WO2020168148A1 - Composés bicycliques substitués utilisés en tant que modulateurs du récepteur farnésoïde x - Google Patents

Composés bicycliques substitués utilisés en tant que modulateurs du récepteur farnésoïde x Download PDF

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Publication number
WO2020168148A1
WO2020168148A1 PCT/US2020/018210 US2020018210W WO2020168148A1 WO 2020168148 A1 WO2020168148 A1 WO 2020168148A1 US 2020018210 W US2020018210 W US 2020018210W WO 2020168148 A1 WO2020168148 A1 WO 2020168148A1
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WO
WIPO (PCT)
Prior art keywords
methyl
oxadiazol
bicyclo
octan
phenyl
Prior art date
Application number
PCT/US2020/018210
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English (en)
Inventor
Dean A. Wacker
Susheel Jethanand NARA
Srinivas CHERUKU
Kandhasamy SARKUNAM
Firoz Ali JAIPURI
Rishikesh Narayan
Subba Reddy BANDREDDY
Srinivas JOGI
Original Assignee
Bristol-Myers Squibb Company
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to EP20711421.6A priority Critical patent/EP3924337A1/fr
Application filed by Bristol-Myers Squibb Company filed Critical Bristol-Myers Squibb Company
Priority to US17/431,006 priority patent/US20230109670A9/en
Priority to KR1020217029609A priority patent/KR20210130757A/ko
Priority to CN202080028340.9A priority patent/CN113677666A/zh
Priority to CA3129533A priority patent/CA3129533A1/fr
Priority to BR112021015963-0A priority patent/BR112021015963A2/pt
Priority to AU2020221370A priority patent/AU2020221370A1/en
Priority to MX2021009570A priority patent/MX2021009570A/es
Priority to SG11202108796YA priority patent/SG11202108796YA/en
Priority to JP2021547477A priority patent/JP7465883B2/ja
Priority to EA202192263A priority patent/EA202192263A1/ru
Publication of WO2020168148A1 publication Critical patent/WO2020168148A1/fr
Priority to IL285570A priority patent/IL285570A/en

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Classifications

    • 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
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
    • C07D217/06—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with the ring nitrogen atom acylated by carboxylic or carbonic acids, or with sulfur or nitrogen analogues thereof, e.g. carbamates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/06—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • FIG.4 shows the general reaction Scheme 23. DETAILED DESCRIPTION
  • X 1 is CR 5a or N
  • each R 1 is independently hydrogen, halo, cyano, hydroxyl, oxo, C 1-6 alkyl, C 2-6 alkenyl, 5 C 2-6 alkynyl, C 1-6 alkoxy, -NH2, -NH( C 1-6 alkyl), -N( C 1-6 alkyl)2, -C(O)(C 1-6
  • R 2 is C 6-8 carbocyclyl, 6- to 7-membered heterocyclyl, phenyl, or 6-membered heteroaryl, wherein each of said carbocyclyl, heterocyclyl, phenyl, and heteroaryl is substituted 20 with zero to 3 R 2b ;
  • X 1 is CR 5a or N
  • X 2 is CR 5b or N
  • X 3 is CR 5c or N
  • X 4 is CR 5d or N; provided that zero or 1 of X 1 , X 2 , X 3 , and X 4 is N.
  • X 1 is CR 5a
  • X 2 is CR 5b
  • X 3 is CR 5c
  • X 4 is CR 5d .
  • One embodiment provides a compound of Formula (I) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt or solvate thereof, wherein each R 1 is independently each R 1 is independently F, Cl, Br, cyano, hydroxyl, oxo, -NR x R x , C 1 ⁇ 5 alkyl, C 1-4 alkoxy, -NR x ( C 1-4 alkyl), -NR x C(O)R y , ⁇ C(O)(C 1-4 alkyl), -C(O)OR x , -C(O)NR w R w , -S(O) 2 ( C 1-4 alkyl), -S(O) 2 ( C 3 -6 cycloalkyl), -NR x S(O) 2 (C 1-4 alkyl), -NR x S(O) 2 (C 3 -6 cycloalkyl), -S(O) 2 NR z R z , -
  • One embodiment provides a compound of Formula (I) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt or solvate thereof, wherein R 3a and R 3b are independently hydrogen, C1 ⁇ 3 alkyl, C1 ⁇ 3 fluoroalkyl, or C3 ⁇ 6 cycloalkyl, or R 3a and R 3b , taken together with the carbon atom to which they are attached, form a C3 ⁇ 6 cycloalkyl. Included in this embodiment are compounds in which R 3a and R 3b are independently hydrogen, C1 ⁇ 2 alkyl, C1 ⁇ 2 fluoroalkyl, or C3 ⁇ 6 cycloalkyl.
  • alkoxy refers to an alkyl group attached to the parent molecular moiety through an oxygen atom, for example, methoxy group (-OCH 3 ).
  • methoxy group for example, “C1 ⁇ 3 alkoxy” denotes alkoxy groups with one to three carbon atoms.
  • aryl refers to a group of atoms derived from a molecule containing aromatic ring(s) by removing one hydrogen that is bonded to the aromatic ring(s).
  • Representative examples of aryl groups include, but are not limited to, phenyl and naphthyl.
  • the aryl ring may be unsubstituted or may contain one or more
  • Exemplary monocyclic heterocyclyl groups include pyrrolidinyl, imidazolinyl, oxazolidinyl, isoxazolinyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, 4-piperidonyl, tetrahydropyranyl, morpholinyl, thiamorpholinyl,
  • Exemplary bicyclic heteroaryl groups include indolyl, benzothiazolyl,
  • phrases“pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • the compounds of the present invention are intended to include all isotopes of atoms occurring in the present compounds.
  • Isotopes include those atoms having the same atomic number but different mass numbers.
  • isotopes of hydrogen include deuterium (D) and tritium (T).
  • Isotopes of carbon include 13 C and 14 C.
  • Isotopically-labeled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate isotopically-labeled reagent in place of the non-labeled reagent otherwise employed.
  • the present invention provides a method for the treatment of a fibrotic disorder, an inflammatory disorder, or a cell-proliferative disorder, comprising administering to a patient in need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention, alone, or, optionally, in combination with another compound of the present invention and/or at least one other type of therapeutic agent.
  • ASK-1 inhibitors e.g., ASK-1 inhibitors, CCR2/5 antagonists, autotaxin inhibitors, LPA1 receptor antagonists or other pharmaceutically active material.
  • other therapeutic agent(s) e.g., ASK-1 inhibitors, CCR2/5 antagonists, autotaxin inhibitors, LPA1 receptor antagonists or other pharmaceutically active material.
  • These coupling reactions can be carried out in presence of metal catalyst (for example, CuBr, Pd(OAc)2, Pd2(dba)3, Pd(PPh3)4, Pd(PPh3)2Cl2, and Pd(dppf)Cl2) and appropriate ligand (including but not limited to ligands such as proline, 1,10- phenanthroline, tricyclohexylphosphine, and dppf) when required.
  • metal catalyst for example, CuBr, Pd(OAc)2, Pd2(dba)3, Pd(PPh3)4, Pd(PPh3)2Cl2, and Pd(dppf)Cl
  • appropriate ligand including but not limited to ligands such as proline, 1,10- phenanthroline, tricyclohexylphosphine, and dppf
  • the Ullmann and Buchwald coupling reactions of intermediate 31b can be carried out with various coupling partners such as heterocyclyl or heteroaryl amines.
  • Scheme 20 describes synthesis of compounds of formula I(e-g) (where‘A’ is amide, sulfonamide, urea or carbamate).
  • Intermediate 25 can be converted to intermediate 73 via Curtius rearrangement (as described in Shioiri, T. et al. J. Am. Chem. Soc.1972, 94, 6203–6205).
  • Intermediate 73 can be subjected to reduction in presence of hydride based reducing agent (e.g. LAH, DIBAL-H, and NaBH4) to afford intermediate 74.
  • the intermediate 74 can be oxidized to aldehyde 75, by methodologies recognized by one skilled in the art using oxidation conditions (e.g.
  • intermediates 103-106 can be carried out with various coupling partners such as heterocyclyl and heteroaryl amines.
  • Intermediates 103-106 can be subjected to Suzuki and Stille cross couplings with coupling partners such as cycloalkyl or alkenyl or aryl or heteroaryl boronic acids, boronic acid esters, and organotin reagents.
  • the coupling reactions can be carried out in presence of base as necessary (including but not limited to Na2CO3, K2CO3, NaHCO3, K3PO4, and NaOtBu) and solvent (e.g.
  • Tetrakis(triphenylphosphine) palladium(0) (0.154 g, 0.134 mmol) was added and the reaction mixture was stirred at 110 °C overnight.
  • the reaction mixture was cooled to room temperature, diluted with water (20 mL) and extracted with EtOAc (3x10 mL). The organic layers were combined, washed with brine solution (10 mL), dried over anhydrous sodium sulphate and concentrated under reduced pressure.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

L'invention concerne des composés de formule (I) : ou un stéréoisomère, un tautomère, ou un de leurs sels ou solvates, où Q représente un alcényle en C2 à C6 ou un alcynyle en C2 à C6<sb /> <sb />, chacun étant substitué par zéro à 2 R1; et les autres variables étant telles que définies dans la description. Ces composés modulent l'activité du récepteur farnésoïde X (FXR), par exemple, en tant qu'agonistes. La présente invention concerne également des compositions pharmaceutiques comprenant ces composés et des méthodes de traitement d'une maladie, d'un trouble ou d'un état associé à un dérèglement de FXR, tels que la fibrose pathologique, le rejet de greffe, le cancer, l'ostéoporose et des troubles inflammatoires, à l'aide des composés et des compositions pharmaceutiques.
PCT/US2020/018210 2019-02-15 2020-02-14 Composés bicycliques substitués utilisés en tant que modulateurs du récepteur farnésoïde x WO2020168148A1 (fr)

Priority Applications (12)

Application Number Priority Date Filing Date Title
BR112021015963-0A BR112021015963A2 (pt) 2019-02-15 2020-02-14 Compostos bicíclicos substituídos como moduladores do receptor de farnesoide x
US17/431,006 US20230109670A9 (en) 2019-02-15 2020-02-14 Substituted bicyclic compounds as farnesoid x receptor modulators
KR1020217029609A KR20210130757A (ko) 2019-02-15 2020-02-14 파르네소이드 x 수용체 조정제로서의 치환된 비시클릭 화합물
CN202080028340.9A CN113677666A (zh) 2019-02-15 2020-02-14 作为类法尼醇x受体调节剂的经取代的双环化合物
CA3129533A CA3129533A1 (fr) 2019-02-15 2020-02-14 Composes bicycliques substitues utilises en tant que modulateurs du recepteur farnesoide x
EP20711421.6A EP3924337A1 (fr) 2019-02-15 2020-02-14 Composés bicycliques substitués utilisés en tant que modulateurs du récepteur farnésoïde x
AU2020221370A AU2020221370A1 (en) 2019-02-15 2020-02-14 Substituted bicyclic compounds as farnesoid x receptor modulators
JP2021547477A JP7465883B2 (ja) 2019-02-15 2020-02-14 ファルネソイドｘ受容体モジュレータとしての置換二環式化合物
SG11202108796YA SG11202108796YA (en) 2019-02-15 2020-02-14 Substituted bicyclic compounds as farnesoid x receptor modulators
MX2021009570A MX2021009570A (es) 2019-02-15 2020-02-14 Compuestos biciclicos sustituidos como moduladores del receptor de farnesoide x.
EA202192263A EA202192263A1 (ru) 2019-02-15 2020-02-14 Замещенные бициклические соединения в качестве регуляторов фарнезоидного х-рецептора
IL285570A IL285570A (en) 2019-02-15 2021-08-12 Bicyclic compounds substituted as farnesoid receptor modulators

Applications Claiming Priority (2)

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US201962806402P 2019-02-15 2019-02-15
US62/806,402 2019-02-15

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AU (1) AU2020221370A1 (fr)
BR (1) BR112021015963A2 (fr)
CA (1) CA3129533A1 (fr)
EA (1) EA202192263A1 (fr)
MX (1) MX2021009570A (fr)
SG (1) SG11202108796YA (fr)
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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021144330A1 (fr) 2020-01-15 2021-07-22 INSERM (Institut National de la Santé et de la Recherche Médicale) Utilisation d'agonistes de fxr pour traiter une infection par le virus de l'hépatite d
WO2022152770A1 (fr) 2021-01-14 2022-07-21 Enyo Pharma Effet synergique d'un agoniste de fxr et d'ifn pour le traitement d'une infection par le virus de l'hépatite b
WO2022229302A1 (fr) 2021-04-28 2022-11-03 Enyo Pharma Potentialisation forte d'effets d'agonistes de tlr3 à l'aide d'agonistes de fxr en tant que traitement combiné
CN115340536A (zh) * 2021-05-13 2022-11-15 华东理工大学 含1,2,4-恶二唑的酰胺类化合物及其盐、制备方法和用途

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021144330A1 (fr) 2020-01-15 2021-07-22 INSERM (Institut National de la Santé et de la Recherche Médicale) Utilisation d'agonistes de fxr pour traiter une infection par le virus de l'hépatite d
WO2022152770A1 (fr) 2021-01-14 2022-07-21 Enyo Pharma Effet synergique d'un agoniste de fxr et d'ifn pour le traitement d'une infection par le virus de l'hépatite b
WO2022229302A1 (fr) 2021-04-28 2022-11-03 Enyo Pharma Potentialisation forte d'effets d'agonistes de tlr3 à l'aide d'agonistes de fxr en tant que traitement combiné
CN115340536A (zh) * 2021-05-13 2022-11-15 华东理工大学 含1,2,4-恶二唑的酰胺类化合物及其盐、制备方法和用途

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CA3129533A1 (fr) 2020-08-20
AU2020221370A1 (en) 2021-10-07
MX2021009570A (es) 2021-09-08
SG11202108796YA (en) 2021-09-29
EA202192263A1 (ru) 2022-01-27
BR112021015963A2 (pt) 2021-10-05

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