 25, 27, 29, 30, 38, 40, 41, 44, 49, 50, 52, 56, 69, 70, 73, 74, 75, 77, 79, 80 and 84; and C 3, 7, 12, 17, 22, 23, 26, 28, 32, 36, 39, 42, 43, 45, 47, 48, 54, 55, 62, 63, 64, 65, 66, 67, 72 and 85.

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Abstract

La présente invention concerne des composés hétérocycliques de formule (I), qui sont thérapeutiquement utiles en tant qu'agents de dégradation de CBP. Lesdits composés sont utiles dans le traitement et/ou la prévention de maladies ou de troubles médiés par le CBP chez un individu. La présente invention concerne également la préparation des composés et des compositions pharmaceutiques comprenant au moins l'un des composés de formule (I) ou un sel pharmaceutiquement acceptable ou un stéréoisomère de ceux-ci.
PCT/IB2024/059098 2023-09-20 2024-09-19 Composés hétérocycliques utilisés en tant qu'agents de dégradation sélectifs de cbp Pending WO2025062330A1 (fr)

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WO2025202979A1 (fr) * 2024-03-28 2025-10-02 Aurigene Oncology Limited Composés hétérocycliques substitués et leurs dérivés en tant qu'agents de dégradation de cbp et/ou p300
WO2025222125A1 (fr) * 2024-04-19 2025-10-23 Foghorn Therapeutics Inc. Composés et leurs utilisations
US12565492B2 (en) 2024-08-09 2026-03-03 Triana Biomedicines, Inc. Anaplastic Lymphoma Kinase (ALK) degraders and uses thereof

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2025202979A1 (fr) * 2024-03-28 2025-10-02 Aurigene Oncology Limited Composés hétérocycliques substitués et leurs dérivés en tant qu'agents de dégradation de cbp et/ou p300
WO2025202978A1 (fr) * 2024-03-28 2025-10-02 Aurigene Oncology Limited Composés hétérocycliques substitués et leurs dérivés en tant qu'agents de dégradation sélectifs de p300
WO2025222125A1 (fr) * 2024-04-19 2025-10-23 Foghorn Therapeutics Inc. Composés et leurs utilisations
US12565492B2 (en) 2024-08-09 2026-03-03 Triana Biomedicines, Inc. Anaplastic Lymphoma Kinase (ALK) degraders and uses thereof

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