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WO2023224963A1 - Antagonistes du récepteur de l'endothéline et de l'angiotensine à double action - Google Patents

Antagonistes du récepteur de l'endothéline et de l'angiotensine à double action Download PDF

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Publication number
WO2023224963A1
WO2023224963A1 PCT/US2023/022342 US2023022342W WO2023224963A1 WO 2023224963 A1 WO2023224963 A1 WO 2023224963A1 US 2023022342 W US2023022342 W US 2023022342W WO 2023224963 A1 WO2023224963 A1 WO 2023224963A1
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alkyl
cycloalkyl
compound
optionally substituted
aryl
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Inventor
Anjali Pandey
Naresh Kumar
Nadim SHAIKH
Somesh Sharma
Kiran BOPPANA
Sundara Raghuram TANGIRALA
Laxmikant Shamlal Datrange
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Aria Pharmaceuticals Inc
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Aria Pharmaceuticals Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • 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
    • 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
    • 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

  • Idiopathic pulmonary fibrosis is a chronic, progressive, fibrotic interstitial lung disease of unknown cause. IPF affects the lung interstitium, the tissue residing between the alveoli which is dense with capillaries in order to facilitate gas exchange during respiration.
  • t, R 1 , and each R 2 are independently as described in the detailed description.
  • the compounds are useful in treating idiopathic pulmonary fibrosis (IPF), and other diseases amenable to treatment with dual-acting angiotensin and endothelin receptor antagonist (DARA).
  • IPF idiopathic pulmonary fibrosis
  • DARA dual-acting angiotensin and endothelin receptor antagonist
  • R 1 , R 2 , X, Ring B, and Ring C are as described in the detailed description.
  • the compounds are useful in treating idiopathic pulmonary fibrosis (IPF), and other diseases amenable to treatment with dual- acting angiotensin and endothelin receptor antagonists (DARAs).
  • a pharmaceutical composition comprising a compound disclosed herein (e.g., of formula A-I or B-I), or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, and a pharmaceutically acceptable excipient.
  • a therapeutically effective amount of a compound disclosed herein e.g., of formula A-I or B-I
  • a pharmaceutically acceptable salt e.g., isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, or a composition described herein, to a patient in need thereof.
  • a dash (“ ” that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, -C(O)NH2 is attached through the carbon atom.
  • a dash at the front or end of a chemical group is a matter of convenience; chemical groups may be depicted with or without one or more dashes without losing their ordinary meaning.
  • a wavy line or a dashed line drawn through a line in a structure indicates a specified point of attachment of a group. Unless chemically or structurally required, no directionality or stereochemistry is indicated or implied by the order in which a chemical group is written or named.
  • the prefix “C u-v ” indicates that the following group has from u to v carbon atoms.
  • C 1-6 alkyl indicates that the alkyl group has from 1 to 6 carbon atoms.
  • Reference to “about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se.
  • the term “about” includes the indicated amount ⁇ 10%.
  • the term “about” includes the indicated amount ⁇ 5%.
  • the term “about” includes the indicated amount ⁇ 1%.
  • to the term “about X” includes description of “X”.
  • the singular forms “a” and “the” include plural references unless the context clearly dictates otherwise.
  • alkyl refers to an unbranched or branched saturated hydrocarbon chain. As used herein, alkyl has 1 to 20 carbon atoms (i.e., C 1-20 alkyl), 1 to 12 carbon atoms (i.e., C 1-12 alkyl), 1 to 8 carbon atoms (i.e., C 1-8 alkyl), 1 to 6 carbon atoms (i.e., C 1-6 alkyl), or 1 to 4 carbon atoms (i.e., C1-4 alkyl).
  • alkyl groups include, e.g., methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl.
  • butyl includes n-butyl (i.e., -(CH 2 ) 3 CH 3 ), sec-butyl (i.e., -CH(CH 3 )CH 2 CH 3 ), isobutyl (i.e., -CH 2 CH(CH 3 ) 2 ), tert-butyl (i.e., -C(CH 3 ) 3 ), and “propyl” includes n-propyl (i.e., -(CH 2 ) 2 CH 3 ) and isopropyl (i.e., -CH(CH 3 ) 2 ).
  • a divalent group such as a divalent “alkyl” group, a divalent “aryl” group, etc.
  • a divalent group such as a divalent “alkyl” group, a divalent “aryl” group, etc.
  • combinations of groups are referred to herein as one moiety, e.g., arylalkyl or aralkyl, the last mentioned group contains the atom by which the moiety is attached to the rest of the molecule.
  • Alkenyl refers to an alkyl group containing at least one carbon-carbon double bond and having from 2 to 20 carbon atoms (i.e., C 2-20 alkenyl), 2 to 8 carbon atoms (i.e., C 2-8 alkenyl), 2 to 6 carbon atoms (i.e., C 2-6 alkenyl), or 2 to 4 carbon atoms (i.e., C C 2- 4 alkenyl).
  • alkenyl groups include, e.g., ethenyl, propenyl, and butadienyl (including 1,2-butadienyl and 1,3-butadienyl).
  • Alkynyl refers to an alkyl group containing at least one carbon-carbon triple bond and having from 2 to 20 carbon atoms (i.e., C 2-20 alkynyl), 2 to 8 carbon atoms (i.e., C 2-8 alkynyl), 2 to 6 carbon atoms (i.e., C 2-6 alkynyl), or 2 to 4 carbon atoms (i.e., C 2-4 alkynyl).
  • alkynyl also includes those groups having one triple bond and one double bond.
  • Alkoxy refers to the group “alkyl-O-”.
  • alkoxy groups include, e.g., methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy.
  • Alkoxyalkyl refers to the group “alkyl-O-alkyl”.
  • Alkylthio refers to the group “alkyl-S-”.
  • Alkylsulfinyl refers to the group “alkyl-S(O)-”.
  • Alkylsulfonyl refers to the group “alkyl-S(O) 2 -”.
  • Alkylsulfonylalkyl refers to -alkyl-S(O) 2 -alkyl.
  • “Acyl” refers to a group -C(O)R y , wherein R y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted, as defined herein.
  • Examples of acyl include, e.g., formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethyl-carbonyl, and benzoyl.
  • “Amido” refers to both a “C-amido” group which refers to the group -C(O)NR y R z and an “N-amido” group which refers to the group -NR y C(O)R z , wherein R y and R z are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein, or R y and R z are taken together to form a cycloalkyl or heterocyclyl; each of which may be optionally substituted, as defined herein.
  • Amino refers to the group -NR y R z wherein R y and R z are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted as defined herein
  • Aminoalkyl refers to the group “-alkyl-NR y R z ,” wherein R y and R z are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein.
  • “Amidino” refers to -C(NR y )(NR z 2 ), wherein R y and R z are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein.
  • “Aryl” refers to an aromatic carbocyclic group having a single ring (e.g., monocyclic) or multiple rings (e.g., bicyclic or tricyclic) including fused systems.
  • aryl has 6 to 20 ring carbon atoms (i.e., C 6-20 aryl), 6 to 12 carbon ring atoms (i.e., C 6-12 aryl), or 6 to 10 carbon ring atoms (i.e., C 6-10 aryl).
  • aryl groups include, e.g., phenyl, naphthyl, fluorenyl, and anthryl. Aryl, however, does not encompass or overlap in any way with heteroaryl defined below. If one or more aryl groups are fused with a heteroaryl, the resulting ring system is heteroaryl. If one or more aryl groups are fused with a heterocyclyl, the resulting ring system is heterocyclyl.
  • Arylalkyl or “Aralkyl” refers to the group “aryl-alkyl-”.
  • Carbamoyl refers to both an “O-carbamoyl” group which refers to the group -O-C(O)NR y R z and an “N-carbamoyl” group which refers to the group -NR y C(O)OR z , wherein R y and R z are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein.
  • Carboxyl ester or “ester” refer to both -OC(O)R x and -C(O)OR x , wherein R x is alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein.
  • Cyanoalkyl refers to refers to an alkyl group as defined above, wherein one or more (e.g., one to three) hydrogen atoms are replaced by a cyano (-CN) group.
  • Cycloalkyl refers to a saturated or partially unsaturated cyclic alkyl group having a single ring or multiple rings including fused, bridged and spiro ring systems.
  • the term “cycloalkyl” includes cycloalkenyl groups (i.e., the cyclic group having at least one double bond) and carbocyclic fused ring systems having at least one sp 3 carbon atom (i.e., at least one non-aromatic ring).
  • cycloalkyl has from 3 to 20 ring carbon atoms (i.e., C 3-20 cycloalkyl), 3 to 12 ring carbon atoms (i.e., C 3-12 cycloalkyl), 3 to 10 ring carbon atoms (i.e., C 3-10 cycloalkyl), 3 to 8 ring carbon atoms (i.e., C 3-8 cycloalkyl), or 3 to 6 ring carbon atoms (i.e., C 3-6 cycloalkyl).
  • Monocyclic groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
  • Polycyclic groups include, for example, bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, adamantyl, norbornyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, octahydropentalenyl, and the like.
  • cycloalkyl is intended to encompass any non-aromatic ring which may be fused to an aryl ring, regardless of the attachment to the remainder of the molecule.
  • cycloalkyl also includes “spirocycloalkyl” when there are two positions for substitution on the same carbon atom, for example spiro[2.5]octanyl, spiro[4.5]decanyl, or spiro[5.5]undecanyl.
  • Cycloalkoxy refers to “-O-cycloalkyl.”
  • Cycloalkylalkyl refers to the group “cycloalkyl-alkyl-”.
  • Cycloalkylalkoxy refers to “-O-alkyl-cycloalkyl.”
  • “Hydrazino” refers to -NHNH2.
  • Imino refers to a group -C(NR y )R z , wherein R y and R z are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein.
  • “Imido” refers to a group -C(O)NR y C(O)R z , wherein R y and R z are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein.
  • “Halogen” or “halo” refers to atoms occupying group VIIA of the periodic table, such as fluoro, chloro, bromo or iodo.
  • Haloalkyl refers to an unbranched or branched alkyl group as defined above, wherein one or more (e.g., one to five or one to three) hydrogen atoms are replaced by a halogen.
  • a residue is substituted with more than one halogen, it may be referred to by using a prefix corresponding to the number of halogen moieties attached.
  • Dihaloalkyl and trihaloalkyl refer to alkyl substituted with two (“di”) or three (“tri”) halo groups, which may be, but are not necessarily, the same halogen.
  • haloalkyl examples include, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like.
  • Haloalkoxy refers to an alkoxy group as defined above, wherein one or more (e.g., one to five or one to three) hydrogen atoms are replaced by a halogen.
  • Hydroxyalkyl refers to an alkyl group as defined above, wherein one or more (e.g., one to five or one to three) hydrogen atoms are replaced by a hydroxy group.
  • “Heteroalkyl” refers to an alkyl group in which one or more (e.g., one to five or one to three) of the carbon atoms (and any associated hydrogen atoms) are each independently replaced with the same or different heteroatomic group provided the point of attachment to the remainder of the molecule is through a carbon atom.
  • the term “heteroalkyl” includes unbranched or branched saturated chain having carbon and heteroatoms.
  • 1, 2 or 3 carbon atoms may be independently replaced with the same or different heteroatomic group.
  • Heteroatomic groups include, but are not limited to, -NR y -, -O-, -S-, -S(O)-, -S(O) 2 -, and the like, wherein R y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted, as defined herein.
  • heteroalkyl groups include, e.g., ethers (e.g., -CH 2 OCH 3 , -CH(CH 3 )OCH 3 , -CH 2 CH 2 OCH 3 , -CH 2 CH 2 OCH 2 CH 2 OCH 3 , etc.), thioethers (e.g., -CH 2 SCH 3 , -CH(CH 3 )SCH 3 , -CH 2 CH 2 SCH 3 , -CH 2 CH 2 SCH 2 CH 2 SCH 3 , etc.), sulfones (e.g., -CH 2 S(O) 2 CH 3 , -CH(CH 3 )S(O) 2 CH 3 , -CH 2 CH 2 S(O) 2 CH 3 , -CH 2 CH 2 S(O) 2 CH 2 CH 2 OCH 3 , etc.) and amines (e.g., -CH 2 NR y CH 3 , -CH(CH 3 )NR y CH 3 ,
  • heteroalkyl includes 1 to 10 carbon atoms, 1 to 8 carbon atoms, or 1 to 4 carbon atoms; and 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom.
  • “Heteroalkylene” refers to a divalent alkyl group (i.e., alkylene) in which one or more (e.g., one to five or one to three) of the carbon atoms (and any associated hydrogen atoms) are each independently replaced with the same or different heteroatomic group.
  • “Heteroalkylene” groups must have at least one carbon and at least one heteroatomic group within the chain.
  • the term “heteroalkylene” includes unbranched or branched saturated chain having carbon and heteroatoms.
  • 1, 2 or 3 carbon atoms may be independently replaced with the same or different heteroatomic group.
  • Heteroatomic groups include, but are not limited to, -NR y -, -O-, -S-, -S(O)-, -S(O) 2 -, and the like, wherein R y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted, as defined herein.
  • heteroalkylene groups include, e.g., -CH 2 OCH 2 -, -CH(CH 3 )OCH 2 -, -CH 2 CH 2 OCH 2 -, -CH 2 CH 2 OCH 2 CH 2 OCH 2 -, -CH 2 SCH 2 -, -CH(CH 3 )SCH 2 -, -CH 2 CH 2 SCH 2 -, -CH 2 CH 2 SCH 2 CH 2 SCH 2 -, -CH 2 S(O) 2 CH 2 -, -CH(CH 3 )S(O) 2 CH 2 -, -CH 2 CH 2 S(O) 2 CH 2 -, -CH 2 CH 2 S(O) 2 CH 2 CH 2 OCH 2 -, -CH 2 NR y CH 2 -, -CH(CH 3 )NR y CH 2 -, -CH 2 CH 2 NR y CH 2 -, -CH 2 CH 2 NR y CH 2 CH 2 NR y CH 2 -,
  • heteroalkylene includes 1 to 10 carbon atoms, 1 to 8 carbon atoms, or 1 to 4 carbon atoms; and 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom.
  • heteroalkylene does not include groups such as amides or other functional groups having an oxo present on one or more carbon atoms.
  • “Heteroaryl” refers to an aromatic group having a single ring, multiple rings or multiple fused rings, with one or more ring heteroatoms independently selected from nitrogen, oxygen and sulfur.
  • heteroaryl includes 1 to 20 ring carbon atoms (i.e., C 1-20 heteroaryl), 3 to 12 ring carbon atoms (i.e., C 3-12 heteroaryl), or 3 to 8 carbon ring atoms (i.e., C 3-8 heteroaryl); and 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, oxygen and sulfur.
  • heteroaryl includes 5-10 membered ring systems, 5-7 membered ring systems, or 5-6 membered ring systems, each independently having 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, oxygen and sulfur.
  • heteroaryl groups include, e.g., acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzofuranyl, benzothiazolyl, benzothiadiazolyl, benzonaphthofuranyl, benzoxazolyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, isoquinolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxido
  • fused-heteroaryl rings include, but are not limited to, benzo[d]thiazolyl, quinolinyl, isoquinolinyl, benzo[b]thiophenyl, indazolyl, benzo[d]imidazolyl, pyrazolo[1,5-a]pyridinyl, and imidazo[1,5-a]pyridinyl, where the heteroaryl can be bound via either ring of the fused system. Any aromatic ring, having a single or multiple fused rings, containing at least one heteroatom, is considered a heteroaryl regardless of the attachment to the remainder of the molecule (i.e., through any one of the fused rings).
  • Heteroaryl does not encompass or overlap with aryl as defined above.
  • “Heteroarylalkyl” refers to the group “heteroaryl-alkyl-”.
  • Heterocyclyl refers to a saturated or partially unsaturated cyclic alkyl group, with one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • the term “heterocyclyl” includes heterocycloalkenyl groups (i.e., the heterocyclyl group having at least one double bond), bridged- heterocyclyl groups, fused-heterocyclyl groups, and spiro-heterocyclyl groups.
  • Any non-aromatic ring containing at least one heteroatom is considered a heterocyclyl, regardless of the attachment (i.e., can be bound through a carbon atom or a heteroatom).
  • the term heterocyclyl is intended to encompass any non-aromatic ring containing at least one heteroatom, which ring may be fused to an aryl or heteroaryl ring, regardless of the attachment to the remainder of the molecule.
  • heterocyclyl has 2 to 20 ring carbon atoms (i.e., C 2-20 heterocyclyl), 2 to 12 ring carbon atoms (i.e., C 2-12 heterocyclyl), 2 to 10 ring carbon atoms (i.e., C 2-10 heterocyclyl), 2 to 8 ring carbon atoms (i.e., C 2-8 heterocyclyl), 3 to 12 ring carbon atoms (i.e., C 3-12 heterocyclyl), 3 to 8 ring carbon atoms (i.e., C 3-8 heterocyclyl), or 3 to 6 ring carbon atoms (i.e., C 3-6 heterocyclyl); having 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, sulfur or oxygen.
  • ring carbon atoms i.e., C 2-20 heterocyclyl
  • 2 to 12 ring carbon atoms i.
  • heterocyclyl groups include, e.g., azetidinyl, azepinyl, benzodioxolyl, benzo[b][1,4]dioxepinyl, 1,4- benzodioxanyl, benzopyranyl, benzodioxinyl, benzopyranonyl, benzofuranonyl, dioxolanyl, dihydropyranyl, hydropyranyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, furanonyl, imidazolinyl, imidazolidinyl, indolinyl, indolizinyl, isoindolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-ox
  • heterocyclyl also includes “spiroheterocyclyl” when there are two positions for substitution on the same carbon atom.
  • spiro-heterocyclyl rings include, e.g., bicyclic and tricyclic ring systems, such as 2-oxa-7-azaspiro[3.5]nonanyl, 2-oxa-6-azaspiro[3.4]octanyl and 6-oxa-1- azaspiro[3.3]heptanyl.
  • fused-heterocyclyl rings include, but are not limited to, 1,2,3,4- tetrahydroisoquinolinyl, 4,5,6,7-tetrahydrothieno[2,3-c]pyridinyl, indolinyl and isoindolinyl, where the heterocyclyl can be bound via either ring of the fused system.
  • Heterocyclylalkyl refers to the group “heterocyclyl-alkyl-”.
  • Sulfonyl refers to the group -S(O) 2 R y , where R y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted, as defined herein.
  • sulfonyl examples include methylsulfonyl, ethylsulfonyl, phenylsulfonyl and toluenesulfonyl.
  • “Sulfinyl” refers to the group -S(O)R y , where R y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted, as defined herein.
  • sulfinyl examples include methylsulfinyl, ethylsulfinyl, phenylsulfinyl and toluenesulfinyl.
  • “Sulfonamido” refers to the groups -SO2NR y R z and -NR y SO2R z , where R y and R z are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted, as defined herein.
  • substituted means any of the above groups (i.e., alkyl, alkenyl, alkynyl, alkylene, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, aryl, heterocyclyl, heteroaryl, and/or heteroalkyl) wherein at least one hydrogen atom is replaced by a bond to a non-hydrogen atom such as, but not limited to alkyl, alkenyl, alkynyl, alkoxy, alkylthio, acyl, amido, amino, amidino, aryl, aralkyl, azido, carbamoyl, carboxyl, carboxyl ester, cyano, cycloalkyl, cycloalkylalkyl, guanadino, halo, haloalkyl, haloalkoxy, hydroxyalkyl, heteroalkyl, heteroaryl, heteroaryl
  • R g and R h are the same or different and independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and/or heteroarylalkyl.
  • substituted also means any of the above groups in which one or more (e.g., one to five or one to three) hydrogen atoms are replaced by a bond to an amino, cyano, hydroxyl, imino, nitro, oxo, thioxo, halo, alkyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, and/or heteroarylalkyl, or two of R g and R h and R i are taken together with the atoms to which they are attached to form a heterocyclyl ring optionally substituted with oxo, halo or alkyl optionally substituted with oxo, halo, amino, hydroxyl, or alkoxy.
  • impermissible substitution patterns e.g., methyl substituted with 5 fluorines or heteroaryl groups having two adjacent oxygen ring atoms. Such impermissible substitution patterns are well known to the skilled artisan.
  • substituted may describe other chemical groups defined herein.
  • the phrase “one or more” refers to one to five. In certain embodiments, as used herein, the phrase “one or more” refers to one to three.
  • Any compound or structure given herein, is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds.
  • isotopically labeled compounds have structures depicted herein, except that one or more (e.g., one to five or one to three) atoms are replaced by an atom having a selected atomic mass or mass number.
  • isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine and iodine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 36 Cl, 123 I, and 125 I, respectively.
  • isotopically labeled compounds of the present disclosure for example those into which radioactive isotopes such as 3 H and 14 C are incorporated.
  • Such isotopically labelled compounds may be useful in metabolic studies, reaction kinetic studies, detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays or in radioactive treatment of patients.
  • PET positron emission tomography
  • SPECT single-photon emission computed tomography
  • the term “isotopically enriched analogs” includes “deuterated analogs” of compounds described herein in which one or more (e.g., one to five or one to three) hydrogens is/are replaced by deuterium, such as a hydrogen on a carbon atom.
  • Such compounds exhibit increased resistance to metabolism and are thus useful for increasing the half-life of any compound when administered to a mammal, particularly a human. See, for example, Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism,” Trends Pharmacol. Sci.5(12):524-527 (1984).
  • Such compounds are synthesized by means well known in the art, for example by employing starting materials in which one or more (e.g., one to five or one to three) hydrogens have been replaced by deuterium.
  • Deuterium labelled or substituted therapeutic compounds of the disclosure may have improved DMPK (drug metabolism and pharmacokinetics) properties, relating to distribution, metabolism and excretion (ADME).
  • isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life, reduced dosage requirements and/or an improvement in therapeutic index.
  • An 18 F, 3 H, 11 C labeled compound may be useful for PET or SPECT or other imaging studies.
  • Isotopically labeled compounds of this disclosure and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non- isotopically labeled reagent. It is understood that deuterium in this context is regarded as a substituent in a compound described herein.
  • the concentration of such a heavier isotope, specifically deuterium may be defined by an isotopic enrichment factor.
  • any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom.
  • a position is designated specifically as “H” or “hydrogen,” the position is understood to have hydrogen at its natural abundance isotopic composition.
  • any atom specifically designated as a deuterium (D) is meant to represent deuterium.
  • the compounds of this disclosure are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto.
  • “Pharmaceutically acceptable” or “physiologically acceptable” refer to compounds, salts, compositions, dosage forms and other materials which are useful in preparing a pharmaceutical composition that is suitable for human or veterinary pharmaceutical use.
  • the term “pharmaceutically acceptable salt” of a given compound refers to salts that retain the biological effectiveness and properties of the given compound, and which are not biologically or otherwise undesirable.
  • “Pharmaceutically acceptable salts” or “physiologically acceptable salts” include, for example, salts with inorganic acids and salts with an organic acid.
  • the free base can be obtained by basifying a solution of the acid salt.
  • an addition salt, particularly a pharmaceutically acceptable addition salt may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds.
  • Pharmaceutically acceptable acid addition salts may be prepared from inorganic and organic acids. Salts derived from inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
  • Salts derived from organic acids include acetic acid, propionic acid, gluconic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluene-sulfonic acid, salicylic acid, and the like.
  • pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. Salts derived from inorganic bases include, by way of example only, sodium, potassium, lithium, aluminum, ammonium, calcium and magnesium salts.
  • Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, such as alkyl amines (i.e., NfL/alkyl)), dialkyl amines (i.e., HN(alkyl)2), trialkyl amines (i.e., N(alkyl)3), substituted alkyl amines (i.e., NH2(substituted alkyl)), di(substituted alkyl) amines (i.e., HN(substituted alkyl);), tri(substituted alkyl) amines (i.e., N(substituted alkyl);).
  • alkyl amines i.e., NfL/alkyl
  • dialkyl amines i.e., HN(alkyl)2
  • trialkyl amines i.e., N(alkyl)3
  • alkenyl amines i.e., NH2(alkcnyl)
  • dialkcnyl amines i.e., HN(alkcnyl)2), trialkcnyl amines (i.e., N(alkenyl)3)
  • substituted alkenyl amines i.e., NH2(substituted alkenyl)
  • di(substituted alkenyl) amines i.e., HN(substituted alkenyl ⁇
  • tri(substituted alkenyl) amines i.e., N(substituted alkenyl
  • mono-, di- or tri- cycloalkyl amines i.e., NH 2 (cycloalkyl), HN(cycloalkyl) 2 , N(cycloalkyl) 3
  • mono-, di- or tri- arylamines i.e.,
  • Suitable amines include, by way of example only, isopropylamine, trimethyl amine, diethyl amine, tri(iso-propyl) amine, tri(n-propyl) amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like.
  • hydrate refers to the complex formed by the combining of a compound described herein and water.
  • a “solvate” refers to an association or complex of one or more solvent molecules and a compound of the disclosure.
  • solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethylsulfoxide, ethylacetate, acetic acid, and ethanolamine.
  • amide containing compounds may exist in equilibrium with imidic acid tautomers. Regardless of which tautomer is shown and regardless of the nature of the equilibrium among tautomers, the compounds are understood by one of ordinary skill in the art to comprise both amide and imidic acid tautomers. Thus, the amide containing compounds are understood to include their imidic acid tautomers.
  • the imidic acid containing compounds are understood to include their amide tautomers.
  • the compounds, or their pharmaceutically acceptable salts include an asymmetric center and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)- or, as (D)- or (L)- for amino acids.
  • the present disclosure is meant to include all such possible isomers, as well as their racemic and optically pure forms.
  • Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, for example, chromatography and fractional crystallization.
  • Conventional techniques for the preparation/isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC).
  • HPLC high pressure liquid chromatography
  • a “stereoisomer” refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures, which are not interchangeable.
  • the present disclosure contemplates various stereoisomers and mixtures thereof and includes “enantiomers,” which refers to two stereoisomers whose molecules are nonsuperimposeable mirror images of one another.
  • “Diastereomers” are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other.
  • Relative centers of the compounds as depicted herein are indicated graphically using the “thick bond” style (bold or parallel lines) and absolute stereochemistry is depicted using wedge bonds (bold or parallel lines).
  • Prodrugs means any compound which releases an active parent drug according to a structure described herein in vivo when such prodrug is administered to a mammalian subject.
  • Prodrugs of a compound described herein are prepared by modifying functional groups present in the compound described herein in such a way that the modifications may be cleaved in vivo to release the parent compound.
  • Prodrugs may be prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compounds.
  • Prodrugs include compounds described herein wherein a hydroxy, amino, carboxyl, or sulfhydryl group in a compound described herein is bonded to any group that may be cleaved in vivo to regenerate the free hydroxy, amino, or sulfhydryl group, respectively.
  • Examples of prodrugs include, but are not limited to esters (e.g., acetate, formate and benzoate derivatives), amides, guanidines, carbamates (e.g., N,N-dimethylaminocarbonyl) of hydroxy functional groups in compounds described herein and the like. Preparation, selection and use of prodrugs is discussed in T. Higuchi and V.
  • Idiopathic pulmonary fibrosis or “IPF” refers to a chronic, progressive fibrosing interstitial pneumonia of the lungs.
  • a compound of formula A-I or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein: t is 0, 1 or 2; R 1 is a 5- to 10-membered heterocyclyl, a 9-membered heteroaryl, or -O-partially saturated heterocyclyl; wherein: the 5- to 10-membered heterocyclyl of R 1 is selected from:
  • R 1 the 9-membered heteroaryl of R 1 is selected from: X is NR 10 or S(O) 2 ; Ring A is C 3-10 cycloalkyl optionally substituted with 1 to 5 substituents independently selected from oxo and halo, provided that when ring A is C 4-6 cycloalkyl, R 3 is phenyl or (4- to 11-membered heterocyclyl)alkyl; each m is independently 0, 1, or 2; p is 1 or 2; n is 1 or 2; each R is independently hydrogen or C 1-6 alkyl; each R 2 is independently halo, C 1-6 alkoxy, C 1-6 alkoxyalkyl, hydroxyalkyl, (dialkylamino)alkyl, heteroarylalkyl optionally substituted with C 1-6 haloalkyl, -C(O)OR, -C(O)NR 2 , -C 1-6 alkyl-N(S(O) 2 -R)(C 1-6 hal
  • R 1 is a 5- to 10-membered heterocyclyl, or a 9-membered heteroaryl as described above.
  • R 1 is a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, the -O-partially saturated heterocyclyl of R 1 is ; wherein: p is 1 or 2; R 3 is C 1-6 alkyl, C 1-6 haloalkyl, (C 3-8 cycloalkyl)alkyl, (4- to 11-membered heterocyclyl)alkyl, or C6-10 aryl; each R 5 is independently -C(O)NR 6 2, or C 1-6 alkyl optionally substituted with -C(O)NR 6 2, -C(O)NR-(CH 2 )n-NR2, or C6-10 aryl optional
  • R 1 is [0077] In some embodiments of formula A-I, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, R 1 is [0078] In some embodiments, R 1 is [0079] In some embodiments, R 1 is selected from: , and [0080] In some embodiments, R 1 is [0081] In some embodiments, R 1 is [0082] In some embodiments of formula A-I, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, R 1 is [0083] In some embodiments of formula A-I, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, R 1 is selected from:
  • R 5 is selected from
  • R 1 is [0085] In some embodiments of formula A-I, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, R 1 is [0086] In some embodiments of formula A-I, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, R 1 is In some embodiments of formula A-I, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, R 1 is [0087] In some embodiments of formula A-I, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, the moiety or the moiety
  • R 1 is selected from: , and In some embodiments of formula A-I, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, R 1 is . In some embodiments of formula A-I, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, R 1 is .
  • R 1 is . In some embodiments of formula A-I, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, R 1 is . In some embodiments of formula A-I, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, R 1 is . In some embodiments of formula A-I, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, R 1 is .
  • R 1 is . In some embodiments of formula A-I, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, R 1 is . In some embodiments of formula A-I, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, R 1 is . In some embodiments of formula A-I, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, R 1 is . In some embodiments, R 9 is C 1-6 alkyl. In some embodiments, R 9 is C(O)N(R 6 ) 2 .
  • R 10 is hydrogen, C 1-6 alkyl, or -C(O)-(C 3-8 cycloalkyl, -C(O)-(C 1-6 alkyl-C 3-8 cycloalkyl or -C(O)-(4- to 11-membered heterocyclyl), where the cycloalkyl is optionally substituted with halo.
  • R 10 is -C(O)-(CH 2 )n-NR2, -C(O)C1- 6 alkyl or -C(O)C 1-6 haloalkyl.
  • R 11 is independently C 1-6 alkyl.
  • R 11 is -C(O)OR;
  • R 12 is independently cyano, halo, or C 1-6 alkyl optionally substituted with 1 to 3 halo.
  • R 12 is NR 2 .
  • R 13 is H, C 1-6 alkyl, or C 1-6 alkyl- C 3-8 cycloalkyl.
  • R 13 is C 1-6 alkyl-aryl, or -C(O)-(C 3-8 cycloalkyl).
  • R 1 is selected from [0090] In some embodiments of formula A-I, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, R 1 is selected from [0090] In some embodiments of formula A-I, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, R 1 is In some embodiments of formula A-I, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, R 1 is .
  • R 1 is [0091] In some embodiments of formula A-I, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, R 1 is [0092] In some embodiments of formula A-I, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, R 4 is selected from [0093] In some embodiments of formula A-I, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, t is 1; and R 2 is C 1-6 alkoxyalkyl, hydroxyalkyl, (dialkylamino)alkyl, -C 1-6 alkyl-N(S(O) 2 -R)
  • t is 1; and R 2 is C 1-6 alkoxyalkyl.
  • R 2 is C 1-6 alkoxyalkyl, hydroxyalkyl, (dialkylamino)alkyl, -C 1-6 alkyl-N(S(O) 2 -R)(C 1-6 haloalkyl), -C 1-6 alkyl-NHC(O)-C 1-6 alkyl, -C 1-6 alkyl-NH-C 1-6 haloalkyl, or -C 1-6 alkyl-NH-heteroaryl optionally substituted with C 1-6 alkyl.
  • R 2 is C 1-6 alkoxyalkyl.
  • R 2 is selected from
  • R 3 is C 1-6 alkyl. In some embodiments of formula A-I, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, R 3 is C 1-6 haloalkyl. [0099] In some embodiments of formula A-I, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, R 3 is selected from .
  • R 3 is selected from [0101]
  • a compound of formula A-I has the structure of formula A-XII.
  • provided herein is a compound of formula A-XII:
  • R 2 is C 1-6 alkoxyalkyl
  • R 3 is C 1-6 alkyl, C 1-6 haloalkyl, (C 3-8 cycloalkyl)alkyl, (4- to 11-membered heterocyclyl)alkyl, or C6-10 aryl
  • each R 5 is independently -C(O)NR 6 2, or C 1-6 alkyl optionally substituted with -C(O)NR 6 2, -C(O)NR-(CH 2 )n-NR2, or C6-10 aryl optionally substituted with C 1-6 alkoxy
  • each R 6 is independently hydrogen, C 1-6 alkyl, 4- to 11-membered heterocyclyl, C 3-8 cycloalkyl, 5- to 9-membered heteroaryl, or C6-10 aryl, or two R 6 , together with the nitrogen to which they attach, form a 4-
  • X is NR 10 or S(O) 2 ; m is 0, 1, or 2; R 2 is C 1-6 alkoxyalkyl, R 3 is C 1-6 alkyl, C 1-6 haloalkyl, (C 3-8 cycloalkyl)alkyl, (4- to 11-membered heterocyclyl)alkyl, or C6-10 aryl; and R 10 is hydrogen, C 1-6 alkyl, -C(O)-(C 3-8 cycloalkyl), -C(O)-(C 1-6 alkyl-C 3-8 cycloalkyl), -C(O)-(4- to 11-membered heterocyclyl), -C(O)-(CH 2 )n-NR2, -C(O)-C 1-6 alkyl, or -C(O)-C 1-6 haloalky
  • p is 1 or 2. In some embodiments of formula A-I, p is 1. In some embodiments of formula A-I, p is 2. [0106] In some embodiments of formula A-I, one m is 0 or 1 and other m is 1 or 2. [0107] Provided herein is a compound selected from Table A-1 and/or Table A-1A, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof.
  • a compound selected from Table A-1 and/or Table A-1A or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof.
  • the moieties comprise stereoisomers and all such stereoisomers and mixtures of stereoisomers are included within the scope of embodiments presented herein.
  • Compound A-156 may exist as one or more of the following stereoisomers: . It will be understood that the disclosure encompasses all such stereoisomers and mixtures of stereoisomers for various compounds described herein.
  • Provided herein is a compound selected from Table A-2, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof.
  • R 1 is selected from: X is NR 10 , CR 18 R 19 , or O; X 1 is CR 18 R 19 , O, NR 11 , or S(O) 2 ; each m is independently 0, 1, or 2; t is 0, 1, or 2; q is 0, 1, 2, 3, or 4; ring A is a 7- to 11-membered bicyclic spiro heterocyclyl ring optionally substituted with 1 to 5 Z 1 ; each R is independently hydrogen, C 1-6 alkyl, or C3-10 cycloalkyl, where the C 1-6 alkyl or C3-10 cycloalkyl is optionally substituted with 1 to 5 Z 1 ; or two R together with the atom to which they attach, form a 6- to 10-membered ring
  • R 1 is in some embodiments, provided is a compound of formula A-IA: or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein t, R 2 , R 3 , and R 4 are each independently as defined herein.
  • one R 4 is C 3-10 cycloalkyl. In some embodiments, one R 4 is hydrogen and the other is C 3-10 cycloalkyl.
  • R 1 is [0114] In some embodiments, R 1 is [0115] In some embodiments, R 1 is In some embodiments, provided is a compound of formula A-IB: or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein t, R 2 , R 3 , and R 5 are each independently as defined herein. [0116] In some embodiments, one R 5 is -C(O)NR 6 2; and the other R 5 is C 1-6 alkyl; or both R 5 , together with the carbon atoms to which they attach, form a 6- to 10-membered cycloalkyl.
  • R 1 is or [0118] In some embodiments, R 1 is In some embodiments, provided is a compound of formula A-IC: or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein t, m, X, R 2 , and R 3 are each independently as defined herein. [0119] In some embodiments, X is NR 10 . [0120] In some embodiments, one m is 0 or 1 and other m is 1 or 2. [0121] In some embodiments, provided is a compound of formula A-IIC: A-IIC where R 2 , R 3 , and R 10 are each independently as defined herein. [0122] In some embodiments, provided is a compound of formula A-IID:
  • R 10 is C 1-6 alkyl, -C 1-6 alkyl-C3-10 cycloalkyl, C3-10 cycloalkyl, 4- to 11- membered heterocyclyl, -C(O)-(C3-10 cycloalkyl), -C(O)-(5- to 9-membered heteroaryl), -C(O)-(CH 2 )n-NR2, or -C(O)C 1-6 alkyl; where the C 1-6 alkyl, -C(O)-(C3-10 cycloalkyl), or -C(O)-(4- to 11-membered heterocyclyl) is substituted with 1 to 5 R 16 ; and the C3-10 cycloalkyl, -C(O)-C6-10 aryl, or -C(O)-(5- to 9-membered heteroaryl),
  • R 10 is hydrogen. [0125] In some embodiments, R 10 is C 1-6 alkyl substituted with 1 to 5 R 16 . [0126] In some embodiments, R 10 is -C 1-6 alkyl-C3-10 cycloalkyl optionally substituted with 1 to 5 halo or R 16 . In some embodiments, R 10 is -C 1-6 alkyl-C3-10 cycloalkyl. [0127] In some embodiments, R 10 is C3-10 cycloalkyl optionally substituted with 1 to 5 halo or R 16 . In some embodiments, R 10 is C 3-10 cycloalkyl optionally substituted with 1 to 5 halo.
  • R 10 is 4- to 11-membered heterocyclyl optionally substituted with 1 to 5 halo or R 16 . In some embodiments, R 10 is 4- to 11-membered heterocyclyl. In some embodiments, R 10 is 4- to 6- membered heterocyclyl optionally substituted with 1 to 5 halo or R 16 . In some embodiments, R 10 is 4- to 6- membered heterocyclyl. [0129] In some embodiments, R 10 is -C(O)-(C 3-10 cycloalkyl) substituted with 1 to 5 R 16 .
  • R 10 is -C(O)-(C 1-6 alkyl-C 3-10 cycloalkyl) substituted with 1 to 5 R 16 .
  • R 10 is -C(O)-(4- to 11-membered heterocyclyl) substituted with 1 to 5 R 16 .
  • R 10 is -C(O)-C 6-10 aryl optionally substituted with 1 to 5 halo or R 16 .
  • R 10 is -C(O)-(5- to 9-membered heteroaryl) optionally substituted with 1 to 5 halo or R 16
  • R 10 is -C(O)-(CH 2 ) n -NR 2 .
  • n is 0.
  • each R is independently hydrogen, C 1-6 alkyl, or C 3-10 cycloalkyl.
  • R 10 is-C(O)C 1-6 alkyl substituted with 1 to 5 R 16 .
  • R 10 is-C(O)C 1-6 haloalkyl substituted with 1 to 5 R 16 .
  • each R 16 is independently hydroxy, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C3-10 cycloalkyl, C 1-6 alkoxy, -C(O)OH, or -C(O)OC 1-6 alkyl.
  • a compound of formula A-IIC where R 2 and R 3 are each independently as defined herein, and R 10 is 4- to 11-membered heterocyclyl.
  • R 10 is 4- to 11-membered heterocyclyl.
  • R 1 is [0141] In some embodiments, R 1 is in some embodiments, provided is a compound of formula A-ID: or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein t, m, X 1 , R 2 , and R 3 are each independently as defined herein.
  • X 1 is NR 11 .
  • R 11 is C 1-6 alkyl-C3-10 cycloalkyl or C3-10 cycloalkyl.
  • one m is 0 or 1 and other m is 1 or 2.
  • R 1 is [0146] In some embodiments, R 1 is In some embodiments, provided is a compound of formula A-IE: R 3 A-IE or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein ring A, t, R 2 , R 3 , and R 4 are each independently as defined herein. [0147] In some embodiments, R 1 is [0148] In some embodiments, R 1 is .
  • a compound of formula A-IF or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein t, R 2 , R 3 , and R 14 are each independently as defined herein.
  • one R 14 is C 1-6 hydroxyalkyl, C 1-6 alkoxyalkyl, -(CH 2 ) n -NRC(O)R 17 , C 6-10 aryl, or 5- to 9-membered heteroaryl, wherein each is optionally substituted with 1 to 3 substituents independently selected from halo and C 1-6 haloalkyl.
  • one R 14 is C 1-6 alkyl and the other R 14 is C 1-6 hydroxyalkyl, C 1-6 alkoxyalkyl, -(CH 2 )n-NRC(O)R 17 , C6-10 aryl, or 5- to 9-membered heteroaryl, wherein each is optionally substituted with 1 to 3 substituents independently selected from halo and C 1-6 haloalkyl.
  • R 17 is C 1-6 alkyl or C3-10 cycloalkyl, where the C 1-6 alkyl or C3-10 cycloalkyl is optionally substituted with cyano, hydroxy, or C 1-6 alkoxy.
  • R 17 is C 1-6 alkyl optionally substituted with cyano, hydroxy, or C 1-6 alkoxy. In some embodiments, R 17 is C3-10 cycloalkyl optionally substituted with cyano, hydroxy, or C 1-6 alkoxy. [0152] In some embodiments, n is 1. [0153] In some embodiments, R 1 is [0154] In some embodiments, R 1 is . In some embodiments, provided is a compound of formula A-IG: A-IG or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein t, q, R 2 , R 3 , and R 15 are each independently as defined herein.
  • q is 2.
  • two R 15 together with the carbon to which they attach, form a C3-10 cycloalkyl.
  • R 1 is [0158]
  • one R 5 is -C(O)NR 6 2 or C 1-6 alkyl optionally substituted with -C(O)NR 6 2; where at least one R 6 is a 5- to 9-membered heteroaryl substituted with 1 to 3 substituents independently selected from alkyl and haloalkyl.
  • each R 6 is independently hydrogen, C 1-6 alkyl, 4- to 11-membered heterocyclyl, C3-10 cycloalkyl, 5- to 9-membered heteroaryl optionally substituted with 1 to 3 substituents independently selected from alkyl and haloalkyl, or C6-10 aryl.
  • R 3 is C 1-6 alkyl or C 1-6 haloalkyl.
  • t is 1. In some embodiments, t is 2.
  • t is 1; and R 2 is C 1-6 alkoxyalkyl, hydroxyalkyl, (dialkylamino)alkyl, -C 1-6 alkyl-N(S(O) 2 -R)(C 1-6 haloalkyl), -C 1-6 alkyl-NHC(O)-C 1-6 alkyl, -C 1-6 alkyl-NH-C 1-6 haloalkyl, or -C 1-6 alkyl- NH-heteroaryl optionally substituted with C 1-6 alkyl.
  • t is 1; and R 2 is C 1-6 alkoxyalkyl.
  • t is 2; and one R 2 is halo and the other R 2 is C 1-6 alkoxyalkyl.
  • R 2 is C 1-6 alkoxyalkyl, hydroxyalkyl, (dialkylamino)alkyl, -C 1-6 alkyl- N(S(O) 2 -R)(C 1-6 haloalkyl), -C 1-6 alkyl-NHC(O)-C 1-6 alkyl, -C 1-6 alkyl-NH-C 1-6 haloalkyl, or -C 1-6 alkyl-NH-heteroaryl optionally substituted with C 1-6 alkyl.
  • R 2 is C 1-6 alkoxyalkyl.
  • R 2 is selected from
  • R 3 is C 1-6 alkyl. In some embodiments, R 3 is C 1-6 haloalkyl. [0169] In some embodiments, R 3 is selected from . [0170] In some embodiments, R 3 is selected from [0171] In some embodiments, provided herein is a compound selected from Table A-3, Table A-3A, or Table A-4, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof. [0172] Provided herein is a compound selected from Table A-3, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof. TABLE A-3
  • a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, and a pharmaceutically acceptable carrier.
  • a pharmaceutically acceptable carrier comprising a compound described herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof.
  • Ring B is C 5-10 cycloalkyl, 4- to 9-membered heterocyclyl, or 5- to 10-membered heteroaryl, wherein each cycloalkyl, heterocyclyl, or heteroaryl is independently optionally substituted with one to six Z 1 ;
  • Ring C is 4- to 9-membered heterocyclyl or 5- to 10-membered heteroaryl; wherein the 4- to 9- membered heterocyclyl or 5- to 10-membered heteroaryl is independently optionally substituted with one to six Z 1 ;
  • R 1 is where R is C 1-6 alkyl or halo;
  • R 2 is hydrogen or alkoxyalkyl; each Z 1 is independently C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxyalky
  • Ring C is: where Y is -CH 2 - or -S(O) 2 -; X 1 , X 2 , X 3 , and X 4 are independently chosen from CR 4 and N, provided that at least three of X 1 , X 2 , X 3 , and X 4 are CR 4 ; R 3 is C 1-6 alkyl, C 3-7 cycloalkyl, or (C 3-7 cycloalkyl)alkyl; each R 4 is independently hydrogen, halo, C 1-6 alkyl optionally substituted with 1 to 3 halo, C 1-6 alkoxy optionally substituted with 1 to 3 halo, cyano, -N(R 5 ) 2 , -NH-S(O) 2 -R 5 , -C(O)OR 5 , or -C(O)NR 5 2; each R 5 is independently hydrogen, C 1-6 alkyl,
  • the moiety comprises stereoisomers and all such stereoisomers and mixtures of stereoisomers are included within the scope of embodiments presented herein.
  • Ring B is: optionally substituted with C1 6 alkyl or C1 6 alkoxyalkyl
  • provided is a compound of Formula B-I, wherein R 1 is .
  • provided is a compound of Formula B-I, wherein R 1 is .
  • provided is a compound of Formula I, wherein R 1 is .
  • provided is a compound of Formula B-I, wherein R 1 is .
  • n , R 9 , and Ring B are each independently as defined herein.
  • ring B is selected from ring C is selected from [0186]
  • Y is CH 2 .
  • Y is S(O) 2 .
  • R 4 is selected from C 1-6 alkyl, C 1-6 haloalkyl, halo, cyano, -OR 10 , -C(O)OR 10 , - C(O)N(R 10 ) 2 , and -NR 10 S(O)1-2R 10 .
  • R 4 is selected from -CH 3 , -CH 2 CH 3 , -CF3, -CN, halo, -OCH 3 , -OCF3, -C(O)OH, and -C(O)NH2.
  • ring B is selected from ring C is [0189]
  • R 9 is selected from
  • R 3 is selected from [0191] . In some embodiments, R 3 is selected from [0192] In some embodiments, R 2 is hydrogen. In some embodiments, n is 1 or 2.
  • administering refers to introducing an agent into a patient.
  • a therapeutic amount can be administered to the patient, which can be determined by the treating physician, medical professional, or the like.
  • an oral route of administration is provided.
  • the related terms and phrases “administering” and “administration of,” when used in connection with a compound or tablet (and grammatical equivalents) refer both to direct administration, which may be administration to a patient by a medical professional or by self-administration by the patient, and/or to indirect administration, which may be the act of prescribing a drug. Administration entails delivery to the patient of the drug.
  • Treatment is an approach for obtaining beneficial or desired results including clinical results.
  • beneficial or desired clinical results may include one or more of the following: a) inhibiting the disease or condition (e.g., decreasing one or more symptoms resulting from the disease or condition, and/or diminishing the extent of the disease or condition); b) slowing or arresting the development of one or more clinical symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, preventing or delaying the worsening or progression of the disease or condition, and/or preventing or delaying the spread (e.g., metastasis) of the disease or condition); and/or c) relieving the disease, that is, causing the regression of clinical symptoms (e.g., ameliorating the disease state, providing partial or total remission of the disease or condition, enhancing effect of another medication, delaying the progression of the disease, increasing the quality of life and/or prolonging survival.
  • a) inhibiting the disease or condition e.g., decreasing one or more symptoms resulting from the disease or condition,
  • treating does not encompass preventing.
  • prevention or “preventing” means any treatment of a disease or condition that causes the clinical symptoms of the disease or condition not to develop Compounds may in some embodiments be administered to a subject (including a human) who is at risk or has a family history of the disease or condition.
  • Subject or “patient” refers to an animal, such as a mammal (including a human), that has been or will be the object of treatment, observation, or experiment. The methods described herein may be useful in human therapy and/or veterinary applications.
  • the subject is a mammal.
  • the subject is a human.
  • terapéuticaally effective amount or “effective amount” of a compound described herein or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers or prodrug thereof means an amount sufficient to effect treatment when administered to a subject, to provide a therapeutic benefit such as amelioration of symptoms or slowing of disease progression.
  • a therapeutically effective amount may be an amount sufficient to decrease a symptom of a disease or condition of as described herein.
  • the therapeutically effective amount may vary depending on the subject, and disease or condition being treated, the weight and age of the subject, the severity of the disease or condition, and the manner of administering, which can readily be determined by one of ordinary skill in the art.
  • dose refers to the total amount of an active agent (e.g., the dual-acting angiotensin and endothelin receptor antagonist, or a pharmaceutically acceptable salt thereof) administered to a patient in a single day (24-hour period).
  • the desired dose can be administered once daily.
  • the desired dose may be administered in one, two, three, four or more sub-doses at appropriate intervals throughout the day, where the cumulative amount of the sub-doses equals the amount of the desired dose administered in a single day.
  • dose and “dosage” are used interchangeably herein.
  • “In vivo” means within a living individual, as within an animal or human. In this context, the methods described herein may be used therapeutically in an individual. “Ex vivo” means outside of a living individual. Examples of ex vivo cell populations include in vitro cell cultures and biological samples including fluid or tissue samples obtained from individuals. Such samples may be obtained by methods well known in the art. Exemplary biological fluid samples include blood, cerebrospinal fluid, urine and saliva.
  • the compounds and compositions described herein may be used for a variety of purposes, including therapeutic and experimental purposes. For example, the compounds and compositions described herein may be used ex vivo to determine the optimal schedule and/or dosing of administration of a compound of the present disclosure for a given indication, cell type, individual, and other parameters.
  • idiopathic pulmonary fibrosis comprising administering a therapeutically effective amount of a compound disclosed herein (e.g., of formula A-I or B- I), or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, to a patient in need thereof.
  • a DARA agent such as compound disclosed herein (e.g., of formula A-I or B-I), or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, certain side effects associated with known therapy may be avoided.
  • idiopathic pulmonary fibrosis in a patient in need thereof, comprising administering a compound disclosed herein (e.g., of formula A-I or B-I), or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, and having reduced side effects in said patient, selected from diarrhea, gastrointestinal distress, nausea, photosensitivity, and combinations thereof.
  • a compound disclosed herein e.g., of formula A-I or B-I
  • a pharmaceutically acceptable salt isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof
  • a composition comprising a therapeutically effective amount of a compound disclosed herein (e.g., of formula A-I or B-I), or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, and a pharmaceutically acceptable carrier, to a patient in need thereof.
  • the therapeutically effective amount of a compound disclosed herein e.g., of formula A-I or B-I
  • a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof treats idiopathic pulmonary fibrosis in a patient in need thereof by suppressing lung epithelial inflammation and fibrosis.
  • the therapeutically effective amount of a compound disclosed herein e.g., of formula A-I or B-I
  • a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof treats idiopathic pulmonary fibrosis in a patient in need thereof by suppressing lung myofibroblast phenotypic transition.
  • the compounds disclosed herein are antagonists of both endothelin and angiotensin and are also useful in treatment of conditions associated with increased ET levels and/or increased angiotensin levels and treatment of all endothelin-dependent or angiotensin -dependent disorders.
  • the compounds provided herein are useful for treating hypertension, and also in treatment of portal hypertension, hypertension secondary to treatment with erythropoietin and low renin hypertension, pulmonary arterial hypertension (PAH).
  • PAH pulmonary arterial hypertension
  • the compounds provided herein are useful in the treatment of disorders related to renal, glomerular and mesangial cell function, including acute (such as ischemic, nephrotoxic, or glomerulonephritis) and chronic (such as diabetic, hypertensive or immune-mediated) renal failure, diabetic nephropathy, glomerular injury, renal damage secondary to old age or related to dialysis, nephrosclerosis (especially hypertensive nephrosclerosis), nephrotoxicity (including nephrotoxicity related to imaging and contrast agents and to cyclosporine), renal ischemia, primary vesicoureteral reflux, proteinuric glomerular diseases, glomerulosclerosis, focal segmental glomerulosclerosis (FSGS),kidney disease such as chronic kidney disease (CKD), and the like.
  • acute such as ischemic, nephrotoxic, or glomerulonephritis
  • chronic renal failure such as diabetic, hypertensive or immune-mediated renal failure
  • the compounds provided herein are useful in the treatment of disorders related to paracrine and endocrine function, diabetic nephropathy, hypertension- induced nephropathy, IGA-induced nephropathy, endotoxemia or endotoxin shock, hemorrhagic shock, in alleviation of pain associated cancer, such as the pain associated with prostate cancer, and bone pain associated with bone cancer, in the prevention and/or reduction of end-organ damage associated with the cell- proliferative effects of endothelin, hypoxic and ischemic disease, for example, cardiac, renal and cerebral ischemia and reperfusion (such as that occurring following cardiopulmonary bypass surgery), coronary and cerebral vasospasm, and the like.
  • the compounds provided herein are useful as anti-arrhythmic agents; anti-anginal agents; anti-fibrillatory agents; anti-asthmatic agents; anti-atherosclerotic and anti-arteriosclerotic agents (including anti-transplantation arteriosclerotic agents); additives to cardioplegic solutions for cardiopulmonary bypasses; adjuncts to thrombolytic therapy; and anti-diarrheal agents.
  • the compounds of may be useful in therapy for myocardial infarction; therapy for peripheral vascular disease (e.g., Raynaud’s disease, intermittent claudication and Takayasu’s disease); treatment of cardiac hypertrophy (e.g., hypertrophic cardiomyopathy); treatment of primary pulmonary hypertension (e.g., plexogenic, embolic) in adults and in the newborn and pulmonary hypertension secondary to heart failure, radiation and chemotherapeutic injury, or other trauma; treatment of central nervous system vascular disorders, such as stroke, migraine and subarachnoid hemorrhage; treatment of central nervous system behavioral disorders; treatment of gastrointestinal diseases such as ulcerative colitis, Crohn’s disease, gastric mucosal damage, ulcer, inflammatory bowel disease and ischemic bowel disease; treatment of gall bladder or bile duct-based diseases such as cholangitis; treatment of pancreatitis; regulation of cell growth; treatment of benign prostatic hypertrophy; restenosis following angioplasty or following any procedure including transplantation
  • the compounds are useful in therapy for metabolic and neurological disorders; cancer; insulin-dependent and non-insulin-dependent diabetes mellitus; neuropathy; retinopathy; epilepsy; hemorrhagic and ischemic stroke; bone remodeling; psoriasis; and chronic inflammatory diseases such as arthritis, rheumatoid arthritis, osteoarthritis, sarcoidosis and eczematous dermatitis (all types of dermatitis).
  • the compounds described herein are useful in the treatment of disorders involving bronchoconstriction and disorders of chronic or acute pulmonary inflammation such as chronic obstructive pulmonary disease (COPD) and adult respiratory distress syndrome (ARDS), sexual dysfunction in both men (erectile dysfunction, for example, due to diabetes mellitus, spinal cord injury, radical prostatectomy, psychogenic etiology or any other cause) and women by improving blood flow to the genitalia, especially, the corpus cavernosum.
  • the compounds described herein are useful in the treatment of dementia, including Alzheimer’s dementia, senile dementia and vascular dementia, and in the reduction of general morbidity and/or mortality as a result of any of the conditions described above.
  • the patient is 50 years of age or older. In some embodiments, the patient is less than 50 years of age. [0213] In some embodiments, the patient is a smoker. In some embodiments, the patient is not a smoker. [0214] In some embodiments, the patient also suffers from gastroesophageal reflux disease (GERD). In some embodiments, the patient does not also suffer from gastroesophageal reflux disease. [0215] In some embodiments, the patient requires supplemental oxygen. In some embodiments, the patient does not require supplemental oxygen.
  • the patient has a genetic mutation in one or more of the MUC5B, TERT, TERC, RTEL1, PARN, SFTPC, or SFTPA2 genes.
  • the patient has a genetic mutation in the MUC5B gene.
  • the patient has a genetic mutation in the TERT gene.
  • the patient has a genetic mutation in the TERC gene.
  • the patient has a genetic mutation in the RTEL1 gene.
  • the patient has a genetic mutation in the PARN gene.
  • the patient has a genetic mutation in the SFTPC gene.
  • the patient has a genetic mutation in the SFTPA2 gene.
  • the patient has a genetic mutation in more than one gene, said gene selected from the MUC5B, TERT, TERC, RTEL1, PARN, SFTPC, and SFTPA2 genes.
  • the therapeutically effective amount of the dual-acting angiotensin and endothelin receptor antagonist, or a pharmaceutically acceptable salt thereof is administered once daily. In some embodiments, the therapeutically effective amount of the dual-acting angiotensin and endothelin receptor antagonist, or a pharmaceutically acceptable salt thereof, is administered over two doses in a day.
  • the therapeutically effective amount of the dual-acting angiotensin and endothelin receptor antagonist, or a pharmaceutically acceptable salt thereof is formulated for oral administration.
  • the therapeutically effective amount of the dual-acting angiotensin and endothelin receptor antagonist, or a pharmaceutically acceptable salt thereof is in tablet form or capsule form.
  • the therapeutically effective amount of the dual-acting angiotensin and endothelin receptor antagonist, or a pharmaceutically acceptable salt thereof is formulated as an amorphous solid dispersion.
  • the therapeutically effective amount of the dual-acting angiotensin and endothelin receptor antagonist, or a pharmaceutically acceptable salt thereof is formulated for parenteral administration.
  • the therapeutically effective amount of the dual-acting angiotensin and endothelin receptor antagonist, or a pharmaceutically acceptable salt thereof is formulated for inhalation.
  • the therapeutically effective amount of the dual-acting angiotensin and endothelin receptor antagonist, or a pharmaceutically acceptable salt thereof is about 50 mg/day to about 1000 mg/day.
  • the therapeutically effective amount of the dual-acting angiotensin and endothelin receptor antagonist, or a pharmaceutically acceptable salt thereof is about 100 mg/day to about 900 mg/day. In some embodiments, the therapeutically effective amount of the dual-acting angiotensin and endothelin receptor antagonist, or a pharmaceutically acceptable salt thereof, is about 200 mg/day to about 800 mg/day. In some embodiments, the therapeutically effective amount of the dual-acting angiotensin and endothelin receptor antagonist, or a pharmaceutically acceptable salt thereof, is about 400 mg/day to about 600 mg/day.
  • the therapeutically effective amount of the dual-acting angiotensin and endothelin receptor antagonist, or a pharmaceutically acceptable salt thereof is about 200 mg/day. In some embodiments, the therapeutically effective amount of the dual-acting angiotensin and endothelin receptor antagonist, or a pharmaceutically acceptable salt thereof, is about 400 mg/day. In some embodiments, the therapeutically effective amount of the dual-acting angiotensin and endothelin receptor antagonist, or a pharmaceutically acceptable salt thereof, is about 600 mg/day. In some embodiments, the therapeutically effective amount of the dual-acting angiotensin and endothelin receptor antagonist, or a pharmaceutically acceptable salt thereof, is about 800 mg/day.
  • the dual-acting angiotensin and endothelin receptor antagonist, or a pharmaceutically acceptable salt thereof is dosed at about 400 mg/day to a patient in need thereof, in order to treat idiopathic pulmonary fibrosis, while reducing the occurrence of at least one known side effect of currently known IPF therapies, including, but not limited to, diarrhea, gastrointestinal distress, nausea, disinterest in eating, and photosensitivity.
  • methods provided herein further comprise administering one or more of an additional therapeutic agent.
  • the additional therapeutic agent is an anti-inflammatory agent.
  • the anti-inflammatory agent is a corticosteroid, such as beclomethasone, betamethasone, budesonide, clobetasol, flunisolide, fluocinolone, fluocinonide, fluticasone, halobetasol, hydrocortisone, methylprednisone, mometasone, prednisolone, prednisone, and triamcinolone.
  • the anti-inflammatory agent is a non-steroidal anti-inflammatory (NSAIDs), such as a non- selective COX inhibitor or a selective COX-2 inhibitor.
  • NSAIDs non-steroidal anti-inflammatory
  • Non-selective COX inhibitors include, but are not limited to, salicylic acid derivates (e.g., aspirin, sodium salicylates, choline magnesium trisalicylate, salsalate, diflunisal, sulfasalazine, mesalamine, and olsalazine), para-aminophenol derivatives (e.g., acetaminophen), indole and indene acetic acids (e.g., tolmetin, diclofenac, and ketorolac), heteroaryl acetic acids (e.g., flurbiprofen, ketoprofen, fenprofen, ibuprofen, naproxen, and oxaprozin), anthranilic acids or fenamates (e.g., mefenamic acid and meclofenamic acid), enolic acids (e.g., piroxicam and meloxicam), and alkanones
  • Selective COX-2 inhibitors include, but are not limited to, diaryl-substituted pyrazoles (e.g., celecoxib), indole acetic acids (e.g., etodolac), and sulfonanilides (e.g., nimesulide).
  • the additional therapeutic agent is an immunosuppressive agent.
  • Non-limiting examples of immunosuppressive agents include methotrexate, cyclophosphamide, mizoribine, chlorambucil, cyclosporine, tacrolimus, mycophenolate mofetil, azathioprine, sirolimus, deoxyspergualin, leflunomide, and its malononitriloamide analogs.
  • kits that include a compound of the disclosure, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers or prodrug thereof, and suitable packaging.
  • a kit further includes instructions for use.
  • a kit includes a compound of the disclosure, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers or prodrug thereof, and a label and/or instructions for use of the compounds in the treatment of the indications, including the diseases or conditions, described herein.
  • compositions and modes of Administration Compounds provided herein are usually administered in the form of pharmaceutical compositions.
  • pharmaceutical compositions that contain one or more of the compounds described herein a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers or prodrug thereof and one or more pharmaceutically acceptable vehicles selected from carriers, adjuvants and excipients.
  • Suitable pharmaceutically acceptable vehicles may include, for example, inert solid diluents and fillers, diluents, including sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers and adjuvants.
  • Such compositions are prepared in a manner well known in the pharmaceutical art. See, e.g., Remington’s Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa.17th Ed. (1985); and Modern Pharmaceutics, Marcel Dekker, Inc.3rd Ed. (G.S. Banker & C.T. Rhodes, Eds.).
  • the pharmaceutical compositions may be administered in either single or multiple doses.
  • the pharmaceutical composition may be administered by various methods including, for example, rectal, buccal, intranasal and transdermal routes.
  • the pharmaceutical composition may be administered by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, or as an inhalant.
  • intra-arterial injection intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, or as an inhalant.
  • parenteral for example, by injection.
  • Oral administration may be another route for administration of the compounds described herein. Administration may be via, for example, capsule or enteric coated tablets.
  • the active ingredient is usually diluted by an excipient and/or enclosed within such a carrier that can be in the form of a capsule, sachet, paper or other container.
  • a carrier that can be in the form of a capsule, sachet, paper or other container.
  • the excipient serves as a diluent, it can be in the form of a solid, semi- solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient.
  • compositions can be in the form of tablets pills powders lozenges sachets cachets elixirs suspensions emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injectable solutions, and sterile packaged powders.
  • excipients include, e.g., lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup and methyl cellulose.
  • the formulations can additionally include lubricating agents such as talc, magnesium stearate and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl and propylhydroxy-benzoates; sweetening agents; and flavoring agents.
  • compositions that include at least one compound described herein or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers or prodrug thereof can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the subject by employing procedures known in the art.
  • Controlled release drug delivery systems for oral administration include osmotic pump systems and dissolutional systems containing polymer-coated reservoirs or drug-polymer matrix formulations.
  • Another formulation for use in the methods disclosed herein employ transdermal delivery devices (“patches”). Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds described herein in controlled amounts.
  • the construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art.
  • Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.
  • the principal active ingredient may be mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound described herein or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers or prodrug thereof.
  • the active ingredient may be dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.
  • the tablets or pills of the compounds described herein may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action, or to protect from the acid conditions of the stomach.
  • the tablet or pill can include an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
  • the two components can be separated by an enteric layer that serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release.
  • enteric layers or coatings such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.
  • compositions for inhalation or insufflation may include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders.
  • the liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described herein.
  • the compositions are administered by the oral or nasal respiratory route for local or systemic effect.
  • compositions in pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be inhaled directly from the nebulizing device or the nebulizing device may be attached to a facemask tent, or intermittent positive pressure breathing machine.
  • Solution, suspension, or powder compositions may be administered, e.g., orally or nasally, from devices that deliver the formulation in an appropriate manner.
  • Dosing [0240] The specific dose level of a compound of the present application for any particular subject will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination and the severity of the particular disease in the subject undergoing therapy. For example, a dosage may be expressed as a number of milligrams of a compound described herein per kilogram of the subject’s body weight (mg/kg). Dosages of between about 0.1 and 150 mg/kg may be appropriate.
  • 0.1 and 100 mg/kg may be appropriate. In other embodiments a dosage of between 0.5 and 60 mg/kg may be appropriate. In some embodiments, a dosage of from about 0.0001 to about 100 mg per kg of body weight per day, from about 0.001 to about 50 mg of compound per kg of body weight, or from about 0.01 to about 10 mg of compound per kg of body weight may be appropriate. Normalizing according to the subject’s body weight is particularly useful when adjusting dosages between subjects of widely disparate size, such as occurs when using the drug in both children and adult humans or when converting an effective dosage in a non-human subject such as dog to a dosage suitable for a human subject.
  • the compounds may be prepared using the methods disclosed herein and routine modifications thereof, which will be apparent given the disclosure herein and methods well known in the art. Conventional and well-known synthetic methods may be used in addition to the teachings herein. The synthesis of typical compounds described herein may be accomplished as described in the following examples. If available, reagents and starting materials may be purchased commercially, e.g., from Sigma Aldrich or other chemical suppliers. [0242] It will be appreciated that where typical process conditions (i.e., reaction temperatures, times, mole ratios of reactants solvents pressures etc) are given other process conditions can also be used unless otherwise stated.
  • Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures.
  • conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions.
  • Suitable protecting groups for various functional groups as well as suitable conditions for protecting and deprotecting particular functional groups are well known in the art. For example, numerous protecting groups are described in Wuts, P. G. M., Greene, T. W., & Greene, T. W. (2006). Greene's protective groups in organic synthesis. Hoboken, N.J., Wiley-Interscience, and references cited therein.
  • the compounds of this disclosure may contain one or more chiral centers.
  • stereoisomers i.e., as individual enantiomers or diastereomers or as stereoisomer-enriched mixtures. All such stereoisomers (and enriched mixtures) are included within the scope of this disclosure, unless otherwise indicated. Pure stereoisomers (or enriched mixtures) may be prepared using, for example, optically active starting materials or stereoselective reagents well-known in the art. Alternatively, racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, chiral resolving agents, and the like. [0245] The starting materials for the following reactions are generally known compounds or can be prepared by known procedures or obvious modifications thereof.
  • each t, R 1 and R 2 are independently as defined herein, LG is a leaving group (e.g., halo, such as bromo or chloro), and PG is an amine protecting group (e.g., methoxymethyl).
  • Scheme A-I [0247] Referring to Scheme A-I, compound A-I-3 can be provided by contacting amino isoxazole, compound A-I-1, with 2-bromobenzenesulfonyl chloride, compound A-I-2, under standard basic conditions, including, but not limited to, pyridine, 4-dimethylaminopyridine, and the like.
  • Protecting compound A-I-3 with an appropriate amine protecting group including, but not limited to, a methyoxymethyl ether group, under conditions known to those of skill in the art can provide compound A-I-4.
  • methoxymethyl ether is illustrative only, and other conventional amine protecting groups, such as benzyl, 9- fluorenylmethoxycarbonyl (Fmoc), benzyloxycarbonyl (Cbz), p-nitrobenzyloxycarbonyl, and the like could be used.
  • boronic ester compounds of formula A-I-6 can be prepared by contacting bromobenzaldehyde compounds of formula A-I-5 with bis(pinacolato)diboron in the presence of a suitable catalyst, including, but not limited to, PdCl2(dppf), PdCl2(PPh3) 2 , and the like, under conditions known to those of skill in the art.
  • a suitable catalyst including, but not limited to, PdCl2(dppf), PdCl2(PPh3) 2 , and the like, under conditions known to those of skill in the art.
  • Suzuki coupling of boronic ester compounds of formula A-I-6 with protected aryl sulfonamide compounds of formula A-I-4, in the presence of a suitable catalyst, including, but not limited to, PdCl 2 (dppf), PdCl 2 (PPh 3 ) 2 , and the like, under conditions known to those of skill in the art, can provide for biphenyl sulfonamide compounds of formula A-I-7.
  • the aldehyde of biphenyl sulfonamide compounds of formula A-I-7 can be reduced in the presence of a suitable reducing agent, such as sodium borohydride and the like, to provide for benzyl alcohol compounds of formula A-I-8.
  • a suitable reducing agent such as sodium borohydride and the like
  • Conversion of the primary alcohol of compounds of formula A-I-8 to a suitable leaving group in compounds of formula A-I-9 can be accomplished by contacting compounds of formula A-I-8 with a suitable reagent to active the alcohol to an SN2 displacement from a selected nucleophile, including, but not limited to, the Appel reaction using triphenylphosphine and a carbon tetrahalide, methanesulfonyl chloride and a bulky base (e.g., DIPEA, etc.), and the like, under conditions known to those of skill in the art.
  • a suitable reagent including, but not limited to, the Appel reaction using triphenylphosphine and a carbon tetrahalide, methanesulfonyl chloride and a bulky base (e.g., DIPEA, etc.), and the like, under conditions known to those of skill in the art.
  • each of the intermediate or final compounds can be recovered, and optionally purified, by conventional techniques such as neutralization, extraction, precipitation, chromatography, filtration, and the like. Other modifications to arrive at compounds of this disclosure are within the skill of the art.
  • the compounds of this disclosure may contain one or more chiral centers.
  • stereoisomers i.e., as individual enantiomers or diastereomers, or as stereoisomer-enriched mixtures. All such stereoisomers (and enriched mixtures) are included within the scope of this disclosure, unless otherwise indicated.
  • Pure stereoisomers (or enriched mixtures) may be prepared using, for example, optically active starting materials or stereoselective reagents well-known in the art.
  • racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, chiral resolving agents, and the like. It should be appreciated that various isomers of formula A-I can be separated as well.
  • each R 1 , R 2 , X, Ring A, and Ring B are independently as defined herein, LG is a leaving group (e.g., halo, such as bromo or chloro), and PG is an amine protecting group (e.g., methoxymethyl).
  • LG is a leaving group (e.g., halo, such as bromo or chloro)
  • PG is an amine protecting group (e.g., methoxymethyl).
  • compound B-I-3 can be provided by contacting heteroaryl amine, compound B-I-1, with 2-halobenzenesulfonyl chloride, compound B-I-2, under standard basic conditions, including, but not limited to, pyridine, 4-dimethylaminopyridine, and the like.
  • Protecting compound B-I-3 with an appropriate amine protecting group, including, but not limited to, a methyoxymethyl ether group, under conditions known to those of skill in the art can provide compound B-I-4.
  • methoxymethyl ether is illustrative only, and other conventional amine protecting groups, such as benzyl, 9- fluorenylmethoxycarbonyl (Fmoc), benzyloxycarbonyl (Cbz), p-nitrobenzyloxycarbonyl, and the like could be used.
  • Scheme B-II [0253] Referring to Scheme B-II, forming phenyl-Ring B bicycle compounds of formula B-I-7-A, when the attachment point in Ring B is a carbon atom, proceed through general synthetic pathway A.
  • Boronic ester compounds of formula B-I-6-A can be prepared by contacting bromo compounds of formula B-I-5-A with bis(pinacolato)diboron in the presence of a suitable catalyst, including, but not limited to, PdCl 2 (dppf), PdCl 2 (PPh 3 ) 2 , and the like, under conditions known to those of skill in the art.
  • a suitable catalyst including, but not limited to, PdCl 2 (dppf), PdCl 2 (PPh 3 ) 2 , and the like, under conditions known to those of skill in the art, can provide for bicyclic sulfonamide compounds of formula B-I- 7-A.
  • a suitable catalyst including, but not limited to, PdCl 2 (dppf), PdCl 2 (PPh 3 ) 2 , and the like, under conditions known to those of skill in the art, can provide for bicyclic sulfonamide compounds
  • Bicyclic sulfonamide compounds of formula B-I-7-B can be prepared by contacting cyclic amine compounds of formula B-I-6-B with protected aryl sulfonamide compounds of formula B- I-4, in the presence of a suitable base, such as sodium hydride, cesium carbonate, potassium carbonate, and the like, under conditions known to those of skill in the art.
  • a suitable base such as sodium hydride, cesium carbonate, potassium carbonate, and the like
  • the ester of bicyclic compounds of Formula B-I-7-A, or the aldehyde of bicyclic compounds of formula B-I-7-B can be reduced in the presence of a suitable reducing agent, such as diisobutyl aluminum hydride, sodium borohydride, and the like, to provide for bicyclic alcohol compounds of formula B-I-8.
  • Conversion of the primary alcohol of compounds of formula B-I-8 to a suitable leaving group in compounds of formula B-I-9 can be accomplished by contacting compounds of formula B-I-8 with a suitable reagent to activate the alcohol to an SN2 displacement from a selected nucleophile, including, but not limited to, the Appel reaction using triphenylphoshine and a carbon tetrahalide, methanesulfonyl chloride and a bulky base (e.g., DIPEA, etc.), and the like, under conditions known to those of skill in the art.
  • a suitable reagent to activate the alcohol to an SN2 displacement from a selected nucleophile, including, but not limited to, the Appel reaction using triphenylphoshine and a carbon tetrahalide, methanesulfonyl chloride and a bulky base (e.g., DIPEA, etc.), and the like, under conditions known to those of skill in the art.
  • the compounds of this disclosure may contain one or more chiral centers. Accordingly, if desired, such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers, or as stereoisomer-enriched mixtures. All such stereoisomers (and enriched mixtures) are included within the scope of this disclosure, unless otherwise indicated. Pure stereoisomers (or enriched mixtures) may be prepared using, for example, optically active starting materials or stereoselective reagents well-known in the art. Alternatively, racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, chiral resolving agents, and the like.
  • Step-1 Synthesis of 4-bromo-3-(bromomethyl)benzonitrile (2) [0260] To a stirred solution of 4-bromo-3-methylbenzonitrile (150 g, 0.765 mol) in CCl4 (1500 mL) was added BPO (18.5 g, 0.0765 mol) and NBS (135 g, 0.765 mol) at RT and warmed to 80 °C for 8 h.
  • Step-2 Synthesis of 4-bromo-3-(ethoxymethyl)benzo nitrile (3)
  • ethanol 450 mL
  • DMF 450 mL
  • 4-bromo-3-(bromomethyl) benzonitrile 90 g 327.345 mmol
  • the reaction mixture was stirred at rt for 4h. After completion of the reaction (monitored by TLC/LCMS) the reaction mixture was diluted with water and extracted with ethyl acetate (2x200 mL).
  • Step-3 Synthesis of 4-bromo-3-(ethoxymethyl)benzaldehyde (4)
  • 4-bromo-3-(ethoxymethyl)benzaldehyde (4) To a stirred solution of 4-bromo-3-(ethoxymethyl) benzo nitrile (65 g, 249.90 mmol) in DCM (650 mL), was added1 M DIBAL-H in toluene solution (541 mL, 750.0 mmol) at -78 °C, allowed to warm to rt and stirred for 1h at RT. After completion of reaction (monitored by TLC/LCMS) the reaction mixture was quenched with 6N HCl solution (250 mL) and, water (100 mL).
  • Step-4 Synthesis of 3-(ethoxymethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzaldehyde (5)
  • 4-bromo-3-(ethoxymethyl) benzaldehyde 55 g, 227.273 mmol
  • 1,4 dioxane 550 mL
  • 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (86 g 340.909 mmol) and potassium acetate (67 g, 681.818 mmol) at RT.
  • reaction mixture was degassed by bubbling N2 for 5 min, then PdCl2(dppf)DCM (28 g, 34.091 mmol) was added.
  • the reaction mixture was then heated to 90°C and stirred for 4h.
  • the reaction mixture was cooled to rt then filtered through a celite bed washed with ethyl acetate (500 mL) concentrated under reduced pressure to afford crude material.
  • the crude material thus obtained was purified by column chromatography (silica gel) to afford 3-(ethoxymethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzaldehyde.
  • Step-5 Synthesis of N-(4,5-dimethylisoxazol-3-yl)-2'-(ethoxymethyl)-4'-Formyl-N-(methoxymethyl)- [1,1'-biphenyl]-2-sulfonamide (6)
  • 2-bromo-N-(4,5-dimethylisoxazol-3-yl)-N-(methoxymethyl) benzenesulfonamide 60 g, 160 mmol
  • 1,4 dioxane: H2O 540:60 mL
  • 3-(ethoxymethyl)-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzaldehyde 55.680 g, 192.000 mmol
  • potassium carbonate 66 g, 480.00 mmol
  • reaction mixture was degassed using N2 bubbling for 5 min, then Pd(dppf)DCM (13 g, 16.00 mmol) was added.
  • the reaction mixture was heated to 90°C and stirred for 8 h. After completion of the reaction (monitored by TLC/LCMS), the reaction mixture was cooled to rt, filtered through a celite bed, washed with ethyl acetate (500 mL) and concentrated under reduced pressure.
  • Step-6 Synthesis of N-(4,5-dimethylisoxazol-3-yl)-2'-(ethoxymethyl)-4'-(hydroxymethyl)-N- (methoxymethyl)-[1,1'-biphenyl]-2-sulfonamide (7)
  • N-(4,5-dimethylisoxazol-3-yl)-2'-(ethoxymethyl)-4'-Formyl-N- (methoxymethyl)-[1,1'-biphenyl]-2-sulfonamide 49 g, 0.104 mol
  • MeOH 480 mL
  • sodium borohydride (19.9 g, 0.524 mol
  • Example Intermediate A-B Synthesis of 2-bromo-N-(4,5-dimethylisoxazol-3-yl)-N- (methoxymethyl)benzenesulfonamide (11)
  • Step-1 Synthesis of 2-bromo-N-(4,5-dimethylisoxazol-3-yl) benzenesulfonamide (10) [0266] To a solution of commercially available 4,5-dimethylisoxazol-3-amine (150 g, 1.34 mol) in pyridine (750 mL), was added 4-(dimethylamine) pyridine (16.36 g, 0.134 mol).
  • Step-2 Synthesis of 2-bromo-N-(4,5-dimethylisoxazol-3-yl)-N-(methoxymethyl)benzenesulfonamide (11) [0267] To a stirred solution of 2-bromo-N-(4,5-dimethylisoxazol-3-yl) benzenesulfonamide (300 g, 0.906 mol) in DMF (800 mL), was added K 2 CO 3 (125.1 g, 0.906 mmol). The reaction mixture was cooled to 0 °C using ice-salt bath, was added 2-methoxyethoxymethyl chloride (68.83 g, 0.906 mol) dropwise over 20 min.
  • Step-1 Synthesis of benzyl 3-amino-3-cyanopiperidine-1-carboxylate (13) [0268] To a stirred solution of benzyl-3-oxipiperidine-1-carboxylate (5 g, 21.5 mmol) in methanol (50 mL) was added aqueous ammonia solution (75 mL), followed by addition of ammonium chloride (2.3 g, 42.9 mmol) at rt.
  • Step-2 Synthesis of benzyl 3-cyano-3-pentanamidopiperidine-1-carboxylate (14) [0269] To a stirred solution of benzyl 3-amino-3-cyanopiperidine-1-carboxylate (4.5 g, 17.35 mmol) in DCM (80 mL) cooled to 0 o C, was added pentanoyl chloride (6.66 mL, 24.29 mmol), potassium carbonate (3.4 g, 24.29 mmol) in water (80 mL). The reaction mixture was stirred at 0 o C for 2h, then at rt overnight. The reaction mixture was diluted with water (50 mL), extracted with DCM (2 x 50 mL).
  • Step-3 Synthesis of benzyl 2-butyl-4-oxo-1,3,7-triazaspiro[4.5]dec-1-ene-7-carboxylate (15) [0270] To a stirred solution of benzyl 3-cyano-3-pentanamidopiperidine-1-carboxylate (3.6 g, 10.5 mmol) in n-propanol (60 mL) cooled to 0 o C, was added hydrogen chloride (4M in Dioxane) (36 mL, 104.8 mmol). The reaction mixture was heated to 50 o C, stirred overnight. The reaction was monitored by TLC and LCMS.
  • Example A-1 Synthesis of 4'-((2-butyl-7-(cyclopentanecarbonyl)-4-oxo-1,3,7-triazaspiro[4.5]dec-1-en- 3-yl)methyl)-N-(4,5-dimethylisoxazol-3-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide
  • Compound A-1) Step-1: Synthesis of 4'-(chloromethyl)-N-(3,4-dimethylisoxazol-5-yl)-2'-(ethoxymethyl)-N- (methoxymethyl)-[1,1'-biphenyl]-2-sulfonamide (16) [0271] To a solution of N-(3,4-dimethylisoxazol-5-yl)-2'-(ethoxymethyl)-4'-(hydroxymethyl)-N- (methoxymethyl)-[1,1'-biphenyl]-2-sul
  • Step-2 Synthesis of benzyl 2-butyl-3-((2'-(N-(4,5-dimethylisoxazol-3-yl)-N-(methoxymethyl)sulfamoyl)- 2-(ethoxymethyl)-[1,1'-biphenyl]-4-yl)methyl)-4-oxo-1,3,7-triazaspiro[4.5]dec-1-ene-7-carboxylate (17) [0272] To a solution of benzyl 2-butyl-4-oxo-1,3,7-triazaspiro[4.5]dec-1-ene-7-carboxylate (1.1 g, 3.21 mmol) in DMF (10 mL) at 0 °C, was added sodium hydride (0.18 g, 7.30 mmol) and the resulting mixture was stirred for 30 min.
  • Step-3 Synthesis of 4'-((2-butyl-4-oxo-1,3,7-triazaspiro[4.5]dec-1-en-3-yl)methyl)-N-(4,5- dimethylisoxazol-3-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide (Compound A-1) [0273] 2-Butyl-3-((2'-(N-(4,5-dimethylisoxazol-3-yl)-N-(methoxymethyl)sulfamoyl)-2-(ethoxymethyl)- [1,1'-biphenyl]-4-yl)methyl)-4-oxo-1,3,7-triazaspiro[4.5]dec-1-ene-7-carboxylate (0.8 g, 1.02 mmol) was dissolved in TFA (8 mL) and stirred at 60 °C for 1 hour.
  • Example A-2 Synthesis of 4'-((2-butyl-7-(cyclopentanecarbonyl)-4-oxo-1,3,7-triazaspiro[4.5]dec-1-en- 3-yl)methyl)-N-(4,5-dimethylisoxazol-3-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide (Compound A-9) [0274] To a stirred solution of 4'-((2-butyl-4-oxo-1,3,7-triazaspiro[4.5]dec-1-en-3-yl)methyl)-N-(4,5- dimethylisoxazol-3-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide (150 mg, 1 eq) in DMF (2 mL), were added HOBt (50 mg, 1.5 eq), EDC.HCl (71 mg, 1.5 eq) and DIPE
  • reaction mixture was stirred for 1h, then was added sodium cyanoborohydride (0.025 g, 0.395 mmol). The reaction mixture was stirred overnight at rt. The reaction mixture was concentrated, diluted with water (5 mL), extracted with DCM (2 x 5mL). The combined organic layers were washed with brine, concentrated under reduced pressure to afford to crude material. The crude material was purified by automated flash chromatography (silica gel).
  • the compound was further purified by preparative HPLC using Acquity BEH C18 (50mmx2.1mm, 1.7um) and A: 0.05% TFA in water; B: 0.05% TFA in ACN as mobile phase to afford 4'-((2-butyl-7-methyl-4-oxo- 1,3,7-triazaspiro[4.5]dec-1-en-3-yl)methyl)-N-(4,5-dimethylisoxazol-3-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]- 2-sulfonamide (TFA salt) Compound A-3.
  • Synthesis of Compounds A-6, A-11, A-12, and A-13 was carried out using the general procedure described for the synthesis of Compound A-9 using benzyl 3-oxopyrrolidine-1-carboxylate as a starting material instead of benzyl 3-oxopiperidine-1-carboxylate (12).
  • the following compounds were prepared using amine Compound A-1 and appropriate carboxylic acid using coupling reagent as demonstrated but not limited to in the synthetic procedure for Compound A-9.
  • Step-2 Synthesis of ethyl 2-(2-butyl-1-((2'-(N-(4,5-dimethylisoxazol-3-yl)-N- (methoxymethyl)sulfamoyl)-2-(ethoxymethyl)-[1,1'-biphenyl]-4-yl)methyl)-4-methyl-6-oxo-1,6- dihydropyrimidin-5-yl)acetate (20)
  • Step-3 Synthesis of 2-(2-butyl-1-((2'-(N-(4,5-dimethylisoxazol-3-yl)-N-(methoxymethyl)sulfamoyl)-2- (ethoxymethyl)-[1,1'-biphenyl]-4-yl)methyl)-4-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)acetic acid (21) [0282] To a stirred solution of ethyl 2-(2-butyl-1-((2'-(N-(4,5-dimethylisoxazol-3-yl)-N- (methoxymethyl)sulfamoyl)-2-(ethoxymethyl)-[1,1'-biphenyl]-4-y
  • reaction mixture was acidified with citric acid solution (50 mL) and extracted with DCM (2 x 50 mL). The combined organic layers were thoroughly washed with brine, concentrated under reduced pressure to afford the crude material.
  • the crude material was triturated with n- pentane to afford 2-(2-butyl-1-((2'-(N-(4,5-dimethylisoxazol-3-yl)-N-(methoxymethyl)sulfamoyl)-2- (ethoxymethyl)-[1,1'-biphenyl]-4-yl)methyl)-4-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)acetic acid 21.
  • Example A-4 Synthesis 4'-((2-butyl-4-methyl-6-oxo-5-(2-oxo-2-(piperazin-1-yl)ethyl)pyrimidin-1(6H)- yl)methyl)-N-(4,5-dimethylisoxazol-3-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide (Compound A-27)
  • Step-1 Synthesis of 4'-((2-butyl-4-methyl-6-oxo-5-(2-oxo-2-(piperazin-1-yl)ethyl)pyrimidin-1(6H)- yl)methyl)-N-(4,5-dimethylisoxazol-3-yl)-2'-(ethoxymethyl)-N-(methoxymethyl)-[1,1'-biphenyl]-2- sulfonamide (24) [0285] To a solution of 2-(2-butyl-1-((
  • Step-2 Synthesis 4'-((2-butyl-4-methyl-6-oxo-5-(2-oxo-2-(piperazin-1-yl)ethyl)pyrimidin-1(6H)- yl)methyl)-N-(4,5-dimethylisoxazol-3-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide (Compound A-27) [0286] 4'-((2-Butyl-4-methyl-6-oxo-5-(2-oxo-2-(piperazin-1-yl)ethyl)pyrimidin-1(6H)-yl)methyl)-N-(4,5- dimethylisoxazol-3-yl)-2'-(ethoxymethyl)-N-(methoxymethyl)-[1,1'-biphenyl]-2-sulfonamide (0.
  • Example A-5 Synthesis of 2-butyl-1-((2'-(N-(4,5-dimethylisoxazol-3-yl) sulfamoyl)-2-(ethoxymethyl)- [1,1'-biphenyl]-4-yl)methyl)-4-methyl-N-(1-methyl-1H-pyrazol-4-yl)-6-oxo-1,6-dihydropyrimidine-5- carboxamide (Compound A-91)
  • Step-1 Ethyl 2-butyl-6-methyl-4-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (27) [0289] To a stirred solution of pentanimidamide hydrochloride (12 g, 87.84 mmol) in EtOH (60 mL), were added diethyl2-ethylidenemalonate (19.6 mL,105.402 mmol) and KOH (10.84 g, 193.24 mmol) at rt and
  • Step-2 Ethyl 2-butyl-4-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxylate (28) [0290] To a stirred solution of ethyl 2-butyl-6-methyl-4-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (21 g, 92.807 mmol) in 1,4-dioxane (210 mL), was added K2CO3 (32.01 g, 232.018 mmol) and NBS (16.424 g, 92.807 mmol) and was added benzoyl peroxide (4.492 g, 18.561 mmol). The reaction mixture was stirred 85 °C for 5 h.
  • Step-3 Ethyl 2-butyl-1-((2'-(N-(4,5-dimethylisoxazol-3-yl)-N-(methoxymethyl) sulfamoyl)-2- (ethoxymethyl)-[1,1'-biphenyl]-4-yl)methyl)-4-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxylate (29) [0291] To a stirred solution of 4'-(bromomethyl)-N-(4,5-dimethylisoxazol-3-yl)-2'-(ethoxymethyl)-N- (methoxymethyl)-[1,1'-biphenyl]-2-sulfonamide (3.0 g, 5.731 mmol) in DMF (30 mL), was added ethyl 2- butyl-4-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxylate (1.418 g, 6.304 mmol) and
  • Step-4 2-butyl-1-((2'-(N-(4,5-dimethylisoxazol-3-yl)-N-(methoxymethyl)sulfamoyl)-2-(ethoxymethyl)- [1,1'-biphenyl]-4-yl)methyl)-4-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxylic acid (30) [0292] To a stirred solution of ethyl 2-butyl-1-((2'-(N-(4,5-dimethylisoxazol-3-yl)-N-(methoxymethyl) sulfamoyl)-2-(ethoxymethyl)-[1,1'-biphenyl]-4-yl) methyl)-4-methyl-6-oxo-1,6-dihydropyrimidine-5- carboxylate (1.8 g, 2.644 mmol) in MeOH: THF: H2O (5:5:2) (18 mL), was added
  • reaction mixture was stirred for 30 min, was added 1-methyl- 1H-pyrazol-4-amine (0.565 g, 5.821 mmol) and stirred at rt for 16 h. After completion of the reaction (monitored by TLC /LCMS), reaction mixture was diluted with ice cold water and extracted with ethyl acetate (3x100 mL). The combined organic layers were washed with water, brine, dried over Na 2 SO 4 , filtered and concentrated. The crude material thus obtained was purified by column chromatography to afford the title compound. (1.1 g, 52%), LCMS; [M+H] + : 732.58.
  • Step-6 2-butyl-1-((2'-(N-(4,5-dimethylisoxazol-3-yl) sulfamoyl)-2-(ethoxymethyl)-[1,1'-biphenyl]-4- yl)methyl)-4-methyl-N-(1-methyl-1H-pyrazol-4-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide (Compound A-91) [0294] 4 M HCl in 1,4-dioxane (5 mL) and HCl (2 mL) were added to 2-butyl-1-((2'-(N-(4,5- dimethylisoxazol-3-yl)-N-(methoxymethyl)sulfamoyl)-2-(ethoxymethyl)-[1,1'-biphenyl]-4-yl)methyl)-4- methyl-N-(1-methyl-1H-1,2,3-triazol-4-yl)-6-
  • Example A-6 Synthesis of 4'-((3,3-dimethyl-2-oxo-6-(trifluoromethyl) indolin-1-yl) methyl)-N-(4,5 dimethylisoxazol-3-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide (Compound A-106)
  • Step-1 Synthesis of 3,3-dimethyl-6-(trifluoromethyl) indolin-2-one (34) [0296] To a stirred solution of 6-(trifluoromethyl) indolin-2-one (0.5 g, 0.00248 mol) in DMF (5 mL) at 0° C, was added NaH (0.059 g, 0.00248 mol) and stirred for 10 min at 0 °C.
  • Step-2 Synthesis of 4'-((3,3-dimethyl-2-oxo-6-(trifluoromethyl) indolin-1-yl) methyl)-N-(4,5- dimethylisoxazol-3-yl)-2'-(ethoxymethyl)-N-(methoxymethyl)-[1,1'-biphenyl]-2-sulfonamide (35) [0297] To a stirred solution of 4'-(bromomethyl)-N-(4,5-dimethylisoxazol-3-yl)-2'-(ethoxymethyl)-N- (methoxymethyl)-[1,1'-biphenyl]-2-sulfonamide (0.4 g, 0.00076 mol), 3,3-dimethyl-6-(trifluoromethyl) indolin-2-one (0.21 g, 0.00091 mol) in DMF (4 mL) was added Cs2CO3 (0.74 g, 0.00229 mol) at rt and stirred for
  • Step-3 synthesis of 4'-((3,3-dimethyl-2-oxo-6-(trifluoromethyl) indolin-1-yl) methyl)-N-(4,5- dimethylisoxazol-3-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide (Compound A-106) [0298] 4M Dioxane in HCl (3.5 mL) was added to 4'-((3,3-dimethyl-2-oxo-6-(trifluoromethyl) indolin-1- yl) methyl)-N-(4,5-dimethylisoxazol-3-yl)-2'-(ethoxymethyl)-N-(methoxymethyl)-[1,1'-biphenyl]-2- sulfonamide (0.35 g, 0.00052 mol) at 0 o C.
  • reaction mixture was stirred at rt for 2 h. After completion of the reaction, the reaction was quenched with saturated NaHCO 3 solution and extracted with DCM (2 x 50 mL). The combined organic layers were washed with water, brine solution, dried over sodium sulphate and concentrated under reduced pressure.
  • Example A-7 Synthesis of N-(4,5-dimethylisoxazol-3-yl)-2’-(ethoxymethyl)-4’-((6-fluoro-1,3-dimethyl- 2-oxoindolin-3-yl) methyl)-[1,1’-biphenyl]-2-sulfonamide (Compound A-107)
  • Step-1 synthesis of 6-fluoro-1,3-dimethylindolin-2-one (37) [0299] To a stirred solution of 6-fluoroindolin-2-one (500 mg, 3.31 mmol) in DMF (5 mL) was added NaH (119.08 mg, 4.96 mmol) at 0 °C and stirred for 10 min.
  • Step-2 Synthesis of N-(4,5-dimethylisoxazol-3-yl)-2’-(ethoxymethyl)-4’-((6-fluoro-1,3-dimethyl-2- oxoindolin-3-yl) methyl)-N-(methoxymethyl)-[1,1’-biphenyl]-2-sulfonamide (38) [0300] To a stirred solution of 4’-(bromomethyl)-N-(4,5-dimethylisoxazol-3-yl)-2’-(ethoxymethyl)-N- (methoxymethyl)-[1,1’-biphenyl]-2-sulfonamide (500 mg, 1 eq) in DMF (5 mL), was added 6-fluoro-1,3- dimethylindolin-2-one (205 mg, 1.2 eq) and cesium carbonate (934 mg, 3 eq) and stirred at rt for 4 h.
  • Example A-8 Synthesis of N-(4,5-dimethylisoxazol-3-yl)-2'-(ethoxymethyl)-4'-((5-(2-(4- methylpiperazin-1-yl)-2-oxoethyl)-2-propyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-[1,1'-biphenyl]-2- sulfonamide (Compound A-122)
  • Step-1 Synthesis of 5-bromo-2-propyl-3H-imidazo[4,5-b] pyridine (41) [0303] To a stirred solution of 6-bromopyridine-2,3-diamine (5.0 g, 26.59 mmol) in butyric acid (3.17 mL, 34.57 mmol), was added polyphosphoric acid (9.5 mL, 53.18 mmol) and the resulting reaction mixture was heated at 125 °C for 4 h.
  • Step-2 Synthesis of 4'-((5-bromo-2-propyl-1H-imidazo[4,5-b]pyridin-1-yl)methyl)-N-(4,5- dimethylisoxazol-3-yl)-2'-(ethoxymethyl)-N-(methoxymethyl)-[1,1'-biphenyl]-2-sulfonamide (42) [0304] To a stirred solution of 5-bromo-2-propyl-3H-imidazo[4,5-b]pyridine (5.0 g, 20.8 mmol) in DMF (5 mL), was added 4'-(bromomethyl)-N-(4,5-dimethylisoxazol-3-yl)-2'-(ethoxymethyl)-N-(methoxymethyl)- [1,1'-biphenyl]-2-sulfonamide (10.9 g, 20.8 mmol) and potassium carbonate (7.2 g, 52.1 mmol).
  • Step-3 Synthesis of methyl 3-((2'-(N-(4,5-dimethylisoxazol-3-yl)-N-(methoxymethyl)sulfamoyl)-2- (ethoxymethyl)-[1,1'-biphenyl]-4-yl)methyl)-2-propyl-3H-imidazo[4,5-b]pyridine-5-carboxylate (43) [0305] To a stirred solution of 4'-((5-bromo-2-propyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-N-(4,5- dimethylisoxazol-3-yl)-2'-(ethoxymethyl)-N-(methoxymethyl)-[1,1'-biphenyl]-2-sulfonamide (1.0 g, 1.5 mmol) in methanol (100 mL) in autoclave, was added triethylamine (1.0 mL, 4.4 mmol) and 1,1- bis
  • the autoclave was filled with carbon monoxide gas (110 psi) and the reaction mixture was stirred at 85 °C for 14 h. After completion of the reaction, the reaction mixture was diluted with water (150 mL) and extracted with ethyl acetate (2 x 80 mL). The combined organic layers were dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The crude material thus obtained was purified by column chromatography over silica gel to afford the desired compound. (0.6 g, 61%), LCMS; [M+H] + : 662.77.
  • Step-4 Synthesis of N-(4,5-dimethylisoxazol-3-yl)-2'-(ethoxymethyl)-4'-((5-(hydroxymethyl)-2-propyl- 3H-imidazo[4,5-b]pyridin-3-yl)methyl)-N-(methoxymethyl)-[1,1'-biphenyl]-2-sulfonamide (44) [0306] To a stirred solution of methyl 3-((2'-(N-(4,5-dimethylisoxazol-3-yl)-N-(methoxymethyl)sulfamoyl)- 2-(ethoxymethyl)-[1,1'-biphenyl]-4-yl)methyl)-2-propyl-3H-imidazo[4,5-b]pyridine-5-carboxylate (0.32 g, 0.49 mmol) in MeOH (20 mL) and THF (10 mL), was added sodium borohydride (0.37 g, 9.88 mmol).
  • Step-5 Synthesis of (3-((2'-(N-(4,5-dimethylisoxazol-3-yl)-N-(methoxymethyl)sulfamoyl)-2- (ethoxymethyl)-[1,1'-biphenyl]-4-yl)methyl)-2-propyl-3H-imidazo[4,5-b]pyridin-5-yl)methyl methanesulfonate (45) [0307] To a stirred solution of N-(4,5-dimethylisoxazol-3-yl)-2'-(ethoxymethyl)-4'-((5-(hydroxymethyl)-2- propyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-N-(methoxymethyl)-[1,1'-biphenyl]-2-sulfonamide (0.05 g, 0.079 mmol) in DCM (5 mL) at 0 °C, was added triethylamine (0.039 m
  • Step-6 Synthesis of 4'-((5-(cyanomethyl)-2-propyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-N-(4,5- dimethylisoxazol-3-yl)-2'-(ethoxymethyl)-N-(methoxymethyl)-[1,1'-biphenyl]-2-sulfonamide (46) [0308] To a stirred solution of (3-((2'-(N-(4,5-dimethylisoxazol-3-yl)-N-(methoxymethyl)sulfamoyl)-2- (ethoxymethyl)-[1,1'-biphenyl]-4-yl)methyl)-2-propyl-3H-imidazo[4,5-b]pyridin-5-yl)methyl methanesulfonate (0.2 g, 0.281 mmol) in acetonitrile (10 mL) at rt , was added tetraethyl
  • Step-7 Synthesis of 2-(3-((2'-(N-(4,5-dimethylisoxazol-3-yl)-N-(methoxymethyl)sulfamoyl)-2- (ethoxymethyl)-[1,1'-biphenyl]-4-yl)methyl)-2-propyl-3H-imidazo[4,5-b]pyridin-5-yl)acetic acid (47) [0309] To a stirred solution of 4'-((5-(cyanomethyl)-2-propyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-N- (4,5-dimethylisoxazol-3-yl)-2'-(ethoxymethyl)-N-(methoxymethyl)-[1,1'-biphenyl]-2-sulfonamide (0.2 g, 0.311 mmol) in ethanol (10 mL) and water (5 mL), was added 10% aqueous NaOH (0.124 g,
  • Step-8 Synthesis of N-(4,5-dimethylisoxazol-3-yl)-2'-(ethoxymethyl)-N-(methoxymethyl)-4'-((5-(2-(4- methylpiperazin-1-yl)-2-oxoethyl)-2-propyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-[1,1'-biphenyl]-2- sulfonamide (49) [0310] To a solution of 2-(3-((2'-(N-(4,5-dimethylisoxazol-3-yl)-N-(methoxymethyl)sulfamoyl)-2- (ethoxymethyl)-[1,1'-biphenyl]-4-yl)methyl)-2-propyl-3H-imidazo[4,5-b]pyridin-5-yl)acetic acid (0.3 g, 0.45 mmol) in DMF at rt, was added N-methyl pipe
  • Example A-9 Synthesis of N-(4,5-dimethylisoxazol-3-yl)-2'-(ethoxymethyl)-4'-((5-(piperidin-4- ylamino)-2-propyl-1H-imidazo[4,5-b]pyridin-1-yl)methyl)-[1,1'-biphenyl]-2-sulfonamide (Compound A-127)
  • Step-1 Synthesis of benzyl 4-((1-((2'-(N-(4,5-dimethylisoxazol-3-yl)-N-(methoxymethyl)sulfamoyl)-2- (ethoxymethyl)-[1,1'-biphenyl]-4-yl)methyl)-2-propyl-1H-imidazo[4,5-b]pyridin-5-yl)amino)piperidine- 1-carboxylate (51) [0312] To a stirred solution of 4'-((5-bromo-2-propyl-3H
  • Step-2 Synthesis of N-(4,5-dimethylisoxazol-3-yl)-2'-(ethoxymethyl)-4'-((5-(piperidin-4-ylamino)-2- propyl-1H-imidazo[4,5-b]pyridin-1-yl)methyl)-[1,1'-biphenyl]-2-sulfonamide (Compound A-127) [0313] Benzyl 4-((3-((2'-(N-(4,5-dimethylisoxazol-3-yl)-N-(methoxymethyl)sulfamoyl)-2-(ethoxymethyl)- [1,1'-biphenyl]-4-yl)methyl)-2-propyl-3H-imidazo[4,5-b]pyridin-5-yl)amino)piperidine-1-carboxylate (0.16 g, 0.191 mmol) was dissolved in 4M HCl in dioxane (10 mL), heated to
  • Example A-10 Synthesis of 2-(2-butyl-1-((2'-(N-(4,5-dimethylisoxazol-3-yl)sulfamoyl)-2-propoxy-[1,1'- biphenyl]-4-yl)methyl)-4-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)-N-methyl-N-(tetrahydro-2H-pyran- 4-yl)acetamide (Compound A-130) Step-1: Synthesis of Methyl 3-bromo-4-propoxybenzoate (54) [0315] To a stirred solution of methyl 4-bromo-3-hydroxybenzoate (0.3 g, 1.298 mmol) in acetonitrile (10 mL) at rt, was added Cesium carbonate (1.055 g, 3.246 mmol) and 1-bromopropane (0.14 mL, 1.428 mmol).
  • Step-2 Synthesis of methyl 3-propoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (55) [0316] To a stirred solution of methyl 4-bromo-3-propoxybenzoate (0.3 g, 1.098 mmol) in 1,4-dioxane (2 mL), was added bis(pinacolato)diboron (0.39 g, 1.537 mmol), potassium acetate (0.323 g, 3.295 mmol) and 1,1-bis(diphenylphosphino)ferrocene-palladium(II)dichloride (0.09 g, 0.110 mmol).
  • Step-3 Synthesis of methyl 2'-(N-(4,5-dimethylisoxazol-3-yl)-N-(methoxymethyl)sulfamoyl)-2-propoxy- [1,1'-biphenyl]-4-carboxylate (56) [0317] To a stirred solution of methyl 3-propoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (2.4 g, 7.50 mmol) in 1,4-dioxane (20 mL), was added 2-bromo-N-(4,5-dimethylisoxazol-3-yl)-N- (methoxymethyl)benzenesulfonamide (2.25 g, 6.00 mmol), potassium carbonate (2.58 g, 18.73 mmol) and 1,1-bis(diphenylphosphino)ferrocene-palladium(II)dichloride (0.61 g, 0.75 mmol
  • Step-4 Synthesis of N-(4,5-dimethylisoxazol-3-yl)-4'-(hydroxymethyl)-N-(methoxymethyl)-2'-propoxy- [1,1'-biphenyl]-2-sulfonamide (57) [0318] To a stirred solution of methyl 2'-(N-(4,5-dimethylisoxazol-3-yl)-N-(methoxymethyl)sulfamoyl)-2- propoxy-[1,1'-biphenyl]-4-carboxylate (0.7 g, 1.43 mmol) in diethyl ether (10 mL), was added lithium aluminum hydride (3.55 mL, 7.16 mmol).
  • Step-5 Synthesis of 4'-(bromomethyl)-N-(4,5-dimethylisoxazol-3-yl)-N-(methoxymethyl)-2'-propoxy- [1,1'-biphenyl]-2-sulfonamide (58) [0319] To a stirred solution of N-(4,5-dimethylisoxazol-3-yl)-4'-(hydroxymethyl)-N-(methoxymethyl)-2'- propoxy-[1,1'-biphenyl]-2-sulfonamide (0.43 g, 0.93 mmol) in DCM (20 mL), was added triphenylphosphine (0.49 g, 1.87 mmol) followed by the addition of carbon tetrabromide (0.619 g, 1.87 mmol).
  • Step-6 Synthesis of 2-(2-butyl-1-((2'-(N-(methoxymethyl)-N-(4-methylisoxazol-3-yl)sulfamoyl)-2- propoxy-[1,1'-biphenyl]-4-yl)methyl)-4-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)-N-methyl-N- (tetrahydro-2H-pyran-4-yl)acetamide (60) [0320] To a stirred solution of 5'-(bromomethyl)-N-(4,5-dimethylisoxazol-3-yl)-N-(methoxymethyl)-2'- propoxy-[1,1'-biphenyl]-2-sulfonamide (0.25 g, 0.48 mmol) in DMF (5 mL) at rt, was added potassium carbonate (0.33 g, 2.39 mmol) and 2-(2-butyl-4-methyl-6-
  • Step-7 Synthesis of 2-(2-butyl-1-((2'-(N-(4,5-dimethylisoxazol-3-yl)sulfamoyl)-2-propoxy-[1,1'- biphenyl]-4-yl)methyl)-4-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)-N-methyl-N-(tetrahydro-2H-pyran- 4-yl)acetamide (Compound A-130) [0321] To a stirred solution of 2-(2-butyl-1-((2'-(N-(4,5-dimethylisoxazol-3-yl)-N- (methoxymethyl)sulfamoyl)-2-propoxy-[1,1'-biphenyl]-4-yl)methyl)-4-methyl-6-oxo-1,6-dihydropyrimidin- 5-yl)-N-methyl-N-(tetrahydro-2H-pyran-4-yl)
  • Example A-11 Synthesis of 4'-((2-benzyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-N-(4,5- dimethylisoxazol-3-yl)-2'-propoxy-[1,1'-biphenyl]-2-sulfonamide (Compound A-136)
  • Step-1 Synthesis of N-(1-cyanocyclopentyl) benzamide (63) [0322] To a stirred solution 1-aminocyclopentane-1-carbonitrile (0.7 g, 6.36 mmol) in THF (5 mL) and water (20 mL) at 0 °C, was added benzoyl chloride (0.73 mL, 6.364 mmol).
  • Step-2 Synthesis of 2-phenyl-1,3-diazaspiro [4.4] non-1-en-4-one (64) [0323] To a stirred solution N-(1-cyanocyclopentyl)-2-phenylacetamide (1.6 g, 7.467 mmol) in n-propanol (10 mL), was added 4M HCl in Dioxane (10 mL) in a sealed tube. The resulting reaction mixture was heated to 70 °C and stirred for 12 h. After completion of the reaction, the reaction mixture was concentrated to remove the volatiles. The crude material dissolved in water and washed with EtOAc.
  • Step-3 Synthesis of N-(4,5-dimethylisoxazol-3-yl)-N-(methoxymethyl)-4'-((4-oxo-2-phenyl-1,3- diazaspiro[4.4]non-1-en-3-yl)methyl)-2'-propoxy-[1,1'-biphenyl]-2-sulfonamide (65) [0324] To a stirred solution of 2-phenyl-1,3-diazaspiro[4.4]non-1-en-4-one (0.2 g, 0.933 mmol) in DMF (10 mL) at rt, was added Cesium carbonate (1.07 g, 3.267 mmol) and 5'-(bromomethyl)-N-(4,5- dimethylisoxazol-3-yl)-N-(methoxymethyl)-2'-propoxy-[1,1'-biphenyl]-2-sulfonamide (0.782 g, 1.493 mmol).
  • Step-4 Synthesis of N-(4,5-dimethylisoxazol-3-yl)-4'-((4-oxo-2-phenyl-1,3-diazaspiro[4.4]non-1-en-3- yl)methyl)-2'-propoxy-[1,1'-biphenyl]-2-sulfonamide (Compound A-136) [0325] To a stirred solution of N-(4,5-dimethylisoxazol-3-yl)-N-(methoxymethyl)-4'-((4-oxo-2-phenyl-1,3- diazaspiro[4.4]non-1-en-3-yl)methyl)-2'-propoxy-[1,1'-biphenyl]-2-sulfonamide (0.3 g, 0.42 mmol) in DCM (10 mL), was added TFA (6 mL).
  • Example A-12 Synthesis of 4'-((2-butyl-4-methyl-5-(2-morpholino-2-oxoethyl)-6-oxopyrimidin-1(6H)- yl)methyl)-N-(4,5-dimethylisoxazol-3-yl)-2'-(hydroxymethyl)-[1,1'-biphenyl]-2-sulfonamide
  • Step-1 Synthesis of N-(4,5-dimethylisoxazol-3-yl)-4'-formyl-2'-(((4-methoxybenzyl) oxy) methyl)-N- (methoxymethyl)-[1,1'-biphenyl]-2-sulfonamide (67) [0327] To a stirred solution of 2-bromo-N-(4,5-dimethylisoxazol-3-yl)-N-(methoxymethyl) benzenesulfonamide (30 g, 79.94 mmol) in 1,4 dioxan
  • the resulting reaction mixture was degassed using N 2 for 5 min, then was added PdCl 2 (dppf)DCM (6.53 g, 7.99 mmol). The reaction mixture was heated to 90 °C and stirred for 16 h. After completion of the reaction, the reaction mixture was diluted with ice cold water (300 mL) and extracted with ethyl acetate (2x500 mL). The combined organic layers were washed with brine, dried over sodium sulphate and concentrated under reduced pressure.
  • Step-2 Synthesis of N-(4,5-dimethylisoxazol-3-yl)-4'-(hydroxymethyl)-2'-(((4-methoxybenzyl) oxy) methyl)-N-(methoxymethyl)-[1,1'-biphenyl]-2-sulfonamide (68) [0328] To a stirred solution of N-(4,5-dimethylisoxazol-3-yl)-2'-(ethoxymethyl)-4'-Formyl-N-((2- methoxyethoxy) methyl)-[1,1'-biphenyl]-2-sulfonamide (25 g, 45.40 mmol) in methanol (250 ml) at 0 °C, was added NaBH4 (8.58 g, 227.01 mmol).
  • Step-3 Synthesis of 4'-(bromomethyl)-N-(4,5-dimethylisoxazol-3-yl)-2'-(((4-methoxybenzyl) oxy) methyl)-N-(methoxymethyl)-[1,1'-biphenyl]-2-sulfonamide (69) [0329] To a stirred solution of N-(4,5-dimethylisoxazol-3-yl)-2'-(ethoxymethyl)-4'-(hydroxymethyl)-N- (methoxymethyl)-[1,1'-biphenyl]-2-sulfonamide (23 g, 41.61 mmol) in DMF (230 mL), cooled to 0 °C was added TPP (21.83 g, 83.23 mmol), stirred for 5 min, then carbon tetra bromide (27.6 g,
  • Step-4 Synthesis of 4'-((2-butyl-4-methyl-5-(2-morpholino-2-oxoethyl)-6-oxopyrimidin-1(6H)-yl) methyl)-N-(4,5-dimethylisoxazol-3-yl)-2'-(((4-methoxybenzyl) oxy) methyl)-N-(methoxymethyl)-[1,1'- biphenyl]-2-sulfonamide (71) [0330] To a stirred solution of 4'-(bromomethyl)-N-(4,5-dimethylisoxazol-3-yl)-2'-(((4-methoxybenzyl) ) th l) N ( th th l) [11' bi h l] 2 lf id (20 3249 l) i DMF (200 L) t t was added 2-butyl-6-methyl-5-(2-morpholino-2-oxoethyl)
  • reaction mixture was stirred for 16 h. After completion of the reaction, the reaction mixture was diluted with ice cold water (100 mL) and extracted with DCM (2x100 mL). The combined organic layers were washed with brine, dried over sodium sulphate and concentrated under reduced pressure.
  • Step-5 Synthesis of 4'-((2-butyl-4-methyl-5-(2-morpholino-2-oxoethyl)-6-oxopyrimidin-1(6H)-yl) methyl)-N-(4,5-dimethylisoxazol-3-yl)-2'-(hydroxymethyl)-N-(methoxymethyl)-[1,1'-biphenyl]-2- sulfonamide (72) [0331] 4'-(((2-Butyl-6-methyl-5-(2-morpholino-2-oxoethyl) pyrimidin-4-yl) oxy) methyl)-N-(4,5- dimethylisoxazol-3-yl)-2'-(((4-methoxybenzyl) oxy) methyl)-N-(methoxymethyl)-[1,1'-biphenyl]-2- sulfonamide (6.8 g, 8.21 mmol) was dissolved in TFA (35 mL) at
  • Step-6 Synthesis of 4'-((2-butyl-4-methyl-5-(2-morpholino-2-oxoethyl)-6-oxopyrimidin-1(6H)-yl) methyl)-N-(4,5-dimethylisoxazol-3-yl)-2'-(hydroxymethyl)-[1,1'-biphenyl]-2-sulfonamide (Compound A-147) [0332] 4'-((2-Butyl-4-methyl-5-(2-morpholino-2-oxoethyl)-6-oxopyrimidin-1(6H)-yl) methyl)-N-(4,5- dimethylisoxazol-3-yl)-2'-(hydroxymethyl)-N-(methoxymethyl)-[1,1'-biphenyl]-2-sulfonamide (200 mg, 0.282 mmol) was dissolved in 4M HCl
  • reaction mixture was stirred at rt for 2 h. After completion of the reaction, the reaction mixture quenched with saturated NaHCO 3 solution and extracted with DCM (2x50 mL). The combined organic layers were washed with water, brine, dried over sodium sulphate and concentrated under reduced pressure.
  • Example A-12 Synthesis of 4’-((2-butyl-4-methyl-5-(2-morpholino-2-oxoethyl)-6-oxopyrimidin-1(6H)- yl)methyl)-N-(4,5-dimethylisoxazol-3-yl)-2’-((3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-[1,1’- biphenyl]-2-sulfonamide (Compound A-141) Step 1: Synthesis of (4-((2-butyl-4-methyl-5-(2-morpholino-2-oxoethyl)-6-oxopyrimidin-1(6H)- yl)methyl)-2’-(N-(4,5-dimethylisoxazol-3-yl)-N-(methoxymethyl)sulfamoyl)-[1,1’-biphenyl]-2-yl)methyl methane sulfonate (73) [0333] To a
  • reaction mixture was stirred at same temperature for 1 h. After completion of reaction, the reaction mixture was diluted with ice cold water (10 mL), extracted with DCM (2x25 mL). The combined organic layers were dried over sodium sulphate, concentrated under reduced pressure. The crude material (250 mg) thus obtained was used for the next step without further purification.
  • Step 2 Synthesis of 4'-((2-butyl-4-methyl-5-(2-morpholino-2-oxoethyl)-6-oxopyrimidin-1(6H)- yl)methyl)-N-(4,5-dimethylisoxazol-3-yl)-N-(methoxymethyl)-2'-((3-(trifluoromethyl)-1H-pyrazol-1- yl)methyl)-[1,1'-biphenyl]-2-sulfonamide (75) [0334] To a stirred solution of 3-(trifluoromethyl)-1H-pyrazole (250 mg, 0.31 mmol) in DMF (5 mL) at 0 °C, was added NaH (38 mg, 1.59 mmol).
  • reaction mixture was stirred at same temperature for 30 min, then was added (4-((2-butyl-4-methyl-5-(2-morpholino-2-oxoethyl)-6-oxopyrimidin-1(6H)-yl)methyl)-2'-(N- (4,5-dimethy (250 mg, 0.31 mmol).
  • the reaction mixture was heated to 80 °C and stirred for 16 h. After completion of the reaction, the reaction was quenched with ice-cold water (20 mL) and extracted with 10% MeOH:DCM (2 x 50 mL). The combined organic layers were washed with water, brine, dried over sodium sulphate and concentrated under reduced pressure.
  • Example A-13 Synthesis of 4-((2-butyl-4-methyl-5-(2-morpholino-2-oxoethyl)-6-oxopyrimidin-1(6H)- yl)methyl)-2'-(N-(4,5-dimethylisoxazol-3-yl)sulfamoyl)-[1,1'-biphenyl]-2-carboxylic acid (Compound A-151)
  • Step-1 Synthesis of methyl 5-formyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (77) [0337]
  • Step-2 Synthesis of methyl 2'-(N-(4,5-dimethylisoxazol-3-yl)-N-(methoxymethyl) sulfamoyl)-4-formyl- [1,1'-biphenyl]-2-carboxylate (78) [0338] To a stirred solution of methyl 5-formyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (0.5 g, 1.723 mmol) in 1,4-Dioxan (5 mL), was added 2-bromo-N-(4,5-dimethylisoxazol-3-yl)-N- (methoxymethyl)benzenesulfonamide (0.77 g, 2.068 mmol), potassium carbonate (0.59 g, 4.309 mmol), 1,1- bis(diphenylphosphino)ferrocene-palladium(II)dichloride (0.14 g, 0.
  • the resulting reaction mixture was degassed by bubbling N 2 gas, heated to 110 o C and stirred for 16 h.
  • the reaction mixture was filtered through celite bed, diluted with water and extracted with ethyl acetate (2x40 mL). The combined organic layers were dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure.
  • the crude material thus obtained was purified by column chromatography to afford the desired compound. (0.4 g, 50%), LCMS; [M+H] + : 459.48.
  • Step-3 Synthesis of methyl 4-(bromomethyl)-2'-(N-(4,5-dimethylisoxazol-3-yl)-N- (methoxymethyl)sulfamoyl)-[1,1'-biphenyl]-2-carboxylate (79) [0339] i) To a stirred solution of methyl 2'-(N-(4,5-dimethylisoxazol-3-yl)-N-(methoxymethyl)sulfamoyl)-4- formyl-[1,1'-biphenyl]-2-carboxylate (0.1 g, 0.22 mmol) in THF (5 mL), was added sodium borohydride (0.010w g, 0.250 mmol).
  • reaction mixture was stirred at rt for 2 h. After completion of the reaction, the reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (2x40 mL). The combined organic layers were dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to afford the desired compound. (0.07 g, 69%), LCMS; [M+H] + : 461.50.
  • Step-4 Synthesis of methyl 4-((2-butyl-4-methyl-5-(2-morpholino-2-oxoethyl)-6-oxopyrimidin-1(6H)- yl)methyl)-2'-(N-(4,5-dimethylisoxazol-3-yl)-N-(methoxymethyl)sulfamoyl)-[1,1'-biphenyl]-2- carboxylate (80) [0341] To a stirred solution of methyl 4-(bromomethyl)-2'-(N-(4,5-dimethylisoxazol-3-yl)-N- (methoxymethyl)sulfamoyl)-[1,1'-biphenyl]-2-carboxylate (0.7 g, 1.338 mmol) in DMF (7 mL) at 0 °C, was added 2-butyl-6-methyl-5-(2-morpholino-2-oxoethyl)pyrimidin-4(3H)-one (0
  • Step-5 Synthesis of 4-((2-butyl-4-methyl-5-(2-morpholino-2-oxoethyl)-6-oxopyrimidin-1(6H)- yl)methyl)-2'-(N-(4,5-dimethylisoxazol-3-yl)-N-(methoxymethyl)sulfamoyl)-[1,1'-biphenyl]-2-carboxylic acid (81) [0342] To a stirred solution of methyl 4-(bromomethyl)-2'-(N-(4,5-dimethylisoxazol-3-yl)-N- (methoxymethyl)sulfamoyl)-[1,1'-biphenyl]-2-carboxylate (0.2 g, 0.272 mmol) in MeOH (5 mL) and water (15 mL) at rt, was added NaOH (0.054 g, 1.359 mmol).
  • Step-6 Synthesis of 4-((2-butyl-4-methyl-5-(2-morpholino-2-oxoethyl)-6-oxopyrimidin-1(6H)- yl)methyl)-2'-(N-(4,5-dimethylisoxazol-3-yl)sulfamoyl)-[1,1'-biphenyl]-2-carboxylic acid (Compound A-151) [0343] To a stirred solution of 4-((2-butyl-4-methyl-5-(2-morpholino-2-oxoethyl)-6-oxopyrimidin-1(6H)- yl)methyl)-2'-(N-(4,5-dimethylisoxazol-3-yl)-N-(methoxymethyl)sulfamoyl)-[1,1'-biphenyl]-2-carboxylic acid (0.15 g, 0.208 mmol) in 4M HCl in Dioxane (4 mL) at
  • Example A-14 Synthesis of 4-((2-butyl-4-methyl-5-(2-morpholino-2-oxoethyl)-6-oxopyrimidin-1(6H)- yl)methyl)-2'-(N-(4,5-dimethylisoxazol-3-yl)sulfamoyl)-N-methyl-[1,1'-biphenyl]-2-carboxamide (Compound A-152) [0344] To a stirred solution of 4-((2-butyl-4-methyl-5-(2-morpholino-2-oxoethyl)-6-oxopyrimidin-1(6H)- yl)methyl)-2'-(N-(4,5-dimethylisoxazol-3-yl)sulfamoyl)-[1,1'-biphenyl]-2-carboxylic acid (0.10 g, 0.14 mmol) in DCM (10 mL) at rt, was added triethylamine (0.04
  • Example A-15 Synthesis of 4'-((2-(cyclopropylmethyl)-4-oxo-1,3-diazaspiro [4.4] non-1-en-3-yl) methyl)-N-(4,5-dimethylisoxazol-3-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide (Compound A- 155)
  • Step-1 synthesis of 4'-((2-(cyclopropylmethyl)-4-oxo-1,3-diazaspiro [4.4] non-1-en-3-yl) methyl)-N- (4,5-dimethylisoxazol-3-yl)-2'-(ethoxymethyl)-N-(methoxymethyl)-[1,1'-biphenyl]-2-sulfonamide (83) [0345] To a stirred solution of 4'-(bromomethyl)-N-(4,5-dimethylisoxazol-3-yl)-2'
  • Step-2 Synthesis of 4'-((2-(cyclopropylmethyl)-4-oxo-1,3-diazaspiro [4.4] non-1-en-3-yl) methyl)-N- (4,5-dimethylisoxazol-3-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide (Compound A-155) [0346] 4'-((2-(Cyclopropylmethyl)-4-oxo-1,3-diazaspiro [4.4] non-1-en-3-yl) methyl)-N-(4,5- dimethylisoxazol-3-yl)-2'-(ethoxymethyl)-N-(methoxymethyl)-[1,1'-biphenyl]-2-sulfonamide (210 mg, 0.33 mmol) was dissolved in 4M HCl in dioxane (
  • reaction mixture was stirred at rt for 2 h. After completion of the reaction, the reaction was quenched with saturated NaHCO3 solution and extracted with DCM (2 x 25 mL) The combined organic layer was washed with water, brine, dried over sodium sulphate and concentrated under reduced pressure.
  • Step-2 Synthesis of 2-(chloromethyl)-1,3-diazaspiro[4.4]non-1-en-4-one (87) [0348] To a stirred solution 2-chloro-N-(1-cyanocyclopentyl)acetamide (3 g, 16.07 mmol) in n-propanol (10 mL) in a sealed tube, was added 4M HCl in dioxane (10 mL). The resulting reaction mixture was stirred at 70 °C for 12 h. After completion of the reaction, the reaction mixture was concentrated, dissolved in water, and washed with EtOAc.
  • Step-3 Synthesis of 2-((chlorotriphenyl-l5-phosphaneyl)methyl)-1,3-diazaspiro[4.4]non-1-en-4-one (88) [0349] To a stirred solution 2-(chloromethyl)-1,3-diazaspiro[4.4]non-1-en-4-one (1.2 g, 6.44 mmol) in toluene (20 mL), was added triphenylphosphine (2.53 g, 9.658 mmol). The resulting reaction mixture was stirred at 110 °C for 16 h. The reaction mixture was concentrated to remove the solvent completely and washed with ethyl acetate and decanted to afford the desired compound.
  • Step-4 Synthesis of 2-(oxetan-3-ylidenemethyl)-1,3-diazaspiro[4.4]non-1-en-4-one (90) [0350] To a stirred solution 2-(chloromethyl)-1,3-diazaspiro[4.4]non-1-en-4-one (1.5 g, 2.23 mmol) in THF (20 mL) at 0 °C, was added potassium tertiary-butoxide (0.601 g, 4.46 mmol) and oxetan-3- one (0.482 g, 6.683 mmol).
  • Step-5 Synthesis of 2-(oxetan-3-ylmethyl)-1,3-diazaspiro[4.4]non-1-en-4-one (84) [0351] To a stirred solution 2-(oxetan-3-ylidenemethyl)-1,3-diazaspiro[4.4]non-1-en-4-one (0.5 g, 2.45 mmol) in methanol (20 mL), was added Pd/C (0.5 g). The reaction mixture was stirred under hydrogen balloon pressure for two hour at rt. The reaction mixture was filtered through celite bed and concentrated to afford the desired compound. Yield: 0.45 g, 89%, LCMS; [M+H] + : 209.26, purity: 64%.
  • Step-2 Synthesis of 2,6-diethyl-4-nitropyridine 1-oxide (93)
  • 2,6-diethylpyridine 1-oxide (6 g, 39.7 mmol) was added to a mixture of nitric acid (1.66, 39.7 mmol) and sulfuric acid (2.13 mL, 39.7 mmol) at 0 °C.
  • the resulting reaction mixture was heated to 80 °C and stirred for 2h. After completion of the reaction, the reaction mixture was cooled to rt, quenched with aqueous NaOH solution, extracted with ethyl acetate (2x 100 mL).
  • reaction mixture was heated to 100 °C, stirred for 1h.
  • the reaction mixture was filtered through celite bed basified with NaOH extracted with DCM (2x50 mL) The combined organic layers were dried over sodium sulphate, concentrated under reduced pressure.
  • the crude material thus obtained was purified by automated flash chromatography (silica gel) to afford 2,6-diethylpyridin-4-amine. (1.2 g, 44%), LCMS; [M+H] + : 150.99.
  • Step-4 Synthesis of 2,6-diethyl-3-iodopyridin-4-amine (95) [0355] To a stirred solution of 2,6-diethylpyridin-4-amine (1 g, 6.6 mmol) in a mixture of methanol (15 mL) and DCM (5 mL), was added iodine (1.7 g, 6.6 mmol), PhI(CF3COO) 2 (3.2, 9.99 mmol). The reaction mixture was stirred at rt for 16h. After completion of the reaction, the reaction mixture was concentrated, diluted with mixture of sodium metabisulphite (25 mL) and sodium bicarbonate solution (75 mL), extracted with DCM (2x50 mL).
  • Step-5 Synthesis of ethyl (E)-3-(4-amino-2,6-diethylpyridin-3-yl)acrylate (96) [0356] To a stirred solution of 2,6-diethyl-3-iodopyridin-4-amine (1 g, 3.6 mmol) in DMF (10 mL), was added ethyl acrylate (0.44 g, 4.34 mmol) and palladium acetate (0.08 g, 0.36 mmol) under argon atmosphere. The reaction mixture was heated to 130 °C and stirred for 1h. After completion of the reaction, the reaction mixture was diluted with ice cold water (30 mL), extracted with DCM (2 x 30 mL).
  • Step-6 Synthesis of 5,7-diethyl-1,6-naphthyridin-2(1H)-one (97) and 5,7-diethyl-3,4-dihydro-1,6- naphthyridin-2(1H)-one (98) [0357] To a stirred solution of ethyl (E)-3-(4-amino-2,6-diethylpyridin-3-yl)acrylate (0.2 g, 0.81 mmol) in methanol (5 mL), was added sodium methoxide (1M solution) (2.42 mL, 2.42 mmol). The reaction mixture was heated to 70 °C and stirred for 3h.
  • the reaction mixture was concentrated, diluted with ice cold water (30 mL), extracted with DCM (2x25 mL). The combined organic layers were dried over sodium sulphate, concentrated under reduced pressure to get crude 97.
  • the crude 97 was used for synthesis of Compound A-158. [0358]
  • the crude 97 was dissolved in ethanol (5 mL), Pd/C (9 mg, 0.08 mmol) was added.
  • the reaction mixture was stirred under H 2 balloon atmosphere at 50 °C and stirred for 24h.
  • the reaction mixture was filtered through celite, concentrated under reduced pressure to get crude material.
  • Example A-16 Synthesis of 4'-((6-butyl-1-methyl-3-(4-methylpiperazine-1-carbonyl)-4-oxo-1,4- dihydro-5H-pyrazolo[3,4-d] pyrimidin-5-yl) methyl)-N-(4,5-dimethylisoxazol-3-yl)-2'-(ethoxymethyl)- [1,1'-biphenyl]-2-sulfonamide (Compound A-163)
  • Step-1 Synthesis of N-(4-cyano-1-methyl-1H-pyrazol-5-yl) pentanamide (100) [0360]
  • 5-amino-1-methyl-1H-pyrazole-4-carbonitrile 2.0 g, 16.376 mmol
  • pyridine 2.4 mL
  • valeroyl chloride 1.975 g, 16.376 mmol
  • Step-2 Synthesis of 6-butyl-1-methyl-1,5-dihydro-4H-pyrazolo[3,4-d] pyrimidin-4-one (101) [0361] To a stirred solution of NaOH (1.862g, 46.546 mmol) in ethanol at 0 o C, was added N-(4-cyano-1- methyl-1H-pyrazol-5-yl) pentanamide (2.4 g, 11.636 mmol). The resulting reaction mixture was heated to 120 o C and stirred for 16 h. The reaction was monitored by TLC/LCMS.
  • Step-3 Synthesis of 3-bromo-6-butyl-1-methyl-1,5-dihydro-4H-pyrazolo[3,4-d] pyrimidin-4-one (102) [0362] To a stirred solution of 6-butyl-1-methyl-1,5-dihydro-4H-pyrazolo[3,4-d] pyrimidin-4-one (2.1 g, 10.18 mmol) in water (10 mL) at 0 o C, was added bromine (1.05 mL, 20.364 mmol). The resulting reaction mixture was heated to 120 °C and stirred for 16 h. The reaction was monitored by TLC/ LCMS.
  • Step-4 Synthesis of methyl 6-butyl-1-methyl-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d] pyrimidine-3- carboxylate (103) [0363] To a stirred solution of 3-bromo-6-butyl-1-methyl-1,5-dihydro-4H-pyrazolo[3,4-d] pyrimidin-4-one (0.5 g, 1.75 mmol) in methanol (20 mL) in autoclave, was added TEA (0.78 mL, 8.77 mmol) and PdCl2(dppf).DCM (0.14 g, 0.17 mmol). The autoclave was closed and filled with CO gas (100 psi).
  • Step-5 Synthesis of methyl 6-butyl-5-((2'-(N-(4,5-dimethylisoxazol-3-yl)-N-(methoxymethyl) sulfamoyl)-2-(ethoxymethyl)-[1,1'-biphenyl]-4-yl) methyl)-1-methyl-4-oxo-4,5-dihydro-1H- pyrazolo[3,4-d] pyrimidine-3-carboxylate (104) [0364] To a stirred solution of 4'-(bromomethyl)-N-(4,5-dimethylisoxazol-3-yl)-2'-(ethoxymethyl)-N- (methoxymethyl)-[1,1'-biphenyl]-2-sulfonamide (0.5 g, 0.955 mmol) in DMF at rt, was added methyl 6- butyl-1-methyl-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-
  • Step-6 Synthesis of 6-butyl-5-((2'-(N-(4,5-dimethylisoxazol-3-yl)-N-(methoxymethyl) sulfamoyl)-2- (ethoxymethyl)-[1,1'-biphenyl]-4-yl) methyl)-1-methyl-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d] pyrimidine-3-carboxylic acid (105) [0365] To a stirred solution of methyl 6-butyl-5-((2'-(N-(4,5-dimethylisoxazol-3-yl)-N-(methoxymethyl) sulfamoyl)-2-(ethoxymethyl)-[1,1'-biphenyl]-4-yl) methyl)-1-methyl-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d] pyrimidine-3-carboxylate (0.3 g,
  • Step-7 Synthesis of 4'-((6-butyl-1-methyl-3-(4-methylpiperazine-1-carbonyl)-4-oxo-1,4-dihydro-5H- pyrazolo[3,4-d] pyrimidin-5-yl) methyl)-N-(4,5-dimethylisoxazol-3-yl)-2'-(ethoxymethyl)-N- (methoxymethyl)-[1,1'-biphenyl]-2-sulfonamide (107) [0366] To a stirred solution of 6-butyl-5-((2'-(N-(4,5-dimethylisoxazol-3-yl)-N-(methoxymethyl)sulfamoyl)- 2-(ethoxymethyl)-[1,1'-biphenyl]-4-yl)methyl)-1-methyl-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine- 3-carboxylic acid
  • reaction mixture was stirred at rt for 16 h.
  • the reaction was monitored by the TLC and LC-MS.
  • reaction mixture was quenched with ice-cold water (20 mL) and extracted with 5% MeOH in DCM (2x50 mL ). The combined organic layers were washed with water, brine, dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude product was used for the next step without further purification. (0.22 g, 79%), LCMS : (M+H) + : 775.48.
  • Step-8 Synthesis of 4'-((6-butyl-1-methyl-3-(4-methylpiperazine-1-carbonyl)-4-oxo-1,4-dihydro-5H- pyrazolo[3,4-d] pyrimidin-5-yl) methyl)-N-(4,5-dimethylisoxazol-3-yl)-2'-(ethoxymethyl)-[1,1'- biphenyl]-2-sulfonamide (Compound A-163) [0367] To a stirred solution of tert-butyl 2-(6-butyl-5-((2'-(N-(4,5-dimethylisoxazol-3-yl)-N- (methoxymethyl) sulfamoyl)-2-(ethoxymethyl)-[1,1'-biphenyl]-4-yl) methyl)-1-methyl-4-oxo-4,5-dihydro- 1H-pyrazolo[3,4-d] pyrimidine
  • Example A-17 Synthesis of 4'-((2-butyl-4-oxo-4,5,6,7-tetrahydro-3H-pyrrolo[3,4-d] pyrimidin-3-yl) methyl)-N-(4,5-dimethylisoxazol-3-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide (Compound A- 171)
  • Step-1 Synthesis of tert-butyl 3-cyano-4-pentanamido-2,5-dihydro-1H-pyrrole-1-carboxylate (109) [0369] To a stirred solution of tert-butyl 3-amino-4-cyano-2,5-dihydro-1H-pyrrole-1-carboxylate (2 g, 9.56 mmol) in pyridine (20 mL) at 0 °C, was added pentanoyl chloride (1.15 g, 9.56 mmol) in DCM (10
  • reaction mixture was stirred at 0 o C for 2 h, then at rt for 12 h.
  • the reaction was monitored by TLC/LCMS.
  • the reaction mixture was diluted with ice cold water (10 mL), extracted with DCM (2 x 100 mL). The combined organic layers were washed with water, brine, dried over sodium sulphate and concentrated under reduced pressure.
  • the crude material thus obtained was purified by column chromatography to afford the title compound. (1.3 g, 85.5%, LCMS; [M+H] + : 539.1.
  • Step-2 Synthesis of tert-butyl 2-butyl-4-oxo-3,4,5,7-tetrahydro-6H-pyrrolo[3,4-d] pyrimidine-6- carboxylate (110) [0370] To a stirred a solution of tert-butyl 3-cyano-4-pentanamido-2,5-dihydro-1H-pyrrole-1- carboxylate (0.8 g, 2.727 mmol) in MeOH (8.0 mL) at 0 o C, was added NaOH (0.27 g, 6.817 mmol) and 30% H 2 O 2 (8.0 mL). The resulting reaction mixture was allowed to warm to rt and stirred for 16 h.
  • Step-3 Synthesis of tert-butyl 2-butyl-3-((2'-(N-(4,5-dimethylisoxazol-3-yl)-N-(methoxymethyl) sulfamoyl)-2-(ethoxymethyl)-[1,1'-biphenyl]-4-yl) methyl)-4-oxo-3,4,5,7-tetrahydro-6H-pyrrolo[3,4-d] pyrimidine-6-carboxylate (111) [0371] To a stirred solution of 4'-(bromomethyl)-N-(4,5-dimethylisoxazol-3-yl)-2'-(ethoxymethyl)-N- (methoxymethyl)-[1,1'-biphenyl]-2-sulfonamide (0.5 g, 0.955 mmol) and tert-butyl 2-butyl-4-oxo-3,4,5,7- tetrahydro-6H-pyrrolo[3,
  • Step-4 Synthesis of 4'-((2-butyl-4-oxo-4,5,6,7-tetrahydro-3H-pyrrolo[3,4-d] pyrimidin-3-yl) methyl)-N- (4,5-dimethylisoxazol-3-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide (Compound A-171) [0372] To a stirred solution of tert-butyl 2-butyl-3-((2'-(N-(4,5-dimethylisoxazol-3-yl)-N-(methoxymethyl) sulfamoyl)-2-(ethoxymethyl)-[1,1'-biphenyl]-4-yl) methyl)-4-oxo-3,4,5,7-tetrahydro-6H-pyrrolo[3,4-d] pyrimidine-6-carboxylate (0.27 g, 0.367 mmol) in 4
  • Example A-18 Synthesis of 4'-((2-butyl-4-oxo-4,5,6,7-tetrahydro-3H-pyrrolo[3,4-d] pyrimidin-3- yl)methyl)-N-(4,5-dimethylisoxazol-3-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide (Compound A-172) [0374] To a stirred solution of 4'-((2-butyl-4-oxo-4,5,6,7-tetrahydro-3H-pyrrolo[3,4-d] pyrimidin-3-yl) methyl)-N-(4,5-dimethylisoxazol-3-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide (0.065 g, 0.110 mmol) in MeOH (3.2 mL) at 0°C, was added paraformaldehyde (0.01
  • Example A-19 Synthesis of 4'-((2-butyl-6-(cyclobutanecarbonyl)-4-oxo-4,5,6,7-tetrahydro-3H- pyrrolo[3,4-d] pyrimidin-3-yl) methyl)-N-(4,5-dimethylisoxazol-3-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]- 2-sulfonamide (Compound A-173) [0375] To a stirred solution of 4'-((2-butyl-4-oxo-4,5,6,7-tetrahydro-3H-pyrrolo[3,4-d] pyrimidin-3-yl) methyl)-N-(4,5-dimethylisoxazol-3-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide (0.18 g, 0.304 mmol) in DMF (80 mL) was added DIPEA
  • Example Intermediate A-H Synthesis of benzyl 2-butyl-4-oxo-1,3,8-triazaspiro[4.5]dec-1-ene-8- carboxylate (Intermediate 4)
  • benzyl 2-butyl-4-oxo-1,3,8-triazaspiro[4.5]dec-1-ene-8-carboxylate (Intermediate 4) was synthesized using a similar procedure as described for the synthesis of intermediate 15 using benzyl-4-oxipiperidine-1- carboxylate (1) as starting material instead of benzyl-3-oxipiperidine-1-carboxylate as described in Example Intermediate A-C.
  • Example A-20 Synthesis of Compound A-181 and Compound A-191 , Step 1: Synthesis of benzyl 4-amino-4-cyanopiperidine-1-carboxylate (2) [0379] To a stirred solution of benzyl 4-oxopiperidine-1-carboxylate (200 g, 857.386 mmol) in MeOH (1000 mL) was added NH4Cl (91740 g 1714773 mmol) followed by 25% aqueous ammonia solution (1000 mL) at room temperature. Reaction mixture was stirred at room temperature for 10 min. NaCN (101.172 g, 1714.773 mmol) was added and reaction mixture was stirred at room temperature for 16 h.
  • the Reaction was monitored by the TLC and LCMS.
  • the reaction mixture quenched with water (1000 mL), extracted with DCM (2 X 1000 mL). The combined organic layer was washed with brine, dried over sodium sulphate, and concentrated under reduced pressure to afford to crude material.
  • reaction mixture was stirred at 0 °C for 20 min and at 60 °C for 4 h. The reaction was monitored by the TLC and LCMS. After completion of reaction, reaction mixture was diluted with water (1000 mL), extracted with DCM (2 X 1000 mL). The combined organic layer was washed with saturated NaHCO3 solution (500 mL), brine and concentrated under reduced pressure to afford to crude material.
  • Step 4 Synthesis of benzyl 3-((2'-(N-(4,5-dimethylisoxazol-3-yl) sulfamoyl)-2-(ethoxymethyl)-[1,1'- biphenyl]-4-yl) methyl)-2-ethyl-4-oxo-1,3,8-triazaspiro [4.5] dec-1-ene-8-carboxylate (6) [0382] To a stirred solution of 4'-(bromomethyl)-N-(4,5-dimethylisoxazol-3-yl)-2'-(ethoxymethyl)-N- (methoxymethyl)-[1,1'-biphenyl]-2-sulfonamide (190 g, 362.98
  • reaction was monitored by TLC and LCMS.
  • the reaction mixture was quenched with ice-cold water (2000 mL) and extracted with ethyl acetate (3 X 1000 mL).
  • the combined organic layer was washed with water (1000 mL X 2), followed by brine. Separated organic layer was dried over sodium sulphate, filter & concentrated under reduced pressure to get crude material.
  • Step 6 4'-((2-butyl-4-oxo-1,3,8-triazaspiro [4.5] dec-1-en-3-yl) methyl)-N-(4,5-dimethylisoxazol-3-yl)- 2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide (Compound A-181) [0384] To a stirred solution of benzyl 2-butyl-3-((2'-(N-(4,5-dimethylisoxazol-3-yl) sulfamoyl)-2- (ethoxymethyl)-[1,1'-biphenyl]-4-yl) methyl)-4-oxo-1,3,8-triazaspiro [4.5] dec-1-ene-8-carboxylate (40 g, 16.87 mmol) in 4M HCl Dioxane (400 mL) at 0 °C was added concentrated HCl (40 mL)
  • Reaction was monitored by the TLC and LCMS. After completion of reaction, it was slowly basified to the pH 8-9 with saturated NaHCO3 solution and extracted with 10% MeOH: DCM (2 X 300 mL). The combined organic layer was washed with water, brine, dried over sodium sulphate, and concentrated under reduced pressure to get crude material.
  • Example A-22 Synthesis of N-((2-butyl-1-((2'-(N-(4,5-dimethylisoxazol-3-yl)sulfamoyl)-2- (ethoxymethyl)-[1,1'-biphenyl]-4-yl)methyl)-4-methyl-5-oxo-4,5-dihydro-1H-imidazol-4- yl)methyl)cyclopentanecarboxamide (Compound A-256) Step-1: benzyl (2-hydroxypropyl) carbamate (9) [0388] To a stirred solution of 1-aminopropan-2-ol (25 g, 332.84 mmol) in THF (500 mL) and water (250 mL), sodium carbonate (123.48 g, 1164.95 mmol) was added, followed by the addition of Cbz- Cl (56.91 mL, 399.41 mmol) at 0 °C and the reaction mixture was stirred at room temperature for 12
  • reaction was monitored by TLC/LCMS.
  • the reaction mixture was extracted with DCM (3 X 100 mL), dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford crude compound as yellow oil.
  • the crude compound was purified by the column chromatography and eluted with 20-50 % ethyl acetate in petroleum ether to afford desired compound as pale-yellow oil (36.0 g, 51.69 %).
  • reaction mixture was cooled to room temperature and concentrated to remove the solvent completely, residue was dissolved in water and washed with EtOAc.
  • the organic layer was separated and the aqueous layer was basified with NaHCO 3 and extracted with 10 % MeOH:DCM (3 x 250 mL).
  • the combined organic layers were washed with water and brine solution and dried over sodium sulfate, concentrated under reduced pressure to get desired compound (7.6 g, 69.09 %).
  • reaction mixture was quenched with water and extracted with DCM, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford the desired compound.
  • the crude compound was purified by column chromatography and eluted with 50-70% EtOAc in petroleum ether to afford desired compound (10 g, 57.40 %).
  • Step-7 4'-((4-(aminomethyl)-2-butyl-4-methyl-5-oxo-4,5-dihydro-1H-imidazol-1-yl) methyl)-N- (4,5-dimethylisoxazol-3-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide (16) [0395] To a stirred solution benzyl ((2-butyl-1-((2'-(N-(4,5-dimethylisoxazol-3-yl)-N- (methoxymethyl)sulfamoyl)-2-(ethoxymethyl)-[1,1'-biphenyl]-4-yl)methyl)-4-methyl-5-oxo-4,5-dihydro-1H- imidazol-4-yl)methyl)carbamate (0.6 g, 0.79
  • reaction monitored by TLC/LCMS.
  • the reaction mixture was concentrated to remove the solvent completely.
  • the pH of the reaction mixture was adjusted to that of basic with saturated NaHCO 3 and extracted with 10% MeOH:DCM (3 x 30 mL).
  • the combined organic layers were washed with water followed by brine solution, dried over sodium sulphate and concentrated under reduced pressure.
  • the crude material thus obtained was purified by column chromatography to afford title compound (0.009 g, 6 %).
  • Example A-23 Synthesis of 4'-((2-butyl-5',5'-difluoro-5-oxo-3',3a',4',5',6',6a'-hexahydro-1'H- spiro[imidazole-4,2'-pentalen]-1(5H)-yl) methyl)-N-(4,5-dimethylisoxazol-3-yl)-2'-(ethoxymethyl)-[1,1'- biphenyl]-2-sulfonamide (Compound A-283): Step-1: tetrahydro-1H-spiro[pentalene-2,2'-[1,3]dioxolan]-5(3H)-one (19) [0400] To a stirred solution of tetrahydropentalene-2,5(1H,3H)-dione (10 g, 72.380 mmol), ethylene glycol (4.8 mL, 86.856 mmol)
  • Step-2 5,5-difluorohexahydro-1H-spiro[pentalene-2,2'-[1,3]dioxolane] (20) [0401] To a stirred solution of tetrahydro-1H-spiro[pentalene-2,2'-[1,3]dioxolan]-5(3H)-one (2.5 g, 13.72 mmol) in DCM (30 mL), and the temperature was lowered to 0 0 C. DAST (18.4 mL, 137.2 mmol) was added dropwise, after complete addition, the temperature was raised to 45 0 C and stirred for 12 h. The reaction was monitored by TLC.
  • Step-3 5,5-difluorohexahydropentalen-2(1H)-one (21) [0402] To a solution of 5,5-difluorohexahydro-1H-spiro[pentalene-2,2'-[1,3] dioxolane] (3 g, 14.690 mmol) in tetrahydrofuran (15 mL) was added concentrated hydrochloric acid (5 mL) at 0 0 C, stirred the reaction at room temperature for 5 h. The reaction was monitored by TLC.
  • Step-4 2-amino-5,5-difluorooctahydropentalene-2-carbonitrile (22) [0403] To a stirred solution of tetrahydro-1H-spiro[pentalene-2,2'-[1,3]dioxolan]-5(3H)-one (3 g, 18.73 mmol) in ammonia (20 mL) and MeOH (10 mL) was added NaCN (1.8 g, 37.46 mmol) and NH4Cl (1.99 g, 37.46 mmol). The reaction mixture was stirred at room temperature for 12 h. The reaction was monitored by TLC.
  • Step-5 N-(2-cyano-5,5-difluorooctahydropentalen-2-yl)pentanamide (23) [0404] To a stirred solution of 2-amino-5,5-difluorooctahydropentalene-2-carbonitrile (3 g, 16.11 mmol) in DMF (30 mL) was added EDC.HCl (6.1 g, 32.22 mmol) and DMAP (3.9 g, 32.22 mmol) at room temperature and stirred for 5 min followed by addition of pentanoic acid (5.4 mL, 48.33 mmol). The reaction mixture was stirred at room temperature for 5 h and was monitored by TLC and LCMS.
  • the reaction mixture was poured into cold water (100 mL) and extracted with DCM (3 x 100 mL) and the combined organic layers were dried over Na 2 SO 4 .
  • the compound was purified by column chromatography (100-200 mesh), eluted in 50% ethyl acetate in petroleum ether to afford the title compound (2.5 g, 57 %).
  • the reaction mixture was stirred at 70 0 C for 2 h.
  • the reaction was monitored by TLC/LCMS.
  • the pH of the reaction mixture was adjusted to basic with NaHCO3 solution and extracted with DCM (3 x 100 mL).
  • the combined organic layers were washed with water and brine solution and dried over sodium sulfate, concentrated under reduced pressure, the compound was purified by column chromatography (100-200 mesh), eluted in 60 % ethyl acetate in petroleum ether to afford the title compound (1.0 g, 66.7 %).
  • reaction mixture was stirred at room temperature for 12 h.
  • the reaction was monitored by TLC/LCMS.
  • the reaction mixture was poured into ice cold water (50 mL) and extracted with ethyl acetate (3 X 50 mL). The combined organic layers were dried over Na2SO4.
  • the compound was purified by column purification & eluted in 30% ethyl acetate in petroleum ether to afford title compound as brown liquid (1.0 g, 75.84 %).
  • Step-8 4'-((2-butyl-5',5'-difluoro-5-oxo-3',3a',4',5',6',6a'-hexahydro-1'H-spiro[imidazole-4,2'- pentalen]-1(5H)-yl) methyl)-N-(4,5-dimethylisoxazol-3-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2- sulfonamide (Compound A-283) [0407] To a stirred solution of 4'-((2-butyl-5',5'-difluoro-5-oxo-3',3a',4',5',6',6a'-hexahydro-1'H- spiro[imidazole-4,2'-pentalen]-1(5H)-yl)
  • Compound A-253 was separated to afford Compound A-291 and Compound A-293 as single unknown stereoisomers.
  • Compound A-291 (Enantiomer 1, Peak 1): M.phase A: - 0.1% FA in water
  • Mobile phase B - Acetonitrile, luna omega (21.2*250) mm 5 u Flow: - 15ml/min, Retention time: 9.73 min
  • Compound A-293 (Enantiomer 2, Peak 2): Mobile phase A: -0.1% FA
  • Mobile phase B - Acetonitrile
  • Example A-24 Synthesis of 4'-((2-butyl-4-oxo-8-(pyridazine-4-carbonyl)-1,3,8-triazaspiro[4.5]dec-1- en-3-yl)methyl)-N-(4,5-dimethylisoxazol-3-yl
  • reaction mixture was stirred for 10 min and pyridazine-4-carboxylic acid (0.18 g, 1.48 mmol) was added and stirring was continued at room temperature for 4 h.
  • the reaction was monitored by TLC and LCMS. After completion of the reaction, reaction mixture was diluted with ice cold water and extracted with ethyl acetate (3 x 50 mL), combined organic layer was washed with water, brine and dried over sodium sulphate, filtered and concentrated to get crude compound.
  • Example A-25 Synthesis of 4'-((2-butyl-8-(3-fluoropropanoyl)-4-oxo-1,3,8-triazaspiro[4.5]dec-1-en-3- yl)methyl)-N-(4,5-dimethylisoxazol-3-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide (Compound A-247)
  • Step 1 Preparation of 4'-((2-butyl-4-oxo-1,3,8-triazaspiro[4.5]dec-1-en-3-yl)methyl)-N-(4,5- dimethylisoxazol-3-yl)-2'-(ethoxymethyl)-N-(methoxymethyl)-[1,1'-biphenyl]-2-sulfonamide (2) [0412] To a stirred solution of benzyl 2-butyl-3-((2'-(N-(4,5-dimethylisox
  • reaction was monitored by TLC and LCMS.
  • the pH of the reaction mixture was adjusted to basic with saturated NaHCO 3 solution and washed with DCM (3 x 50 mL). The combined organic layers were dried over Na 2 SO 4 .
  • the compound was purified by prep HPLC to afford title compound (0.061 g, 21 %), LCMS; [M+H] + : 682.56.
  • Example A-27 Synthesis of 4'-((2-butyl-4,4-bis(2-fluoroethyl)-5-oxo-4,5-dihydro-1H-imidazol-1- yl)methyl)-N-(4,5-dimethylisoxazol-3-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide (Compound A-264) Step-1: Preparation of diethyl 2,2'-(1,3-dioxolane-2,2-diyl) diacetate (5) [0416] To a stirred solution of diethyl 3-oxopentanedioate (50 g, 247.3 mmol) in toluene (500 mL), ethane- 1,2-diol (44.11 mL, 747.813 mmol) was added, followed by the addition of PTSA monohydrate (2.35 g, 12.364 mmol) and
  • reaction mixture was quenched with NaHCO 3 solution (300 mL) and washed with Ethyl acetate (3 x 150 mL), dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford desired compound as a pale-yellow oil.
  • Step-2 Preparation of 2,2'-(1,3-dioxolane-2,2-diyl) bis(ethan-1-ol) (6) [0417] To a stirred solution of 2.0 M LAH (106.5 mL, 213.19 mmol) at 0 °C diethyl 2,2'-(1,3-dioxolane-2,2- diyl) diacetate (21 g, 85.276 mmol) in THF (300 mL) was added and the reaction mixture was stirred at room temperature for 3 h.
  • Step-4 Preparation of 1,5-bis(benzyloxy)pentan-3-one (8) [0419] To a stirred solution of 2,2-bis(2-(benzyloxy)ethyl)-1,3-dioxolane (1.7 g, 4.964 mmol) in acetone (50 mL) at room temperature, p-toluene sulfonic acid monohydrate (0.094 g, 0.496 mmol) was added and the reaction mixture was stirred at room temperature for 12 h.
  • reaction mixture was quenched with water (5 mL) and washed with DCM (2 x 25 mL).
  • Step-7 Preparation of 5,5-bis(2-(benzyloxy)ethyl)-2-butyl-3,5-dihydro-4H-imidazol-4-one (11) [0422] To a stirred solution of 2N-(1,5-bis(benzyloxy)-3-cyanopentan-3-yl) pentanamide (1.2 g, 2.397 mmol) in EtOH (5 mL) was added 4 M-HCl in Dioxane (5 mL) at room temperature. Then the reaction mixture was heated at 60 °C for 3 h. Reaction was monitored by TLC. The reaction mixture was quenched with saturated sodium bicarbonate solution (30 mL) and washed with DCM (2 x 50 mL).
  • reaction mixture was stirred at room temperature for 2 h. Reaction was monitored by TLC. The reaction mixture was quenched with saturated NaHCO3 solution and washed with DCM (2 x 20mL), dried over sodium sulphate, filtered and concentrated under reduced pressure completely to afford crude compound (0.27 g, 98%), LCMS; [M+H] + : 233.38.
  • Step-10 Preparation of 4'-((2-butyl-4,4-bis(2-fluoroethyl)-5-oxo-4,5-dihydro-1H-imidazol-1- yl)methyl)-N-(4,5-dimethylisoxazol-3-yl)-2'-(ethoxymethyl)-N-(methoxymethyl)-[1,1'-biphenyl]-2- sulfonamide (15) [0425] To a stirred solution of 2-butyl-5,5-bis(2-fluoroethyl)-3,5-dihydro-4H-imidazol-4-o (0.32 g, 1.378 mmol) in DMF (5 mL), Cesium carbonate (1.57 g, 4.82 mmol) was added followed by 4'- (bromomethyl)-N-(4,5-dimethylisoxazol-3-yl)-2'-(ethoxymethyl)-N-(methoxymethyl)-[1,
  • reaction mixture was concentrated to remove the volatiles completely.
  • the pH of the reaction mixture was adjusted to basic with saturated NaHCO3 and washed with 10% MeOH:DCM (3 x 20 mL).
  • the combined organic layer was washed with water and brine, dried over sodium sulphate, filtered, and the filtrate concentrated under reduced pressure to get desired compound as light brown syrup.
  • the crude compound was purified by Prep-HPLC to afford desired compound (0.016 g, 6%), LCMS; [M+H] + : 625.8 [0427] Prep.
  • Example A-28 Synthesis of 4'-((2-butyl-4-ethyl-4-(2-hydroxyethyl)-5-oxo-4,5-dihydro-1H-imidazol-1- yl)methyl)-N-(4,5-dimethylisoxazol-3-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide (Compound A-267)
  • E P 1 2 Step-5 Step-6 T
  • Compound A-267 Step-1 Preparation of ethyl 2-(2-ethyl-1,3-dioxolan-2-yl) acetate (17) [0429] To a stirred solution of ethyl 2-oxopentanoate (10 g, 69.363 mmol) in Toluene (100 mL), ethane-1,2- diol (11.5 mL, 208.088 mmol) was added followed by PTSA monohydrate (0.660
  • reaction mixture was quenched with saturated NaHCO3 solution (150 mL), washed with ethyl acetate (3 x 150 mL), dried over anhydrous sodium sulphate, solids filtered, and the filtrate was concentrated under reduced pressure to afford desired compound as pale-yellow oil.
  • the crude compound was purified by column chromatography over 100-200 mesh silica gel and eluted with 10-20 % ethyl acetate in petroleum ether to afford the desired compound as pale-yellow oil. (6.2 g, 47.5 %), LCMS; [M+H] + :189.10.
  • Step-2 Preparation of 2-(2-ethyl-1,3-dioxolan-2-yl)ethan-1-ol (18) [0430] To a stirred solution of ethyl 2-(2-ethyl-1,3-dioxolan-2-yl) acetate (10 g, 53.13 mmol) in THF (100 mL) at 0 °C, 2.4 M Lithium aluminum hydride (44 mL,106.26 mmol) in THF (100 mL) was added slowly, and the reaction mixture was stirred at room temperature for 4 h. The completion of the reaction was monitored by TLC.
  • p-Methoxy benzyl chloride (4.472 mL, 32.835 mmol) was added dropwise at 0 °C and the reaction mixture was stirred at room temperature for 16 h. The reaction was monitored by TLC and LCMS. The reaction mixture was quenched with ice cold water (100 mL) at 10 °C and washed with ethyl acetate (2 X 100 mL). The combined organic layer was separated, washed with saturated aqueous NaHCO3 solution, dried over anhydrous sodium sulphate, solids filtered, and the filtrate concentrated under reduced pressure to get crude product.
  • reaction mixture was stirred at room temperature for 4 h. The reaction was monitored by TLC and LCMS. After completion of reaction, reaction mixture was diluted with water (10 mL), washed with DCM (2 x 25 mL). The combined organic layer was thoroughly washed with brine, concentrated under reduced pressure to afford to crude material. This was purified by prep HPLC to afford the required compound (26 mg, 13.5 %), LCMS; [M+H] + : 611.77 [0438] prep HPLC method; Mobile Phase-A 10mM Ammonium Bicarbonate in water Mobile Phase-B Acetonitrile.
  • Step-3 Preparation of 4'-((2-butyl-4-ethyl-4-(2-methoxyethyl)-5-oxo-4,5-dihydro-1H-imidazol-1- yl)methyl)-N-(4,5-dimethylisoxazol-3-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide (Compound A-266) [0442] To a stirred solution of 4'-((2-butyl-4-ethyl-4-(2-methoxyethyl)-5-oxo-4,5-dihydro-1H-imidazol-1- yl)methyl)-N-(4,5-dimethylisoxazol-3-yl)-2'-(ethoxymethyl)-N-(methoxymethyl)-[1,1'-biphenyl]-2-
  • Step-2 Preparation of 4'-((2-butyl-4-ethyl-4-(2-fluoroethyl)-5-oxo-4,5-dihydro-1H-imidazol-1- yl)methyl)-N-(4,5-dimethylisoxazol-3-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide (Compound A-265) [0446] To a stirred solution of 4'-((2-butyl-4-ethyl-4-(2-fluoroethyl)-5-oxo-4,5-dihydro-1H-imidazol-1- yl)methyl)-N-(4,5-dimethylisoxazol-3-yl)-2'-(ethoxymethyl)-N-(methoxy
  • Example A-31 Preparation of 4'-((2-butyl-4-ethyl-5-oxo-4-(pyridin-4-yl)-4,5-dihydro-1H-imidazol-1- yl)methyl)-N-(4,5-dimethylisoxazol-3-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide (Compound A-268) Step 1: Synthesis of 2-amino-2-(pyridin-4-yl)butanenitrile (31) [0449] To a stirred solution of 1-(pyridin-4-yl)propan-1-one (2 g, 14.81 mmol) in MeOH (10 mL) and 25% aqueous ammonia solution (10 mL) was added NaCN (1.45 g, 29.63 mmol) and NH4Cl (1.58 g, 29.63 mmol), stirred the reaction at room temperature for 12 h.
  • reaction mixture was diluted with water (50 mL), washed with DCM (2 x 50 mL), the combined organic layer was dried over Na2SO4 and concentrated under reduced pressure to afford crude compound (1.8 g, 75 %).
  • reaction mixture was poured into cold water (20 mL) and washed with DCM (3 x 50 mL) and the combined organic layer was dried over Na2SO4.
  • the compound was purified by column chromatography (100-200 mesh), eluted in 50% ethyl acetate in petroleum ether to afford title compound (1.4 g, 51 %).
  • reaction mixture was stirred at room temperature for 5 h.
  • the reaction was monitored by TLC and LCMS.
  • the reaction mixture was poured into ice cold water (50 mL) and washed with ethyl acetate (3 X 50 mL).
  • the combined organic layer was dried over Na2SO4.
  • the compound was purified by column purification eluted in 30% ethyl acetate in petroleum ether to afford title compound (1.0 g, 75.84 %).
  • reaction mixture was stirred at room temperature for 3 h.
  • the reaction was monitored by TLC and LCMS.
  • the pH of the reaction mixture was adjusted to basic with NaHCO 3 solution and washed with DCM (3 x 50 mL).
  • the combined organic layer was dried over Na 2 SO 4 .
  • the compound was purified by prep HPLC to afford title compound (0.1 g, 35 %).
  • Compound A-269 was separated to afford Compound A-271 and Compound A-272 as single unknown stereoisomers using the following conditions: SFC Method: Column: (R, R) WHELK-01 (4.6*250mm)5 ⁇ m Co-solvent: IPA Total flow: 3 mL/min % of CO2: 70 % of Co-Solvent: 30 ABPR: 1500psi, Temperature: 30°C Compound A-271: Individual enantiomer: Retention time for interconvertible atropisomers: 5.21 min and 6.91 min Compound A-272: Individual enantiomer: Retention time for interconvertible atropisomers: 9.86 min and 12.75 min [0456] Compound A-270 was separated to afford Compound A-273 and Compound A-274 as single unknown stereoisomers using the following conditions: SFC Method: Column: (R, R) WHELK-01 (4.6*250mm)5 ⁇ m Co-solvent: IPAI Total flow: 3 mL/min% of CO
  • Example B-1 Intermediate 9: Synthesis of 2-(4-(chloromethyl)-2-methylbenzofuran-7-yl)-N-(4,5- dimethylisoxazol-3-yl)-N-(methoxymethyl)benzenesulfonamide (Int-9)
  • Step-1 Synthesis of methyl 4-bromo-3-(prop-2-yn-1-yloxy) benzoate (Int-3)
  • propargyl bromide 5.785 ml, 64.924 mmol
  • K2CO3 (11.962 g, 86.565 mmol
  • reaction mixture was stirred for 16 h at rt. After completion of the reaction (monitored by LCMS and TLC), the reaction mixture was diluted with ice cold water (200 mL) and extracted with ethyl acetate (2 x 200 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to afford the title compound (8.5 g, 72.98%), LCMS; [M+H] + : 271.15.
  • Step-2 Synthesis of methyl 7-bromo-2-methylbenzofuran-4-carboxylate (Int-4) [0463] To a stirred solution of methyl 4-bromo-3-(prop-2-yn-1-yloxy) benzoate (10 g, 37.441 mmol) in N, N-diethyl aniline (100 mL) was added CsF (8.5 g, 56.16 mmol). The reaction mixture was heated to 220 °C and stirred for 6 h at the same temperature. After completion of the reaction (monitored by TLC/LCMS), the reaction mixture was diluted with ice cold water (30 mL), and acidified to pH-4-5 with 6N hydrochloric acid.
  • Step-3 Synthesis of methyl 2-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzofuran-4- carboxylate (Int-5) [0464] To a stirred solution of methyl 7-bromo-2-methylbenzofuran-4-carboxylate (6.5 g, 24.15 mmol) in 1,4 dioxane (60 mL), were added bis(pinacolato)diboron (7.3 g, 28.986 mmol) and KOAc (5.9 g, 60.388 mmol).
  • reaction mixture was degassed with argon gas for 10 min, then PdCl2(dppf).dcm (1.97 g, 2.416 mmol) was added.
  • the resulting reaction mixture was heated to 110 °C and stirred for 3 h.
  • the reaction mixture was diluted with water (150 mL) and extracted into ethyl acetate (2 x 200 mL). The combined organic layers were washed with water, brine solution, dried over sodium sulfate, filtered, and filtrate was concentrated under reduced pressure.
  • Step-4 Synthesis of methyl 7-(2-(N-(4,5-dimethylisoxazol-3-yl)-N-(methoxymethyl)sulfamoyl)phenyl)- 2-methylbenzofuran-4-carboxylate (Int-7) [0465] To a stirred solution of 2-bromo-N-(4,5-dimethylisoxazol-3-yl)-N-(methoxymethyl) benzenesulfonamide (3 g, 7.995 mmol) in 1,4 Dioxane (30 mL) and water (5 mL), was added methyl 2- methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzofuran-4-carboxylate (3.792 g, 11.992 mmol), K2CO3 (3.314 g, 23.985 mmol), and PdCl2dppf.dcm (0.979 g, 1.199 mmol).
  • Step-5 Synthesis N-(4,5-dimethylisoxazol-3-yl)-2-(4-(hydroxymethyl)-2-methylbenzofuran-7-yl)-N- (methoxymethyl) benzenesulfonamide (Int-8) [0466] To a stirred solution of methyl 7-(2-(N-(4,5-dimethylisoxazol-3-yl)-N-(methoxymethyl) sulfamoyl) phenyl)-2-methylbenzofuran-4-carboxylate (1.2 g, 2.479 mmol ) in DCM (25 mL) was added DIBAL-H ( 1.5 M in toluene, 3.5 mL, 7.482 mmol ) at -70 °C.
  • reaction mixture was allowed to warm to rt and stirred for 4-5 h. After completion of the reaction (monitored by TLC/LCMS), the reaction mixture was cooled to 0°C and quenched with saturated ammonium chloride (20 mL) solution and stirred at rt for 5-6 h. The resulting mixture was diluted with water (100 mL) and extracted with DCM (2x 50 mL). The combined organic layers were washed with water, brine, dried over sodium sulfate, and concentrated under reduced pressure.
  • Step-6 Synthesis of 2-(4-(chloromethyl)-2-methylbenzofuran-7-yl)-N-(4,5-dimethylisoxazol-3-yl)-N- (methoxymethyl) benzenesulfonamide (Int-9) [0467] To a stirred solution of N-(3,4-dimethylisoxazol-5-yl)-2'-(ethoxymethyl)-4'-(hydroxymethyl)-N- (methoxymethyl)-[1,1'-biphenyl]-2-sulfonamide (0.25 g, 0.55 mmol) in DCM (15 mL), was added DIPEA (0.48 mL, 2.74 mmol) and methane sulfonyl chloride (0.13 mL, 1.64 mmol) at 0 °C.
  • Example B-2 Synthesis of 2-(4-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-2- methylbenzofuran-7-yl)-N-(4,5-dimethylisoxazol-3-yl)benzenesulfonamide
  • Compound B-9) Step-1: Synthesis of 2-(4-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-2- methylbenzofuran-7-yl)-N-(4,5-dimethylisoxazol-3-yl)benzenesulfonamide (Int-10) [0468] To a stirred solution of 2-butyl-1,3-diazaspiro [4.4] non-1-en-4-one (146 mg, 0.758 mmol) in DMF (6 mL) was added sodium hydride (45.48 mg, 1.90 m
  • Step-2 Synthesis of 2-(4-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-2- methylbenzofuran-7-yl)-N-(4,5-dimethylisoxazol-3-yl)benzenesulfonamide (Compound B-9) [0469] 2-(4-((2-Butyl-4-oxo-1,3-diazaspiro[4.4] non-1-en-3-yl)methyl)-2-methylbenzofuran-7-yl)-N-(4,5- dimethylisoxazol-3-yl)-N-(methoxymethyl)benzenesulfonamide (0.2 g, 0.32 mmol) was dissolved in TFA (2 mL) and heated to 60 °C for 2 h After completion of the reaction (monitored by TLC/LCMS) the reaction mixture concentrated under reduced pressure.
  • Example B-3 Synthesis of 2-(4-((2-butyl-4-methyl-5-(2-morpholino-2-oxoethyl)-6-oxopyrimidin-1(6H)- yl) methyl)-2-methylbenzofuran-7-yl)-N-(4,5-dimethylisoxazol-3-yl)benzenesulfonamide (Compound B- 11)
  • Step-1 Preparation of (2'-(N-(3,4-dimethylisoxazol-5-yl)-N-(methoxymethyl) sulfamoyl)-2- (ethoxymethyl)-[1,1'-biphenyl]-4-yl)methyl methane sulfonate (Int-12) [0470] To a stirred solution of 2-(4-(chloromethyl)-2-methylbenzofuran-7-yl)-N-(4,5-dimethylisoxazol-3- yl)-N-(methoxymethyl)
  • the resulting reaction mixture was heated to 100 °C and stirred for 16 h at the same temperature. After completion of the reaction (monitored by TLC/LCMS), the reaction mixture was diluted with ice cold water (50 mL) and extracted with 10% MeOH in DCM (2 x 30 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The crude material thus obtained was purified by automated flash chromatography (silica gel) by using a mixture of ethyl acetate and petroleum ether (20 to 60%) to afford the title compound (240 mg, 62%), LCMS; [M+H] + : 732.36.
  • Step-2 Preparation of 2-(4-((2-butyl-4-methyl-5-(2-morpholino-2-oxoethyl)-6-oxopyrimidin-1(6H)- yl)methyl)-2-methylbenzofuran-7-yl)-N-(4,5-dimethylisoxazol-3-yl)benzenesulfonamide (Compound B- 11) [0471] To a stirred solution of 2-(4-((2-butyl-4-methyl-5-(2-morpholino-2-oxoethyl)-6-oxopyrimidin-1(6H)- yl)methyl)-2-methylbenzofuran-7-yl)-N-(4,5-dimethylisoxazol-3-yl)-N (methoxymethyl) benzenesulfonamide (200 mg, 0.27 mmol ) in ethanol (2.5 mL), was added conc.
  • Step-2 Synthesis of N-(4,5-dimethylisoxazol-3-yl)-2-(3-(hydroxymethyl)-1H-indol-1-yl)-N- (methoxymethyl) benzenesulfonamide (21) [0474] To a stirred solution of N-(4,5-dimethylisoxazol-3-yl)-2-(4-formyl-1H-indol-1-yl)-N- (methoxymethyl) benzene sulfonamide (0.48 g, 1.09 mmol) in MeOH (30 mL), was added NaBH4 (0.08 g, 2.18 mmol) at 0 °C.
  • Step-3 Synthesis of 2-(3-((2-butyl-5-chloro-1H-benzo[d]imidazol-1-yl)methyl)-1H-indol-1-yl)-N-(4,5- dimethylisoxazol-3-yl)benzenesulfonamide (Compound B-27) and 2-(3-((2-butyl-6-chloro-1H- benzo[d]imidazol-1-yl)methyl)-1H-indol-1-yl)-N-(4,5-dimethylisoxazol-3-yl)benzenesulfonamide (Compound B-24) [0475] To a stirred solution of N-(4,5-dimethylisoxazol-3-yl)-2-(3-(hydroxymethyl)-1H-indol-1-yl)-N- (methoxymethyl)benzenesulfonamide (0.5 g, 1.13 mmol) in DCM (5 mL), was added methan
  • reaction mixture was stirred at rt for 2 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with ice cold water (30 mL) and extracted with DCM (2 x 50 mL). The combined organic layers were washed with dried over sodium sulfate, concentrated under reduced pressure. The crude material thus obtained was used for next step without further purification.
  • Example B-5 Synthesis of 2-(3-((2-butyl-4-oxo-1,3-diazaspiro [4.4] non-1-en-3-yl) methyl)-1H-pyrrol- 1-yl)-N-(4,5-dimethylisoxazol-3-yl) benzenesulfonamide (Compound B-17)
  • Step-1 Synthesis of 1-tosyl-1H-pyrrole-3-carbaldehyde (24) [0478] To a stirred solution of 1H-pyrrole-3-carbaldehyde (30 g, 0.31 mol) in DCM (200 mL), was added DMAP (1 g) and TEA (85 mL, 0.62 mol ) at 0 °C.
  • reaction mixture was stirred at same temperature for 10 min, then was added 4-toluenesulfonyl chloride (62.4 g, 0.34 mol). The reaction mixture was allowed to warm to rt and stirred for 16 h. After completion of the reaction, the reaction mixture was diluted with ice cold water (200 mL), extracted with DCM (4x100 mL). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The crude residue thus obtained was purified by automated flash chromatography by using a mixture of ethyl acetate and petroleum ether (20 to 60%) to afford 1-tosyl-1H-pyrrole-3-carbaldehyde.
  • Step-2 Synthesis of (1-tosyl-1H-pyrrol-3-yl) methanol (25) [0479] To a stirred solution of 1-tosyl-1H-pyrrole-3-carbaldehyde (55 g, 0.22 mol) in MeOH (150 mL) at 0 °C, was added sodium borohydride (16.6 g, 0.44 mol). The reaction mixture was allowed to warm to rt and stirred for 16 h. After completion of the reaction (monitored by TLC/LCMS), the reaction mixture was diluted with ice cold water and extracted with DCM (2x100 mL).
  • Step-3 synthesis of 3-( bromo methyl)-1-tosyl-1H-pyrrole (26)
  • triphenylphosphine 93.9 g, 0.36 mol
  • carbon tetrabromide 119 g, 0.36 mmol
  • Step-4 synthesis of 2-butyl-3-((1-tosyl-1H-pyrrol-3-yl) methyl)-1,3-diazaspiro [4.4] non-1-en-4-one (27) [0481] To a stirred solution of 3-(bromomethyl)-1-tosyl-1H-pyrrole (30 g, 95.5mmol) in DMF (300 mL), was added 2-butyl-1,3-diazaspiro[4.4]non-1-en-4-one (20.4 g, 105.10 mmol) and cesium carbonate (93.3 g, 286.50 mmol) at rt and stirred for 4 h.
  • Step-5 synthesis of 3-((1H-pyrrol-3-yl) methyl)-2-butyl-1,3-diazaspiro [4.4] non-1-en-4-one (28) [0482] To a stirred solution of 2-butyl-3-((1-tosyl-1H-pyrrol-3-yl) methyl)-1,3-diazaspiro [4.4] non-1-en-4- one (21 g, 49.1 mmol) in MeOH (140 mL) at 0° C, was added 5 N aq NaOH (70 mL), allowed to warm to rt and stirred 16 h. After completion of the reaction, the solvent was evaporated under reduced pressure, the residue was diluted with water (100 mL).
  • Step-6 Synthesis of 2-(3-((2-butyl-4-oxo-1,3-diazaspiro [4.4] non-1-en-3-yl) methyl)-1H-pyrrol-1-yl)-N- (4,5-dimethylisoxazol-3-yl)-N-(methoxymethyl)benzenesulfonamide (29) [0483] To a stirred solution of 3-((1H-pyrrol-3-yl) methyl)-2-butyl-1,3-diazaspiro [4.4] non-1-en-4-one (13 g, 47.55 mmol) in DMSO (100 mL) at 0° C, was added sodium tert-butoxide (11.4 g, 118.75 mmol).
  • Step-7 synthesis of 2-(3-((2-butyl-4-oxo-1,3-diazaspiro [4.4] non-1-en-3-yl) methyl)-1H-pyrrol-1-yl)-N- (4,5-dimethylisoxazol-3-yl) benzene sulfone amide (Compound B-17) [0484] To a stirred solution of 2-(3-((2-butyl-4-oxo-1,3-diazaspiro [4.4] non-1-en-3-yl) methyl)-1H-pyrrol- 1-yl)-N-(4,5-dimethylisoxazol-3-yl)-N-(methoxymethyl) benzenesulfonamide (10 g, 17.60 mmol) in DMF (100 mL), was added Cesium carbonate (17.2 g, 52.81 mmol).
  • reaction mixture was heated to 130 °C and stirred for 16 h. After completion of the reaction, the reaction mixture was cooled to rt, then filtered through celite bed washed with ethyl acetate (300 mL) and concentrated under reduced pressure.
  • the crude material thus obtained was purified by Prep-HPLC using Cogent C18 (150*20*5 ⁇ ) column, 10mM ABC in water and acetonitrile as mobile phase to afford 2-(3-((2-butyl-4-oxo-1,3-diazaspiro [4.4] non-1-en-3-yl) methyl)-1H-pyrrol-1-yl)-N-(4,5-dimethylisoxazol-3-yl)benzenesulfonamide.
  • Example B-6 Synthesis of 2-(4-((2-butyl-4-oxo-1,3-diazaspiro [4.4] non-1-en-3-yl) methyl) piperidin-1- yl)-N-(4,5-dimethylisoxazol-3-yl) benzenesulfonamide (Compound B-2)
  • Step-1 Synthesis of tert-butyl 4-((2-butyl-4-oxo-1,3-diazaspiro [4.4] non-1-en-3yl) methyl) piperidine- 1-carboxylate (31) [0486] To a stirred solution of 2-butyl-1,3-diazaspiro [4.4] non-1-en-4-one (0.418 g, 0.0021 mol) in DMF (5 mL), was added KOH (0.30 g, 5.35 mmol).
  • reaction mixture was stirred at 10 min at rt, then was added tert-butyl 4-(bromomethyl) piperidine-1-carboxylate (0.5 g, 1.79 mmol) at 0 °C.
  • the reaction mixture was stirred at rt for 12 h.
  • the reaction mixture was diluted with water and extracted with ethyl acetate (2 x 50 mL). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under reduced pressure.
  • Step-2 Synthesis 2-butyl-3-(piperidin-4-ylmethyl)-1,3-diazaspiro [4.4] non-1-en-4-one (32) [0487] tert-Butyl 4-((2-butyl-4-oxo-1,3-diazaspiro [4.4] non-1-en-3-yl) methyl) piperidine-1-carboxylate (0.42 g, 0.001072 mol) was dissolved in 4M HCl dioxane (4.2 mL) at 0 °C. The reaction mixture was allowed to warm to rt and stirred for 2 h. After completion of the reaction, the reaction was quenched with saturated NaHCO3 solution and extract compound with DCM (2 x 50 mL).
  • Step-3 Synthesis of 2-(4-((2-butyl-4-oxo-1,3-diazaspiro [4.4] non-1-en-3-yl) methyl) piperidin-1-yl)-N- (4,5-dimethylisoxazol-3-yl) benzenesulfonamide (Compound B-2) [0488] To a stirred solution of 2-butyl-3-(piperidin-4-ylmethyl)-1,3-diazaspiro [4.4] non-1-en-4-one (0.26 g, 0.893 mmol) in DMF (2.6 mL), was added N-(4,5-dimethylisoxazol-3-yl)-2-fluoro-N-(methoxymethyl) benzenesulfonamide (0.30 g, 0.98 mmol) and K2CO3 (0.37 g, 2.68 mmol).
  • reaction mixture was stirred at 130 °C for 12 h. After completion of the reaction, the reaction mixture was diluted with water (50 mL) and extracted with DCM (2 x 50 mL). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under reduced pressure.
  • Example B-7 Intermediate 19: Synthesis of N-(4,5-dimethylisoxazol-3-yl)-2-fluoro-N-(methoxymethyl) benzenesulfonamide (19)
  • Step-1 Synthesis 2-butyl-3-(piperidin-4-ylmethyl)-1,3-diazaspiro [4.4] non-1-en-4-one (35)
  • 2-fluro benzene sulfonyl chloride 17.35 g, 89.2 mmol
  • Step-2 SynthesisN-(4,5-dimethylisoxazol-3-yl)-2-fluoro-N-(methoxymethyl)benzenesulfonamide (19) [0490] To a stirred solution of N-(3,4-dimethylisoxazol-5-yl)-2-fluorobenzenesulfonamide (20 g, 74.07 mmol) in DMF (100 mL) at 0 °C, was added K 2 CO 3 (10.22 g, 74.07 mmol) and 2-methoxyethoxymethyl chloride (5.96 mL, 74.07 mmol) was added dropwise over 10 min. Then reaction mixture was stirred at same temperature for 20 min.
  • Example B-8 Synthesis of 2-(5-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)isoquinolin-7- yl)-N-(4,5-dimethylisoxazol-3-yl)benzenesulfonamide (Compound B-1)
  • Step-1 Synthesis of 5-bromoisoquinoline (37) [0492] In a double neck round bottle flask (1L), was added H 2 SO 4 (500 mL) and cooled to 0 o C. To this was added isoquinoline (50 g, 387.1 mmol) slowly over a period of 20 min.
  • reaction mixture was cooled -15 o C to -20 o C and was added NBS (137.8 g, 774.2 mmol) portion wise over a period of 3h maintaining the same temperature
  • NBS 137.8 g, 774.2 mmol
  • the resulting reaction mixture was allowed to warm up to rt and stirred for 2 h
  • the reaction mixture was quenched with aq. ammonia ( ⁇ 2 L) carefully until the pH was about 10.
  • the formed precipitate was filtered and purified by column chromatography (silica gel) to afford 5-bromoisoquinoline. (15 g, 18.6%); LCMS; [M+H] + : 207.92.
  • Step-2 Synthesis of methyl isoquinoline-5-carboxylate (38) [0493]
  • the 250 mL autoclave was charged with 5-bromoisoquinoline (15 g, 72.1 mmol), TEA (30.1 mL, 216.28 mmol) and methanol (150 mL) and PdCl2(dppf) (5.28 g, 7.21 mmol).
  • the reaction mixture was degassed by bubbling argon gas for 10 min, the autoclave was filled with CO gas until 150 psi pressure.
  • the reaction mixture was heated to 100 °C stirred for 16 h.
  • the reaction mixture was filtered through celite and concentrated under reduce pressure to get crude material.
  • the reaction mixture was cooled to -20 o C and added NBS (5.56 g, 31.25 mmol) portion wise over a period of 1h maintaining the same temperature.
  • the reaction mixture was allowed to warm to rt and stirred for 2 h.
  • the reaction mixture was quenched with aq. ammonia ( ⁇ 200 mL) carefully until the pH of the solution reached to 10.
  • the formed ppt was filtered and purified by chromatography (silica gel) to afford methyl 5- bromoisoquinoline-8-carboxylate. (2.8 g, 43.8%), LCMS; [M+H] + : 268.44.
  • Step-4 Synthesis of methyl 8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinoline-5-carboxylate (40) [0495] To a stirred solution of methyl 8-bromoisoquinoline-5-carboxylate (2.8 g, 1.88 mmol) in 1,4- Dioxane (60 mL) was added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (6.68 g, 26.3 mmol), potassium acetate (3.1 g, 31.57 mmol) and PdCl2(dppf) (0.77 g, 1.05 mmol) under argon atmosphere.
  • reaction mixture was degassed by bubbling with argon for 10 min, heated to 110 o C and stirred for 5h. After completion of the reaction, the reaction mixture was concentrated, diluted with ice cold water (50 mL), extracted with EtOAc (2 x 50 mL). The combined organic layers were dried over sodium sulfate, concentrated under reduced pressure. The crude was purified by automated flash chromatography (silica gel) to afford methyl 8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) isoquinoline-5-carboxylate. (1.8 g, 55%), LCMS; [M+H] + : 232.57.
  • Step-5 Synthesis of methyl 8-(2-(N-(4,5-dimethylisoxazol-3-yl)-N (methoxymethyl)sulfamoyl)phenyl)isoquinoline-5-carboxylate (41) [0496] To a stirred solution of 2-bromo-N-(4,5-dimethylisoxazol-3-yl)-N- (methoxymethyl)benzenesulfonamide(1.8 g, 4.8 mmol) and methyl 8-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)isoquinoline-5-carboxylate (1.5 g, 0.762 mmol) in 1,4-Dioxane (25 mL), was added potassium carbonate (1.99 g, 14.39 mmol) in water (3 mL) and PdCl 2 (dppf) (0.35 g, 0.48 mmol).
  • the resulting reaction mixture was degassed by bubbling with argon for 10 min, was heated to 110 o C and stirred for 16 h. After completion of the reaction, the reaction mixture was concentrated, diluted with ice cold water (50 mL), extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure. The crude material thus obtained was purified by flash chromatography (silica gel) to afford methyl 8-(2-(N-(4,5-dimethylisoxazol-3-yl)-N (methoxymethyl)sulfamoyl)phenyl)isoquinoline-5-carboxylate.
  • Step-6 Synthesis of N-(4,5-dimethylisoxazol-3-yl)-2-(5-(hydroxymethyl)isoquinolin-8-yl)-N- (methoxymethyl)benzenesulfonamide (42) [0497] To a stirred solution of methyl 8-(2-(N-(4,5-dimethylisoxazol-3-yl)-N- (methoxymethyl)sulfamoyl)phenyl)isoquinoline-5-carboxylate (1.7 g, 3.53 mmol) in methanol (35 mL) at 0 °C, was added sodiumborohydride (1.35 g, 35.3 mmol).
  • Step-7 Synthesis of 2-(8-(chloromethyl)isoquinolin-6-yl)-N-(3,4-dimethylisoxazol-5-yl)-N- (methoxymethyl)benzenesulfonamide (43) [0498] To a solution of N-(3,4-dimethylisoxazol-5-yl)-2-(8-(hydroxymethyl)isoquinolin-6-yl)-N- (methoxymethyl)benzenesulfonamide (0.22 g, 0.48 mmol) in DCM (3 mL), was added methanesulfonyl chloride (0.061 mL, 0.79 mmol) and DIPEA (0.28, 1.56 mmol) .
  • Step-8 Synthesis of 2-(8-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)isoquinolin-6-yl)-N- (4,5-dimethylisoxazol-3-yl)-N-(methoxymethyl)benzenesulfonamide (44) [0499] To a solution of benzyl 2-butyl-1,3-diazaspiro[4.4]non-1-en-4-one (0.1 g, 0.51 mmol) in DMF (5 mL) at 0 °C, was added sodium hydride (0.037 g, 1.53 mmol) and the resulting mixture was stirred for 30 min.
  • Step-9 Synthesis of 2-(5-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)isoquinolin-7-yl)-N- (4,5-dimethylisoxazol-3-yl)benzenesulfonamide(Compound B-1) [0500] 2-(5-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)isoquinolin-7-yl)-N-(4,5- dimethylisoxazol-3-yl)-N-(methoxymethyl)benzenesulfonamide (0.11 g, 0.17 mmol), was dissolved in TFA (8 mL) and stirred at 60 °C for 1 hour.
  • Example B-9 Synthesis of 2-(3-((2-butyl-5-(2-(4-cyclopropylpiperazin-1-yl)-2-oxoethyl)-4-methyl-6- oxopyrimidin-1(6H)-yl)methyl)-1H-indol-1-yl)-N-(4,5-dimethylisoxazol-3-yl)benzenesulfonamide (Compound B-14) Step-1: Synthesis of methyl 2-(2-butyl-1-((1-(2-(N-(4,5-dimethylisoxazol-3-yl)-N- (methoxymethyl)sulfamoyl)phenyl)-1H-indol-3-yl)methyl)-4-methyl-6-oxo-1,6-dihydropyrimidin-5- yl)acetate [0501] To a stirred solution of N-(4,5-dimethylisoxazol-3-yl)-2-(3-(hydroxymethyl
  • the resulting reaction mixture was stirred at 110 °C for 2 h. The completion of the reaction was monitored by the TLC. After completion of the reaction, the reaction mixture was diluted with ice cold water (30 mL) extracted with ethyl acetate (2 x 100 mL). The combined organic layers were dried over sodium sulphate, concentrated under reduced pressure.
  • Step-2 Synthesis of 2-(2-butyl-1-((1-(2-(N-(4,5-dimethylisoxazol-3-yl)-N- (methoxymethyl)sulfamoyl)phenyl)-1H-indol-3-yl)methyl)-4-methyl-6-oxo-1,6-dihydropyrimidin-5- yl)acetic acid [0502] To a stirred solution of methyl 2-(2-butyl-1-((1-(2-(N-(4,5-dimethylisoxazol-3-yl)-N- (methoxymethyl)sulfamoyl)phenyl)-1H-indol-3-yl)methyl)-4-methyl-6-oxo-1,6-dihydropyrimidin-5- yl)acetate (0.9 g, 1.48 mmol) in THF:H 2 O (20 mL) at rt, was added LiOH.H 2 0 (0.16 g, 7.39
  • Step-3 Synthesis of 2-(3-((2-butyl-5-(2-(4-cyclopropylpiperazin-1-yl)-2-oxoethyl)-4-methyl-6- oxopyrimidin-1(6H)-yl)methyl)-1H-indol-1-yl)-N-(4,5-dimethylisoxazol-3-yl)-N- (methoxymethyl)benzenesulfonamide [0503] To a stirred solution of 2-(2-butyl-1-((1-(2-(N-(4,5-dimethylisoxazol-3-yl)-N- (methoxymethyl)sulfamoyl)phenyl)-1H-indol-3-yl)methyl)-4-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)acetic acid (0.2 g, 0.309 mmol) in DMF (2 mL) at rt, was added 1-ethyl
  • reaction mixture was stirred for 6h at rt. After completion of the reaction (monitored by the TLC), the reaction mixture was concentrated under reduced pressure and diluted with water (25 mL) and extracted with DCM (2X 50 mL). The combined organic layer was dried over sodium sulphate and concentrated under reduced pressure.
  • Step-4 Synthesis of 2-(3-((2-butyl-5-(2-(4-cyclopropylpiperazin-1-yl)-2-oxoethyl)-4-methyl-6- oxopyrimidin-1(6H)-yl)methyl)-1H-indol-1-yl)-N-(4,5-dimethylisoxazol-3-yl)benzenesulfonamide (Compound B-14) [0504] To a stirred solution of 2-(3-((2-butyl-5-(2-(4-cyclopropylpiperazin-1-yl)-2-oxoethyl)-4-methyl-6- oxopyrimidin-1(6H)-yl)methyl)-1H-indol-1-yl)-N-(4,5-dimethylisoxazol-3-yl)-N- (methoxymethyl)benzenesulfonamide (0.12 g, 0.16 mmol) in DMF (2 mL
  • the resulting reaction mixture was stirred at 140 °C for 12 h. After completion of the reaction (monitored by LCMS), the reaction mixture was quenched by addition of water (10 mL) and extracted with DCM (3X 20 mL). The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The crude material thus obtained was purified by Prep. HPLC on Hi chrome c18 (250*22*5u) column, using 10mM ABC in water and acetonitrile as eluents.
  • Example B-10 Synthesis of 2-(3-((2-butyl-4-methyl-6-oxo-5-(2-oxo-2-(2,6-diazaspiro [3.4] octan-2-yl) ethyl) pyrimidin-1(6H)-yl) methyl)-1H-indol-1-yl)-N-(4,5-dimethylisoxazol-3-yl) benzenesulfonamide (Compound B-22) Step-1: Synthesis of tert-butyl 2-(2-(2-butyl-1-((1-(2-(N-(4,5-dimethylisoxazol-3-yl)-N-(methoxymethyl) sulfamoyl) phenyl)-1H-indol-3-yl) methyl)-4-methyl-6-oxo-1,6-dihydropyrimidin-5-yl) acetyl)-2,6- diazaspiro [3.4] o
  • reaction mixture was stirred for 30 min, was added tert-butyl 2,6-diazaspiro[3.4]octane-6-carboxylate (0.157 g, 0.741 mmol) and stirred for 16 h at rt. After completion of the reaction, the reaction mixture was diluted with DCM (50 mL), washed with water (2x50 mL), brine (50 mL), dried over sodium sulphate and concentrated under reduced pressure.
  • Step-2 Synthesis of tert-butyl 2-(2-(2-butyl-1-((1-(2-(N-(4,5-dimethylisoxazol-3-yl)sulfamoyl)phenyl)- 1H-indol-3-yl)methyl)-4-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)acetyl)-2,6-diazaspiro[3.4]octane-6- carboxylate [0506] To a stirred solution of tert-butyl 2-(2-(2-butyl-1-((1-(2-(N-(4,5-dimethylisoxazol-3-yl)-N- (methoxymethyl)sulfamoyl)phenyl)-1H-indol-3-yl)methyl)-4-methyl-6-oxo-1,6-dihydropyrimidin-5- yl)acetyl)-2,6-diazaspiro
  • reaction mixture was heated to 160 °C and stirred for 6 h. After completion of reaction, reaction mixture was diluted with ice cold water and extracted with DCM (2 x 25 mL). The combined organic layers were washed with water (20 mL), brine (20 mL) and dried over Na2SO4, filtered and concentrated. The crude material thus obtained was triturated with ether and dried to afford the title compound. (0.075 g, 66%), LCMS; [M+H] + : 798.83.
  • Step-3 Synthesis of 2-(3-((2-butyl-4-methyl-6-oxo-5-(2-oxo-2-(2,6-diazaspiro[3.4]octan-2- yl)ethyl)pyrimidin-1(6H)-yl)methyl)-1H-indol-1-yl)-N-(4,5-dimethylisoxazol-3 yl)benzenesulfonamide [0507] To a stirred solution of tert-butyl 2-(2-(2-butyl-1-((1-(2-(N-(4,5-dimethylisoxazol-3- yl)sulfamoyl)phenyl)-1H-indol-3-yl)methyl)-4-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)acetyl)-2,6- diazaspiro[3.4]octane-6-carboxylate (0.13 g, 0.163
  • reaction mixture was stirred at same temp for 3-4 h. After completion of reaction, reaction mixture was concentrated under reduced pressure, diluted with ice cold water (20 mL), basified with sat. NaHCO3 solution and extract with 20% MeOH in DCM (3 x 25 mL). The combined organic layers were washed with water, brine, dried over sodium sulphate, and concentrated under reduced pressure.
  • the crude material thus obtained was purified by Prep HPLC on hichrome 21.2*150 mm, using 10 mm ABC in water and acetonitrile as eluents.

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Abstract

La présente invention concerne de manière générale des antagonistes du récepteur de l'angiotensine et de l'endothéline à double action, ou des sels pharmaceutiquement acceptables, des analogues, des stéréoisomères, des mélanges de stéréoisomères enrichis isotopiquement, ou des promédicaments de ceux-ci, et des procédés de fabrication et d'utilisation de ceux-ci.
PCT/US2023/022342 2022-05-16 2023-05-16 Antagonistes du récepteur de l'endothéline et de l'angiotensine à double action Ceased WO2023224963A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997029748A1 (fr) * 1996-02-20 1997-08-21 Bristol-Myers Squibb Company Biphenyl isoxazolyl sulfonamides, substitues
US5939446A (en) * 1996-04-09 1999-08-17 Bristol-Myers Squibb Co. Heteroaryl substituted phenyl isoxazole sulfonamide endothelin antagonists
WO2000001389A1 (fr) * 1998-07-06 2000-01-13 Bristol-Myers Squibb Co. Biphenyl sulfonamides en tant que doubles antagonistes de recepteurs d'angiotensine et d'endotheline
US20040106833A1 (en) * 1998-07-06 2004-06-03 San Natesan Murug Biphenyl sulfonamides as dual angiotensin endothelin receptor antagonists

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997029748A1 (fr) * 1996-02-20 1997-08-21 Bristol-Myers Squibb Company Biphenyl isoxazolyl sulfonamides, substitues
US5939446A (en) * 1996-04-09 1999-08-17 Bristol-Myers Squibb Co. Heteroaryl substituted phenyl isoxazole sulfonamide endothelin antagonists
WO2000001389A1 (fr) * 1998-07-06 2000-01-13 Bristol-Myers Squibb Co. Biphenyl sulfonamides en tant que doubles antagonistes de recepteurs d'angiotensine et d'endotheline
US20040106833A1 (en) * 1998-07-06 2004-06-03 San Natesan Murug Biphenyl sulfonamides as dual angiotensin endothelin receptor antagonists

Non-Patent Citations (2)

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Title
DATABASE PUBCHEM COMPOUND ANONYMOUS : "5-Cyclopropyl-1,2-dimethyl-1Hbenzo[d]imidazole", XP093114453, retrieved from PUBCHEM *
HAO LI-PING, XUE WEI-ZHE, HAN XIAO-FENG, HE XING, ZHANG JUN, ZHOU ZHI-MING: "Design, synthesis and biological activity of 4′-[(benzimidazol-1-yl)methyl]biphenyl-2-sulphonamides as dual angiotensin II and endothelin A receptor antagonists", MEDCHEMCOMM, ROYAL SOCIETY OF CHEMISTRY, UNITED KINGDOM, vol. 6, no. 4, 1 January 2015 (2015-01-01), United Kingdom , pages 715 - 718, XP093114455, ISSN: 2040-2503, DOI: 10.1039/C4MD00499J *

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