WO2021127333A1 - Trpml modulators - Google Patents

Trpml modulators Download PDF

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WO2021127333A1
WO2021127333A1 PCT/US2020/065845 US2020065845W WO2021127333A1 WO 2021127333 A1 WO2021127333 A1 WO 2021127333A1 US 2020065845 W US2020065845 W US 2020065845W WO 2021127333 A1 WO2021127333 A1 WO 2021127333A1
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compound
aliphatic
optionally substituted
heteroatoms selected
alkylenyl
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PCT/US2020/065845
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French (fr)
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Jorge Garcia FORTANET
Jeffrey Owen SAUNDERS
Harit Umesh VORA
Jian Lin
Andrew Thomas Maynard
Erik Lee MEREDITH
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Casma Therapeutics, Inc.
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Publication of WO2021127333A1 publication Critical patent/WO2021127333A1/en

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    • 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
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    • 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
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    • 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
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    • 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
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    • C07D498/10—Spiro-condensed systems

Definitions

  • Transient Receptor Potential Mucolipin-1 (also known as TRPML1 or ML1) is a Ca 2+ channel in the lysosome that regulates certain aspects of lysosome trafficking, including autophagy.
  • TRPML1 is an inwardly rectifying current channel that transports cations from the lumen of the lysosome to the cytosol.
  • the present disclosure provides, among other things, technologies for regulating (e.g., up- regulating) autophagy.
  • the present disclosure demonstrates effectiveness of certain approaches to TRPMLl modulation (e.g., TRPMLl agonism) in enhancing autophagy.
  • TRPMLl modulation e.g., TRPMLl agonism
  • the present disclosure demonstrates that targeting TRPMLl as described herein can enhance autophagy.
  • the present disclosure also provides certrain technologies for use in medicine, and in particular for treating certain diseases, disorders or conditions and/or for identifying, characterizing, and/or manufacturing certain agents and/or compositions or that comprise or deliver them that are useful in treating such diseases, disorders or conditions.
  • the present disclosure demonstrates that modulating (e.g., agonizing) TRPLM1 and/or otherwise enhancing autophagy is useful in the treatment of certain diseases, disorders or conditions.
  • TRPMLl modulators useful for promoting autophagy and/or treating certain diseases, disorders, or conditions.
  • the present application provides technologies useful for modulating TRPMLl.
  • the present application provides compounds having a structure as set forth in Formula I:
  • A is 9- to 12-membered bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, or 9- to 16- membered bicyclic or polycyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S, wherein A is substituted with 0, 1, 2, 3 or 4 R a ;
  • Cy is absent or a bivalent moiety selected from 4- to 12-membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, P, and S, 5- to 12-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, P, and S, Ci- 6 aliphatic, or C3-12 cycloalkyl, wherein Cy is optionally substituted with one or more of R 1 ;
  • L 1 is absent, -NR 3 -, -O-, -S-, Ci- 6 alkylenyl, C2-6 alkynylenyl, -NR 3 -CI- 6 alkylenyl,-0-Ci- 6 alkylenyl, -C(0)Co-e alkylenyl; -C(0)NR 3 -, or -C(0)-C(0)-;
  • L 2 is absent, -(NR 3 ) s -S(0)-Co- 6 alkylenyl-, -(NR 3 ) s -S(0)2-Co- 6 alkylenyl-, -(NR 3 ) s -S(0)(NR 3 )-, -S(0)2-NR 3 -, -NR 3 -CI- 6 haloalkylenyl, -(NR 3 ) s -P(0)(R 3 )-, -Ci-e alkylenyl-S(O)-, -Ci-e alkylenyl-S(0)2-, -C(0)-(NR 3 ) s -, -(NR 3 ) s -C(0)-, or an optionally substituted 4- to 12- membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S;
  • V is selected from Ci- 6 aliphatic, Ce-u aryl, 4- to 12-membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S, 5- to 12-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S,
  • Z is Ci- 6 aliphatic, 2- to 10-membered heteroaliphatic, P(0)(R 3 )2, -C(0)Ci- 6 aliphatic, C(0)N(R 3 )2, C6-12 aryl, C3-12 cycloalkyl, 4- to 16-membered monocyclic or polycyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S, or 5- to 12-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, wherein Z is substituted with (R 2 )q; each R a is independently halo, oxo, or optionally substituted Ci- 6 aliphatic; each R 1 is independently selected from N(R 3 )2, OH, CN, C(0)NHR 3 , and an optionally substituted group selected from Ci- 6 aliphatic and N(R 3 )-C(0)-CI- 6 alkyl; each R 2 is independently selected from halo, CN,
  • A’ is a fused phenyl or 6-membered heteroaryl ring comprising 1 to 3 nitrogen atoms, optionally substituted with R a ;
  • X 1 and X 7 are each independently selected from N, NR a , C, CR a , and C(R a )2, as valency permits, wherein X 1 and X 7 are N, C, or CR a when bound to Cy-L'-Z;
  • Cy is absent, or a bivalent moiety selected from 4- to 12-membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, P, and S, 5- to 12-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, Ci- 6 aliphatic, Ce-u aryl, or C3-12 cycloalkyl, wherein Cy is optionally substituted with one or more of R 1 ;
  • L 1 is absent, -NR 3 -, -S-, C(0)NR 3 -, -C(0)-C(0)-, or an optionally substituted bivalent moiety selected from Ci- 6 alkylenyl, C2-6 alkenylenyl, C2-6 alkynylenyl, C3-6 cycloalkyl, -NR 3 -CI- 6 alkylenyl, -O-Co- 6 alkylenyl, and -C(0)Co- 6 alkylenyl;
  • L 2 is an optionally substituted bivalent moiety selected from -(NR 3 ) s -S(0)-Co- 6 alkylenyl-, - (NR 3 )S-S(0)2-CO-6 alkylenyl-, -Ci-6 alkylenyl-S(0)-(NR 3 ) s -, -Ci-6 alkylenyl-S(0)2-(NR 3 ) s -, - (NR 3 )s-Co-6 alkylenyl, -(NR 3 ) s -C(0)-Co- 6 alkylenyl, and 4- to 12-membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S;
  • V is Ci- 6 aliphatic, C6-12 aryl, C3-12 cycloalkyl, 4- to 12-membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S, 5- to 12-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, or 5- to 16-membered monocyclic or polycyclic aryl, wherein Vis substituted with (R 6 ) m ;
  • Z is Ci-6 aliphatic, 2- to 10-membered heteroaliphatic, P(0)(R 3 )2, -C(0)Ci-6 aliphatic, C(0)N(R 3 )2, C6-12 aryl, C3-12 cycloalkyl, 4- to 16-membered monocyclic or polycyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S, or 5- to 12-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, wherein Z is substituted with (R 2 )q; each R a is independently H, halo, CN, oxo, or an optionally substituted group selected from Ci-6 aliphatic and O-Ci-6 aliphatic; each R 1 is independently selected from halo, oxo, N(R 3 )2, -OH, -CN, -C(0)N(R 3 )2, and an optionally substituted group selected from Ci-6 aliphatic and N
  • X r , X 2” , and X 7 are each independently selected from N, NR a , C, and CR ax , wherein X r , X 2” , and X 7 are N, C, or CR a when bound to Cy-L'-Z or L 2 -V X 3” , X 4 , X 5 , and X 6 are each independently selected from N, C, and CR a , wherein X 3 , X 4 , X 5 , and X 6 are N or C when bound to Cy-L'-Z or L 2 -V;
  • Cy is absent or a bivalent moiety selected from 4- to 12-membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, P, and S, 5- to 12-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, P,and S, Ci-6 aliphatic, Ce-u aryl, or C3-12 cycloalkyl, wherein Cy is optionally substituted with one or more of R 1 ;
  • L 1 is absent, -NR 3 -, -0-, -S-, Ci-6 alkylenyl, C2-6 alkynylenyl, -NR 3 -CI-6 alkylenyl,-0-Ci-6 alkylenyl, -C(0)Co-e alkylenyl; -C(0)NR 3 -, or -C(0)-C(0)-;
  • L 2 is -(NR 3 ) S -S(0)-CO-6 alkylenyl-, -(NR 3 )s-S(0) 2 -Co-6 alkylenyl-, -(NR 3 ) s -S(0)(NR 3 )-, -S(0)2-NR 3 -, -NR 3 -CI-6 haloalkylenyl, -(NR 3 ) s -P(0)(R 3 )-, -Ci-e alkylenyl-S(O)-, -Ci-e alkylenyl-S(0)2-, -C(0)-(NR 3 ) s -, -(NR 3 ) s -C(0)-, or an optionally substituted 4- to 12- membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S;
  • V is selected from Ci-6 aliphatic, C6-12 aryl, 4- to 12-membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S, 5- to 12-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S,
  • Z is Ci-6 aliphatic, 2- to 10-membered heteroaliphatic, P(0)(R 3 )2, -C(0)Ci-6 aliphatic, C(0)N(R 3 )2, C6-12 aryl, C3-12 cycloalkyl, 4- to 16-membered monocyclic or polycyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S, or 5- to 12-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, wherein Z is substituted with (R 2 )q; each R a is independently halo, oxo, or optionally substituted Ci-6 aliphatic; each R 1 is independently selected from N(R 3 )2, OH, CN, C(0)NHR 3 , and an optionally substituted group selected from Ci-6 aliphatic and N(R 3 )-C(0)-CI-6 alkyl; each R 2 is independently selected from halo, CN, C(0)0H,
  • X 1 , X 2 , and X 7 are each independently selected from N, NR a , C, CR a , and C(R a )2 as valency permits, wherein X r , X 2 , and X 7 are N, C, or CR a when bound to Cy-L'-Z or L 2 -V X 3” , X 4 , X 5 , and X 6 are each independently selected from N, C, and CR a , wherein X 3 , X 4 , X 5 , and X 6 are C when bound to -Cy-L'-Z or -L 2 -V;
  • Cy is absent, or a bivalent moiety selected from 4- to 12-membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, P, and S, 5- to 12-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, Ci-6 aliphatic, C6-12 aryl, or C3-12 cycloalkyl, wherein Cy is optionally substituted with one or more of R 1 ;
  • L 1 is absent, -NR 3 -, -S-, C(0)NR 3 -, -C(0)-C(0)-, or an optionally substituted bivalent moiety selected from Ci-6 alkylenyl, C2-6 alkynylenyl, C3-6 cycloalkyl, -NR 3 -CI-6 alkylenyl, -O-Co-6 alkylenyl, and -C(0)Co-6 alkylenyl;
  • L 2 is an optionally substituted bivalent moiety selected from -(NR 3 ) s -S(0)-Co- 6 alkylenyl-, - (NR 3 )S-S(0)2-CO-6 alkylenyl-, -Ci-6 alkylenyl-S(0)-(NR 3 ) s -, -Ci-6 alkylenyl-S(0)2-(NR 3 ) s -, - (NR 3 )s-Co-6 alkylenyl, -(NR 3
  • V is Ci- 6 aliphatic, Ce-u aryl, C3-12 cycloalkyl, 4- to 12-membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S, 5- to 12-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, or 5- to 16-membered monocyclic or polycyclic aryl, wherein Vis substituted with (R 6 ) m ;
  • Z is Ci-6 aliphatic, 2- to 10-membered heteroaliphatic, P(0)(R 3 )2, -C(0)Ci-6 aliphatic, C(0)N(R 3 )2, C6-12 aryl, C3-12 cycloalkyl, 4- to 16-membered monocyclic or polycyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S, or 5- to 12-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, wherein Z is substituted with (R 2 )q; each R a is independently H, halo, CN, oxo, or an optionally substituted group selected from Ci- 6 aliphatic and O-Ci- 6 aliphatic; each R 1 is independently selected from halo, oxo, N(R 3 )2, -OH, -CN, -C(0)N(R 3 )2, and an optionally substituted group selected from Ci- 6 alipha
  • agonist generally refers to an agent whose presence or level correlates with elevated level or activity of a target, as compared with that observed absent the agent (or with the agent at a different level).
  • an agonist is one whose presence or level correlates with a target level or activity that is comparable to or greater than a particular reference level or activity (e.g., that observed under appropriate reference conditions, such as presence of a known agonist, e.g., a positive control).
  • an agonist may be a direct agonist in that it exerts its influence directly on (e.g., interacts directly with) the target; in some embodiments, an agonist may be an indirect agonist in that it exerts its influence indirectly (e.g., by acting on, such as interacting with, a regulator of the target, or with some other component or entity.
  • Aliphatic refers to a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as “cycloaliphatic”), that has a single point or more than one points of attachment to the rest of the molecule. Unless otherwise specified, aliphatic groups contain 1-12 aliphatic carbon atoms.
  • aliphatic groups contain 1-6 aliphatic carbon atoms (e.g., Ci- 6 ). In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms (e.g., Ci- 5). In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms (e.g., C1-4). In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms (e.g., C1-3), and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms (e.g., C1-2).
  • cycloaliphatic refers to a monocyclic C3-8 hydrocarbon or a bicyclic C7-10 hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point or more than one points of attachment to the rest of the molecule.
  • Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkylenyl, alkenyl, alkenylenyl, alkynyl, or alkynylenyl groups and hybrids thereof.
  • a preferred aliphatic group is Ci-6 alkyl.
  • aliphatic is multivalent (i.e., has multiple points of attachment to the rest of the molecule). In some embodiments, aliphatic is bivalent (i.e., has two points of attachment to the rest of the molecule).
  • An example bivalent aliphatic group can be referred to as “alkylenyl”.
  • alkyl refers to a saturated, optionally substituted straight or branched chain or cyclic hydrocarbon group having (unless otherwise specified) 1-12, 1-10, 1-8, 1-6, 1-4, 1-3, or 1-2 carbon atoms (e.g., Ci-12, Ci-10, Ci-8, Ci- 6, Ci-4, Ci-3, or C1-2).
  • exemplary alkyl groups include methyl, ethyl, propyl, butyl, pentyl, hexyl, and heptyl.
  • cycloalkyl refers to an optionally substituted saturated ring system of about 3 to about 10 ring carbon atoms.
  • Exemplary monocyclic cycloalkyl rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
  • Alkylene refers to a bivalent alkyl group.
  • alkylene is a bivalent straight or branched alkyl group.
  • an "alkylene chain” is a polymethylene group, i.e., -(CH2)n-, wherein n is a positive integer, e.g., from 1 to 6, from 1 to 4, from 1 to 3, from 1 to 2, or from 2 to 3.
  • An optionally substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms is optionally replaced with a substituent.
  • Suitable substituents include those described below for a substituted aliphatic group and also include those described in the specification herein. It will be appreciated that two substituents of the alkylene group may be taken together to form a ring system. In certain embodiments, two substituents can be taken together to form a 3- to 7-membered ring. The substituents can be on the same or different atoms.
  • haloalkylenyl refers to an straight-chain or branched alkylenyl group substituted by one or more halogen atoms (e.g., one, two, three or four halo, such as fluoro, iodo, bromo, or chi or o).
  • Alkenyl refers to an optionally substituted straight or branched chain or cyclic hydrocarbon group having at least one double bond and having (unless otherwise specified) 2-12, 2-10, 2-8, 2-6, 2-4, or 2-3 carbon atoms (e.g., C2-12, C2-10, C2-8, C2-6, C2-4, or C2-3).
  • alkenyl groups include ethenyl, propenyl, butenyl, pentenyl, hexenyl, and heptenyl.
  • cycloalkenyl refers to an optionally substituted non-aromatic monocyclic or multicyclic ring system containing at least one carbon- carbon double bond and having about 3 to about 10 carbon atoms.
  • Exemplary monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl, and cycloheptenyl.
  • jOOlSJ Alkenylene The term “alkenylene” and “alkenylenyl” are used interchangeably and refers to a bivalent alkenyl group. In some embodiments, “alkenylene” is a bivalent straight or branched alkenyl group.
  • alkynyl refers to an optionally substituted straight or branched chain hydrocarbon group having at least one triple bond and having (unless otherwise specified) 2-12, 2-10, 2-8, 2-6, 2-4, or 2-3 carbon atoms (e.g., C2-12, C2-10, C2-8, C2-6, C2-4, or C2-3).
  • alkynyl groups include ethynyl, propynyl, butynyl, pentynyl, hexynyl, and heptynyl.
  • alkynylene (0020] Alkynylene.
  • alkynylene and alkynylenyl are used interchangeably and refers to a bivalent alkynyl group.
  • alkynylene is a bivalent straight or branched alkynyl group.
  • an analog refers to a substance that shares one or more particular structural features, elements, components, or moieties with a reference substance. Typically, an “analog” shows significant structural similarity with the reference substance, for example sharing a core or consensus structure, but also differs in certain discrete ways.
  • an analog is a substance that can be generated from the reference substance, e.g., by chemical manipulation of the reference substance. In some embodiments, an analog is a substance that can be generated through performance of a synthetic process substantially similar to (e.g., sharing a plurality of steps with) one that generates the reference substance. In some embodiments, an analog is or can be generated through performance of a synthetic process different from that used to generate the reference substance.
  • Antagonist generally refers to an agent whose presence or level correlates with decreased level or activity of a target, as compared with that observed absent the agent (or with the agent at a different level).
  • an antagonist is one whose presence or level correlates with a target level or activity that is comparable to or less than a particular reference level or activity (e.g., that observed under appropriate reference conditions, such as presence of a known antagonist, e.g., a positive control).
  • an antagonist may be a direct antagonist in that it exerts its influence directly on (e.g., interacts directly with) the target; in some embodiments, an antagonist may be an indirect antagonist in that it exerts its influence indirectly (e.g., by acting on, such as interacting with, a regulator of the target, or with some other component or entity.
  • Aryl refers to monocyclic and bicyclic ring systems having a total of five to fourteen ring members (e.g., C5-14), wherein at least one ring in the system is aromatic and wherein each ring in the system contains three to seven ring members. In some embodiments, an “aryl” group contains between six and twelve total ring members (e.g., C6-12). The term “aryl” may be used interchangeably with the term “aryl ring”. In certain embodiments of the present invention, “aryl” refers to an aromatic ring system which includes, but not limited to, phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents.
  • aryl groups are hydrocarbons.
  • an “aryl” ring system is an aromatic ring (e.g., phenyl) that is fused to a non-aromatic ring (e.g., cycloalkyl). Examples of aryl rings include that are fused include . j0024J Associated: Two events or entities are “associated” with one another, as that term is used herein, if the presence, level and/or form of one is correlated with that of the other.
  • a particular entity e.g., polypeptide, genetic signature, metabolite, microbe, etc
  • a particular disease, disorder, or condition if its presence, level and/or form correlates with incidence of and/or susceptibility to the disease, disorder, or condition (e.g., across a relevant population).
  • two or more entities are physically “associated” with one another if they interact, directly or indirectly, so that they are and/or remain in physical proximity with one another.
  • two or more entities that are physically associated with one another are covalently linked to one another; in some embodiments, two or more entities that are physically associated with one another are not covalently linked to one another but are non-covalently associated, for example by means of hydrogen bonds, van der Waals interaction, hydrophobic interactions, magnetism, and combinations thereof.
  • Biological sample typically refers to a sample obtained or derived from a biological source (e.g., a tissue or organism or cell culture) of interest, as described herein.
  • a source of interest comprises an organism, such as an animal or human.
  • a biological sample is or comprises biological tissue or fluid.
  • a biological sample may be or comprise bone marrow; blood; blood cells; ascites; tissue or fine needle biopsy samples; cell-containing body fluids; free floating nucleic acids; sputum; saliva; urine; cerebrospinal fluid, peritoneal fluid; pleural fluid; feces; lymph; gynecological fluids; skin swabs; vaginal swabs; oral swabs; nasal swabs; washings or lavages such as a ductal lavages or broncheoalveolar lavages; aspirates; scrapings; bone marrow specimens; tissue biopsy specimens; surgical specimens; feces, other body fluids, secretions, and/or excretions; and/or cells therefrom, etc.
  • a biological sample is or comprises cells obtained from an individual.
  • obtained cells are or include cells from an individual from whom the sample is obtained.
  • a sample is a “primary sample” obtained directly from a source of interest by any appropriate means.
  • a primary biological sample is obtained by methods selected from the group consisting of biopsy (e.g., fine needle aspiration or tissue biopsy), surgery, collection of body fluid (e.g., blood, lymph, feces etc.), etc.
  • sample refers to a preparation that is obtained by processing (e.g., by removing one or more components of and/or by adding one or more agents to) a primary sample. For example, filtering using a semi-permeable membrane.
  • processing e.g., by removing one or more components of and/or by adding one or more agents to
  • a primary sample For example, filtering using a semi-permeable membrane.
  • Such a “processed sample” may comprise, for example, nucleic acids or proteins extracted from a sample or obtained by subjecting a primary sample to techniques such as amplification or reverse transcription of mRNA, isolation and/or purification of certain components, etc.
  • Biomarker is used herein, consistent with its use in the art, to refer to a to an entity (or form thereof) whose presence, or level, correlates with a particular biological event or state of interest, so that it is considered to be a “marker” of that event or state.
  • a biomarker may be or comprise a marker for a particular disease state, or for likelihood that a particular disease, disorder or condition may develop, occur, or reoccur.
  • a biomarker may be or comprise a marker for a particular disease or therapeutic outcome, or likelihood thereof.
  • a biomarker is predictive, in some embodiments, a biomarker is prognostic, in some embodiments, a biomarker is diagnostic, of the relevant biological event or state of interest.
  • Carrier refers to a diluent, adjuvant, excipient, or vehicle with which a composition is administered.
  • carriers can include sterile liquids, such as, for example, water and oils, including oils of petroleum, animal, vegetable or synthetic origin, such as, for example, peanut oil, soybean oil, mineral oil, sesame oil and the like.
  • carriers are or include one or more solid components. (002$)
  • Combination therapy refers to those situations in which a subject is simultaneously exposed to two or more therapeutic regimens (e.g., two or more therapeutic agents or modality(ies)).
  • the two or more regimens may be administered simultaneously; in some embodiments, such regimens may be administered sequentially (e.g., all “doses” of a first regimen are administered prior to administration of any doses of a second regimen); in some embodiments, such agents are administered in overlapping dosing regimens.
  • “administration” of combination therapy may involve administration of one or more agent(s) or modality(ies) to a subject receiving the other agent(s) or modality(ies) in the combination.
  • combination therapy does not require that individual agents be administered together in a single composition (or even necessarily at the same time), although in some embodiments, two or more agents, or active moieties thereof, may be administered together in a combination composition, or even in a combination compound (e.g., as part of a single chemical complex or covalent entity).
  • Comparable refers to two or more agents, entities, situations, sets of conditions, etc., that may not be identical to one another but that are sufficiently similar to permit comparison therebetween so that one skilled in the art will appreciate that conclusions may reasonably be drawn based on differences or similarities observed.
  • comparable sets of conditions, circumstances, individuals, or populations are characterized by a plurality of substantially identical features and one or a small number of varied features. Those of ordinary skill in the art will understand, in context, what degree of identity is required in any given circumstance for two or more such agents, entities, situations, sets of conditions, etc. to be considered comparable.
  • composition may be used to refer to a discrete physical entity that comprises one or more specified components.
  • a composition may be of any form - e.g., gas, gel, liquid, solid, etc.
  • dosage form may be used to refer to a physically discrete unit of an active agent (e.g ., a therapeutic or diagnostic agent) for administration to a subject. Typically, each such unit contains a predetermined quantity of active agent.
  • such quantity is a unit dosage amount (or a whole fraction thereof) appropriate for administration in accordance with a dosing regimen that has been determined to correlate with a desired or beneficial outcome when administered to a relevant population (/. ., with a therapeutic dosing regimen).
  • a dosing regimen that has been determined to correlate with a desired or beneficial outcome when administered to a relevant population (/. ., with a therapeutic dosing regimen).
  • the total amount of a therapeutic composition or agent administered to a particular subject is determined by one or more attending physicians and may involve administration of multiple dosage forms.
  • Dosing regimen or therapeutic regimen may be used to refer to a set of unit doses (typically more than one) that are administered individually to a subject, typically separated by periods of time.
  • a given therapeutic agent has a recommended dosing regimen, which may involve one or more doses.
  • a dosing regimen comprises a plurality of doses each of which is separated in time from other doses.
  • individual doses are separated from one another by a time period of the same length; in some embodiments, a dosing regimen comprises a plurality of doses and at least two different time periods separating individual doses.
  • all doses within a dosing regimen are of the same unit dose amount. In some embodiments, different doses within a dosing regimen are of different amounts. In some embodiments, a dosing regimen comprises a first dose in a first dose amount, followed by one or more additional doses in a second dose amount different from the first dose amount. In some embodiments, a dosing regimen comprises a first dose in a first dose amount, followed by one or more additional doses in a second dose amount same as the first dose amount. In some embodiments, a dosing regimen is correlated with a desired or beneficial outcome when administered across a relevant population (/. ., is a therapeutic dosing regimen).
  • Engineered refers to the aspect of having been manipulated by the hand of man.
  • a small molecule may be considered to be engineered if its structure and/or production is designed and/or implemented by the hand ot man.
  • a polynucleotide may be considered to be “engineered” when two or more sequences, that are not linked together in that order in nature, are manipulated by the hand of man to be directly linked to one another in the engineered polynucleotide.
  • an engineered polynucleotide comprises a regulatory sequence that is found in nature in operative association with a first coding sequence but not in operative association with a second coding sequence, is linked by the hand of man so that it is operatively associated with the second coding sequence.
  • a cell or organism is considered to be “engineered” if it has been manipulated so that its genetic information is altered (e.g ., new genetic material not previously present has been introduced, for example by transformation, mating, somatic hybridization, transfection, transduction, or other mechanism, or previously present genetic material is altered or removed, for example by substitution or deletion mutation, or by mating protocols).
  • engineered polynucleotide As is common practice and is understood by those in the art, expression products of an engineered polynucleotide, and/or progency of an engineered polynucleotide or cell are typically still referred to as “engineered” even though the actual manipulation was performed on a prior entity.
  • Excipient refers to a non-therapeutic agent that may be included in a pharmaceutical composition, for example, to provide or contribute to a desired consistency or stabilizing effect.
  • suitable pharmaceutical excipients include, for example, starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like.
  • heteroaliphatic or “heteroaliphatic group”, as used herein, denotes an optionally substituted hydrocarbon moiety having, in addition to carbon atoms, from one to five heteroatoms, that may be straight-chain ( i.e unbranched), branched, or cyclic (“heterocyclic”) and may be completely saturated or may contain one or more units of unsaturation, but which is not aromatic.
  • heteroatom refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen.
  • nitrogen also includes a substituted nitrogen.
  • heteroaliphatic groups contain 1-10 carbon atoms wherein 1-3 carbon atoms are optionally and independently replaced with heteroatoms selected from oxygen, nitrogen, and sulfur. In some embodiments, heteroaliphatic groups contain 1-4 carbon atoms, wherein 1-2 carbon atoms are optionally and independently replaced with heteroatoms selected from oxygen, nitrogen, and sulfur. In yet other embodiments, heteroaliphatic groups contain 1-3 carbon atoms, wherein 1 carbon atom is optionally and independently replaced with a heteroatom selected from oxygen, nitrogen, and sulfur. Suitable heteroaliphatic groups include, but are not limited to, linear or branched, heteroalkyl, heteroalkenyl, and heteroalkynyl groups. For example, a 1- to 10 atom heteroaliphatic group includes the following exemplary groups: -O-CH3, -CH2-O-CH3, -O-CH2- CH2-O-CH2-CH2-O-CH3, and the like.
  • Heteroaryl and “heteroar-”, used alone or as part of a larger moiety, e.g., “heteroaralkyl”, or “heteroaralkoxy”, refer to monocyclic or bicyclic ring groups having 5 to 12 ring atoms (e.g., 5- to 6- membered monocyclic heteroaryl or 9- to 12-membered bicyclic heteroaryl); having 6, 10, or 14 p-electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms.
  • heteroatom refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen.
  • Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, pteridinyl, imidazo[l,2-a]pyrimidinyl, imidazo[l,2-a]pyridyl, imidazo[4,5-b]pyridyl, imidazo[4,5-c]pyridyl,
  • heteroaryl and “heteroar-”, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring (i.e., a bicyclic heteroaryl ring having 1 to 3 heteroatoms).
  • Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzotriazolyl, benzothiazolyl, benzothiadiazolyl, benzoxazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, AH quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, pyrido[2,3-b]-l,4-oxazin-3(4H)-one, and benzoisoxazolyl.
  • heteroaryl group may be mono- or bicyclic.
  • heteroaryl may be used interchangeably with the terms “heteroaryl ring”, “heteroaryl group”, or “heteroaromatic”, any of which terms include rings that are optionally substituted.
  • heteroarylkyl refers to an alkyl group substituted by a heteroaryl, wherein the alkyl and heteroaryl portions independently are optionally substituted.
  • jO037J Heteroatom The term “heteroatom” as used herein refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen.
  • heterocycle As used herein, the terms “heterocycle”, “heterocyclyl”, “heterocyclic radical”, and “heterocyclic ring” are used interchangeably and refer to a stable 3- to 8-membered monocyclic, a 7- to 12-membered bicyclic, or a 10- to 16-membered polycyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, such as one to four, heteroatoms, as defined above.
  • nitrogen includes a substituted nitrogen.
  • the nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR + (as in N-substituted pyrrolidinyl).
  • a heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted.
  • saturated or partially unsaturated heterocyclic radicals include, without limitation, azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, piperidinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and thiamorpholinyl.
  • a heterocyclyl group may be mono-, bi-, tri-, or polycyclic, preferably mono-, bi-, or tricyclic, more preferably mono- or bicyclic.
  • heterocyclylalkyl refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted.
  • a bicyclic heterocyclic ring also includes groups in which the heterocyclic ring is fused to one or more aryl rings.
  • bicyclic heterocyclic groups include indolinyl, isoindolinyl, benzodioxolyl, 1,3- dihydroisobenzofuranyl, 2,3-dihydrobenzofuranyl, tetrahydroquinolinyl, bicyclic heterocyclic ring can also be a spirocyclic ring system (e.g., 7- to 11-membered spirocyclic fused heterocyclic ring having, in addition to carbon atoms, one or more heteroatoms as defined above (e.g., one, two, three or four heteroatoms)).
  • spirocyclic ring system e.g., 7- to 11-membered spirocyclic fused heterocyclic ring having, in addition to carbon atoms, one or more heteroatoms as defined above (e.g., one, two, three or four heteroatoms)
  • a bicyclic heterocyclic ring can also be a bridged ring system (e.g., 7- to 11-membered bridged heterocyclic ring having one, two, or three bridging atoms.
  • exemplary bridged ring systems include ⁇ Z and - / .
  • oral administration and “administered orally” as used herein have their art-understood meaning referring to administration by mouth of a compound or composition.
  • parenteral The phrases “parenteral administration” and “administered parenterally” as used herein have their art-understood meaning referring to modes of administration other than enteral and topical administration, usually by injection, and include, without limitation, intravenous, intramuscular, intra-arterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticulare, subcapsular, subarachnoid, intraspinal, and intrasternal injection and infusion.
  • Partially unsaturated refers to a ring moiety that includes at least one double or triple bond between ring atoms.
  • the term “partially unsaturated” is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aromatic (e.g., aryl or heteroaryl) moieties, as herein defined.
  • Patient or subject refers to any organism to which a provided composition is or may be administered, e.g., for experimental, diagnostic, prophylactic, cosmetic, and/or therapeutic purposes. Typical patients or subjects include animals (e.g., mammals such as mice, rats, rabbits, non-human primates, and/or humans). In some embodiments, a patient is a human. In some embodiments, a patient or a subject is suffering from or susceptible to one or more disorders or conditions. In some embodiments, a patient or subject displays one or more symptoms of a disorder or condition. In some embodiments, a patient or subject has been diagnosed with one or more disorders or conditions. In some embodiments, a patient or a subject is receiving or has received certain therapy to diagnose and/or to treat a disease, disorder, or condition.
  • animals e.g., mammals such as mice, rats, rabbits, non-human primates, and/or humans.
  • a patient is a human.
  • a patient or a subject is suffering from or susceptible to one or more disorders or conditions
  • composition refers to an active agent, formulated together with one or more pharmaceutically acceptable carriers.
  • the active agent is present in unit dose amount appropriate for administration in a therapeutic or dosing regimen that shows a statistically significant probability of achieving a predetermined therapeutic effect when administered to a relevant population.
  • compositions may be specially formulated for administration in solid or liquid form, including those adapted for the following: oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., those targeted for buccal, sublingual, and systemic absorption, boluses, powders, granules, pastes for application to the tongue; parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained-release formulation; topical application, for example, as a cream, ointment, or a controlled-release patch or spray applied to the skin, lungs, or oral cavity; intravaginally or intrarectally, for example, as a pessary, cream, or foam; sublingually; ocularly; transdermally; or nasally, pulmonary, and to other mucosal surfaces.
  • oral administration for example, drenches (aqueous or non-aqueous solutions or suspension
  • compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • compositions or vehicles such as a liquid or solid filler, diluent, excipient, or solvent encapsulating material, involved in carrying or transporting the subject compound from one organ, or portion of the body, to another organ, or portion of the body.
  • Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
  • materials which can serve as pharmaceutically-acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as com starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline;
  • Pharmaceutically acceptable salt refers to salts of such compounds that are appropriate for use in pharmaceutical contexts, i.e., salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences , 66: 1-19 (1977).
  • pharmaceutically acceptable salts include, but are not limited to, nontoxic acid addition salts, which are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • nontoxic acid addition salts which are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • pharmaceutically acceptable salts include, but are not limited to, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2- hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palm
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, alkyl having from 1 to 6 carbon atoms, sulfonate and aryl sulfonate.
  • polycyclic refers to a saturated or unsaturated ring system having two or more rings (for example, heterocyclyl rings, heteroaryl rings, cycloalkyl rings, or aryl rings), having between 7 and 20 atoms, in which one or more carbon atoms are common to two adjacent rings.
  • the rings in a polycyclic ring system may be fused (i.e., bicyclic or tricyclic), spirocyclic, or a combination thereof.
  • Exemplary polyclic systems include
  • Prevent or prevention when used in connection with the occurrence of a disease, disorder, and/or condition, refer to reducing the risk of developing the disease, disorder and/or condition and/or to delaying onset of one or more characteristics or symptoms of the disease, disorder or condition. Prevention may be considered complete when onset of a disease, disorder or condition has been delayed for a predefined period of time.
  • Reference As used herein describes a standard or control relative to which a comparison is performed. For example, in some embodiments, an agent, animal, individual, population, sample, sequence or value of interest is compared with a reference or control agent, animal, individual, population, sample, sequence or value. In some embodiments, a reference or control is tested and/or determined substantially simultaneously with the testing or determination of interest. In some embodiments, a reference or control is a historical reference or control, optionally embodied in a tangible medium. Typically, as would be understood by those skilled in the art, a reference or control is determined or characterized under comparable conditions or circumstances to those under assessment. Those skilled in the art will appreciate when sufficient similarities are present to justify reliance on and/or comparison to a particular possible reference or control.
  • sample typically refers to an aliquot of material obtained or derived from a source of interest.
  • a source of interest is a biological or environmental source.
  • a source of interest may be or comprise a cell, tissue, or organism, such as a microbe, a plant, or an animal (e.g., a human).
  • a source of interest is or comprises biological tissue or fluid.
  • a source of interest may be or comprise a preparation generated in a production run.
  • a sample is a “primary sample” obtained directly from a source of interest by any appropriate means.
  • sample refers to a preparation that is obtained by processing (e.g., by removing one or more components of and/or by adding one or more agents to) a primary sample.
  • the term “specific”, when used herein with reference to an agent having an activity, is understood by those skilled in the art to mean that the agent discriminates between potential target entities or states.
  • an agent is said to bind “specifically” to its target if it binds preferentially with that target in the presence of one or more competing alternative targets.
  • specific interaction is dependent upon the presence of a particular structural feature of the target entity (e.g., an epitope, a cleft, a binding site). It is to be understood that specificity need not be absolute. In some embodiments, specificity may be evaluated relative to that of the binding agent for one or more other potential target entities (e.g., competitors).
  • specificity is evaluated relative to that of a reference specific binding agent. In some embodiments, specificity is evaluated relative to that of a reference non-specific binding agent. In some embodiments, the agent or entity does not detectably bind to the competing alternative target under conditions of binding to its target entity. In some embodiments, a binding agent binds with higher on-rate, lower off-rate, increased affinity, decreased dissociation, and/or increased stability to its target entity as compared with the competing alternative target(s).
  • substituted means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. “Substituted” applies to one or more hydrogens that are either explicit or implicit from the otherwise indicated, an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds.
  • stable refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes provided herein.
  • Groups described as being “substituted” preferably have between 1 and 4 substituents, more preferably 1 or 2 substituents.
  • Groups described as being “optionally substituted” may be unsubstituted or be “substituted” as described above.
  • Suitable monovalent substituents on R° are independently halogen, -(CH 2 )o- 2 R*, -(haloR*), -(CH 2 )O- 2 OH, -(CH 2 )O- 2 OR ⁇ , -(CH 2 )O- 2 CH(OR*) 2 , -O(haloR'), -CN, -Ns, -(CH 2 )o- 2 C(0)R ⁇ , -(CH 2 )O- 2 C(0)OH, -(CH 2 )O- 2 C(0)OR ⁇ , -(CH 2 )O- 2 SR*, -(CH 2 )O- 2 SH, -(CH 2 )O- 2 NH 2 , - (CH 2 )O- 2 NHR ⁇ , -(CH 2 )O- 2 NR* 2 , -N0 2 , -SiR*
  • Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: -0(CR * 2)2-30-, wherein each independent occurrence of R * is selected from hydrogen, Ci-6 aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Suitable substituents on the aliphatic group of R * include halogen, -R*, -(haloR*), -OH, - OR*, -0(haloR*), -CN, -C(0)0H, -C(0)0R*, -NHz, -NHR*, -NR* 2 , or -NO2, wherein each R* is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently Ci-4 aliphatic, -CH2PI1, -0(CH2)o-iPh, or a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Suitable substituents on a substitutable nitrogen of an “optionally substituted” group include -R ⁇ , -NR ⁇ 2 , -C(0)R ⁇ , -C(0)0R ⁇ , -C(0)C(0)R ⁇ ,
  • each R ⁇ is independently hydrogen, Ci-6 aliphatic which may be substituted as defined below, unsubstituted -OPh, or an unsubstituted 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R ⁇ , taken together with their intervening atom(s) form an unsubstituted 3- to 12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Suitable substituents on the aliphatic group of R ⁇ are independently halogen, - R*, -(haloR*), -OH, -OR*, -O(haloR'), -CN, -C(0)OH, -C(0)OR*, -NH2, -NHR*, -NR* 2 , or -NO2, wherein each R* is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently Ci ⁇ aliphatic, -CH2PI1, -0(CH2)o-iPh, or a 3- to 6- membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Small molecule means a low molecular weight organic and/or inorganic compound.
  • a “small molecule” is a molecule that is less than about 5 kilodaltons (kD) in size.
  • a small molecule is less than about 4 kD, 3 kD, about 2 kD, or about 1 kD.
  • the small molecule is less than about 800 daltons (D), about 600 D, about 500 D, about 400 D, about 300 D, about 200 D, or about 100 D.
  • a small molecule is less than about 2000 g/mol, less than about 1500 g/mol, less than about 1000 g/mol, less than about 800 g/mol, or less than about 500 g/mol. In some embodiments, a small molecule is not a polymer. 0060 j In some embodiments, a small molecule does not include a polymeric moiety. In some embodiments, a small molecule is not and/or does not comprise a protein or polypeptide (e.g., is not an oligopeptide or peptide). In some embodiments, a small molecule is not and/or does not comprise a polynucleotide (e.g., is not an oligonucleotide).
  • a small molecule is not and/or does not comprise a polysaccharide; for example, in some embodiments, a small molecule is not a glycoprotein, proteoglycan, glycolipid, etc). In some embodiments, a small molecule is not a lipid.
  • a small molecule is a modulating agent (e.g., is an inhibiting agent or an activating agent).
  • a small molecule is biologically active.
  • a small molecule is detectable (e.g., comprises at least one detectable moiety).
  • a small molecule is a therapeutic agent.
  • small molecule compounds have structures that can exist in one or more steroisomeric forms.
  • such a small molecule may be utilized in accordance with the present disclosure in the form of an individual enantiomer, diastereomer or geometric isomer, or may be in the form of a mixture of stereoisomers; in some embodiments, such a small molecule may be utilized in accordance with the present disclosure in a racemic mixture form.
  • certain small molecule compounds have structures that can exist in one or more tautomeric forms. In some embodiments, such a small molecule may be utilized in accoradance with the present disclosure in the form of an individual tautomer, or in a form that interconverts between tautomeric forms.
  • 0065j Those of skill in the art will appreciate that certain small molecule compounds have structures that permit isotopic substitution (e.g., 2 H or 3 H for H;, U C, 13 C or 14 C for 12C; , 13 N or 15 N for 14N; 17 0 or 18 0 for 160; 36 C1 for XXC; 18 F for XXF; 1311 for XXXI; etc).
  • such a small molecule may be utilized in accordance with the present disclosure in one or more isotopically modified forms, or mixtures thereof.
  • reference to a particular small molecule compound may relate to a specific form of that compound.
  • a particular small molecule compound may be provided and/or utilized in a salt form (e.g., in an acid-addition or base-addition salt form, depending on the compound); in some such embodiments, the salt form may be a pharmaceutically acceptable salt form.
  • a small molecule compound is one that exists or is found in nature
  • that compound may be provided and/or utilized in accordance in the present disclosure in a form different from that in which it exists or is found in nature.
  • a reference preparation of interest e.g., in a primary sample from a source of interest such as a biological or environmental source
  • a preparation of a single stereoisomer of a small molecule compound may be considered to be a different form of the compound than a racemic mixture of the compound; a particular salt of a small molecule compound may be considered to be a different form from another salt form of the compound; a preparation that contains only a form of the compound that contains one conformational isomer ((Z) or (E)) of a double bond may be considered to be a different form of the compound from one that contains the other conformational isomer ((E) or (Z)) of the double bond; a preparation in which one or more atoms is a different isotope than is present in a reference preparation may be considered to be a different form; etc.
  • a bond designated as ⁇ in a small molecule structure refers to a bond that, in some embodiments, is a single (e.g., saturated) bond, and in some embodiments, is a double (e.g., unsaturated) bond.
  • the following structure is intended to encompass both H and H
  • therapeutic agent in general refers to any agent that elicits a desired pharmacological effect when administered to an organism.
  • an agent is considered to be a therapeutic agent if it demonstrates a statistically significant effect across an appropriate population.
  • the appropriate population may be a population of model organisms.
  • an appropriate population may be defined by various criteria, such as a certain age group, gender, genetic background, preexisting clinical conditions, etc.
  • a therapeutic agent is a substance that can be used to alleviate, ameliorate, relieve, inhibit, prevent, delay onset of, reduce severity of, and/or reduce incidence of one or more symptoms or features of a disease, disorder, and/or condition.
  • a “therapeutic agent” is an agent that has been or is required to be approved by a government agency before it can be marketed for administration to humans.
  • a “therapeutic agent” is an agent for which a medical prescription is required for administration to humans.
  • treat refers to any method used to partially or completely alleviate, ameliorate, relieve, inhibit, prevent, delay onset of, reduce severity of, and/or reduce incidence of one or more symptoms or features of a disease, disorder, and/or condition.
  • Treatment may be administered to a subject who does not exhibit signs of a disease, disorder, and/or condition.
  • treatment may be administered to a subject who exhibits only early signs of the disease, disorder, and/or condition, for example, for the purpose of decreasing the risk of developing pathology associated with the disease, disorder, and/or condition.
  • Autophagy is a mechanism of the cell that degrades cytoplasmic material and organelles.
  • autophagy There are multiple types of autophagy: (1) macroautophagy (generally referred to as autophagy); (2) microautophagy; and (3) chaperone-mediateed autophagy. See Eskelinen & Saftig, Biochimica et Biophysica Acta - Mol. Cell Res., 1793(4):664-673 (2009).
  • macroautophagy the autophagosome engulfs waste materials in the cytoplasm and fuses to the lysosome, where materials are delivered for degradation.
  • the lysosome is as a subcellular organelle containing more than 50 soluble acid hydrolases useful for digesting cellular components. Fusion of the lysosome to the autophagosome is activated, in part, by release of ions through ion channels in the membrane of the lysome, including Ca 2+ . See Cao, etal. , J. Bio. Chem., 292(20)8424-8435 (2017). ⁇ O073J Transient Receptor Potential Mucolipin-1 (also known as TRPMLl or MLl) is a Ca 2+ channel in the lysosome that regulates autophagy. See Wang, etal. , PNAS, E1373-E1381 (March 2, 2015).
  • TRPMLl is an inwardly rectifying current channel that transports cations from the lumen of the lysosome to the cytosol.
  • TRPMLl is an inwardly rectifying current channel that transports cations from the lumen of the lysosome to the cytosol.
  • TRPMLl modulators useful for promoting autophagy and/or treating certain diseases, disorders, or conditions.
  • TRMPL1 may represent a particularly desirable target that, among other things, may permit modulation (e.g., enhancement) of autophagy in certain contexts.
  • TRMPL1 modulators that are small molecule compounds having a chemical structure as indicated below in Formula I:
  • A is 9- to 12-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, or 9- to 16- membered bicyclic or polycyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S, wherein A is substituted with 0, 1, 2, 3 or 4 R a ;
  • Cy is absent or a bivalent moiety selected from 4- to 12-membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, P, and S, 5- to 12-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, P, and S, Ci-6 aliphatic, or C3-12 cycloalkyl, wherein Cy is optionally substituted with one or more of
  • L 1 is absent, -NR 3 -, -0-, -S-, Ci-6 alkylenyl, C2-6 alkynylenyl, -NR 3 -CI-6 alkylenyl,-0-Ci-6 alkylenyl, -C(0)Co-e alkylenyl; -C(0)NR 3 -, or -C(0)-C(0)-;
  • L 2 is absent, -(NR 3 ) s -S(0)-Co-6 alkylenyl-, -(NR 3 ) s -S(0)2-Co-6 alkylenyl-, -(NR 3 ) s -S(0)(NR 3 )-, -S(0)2-NR 3 -, -NR 3 -CI-6 haloalkylenyl, -(NR 3 ) s -P(0)(R 3 )-, -Ci-e alkylenyl-S(O)-,
  • V is selected from Ci-6 aliphatic, C6-12 aryl, 4- to 12-membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S, 5- to 12-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, 5- to 12-membered monocyclic of bicyclic aryl, and C3-12 cycloalkyl, wherein Vis substituted with (R 6 ) m ;
  • Z is Ci-6 aliphatic, 2- to 10-membered heteroaliphatic, P(0)(R 3 )2, -C(0)Ci-6 aliphatic, C(0)N(R 3 )2, C6-12 aryl, C3-12 cycloalkyl, 4- to 16-membered monocyclic or polycyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S, or 5- to 12-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, wherein Z is substituted with (R 2 )q; each R a is independently halo, oxo, or optionally substituted Ci-6 aliphatic; each R 1 is independently selected from N(R 3 )2, OH, CN, C(0)NHR 3 , and an optionally substituted group selected from Ci-6 aliphatic and N(R 3 )-C(0)-CI-6 alkyl; each R 2 is independently selected from halo, CN, C(0)0H,
  • A is 9- to 12-membered bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, or 9- to 16- membered bicyclic or polycyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S, and A is substituted with 0, 1, 2, 3 or 4 R a .
  • A is substituted with 0, 1, 2, 3, or 4 R a .
  • A is unsubstituted (i.e, is substituted with 0 R a ).
  • A is substituted with 1 R a .
  • A is substituted with 2 R a .
  • A is substituted with 3 R a .
  • A is substituted with 4 R a .
  • A is a multivalent moiety (i.e., has two or more points of attachment to the rest of the molecule, whether explicitly referred to as “multivalent” or not).
  • A is 9- to 12-membered bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S.
  • A is 9- to 12-membered bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, A is 9-membered bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, A is 10-membered bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, A is 11-membered bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, A is 12-membered bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S.
  • A is 9- to 16- membered bicyclic or polycyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, A is 10- to 16- membered polycyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, A is 10-membered polycyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, A is 10-membered bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S.
  • A is 10- membered spirocyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, A is 11-membered polycyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, A is 11-membered bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, A is 11- membered spirocyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, A is 12-membered polycyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S.
  • A is 12-membered bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, A is 12- membered spirocyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, A is 13-membered polycyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, A is 13-membered bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, A is 13- membered spirocyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S.
  • A is 14-membered polycyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, A is 14-membered bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, A is 14- membered spirocyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, A is 15-membered polycyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, A is 15-membered bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, A is 15- membered spirocyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S.
  • A is selected from:
  • the present application provides compounds having a structure as set forth in Formula G : or a pharmaceutically acceptable salt thereof, wherein
  • A’ is a fused phenyl or 6-membered heteroaryl ring comprising 1 to 3 nitrogen atoms, optionally substituted with R a ;
  • X 1 and X 7 are each independently selected from N, NR a , C, CR a , and C(R a )2, as valency permits, wherein X 1 and X 7 are N, C, or CR a when bound to Cy-L'-Z; Cy is absent, or a bivalent moiety selected from 4- to 12-membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, P, and S, 5- to 12-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, Ci- 6 aliphatic, Ce-u aryl, or C3-12 cycloalkyl, wherein Cy is optionally substituted with one or more of R 1 ;
  • L 1 is absent, -NR 3 -, -S-, C(0)NR 3 -, -C(0)-C(0)-, or an optionally substituted bivalent moiety selected from Ci- 6 alkylenyl, C2-6 alkenylenyl, C2-6 alkynylenyl, C3-6 cycloalkyl, -NR 3 -CI- 6 alkylenyl, -O-Co- 6 alkylenyl, and -C(0)Co- 6 alkylenyl;
  • L 2 is an optionally substituted bivalent moiety selected from -(NR 3 ) s -S(0)-Co- 6 alkylenyl-, - (NR 3 )S-S(0)2-CO-6 alkylenyl-, -Ci-6 alkylenyl-S(0)-(NR 3 ) s -, -Ci-6 alkylenyl-S(0)2-(NR 3 ) s -, - (NR 3 )s-Co-6 alkylenyl, -(NR 3 ) s -C(0)-Co- 6 alkylenyl, and 4- to 12-membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S;
  • V is Ci- 6 aliphatic, C6-12 aryl, C3-12 cycloalkyl, 4- to 12-membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S, 5- to 12-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, or 5- to 16-membered monocyclic or polycyclic aryl, wherein Vis substituted with (R 6 ) m ;
  • Z is Ci-6 aliphatic, 2- to 10-membered heteroaliphatic, P(0)(R 3 )2, -C(0)Ci-6 aliphatic, C(0)N(R 3 )2, C6-12 aryl, C3-12 cycloalkyl, 4- to 16-membered monocyclic or polycyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S, or 5- to 12-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, wherein Z is substituted with (R 2 )q; each R a is independently H, halo, CN, oxo, or an optionally substituted group selected from Ci- 6 aliphatic and O-Ci- 6 aliphatic; each R 1 is independently selected from halo, oxo, N(R 3 )2, -OH, -CN, -C(0)N(R 3 )2, and an optionally substituted group selected from Ci- 6 alipha
  • a compound of Formula F is: comprising 1 to 3 nitrogen atoms.
  • A’ is a fused phenyl or 6-membered heteroaryl ring comprising 1 to 2 nitrogen atoms.
  • A’ is a fused phenyl or fused pyridinyl.
  • A’ is a fused phenyl.
  • A’ is a 6- membered heteroaryl ring comprising 1 to 2 nitrogen atoms.
  • A’ is selected from:
  • the present disclosure provides a compound of Formula II:
  • X r , X , and X 7 are each independently selected from N, NR a , C, and CR a , wherein X r , X 2 , and X 7 are N, C, or CR a when bound to Cy-L'-Z or L 2 -V
  • X 3” , X 4 , X 5 , and X 6 are each independently selected from N, C, and CR a , wherein X 3 , X 4 , X 5 , and X 6 are N or C when bound to Cy-L'-Z or L 2 -V;
  • Cy is absent, 4- to 12-membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, P, and S, 5- to 12-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, Ci-6 aliphatic, C6-12 aryl, or C3-12 cycloalkyl, wherein Cy is optionally substituted with one or more of R 1 ;
  • L 1 is absent, -NR 3 -, -0-, -S-, Ci-6 alkylenyl, C2-6 alkynylenyl, -NR 3 -CI-6 alkylenyl,-0-Ci-6 alkylenyl, -C(0)Co-e alkylenyl; -C(0)NR 3 -, -C(0)-C(0)-;
  • L 2 is -(NR 3 ) S -S(0)-CO-6 alkylenyl-, -(NR 3 )s-S(0) 2 -Co-6 alkylenyl-, -(NR 3 ) s -S(0)(NR 3 )-, -S(0) 2 - NR 3 -, -NR 3 -CI-6 haloalkylenyl, -(NR 3 ) s -P(0)(R 3 )-, -Ci-6 alkylenyl-S(O)-, -Ci-6 alkylenyl- S(0)2-, -C(0)-(NR 3 ) S -, -(NR 3 ) S -C(0)-, or an optionally substituted 4- to 12-membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S;
  • V is selected from Ci-6 aliphatic, C6-12 aryl, 4- to 12-membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S, 5- to 12-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, 5- to 12- membered monocyclic of bicyclic aryl, and C3-12 cycloalkyl, wherein V is substituted with
  • Z is Ci-6 aliphatic, 2- to 10-membered heteroaliphatic, P(0)(R 3 )2, -C(0)Ci-6 aliphatic, C(0)N(R 3 )2, C6-12 aryl, C3-12 cycloalkyl, 4- to 16-membered monocyclic or polycyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S, or 5- to 12-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, wherein Z is substituted with (R 2 )q; each R a is independently halo, oxo, or optionally substituted Ci-6 aliphatic; each R 1 is independently selected from N(R 3 )2, OH, CN, C(0)NHR 3 , and an optionally substituted group selected from Ci-6 aliphatic and N(R 3 )-C(0)-CI-6 alkyl; each R 2 is independently selected from halo, -CN, C(0)0H
  • the present disclosure provides a compound of Formula IF:
  • X 1 , X 2 , and X 7 are each independently selected from N, NR a , C, CR a , and C(R a )2 as valency permits, wherein X r , X 2” , and X 7 are N, C, or CR a when bound to Cy-L'-Z or L 2 -V X 3” , X 4 , X 5 , and X 6 are each independently selected from N, C, and CR a , wherein X 3 , X 4 , X 5 , and X 6 are C when bound to -Cy-L'-Z or -L 2 -V;
  • Cy is absent, or a bivalent moiety selected from 4- to 12-membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, P, and S, 5- to 12-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, Ci- 6 aliphatic, Ce-n aryl, or C3-12 cycloalkyl, wherein Cy is optionally substituted with one or more of R 1 ;
  • L 1 is absent, -NR 3 -, -S-, C(0)NR 3 -, -C(0)-C(0)-, or an optionally substituted bivalent moiety selected from Ci- 6 alkylenyl, C2-6 alkynylenyl, C3-6 cycloalkyl, -NR 3 -CI- 6 alkylenyl, -O-Co- 6 alkylenyl, and -C(0)Co- 6 alkylenyl;
  • L 2 is an optionally substituted bivalent moiety selected from -(NR 3 ) s -S(0)-Co- 6 alkylenyl-, - (NR 3 )S-S(0)2-CO-6 alkylenyl-, -Ci-6 alkylenyl-S(0)-(NR 3 ) s -, -Ci-6 alkylenyl-S(0)2-(NR 3 ) s -, - (NR 3 )s-Co-6 alkylenyl, -(NR 3 ) s -C(0)-Co- 6 alkylenyl, and 4- to 12-membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S;
  • V is Ci- 6 aliphatic, C6-12 aryl, C3-12 cycloalkyl, 4- to 12-membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S, 5- to 12-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, or 5- to 16-membered monocyclic or polycyclic aryl, wherein Vis substituted with (R 6 ) m ;
  • Z is Ci-6 aliphatic, 2- to 10-membered heteroaliphatic, P(0)(R 3 )2, -C(0)Ci-6 aliphatic, C(0)N(R 3 )2, C6-12 aryl, C3-12 cycloalkyl, 4- to 16-membered monocyclic or polycyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S, or 5- to 12-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, wherein Z is substituted with (R 2 )q; each R a is independently H, halo, CN, oxo, or an optionally substituted group selected from Ci- 6 aliphatic and O-Ci- 6 aliphatic; each R 1 is independently selected from halo, oxo, N(R 3 )2, -OH, -CN, -C(0)N(R 3 )2, and an optionally substituted group selected from Ci- 6 alipha
  • moieties -Cy-L'-Z and -L 2 -V can be bound to any of X r , X 2” , X 3 , X 4 , X 5 , X 6 or X 7” .
  • -Cy-L'-Z and -L 2 -V are not bound to X 1” , X 2 , X 3 , X 4 , X 5 , X 6 or X 7 at the same time.
  • X 1” , X 2” , and X 7 are each independently selected from N, NR a , C, CR a , and C(R a )2 as valency permits, wherein X 1 , X 2 , and X 7 are N, C, or CR a when bound to Cy-L'-Z or L 2 -V.
  • X 1 is CR a
  • X 2 is N- L 2 -V
  • X 7 is C-Cy-L'-Z.
  • X 1 is CH, X 2 is N- L 2 -V, and X 7 is C-Cy-L'-Z In some embodiments, X 1 is C(O), X 2 is N- L 2 -V, and X 7 is C(CH3)-Cy-L 1 -Z. In some embodiments, X 1 is CFh, X 2 is N- L 2 -V, and X 7 is C(CH3)-Cy-L 1 -Z. In some embodiments, X 1 is N, X 2 is N- L 2 -V, and X 7 is C- Cy-L 4 -Z.
  • X 3” , X 4” , X 5 , and X 6 are each independently selected from N, C, and CR a , wherein X 3 , X 4 , X 5 , and X 6 are N or C when bound to Cy-L'-Z or L 2 -V.
  • each of X 3 , X 4 , X 5 , and X 6 is independently selected from N and CR a .
  • each of X , X 4 , X 5 , and X 6 is CR a .
  • each of X 3 , X 4 , X 5 , and X 6 is CH.
  • X 3 , X 4 , and X 5 are each CR a , and X 6 is N.
  • X 4” , X 5 , and X 6 are each CR a , and X 3 is N.
  • X 3 , X 5 , and X 6 are each CR a , and X 4 is N.
  • X 3 , X 4 , and X 6 are each CR a
  • X 5 is N.
  • X 4 and X 5 are each CR a , and X 3 and X 6 are each N.
  • each R a is H, halo, oxo, or an optionally substituted group selected from Ci-6 aliphatic and O-Ci-6 aliphatic.
  • R a is H.
  • each R a is halo, oxo, or an optionally substituted group selected from Ci-6 aliphatic and O-Ci-6 aliphatic.
  • R a is Ci-6 alkyl. In some embodiments, R a is C1-3 alkyl. In some embodiments, R a is methyl.
  • R a is halo. In some embodiments, R a is bromo, chloro, fluoro, or iodo. In some embodiments, R a is bromo. In some embodiments, R a is chloro. In some embodiments, R a is fluoro. In some embodiments, R a is iodo.
  • R a is oxo
  • Cy is absent or a bivalent moiety selected from 4- to 12- membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, P, and S, 5- to 12-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, P, and S, Ci-6 aliphatic, Ce-u aryl, or C3-12 cycloalkyl, wherein Cy is optionally substituted with one or more R 1 .
  • Cy is optionally substituted with one or more R 1 , i.e., is substituted with 0, 1, 2, 3, or 4 R 1 .
  • Cy is unsubstituted (i.e., is substituted with 0 R 1 ).
  • Cy is substituted with 1, 2, 3, or 4 R 1 .
  • Cy is substituted with 1 R 1 .
  • Cy is substituted with 2 R 1 .
  • Cy is substituted with 3 R 1 .
  • Cy is substituted with 4 R 1 .
  • Cy is absent.
  • Cy is 4- to 12-membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, Cy is 4- to 6- membered monocyclic heterocyclic comprising 1 to 3 heteroatoms selected from N, O, P, and S. In some embodiments, Cy is 4-membered monocyclic heterocyclic comprising 1 heteroatom selected from N, O, P, and S. In some embodiments, Cy is 5-membered monocyclic heterocyclic comprising 1 to 2 heteroatoms selected from N, O, P, and S. In some embodiments, Cy is 6- membered monocyclic heterocyclic comprising 1 to 3 heteroatoms selected from N, O, P, and S.
  • Cy is azetidinyl, pyrrolidinyl, piperdinyl, or piperazinyl. fO!O!j In some embodiments, Cy is azetidinyl, optionally substituted With one or more R 1 . ⁇ 0102] In some embodiments, Cy is piperdinyl optionally substituted with one or more R 1 . In some embodiments, Cy is unsubstituted piperdinyl. In some embodiments, Cy is piperdinyl substituted with one or more R 1 .
  • Cy is piperazinyl optionally substituted with one or more R 1 . In some embodiments, Cy is unsubstituted piperazinyl. In some embodiments, Cy is piperazinyl substituted with one or more R 1 .
  • Cy is 7- to 12-membered bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, P, and S. In some embodiments, Cy is 10- to 12-membered bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, P, and S. In some embodiments, Cy is 10- membered bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, P, and S. In some embodiments, Cy is 11- membered bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, P, and S. In some embodiments, Cy is 12-membered bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, P, and S.
  • Cy is 5- to 12-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, P, and S. In some embodiments, Cy is 5- or 6- membered monocyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, Cy is 5-membered monocyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, Cy is 6-membered monocyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S.
  • Cy is 7- to 12-membered bicyclic heteroaryl comprising comprising 1 to 4 heteroatoms selected from N, O, P, and S. In some embodiments, Cy is 9- to 12-membered bicyclic heteroaryl comprising comprising 1 to 4 heteroatoms selected from N, O, P, and S. In some embodiments, Cy is 9-membered bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, P, and S. In some embodiments, Cy is 10-membered bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, P, and S.
  • Cy is 11-membered bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, P, and S. In some embodiments, Cy is 12-membered bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, P, and S.
  • Cy is Ci-6 aliphatic. In some embodiments, Cy is Ci-6 alkylenyl. 0108] In some embodiments, Cy is C3-12 cycloaliphatic. In some embodiments, Cy is cy cobutyl, cyclopentyl, or cyclohexyl. In some embodiments, Cy is cyclobutyl. In some embodiments, Cy is cyclopentyl. In some embodiments, Cy is cyclohexyl.
  • Cy is C6-12 aryl. In some embodiments, Cy is phenyl.
  • each R 1 is independently selected from N(R 3 )2, -OH, -CN, - C(0)N(R 3 )2, and an optionally substituted group selected from Ci-6 aliphatic and N(R 3 )-C(0)-Ci- 6 aliphatic.
  • each R 1 is independently selected from N(R 3 )2, OH, CN, C(0)NHR 3 , and an optionally substituted group selected from Ci-6 aliphatic and N(R 3 )-C(0)-CI-6 alkyl.
  • R 1 is N(R 3 )2. In some embodiments, R 1 is NH2. In some embodiments, R 1 is N(H)(CH3). In some embodiments, R 1 is N(03 ⁇ 4)2. In some embodiments, R 1 is OH. In some embodiments, R 1 is CN. In some embodiments, R 1 is C(0)N(R 3 )2. In some embodiments, R 1 is C(0)NHR 3 . In some embodiments, R 1 is C(0)NH2. In some embodiments, R 1 is optionally substituted Ci-6 aliphatic. In some embodiments, R 1 is optionally substituted Ci-6 alkyl. In some embodiments, R 1 is optionally substituted Ci-4 alkyl. In some embodiments, R 1 is optionally substituted Ci alkyl. In some embodiments, N(R 3 )-C(0)-CI-6 aliphatic. In some embodiments, N(R 3 )-C(0)-CI-6 alkyl.
  • a substituent on an optionally substituted carbon atom of an optionally substituted R 1 group is selected from: halo, OH, NH2, and oxo.
  • L 1 is absent, -NR 3 -, -S-, C(0)NR 3 -, -C(0)-C(0)-, or a bivalent optionally substituted group selected from Ci-6 alkylenyl, C2-6 alkynylenyl, -NR 3 -CI-6 alkylenyl, O-Co-6 alkylenyl, and -C(0)Co-6 alkylenyl.
  • L 1 is absent, -NR 3 -, -0-, -S-, Ci-6 alkylenyl, C2-6 alkenylenyl, C2-6 alkynylenyl, -NR 3 -CI-6 alkylenyl, -O-C 1-6 alkylenyl, -C(0)Co- 6 alkylenyl, -C(0)NR 3 -, or -C(0)-C(0)-.
  • L 1 is absent. In some embodiments, L 1 is -NR 3 -. In some embodiments, L 1 is -N(03 ⁇ 4)-. In some embodiments, L 1 is -NH-.
  • L 1 is -S-. In some embodiments, L 1 is -C(0)NR 3 -. In some embodiments, L 1 is -C(0)-C(0)-.
  • L 3 is Ci-6 alkylenyl. In some embodiments, L 1 is Ci-6 alkyl. In some embodiments, L 1 is -CH2-. In some embodiments, L 1 is -CH(CH3)- In some embodiments, L 1 is
  • L 1 is .
  • L 1 is -NR 3 -CI-6 alkylenyl.
  • L 1 is -O-Co- 6 alkylenyl. In some embodiments, L 1 is -0-. In some embodiments, L 1 is -O-Ci- 6 alkylenyl. In some embodiments, L 1 is -O-Ci- 6 alkyl. In some embodiments, L 1 is -O-C1-3 alkyl. In some embodiments, L 1 is -O-CH2-.
  • L 1 is -C(0)Co- 6 alkylenyl. In some embodiments, L 1 is -C(O). In some embodiments, L 1 is -C(0)Ci- 6 alkylenyl.
  • 0i 22 j As defined generally above, Z is Ci- 6 aliphatic, 2- to 10-membered heteroaliphatic, P(0)(R 3 )2, -C(0)CI- 6 aliphatic, C(0)N(R 3 )2, C6-12 aryl, C3-12 cycloalkyl, 4- to 16-membered monocyclic or polycyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S, or 5- to 12-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, wherein Z is substituted with (R 2 )q.
  • Z is C6-12 aryl or 4- to 16-membered monocyclic or polycyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S.
  • Z is substituted with (R 2 )q.
  • q is 0, 1, 2, 3, or 4. That is, in some embodiments, Z is substituted with 0, 1, 2, 3, or 4 R 2 .
  • Z is unsubstituted (i.e., q is 0).
  • q is 1.
  • q is 2.
  • q is 3.
  • q is 4.
  • Z is Ci-6 aliphatic. In some embodiments, Z is Ci-6 alkyl. In some embodiments, Z is C1-3 alkyl. In some embodiments, Z is methyl. In some embodiments, Z is ethyl.
  • Z is 2- to 10-membered heteroaliphatic. In some embodiments, Z is 2- to 5-membered heteroaliphatic. In some embodiments, Z is 3-membered heteroaliphatic. In some embodiments, Z is -O-CH3, -CH2-O-CH3, -O-CH2-CH2-O-CH2-CH2-O-CH3. In some embodiments, Z is -O-CH3. In some embodiments, Z is -CH2-O-CH3. In some embodiments, Z is -O-CH2-CH2-O-CH2-CH2-O-CH3.
  • Z is C6-12 aryl. In some embodiments, Z is phenyl substituted with (R 2 ) q . In some embodiments, Z is phenyl substituted with 0, 1, 2, 3, or 4 R 2 . In some embodiments, Z is unsubstituted phenyl. In some embodiments, Z is phenyl substituted with 1, 2, 3, or 4 R 2 . In some embodiments, Z is phenyl substituted with 1 or 2 R 2 . In some emboidments, Z is phenyl substituted with 1 or 2 halo.
  • Z is C3-12 cycloalkyl. In some embodiments, Z is cyclobutyl. In some embodiments, Z is cyclopentyl. In some embodiments, Z is cyclohexyl.
  • Z is 4- to 16-membered monocyclic or polycyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, Z is 4- to 6- membered monocyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, Z is 4-membered monocyclic heterocyclyl comprising 1 heteroatom selected from N, O, and S. In some embodiments, Z is 5-membered monocyclic heterocyclyl comprising 1-2 heteroatoms selected from N, O, and S. In some embodiments, Z is 6-membered monocyclic heterocyclyl comprising 1-4 heteroatoms selected from N, O, and S. In some embodiments, Z is tetrahydropyranyl .
  • Z is 10- to 12-membered bicyclic heterocyclyl. In some embodiments, Z is 10- to 12-membered fused bicyclic heterocyclyl. In some embodiments, Z is 10- to 12-membered bridged bicyclic heterocyclyl.
  • Z is 10- to 16-membered polycyclic hetercyclyl. In some embodiments, Z is 10-membered polycyclic heterocyclyl. In some embodiments, Z is 11- membered polycyclic heterocyclyl. In some embodiments, Z is 12-membered polycyclic heterocyclyl. In some embodiments, Z is 13-membered polycyclic heterocyclyl. In some embodiments, Z is 14-membered polycyclic heterocyclyl. In some embodiments, Z is 15- membered polycyclic heterocyclyl. In some embodiments, Z is 16-membered polycyclic heterocyclyl. In some embodiments, a polycyclic Z moiety is a spirocyclic or fused tricyclic moiety.
  • Z is 9- to 12-membered spirocyclic heterocyclyl. In some embodiments, Z is 9-membered spirocyclic heterocyclyl. In some embodiments, Z is 10- membered spirocyclic heterocyclyl. In some embodiments, Z is 11-membered spirocyclic heterocyclyl. In some embodiments, Z is 12-membered spirocyclic heterocyclyl.
  • Z is 5- to 12-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, Z is 5- to 6- membered monocyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, Z is 5-membered monocyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, Z is 6-membered monocyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S.
  • Z is 8- to 12-membered bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, Z is 8-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, Z is 9-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, Z is 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, Z is 11-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, Z is 12-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S.
  • each R 2 is independently selected from halo, oxo, -CN, 0-R 2a , -C(0)-R 2a , -C(0)0-R 2a , and an optionally group selected from Ci-6 aliphatic, Ce-u aryl, and 5- to 12-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S.
  • each R 2 is independently selected from halo, CN, C(0)0H, and an optionally substituted group selected from Ci-6 aliphatic, C(0)Ci-6 aliphatic, and O-Ci-6 aliphatic.
  • R 2 is halo.
  • R 2 is selected from fluoro, chloro, bromo, and iodo.
  • R 2 is oxo
  • R 2 is CN
  • R 2 is 0-R 2a . In some embodiments, R 2 is -OH. In some embodiments, R 2 is an optionally substituted O-Ci-6 aliphatic. In some embodiments, R 2 is optionally substituted O-Ci-6 alkyl. In some embodiments, R 2 is optionally substituted O-Ci-4 alkyl. In some embodiments, R 2 is optionally substituted O-C1-2 alkyl. In some embodiments, R 2 is O-methyl. In some embodiments, R 2 is O-ethyl.
  • R 2 is -C(0)-R 2a .
  • R 2 is -C(0)0-R 2a .
  • R 2 is an optionally substituted Ci-6 aliphatic. In some embodiments, R 2 is optionally substituted Ci-6 alkyl. In some embodiments, R 2 is optionally substituted Ci-4 alkyl. In some embodiments, R 2 is optionally substituted C1-2 alkyl. In some embodiments, R 2 is methyl. In some embodiments, R 2 is ethyl.
  • R 2 is optionally substituted C6-12 aryl. In some embodiments, R 2 is optionally substituted phenyl.
  • R 2 is optionally substituted 5- to 12-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, R 2 is optionally substituted 5- to 6-membered monocyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S.
  • a substituent on an optionally substituted carbon atom of an optionally substituted R 2 group is halo (e.g., bromo, chloro, fluoro, iodo).
  • each R 2a is independently H or an optionally substituted group selected from Ci-6 aliphatic, C3-12 cycloalphatic, and 4- to 12-membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S.
  • R 2a is H.
  • R 2a is optionally substituted Ci-6 aliphatic.
  • R 2a is optionally substituted C3-12 cycloalphatic.
  • R 2a is optionally substituted 4- to 12-membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S.
  • each R 3 is independently selected from H and optionally substituted Ci-6 aliphatic.
  • R 3 is H.
  • R 3 is an optionally substituted Ci-6 aliphatic.
  • R 3 is optionally substituted Ci-6 alkyl.
  • R 3 is optionally substituted Ci-4 alkyl.
  • R 3 is optionally substituted C1-2 alkyl.
  • R 3 is methyl.
  • R 3 is ethyl.
  • a substituent on an optionally substituted carbon atom of an optionally substituted R 3 group is halo (e.g., bromo, chloro, fluoro, iodo).
  • Z is selected from Table Z
  • L 2 an optionally substituted group selected from -(NR 3 ) s -S(0)- Co-6 alkylenyl-, -(NR 3 ) s -S(0)2-Co-6 alkylenyl-, -Ci-6 alkylenyl-S(0)-(NR 3 ) s -, -Ci-6 alkylenyl-S(0)2- (NR 3 ) S -, -(NR 3 ) S -CO-6 alkylenyl, -(NR 3 ) s -C(0)-Co-6 alkylenyl, and 4- to 12-membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S.
  • L 2 is absent, -(NR 3 ) s -S(0)-Co-6 alkylenyl-, -(NR 3 ) s -S(0)2-Co-6 alkylenyl-, -(NR 3 ) s -S(0)(NR 3 )-, -S(0) 2 -NR 3 -, -NR 3 -CI- 6 haloalkylenyl, -(NR 3 ) s -P(0)(R 3 )-, -Ci-e alkylenyl-S(O)-, -Ci-6 alkylenyl-S(0)2-, -C(0)-(NR 3 ) s -, -(NR 3 ) s -C(0)-, or an optionally substituted 4- to 12-membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S.
  • L 2 is absent. 0154] In some embodiments, L 2 is -(NR 3 ) s -S(0)(NR 3 )-. In some embodiments, L 2 is -S(0)(NH)- . In some embodiments, L 2 is -(NR 3 )-S(0)(NR 3 )-. In some embodiments, L 2 is -NH-S(0)(NH)-. In some embodiments, L 2 is -N(CH3)-S(0)(NH)-.
  • L 2 is -S(0)2-NR 3 -. In some embodiments, L 2 is -S(0)2-NH-. In some embodiments, L 2 is -S(0)2-N(CH3)-.
  • L 2 is -(NR 3 ) s -C(0)-(NR 3 ) s -. In some embodiments, L 2 is -C(O)- (NR 3 ) S -. In some embodiments, L 2 is -C(0)NH-. In some embodiments, L 2 is -C(O)-. In some embodiments, L 2 is -N(R 3 )-C(0)-. In some embodiments, L 2 is -NH-C(O)-.
  • L 2 is -(NR 3 ) s -C(0)-Co-6 alkylenyl. In some embodiments, L 2 is -
  • L 2 is -(NR 3 ) s -P(0)(R 3 )-. In some embodiments, L 2 is -P(0)(R 3 ). In some embodiments, L 2 is -(NR 3 )-P(0)(R 3 )-. In some embodiments, L 2 is -P(0)(CH3)-. In some embodiments, L 2 is -NH-P(0)(CH3)-.
  • L 2 is -(NR 3 ) S -S(0)-CH2-. In some embodiments, L 2 is -(NR 3 ) s -S(0)-. In some embodiments, L 2 is - S(O)-. In some embodiments, L 2 is -NR 3 -S(0)-. In some embodiments, L 2 is -NH-S(O)-. In some embodiments, L 2 is -N(CH3)-S(0)-. fO!tjQj In some embodiments, L 2 is -(NR 3 ) s -S(0)2- Co-6 alkylenyl. In some embodiments, L 2 is - (NR 3 ) S -S(0)2- Ci-6 alkylenyl.
  • L 2 is -(NR 3 ) s -S(0)2-CH2-. In some embodiments, L 2 is -(NR 3 ) s -S(0)2-. In some embodiments, L 2 is -S(0)2-. In some embodiments, L 2 is -NR 3 -S (0)2-. In some embodiments, L 2 is -NH-S(0)2-. In some embodiments, L 2 is - N(CH 3 )-S(0)2-. some embodiments, L 2 is -NR 3 -Ci-6haloalkylenyl. j0162] In some embodiments, L 2 is optionally substituted -Ci-6 alkylenyl-S(0)-(NR 3 ) s -.
  • L 2 is optionally substituted -Ci-6 alkylenyl-S(0)-N(R 3 )-. In some embodiments, L 2 is optionally substituted -Ci-6 alkylenyl-S(0)-NH-. In some embodiments, L 2 is optionally substituted -Ci-6 alkylenyl-S(O)-. In some embodiments, L 2 is -CH2-S(0)-.
  • L 2 is optionally substituted -Ci-6 alkylenyl-S(0)2-(NR 3 ) s -. In some embodiments, L 2 is optionally substituted -Ci-6 alkylenyl-S(O) 2-N(R 3 )-. In some embodiments, L 2 is optionally substituted -Ci-6 alkylenyl-S(O) 2-NH-. In some embodiments, L 2 is optionally substituted -Ci-6 alkylenyl-S(O) 2-. In some embodiments, L 2 is -CH2-S(0) 2-.
  • L 2 is optionally substituted -(NR 3 ) s -Co-6 alkylenyl. In some embodiments, L 2 is optionally substituted -(NR 3 ) s -Co-6 alkylenyl. In some embodiments, L 2 is optionally substituted -NR 3 -CI-6 alkylenyl. In some embodiments, L 2 is optionally substituted - NR 3 -Ci-3alkylenyl. In some embodiments, L 2 is optionally substituted -NR 3 -CI alkylenyl. In some embodiments, L 2 is -NH-CH2-. In some embodiments, L 2 is -NH-CH(CF3)-.
  • L 2 is optionally substituted 4- to 12-membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S.
  • L 2 is a 4- to 6-membered monocyclic heterocyclcyl comprising 1 to 4 heteroatoms selected from N, O, and S.
  • L 2 is a 4-membered monocyclic heterocyclcyl comprising 1 heteroatom selected from N, O, and S.
  • L 2 is a 5-membered monocyclic heterocyclcyl comprising 1 to 4 heteroatoms selected from N, O, and S.
  • L 2 is a 6-membered monocyclic heterocyclcyl comprising 1 to 4 heteroatoms selected from N, O, and S. j0166
  • L 2 is optionally substituted 10-membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, L 2 is optionally substituted 11-membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, L 2 is optionally substituted 12-membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S.
  • a substituent on an optionally substituted carbon atom of an optionally substituted L 2 group is halo (e.g., bromo, chloro, fluoro, iodo) or Ci-6 alkyl.
  • V is Ci-6 aliphatic, Ce-u aryl, C3-12 cycloalkyl, 4- to 12- membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S, 5- to 12-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, or 5- to 16-membered monocyclic or polycyclic aryl, wherein V is substituted with (R 6 ) m .
  • V is selected from Ci-6 aliphatic, C6-12 aryl, 4- to 12-membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S, 5- to 12-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from
  • N, O, and S 5- to 12- membered monocyclic or bicyclic aryl, and C3-12 cycloalkyl, wherein V is substituted with (R 6 ) m .
  • V is substituted with (R 6 ) m .
  • m is
  • V is substituted with 0, 1, 2, 3, or 4 R 6 .
  • V is unsubstituted (i.e., m is 0).
  • m is 1.
  • m is 2.
  • m is 3.
  • m is 4. j0171J
  • V is Ci-6 aliphatic.
  • V is is Ci-6 alkyl.
  • V is selected from methyl, ethyl, propyl, butyl, propyl, and hexyl.
  • V is Ce-n aryl. In some embodiments, V is phenyl.
  • V is C3-12 cycloalkyl. In some embodiments, V is C3-6 cycloalkyl. In some embodiments, V is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, V is cyclopropyl. In some embodiments, V is cyclobutyl. In some embodiments, V is cyclopentyl. In some embodiments, V is cyclohexyl.
  • V is 4- to 12-membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, V is 4- to 6- membered monocyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, V is 4-membered heterocyclic comprising 1 heteroatom selected from N, O, and S. In some embodiments, V is 5-membered heterocyclic comprising 1 to 4 heteroatom selected from N, O, and S. In some embodiments, V is 6-membered heterocyclic comprising 1 to 4 heteroatom selected from N, O, and S. In some embodiments, V is morpholinyl.
  • V is 7- to 12-membered bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, V is 7-membered bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, V is 8-membered bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, V is 9-membered bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, V is 10-membered bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S.
  • V is 11-membered bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, V is 12-membered bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S.
  • V is 5- to 12-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, V is 5- to 6- membered monocyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, V is 5- membered monocyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, V is 6-membered monocyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, V is pyridyl.
  • V is 7- to 12-membered bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, V is 7- membered bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, V is 8- membered bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, V is 9- membered bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, V is 10- membered bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S.
  • V is 11- membered bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, V is 12-membered bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, V is indolyl.
  • each R 6 is halo, -S(0)-R 5 , -S(0)2-R 5 , -S(0)(NH)-R 5 , -CN, - C(0)-R 5 , -C(0)0-R 5 , -C(0)-NH(R 5 ), -C(0)-N(R 5 )2, -P(0)(R 5 )2, or an optionally substituted group selected from O-Ci-6 aliphatic, Ci-6 aliphatic, C3-12 cycloalkyl, and C6-12 aryl.
  • each R 6 is independently selected from halo, -S(0)-R 5 , -S(0)2-R 5 , -S(0)(NH)-R 5 , -CN, -C(0)-R 5 , -C(0)0-R 5 , -C(0)-NH(R 5 ), -C(0)-N(R 5 ) 2, -P(0)(R 5 ) 2 , or an optionally substituted group selected from O-Ci-6 alkyl, Ci-6 alkyl, and C6-12 aryl.
  • R 6 is -S(0)-R 5 , -S(0)2-R 5 , or an optionally substituted Ci-6 alkyl. [0182J In some embodiments, R 6 is halo. In some embodiments, R 6 is chloro, fluoro, bromo, or iodo. In some embodiments, R 6 is fluoro. In some embodiments, R 6 is chloro. In some embodiments, R 6 is bromo. In some embodiments, R 6 is iodo.
  • R 6 is -S(0)-R 5 . In some embodiments, R 6 is -S(0)-CH3.
  • R 6 is -S(0)2-R 5 . In some embodiments, R 6 is -S(0)2-Ci-6 alkyl. In some embodiments, R 6 is -S(0)2-CH3. In some embodiments, R 6 is -S(0)2-CH2CH3. In some embodiments, R 6 is -S(0)2-CHF2. In some embodiments, R 6 is -S(0)2-CF3.
  • R 6 is -S(0)2-N(CI-6 alkyl)2. In some embodiments, R 6 is -S(0)2- N(CH 3 )2.
  • R 6 is S(0)(NH)-R 5 . In some embodiments, R 6 is -S(0)(NH)-CH3. [0187) In some embodiments, R 6 is -CN.
  • R 6 is -C(0)-R 5 . In some embodiments, R 6 is -C(0)-CH3. In some embodiments, R 6 is -C(0)-CF3. In some embodiments, R 6 is -C(0)-pyrolidinyl.
  • R 6 is -C(0)0-R 5 . In some embodiments, R 6 is -C(0)0-Ci-6 alkyl. In some embodiments, R 6 is -C(0)0-CH3. In some embodiments, R 6 is -C(0)0-CH2CH3.
  • R 6 is -C(0)-N(R 5 )2. In some embodiments, R 6 is -C(0)-N(CH3)2.
  • R 6 is optionally substituted O-Ci- 6 aliphatic. In some embodiments, R 6 is optionally substituted O-Ci- 6 alkyl. In some embodiments, R 6 is O-CH3. In some embodiments, R 6 is O-CH2CH3. In some embodiments, R 6 is O-CF3.
  • R 6 is optionally substituted Ci- 6 aliphatic. In some embodiments, R 6 is Ci- 6 alkyl. In some embodiments, R 6 is Ci-4 alkyl. In some embodiments, R 6 is methyl. In some embodiments, R 6 is ethyl. In some embodiments, R 6 is propyl. In some embodiments, R 6 is butyl. In some embodimetns, R 6 is /er/-butyl. In some embodiments, R 6 is -CH2F. In some embodiments, R 6 is -CHF2. In some embodiments, R 6 is CF3. 0195] In some embodiments, R 6 is C3-12 cycloalkyl. In some embodiments, R 6 is C3-16 cycloalkyl. In some embodiments, R 6 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • R 6 is optionally substituted C6-12 aryl.
  • a substituent on an optionally substituted carbon atom of an optionally substituted R 6 is halo (e.g., bromo, chloro, fluoro, iodo), Ci- 6 alkyl, OH, or oxo. 0198]
  • each R 5 is independently -OR 3 , C(0)-R 3 , P(0)(R 3 )2, -N(R 3 )2, or an optionally substituted group selected from Ci- 6 aliphatic, C3-12 cycloalkyl, and 4- to 12- membered heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S.
  • each R 5 is independently selected from Ci-6 alkyl, -N(R 3 )2, -O-Ci-6 alkyl, C(0)-Ci-6 alkyl, P(0)(Ci-6 alkyl)2, C3-12 cycloalkyl, and 5- to 12-membered heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S, wherein R 5 is optionally substituted with one or more substituents selected from halo and OH.
  • R 5 is Ci-6 alkyl. In some embodiments, R 5 is -N(R 3 )2. In some embodiments, R 5 is -NH2. In some embodiments, R 5 is -NH(CI-6 aliphatic). In some embodiments, R 5 is -NH(CH3). In some embodiments, R 5 is -O-Ci-6 alkyl. In some embodiments, R 5 is C(0)-Ci-6 alkyl. In some embodiments, R 5 is P(0)(Ci-6 alkyl)2. In some embodiments, R 5 is C3-12 cycloalkyl.
  • R 5 is 5- to 12-membered heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S, wherein R 5 is optionally substituted with one or more substituents selected from halo and OH.
  • 0201j In some embodiments, V is selected from Table V
  • the present application provides a compound of formula Ila:
  • X 6 is CH. In some embodiments of formula Ila, X 6” is N.
  • the present application provides a compound of formula IIa-1:
  • the present application provides a compound of formula IIa-1-ii:
  • the present application provides a compound of formula IIa-1-iii:
  • the present application provides a compound of formula IIa-2:
  • the present application sprovides a compound of formula IIa-2-i:
  • the present application provides a compound of formula IIa-3:
  • the present application provides a compound of formula IIa-3-i:
  • the present application provides a compound of formula IIa-3-iii:
  • the present application provides a compound of formula IIa-4: or a pharmaceutically acceptable salt thereof, wherein Z, R 6 , and m are defined herein.
  • 0215j In some embodiments, the present application provides a compound of formula IIa-4-i:
  • the present application provides a compound of formula IIa-5-i:
  • R 6 , R 2 , m, and q are defined herein.
  • a compound of the present disclosure i.e., a compound of formula I-IIb-1) is selected from Table A:
  • a compound of the present invention i.e., a compound of any one of formulas I to IIb-1) is selected from Table B:
  • the present disclosure describes one or more characteristics of certain TRPML1 modulators provided by and/or useful in the practice of the present disclosure.
  • the present disclosure provides technologies for assessing one or more relevant characteristics and/or for identifying, selecting, prioritizing, and/or characterizing one or more useful TRPML1 modulators.
  • the present disclosure provides certain biological and/or chemical assays (e.g., that facilitate and/or permit assessment of one or more feature(s) of TRMPL1 expression and/or activity, and/or of impact of TRPMLl modulator(s) on such expression and/or activity.
  • the present disclosure provides technologies for identifying and/or characterizing one or more aspects of biological pathway(s) (e.g., autophagy pathway(s)) involving TRMPL1, and thus permits identification and/or characterization of additional useful targets within such pathway(s) and/or of modulator(s) that impact such pathway(s) (whether or not targeting TRPMLl itself).
  • the present disclosure provides and/or utilizes a composition that comprises and/or delivers a compound as described herein (e.g., together with one or more other components).
  • compositions that comprise and/or deliver compounds reported herein (e.g., compounds of Formula I-II), or an intermediate, degradant, or an active metabolite thereof, e.g., when contacted with or otherwise administered to a system or environment e.g., which system or environment may include TRPMLl activity; in some embodiments, administration of such a composition to the system or environment achieves the regulation of autophagy and lysosomal biogenesis as described herein.
  • compounds reported herein e.g., compounds of Formula I-II
  • an intermediate, degradant, or an active metabolite thereof e.g., when contacted with or otherwise administered to a system or environment e.g., which system or environment may include TRPMLl activity
  • administration of such a composition to the system or environment achieves the regulation of autophagy and lysosomal biogenesis as described herein.
  • a provided composition as described herein may be a pharmaceutical composition in that it comprises an active agent (e.g., a compound of Formula I-II or an active metabolite thereof) and one or more pharmaceutically acceptable excipients (e.g., one or more pharmaceutically acceptable adjuvants, carriers, excipients, and/or vehicles); in some such embodiments, a provided pharmaceutical composition comprises and/or delivers a compound described herein (e.g., a compound of Formula I-IIb-1), or an active metabolite thereof to a relevant system or environment (e.g., to a subject in need thereof) as described herein.
  • an active agent e.g., a compound of Formula I-II or an active metabolite thereof
  • pharmaceutically acceptable excipients e.g., one or more pharmaceutically acceptable adjuvants, carriers, excipients, and/or vehicles
  • a provided pharmaceutical composition comprises and/or delivers a compound described herein (e.g., a compound of Formula I
  • a provided composition (e.g., a pharmaceutical composition) includes a compound (e.g., as described herein) in a salt form such as a pharmaceutically acceptable salt form.
  • a provided composition may be formulated for administration to a subject (e.g., a human) according to a particular route (e.g., orally, parenterally, by inhalation or nasal spray, topically (e.g., as by powders, ointments, or drops), rectally, buccally, intravaginally, intraperitoneally, intracistemally or via an implanted reservoir, etc).
  • a particular route e.g., orally, parenterally, by inhalation or nasal spray, topically (e.g., as by powders, ointments, or drops), rectally, buccally, intravaginally, intraperitoneally, intracistemally or via an implanted reservoir, etc).
  • a provided composition (e.g., a pharmaceutical composition) comprises or delivers an amount of a compound as described herein (or an active metabolite thereof) that is effective to measurably modulate TRPMLl activity, and/or to induce autophagy and/or lysosomal biogenesis in a biological sample or in a subject, when administered in accordance with a therapeutic regimen.
  • a provided compound or composition is formulated for administration to a patient in need of such composition.
  • a compound or composition as described herein may be administered in a dose amount and/or by a route of administration effective for treating or lessening the severity of a disease or disorder described herein.
  • a composition e.g., a pharmaceutical composition
  • a composition as described herein may be formulated in unit form (e.g., which may offer ease of administration and/or uniformity of dosage).
  • effective dose amounts may vary from subject to subject, for example depending on a variety of factors, including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed and its route of administration; the species, age, body weight, sex and diet of the patient; the general condition of the subject; the time of administration; the rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed, and the like.
  • an appropriate dosage level may be within a range of about 0.01 mg/kg to about 50 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect.
  • the present disclosure provides technologies for modulating TRPMLl activty.
  • the present application relates to a method of modulating TRPMLl activty in a subject comprising administering to the subject a provided compound, or a composition as described herein.
  • compositions as described herein may be useful in medicine (e.g., in the treatment of one or more diseases, disorders, or conditions).
  • targeting e.g., agonizing
  • TRPMLl may be a particularly effective strategy for modulating (e.g., enhancing) autophagy and/or lysosomal biogenesis.
  • a disease, disorder or condition that may be treated as described herein may be or comprise a disease, disorder or condition associated with TRPMLl deficiency.
  • the present disclosure identifies that TRMPL1 deficiency is associated with particular diseases, disorders or conditions, some or all of which may be treated in accordance with the present disclosure.
  • treatment provided herein involves administration of a TRMPL1 modulator as described herein in an amount effective to modulate TRMPL1 activity in a lysosome and/or increase autophagy.
  • a disease, disorder, or condition amenable to treatment as described herein is or comprises a liver disease, a neurodegenerative disorder, cancer, or a heart disease.
  • a disease, disorder, or condition amenable to treatment as described herein is or comprises a lysosomal storage disease, such as Niemann-Pick C (NPC) disease, Gaucher disease, and Pompe disease.
  • NPC Niemann-Pick C
  • a disease, disorder, or condition amenable to treatment as described herein is an age-related common neurodegenerative disease, such as Alzheimer’s Disease, Parkinson’s Disease, and Huntington’s Disease.
  • a disease, disorder, or condition amenable to treatment as described herein is a type IV Mucolipidosis (ML4) neurodegenerative lysosomal storage disease caused by mutations in TRPMLl.
  • ML4 Mucolipidosis
  • a disease, disorder, or condition amenable to treatment as described herein is related to reactive oxygen species or oxidative stress.
  • the present application relates to use of a compound and/or composition described herein for use in the manufacture of a medicament e.g., for modulation of TRPMLl activity.
  • the present application relates to use of a compound and/or composition described herein for use in the manufacture of a medicament for treating a disease, disorder or condition, e.g., through modulation of TRPMLl activity; in some emebodiments, the disease, disorder, or condition is a liver disease, a neurodegenerative disorder, cancer, or a heart disease.
  • a disease, disorder, or condition is a muscular disease, a liver disease, a metabolic disease, an atherosclerotic disease, an inflammatory bowel disease, an atherosclerotic disease, a neurodegenerative disease, or an oncological disease.
  • a disease, disorder, or condition is a muscular disease.
  • a muscular disease is a muscular dystrophy.
  • a muscular dystrophy is Duchenne muscular dystrophy.
  • a disease, disorder, or condition is an infectious disease.
  • an infectious disease is an infection of Heliobacter pylori or Mycobacterium tuberculosis.
  • a disease, disorder, or condition is tuberculosis.
  • X r , X 2” , and X 7 are each independently selected from N, NR a , C, and CR ax , wherein X r , X 2” , and X 7 are N, C, or CR a when bound to Cy-L'-Z or L 2 -V X 3” , X 4 , X 5 , and X 6 are each independently selected from N, C, and CR a , wherein X 3 , X 4 , X 5 , and X 6 are N or C when bound to Cy-L'-Z or L 2 -V;
  • Cy is absent, 4- to 12-membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, P, and S, 5- to 12-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, Ci-6 aliphatic, or C3-12 cycloalkyl, wherein Cy is optionally substituted with one or more of R 1 ;
  • L 1 is absent, -NR 3 -, -0-, -S-, Ci-6 alkylenyl, C2-6 alkynylenyl, -NR 3 -CI-6 alkylenyl,-0-Ci-6 alkylenyl,
  • L 2 is -(NR 3 ) S -S(0)-CO-6 alkylenyl-, -(NR 3 )s-S(0) 2 -Co-6 alkylenyl-, -(NR 3 ) s -S(0)(NR 3 )-, -S(0) 2 - NR 3 -, -NR 3 -Ci-6haloalkylenyl, -(NR 3 ) s -P(0)(R 3 )-, -Ci-6 alkylenyl-S(O)-, -Ci-6 alkylenyl- S(0)2-, -C(0)-(NR 3 ) S -, -(NR 3 ) S -C(0)-, or an optionally substituted 4- to 12-membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S;
  • V is selected from Ci- 6 aliphatic, Ce-u aryl, 4- to 12-membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S, 5- to 12-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S,
  • Z is Ci- 6 aliphatic, 2- to 10-membered heteroaliphatic, P(0)(R 3 )2, -C(0)Ci- 6 aliphatic, C(0)N(R 3 )2, C6-12 aryl, C3-12 cycloalkyl, 4- to 16-membered monocyclic or polycyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S, or 5- to 12-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, wherein Z is substituted with (R 2 )q; each R a is independently halo, oxo, or optionally substituted Ci- 6 aliphatic; each R 1 is independently selected from N(R 3 )2, OH, CN, C(0)NHR 3 , and an optionally substituted group selected from Ci- 6 aliphatic and N(R 3 )-C(0)-CI- 6 alkyl; each R 2 is independently selected from halo, -CN
  • Cy is 4- to 6- membered monocyclic heterocyclic comprising 1 to 3 heteroatoms selected from N, O, and S.
  • Z is C6-12 aryl, 2- to 10- membered heteroaliphatic, 4- to 12-membered monocyclic or polycyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S, or 5- to 12-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, wherein Z is substituted with (R 2 ) q.
  • Z is C6-12 aryl or 4- to 12-membered monocyclic or polycyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S.
  • V is C6-12 aryl or 4- to 12-membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S.
  • V is Ce-n aryl.
  • a pharmaceutical composition comprising a compound of any one of the preceding embodiments and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
  • a method of modulating TRPMLl comprising administering to a subject a compound of any one of the preceding embodiments.
  • 45. A method of treating a disease, disorder, or condition in a subject comprising administering a compound of any one of the preceding embodiments.
  • lysosomal storage disorder is selected from Niemann-Pick C disease, Gaucher disease, and Pompe disease.
  • Step-1 Synthesis of l-(2,3-dimethoxyphenyl)ethan-l-ol: j0254
  • THF 2,3-dimethoxybenzaldehyde
  • a 3 M solution of methyl magnesium bromide in diethyl ether 3ml, 9.03 mmol, 1.5 eq
  • the reaction mixture was stirred at room temperature for overnight. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was diluted with water and extracted with ethyl acetate.
  • Step-2 Synthesis of l-(2,3-dimethoxyphenyl)ethan-l-one: 02 SS I
  • l-(2,3-dimethoxyphenyl)ethan-l-ol 0.8 g, 4.39 mmol, 1 eq
  • 2 M Jones reagent in aq. H2SO4 (6.6 ml, 13.18 mmol, 3 eq) at room temperature.
  • the reaction mixture was stirred at room temperature for 30 min. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with isopropanol and concentrated under reduced pressure.
  • the crude product was purified by column chromatography to afford the desired product l-(2,3-dimethoxyphenyl)ethan- 1-one (0.6 g, 76%).
  • LCMS 181.08 [M+l] + .
  • Step-1 Synthesis of 1 -methyl- lH-indole-4-carbaldehyde:
  • Step-1 General procedure for synthesis of l-Boc-4-aryl-3,6-dihydropyridine derivatives: j0257l
  • Tetrakis(triphenylphosphine)palladium(0) (0.1 eq) was added to then reaction under an argon atmosphere and purged the reaction mixture with argon for 15 min. The tube was then fitted with a screw cap and the reaction was stirred at 90 °C for 3 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture cooled to room temperature, filtered through a pad of Celite and the Celite pad was washed with ethyl acetate. The filtrate was diluted with water and extracted ethyl acetate. The combine organic layers were washed with water and brine, dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel to afford respective l-Boc-4-aryl-3,6-dihydropyridine derivative.
  • aryl halide 1.1 eq
  • tert- butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-l(2H)-carboxylate (1 eq)
  • cesium carbonate (2 eq) in a mixture of 1,4 dioxaneiLLO (4:1, 10 vol) and the reaction mixture was purged with
  • Step-2 General procedure for synthesis of l-Boc-4-arylpiperidine derivatives:
  • Step-3 General procedure for synthesis of 4-arylpiperidine derivatives: j0262]
  • Step-1 Synthesis of tert-butyl (E)-4-((hydroxyimino)methyl)piperidine-l-carboxylate:
  • Step-3 Synthesis of tert-butyl 4-(5-(trimethylsilyl)isoxazol-3-yl)piperidine-l-carboxylate:
  • Step-4 Synthesis of tert-butyl 4-(isoxazol-3-yl)piperidine-l-carboxylate:
  • Step 1 Synthesis of 3-formyl-2-hydroxybenzonitrile: j0269
  • Step 2 Synthesis of 2-formyl-2-methoxyhenzonitrile: jO270
  • PdCl2(dppf) (183 mg, 0.25 mmol, 0.03 eq) was then added to the reaction under an argon atmosphere and the purging with argon was continued for 5 min.
  • the tube was then sealed with a screw cap and the reaction was heated at 100 °C for 12 h. The progress of the reaction was monitored by TLC.
  • the reaction was cooled to room temperature and the reaction mixture was filtered through a pad of Celite and the Celite pad was washed with ethyl acetate. The filtrate was diluted with ethyl acetate and washed with water and brine.
  • Step-1 Synthesis of 4-chloro-3-methoxypyridine :
  • Step-2 Synthesis of 4-chloro-5-methoxynicotinaldehyde: j027$j
  • a stirred solution of 4-chloro-3-methoxypyridine (180 mg, 1.25 mmol, 1 eq) in THF (5 mL) was cooled to -78 °C and to which a 2 M solution of LDA in THF (1.25 mL, 2.51 mmol, 2 eq) was added. The reaction was stirred at the same temperature for 30 min. N,N- Dimethylformamide (0.19 mL, 2.51 mmol, 2 eq) was then added to the reaction at -78 °C. The reaction was gradually warmed to room temperature and stirred for 2.5 h.
  • Step-3 Synthesis of 4,5-dimethoxynicotinaldehyde: j0276
  • 4-chloro-5-methoxynicotinaldehyde 200 mg, 1.16 mmol, 1 eq
  • methanol 5 mL
  • sodium methoxide 126 mg, 2.33 mmol, 2 eq
  • Step-1 Synthesis of tert-butyl 4-(4-chlorophenyl)-3,6-dihydropyridine-l(2H)-carboxylate j0278l
  • a pyrex tube was charged with a solution of l-bromo-4-chlorobenzene (2 g, 10.44 mmol, 1 eq), tert- butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-l(2H)- carboxylate (3.87 g, 12.53 mmol, 1.2 eq) and potassium carbonate (2.8 g, 20.6 mmol, 2.5 eq) in a mixture of water (4 mL) and DMF (20 mL).
  • Step-2 Synthesis of tert-butyl 4-(4-chlorophenyl)piperidine-l-carboxylate j0279J
  • tert-butyl 4-(4-chlorophenyl)-3,6-dihydropyridine-l(2H)- carboxylate (1 g, 3.4 mmol, 1 eq) in ethyl acetate (20 mL)
  • platinum(IV) oxide 150 mg, 15% w/w
  • the reaction mixture was then purged with hydrogen for 2 min and stirred at room temperature for 3 h under an atmosphere of hydrogen via hydrogen balloon. The progress of the reaction was monitored by TLC.
  • Step-2 Procedure for synthesis of tert-butyl 3-(hydroxymethyl)pyrrolidine-l-carboxylate:
  • Step-3 Procedure for synthesis of tert-butyl 3-(((methylsulfonyl)oxy)methyl)pyrrolidine-l- carboxylate:
  • Example Bl Synthetic scheme for synthesis of 4-((3-(6'-fluoro-l'- methylspiro[cyclohexane-l,3'-indolin]-4-yl)-lH-indol-l-yl)sulfonyl)-N,N- dimethylbenzenesulfonamide (B-5):
  • Example B2 Synthetic scheme for synthesis of G-(1-((4-(N,N- dimethylsulfamoyl)phenyl)sulfonyl)-lH-indazol-3-yl)-6-fluoro-l,l-dimethylspiro[indoline- 3,4'-piperidin]-l-ium formate B-21):
  • Example B3 Synthesis of 4-((3-(l-(4-chloro-2-fluorophenyl)piperidin-4-yl)-lH-indol-l- yl)sulfonyl)-N,N-dimethylbenzenesulfonamide (B-138)
  • reaction mixture was stirred at room temperature for 12 h. The progress of reaction was monitored by TLC. After completion, the reaction mixture was concentrated, diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with water, brine, dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure to the desired product.
  • the crude was purified by prep HPLC to provide 4-((3- ( 1 -(4-chloro-2-fluorophenyl)piperidin-4-yl)- lH-indol- 1 -yl)sulfonyl)-N,N- dimethylbenzenesulfonamide (B-138).
  • Example B4 Synthetic scheme for Synthesis of 4-((3-(4-((dimethylamino)methyl)-4-(4- fluorophenyl)piperidin-l-yl)-lH-indazol-l-yl)sulfonyl)-N,N-dimethylbenzenesulfonamide
  • Example B5 General procedure for synthesis of 3-(8-(5-chloropyridin-2-yl)-3,8- diazabicyclo[3.2.1]octan-3-yl)-l-tosyl-lH-pyrazolo[4,3-b]pyridine (B-77):
  • Step-1 General procedure for synthesis of 3-(3,8-diazabicyclo[3.2.1]octan-3-yl)-l-tosyl-lH- pyrazolo[4,3-b]pyridine B5.2:
  • Step-2 General procedure for synthesis of 3-(8-(5-chloropyridin-2-yl)-3,8- diazabicyclo[3.2.1]octan-3-yl)-l-tosyl-lH-pyrazolo[4,3-b]pyridine (B-77): 0299)
  • the reaction mixture was stirred at 120 °C for 12h. The reaction progress was monitored by TLC. After completion, the reaction mixture was concentrated and resulting residue was partitioned between water and ethyl acetate. The organic layer was separated, washed with water and 1% HC1, dried over Na2SC>4 and concentrated. The crude was purified by silica gel column chromatography to provide 3-(8-(5-chloropyridin-2-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-l-tosyl-lH- pyrazolo[4,3-b]pyridine (B-77).
  • Example B6 Synthetic scheme for Synthesis of 3-(4-(5-chloro-3-fluoropyridin-2- yl)piperidin-l-yl)-l-((4-methoxyphenyl)sulfonyl)-lH-pyrazolo[4,3-b]pyridine (B-49): j0301l
  • B6.1 3.7 g, 31.09 mmol, 1 eq
  • bromine 5.92 g, 37.31 mmol, 1.2 eq
  • Step-2 Synthesis of 3-bromo-l-((4-methoxyphenyl)sulfonyl)-lH-pyrazolo[4,3-b]pyridine
  • B6.4 jO302J
  • DCM DCM
  • potassium hydroxide 0.568 g, 10.15 mmol, 2 eq
  • TBA.HSCL 0.258 g, 0.761 mmol, 0.15 eq
  • Step-3 Synthesis of 3-(4-(5-chloro-3-fluoropyridin-2-yl)piperidin-l-yl)-l-((4- methoxyphenyl)sulfonyl)-lH-pyrazolo[ 4, 3-b ] pyridine (B-49): j0303
  • 5-chloro-3-fluoro-2-(piperidin-4-yl)pyridine B6.5 500 mg, 2.33 mmol, 1 eq
  • 3-bromo-l-((4-methoxyphenyl)sulfonyl)-lH-pyrazolo[4,3-b]pyridine B6.4 (943 mg, 2.57 mmol, 1.1 eq) in propionitrile (10 mL), DIPEA (1.22 mL, 7.01 mmol, 3 eq) was added.
  • Example B7 Synthetic scheme for synthesis of ethyl 4-(2,4-difluorophenyl)-l-(l-((4-(N,N- dimethylsulfamoyl)phenyl)sulfonyl)-lH-indazol-3-yl)piperidine-4-carboxylate (B-29) and 4- ((3-(4-(2,4-difluorophenyl)-4-(hydroxymethyl)piperidin-l-yl)-lH-indazol-l-yl)sulfonyl)- N,N-dimethylbenzenesulfonamide (B-27):
  • Step-1 Synthesis of 4-(2,4-difluorophenyl)-l-(lH-indazol-3-yl)piperidine-4-carboxamide B7.2 and ethyl 4-(2,4-difluorophenyl)-l-(lH-indazol-3-yl)piperidine-4-carboxylate B7.3: j0305
  • 4-(2,4-difluorophenyl)-l-(lH-indazol-3-yl)piperidine-4- carbonitrile B7.1 (0.9 g, 2.6 mmol, 1 eq) in ethanol (20 mL)
  • concentrated sulfuric acid (10 mL) was added dropwise at 0 °C.
  • reaction was warmed to room temperature and heated at 100 °C for 24 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature, quenched with saturated aqueous NaHCCb solution and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure.
  • Step-2 Synthesis of ethyl 4-(2,4-difluorophenyl)-l-(l-((4-(N,N- dimethylsulfamoyl)phenyl)sulfonyl)-lH-indazol-3-yl)piperidine-4-carboxylate (B-29):
  • Step-3 Synthesis of 4-((3-(4-(2,4-difluorophenyl)-4-(hydroxymethyl)piperidin-l-yl)-lH-indazol- l-yl)sulfonyl)-N,N-dimethylbenzenesulfonamide (B-27):
  • Example B8 Synthetic scheme for synthesis of 4-(2,4-difluorophenyl)-l-(l-((4-(N,N- dimethylsulfamoyl)phenyl)sulfonyl)-lH-indazol-3-yl)piperidine-4-carboxamide (B-28):
  • Step-1 Synthesis of 4-(2,4-difluorophenyl)-l-(l-((4-(N,N-di ethylsulfamoyl)phenyl)sulfonyl)- lH-indazol-3-yl)piperidine-4-carboxamide /B-28):
  • Example B9 Synthetic scheme for synthesis of N-(l-(l-(5-chloro-3-fluoropyridin-2- yl)piperidin-4-yl)-lH-indazol-6-yl)-4-methoxybenzenesulfonamide (B-58):
  • Step-1 Synthesis of l-( 1 -(5-chloro-3-fluoropyridin-2-yl)piperidin-4-yl)-6-nitro-lH-mdazole B9.3:
  • Step-2 Synthesis of N-(l-(l-(5-chloro-3-fluoropyridin-2-yl)piperidin-4-yl)-lH-indazol-6- yl)acetamide B9.4:
  • Step-3 Synthesis of l-(l-(5-chloro-3-fluoropyridin-2-yl)piperidin-4-yl)-lH-indazol-6-amine B9.5:
  • Step-4 Synthesis of N-( 1-(1 -(5-chloro-3-fluoropyridin-2-yl)piperidin-4-yl)-lH-indazol-6-yl)-4- methoxybenzene sulfonamide (B-58) : j0312J
  • B-58 j0312J
  • l-(l-(5-chloro-3-fluoropyridin-2-yl)piperidin-4-yl)-lH-indazol-6- amine B9.5 200 mg, 0.579 mmol, 1 eq) and pyridine (0.1 mL, 1.16 mmol, 2 eq) in acetonitrile (5 mL)
  • 4-methoxybenzenesulfonyl chloride B9.6 143 mg, 0.695 mmol, 1.2 eq
  • Example B10 Synthetic scheme for synthesis of N-(l-(l-(5-chloro-3-fluoropyridin-2- yl)piperidin-4-yl)-lH-indazol-7-yl)-4-methoxybenzenesulfonamide (B-62):
  • Step-1 Synthesis of l-( 1 -(5-chloro-3-fluoropyridin-2-yl)piperidin-4-yl)-7-nitro-lH-mdazole BIO.3:
  • Step-2 Synthesis of N-(l-(l-(5-chloro-3-fluoropyridin-2-yl)piperidin-4-yl)-lH-indazol-7- yl)acetamide BIO.4: j0314J
  • l-(l-(5-chloro-3-fluoropyridin-2-yl)piperidin-4-yl)-7-nitro-lH- indazole BIO.3 1.7 g, 4.53 mmol, 1 eq
  • iron powder (1 g, 18.13 mmol, 4 eq
  • Step-3 Synthesis of l-(l-(5-chloro-3-fluoropyridin-2-yl)piperidin-4-yl)-lH-indazol-7 -amine BIO.5:
  • Step-4 Synthesis of N-( l-(l -(5-chloro-3-fluoropyridin-2-yl)piperidin-4-yl)-lH-indazol-7-yl)-4- methoxybenzene sulfonamide (B-62):
  • Example Bll Synthetic scheme for synthesis of 7-(4-(5-chloro-3-fluoropyridin-2- yl)piperazin-l-yl)-2-((4-methoxyphenyl)sulfonyl)-2H-indazole (B-64): j0317l
  • a pyrex tube was charged with a solution of l-(5-chloro-3-fluoropyridin-2-yl)piperazine Bl l.l (400 mg, 1.86 mmol, 1 eq), 7-bromo-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-indazole B11.2 (727 mg, 2.2 mmol, 1.2 eq) and cesium carbonate (1.2 g, 3.7 mmol, 2 eq) in 1,4-dioxane.
  • the tube was sealed with a septum and purged with argon for 10 min.
  • X-Phos palladacycle (G3) 47 mg, 0.055 mmol, 0.03 eq
  • the tube was then sealed with a screw cap and the reaction was heated at 130 °C for overnight.
  • the progress of the reaction was monitored by TLC.
  • the reaction was cooled to room temperature, filtered through a pad of Celite and the Celite pad was washed with ethyl acetate.
  • Step-2 Synthesis of 7-(4-(5-chloro-3-fluoropyridin-2-yl)piperazin-l-yl)-3a, 7a-dihydro-lH- indazole Bll.4: j0318J
  • Step-3 Synthesis of 7-(4-(5-chloro-3-fluoropyridin-2-yl)piperazin-l-yl)-2-((4- methoxyphenyl)sulfonyl)-2H-indazole (B-64):
  • Example B12 Synthetic scheme for synthesis of 4-((3-(4-chloro-2-fluorophenyl)-lH- indol-l-yl)sulfonyl)-N,N-dimethylbenzenesulfonamide (B-40):
  • Step-2 Synthesis of tert-butyl 3-(4-chloro-2-fluorophenyl)-lH-indole-l-carboxylate B 12.4:
  • a pyrex tube was charged with a solution of tert- butyl 3-bromo-lH-indole-l-carboxylate B12.2 (1 g, 3.3 mmol, 1 eq), (4-chloro-2-fluorophenyl)boronic acid B12.3 (878 mg, 5.05 mmol, 1.5 eq), sodium carbonate (874 mg, 8.25 mmol, 2.5 eq) in THF (20 mL) and water (4 mL). The tube was sealed with a septum and the reaction mixture was purged with argon via an argon balloon for 15 min.
  • PdCl2(dppf) (147 mg, 0.2 mmol, 0.06 eq) was then added to the reaction under an argon atmosphere and the purging with argon was continued for 5 min.
  • the tube was then sealed with a screw cap and the reaction was heated at 100 °C for 12 h. The progress of the reaction was monitored by TLC.
  • the reaction was cooled to room temperature and the reaction mixture was filtered through a pad of Celite and the Celite pad was washed with ethyl acetate. The filtrate was diluted with ethyl acetate and washed with water and brine.
  • the organic layer was dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure.
  • Step-3 Synthesis of 3-(4-chloro-2-fluorophenyl)-lH-indole B12.5: j0322
  • DCM dimethylethyl sulfoxide
  • trifluoroacetic acid 10 mL was added at 0 °C.
  • the reaction was warmed to room temperature and stirred for 12 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure.
  • Step-4 Synthesis of 4-((3-(4-chloro-2-fluorophenyl)-lH-indol-l-yl)sulfonyl)-N,N- dimethylbenzenesulfonamide (B-40):
  • Example B13 Synthetic scheme for synthesis of 4-((4-(4-chloro-2-fluorophenoxy)- lH-indazol-l-yl)sulfonyl)-N,N-dimethylbenzenesulfonamide (B-26):
  • Step-1 Synthesis of 2-(4-chloro-2-fluorophenoxy)-6-fluorobenzaldehyde B13.3:
  • Step-2 Synthesis of 4-(4-chloro-2-fluorophenoxy)-lH-indazole B13.5: j0326j
  • 2-(4-chloro-2-fluorophenoxy)-6-fluorohenzaldehyde B13.3 (1 g, 3.722 mmol, 1 eq) in DMSO (20 mL)
  • hydrazine hydrate (5 mL, 5 vol) was added.
  • the reaction mixture was stirred at 130 °C for 12 h.
  • the progress of the reaction was monitored by TLC.
  • the reaction mixture was cooled to room temperature, poured into water and extracted with ethyl acetate.
  • Step-3 Synthesis of 4-((4-(4-chloro-2-fluorophenoxy)-lH-indazol-l-yl)sulfonyl)-N,N- dimethylbenzenesulfonamide (B-26):
  • Example B14 Synthetic scheme for synthesis of 4-((4-((4-fluorophenyl)thio)-lH- indazol-l-yl)sulfonyl)-N,N-dimethylbenzenesulfonamide (B-24): Step-1: Synthesis of 4-((4-fluorophenyl)thio)-lH-indazole B14.2:
  • Step-2 Synthesis of 4-((4-((4-fluorophenyl)thio)-lH-indazol-l-yl)sulfonyl)-N,N- dimethylbenzenesulfonamide (B-24):
  • Example B15 General procedure for synthesis of 4-((4-((4-chloro-2- fluorophenyl)amino)-lH-indazol-l-yl)sulfonyl)-N,N-dimethylbenzenesulfonamide (B-123):
  • Step-1 General procedure for synthesis of 4-((4-((4-chloro-2-fluorophenyl)amino)-lH-indazol-l- yl)sulfonyl)-N,N-dimethylbenzenesulfonamide (B-123):
  • Example B16 Synthetic scheme for synthesis of 4-((4-((4-chloro-2- fluorophenyl)amino)-3-methyl-lH-indazol-l-yl)sulfonyl)-N,N-dimethylbenzenesulfonamide
  • Step-1 Synthesis of 4-((4-((4-chloro-2-fluorophenyl)amino)-3-methyl-lH-indazol-l-yl)sulfonyl)- N,N-dimethylbenzenesulfonamide (B-76):
  • Methyl iodide (0.051 mL, 0.82 mmol, 1.2 eq) was then added to the reaction at 0 °C. The reaction was warmed to room temperature and stirred for overnight. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to 0 °C and quenched with saturated aqueous NTBCl solution, and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure.
  • Example B17 Synthetic scheme for synthesis of 4-(l-(3-(4-(5-chloro-3-fluoropyridin-2- yl)piperazin-l-yl)-lH-pyrazolo[4,3-b]pyridin-l-yl)ethyl)-N,N-dimethylbenzenesulfonamide
  • Step-1 Procedure for synthesis of 4-(l-(3-(4-(5-chloro-3-fluoropyridin-2-yl)piperazin-l-yl)-lH- pyrazolo[4,3-b]pyridin-l-yl)ethyl)-N,N-dimethylbenzenesulfonamide (B-31):
  • Example B18 Synthetic scheme for synthesis of (3-(4-(5-chloro-3-fluoropyridin-2- yl)piperazin-l-yl)-2H-pyrazolo[4,3-b]pyridin-2-yl)(p-tolyl)methanone (B-42):
  • Step-32 Procedure for synthesis of (3-(4-(5-chloro-3-fluoropyridin-2-yl)piperazin-l-yl)-2H- pyrazolo[4,3-b]pyridin-2-yl)(p-tolyl)methanone (B-42): j0334J
  • 3-(4-(5-chloro-3-fluoropyridin-2-yl)piperazin-l-yl)-lH- pyrazolo[4,3-b]pyridine B18.1 (150 mg, 0.45 mmol, 1 eq) and 4-methylbenzoic acid B18.2 (73 mg, 0.54 mmol, 1.2 eq)
  • PyBOP (351 mg, 0.68 mmol, 1.5 eq)
  • DMAP (6 mg, 0.045 mmol, 0.1 eq) in DMSO (5 mL) and triethyl amine (0.12 mL, 0.90 mmol, 2 eq
  • reaction mixture was heated at 65 °C for 16 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature, quenched with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel to afford (3-(4-(5-chloro-3-fluoropyridin-2- yl)piperazin-l-yl)-2H-pyrazolo[4,3-b]pyridin-2-yl)(p-tolyl)methanone (B-42).
  • Example B19 Synthetic scheme for synthesis of 4-((3-(6-fluoro-l- methylspiro[indoline-3,4'-piperidin]-l'-yl)-lH-indazol-l-yl)sulfonyl)-N,N- dimethylbenzenesulfonamide (B-10):
  • Step-1 Synthesis of 6-fluoro-l-methylspiro[indoline-3,4'-piperidine] B19.2:
  • Step-2 Synthesis of (6-fluoro-l-methylspiro[indoline-3,4'-piperidin]-r-yl)(2- fluorophenyl)methanone B19.4:
  • Step-3 Synthesis of (6-fluoro-l-methylspiro[indoline-3,4'-piperidin]-r-yl)(2- fluorophenyl)methanethione B19.5:
  • Step-4 Synthesis of 6-fluoro-r-(lH-indazol-3-yl)-l-methylspiro[indoline-3,4'-piperidine] B19.6:
  • Step-5 Synthesis of 4-((3-( 6-fluoro-l-methylspiro[ indoline-3, 4 ’-piperidin /-/ '-yl)-lH-indazol-l- yl)sulfonyl)-N,N-dimethylbenzenesulfonamide (B-10):
  • Example B20 Synthetic scheme for synthesis of 4-((3-(6-fluoro-l- methylspiro[indoline-3,4'-piperidin]-l'-yl)-lH-pyrazolo[4,3-b]pyridin-l-yl)sulfonyl)-N,N- dimethylbenzenesulfonamide (B-12):
  • 0341j To a stirred solution of 4-((3-bromo-lH-pyrazolo[4,3-b]pyridin-l-yl)sulfonyl)-N,N- dimethylbenzenesulfonamide B20.1 (150 mg, 0.338 mmol, 1 eq) in propionitrile (3 mL) in a microwave tube, 6-fluoro-l-methylspiro[indoline-3,4'-piperidine] B20.2 (89.2 mg, 0.405 mmol, 1.2 eq) and DIPEA (0.12
  • the tube was sealed with a septum and aluminium cap.
  • the reaction mixture was irradiated in a microwave reactor at 160 °C for 2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature and concentrated under reduced pressure.
  • the crude product was purified by reverse phase preparative HPLC to afford 4-((3-(6-fluoro-l- methylspiro[indoline-3,4'-piperidin]-r-yl)-lH-pyrazolo[4,3-b]pyridin-l-yl)sulfonyl)-N,N- dimethylbenzenesulfonamide (B-12).
  • Example B21 Synthetic scheme for synthesis of 4-((4-(6-fluoro-l- methylspiro[indoline-3,4'-piperidin]-l'-yl)-lH-indazol-l-yl)sulfonyl)-N,N- dimethylbenzenesulfonamide (B-13):
  • Step-1 Synthesis of 4-((4-bromo-lH-indazol-l-yl)sulfonyl)-N,N-dimethylbenzenesulfonamide B21.3:
  • Step-2 Synthesis of 4-((4-( 6-fluoro-l-methylspiro[ indoline-3, 4 '-piperidin ]-l '-yl)-lH-indazol-l- yl)sulfonyl)-N,N-dimethylbenzenesulfonamide (B-13):
  • Tris(dibenzylideneacetone)dipalladium(0) (20 mg, 0.023 mmol, 0.05 eq) and Xantphos (18 mg, 0.032 mmol, 0.07 eq) were added to the reaction mixture under an argon atmosphere.
  • the tube was then fitted with a screw cap and the reaction mixture was heated at 80 °C for 12 h. The progress of the reaction was monitored by TLC.
  • the reaction mixture was cooled to room temperature, filtered through a pad of Celite and the Celite pad was washed with ethyl acetate. The filtrated was diluted with water and extracted with ethyl acetate.
  • Example B24 Synthesis of 4-((3-(4-(4-chloro-2-fluorophenyl)piperazin-l-yl)-lH-indazol-l- yl)sulfonyl)-N,N-dimethylbenzenesulfonimidamide (B-83)
  • Step-1 General synthesis of N-((4-((3-(4-(4-chloro-2-fluorophenyl)piperazin-l-yl)-lH-indazol-l- y Ijsulfony Ijpheny l) (dime thy lam ino)(oxo)-l6 ) -sulfaneylidene)-2,2,2-trifluoroacetamide B24.3:
  • reaction mixture was warmed to room temperature and stirred at ambient temperature for 12 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with water and the product was extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure.
  • Step-2 General Synthesis 4-((3-(4-(4-chloro-2-fluorophenyl)piperazin-l-yl)-lH-indazol-l- yl)sulfonyl)-N,N-dimethylbenzenesulfonimidamide (B-83):
  • Example B25 Synthesis of 4-((3-(4-(4-chloro-2-fluorophenyl)piperazin-l-yl)-lH-indazol-l- yl)sulfonyl)-N,N-dimethylbenzenesulfonamide (B-134)
  • Step-1 General synthesis of (4-(4-chloro-2-fluorophenyl)piperazin-l-yl)(2- fluorophenyl)methanone 5.3:
  • Step-2 General synthesis of (4-(4-chloro-2-fluorophenyl)piperazin-l-yl)(2- fluorophenyl)methanethione B25.4 j0347]
  • the reaction mixture was reflux for 12 h. The progress of reaction was monitored by TLC.
  • Step-3 General synthesis of 3-(4-(4-chloro-2-fluorophenyl)piperazin-l-yl)-lH-indazole 5.5 j0348]
  • compound (4-(4-chloro-2-fluorophenyl)piperazin-l-yl)(2- fluorophenyl)methanethione B25.4 (0.78 mg, 1.07 mmol, 1 eq) in DMSO (40 mL) was added 1M hydrazine hydrate solution in THF (12 mL, 10.7 mmol, 10 eq).
  • THF 1M hydrazine hydrate solution in THF
  • Step-4 General synthesis of 4-((3-(4-(4-chloro-2-fluorophenyl)piperazin-l-yl)-lH-indazol-l- yl)sulfonyl) -N, N-dimethylbenzene sulfonamide (B - 134)
  • reaction mixture was concentrated under reduced pressure.
  • the crude was triturated with methanol.
  • the crude was purified by prep HPLC to afford the titled compound 4-((3-(4-(4- chloro-2-fluorophenyl)piperazin- 1 -yl)- lH-indazol- 1 -yl)sulfonyl)-N,N- dimethylbenzenesulfonamide (B-134).
  • Example B26 Synthesis of 4-((3-(4-(4-chloro-2-fluorophenyl)-4-hydroxypiperidin-l-yl)-lH- pyrazolo[4,3-b]pyridin-l-yl)sulfonyl)-N,N-dimethylbenzenesulfonimidamide (B-30)
  • Step-1 Synthesis of N-((4-((3-(4-(4-chloro-2-fluorophenyl)-4-hydroxypiperidin-l-yl)-lH- pyrazolo[ 4, 3-b ]pyridin-l-yl)sulfonyl)phenyl)(dimethylamino)(oxo)-l6-sulfaneylidene)-2, 2, 2- trifluoroacetamide B26.3:
  • Step-2 Synthesis of 4-((3-(4-(4-chloro-2-fluorophenyl)-4-hydroxypiperidin-l-yl)-lH- pyrazolo[4,3-b]pyridin-l-yl)sulfonyl)-N,N-dimethylbenzenesulfonimidamide (B-30):
  • Example B27 Synthetic scheme for synthesis of 4-((3-(4-(aminomethyl)-4-(2,4- difluorophenyl)piperidin-l-yl)-lH-indazol-l-yl)sulfonyl)-N,N- dimethylbenzenesulfonamide, formate salt (B-34): Step-1: Synthesis of 4-((3-(4-(aminomethyl)-4-(2, 4-difluorophenyl)piperidin-l-yl)-lH-indazol-l- yl)sulfonyl)-N,N-dimethylbenzenesulfonamide, formate salt (B-34):
  • Example B28 Synthetic scheme for synthesis of 4-((3-(l-(4-chloro-2- fluorophenyl)piperidin-4-yl)-lH-indazol-l-yl)sulfonyl)-N,N-dimethylbenzenesulfonamide
  • Example B29 Synthetic Scheme for synthesis of l-((4-(tert-butyl)phenyl)sulfonyl)-3-(4-(5- chloro-3-fluoropyridin-2-yl)piperazin-l-yl)-lH-pyrazolo[4,3-b]pyridine (B-65) j0356J
  • Step-2 General procedure for synthesis of 3-(4-(5-chloro-3-fluoropyridin-2-yl)piperazin-l-yl)-l- tosyl-lH-pyrazolo [ 4, 3-b ] pyridine
  • B29.4 General procedure for synthesis of 3-(4-(5-chloro-3-fluoropyridin-2-yl)piperazin-l-yl)-l- tosyl-lH-pyrazolo [ 4, 3-b ] pyridine
  • Step-3 General procedure for synthesis of 3-(4-(5-chloro-3-fluoropyridin-2-yl)piperazin-l-yl)- 1 H-py razol o [4, 3 -b ] py ri dine B29.5:
  • Step-4 Synthesis of l-((4-(tert-butyl)phenyl)sulfonyl)-3-(4-(5-chloro-3-fluoropyridin-2- yl)piperazin-l-yl)-lH-pyrazolo[ 4, 3-b ] pyridine (B-65): 0359] A solution of 3-(4-(5-chloro-3-fluoropyridin-2-yl)piperazin-l-yl)-lH-pyrazolo[4,3- bjpyridine B29.5 (150 mg, 0.45 mmol, 1 eq), compound 4-(/er/-butyl)benzenesulfonyl chloride B29.6 (125 mg, 0.54 mmol, 1.2 eq), potassium hydroxide (50 mg, 0.90 mmol, 2 eq) and TB A.HSCri (23 mg, 0.07 mmol, 0.15 eq) in DCM (10 mL
  • Example B30 4-((4-(4-chloro-2-fluorophenyl)-lH-indazol-l-yl)sulfonyl)-N,N- dimethylbenzenesulfonamide (B-121):
  • Step-1 General procedure for synthesis of 4-((4-bromo-lH-indazol-l-yl)sulfonyl)-N,N- dimethylhenzenesulfonamide (B-75):
  • reaction mixture was stirred at 95°C for 12h. The progress of the reaction was monitored by TLC. After completion of the reaction, reaction mixture was evaporated to dryness. The residue was taken in ethyl acetate, washed with water, brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography/preparative HPLC to afford the desired product 4-((4-(4-chloro-2-fluorophenyl)- lH-indazol-l-yl)sulfonyl)-N,N-dimethylbenzenesulfonamide B-121.
  • Example B31 Synthetic scheme for synthesis of 4-((4-(4-chloro-2,6-difluorophenyl)-lH- indazol-l-yl)sulfonyl)-N,N-dimethylbenzenesulfonamide (B-88)
  • Step-1 General procedure for synthesis of 4-(4-chloro-2,6-difluorophenyl)-lH-indazole (B31.3):
  • Step-2 General procedure for synthesis of 4-((4-(4-chloro-2,6-difluorophenyl)-lH-indazol-l- yl)sulfonyl)-N,N-dimethylbenzenesulfonamide (B-88):
  • Example B32 Synthetic scheme for synthesis of 4-((4-(4-chloro-2-fluorophenyl)-lH- benzo[d]imidazol-l-yl)sulfonyl)-N,N-dimethylbenzenesulfonamide (B-100):
  • Step-1 General procedure for synthesis of 4-(4-chloro-2-fluorophenyl)-lH-benzo[d]imidazole (B32.3):
  • Step-2 General procedure for synthesis of 4-((4-(4-chloro-2-fluorophenyl)-lH-benzo[d]imidazol- l-yl)sulfonyl)-N,N-dimethylbenzenesulfonamide ⁇ B-100): j0367
  • 4-(4-chloro-2-fluorophenyl)-lH-benzo[d]imidazole B32.3 (0.25 g, 1.01 mmol, 1 eq)
  • 4-(N,N-dimethylsulfamoyl)benzenesulfonyl chloride B32.4 (316 mg, 1.11 mmol, 1.1 eq) in ACN (10 mL) was added pyridine (0.24 mL, 3.04 mmol, 3 eq) at 0°C.
  • Example B33 Synthesis of 4-((3-(4-chloro-2-fluorophenyl)-3-methylindolin-l- yl)sulfonyl)-N,N-dimethylbenzenesulfonamide (B-32): j0369
  • Step-1 Synthesis of methyl 2-(4-chloro-2-fluorophenyl)-2-(2-nitrophenyl)acetate (B33.3): 10370]
  • DMF 15 mL
  • NaH 427 mg, 17.82 mmol, 2 eq
  • stirred the reaction mixture for 15 min at room temperature followed by addition of l-fluoro-2-nitrobenzene (B33.2) (1.5 g, 10.69 mmol, 1.2 eq).
  • Step-3 Synthesis of 3-(4-chloro-2-fluorophenyl)-3-methylindolin-2-one (B33.5):
  • Step-4 Synthesis of 3-(4-chloro-2-fluorophenyl)-3-methylindoline (B33.6):
  • Step-5 Synthesis of 4-((3-(4-chloro-2-fluorophenyl)-3-methylindolin-l-yl)sulfonyl)-N,N- dimethylbenzenesulfonamide (B-32):
  • Example B35 Synthesis of N,N-dimethyl-4-( ⁇ 3-[(5r,8r)-3,3-dimethyl-2- oxaspiro[4.5]decan-8-yl]-lH-pyrazolo[4,3-b]pyridin-l-yl ⁇ sulfonyl)benzene-l-sulfonamide (B-200), and N,N-dimethyl-4-( ⁇ 3-[(5s,8s)-3,3-dimethyl-2-oxaspiro[4.5]decan-8-yl]-lH- pyrazolo[4,3-b]pyridin-l-yl ⁇ sulfonyl) benzene-l-sulfonamide (B-201): j0379J Step-1. Synthesis of 3,3-dimethyl-2-oxaspiro[4.5]dec-7-en-8-yl trifluoromethanesulfonate (B35.3)
  • Step-2 Synthesis of 4,4,5,5-tetramethyl-2-(l,4-dioxaspiro[4.5]dec-7-en-8-yl)-l,3,2- di oxab orol ane (B 35.5 )
  • Step-5 Synthesis of 3- ⁇ 3,3-dimethyl-2-oxaspiro[4.5]decan-8-yl ⁇ -lH-pyrazolo[4,3- bjpyridine (B35.9)
  • Triethylsilane (1.63 g, 14.1 mmol) was added dropwise to the stirred mixture of 3- ⁇ 3,3- dimethyl-2-oxaspiro[4.5]dec-7-en-8-yl ⁇ -lH-pyrazolo[4,3-b]pyridine B35.8 (0.4 g, 1.41 mmol) and 10% Pd/C (0.15 g, 0.141 mmol) in methanol (30 mL) keeping the mixture temperature below 5 °C.
  • Step-6 Synthesis of N,N-dimethyl-4-( ⁇ 3-[(5r,8r)-3,3-dimethyl-2-oxaspiro[4.5]decan-8- yl]-lH-pyrazolo[4,3-b]pyridin-l-yl ⁇ sulfonyl)benzene-l-sulfonamide (B-200, B-201)
  • Example B37 Synthesis of 4-[(3- ⁇ 3,3-dimethyl-2-oxa-8-azaspiro[4.5]decan-8-yl ⁇ -lH- indazol-l-yl)sulfonyl]-N,N-dimethylbenzene-l-sulfonamide (B-183):
  • Step-2 Synthesis of 4-[(3- ⁇ 3,3-dimethyl-2-oxa-8-azaspiro[4.5]decan-8-yl ⁇ -lH-indazol-l- yl)sulfonyl]-N,N-dimethylbenzene-l -sulfonamide (B-183)
  • Example B38 Synthesis of N,N-dimethyl-4-[(3- ⁇ 7-oxa-l-azaspiro[4.5]decan-l-yl ⁇ - lH-indazol-l-yl)sulfonyl]benzene-l-sulfonamide (B-179): 0402 j Step-1. Synthesis of l-(2-fluorobenzoyl)-7-oxa-l-azaspiro[4.5]decane (B38.3)
  • Triethylamine (1.91 g, 18.9 mmol) and 2-fluorobenzoyl chloride B38.1 (0.408 g, 1.53 mmol) were added to a solution of 7-oxa-l-azaspiro[4.5]decane B38.2 (2 g, 12.6 mmol) in dichloromethane (100 mL) at 0 °C.
  • Step-2 Synthesis of l-(2-fluorobenzenecarbothioyl)-7-oxa-l-azaspiro[4.5]decane (B38.4)
  • Lawesson's reagent (4.04 g, 10.0 mmol) was added to a stirred solution of l-(2- fluorobenzoyl)-7-oxa-l-azaspiro[4.5]decane B38.3 (2.4 g, 9.11 mmol) in toluene (100 mL). The reaction mixture was refluxed for 18 h.
  • Step-3 Synthesis of l-(lH-indazol-3-yl)-7-oxa-l-azaspiro[4.5]decane (B38.5)
  • Step-4 Synthesis of N,N-dimethyl-4-[(3- ⁇ 7-oxa-l-azaspiro[4.5]decan-l-yl ⁇ -lH-indazol- 1 -yl)sulfonyl]benzene- 1 -sulfonamide (B- 179)
  • Step-1 Synthesis of /c/7-butyl 4-ethyl-4-hydroxypiperidine-l-carboxylate (B39.2) 121 73 ⁇ 4r/-butyl 4-oxopiperidine-l-carboxylate B39.1 (20 g, 100 mmol) in tetrahydrofuran (200 mL) was added dropwise over 30 minutes to a stirred, cooled to 0 °C solution of ethyl magnesium bromide (3.0 M in tetrahydrofuran, 333 mL, 1 mol) in tetrahydrofuran (300 mL). The mixture was allowed to warm up to room temperature and stir for 4 hours.
  • Step-3 Synthesis of /er/-butyl 4-ethyl-4-methoxypiperidine-l-carboxylate (B39.4)
  • Example B40 Synthesis of N,N-dimethyl-4-( ⁇ 3-[(5s,8s)-3,3-dimethyl-2- oxaspiro[4.5]decan-8-yl]-lH-pyrrolo[3,2-c]pyridin-l-yl ⁇ sulfonyl)benzene-l-sulfonamide, (B-198) and N,N-dimethyl-4-( ⁇ 3-[(5r,8r)-3,3-dimethyl-2-oxaspiro[4.5]decan-8-yl]-lH- pyrrolo[3,2-c]pyridin-l-yl ⁇ sulfonyl)benzene-l-sulfonamide (B-190):
  • Triethylsilane (7.77 g, 66.9 mmol) was added dropwise to the stirred mixture of 3- ⁇ 3,3- dimethyl-2-oxaspiro[4.5]dec-7-en-8-yl ⁇ -lH-pyrrolo[3,2-c]pyridine B40.3 (1.89 g, 6.69 mmol) and 10% Pd/C (0.711 g) in methanol (50 mL) keeping reaction mixture temperature below 5 °C. Obtained mixture was stirred at room temperature overnight, filtered, the precipitate washed with methanol (10 mL).
  • Step-1 Synthesis of 3- ⁇ l,4-dioxaspiro[5.5]undec-8-en-9-yl ⁇ -lH-pyrrolo[3,2-b]pyridine (B41.3)
  • Step-2 Synthesis of 3- ⁇ l,4-dioxaspiro[5.5]undecan-9-yl ⁇ -lH-pyrrolo[3,2-b]pyridine (B41.4)
  • Step-3 Synthesis of N,N-dimethyl-4-( ⁇ 3-[(6s,9s)-l,4-dioxaspiro[5.5]undecan-9-yl]-lH- pyrrolo[3,2-b]pyri din- l-yl ⁇ sulfonyl)benzene-l -sulfonamide (B-185, B-186)
  • reaction mixture was concentrated, diluted with water (10 mL) and the product was extracted with ethyl acetate (10 mL x 2). The combined organic extracts were washed with water (10 mL), brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.
  • reaction mixture was hydrogenated at ambient pressure and room temperature for 16h. After completion (TLC control) the mixture was filtered through Celite pad, it was washed with methanol (30 mL). The combined filtrates were evaporated under reduced pressure to afford (2S,6R)-4-((4-(lH-pyrrolo[3,2-b]pyridin-3-yl)cyclohexyl)methyl)-2,6- dimethylmorpholine B42.7 (0.55 g, 1.67 mmol, 85% purity, 38.9% yield) that was used in next step without further purification.
  • Step-5 Synthesis of 4-((3-(4-(((2S,6R)-2,6-dimethylmorpholino)methyl)cyclohexyl)-lH- pyrrolo[3 ,2-b]pyridin- 1 -yl)sulfonyl)-N,N-dimethylbenzenesulfonamide (B- 196, B- 195)
  • reaction mixture was allowed to warm and stir at room temperature for 12 h. After reaction completion (TLC control), the reaction mixture was concentrated under reduced pressure, diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic extracts were washed with water (20 mL), brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give crude product as mixture of diastereomers.
  • Example B43 Synthesis of 4-((3-(l,4-dioxanspiro[4.5]decan-8-yl)-lH-pyrrolo[3,2- b]pyridin-l-yl)sulfonyl)-N,N-dimethylbenzenesulfonamide (B-160) and N,N-dimethyl-4-((3- (2,2,3,3-tetramethyl-l,4-dioxanspiro[4.5]decan-8-yl)-lH-pyrrolo[3,2-b]pyridin-l- yl)sulfonyl)-benzenesulfonamide (B-164):
  • Step-1 Synthesis of 3-(l,4-dioxaspiro[4.5]dec-7-en-8-yl)-lH-pyrrolo[3,2-b]pyridine (B43.3):
  • Step-2 Synthesis of 3-(l,4-dioxaspiro[4.5]decan-8-yl)-lH-pyrrolo[3,2-b]pyridine (B43.4): 0445 j To a stirred solution of 3-(l,4-dioxaspiro[4.5]dec-7-en-8-yl)-lH-pyrrolo[3,2-b]pyridine 3 (7.0 g, 2.7 mmol, 1 eq) in MeOH (50 mL) was added Pd/C (20%, 2.1 g) under nitroden atmosphere. The resulting reaction mixture was hydrogenated (70 psi) at room temperature for 12 h. The progress of the reaction was monitored by TLC.
  • Step-3 Synthesis of 4-((3-(l,4-dioxanspiro[4.5]decan-8-yl)-lH-pyrrolo[3,2-b]pyridin-l- yl)sulfonyl)-N,N-dimethylbenzenesulfonamide (B-160):
  • Step-5 Synthesis of N,N-dimethyl-4-((3-(2,2,3,3-tetramethyl-l,4-dioxanspiro[4.5]decan- 8-yl)-lH-pyrrolo[3,2-b]pyridin-l-yl)sulfonyl)-benzenesulfonamide (B-164):
  • Example B44 Synthesis of 4-((3-(4-(methoxymethyl)-4-methylcyclohexyl)-lH- pyrrolo[3,2-b]pyridin-l-yl)sulfonyl)-N,N-dimethylbenzenesulfonamide (B-215 and B-216):
  • Step-3 Synthesis of (8-methyl-l,4-dioxaspiro[4.5]decan-8-yl)methanol (B44.5): [0457] A solution 8-methyl-l,4-dioxaspiro[4.5]decane-8-carboxylate B44.4 (4.7 g, 20.6 mmol) in THF (50 mL) was cooled to 0 °C and Lithium aluminium hydride (1M in THF, 41.2 niL, 41.2 mmol) was added dropwise. The mixture was stirred at room temperature for 1.5 h. After completion of reaction, the reaction was cooled to 0 °C and quenched with sat. aq. Na2SC>4.
  • Step-4 Procedure for the synthesis of 8-(methoxymethyl)-8-m ethyl- 1,4- dioxaspiro[4.5]decane (B44.6):
  • Step-5 Synthesis of 4-(methoxymethyl)-4-methylcyclohexan-l-one (B44.7):
  • Step-6 Synthesis of 3-(4-(methoxymethyl)-4-methylcyclohex-l-en-l-yl)-lH-pyrrolo[3,2- bjpyridine (B44.9): 0463 j
  • 4-(methoxymethyl)-4-methylcyclohexan-l-one B44.7 (0.9 g, 5.7 mmol) in MeOH (18 mL) were added lH-pyrrolo[3,2-b]pyridine (B44.8) (0.74 g, 6.3 mmol) and KOH (0.96 g, 17.3 mmol).
  • the reaction mixture was allowed to reflux for 5 h. The progress of the reaction was monitored by TLC.
  • Step-8 Synthesis of 4-((3-(4-(methoxymethyl)-4-methylcyclohexyl)-lH-pyrrolo[3,2- b]pyridin-l-yl)sulfonyl)-N,N-dimethylbenzenesulfonamide (two isomers: B-215 and B-216): [0467) To a stirred solution of compound B44.10 (1 eq) in DCM (5 mL), KOH (2.5 eq) and TBA.HSO4 (0.2 eq) were added at 0 °C. To the resulting reaction mixture compound (B44.11) (1.3 eq) was added at 0 °C.
  • Example B45 Synthesis of 4-((3-(4-((difluoromethoxy)methyl)piperidin-l-yl)-lH- indazol-l-yl)sulfonyl)-N,N-dimethylbenzenesulfonamide (B-159):
  • Example B46 Synthesis of N,N-dimethyl-4-((3-(piperidin-l-yl)-lH-indol-l- yl)sulfonyl)-benzenesulfonamide (B-174): j0473J Step-1: Synthesis of l-(3-(piperidin-l-yl)-lH-indol-l-yl)ethan-l-one (B46.3):
  • Example B47 Synthesis of N,N-dimethyl-4-((3-methyl-2-oxo-3-(tetrahydro-2H- pyran-4-yl)indolin-l-yl)sulfonyl)benzenesulfonamide (B-153): . .
  • Step-1 Synthesis of 3 -methyl-3 -(tetrahydro-2H-pyran-4-yl)indolin-2-one (B47.3):
  • Step-2 Synthesis of N,N-dimethyl-4-((3-methyl-2-oxo-3-(tetrahydro-2H-pyran-4- yl)indolin- 1 -yl)sulfonyl)benzenesulfonamide (B-153):
  • Example B48 Synthesis of l-((2,3-dihydro-lH-inden-5-yl)sulfonyl)-3-methyl-3-
  • Step-1 Synthesis of 3 -methyl-3 -(tetrahydro-2H-pyran-4-yl)indoline (B48.2): j0485J
  • 3 -methyl-3 -(tetrahydro-2H-pyran-4-yl)indolin-2-one B48.1 (1 g, 4.3 mmol, 1 eq) in THF (50 mL) was added a 1 M solution of lithium aluminium hydride (12.9 mL, 12.9 mmol, 3 eq) at 0 °C.
  • the reaction mixture was warmed to room temperature and stirred at 60°C for 8 h. The progress of the reaction was monitored by TLC.
  • Step-2 Synthesis of l-((2,3-dihydro-lH-inden-5-yl)sulfonyl)-3-methyl-3-(tetrahydro-2H- pyran-4-yl)indoline (B-176): j0487l To a stirred solution of 3 -methyl-3 -(tetrahydro-2H-pyran-4-yl)indoline B48.2 (150 mg, 0.6 mmol, 1 eq) in acetonitrile (10 mL) were added pyridine (66 mg, 1.3 mmol, 2 eq) and 2,3-dihydro- lH-indene-5-sulfonyl chloride B48.3 (179 mg, 0.8 mmol, 1.2 eq) at room temperature and the reaction mixture was stirred for 16 h.
  • Example B49 Synthesis of 4-((3-((lr,4r)-4-(methoxymethyl)-4-methylcyclohexyl)- lH-pyrazolo[4,3-b]pyridine-l-yl)sulfonyl)-N,N-dimethylbenzenesulfonamide (B-166) and 4- ((3-((ls,4s)-4-(methoxymethyl)-4-methylcyclohexyl)-lH-pyrazolo[4,3-b]pyridine-l- yl)sulfonyl)-N,N-dimethylbenzenesulfonamide (B-167):
  • Step-1 Synthesis of 4-(methoxymethyl)-4-methylcyclohex-l-en-l-yl 1, 1,2, 2, 3, 3, 4,4,4- nonafluorobutane- 1 -sulfonate (B49.3 ) :
  • the resultant mixture was degassed using argon for for 30 min.
  • the reaction mixture was stirred at 90 °C for 12 h.
  • the progress of the reaction was monitored by TLC.
  • the reaction mixture was concentrated under reduced pressure to dryness.
  • the crude product was purified by column chromatography to afford 2-(4-(methoxymethyl)-4-methylcyclohex-l-en-l- yl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane B49.4 (1.82 g, 81.25%).
  • Step-3 Synthesis of 3-(4-(methoxymethyl)-4-methylcyclohex-l-en-l-yl)-lH- pyrazolo[4,3-b]pyridne (B49.6):
  • Step-4 Synthesis of 3-(4-(methoxymethyl)-4-methylcyclohexyl)-lH-pyrazolo[4,3- bjpyridine (B49.7):
  • 0496j To a stirred solution of 3-(4-(methoxymethyl)-4-methylcyclohex-l-en-l-yl)-lH- pyrazolo[4,3-b]pyridne B49.6 (0.23 g, 8.94 mmol, 1 eq) in MeOH (10 mL) was added Pd/C (10%, 0.035 g) under nitroden atmosphere. The resulting reaction mixture was hydrogenated (70 psi) at room temperature for 12 h.
  • Step-5 Procedure for the synthesis of 4-((3-((lr,4r)-4-(methoxymethyl)-4- methylcyclohexyl)-lH-pyrazolo[4,3-b]pyridine-l-yl)sulfonyl)-N,N-dimethylbenzenesulfonamide (B-166) and 4-((3-((ls,4s)-4-(methoxymethyl)-4-methylcyclohexyl)-lH-pyrazolo[4,3-b]pyridine-
  • Example B50 Synthesis of tert- butyl 4-(l-((4-(methylsulfonyl)phenyl)sulfonyl)-lH- pyrazolo[4,3-b]pyridin-3-yl)piperazine-l-carboxylate (B50.7):
  • Step-1 Synthesis of te/7-butyl 4-(3-fluoropicolinoyl)piperazine-l-carboxylate (B50.3): jOSOIJ
  • 3-fluoropicolinic acid B50.1 (1 eq) and /er/-butyl piperazine-1- carboxylate (B50.2) (1.1 eq) in DMF was added HATU (2 eq) followed by DIPEA (3 eq) at room temperature and the reaction mixture was stirred for overnight. The progress of reaction was monitored by TLC. After completion, the reaction mixture was diluted with water and extracted with ethyl acetate.
  • Step-2 Synthesis of /er/-butyl 4-(3-fluoropyridine-2-carbonothioyl)piperazine-l- carboxylate (B50.4):
  • 0503j To a stirred solution of tert- butyl 4-(3-fluoropicolinoyl)piperazine-l-carboxylate B50.3 (1 eq) in toluene was added Lawesson’s reagent (1.5 eq). The reaction mixture was heated at 120 °C for 3 h. The progress of reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate.
  • Step-3 Synthesis of /ert-butyl 4-(lH-pyrazolo[4,3-b]pyridine-3-yl)piperazine-l- carboxylate (B50.5): 05051
  • a stirred solution of tert- butyl 4-(3-fluoropyridine-2-carbonothioyl)piperazine-l- carboxylate B50.4 (1 eq) in DMSO was added a 1 M solution of hydrazine in THF (5.7 eq). The reaction mixture was stirred at 130 °C for overnight. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate.
  • Step-4 Synthesis of /ert-butyl 4-(l-((4-(methylsulfonyl)phenyl)sulfonyl)-lH- pyrazolo[4,3-b]pyridin-3-yl)piperazine-l-carboxylate (B50.7):
  • Example B51 Synthesis of 4-((3-(3-oxa-9-azaspiro[5.5]undecan-9-yl)-lH-indazol-l- yl)sulfonyl)-N,N-dimethylbenzenesulfonamide (B-168):
  • Step-1 Synthesis of 3-bromo-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-indazole (B51.2): j0510]
  • 3- bromo-lH-indazole B51.1 5.0 g, 25.00 mmol, 1 eq
  • SEM-CI 4.8 mL, 27.0 mmol, 1.1 eq
  • Step-1 Synthesis of 3-methylindolin-2-one (B52.2):
  • Step-2 Synthesis of 3 -methyl-3 -morpholinoindolin-2-one (B52.4):

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Abstract

The present invention provides compounds, pharmaceutically acceptable compositions thereof, and methods of using the same.

Description

TRPML MODULATORS
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] The present application claims priority to U.S. Provisional Application No. 63/119,895, filed December 1, 2020; U.S. Provisional Application No. 62/950,799, filed December 19, 2019; and U.S. Provisional Application No. 62/950,818, filed December 19, 2019, each of which is incorporated herein in its entirety.
BACKGROUND
[0002] Transient Receptor Potential Mucolipin-1 (also known as TRPML1 or ML1) is a Ca2+ channel in the lysosome that regulates certain aspects of lysosome trafficking, including autophagy. See Wang, et al. , PNAS, E1373-E1381 (March 2, 2015). In particular, TRPML1 is an inwardly rectifying current channel that transports cations from the lumen of the lysosome to the cytosol. See Di Paolda, et al, Cell Calcium 69:112-121 (2018). Release of Ca2+ from the lysosome via TRPML 1 modulates transcription factor EB activity. See Medina, et al. , Nat. Cell. Biol., 17(3):288-299 (2015).
SUMMARY
{0003] It has recently been discovered that upregulation of autophagy is beneficial to patients suffering from a number of diseases and disorders. For example, it has been reported that inducing autophagy promotes clearance of hepatotoxic alpha- 1 -anti -trypsin (ATZ) in the liver. See Pastore, et al., EMBO Mol. Med. 5(3): 397-412 (Mar. 2013). Moreover, autophagy was recently found to be useful in the treatment of neurodegenerative disorders, cancer, and heart disease. See Pierzynowska, et al, Metab. Brain Dis., 33(4); 989-1008 (2018) (discussing neurodegenerative disorders); Nelson & Shacka, Curr. Pathobiol. Rep., 1(4): 239-245 (2013) (discussing cancer); Sciaretta, et al, Annual Review of Physiology, 80:1-26 (2018) (discussing heart disease); Maiuri & Kroemer, Cell Death & Differentiation, 26: 680-689 (2019) (discussing therapeutic applications of autophagy, generally).
[0004] The present disclosure provides, among other things, technologies for regulating (e.g., up- regulating) autophagy. For example, in some embodiments, the present disclosure demonstrates effectiveness of certain approaches to TRPMLl modulation (e.g., TRPMLl agonism) in enhancing autophagy. Thus, among other things, the present disclosure demonstrates that targeting TRPMLl as described herein can enhance autophagy. 0005 j The present disclosure also provides certrain technologies for use in medicine, and in particular for treating certain diseases, disorders or conditions and/or for identifying, characterizing, and/or manufacturing certain agents and/or compositions or that comprise or deliver them that are useful in treating such diseases, disorders or conditions.
[0006 J In some embodiments, the present disclosure demonstrates that modulating (e.g., agonizing) TRPLM1 and/or otherwise enhancing autophagy is useful in the treatment of certain diseases, disorders or conditions.
[00071 It is, therefore, desirable to identify methods and modes of promoting autophagy. Given TRPMLL s role in autophagy, described herein are TRPMLl modulators useful for promoting autophagy and/or treating certain diseases, disorders, or conditions.
[00081 In particular, the present application provides technologies useful for modulating TRPMLl.
[00091 In some embodiments, the present application provides compounds having a structure as set forth in Formula I:
Z-L^Cy-A-L^V
I or a pharmaceutically acceptable salt thereof, wherein
A is 9- to 12-membered bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, or 9- to 16- membered bicyclic or polycyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S, wherein A is substituted with 0, 1, 2, 3 or 4 Ra;
Cy is absent or a bivalent moiety selected from 4- to 12-membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, P, and S, 5- to 12-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, P, and S, Ci-6 aliphatic, or C3-12 cycloalkyl, wherein Cy is optionally substituted with one or more of R1;
L1 is absent, -NR3-, -O-, -S-, Ci-6 alkylenyl, C2-6 alkynylenyl, -NR3-CI-6 alkylenyl,-0-Ci-6 alkylenyl, -C(0)Co-e alkylenyl; -C(0)NR3-, or -C(0)-C(0)-;
L2 is absent, -(NR3)s-S(0)-Co-6 alkylenyl-, -(NR3)s-S(0)2-Co-6 alkylenyl-, -(NR3)s-S(0)(NR3)-, -S(0)2-NR3-, -NR3-CI-6 haloalkylenyl, -(NR3)s-P(0)(R3)-, -Ci-e alkylenyl-S(O)-, -Ci-e alkylenyl-S(0)2-, -C(0)-(NR3)s-, -(NR3)s-C(0)-, or an optionally substituted 4- to 12- membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S;
V is selected from Ci-6 aliphatic, Ce-u aryl, 4- to 12-membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S, 5- to 12-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S,
5- to 12-membered monocyclic of bicyclic aryl, and C3-12 cycloalkyl, wherein Vis substituted with (R6)m;
Z is Ci-6 aliphatic, 2- to 10-membered heteroaliphatic, P(0)(R3)2, -C(0)Ci-6 aliphatic, C(0)N(R3)2, C6-12 aryl, C3-12 cycloalkyl, 4- to 16-membered monocyclic or polycyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S, or 5- to 12-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, wherein Z is substituted with (R2)q; each Ra is independently halo, oxo, or optionally substituted Ci-6 aliphatic; each R1 is independently selected from N(R3)2, OH, CN, C(0)NHR3, and an optionally substituted group selected from Ci-6 aliphatic and N(R3)-C(0)-CI-6 alkyl; each R2 is independently selected from halo, CN, C(0)0H, and an optionally substituted group selected from Ci-6 aliphatic, C(0)Ci-6 aliphatic, and O-Ci-6 aliphatic; each R3 is independently selected from H and optionally substituted Ci-6 aliphatic; each R5 is independently selected from Ci-6 alkyl, -N(R3)2, -O-Ci-6 alkyl, C(0)-Ci-6 alkyl, P(0)(Ci-6 alkyl)2, C3-12 cycloalkyl, and 5- to 12-membered heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S, wherein R5 is optionally substituted with one or more substituents selected from halo and OH; each R6 is halo, -S(0)-R5, -S(0)2-R5, -S(0)(NH)-R5, -CN, -C(0)-R5, -C(0)0-R5, -C(0)-NH(R5), -C(0)-N(R5)2, -P(0)(R5)2, or an optionally substituted group selected from O-Ci-6 alkyl, Ci-6 alkyl, and C6-12 aryl; m is 0, 1, 2, 3, or 4; n is 0 or 1; q is 0, 1, 2, 3, or 4; and s is 0 or 1. jOOlOJ In some embodiments, the present application provides compounds having a structure as set forth in Formula G :
Figure imgf000005_0001
or a pharmaceutically acceptable salt thereof, wherein
A’ is a fused phenyl or 6-membered heteroaryl ring comprising 1 to 3 nitrogen atoms, optionally substituted with Ra;
X1 and X7 are each independently selected from N, NRa, C, CRa, and C(Ra)2, as valency permits, wherein X1 and X7 are N, C, or CRa when bound to Cy-L'-Z;
Cy is absent, or a bivalent moiety selected from 4- to 12-membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, P, and S, 5- to 12-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, Ci-6 aliphatic, Ce-u aryl, or C3-12 cycloalkyl, wherein Cy is optionally substituted with one or more of R1;
L1 is absent, -NR3-, -S-, C(0)NR3-, -C(0)-C(0)-, or an optionally substituted bivalent moiety selected from Ci-6 alkylenyl, C2-6 alkenylenyl, C2-6 alkynylenyl, C3-6 cycloalkyl, -NR3-CI-6 alkylenyl, -O-Co-6 alkylenyl, and -C(0)Co-6 alkylenyl;
L2 is an optionally substituted bivalent moiety selected from -(NR3)s-S(0)-Co-6 alkylenyl-, - (NR3)S-S(0)2-CO-6 alkylenyl-, -Ci-6 alkylenyl-S(0)-(NR3)s-, -Ci-6 alkylenyl-S(0)2-(NR3)s-, - (NR3)s-Co-6 alkylenyl, -(NR3)s-C(0)-Co-6 alkylenyl, and 4- to 12-membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S;
V is Ci-6 aliphatic, C6-12 aryl, C3-12 cycloalkyl, 4- to 12-membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S, 5- to 12-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, or 5- to 16-membered monocyclic or polycyclic aryl, wherein Vis substituted with (R6)m;
Z is Ci-6 aliphatic, 2- to 10-membered heteroaliphatic, P(0)(R3)2, -C(0)Ci-6 aliphatic, C(0)N(R3)2, C6-12 aryl, C3-12 cycloalkyl, 4- to 16-membered monocyclic or polycyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S, or 5- to 12-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, wherein Z is substituted with (R2)q; each Ra is independently H, halo, CN, oxo, or an optionally substituted group selected from Ci-6 aliphatic and O-Ci-6 aliphatic; each R1 is independently selected from halo, oxo, N(R3)2, -OH, -CN, -C(0)N(R3)2, and an optionally substituted group selected from Ci-6 aliphatic and N(R3)-C(0)-CI-6 aliphatic; each R2 is independently selected from halo, oxo, -CN, -OH, 0-R2a, -C(0)-R2a, -C(0)0-R2a, and an optionally group selected from Ci-6 aliphatic, C6-12 aryl, and 5- to 12-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S; each R2a is independently H or an optionally substituted group selected from Ci-6 aliphatic, C3-12 cycloalphatic, and 4- to 12-membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S; each R3 is independently selected from H and optionally substituted Ci-6 aliphatic; each R5 is independently -OR3, C(0)-R3, P(0)(R3)2, -N(R3)2, or an optionally substituted group selected from from Ci-6 aliphatic, C3-12 cycloalkyl, and 4- to 12-membered heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S; each R6 is halo, -S(0)-R5, -S(0)2-R5, -S(0)(NH)-R5, -CN, -C(0)-R5, -C(0)0-R5, -C(0)-NH(R5), -C(0)-N(R5)2, -P(0)(R5)2, or an optionally substituted group selected from O-Ci-6 aliphatic, Ci-6 aliphatic, C3-C12 cycloalkyl, and C6-12 aryl; m is 0, 1, 2, 3, or 4; q is 0, 1, 2, 3, or 4; and s is 0 or 1.
JOOl l] In some embodiments, the present application provides compounds having a structure as set forth in Formula II:
Figure imgf000006_0001
II or a pharmaceutically acceptable salt thereof, wherein
Xr , X2”, and X7 are each independently selected from N, NRa, C, and CRax, wherein Xr , X2”, and X7 are N, C, or CRa when bound to Cy-L'-Z or L2-V X3”, X4 , X5 , and X6 are each independently selected from N, C, and CRa, wherein X3 , X4 , X5 , and X6 are N or C when bound to Cy-L'-Z or L2-V;
Cy is absent or a bivalent moiety selected from 4- to 12-membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, P, and S, 5- to 12-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, P,and S, Ci-6 aliphatic, Ce-u aryl, or C3-12 cycloalkyl, wherein Cy is optionally substituted with one or more of R1;
L1 is absent, -NR3-, -0-, -S-, Ci-6 alkylenyl, C2-6 alkynylenyl, -NR3-CI-6 alkylenyl,-0-Ci-6 alkylenyl, -C(0)Co-e alkylenyl; -C(0)NR3-, or -C(0)-C(0)-;
L2 is -(NR3)S-S(0)-CO-6 alkylenyl-, -(NR3)s-S(0)2-Co-6 alkylenyl-, -(NR3)s-S(0)(NR3)-, -S(0)2-NR3-, -NR3-CI-6 haloalkylenyl, -(NR3)s-P(0)(R3)-, -Ci-e alkylenyl-S(O)-, -Ci-e alkylenyl-S(0)2-, -C(0)-(NR3)s-, -(NR3)s-C(0)-, or an optionally substituted 4- to 12- membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S;
V is selected from Ci-6 aliphatic, C6-12 aryl, 4- to 12-membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S, 5- to 12-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S,
5- to 12-membered monocyclic of bicyclic aryl, and C3-12 cycloalkyl, wherein Vis substituted with (R6)m;
Z is Ci-6 aliphatic, 2- to 10-membered heteroaliphatic, P(0)(R3)2, -C(0)Ci-6 aliphatic, C(0)N(R3)2, C6-12 aryl, C3-12 cycloalkyl, 4- to 16-membered monocyclic or polycyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S, or 5- to 12-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, wherein Z is substituted with (R2)q; each Ra is independently halo, oxo, or optionally substituted Ci-6 aliphatic; each R1 is independently selected from N(R3)2, OH, CN, C(0)NHR3, and an optionally substituted group selected from Ci-6 aliphatic and N(R3)-C(0)-CI-6 alkyl; each R2 is independently selected from halo, CN, C(0)0H, and an optionally substituted group selected from Ci-6 aliphatic, C(0)Ci-6 aliphatic, and O-Ci-6 aliphatic; each R3 is independently selected from H and optionally substituted Ci-6 aliphatic; each R5 is independently selected from Ci-6 alkyl, -N(R3)2, -O-Ci-6 alkyl, C(0)-Ci-6 alkyl, P(0)(Ci-6 alkyl)2, C3-12 cycloalkyl, and 5- to 12-membered heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S, wherein R5 is optionally substituted with one or more substituents selected from halo and OH; each R6 is halo, -S(0)-R5, -S(0)2-R5, -S(0)(NH)-R5, -CN, -C(0)-R5, -C(0)0-R5, -C(0)-NH(R5), -C(0)-N(R5)2, -P(0)(R5)2, or an optionally substituted group selected from O-Ci-6 alkyl, Ci-6 alkyl, and C6-12 aryl; m is 0, 1, 2, 3, or 4; q is 0, 1, 2, 3, or 4; and s is 0 or 1. 0012] In some embodiments, the present disclosure provides a compound of Formula IF:
Figure imgf000008_0001
or a pharmaceutically acceptable salt thereof, wherein
X1 , X2 , and X7 are each independently selected from N, NRa, C, CRa, and C(Ra)2 as valency permits, wherein Xr , X2 , and X7 are N, C, or CRa when bound to Cy-L'-Z or L2-V X3”, X4 , X5 , and X6 are each independently selected from N, C, and CRa, wherein X3 , X4 , X5 , and X6 are C when bound to -Cy-L'-Z or -L2-V;
Cy is absent, or a bivalent moiety selected from 4- to 12-membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, P, and S, 5- to 12-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, Ci-6 aliphatic, C6-12 aryl, or C3-12 cycloalkyl, wherein Cy is optionally substituted with one or more of R1;
L1 is absent, -NR3-, -S-, C(0)NR3-, -C(0)-C(0)-, or an optionally substituted bivalent moiety selected from Ci-6 alkylenyl, C2-6 alkynylenyl, C3-6 cycloalkyl, -NR3-CI-6 alkylenyl, -O-Co-6 alkylenyl, and -C(0)Co-6 alkylenyl; L2 is an optionally substituted bivalent moiety selected from -(NR3)s-S(0)-Co-6 alkylenyl-, - (NR3)S-S(0)2-CO-6 alkylenyl-, -Ci-6 alkylenyl-S(0)-(NR3)s-, -Ci-6 alkylenyl-S(0)2-(NR3)s-, - (NR3)s-Co-6 alkylenyl, -(NR3)s-C(0)-Co-6 alkylenyl, and 4- to 12-membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S;
V is Ci-6 aliphatic, Ce-u aryl, C3-12 cycloalkyl, 4- to 12-membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S, 5- to 12-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, or 5- to 16-membered monocyclic or polycyclic aryl, wherein Vis substituted with (R6)m;
Z is Ci-6 aliphatic, 2- to 10-membered heteroaliphatic, P(0)(R3)2, -C(0)Ci-6 aliphatic, C(0)N(R3)2, C6-12 aryl, C3-12 cycloalkyl, 4- to 16-membered monocyclic or polycyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S, or 5- to 12-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, wherein Z is substituted with (R2)q; each Ra is independently H, halo, CN, oxo, or an optionally substituted group selected from Ci-6 aliphatic and O-Ci-6 aliphatic; each R1 is independently selected from halo, oxo, N(R3)2, -OH, -CN, -C(0)N(R3)2, and an optionally substituted group selected from Ci-6 aliphatic and N(R3)-C(0)-CI-6 aliphatic; each R2 is independently selected from halo, oxo, -CN, -OH, 0-R2a, -C(0)-R2a, -C(0)0-R2a, and an optionally group selected from Ci-6 aliphatic, C6-12 aryl, and 5- to 12-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S; each R2a is independently H or an optionally substituted group selected from Ci-6 aliphatic, C3-12 cycloalphatic, and 4- to 12-membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S; each R3 is independently selected from H and optionally substituted Ci-6 aliphatic; each R5 is independently -OR3, C(0)-R3, P(0)(R3)2, -N(R3)2, or an optionally substituted group selected from from Ci-6 aliphatic, C3-12 cycloalkyl, and 4- to 12-membered heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S; each R6 is halo, -S(0)-R5, -S(0)2-R5, -S(0)(NH)-R5, -CN, -C(0)-R5, -C(0)0-R5, -C(0)-NH(R5), -C(0)-N(R5)2, -P(0)(R5)2, or an optionally substituted group selected from O-Ci-6 aliphatic, Ci-6 aliphatic, C3-C12 cycloalkyl, and C6-12 aryl; m is 0, 1, 2, 3, or 4; q is 0, 1, 2, 3, or 4; and s is 0 or 1.
DEFINITIONS
|0013! Agonist. As will be understood by those skilled in the art, the term “agonist” generally refers to an agent whose presence or level correlates with elevated level or activity of a target, as compared with that observed absent the agent (or with the agent at a different level). In some embodiments, an agonist is one whose presence or level correlates with a target level or activity that is comparable to or greater than a particular reference level or activity (e.g., that observed under appropriate reference conditions, such as presence of a known agonist, e.g., a positive control). In some embodiments, an agonist may be a direct agonist in that it exerts its influence directly on (e.g., interacts directly with) the target; in some embodiments, an agonist may be an indirect agonist in that it exerts its influence indirectly (e.g., by acting on, such as interacting with, a regulator of the target, or with some other component or entity. 00 ί 41 Aliphatic: The term “aliphatic” refers to a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as “cycloaliphatic”), that has a single point or more than one points of attachment to the rest of the molecule. Unless otherwise specified, aliphatic groups contain 1-12 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-6 aliphatic carbon atoms (e.g., Ci-6). In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms (e.g., Ci- 5). In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms (e.g., C1-4). In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms (e.g., C1-3), and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms (e.g., C1-2). In some embodiments, “cycloaliphatic” refers to a monocyclic C3-8 hydrocarbon or a bicyclic C7-10 hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point or more than one points of attachment to the rest of the molecule. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkylenyl, alkenyl, alkenylenyl, alkynyl, or alkynylenyl groups and hybrids thereof. A preferred aliphatic group is Ci-6 alkyl. In some embodiments, aliphatic is multivalent (i.e., has multiple points of attachment to the rest of the molecule). In some embodiments, aliphatic is bivalent (i.e., has two points of attachment to the rest of the molecule). An example bivalent aliphatic group can be referred to as “alkylenyl”. fOO!Sj Alkyl: The term “alkyl”, used alone or as part of a larger moiety, refers to a saturated, optionally substituted straight or branched chain or cyclic hydrocarbon group having (unless otherwise specified) 1-12, 1-10, 1-8, 1-6, 1-4, 1-3, or 1-2 carbon atoms (e.g., Ci-12, Ci-10, Ci-8, Ci- 6, Ci-4, Ci-3, or C1-2). Exemplary alkyl groups include methyl, ethyl, propyl, butyl, pentyl, hexyl, and heptyl. The term “cycloalkyl” refers to an optionally substituted saturated ring system of about 3 to about 10 ring carbon atoms. Exemplary monocyclic cycloalkyl rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
10016) Alkylene: The term "alkylene" and “alkylenyl” are used interchangeably and refers to a bivalent alkyl group. In some embodiments, “alkylene” is a bivalent straight or branched alkyl group. In some embodiments, an "alkylene chain" is a polymethylene group, i.e., -(CH2)n-, wherein n is a positive integer, e.g., from 1 to 6, from 1 to 4, from 1 to 3, from 1 to 2, or from 2 to 3. An optionally substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms is optionally replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group and also include those described in the specification herein. It will be appreciated that two substituents of the alkylene group may be taken together to form a ring system. In certain embodiments, two substituents can be taken together to form a 3- to 7-membered ring. The substituents can be on the same or different atoms. The term “haloalkylenyl” refers to an straight-chain or branched alkylenyl group substituted by one or more halogen atoms (e.g., one, two, three or four halo, such as fluoro, iodo, bromo, or chi or o).
10017! Alkenyl: The term “alkenyl”, used alone or as part of a larger moiety, refers to an optionally substituted straight or branched chain or cyclic hydrocarbon group having at least one double bond and having (unless otherwise specified) 2-12, 2-10, 2-8, 2-6, 2-4, or 2-3 carbon atoms (e.g., C2-12, C2-10, C2-8, C2-6, C2-4, or C2-3). Exemplary alkenyl groups include ethenyl, propenyl, butenyl, pentenyl, hexenyl, and heptenyl. The term “cycloalkenyl” refers to an optionally substituted non-aromatic monocyclic or multicyclic ring system containing at least one carbon- carbon double bond and having about 3 to about 10 carbon atoms. Exemplary monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl, and cycloheptenyl. jOOlSJ Alkenylene: The term "alkenylene" and “alkenylenyl” are used interchangeably and refers to a bivalent alkenyl group. In some embodiments, “alkenylene” is a bivalent straight or branched alkenyl group.
|0019j Alkynyl: The term “alkynyl”, used alone or as part of a larger moiety, refers to an optionally substituted straight or branched chain hydrocarbon group having at least one triple bond and having (unless otherwise specified) 2-12, 2-10, 2-8, 2-6, 2-4, or 2-3 carbon atoms (e.g., C2-12, C2-10, C2-8, C2-6, C2-4, or C2-3). Exemplary alkynyl groups include ethynyl, propynyl, butynyl, pentynyl, hexynyl, and heptynyl.
(0020] Alkynylene. The term "alkynylene" and “alkynylenyl” are used interchangeably and refers to a bivalent alkynyl group. In some embodiments, “alkynylene” is a bivalent straight or branched alkynyl group.
(0021 ] Analog: As used herein, the term “analog” refers to a substance that shares one or more particular structural features, elements, components, or moieties with a reference substance. Typically, an “analog” shows significant structural similarity with the reference substance, for example sharing a core or consensus structure, but also differs in certain discrete ways. In some embodiments, an analog is a substance that can be generated from the reference substance, e.g., by chemical manipulation of the reference substance. In some embodiments, an analog is a substance that can be generated through performance of a synthetic process substantially similar to (e.g., sharing a plurality of steps with) one that generates the reference substance. In some embodiments, an analog is or can be generated through performance of a synthetic process different from that used to generate the reference substance.
(0022] Antagonist. As will be understood by those skilled in the art, the term “antagonist” generally refers to an agent whose presence or level correlates with decreased level or activity of a target, as compared with that observed absent the agent (or with the agent at a different level). In some embodiments, an antagonist is one whose presence or level correlates with a target level or activity that is comparable to or less than a particular reference level or activity (e.g., that observed under appropriate reference conditions, such as presence of a known antagonist, e.g., a positive control). In some embodiments, an antagonist may be a direct antagonist in that it exerts its influence directly on (e.g., interacts directly with) the target; in some embodiments, an antagonist may be an indirect antagonist in that it exerts its influence indirectly (e.g., by acting on, such as interacting with, a regulator of the target, or with some other component or entity.
[0023] Aryl: The term “aryl” refers to monocyclic and bicyclic ring systems having a total of five to fourteen ring members (e.g., C5-14), wherein at least one ring in the system is aromatic and wherein each ring in the system contains three to seven ring members. In some embodiments, an “aryl” group contains between six and twelve total ring members (e.g., C6-12). The term “aryl” may be used interchangeably with the term “aryl ring”. In certain embodiments of the present invention, “aryl” refers to an aromatic ring system which includes, but not limited to, phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents. Unless otherwise specified, “aryl” groups are hydrocarbons. In some embodiments, an “aryl” ring system is an aromatic ring (e.g., phenyl) that is fused to a non-aromatic ring (e.g., cycloalkyl). Examples of aryl rings include that are fused include
Figure imgf000013_0001
. j0024J Associated: Two events or entities are “associated” with one another, as that term is used herein, if the presence, level and/or form of one is correlated with that of the other. For example, a particular entity (e.g., polypeptide, genetic signature, metabolite, microbe, etc) is considered to be associated with a particular disease, disorder, or condition, if its presence, level and/or form correlates with incidence of and/or susceptibility to the disease, disorder, or condition (e.g., across a relevant population). In some embodiments, two or more entities are physically “associated” with one another if they interact, directly or indirectly, so that they are and/or remain in physical proximity with one another. In some embodiments, two or more entities that are physically associated with one another are covalently linked to one another; in some embodiments, two or more entities that are physically associated with one another are not covalently linked to one another but are non-covalently associated, for example by means of hydrogen bonds, van der Waals interaction, hydrophobic interactions, magnetism, and combinations thereof.
[0025] Biological sample: As used herein, the term “biological sample” typically refers to a sample obtained or derived from a biological source (e.g., a tissue or organism or cell culture) of interest, as described herein. In some embodiments, a source of interest comprises an organism, such as an animal or human. In some embodiments, a biological sample is or comprises biological tissue or fluid. In some embodiments, a biological sample may be or comprise bone marrow; blood; blood cells; ascites; tissue or fine needle biopsy samples; cell-containing body fluids; free floating nucleic acids; sputum; saliva; urine; cerebrospinal fluid, peritoneal fluid; pleural fluid; feces; lymph; gynecological fluids; skin swabs; vaginal swabs; oral swabs; nasal swabs; washings or lavages such as a ductal lavages or broncheoalveolar lavages; aspirates; scrapings; bone marrow specimens; tissue biopsy specimens; surgical specimens; feces, other body fluids, secretions, and/or excretions; and/or cells therefrom, etc. In some embodiments, a biological sample is or comprises cells obtained from an individual. In some embodiments, obtained cells are or include cells from an individual from whom the sample is obtained. In some embodiments, a sample is a “primary sample” obtained directly from a source of interest by any appropriate means. For example, in some embodiments, a primary biological sample is obtained by methods selected from the group consisting of biopsy (e.g., fine needle aspiration or tissue biopsy), surgery, collection of body fluid (e.g., blood, lymph, feces etc.), etc. In some embodiments, as will be clear from context, the term “sample” refers to a preparation that is obtained by processing (e.g., by removing one or more components of and/or by adding one or more agents to) a primary sample. For example, filtering using a semi-permeable membrane. Such a “processed sample” may comprise, for example, nucleic acids or proteins extracted from a sample or obtained by subjecting a primary sample to techniques such as amplification or reverse transcription of mRNA, isolation and/or purification of certain components, etc.
10026) Biomarker. The term “biomarker” is used herein, consistent with its use in the art, to refer to a to an entity (or form thereof) whose presence, or level, correlates with a particular biological event or state of interest, so that it is considered to be a “marker” of that event or state. To give but a few examples, in some embodiments, a biomarker may be or comprise a marker for a particular disease state, or for likelihood that a particular disease, disorder or condition may develop, occur, or reoccur. In some embodiments, a biomarker may be or comprise a marker for a particular disease or therapeutic outcome, or likelihood thereof. Thus, in some embodiments, a biomarker is predictive, in some embodiments, a biomarker is prognostic, in some embodiments, a biomarker is diagnostic, of the relevant biological event or state of interest.
10027) Carrier: As used herein, the term “carrier” refers to a diluent, adjuvant, excipient, or vehicle with which a composition is administered. In some exemplary embodiments, carriers can include sterile liquids, such as, for example, water and oils, including oils of petroleum, animal, vegetable or synthetic origin, such as, for example, peanut oil, soybean oil, mineral oil, sesame oil and the like. In some embodiments, carriers are or include one or more solid components. (002$) Combination therapy: As used herein, the term “combination therapy” refers to those situations in which a subject is simultaneously exposed to two or more therapeutic regimens (e.g., two or more therapeutic agents or modality(ies)). In some embodiments, the two or more regimens may be administered simultaneously; in some embodiments, such regimens may be administered sequentially (e.g., all “doses” of a first regimen are administered prior to administration of any doses of a second regimen); in some embodiments, such agents are administered in overlapping dosing regimens. In some embodiments, “administration” of combination therapy may involve administration of one or more agent(s) or modality(ies) to a subject receiving the other agent(s) or modality(ies) in the combination. For clarity, combination therapy does not require that individual agents be administered together in a single composition (or even necessarily at the same time), although in some embodiments, two or more agents, or active moieties thereof, may be administered together in a combination composition, or even in a combination compound (e.g., as part of a single chemical complex or covalent entity).
[0029 J Comparable. As used herein, the term “comparable” refers to two or more agents, entities, situations, sets of conditions, etc., that may not be identical to one another but that are sufficiently similar to permit comparison therebetween so that one skilled in the art will appreciate that conclusions may reasonably be drawn based on differences or similarities observed. In some embodiments, comparable sets of conditions, circumstances, individuals, or populations are characterized by a plurality of substantially identical features and one or a small number of varied features. Those of ordinary skill in the art will understand, in context, what degree of identity is required in any given circumstance for two or more such agents, entities, situations, sets of conditions, etc. to be considered comparable. For example, those of ordinary skill in the art will appreciate that sets of circumstances, individuals, or populations are comparable to one another when characterized by a sufficient number and type of substantially identical features to warrant a reasonable conclusion that differences in results obtained or phenomena observed under or with different sets of circumstances, individuals, or populations are caused by or indicative of the variation in those features that are varied.
[0030J Composition: Those skilled in the art will appreciate that the term “composition” may be used to refer to a discrete physical entity that comprises one or more specified components. In general, unless otherwise specified, a composition may be of any form - e.g., gas, gel, liquid, solid, etc. 00311 Dosage form or unit dosage form: Those skilled in the art will appreciate that the term “dosage form” may be used to refer to a physically discrete unit of an active agent ( e.g ., a therapeutic or diagnostic agent) for administration to a subject. Typically, each such unit contains a predetermined quantity of active agent. In some embodiments, such quantity is a unit dosage amount (or a whole fraction thereof) appropriate for administration in accordance with a dosing regimen that has been determined to correlate with a desired or beneficial outcome when administered to a relevant population (/. ., with a therapeutic dosing regimen). Those of ordinary skill in the art appreciate that the total amount of a therapeutic composition or agent administered to a particular subject is determined by one or more attending physicians and may involve administration of multiple dosage forms.
(0032J Dosing regimen or therapeutic regimen: Those skilled in the art will appreciate that the terms “dosing regimen” and “therapeutic regimen” may be used to refer to a set of unit doses (typically more than one) that are administered individually to a subject, typically separated by periods of time. In some embodiments, a given therapeutic agent has a recommended dosing regimen, which may involve one or more doses. In some embodiments, a dosing regimen comprises a plurality of doses each of which is separated in time from other doses. In some embodiments, individual doses are separated from one another by a time period of the same length; in some embodiments, a dosing regimen comprises a plurality of doses and at least two different time periods separating individual doses. In some embodiments, all doses within a dosing regimen are of the same unit dose amount. In some embodiments, different doses within a dosing regimen are of different amounts. In some embodiments, a dosing regimen comprises a first dose in a first dose amount, followed by one or more additional doses in a second dose amount different from the first dose amount. In some embodiments, a dosing regimen comprises a first dose in a first dose amount, followed by one or more additional doses in a second dose amount same as the first dose amount. In some embodiments, a dosing regimen is correlated with a desired or beneficial outcome when administered across a relevant population (/. ., is a therapeutic dosing regimen). J0033] Engineered: In general, the term “engineered” refers to the aspect of having been manipulated by the hand of man. For example, in some embodiments, a small molecule may be considered to be engineered if its structure and/or production is designed and/or implemented by the hand ot man. Analogously, in some embodiments, a polynucleotide may be considered to be “engineered” when two or more sequences, that are not linked together in that order in nature, are manipulated by the hand of man to be directly linked to one another in the engineered polynucleotide. For example, in some embodiments of the present invention, an engineered polynucleotide comprises a regulatory sequence that is found in nature in operative association with a first coding sequence but not in operative association with a second coding sequence, is linked by the hand of man so that it is operatively associated with the second coding sequence. Comparably, a cell or organism is considered to be “engineered” if it has been manipulated so that its genetic information is altered ( e.g ., new genetic material not previously present has been introduced, for example by transformation, mating, somatic hybridization, transfection, transduction, or other mechanism, or previously present genetic material is altered or removed, for example by substitution or deletion mutation, or by mating protocols). As is common practice and is understood by those in the art, expression products of an engineered polynucleotide, and/or progency of an engineered polynucleotide or cell are typically still referred to as “engineered” even though the actual manipulation was performed on a prior entity.
[0034) Excipient: As used herein, the term “excipient” refers to a non-therapeutic agent that may be included in a pharmaceutical composition, for example, to provide or contribute to a desired consistency or stabilizing effect. Suitable pharmaceutical excipients include, for example, starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like.
[0035] Heteroaliphatic. The term “heteroaliphatic” or “heteroaliphatic group”, as used herein, denotes an optionally substituted hydrocarbon moiety having, in addition to carbon atoms, from one to five heteroatoms, that may be straight-chain ( i.e unbranched), branched, or cyclic (“heterocyclic”) and may be completely saturated or may contain one or more units of unsaturation, but which is not aromatic. The term “heteroatom” refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen. The term “nitrogen” also includes a substituted nitrogen. Unless otherwise specified, heteroaliphatic groups contain 1-10 carbon atoms wherein 1-3 carbon atoms are optionally and independently replaced with heteroatoms selected from oxygen, nitrogen, and sulfur. In some embodiments, heteroaliphatic groups contain 1-4 carbon atoms, wherein 1-2 carbon atoms are optionally and independently replaced with heteroatoms selected from oxygen, nitrogen, and sulfur. In yet other embodiments, heteroaliphatic groups contain 1-3 carbon atoms, wherein 1 carbon atom is optionally and independently replaced with a heteroatom selected from oxygen, nitrogen, and sulfur. Suitable heteroaliphatic groups include, but are not limited to, linear or branched, heteroalkyl, heteroalkenyl, and heteroalkynyl groups. For example, a 1- to 10 atom heteroaliphatic group includes the following exemplary groups: -O-CH3, -CH2-O-CH3, -O-CH2- CH2-O-CH2-CH2-O-CH3, and the like.
|0036j Heteroaryl: The terms “heteroaryl” and “heteroar-”, used alone or as part of a larger moiety, e.g., “heteroaralkyl”, or “heteroaralkoxy”, refer to monocyclic or bicyclic ring groups having 5 to 12 ring atoms (e.g., 5- to 6- membered monocyclic heteroaryl or 9- to 12-membered bicyclic heteroaryl); having 6, 10, or 14 p-electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms. The term “heteroatom” refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen. Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, pteridinyl, imidazo[l,2-a]pyrimidinyl, imidazo[l,2-a]pyridyl, imidazo[4,5-b]pyridyl, imidazo[4,5-c]pyridyl, pyrrol opyridyl, pyrrolopyrazinyl, thienopyrimidinyl, triazolopyridyl, and benzoisoxazolyl. The terms “heteroaryl” and “heteroar-”, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring (i.e., a bicyclic heteroaryl ring having 1 to 3 heteroatoms). Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzotriazolyl, benzothiazolyl, benzothiadiazolyl, benzoxazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, AH quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, pyrido[2,3-b]-l,4-oxazin-3(4H)-one, and benzoisoxazolyl. A heteroaryl group may be mono- or bicyclic. The term “heteroaryl” may be used interchangeably with the terms “heteroaryl ring”, “heteroaryl group”, or “heteroaromatic”, any of which terms include rings that are optionally substituted. The term “heteroaralkyl” refers to an alkyl group substituted by a heteroaryl, wherein the alkyl and heteroaryl portions independently are optionally substituted. jO037J Heteroatom: The term “heteroatom” as used herein refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen. |0038j Heterocycle: As used herein, the terms “heterocycle”, “heterocyclyl”, “heterocyclic radical”, and “heterocyclic ring” are used interchangeably and refer to a stable 3- to 8-membered monocyclic, a 7- to 12-membered bicyclic, or a 10- to 16-membered polycyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, such as one to four, heteroatoms, as defined above. When used in reference to a ring atom of a heterocycle, the term "nitrogen" includes a substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR+ (as in N-substituted pyrrolidinyl). A heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, without limitation, azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, piperidinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and thiamorpholinyl. A heterocyclyl group may be mono-, bi-, tri-, or polycyclic, preferably mono-, bi-, or tricyclic, more preferably mono- or bicyclic. The term “heterocyclylalkyl” refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted. A bicyclic heterocyclic ring also includes groups in which the heterocyclic ring is fused to one or more aryl rings. Exemplary bicyclic heterocyclic groups include indolinyl, isoindolinyl, benzodioxolyl, 1,3- dihydroisobenzofuranyl, 2,3-dihydrobenzofuranyl, tetrahydroquinolinyl,
Figure imgf000019_0001
Figure imgf000019_0002
bicyclic heterocyclic ring can also be a spirocyclic ring system (e.g., 7- to 11-membered spirocyclic fused heterocyclic ring having, in addition to carbon atoms, one or more heteroatoms as defined above (e.g., one, two, three or four heteroatoms)). A bicyclic heterocyclic ring can also be a bridged ring system (e.g., 7- to 11-membered bridged heterocyclic ring having one, two, or three bridging atoms. Exemplary bridged ring systems include \Z and - / . Exemplary
Figure imgf000020_0001
100391 Oral: The phrases “oral administration” and “administered orally” as used herein have their art-understood meaning referring to administration by mouth of a compound or composition. j0040| Parenteral: The phrases “parenteral administration” and “administered parenterally” as used herein have their art-understood meaning referring to modes of administration other than enteral and topical administration, usually by injection, and include, without limitation, intravenous, intramuscular, intra-arterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticulare, subcapsular, subarachnoid, intraspinal, and intrasternal injection and infusion.
[00411 Partially unsaturated: As used herein, the term “partially unsaturated” refers to a ring moiety that includes at least one double or triple bond between ring atoms. The term “partially unsaturated” is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aromatic (e.g., aryl or heteroaryl) moieties, as herein defined.
[0042] Patient or subject: As used herein, the term “patient” or “subject” refers to any organism to which a provided composition is or may be administered, e.g., for experimental, diagnostic, prophylactic, cosmetic, and/or therapeutic purposes. Typical patients or subjects include animals (e.g., mammals such as mice, rats, rabbits, non-human primates, and/or humans). In some embodiments, a patient is a human. In some embodiments, a patient or a subject is suffering from or susceptible to one or more disorders or conditions. In some embodiments, a patient or subject displays one or more symptoms of a disorder or condition. In some embodiments, a patient or subject has been diagnosed with one or more disorders or conditions. In some embodiments, a patient or a subject is receiving or has received certain therapy to diagnose and/or to treat a disease, disorder, or condition.
[0043] Pharmaceutical composition: As used herein, the term “pharmaceutical composition” refers to an active agent, formulated together with one or more pharmaceutically acceptable carriers. In some embodiments, the active agent is present in unit dose amount appropriate for administration in a therapeutic or dosing regimen that shows a statistically significant probability of achieving a predetermined therapeutic effect when administered to a relevant population. In some embodiments, pharmaceutical compositions may be specially formulated for administration in solid or liquid form, including those adapted for the following: oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., those targeted for buccal, sublingual, and systemic absorption, boluses, powders, granules, pastes for application to the tongue; parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained-release formulation; topical application, for example, as a cream, ointment, or a controlled-release patch or spray applied to the skin, lungs, or oral cavity; intravaginally or intrarectally, for example, as a pessary, cream, or foam; sublingually; ocularly; transdermally; or nasally, pulmonary, and to other mucosal surfaces.
J0044) Pharmaceutically acceptable: As used herein, the phrase “pharmaceutically acceptable” refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
[0045] Pharmaceutically acceptable carrier: As used herein, the term “pharmaceutically acceptable carrier” means a pharmaceutically-acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, or solvent encapsulating material, involved in carrying or transporting the subject compound from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which can serve as pharmaceutically-acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as com starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer’s solution; ethyl alcohol; pH buffered solutions; polyesters, polycarbonates and/or polyanhydrides; and other non toxic compatible substances employed in pharmaceutical formulations.
10046) Pharmaceutically acceptable salt: The term “pharmaceutically acceptable salt”, as used herein, refers to salts of such compounds that are appropriate for use in pharmaceutical contexts, i.e., salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences , 66: 1-19 (1977). In some embodiments, pharmaceutically acceptable salts include, but are not limited to, nontoxic acid addition salts, which are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. In some embodiments, pharmaceutically acceptable salts include, but are not limited to, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2- hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, / oluenesulfonate, undecanoate, valerate salts, and the like. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. In some embodiments, pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, alkyl having from 1 to 6 carbon atoms, sulfonate and aryl sulfonate. j0047l Polycyclic: As used herein, the term “polycyclic” refers to a saturated or unsaturated ring system having two or more rings (for example, heterocyclyl rings, heteroaryl rings, cycloalkyl rings, or aryl rings), having between 7 and 20 atoms, in which one or more carbon atoms are common to two adjacent rings. The rings in a polycyclic ring system may be fused (i.e., bicyclic or tricyclic), spirocyclic, or a combination thereof. Exemplary polyclic systems include
Figure imgf000023_0001
[00481 Prevent or prevention: As used herein, the terms “prevent” or “prevention”, when used in connection with the occurrence of a disease, disorder, and/or condition, refer to reducing the risk of developing the disease, disorder and/or condition and/or to delaying onset of one or more characteristics or symptoms of the disease, disorder or condition. Prevention may be considered complete when onset of a disease, disorder or condition has been delayed for a predefined period of time.
[0049] Reference: As used herein describes a standard or control relative to which a comparison is performed. For example, in some embodiments, an agent, animal, individual, population, sample, sequence or value of interest is compared with a reference or control agent, animal, individual, population, sample, sequence or value. In some embodiments, a reference or control is tested and/or determined substantially simultaneously with the testing or determination of interest. In some embodiments, a reference or control is a historical reference or control, optionally embodied in a tangible medium. Typically, as would be understood by those skilled in the art, a reference or control is determined or characterized under comparable conditions or circumstances to those under assessment. Those skilled in the art will appreciate when sufficient similarities are present to justify reliance on and/or comparison to a particular possible reference or control. [0050) Sample: As used herein, the term “sample” typically refers to an aliquot of material obtained or derived from a source of interest. In some embodiments, a source of interest is a biological or environmental source. In some embodiments, a source of interest may be or comprise a cell, tissue, or organism, such as a microbe, a plant, or an animal (e.g., a human). In some embodiments, a source of interest is or comprises biological tissue or fluid. In some embodiments, a source of interest may be or comprise a preparation generated in a production run. In some embodiments, a sample is a “primary sample” obtained directly from a source of interest by any appropriate means. In some embodiments, as will be clear from context, the term “sample” refers to a preparation that is obtained by processing (e.g., by removing one or more components of and/or by adding one or more agents to) a primary sample.
[0051 ) Specific: The term “specific”, when used herein with reference to an agent having an activity, is understood by those skilled in the art to mean that the agent discriminates between potential target entities or states. For example, in some embodiments, an agent is said to bind “specifically” to its target if it binds preferentially with that target in the presence of one or more competing alternative targets. In many embodiments, specific interaction is dependent upon the presence of a particular structural feature of the target entity (e.g., an epitope, a cleft, a binding site). It is to be understood that specificity need not be absolute. In some embodiments, specificity may be evaluated relative to that of the binding agent for one or more other potential target entities (e.g., competitors). In some embodiments, specificity is evaluated relative to that of a reference specific binding agent. In some embodiments, specificity is evaluated relative to that of a reference non-specific binding agent. In some embodiments, the agent or entity does not detectably bind to the competing alternative target under conditions of binding to its target entity. In some embodiments, a binding agent binds with higher on-rate, lower off-rate, increased affinity, decreased dissociation, and/or increased stability to its target entity as compared with the competing alternative target(s). jO052J Substituted or optionally substituted: As described herein, compounds of the invention may contain “optionally substituted” moieties. In general, the term “substituted,” whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. “Substituted” applies to one or more hydrogens that are either explicit or implicit from the
Figure imgf000025_0001
Figure imgf000025_0002
otherwise indicated, an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds. The term “stable,” as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes provided herein. Groups described as being “substituted” preferably have between 1 and 4 substituents, more preferably 1 or 2 substituents. Groups described as being “optionally substituted” may be unsubstituted or be “substituted” as described above.
}0053J Suitable monovalent substituents on a substitutable carbon atom of an “optionally substituted” group are independently halogen; -(CH2)o-4R°; -(CH2)o-40R°; -0(CH2)o-4R°, -O- (CH2)O-4C(0)OR°; -(CH2)O-4CH(OR°)2; -(CH2)O-4SR°; -(CFbjo- Ph, which may be substituted with R°; -(CFbjo- CXCFbjo-iPh which may be substituted with R°; -CH=CHPh, which may be substituted with R°; -(CH2)o-40(CH2)o-i-pyridyl which may be substituted with R°; -NO2; -CN; -Ns; -(CH2)O-4N(R°)2; -(CH2)O^N(R0)C(0)R°; -N(R°)C(S)R°; -(CH2)O-
4N(R°)C(0)NR°2; -N(R°)C(S)NR°2; (CH2)O-4N(R°)C(0)OR°; N(R°)N(R°)C(0)R°; -N(R°)N(R0)C(0)NR°2; -N(R°)N(R°)C(0)0R°; -(CH2)o-4C(0)R°; C(S)R°; -(CH2)O-4C(0)OR°; -(CH2)O-4C(0)SR°; -(CH2)o^C(0)OSiR°3; -(CH2)o-4OC(0)R0; -
OC(0)(CH2)O-4SR°; -(CH2)O-4 SC (0)R° ; -(CH2)o-4C(0)NR°2; -C(S)NR°2; -C(S)SR°; -
SC(S)SR°, -(CH2)O-40C(0)NR°2; -C(0)N(0R°)R°; -C(0)C(0)R°; -C(0)CH2C(0)R°; - C(NOR°)R°; -(CH2)O-4SSR°; -(CH2)O-4S(0)2R°; -(CH2)O-4S(0)2OR°; -(CH2)O^OS(0)2R°; - S(0)2NR°2; -(CH2)O-4S(0)R°; -N(R°)S(0)2NR°2; -N(R°)S(0)2R°; -N(OR°)R°; -C(NH)NR°2; - P(0)2R°; -P(0)R°2; -0P(0)R°2; -0P(0)(0R°)2; SiR°3; -(Ci-4 straight or branched alkylene)0- N(R°)2; or — (Ci-4 straight or branched alkylene)C(0)0-N(R°)2, wherein each R° may be substituted as defined below and is independently hydrogen, Ci-6 aliphatic, -CHzPh, -0(CH2)o- lPh, -CH2-(5- to 6-membered heteroaryl ring), or a 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R°, taken together with their intervening atom(s), form a 3- to 12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.
10054 [ Suitable monovalent substituents on R° (or the ring formed by taking two independent occurrences of R° together with their intervening atoms), are independently halogen, -(CH2)o-2R*, -(haloR*), -(CH2)O-2OH, -(CH2)O-2OR·, -(CH2)O-2CH(OR*)2, -O(haloR'), -CN, -Ns, -(CH2)o- 2C(0)R·, -(CH2)O-2C(0)OH, -(CH2)O-2C(0)OR·, -(CH2)O-2SR*, -(CH2)O-2SH, -(CH2)O-2NH2, - (CH2)O-2NHR·, -(CH2)O-2NR*2, -N02, -SiR*3, -OSiR’s, -C(0)SR* -(Ci-4 straight or branched alkylene)C(0)OR*, or -SSR* wherein each R* is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently selected from Ci-4 aliphatic, - CH2Ph, -0(CH2)o-iPh, or a 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R° include =0 and =S.
|0055j Suitable divalent substituents on a saturated carbon atom of an “optionally substituted” group include the following: =0 (“oxo”), =S, =NNR% =NNHC(0)R*, =NNHC(0)0R*, =NNHS(0)2R*, =NR*, =NOR*, -0(C(R%))2-30-, or -S(C(R* 2))2-3S-, wherein each independent occurrence of R* is selected from hydrogen, Ci-6 aliphatic which may be substituted as defined below, or an unsubstituted 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: -0(CR* 2)2-30-, wherein each independent occurrence of R* is selected from hydrogen, Ci-6 aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. j0056l Suitable substituents on the aliphatic group of R* include halogen, -R*, -(haloR*), -OH, - OR*, -0(haloR*), -CN, -C(0)0H, -C(0)0R*, -NHz, -NHR*, -NR*2, or -NO2, wherein each R* is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently Ci-4 aliphatic, -CH2PI1, -0(CH2)o-iPh, or a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
[0057] Suitable substituents on a substitutable nitrogen of an “optionally substituted” group include -R†, -NR† 2, -C(0)R†, -C(0)0R†, -C(0)C(0)R†,
C(0)CH2C(0)R†, -S(0)2R†, -S(0)2NR†2, -C(S)NR†2, -C(NH)NR†2, or -N(R†)S(0)2R†; wherein each R† is independently hydrogen, Ci-6 aliphatic which may be substituted as defined below, unsubstituted -OPh, or an unsubstituted 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R†, taken together with their intervening atom(s) form an unsubstituted 3- to 12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
[0058) Suitable substituents on the aliphatic group of R† are independently halogen, - R*, -(haloR*), -OH, -OR*, -O(haloR'), -CN, -C(0)OH, -C(0)OR*, -NH2, -NHR*, -NR*2, or -NO2, wherein each R* is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently Ci^ aliphatic, -CH2PI1, -0(CH2)o-iPh, or a 3- to 6- membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
[0059] Small molecule: As used herein, the term “small molecule” means a low molecular weight organic and/or inorganic compound. In general, a “small molecule” is a molecule that is less than about 5 kilodaltons (kD) in size. In some embodiments, a small molecule is less than about 4 kD, 3 kD, about 2 kD, or about 1 kD. In some embodiments, the small molecule is less than about 800 daltons (D), about 600 D, about 500 D, about 400 D, about 300 D, about 200 D, or about 100 D. In some embodiments, a small molecule is less than about 2000 g/mol, less than about 1500 g/mol, less than about 1000 g/mol, less than about 800 g/mol, or less than about 500 g/mol. In some embodiments, a small molecule is not a polymer. 0060 j In some embodiments, a small molecule does not include a polymeric moiety. In some embodiments, a small molecule is not and/or does not comprise a protein or polypeptide (e.g., is not an oligopeptide or peptide). In some embodiments, a small molecule is not and/or does not comprise a polynucleotide (e.g., is not an oligonucleotide). In some embodiments, a small molecule is not and/or does not comprise a polysaccharide; for example, in some embodiments, a small molecule is not a glycoprotein, proteoglycan, glycolipid, etc). In some embodiments, a small molecule is not a lipid.
10061] In some embodiments, a small molecule is a modulating agent (e.g., is an inhibiting agent or an activating agent). In some embodiments, a small molecule is biologically active. In some embodiments, a small molecule is detectable (e.g., comprises at least one detectable moiety). In some embodiments, a small molecule is a therapeutic agent.
[0062] Those of ordinary skill in the art, reading the present disclosure, will appreciate that certain small molecule compounds described herein may be provided and/or utilized in any of a variety of forms such as, for example, crystal forms (e.g., polymorphs, solvates, etc), salt forms, protected forms, pro-drug forms, ester forms, isomeric forms (e.g., optical and/or structural isomers), isotopic forms, etc.
[0063] Those of ordinary skill in the art will appreciate that certain small molecule compounds have structures that can exist in one or more steroisomeric forms. In some embodiments, such a small molecule may be utilized in accordance with the present disclosure in the form of an individual enantiomer, diastereomer or geometric isomer, or may be in the form of a mixture of stereoisomers; in some embodiments, such a small molecule may be utilized in accordance with the present disclosure in a racemic mixture form.
[0064] Those of skill in the art will appreciate that certain small molecule compounds have structures that can exist in one or more tautomeric forms. In some embodiments, such a small molecule may be utilized in accoradance with the present disclosure in the form of an individual tautomer, or in a form that interconverts between tautomeric forms. |0065j Those of skill in the art will appreciate that certain small molecule compounds have structures that permit isotopic substitution (e.g., 2H or 3H for H;, UC, 13C or 14C for 12C; , 13N or 15N for 14N; 170 or 180 for 160; 36C1 for XXC; 18F for XXF; 1311 for XXXI; etc). In some embodiments, such a small molecule may be utilized in accordance with the present disclosure in one or more isotopically modified forms, or mixtures thereof. 0066 j In some embodiments, reference to a particular small molecule compound may relate to a specific form of that compound. In some embodiments, a particular small molecule compound may be provided and/or utilized in a salt form (e.g., in an acid-addition or base-addition salt form, depending on the compound); in some such embodiments, the salt form may be a pharmaceutically acceptable salt form.
(0067] In some embodiments, where a small molecule compound is one that exists or is found in nature, that compound may be provided and/or utilized in accordance in the present disclosure in a form different from that in which it exists or is found in nature. Those of ordinary skill in the art will appreciate that, in some embodiments, a preparation of a particular small molecule compound that contains an absolute or relative amount of the compound, or of a particular form thereof, that is different from the absolute or relative (with respect to another component of the preparation including, for example, another form of the compound) amount of the compound or form that is present in a reference preparation of interest (e.g., in a primary sample from a source of interest such as a biological or environmental source) is distinct from the compound as it exists in the reference preparation or source. Thus, in some embodiments, for example, a preparation of a single stereoisomer of a small molecule compound may be considered to be a different form of the compound than a racemic mixture of the compound; a particular salt of a small molecule compound may be considered to be a different form from another salt form of the compound; a preparation that contains only a form of the compound that contains one conformational isomer ((Z) or (E)) of a double bond may be considered to be a different form of the compound from one that contains the other conformational isomer ((E) or (Z)) of the double bond; a preparation in which one or more atoms is a different isotope than is present in a reference preparation may be considered to be a different form; etc.
{0068] Those skilled in the art will appreciate that a bond designated as ~ in a small molecule structure, as used herein, refers to a bond that, in some embodiments, is a single (e.g., saturated) bond, and in some embodiments, is a double (e.g., unsaturated) bond. For example, the following structure:
Figure imgf000030_0001
is intended to encompass both H and H
[O069J Those skilled in the art will further appreciate that, in small molecule structures, the symbol~w , as used herein, refers to a point of attachment between two atoms.
[0070J Therapeutic agent: As used herein, the phrase “therapeutic agent” in general refers to any agent that elicits a desired pharmacological effect when administered to an organism. In some embodiments, an agent is considered to be a therapeutic agent if it demonstrates a statistically significant effect across an appropriate population. In some embodiments, the appropriate population may be a population of model organisms. In some embodiments, an appropriate population may be defined by various criteria, such as a certain age group, gender, genetic background, preexisting clinical conditions, etc. In some embodiments, a therapeutic agent is a substance that can be used to alleviate, ameliorate, relieve, inhibit, prevent, delay onset of, reduce severity of, and/or reduce incidence of one or more symptoms or features of a disease, disorder, and/or condition. In some embodiments, a “therapeutic agent” is an agent that has been or is required to be approved by a government agency before it can be marketed for administration to humans. In some embodiments, a “therapeutic agent” is an agent for which a medical prescription is required for administration to humans.
[00711 Treat: As used herein, the terms “treat,” “treatment,” or “treating” refer to any method used to partially or completely alleviate, ameliorate, relieve, inhibit, prevent, delay onset of, reduce severity of, and/or reduce incidence of one or more symptoms or features of a disease, disorder, and/or condition. Treatment may be administered to a subject who does not exhibit signs of a disease, disorder, and/or condition. In some embodiments, treatment may be administered to a subject who exhibits only early signs of the disease, disorder, and/or condition, for example, for the purpose of decreasing the risk of developing pathology associated with the disease, disorder, and/or condition. DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS
TRPML1 andAutophagy jO072| Autophagy is a mechanism of the cell that degrades cytoplasmic material and organelles. There are multiple types of autophagy: (1) macroautophagy (generally referred to as autophagy); (2) microautophagy; and (3) chaperone-mediateed autophagy. See Eskelinen & Saftig, Biochimica et Biophysica Acta - Mol. Cell Res., 1793(4):664-673 (2009). In macroautophagy, the autophagosome engulfs waste materials in the cytoplasm and fuses to the lysosome, where materials are delivered for degradation. The lysosome is as a subcellular organelle containing more than 50 soluble acid hydrolases useful for digesting cellular components. Fusion of the lysosome to the autophagosome is activated, in part, by release of ions through ion channels in the membrane of the lysome, including Ca2+. See Cao, etal. , J. Bio. Chem., 292(20)8424-8435 (2017). {O073J Transient Receptor Potential Mucolipin-1 (also known as TRPMLl or MLl) is a Ca2+ channel in the lysosome that regulates autophagy. See Wang, etal. , PNAS, E1373-E1381 (March 2, 2015). In particular, TRPMLl is an inwardly rectifying current channel that transports cations from the lumen of the lysosome to the cytosol. See Di Paolda, et al., Cell Calcium 69:112-121 (2018). Release of Ca2+ from the lysosome via TRPMLl modulates transcription factor EB activity via local calcineurin activation, which ultimately induces autophagy and lysosomal biogenesis. See Medina, et al., Nat. Cell. Biol., 17(3):288-299 (2015).
|0074j It has recently been discovered that upregulation of autophagy is beneficial to patients suffering from a number of diseases and disorders. For example, it has been reported that inducing autophagy promotes clearance of hepatotoxic alpha- 1 -anti -trypsin (ATZ) in the liver. See Pastore, et al., EMBO Mol. Med. 5(3): 397-412 (Mar. 2013). Moreover, autophagy was recently found to be useful in the treatment of neurodegenerative disorders, cancer, and heart disease. See Pierzynowska, et al, Metab. Brain Dis., 33(4); 989-1008 (2018) (discussing neurodegenerative disorders); Nelson & Shacka, Curr. Pathobiol. Rep., 1(4): 239-245 (2013) (discussing cancer); Sciaretta, et al, Annual Review of Physiology, 80:1-26 (2018) (discussing heart disease); Maiuri & Kroemer, Cell Death & Differentiation, 26: 680-689 (2019) (discussing therapeutic applications of autophagy, generally). It is, therefore, desirable to identify methods and modes of promoting autophagy. Given TRPMLl’s role in autophagy, described herein are TRPMLl modulators useful for promoting autophagy and/or treating certain diseases, disorders, or conditions.
}O075J The present disclosure provides the insight that TRMPL1 may represent a particularly desirable target that, among other things, may permit modulation (e.g., enhancement) of autophagy in certain contexts.
TRPMLl Modulators
Structure
[0076J In some embodiments, the present disclosure provides and/or utilizes TRMPL1 modulators that are small molecule compounds having a chemical structure as indicated below in Formula I:
Z-L^Cy-A-L^V
I or a pharmaceutically acceptable salt thereof, wherein
A is 9- to 12-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, or 9- to 16- membered bicyclic or polycyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S, wherein A is substituted with 0, 1, 2, 3 or 4 Ra;
Cy is absent or a bivalent moiety selected from 4- to 12-membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, P, and S, 5- to 12-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, P, and S, Ci-6 aliphatic, or C3-12 cycloalkyl, wherein Cy is optionally substituted with one or more of
R1;
L1 is absent, -NR3-, -0-, -S-, Ci-6 alkylenyl, C2-6 alkynylenyl, -NR3-CI-6 alkylenyl,-0-Ci-6 alkylenyl, -C(0)Co-e alkylenyl; -C(0)NR3-, or -C(0)-C(0)-;
L2 is absent, -(NR3)s-S(0)-Co-6 alkylenyl-, -(NR3)s-S(0)2-Co-6 alkylenyl-, -(NR3)s-S(0)(NR3)-, -S(0)2-NR3-, -NR3-CI-6 haloalkylenyl, -(NR3)s-P(0)(R3)-, -Ci-e alkylenyl-S(O)-,
-Ci-6 alkylenyl-S(0)2-, -C(0)-(NR3)s-, -(NR3)s-C(0)-, or an optionally substituted 4- to 12- membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S;
V is selected from Ci-6 aliphatic, C6-12 aryl, 4- to 12-membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S, 5- to 12-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, 5- to 12-membered monocyclic of bicyclic aryl, and C3-12 cycloalkyl, wherein Vis substituted with (R6)m;
Z is Ci-6 aliphatic, 2- to 10-membered heteroaliphatic, P(0)(R3)2, -C(0)Ci-6 aliphatic, C(0)N(R3)2, C6-12 aryl, C3-12 cycloalkyl, 4- to 16-membered monocyclic or polycyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S, or 5- to 12-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, wherein Z is substituted with (R2)q; each Ra is independently halo, oxo, or optionally substituted Ci-6 aliphatic; each R1 is independently selected from N(R3)2, OH, CN, C(0)NHR3, and an optionally substituted group selected from Ci-6 aliphatic and N(R3)-C(0)-CI-6 alkyl; each R2 is independently selected from halo, CN, C(0)0H, and an optionally substituted group selected from Ci-6 aliphatic, C(0)Ci-6 aliphatic, and O-Ci-6 aliphatic; each R3 is independently selected from H and optionally substituted Ci-6 aliphatic; each R5 is independently selected from Ci-6 alkyl, -N(R3)2, -O-Ci-6 alkyl, C(0)-Ci-6 alkyl, P(0)(Ci-6 alkyl)2, C3-12 cycloalkyl, and 5- to 12-membered heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S, wherein R5 is optionally substituted with one or more substituents selected from halo and OH; each R6 is halo, -S(0)-R5, -S(0)2-R5, -S(0)(NH)-R5, -CN, -C(0)-R5, -C(0)0-R5, -C(0)-NH(R5), -C(0)-N(R5)2, -P(0)(R5)2, or an optionally substituted group selected from O-Ci-6 alkyl, Ci-6 alkyl, and C6-12 aryl; m is 0, 1, 2, 3, or 4; n is 0 or 1; q is 0, 1, 2, 3, or 4; and s is 0 or 1. j0077l As defined generally above, A is 9- to 12-membered bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, or 9- to 16- membered bicyclic or polycyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S, and A is substituted with 0, 1, 2, 3 or 4 Ra.
[0078] As defined generally above, A is substituted with 0, 1, 2, 3, or 4 Ra. In some embodiments, A is unsubstituted (i.e, is substituted with 0 Ra). In some embodiments, A is substituted with 1 Ra. In some embodiments, A is substituted with 2 Ra. In some embodiments, A is substituted with 3 Ra. In some embodiments, A is substituted with 4 Ra.
10079 [ It is understood that A is a multivalent moiety (i.e., has two or more points of attachment to the rest of the molecule, whether explicitly referred to as “multivalent” or not). In some embodiments, A is 9- to 12-membered bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S.
[0080) In some embodiments, A is 9- to 12-membered bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, A is 9-membered bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, A is 10-membered bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, A is 11-membered bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, A is 12-membered bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S.
[0081 ) In some embodiments, A is 9- to 16- membered bicyclic or polycyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, A is 10- to 16- membered polycyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, A is 10-membered polycyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, A is 10-membered bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, A is 10- membered spirocyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, A is 11-membered polycyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, A is 11-membered bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, A is 11- membered spirocyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, A is 12-membered polycyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, A is 12-membered bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, A is 12- membered spirocyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, A is 13-membered polycyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, A is 13-membered bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, A is 13- membered spirocyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, A is 14-membered polycyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, A is 14-membered bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, A is 14- membered spirocyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, A is 15-membered polycyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, A is 15-membered bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, A is 15- membered spirocyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S.
[0082] In some embodiments, A is selected from:
Figure imgf000035_0001
[0083] In some embodiments, the present application provides compounds having a structure as set forth in Formula G :
Figure imgf000035_0002
or a pharmaceutically acceptable salt thereof, wherein
A’ is a fused phenyl or 6-membered heteroaryl ring comprising 1 to 3 nitrogen atoms, optionally substituted with Ra;
X1 and X7 are each independently selected from N, NRa, C, CRa, and C(Ra)2, as valency permits, wherein X1 and X7 are N, C, or CRa when bound to Cy-L'-Z; Cy is absent, or a bivalent moiety selected from 4- to 12-membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, P, and S, 5- to 12-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, Ci-6 aliphatic, Ce-u aryl, or C3-12 cycloalkyl, wherein Cy is optionally substituted with one or more of R1;
L1 is absent, -NR3-, -S-, C(0)NR3-, -C(0)-C(0)-, or an optionally substituted bivalent moiety selected from Ci-6 alkylenyl, C2-6 alkenylenyl, C2-6 alkynylenyl, C3-6 cycloalkyl, -NR3-CI-6 alkylenyl, -O-Co-6 alkylenyl, and -C(0)Co-6 alkylenyl;
L2 is an optionally substituted bivalent moiety selected from -(NR3)s-S(0)-Co-6 alkylenyl-, - (NR3)S-S(0)2-CO-6 alkylenyl-, -Ci-6 alkylenyl-S(0)-(NR3)s-, -Ci-6 alkylenyl-S(0)2-(NR3)s-, - (NR3)s-Co-6 alkylenyl, -(NR3)s-C(0)-Co-6 alkylenyl, and 4- to 12-membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S;
V is Ci-6 aliphatic, C6-12 aryl, C3-12 cycloalkyl, 4- to 12-membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S, 5- to 12-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, or 5- to 16-membered monocyclic or polycyclic aryl, wherein Vis substituted with (R6)m;
Z is Ci-6 aliphatic, 2- to 10-membered heteroaliphatic, P(0)(R3)2, -C(0)Ci-6 aliphatic, C(0)N(R3)2, C6-12 aryl, C3-12 cycloalkyl, 4- to 16-membered monocyclic or polycyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S, or 5- to 12-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, wherein Z is substituted with (R2)q; each Ra is independently H, halo, CN, oxo, or an optionally substituted group selected from Ci-6 aliphatic and O-Ci-6 aliphatic; each R1 is independently selected from halo, oxo, N(R3)2, -OH, -CN, -C(0)N(R3)2, and an optionally substituted group selected from Ci-6 aliphatic and N(R3)-C(0)-CI-6 aliphatic; each R2 is independently selected from halo, oxo, -CN, -OH, 0-R2a, -C(0)-R2a, -C(0)0-R2a, and an optionally group selected from Ci-6 aliphatic, C6-12 aryl, and 5- to 12-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S; each R2a is independently H or an optionally substituted group selected from Ci-6 aliphatic, C3-12 cycloalphatic, and 4- to 12-membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S; each R3 is independently selected from H and optionally substituted Ci-6 aliphatic; each R5 is independently -OR3, C(0)-R3, P(0)(R3)2, -N(R3)2, or an optionally substituted group selected from from Ci-6 aliphatic, C3-12 cycloalkyl, and 4- to 12-membered heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S; each R6 is halo, -S(0)-R5, -S(0)2-R5, -S(0)(NH)-R5, -CN, -C(0)-R5, -C(0)0-R5, -C(0)-NH(R5), -C(0)-N(R5)2, -P(0)(R5)2, or an optionally substituted group selected from O-Ci-6 aliphatic, Ci-6 aliphatic, C3-C12 cycloalkyl, and C6-12 aryl; m is 0, 1, 2, 3, or 4; q is 0, 1, 2, 3, or 4; and s is 0 or 1.
|0084| It is understood that moiety -Cy-L'-V can be attached to either ring of Formula G. That is, in some embodiments, a compound of Formula F is:
Figure imgf000037_0001
comprising 1 to 3 nitrogen atoms. In some embodiments, A’ is a fused phenyl or 6-membered heteroaryl ring comprising 1 to 2 nitrogen atoms. In some embodiments, A’ is a fused phenyl or fused pyridinyl. In In some embodiments, A’ is a fused phenyl. In some embodiments, A’ is a 6- membered heteroaryl ring comprising 1 to 2 nitrogen atoms. In some embodiments, A’ is selected from:
Figure imgf000037_0002
[00861 In some embodiments, the present disclosure provides a compound of Formula II:
Figure imgf000038_0001
II or a pharmaceutically acceptable salt thereof, wherein
Xr , X , and X7 are each independently selected from N, NRa, C, and CRa, wherein Xr , X2 , and X7 are N, C, or CRa when bound to Cy-L'-Z or L2-V
X3”, X4 , X5 , and X6 are each independently selected from N, C, and CRa, wherein X3 , X4 , X5 , and X6 are N or C when bound to Cy-L'-Z or L2-V;
Cy is absent, 4- to 12-membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, P, and S, 5- to 12-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, Ci-6 aliphatic, C6-12 aryl, or C3-12 cycloalkyl, wherein Cy is optionally substituted with one or more of R1;
L1 is absent, -NR3-, -0-, -S-, Ci-6 alkylenyl, C2-6 alkynylenyl, -NR3-CI-6 alkylenyl,-0-Ci-6 alkylenyl, -C(0)Co-e alkylenyl; -C(0)NR3-, -C(0)-C(0)-;
L2 is -(NR3)S-S(0)-CO-6 alkylenyl-, -(NR3)s-S(0)2-Co-6 alkylenyl-, -(NR3)s-S(0)(NR3)-, -S(0)2- NR3-, -NR3-CI-6 haloalkylenyl, -(NR3)s-P(0)(R3)-, -Ci-6 alkylenyl-S(O)-, -Ci-6 alkylenyl- S(0)2-, -C(0)-(NR3)S-, -(NR3)S-C(0)-, or an optionally substituted 4- to 12-membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S;
V is selected from Ci-6 aliphatic, C6-12 aryl, 4- to 12-membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S, 5- to 12-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, 5- to 12- membered monocyclic of bicyclic aryl, and C3-12 cycloalkyl, wherein V is substituted with
(R6)m;
Z is Ci-6 aliphatic, 2- to 10-membered heteroaliphatic, P(0)(R3)2, -C(0)Ci-6 aliphatic, C(0)N(R3)2, C6-12 aryl, C3-12 cycloalkyl, 4- to 16-membered monocyclic or polycyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S, or 5- to 12-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, wherein Z is substituted with (R2)q; each Ra is independently halo, oxo, or optionally substituted Ci-6 aliphatic; each R1 is independently selected from N(R3)2, OH, CN, C(0)NHR3, and an optionally substituted group selected from Ci-6 aliphatic and N(R3)-C(0)-CI-6 alkyl; each R2 is independently selected from halo, -CN, C(0)0H, and an optionally substituted group selected from Ci-6 alkyl, C(0)Ci-6 aliphatic, and O-Ci-6 aliphatic; each R3 is independently selected from H and optionally substituted Ci-6 aliphatic; each R5 is independently selected from Ci-6 alkyl, -N(CI-6 alkyl)2, -O-Ci-6 alkyl, C(0)-Ci-6 alkyl, P(0)(Ci-6 alkyl)2, C3-12 cycloalkyl, and 5- to 12-membered heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S, wherein R5 is optionally substituted with one or more substituents selected from halo and OH; each R6 is halo, -S(0)-R5, -S(0)2-R5, -S(0)(NH)-R5, -CN, -C(0)-R5, -C(0)0-R5, -C(0)-NH(R5), -C(0)-N(R5)2, -P(0)(R5)2, or an optionally substituted group selected from O-Ci-6 alkyl, Ci-6 alkyl, and C6-12 aryl; m is 0, 1, 2, 3, or 4; q is 0, 1, 2, 3, or 4; and s is 0 or 1.
{O087J In some embodiments, the present disclosure provides a compound of Formula IF:
Figure imgf000039_0001
IF or a pharmaceutically acceptable salt thereof, wherein
X1 , X2 , and X7 are each independently selected from N, NRa, C, CRa, and C(Ra)2 as valency permits, wherein Xr , X2”, and X7 are N, C, or CRa when bound to Cy-L'-Z or L2-V X3”, X4 , X5 , and X6 are each independently selected from N, C, and CRa, wherein X3 , X4 , X5 , and X6 are C when bound to -Cy-L'-Z or -L2-V;
Cy is absent, or a bivalent moiety selected from 4- to 12-membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, P, and S, 5- to 12-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, Ci-6 aliphatic, Ce-n aryl, or C3-12 cycloalkyl, wherein Cy is optionally substituted with one or more of R1;
L1 is absent, -NR3-, -S-, C(0)NR3-, -C(0)-C(0)-, or an optionally substituted bivalent moiety selected from Ci-6 alkylenyl, C2-6 alkynylenyl, C3-6 cycloalkyl, -NR3-CI-6 alkylenyl, -O-Co-6 alkylenyl, and -C(0)Co-6 alkylenyl;
L2 is an optionally substituted bivalent moiety selected from -(NR3)s-S(0)-Co-6 alkylenyl-, - (NR3)S-S(0)2-CO-6 alkylenyl-, -Ci-6 alkylenyl-S(0)-(NR3)s-, -Ci-6 alkylenyl-S(0)2-(NR3)s-, - (NR3)s-Co-6 alkylenyl, -(NR3)s-C(0)-Co-6 alkylenyl, and 4- to 12-membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S;
V is Ci-6 aliphatic, C6-12 aryl, C3-12 cycloalkyl, 4- to 12-membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S, 5- to 12-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, or 5- to 16-membered monocyclic or polycyclic aryl, wherein Vis substituted with (R6)m;
Z is Ci-6 aliphatic, 2- to 10-membered heteroaliphatic, P(0)(R3)2, -C(0)Ci-6 aliphatic, C(0)N(R3)2, C6-12 aryl, C3-12 cycloalkyl, 4- to 16-membered monocyclic or polycyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S, or 5- to 12-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, wherein Z is substituted with (R2)q; each Ra is independently H, halo, CN, oxo, or an optionally substituted group selected from Ci-6 aliphatic and O-Ci-6 aliphatic; each R1 is independently selected from halo, oxo, N(R3)2, -OH, -CN, -C(0)N(R3)2, and an optionally substituted group selected from Ci-6 aliphatic and N(R3)-C(0)-CI-6 aliphatic; each R2 is independently selected from halo, oxo, -CN, -OH, 0-R2a, -C(0)-R2a, -C(0)0-R2a, and an optionally group selected from Ci-6 aliphatic, C6-12 aryl, and 5- to 12-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S; each R2a is independently H or an optionally substituted group selected from Ci-6 aliphatic, C3-12 cycloalphatic, and 4- to 12-membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S; each R3 is independently selected from H and optionally substituted Ci-6 aliphatic; each R5 is independently -OR3, C(0)-R3, P(0)(R3)2, -N(R3)2, or an optionally substituted group selected from from Ci-6 aliphatic, C3-12 cycloalkyl, and 4- to 12-membered heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S; each R6 is halo, -S(0)-R5, -S(0)2-R5, -S(0)(NH)-R5, -CN, -C(0)-R5, -C(0)0-R5, -C(0)-NH(R5), -C(0)-N(R5)2, -P(0)(R5)2, or an optionally substituted group selected from O-Ci-6 aliphatic, Ci-6 aliphatic, C3-C12 cycloalkyl, and C6-12 aryl; m is 0, 1, 2, 3, or 4; q is 0, 1, 2, 3, or 4; and s is 0 or 1.
[00881 Compounds of formula provided herein (e.g., any one of formulae I-IIb-1) are described with respect to the exemplary embodiments herein.
[0089J Descriptions of embodiments for various variables and examples can be applied to all formula described herein (e.g., for any one of formula I-IIb-1).
[0090) It is understood that for embodiments of compounds of Formula II and IF comprising a 5,6 bicyclic fused ring, moieties -Cy-L'-Z and -L2-V can be bound to any of Xr , X2”, X3 , X4 , X5 , X6 or X7”. In some embodiments, -Cy-L'-Z and -L2-V are not bound to X1”, X2 , X3 , X4 , X5 , X6 or X7 at the same time.
[0091 ! As defined generally above, X1”, X2”, and X7 are each independently selected from N, NRa, C, CRa, and C(Ra)2 as valency permits, wherein X1 , X2 , and X7 are N, C, or CRa when bound to Cy-L'-Z or L2-V. In some embodiments, X1 is CRa, X2 is N- L2-V, and X7 is C-Cy-L'-Z. In some embodiments, X1 is CH, X2 is N- L2-V, and X7 is C-Cy-L'-Z In some embodiments, X1 is C(O), X2 is N- L2-V, and X7 is C(CH3)-Cy-L1-Z. In some embodiments, X1 is CFh, X2 is N- L2-V, and X7 is C(CH3)-Cy-L1-Z. In some embodiments, X1 is N, X2 is N- L2-V, and X7 is C- Cy-L4-Z.
I0092l As defined generally above, X3”, X4”, X5 , and X6 are each independently selected from N, C, and CRa, wherein X3 , X4 , X5 , and X6 are N or C when bound to Cy-L'-Z or L2-V. In some embodiments, each of X3 , X4 , X5 , and X6 is independently selected from N and CRa. In some embodiments, each of X , X4 , X5 , and X6 is CRa. In some embodiments, each of X3 , X4 , X5 , and X6 is CH. In some embodiments, X3 , X4 , and X5 are each CRa, and X6 is N. In some embodiments, X4”, X5 , and X6 are each CRa, and X3 is N. In some embodiments, X3 , X5 , and X6 are each CRa, and X4 is N. In some embodiments, X3 , X4 , and X6 are each CRa, and X5 is N. In some embodiments, X4 and X5 are each CRa, and X3 and X6 are each N.
[0093] As defined generally above, each Ra is H, halo, oxo, or an optionally substituted group selected from Ci-6 aliphatic and O-Ci-6 aliphatic. In some embodiments, Ra is H. In some embodiments, each Ra is halo, oxo, or an optionally substituted group selected from Ci-6 aliphatic and O-Ci-6 aliphatic.
[0094] In some embodiments, Ra is Ci-6 alkyl. In some embodiments, Ra is C1-3 alkyl. In some embodiments, Ra is methyl.
[0095) In some embodiments, Ra is halo. In some embodiments, Ra is bromo, chloro, fluoro, or iodo. In some embodiments, Ra is bromo. In some embodiments, Ra is chloro. In some embodiments, Ra is fluoro. In some embodiments, Rais iodo.
[0096] In some embodiments, Ra is oxo.
[0097] As defined generally above, Cy is absent or a bivalent moiety selected from 4- to 12- membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, P, and S, 5- to 12-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, P, and S, Ci-6 aliphatic, Ce-u aryl, or C3-12 cycloalkyl, wherein Cy is optionally substituted with one or more R1.
[0098] In some embodiments, Cy is optionally substituted with one or more R1, i.e., is substituted with 0, 1, 2, 3, or 4 R1. In some embodiments, Cy is unsubstituted (i.e., is substituted with 0 R1). In some embodiments, Cy is substituted with 1, 2, 3, or 4 R1. In some embodiments, Cy is substituted with 1 R1. In some embodiments, Cy is substituted with 2 R1. In some embodiments, Cy is substituted with 3 R1. In some embodiments, Cy is substituted with 4 R1.
[0099] In some embodiments, Cy is absent.
[0100] In some embodiments, Cy is 4- to 12-membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, Cy is 4- to 6- membered monocyclic heterocyclic comprising 1 to 3 heteroatoms selected from N, O, P, and S. In some embodiments, Cy is 4-membered monocyclic heterocyclic comprising 1 heteroatom selected from N, O, P, and S. In some embodiments, Cy is 5-membered monocyclic heterocyclic comprising 1 to 2 heteroatoms selected from N, O, P, and S. In some embodiments, Cy is 6- membered monocyclic heterocyclic comprising 1 to 3 heteroatoms selected from N, O, P, and S. In some embodiments, Cy is azetidinyl, pyrrolidinyl, piperdinyl, or piperazinyl. fO!O!j In some embodiments, Cy is azetidinyl, optionally substituted With one or more R1. {0102] In some embodiments, Cy is piperdinyl optionally substituted with one or more R1. In some embodiments, Cy is unsubstituted piperdinyl. In some embodiments, Cy is piperdinyl substituted with one or more R1.
[0103] In some embodiments, Cy is piperazinyl optionally substituted with one or more R1. In some embodiments, Cy is unsubstituted piperazinyl. In some embodiments, Cy is piperazinyl substituted with one or more R1.
| 104| In some embodiments, Cy is 7- to 12-membered bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, P, and S. In some embodiments, Cy is 10- to 12-membered bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, P, and S. In some embodiments, Cy is 10- membered bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, P, and S. In some embodiments, Cy is 11- membered bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, P, and S. In some embodiments, Cy is 12-membered bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, P, and S.
{0105] In some embodiments, Cy is 5- to 12-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, P, and S. In some embodiments, Cy is 5- or 6- membered monocyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, Cy is 5-membered monocyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, Cy is 6-membered monocyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S.
] 0106] In some embodiments, Cy is 7- to 12-membered bicyclic heteroaryl comprising comprising 1 to 4 heteroatoms selected from N, O, P, and S. In some embodiments, Cy is 9- to 12-membered bicyclic heteroaryl comprising comprising 1 to 4 heteroatoms selected from N, O, P, and S. In some embodiments, Cy is 9-membered bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, P, and S. In some embodiments, Cy is 10-membered bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, P, and S. In some embodiments, Cy is 11-membered bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, P, and S. In some embodiments, Cy is 12-membered bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, P, and S.
[0107] In some embodiments, Cy is Ci-6 aliphatic. In some embodiments, Cy is Ci-6 alkylenyl. 0108] In some embodiments, Cy is C3-12 cycloaliphatic. In some embodiments, Cy is cy cobutyl, cyclopentyl, or cyclohexyl. In some embodiments, Cy is cyclobutyl. In some embodiments, Cy is cyclopentyl. In some embodiments, Cy is cyclohexyl.
10109] In some embodiments, Cy is C6-12 aryl. In some embodiments, Cy is phenyl.
[0110] As defined generally above, each R1 is independently selected from N(R3)2, -OH, -CN, - C(0)N(R3)2, and an optionally substituted group selected from Ci-6 aliphatic and N(R3)-C(0)-Ci- 6 aliphatic.
101111 In some embodiments, each R1 is independently selected from N(R3)2, OH, CN, C(0)NHR3, and an optionally substituted group selected from Ci-6 aliphatic and N(R3)-C(0)-CI-6 alkyl.
10112] In some embodiments, R1 is N(R3)2. In some embodiments, R1 is NH2. In some embodiments, R1 is N(H)(CH3). In some embodiments, R1 is N(0¾)2. In some embodiments, R1 is OH. In some embodiments, R1 is CN. In some embodiments, R1 is C(0)N(R3)2. In some embodiments, R1 is C(0)NHR3. In some embodiments, R1 is C(0)NH2. In some embodiments, R1 is optionally substituted Ci-6 aliphatic. In some embodiments, R1 is optionally substituted Ci-6 alkyl. In some embodiments, R1 is optionally substituted Ci-4 alkyl. In some embodiments, R1 is optionally substituted Ci alkyl. In some embodiments, N(R3)-C(0)-CI-6 aliphatic. In some embodiments, N(R3)-C(0)-CI-6 alkyl.
[0113] In some embodiments, a substituent on an optionally substituted carbon atom of an optionally substituted R1 group is selected from: halo, OH, NH2, and oxo.
Figure imgf000044_0001
Figure imgf000045_0001
[0115] As defined generally above, L1 is absent, -NR3-, -S-, C(0)NR3-, -C(0)-C(0)-, or a bivalent optionally substituted group selected from Ci-6 alkylenyl, C2-6 alkynylenyl, -NR3-CI-6 alkylenyl, O-Co-6 alkylenyl, and -C(0)Co-6 alkylenyl. In some embodiments, L1 is absent, -NR3-, -0-, -S-, Ci-6 alkylenyl, C2-6 alkenylenyl, C2-6 alkynylenyl, -NR3-CI-6 alkylenyl, -O-C 1-6 alkylenyl, -C(0)Co- 6 alkylenyl, -C(0)NR3-, or -C(0)-C(0)-.
[0116] In some embdiments, L1 is absent. In some embodiments, L1 is -NR3-. In some embodiments, L1 is -N(0¾)-. In some embodiments, L1 is -NH-.
[0117] In some embodiments, L1 is -S-. In some embodiments, L1 is -C(0)NR3-. In some embodiments, L1 is -C(0)-C(0)-.
[01 IS] In some embodiments, L3is Ci-6 alkylenyl. In some embodiments, L1 is Ci-6 alkyl. In some embodiments, L1 is -CH2-. In some embodiments, L1 is -CH(CH3)- In some embodiments, L1 is
C2-6 alkynylenyl. In some embodiments, L1 is
Figure imgf000045_0002
.
[0119] In some embodiments, L1 is -NR3-CI-6 alkylenyl.
[0120] In some embodiments, L1 is -O-Co-6 alkylenyl. In some embodiments, L1 is -0-. In some embodiments, L1 is -O-Ci-6 alkylenyl. In some embodiments, L1 is -O-Ci-6 alkyl. In some embodiments, L1 is -O-C1-3 alkyl. In some embodiments, L1 is -O-CH2-.
[0121] In some embodiments, L1 is -C(0)Co-6 alkylenyl. In some embodiments, L1 is -C(O). In some embodiments, L1 is -C(0)Ci-6 alkylenyl. |0i 22 j As defined generally above, Z is Ci-6 aliphatic, 2- to 10-membered heteroaliphatic, P(0)(R3)2, -C(0)CI-6 aliphatic, C(0)N(R3)2, C6-12 aryl, C3-12 cycloalkyl, 4- to 16-membered monocyclic or polycyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S, or 5- to 12-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, wherein Z is substituted with (R2)q.
|0i 23 j In some embodiments, Z is C6-12 aryl or 4- to 16-membered monocyclic or polycyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S.
(0124| In some embodiments, Z is substituted with (R2)q. As defined generally above, q is 0, 1, 2, 3, or 4. That is, in some embodiments, Z is substituted with 0, 1, 2, 3, or 4 R2. In some embodiments, Z is unsubstituted (i.e., q is 0). In some embodiments, q is 1. In some embodiments, q is 2. In some embodiments, q is 3. In some embodiments, q is 4.
(0125] In some embodiments, Z is Ci-6 aliphatic. In some embodiments, Z is Ci-6 alkyl. In some embodiments, Z is C1-3 alkyl. In some embodiments, Z is methyl. In some embodiments, Z is ethyl.
|0i 26 j In some embodiments, Z is 2- to 10-membered heteroaliphatic. In some embodiments, Z is 2- to 5-membered heteroaliphatic. In some embodiments, Z is 3-membered heteroaliphatic. In some embodiments, Z is -O-CH3, -CH2-O-CH3, -O-CH2-CH2-O-CH2-CH2-O-CH3. In some embodiments, Z is -O-CH3. In some embodiments, Z is -CH2-O-CH3. In some embodiments, Z is -O-CH2-CH2-O-CH2-CH2-O-CH3.
(0127) In some embodiments, Z is C6-12 aryl. In some embodiments, Z is phenyl substituted with (R2)q. In some embodiments, Z is phenyl substituted with 0, 1, 2, 3, or 4 R2. In some embodiments, Z is unsubstituted phenyl. In some embodiments, Z is phenyl substituted with 1, 2, 3, or 4 R2. In some embodiments, Z is phenyl substituted with 1 or 2 R2. In some emboidments, Z is phenyl substituted with 1 or 2 halo.
10128J In some embodiments, Z is C3-12 cycloalkyl. In some embodiments, Z is cyclobutyl. In some embodiments, Z is cyclopentyl. In some embodiments, Z is cyclohexyl.
(0129] In some embodiments, Z is 4- to 16-membered monocyclic or polycyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, Z is 4- to 6- membered monocyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, Z is 4-membered monocyclic heterocyclyl comprising 1 heteroatom selected from N, O, and S. In some embodiments, Z is 5-membered monocyclic heterocyclyl comprising 1-2 heteroatoms selected from N, O, and S. In some embodiments, Z is 6-membered monocyclic heterocyclyl comprising 1-4 heteroatoms selected from N, O, and S. In some embodiments, Z is tetrahydropyranyl .
{0130] In some embodiments, Z is 10- to 12-membered bicyclic heterocyclyl. In some embodiments, Z is 10- to 12-membered fused bicyclic heterocyclyl. In some embodiments, Z is 10- to 12-membered bridged bicyclic heterocyclyl.
101311 In some embodiments, Z is 10- to 16-membered polycyclic hetercyclyl. In some embodiments, Z is 10-membered polycyclic heterocyclyl. In some embodiments, Z is 11- membered polycyclic heterocyclyl. In some embodiments, Z is 12-membered polycyclic heterocyclyl. In some embodiments, Z is 13-membered polycyclic heterocyclyl. In some embodiments, Z is 14-membered polycyclic heterocyclyl. In some embodiments, Z is 15- membered polycyclic heterocyclyl. In some embodiments, Z is 16-membered polycyclic heterocyclyl. In some embodiments, a polycyclic Z moiety is a spirocyclic or fused tricyclic moiety.
|0132j In some embodiments, Z is 9- to 12-membered spirocyclic heterocyclyl. In some embodiments, Z is 9-membered spirocyclic heterocyclyl. In some embodiments, Z is 10- membered spirocyclic heterocyclyl. In some embodiments, Z is 11-membered spirocyclic heterocyclyl. In some embodiments, Z is 12-membered spirocyclic heterocyclyl.
{0133] In some embodiments, Z is 5- to 12-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, Z is 5- to 6- membered monocyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, Z is 5-membered monocyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, Z is 6-membered monocyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S.
|0134| In some embodiments, Z is 8- to 12-membered bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, Z is 8-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, Z is 9-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, Z is 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, Z is 11-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, Z is 12-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S.
[0135] As defined generally above, each R2 is independently selected from halo, oxo, -CN, 0-R2a, -C(0)-R2a, -C(0)0-R2a, and an optionally group selected from Ci-6 aliphatic, Ce-u aryl, and 5- to 12-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S.
[0136] In some embodiments, each R2 is independently selected from halo, CN, C(0)0H, and an optionally substituted group selected from Ci-6 aliphatic, C(0)Ci-6 aliphatic, and O-Ci-6 aliphatic. [0137) In some embodiments, R2 is halo. In some embodiments, R2 is selected from fluoro, chloro, bromo, and iodo.
[0138] In some embodiments, R2 is oxo.
[0130] In some embodiments, R2 is CN.
[0140] In some embodiments, R2 is 0-R2a. In some embodiments, R2 is -OH. In some embodiments, R2 is an optionally substituted O-Ci-6 aliphatic. In some embodiments, R2 is optionally substituted O-Ci-6 alkyl. In some embodiments, R2 is optionally substituted O-Ci-4 alkyl. In some embodiments, R2 is optionally substituted O-C1-2 alkyl. In some embodiments, R2 is O-methyl. In some embodiments, R2 is O-ethyl.
[0141] In some embodiments, R2 is -C(0)-R2a.
[0142] In some embodiments, R2 is -C(0)0-R2a.
[0143] In some embodiments, R2 is an optionally substituted Ci-6 aliphatic. In some embodiments, R2 is optionally substituted Ci-6 alkyl. In some embodiments, R2 is optionally substituted Ci-4 alkyl. In some embodiments, R2 is optionally substituted C1-2 alkyl. In some embodiments, R2 is methyl. In some embodiments, R2 is ethyl.
[0144] In some embodiments, R2 is optionally substituted C6-12 aryl. In some embodiments, R2 is optionally substituted phenyl.
[0145] In some embodiments, R2 is optionally substituted 5- to 12-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, R2 is optionally substituted 5- to 6-membered monocyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S.
[0146] In some embodiments, a substituent on an optionally substituted carbon atom of an optionally substituted R2 group is halo (e.g., bromo, chloro, fluoro, iodo). [0147] As defined generally above, each R2a is independently H or an optionally substituted group selected from Ci-6 aliphatic, C3-12 cycloalphatic, and 4- to 12-membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, R2a is H. In some embodiments, R2a is optionally substituted Ci-6 aliphatic. In some embodiments, R2a is optionally substituted C3-12 cycloalphatic. In some embodiments, R2a is optionally substituted 4- to 12-membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S.
[0148] As defined generally above, each R3 is independently selected from H and optionally substituted Ci-6 aliphatic. In some embodiments, R3 is H. In some embodiments, R3 is an optionally substituted Ci-6 aliphatic. In some embodiments, R3 is optionally substituted Ci-6 alkyl. In some embodiments, R3 is optionally substituted Ci-4 alkyl. In some embodiments, R3 is optionally substituted C1-2 alkyl. In some embodiments, R3 is methyl. In some embodiments, R3 is ethyl.
[0149) In some embodiments, a substituent on an optionally substituted carbon atom of an optionally substituted R3 group is halo (e.g., bromo, chloro, fluoro, iodo).
IOISOI In some embodiments, Z is selected from Table Z
Table Z halo, -CH3, -CH2CH3, -CH2-CH2-0-CH3,-0-CH3, -O-CH2-CH3, -CH2-O-CH3, -O-CH2-CH2-O- CH2-CH2-O-CH3,
Figure imgf000049_0001
Figure imgf000050_0001
Figure imgf000051_0001
Figure imgf000052_0001
10151] As defined generally above, L2 an optionally substituted group selected from -(NR3)s-S(0)- Co-6 alkylenyl-, -(NR3)s-S(0)2-Co-6 alkylenyl-, -Ci-6 alkylenyl-S(0)-(NR3)s-, -Ci-6 alkylenyl-S(0)2- (NR3)S-, -(NR3)S-CO-6 alkylenyl, -(NR3)s-C(0)-Co-6 alkylenyl, and 4- to 12-membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S. j0152] In some embodiments, L2 is absent, -(NR3)s-S(0)-Co-6 alkylenyl-, -(NR3)s-S(0)2-Co-6 alkylenyl-, -(NR3)s-S(0)(NR3)-, -S(0)2-NR3-, -NR3-CI-6 haloalkylenyl, -(NR3)s-P(0)(R3)-, -Ci-e alkylenyl-S(O)-, -Ci-6 alkylenyl-S(0)2-, -C(0)-(NR3)s-, -(NR3)s-C(0)-, or an optionally substituted 4- to 12-membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S. j0153] In some embodiments, L2 is absent. 0154] In some embodiments, L2 is -(NR3)s-S(0)(NR3)-. In some embodiments, L2 is -S(0)(NH)- . In some embodiments, L2 is -(NR3)-S(0)(NR3)-. In some embodiments, L2 is -NH-S(0)(NH)-. In some embodiments, L2 is -N(CH3)-S(0)(NH)-.
[0155] In some embodiments, L2 is -S(0)2-NR3-. In some embodiments, L2 is -S(0)2-NH-. In some embodiments, L2 is -S(0)2-N(CH3)-.
[0156] In some embodiments, L2 is -(NR3)s-C(0)-(NR3)s-. In some embodiments, L2 is -C(O)- (NR3)S-. In some embodiments, L2 is -C(0)NH-. In some embodiments, L2 is -C(O)-. In some embodiments, L2 is -N(R3)-C(0)-. In some embodiments, L2 is -NH-C(O)-.
[0157] In some embodiments, L2 is -(NR3)s-C(0)-Co-6 alkylenyl. In some embodiments, L2 is -
C(O)-.
[0158] In some embodiments, L2 is -(NR3)s-P(0)(R3)-. In some embodiments, L2 is -P(0)(R3). In some embodiments, L2 is -(NR3)-P(0)(R3)-. In some embodiments, L2 is -P(0)(CH3)-. In some embodiments, L2 is -NH-P(0)(CH3)-. |0i 59 j In some embodiments, L2 is optionally substituted -(NR3)s-S(0)-Co-6 alkylenyl. In some embodiments, L2 is optionally substituted -(NR3)S-S(0)-CI-6 alkylenyl. In some embodiments, L2 is -(NR3)S-S(0)-CH2-. In some embodiments, L2 is -(NR3)s-S(0)-. In some embodiments, L2 is - S(O)-. In some embodiments, L2 is -NR3-S(0)-. In some embodiments, L2 is -NH-S(O)-. In some embodiments, L2 is -N(CH3)-S(0)-. fO!tjQj In some embodiments, L2 is -(NR3)s-S(0)2- Co-6 alkylenyl. In some embodiments, L2 is - (NR3)S-S(0)2- Ci-6 alkylenyl. In some embodiments, L2 is -(NR3)s-S(0)2-CH2-. In some embodiments, L2 is -(NR3)s-S(0)2-. In some embodiments, L2 is -S(0)2-. In some embodiments, L2 is -NR3 -S (0)2-. In some embodiments, L2 is -NH-S(0)2-. In some embodiments, L2 is - N(CH3)-S(0)2-. some embodiments, L2 is -NR3-Ci-6haloalkylenyl. j0162] In some embodiments, L2 is optionally substituted -Ci-6 alkylenyl-S(0)-(NR3)s-. In some embodiments, L2 is optionally substituted -Ci-6 alkylenyl-S(0)-N(R3)-. In some embodiments, L2 is optionally substituted -Ci-6 alkylenyl-S(0)-NH-. In some embodiments, L2 is optionally substituted -Ci-6 alkylenyl-S(O)-. In some embodiments, L2 is -CH2-S(0)-.
|01€$| In some embodiments, L2 is optionally substituted -Ci-6 alkylenyl-S(0)2-(NR3)s-. In some embodiments, L2 is optionally substituted -Ci-6 alkylenyl-S(O) 2-N(R3)-. In some embodiments, L2 is optionally substituted -Ci-6 alkylenyl-S(O) 2-NH-. In some embodiments, L2 is optionally substituted -Ci-6 alkylenyl-S(O) 2-. In some embodiments, L2 is -CH2-S(0) 2-.
J0164] In some embodiments, L2 is optionally substituted -(NR3)s-Co-6 alkylenyl. In some embodiments, L2 is optionally substituted -(NR3)s-Co-6 alkylenyl. In some embodiments, L2 is optionally substituted -NR3-CI-6 alkylenyl. In some embodiments, L2 is optionally substituted - NR3-Ci-3alkylenyl. In some embodiments, L2 is optionally substituted -NR3-CI alkylenyl. In some embodiments, L2 is -NH-CH2-. In some embodiments, L2 is -NH-CH(CF3)-.
|0M5| In some embodiments, L2 is optionally substituted 4- to 12-membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, L2 is a 4- to 6-membered monocyclic heterocyclcyl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, L2 is a 4-membered monocyclic heterocyclcyl comprising 1 heteroatom selected from N, O, and S. In some embodiments, L2 is a 5-membered monocyclic heterocyclcyl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, L2 is a 6-membered monocyclic heterocyclcyl comprising 1 to 4 heteroatoms selected from N, O, and S. j0166| In some embodiments, L2 is optionally substituted 8- to 12-membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, L2 is optionally substituted 8-membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, L2 is optionally substituted 9-membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, L2 is optionally substituted 10-membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, L2 is optionally substituted 11-membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, L2 is optionally substituted 12-membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S.
[0167) In some embodiments, a substituent on an optionally substituted carbon atom of an optionally substituted L2 group is halo (e.g., bromo, chloro, fluoro, iodo) or Ci-6 alkyl.
I0168J As defined generally above, V is Ci-6 aliphatic, Ce-u aryl, C3-12 cycloalkyl, 4- to 12- membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S, 5- to 12-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, or 5- to 16-membered monocyclic or polycyclic aryl, wherein V is substituted with (R6)m. j0169J In some embodiments, V is selected from Ci-6 aliphatic, C6-12 aryl, 4- to 12-membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S, 5- to 12-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from
N, O, and S, 5- to 12- membered monocyclic or bicyclic aryl, and C3-12 cycloalkyl, wherein V is substituted with (R6)m.
[0170) As defined generally above, V is substituted with (R6)m. As defined generally above, m is
O, 1, 2, 3, or 4. That is, in some embodiments, V is substituted with 0, 1, 2, 3, or 4 R6. In some embodiments, V is unsubstituted (i.e., m is 0). In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. j0171J In some embodiments, V is Ci-6 aliphatic. In some embodiments, V is is Ci-6 alkyl. In some embodiments, V is selected from methyl, ethyl, propyl, butyl, propyl, and hexyl. |0i 72 j In some embodiments, V is Ce-n aryl. In some embodiments, V is phenyl.
|0173] In some embodiments, V is C3-12 cycloalkyl. In some embodiments, V is C3-6 cycloalkyl. In some embodiments, V is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, V is cyclopropyl. In some embodiments, V is cyclobutyl. In some embodiments, V is cyclopentyl. In some embodiments, V is cyclohexyl.
(0174] In some embodiments, V is 4- to 12-membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, V is 4- to 6- membered monocyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, V is 4-membered heterocyclic comprising 1 heteroatom selected from N, O, and S. In some embodiments, V is 5-membered heterocyclic comprising 1 to 4 heteroatom selected from N, O, and S. In some embodiments, V is 6-membered heterocyclic comprising 1 to 4 heteroatom selected from N, O, and S. In some embodiments, V is morpholinyl. 0175] In some embodiments, V is 7- to 12-membered bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, V is 7-membered bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, V is 8-membered bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, V is 9-membered bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, V is 10-membered bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, V is 11-membered bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, V is 12-membered bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S. |0176] In some embodiments, V is 5- to 12- membered monocyclic or bicyclic aryl. In some embodiments, V is 5- to 6-membered aryl. In some embodiments, V is phenyl.
|0177 j In some embodiments, V is 5- to 12-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, V is 5- to 6- membered monocyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, V is 5- membered monocyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, V is 6-membered monocyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, V is pyridyl. j0178] In some embodiments, V is 7- to 12-membered bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, V is 7- membered bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, V is 8- membered bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, V is 9- membered bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, V is 10- membered bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, V is 11- membered bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, V is 12-membered bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, V is indolyl.
[0179) As defined generally above, each R6 is halo, -S(0)-R5, -S(0)2-R5, -S(0)(NH)-R5, -CN, - C(0)-R5, -C(0)0-R5, -C(0)-NH(R5), -C(0)-N(R5)2, -P(0)(R5)2, or an optionally substituted group selected from O-Ci-6 aliphatic, Ci-6 aliphatic, C3-12 cycloalkyl, and C6-12 aryl.
|0180| In some embodiments, each R6 is independently selected from halo, -S(0)-R5, -S(0)2-R5, -S(0)(NH)-R5, -CN, -C(0)-R5, -C(0)0-R5, -C(0)-NH(R5), -C(0)-N(R5)2, -P(0)(R5)2, or an optionally substituted group selected from O-Ci-6 alkyl, Ci-6 alkyl, and C6-12 aryl.
[0181] In some embodiments, R6 is -S(0)-R5, -S(0)2-R5, or an optionally substituted Ci-6 alkyl. [0182J In some embodiments, R6 is halo. In some embodiments, R6 is chloro, fluoro, bromo, or iodo. In some embodiments, R6 is fluoro. In some embodiments, R6 is chloro. In some embodiments, R6 is bromo. In some embodiments, R6 is iodo.
[0183) In some embodiments, R6 is -S(0)-R5. In some embodiments, R6 is -S(0)-CH3.
[0184) In some embodiments, R6 is -S(0)2-R5. In some embodiments, R6 is -S(0)2-Ci-6 alkyl. In some embodiments, R6 is -S(0)2-CH3. In some embodiments, R6 is -S(0)2-CH2CH3. In some embodiments, R6 is -S(0)2-CHF2. In some embodiments, R6 is -S(0)2-CF3.
[0185) In some embodiment, R6 is -S(0)2-N(CI-6 alkyl)2. In some embodiments, R6 is -S(0)2- N(CH3)2.
[0186) In some embodiments, R6 is S(0)(NH)-R5. In some embodiments, R6 is -S(0)(NH)-CH3. [0187) In some embodiments, R6 is -CN.
[0188) In some embodiments, R6 is -C(0)-R5. In some embodiments, R6 is -C(0)-CH3. In some embodiments, R6 is -C(0)-CF3. In some embodiments, R6 is -C(0)-pyrolidinyl.
[0189) In some embodiments, R6 is -C(0)0-R5. In some embodiments, R6 is -C(0)0-Ci-6 alkyl. In some embodiments, R6 is -C(0)0-CH3. In some embodiments, R6 is -C(0)0-CH2CH3. |0!90j In some embodiments, R6 is -C(0)-NH(R5). In some embodiments, R6 is -C(0)-NH(CH3). In some embodiments, R6 is -C(0)-NH-cyclopropyl.
|019I I In some embodiments, R6 is -C(0)-N(R5)2. In some embodiments, R6 is -C(0)-N(CH3)2. |0t92] In some embodiments, R6 is -P(0)(R5)2. In some embodiments, R6 is -R(0)(O¾)2.
10193] In some embodiments, R6 is optionally substituted O-Ci-6 aliphatic. In some embodiments, R6 is optionally substituted O-Ci-6 alkyl. In some embodiments, R6 is O-CH3. In some embodiments, R6 is O-CH2CH3. In some embodiments, R6 is O-CF3.
10194] In some embodiments, R6 is optionally substituted Ci-6 aliphatic. In some embodiments, R6 is Ci-6 alkyl. In some embodiments, R6 is Ci-4 alkyl. In some embodiments, R6 is methyl. In some embodiments, R6 is ethyl. In some embodiments, R6 is propyl. In some embodiments, R6 is butyl. In some embodimetns, R6 is /er/-butyl. In some embodiments, R6 is -CH2F. In some embodiments, R6 is -CHF2. In some embodiments, R6 is CF3. 0195] In some embodiments, R6 is C3-12 cycloalkyl. In some embodiments, R6 is C3-16 cycloalkyl. In some embodiments, R6 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
|0196j In some embodiments, R6 is optionally substituted C6-12 aryl.
|0197] In some embodiments, a substituent on an optionally substituted carbon atom of an optionally substituted R6 is halo (e.g., bromo, chloro, fluoro, iodo), Ci-6 alkyl, OH, or oxo. 0198] As defined generally above, each R5 is independently -OR3, C(0)-R3, P(0)(R3)2, -N(R3)2, or an optionally substituted group selected from Ci-6 aliphatic, C3-12 cycloalkyl, and 4- to 12- membered heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S.
]0199] In some embodiments, each R5 is independently selected from Ci-6 alkyl, -N(R3)2, -O-Ci-6 alkyl, C(0)-Ci-6 alkyl, P(0)(Ci-6 alkyl)2, C3-12 cycloalkyl, and 5- to 12-membered heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S, wherein R5 is optionally substituted with one or more substituents selected from halo and OH.
I0200J In some embodiments, R5 is Ci-6 alkyl. In some embodiments, R5 is -N(R3)2. In some embodiments, R5 is -NH2. In some embodiments, R5 is -NH(CI-6 aliphatic). In some embodiments, R5 is -NH(CH3). In some embodiments, R5 is -O-Ci-6 alkyl. In some embodiments, R5 is C(0)-Ci-6 alkyl. In some embodiments, R5 is P(0)(Ci-6 alkyl)2. In some embodiments, R5 is C3-12 cycloalkyl. In some embodiments, R5 is 5- to 12-membered heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S, wherein R5 is optionally substituted with one or more substituents selected from halo and OH. |0201j In some embodiments, V is selected from Table V
Table V
-CH2CH2CH3,
Figure imgf000058_0001
Figure imgf000059_0001
Figure imgf000060_0001
10202 J In some embodiments, the present application provides a compound of formula Ila:
Figure imgf000060_0002
Ila or a pharmaceutically acceptable salt thereof, wherein Cy, L1, Z, L2, V, and X6 are as defined herein. In some embodiments of formula Ila, X6 is CH. In some embodiments of formula Ila, X6” is N.
JO203] In some embodiments, the present application provides a compound of formula IIa-1:
Figure imgf000061_0001
IIa-1 or a pharmaceutically acceptable salt thereof, wherein Cy, Z, R6, and m are defined herein. 0204] In some embodiments, the present application provides a compound of formula IIa-1-i:
Figure imgf000061_0002
IIa-1-i or a pharmaceutically acceptable salt thereof, wherein Z, R6, and m are defined herein. 0205) In some embodiments, the present application provides a compound of formula IIa-1-ii:
Figure imgf000061_0003
IIa-1-ii or a pharmaceutically acceptable salt thereof, wherein Z, R6, and m are defined herein.
|O206j In some embodiments, the present application provides a compound of formula IIa-1-iii:
Figure imgf000062_0001
IIa-1-iii or a pharmaceutically acceptable salt thereof, wherein Z, R6, and m are defined herein.
|0207j In some embodiments, the present application provides a compound of formula IIa-2:
Figure imgf000062_0002
IIa-2 or a pharmaceutically acceptable salt thereof, wherein Z, R6, and m are defined herein. 0208) In some embodiments, the present application sprovides a compound of formula IIa-2-i:
Figure imgf000062_0003
IIa-2-i or a pharmaceutically acceptable salt thereof, wherein Cy, Z, R6, and m are defined herein. fO209J In some embodiments, the present application provides a compound of formula IIa-2-ii:
Figure imgf000063_0001
IIa-2-ii or a pharmaceutically acceptable salt thereof, wherein Z, R6, and m are defined herein.
[02101 In some embodiments, the present application provides a compound of formula IIa-3:
Figure imgf000063_0002
IIa-3 or a pharmaceutically acceptable salt thereof, wherein Z is defined herein.
[0211 ) In some embodiments, the present application provides a compound of formula IIa-3-i:
Figure imgf000063_0003
IIa-3-i or a pharmaceutically acceptable salt thereof, wherein Cy, Z, R6 and m are as defined here. 0212] In some embodiments, the present application provides a compound of formula IIa-3-ii:
Figure imgf000064_0001
IIa-3-ii or a pharmaceutically acceptable salt thereof, wherein Z, R6 and m are as defined herein.
10213] In some embodiments, the present application provides a compound of formula IIa-3-iii:
Figure imgf000064_0002
IIa-3-iii or a pharmaceutically acceptable salt thereof, wherein Z is defined herein. 0214) In some embodiments, the present application provides a compound of formula IIa-4:
Figure imgf000064_0003
or a pharmaceutically acceptable salt thereof, wherein Z, R6, and m are defined herein. |0215j In some embodiments, the present application provides a compound of formula IIa-4-i:
Figure imgf000065_0001
IIa-4-i or a pharmaceutically acceptable salt thereof, wheein Cy, Z, R6 and m are as defined herein. j0216J In some embodiments, the present application provides a compound of formula IIa-5:
Figure imgf000065_0002
IIa-5 or a pharmaceutically acceptable salt thereof, wherein Z, R6, and m as as defined herein.
In some embodiments, the present application provides a compound of formula IIa-5-i:
Figure imgf000065_0003
IIa-5-i or a pharmaceutically acceptable salt thereof, wherein Cy, Z, R6 and m are as defined herein. I0218J In some embodiments, the present application provides a compound of formula IIb-1:
Figure imgf000066_0001
or a pharmaceutically acceptable salt thereof, wherein R6, R2, m, and q are defined herein.
)0219] It is to be understood that the above embodiments may be combined together, as if each and every combination were specifically and individually listed. 0220) In some embodiments, a compound of the present disclosure (i.e., a compound of formula I-IIb-1) is selected from Table A:
Table A
Figure imgf000066_0002
Figure imgf000066_0003
Figure imgf000067_0001
Figure imgf000067_0002
Figure imgf000068_0001
Figure imgf000068_0002
Figure imgf000069_0002
Figure imgf000069_0001
Figure imgf000070_0002
Figure imgf000070_0001
Figure imgf000071_0002
Figure imgf000071_0001
Figure imgf000072_0002
Figure imgf000072_0001
Figure imgf000073_0001
Figure imgf000073_0002
Figure imgf000074_0002
Figure imgf000074_0001
Figure imgf000075_0001
Figure imgf000075_0002
Figure imgf000076_0002
Figure imgf000076_0001
Figure imgf000077_0001
Figure imgf000077_0002
Figure imgf000078_0002
Figure imgf000078_0001
Figure imgf000079_0002
Figure imgf000079_0001
Figure imgf000080_0001
Figure imgf000080_0002
Figure imgf000081_0002
Figure imgf000081_0001
Figure imgf000082_0002
Figure imgf000082_0001
Figure imgf000083_0001
Figure imgf000083_0002
Figure imgf000084_0002
Figure imgf000084_0001
Figure imgf000085_0001
Figure imgf000085_0002
Figure imgf000086_0001
Figure imgf000086_0002
Figure imgf000087_0002
Figure imgf000087_0001
Figure imgf000088_0002
Figure imgf000088_0001
Figure imgf000089_0001
Figure imgf000089_0002
Figure imgf000090_0002
Figure imgf000090_0001
Figure imgf000091_0002
Figure imgf000091_0001
Figure imgf000092_0002
Figure imgf000092_0001
Figure imgf000093_0002
Figure imgf000093_0001
Figure imgf000094_0001
Figure imgf000094_0002
Figure imgf000095_0002
Figure imgf000095_0001
Figure imgf000096_0002
Figure imgf000096_0001
Figure imgf000097_0002
Figure imgf000097_0001
Figure imgf000098_0001
Figure imgf000098_0002
Figure imgf000099_0001
Figure imgf000099_0002
Figure imgf000100_0001
Figure imgf000100_0002
Figure imgf000101_0002
Figure imgf000101_0001
Figure imgf000102_0002
|0221j In some embodiments, a compound of the present invention (i.e., a compound of any one of formulas I to IIb-1) is selected from Table B:
Table B
Figure imgf000102_0001
Figure imgf000103_0001
Figure imgf000104_0001
Figure imgf000105_0001
Figure imgf000106_0001
Figure imgf000107_0001
Figure imgf000108_0001
Figure imgf000109_0001
Figure imgf000110_0001
Figure imgf000111_0001
Figure imgf000112_0001
Figure imgf000113_0001
Figure imgf000114_0001
Figure imgf000115_0001
Figure imgf000116_0001
Figure imgf000117_0001
Figure imgf000118_0001
Characteristics j0222| Among other things, in some embodiments, the present disclosure describes one or more characteristics of certain TRPML1 modulators provided by and/or useful in the practice of the present disclosure.
I0223J In some embodiments, the present disclosure provides technologies for assessing one or more relevant characteristics and/or for identifying, selecting, prioritizing, and/or characterizing one or more useful TRPML1 modulators.
|0224| In some embodiments, the present disclosure provides certain biological and/or chemical assays (e.g., that facilitate and/or permit assessment of one or more feature(s) of TRMPL1 expression and/or activity, and/or of impact of TRPMLl modulator(s) on such expression and/or activity. Alternatively or additionally, the present disclosure provides technologies for identifying and/or characterizing one or more aspects of biological pathway(s) (e.g., autophagy pathway(s)) involving TRMPL1, and thus permits identification and/or characterization of additional useful targets within such pathway(s) and/or of modulator(s) that impact such pathway(s) (whether or not targeting TRPMLl itself).
Compositions j0225| In some embodiments, the present disclosure provides and/or utilizes a composition that comprises and/or delivers a compound as described herein (e.g., together with one or more other components).
|0226) In some embodiments, the present disclosure provides compositions that comprise and/or deliver compounds reported herein (e.g., compounds of Formula I-II), or an intermediate, degradant, or an active metabolite thereof, e.g., when contacted with or otherwise administered to a system or environment e.g., which system or environment may include TRPMLl activity; in some embodiments, administration of such a composition to the system or environment achieves the regulation of autophagy and lysosomal biogenesis as described herein.
[0227] In some embodiments, a provided composition as described herein may be a pharmaceutical composition in that it comprises an active agent (e.g., a compound of Formula I-II or an active metabolite thereof) and one or more pharmaceutically acceptable excipients (e.g., one or more pharmaceutically acceptable adjuvants, carriers, excipients, and/or vehicles); in some such embodiments, a provided pharmaceutical composition comprises and/or delivers a compound described herein (e.g., a compound of Formula I-IIb-1), or an active metabolite thereof to a relevant system or environment (e.g., to a subject in need thereof) as described herein.
[0228] In some embodiments, a provided composition (e.g., a pharmaceutical composition) includes a compound (e.g., as described herein) in a salt form such as a pharmaceutically acceptable salt form.
[0229] Is some embodiments, a provided composition (e.g., a pharmaceutical composition) may be formulated for administration to a subject (e.g., a human) according to a particular route (e.g., orally, parenterally, by inhalation or nasal spray, topically (e.g., as by powders, ointments, or drops), rectally, buccally, intravaginally, intraperitoneally, intracistemally or via an implanted reservoir, etc).
[0230] In some embodiments, a provided composition (e.g., a pharmaceutical composition) comprises or delivers an amount of a compound as described herein (or an active metabolite thereof) that is effective to measurably modulate TRPMLl activity, and/or to induce autophagy and/or lysosomal biogenesis in a biological sample or in a subject, when administered in accordance with a therapeutic regimen.
[0231 ] In certain embodiments, a provided compound or composition is formulated for administration to a patient in need of such composition. In some embodiments, a compound or composition as described herein may be administered in a dose amount and/or by a route of administration effective for treating or lessening the severity of a disease or disorder described herein.
[0232] In some embodiments, a composition (e.g., a pharmaceutical composition) as described herein may be formulated in unit form (e.g., which may offer ease of administration and/or uniformity of dosage). 10233) Those skilled in the art will appreciate that effective dose amounts may vary from subject to subject, for example depending on a variety of factors, including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed and its route of administration; the species, age, body weight, sex and diet of the patient; the general condition of the subject; the time of administration; the rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed, and the like. j0234| In some embodiments, an appropriate dosage level may be within a range of about 0.01 mg/kg to about 50 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect.
Applications and Uses
|0235j The present application provides a variety of uses and applications for compounds and/or compositions as described herein, for example in light of their activities and/or characteristics as described herein. In some embodiments, such uses may include therapeutic and/or diagnostic uses. Alternatively, in some embodiments such uses may include research, production, and/or other technological uses.
10236| Among other things, in some embodiments, the present disclosure provides technologies for modulating TRPMLl activty. In some embodiments, the present application relates to a method of modulating TRPMLl activty in a subject comprising administering to the subject a provided compound, or a composition as described herein.
Diseases, Disorders, and Conditions
10237) The present disclosure demonstrates that compounds and/or compositions as described herein may be useful in medicine (e.g., in the treatment of one or more diseases, disorders, or conditions).
10238| Among other things, as described herein, the present disclosure provides an insight that targeting (e.g., agonizing) TRPMLl may be a particularly effective strategy for modulating (e.g., enhancing) autophagy and/or lysosomal biogenesis.
|0239 j In some embodiments, a disease, disorder or condition that may be treated as described herein may be or comprise a disease, disorder or condition associated with TRPMLl deficiency. Furthermore, in some embodiments, the present disclosure identifies that TRMPL1 deficiency is associated with particular diseases, disorders or conditions, some or all of which may be treated in accordance with the present disclosure.
{0240] In some embodiments, treatment provided herein involves administration of a TRMPL1 modulator as described herein in an amount effective to modulate TRMPL1 activity in a lysosome and/or increase autophagy.
{0241J In some embodiments, a disease, disorder, or condition amenable to treatment as described herein is or comprises a liver disease, a neurodegenerative disorder, cancer, or a heart disease. {0242] In some embodiments, a disease, disorder, or condition amenable to treatment as described herein is or comprises a lysosomal storage disease, such as Niemann-Pick C (NPC) disease, Gaucher disease, and Pompe disease.
{0243! In some embodiments, a disease, disorder, or condition amenable to treatment as described herein is an age-related common neurodegenerative disease, such as Alzheimer’s Disease, Parkinson’s Disease, and Huntington’s Disease.
{0244] In some embodiments, a disease, disorder, or condition amenable to treatment as described herein is a type IV Mucolipidosis (ML4) neurodegenerative lysosomal storage disease caused by mutations in TRPMLl.
{0245] In some embodiments, a disease, disorder, or condition amenable to treatment as described herein is related to reactive oxygen species or oxidative stress.
{0240] In some embodiments, the present application relates to use of a compound and/or composition described herein for use in the manufacture of a medicament e.g., for modulation of TRPMLl activity.
{0247] In some embodiments, the present application relates to use of a compound and/or composition described herein for use in the manufacture of a medicament for treating a disease, disorder or condition, e.g., through modulation of TRPMLl activity; in some emebodiments, the disease, disorder, or condition is a liver disease, a neurodegenerative disorder, cancer, or a heart disease.
{0248] In some embodiments, a disease, disorder, or condition is a muscular disease, a liver disease, a metabolic disease, an atherosclerotic disease, an inflammatory bowel disease, an atherosclerotic disease, a neurodegenerative disease, or an oncological disease. In some embodiments, a disease, disorder, or condition is a muscular disease. In some embodiments, a muscular disease is a muscular dystrophy. In some embodiments, a muscular dystrophy is Duchenne muscular dystrophy.
[0249] In some embodiments, a disease, disorder, or condition is an infectious disease. In some embodiments, an infectious disease is an infection of Heliobacter pylori or Mycobacterium tuberculosis.
[0250] In some embodiments, a disease, disorder, or condition is tuberculosis.
Exemplary Embodiments
[0251] The following numbered embodiments, while non-limiting, are exemplary of certain aspects of the disclosure:
1. A compound of Formula II:
Figure imgf000122_0001
II or a pharmaceutically acceptable salt thereof, wherein
Xr , X2”, and X7 are each independently selected from N, NRa, C, and CRax, wherein Xr , X2”, and X7 are N, C, or CRa when bound to Cy-L'-Z or L2-V X3”, X4 , X5 , and X6 are each independently selected from N, C, and CRa, wherein X3 , X4 , X5 , and X6 are N or C when bound to Cy-L'-Z or L2-V;
Cy is absent, 4- to 12-membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, P, and S, 5- to 12-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, Ci-6 aliphatic, or C3-12 cycloalkyl, wherein Cy is optionally substituted with one or more of R1;
L1 is absent, -NR3-, -0-, -S-, Ci-6 alkylenyl, C2-6 alkynylenyl, -NR3-CI-6 alkylenyl,-0-Ci-6 alkylenyl,
-C(0)Co-6 alkylenyl; -C(0)NR3-, -C(0)-C(0)-;
L2 is -(NR3)S-S(0)-CO-6 alkylenyl-, -(NR3)s-S(0)2-Co-6 alkylenyl-, -(NR3)s-S(0)(NR3)-, -S(0)2- NR3-, -NR3-Ci-6haloalkylenyl, -(NR3)s-P(0)(R3)-, -Ci-6 alkylenyl-S(O)-, -Ci-6 alkylenyl- S(0)2-, -C(0)-(NR3)S-, -(NR3)S-C(0)-, or an optionally substituted 4- to 12-membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S;
V is selected from Ci-6 aliphatic, Ce-u aryl, 4- to 12-membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S, 5- to 12-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S,
5- to 12-membered monocyclic of bicyclic aryl, and C3-12 cycloalkyl, wherein Vis substituted with (R6)m;
Z is Ci-6 aliphatic, 2- to 10-membered heteroaliphatic, P(0)(R3)2, -C(0)Ci-6 aliphatic, C(0)N(R3)2, C6-12 aryl, C3-12 cycloalkyl, 4- to 16-membered monocyclic or polycyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S, or 5- to 12-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, wherein Z is substituted with (R2)q; each Ra is independently halo, oxo, or optionally substituted Ci-6 aliphatic; each R1 is independently selected from N(R3)2, OH, CN, C(0)NHR3, and an optionally substituted group selected from Ci-6 aliphatic and N(R3)-C(0)-CI-6 alkyl; each R2 is independently selected from halo, -CN, C(0)0H, and an optionally substituted group selected from Ci-6 alkyl, C(0)Ci-6 aliphatic, and O-Ci-6 aliphatic; each R3 is independently selected from H and optionally substituted Ci-6 aliphatic; each R5 is independently selected from Ci-6 alkyl, -N(CI-6 alkyl)2, -O-Ci-6 alkyl, C(0)-Ci-6 alkyl, P(0)(Ci-6 alkyl)2, C3-12 cycloalkyl, and 5- to 12-membered heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S, wherein R5 is optionally substituted with one or more substituents selected from halo and OH; each R6 is halo, -S(0)-R5, -S(0)2-R5, -S(0)(NH)-R5, -CN, -C(0)-R5, -C(0)0-R5, -C(0)-NH(R5), -C(0)-N(R5)2, -P(0)(R5)2, or an optionally substituted group selected from O-Ci-6 alkyl, Ci-6 alkyl, and C6-12 aryl; m is 0, 1, 2, 3, or 4; q is 0, 1, 2, 3, or 4; and s is 0 or 1. 2. The compound of any one of the preceding embodiments, wherein Cy is absent or 4- to 12-membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from
N, O, and S.
3. The compound of any one of the preceding embodiments, wherein Cy is absent.
4. The compound of any one of the preceding embodiments, wherein Cy is 4- to 12- membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N,
O, and S.
5. The compound of any one of the preceding embodiments, wherein Cy is 4- to 6- membered monocyclic heterocyclic comprising 1 to 3 heteroatoms selected from N, O, and S.
6. The compound of any one of the preceding embodiments, wherein Cy is piperdinyl or piperzinyl.
7. The compound of any one of the preceding embodiments, wherein Cy is selected from Table Cy.
8. The compound of any one of the preceding embodiments, wherein L1 is absent, -NR3-, or Ci-6 alkylenyl.
9. The compound of any one of the preceding embodiments, wherein L1 is absent.
10. The compound of any one of the preceding embodiments, wherein L1 is-NR3-.
11. The compound of any one of the preceding embodiments, wherein L2 is absent, -(NR3)S-S(0)-CO-6 alkylenyl, or -(NR3)s-S(0)2-Co-6 alkylenyl.
12. The compound of any one of the preceding embodiments, wherein L2 is absent, -(NR3)S- S(O)-, or -(NR3)S-S(0)2-. 13. The compound of any one of the preceding embodiments, wherein L2 is absent or -(NR3)S-S(0)2,
14. The compound of any one of the preceding embodiments, wherein L2 is -NR3-S(0)2-.
15. The compound of any one of the preceding embodiments, wherein L2 is -NH-S(0)2-.
16. The compound of any one of the preceding embodiments, wherein Z is C6-12 aryl, 2- to 10- membered heteroaliphatic, 4- to 12-membered monocyclic or polycyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S, or 5- to 12-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, wherein Z is substituted with (R2)q.
17. The compound of any one of the preceding embodiments, wherein Z is C6-12 aryl or 4- to 12-membered monocyclic or polycyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S.
18. The compound of any one of the preceding embodiments, wherein Z is C6-12 aryl.
19. The compound of any one of the preceding embodiments, wherein Z is C6-12 aryl substituted with 1, 2, 3, or 4 R2.
20. The compound of any one of the preceding embodiments, wherein R2 is halo.
21. The compound of any one of the preceding embodiments, wherein Z is selected from Table Z.
22. The compound of any one of the preceding embodiments, wherein V is C6-12 aryl or 4- to 12-membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S. 23. The compound of any one of the preceding embodiments, wherein V is Ce-n aryl.
24. The compound of any one of the preceding embodiments, wherein V is Ce-n aryl substituted with 1, 2, 3, or 4 R6.
25. The compound of any one of the preceding embodiments, wherein R6 is halo, S(0)-R5, S(0)2-R5, S(0)(NH)-R5, or an optionally substituted O-Ci-6 alkyl.
26. The compound of any one of the preceding embodiments, wherein R6 is S(0)-R5, S(0)2-R5, or an optionally substituted Ci-6 alkyl.
27. The compound of any one of the preceding embodiments, wherein R6 is halo.
28. The compound of any one of the preceding embodiments, wherein R6 is fluoro or chloro.
29. The compound of any one of the preceding embodiments, wherein R6 is S(0)2-R5.
30. The compound of any one of the preceding embodiments, wherein R6 is -S(0)2-Ci-6 alkyl.
31. The compound of any one of the preceding embodiments, wherein R6 is -S(0)2-CH3.
32. The compound of any one of the preceding embodiments, wherein R6 is -S(0)2-N(CI-6 alkyl)2.
33. The compound of any one of the preceding embodiments, wherein R6 is -S(0)2-N(CH3)2.
34. The compound of any one of the preceding embodiments, wherein V is selected from Table V. 35. The compound of any one of the preceding embodiments, wherein V is selected from - CH2CH2CH3,
Figure imgf000127_0001
Figure imgf000128_0001
36. The compound of any one of the preceding embodiments, wherein the compound is of formula IIa-1-i:
Figure imgf000129_0001
IIa-1-i or a pharmaceutically acceptable salt thereof.
37. The compound of any one of the preceding embodiments, wherein the compound is of formula IIa-1-ii:
Figure imgf000129_0002
or a pharmaceutically acceptable salt thereof.
38. The compound of any one of the preceding embodiments, wherein the compound is of formula IIa-2:
Figure imgf000130_0001
or a pharmaceutically acceptable salt thereof.
39. The compound of any one of the preceding embodiments, wherein the compound is of formula IIa-3 :
Figure imgf000130_0002
IIa-3 or a pharmaceutically acceptable salt thereof.
40. The compound of any one of the preceding embodiments, wherein the compound is of formula IIa-4:
Figure imgf000131_0001
IIa-4 or a pharmaceutically acceptable salt thereof.
41. The compound of any one of the preceding embodiments, wherein the compound is of formula IIb-1:
Figure imgf000131_0002
IIb-1 or a pharmaceutically acceptable salt thereof.
41. A compound selected from Table A.
42. A compound selected from Table B.
43. A pharmaceutical composition comprising a compound of any one of the preceding embodiments and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
44. A method of modulating TRPMLl comprising administering to a subject a compound of any one of the preceding embodiments. 45. A method of treating a disease, disorder, or condition in a subject comprising administering a compound of any one of the preceding embodiments.
46. The method of embodiment 45, wherein the disease, disorder, or condition is a lysosomal storage disorder.
47. The method of embodiment 46, wherein the lysosomal storage disorder is selected from Niemann-Pick C disease, Gaucher disease, and Pompe disease.
48. The method of embodiment 45, wherein the disease, disorder, or condition is age-related common neurodegenerative disease.
49. The method of embodiment 48, wherein the disease, disorder, or condition is selected from Alzheimer’s Disease, Parkinson’s Disease, and Huntington’s Disease.
50. The method of embodiment 45, wherein the disease, disorder, or condition is a type IV Mucolipidosis (ML4) neurodegenerative lysosomal storage disease caused by mutations in TRPML1.
EXEMPLIFICATION
I0252J The present teachings include descriptions provided in the Examples that are not intended to limit the scope of any claim. Unless specifically presented in the past tense, inclusion in the Examples is not intended to imply that the experiments were actually performed. The following non-limiting examples are provided to further illustrate the present teachings. Those of skill in the art, in light of the present application, will appreciate that many changes can be made in the specific embodiments that are provided herein and still obtain a like or similar result without departing from the spirit and scope of the present teachings
Table of Abbreviatons
ACN
Figure imgf000132_0001
Acetonitrile
Figure imgf000132_0002
Figure imgf000133_0001
Figure imgf000134_0002
Synthetic Examples j0253| As depicted in the Examples below, in certain exemplary embodiments, compounds are prepared according to the following general procedures. It will be appreciated that, although the general methods depict the synthesis of certain compounds of the present invention, the following general methods, and other methods known to one of ordinary skill in the art, can be applied to all compounds and subclasses and species of each of these compounds, as described herein.
Certain Synthetic Intermediates
Scheme 1:
Procedure for synthesis of l-(2, 3-dimethoxyphenyl)ethan-l-one
Figure imgf000134_0001
Step 1 ep
Step-1: Synthesis of l-(2,3-dimethoxyphenyl)ethan-l-ol: j0254| To a stirred solution of 2,3-dimethoxybenzaldehyde (1 g, 6.01 mmol, 1 eq) in THF (20 mL ) was added dropwise a 3 M solution of methyl magnesium bromide in diethyl ether (3ml, 9.03 mmol, 1.5 eq) at 0° C. The reaction mixture was stirred at room temperature for overnight. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layers were washed with water, brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by silica gel column chromatography to afford the titled compound l-(2,3- dimethoxyphenyl)ethan-l-ol (0.7 g, 64%). LCMS: 183.09 [M+H]+.
Step-2: Synthesis of l-(2,3-dimethoxyphenyl)ethan-l-one: 02 SS I To a stirred mixture of l-(2,3-dimethoxyphenyl)ethan-l-ol (0.8 g, 4.39 mmol, 1 eq) in acetone (20 ml), was added 2 M Jones reagent in aq. H2SO4 (6.6 ml, 13.18 mmol, 3 eq) at room temperature. The reaction mixture was stirred at room temperature for 30 min. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with isopropanol and concentrated under reduced pressure. The crude product was purified by column chromatography to afford the desired product l-(2,3-dimethoxyphenyl)ethan- 1-one (0.6 g, 76%). LCMS: 181.08 [M+l]+.
Procedure for synthesis of 1 -methyl- lH-indole-4-carbaldehyde
Figure imgf000135_0001
Step 1
Step-1: Synthesis of 1 -methyl- lH-indole-4-carbaldehyde:
[0256] To a stirred solution of lH-indole-4-carbaldehyde (1 g, 6.8 mmol, 1 eq) in DMF (10 mL) was added NaH (0.130 g, 7.4 mmol, 1.1 eq) at 0 °C under the nitrogen atmosphere followed by addition of methyl iodide (1.06 g, 7.5 mmol, 1.1 eq). The reaction mixture was stirred at 0°C for 1 hour. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was quenched with water and extracted with ethyl acetate. The organic layers were washed with water, brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography to afford the titled compound 1 -methyl - lH-indole-4-carbaldehyde (0.90 g, 82.56%). LCMS: 160.07 [M+H]+. Scheme 2
Figure imgf000136_0001
Step-1: General procedure for synthesis of l-Boc-4-aryl-3,6-dihydropyridine derivatives: j0257l Method A (Ar=a/c/f): A pyrex tube was charged with respective aryl halides (1.1 eq), tert- butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-l(2H)-carboxylate (1 eq), 2 M Na2CCb solution (3 eq) in a mixture of 1,4 dioxane:H20 (4:1, 10 vol) and the reaction mixture was purged with argon for 15 min. Tetrakis(triphenylphosphine)palladium(0) (0.1 eq) was added to then reaction under an argon atmosphere and purged the reaction mixture with argon for 15 min. The tube was then fitted with a screw cap and the reaction was stirred at 90 °C for 3 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture cooled to room temperature, filtered through a pad of Celite and the Celite pad was washed with ethyl acetate. The filtrate was diluted with water and extracted ethyl acetate. The combine organic layers were washed with water and brine, dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel to afford respective l-Boc-4-aryl-3,6-dihydropyridine derivative.
I0258J Method B (Ar=b/e/g): A pyrex tube was charged with respective aryl halide (1.1 eq), tert- butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-l(2H)-carboxylate (1 eq), potassium carbonate (2 eq) in a mixture of DMEvThO (5:1, 10 vol) and the reaction mixture was purged with argon for 10 min. [l,T-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.1 eq) was then added to the reaction under an argon atmosphere and purged the reaction mixture with argon for 5 min. The tube was then fitted with a screw cap and the reaction was stirred at 80 °C for 16 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was cooled to room temperature, filtered through a pad of Celite and the Celite pad was washed with ethyl acetate. The filtrate was diluted with water and extracted ethyl acetate. The combine organic layers were washed with water and brine, dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel to afford respective l-Boc-4-aryl-3,6-dihydropyridine derivative. [0259] Method C (Ar=d): A pyrex tube was charged with respective aryl halide (1.1 eq), tert- butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-l(2H)-carboxylate (1 eq), cesium carbonate (2 eq) in a mixture of 1,4 dioxaneiLLO (4:1, 10 vol) and the reaction mixture was purged with argon for 10 min. Diehl orobis(triphenylphosphine)palladium(II) (0.1 eq) was then added to the reaction under an argon atmosphere and purged the reaction mixture with argon for 15 min. The tube was then fitted with a screw cap and the reaction was stirred at 80 °C for 12 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture cooled to room temperature, filtered through a pad of Celite and the Celite pad was washed with ethyl acetate. The filtrate was diluted with water and extracted ethyl acetate. The combine organic layers were washed with water and brine, dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel to afford respective l-Boc-4-aryl-3,6-dihydropyridine derivative.
Step-2: General procedure for synthesis of l-Boc-4-arylpiperidine derivatives:
[0260] Method A (Ar=a/b): A solution of respective l-Boc-4-aryl-3,6-dihydropyridine (1 eq) in ethyl acetate was purged with nitrogen for 10 min. Platinum(IV) oxide (10% w/w) was added to the reaction under a nitrogen atmosphere at room temperature. The reaction mixture was purged with hydrogen for 2 - 3 minutes and stirred at room temperature for 3 h under an atmosphere of hydrogen (100 Psi pressure). The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through a pad of Celite and the Celite pad was washed with ethyl acetate. The filtrate was concentrated under reduced pressure to dryness to afford respective l-Boc-4-arylpiperidine derivative. The crude product was used in the next step without further purification.
[0261 j Method B (Ar=c/d/e/f/g): A solution of respective l-Boc-4-aryl-3,6-dihydropyridine (1 eq) in methanol was purged with nitrogen for 10 min. 10-20% Palladium on carbon (10% w/w) was added to the reaction under nitrogen atmosphere at room temperature. The reaction mixture was purged with hydrogen for 2-3 minutes and stirred at room temperature for 12 h under an atmosphere of hydrogen under balloon pressure. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was filtered through a pad of Celite and the Celite pad was washed with methanol. The filtrate was concentrated under reduced pressure to dryness to afford respective l-Boc-4-arylpiperidine derivative. The crude product was used in the next step without further purification.
Step-3: General procedure for synthesis of 4-arylpiperidine derivatives: j0262] Method A (Ar=a/c/e/f/g): To stirred solution of respective l-Boc-4-arylpiperidine (1 eq) in DCM (5 vol), a 50% solution of trifluoroacetic acid solution in DCM (5 Vol) was added dropwise at 0 °C. The reaction mixture was warmed to room temperature and stirred for 2 to 16 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with saturated aqueous NaHCCh solution and extracted with DCM. The combined organic layers were washed with water and brine, dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure to dryness to afford the respective 4-arylpiperidine derivative. The crude product was used in the next step without further purification. j0263] Method B (Ar=b/d): To a stirred solution of respective l-Boc-4-arylpiperidine (1 eq) in 1,4-dioxane (10 vol), a 4 M solution of HC1 in 1,4-dioxane (5 vol) was added at 5 to 10 °C. The reaction mixture was warmed to room temperature and stirred for 4 to 16 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, the residue was dissolved in saturated aqueous NaHCCh solution and extracted with DCM. The combined organic layers were washed with water and brine, dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure to dryness to afford the respective 4-arylpiperidine derivative. The crude product was used in the next step without further purification.
Figure imgf000139_0001
Figure imgf000140_0005
Synthesis of 3-(piperidin-4-yl)isoxazole
Boc
Figure imgf000140_0001
/ \
Boc
Figure imgf000140_0002
0 °C-rt, 2 h
Step 5
Figure imgf000140_0004
Figure imgf000140_0003
Step-1: Synthesis of tert-butyl (E)-4-((hydroxyimino)methyl)piperidine-l-carboxylate:
|0264j To a stirred solution of tert- butyl 4-formylpiperidine-l-carboxylate (1 g, 4.6 mmol, 1 eq) in water (10 mL) in methanol (10 mL), hydroxyl amine hydrochloride (390 mg, 5.6 mmol, 1.2 eq) followed by Na2CCb (248 mg, 2.3 mmol, 0.5 eq) were added. The reaction mixture was stirred at room temperature for 12 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure to dryness to afford the titled compound /er/-butyl (E)- 4-((hydroxyimino)methyl)piperidine-l-carboxylate (The reaction was repeated on 1 g scale) (1.9 g, crude, combined yields from 1 g x 2 batches). This compound was used in the next step without further purification. LCMS: 229.15 [M+H]+. Step-2: Synthesis of tert-butyl (Z)-4-(chloro(hydroxyimino)methyl)piperidine-l-carboxylate:
[02651 To a stirred solution of tert- butyl (E)-4-((hydroxyimino)methyl)piperidine-l-carboxylate (1 g, 4.4 mmol, 1 eq) in DMF (3 mL), N-chlorosuccinimide (0.59 g, 4.4 mmol, 1 eq) was added. The reaction mixture was stirred at room temperature for overnight. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water, the resulting solid was filtered out and dried under reduced pressure to afford the titled compound /cvV-butyl (Z)-4-(chloro(hydroxyimino)methyl)piperidine-l-carboxylate (1 g, Crude). This compound was used in the next step without further purification. LCMS: 263.11 [M+H]+.
Step-3: Synthesis of tert-butyl 4-(5-(trimethylsilyl)isoxazol-3-yl)piperidine-l-carboxylate:
[0266) To a stirred solution of tert- butyl (Z)-4-(chloro(hydroxyimino)methyl)piperidine-l- carboxylate (1.7 g, 6.4 mmol, 1 eq) in ethyl acetate (100 mL), ethynyltrimethylsilane (3.14 g, 32 mmol, 5 eq) followed by triethyl amine (1.24 g, 9.6 mmol, 1.5 eq) were added at 0 °C. The reaction mixture was warmed to room temperature and stirred for 12 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel to afford the titled compound /cvV-butyl 4-(5 -(trimethyl silyl)isoxazol- 3-yl)piperidine-l-carboxylate (2 g, 96%). LCMS: 325.19 [M+H]+.
Step-4: Synthesis of tert-butyl 4-(isoxazol-3-yl)piperidine-l-carboxylate:
[0267] To a stirred solution of /er/-butyl 4-(5-(trimethylsilyl)isoxazol-3-yl)piperidine-l- carboxylate (1.4 g, 4.3 mmol, 1 eq) in a mixture of water (1 mL) and methanol (10 mL), potassium bifluoride (33 mg, 0.43 mmol, 0.1 eq) was added. The reaction mixture was stirred at room temperature for 6 days. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and the residue was dissolved in ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous Na2SC>4 and concentrated under reduced pressure to afford the titled compound tert- butyl 4-(isoxazol-3-yl)piperidine-l-carboxylate (1 g, crude). This compound was used in the next step without further purification. LCMS: 253.15 [M+H]+. Step-5: Synthesis of 3-(piperidin-4-yl)isoxazole:
[02681 To a stirred solution of /ert-butyl 4-(isoxazol-3-yl)piperidine-l-carboxylate (1 g, 4 mmol, 1 eq) in DCM (20 mL), trifluoroacetic acid (10 mL) was added dropwise at 0 °C. The reaction mixture was warmed to room temperature and stirred for 2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to dryness to afford the titled compound 3-(piperidin-4-yl)isoxazole (1 g. crude). This compound was used in the next step without further purification. LCMS: 153.09 [M+H]+.
Synthesis of 3-formyl-2-methoxybenzonitrile
Figure imgf000142_0001
Step 1: Synthesis of 3-formyl-2-hydroxybenzonitrile: j0269| To a stirred solution of 2-hydroxybenzonitrile (1 g, 8.39 mmol, 1 eq) in acetic acid (10 mL), hexamethylenetetramine (1.8 g, 12.59 mmol, 1.5 eq) was added. The reaction was stirred at 120 °C for 2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with water. The organic layer was dried over anhydrous Na2S04, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel to afford the titled compound 3- formyl-2-hydroxybenzonitrile (105 mg, 8.5%) and 5-formyl-2-hydroxybenzonitrile (330 mg, 27%). LCMS: No ionization. Step 2: Synthesis of 2-formyl-2-methoxyhenzonitrile: jO270| To a stirred solution of 3-formyl-2-hydroxybenzonitrile (100 mg, 0.68 mmol, 1 eq) in DMF (2 mL), potassium carbonate (188 mg, 1.36 mmol, 2 eq) followed by iodomethane (145 mg, 1.02 mmol, 1.5 eq) were added. The reaction was stirred at room temperature for 5 h. The progress of the reaction was monitored by TLC. After completion of the reaction, water was added to the reaction mixture and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure to dryness to afford the titled compound 3-formyl-2-methoxybenzonitrile (100 mg, crude). This compound was used in the next step without further purification. LCMS: No ionization.
Synthesis of (pyridin-2-ylmethoxy)benzaldehyde derivatives
Figure imgf000143_0001
Step 1
General procedure for synthesis of (pyridin-2-ylmethoxy)benzaldehyde derivatives:
|02711 To a stirred solution of respective hydroxybenzaldehyde (1 eq) in DMF (10 vol), potassium carbonate (3 eq) followed by 2-(chloromethyl)pyridine hydrochloride (1.1 eq) were added. The reaction was stirred at 80 °C for 12 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction was cooled to room temperature; ice-cold water was added and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel to afford the respective (pyridin-2-ylmethoxy)benzaldehyde derivative.
Figure imgf000143_0002
Figure imgf000144_0002
Synthesis of [l,l'-biphenyl]-4-carbaldehyde
Figure imgf000144_0001
Step 1
|0272j A pyrex tube was charged with a solution of 4-bromobenzaldehyde (1.86 g, 10.06 mmol, 1.2 eq), phenylboronic acid (1 g, 8.38 mmol, 1 eq) and K3PO4 (4.44 g, 20.9 mmol, 2.5 eq) in water (3 mL) and 1,4-dioxane (6 mL). The tube was sealed with a septum and the reaction mixture was purged with argon via an argon balloon for 15 min. PdCl2(dppf) (183 mg, 0.25 mmol, 0.03 eq) was then added to the reaction under an argon atmosphere and the purging with argon was continued for 5 min. The tube was then sealed with a screw cap and the reaction was heated at 100 °C for 12 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction was cooled to room temperature and the reaction mixture was filtered through a pad of Celite and the Celite pad was washed with ethyl acetate. The filtrate was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure to dryness to afford the titled compound [1, l'-biphenyl]- 4-carbaldehyde (500 mg, crude). This compound was used in the next without further purification. LCMS: No ionization. Synthesis of 3,4-dimethoxypicolinaldehyde
Figure imgf000145_0001
[0273) To a stirred solution of 3,4-dimethoxypyridine (250 mg, 1.79 mmol, 1 eq) in THF (5 mL), 1.6 M solution of n-BuLi in hexane (1.2 mL, 1.97 mmol, 1.1 eq) was added dropwise at -78 °C under an argon atmosphere. The reaction was stirred at the same temperature for 30 min. DMF (0.31 mL, 3.95 mmol, 2.2 eq) was then added to the reaction at -78 °C under an argon atmosphere. The reaction was stirred at the same temperature for 30 min under an argon atmosphere. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction was quenched with saturated aqueous MLCl solution and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel to afford the titled compound 3,4-dimethoxypicolinaldehyde (62 mg, 20.6%). LCMS: 168.10 [M+H]+.
Synthesis of 4,5-dimethoxynicotinaldehyde
Figure imgf000145_0002
Step-1: Synthesis of 4-chloro-3-methoxypyridine :
[0274) To a stirred solution of 4-chl oropyri din-3 -ol (1 g, 7.71 mmol, 1 eq) in toluene (10 mL), a solution of cyanomethyltributylphosphorane (CMBP) 1 M in toluene (23.1 mL, 23.1 mmol, 3 eq) followed by methanol (0.93 mL, 23.1 mmol, 3 eq) were added at 0 °C. The reaction was warmed to room temperature and stirred for 3 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel to afford the titled compound 4-chl oro-3-methoxypyri dine (280 mg, 25.45%). LCMS: 144.00 [M+H]+. Step-2: Synthesis of 4-chloro-5-methoxynicotinaldehyde: j027$j A stirred solution of 4-chloro-3-methoxypyridine (180 mg, 1.25 mmol, 1 eq) in THF (5 mL) was cooled to -78 °C and to which a 2 M solution of LDA in THF (1.25 mL, 2.51 mmol, 2 eq) was added. The reaction was stirred at the same temperature for 30 min. N,N- Dimethylformamide (0.19 mL, 2.51 mmol, 2 eq) was then added to the reaction at -78 °C. The reaction was gradually warmed to room temperature and stirred for 2.5 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to 0 °C, quenched with saturated aqueous MLCl solution and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure to dryness to afford the titled compound 4-chloro-5- methoxynicotinaldehyde (210 mg, crude). This compound was used in the next step without further purification. LCMS: 172.00 [M+H]+.
Step-3: Synthesis of 4,5-dimethoxynicotinaldehyde: j0276| To a stirred solution 4-chloro-5-methoxynicotinaldehyde (200 mg, 1.16 mmol, 1 eq) in methanol (5 mL), sodium methoxide (126 mg, 2.33 mmol, 2 eq) was added and the reaction was stirred at 60 °C for 5 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure to dryness. The crude product was purified by column chromatography on silica gel to afford the titled compound 4,5- dimethoxynicotinaldehyde (83 mg, 43%). LCMS: 168.10 [M+H]+.
Synthesis of 2,3-dimethoxyisonicotinaldehyde
Figure imgf000146_0001
ep j0277J To a stirred solution of 2,3-dimethoxypyridine (1 g, 7.18 mmol, 1 eq) in THF, 2.5 M solution of n-BuLi in hexane (6.33 mL, 15.7 mmol, 2.2 eq) was added dropwise at -78 °C under an argon atmosphere. The reaction was warmed to 0 °C and stirred for 1 h. DMF (2.4 mL, 31.4 mmol, 4.38 eq) was then added dropwise to the reaction at -78 °C under an argon atmosphere. The reaction was warmed to 0 °C and stirred for 30 min under an argon atmosphere. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction was quenched with saturated aqueous NFLCl solution and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel to afford the titled compound 2,3-dimethoxyisonicotinaldehyde (250 mg, 20.83%). LCMS: 168.00 [M+H]+.
Synthesis of 4-(4-chlorophenyl)piperidine
Figure imgf000147_0001
Step-1: Synthesis of tert-butyl 4-(4-chlorophenyl)-3,6-dihydropyridine-l(2H)-carboxylate j0278l A pyrex tube was charged with a solution of l-bromo-4-chlorobenzene (2 g, 10.44 mmol, 1 eq), tert- butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-l(2H)- carboxylate (3.87 g, 12.53 mmol, 1.2 eq) and potassium carbonate (2.8 g, 20.6 mmol, 2.5 eq) in a mixture of water (4 mL) and DMF (20 mL). The tube was sealed with a septum and the reaction mixture was purged with argon via an argon balloon for 15 min. [1,1'- Bis(diphenylphosphino)ferrocene]palladium(II) dichloride (752 mg, 1.04 mmol, 0.1 eq) was then added to the reaction under an argon atmosphere and the purging with argon was continued for 5 min. The tube was then sealed with a screw cap and the reaction was heated at 80 °C for 12 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction was cooled to room temperature and the reaction mixture was filtered through a pad of Celite and the Celite pad was washed with ethyl acetate. The filtrate was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel to afford the titled compound tert- butyl 4-(4-chlorophenyl)-3,6-dihydropyridine- 1 (2H)-carboxylate (1.5 g, 49%). LCMS: 294.10 [M+H]+. Step-2: Synthesis of tert-butyl 4-(4-chlorophenyl)piperidine-l-carboxylate j0279J To a stirred solution of tert-butyl 4-(4-chlorophenyl)-3,6-dihydropyridine-l(2H)- carboxylate (1 g, 3.4 mmol, 1 eq) in ethyl acetate (20 mL), the reaction mixture was purged with nitrogen for 5 min and platinum(IV) oxide (150 mg, 15% w/w) was added under an atmosphere of nitrogen. The reaction mixture was then purged with hydrogen for 2 min and stirred at room temperature for 3 h under an atmosphere of hydrogen via hydrogen balloon. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through a pad of Celite and the Celite pad was washed with ethyl acetate. The filtrate was concentrated under reduced pressure to dryness to afford the titled compound tert-butyl 4-(4- chlorophenyl)piperidine-l-carboxylate (900 mg, crude). This compound was used in the next step without further purification. LCMS: 296.10 [M+H]+.
Step-3: Synthesis of 4-(4-chlorophenyl)piperidine
|0280| To a stirred solution of tert- butyl 4-(4-chlorophenyl)piperidine-l-carboxylate (990 mg, 3.35 mmol, 1 eq) in DCM (5 mL), trifluoroacetic acid (5 mL) was added dropwise at 0 °C. The reaction was warmed to room temperature and stirred for 2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in saturated aqueous NaHCCb solution and extracted with DCM. The combined organic layers were dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel to afford the titled compound 4-(4-chlorophenyl)piperidine (600 g, 91.6%). LCMS: 196.10 [M+H]+.
Synthesis of tert-butyl 3-(((methylsulfonyl)oxy)methyl)pyrrolidine-l-carboxylate
Figure imgf000148_0001
0 C-rt, 4 h feoc steP'1 feoc Step-2 feoc Step-3 feoc Step-1: Procedure for synthesis of l-(tert-butyl) 3-methyl pyrrolidine-1, 3-dicar boxy late
[02811 To a stirred solution of 1 -( / -butoxy carbonyl )py rrol i di ne-3 -carboxyl i c acid (5 g, 23.23 mmol, 1 eq) in acetone (20 mL), cesium carbonate (15.14 g, 46.46 mmol, 2 eq) followed by iodomethane (4.9 g, 34.85 mmol, 1.5 eq) were added. The reaction was stirred at room temperature for 4 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was dissolve in water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure to dryness to afford the titled compound 1 -{tert- butyl) 3 -methyl pyrrolidine- 1, 3 -dicarboxylate (3 g, crude). This compound was used in the next step without further purification. LCMS: 230.15 [M+H]+.
Step-2: Procedure for synthesis of tert-butyl 3-(hydroxymethyl)pyrrolidine-l-carboxylate:
10282 j To a stirred solution of 1 -(/cvV-butyl) 3-methyl pyrrolidine- 1,3 -dicarboxylate (3 g, 13.33 mmol, 1 eq) in methanol (10 mL), sodium borohydride (1.5 g, 39.99 mmol, 3 eq) was added in portions at 0 °C. The reaction was warmed to room temperature and stirred for 2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction was quenched with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel to afford the titled compound /cvV-butyl 3- (hydroxymethyl)pyrrolidine-l-carboxylate (1 g, 50%). LCMS: 202.15 [M+H]+.
Step-3: Procedure for synthesis of tert-butyl 3-(((methylsulfonyl)oxy)methyl)pyrrolidine-l- carboxylate:
[0283] To a stirred solution of tert- butyl 3-(hydroxymethyl)pyrrolidine-l-carboxylate (500 mg, 2.53 mmol, 1 eq), triethyl amine (0.71 mL, 5.07 mmol, 2 eq) and DMAP (31 mg, 0.025 mmol, 0.01 eq) in DCM (5 mL), methanesulfonyl chloride (0.24 mL, 3.04 mmol, 1.2 eq) was added dropwise at 0 °C. The reaction was warmed to room temperature and stirred for 4 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction was quenched with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure to dryness to afford the titled compound tert-butyl 3 -(((methyl sulfonyl)oxy)methyl)pyrrolidine-l-carboxylate (600 mg, crude). This compound was used in the next step without further purification. Synthetic Examples
Example Bl: Synthetic scheme for synthesis of 4-((3-(6'-fluoro-l'- methylspiro[cyclohexane-l,3'-indolin]-4-yl)-lH-indol-l-yl)sulfonyl)-N,N- dimethylbenzenesulfonamide (B-5):
Figure imgf000150_0001
Procedure for synthesis of 8-(2,4-difluorophenyl)-l ,4-dioxaspiro[4.5]decane-8-carbonitrile B1.3:
|0284) To a stirred solution of l-(2,4-difluorophenyl)-4-oxocyclohexane-l-carbonitrile Bl.l (5.4 g, 22.9 mmol, 1 eq) in toluene (60 mL) was added p-toluenesulfonyl chloride (0.872 g, 4.59 mmol, 0.2 eq) and ethylene glycol B1.2 (4.25 g, 68.7 mmol, 3 eq). The reaction mixture was heated at 110 °C for 16 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The crude product was purified by Combiflash chromatography on silica gel to afford the titled compound 8-(2,4-difluorophenyl)-l,4- dioxaspiro[4.5]decane-8-carbonitrile B1.3 (5.18 g, 81.2%). LCMS: 280.10 [M+H]+.
Procedure for synthesis of 6-fluorodispiro [indoline-3, -cyclohexane -4' 2"-[ 1 ,3]dioxolane] B 1.4 :
|0285j To a stirred solution of 8-(2,4-difluorophenyl)-l,4-dioxaspiro[4.5]decane-8-carbonitrile B1.3 (5.15 g, 18.4 mmol, 1 eq) in THF (60 mL) was added a 2 M solution of LAH in THF (10.14 mL, 20.2 mmol, 1.1 eq) at 0 °C. The reaction mixture was warmed to room temperature and heated at 70 °C for 16 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature, quenched with saturated aqueous Na2SC>4 solution, the resultant precipitate was filtered off and the filtration cake was washed with ethyl acetate. The filtrate was diluted with ethyl acetate, washed with brine, dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The crude product was purified by Combiflash chromatography on silica gel to afford the titled compound 6-fluorodispiro[indoline- 3 , 1 '-cyclohexane-4',2"-[ 1 ,3 ]dioxolane] B1.4 (4.12 g, 80.2%). LCMS: 264.10 [M+H]+.
Procedure for synthesis of 6-fluoro-l-methyldispiro[indoline-3,l '-cyclohexane-4', 2"-
[1,3 ] dioxolane ] Bl.5:
[0284] To a stirred solution of 6-fluorodispiro[indoline-3,r-cyclohexane-4',2"-[l,3]dioxolane] B1.4 (4.1 g, 15.5 mmol, 1 eq) in DMF (40 mL), a 60% suspension of sodium hydride in mineral oil (1.24 g, 31.1 mmol, 2 eq) was added at 0 °C. The reaction mixture was stirred at the same temperature for 10 min. To the resulting reaction mixture, methyl iodide (1.93 mL, 31.1 mmol, 2 eq) was added at 0 °C. The reaction mixture was warmed to room temperature and stirred for 3 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with cold water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The crude product was purified by Combiflash chromatography on silica gel to afford the titled compound 6-fluoro-l-methyldispiro[indoline-3,T-cyclohexane-4',2"-
[1,3] dioxolane] B1.5 (2.81 g, 65.2%). LCMS: 278.15 [M+H]+.
Procedure for synthesis of 6'-fluoro-l'-methylspiro[cyclohexane-l,3'-indolin]-4-one B1.6
[02871 To a stirred solution of 6-fluoro-l-methyldispiro[indoline-3,T-cyclohexane-4',2"-
[1,3] dioxolane] B1.5 (2.8 g, 10.1 mmol, 1 eq) in THF (20 mL) was added a 50% aqueous HC1 solution (4 mL). The reaction mixture was heated at 70 °C for 1 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure to dryness to afford the titled compound 6'-fluoro-r-methylspiro[cyclohexane-l,3'- indolin]-4-one B1.6 (1.58 g, crude). This compound was used in the next step without further purification. LCMS: 234.10 [M+H]+. General procedure for synthesis of 6'-fluoro-4-(lH-indol-3-yl)-r-methylspiro[cyclohexane-l,3'~ indolin]-3-ene B1.8
|0288| To a stirred solution of 6'-fluoro-T-methylspiro[cyclohexane-l,3'-indolin]-4-one B1.6 (1 eq) in methanol (20 vol) was added potassium hydroxide (5 eq) and followed by the addition of lH-indole B1.7 (1 eq). The reaction mixture was heated at 100 °C for 24 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with water, acidified with 2 N aqueous HC1 and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The crude product was purified by Combiflash chromatography on silica gel to afford the titled compound d’-fluoro-l’^lH-indol-S-yl^r-methylspirofcyclohexane-l^'-indolinJ-S-ene B1.8. LCMS: 333.20 [M+H]+.
General procedure for synthesis of 6'-fluoro-4-(lH-indol-3-yl)-r-methylspiro[cyclohexane-l,3'~ indoline] B 1.9:
[0289] A stirred solution of 6’-fluoro- -(lH-indol-3-yl)- -methylspiro[cyclohexane-l,3'- indolin]-3-ene B1.8 (1 eq) in methanol (20 vol) was purged with nitrogen for 10 min. 10% Palladium on carbon (30% w/w) was added to the reaction under nitrogen atmosphere. The reaction mixture was purged with hydrogen and the reaction mixture was stirred at room temperature for 2 h under a hydrogen atmosphere (50 psi). The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through a pad of Celite and the Celite pad was washed with methanol. The filtrate was concentrated under reduced pressure to dryness to afford the titled compound 6'-fluoro-4-(lH-indol-3-yl)-T- methylspiro[cyclohexane-l,3'-indoline] B1.9 (crude). This compound was used in the next step without further purification. LCMS: 335.20 [M+H]+. General procedure for synthesis of 4-((3-(6'-fluoro-r-methylspiro[cyclohexane-l,3'-indolin]-4- yl)-lH-indol-l-yl)sulfonyl)-N,N-dimethylhenzenesulfonamide (B-5): j0290l To a stirred solution of 6'-fluoro-4-(lH-indol-3-yl)-r-methylspiro[cyclohexane-l,3'- indoline] B1.9 (1 eq) in DCM (20 vol), potassium hydroxide (2 eq) and TBA.HSO4 (0.2 eq) were added at 0 °C. To the resulting reaction mixture 4-(N,N-dimethylsulfamoyl)benzenesulfonyl chloride Bl.10 (1.2 eq) was added at 0 °C. The reaction mixture was warmed to room temperature and stirred for 5 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The crude product was purified by Combiflash chromatography on silica gel to afford the titled compound 4-((3-(6'-fluoro-r-methylspiro[cyclohexane-l,3'-indolin]-4-yl)- lH-indol-l-yl)sulfonyl)-N,N-dimethylbenzenesulfonamide (B-5). Yield: 15 mg, 11%; Appearance: Light yellow solid; ¾ NMR (400 MHz, DMSO-de) d 8.18 (d, J= 8.0 Hz, 2H), 7.91 (d, J= 12 Hz, 3H), 7.66 (d, J= 7.6 Hz, 1H), 7.59 (s, 1H), 7.36 (t, J= 7.6 Hz, 1H), 7.28 (t, J= 12 Hz, 1H), 6.96 (t, J= 6.4 Hz, 1H), 6.36 - 6.27 (m, 2H), 2.88 - 2.80 (m, 1H), 2.74 (s, 3H), 2.59 (s, 6H), 1.90 (d, J = 12.4 Hz, 2H), 1.81 - 1.54 (m, 6H), (2H merged with the moisture peak); HPLC purity: 98.82%; LCMS calculated for C30H32FN3O4S2: 581.18; Observed: 582.25 [M+H]+.
10291] The following examples were prepared using standard chemical manipulations and procedures similar to those used for the preparation of the previous example.
Figure imgf000153_0001
Example B2: Synthetic scheme for synthesis of G-(1-((4-(N,N- dimethylsulfamoyl)phenyl)sulfonyl)-lH-indazol-3-yl)-6-fluoro-l,l-dimethylspiro[indoline- 3,4'-piperidin]-l-ium formate B-21):
Figure imgf000154_0001
J0292] To a stirred solution of 4-((3-(4-(aminomethyl)-4-(2,4-difluorophenyl)piperidin-l-yl)-lH- indazol-l-yl)sulfonyl)-N,N-dimethylbenzenesulfonamide (B-34, see Example B27) (300 mg, 0.50 mmol, 1 eq) and 37% aqueous formaldehyde solution (0.41 mL, 5.09 mmol, 10 eq) in acetonitrile (20 mL), titanium tetra-isopropoxide (1.44 mL, 5.09 mmol, 10 eq) was added at room temperature and the reaction mixture was stirred at the same temperature for 12 h. To the resulting reaction mixture sodium cyanoborohydride (157 mg, 2.50 mmol, 5 eq) was added at room temperature and the reaction mixture was stirred at the same temperature for 3 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The crude product was purified by reverse phase preparative HPLC to afford the titled compound 1'-(1-((4-(N,N- dimethylsulfamoyl)phenyl)sulfonyl)-lH-indazol-3-yl)-6-fluoro-l,l-dimethylspiro[indoline-3,4'- piperidin]-l-ium formate (B-21). Yield: 20 mg, 6%; Appearance: White solid; ¾ NMR (400 MHz, DMSO-de) d 8.11 (d, J= 8.5 Hz, 1H), 8.07 - 7.97 (m, 4H), 7.90 (d, J= 8.0 Hz, 2H), 7.73 - 7.60 (m, 2H), 7.52 (t, J= 8.5 Hz, 1H), 7.41 (t, J= 7.2 Hz, 1H), 4.43 (s, 2H), 4.06 (d, J= 12.0 Hz, 2H), 3.62 (s, 6H), 3.09 (t, J= 12.5 Hz, 2H), 2.61 (s, 6H), 2.13 (t, J= 11.0 Hz, 2H), 1.96 (d, J = 12.5 Hz, 2H); HPLC purity: 97.33%; LCMS Calculated for C29H33FN5O4S2: 598.20; Observed: 597.95 [M]+. Example B3: Synthesis of 4-((3-(l-(4-chloro-2-fluorophenyl)piperidin-4-yl)-lH-indol-l- yl)sulfonyl)-N,N-dimethylbenzenesulfonamide (B-138)
Scheme 1
Figure imgf000155_0001
General synthesis of 3-(l-(4-chloro-2-fluorophenyl)-l,2,3,6-tetrahydropyridin-4-yl)-lH-indole B3.3
}0293J To a stirred solution of indole B3.2 (100 mg, 0.85 mmol, 1 eq) and l-(4-chloro-2- fluorophenyl)piperidin-4-one B3.1 (388 mg, 1.90 mmol, 3 eq) in methanol (10 mL) was added KOH (130 mg, 3.4 mmol, 4 eq) at room temperature. The reaction mixture was stirred at 65 °C for 24 h. The progress of reaction was monitored by TLC. After completion, the reaction mixture was quenched with 2 N HC1, concentrated under reduced pressure. The crude was diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with water, brine, dried over anhydrous Na2SC>4, filtered and concentrated under reduced to afford the 3-(l-(4-chloro- 2-fluorophenyl)-l,2,3,6-tetrahydropyridin-4-yl)-lH-indole B3.3 (110 mg, 39.5%). LCMS: 327.10 [M+H]+.
General synthesis of 3-(l-(4-chloro-2-fluorophenyl)piperidin-4-yl)-lH-indole B3.4 j0294l To a stirred solution of 3-(l-(4-chloro-2-fluorophenyl)-l,2,3,6-tetrahydropyridin-4-yl)- lH-indole B3.3 (110 mg, 0.3 mmol, 1 eq) in a mixture of methanol and ethyl acetate (1:1, 6 mL) was added Pd/C at 0 °C, stirred the reaction mixture for 10 min followed by drop wise addition of tri ethyl silane (0.8 mL, 5 mmol, 15 eq). The reaction mixture was stirred under hydrogen atmosphere (balloon pressure) at room temperature for 16h. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was filtered through a pad of Celite and the Celite pad was washed with methanol. The filtrate was evaporated under reduced pressure to afford 3-(l-(4-chloro-2-fluorophenyl)piperidin-4-yl)-lH-indole B3.4 (110 mg, crude). The crude was used as such for next step without purification. LCMS: 329.11 [M+H]+.
General synthesis of 4-((3-(l-(4-chloro-2-fluorophenyl)piperidin-4-yl)-lH-indol-l-yl)sulfonyl)- N,N-dimethylbenzenesulfonamide (B-138) f0295j To a stirred solution of 3-(l-(4-chloro-2-fluorophenyl)piperidin-4-yl)-lH-indole B3.4 (110 mg, 0.33 mmol, 1 eq) in THF (10 mL) was added potassium tertiary butoxide (0.6 mL, 0.66 mmol, 2 eq) and 18-crown-6 (17 mg, 0.06 mmol, 0.2 eq) at 0 °C, stirred the reaction mixture for 10 min at same temperature followed by addition of 4-(N,N-dimethylsulfamoyl)benzenesulfonyl chloride B3.5 (142 mg, 0.5 mmol, 1.5 eq). The reaction mixture was stirred at room temperature for 12 h. The progress of reaction was monitored by TLC. After completion, the reaction mixture was concentrated, diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with water, brine, dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure to the desired product. The crude was purified by prep HPLC to provide 4-((3- ( 1 -(4-chloro-2-fluorophenyl)piperidin-4-yl)- lH-indol- 1 -yl)sulfonyl)-N,N- dimethylbenzenesulfonamide (B-138). Yield: 35 mg, 18.2%; Appearance: white solid; ¾ NMR (400 MHz, DMSO-de) d 8.23 - 8.21 (m, 2H), 7.96 - 7.91 (m, 3H), 7.71 - 7.69 (m, 1H), 7.64 (m, 1H), 7.40 - 7.28 (m, 3H),7.21 - 7.18 (m, 1H), 7.12 - 7.08 (m, 1H), 3.44 - 3.36 (m, 2H), 2.96 - 2.82 (m, 3H), 2.6 (s, 6H), 2.08 - 2.02 (m, 2H), 1.88 (m, 2H); HPLC purity: 97.98%; LCMS Calculated for C27H27CIFN3O4S2: 575.11; Observed: 576.2 [M+H]+.
[0296J The following examples were prepared using standard chemical manipulations and procedures similar to those used for the preparation of the previous example as indicated in the table below:
Figure imgf000157_0001
Figure imgf000158_0001
Example B4: Synthetic scheme for Synthesis of 4-((3-(4-((dimethylamino)methyl)-4-(4- fluorophenyl)piperidin-l-yl)-lH-indazol-l-yl)sulfonyl)-N,N-dimethylbenzenesulfonamide
(B-15):
Figure imgf000159_0001
10297] To a stirred solution of l-(l-((4-(N,N-dimethylsulfamoyl)phenyl)sulfonyl)-lH-indazol-3- yl)-4-(4-fluorophenyl)-N,N-dimethylpiperidine-4-carboxamide (B-14) (1 g, 1.6 mmol, 1 eq) in THF (30 mL), a 1 M solution of BH3.DMS in THF (4.8 mL, 4.8 mmol, 3 eq) was added at room temperature. The reaction mixture was then heated at 80 °C for 12 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature and quenched with methanol. The mixture was concentrated under reduced pressure, the residue was dissolved in saturated aqueous NaHCCb solution and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The crude product was purified by reverse phase preparative HPLC to afford the 4-((3 -(4-((dimethylamino)methyl)-4-(4-fluorophenyl)piperi din- 1 -yl)- 1 H-indazol- 1 -yl)sulfonyl)- N,N-dimethylbenzenesulfonamide (B-15). Yield: 70 mg, 7.16%; Appearance: Off white solid; 'H NMR (400 MHz, CD3OD) d 8.14 (d, J= 8.4 Hz, 1H), 8.00 (d, J= 8.8 Hz, 2H), 7.84 - 7.78 (m, 3H), 7.63 - 7.56 (m, 3H), 7.35 (t, J= 7.6 Hz, 1H), 7.22 - 7.15 (m, 2H), 3.90 - 3.82 (m, 2H), 3.20 (s, 2H), 3.14 - 3.05 (m, 2H), 2.67 - 2.60 (m, 2H), 2.63 (s, 6H), 2.27 (s, 6H), 2.12 - 2.02 (m, 2H); HPLC purity: 98.56%; LCMS Calculated for C29H34FN5O4S2: 599.20; Observed: 600.25 [M+H]+. Example B5: General procedure for synthesis of 3-(8-(5-chloropyridin-2-yl)-3,8- diazabicyclo[3.2.1]octan-3-yl)-l-tosyl-lH-pyrazolo[4,3-b]pyridine (B-77):
Figure imgf000160_0001
Step-1: General procedure for synthesis of 3-(3,8-diazabicyclo[3.2.1]octan-3-yl)-l-tosyl-lH- pyrazolo[4,3-b]pyridine B5.2:
I0298J To a stirred solution of /ert-butyl 3-(l-tosyl-lH-pyrazolo[4,3-b]pyridin-3-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate B5.1 (805 mg, 1.66 mmol, 1 eq) in dry DCM (4 mL) dropwise TFA (4 mL) was added at 0°C and the reaction mixture was stirred at room temperature for 4 h. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was diluted with water & extracted with DCM. The organic layer was separated & concentrated under reduced pressure to afford 3-(3,8-diazabicyclo[3.2.1]octan-3-yl)-l-tosyl-lH-pyrazolo[4,3- bjpyridine B5.2 (0.55 g, Crude). The crude was used as such next step without purification. LCMS: 384.14 [M+H]+.
Step-2: General procedure for synthesis of 3-(8-(5-chloropyridin-2-yl)-3,8- diazabicyclo[3.2.1]octan-3-yl)-l-tosyl-lH-pyrazolo[4,3-b]pyridine (B-77): 0299) To a stirred solution of 3-(3,8-diazabicyclo[3.2.1]octan-3-yl)-l-tosyl-lH-pyrazolo[4,3- bjpyridine B5.2 (100 mg, 0.7 mmol, 1 eq) and 2-bromo-5-chloropyridine B5.3 (320 mg, 0.84 mmol, 1.1 eq) in DMF (10 mL) was added DIPEA (245 mg, 1.9 mmol, 2.5 eq) at room temperature. The reaction mixture was stirred at 120 °C for 12h. The reaction progress was monitored by TLC. After completion, the reaction mixture was concentrated and resulting residue was partitioned between water and ethyl acetate. The organic layer was separated, washed with water and 1% HC1, dried over Na2SC>4 and concentrated. The crude was purified by silica gel column chromatography to provide 3-(8-(5-chloropyridin-2-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-l-tosyl-lH- pyrazolo[4,3-b]pyridine (B-77). Yield: 8 mg, 2.23 %; Appearance: Off-white solid; ¾NMK (400 MHz, DMSO-de) d 8.61 (d, J= 4.5 Hz, 1H), 8.39 (d, J= 8.5 Hz, 1H), 8.13 (d, J= 2.5 Hz, 1H), 7.69 - 7.57 (m, 4H), 7.31 (d, J= 8.1 Hz, 2H), 6.92 (d, J= 9.0 Hz, 1H), 4.71 - 4.65 (m, 2H), 4.36 (d, J= 12.4 Hz, 2H), 3.23 (d, J= 12.2 Hz, 2H), 2.29 (s, 3H), 1.92 (dd, J= 8.4, 4.1 Hz, 2H), 1.74 (t, J= 6.6 Hz, 2H); HPLC purity: >99%; LCMS Calculated for C24H23CIN6O2S: 494.13; Observed: 495.10 [M+H]+. j0300l The following examples were prepared using standard chemical manipulations and procedures similar to those used for the preparation of the previous example as indicated in the table below.
Figure imgf000161_0001
Example B6: Synthetic scheme for Synthesis of 3-(4-(5-chloro-3-fluoropyridin-2- yl)piperidin-l-yl)-l-((4-methoxyphenyl)sulfonyl)-lH-pyrazolo[4,3-b]pyridine (B-49):
Figure imgf000162_0001
j0301l To a stirred solution of lH-pyrazolo[4,3-b]pyridine B6.1 (3.7 g, 31.09 mmol, 1 eq) in a mixture of methanol (25 mL) and water (25 mL), bromine (5.92 g, 37.31 mmol, 1.2 eq) was added dropwise at 0 °C. The reaction was stirred at the same temperature for 1 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was neutralized with saturated aqueous NaHCCb solution and observed the precipitation. The precipitate was filtered out, washed with water and dried under reduced pressure to dryness to afford 3-bromo-lH-pyrazolo[4,3-b]pyridine B6.2 (5.9 g, crude). This compound was used in the next step without further purification. LCMS: 198.00 [M+H]+.
Step-2: Synthesis of 3-bromo-l-((4-methoxyphenyl)sulfonyl)-lH-pyrazolo[4,3-b]pyridine B6.4: jO302J To a stirred solution of 3-bromo-lH-pyrazolo[4,3-b]pyridine B6.2 (1 g, 5.07 mmol, 1 eq) in DCM (10 mL), potassium hydroxide (0.568 g, 10.15 mmol, 2 eq) and TBA.HSCL (0.258 g, 0.761 mmol, 0.15 eq) were added at 0 °C and the reaction was for 10 min. 4- methoxybenzenesulfonyl chloride B6.3 (1.25 g, 6.09 mmol, 1.2 eq) was then added to the reaction at 0 °C. The reaction was warmed to room temperature and stirred for 12 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was added water and extracted with DCM. The combined organic layers were dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel to afford 3-bromo-l-((4-methoxyphenyl)sulfonyl)-lH-pyrazolo[4,3- b]pyridine B6.4 (1.8 g, 97%). LCMS: 368.00 [M+H]+. Step-3: Synthesis of 3-(4-(5-chloro-3-fluoropyridin-2-yl)piperidin-l-yl)-l-((4- methoxyphenyl)sulfonyl)-lH-pyrazolo[ 4, 3-b ] pyridine (B-49): j0303| To a stirred solution of 5-chloro-3-fluoro-2-(piperidin-4-yl)pyridine B6.5 (500 mg, 2.33 mmol, 1 eq) and 3-bromo-l-((4-methoxyphenyl)sulfonyl)-lH-pyrazolo[4,3-b]pyridine B6.4 (943 mg, 2.57 mmol, 1.1 eq) in propionitrile (10 mL), DIPEA (1.22 mL, 7.01 mmol, 3 eq) was added. The reaction was stirred at 150 °C for 12 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in DCM, washed with water and brine. The combined organic layers were dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel followed by reverse phase preparative HPLC to afford 3-(4-(5-chloro-3-fluoropyridin-2- yl)piperidin-l-yl)-l-((4-methoxyphenyl)sulfonyl)-lH-pyrazolo[4,3-b]pyridine (B-49). Yield: 25 mg, 2.13%; Appearance: Off white solid; *H NMR (400 MHz, DMSOe) d 8.63 (d, J = 4.4 Hz, 1H), 8.44 - 8.39 (m, 2H), 8.03 (dd, J= 2.0, 10.0 Hz, 1H), 7.72 (d, J= 8.8 Hz, 2H), 7.62 (dd, J = 4.4, 8.4 Hz, 1H), 7.02 (d, J= 8.8 Hz, 2H), 4.78 (d, J= 12.8 Hz, 2H), 3.76 (s, 3H), 3.35 - 3.25 (m, 1H), 3.18 - 3.10 (m, 2H), 1.83 - 1.75 (m, 4H); HPLC purity: 99.63%; LCMS calculated for C23H21CIFN5O3S: 501.10; Observed: 502.05 [M+H]+.
(0304] The following examples were prepared using standard chemical manipulations and procedures similar to those used for the preparation of the previous example as indicated in the table.
Figure imgf000163_0001
Figure imgf000164_0001
Figure imgf000165_0001
Example B7: Synthetic scheme for synthesis of ethyl 4-(2,4-difluorophenyl)-l-(l-((4-(N,N- dimethylsulfamoyl)phenyl)sulfonyl)-lH-indazol-3-yl)piperidine-4-carboxylate (B-29) and 4- ((3-(4-(2,4-difluorophenyl)-4-(hydroxymethyl)piperidin-l-yl)-lH-indazol-l-yl)sulfonyl)- N,N-dimethylbenzenesulfonamide (B-27):
Figure imgf000166_0001
Step-1: Synthesis of 4-(2,4-difluorophenyl)-l-(lH-indazol-3-yl)piperidine-4-carboxamide B7.2 and ethyl 4-(2,4-difluorophenyl)-l-(lH-indazol-3-yl)piperidine-4-carboxylate B7.3: j0305| To a stirred solution of 4-(2,4-difluorophenyl)-l-(lH-indazol-3-yl)piperidine-4- carbonitrile B7.1 (0.9 g, 2.6 mmol, 1 eq) in ethanol (20 mL), concentrated sulfuric acid (10 mL) was added dropwise at 0 °C. The reaction was warmed to room temperature and heated at 100 °C for 24 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature, quenched with saturated aqueous NaHCCb solution and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel to afford the title 4-(2,4-difluorophenyl)-l-(lH-indazol-3- yl)piperidine-4-carboxamide B7.2 (0.25 g), LCMS: 357.14 [M+H]+ and ethyl 4-(2,4- difluorophenyl)-l-(lH-indazol-3-yl)piperidine-4-carboxylate B7.3 (0.4 g). LCMS: 385.16 [M+H]+.
Step-2: Synthesis of ethyl 4-(2,4-difluorophenyl)-l-(l-((4-(N,N- dimethylsulfamoyl)phenyl)sulfonyl)-lH-indazol-3-yl)piperidine-4-carboxylate (B-29):
|0306j To a stirred solution of ethyl 4-(2,4-difluorophenyl)-l-(lH-indazol-3-yl)piperidine-4- carboxylate B7.3 (400 mg, 1 mmol, 1 eq) and 4-(N,N-dimethylsulfamoyl)benzenesulfonyl chloride B7.4 (350 mg, 1.24 mmol, 1.2 eq) in DCM (30 mL), potassium hydroxide (116 mg, 2.07 mmol, 2 eq) and TBA.HSO4 (52 mg, 0.15 mmol, 0.15 eq) were added at room temperature. The reaction mixture was stirred at the same temperature for 12 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with water and extracted with DCM. The combined organic layers were dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel to afford ethyl 4-(2,4-difluorophenyl)-l-(l-((4-(N,N- dimethylsulfamoyl)phenyl)sulfonyl)-lH-indazol-3-yl)piperidine-4-carboxylate (B-29). Yield: 35 mg, 63%; Appearance: White solid; ¾ NMR (400 MHz, DMSO-de) d 8.07 (d, J= 8.3 Hz, 1H), 8.00 (d, J= 8.3 Hz, 2H), 7.94 (d, J= 7.8 Hz, 1H), 7.83 (d, J= 8.3 Hz, 2H), 7.65 (t, J= 7.8 Hz, 1H), 7.56 - 7.48 (m, 1H), 7.38 (t, J= 7.8 Hz, 1H), 7.29 - 7.18 (m, 1H), 7.14 - 7.07 (m, 1H), 4.12 (q, J= 6.8 Hz, 2H), 3.82 (d, J= 13.7 Hz, 2H), 3.38 (t, 7= 11.0 Hz, 2H), 2.55 (s, 6H), 2.37 (d, J = 13.7 Hz, 2H), 2.08 (t, J= 10.5 Hz, 2H), 1.11 (t, J= 7.1 Hz, 3H); HPLC purity: 95.01%; LCMS Calculated for C29H30F2N4O6S2: 632.16; Observed: 633.10 [M+H]+.
Step-3: Synthesis of 4-((3-(4-(2,4-difluorophenyl)-4-(hydroxymethyl)piperidin-l-yl)-lH-indazol- l-yl)sulfonyl)-N,N-dimethylbenzenesulfonamide (B-27):
[0307] To a stirred solution of ethyl 4-(2,4-difluorophenyl)-l-(l-((4-(N,N- dimethylsulfamoyl)phenyl)sulfonyl)-lH-indazol-3-yl)piperidine-4-carboxylate (B-29) (300 mg, 0.47 mmol, 1 eq) in THF (20 mL), LAH (27 mg, 0.71 mmol, 1.5 eq) was added at 0 °C. The reaction mixture was stirred at the same temperature for 2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with saturated aqueous Na2SC>4 solution, filtered and the filtrated was concentrated under reduced pressure. The crude product was purified by reverse phase preparative HPLC to afford 4-((3-(4- (2,4-difluorophenyl)-4-(hydroxymethyl)piperidin- 1 -yl)- lH-indazol- 1 -yl)sulfonyl)-N,N- dimethylbenzenesulfonamide (B-27). Yield: 80 mg, 28%; Appearance: Off-white solid; *H NMR (400 MHz, DMSO-de) d 8.05 (d, J= 8.5 Hz, 1H), 7.97 (d, J= 8.5 Hz, 2H), 7.91 (d, J= 8.0 Hz, 1H), 7.83 (d, J= 8.5 Hz, 2H), 7.63 (t, J= 7.7 Hz, 1H), 7.49 - 7.40 (m, 1H), 7.36 (t, J = 7.7 Hz, 1H), 7.20 - 7.10 (m, 1H), 7.06 (t, J= 8.2 Hz, 1H), 4.76 (t, J= 5.5 Hz, 1H), 3.78 - 3.68 (m, 2H), 3.55 (d, J= 5.5 Hz, 2H), 3.17 (t, J= 10.5 Hz, 2H), 2.54 (s, 6H), 2.23 (d, J= 13.0 Hz, 2H), 1.94 (t, J = 10 5 Hz, 2H); HPLC purity: 97 72%; LCMS Calculated for C27H28F2N4O5S2: 590 15; Observed 591.05 [M+H]+.
Example B8: Synthetic scheme for synthesis of 4-(2,4-difluorophenyl)-l-(l-((4-(N,N- dimethylsulfamoyl)phenyl)sulfonyl)-lH-indazol-3-yl)piperidine-4-carboxamide (B-28):
Figure imgf000168_0001
Step-1: Synthesis of 4-(2,4-difluorophenyl)-l-(l-((4-(N,N-di ethylsulfamoyl)phenyl)sulfonyl)- lH-indazol-3-yl)piperidine-4-carboxamide /B-28):
|0308j To a stirred solution of 4-(2,4-difluorophenyl)-l-(lH-indazol-3-yl)piperidine-4- carboxamide B8.1 (250 mg, 0.70 mmol, 1 eq) and 4-(N,N-dimethylsulfamoyl)benzenesulfonyl chloride B8.2 (239 mg, 0.84 mmol, 1.2 eq) in DCM (20 mL), potassium hydroxide (78 mg, 1.40 mmol, 2 eq) and TBA.HSCB (35 mg, 0.10 mmol, 0.15 eq) were added at room temperature and the reaction mixture was stirred at the same temperature for 16 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with DCM. The combined organic layers were dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel followed by reverse phase preparative HPLC to afford 4-(2,4- difluorophenyl)-l-(l-((4-(N,N-dimethylsulfamoyl)phenyl)sulfonyl)-lH-indazol-3-yl)piperidine- 4-carboxamide (B-28). Yield: 30 mg, 7%; Appearance: White solid; ¾ NMR (400 MHz, CHLOROFORM-d) d 8.14 (d, J= 8.5 Hz, 1H), 7.99 (d, J= 8.5 Hz, 2H), 7.75 (d, J= 8.5 Hz, 2H), 7.65 (d, J= 8.0 Hz, 1H), 7.52 (t, J= 7.7 Hz, 1H), 7.45 - 7.35 (m, 1H), 7.32 - 7.29 (m, 1H), 7.01 - 6.92 (m, 1H), 6.91 - 6.83 (m, 1H), 5.41 - 5.26 (m, 2H), 3.77 - 3.63 (m, 4H), 2.70 (s, 6H), 2.56 - 2.47 (m, 2H), 2.31 - 2.21 (m, 2H); HPLC purity: 98.19%; LCMS Calculated for C27H27F2N5O5S2: 603.14; Observed: 604.10 [M+H]+.
Example B9: Synthetic scheme for synthesis of N-(l-(l-(5-chloro-3-fluoropyridin-2- yl)piperidin-4-yl)-lH-indazol-6-yl)-4-methoxybenzenesulfonamide (B-58):
Figure imgf000169_0001
Step-1: Synthesis of l-( 1 -(5-chloro-3-fluoropyridin-2-yl)piperidin-4-yl)-6-nitro-lH-mdazole B9.3:
|0309j To a stirred solution of 6-nitro-l-(piperidin-4-yl)-lH-indazole.TFA B9.1 (1.2 g, 4.87 mmol, 1 eq) and 5-chloro-2,3-difluoropyridine B9.2 (729 mg, 4.87 mmol, 1 eq) in DMF (20 mL), potassium carbonate (2 g, 14.63 mmol, 3 eq) was added. The reaction was stirred at 120 °C for 12 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with ice-cold water and extracted with ethyl acetate. The combined organic layers were washed with ice-cold water, dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel to afford l-(l-(5-chloro-3-fluoropyridin-2-yl)piperidin-4- yl)-6-nitro-lH-indazole B9.3 (1.2 g, 65.57%). LCMS: 376.10 [M+H]+.
Step-2: Synthesis of N-(l-(l-(5-chloro-3-fluoropyridin-2-yl)piperidin-4-yl)-lH-indazol-6- yl)acetamide B9.4:
(0310] To a stirred solution of -(l-(5-chloro-3-fluoropyridin-2-yl)piperidin-4-yl)-6-nitro-lH- indazole B9.3 (1.2 g, 3.2 mmol, 1 eq) in acetic acid (20 mL), iron powder (710 mg, 12.8 mmol, 4 eq) was added. The reaction was stirred at 120 °C for 6 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with DCM and allowed to stir for 10 min. The mixture was then filtered through a pad of Celite and the Celite pad was washed with DCM, and the filtrate was concentrated under reduced pressure to dryness. Saturated aqueous NaHCCb was added to the residue and the resulting precipitate was filtered out, the solid was washed with water and dried under reduced pressure to dryness to afford N-(l-(l-(5-chloro-3-fluoropyridin-2-yl)piperidin-4-yl)-lH-indazol- 6-yl)acetamide B9.4 (600 mg, crude). This compound was used in the next step without further purification. LCMS: 388.10 [M+H]+.
Step-3: Synthesis of l-(l-(5-chloro-3-fluoropyridin-2-yl)piperidin-4-yl)-lH-indazol-6-amine B9.5:
|03!lj To a stirred solution of N-(l-(l-(5-chloro-3-fluoropyridin-2-yl)piperidin-4-yl)-lH- indazol-6-yl)acetamide B9.4 (300 mg, 0.773 mmol) in methanol (5 mL), 5 N aqueous HC1 solution (5 mL) was added. The reaction was stirred at 70 °C for 6 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature and neutralized with saturated aqueous NaHCCh solution and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure to dryness to afford l-(l-(5-chloro-3-fluoropyridin-2-yl)piperidin-4-yl)- lH-indazol-6-amine B9.5 (205 mg, crude). This compound was used in the next step without further purification. LCMS: 346.10 [M+H]+. Step-4: Synthesis of N-( 1-(1 -(5-chloro-3-fluoropyridin-2-yl)piperidin-4-yl)-lH-indazol-6-yl)-4- methoxybenzene sulfonamide (B-58) : j0312J To a stirred solution of l-(l-(5-chloro-3-fluoropyridin-2-yl)piperidin-4-yl)-lH-indazol-6- amine B9.5 (200 mg, 0.579 mmol, 1 eq) and pyridine (0.1 mL, 1.16 mmol, 2 eq) in acetonitrile (5 mL), 4-methoxybenzenesulfonyl chloride B9.6 (143 mg, 0.695 mmol, 1.2 eq) was added. The reaction was stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was treated with 1 N aqueous HC1 solution and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure to dryness. The crude product was purified by column chromatography on silica gel to afford N-(l-(l-(5-chloro-3-fluoropyridin-2-yl)piperidin-4-yl)-lH-indazol-6-yl)-4- methoxybenzenesulfonamide (B-58). Yield: 100 mg, 33%; Appearance: White solid; 'H NMR (400 MHz, DMSOe) d 10.28 (s, 1H), 8.12 (d, J= 2.0 Hz, 1H), 7.93 (s, 1H), 7.84 (dd, J= 1.2, 12.4 Hz, 1H), 7.72 (d, J= 8.8 Hz, 2H), 7.58 (d, J= 8.4 Hz, 1H), 7.33 (s, 1H), 7.03 (d, J= 8.4 Hz, 2H), 6.84 (d, J= 8.8 Hz, 1H), 4.80 - 4.70 (m, 1H), 4.12 (d, J= 13.2 Hz, 2H), 3.76 (s, 3H), 3.22 (t, J = 12.4 Hz, 2H), 2.15 - 2.03 (m, 2H), 1.95 - 1.87 (m, 2H); HPLC purity: 97.16%; LCMS calculated for C24H23CIFN5O3S: 515.12; Observed: 516.10 [M+H]+.
Example B10: Synthetic scheme for synthesis of N-(l-(l-(5-chloro-3-fluoropyridin-2- yl)piperidin-4-yl)-lH-indazol-7-yl)-4-methoxybenzenesulfonamide (B-62):
Figure imgf000172_0001
Step-1: Synthesis of l-( 1 -(5-chloro-3-fluoropyridin-2-yl)piperidin-4-yl)-7-nitro-lH-mdazole BIO.3:
[0313) To a stirred solution of l-(5-chloro-3-fluoropyridin-2-yl)piperidin-4-ol B10.1 (2 g, 8.69 mmol, 1 eq) and 7-nitro-lH-indazole BIO.2 (1.4 g, 8.95 mmol, 1.03 eq) in THF (40 mL), triphenylphosphine (4.1 g, 15.65 mmol, 1.8 eq) was added, followed by addition of DEAD (2.4 mL, 15.65 mmol, 1.8 eq) dropwise at 0 °C. The reaction was warmed to room temperature and stirred for 12 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction was quenched by addition of water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel to afford l-(l-(5-chloro-3-fluoropyridin-2-yl)piperidin-4-yl)-7-nitro-lH-indazole BIO.3 (1.7 g, 52.14%). LCMS: 376.10 [M+H]+. Step-2: Synthesis of N-(l-(l-(5-chloro-3-fluoropyridin-2-yl)piperidin-4-yl)-lH-indazol-7- yl)acetamide BIO.4: j0314J To a stirred solution of l-(l-(5-chloro-3-fluoropyridin-2-yl)piperidin-4-yl)-7-nitro-lH- indazole BIO.3 (1.7 g, 4.53 mmol, 1 eq) in acetic acid (25 mL), iron powder (1 g, 18.13 mmol, 4 eq) was added. The reaction was stirred at 120 °C for 12 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with DCM and allowed to stir for 10 min. The mixture was then filtered through a pad of Celite and the Celite pad was washed with DCM, and the filtrate was concentrated under reduced pressure to dryness. Saturated aqueous NaHCCb was added to the residue and the resulting precipitate was filtered out, the solid was washed with water and dried under reduced pressure to dryness to afford N-(l-(l-(5-chloro-3-fluoropyridin-2-yl)piperidin-4-yl)-lH-indazol- 7-yl)acetamide BIO.4 (1.2 g, crude). This compound was used in the next step without further purification. LCMS: 388.10 [M+H]+.
Step-3: Synthesis of l-(l-(5-chloro-3-fluoropyridin-2-yl)piperidin-4-yl)-lH-indazol-7 -amine BIO.5:
J0315] To a stirred solution of N-(l-(l-(5-chloro-3-fluoropyridin-2-yl)piperidin-4-yl)-lH- indazol-7-yl)acetamide BIO.4 (500 mg, 1.29 mmol) in methanol (10 mL), 5 N aqueous HC1 solution (10 mL) was added. The reaction was stirred at 80 °C for 5 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature, neutralized with saturated aqueous NaHCCh solution and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure to dryness to afford l-(l-(5-chloro-3-fluoropyridin-2-yl)piperidin-4-yl)-lH- indazol-7-amine B10.5 (330 mg, crude). This compound was used in the next step without further purification. LCMS: 346.10 [M+H]+.
Step-4: Synthesis of N-( l-(l -(5-chloro-3-fluoropyridin-2-yl)piperidin-4-yl)-lH-indazol-7-yl)-4- methoxybenzene sulfonamide (B-62):
J0316] To a stirred solution of l-(l-(5-chloro-3-fluoropyridin-2-yl)piperidin-4-yl)-lH-indazol-7- amine B10.5 (330 mg, 0.956 mmol, 1 eq) and pyridine (0.15 mL, 1.91 mmol, 2 eq) in acetonitrile (5 mL), 4-methoxybenzenesulfonyl chloride B10.6 (237 mg, 1.15 mmol, 1.2 eq) was added and stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was treated with 1 N aqueous HC1 solution and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure to dryness. The crude product was purified by column chromatography on silica gel to afford N-(l-(l-(5-chloro-3-fluoropyridin-2-yl)piperidin-4-yl)-lH-indazol-7-yl)-4- methoxybenzenesulfonamide (B-62). Yield: 110 mg, 22.35%; Appearance: White solid; 1HNMR (400 MHz, DMSOe) d 9.89 (s, 1H), 8.14 - 8.10 (m, 2H), 7.85 (dd, J= 1.2, 13.2 Hz, 1H), 7.68 (d, J= 8.0 Hz, 1H), 7.64 (d, J= 8.8 Hz, 2H), 7.12 (d, J= 8.8 Hz, 2H), 6.93 (t, J= 7.6 Hz, 1H), 6.48 (d, J = 7.2 Hz, 1H), 4.60 - 5.50 (m, 1H), 4.16 (d, J= 13.2 Hz, 2H), 3.85 (s, 3H), 3.03 (t, J= 12.4 Hz, 2H), 2.23 - 2.11 (m, 2H), 2.05 - 1.96 (m, 2H); HPLC purity: 99.63%; LCMS calculated for C24H23CIFN5O3S: 515.12; Observed: 516.10 [M+H]+.
Example Bll: Synthetic scheme for synthesis of 7-(4-(5-chloro-3-fluoropyridin-2- yl)piperazin-l-yl)-2-((4-methoxyphenyl)sulfonyl)-2H-indazole (B-64):
Figure imgf000174_0001
j0317l A pyrex tube was charged with a solution of l-(5-chloro-3-fluoropyridin-2-yl)piperazine Bl l.l (400 mg, 1.86 mmol, 1 eq), 7-bromo-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-indazole B11.2 (727 mg, 2.2 mmol, 1.2 eq) and cesium carbonate (1.2 g, 3.7 mmol, 2 eq) in 1,4-dioxane. The tube was sealed with a septum and purged with argon for 10 min. X-Phos palladacycle (G3) (47 mg, 0.055 mmol, 0.03 eq) was added to the reaction under an atmosphere of argon and the purging with argon as continued for 5 min. The tube was then sealed with a screw cap and the reaction was heated at 130 °C for overnight. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction was cooled to room temperature, filtered through a pad of Celite and the Celite pad was washed with ethyl acetate. The filtrate was diluted with ethyl acetate, washed with water and brine, dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel to afford 7-(4-(5 -chloro-3 -fluoropyridin-2-yl)piperazin- 1 -yl)- 1 -((2-
(trimethylsilyl)ethoxy)methyl)-3a,7a-dihydro-lH-indazole B11.3 (600 mg, 70%). LCMS: 464.20 [M+H]+.
Step-2: Synthesis of 7-(4-(5-chloro-3-fluoropyridin-2-yl)piperazin-l-yl)-3a, 7a-dihydro-lH- indazole Bll.4: j0318J A stirred solution of 7-(4-(5-chloro-3-fluoropyridin-2-yl)piperazin-l-yl)-l-((2- (trimethylsilyl)ethoxy)methyl)-3a,7a-dihydro-lH-indazole B11.3 (600 mg, 1.3 mmol, 1 eq) in DCM (15 mL) was cooled to 0 °C, to which a 4 M solution of HC1 in 1,4-dioxane (5 mL) was added. The reaction was warmed to room temperature was stirred for overnight. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to dryness. The residue was dissolved in saturated aqueous NaHCCb solution and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure to dryness to afford 7-(4-(5- chloro-3-fluoropyridin-2-yl)piperazin-l-yl)-3a,7a-dihydro-lH-indazole B11.4 (200 mg, crude). This compound was used in the next step without further purification. LCMS: 334.10 [M+H]+.
Step-3: Synthesis of 7-(4-(5-chloro-3-fluoropyridin-2-yl)piperazin-l-yl)-2-((4- methoxyphenyl)sulfonyl)-2H-indazole (B-64):
J0319] A stirred solution of 7-(4-(5-chloro-3-fluoropyridin-2-yl)piperazin-l-yl)-3a,7a-dihydro- lH-indazole B11.4 (200 mg, 0.6 mmol, 1 eq) in DCM (15 mL) was cooled to 0 °C, to which potassium hydroxide (67 mg, 1.2 mmol, 2 eq) followed by TBA.HSCri (30 mg, 0.09 mmol, 0.15 eq) were added. The reaction was stirred for 20 min at 0 °C. 4-methoxybenzenesulfonyl chloride Bl l.5 (137 mg, 0.66 mmol, 1.1 eq) was then added to the reaction, warmed to room temperature and stirred for overnight. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction was quenched with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel followed by reverse phase preparative HPLC to afford 7-(4-(5-chloro-3-fluoropyridin-2- yl)piperazin-l-yl)-2-((4-methoxyphenyl)sulfonyl)-2H-indazole (B-64). Yield: 23 mg, 7%; Appearance: Light green solid; ¾ NMR (400 MHz, DMSOe) d 9.01 (s, 1H), 8.12 (s, 1H), 8.04 (d, J= 8.8 Hz, 2H), 7.87 (dd, 7= 2.0, 12.8 Hz, 1H), 7.23 - 7.17 (m, 3H), 7.01 (t, 7= 8.0 Hz, 1H), 6.56 (d, J= 7.2 Hz, 1H), 3.84 (s, 3H), 3.63 - 3.57 (m, 4H), 3.52 - 3.47 (m, 4H); HPLC purity: 95.74%; LCMS calculated for C23H21CIFN5O3S: 501.10; Observed: 502.05 [M+H]+.
Example B12: Synthetic scheme for synthesis of 4-((3-(4-chloro-2-fluorophenyl)-lH- indol-l-yl)sulfonyl)-N,N-dimethylbenzenesulfonamide (B-40):
Figure imgf000176_0001
|0320| To a stirred solution of 3-bromo-lH-indole B12.1 (1 g, 5.1 mmol, 1 eq) in DCM (25 mL), triethyl amine (1.78 mL, 12.7 mmol, 2.5 eq) was added at 0 °C and the reaction was stirred for 5 min. Di-/er/-butyl di carbonate (2.22 g, 10.2 mmol, 2 eq) followed by DMAP (62 mg, 0.51 mmol, 0.1 eq) were added to the reaction at 0 °C. The reaction was warmed to room temperature and stirred for 6 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction was quenched with water and extracted with DCM. The combined organic layers were dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel to afford /cvV-butyl 3-bromo- lH-indole-l-carboxylate B12.2 (930 mg, 61.58%). LCMS: No ionization.
Step-2: Synthesis of tert-butyl 3-(4-chloro-2-fluorophenyl)-lH-indole-l-carboxylate B 12.4:
(0321] A pyrex tube was charged with a solution of tert- butyl 3-bromo-lH-indole-l-carboxylate B12.2 (1 g, 3.3 mmol, 1 eq), (4-chloro-2-fluorophenyl)boronic acid B12.3 (878 mg, 5.05 mmol, 1.5 eq), sodium carbonate (874 mg, 8.25 mmol, 2.5 eq) in THF (20 mL) and water (4 mL). The tube was sealed with a septum and the reaction mixture was purged with argon via an argon balloon for 15 min. PdCl2(dppf) (147 mg, 0.2 mmol, 0.06 eq) was then added to the reaction under an argon atmosphere and the purging with argon was continued for 5 min. The tube was then sealed with a screw cap and the reaction was heated at 100 °C for 12 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction was cooled to room temperature and the reaction mixture was filtered through a pad of Celite and the Celite pad was washed with ethyl acetate. The filtrate was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel to afford /tvV-butyl 3-(4- chloro-2-fluorophenyl)-lH-indole-l-carboxylate B12.4 (789 mg, 67%). LCMS: 346.10 [M+H]+.
Step-3: Synthesis of 3-(4-chloro-2-fluorophenyl)-lH-indole B12.5: j0322| To a stirred solution of tert- butyl 3-(4-chloro-2-fluorophenyl)-lH-indole-l-carboxylate B12.4 (700 mg, 2.03 mmol, 1 eq) in DCM (10 mL), trifluoroacetic acid (10 mL) was added at 0 °C. The reaction was warmed to room temperature and stirred for 12 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in saturated aqueous NaHCCh solution and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The residue was triturated with diethyl ether and n-pentane. The solids were filtered out and dried under reduced pressure to afford 3-(4-chloro-2- fluorophenyl)-lH-indole B12.5 (330 mg, crude). This compound was used in the next step without further purification. LCMS: 246.10 [M+H]+.
Step-4: Synthesis of 4-((3-(4-chloro-2-fluorophenyl)-lH-indol-l-yl)sulfonyl)-N,N- dimethylbenzenesulfonamide (B-40):
|0323| To a stirred solution of 3-(4-chloro-2-fluorophenyl)-lH-indole B 12.5 (260 mg, 1.06 mmol, 1 eq) in DCM (15 mL) was cooled to 0 °C, to which potassium hydroxide (118 mg, 2.12 mmol, 2 eq) followed by TBA.HSCri (53 mg, 0.159 mmol, 0.15 eq) were added. The reaction was stirred for 20 min at 0 °C. 4-(N,N-dimethylsulfamoyl)benzenesulfonyl chloride B12.6 (598 mg, 2.12 mmol, 2 eq) was then added to the reaction. The reaction was warmed to room temperature and stirred for 12 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction was quenched with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel followed by reverse phase preparative HPLC to afford 4-((3-(4-chloro-2-fluorophenyl)-lH-indol-l- yl)sulfonyl)-N,N-dimethylbenzenesulfonamide (B-40). Yield: 18 mg, 3.44%; Appearance: White solid; ¾ NMR (400 MHz, DMSO-de) d 8.32 (d, J= 8.4 Hz, 2H), 8.14 (s, 1H), 8.04 (d, 7= 8.4 Hz, 1H), 7.96 (d, J= 8.4 Hz, 2H), 7.70 - 7.71 (m, 1H), 7.65 - 7.58 (m, 2H), 7.49 - 7.41 (m, 2H), 7.39 - 7.34 (m, 1H), 2.62 (s, 6H); HPLC purity: 97.55%; LCMS Calculated for C22H18CIFN2O4S2: 492.04; Observed: 492.90 [M+H]+. j0324| The following examples were prepared using standard chemical manipulations and procedures similar to those used for the preparation of the previous example as indicated in the table below.
Figure imgf000178_0001
Example B13: Synthetic scheme for synthesis of 4-((4-(4-chloro-2-fluorophenoxy)- lH-indazol-l-yl)sulfonyl)-N,N-dimethylbenzenesulfonamide (B-26):
Figure imgf000179_0001
Step-1: Synthesis of 2-(4-chloro-2-fluorophenoxy)-6-fluorobenzaldehyde B13.3:
[0325J To a stirred solution of 2,6-difluorobenzaldehyde B13.1 (500 mg, 3.543 mmol, 1 eq) and 4-chloro-2-fluorophenol B13.2 (519 mg, 3.543 mmol, 1 eq) in DMF (20 mL), potassium carbonate (1.4 g, 10.629 mmol, 3 eq) was added. The reaction mixture was stirred at 100 °C for 2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was poured into ice-cold water. The resulting precipitate was filtered out and dried under reduced pressure to afford 2-(4-chloro-2-fluorophenoxy)-6-fluorobenzaldehyde B13.3 along with the disubstituted 2,6-bis(4-chloro-2-fluorophenoxy)benzaldehyde B13.4 (1 g, crude). This compound was used in the next step without further purification. LCMS: 269.00/395.00 [M+H]+.
Step-2: Synthesis of 4-(4-chloro-2-fluorophenoxy)-lH-indazole B13.5: j0326j To a stirred solution of 2-(4-chloro-2-fluorophenoxy)-6-fluorohenzaldehyde B13.3 (1 g, 3.722 mmol, 1 eq) in DMSO (20 mL), hydrazine hydrate (5 mL, 5 vol) was added. The reaction mixture was stirred at 130 °C for 12 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature, poured into water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel to afford 4-(4-chloro-2-fluorophenoxy)-lH-indazole B 13.5 (220 mg, 22.51%). LCMS: 263.00 [M+H]+.
Step-3: Synthesis of 4-((4-(4-chloro-2-fluorophenoxy)-lH-indazol-l-yl)sulfonyl)-N,N- dimethylbenzenesulfonamide (B-26):
J0327] To a stirred solution of 4-(4-chloro-2-fluorophenoxy)-lH-indazole B13.5 (220 mg, 0.837 mmol, 1 eq) and 4-(N,N-dimethylsulfamoyl)benzenesulfonyl chloride 13.6 (285 mg, 1 mmol, 1.2 eq) in DCM (10 mL), potassium hydroxide (93 mg, 1.674 mmol, 2 eq) followed by TBA.HSCri (42 mg, 0.125 mmol, 0.15 eq) were added at room temperature and the reaction mixture was stirred at the same temperature for 12 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with DCM. The combined organic layers were dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The crude product was purified by reverse phase preparative HPLC to afford 4- ((4-(4-chloro-2-fluorophenoxy)- l//-indazol- 1 -yl)sulfonyl)-N,N-dimethylbenzenesulfonamide (B- 26). Yield: 7 mg, 2.4%; Appearance: White solid; ¾ NMR (400 MHz, CDCb) d; 8.32 (s, 1H), 8.17 (d, J= 8.8 Hz, 2H), 7.92 - 7.85 (m, 3H), 7.45 (t, J= 8.4 Hz, 1H), 7.29 - 7.24 (m, 1H), 7.20 - 7.09 (m, 2H), 6.56 (d, J= 8.0 Hz, 1H), 2.74 (s, 6H); HPLC purity: 99.74%; LCMS calculated for C21H17CIFN3O5S2: 509.03; Observed: 510.00 [M+H]+.
Example B14: Synthetic scheme for synthesis of 4-((4-((4-fluorophenyl)thio)-lH- indazol-l-yl)sulfonyl)-N,N-dimethylbenzenesulfonamide (B-24):
Figure imgf000180_0001
Step-1: Synthesis of 4-((4-fluorophenyl)thio)-lH-indazole B14.2:
[0328] To a stirred solution of 2-fluoro-6-((4-fluorophenyl)thio)benzaldehyde B14.1 (1.1 g, 4.39 mmol, 1 eq) in DMSO (25 mL), a 1 M solution of hydrazine in THF (25 mL, 25 vol) was added at room temperature. The reaction mixture was stirred at 130 °C for 12 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel to afford 4-((4-fluorophenyl)thio)-lH-indazole B14.2 (330 mg, 30%). LCMS: 245.00 [M+H]+.
Step-2: Synthesis of 4-((4-((4-fluorophenyl)thio)-lH-indazol-l-yl)sulfonyl)-N,N- dimethylbenzenesulfonamide (B-24):
[0329J To a stirred solution of 4-((4-fluorophenyl)thio)-lH-indazole B14.2 (300 mg, 1.22 mmol, 1 eq) and 4-(N,N-dimethylsulfamoyl)benzenesulfonyl chlorideB14.3 (382 mg, 1.35 mmol, 1.1 eq) in DCM (20 mL), potassium hydroxide (136 mg, 2.44 mmol, 2 eq) followed by TBA.HSCL (62 mg, 0.183 mmol, 0.15 eq) were added at room temperature and the reaction mixture was stirred at the same temperature for 12 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with DCM. The combined organic layers were dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel to afford 4-((4-((4-fluorophenyl)thio)-lH-indazol-l-yl)sulfonyl)-N,N-dimethylbenzenesulfonamide (B-24). Yield: 150 mg, 24%; Appearance: Off white solid; ¾NMR (400 MHz, DMSO-de) d; 8.57 (s, 1H), 8.19 (d, J= 8.0 Hz, 2H), 8.04 (d, J= 8.4 Hz, 1H), 7.97 (d, J= 8.0 Hz, 2H), 7.62 (t, J= 8.0 Hz, 1H), 7.56 - 7.50 (m, 2H), 7.32 - 7.24 (m, 2H), 7.09 (d, J= 7.2 Hz, 1H), 2.62 (s, 6H); HPLC purity: 99.44%; LCMS calculated for C21H18FN3O4S3: 491.04; Observed: 491.95 [M+H]+. Example B15: General procedure for synthesis of 4-((4-((4-chloro-2- fluorophenyl)amino)-lH-indazol-l-yl)sulfonyl)-N,N-dimethylbenzenesulfonamide (B-123):
Figure imgf000182_0001
Step-1: General procedure for synthesis of 4-((4-((4-chloro-2-fluorophenyl)amino)-lH-indazol-l- yl)sulfonyl)-N,N-dimethylbenzenesulfonamide (B-123):
[0330] To a stirred solution of 4-((4-bromo-lH-indazol-l-yl)sulfonyl)-N,N- dimethylbenzenesulfonamide (B-75; see Example B30) (0. 5 g, 1.13 mmol, 1 eq) in 1,4-dioxane (15 mL) was added 4-chloro-2-fluoroaniline B15.1 (0.16 g, 1.13 mmol, 1 eq) and CS2CO3 (1.1 g, 3.38 mmol, 3 eq) purged reaction mixture with argon for 20 min followed by the addition Xantphos (0.065 g, 0.11 mmol, 0.1 eq) Tris(dibenzylideneacetone)dipalladium(0) (0.05 g, 0.056 mmol, 0.05 eq). The reaction mixture was stirred at 90 °C for 12 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The crude was diluted with water and ethyl acetate. The organic layer was separated washed with water, brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography followed by prep HPLC to afford 4-((4-((4-chloro-2-fluorophenyl)amino)- l//-indazol- 1 -yl)sulfonyl)-N,N- dimethylbenzenesulfonamide (B-123). Yield: 50 mg, 8.7 %; Appearance: Off-white solid; 'H NMR (400 MHz, DMSO-de) d 10.74 (s, 1H), 8.44 (s, 1H), 7.96 (t, J= 9.2 Hz, 4H), 7.46 (dd, J = 11.2 Hz, 11.2 Hz, 1H), 7.37 (t, J= 8 Hz, 1H), 7,26 - 7.16 (m, 2H), 6.69 (d, J= 8 Hz, 1H), 6.55 (d, J = 8 Hz, 1H), 2.61 (m, 6H); HPLC purity: >99%; LCMS Calculated for C21H18CIFN4O4S2: 508.04; Observed: 509.00 [M + H]+.
10331 J The following examples were prepared using standard chemical manipulations and procedures similar to those used for the preparation of the previous example as indicated in the table below.
Figure imgf000183_0002
Example B16: Synthetic scheme for synthesis of 4-((4-((4-chloro-2- fluorophenyl)amino)-3-methyl-lH-indazol-l-yl)sulfonyl)-N,N-dimethylbenzenesulfonamide
(B-76):
Figure imgf000183_0001
Step-1: Synthesis of 4-((4-((4-chloro-2-fluorophenyl)amino)-3-methyl-lH-indazol-l-yl)sulfonyl)- N,N-dimethylbenzenesulfonamide (B-76):
(0332) To a stirred solution of 4-((4-((4-chloro-2-fluorophenyl)amino)-lH-indazol-l- yl)sulfonyl)-N,N-dimethylbenzenesulfonamide (B-123; see Example B15) (350 mg, 0.68 mmol, 1 eq) in THF (6 mL), a 60% suspension of sodium hydride in mineral oil (55 mg, 1.37 mmol, 2 eq) was added at 0 °C and the reaction was stirred at the same temperature for 30 min. Methyl iodide (0.051 mL, 0.82 mmol, 1.2 eq) was then added to the reaction at 0 °C. The reaction was warmed to room temperature and stirred for overnight. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to 0 °C and quenched with saturated aqueous NTBCl solution, and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The crude product was purified by reverse phase preparative HPLC to afford 4-((4-((4-chloro-2- fluorophenyl)amino)-3-methyl-lH-indazol-l-yl)sulfonyl)-N,N-dimethylbenzenesulfonamide (B- 76). Yield: 100 mg, 28%; Appearance: White solid; ¾ NMR (400 MHz, DMSO-de) d; 10.68 (bs, 1H), 7.94 - 7.86 (m, 4H), 7.56 (t, J= 8.4 Hz, 1H), 7.43 (dd, J= 2.0, 11.2 Hz, 1H), 7.25 (d, J= 8.8 Hz, 1H), 7.17 (d, J= 8.0 Hz, 1H), 7.10 (t, J= 8.8 Hz, 1H), 6.81 (d, J= 8.0 Hz, 1H), 3.22 (s, 3H), 2.60 (s, 6H); HPLC purity: 96.91%; LCMS calculated for C22H20CIFN4O4S2: 522.06; Observed: 523.05 [M+H]+.
Example B17: Synthetic scheme for synthesis of 4-(l-(3-(4-(5-chloro-3-fluoropyridin-2- yl)piperazin-l-yl)-lH-pyrazolo[4,3-b]pyridin-l-yl)ethyl)-N,N-dimethylbenzenesulfonamide
(B-31):
Figure imgf000184_0001
Step-1: Procedure for synthesis of 4-(l-(3-(4-(5-chloro-3-fluoropyridin-2-yl)piperazin-l-yl)-lH- pyrazolo[4,3-b]pyridin-l-yl)ethyl)-N,N-dimethylbenzenesulfonamide (B-31):
[0333) To a stirred solution of 3-(4-(5-chloro-3-fluoropyridin-2-yl)piperazin-l-yl)-lH- pyrazolo[4,3-b]pyridine B17.1 (200 mg, 6.5 mmol, 1 eq) and l-(4-(N,N- dimethylsulfamoyl)phenyl)ethyl methanesulfonate B17.2 (237 mg, 7.1 mmol, 1.1 eq) in DMF (5 mL), potassium carbonate (269 mg, 1.95 mmol, 3 eq) was added at room temperature. The reaction mixture was heated at 110 °C for 16 h. The progress of the reaction was monitored by LCMS. After completion of the reaction, water was added to the reaction mixture and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel followed by revers phase preparative HPLC to afford 4-(l-(3-(4-(5-chloro-3-fluoropyridin-2- yl)piperazin-l-yl)-lH-pyrazolo[4,3-b]pyridin-l-yl)ethyl)-N,N-dimethylbenzenesulfonamide (B- 31). Yield: 20 mg, 6%; Appearance: Off-white solid; 1HNMR (400 MHz, DMSO-de) d 8.37 (d, J = 4.5 Hz, 1H), 8.12 (s, 1H), 8.04 (d, J= 8.5 Hz, 1H), 7.87 (d, J= 12.5 Hz, 1H), 7.68 (d, J= 8.5 Hz, 2H), 7.56 (d, J= 8.0 Hz, 2H), 7.34 (dd, J= 4.0, 8.5 Hz, 1H), 6.05 (q, J= 6.8 Hz, 1H), 3.88 - 3.75 (m, 4H), 3.60 (d, J= 4.0 Hz, 4H), 2.56 (s, 6H), 1.88 (d, J= 7.0 Hz, 3H); HPLC purity: >99%; LCMS Calculated for C25H27CIFN7O2S: 543.16; Observed: 544.00 [M+H]+.
Example B18: Synthetic scheme for synthesis of (3-(4-(5-chloro-3-fluoropyridin-2- yl)piperazin-l-yl)-2H-pyrazolo[4,3-b]pyridin-2-yl)(p-tolyl)methanone (B-42):
Figure imgf000185_0001
Step-32: Procedure for synthesis of (3-(4-(5-chloro-3-fluoropyridin-2-yl)piperazin-l-yl)-2H- pyrazolo[4,3-b]pyridin-2-yl)(p-tolyl)methanone (B-42): j0334J To a stirred solution of 3-(4-(5-chloro-3-fluoropyridin-2-yl)piperazin-l-yl)-lH- pyrazolo[4,3-b]pyridine B18.1 (150 mg, 0.45 mmol, 1 eq) and 4-methylbenzoic acid B18.2 (73 mg, 0.54 mmol, 1.2 eq), PyBOP (351 mg, 0.68 mmol, 1.5 eq) DMAP (6 mg, 0.045 mmol, 0.1 eq) in DMSO (5 mL) and triethyl amine (0.12 mL, 0.90 mmol, 2 eq) were added at room temperature. The reaction mixture was heated at 65 °C for 16 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature, quenched with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel to afford (3-(4-(5-chloro-3-fluoropyridin-2- yl)piperazin-l-yl)-2H-pyrazolo[4,3-b]pyridin-2-yl)(p-tolyl)methanone (B-42). Yield: 104 mg, 51%; Appearance: White solid; ¾ NMR (400 MHz, DMSO-de) d 8.78 - 8.65 (m, 2H), 8.12 (s, 1H), 8.02 (d, J= 7.9 Hz, 2H), 7.91 - 7.82 (m, 1H), 7.67 (dd, J= 4.4, 8.3 Hz, 1H), 7.37 (d, J= 7.9 Hz, 2H), 3.95 (s, 4H), 3.59 (s, 4H), 2.42 (s, 3H); HPLC purity: >99%; LCMS Calculated for C23H20CIFN6O: 450.14; Observed: 451.20 [M+H]+.
|0335| The following examples were prepared using standard chemical manipulations and procedures similar to those used for the preparation of the previous example as indicated in the table.
Figure imgf000186_0001
Example B19: Synthetic scheme for synthesis of 4-((3-(6-fluoro-l- methylspiro[indoline-3,4'-piperidin]-l'-yl)-lH-indazol-l-yl)sulfonyl)-N,N- dimethylbenzenesulfonamide (B-10):
Figure imgf000187_0001
Step-1: Synthesis of 6-fluoro-l-methylspiro[indoline-3,4'-piperidine] B19.2:
[0336) To a stirred solution of /er/-butyl 6-fluoro-l-methylspiro[indoline-3,4'-piperidine]-T- carboxylate B19.1/A-245 (1.3 g, 4.06 mmol, 1 eq) in 1,4-dioxane (7 mL), a 4 M solution of HCI in 1,4-dioxane was added dropwise at 0 °C. The reaction mixture was warmed to room temperature and stirred for 12 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated and the residue was triturated with diethyl ether. The solids were filtered out, dissolved in saturated aqueous NaHCCb solution and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure to dryness to afford 6-fluoro-l-methylspiro[indoline-3,4'- piperidine] B19.2 (703 mg, crude). LCMS: 221.15 [M+H]+.
Step-2: Synthesis of (6-fluoro-l-methylspiro[indoline-3,4'-piperidin]-r-yl)(2- fluorophenyl)methanone B19.4:
[0337] To a stirred solution of 2-fluorobenzoyl chlorideB19.3 (250 mg, 1.58 mmol, 1 eq) inDCM (3 mL), triethyl amine (0.65 mL, 4.73 mmol, 3 eq) and followed by 6-fluoro-l- methylspiro[indoline-3,4'-piperidine] B19.2 (417 mg, 1.89 mmol, 1.2 eq) were added at 0 °C. The reaction mixture was warmed to room temperature and stirred for 12 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was added water and extracted with DCM. The combined organic layers were dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The crude product was purified by Combiflash chromatography on silica gel to afford (6-fluoro-l-methylspiro[indoline-3,4'-piperidin]-T-yl)(2- fluorophenyl)methanone B19.4 (450 mg, 83%). LCMS: 343.15 [M+H]+.
Step-3: Synthesis of (6-fluoro-l-methylspiro[indoline-3,4'-piperidin]-r-yl)(2- fluorophenyl)methanethione B19.5:
|0338) To a stirred solution of (6-fluoro-l-methylspiro[indoline-3,4'-piperidin]-T-yl)(2- fluorophenyl)methanone B19.4 (400 mg, 1.17 mmol, 1 eq) in toluene (4 mL), Lawesson’s reagent (472 mg, 1.17 mmol, 1 eq) was added at room temperature. The reaction mixture was heated at 110 °C for 12 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel to afford (6-fluoro-l-methylspiro[indoline-3,4'-piperidin]-T-yl)(2- fluorophenyl)methanethione B19.5 (250 mg, 59%). LCMS: 359.15 [M+H]+.
Step-4: Synthesis of 6-fluoro-r-(lH-indazol-3-yl)-l-methylspiro[indoline-3,4'-piperidine] B19.6:
J0339] To a stirred solution of (6-fluoro-l-methylspiro[indoline-3,4'-piperidin]-r-yl)(2- fluorophenyl)methanethione B19.5 (250 mg, 0.698 mmol, 1 eq) in DMSO (3 mL), a 1 M solution of hydrazine (6.98 mL, 6.98 mmol, 10 eq) was added at room temperature. The reaction mixture was heated 145 °C for 8 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure to dryness to afford 6-fluoro-T-(lH-indazol-3- yl)-l-methylspiro[indoline-3,4'-piperidine] B19.6 (130 mg, crude). This compound was used in the next step without further purification. LCMS: 337.20 [M+H]+. Step-5: Synthesis of 4-((3-( 6-fluoro-l-methylspiro[ indoline-3, 4 ’-piperidin /-/ '-yl)-lH-indazol-l- yl)sulfonyl)-N,N-dimethylbenzenesulfonamide (B-10):
10340] To a stirred solution of 6-fluoro-r-(lH-indazol-3-yl)-l-methylspiro[indoline-3,4'- piperi dine] B 19.6 (100 mg, 0.297 mmol, 1 eq) inDCM (2 mL), potassium hydroxide (33 mg, 0.595 mmol, 2 eq) and TBA.HSO4 (15 mL, 0.044 mmol, 0.15 eq) were added at 0 °C. To the resulting reaction mixture 4-(N,N-dimethylsulfamoyl)benzenesulfonyl chloride B 19.7 (92 mg, 0.327 mmol, 1.1 eq) was added at 0 °C. The reaction mixture was warmed to room temperature and stirred for 12 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with DCM, filtered through a pad of Celite and the Celite pad was washed with DCM. The filtrated was concentrated under reduced pressure. The crude product was purified by reverse phase preparative HPLC to afford 4-((3-(6-fluoro-l-methylspiro[indoline-3,4'- piperidin]-r-yl)-lH-indazol-l-yl)sulfonyl)-N,N-dimethylbenzenesulfonamide (B-10). Yield: 55 mg, 31%; Appearance: Yellow solid; 1H NMR (400 MHz, DMSO-de) d 8.09 (d, J= 8.4 Hz, 1H), 8.01 (d, J= 8.8 Hz, 2H), 7.95 (d, J= 8.4 Hz, 1H), 7.89 (d, J= 8.4 Hz, 2H), 7.66 (t, J= 8.0 Hz, 1H), 7.39 (t, J= 7.6 Hz, 1H), 6.91 - 6.86 (m, 1H), 6.36 - 6.29 (m, 2H), 6.97 (d, J= 13.2 Hz, 2H), 3.35 (s, 2H), 3.13 (t, J= 12.0 Hz, 2H), 2.74 (s, 3H), 2.59 (s, 6H), 1.90 - 1.80 (m, 2H), 1.67 (d, J = 13.2 Hz, 2H); HPLC purity: 98.55%; LCMS Calculated for C28H30FN5O4S2: 583.17; Observed: 584.30 [M+H]+.
Example B20: Synthetic scheme for synthesis of 4-((3-(6-fluoro-l- methylspiro[indoline-3,4'-piperidin]-l'-yl)-lH-pyrazolo[4,3-b]pyridin-l-yl)sulfonyl)-N,N- dimethylbenzenesulfonamide (B-12):
Figure imgf000189_0001
|0341j To a stirred solution of 4-((3-bromo-lH-pyrazolo[4,3-b]pyridin-l-yl)sulfonyl)-N,N- dimethylbenzenesulfonamide B20.1 (150 mg, 0.338 mmol, 1 eq) in propionitrile (3 mL) in a microwave tube, 6-fluoro-l-methylspiro[indoline-3,4'-piperidine] B20.2 (89.2 mg, 0.405 mmol, 1.2 eq) and DIPEA (0.12 mL, 0.576 mmol, 2 eq) were added. The tube was sealed with a septum and aluminium cap. The reaction mixture was irradiated in a microwave reactor at 160 °C for 2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude product was purified by reverse phase preparative HPLC to afford 4-((3-(6-fluoro-l- methylspiro[indoline-3,4'-piperidin]-r-yl)-lH-pyrazolo[4,3-b]pyridin-l-yl)sulfonyl)-N,N- dimethylbenzenesulfonamide (B-12). Yield: 15 mg, 7.6%; Appearance: Off white solid; 1HNMR (400 MHz, DMSO-de) d 8.67 (d, J= 4.8 Hz, 1H), 8.45 (d, J= 8.4 Hz, 1H), 8.04 (d, J= 8.4 Hz, 2H), 7.90 (d, J= 8.4 Hz, 2H), 7.68 (dd, J= 4.4, 8.4 Hz, 1H), 6.84 (dd, J= 6.0, 7.2 Hz, 1H), 6.36 - 6.27 (m, 2H), 4.61 (d, J= 13.2 Hz, 2H), 3.19 (t, J= 12.0 Hz, 2H), 2.74 (s, 3H), 2.60 (s, 6H), 1.81 - 1.71 (m, 2H), 1.66 (d, J = 12.8 Hz, 2H), (2H merged with the moisture peak); HPLC purity: 98.85%; LCMS Calculated for C27H29FN6O4S2: 584.17; Observed: 585.15 [M+H]+.
Example B21: Synthetic scheme for synthesis of 4-((4-(6-fluoro-l- methylspiro[indoline-3,4'-piperidin]-l'-yl)-lH-indazol-l-yl)sulfonyl)-N,N- dimethylbenzenesulfonamide (B-13):
Figure imgf000190_0001
Step-1: Synthesis of 4-((4-bromo-lH-indazol-l-yl)sulfonyl)-N,N-dimethylbenzenesulfonamide B21.3:
(0342) To a stirred solution of 4-bromo-lH-indazole B21.1 (1 g, 5.08 mmol, 1 eq) in DCM (10 mL), potassium hydroxide (0.568 g, 10.15 mmol, 2 eq) and TBA.HSO4 (0.258 g, 0.76 mmol, 0.15 eq) were added at 0 °C and the reaction was stirred at the same temperature for 15 min. To the resulting reaction mixture, 4-(N,N-dimethylsulfamoyl)benzenesulfonyl chloride B21.2 (1.72 g, 6.09 mmol, 1.2 eq) was added. The reaction mixture was warmed to room temperature and stirred for 12 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with DCM. The combined organic layers were dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The crude product was purified by Combiflash chromatography on silica gel to afford 4-((4-bromo-lH- indazol-l-yl)sulfonyl)-N,N-dimethylbenzenesulfonamide B21.3 (0.9 g, 40%). LCMS: 444.00 [M+H]+.
Step-2: Synthesis of 4-((4-( 6-fluoro-l-methylspiro[ indoline-3, 4 '-piperidin ]-l '-yl)-lH-indazol-l- yl)sulfonyl)-N,N-dimethylbenzenesulfonamide (B-13):
|0343j A pyrex tube was charged with a solution of 6-fluoro-l-methylspiro[indoline-3,4'- piperidine] B21.4 (100 mg, 0.454 mmol, 1 eq), 4-((4-bromo-lH-indazol-l-yl)sulfonyl)-N,N- dimethylbenzenesulfonamide B21.3 (222 mg. 0.499 mmol, 1.1 eq) and cesium carbonate (443 mg, 1.36 mmol, 3 eq) in 1,4-dioxane (5 mL). The tube was sealed with a septum and the reaction mixture was purged with argon for 15 min. Tris(dibenzylideneacetone)dipalladium(0) (20 mg, 0.023 mmol, 0.05 eq) and Xantphos (18 mg, 0.032 mmol, 0.07 eq) were added to the reaction mixture under an argon atmosphere. The tube was then fitted with a screw cap and the reaction mixture was heated at 80 °C for 12 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature, filtered through a pad of Celite and the Celite pad was washed with ethyl acetate. The filtrated was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel to afford 4-((4-(6-fluoro-l-methylspiro[indoline-3,4'- piperidin]-r-yl)-lH-indazol-l-yl)sulfonyl)-N,N-dimethylbenzenesulfonamide (B-13). Yield: 25 mg, 9.43%; Appearance: Off white solid; ¾ NMR (400 MHz, DMSO-de) d 8.67 (s, 1H), 8.14 (d, J= 8.4 Hz, 2H), 7.96 (d, J= 8.4 Hz, 2H), 7.62 (d, J= 8.4 Hz, 1H), 7.53 (t, J= 8.0 Hz, 1H), 7.05 - 6.99 (m, 1H), 6.84 (d, J= 8.0 Hz, 1H), 6.37 - 6.30 (m, 2H), 3.60 (bd, J= 12.0 Hz, 2H), 2.98 (t, J = 11.6 Hz, 2H), 2.74 (s, 3H), 2.62 (s, 6H), 2.06 - 1.95 (m, 2H), 1.73 (bd, J= 13.2 Hz, 2H), (2H merged with the moisture peak); HPLC purity: 98.57%; LCMS Calculated for C28H30FN5O4S2: 583.17; Observed: 584.25 [M+H]+.
Example B24: Synthesis of 4-((3-(4-(4-chloro-2-fluorophenyl)piperazin-l-yl)-lH-indazol-l- yl)sulfonyl)-N,N-dimethylbenzenesulfonimidamide (B-83)
Figure imgf000192_0001
Step-1: General synthesis of N-((4-((3-(4-(4-chloro-2-fluorophenyl)piperazin-l-yl)-lH-indazol-l- y Ijsulfony Ijpheny l) (dime thy lam ino)(oxo)-l6)-sulfaneylidene)-2,2,2-trifluoroacetamide B24.3:
(0344) To a solution of 3-(4-(4-chloro-2-fluorophenyl)piperazin-l-yl)-lH-indazole B24.1 (0.5 g, 1.57 mmol, 1 eq) in acetonitrile (20 mL) was added pyridine (0.36 g, 4.54 mmol, 3 eq) followed by 4-(N,N-dimethyl-N'-(2,2,2-trifluoroacetyl)sulfamidimidoyl)benzenesulfonyl chloride B24.2 (0.86 g, 2.27 mmol, 1.5 eq) at 0 °C. The reaction mixture was warmed to room temperature and stirred at ambient temperature for 12 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with water and the product was extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel to afford the titled compound N-((4-((3-(4-(4-chloro-2- fluorophenyl)piperazin- 1 -yl)- lH-indazol- 1 -yl)sulfonyl)phenyl)(dimethylamino)(oxo)-16- sulfaneyhdene)-2,2,2-trifluoroacetamide B24.3 (0.45 g, 44.55%). LCMS: 673.10 [M+H]+.
Step-2: General Synthesis 4-((3-(4-(4-chloro-2-fluorophenyl)piperazin-l-yl)-lH-indazol-l- yl)sulfonyl)-N,N-dimethylbenzenesulfonimidamide (B-83):
|0345) To a stirred solution of N-((4-((3-(4-(4-chloro-2-fluorophenyl)piperazin-l-yl)-lH-indazol- l-yl)sulfonyl)phenyl)(dimethylamino)(oxo)46-sulfaneylidene)-2,2,2-trifluoroacetamide B24.3 (0.45 g, 0.66 mmol, 1 eq) in methanol (25 mL), sodium carbonate (0.142 g, 1.33 mmol, 2 eq) was added. The reaction was stirred at room temperature for 12 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and the residue was treated with water, and the product was extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel followed by reverse phase preparative HPLC to afford the titled compound 4-((3-(4-(4-chloro-2- fluorophenyl)piperazin- 1 -yl)- lH-indazol- 1 -yl)sulfonyl)-N,N-dimethylbenzenesulfonimidamide (B-83). Yield: 70 mg, 18.18%; Appearance: Off white solid; ¾ NMR (400 MHz, DMSO-de) d 8.08 (d, J= 8.0 Hz, 1H), 7.99 - 7.93 (m, 3H), 7.89 - 7.85 (m, 2H), 7.66 (t, J= 7.6 Hz, 1H), 7.42 - 7.34 (m, 2H), 7.23 - 71.9 (m, 1H), 7.09 (t, J= 8.8 Hz, 1H), 4.70 (s, 1H), 3.64 - 3.58 (m, 4H), 3.15 - 3.10 (m, 4H), 2.48 (s, 6H); HPLC purity: 99.52%; LCMS Calculated for C25H26CIFN6O3S2: 576.12; Observed: 577.05 [M+H]+.
Example B25: Synthesis of 4-((3-(4-(4-chloro-2-fluorophenyl)piperazin-l-yl)-lH-indazol-l- yl)sulfonyl)-N,N-dimethylbenzenesulfonamide (B-134)
Figure imgf000193_0001
Step-1: General synthesis of (4-(4-chloro-2-fluorophenyl)piperazin-l-yl)(2- fluorophenyl)methanone 5.3:
10346) To a stirred solution of l-(4-chloro-2-fluorophenyl)piperazine hydrochloride B25.1 (2.5 g, 10 mmol, 1 eq) in DCM (100 mL) was added drop wise TEA (5.31 mL, 40 mmol, 4 eq) at 0 °C, stirred the reaction mixture for 10 min followed by addition of 2-fluorobenzoyl chloride B25.2 (1.18 mL, 0.01 mmol, 1 eq). The reaction mixture was stirred at room temperature for 12 h. The progress of reaction was monitored by TLC. After completion, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with water, brine, dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure to provide a crude residue which was purified by silica gel column chromatography to afford (4-(4- chloro-2-fluorophenyl)piperazin-l-yl)(2-fluorophenyl)methanone B25.3 (1.5 g, 44 %). LCMS: 337.08 [M+H]+.
Step-2: General synthesis of (4-(4-chloro-2-fluorophenyl)piperazin-l-yl)(2- fluorophenyl)methanethione B25.4 j0347] To a stirred solution of (4-(4-chloro-2-fluorophenyl)piperazin-l-yl)(2- fluorophenyl)methanone B25.3 (1 g, 2.96 mmol, 1 eq) in toluene (40 mL) was added Lawesson's reagent (1.2 g, 2.96 mmol, 1 eq). The reaction mixture was reflux for 12 h. The progress of reaction was monitored by TLC. After completion, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with water, brine, dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure to provide a crude residue which was purified by silica gel column chromatography to afford (4-(4-chloro-2- fluorophenyl)piperazin-l-yl)(2-fluorophenyl)methanethione B25.4 (0.85 g, 81 %). LCMS: 353.06 [M+H]+.
Step-3: General synthesis of 3-(4-(4-chloro-2-fluorophenyl)piperazin-l-yl)-lH-indazole 5.5 j0348] To a stirred solution of compound (4-(4-chloro-2-fluorophenyl)piperazin-l-yl)(2- fluorophenyl)methanethione B25.4 (0.78 mg, 1.07 mmol, 1 eq) in DMSO (40 mL) was added 1M hydrazine hydrate solution in THF (12 mL, 10.7 mmol, 10 eq). The reaction mixture was stirred at 130 °C for 16 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cool, water was added and obtained solid was filtered washed with water dried under reduced pressure to afford to afford 3-(4-(4-chloro-2- fluorophenyl)piperazin-l-yl)-lH-indazole B25.5 (170 mg, 23 %). LCMS: 331.10 [M+H]+.
Step-4: General synthesis of 4-((3-(4-(4-chloro-2-fluorophenyl)piperazin-l-yl)-lH-indazol-l- yl)sulfonyl) -N, N-dimethylbenzene sulfonamide (B - 134)
[0349J To a stirred solution of 3-(4-(4-chloro-2-fluorophenyl)piperazin-l-yl)-lH-indazole B25.5 (170 mg, 0.51 mmol, 1 eq) and 4-(N,N-dimethylsulfamoyl)benzenesulfonyl chloride B25.6 (60 mg, 0.56 mmol, 1.1 eq) in DCM (15 mL) was added KOH (57 mg, 1.03 mmol, 2 eq) and TBA.HS04 (26 mg, 0.08 mmol, 0.15 eq) at room temperature. The reaction mixture was stirred at room temperature for 12 h. The progress of the reaction was monitored by TLC. After completion of the reaction, reaction mixture was concentrated under reduced pressure. The crude was triturated with methanol. The crude was purified by prep HPLC to afford the titled compound 4-((3-(4-(4- chloro-2-fluorophenyl)piperazin- 1 -yl)- lH-indazol- 1 -yl)sulfonyl)-N,N- dimethylbenzenesulfonamide (B-134). Yield: 100 mg, 33%; Appearance: White solid; ¾ NMR (400 MHz, DMSO-de) d 8.09 (d, J= 8.5 Hz, 1H), 8.05 - 7.93 (m, 3H), 7.91 - 7.83 (m, 2H), 7.71 - 7.62 (m, 1H), 7.44 - 7.33 (m, 2H), 7.22 (ddd, J= 8.8, 2.4, 1.0 Hz, 1H), 7.09 (t, J= 9.1 Hz, 1H), 3.62 (t, J = 5.0 Hz, 4H), 3.12 (t, J = 4.8 Hz, 4H), 2.55 (s, 6H); HPLC purity: 98.35%; LCMS Calculated for C25H25CIFN5O4S2: 577.10; Observed: 578.3 [M+H]+. j0350| The following examples were prepared using standard chemical manipulations and procedures similar to those used for the preparation of the previous example as indicated in the the table below:
Figure imgf000195_0001
Figure imgf000196_0001
Figure imgf000197_0001
Figure imgf000198_0001
Figure imgf000199_0001
Figure imgf000200_0001
Figure imgf000201_0001
Figure imgf000202_0001
Figure imgf000203_0001
Figure imgf000204_0001
Figure imgf000205_0001
Figure imgf000206_0001
Figure imgf000207_0001
Figure imgf000208_0001
Figure imgf000209_0001
Figure imgf000210_0002
Example B26: Synthesis of 4-((3-(4-(4-chloro-2-fluorophenyl)-4-hydroxypiperidin-l-yl)-lH- pyrazolo[4,3-b]pyridin-l-yl)sulfonyl)-N,N-dimethylbenzenesulfonimidamide (B-30)
Figure imgf000210_0001
Step-1: Synthesis of N-((4-((3-(4-(4-chloro-2-fluorophenyl)-4-hydroxypiperidin-l-yl)-lH- pyrazolo[ 4, 3-b ]pyridin-l-yl)sulfonyl)phenyl)(dimethylamino)(oxo)-l6-sulfaneylidene)-2, 2, 2- trifluoroacetamide B26.3:
10351 ) To a stirred solution of 4-(4-chloro-2-fluorophenyl)-l-(lH-pyrazolo[4,3-b]pyridin-3- yl)piperidin-4-ol B26.1 (400 mg, 1.15 mmol, 1 eq) in acetonitrile (10 mL), pyridine (0.27 mL, 3.46 mmol, 3 eq) was added at 0 °C and the reaction was stirred at the same temperature for 5 min. 4- (N,N-dimethyl-N'-(2,2,2-trifluoroacetyl)sulfamidimidoyl)benzenesulfonyl chloride B26.2 (650 mg, 1.7 mmol, 1.5 eq) was then added in portions to the reaction at 0 °C. The reaction was warmed to room temperature and stirred for 12 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel to afford the title N-((4-((3-(4-(4-chloro-2-fluorophenyl)-4-hydroxypiperidin-l-yl)- lH-pyrazolo[4,3-b]pyridin-l-yl)sulfonyl)phenyl)(dimethylamino)(oxo)-16-sulfaneylidene)-2,2,2- trifluoroacetamide B26.3 (300 mg, 37.97%). LCMS: 689.10 [M+H]+.
Step-2: Synthesis of 4-((3-(4-(4-chloro-2-fluorophenyl)-4-hydroxypiperidin-l-yl)-lH- pyrazolo[4,3-b]pyridin-l-yl)sulfonyl)-N,N-dimethylbenzenesulfonimidamide (B-30):
[0352J To a stirred solution of N-((4-((3-(4-(4-chloro-2-fluorophenyl)-4-hydroxypiperidin-l-yl)- lH-pyrazolo[4,3-b]pyridin-l-yl)sulfonyl)phenyl)(dimethylamino)(oxo)-16-sulfaneylidene)-2,2,2- trifluoroacetamide B26.3 (300 mg, 043 mmol, 1 eq) in methanol (10 mL), sodium carbonate (55 mg, 0.52 mmol, 1.2 eq) was added. The reaction was stirred at room temperature for 2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel to afford the 4-((3-(4-(4-chloro-2- fluorophenyl)-4-hydroxypiperidin-l-yl)-lH-pyrazolo[4,3-b]pyridin-l-yl)sulfonyl)-N,N- dimethylbenzenesulfonimidamide (B-30). Yield: 50 mg, 19.38%; Appearance: white solid; ¾ NMR (400 MHz, DMSOe) d; 8.65 (d, J= 4.0 Hz, 1H), 8.43 (d, J= 8.4 Hz, 1H), 7.98 (d, J= 8.4 Hz, 2H), 7.88 (d, J= 8.4 Hz, 2H), 7.65 (dd, J= 4.4, 8.4 Hz, 1H), 7.30 - 7.22 (m, 2H), 7.16 - 7.09 (m, 1H), 5.40 (s, 1H), 4.70 (s, 1H), 4.50 (t, J= 10.8 Hz, 2H), 3.45 (t, J= 12.4 Hz, 2H), 2.48 (s, 6H), 2.28 - 2.15 (m, 2H), 2.15 - 2.08 (m, 2H); HPLC purity: 97.17%; LCMS calculated for C25H26CIFN6O4S2: 592.11; Observed: 593.05 [M+H]+. 03 S31 The following examples were prepared using standard chemical manipulations and procedures similar to those used for the preparation of the previous example as indicated in the table below.
Figure imgf000212_0002
Example B27: Synthetic scheme for synthesis of 4-((3-(4-(aminomethyl)-4-(2,4- difluorophenyl)piperidin-l-yl)-lH-indazol-l-yl)sulfonyl)-N,N- dimethylbenzenesulfonamide, formate salt (B-34):
Figure imgf000212_0001
Step-1: Synthesis of 4-((3-(4-(aminomethyl)-4-(2, 4-difluorophenyl)piperidin-l-yl)-lH-indazol-l- yl)sulfonyl)-N,N-dimethylbenzenesulfonamide, formate salt (B-34):
[0354J To a stirred solution of 4-((3-(4-cyano-4-(2,4-difluorophenyl)piperidin-l-yl)-lH-indazol- l-yl)sulfonyl)-N,N-dimethylbenzenesulfonamide B-39 (0.9 g, 1.5 mmol, 1 eq) in THF (40 mL), a 1 M solution of BTb.DMS in THF (6.1 mL, 6.1 mmol, 4 eq) was added at 0 °C. The reaction mixture was warmed to room temperature and stirred for 15 min. The reaction was then heated at 80 °C for 3 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature, quenched with methanol and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel followed by reverse phase preparative HPLC to afford the 4-((3-(4- (aminomethyl)-4-(2,4-difluorophenyl)piperidin- 1 -yl)- lH-indazol- 1 -yl)sulfonyl)-N,N- dimethylbenzenesulfonamide, formate salt B-34. Yield: 100 mg, 11%; Appearance: white solid; ¾NMR (400 MHz, DMSO-de) d 8.25 (s, 1H), 8.06 (d, J= 8.8 Hz, 1H), 7.97 (d, J= 8.3 Hz, 2H), 7.91 (d, J= 8.3 Hz, 1H), 7.82 (d, J= 8.3 Hz, 2H), 7.63 (t, J= 7.6 Hz, 1H), 7.47 - 7.33 (m, 2H), 7.23 - 7.13 (m, 1H), 7.12 - 7.04 (m, 1H), 3.76 - 3.65 (m, 3H), 3.26 - 3.15 (m, 2H), 2.86 (s, 2H), 2.55 (s, 6H), 2.26 (d, J= 11.7 Hz, 2H), 1.92 (t, J= 10.5 Hz, 2H); HPLC purity: 98.46%; LCMS Calculated for C27H29F2N5O4S2: 589.16; Observed: 590.10 [M+H]+.
Example B28: Synthetic scheme for synthesis of 4-((3-(l-(4-chloro-2- fluorophenyl)piperidin-4-yl)-lH-indazol-l-yl)sulfonyl)-N,N-dimethylbenzenesulfonamide
(B-133):
Figure imgf000213_0001
Step-1: Procedure for synthesis of 4-((3-(l-(4-chloro-2-fluorophenyl)piperidin-4-yl)-lH-indazol- l-yl)sulfonyl)-N,N-dimethylbenzenesulfonamide (B-133):
(0355] To a stirred solution of N,N-dimethyl-4-((3-(piperidin-4-yl)-lH-indazol-l- yl)sulfonyl)benzenesulfonamide B28.1 (0.35 g, 0.78 mmol, 1 eq) and l-bromo-4-chloro-2- fluorobenzene B28.2 (245 mg, 1.17 mmol, 1.5 eq) in 1,4-dioxane (5 mL) was added Cs2C03 (435 mg, 1.95 mmol, 2.5 eq), reaction mixture was purged with nitrogen for 15 min followed by addition of Pd2(dba)3 (21.44 mg, 0.02 mmol, 0.03 eq) and Xanthphos (27.211 mg, 0.05 mmol, 0.06 eq).The reaction mixture was stirred at 80 °C forl2 h; the reaction progress was monitored by TLC. After completion, the reaction mixture was partitioned between water and ethyl acetate. The organic layers were separated, washed with water dried over Na2SC>4 and concentrated. The crude residue was purified by prep HPLC to provide 4-((3-(l-(4-chloro-2-fluorophenyl)piperidin-4-yl)-lH- indazol-l-yl)sulfonyl)-N,N-dimethylbenzenesulfonamide B-133. Yield: 0.016 g, 9%; Appearance: Off-white solid; ¾ NMR (400 MHz, DMSO-de) d 8.15 - 8.07 (m, 3H), 8.01 - 7.88 (m, 3H), 7.70 (m, 1H), 7.46 (t, J= 7.5 Hz, 1H), 7.34 (m, 1H), 7.24 - 7.16 (m, 1H), 7.10 (t, J= 8.9 Hz, 1H), 3.32 (d, J= 1.3 Hz, 2H), 2.87 (t, 7= 11.6 Hz, 2H), 2.57 (s, 6H), 2.10 - 2.00 (m, 2H), 1.91 (m, 2H), (1H merged in solvent peak); HPLC purity: 97.71%; LCMS Calculated for C26H26CIFN4O4S2: 576.11; Observed: 577.0 [M+H]+.
Example B29: Synthetic Scheme for synthesis of l-((4-(tert-butyl)phenyl)sulfonyl)-3-(4-(5- chloro-3-fluoropyridin-2-yl)piperazin-l-yl)-lH-pyrazolo[4,3-b]pyridine (B-65)
Figure imgf000215_0001
j0356J A solution of 3-bromo-lH-pyrazolo[4,3-b]pyridine B29.1 (2 g, 10.15 mmol, 1 eq) and potassium hydroxide (1.1 g, 20.3 mmol, 2 eq) in THF (30 mL) was stirred at room temperature for 20 min. To the resulting reaction mixture, tosyl chloride (2.8 g, 15.22 mmol, 1.5 eq) was added and the reaction mixture was stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel to afford 3-bromo-l-tosyl-lH-pyrazolo[4,3-b]pyridine B29.2 (2.1 g, 60%). LCMS: 351.97 [M+H]+.
Step-2: General procedure for synthesis of 3-(4-(5-chloro-3-fluoropyridin-2-yl)piperazin-l-yl)-l- tosyl-lH-pyrazolo [ 4, 3-b ] pyridine B29.4:
[0357J To a stirred solution of 3-bromo-l-tosyl-lH-pyrazolo[4,3-b]pyridine B29.2 (1 g, 2.85 mmol, 1 eq) and l-(5-chloro-3-fluoropyridin-2-yl)piperazine B29.3 (0.93 g, 4.85 mmol, 1.5 eq) in propionitrile (15 mL) in a microwave tube, DIPEA (1.48 mL, 8.55 mmol, 3 eq) was added. The tube was sealed with a septum and an aluminium cap, and the reaction mixture was irradiated in a microwave at 170 °C for 2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel to afford 3-(4-(5-chloro-3-fluoropyridin-2-yl)piperazin-l-yl)-l- tosyl - 1 H-py razol o [4, 3 -b] py ri dine B 29.4 (0.70 g, 53%). LCMS: 487.10 [M+H]+.
Step-3: General procedure for synthesis of 3-(4-(5-chloro-3-fluoropyridin-2-yl)piperazin-l-yl)- 1 H-py razol o [4, 3 -b ] py ri dine B29.5:
10358] A solution of 3-(4-(5-chloro-3-fluoropyridin-2-yl)piperazin-l-yl)-l-tosyl-lH- pyrazolo[4,3-b]pyridine B29.4 (300 mg, 0.62 mmol, 1 eq) and sodium hydroxide (61 mg, 1.54 mmol, 2.5 eq) in mixture of ethanol (5 mL) and water (2 mL) in a microwave tube was irradiated in a microwave at 150 °C for 30 min. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The same reaction was repeated on 400 mg scale and crude mixture of two batches were combined, and purified by column chromatography on silica gel to afford 3-(4-(5-chloro-3-fluoropyridin-2-yl)piperazin-l-yl)-lH- pyrazolo[4,3-b]pyridine B29.5 (300 mg, 62%, combined yields from two batches). LCMS: 333.10 [M+H]+.
Step-4: Synthesis of l-((4-(tert-butyl)phenyl)sulfonyl)-3-(4-(5-chloro-3-fluoropyridin-2- yl)piperazin-l-yl)-lH-pyrazolo[ 4, 3-b ] pyridine (B-65): 0359] A solution of 3-(4-(5-chloro-3-fluoropyridin-2-yl)piperazin-l-yl)-lH-pyrazolo[4,3- bjpyridine B29.5 (150 mg, 0.45 mmol, 1 eq), compound 4-(/er/-butyl)benzenesulfonyl chloride B29.6 (125 mg, 0.54 mmol, 1.2 eq), potassium hydroxide (50 mg, 0.90 mmol, 2 eq) and TB A.HSCri (23 mg, 0.07 mmol, 0.15 eq) in DCM (10 mL) was stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with water and extracted with DCM. The combined organic layers were dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The crude product was purified by reverse phase preparative HPLC to afford the titled compound (B-65). Yield: 63 mg, 26%; Appearance: Off white solid; ¾NMR (400 MHz, DMSO-de) d 8.65 (d, J= 3.9 Hz, 1H), 8.44 (d, J= 8.4 Hz, 1H), 8.11 (s, 1H), 7.87 (d, J= 12.8 Hz, 1H), 7.73 (d, J= 8.4 Hz, 2H), 7.65 (dd, J= 4.4, 8.4 Hz, 1H), 7.55 (d, J= 8.4 Hz, 2H), 3.91 (s, 4H), 3.47 (s, 4H), 1.18 (s, 9H); HPLC purity: >99%; LCMS Calculated for CisHzeCIFNeChS: 528.15; Observed: 529.10 [M+H]+.
Example B30: 4-((4-(4-chloro-2-fluorophenyl)-lH-indazol-l-yl)sulfonyl)-N,N- dimethylbenzenesulfonamide (B-121):
Figure imgf000217_0001
Step-1: General procedure for synthesis of 4-((4-bromo-lH-indazol-l-yl)sulfonyl)-N,N- dimethylhenzenesulfonamide (B-75):
(0360] To a stirred solution of 4-bromo-lH-indazole B30.1 (3 g, 15.23 mmol, 1 eq) in dry THF (35 mL) was added 1 M solution of potassium tertiary butoxide (31 mL, 30.45 mmol, 2 eq) in butanol at 0 °C, stirred the reaction mixture at same temperature for 10 min. followed by addition of 4-(N,N-dimethylsulfamoyl)benzenesulfonyl chloride B30.2 (6.5 g, 22.83 mmol, 1.5 eq) and 18- crown-6 (0.8 g, 3.05 mmol, 0.2 eq). The reaction mixture was stirred at room temperature for 12 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and ethyl acetate. The organic layer was separated washed with water, brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography to afford 4-((4-bromo-lH-indazol-l- yl)sulfonyl)-N,N-dimethylbenzenesulfonamide B-75 (2 g, 29.8 %). LCMS: 443.96 [M+H]+. Step-2: General procedure for synthesis of (B-121):
(03611 To a mixture of 4-((4-bromo-lH-indazol-l-yl)sulfonyl)-N,N- dimethylbenzenesulfonamide B-75 (0.5 g, 1.13 mmol, 1 eq) in 1,4-dioxane (20 mL) was added dropwise 2M solution of Na2CC>3 (0.36 g, 3.38 mmol, 3 eq) in water (1.7 mL) and (4-chloro-2- fluorophenyl)boronic acid B30.3 (0.2 g, 1.13 mmol, 1.1 eq) reaction mixture purged with nitrogen for 20 min followed by the addition of Bis(triphenylphosphine)palladium(II) dichloride (0.08 g, 0.11 mmol, 0.1 eq). The reaction mixture was stirred at 95°C for 12h. The progress of the reaction was monitored by TLC. After completion of the reaction, reaction mixture was evaporated to dryness. The residue was taken in ethyl acetate, washed with water, brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography/preparative HPLC to afford the desired product 4-((4-(4-chloro-2-fluorophenyl)- lH-indazol-l-yl)sulfonyl)-N,N-dimethylbenzenesulfonamide B-121. Yield: 50 mg, 8.7 %; Appearance: Off-white solid; 1H NMR (400 MHz, DMSO-de) d 8.48 - 8.47 (m, 1H), 8.20 (t, J = 7.6 Hz, 3H), 7.94 (d, J= 8 Hz, 2H), 7.79 (t, J= 8 Hz, 1H), 7.62 - 7.57 (m, 2H), 7.49 (d, J= 7.2 Hz, 1H), 7.43 - 7.41 (m, 1H), 2.59 (s, 6H); HPLC purity: 98.25%; LCMS Calculated for C21H17CIFN3O4S2: 493.03; Observed: 494.00 [M + H]+.
[0362] The following examples were prepared using standard chemical manipulations and procedures similar to those used for the preparation of the previous example as indicated in the table below.
Figure imgf000218_0001
Example B31: Synthetic scheme for synthesis of 4-((4-(4-chloro-2,6-difluorophenyl)-lH- indazol-l-yl)sulfonyl)-N,N-dimethylbenzenesulfonamide (B-88)
Figure imgf000219_0001
Step-1: General procedure for synthesis of 4-(4-chloro-2,6-difluorophenyl)-lH-indazole (B31.3):
|0363j To a stirred solution of (lH-indazol-4-yl)boronic acid B31.1 (0.14 g, 0.88 mmol, 1 eq), 2- bromo-5-chloro-l,3-difluorobenzene B31.2 (0.2 g, 0.88 mmol, 1 eq) and cesium carbonate (857 mg, 2.6 mmol, 3 eq) in DMETLLO mixture (4:1, 10 mL) were added and purged with argon for 15 min followed by the addition of Tetrakis(triphenylphosphine)palladium(0) (0.1 eq) and stirred at 90°C for 12 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled and evaporated to dryness. The residue was taken in ethyl acetate, washed with water, brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography to afford 4-(4- chloro-2,6-difluorophenyl)-lH-indazole B31.2 (200 mg, 86%). LCMS: 264.03 [M + H]+.
Step-2: General procedure for synthesis of 4-((4-(4-chloro-2,6-difluorophenyl)-lH-indazol-l- yl)sulfonyl)-N,N-dimethylbenzenesulfonamide (B-88):
[0364J To a stirred solution of 4-(4-chloro-2,6-difluorophenyl)-lH-indazole B31.3 (0.2 g, 0.75 mmol, 1 eq) and 4-(N,N-dimethylsulfamoyl)benzenesulfonyl chloride B31.4 (0.24 g, 0.83 mmol, 1.1 eq) in DCM (20 mL) were added KOH (85 mg, 1.5 mmol, 2 eq) and TBA.HSCri (38 mg, 1.1 mmol, 0.15 eq) at 0°C. The reaction mixture was stirred at room temperature for 12 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was separated washed with water, brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by prep HPLC to afford 4-((4-(4-chloro-2,6-difluorophenyl)-lH- indazol-l-yl)sulfonyl)-N,N-dimethylbenzenesulfonamide B-88. |0365j The following examples were prepared using standard chemical manipulations and procedures similar to those used for the preparation of the previous example as indicated in the table.
Figure imgf000220_0002
Example B32: Synthetic scheme for synthesis of 4-((4-(4-chloro-2-fluorophenyl)-lH- benzo[d]imidazol-l-yl)sulfonyl)-N,N-dimethylbenzenesulfonamide (B-100):
OH
6
Figure imgf000220_0001
Step-1: General procedure for synthesis of 4-(4-chloro-2-fluorophenyl)-lH-benzo[d]imidazole (B32.3):
10366 [ To a mixture of 4-bromo-lH-benzo[d]imidazole B32.1 (0.5 g, 2.53 mmol, 1 eq) (4-chloro- 2-fluorophenyl)boronic acid B32.2 (663 mg, 3.80 mmol, 1.5 eq) in 1,4 dioxane (8 mL) & H2O (3 mL) was added cesium carbonate (1.64 g, 5.06 mmol, 2 eq) and purged with nitrogen for 15 min followed by the addition of Dichlorobis(triphenylphosphine)palladium(II) (106 mg, 0.15 mmol, 0.06 eq) and stirred at 100°C for 10 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was poured into water and extracted with ethyl acetate, washed with water, brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography to afford 4-(4- chloro-2-fluorophenyl)-lH-benzo[d]imidazole B32.3 (0.29 g, 46.32 %). LCMS: 247.04 [M + H]+.
Step-2: General procedure for synthesis of 4-((4-(4-chloro-2-fluorophenyl)-lH-benzo[d]imidazol- l-yl)sulfonyl)-N,N-dimethylbenzenesulfonamide {B-100): j0367| To a stirred solution of 4-(4-chloro-2-fluorophenyl)-lH-benzo[d]imidazole B32.3 (0.25 g, 1.01 mmol, 1 eq) and 4-(N,N-dimethylsulfamoyl)benzenesulfonyl chloride B32.4 (316 mg, 1.11 mmol, 1.1 eq) in ACN (10 mL) was added pyridine (0.24 mL, 3.04 mmol, 3 eq) at 0°C. The reaction mixture was stirred at room temperature for 12h; the reaction progress was monitored by TLC. After completion, the reaction mixture was poured in ice water, obtained solid was separated und concentrated under reduced pressure to obtained crude residue. The crude was purified by column chromatography to afford 4-((4-(4-chloro-2-fluorophenyl)-lH-benzo[d]imidazol-l-yl)sulfonyl)- N,N-dimethylbenzenesulfonamide B-100. Yield: 0.1 g, 20%; Appearance: White solid; 1H NMR (400 MHz, DMSO-de) d 8.97 (s, 1H), 8.47 (d, J= 8.2 Hz, 2H), 8.01 (dd, J= 14.6, 8.1 Hz, 3H), 7.70 - 7.47 (m, 4H), 7.45 - 7.37 (m, 1H), 2.64 (s, 6H); HPLC purity: >99%; LCMS Calculated for C21H17CIFN3O4S2: 493.03: Observed: 494.0 [M + H]+.
|0368j The following examples were prepared using standard chemical manipulations and procedures similar to those used for the preparation of the previous example as indicated in the table below.
Figure imgf000222_0001
Figure imgf000223_0001
Figure imgf000224_0001
Example B33: Synthesis of 4-((3-(4-chloro-2-fluorophenyl)-3-methylindolin-l- yl)sulfonyl)-N,N-dimethylbenzenesulfonamide (B-32):
Figure imgf000225_0001
j0369| Step-1: Synthesis of methyl 2-(4-chloro-2-fluorophenyl)-2-(2-nitrophenyl)acetate (B33.3): 10370] To a stirred solution of methyl 2-(4-chloro-2-fluorophenyl)acetate B33.1 (1.7 g, 8.91 mmol, 1 eq) in DMF (15 mL) was added NaH (427 mg, 17.82 mmol, 2 eq) at 0 °C, stirred the reaction mixture for 15 min at room temperature followed by addition of l-fluoro-2-nitrobenzene (B33.2) (1.5 g, 10.69 mmol, 1.2 eq). The reaction mixture was stirred at room temperature for 12h. After completion of reaction, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with water, brine, dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The crude was purified by column chromatography to afford titled methyl 2-(4-chloro-2-fluorophenyl)-2-(2-nitrophenyl)acetate B33.3 (1.5 g, 55.55%). LCMS: 324.04 [M+H]+.
I0371J Step-2: Synthesis of methyl 2-(4-chloro-2-fluorophenyl)-2-(2-nitrophenyl)propanoate (B33.4):
|0372j To a stirred solution of methyl 2-(4-chloro-2-fluorophenyl)-2-(2-nitrophenyl)acetate B33.3 (1.5 g, 4.64 mmol, 1 eq) in DMF (15 mL) was added NaH (167 mg, 6.96 mmol, 1.5 eq) at 0 °C, and the reaction mixture was stirred for 15 min at same temperature followed by addition of methyl iodide (982, 6.96 mmol, 1.5 eq). The stirring was continued at ambient temperature for 16h. After completion of reaction, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with water, brine, dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The crude was purified by column chromatography to afford titled compound methyl 2-(4-chloro-2-fluorophenyl)-2-(2- nitrophenyl)propanoate B33.4 (1.5 g, 96%). LCMS: 338.05 [M+H]+.
(0373] Step-3: Synthesis of 3-(4-chloro-2-fluorophenyl)-3-methylindolin-2-one (B33.5):
(0374] To a stirred solution of methyl 2-(4-chloro-2-fluorophenyl)-2-(2-nitrophenyl)propanoate B33.4 (1.3 g, 3.85 mmol, 1 eq) in THF (10 mL) was added Zn dust (2.8 g) acetic acid (8 mL). The reaction mixture was stirred at 70 °C for 12 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through celite and washed with ethyl acetate; the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography to afford the desired product 3-(4-chloro-2-fluorophenyl)-3- methylindolin-2-one B33.5 (750 mg, 70%). LCMS: 276.05 [M+H]+.
(0375] Step-4: Synthesis of 3-(4-chloro-2-fluorophenyl)-3-methylindoline (B33.6):
(0376] To a stirred solution of 3-(4-chloro-2-fluorophenyl)-3-methylindolin-2-one B33.5 (400 mg, 1.45 mmol, 1 eq) in THF (10 mL) BH3.DMS (10 mL) was added dropwise at 0 °C. The reaction mixture was stirred at room temperature for 12 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was diluted with MeOH and concentrated under reduced pressure. The crude was diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with water, brine, dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The crude was purified by column chromatography to afford titled compound 3-(4-chloro-2-fluorophenyl)-3-methylindoline B33.6 (250 mg, 65%). LCMS: 262.07 [M+H]+.
(0377] Step-5: Synthesis of 4-((3-(4-chloro-2-fluorophenyl)-3-methylindolin-l-yl)sulfonyl)-N,N- dimethylbenzenesulfonamide (B-32):
(0378] To a stirred solution of 3-(4-chloro-2-fluorophenyl)-3-methylindoline B33.6 (200 mg, 0.77 mmol, 1 eq) and 4-(N,N-dimethylsulfamoyl)benzenesulfonyl chloride B33.7 (261.0.92 mmol, 1.2 eq) in acetonitrile (3 mL) was added pyridine (302 mg, 3.83 mmol, 5 eq). The reaction mixture was stirred at 80 °C for 12h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was concentrated; crude was diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with water, brine, dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The crude was purified by column chromatography to afford titled compound 4-((3-(4-chloro-2-fluorophenyl)-3- methylindolin-l-yl)sulfonyl)-N,N-dimethylbenzenesulfonamide B-32. Yield: 50 mg, 12.85%; Appearance: White solid; ¾ NMR (400 MHz, DMSO-de) d 8.02 - 7.94 (m, 2H), 7.87 - 7.79 (m, 2H), 7.63 (d, J = 8.2 Hz, 1H), 7.40 - 7.24 (m, 2H), 7.16 - 7.01 (m, 3H), 6.93 - 6.84 (m, 1H), 4.13 (d, J = 11.2 Hz, 1H), 4.05 (d, J = 11.3 Hz, 1H), 2.59 (d, J = 1.5 Hz, 6H), 1.47 (s, 3H); HPLC purity: 99%; LCMS Calculated for C23H22CIFN2O4S2: 508.07; Observed: 509.00 [M+H]+.
Example B35: Synthesis of N,N-dimethyl-4-({3-[(5r,8r)-3,3-dimethyl-2- oxaspiro[4.5]decan-8-yl]-lH-pyrazolo[4,3-b]pyridin-l-yl}sulfonyl)benzene-l-sulfonamide (B-200), and N,N-dimethyl-4-({3-[(5s,8s)-3,3-dimethyl-2-oxaspiro[4.5]decan-8-yl]-lH- pyrazolo[4,3-b]pyridin-l-yl}sulfonyl) benzene-l-sulfonamide (B-201):
Figure imgf000227_0001
j0379J Step-1. Synthesis of 3,3-dimethyl-2-oxaspiro[4.5]dec-7-en-8-yl trifluoromethanesulfonate (B35.3)
|038 | Bis(trimethylsilyl)amine (2.51 g, 15.5 mmol), 2.5M BuLi solution in hexane (1.02 g, 15.5 mmol, 6.19 mL) were added dropwise under argon atmosphere at -78 °C to a solution of 3,3- dimethyl-2-oxaspiro[4.5]decan-8-one B35.1 (2.18 g, 11.96 mmol) and 1,1,1-trifluoro-N-phenyl- N-trifluoromethanesulfonylmethanesulfonamide B35.2 (5.56 g, 15.55 mmol) in dry tetrahydrofuran (150 mL). The mixture was stirred at -78 °C for 30 min and warmed to room temperature. The reaction was quenched with NH4CI sat. aq. solution (150 mL) and the product was extracted with ethyl acetate (150 mL x 3). The combined organic layers were washed with brine (150 mL), dried over anhydrous sodium sulfate, filtered and concentrated to dryness. The residue was purified by silica gel chromatography (Hexane/EtOAc) to give the 3, 3 -dimethyl-2 - oxaspiro[4.5]dec-7-en-8-yl trifhioromethanesulfonate as a light yellow oil B35.3 (3.76 g, 11.9 mmol, 75% purity, 75.4% yield).
|038I ) Step-2. Synthesis of 4,4,5,5-tetramethyl-2-(l,4-dioxaspiro[4.5]dec-7-en-8-yl)-l,3,2- di oxab orol ane (B 35.5 )
(0382) A solution of 3,3-dimethyl-2-oxaspiro[4.5]dec-7-en-8-yl trifluoromethanesulfonate (B35.3) (3.76 g, 11.96 mmol) in dioxane (20 mL) was purged with argonefor 30 min. Then 4, 4, 5, 5- tetramethyl-2-(tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane B35.4 (2.49 g, 9.80 mmol), potassium acetate (2.89 g, 29.4 mmol), [1,1'- Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1.6 g, 1.95 mmol) were added and the solution was stirred at 80 °C overnight. After the mixture was cooled to room temperature and filtered through a pad of celite. The filtrate was diluted with ethyl acetate (50 mL), this solution was washed with brine (50 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (ethyl acetate/hexane=l : 1) to give 4,4,5,5-tetramethyl-2-(l,4-dioxaspiro[4.5]dec- 7-en-8-yl)-l,3,2-dioxaborolane (B35.5) (1.48 g, 5.06 mmol, 95% purity, 40.3% yield).
(0383) Step-3. Synthesis of 3-bromo-lH-pyrazolo[4,3-b]pyridine B35.7
(0384) The solution of bromine (3.19 g, 20.0 mmol) in a MeOH/LLO mixture (1/1 vol, 10 mL) was added dropwise to the stirred solution of lH-pyrazolo[4,3-b]pyridine B35.6 (2 g, 16.7 mmol) in MeOH/LLO mixture (1/1 vol, 24 mL) maintaining the reaction mixture temperature at 0 °C during the addition. After, the reaction mixture was stirred at this temperature for 40 min. The resulting precipitate was filtered, washed with NaiCCh saturated solution and dried on the air affording 3-bromo-lH-pyrazolo[4,3-b]pyridine B35.7 (2.50 g, 12.6 mmol, 95% purity, 71.8% yield).
(0385) Step-4. Synthesis of 3-{3,3-dimethyl-2-oxaspiro[4.5]dec-7-en-8-yl}-lH-pyrazolo[4,3- bjpyridine (B35.8) (0386] The mixture of 3-bromo-lH-pyrazolo[4,3-b]pyridine B35.7 (1 g, 5.04 mmol), 2-{3,3- dimethyl-2-oxaspiro-[4.5]dec-7-en-8-yl}-4,4,5,5-tetramethyl-l,3,2-dioxaborolane B35.5 (1.48 g, 5.06 mmol), bis((cyclopenta-2,4-dien-l-yl)diphenylphosphane) dichloromethane dichloropalladium iron (0.818 g, 1.00 mmol), dicaesium(l+) carbonate (4.91 g, 15.1 mmol) in dioxane (20 mL) was stirred at 90 °C under argon atmosphere overnight. Then cooled mixture was diluted with water (50 mL) and extracted with ethyl acetate (20mL x 3). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and evaporated in vacuo. Crude product was purified by flash column chromatography (MeOH/DCM) to give 3- {3,3-dimethyl-2-oxaspiro[4.5]dec-7-en-8-yl}-lH-pyrazolo[4,3-b]pyridine B35.8 (400 mg, 1.41 mmol, 95% purity, 26.7% yield).
(0387] Step-5. Synthesis of 3-{3,3-dimethyl-2-oxaspiro[4.5]decan-8-yl}-lH-pyrazolo[4,3- bjpyridine (B35.9)
(0388] Triethylsilane (1.63 g, 14.1 mmol) was added dropwise to the stirred mixture of 3-{3,3- dimethyl-2-oxaspiro[4.5]dec-7-en-8-yl}-lH-pyrazolo[4,3-b]pyridine B35.8 (0.4 g, 1.41 mmol) and 10% Pd/C (0.15 g, 0.141 mmol) in methanol (30 mL) keeping the mixture temperature below 5 °C. The reaction mixture was stirred at room temperature overnight, filtered, the precipitate washed with methanol (10 mL x 2) and combined filtrates were evaporated in vacuo affording 3- {3,3-dimethyl-2-oxaspiro[4.5]decan-8-yl}-lH-pyrazolo[4,3-b]pyridine B35.9 (0.2 g, 0.7 mmol, 88% purity, 43.7% yield) that was used in next step without further purification.
(0389] Step-6. Synthesis of N,N-dimethyl-4-({3-[(5r,8r)-3,3-dimethyl-2-oxaspiro[4.5]decan-8- yl]-lH-pyrazolo[4,3-b]pyridin-l-yl}sulfonyl)benzene-l-sulfonamide (B-200, B-201)
(0390] Solution of 3-3,3-dimethyl-2-oxaspiro[4.5]decan-8-yl-lH-pyrazolo[4,3-b]pyridine (B35.9) (0.2 g, 0.7 mmol), 4-(dimethylsulfamoyl)benzene-l-sulfonyl chloride (B35.10) (0.193 g, 0.680 mmol), triethylamine (0.156 g, 1.54 mmol, 0.220 mL) and N,N-dimethylpyridin-4-amine (0.0075 g, 0.062 mmol) in chloroform (5 mL) was stirred at room temperature overnight and evaporated under reduced pressure. The crude mixture of diastereomers was purified by HPLC (deionized water/HPLC-grade acetonitrile) to give: cis-isomer, N,N-dimethyl-4-({3-[(5r,8r)-3,3- dimethyl-2-oxaspiro[4.5]decan-8-yl]- lH-pyrazolo[4,3 -bjpyridin- 1 -yl } sulfonyl)benzene- 1 - sulfonamide B-200. Yield: 40.4 mg, 10.2%; Appearance: White solid; *H NMR (400 MHz, DMSO-d6) d 8.79 - 8.71 (m, 1H), 8.53 - 8.46 (m, 1H), 8.16 - 8.09 (m, 2H), 7.94 (d, J = 8.6 Hz, 2H), 7.69 (dd, J = 8.6, 4.5 Hz, 1H), 3.49 (s, 2H), 3.17 - 3.04 (m, 1H), 2.59 (s, 6H), 1.95 - 1.84 (m, 2H), 1.74 (q, J = 12.2 Hz, 2H), 1.62 (d, J = 9.4 Hz, 4H), 1.49 - 1.39 (m, 2H), 1.19 (s, 6H); HPLC purity: 100%; LCMS Calculated for C25H32N4O5S2: 532.67; Observed: 533 2 [M-H]+, and trans-isomer, N,N-dimethyl-4-({3-[(5s,8s)-3,3-dimethyl-2-oxaspiro[4.5]decan-8-yl]-lH- pyrazolo[4,3-b]pyridin-l-yl}sulfonyl) benzene- 1 -sulfonamide B-201. Yield: 52.9 mg, 13.4 %; Appearance: White solid; Ή NMR (600 MHz, DMSO-d6) d 8.72 (dd, J = 4.5, 1.3 Hz, 1H), 8.46 (dd, J = 8.6, 1.3 Hz, 1H), 8.11 - 8.08 (m, 2H), 7.93 - 7.89 (m, 2H), 7.66 (dd, J = 8.6, 4.5 Hz, 1H), 3.57 (s, 2H), 3.09 (tt, J = 7.7, 3.4 Hz, 1H), 2.57 (s, 6H), 1.86 (dt, J = 12.7, 3.7 Hz, 2H), 1.72 - 1.60 (m, 4H), 1.55 (s, 2H), 1.46 (td, J = 13.1, 3.8 Hz, 2H), 1.16 (s, 6H); HPLC purity: 100%; LCMS Calculated for C25H32N4O5S2: 532.67; Observed: 533 2 [M-H]+
Example B36: Synthesis of N,N-dimethyl-4-[3-(oxan-4-yl)-lH-pyrrolo[3,2-b]pyridin- l-yl]sulfonylbenzene-l-sulfonamide (B-191):
Figure imgf000230_0001
[0391 ) Step-1. Synthesis of 3-(3,6-dihydro-2H-pyran-4-yl)-lH-pyrrolo[3,2-b]pyridine (B36.3) (0392] 3-Bromo-lH-pyrrolo[3,2-b]pyridine B36.1 (2.06 g, 10.4 mmol), 2-(3,6-dihydro-2H- pyran-4-yl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane B36.2 (3.27 g, 15.6 mmol) and cesium carbonate (8.47 g, 26 mmol) were mixtured in dioxane (16 mL) and water (4 mL), then [1,T- bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (0.594 g, 0.728 mmol) was added under argon atmosphere. The reaction mixture was stirred at 80 °C overnight. After, the mixture was cooled to room temperature and diluted with DCM (20 mL). The organic layer was separated, washed with water (20 mL) and brine (20 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was subjected to column chromatography purification (MTBE/methanol) to afford 3-(3,6-dihydro-2H-pyran-4-yl)-lH-pyrrolo[3,2- bjpyridine as white solid B36.3 (0.3 g, 1.49 mmol, 100% purity, 14.4% yield).
J0393j Step-2. Synthesis of 3-(oxan-4-yl)-lH-pyrrolo[3,2-b]pyridine (B36.4) |0394j 10% Pd/C (0.05 g) was added to the solution of 3-(3,6-dihydro-2H-pyran-4-yl)-lH- pyrrolo[3,2-b]pyridine B36.3 (0.3 g, 1.49 mmol) in methanol (5 mL). The resulting mixture was hydrogenated at ambient pressure and room temperature until the reaction was completed (LCMS control, 6 h). The catalyst was filtered off and the filtrate was evaporated to afford 3-(oxan-4-yl)- lH-pyrrolo[3,2-b]pyridine B36.4 (0.2 g, 0.988 mmol, 100% purity, 66.4% yield). f0395j Step-3. Synthesis of N,N-dimethyl-4-[3-(oxan-4-yl)-lH-pyrrolo[3,2-b]pyridin-l- yl] sulfonylbenzene- 1 - sulfonamide (B - 191 ) j0396J 4-(dimethylsulfamoyl)benzene-l-sulfonyl chloride B36.5 (0.334 g, 1.18 mmol) was added to the mixture of 3-(oxan-4-yl)-lH-pyrrolo[3,2-b]pyridine B36.4 (0.2 g, 0.988 mmol), N,N- dimethylpyridin-4-amine (0.0723 g, 0.592 mmol) and triethylamine (0.199 g, 1.97 mmol, 280.0 mΐ) in dry dichloromethane (5 mL). The reaction mixture was stirred overnight. After completion, it was diluted with water (5 mL) and extracted with dichloromethane (5 mL x 2). Combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was subjected to HPLC purification (deionized water/ HPLC-grade acetonitrile, ammonia) to afford N,N-dimethyl-4-[3 -(oxan-4-yl)- lH-pyrrolo[3 ,2-b]pyridin- 1 -yljsulfonylbenzene- 1 - sulfonamide B-191. Yield: 133.6 mg, 28.3 %; Appearance: White solid; *H NMR (400 MHz, DMSO-d6) d 8.53 (dt, J = 3.4, 1.6 Hz, 1H), 8.34 - 8.22 (m, 3H), 7.94 (dt, J = 9.8, 2.7 Hz, 3H), 7.42 - 7.36 (m, 1H), 3.96 - 3.88 (m, 2H), 3.51 - 3.41 (m, 2H), 3.11 (t, J = 11.9 Hz, 1H), 2.60 (s, 6H), 1.91 (d, J = 13.0 Hz, 2H), 1.79 (tt, J = 13.7, 6.8 Hz, 2H); HPLC purity: 100%; LCMS Calculated for C20H23N3O5S2: 449.54; Observed: 450 0 [M-H]+
Example B37: Synthesis of 4-[(3-{3,3-dimethyl-2-oxa-8-azaspiro[4.5]decan-8-yl}-lH- indazol-l-yl)sulfonyl]-N,N-dimethylbenzene-l-sulfonamide (B-183):
Figure imgf000231_0001
|03 7j Step-1. Synthesis of 4-[(3-chloro-lH-indazol-l-yl)sulfonyl]-N,N-dimethylbenzene-l- sulfonamide (B37.3) j0398] Triethylamine (0.516 g, 5.09 mmol) was added dropwise to a solution of 3-chloro-lH- indazole (B37.1) (0.6 g, 3.93 mmol) and 4-(dimethylsulfamoyl)benzene-l-sulfonyl chloride B37.2 (1.17 g, 4.12 mmol) in dichloromethane (10 mL). Reaction mixture was stirring at room temperature overnight. After completion (LCMS control), the reaction mixture was concentrated, diluted with water (20 mL) and extracted with dichloromethane (20 mL x 2). Combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain 4-[(3-chloro-lH-indazol-l-yl)sulfonyl]-N,N-dimethylbenzene-l-sulfonamide B37.3 (1.45 g, 3.62 mmol, 95% purity, 87.2% yield).
[0399] Step-2. Synthesis of 4-[(3-{3,3-dimethyl-2-oxa-8-azaspiro[4.5]decan-8-yl}-lH-indazol-l- yl)sulfonyl]-N,N-dimethylbenzene-l -sulfonamide (B-183)
(0400] Ethylbis(propan-2-yl)amine (0.39 g, 2.25 mmol) was added to a solution of 3,3-dimethyl- 2-oxa-8-azaspiro[4.5]decane hydrochloride (B37.4) (0.309 g, 3.01 mmol) in propionitrile (6 mL), the mixture was stirred for 5 min and 4-[(3-chloro-lH-indazol-l-yl)sulfonyl]-N,N- dimethylbenzene-1 -sulfonamide B37.3 (0.4 g, 1 mmol) was added. The reaction was performed at 150° C for lh under MW irradiation. After completion, the reaction mixture was cooled to room temperature, filtered and the filtrate was evaporated to give crude product. The residue was subjected to HPLC purification (deionized water/ HPLC-grade acetonitrile) to afford 4-[(3-{3,3- dimethyl-2-oxa-8-azaspiro[4.5]decan-8-yl}-lH-indazol-l-yl)sulfonyl]-N,N-dimethylbenzene-l- sulfonamide B-183. Yield: 22.6 mg, 4.02 %; Appearance: Yellow solid; *H NMR (600 MHz, DMSO-d6) d 8.04 (d, J = 8.5 Hz, 1H), 7.95 - 7.91 (m, 2H), 7.87 (d, J = 8.1 Hz, 1H), 7.86 - 7.82 (m, 2H), 7.62 (ddd, J = 8.4, 7.1, 1.1 Hz, 1H), 7.35 (ddd, J = 8.1, 7.2, 1.0 Hz, 1H), 3.53 (d, J = 1.0 Hz, 2H), 3.43 (ddd, J = 11.4, 6.5, 4.3 Hz, 2H), 3.40 - 3.35 (m, 2H), 2.55 (d, J = 1.0 Hz, 6H), 1.59 (s, 2H), 1.54 (dt, J = 7.3, 4.0 Hz, 4H), 1.17 (s, 6H). HPLC purity: 100%; LCMS Calculated for C25H32N4O5S2: 532.67; Observed: 533.2 [M-H]+.
[0401] The following examples were prepared using standard chemical manipulations and procedures similar to those used for the preparation of the previous example.
Figure imgf000233_0001
Figure imgf000234_0002
Example B38: Synthesis of N,N-dimethyl-4-[(3-{7-oxa-l-azaspiro[4.5]decan-l-yl}- lH-indazol-l-yl)sulfonyl]benzene-l-sulfonamide (B-179):
Figure imgf000234_0001
0402 j Step-1. Synthesis of l-(2-fluorobenzoyl)-7-oxa-l-azaspiro[4.5]decane (B38.3)
[0403] Triethylamine (1.91 g, 18.9 mmol) and 2-fluorobenzoyl chloride B38.1 (0.408 g, 1.53 mmol) were added to a solution of 7-oxa-l-azaspiro[4.5]decane B38.2 (2 g, 12.6 mmol) in dichloromethane (100 mL) at 0 °C. The mixture was stirred at room temperature for 3h, after washed with water (100 mL), brine (100 mL), dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to give l-(2-fluorobenzoyl)-7-oxa-l-azaspiro[4.5]decane B38.3 (2.4 g, 9.11 mmol, 95% purity, 68.8% yield).
[0404] Step-2. Synthesis of l-(2-fluorobenzenecarbothioyl)-7-oxa-l-azaspiro[4.5]decane (B38.4) [0405] Lawesson's reagent (4.04 g, 10.0 mmol) was added to a stirred solution of l-(2- fluorobenzoyl)-7-oxa-l-azaspiro[4.5]decane B38.3 (2.4 g, 9.11 mmol) in toluene (100 mL). The reaction mixture was refluxed for 18 h. After completion, the reaction mixture was cooled to room temperature, concentrated under reduced pressure, the residue was diluted with water (100 mL) and extracted with ethyl acetate (100 mL x 2). The combined organic extracts were washed with water (100 mL), brine (100 mL), dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to give l-(2-fluorobenzenecarbothioyl)-7-oxa-l-azaspiro[4.5]decane as a beige solid B38.4 (3.5 g, 3.75 mmol, 30% purity, 41.3% yield) that was used in the next step without further purification.
[0406] Step-3. Synthesis of l-(lH-indazol-3-yl)-7-oxa-l-azaspiro[4.5]decane (B38.5)
[0407] Hydrazine hydrate (30 g, 599 mmol) was added to a stirred solution of l-(2- fluorobenzenecarbothioyl)-7-oxa-l-azaspiro[4.5]decane B38.4 (2 g, 7.15 mmol) in dioxane (100 mL). The reaction mixture was refluxed for 48 h. After completion, it was cooled to room temperature, concentrated under reduced pressure, diluted with water (100 mL) and extracted with ethyl acetate (100 mL x 2). The combined organic extracts were washed with water (100 mL), brine (100 mL), dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to give 1.2 g of crude product (27% by LCMS). It's HPLC purification (deionized water/HPLC -grade acetonitrile) afforded l-(lH-indazol-3-yl)-7-oxa-l-azaspiro[4.5]decane B38.5 (0.085 g, 0.330 mmol, 100% purity, 4.64% yield).
[0408] Step-4. Synthesis of N,N-dimethyl-4-[(3-{7-oxa-l-azaspiro[4.5]decan-l-yl}-lH-indazol- 1 -yl)sulfonyl]benzene- 1 -sulfonamide (B- 179)
[0400] Triethylamine (0.049 g, 0.485 mmol) and 4-(dimethylsulfamoyl)benzene-l-sulfonyl chloride B38.6 (0.101 g, 0.356 mmol) were added to a l-(lH-indazol-3-yl)-7-oxa-l- azaspiro[4.5]decane (B38.5) (0.0835 g, 0.324 mmol) in acetonitrile (50 mL). The reaction mixture was stirred at room temperature for 18h. The solvent was evaporated under reduced pressure and the residue was subjected to HPLC purification (deionized water/HPLC-grade acetonitrile) that afforded N,N-dimethyl-4-[(3-{7-oxa-l-azaspiro[4.5]decan-l-yl}-lH-indazol-l- yl)sulfonyl]benzene-l -sulfonamide B-179. Yield: 26.4 mg, 15.3 %; Appearance: Yellow solid; ¾ NMR (400 MHz, DMSO-d6) d 8.06 (d, J = 8.4 Hz, 1H), 7.97 (d, J = 7.9 Hz, 2H), 7.95 - 7.88 (m, 3H), 7.63 (t, J = 7.9 Hz, 1H), 7.34 (t, J = 7.8 Hz, 1H), 4.27 (d, J = 10.5 Hz, 1H), 3.83 (d, J = 9.5 Hz, 3H), 3.29 (d, J = 12.5 Hz, 2H), 2.89 (q, J = 10.4 Hz, 1H), 2.65 - 2.55 (m, 6H), 2.28 - 2.18 (m, 1H), 1.89 (t, J = 6.9 Hz, 2H), 1.73 (t, J = 10.3 Hz, 1H), 1.64 (s, 2H), 1.15 (d, J = 12.4 Hz, 1H); HPLC purity: 100%; LCMS Calculated for C23H28N4O5S2: 504.62; Observed: 505 0 [M-H]+ {0410] The following examples were prepared using standard chemical manipulations and procedures similar to those used for the preparation of the previous example.
Figure imgf000236_0001
Figure imgf000237_0001
Example B39: Synthesis of 4-{[3-(4-ethyl-4-methoxypiperidin-l-yl)-lH-indazol-l- yl]sulfonyl}-N,N-dimethylbenzene-l-sulfonamide (B-199):
Figure imgf000238_0001
104 ί 11 Step-1. Synthesis of /c/7-butyl 4-ethyl-4-hydroxypiperidine-l-carboxylate (B39.2) 121 7¾r/-butyl 4-oxopiperidine-l-carboxylate B39.1 (20 g, 100 mmol) in tetrahydrofuran (200 mL) was added dropwise over 30 minutes to a stirred, cooled to 0 °C solution of ethyl magnesium bromide (3.0 M in tetrahydrofuran, 333 mL, 1 mol) in tetrahydrofuran (300 mL). The mixture was allowed to warm up to room temperature and stir for 4 hours. After the mixture was poured into saturated aqueous ammonium chloride solution (400 mL) and extracted with ethyl acetate (400 mL x 2). The combined organic layers were washed with brine (500 mL), dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Hexane/MTBE=3/1) to give /w7-butyl 4-ethyl-4-hydroxypiperidine- 1-carboxylate B39.2 (5 g, 21.8 mmol, 95% purity, 20.7% yield). 0 131 Step-2. Synthesis of /ert-butyl 4-ethyl-4-methoxypiperidine-l-carboxylate (B39.3)
[0414J Sodium hydride (60 w%, 0.955 g, 23.9 mmol) was added to a solution of tert- butyl 4-ethyl- 4-hydroxypiperidine-l-carboxylate B39.2 (5 g, 21.8 mmol) in DMF (100 mL). The mixture was stirred at room temperature for 30 min, cooled to 0 °C and methyl iodide (9.26 g, 65.3 mmol) was added dropwise to the mixture at this temperature. After the mixture was stirred at 50 °C for 3 h, cooled to room temperature, diluted with water (200 mL) and extracted with ethyl acetate (500 mL). The organic layer was separated, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / MTBE = 9/1) to give tert- butyl 4-ethyl-4-methoxypiperidine-l-carboxylate B39.3 (2 g, 8.21 mmol, 80% purity, 30.1% yield) that was used in next step without further purification.
[0415] Step-3. Synthesis of /er/-butyl 4-ethyl-4-methoxypiperidine-l-carboxylate (B39.4)
|0416j A solution of /er/-butyl 4-ethyl-4-methoxypiperidine-l-carboxylate B39.3 (2 g, 8.21 mmol) in dioxane (10 mL) was added to a saturated solution of hydrochloric acid in dioxane (50 mL) at room temperature, the solution was stirred for 12 h and evaporated under reduced pressure. The residue was treated with MTBE (30 mL), the precipitate was filtered and dried on air to afford 4-ethyl-4-methoxypiperidine hydrochloride B39.4 (0.5 g, 2.78 mmol, 100 % purity, 34.0% yield). 0417] Step-4. Synthesis of 4-{[3-(4-ethyl-4-methoxypiperidin-l-yl)-lH-indazol-l-yl]sulfonyl}- N,N-dimethylbenzene- 1 -sulfonamide (B- 199)
10418] 4-[(3-chloro-lH-indazol-l-yl)sulfonyl]-N,N-dimethylbenzene-l -sulfonamide B39.5 (0.695 g, 1.74 mmol) was added to the mixture of te/V-butyl 4-ethyl-4-methoxypiperidine-l- carboxylate B39.4 (0.3 g, 2.09 mmol) and ethylbis(propan-2-yl)amine (0.674 g, 5.22 mmol) in dry propionitrile (5 mL). The reaction mixture was stirred at 150 °C for lh under MW irradiation, cooled to room temperature and evaporated under reduced pressure. The residue was subjected to HPLC purification (deionized water/HPLC-grade methanol) to afford 4-{[3-(4-ethyl-4- methoxypiperidin-l-yl)-lH-indazol-l-yl]sulfonyl}-N,N-dimethylbenzene-l -sulfonamide B-199. Yield: 12.4 mg, 1.32 %; Appearance: Light brown solid; *H NMR (400 MHz, CDCb) d 8.16 (d, J = 8.4 Hz, 1H), 8.01 (d, J = 8.1 Hz, 2H), 7.78 (d, J = 8.2 Hz, 2H), 7.70 (d, J = 8.1 Hz, 1H), 7.53 (t, J = 7.8 Hz, 1H), 7.30 (s, 1H), 3.76 (dt, J = 13.1, 3.7 Hz, 2H), 3.33 (td, J = 12.4, 2.6 Hz, 2H), 3.18 (s, 3H), 2.71 (s, 6H), 1.86 (d, J = 13.7 Hz, 2H), 1.66 - 1.47 (m, 4H), 0.88 (t, J = 7.4 Hz, 3H); HPLC purity: 100%; LCMS Calculated for C23H30N5O5S2: 506 64; Observed: 5072 [M-H]+
Example B40: Synthesis of N,N-dimethyl-4-({3-[(5s,8s)-3,3-dimethyl-2- oxaspiro[4.5]decan-8-yl]-lH-pyrrolo[3,2-c]pyridin-l-yl}sulfonyl)benzene-l-sulfonamide, (B-198) and N,N-dimethyl-4-({3-[(5r,8r)-3,3-dimethyl-2-oxaspiro[4.5]decan-8-yl]-lH- pyrrolo[3,2-c]pyridin-l-yl}sulfonyl)benzene-l-sulfonamide (B-190):
Figure imgf000240_0001
B-198 B-190 j0419l Step-1. Synthesis of 3-3,3-dimethyl-2-oxaspiro[4.5]dec-7-en-8-yl-lH-pyrrolo[3,2- cjpyridine (B40.3)
J0420] Potassium hydroxide (1.18 g, 21.02 mmol) was added to a stirred solution of 1H- pyrrolo[3,2-c]pyridine B40.1 (0.828 g, 7.01 mmol) and 3,3-dimethyl-2-oxaspiro[4.5]decan-8-one B40.2 (1.28 g, 7.02 mmol) in methanol (15 mL) and the mixture was refluxed overnight. Then the reaction mixture was cooled down to room temperature and poured into ice-cold water (50 mL). Formed precipitate was filtered, washed with water (25 mL x 2), dried on air to give 3-3,3- dimethyl-2-oxaspiro[4.5]dec-7-en-8-yl-lH-pyrrolo[3,2-c]pyridine B40.3 (1.89 g, 6.69 mmol, 88.0% purity, 84.2% yield) that was used in next step without further purification.
|042 j Step-2. Synthesis of 3-{3,3-dimethyl-2-oxaspiro[4.5]decan-8-yl}-lH-pyrrolo[3,2- cjpyridine (B40.4)
J0422] Triethylsilane (7.77 g, 66.9 mmol) was added dropwise to the stirred mixture of 3-{3,3- dimethyl-2-oxaspiro[4.5]dec-7-en-8-yl}-lH-pyrrolo[3,2-c]pyridine B40.3 (1.89 g, 6.69 mmol) and 10% Pd/C (0.711 g) in methanol (50 mL) keeping reaction mixture temperature below 5 °C. Obtained mixture was stirred at room temperature overnight, filtered, the precipitate washed with methanol (10 mL). Combined filtrates were evaporated in vacuo to give 3-{3,3-dimethyl-2- oxaspiro[4.5]decan-8-yl}-lH-pyrrolo[3,2-c]pyridineB40.4 (1.55 g, 6.69 mmol, 860% purity, 70.0 % yield) that was used in next step without further purification.
I0423J Step-3. Synthesis of N,N-dimethyl-4-({3-[(5s,8s)-3,3-dimethyl-2-oxaspiro[4.5]decan-8- yl]- lH-pyrrolo[3 ,2-c]pyridin- 1 -yl } sulfonyl)benzene- 1 -sulfonamide (B-198, B- 190) |0424j Solution of 3-{3,3-dimethyl-2-oxaspiro[4.5]decan-8-yl}-lH-pyrrolo[3,2-c]pyridine B40.4 (0.3 g, 1.05 mmol), 4-(dimethylsulfamoyl)benzene-l-sulfonyl chloride B40.5 (0.326 g, 1.14 mmol), triethylamine (0.265 g, 2.62 mmol) and N,N-dimethylpyridin-4-amine (0.0128 g, 0.105 mmol) in dichloromethane (40 mL) was stirred overnight at room temperature. The mixture was washed with saturated NaHCCb solution (20 mL), brine (20 mL x 2), dried over sodium sulfate, filtered and evaporated in vacuo. The crude mixture of diastereomers was subjected to HPLC purification (deionized water/HPLC-acetonitrile) to afford cis-isomer N,N-dimethyl-4-({3- [(5s,8s)-3,3-dimethyl-2-oxaspiro[4.5]decan-8-yl]-lH-pyrrolo[3,2-c]pyridin-l- yl}sulfonyl)benzene-l -sulfonamide B-198. Yield: 34.5 mg, 6.37 %; Appearance: White solid; ¾ NMR (400 MHz, DMSO-d6) d 8.98 (s, 1H), 8.48 (d, J = 5.8 Hz, 1H), 8.29 (d, J = 8.2 Hz, 2H), 7.96 (d, J = 8.1 Hz, 2H), 7.90 (d, J = 5.7 Hz, 1H), 7.70 (s, 1H), 3.49 (s, 2H), 2.78 (d, J = 11.5 Hz, 1H), 2.62 (s, 6H), 1.94 - 1.86 (m, 2H), 1.67 (d, J = 15.4 Hz, 4H), 1.49 (dt, J = 31.2, 12.3 Hz, 4H), 1.21 (s, 6H) ; HPLC purity: 95 29%; LCMS Calculated for C26H33N3O5S2: 531.69; Observed: 532.4 [M-H]+; and trans-isomer N, N-dimethyl-4-({3-[(5r, 8r)-3, 3-dimethyl-2-oxaspiro[4.5]decan- 8-yl]-lH-pyrrolo[3,2-c]pyridin-l-yl}sulfonyl)benzene-l-sulfonamide B-190. Yield: 5 mg, 0.85 %; Appearance: Beige solid; ¾ NMR (600 MHz, DMSO-d6) d 8.95 (s, 1H), 8.45 (d, J = 5.7 Hz, 1H), 8.28 - 8.23 (m, 2H), 7.97 - 7.90 (m, 2H), 7.87 (d, J = 5.7 Hz, 1H), 7.65 (s, 1H), 3.64 (s, 2H), 2.81 - 2.73 (m, 1H), 2.59 (s, 6H), 1.84 (d, J = 12.4 Hz, 2H), 1.74 (d, J = 11.3 Hz, 2H), 1.55 (s, 2H), 1.53 - 1.38 (m, 4H), 1.17 (s, 6H); HPLC purity: 95.29%; LCMS Calculated for C26H33N3O5S2: 531.69; Observed: 532.2 [M-H]+.
10425 [ The following examples were prepared using standard chemical manipulations and procedures similar to those used for the preparation of the previous example.
Figure imgf000242_0001
Figure imgf000243_0001
Example B41: Synthesis of N,N-dimethyl-4-({3-[(6s,9s)-l,4-dioxaspiro[5.5] undecan-
9-yl]-lH-pyrrolo[3,2-b]pyridin-l-yl}sulfonyl)benzene-l-sulfonamide (B-185) and N,N- dimethyl-4-({3-[(6r,9r)-l,4-dioxaspiro[5.5]undecan-9-yl]-lH-pyrrolo[3,2-b]pyridin-l- yl}sulfonyl)benzene-l-sulfonamide (B-186):
Figure imgf000244_0001
[0426] Step-1. Synthesis of 3-{l,4-dioxaspiro[5.5]undec-8-en-9-yl}-lH-pyrrolo[3,2-b]pyridine (B41.3)
[0427] KOH (0.566 g, 10.1 mmol) was added to a stirred solution of lH-pyrrolo[3,2-b]pyridine (B41.1) (0.3 g, 2.53 mmol) and l,4-dioxaspiro[5.5]undecan-9-one B41.2 (1.29 g, 7.58 mmol) in methanol (10 mL) at room temperature. The reaction mixture was stirred at 65 °C for 24 h. After completion (TLC control), the reaction mixture was quenched with 2 N HC1 aq solution till pH=7 and concentrated under reduced pressure. The crude material was diluted with water (20 mL) and the product was extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed with water (40 mL), brine (40 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced to afford 3-{ 1, 4-dioxaspiro[5.5]undec-8-en-9-yl}-lH-pyrrolo[3, 2- bjpyridine B41.3 (0.2 g, 0.739 mmol, 85.7% purity, 25.0%) that was used in next step without further purification.
[0428] Step-2. Synthesis of 3-{l,4-dioxaspiro[5.5]undecan-9-yl}-lH-pyrrolo[3,2-b]pyridine (B41.4)
[0429] 10% Pd/C was added at 0 °C to a stirred solution of 3-{l,4-dioxaspiro[5.5]undec-8-en-9- yl}-lH-pyrrolo[3,2-b]pyridine B41.3 (0.2 g, 0.739 mmol) in a mixture of methanol and ethyl acetate (lmL/1.8 mL), the reaction mixture was stirred for 10 min followed by dropwise addition of triethyl silane (1.27 g, 11 mmol). The reaction mixture was stirred under hydrogen atmosphere (balloon pressure) at room temperature for 16 h. After completion (TLC control), the reaction mixture was filtered through a pad of Celite and the Celite pad was washed with methanol. The combined filtrates were evaporated under reduced pressure to afford 3-{ 1,4- dioxaspiro[5.5]undecan-9-yl}-lH-pyrrolo[3,2-b]pyridine B41.4 (0.180 g, 0.660 mmol, 95% purity, 85.0% yield).
[0430] Step-3. Synthesis of N,N-dimethyl-4-({3-[(6s,9s)-l,4-dioxaspiro[5.5]undecan-9-yl]-lH- pyrrolo[3,2-b]pyri din- l-yl}sulfonyl)benzene-l -sulfonamide (B-185, B-186)
[0431 ] Sodium hydride (0.022 g, 0.55 mmol) was added to a stirred solution of 3-{ 1,4- dioxaspiro[5.5]undecan-9-yl}-lH-pyrrolo[3,2-b]pyridine B41.4 (0.1 g, 0.36 mmol) in THF (10 mL) at 0 °C, the reaction mixture was stirred for 10 min at same temperature followed by addition of 4-(dimethylsulfamoyl)benzene-l-sulfonyl chloride B41.5 (0.109 g, 0.38 mmol). The reaction mixture was allowed to warm up to room temperature and stirred for 12 h. After completion (TLC control), the reaction mixture was concentrated, diluted with water (10 mL) and the product was extracted with ethyl acetate (10 mL x 2). The combined organic extracts were washed with water (10 mL), brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by prep HPLC (deionized water/HPLC -grade methanol) to provide 4-[(3-{l,4-dioxaspiro[5.5]undecan-9-yl}-lH-pyrrolo[3,2-b]pyridin-l- yl)sulfonyl]-N,N-dimethylbenzene-l -sulfonamide (0.05 g) as mixture of diastereomers. The separation on IA (250*20, 5mkm) column (hexane/IPA/methanol=50/25/25) afforded cis-isomer N,N-dimethyl-4-({3-[(6s,9s)-l,4-dioxaspiro[5.5] undecan-9-yl]-lH-pyrrolo[3,2-b]pyridin-l- yl}sulfonyl)benzene-l -sulfonamide B-185. Yield: 5.4 mg, 2.69 %; Appearance: White solid; *H NMR (600 MHz, DMSO-d6) 58.51 (dd, J = 4.7, 1.5 Hz, 1H), 8.25 (ddt, J = 11.0, 8.9, 1.9 Hz, 3H), 7.91 (dd, J = 8.7, 2.1 Hz, 2H), 7.80 (d, J = 1.0 Hz, 1H), 7.38 - 7.33 (m, 1H), 3.58 (dd, J = 6.1, 3.2 Hz, 2H), 3.53 (dd, J = 5.9, 3.4 Hz, 2H), 3.33 (s, 2H), 2.84 (t, J = 12.2 Hz, 1H), 2.58 (d, J = 2.2 Hz, 6H), 2.01 (d, J = 13.3 Hz, 2H), 1.83 (d, J = 12.4 Hz, 2H), 1.74 - 1.65 (m, 2H), 1.27 (td, J = 13.6, 3 8 Hz, 2H); HPLC purity: 100%; LCMS Calculated for C24H29N3O6S2: 519.63; Observed: 520.2 [M-H]+, and trans-isomer N,N-dimethyl-4-({3-[(6r,9r)-l,4-dioxaspiro[5.5]undecan-9-yl]- lH-pyrrolo[3,2-b]pyridin-l-yl}sulfonyl)benzene-l-sulfonamide B-186. Yield: 6.8 mg, 3.4 %; Appearance: Yellow solid; Ή NMR (600 MHz, DMSO-d6) 5 8.50 (dd, J = 4.7, 1.4 Hz, 1H), 8.25 (dd, J = 8.4, 1.4 Hz, 1H), 8.23 - 8.18 (m, 2H), 7.94 - 7.86 (m, 3H), 7.35 (dd, J = 8.4, 4.7 Hz, 1H), 3.64 - 3.59 (m, 3H), 3.56 - 3.50 (m, 2H), 2.95 - 2.89 (m, 1H), 2.58 (s, 6H), 2.01 (d, J = 13.0 Hz, 2H), 1.90 (d, J = 13.1 Hz, 2H), 1.62 (q, J = 11.8, 11.4 Hz, 2H), 1.42 - 1.35 (m, 2H); HPLC purity: 100%; LCMS Calculated for C24H29N3O6S2: 519.63; Observed: 520 2 [M-H]+ Example B42: Synthesis ofN,N-dimethyl-4-({3-[(ls,4s)-4-{[(2R,6S)-2,6- dimethylmorpholin-4-yl]methyl}cyclohexyl]-lH-pyrrolo[3,2-b]pyridin-l- yl}sulfonyl)benzene-l-sulfonamide (B-196) and N,N-dimethyl-4-({3-[(lr,4r)-4-{[(2R,6S)- 2,6-dimethylmorpholin-4-yl]methyl}cyclohexyl]-lH-pyrrolo[3,2-b]pyridin-l- yl}sulfonyl)benzene-l-sulfonamide (B-195):
Figure imgf000246_0001
|0432j Step-1. Synthesis of (2R,6S)-4-({l,4-dioxaspiro[4.5]decan-8-yl}methyl)-2,6- dimethylmorpholine (B42.3) j0433| (2S,6R)-2,6-dimethylmorpholine B42.2 (2.01 g, 17.5 mmol) and acetic acid (0.42 g, 6.99 mmol, 0.4 mL) were added to a solution of l,4-dioxaspiro[4.5]decane-8-carbaldehyde (B42.1) (2 g, 11.7 mmol) in a mixture of dichloroethane/tetrahydrofuran (40 mL/4 mL). After the mixture was stirred for 30 minutes, and NaBH(OAc)3 (4.95 g, 23.4 mmol) was added. The mixture was stirred at room temperature for 2 days, after poured into NaHCCb sat. aq. solution (100 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give (2S,6R)-4-((l,4- dioxaspiro[4.5]decan-8-yl)methyl)-2,6-dimethylmorpholineB42.3 (3.2 g, 11.8 mmol, 90% purity, 91.4% yield). |0434j Step-2. Synthesis of 4-{[(2R,6S)-2,6-dimethylmorpholin-4-yl]methyl}cyclohexan-l-one (B42.4) j0435J 2 M HC1 solution (30 mL) was added to a stirred solution of (2S,6R)-4-((l,4- dioxaspiro[4.5]decan-8-yl)methyl)-2,6-dimethylmorpholine B42.3 (3.2 g, 11.8 mmol) in tetrahydrofuran (10 mL). The resulting mixture was refluxed until reaction completion (TLC control, 3 days), basified with 10% Na2CCb aq. solution until pH = 8. The product was extracted with ethyl acetate (50 mL x 2). Organic layers were combined, dried over sodium sulfate, filtered and evaporated under reduced pressure to give 4-{[(2R,6S)-2,6-dimethylmorpholin-4- yl]methyl}cyclohexan-l-one B42.4 (1.9 g, 8.43 mmol, 86% purity, 61.5% yield) that was used in the next step without further purification.
J0436] Step-3. Synthesis of (2S,6R)-4-((4-(lH-pyrrolo[3,2-b]pyridin-3-yl)cyclohex-3-en-l- yl)methyl)-2,6-dimethylmorpholine (B42.6)
J0437] Sodium (0.365 g, 15.9 mmol) was added portionwise to a well-stirred pre-cooled methanol (20 mL). After sodium complete dissolving lH-pyrrolo[3,2-b]pyridine B42.5 (0.353 g, 2.99 mmol) and 4-(((2S,6R)-2,6-dimethylmorpholino)methyl)cyclohexan-l-one B42.4 (0.9 g, 3.99 mmol) were added at room temperature. The reaction mixture was refluxed for 72 h. After completion (TLC control), the reaction mixture was quenched with 2N HC1 solution (20 mL), and concentrated under reduced pressure. The crude residue was diluted with water (20 mL), basified with 10% Na2CCb aq. sat. solution and the product was extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed with water (40 mL), brine (40 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced to afford (2S,6R)-4-((4-(lH-pyrrolo[3,2- b]pyridin-3-yl)cyclohex-3-en-l-yl)methyl)-2,6-dimethylmorpholine B42.6 (1.2 g, 3.68 mmol, 85% purity, 79% yield) that was used in the next step without further purification.
|0438j Step-4. Synthesis of (2S,6R)-4-((4-(lH-pyrrolo[3,2-b]pyridin-3-yl)cyclohexyl)methyl)- 2,6-dimethylmorpholine (B42.7) j0439| 10% Pd/C (0.1 g) was added to a stirred solution of (2S,6R)-4-((4-(lH-pyrrolo[3,2- b]pyridin-3-yl)cyclohex-3-en-l-yl)methyl)-2,6-dimethylmorpholine B42.6 (1.2 g, 3.68 mmol) in a mixture of methanol and ethyl acetate (1/1, 30 mL) followed by dropwise addition of triethyl silane (0.855 g, 7.36 mmol). The reaction mixture was hydrogenated at ambient pressure and room temperature for 16h. After completion (TLC control) the mixture was filtered through Celite pad, it was washed with methanol (30 mL). The combined filtrates were evaporated under reduced pressure to afford (2S,6R)-4-((4-(lH-pyrrolo[3,2-b]pyridin-3-yl)cyclohexyl)methyl)-2,6- dimethylmorpholine B42.7 (0.55 g, 1.67 mmol, 85% purity, 38.9% yield) that was used in next step without further purification.
{0440] Step-5. Synthesis of 4-((3-(4-(((2S,6R)-2,6-dimethylmorpholino)methyl)cyclohexyl)-lH- pyrrolo[3 ,2-b]pyridin- 1 -yl)sulfonyl)-N,N-dimethylbenzenesulfonamide (B- 196, B- 195)
10441 j Potassium tertiary butoxide (0.17g, 1.52 mmol) and 18-crown-6 (0.04 g, 0.15 mmol) were added at 0 °C to a stirred solution of (2S,6R)-4-((4-(lH-pyrrolo[3,2-b]pyridin-3- yl)cyclohexyl)methyl)-2,6-dimethylmorpholine B42.7 (0.25 g, 0.76 mmol) in tetrahydrofuran (20 mL), the reaction mixture was stirred for 30 minutes and 4-(N,N- dimethylsulfamoyl)benzenesulfonyl chloride B42.8 (0.323 g, 1.14 mmol) was added at the same temperature. The reaction mixture was allowed to warm and stir at room temperature for 12 h. After reaction completion (TLC control), the reaction mixture was concentrated under reduced pressure, diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic extracts were washed with water (20 mL), brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give crude product as mixture of diastereomers. It's purification by HPLC (deionized water/HPLC -grade acetonitrile) afforded cis- isomer N,N-dimethyl-4-({3-[(ls,4s)-4-{[(2R,6S)-2,6-dimethylmorpholin-4- yljmethyl } cyclohexyl]- lH-pyrrolo[3 ,2-b]pyridin- 1 -yl } sulfonyl)benzene- 1 -sulfonamide B- 196. Yield: 6.6 mg, 14.3 %; Appearance: Yellow solid; ¾ NMR (600 MHz, DMSO-d6) d 8.50 (d, J = 4.8 Hz, 1H), 8.27 (dd, J = 8.4, 1.3 Hz, 1H), 8.21 (d, J = 8.3 Hz, 2H), 7.89 (d, J = 8.3 Hz, 2H), 7.84 (s, 1H), 7.35 (dd, J = 8.4, 4.7 Hz, 1H), 3.51 (t, J = 8.0 Hz, 2H), 2.96 (t, J = 8.0 Hz, 1H) 2.70 (d, J = 10.9 Hz, 2H), 2.57 (s, 10H), 2.20 (d, J = 7.6 Hz, 3H), 1.83 (s, 3H), 1.70 (s, 2H), 1.54 (t, J = 10.5 Hz, 4H), 1.43 (s, 2H), 1.01 (d, J = 6.3 Hz, 6H); HPLC purity: 100%; LCMS Calculated for C28H38N4O5S2: 574.76; Observed: 575.2 [M-H]+; and trans-isomer N,N-dimethyl-4-({3-[(lr,4r)- 4-{[(2R,6S)-2,6-dimethylmorpholin-4-yl]methyl}cyclohexyl]-lH-pyrrolo[3,2-b]pyridin-l- yl}sulfonyl)benzene-l -sulfonamide B-195. Yield: 58.3 mg, 6.37 %; Appearance: Beige solid; *H NMR (600 MHz, DMSO-d6) d 8.50 (dd, J = 4.7, 1.4 Hz, 1H), 8.26 (dd, J = 8.4, 1.4 Hz, 1H), 8.21 (d, J = 8.5 Hz, 2H), 7.92 - 7.88 (m, 2H), 7.79 (s, 1H), 3.54 - 3.50 (m, 2H), 2.77 (d, J = 12.1 Hz, 1H), 2.67 (d, J = 10.8 Hz, 2H), 2.58 (s, 6H), 2.06 (d, J = 7.2 Hz, 2H), 2.00 (d, J = 12.6 Hz, 2H), 1.83 (d, J = 12.8 Hz, 2H), 1.56 (s, 1H), 1.51 (t, J = 10.9 Hz, 4H), 1.01 (d, J = 6.2 Hz, 6H), 1.00 - 0 93 (m, 3H); HPLC purity: 96 07%; LCMS Calculated for C28H38N4O5S2: 574.76; Observed: 575.2 [M-H]+
Example B43: Synthesis of 4-((3-(l,4-dioxanspiro[4.5]decan-8-yl)-lH-pyrrolo[3,2- b]pyridin-l-yl)sulfonyl)-N,N-dimethylbenzenesulfonamide (B-160) and N,N-dimethyl-4-((3- (2,2,3,3-tetramethyl-l,4-dioxanspiro[4.5]decan-8-yl)-lH-pyrrolo[3,2-b]pyridin-l- yl)sulfonyl)-benzenesulfonamide (B-164):
Figure imgf000249_0001
|0442) Step-1: Synthesis of 3-(l,4-dioxaspiro[4.5]dec-7-en-8-yl)-lH-pyrrolo[3,2-b]pyridine (B43.3):
J0443] To a stirred solution of l,4-dioxaspiro[4.5]decan-8-one B43.1 (5.28 g, 3.38 mmol, 1 eq) and lH-pyrrolo[3,2-b]pyridine B43.2 (4.0 g, 3.38 mmol, 1 eq) in MeOH (80 mL) was added KOH (4.74 g, 8.46 mmol, 2.5 eq) at room temperature and the reaction mixture was stirred at 80 °C for 12 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was allowed to cool to RT, diluted with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure to dryness. The crude product was purified by flash column to afford 3-(l,4- dioxaspiro[4.5]dec-7-en-8-yl)-lH-pyrrolo[3,2-b]pyridine B43.3 (7.0 g, 80%) as an off white solid. LCMS: 256.7 [M+H]+.
|0444j Step-2: Synthesis of 3-(l,4-dioxaspiro[4.5]decan-8-yl)-lH-pyrrolo[3,2-b]pyridine (B43.4): 0445 j To a stirred solution of 3-(l,4-dioxaspiro[4.5]dec-7-en-8-yl)-lH-pyrrolo[3,2-b]pyridine 3 (7.0 g, 2.7 mmol, 1 eq) in MeOH (50 mL) was added Pd/C (20%, 2.1 g) under nitroden atmosphere. The resulting reaction mixture was hydrogenated (70 psi) at room temperature for 12 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through celite and concentrated under reduced pressure to afford 3 -(1,4- dioxaspiro[4.5]decan-8-yl)-lH-pyrrolo[3,2-b]pyridineB43.4 (5.6 g, 79%) as abrown coloured oil. This compound was used in the next step without further purification. LCMS: 258.6 [M+H]+. j0446J Step-3: Synthesis of 4-((3-(l,4-dioxanspiro[4.5]decan-8-yl)-lH-pyrrolo[3,2-b]pyridin-l- yl)sulfonyl)-N,N-dimethylbenzenesulfonamide (B-160):
|0447| To a stirred solution of 3-(l,4-dioxaspiro[4.5]decan-8-yl)-lH-pyrrolo[3,2-b]pyridine B43.4 (2.0 g, 7.7 mmol, 1 eq) and 4-(N,N-dimethylsulfamoyl)benzenesulfonyl chloride B43.5 (2.64 g, 9.3 mmol, 1.2 eq) in DCM (50 mL) was added KOH (0.86 g, 15.5 mmol, 2 eq) followed by TBA.HSO4 (0.39 g, 1.16 mmol, 0.15 eq). The reaction mixture was stirred at room temperature for 12 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated, diluted with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure to dryness. The crude product was purified by flash column chromatography to afford 4-((3-(l,4-dioxanspiro[4.5]decan-8-yl)-lH-pyrrolo[3,2-b]pyridin-l-yl)sulfonyl)-N,N- dimethylbenzenesulfonamide B-160. Yield: 3.0 g, 76%; Appearance: White solid; 1HNMR (400 MHz, DMSO-de) d 8.54 (d, J= 3.91 Hz, 1 H), 8.30 - 8.25 (m, 3 H), 7.94 (d, J= 8.31 Hz, 2 H), 7.86 (s, 1 H), 7.40 (dd, J= 8.07, 4.65 Hz, 1 H), 3.88 (s, 4 H), 2.90 (d, J=6.85 Hz, 1 H), 2.60 (s, 6 H), 2.01 (d, J=10.76 Hz, 2 H), 1.80 - 1.73 (m, 4 H), 1.64 - 1.58 (m, 2 H); HPLC purity: 98.56%; LCMS calculated for C23H27N3O6S2 : 505.13; Observed: 506 2 [M+H]+
|0448j Step-4: Synthesis of N,N-dimethyl-4-((3-(4-oxocyclohexyl)-lH-pyrrolo[3,2-b]pyridin-l- yl)sulfonyl)benzenesulfonamide (6): j0449| To a stirred solution of compound B-160 (1.0 g, 1.98 mmol, 1 eq) in THF (20 mL) was added concentrated HC1 (15 mL) at 0 °C. The reaction mixture was stirred at room temperature for 12 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, neutralized using saturated NaOH solution and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure to dryness. The crude product was purified by flash column chromatography to afford N,N-dimethyl-4-((3-(4-oxocyclohexyl)-lH- pyrrolo[3,2-b]pyridin-l-yl)sulfonyl)benzenesulfonamide B43.6 (0.75 g, 82%) as a white solid. LCMS: 461.9 [M+H]+.
J0450] Step-5: Synthesis of N,N-dimethyl-4-((3-(2,2,3,3-tetramethyl-l,4-dioxanspiro[4.5]decan- 8-yl)-lH-pyrrolo[3,2-b]pyridin-l-yl)sulfonyl)-benzenesulfonamide (B-164):
|0451j To a stirred solution of N,N-dimethyl-4-((3-(4-oxocyclohexyl)-lH-pyrrolo[3,2-b]pyridin- l-yl)sulfonyl)benzenesulfonamide B43.6 (0.5 g, 1.08 mmol, 1 eq) and 2,3-dimethylbutane-2,3- diol (B43.7) (0.19 g, 1.6 mmol, 1.5 eq) in toluene (30 mL) was added p-TSA (0.093 g, 0.54 mmol, 0.5 eq) at room temperature. The reaction mixture was stirred at 140 °C for 12 h. The progress of the reaction was monitored by LCMS (no desired product formation observed). The reaction mixture was concentrated under reduced pressure. To a stirred solution of the reaction mixture in DCM (20 mL) was added p-TSA (0.093 g, 0.54 mmol, 0.5 eq) and compound B43.7 (0.13 g, 1.08 mmol, 1 eq). The reaction mixture was stirred at room temperature for 12 h. The progress of the reaction was monitored by LCMS (LCMS showed 25% desired product). The reaction mixture was diluted with water and extracted with DCM. The combined organic layers were dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure to dryness. The crude product was purified by preparative HPLC to afford the titled compound B-164. Yield: 0.05 g, 8%; Appearance: White solid; ¾ NMR (400 MHz, DMSO-de) d 8.53 (br d, J= 3.42 Hz, 1 H), 8.30 - 8.26 (m, 3 H), 7.94 (br d, J= 8.80 Hz, 2 H), 7.86 (s, 1 H), 7.39 - 7.36 (m, 1 H), 2.92 - 2.80 (m, 1 H), 2.61 (s, 6 H), 2.00 - 1.97 (m, 2 H), 1.83 - 1.64 (m, 6 H), 1.19 (d, J=6.85 Hz, 12 H); HPLC purity: 9929%; LCMS calculated for C27H35N3O6S2 :561.20; Observed: 562 1 [M+H]+
Example B44: Synthesis of 4-((3-(4-(methoxymethyl)-4-methylcyclohexyl)-lH- pyrrolo[3,2-b]pyridin-l-yl)sulfonyl)-N,N-dimethylbenzenesulfonamide (B-215 and B-216):
Figure imgf000252_0001
[0452J Step-1: Synthesis of ethyl l,4-dioxaspiro[4.5]decane-8-carboxylate (B44.3):
[04531 To a stirred solution of ethyl 4-oxocyclohexane-l-carboxylate (B44.1) (10 g, 58.82 mmol) in toluene (100 mL) was added ethane- 1,2-diol B44.2 (5.47 g, 88.23 mmol) and p-Toluenesulfonic acid monohydrate (0.565 g, 2.94 mmol) at room temperature. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with EtOAc, washed with sat. NaHCCb, water and brine. The organic layer was dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel to afford ethyl l,4-dioxaspiro[4.5]decane-8-carboxylate B44.3 (10.7 g, 85%) %). LCMS: 214.85 [M]+.
[04541 Step-2: Synthesis of ethyl 8-methyl- l,4-dioxaspiro[4.5]decane-8-carboxylate (B44.4): [04551 A solution of ethyl l,4-dioxaspiro[4.5]decane-8-carboxylate B44.3 (5.0 g, 23.3 mmol) in THF (50 mL) was cooled to -78 °C and lithium diisopropylamide (1M in THF, 46.6 mL, 46.6 mmol) was added dropwise. The reaction mixture was allowed to stir at the same temperature for 1 h. Methyl Iodide (2.18 mL, 35.0 mmol) was then added at -78 °C. The reaction mixture was allowed to gradually warm to room temperature and stirred for overnight. The reaction was quenched with sat. aq. MLCl and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2S04, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel to afford ethyl 8-methyl-l,4-dioxaspiro[4.5]decane-8-carboxylate B44.4 (4.7 g, 88%). %). LCMS: 229.30 [M+H]+.
[0456j Step-3: Synthesis of (8-methyl-l,4-dioxaspiro[4.5]decan-8-yl)methanol (B44.5): [0457] A solution 8-methyl-l,4-dioxaspiro[4.5]decane-8-carboxylate B44.4 (4.7 g, 20.6 mmol) in THF (50 mL) was cooled to 0 °C and Lithium aluminium hydride (1M in THF, 41.2 niL, 41.2 mmol) was added dropwise. The mixture was stirred at room temperature for 1.5 h. After completion of reaction, the reaction was cooled to 0 °C and quenched with sat. aq. Na2SC>4. The insoluble precipitate was then removed by filtration and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel to afford (8-methyl-l,4-dioxaspiro[4.5]decan-8-yl)methanol B44.5 (3.2 g, 83%). LCMS: No ionization.
[0458] Step-4: Procedure for the synthesis of 8-(methoxymethyl)-8-m ethyl- 1,4- dioxaspiro[4.5]decane (B44.6):
[0459] A solution (8-methyl-l,4-dioxaspiro[4.5]decan-8-yl)methanol B44.5 (3.2 g, 17.1 mmol) in THF (40 mL) was cooled to 0 °C and sodium hydride (60% dispersion in mineral oil, 0.82 g, 34.3 mmol) was added in portions. The reaction mixture was allowed to stir at the same temperature for 10 min, methyl Iodide (1.39 mL, 22.3 mmol) was then added at 0 °C. The reaction mixture was allowed to gradually warm to room temperature and stirred for 3 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was quenched with water and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel to afford 8-(methoxymethyl)-8-methyl-l,4-dioxaspiro[4.5]decane (B44.6) (3.2 g, 93%). LCMS: No ionization.
[0460] Step-5: Synthesis of 4-(methoxymethyl)-4-methylcyclohexan-l-one (B44.7):
[0461) A solution 8-(methoxymethyl)-8-methyl-l,4-dioxaspiro[4.5]decane B44.6 (3.2 g, 15.9 mmol) in THF (16 mL) was cooled to 0 °C and 2N HC1 (16 mL) was added. The reaction mixture was allowed to gradually warm to room temperature and stirred for 3 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was neutralized by addition of sat. aq. NaHCCh extracted with EtOAc. The combined organic layers were dried over anhydrous Na2S04, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel to afford 4-(methoxymethyl)-4- methylcyclohexan-l-one B44.7 (2.4 g, 96%). LCMS: 157.45 [M+H]+.
[0462] Step-6: Synthesis of 3-(4-(methoxymethyl)-4-methylcyclohex-l-en-l-yl)-lH-pyrrolo[3,2- bjpyridine (B44.9): 0463 j To a solution of 4-(methoxymethyl)-4-methylcyclohexan-l-one B44.7 (0.9 g, 5.7 mmol) in MeOH (18 mL) were added lH-pyrrolo[3,2-b]pyridine (B44.8) (0.74 g, 6.3 mmol) and KOH (0.96 g, 17.3 mmol). The reaction mixture was allowed to reflux for 5 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was evaporated to dryness. The residue was partitioned between water and EtOAc. The organic layer was separated, dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel to afford 3-(4- (methoxymethyl)-4-methylcyclohex-l-en-l-yl)-lH-pyrrolo[3,2-b]pyridine B44.9 (0.65 g, 44%). [0464) Step-7: Synthesis of 3-(4-(methoxymethyl)-4-methylcyclohexyl)-lH-pyrrolo[3,2- bjpyridine (B44.10):
[0465] An autoclave was charged with a solution of 3-(4-(methoxymethyl)-4-methylcyclohex-l- en-l-yl)-lH-pyrrolo[3,2-b]pyridine B44.9 (0.65 g, 2.5 mmol, 1 eq) in MeOH (10 mL) and the reaction mixture was purged with nitrogen for 5 min. 10% Palladium on carbon (0.13 g, 20% w/w) was added to the reaction mixture under nitrogen atmosphere. The reaction mixture was purged with hydrogen and stirred at room temperature for 12 h under hydrogen atmosphere (100 psi). The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was filtered through a pad of Celite and the Celite pad was washed with MeOH. The filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel to afford 3-(4-(methoxymethyl)-4-methylcyclohexyl)-lH-pyrrolo[3,2-b]pyridine B44.10 (0.51 g, 78%). j0466J Step-8: Synthesis of 4-((3-(4-(methoxymethyl)-4-methylcyclohexyl)-lH-pyrrolo[3,2- b]pyridin-l-yl)sulfonyl)-N,N-dimethylbenzenesulfonamide (two isomers: B-215 and B-216): [0467) To a stirred solution of compound B44.10 (1 eq) in DCM (5 mL), KOH (2.5 eq) and TBA.HSO4 (0.2 eq) were added at 0 °C. To the resulting reaction mixture compound (B44.11) (1.3 eq) was added at 0 °C. The reaction mixture was warmed to room temperature and stirred for 12 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with DCM, filtered through a pad of Celite and the Celite pad was washed with DCM. The filtrated was concentrated under reduced pressure. The crude product was purified by reverse phase preparative HPLC to afford the titled compound 4-((3-(4- (methoxymethyl)-4-methylcyclohexyl)-lH-pyrrolo[3,2-b]pyridin-l-yl)sulfonyl)-N,N- dimethylbenzenesulfonamide (two isomers: B-215 and B-216). |0468j The following examples were prepared using standard chemical manipulations and procedures similar to those used for the preparation of the previous example.
Figure imgf000255_0001
Figure imgf000256_0001
Figure imgf000257_0001
Figure imgf000258_0001
Figure imgf000259_0002
Example B45: Synthesis of 4-((3-(4-((difluoromethoxy)methyl)piperidin-l-yl)-lH- indazol-l-yl)sulfonyl)-N,N-dimethylbenzenesulfonamide (B-159):
Figure imgf000259_0001
[04691 Step-1: Synthesis of 4-((3-(4-(hydroxymethyl)piperidin-l-yl)-lH-indazol-l-yl)sulfonyl)- N,N-dimethylbenzenesulfonamide (B45.2):
10470! To a stirred solution of 4-((3-(4-(methoxymethyl)piperidin-l-yl)-lH-indazol-l- yl)sulfonyl)-N,N-dimethylbenzenesulfonamide B-207 (0.5 g, 1.01 mmol, 1 eq) in DCM (50 mL) was added BBn (1 M solution in DCM, 2 mL, 2.02 mmol, 2 eq) at 0 °C. The reaction mixture was stirred at room temperature for 12 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure to afford 4-((3-(4-(hydroxymethyl)piperidin-l-yl)-lH- indazol-l-yl)sulfonyl)-N,N-dimethylbenzenesulfonamide B45.2 (0.4 g, crude). This compound was used in the next step without further purification. LCMS: 478.9 [M+H]+.
[047IJ Step-2: Synthesis of 4-((3-(4-((difluoromethoxy)methyl)piperidin-l-yl)-lH-indazol-l- yl)sulfonyl)-N,N-dimethylbenzenesulfonamide (B-159): |0472j To a stirred solution of 4-((3-(4-(hydroxymethyl)piperidin-l-yl)-lH-indazol-l- yl)sulfonyl)-N,N-dimethylbenzenesulfonamide B45.2 (0.3 g, 0.62 mmol, 1 eq) in MeCN (25 mL) was added Cul (0.023 g, 0.012 mmol, 0.2 eq). To the resultant reaction mixture was added 2,2- difluoro-2-(fluorosulfonyl)acetic acid B45.3 (0.12 mL, 1.2 mmol, 2 eq) at 45 °C. The reaction mixture was stirred at 45 °C for 3 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was quenched with NaHCCb solution and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure to dryness. The crude product was triturated and purified by prep HPLC to afford the titled compound B-159 Yield: 0.015 g, 5%; Appearance: Off white solid; ¾NMR (400 MHz, DMSO-de) d 8.07 - 8.15 (m, 1 H), 7.98 - 7.85 (m, 5 H), 7.66 (t, J= 7.58 Hz, 1 H), 7.39 (t, J= 7.58 Hz, 1 H), 6.85 - 6.47 (m, 1 H), 4.02 - 3.99 (m, 2 H), 3.70 (d, J= 6.36 Hz, 2 H), 2.96 - 2.91 (m, 2 H), 2.57 (s, 6 H), 1.86 (bs, 1H), 1.75 (d, J= 11.74 Hz, 2 H), 1.31 - 1.23 (m, 2 H); HPLC purity: 95 24%; LCMS Calculated for C22H26N4O5S2: 528.13; Observed: 529.0 [M+H]+.
Example B46: Synthesis of N,N-dimethyl-4-((3-(piperidin-l-yl)-lH-indol-l- yl)sulfonyl)-benzenesulfonamide (B-174):
Figure imgf000260_0001
j0473J Step-1: Synthesis of l-(3-(piperidin-l-yl)-lH-indol-l-yl)ethan-l-one (B46.3):
J0474] To a stirred solution of l-acetylindolin-3-one B46.1 (1.0 g, 5.7 mmol, 1 eq) in EtOH (40 mL) was added Ti(OiPr)4 (2.43 g, 8.57 mmol, 1.5 eq) followed by piperidine B46.2 (0.72 g, 8.57 mmol, 1.5 eq) at room temperature and stirred for 5 h. To the resultant reaction mixture was added STAB (2.41 g, 11.4 mmol, 2 eq) and stirred at room temperature for 12 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with aqueous saturated NaHCCb solution and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography to afford 1 -(3 -(piperidin- 1 -yl)- lH-indol- 1 -yl)ethan- 1 -one B46.3 (1.0 g, 72%). LCMS: 243.0 [M+H]+. j0475| Step-2: Synthesis of 3-(piperidin-l-yl)-lH-indole (B46.4):
|0476) To a stirred solution of l-(3-(piperidin-l-yl)-lH-indol-l-yl)ethan-l-one B46.3 (1.0 g, 4.1 mmol, 1 eq) in EtOH (30 mL) was added KOH (0.46 g, 8.2 mmol, 2 eq) at room temperature. The reaction mixture was stirred at room temperature for 30 minutes. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, diluted with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure to dryness. The crude product was purified by flash column chromatography to afford 3-(piperidin-l-yl)-lH- indole B46.4 (0.7 g, 85%). LCMS: 201.26 [M+H]+.
I0477J Step-3: Synthesis of N,N-dimethyl-4-((3-(piperidin-l-yl)-lH-indol-l-yl)sulfonyl)- benzenesulfonamide (B-174):
|0478| To a stirred solution of 3-(piperidin-l-yl)-lH-indole B46.4 (0.5 g, 2.5 mmol, 1 eq) in DMF (10 mL) was added NaH (60%, 0.15 g, 3.7 mmol, 1.5 eq) at 0 °C and stirred at room temperature for 30 minutes. To the resultant reaction mixture was added 4-(N,N- dimethylsulfamoyl)benzenesulfonyl chloride B46.5 (0.84 g, 3.0 mmol, 1.2 eq) at room temperature and stirred for 2 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure to dryness. The crude product was purified by flash column chromatography to afford N,N-dimethyl-4-((3-(piperidin-l-yl)-lH-indol-l-yl)sulfonyl)- benzenesulfonamide (B-174). Yield: 0.2 g, 10%; Appearance: Off white solid; *H NMR (400 MHz, DMSO-de) d 8.13 (d, J= 8.39 Hz, 2 H), 7.96 (d, J= 8.14 Hz, 1 H), 7.88 (d, J= 8.39 Hz, 2 H), 7.57 (d, J=7.88 Hz, 1 H), 7.37 (t, J= 7.63 Hz, 1 H), 7.28 - 7.24 (m, 1 H), 7.08 (s, 1 H), 3.00 - 2.96 (m, 4 H), 2.59 (s, 6 H), 1.71 - 1.64 (m, 4 H), 1.55 (d, J= 4.58 Hz, 2 H); HPLC purity: 99.57%; LCMS Calculated for C21H25N3O4S2: 447.13; Observed: 448 0 [M+H]+
Example B47 : Synthesis of N,N-dimethyl-4-((3-methyl-2-oxo-3-(tetrahydro-2H- pyran-4-yl)indolin-l-yl)sulfonyl)benzenesulfonamide (B-153):
Figure imgf000262_0001
. .
[0479) Step-1: Synthesis of 3 -methyl-3 -(tetrahydro-2H-pyran-4-yl)indolin-2-one (B47.3):
[0480] To a stirred solution of 3-methylindolin-2-one B47.1 (1.0 g, 7.09 mmol, 1 eq) in THF (25 mL) was added NH2(CH3)2NH2 (0.57 g, 7.7 mmol, 1.1 eq) followed by n-BuLi (1.4 M in Hexane, 11.6 mL, 16.30 mmol, 2.3 eq) at -78 °C. The reaction mixture was stirred for 10 minutes followed by addition of 4-bromotetrahydro-2H-pyran B47.2 (1.40 g, 8.5 mmol, 1.2 eq) at the same temperature. The reaction mixture was stirred at room temperature for 12 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with aqueous MLCl solution and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure to dryness. The crude product was purified by combiflash chromatography to afford 3-methyl-3- (tetrahydro-2H-pyran-4-yl)indolin-2-one B47.3 (0.35 g, 21.4%). LCMS: 232.13 [M+H]+.
[0481J Step-2: Synthesis of N,N-dimethyl-4-((3-methyl-2-oxo-3-(tetrahydro-2H-pyran-4- yl)indolin- 1 -yl)sulfonyl)benzenesulfonamide (B-153):
[0482] To a stirred solution of 3 -methyl-3 -(tetrahydro-2H-pyran-4-yl)indolin-2-one B47.3 (0.35 g, 1.51 mmol, 1 eq) and 4-(N,N-dimethylsulfamoyl)benzenesulfonyl chloride (B47.4) (0.51 g, 1.81 mmol, 1.2 eq) in DCM (30 mL) was added KOH (0.169 g, 3.02 mmol, 2 eq) followed by TBA.HSO4 (0.077 g, 0.23 mmol, 0.15 eq). The reaction mixture was stirred at room temperature for 12 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was concentrated, diluted with water and extracted with DCM. The combined organic layers were dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure to dryness. The crude product was purified by combi flash chromatography to afford N,N- dimethyl-4-((3-methyl-2-oxo-3-(tetrahydro-2H-pyran-4-yl)indolin-l- yl)sulfonyl)benzenesulfonamide B-153. Yield: 0.05 g, 7%; Appearance: Off white solid; *H NMR (400 MHz, DMSO-de) d 8.27 (d, J= 7.83 Hz, 2 H), 8.03 (d, J= 8.31 Hz, 2 H), 7.86 (d, J= 8.31 Hz, 1 H), 7.46 - 7.40 (m, 2 H), 7.31 - 7.27 (m, 1 H), 3.66 (d, J= 10.27 Hz, 2 H), 3.08 (t, J= 11.00 Hz, 2 H), 2.62 (s, 6 H), 1.98 - 1.91 (m, 1 H), 1.27 (s, 3 H), 1.23 - 1.17 (m, 1 H), 1.05 - 0.97 (m, 2 H), 0.90 - 0.81 (m, 1 H); HPLC purity: 99.81%; LCMS Calculated for C22H26N2O6S2: 478.12; Observed: 478.9 [M+H]+.
|0483) The following example was synthesized adopting the procedure as described above.
Figure imgf000263_0002
Example B48: Synthesis of l-((2,3-dihydro-lH-inden-5-yl)sulfonyl)-3-methyl-3-
(tetr ahydro-2H-pyr an-4-yl)indoline (B- 176):
Figure imgf000263_0001
|0484| Step-1: Synthesis of 3 -methyl-3 -(tetrahydro-2H-pyran-4-yl)indoline (B48.2): j0485J To a stirred solution of 3 -methyl-3 -(tetrahydro-2H-pyran-4-yl)indolin-2-one B48.1 (1 g, 4.3 mmol, 1 eq) in THF (50 mL) was added a 1 M solution of lithium aluminium hydride (12.9 mL, 12.9 mmol, 3 eq) at 0 °C. The reaction mixture was warmed to room temperature and stirred at 60°C for 8 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was quenched with saturated aqueous NaiSCri solution, filtered through a pad of Celite and the Celite pad was washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The crude product was purified by combiflash chromatography on silica gel to afford 3-methyl-3-(tetrahydro-2H-pyran-4-yl)indoline B48.2 (600 mg, 64%). LCMS: 218.15 [M+H]+.
|0486| Step-2: Synthesis of l-((2,3-dihydro-lH-inden-5-yl)sulfonyl)-3-methyl-3-(tetrahydro-2H- pyran-4-yl)indoline (B-176): j0487l To a stirred solution of 3 -methyl-3 -(tetrahydro-2H-pyran-4-yl)indoline B48.2 (150 mg, 0.6 mmol, 1 eq) in acetonitrile (10 mL) were added pyridine (66 mg, 1.3 mmol, 2 eq) and 2,3-dihydro- lH-indene-5-sulfonyl chloride B48.3 (179 mg, 0.8 mmol, 1.2 eq) at room temperature and the reaction mixture was stirred for 16 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with water, dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel to afford l-((2,3-dihydro-lH-inden-5-yl)sulfonyl)-3-methyl-3- (tetrahydro-2H-pyran-4-yl)indoline B-176. Yield: 250 mg, 92%; Appearance: Off white solid; ¾ NMR (400 MHz, DMSO-de) d 7.69 (s, 1 H) 7.59 (dd, J=7.88, 1.27 Hz, 1 H) 7.48 (d, J=7.88 Hz, 1 H) 7.40 (d, J=7.88 Hz, 1 H) 7.23 - 7.19 (m, 1 H) 7.11 (d, J=7.38 Hz, 1 H) 7.02 - 6.98 (m, 1 H) 3.89 - 3.75 (m, 2 H) 3.67 - 3.64 (m, 1 H) 3.41 (d, J=10.94 Hz, 1 H) 3.11 - 2.99 (m, 2 H) 2.88 (t, J=7.50 Hz, 4 H) 2.04 -1.97 (m, 2 H) 1.51 - 1.43 (m, 2 H) 1.10 (s, 3 H) 1.06 - 1.05 (m, 1 H) 0.96 - 0 86 (m, 2 H); HPLC purity: 99 59%; LCMS calculated for C23H27NO3S: 397 17; Observed: 398.10 [M+H]+.
|0488] The following example was synthesized adopting the procedure as described above.
Figure imgf000265_0002
Example B49: Synthesis of 4-((3-((lr,4r)-4-(methoxymethyl)-4-methylcyclohexyl)- lH-pyrazolo[4,3-b]pyridine-l-yl)sulfonyl)-N,N-dimethylbenzenesulfonamide (B-166) and 4- ((3-((ls,4s)-4-(methoxymethyl)-4-methylcyclohexyl)-lH-pyrazolo[4,3-b]pyridine-l- yl)sulfonyl)-N,N-dimethylbenzenesulfonamide (B-167):
Figure imgf000265_0001
B-166 B-167
{0489] Step-1: Synthesis of 4-(methoxymethyl)-4-methylcyclohex-l-en-l-yl 1, 1,2, 2, 3, 3, 4,4,4- nonafluorobutane- 1 -sulfonate (B49.3 ) :
{0490] To a stirred solution of 4-(methoxymethyl)-4-methylcyclohexan-l-one B49.1 (1.49 g, 9.54 mmol, 1 eq) in dry THF (15 mL) was added DBU (2.85 mL, 19.07 mmol, 2 eq) at 0 °C and stirred for 30 minutes followed by the addition of 1,1,2,2,3,3,4,4,4-nonafluorobutane-l-sulfonyl fluoride B49.2 (2.57 g, 14.30 mmol, 1.5 eq) at 0 °C. The reaction mixture was stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure to dryness. The crude product was purified by flash column chromatography to afford 4- (methoxymethyl)-4-methylcyclohex- 1 -en- 1 -yl 1,1 ,2,2,3 ,3 ,4,4,4-nonafluorobutane- 1 -sulfonate B49.3 (3.76 g, 90%). Monitored by TLC. j0491j Step-2: Synthesis of 2-(4-(methoxymethyl)-4-methylcyclohex-l-en-l-yl)-4, 4,5,5- tetramethyl-l,3,2-dioxaborolane (B49.4):
|0492) To a stirred solution of 4-(methoxymethyl)-4-methylcyclohex-l-en-l-yl 1, 1,2, 2, 3, 3, 4,4,4- nonafluorobutane-1 -sulfonate B49.3 (3.7 g, 8.45 mmol, 1 eq), Bis(pinacolato)diboron (2.57 g, 10.14 mmol, 1.2 eq) and KOAc (2.35 g, 25.35 mmol, 3 eq) in 1,4-dioxane (50 mL) were added Pd(dppf)Cl2 (0.29 g, 0.43 mmol, 0.05 eq) and dppf (0.22 g, 0.43 mmol, 0.05 eq). The resultant mixture was degassed using argon for for 30 min. The reaction mixture was stirred at 90 °C for 12 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to dryness. The crude product was purified by column chromatography to afford 2-(4-(methoxymethyl)-4-methylcyclohex-l-en-l- yl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane B49.4 (1.82 g, 81.25%).
J0493] Step-3: Synthesis of 3-(4-(methoxymethyl)-4-methylcyclohex-l-en-l-yl)-lH- pyrazolo[4,3-b]pyridne (B49.6):
J0494| To a stirred solution of 2-(4-(methoxymethyl)-4-methylcyclohex-l-en-l-yl)-4, 4,5,5- tetramethyl-l,3,2-dioxaborolane B49.4 (1.3 g, 4.89 mmol, 1 eq), 3-bromo-lH-pyrazolo[4,3- bjpyridine (B49.5) (0.48 g, 2.45 mmol, 0.5 eq) and K2CO3 (1.65 g, 14.7 mmol, 3 eq) in DMF (20 mL), H2O (4 mL) was added PdCl2(dppf).DCM (0.32 g, 0.49 mmol, 0.1 eq). The resultant mixture was degassed with argon for 30 min. and was stirred at 120 °C for 16 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure to dryness. The crude product was purified by column chromatography to afford 3-(4-(methoxymethyl)-4-methylcyclohex-l-en-l- yl)-lH-pyrazolo[4,3-b]pyridne B49.6 (0.485 g, 38.80%). LCMS: 258.3 [M+H]+.
}0495J Step-4: Synthesis of 3-(4-(methoxymethyl)-4-methylcyclohexyl)-lH-pyrazolo[4,3- bjpyridine (B49.7): |0496j To a stirred solution of 3-(4-(methoxymethyl)-4-methylcyclohex-l-en-l-yl)-lH- pyrazolo[4,3-b]pyridne B49.6 (0.23 g, 8.94 mmol, 1 eq) in MeOH (10 mL) was added Pd/C (10%, 0.035 g) under nitroden atmosphere. The resulting reaction mixture was hydrogenated (70 psi) at room temperature for 12 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through celite and concentrated under reduced pressure to afford 3-(4-(methoxymethyl)-4-methylcyclohexyl)-lH-pyrazolo[4,3-b]pyridine B49.7 (0.202 g, crude). This compound was used in the next step without further purification. LCMS: 259.7 [M+H]+.
|0497) Step-5: Procedure for the synthesis of 4-((3-((lr,4r)-4-(methoxymethyl)-4- methylcyclohexyl)-lH-pyrazolo[4,3-b]pyridine-l-yl)sulfonyl)-N,N-dimethylbenzenesulfonamide (B-166) and 4-((3-((ls,4s)-4-(methoxymethyl)-4-methylcyclohexyl)-lH-pyrazolo[4,3-b]pyridine-
1 -yl)sulfonyl)-N,N-dimethylbenzenesulfonamide (B- 167):
10498) To a stirred solution of 3-(4-(methoxymethyl)-4-methylcyclohexyl)-lH-pyrazolo[4,3- bjpyridine B49.7 (0.4 g, 1.54 mmol, 1 eq) and 4-(N,N-dimethylsulfamoyl)benzenesulfonyl chloride B49.8 (0.65 g, 2.32 mmol, 1.5 eq) in THF (15 mL) was added KOH (0.25 g, 4.62 mmol, 3 eq) followed by TBA.HSCL (0.101 g, 0.31 mmol, 0.2 eq). The reaction mixture was stirred at room temperature for 2 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was concentrated, diluted with water and extracted with DCM. The combined organic layers were dried over anhydrous Na2S04, filtered and concentrated under reduced pressure to dryness. The crude product was purified by flash column chromatography followed by chiral prep-HPLC to afford 4-((3-((lr,4r)-4-(methoxymethyl)-4-methylcyclohexyl)- lH-pyrazolo[4,3-b]pyridine-l-yl)sulfonyl)-N,N-dimethylbenzenesulfonamide B-166: Yield: 0.02 g, 2.56%; Appearance: Off white solid; ¾ NMR (400 MHz, METHANOL-d4) d 8.70 (dd, J= 4.4, 1.2 Hz, 1 H), 8.57 (dd, J= 8.56, 1.22 Hz, 1 H), 8.19 (d, J= 8.80 Hz, 2 H), 7.95 (d, J= 8.31 Hz,
2 H), 7.65 (dd, J= 8.80, 4.40 Hz, 1 H), 3.38 (s, 3 H), 3.34 (s, 2 H), 3.20 - 3.17 (m, 1 H). 2.67 (s, 6 H), 1.93 - 1.73 (m, 6 H), 1.34 - 1.27 (m, 2 H), 0.99 (s, 3 H); HPLC purity: 97.04%; LCMS Calculated for C23H30N4O5S2: 506.17; Observed: 507.18 [M+H]+.and 4-((3-((ls,4s)-4- (methoxymethyl)-4-methylcyclohexyl)-lH-pyrazolo[4,3-b]pyridine-l-yl)sulfonyl)-N,N- dimethylbenzenesulfonamide B-167: Yield: 0.025 g, 2.59%; Appearance: Off white solid; *H NMR (400 MHz, METHANOL-d4) d 8.70 (dd, J= 4.65, 1.22 Hz, 1 H), 8.58 (dd, J= 8.56, 1.22 Hz, 1 H), 8.19 (d, J= 8.80 Hz, 2 H), 7.96 (d, J= 8.31 Hz, 2 H), 7.65 (dd, J= 8.80, 4.40 Hz, 1 H), 3.35 (s, 3 H), 3.12 (s, 3 H), 2.67 (s, 6 H), 1.97 - 1.83 (m, 4 H), 1.53 - 1.51 (m, 4 H), 1.04 (s, 3 H); HPLC purity: 99 86%; LCMS Calculated for C23H30N4O5S2: 506 17; Observed: 507.11 [M+H]+
}0499J The following compound was synthesized adopting the procedure as described above.
Figure imgf000268_0002
Example B50: Synthesis of tert- butyl 4-(l-((4-(methylsulfonyl)phenyl)sulfonyl)-lH- pyrazolo[4,3-b]pyridin-3-yl)piperazine-l-carboxylate (B50.7):
Figure imgf000268_0001
JOSOO] Step-1: Synthesis of te/7-butyl 4-(3-fluoropicolinoyl)piperazine-l-carboxylate (B50.3): jOSOIJ To a stirred solution of 3-fluoropicolinic acid B50.1 (1 eq) and /er/-butyl piperazine-1- carboxylate (B50.2) (1.1 eq) in DMF was added HATU (2 eq) followed by DIPEA (3 eq) at room temperature and the reaction mixture was stirred for overnight. The progress of reaction was monitored by TLC. After completion, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous NaiSCri, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel to afford tert- butyl 4-(3- fluoropicolinoyl)piperazine-l-carboxylate B50.3.
105021 Step-2: Synthesis of /er/-butyl 4-(3-fluoropyridine-2-carbonothioyl)piperazine-l- carboxylate (B50.4): |0503j To a stirred solution of tert- butyl 4-(3-fluoropicolinoyl)piperazine-l-carboxylate B50.3 (1 eq) in toluene was added Lawesson’s reagent (1.5 eq). The reaction mixture was heated at 120 °C for 3 h. The progress of reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel to afford /cvV-butyl 4-(3-fluoropyridine-2- carbonothioyl)piperazine-l-carboxylate B50.4.
|O504) Step-3: Synthesis of /ert-butyl 4-(lH-pyrazolo[4,3-b]pyridine-3-yl)piperazine-l- carboxylate (B50.5): 05051 To a stirred solution of tert- butyl 4-(3-fluoropyridine-2-carbonothioyl)piperazine-l- carboxylate B50.4 (1 eq) in DMSO was added a 1 M solution of hydrazine in THF (5.7 eq). The reaction mixture was stirred at 130 °C for overnight. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel to afford /ert-butyl 4-(lH- pyrazolo[4,3-b]pyridine-3-yl)piperazine-l-carboxylate B50.5.
|O506| Step-4: Synthesis of /ert-butyl 4-(l-((4-(methylsulfonyl)phenyl)sulfonyl)-lH- pyrazolo[4,3-b]pyridin-3-yl)piperazine-l-carboxylate (B50.7):
}0507J To a stirred solution of tert- butyl 4-(lH-pyrazolo[4,3-b]pyridin-3-yl)piperazine-l- carboxylate B50.5 (1 eq) and 4-methylbenzenesulfonyl chloride B50.6 (1 eq) in DCM was added potassium hydroxide (2 eq) and TBA.HSCri (0.15 eq) at 0 °C. The reaction mixture was warmed to room temperature and stirred for overnight. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was diluted with water and extracted with DCM. The combined organic extracts were washed with water and brine, dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The crude was triturated with methanol and purified by column chromatography on silica gel to afford /cvV-butyl 4-(l-((4- (methylsulfonyl)phenyl)sulfonyl)-lH-pyrazolo[4,3-b]pyridin-3-yl)piperazine-l-carboxylate B50.7. |0508j The following examples were prepared using standard chemical manipulations and procedures similar to those used for the preparation of the previous example.
Figure imgf000270_0002
Example B51: Synthesis of 4-((3-(3-oxa-9-azaspiro[5.5]undecan-9-yl)-lH-indazol-l- yl)sulfonyl)-N,N-dimethylbenzenesulfonamide (B-168):
Figure imgf000270_0001
[0509] Step-1: Synthesis of 3-bromo-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-indazole (B51.2): j0510] To a stirred solution of NaH (1.4 g, 30.40 mmol, 1.2 eq) in DMF (30 mL) was added 3- bromo-lH-indazole B51.1 (5.0 g, 25.00 mmol, 1 eq) at 0 °C and stirred for 20 min. SEM-CI (4.8 mL, 27.0 mmol, 1.1 eq) was added drop wise to the reaction mixture at 0 °C and stirred for another 2 h at room temperature. After completion of reaction, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure to dryness. The crude product was purified by silica gel column chromatography to afford 3-bromo-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-indazole B51.2 (4.5 g, 55%). LCMS: 328.75 [M+H]+. jOSllJ Step-2: Synthesis of 9-(l-((2-(trimethylsilyl)ethoxy)methyl)-lH-indazol-3-yl)-3-oxa-9- azaspiro[5.5]undecane (B51.4):
|05J2| To a stirred solution of 3-bromo-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-indazole B51.2 (0.3 g, 1.0 mmol, 1 eq), and 3-oxa-9-azaspiro[5.5]undecane B51.3 (0.69 g, 2.1 mmol, 1.1 eq),) in toluene (10 mL) and t-BuOH (1 mL) was added CS2CO3 (1.2 g, 3.8 mmol, 2.0 eq). The resulting reaction mixture was degassed using Argon for 10 min. Pd2(dba)3 (173 mg, 0.1 mmol, 0.1 eq) and X-Phos (188 mg, 0.2 mmol, 0.2 eq) were added to the reaction mixture and further degassed for 5 min. The reaction mixture was stirred at 100 °C for 16 h in sealed tube. After completion of the reaction, the reaction mixture was filtered and the filtrate was partitioned between ethyl acetate and water. The combined organic layers were washed with brine, dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure to dryness. The crude product was purified by silica gel column chromatography to afford 9-(l-((2-(trimethylsilyl)ethoxy)methyl)-lH-indazol- 3-yl)-3-oxa-9-azaspiro[5.5]undecane B51.4 (0.3 g, 39%). LCMS: No ionization. j0513l Step-3: Synthesis of 9-(lH-indazol-3-yl)-3-oxa-9-azaspiro[5.5]undecane (B51.5):
|0514| To a stirred solution of 9-(l-((2-(trimethylsilyl)ethoxy)methyl)-lH-indazol-3-yl)-3-oxa-9- azaspiro[5.5]undecane B51.4 (0.3 g, 0.74 mmol, 1 eq) in DCM (5 mL) was added HC1 in dioxane (4M) (1.0 mL) and stirred at room temperature for 12 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the volatiles were removed under reduced pressure. The obtained residue was dissolved in DCM (5 mL), aqueous ammonia (1.5 mL) was added and the reaction mixture was further stirred at room temperature for 6 h. The reaction mixture was concentrated under reduced pressure to obtain 9-(lH-indazol-3-yl)-3-oxa-9- azaspiro[5.5]undecane B51.5 (150 mg, 74%). This compound was used in the next step without further purification. LCMS: 272.05 [M+H]+. jOSiSJ Step-4: Procedure for the synthesis of 4-((3-(3-oxa-9-azaspiro[5.5]undecan-9-yl)-lH- indazol-l-yl)sulfonyl)-N,N-dimethylbenzenesulfonamide (B-168):
|05J6| To a stirred solution of 9-(lH-indazol-3-yl)-3-oxa-9-azaspiro[5.5]undecane B51.5 (150 mg, 0.55 mmol, 1 eq) in THF (7 mL) under N2 atmosphere, was added KOH (61 mg, 1.1 mmol, 2 eq) and TBA.HSCri (27 mg, 0.8 mmol, 0.15 eq) at 0 °C and stirred for 10 min. 4-(N,N- dimethylsulfamoyl)benzenesulfonyl chloride B51.6)(187 mg, 0.66 mmol, 1.2 eq) was then added to the reaction mixture and stirred at 0 °C for 6 h. The progress of the reaction was monitored by LCMS. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with water, brine, dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure to dryness. The crude product was purified using preparative HPLC to afford 4-((3-(3-oxa-9-azaspiro[5.5]undecan-9-yl)-lH- indazol-l-yl)sulfonyl)-N,N-dimethylbenzenesulfonamide B-168. Yield: 23 mg; 8%; Appearance: Yellow solid; ¾ NMR (400 MHz, CHLOROFORM-d) d 8.16 (d, J= 8.4 Hz, 1 H), 8.00 (br d, J= 8.31 Hz, 2 H), 7.77 (br d, J= 8.31 Hz, 2 H), 7.67 (d, J= 7.6 Hz, 1 H), 7.54 (br t, J=7.58 Hz, 1 H), 7.30 - 7.28 (m, 1H), 3.70 - 3.68 (m, 4 H), 3.48 - 3.47 (m, 4 H), 2.70 (s, 6 H), 1.68 - 1.67 (m, 4 H), 1.58 - 1.54 (m, 4 H); HPLC purity: 99.32%; LCMS Calculated for C24H30N4O5S2: 518.17; Observed: 519.20 [M+H]+.
Example B52: Synthesis of N,N-dimethyl-4-((3-methyl-3-morpholino-2-oxoindolin-l- yl)sulfonyl)benzenesulfonamide (B-169):
Figure imgf000272_0001
10517! Step-1: Synthesis of 3-methylindolin-2-one (B52.2):
[0518) To a stirred solution of 3-methyl-lH-indole B52.1 (5.0 g, 38.12 mmol, 1 eq) in DCM (60 mL) was added NBS (5.42 g, 30.5 mmol, 0.8 eq) at 0 °C. The reaction mixture was stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the volatiles were removed under reduced pressure to dryness. The crude was purified by flash column chromatography to obtain 3-methylindolin-2-one B52.2 (2.21 g, 39.46%) as a pale yellow solid. LCMS: 147.8 [M+H]+.
[0519| Step-2: Synthesis of 3 -methyl-3 -morpholinoindolin-2-one (B52.4):
I0520J To a stirred solution of 3-methylindolin-2-one B52.2 (5.0 g, 13.6 mmol, 1 eq) in DCM (30 mL) were added morpholine B52.3 (2.37 g, 27.21 mmol, 2 eq), iodine (0.69 g, 2.72 mmol, 0.2 eq) and TBHP (2.45 g, 27.2 mmol, 2 eq). The reaction mixture was stirred at 60 °C for 2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the volatiles were removed under reduced pressure to dryness. The crude was purified by flash column chromatography to obtain 3-methyl-3-morpholinoindolin-2-one B52.4 (1.42 g, 45%) as a yellow semi-solid. LCMS: 232.9 [M+H]+.
J0521] Step-3: Synthesis of N,N-dimethyl-4-((3 -methyl-3 -morpholino-2-oxoindolin- 1- yl)sulfonyl)benzenesulfonamide (B- 169) :
|0522j To a stirred solution of 3 -methyl-3 -morpholinoindolin-2-one B52.4 (200 mg, 0.86 mmol, 1 eq) in THF (10 mL) under nitrogen gas atmosphere, was added KOH (145 mg, 2.8 mmol, 3 eq) and TBA.HSO4 (59 mg, 0.17 mmol, 0.2 eq) at 0 °C and stirred for 10 minutes. 4-(N,N- dimethylsulfamoyl)benzenesulfonyl chloride B52.5 (372 mg, 1.2 mmol, 1.5 eq) was then added to the reaction mixture at 0 °C. The reaction mixture was stirred at 0 °C for 6 h. The progress of the reaction was monitored by LCMS. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure to dryness. The crude product was purified by prep. HPLC to afford N,N-dimethyl-4-((3- methyl-3-morpholino-2-oxoindolin-l-yl)sulfonyl)benzenesulfonamide B-169. Yield: 15 mg; 4%; Appearance: White solid; ¾ NMR (400 MHz, CHLOROFORM-d) d 8.28 (d, J=7.83 Hz, 2 H), 7.95 (d, J=6.85 Hz, 3 H), 7.42 (t, J= 7.58 Hz, 1 H), 7.33 - 7.31 (m, 1 H), 7.26 - 7.24 (m, 1 H), 3.56 - 3.51 (m, 4 H), 2.75 (s, 6 H), 2.49 - 2.39 (m, 4 H), 1.43 (s, 3 H); HPLC purity: 99.75%; LCMS Calculated for C21H25N3O6S2: 479.12; Observed: 479 8 [M+H]+
Example B53: Synthesis of N,N-dimethyl-4-((3-morpholino-lH-indazol-l- yl)sulfonyl)benzenesulfonamide (B-177):
Figure imgf000273_0001
|0523j Step-1: Synthesis of /er/-butyl 3-morpholino-lH-indazole-l-carboxylate (B53.3): [0524) A pyrex tube was charged with a solution of /ert-butyl 3-iodo-lH-indazole-l-carboxylate B53.1 (1.8 g, 5.2 mmol, 1 eq), morpholine B53.2 (0.68 g, 7.8 mmol, 1.5 eq), and CS2CO3 (4.2 g, 13 mmol, 2.5 eq) in 1,4-dioxane (10 mL). The tube was fitted with a septum and the reaction mixture was purged with argon for 15 min. Pd(OAc)2 (116 mg, 0.5 mmol, 0.1 eq) and Xantphos (0.3 g, 1 mmol, 0.2 eq) were added to the reaction mixture under an argon atmosphere. The tube was then fitted with a screw cap and the reaction mixture was stirred at 90 °C for overnight. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was cooled to room temperature, filtered through a pad of Celite and the Celite pad was washed with ethyl acetate. The filtrate was diluted with ethyl acetate, washed with water and brine. The organic layer was dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel to afford fe/V-butyl 3- morpholino-lH-indazole-l-carboxylate B53.3 (1.1 g, 69.6%). LCMS: 305.16 [M+H]+.
J0525] Step-2: Synthesis of 4-(lH-indazol-3-yl)morpholine (B53.4):
[0526) To a stirred solution of tert- butyl 3-morpholino-lH-indazole-l-carboxylate B53.3 (1.1 g, 3.6 mmol, 1 eq) in DCM (20 mL) was added trifluoroacetic acid (2 mL) at 0 °C. The reaction mixture was warmed to room temperature and stirred for 4 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was concentrated under reduced pressure to dryness. The residue was dissolved in minimum amount of water and neutralized with saturated aqueous NaHCCh solution. The reaction mixture was extracted with ethyl acetate. The combined organic layers were washed with cold water and brine, dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure to dryness to afford 4-(lH- indazol-3-yl)morpholine B53.4 (0.8 g, crude). This compound was used in the next step without further purification. LCMS: Not done.
[0527] Step-3: Synthesis of N,N-dimethyl-4-((3-morpholino-lH-indazol-l- yl)sulfonyl)benzenesulfonamide (B- 177) :
[0528) To a stirred solution of 4-(lH-indazol-3-yl)morpholine B53.4 (400 mg, 1.9 mmol, 1 eq) and 4-(N,N-dimethylsulfamoyl)benzenesulfonyl chloride B53.5 (669 mg, 2.3 mmol, 1.2 eq) in THF (10 mL) at 0 °C were added KOH (220 mg, 3.9 mmol, 2 eq) and TBA.HSO4 (100 mg, 0.2 mmol, 0.15 eq). The reaction mixture was stirred at room temperature for 12 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The crude product was purified by reverse phase preparative HPLC to afford N,N-dimethyl-4-((3-morpholino-lH- indazol-l-yl)sulfonyl)benzenesulfonamide B-177. Yield: 100 mg, 11%; Appearance: Off white solid; ¾ NMR (400 MHz, DMSO-de) d 8.08 (d, J=7.88 Hz, 1 H) 8.00 - 7.94 (m, 3 H) 7.88 (d, J=7.63 Hz, 2 H) 7.65 (t, J=7.25 Hz, 1 H) 7.37 (t, J=7.25 Hz, 1 H) 3.74 - 3.64 (m, 4 H) 3.49 - 3.37 (m, 4 H) 2.58 (s, 6 H); HPLC purity: 99.62%; LCMS Calculated for C19H22N4O5S2: 450.10; Observed: 451.00 [M+H]+.
Example B54: Synthesis of 4-((3-(4-acetylcyclohexyl)-lH-pyrrolo[3,2-b]pyridin-l- yl)sulfonyl)-N,N-dimethylbenzenesulfonamide (B-156), and 4-((3-(4-(l,l- difluoroethyl)cyclohexyl)-lH-pyrrolo[3,2-b]pyridin-l-yl)sulfonyl)-N,N- dimethylbenzenesulfonamide (B-172, B-173):
Figure imgf000275_0001
0529] Step-1: Synthesis of 4-((3-(4-acetylcyclohexyl)-lH-pyrrolo[3,2-b]pyridin-l-yl)sulfonyl)- N,N-dimethylbenzenesulfonamide (B-156):
(0530] To a stirred solution of ethyl 4-(l-((4-(N,N-dimethylsulfamoyl)phenyl)sulfonyl)-lH- pyrrolo[3,2-b]pyri din-3 -yl)cy cl ohexane-1 -carboxyl ate B54.1 (400 mg, 0.77 mmol, 1 eq) in THF (5 mL) was added N,O-Dimethylhydroxylamine hydrochloride B54.2 (97 mg, 1.0 mmol, 1.3 eq) at 0 °C and stirred for 15 min. A I M solution of methyl magnesium bromide solution in THF (2.5 mL, 2.5 mmol, 3.2 eq) was then added at 0 °C. The reaction mixture was stirred at 10 °C for 1 h. A I M solution of methyl magnesium bromide solution in THF (2.5 mL, 2.5 mmol, 3.2 eq) was again added at 10 °C and the reaction mixture further stirred at room temperature for 1.5 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was quenched with saturated aqueous NH4CI solution and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The crude product was purified by reverse phase preparative HPLC to afford 4-((3-(4-acetylcyclohexyl)-lH-pyrrolo[3,2-b]pyridin-l-yl)sulfonyl)-N,N- dimethylbenzenesulfonamide B-156. Yield: 40 mg, 10.6%; Appearance: Off white solid; ¾ NMR (400 MHz, DMSO-de) d 8.52 - 8.51 (m, 1 H) 8.29 - 8.23 (m, 3 H) 7.92 (d, J=8.80 Hz, 2 H) 7.81 (s, 1 H) 7.38 (dd, J=8.31, 4.40 Hz, 1 H) 3.04 - 2.92 (m, 1 H) 2.65 - 2.62 (m, 1 H) 2.60 (s, 6 H) 2.14 (s, 3 H) 1.97 - 1.94 (m, 2 H) 1.87 - 1.84 (m, 2 H) 1.77 - 1.60 (m, 4 H); HPLC purity: 98.55%; LCMS calculated for C23H27N3O5S2: 489.14; Observed: 490.10 [M+H]+.
|053!| Step-2: Synthesis of 4-((3-(4-(l,l-difluoroethyl)cyclohexyl)-lH-pyrrolo[3,2-b]pyridin-l- yl)sulfonyl)-N,N-dimethylbenzenesulfonamide (B-172, B-173):
[0532) To a stirred solution of 4-((3-(4-acetylcyclohexyl)-lH-pyrrolo[3,2-b]pyridin-l- yl)sulfonyl)-N,N-dimethylbenzenesulfonamide B-156 (1.0 g, 2.04 mmol, 1 eq) in DCE (10 mL) was added DAST (3.29 g, 20.4 mmol, 10 eq) at 0 °C. The resulting reaction mixture was warmed to room temperature and stirred at 60 °C for 24 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with saturated NaHCCb solution and extracted with DCM. The combined organic layers were dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure to dryness. The crude product was purified by reverse phase preparative HPLC to afford 4-((3-(4-(l,l-difluoroethyl)cyclohexyl)-lH- pyrrolo[3,2-b]pyridin-l-yl)sulfonyl)-N,N-dimethylbenzenesulfonamide B-172: Yield: 101 mg; 10%; Appearance: Off white solid; ¾ NMR (400 MHz, DMSO-de) d 8.54 (d, J=4.40 Hz, 1 H) 8.33 (d, J=8.31 Hz, 1 H) 8.23 (d, J=8.31 Hz, 2 H) 7.90 - 7.86 (m, 3 H) 7.40 (dd, J=8.31, 4.40 Hz, 1 H) 3.28 (br s, 1 H) 2.59 (s, 6 H) 2.38 (d, J=12.23 Hz, 2 H) 1.92 - 1.87 (m, 1 H) 1.76 (t, J=12.96 Hz, 2 H) 1.62 - 1.46 (m, 5 H) 1.34 - 1.24 (m, 2 H); HHPLC purity: 96.18%; LCMS calculated for C23H27F2N3O4S2: 511.14; Observed: 512.1 [M+H]+. (B-173): Yield: 36 mg; 3.6%;
Appearance: Off white solid; ¾ NMR (400 MHz, DMSO-de) d 8.53 (d, J=3.42 Hz, 1 H) 8.30 - 8.24 (m, 3 H) 7.93 (d, J=8.80 Hz, 2 H) 7.85 (s, 1 H) ) 7.40 - 7.37 (m, 1 H) 2.86 - 2.81 (m, 1 H) 2.61 (s, 6 H) 2.14 - 2.11 (m, 2 H) 1.92 - 1.84 (m, 3 H) 1.64 - 1.51 (m, 5 H) 1.37 - 1.32 (m, 2 H); HPLC purity: 99 62%; LCMS calculated for C23H27F2N3O4S2: 511.14; Observed: 511 9 [M+H]+. Example B55: Synthesis of l-[(l-phenylcyclopropyl)sulfonyl]-3-(piperidin-l-yl)-lH- indazole, B-283:
Figure imgf000277_0001
55.1 B-283
J0533] Sodium hydride (0.00671 g, 0.280 mmol) was added to a solution of 1- phenylmethanesulfonyl-3-(piperidin-l-yl)-lH-indazole (0.05 g, 0.140 mmol) and 1,2- dibromoethane (0.0394 g, 0.210 mmol) in anhydrous DMF (1 mL) at 0°C. Then the reaction mass was stirred for 18 h at room temperature, diluted with water (5 mL), and extracted with ethyl acetate (5 mL x 2). The organic layer was washed with water (10 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was subjected to HPLC purification (deionized water/HPLC-grade acetonitrile) that afforded l-[(l-phenylcyclopropyl)sulfonyl]-3- (piperidin-l-yl)-lH-indazole B-283. Yield: 10 mg, 17.7 %; Appearance: Beige solid; *H NMR (600 MHz, DMSO-d6) d 7.80 (d, J= 8.0 Hz, 1H), 7.29 (d, J= 8.3 Hz, 1H), 7.21 - 7.16 (m, 1H), 7.14 (t, J= 7.4 Hz, 1H), 7.08 (t, J= 7.4 Hz, 1H), 6.96 (t, J= 7.6 Hz, 2H), 6.88 (dd, J= 7.9, 1.4 Hz, 2H), 3.41 (t, J= 5.3 Hz, 4H), 1.88 - 1.83 (m, 2H), 1.69 (p , J= 5.4 Hz, 4H), 1.64 (t, J= 5.6 Hz, 2H), 1.38 - 1.33 (m, 2H); HPLC purity: 100%; LCMS Calculated for C21H23N3O2S: 381.49; Observed: 382.2 [M+H]+. j0534J The following examples were prepared using standard chemical manipulations and procedures similar to those used for the preparation of the previous example as indicated in the table below:
Figure imgf000278_0001
Example B56: Synthesis of 4-({3-[(3R,5S)-3,5-dimethylmorpholin-4-yl]-lH-indazol-l- yl}sulfonyl)-N,N-dimethylbenzene-l-sulfonamide, B-294:
Figure imgf000279_0001
Step-4 B-294
|0535) Step-1. Synthesis of 4-(2-fluorobenzoyl)-3,5-dimethylmorpholine |0536j Ethylbis(propan-2-yl)amine (1.84 g, 14.3 mmol) and 2-fluorobenzoyl chloride (1.523 g, 9.58 mmol) were added to a solution of 3,5-dimethylmorpholine (1.2 g, 10.5 mmol) in dichloromethane (50 mL) at 0 °C. The mixture was stirred at room temperature for 16 h, after washed with water (15 mL), brine (15 mL), dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to give 4-(2-fluorobenzoyl)-3,5-dimethylmorpholine (2.2 g, 8.78 mmol, 94.74% purity, 91.6% yield).
|0537| Step-2. Synthesis of 4-(2-fluorobenzenecarbothioyl)-3,5-dimethylmorpholine j0538J Lawessoifs reagent (4.08 g, 10.1 mmol) was added to a stirred solution of 4-(2- iluorobenzoyl)-3 5~dimethylmorphoHne (2.2 g, 9.27 mmol) in toluene (50 mL). The reaction mixture was refluxed for 18 h. After completion, the reaction mixture was cooled to room temperature, concentrated under reduced pressure to give crude 4-(2-fluorobenzenecarbothioyl)- 3,5-dimethylmorpholine (6.7 g, 19.2 mmol, 72.85% purity) that was used immediately in the next step without further purification.
[0539J Step-3. Synthesis of 3-(3,5-dimethylmorpholin-4-yl)-lH-indazole |0540j Hydrazine hydrate (15 mL) was added to a stirred solution of crude 4-(2- fluorobenzenecarbothioyl)-3,5-dimethylmorpholine (6.7 g, 9.23 mmol) in dioxane (50 mL). The reaction mixture was refluxed for 48 h. After completion, it was cooled to room temperature, concentrated under reduced pressure, diluted with water (100 mL) and extracted with ethyl acetate (100 mL x 2). The combined organic extracts were washed with water (100 mL), brine (100 mL), dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. Flash chromatography (Hexane/MTBE) purification of residue afforded 3-(3,5-dimethylmorpholin-4- yl)-lH-indazole (0.4 g, 1.72 mmol, 100% purity, 18.7% yield after two stages).
[0541 ) Step-4. Synthesis of 4-({3-[(3R,5S)-3,5-dimethylmorpholin-4-yl]-lH-indazol-l- yl } sulfonyl)-N,N-dimethylbenzene- 1 -sulfonamide
[0542] Ethylbis(propan-2-yl)amine (0.0837 g, 0.648 mmol) and 4-(dimethylsulfamoyl)benzene- 1-sulfonyl chloride (0.134 g, 0.475 mmol) were added to a 3-(3,5-dimethylmorpholin-4-yl)-lH- indazole (0.1 g, 0.432 mmol) in acetonitrile (10 mL). The reaction mixture was stirred at room temperature for 18 h. The solvent was evaporated under reduced pressure and the residue was subjected to HPLC purification (deionized water/HPLC-grade methanol) that afforded 4-({3- [(3R, 5 S)-3 , 5-dimethylmorpholin-4-yl]- lH-indazol- 1 -yl } sulfonyl)-N,N-dimethylbenzene- 1 - sulfonamide as yellow oil (0.0245 g, 0.0486 mmol, 95% purity, 11.2% yield). The analytical data provided for this compound provisionally supports the proposed structure for 4-({3-[(3R,5S)-3,5- dimethylmorpholin-4-yl]- lH-indazol- 1 -yl } sulfonyl)-N,N-dimethylbenzene- 1 -sulfonamide B-
294. Yield: 24.5 mg, 11.2 %; Appearance: Yellow oil;
Figure imgf000280_0001
NMR (400 MHz, DMSO -d6) d 8.12 (d, J= 8.4 Hz, 1H), 7.95 - 7.84 (m, 5H), 7.66 (t, J= 7.9 Hz, 1H), 7.39 (t, J= 7.7 Hz, 1H), 4.07 (d, J= 7.6 Hz, 2H), 3.66 (t, J= 3.7 Hz, 4H), 2.54 (s, 6H), 1.06 (d, J= 6.6 Hz, 6H); HPLC purity: 97.92%; LCMS Calculated for C21H26N4O5S2: 478.58; Observed: 479.0 [M+H]+.
[0543] The following examples were prepared using standard chemical manipulations and procedures similar to those used for the preparation of the previous example as indicated in the table below:
Figure imgf000281_0001
Figure imgf000282_0001
Figure imgf000283_0001
Example B57: Synthesis of 4-({3-[(2R,6R)-2,6-dimethylmorpholin-4-yl]-lH-indazol-l- yl}sulfonyl)-N,N-dimethylbenzene-l-sulfonoimidamide, B-293
Figure imgf000284_0001
Step-4 Step-5 B-293
10544 j Step-1. Synthesis of (2S,6S)-4-(2-fluorobenzoyl)-2,6-dimethylmorpholine |0545| 2-fluorobenzoyl chloride (1.37 g, 8.68 mmol) was added to the mixture of (2S,6S)-2,6- dimethylmorpholine (1 g, 8.68 mmol) and triethylamine (1.31 g, 13.0 mmol) in dry acetonitrile (20 mL). The reaction mixture was stirred for 16 h and evaporated under reduced pressure. The residue was diluted with water (50 mL) and ethyl acetate (50 mL). The organic layer was separated, dried over sodium sulfate, filtered and evaporated under reduced pressure to give (2S,6S)-4-(2- fluorobenzoyl)-2,6-dimethylmorpholine (1.8 g, 7.58 mmol, 95% purity, 83.4% yield).
J0546] Step-2. Synthesis of (2S,6S)-4-(2-fluorobenzenecarbothioyl)-2,6-dimethylmorpholine j0547J bis(4-methoxyphenyl)-l,3,2 5,4 5-dithiadiphosphetane-2,4-dithione (4.57 g, 11.3 mmol) was added to the solution of (2S,6S)-4-(2-fluorobenzoyl)-2,6-dimethylmorpholine (1.8 g, 7.58 mmol) in toluene (40 mL). The mixture was refluxed for 20 h, then evaporated under reduced pressure. The residue was diluted in water/ethyl acetate mixture (20 mL/50 mL). The organic layer was separated, dried over sodium sulfate, filtered and evaporated under reduced pressure to give crude (2S,6S)-4-(2-fluorobenzenecarbothioyl)-2,6-dimethylmorpholine (1.6 g) that was used directly in next step without QC/further purification. j0548J Step-3. Synthesis of 3-[(2S,6S)-2,6-dimethylmorpholin-4-yl]-lH-indazole J0549] Hydrazine hydrate (3.15 g, 63 mmol) was added to the solution of crude (2S,6S)-4-(2- fluorobenzenecarbothioyl)-2,6-dimethylmorpholine (1.6 g) in dioxane (40 mL), the mixture was refluxed for 20 h, then evaporated under reduced pressure. The residue was subjected to flash chromatography (chloroform/MTBE) to give 3-[(2S,6S)-2,6-dimethylmorpholin-4-yl]-lH- indazole (0.8 g, 3.45 mmol, 90% purity, 49.6% yield).
|05$0) Step-4. Synthesis of N-(/c/7-butyl dimethyl si lyl)-4-( J 3 -[(2R,6R)-2,6-di methyl morpholin- 4-yl]- lH-indazol- 1 -yl } sulfonyl)-N,N-dimethylbenzene- 1 -sulfonoimidamide 105511 4-(N'-(/er/-butyldimethylsilyl)-N,N-dimethylsulfamimidoyl)benzene-l-sulfonyl chloride (1.85 g, 4.66 mmol) was added to the mixture of (2R,6R)-4-(lH-indazol-3-yl)-2,6- dimethylmorpholine (0.72 g, 3.11 mmol) and pyridine (2.45 g, 31 mmol) in dry acetonitrile (20 mL). The reaction mixture was stirred for 12 h and evaporated in vacuo to give crude N '-{tert- butyldimethylsilyl)-4-((3-((2R,6R)-2,6-dimethylmorpholino)-lH-indazol-l-yl)sulfonyl)-N,N- dimethylbenzenesulfonimidamide as a dark resin (1.8 g, 0.929 mmol, 30.57% purity, 29.8% yield), which was used in the next step without purification.
J0552] Step-5. Synthesis of 4-((3-((2R,6R)-2,6-dimethylmorpholino)-lH-indazol-l-yl)sulfonyl)- N,N-dimethylbenzenesulfonimidamide
J0553j 1 M THF solution of TBAF (3.04 mL, 0.794 g, 3.04 mmol) was added to a solution of N'- (/c77-butyl dimethyl si lyl)-4-((3-((2R,6R)-2,6-di methyl morpholino)- ! H-indazol- l-yl)sulfonyl)- N,N-dimethylbenzenesulfonimidamide (1.8 g, 0.929 mmol, 30.57% purity) in dry THF (20 mL) under argon atmosphere. The reaction mixture was stirred for 12 h and evaporated in vacuo. The residue was subjected to HPLC purification (deionized water/HPLC-grade acetonitrile) that afforded 4-({3- [(2R, 6R)-2, 6-dimethylmorpholin-4-yl]- 1 H-indazol- 1 -yl } sulfonyl)-N,N- dimethylbenzene-1 -sulfonoimidamide B-293. Yield: 400.2 mg, 85.7 %; Appearance: Yellow solid; NMR (400 MHz, DMSO -d6) d 8.07 (d, J= 8.4 Hz, 1H), 7.95 (d, J= 8.5 Hz, 2H), 7.92 - 7.85 (m, 3H), 7.65 (t, J= 7.8 Hz, 1H), 7.37 (t, J= 7.6 Hz, 1H), 4.68 (s, 1H), 4.04 (qd, J= 6.4, 3.3 Hz, 2H), 3.49 (dd, 7= 12.6, 3.3 Hz, 2H), 3.18 (dd, 7= 12.6, 6.1 Hz, 2H), 2.50 (s, 6H), 1.15 (d, J= 6 3 Hz, 6H); HPLC purity: 100%; LCMS Calculated for C21H27N5O4S2: 477.17; Observed: 478.2 [M+H]+. f0554j The following examples were prepared using standard chemical manipulations and procedures similar to those used for the preparation of the previous example as indicated in the table below:
Figure imgf000286_0001
Figure imgf000287_0002
Example B58: Synthesis of 4-{[3-(4,4-difluoropiperidin-l-yl)-lH-pyrazolo[4,3-b]pyridin-l- yl] sulfonyl}-N,N-dimethylbenzene-l-sulfonamide, B-300
Figure imgf000287_0001
Step-4 Step- 5 B-300
|0555) Step-1. Synthesis of 3-bromo-lH-pyrazolo[4,3-b]pyridine
|0556j lH-pyrazolo[4,3-b]pyridine (1 g, 8.39 mmol) was dissolved in 2M NaOH aq. solution (8.5 mL) and a solution of bromine (1.35 g) in 2M NaOH aq. solution (4.2 mL) was added dropwise. After stirring for 3 hours at room temperature NaHS03 sat. aq. solution (1 mL) was added followed by addition of 4N HC1 aq. solution to pH~2-3. Formed solid was collected by filtration, washed with water (10 mL x 2) and air dried affording 3-bromo-lH-pyrazolo[4,3-b]pyridine as a white- off solid (0.73 g, 3.68 mmol, 90% purity, 39.5% yield) that was used in next step without further purification.
[0557J Step-2. Synthesis of 3-bromo-l-(oxan-2-yl)-lH-pyrazolo[4,3-b]pyridine [0558] 3,4-dihydro-2H-pyran (0.835 g, 9.93 mmol) and 4-methylbenzene-l -sulfonic acid (0.0569 g, 0.331 mmol) were added at room temperature to a stirred solution of 3-bromo-l H-pyrazolo[4,3- bjpyridine (0.73 g, 90%purity, 3.31 mmol) in THF (10 mL). The resulting solution was stirred at reflux for 48 hours. After the reaction was cooled to room temperature, diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 2). The organic layer was washed with NaHCCb sat. aq. solution (40 mL) and brine (40 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (chloroform/MTBE) to afford 3-bromo-l-(oxan-2-yl)-lH-pyrazolo[4,3-b]pyridine (0.6 g, 2.12 mmol, 95% purity, 61% yield).
|0559j Step-3. Synthesis of provide 4,4-difluoro-l-[l-(oxan-2-yl)-lH-pyrazolo[4,3-b]pyridin-3- yljpiperidine
[05601 The mixture of 3-bromo-l-(oxan-2-yl)-lH-pyrazolo[4,3-b]pyridine (0.27 g, 0.956 mmol), 4,4-difluoropiperidine hydrochloride (0.3 g, 1.91mmol), RuPhos Pd G4 (0.0812 g, 0.0956 mmol) and sodium /cvV-but oxide (0.274 g, 2.86 mmol) in toluene (3 mL) was stirred under argon atmosphere for 12 h at 90 °C. The progress of reaction was monitored by TLC. After completion, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (15 mL x 2). The combined organic extracts were washed with water (30 mL), brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by prep HPLC (deionized water/HPLC -grade acetonitrile) to provide 4,4-difluoro-l- [l-(oxan-2-yl)-lH-pyrazolo[4,3-b]pyridin-3-yl]piperidine (0.064 g, 0.198 mmol, 95% purity, 19.7% yield).
10561 j Step-4. Synthesis of 4,4-difluoro-l-{lH-pyrazolo[4,3-b]pyridin-3-yl}piperidine [0562] TFA (0.745 g, 6.53 mmol, 0.5 mL) was added to a stirred solution of 4,4-difluoro-l-[l- (oxan-2-yl)-lH-pyrazolo[4,3-b]pyridin-3-yl]piperidine (0.064 g, 0.198 mmol) in dichloromethane (1 mL). Resulting mixture was stirred overnight and evaporated. Crude residue was treated with 2M NaOH to pH = 10 and extracted with dichloromethane (10 mL x 3). Organic layers were combined, dried over sodium sulfate, filtered and evaporated to give 4,4-difluoro-l-{lH- pyrazolo[4,3-b]pyridin-3-yl}piperidine (0.05 g, 0.209 mmol, 95% purity, 100% yield). j0563| Step-5. Synthesis of 4-{[3-(4,4-difluoropiperidin-l-yl)-lH-pyrazolo[4,3-b]pyridin-l- yl]sulfonyl}-N,N-dimethylbenzene-l -sulfonamide
|0564| Potassium 2-methylpropan-2-olate (0.04469 g, 0.418 mmol) and 18-crown-6 (0.011 g, 0.0418 mmol) were added at 0 oC to a stirred solution of 4,4-difluoro-l-{lH-pyrazolo[4,3- b]pyridin-3-yl}piperidine (0.05 g, 0.209 mmol) in THF (2 mL), the reaction mixture was stirred for 10 min at same temperature and 4-(N,N-dimethylsulfamoyl)benzenesulfonyl chloride (0.0888 g, 0.313 mmol) was added to it. The reaction mixture was stirred at room temperature for 12 h. The progress of reaction was monitored by TLC. After completion, the reaction mixture was concentrated, diluted with water (5 mL) and extracted with ethyl acetate (5 mL x 2). The combined organic extracts were washed with water (10 mL), brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by prep HPLC (deionized water/HPLC-grade acetonitrile) to provide 4-{[3-(4,4-difluoropiperidin-l-yl)- lH-pyrazolo[4,3-b]pyridin-l-yl]sulfonyl}-N,N-dimethylbenzene-l-sulfonamide (0.044 g, 0.0906 mmol, 95% purity, 41.3% yield). The analytical data provided for this compound provisionally supports the proposed structure for 4-{[3-(4,4-difluoropiperidin-l-yl)-lH-pyrazolo[4,3-b]pyridin- l-yl]sulfonyl}-N,N-dimethylbenzene-l-sulfonamide B-300. Yield: 44 mg, 41.3 %; Appearance: Beige solid; ¾ NMR (400 MHz, DMSO -d6) d 8.07 (d, J= 8.4 Hz, 1H), 8.01 - 7.92 (m, 2H), 7.92 - 7.82 (m, 3H), 7.65 (t, J= 7.8 Hz, 1H), 7.37 (t, J= 7.6 Hz, 1H), 4.68 (s, 1H), 4.04 (qd, J= 6.3, 3.2 Hz, 2H), 3.49 (dd, J= 12.6, 3.3 Hz, 2H), 3.18 (dd, J= 12.6, 6.1 Hz, 2H), 1.15 (d, 7= 6.3 Hz, 6H); HPLC purity: 100%; LCMS Calculated for C21H27N5O4S2: 477.17; Observed: 478.2 [M+H]+.
|0565j The following examples were prepared using standard chemical manipulations and procedures similar to those used for the preparation of the previous example as indicated in the table below:
Figure imgf000290_0001
Figure imgf000291_0002
Example B59: Synthesis of N,N-dimethyl-4-(l-{3-[(5s,8s)-3,3-dimethyl-2- oxaspiro[4.5]decan-8-yl]-lH-pyrrolo[3,2-b]pyridin-l-yl}ethyl)benzene-l-sulfonamide, B-
285:
Figure imgf000291_0001
[0566] Step-1. Synthesis of 4-(l-hydroxyethyl)-N,N-dimethylbenzene-l -sulfonamide [0567] Sodium borohydride (0.662 g, 17.5 mmol) was added in one portion to a stirred solution of 4-acetyl-N,N-dimethylbenzenesulfonamide (2 g, 8.79 mmol) in i-PrOH (20 mL). Resulting mixture was stirred at room temperature for 16 h and evaporated under reduced pressure. The residue was diluted with NH4CI sat. aq. solution (30 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were dried over sodium sulfate, filtered and evaporated under reduced pressure to give 4-(l-hydroxyethyl)-N,N-dimethylbenzene-l -sulfonamide (2 g, 8.72 mmol, 95% purity, 94.5% yield). j0568| Step-2. Synthesis of l-[4-(dimethylsulfamoyl)phenyl]ethyl methanesulfonate J0569] Ethylbis(propan-2-yl)amine (0.210 g, 1.63 mmol) was added to a solution of the 4-(l- hydroxyethyl)-N,N-dimethylbenzenesulfonamide (0.250 g, 1.09 mmol) in dichloromethane (10 mL). The solution was cooled in an ice-water bath and methanesulfonyl chloride (0.148 g, 1.30 mmol) was added dropwise. The mixture was stirred for 1 h at 0 °C and poured into water (20 mL). The layers were separated, and the aqueous phase was washed with dichloromethane (10 mL). The combined organic layers were washed with NaHCCh sat. aq. solution (10 mL), brine (10 mL), dried over sodium sulfate, filtered, and evaporated under reduced pressure to afford l-[4- (dimethylsulfamoyl)phenyl]ethyl methanesulfonate as light-yellow solid (0.28 g, 0.910 mmol, 95% purity, 79.4% yield).
J0570] Step-3. Synthesis of 3-{3,3-dimethyl-2-oxaspiro[4.5]dec-7-en-8-yl}-lH-pyrrolo[3,2- bjpyridine
|0571j Sodium (1 g, 43.6 mmol) was added portionwise to a well-stirred pre-cooled methanol (40 mL). When sodium was dissolved lH-pyrrolo[3,2-b]pyridine (1.03 g, 8.72 mmol) and 3,3- dimethyl-2-oxaspiro[4.5]decan-8-one (2 g, 10.9 mmol) were added at room temperature. The reaction mixture was refluxed for 72 h. After reaction completion, the mixture was quenched with 2 N HC1 aq solution to pH=5 and concentrated under reduced pressure. The crude residue was diluted with water, basified with 10% Na2CCh aq. solution and extracted with ethyl acetate (20 mL x 2). The combined organic extracts were washed with water (20 mL), brine (20 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to afford 3-{3,3-dimethyl- 2-oxaspiro[4.5]dec-7-en-8-yl}-lH-pyrrolo[3,2-b]pyridine (4.3 g, 9.89 mmol, 65% purity, 90.8% yield) that was used in the next step without further purification.
|0S72| Step-4. Synthesis of 3-[(5s,8s)-3,3-dimethyl-2-oxaspiro[4.5]decan-8-yl]-lH-pyrrolo[3,2- bjpyridine
J0573] 10% Pd/C (1 g) was added at 0 °C to a stirred solution of crude 3 -(3, 3 -dimethyl-2 - oxaspiro[4.5]dec-7-en-8-yl)-lH-pyrrolo[3,2-b]pyridine (4.3 g, 9.88 mmol) in methanol (100 mL), the mixture was stirred for 10 min followed by dropwise addition of tri ethyl silane (2.29 g, 19.7 mmol). The reaction mixture was stirred under hydrogen atmosphere (balloon pressure) at room temperature for 16 h. After reaction completion the mixture was filtered through a pad of Celite and the Celite pad was washed with methanol. The filtrate was evaporated under reduced pressure. Flash chromatography (chloroform/MTBE) of residue afforded 3-[(5s,8s)-3,3-dimethyl-2- oxaspiro[4.5]decan-8-yl]-lH-pyrrolo[3,2-b]pyridine (0.8 g, 2.81 mmol, 85% purity, 24.2% yield) that was used in the next step without further purification.
|0574| Step-5. Synthesis of 4-(l-(3-((5s,8s)-3,3-dimethyl-2-oxaspiro[4.5]decan-8-yl)-lH- pyrrolo[3,2-b]pyridin-l-yl)ethyl)-N,N-dimethylbenzenesulfonamide j0575l Sodium hydride (0.0208 g, 0.521 mmol, 60% in mineral oil) was added to a stirred solution of 3-[(5s,8s)-3,3-dimethyl-2-oxaspiro[4.5]decan-8-yl]-lH-pyrrolo[3,2-b]pyridine (0.135 g, 0.474 mmol) in dry DMF (5 mL). Resulting mixture was stirred for 30 min and l-[4- (dimethylsulfamoyl)phenyl]ethyl methanesulfonate (0.160 g, 0.521 mmol) was added to it. The reaction mixture was stirred at 50 °C (oil bath) for 12 h. After cooling the reaction mixture was poured into water (25 mL), the product was extracted with ethyl acetate (30 mL). The organic layer was washed with water (20 mL), brine (20 mL), dried over sodium sulfate, filtered and evaporated under reduced pressure. Afforded residue was purified by HPLC (deionized water/HPLC-grade acetonitrile) to obtain N,N-dimethyl-4-(l-{3-[(5s,8s)-3,3-dimethyl-2-oxaspiro[4.5]decan-8-yl]- lH-pyrrolo[3,2-b]pyridin-l-yl}ethyl)benzene-l-sulfonamide B-285. Yield: 101 mg, 40.9 %; Appearance: Yellow solid; Ή NMR (600 MHz, DMSO-</6) d 8.27 (dd, J = 4.5, 1.3 Hz, 1H), 7.77 - 7.71 (m, 2H), 7.67 (d, J= 8.4 Hz, 2H), 7.45 (d, J= 8.3 Hz, 2H), 7.03 (dd, 7= 8.3, 4.5 Hz, 1H), 5.92 (q, J= 7.1 Hz, 1H), 3.49 (s, 2H), 2.87 (t , J= 11.5 Hz, 1H), 2.55 (s, 6H), 1.99 (d, 7= 12.9 Hz, 2H), 1.89 (d, J= 7.0 Hz, 3H), 1.72 - 1.58 (m, 6H), 1.46 (dt, J= 13.4, 6.4 Hz, 2H), 1.20 (s, 6H); HPLC purity: 100%; LCMS Calculated for C28H37N3O3S: 495.68; Observed: 496 2 [M+H]+.
|0576) The following example was prepared using standard chemical manipulations and procedures similar to those used for the preparation of the previous example as indicated in the table below:
Figure imgf000294_0002
Example B60: Synthesis of 4-[(3-cyclohexyl-4-fluoro-lH-indol-l-yl)sulfonyl]-N,N- dimethylbenzene-l-sulfonamide, B-286:
Figure imgf000294_0001
|0577j Step-1. Synthesis of 3-(cyclohex-l-en-l-yl)-4-fluoro-lH-indole
|0S78| A solution of 4-fluoro-lH-indole (2.3 g, 17 mmol), cyclohexanone (1.66 g, 17 mmol), and potassium hydroxide (4.76 g, 85 mmol) in methanol (25 mL) was heated to reflux for 18 h. The mixture was cooled to room temperature, poured into water (100 mL) and extracted with dichloromethane (100 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered, and the solvent was removed in vacuo. Flash chromatography of residue (petroleum ether/ethyl acetate) afforded 3-(cyclohex-l-en-l-yl)-4-fluoro-lH-indole (0.91 g, 4.22 mmol, 90% purity, 22.4% yield) that was used in next step without further purification.
|0579) Step-2. Synthesis of 3-cyclohexyl-4-fluoro-lH-indole fOSBOj 10% Pd/C (0.05 g) was added to a stirred solution of 3-(cyclohex-l-en-l-yl)-4-fluoro-lH- indole (0.91 g, 4.22mmol) in a mixture of methanol and ethyl acetate (1/1, 20 mL), the reaction mixture was stirred for 10 min followed by drop wise addition of triethyl silane (0.981 g, 8.44 mmol). The reaction mixture was stirred under hydrogen atmosphere (balloon pressure) at room temperature for 16 h. After completion, the reaction mixture was filtered through a pad of Celite and the Celite pad was washed with methanol. The filtrate was evaporated under reduced pressure to afford crude 3-cyclohexyl-4-fluoro-lH-indole flash chromatography (petroleum ether/MTBE) afforded 3-cyclohexyl-4-fluoro-lH-indole (0.1 g, 0.460 mmol, 98.7% purity, 10.7% yield).
|058f ) Step-3. Synthesis of 4-[(3-cyclohexyl-4-fluoro-lH-indol-l-yl)sulfonyl]-N,N- dimethylbenzene-1 -sulfonamide j 05821 Potassium tertiary butoxide (0.103 g, 0.92 mmol) and 18-crown-6 (0.0243 g, 0.092 mmol) were added at 0 °C to a stirred solution of 3-cyclohexyl-4-fluoro-lH-indole (0.110 g, 0.46 mmol) in THF (5 mL), the reaction mixture was stirred for 10 min at the same temperature followed by addition of 4-(N,N-dimethylsulfamoyl)benzenesulfonyl chloride (0.195 g, 0.69 mmol). The reaction mixture was stirred at room temperature for 12 h. After completion, it was concentrated, diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 2). The combined organic extracts were washed with water (10 mL), brine (10 mL), dried over anhydrous spdium sulfate, filtered and concentrated under reduced pressure. HPLC purification (deionized water/HPLC -grade acetonitrile, ammonia) of residue afforded 4-[(3-cyclohexyl-4-fluoro-lH- indol-l-yl)sulfonyl]-N,N-dimethylbenzene-l-sulfonamide B-286. Yield: 88.2 mg, 39.2 %; Appearance: White solid; ¾ NMR (600 MHz, DMSO-</6) d 8.21 (d, J = 8.5 Hz, 2H), 7.98 - 7.88 (m, 2H), 7.75 (d, J= 8.3 Hz, 1H), 7.52 (s, 1H), 7.34 (td, J= 8.2, 5.2 Hz, 1H), 7.07 (dd, J = 11.0, 8.1 Hz, 1H), 2.84 - 2.73 (m, 1H), 2.59 (s, 6H), 1.94 (d, J= 9.4 Hz, 2H), 1.83 - 1.73 (m, 2H), 1.69 (d, J = 12.9 Hz, 1H), 1.36 (q, J = 10.1, 9.0 Hz, 4H), 1.28 - 1.15 (m, 1H); HPLC purity: 100%; LCMS Calculated for C22H25FN2O4S2: 464.57; Observed: 465.2 [M+H]+. Example B61: Synthesis of 4-[(3-cyclohexyl-4-fluoro-lH-indazol-l-yl)sulfonyl]-N,N- dimethylbenzene-l-sulfonamide, B-276:
Figure imgf000296_0001
B-276
[0583) Step-1. Synthesis of cyclohexyl(2,6-difluorophenyl)methanone
[0584] 2.5 M n-butyllithium (2.52 g, 39.4 mmol) solution in hexane (15.7 mL) was added dropwise at -78 °C to a stirred solution of 1,3-difluorobenzene (4.5 g, 39.4 mmol) in dry tetrahydrofuran (250 mL) under argon atmosphere and the reaction mixture was stirred at -78 °C for 2 h. Solution of N-methoxy-N-methylcyclohexanecarboxamide (10.1 g, 59.1 mmol) in dry tetrahydrofuran (50 mL) was added at -78 °C, after the reaction mixture was allowed to warm up to room temperature and stir overnight. The suspension was diluted with water (500 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic extracts were washed with water (100 mL), brine (100 mL), dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography (Hexane/MTBE) that afforded cyclohexyl(2,6-difluorophenyl)methanone as white solid (3.5 g, 15.6 mmol, 95% purity, 37.5 % yield). The analytical data provided for this compound provisionally supports the proposed structure for cyclohexyl(2,6-difluorophenyl)methanone.
[0585] Step-2. Synthesis of 3-cyclohexyl-4-fluoro-lH-indazole
[0586] Hydrazine hydrate (1.67 g, 33.4 mmol) was added to a stirred solution of cyclohexyl(2,6- difluorophenyl)methanone (2 g, 7.15 mmol) in dioxane (50 mL). The reaction mixture was refluxed for 18 h. After completion, it was cooled to room temperature, concentrated under reduced pressure, diluted with water (100 mL) and extracted with ethyl acetate (100 mL x 2). The combined organic extracts were washed with water (100 mL), brine (100 mL), dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to afford 3-cyclohexyl-4-fluoro-lH- indazole as beige oil (1.3 g, 5.95 mmol, 90% purity, 80.6% yield) that was used in the next step without further purification. f0587j Step-3. Synthesis of 4-[(3-cyclohexyl-4-fluoro-lH-indazol-l-yl)sulfonyl]-N,N- dimethylbenzene-1 -sulfonamide
}0588J Triethylamine (0.347 g, 3.43 mmol, 477 pL) and 4-(dimethylsulfamoyl)benzene-l- sulfonyl chloride (0.777 g, 2.74 mmol) were added to a 3-cyclohexyl-4-fluoro-lH-indazole (0.5 g, 2.29 mmol) in acetonitrile (50 mL). The reaction mixture was stirred at room temperature for 18h. The obtained solid was filtered, washed with acetonitrile (20 mL x 2), water (20 mL x 2). The residue was subjected to HPLC purification (deionized water/HPLC-grade acetonitrile) to afford 4-[(3 -cyclohexyl-4-fluoro- lH-indazol- 1 -yl)sulfonyl]-N,N-dimethylbenzene- 1 -sulfonamide B- 276. Yield: 76.9 mg, 6.88 %; Appearance: White solid; Ή NMR (400 MHz, DMSO -d6) d 8.15 - 8.04 (m, 2H), 7.94 (dt, J= 8.3, 2.7 Hz, 3H), 7.70 (td, J= 8.1, 5.0 Hz, 1H), 7.30 - 7.18 (m, 1H), 3.05 (t, J= 11.5 Hz, 1H), 2.60 (d, J= 1.4 Hz, 6H), 1.91 (d, J= 12.5 Hz, 2H), 1.76 (d, J= 12.4 Hz, 2H), 1.68 (d, 7= 12.1 Hz, 1H), 1.58 - 1.43 (m, 2H), 1.37 (q, J= 12.4 Hz, 2H), 1.25 (d, J= 12.4 Hz, 1H); HPLC purity: 100%; LCMS Calculated for C21H24FN3O4S2: 465.56; Observed: 466.2 [M+H]+.
Example B62: Synthesis of Certain Compounds
{0589J The following compounds were made according to the methods described herein using chemical synthetic transformations known to those of skill in the art.
Figure imgf000297_0001
Figure imgf000298_0001
Figure imgf000299_0001
Figure imgf000300_0001
Figure imgf000301_0001
Biological Activity
|0590] For the TFEB nuclear translocation assay, HeLa wt or HeLa TRPML1 KO cells were plated at 2700 cells/well into black-walled, 384-well Cell carrier Ultra tissue culture treated plates in complete media and incubated overnight. The next day, cells are treated for 2 hrs with compounds and incubated at 37 °C. Cells were then fixed for 30 minutes at room temperature in 4% final PFA and washed five times with 90 pL PBS. PBS is aspirated from the wells and the cells are blocked with 7.5 pL blocking buffer (1 : 1 PBS/Odyssey block buffer containing 0.1% triton x-100 and 1% goat serum). After 30-60 minutes of block, 7.5 pL of primary anti-TFEB (rabbit) antibody is added for a final dilution of 1:200 antibody in 15 pL blocking buffer. Plates are incubated overnight at 4 °C. The following day, plates are washed again into PBS, 90 pL with 5 washes, all PBS is aspirated from the wells and the cells are incubated for 1 hr in 1 : 1000 goat-anti rabbit Alexa 488 secondary antibody, also containing 10 pg/mL Hoechst 33342. After the 1 hr room temperature incubation, plates are washed a final time into PBS, sealed with foil and imaged with an automated epifluorescence microscopy (PerkinElmer Operetta CLS). Four different fields were imaged per well using x20 magnification for DAPI and FITC filter sets. Images were quantified using PerkinElmer Harmony software, briefly: apply flatfield correction (basic/ advanced) for input images. Use the Find Nuclei building block with channel set at Hoechst to find the nuclei. Use the Find cytoplasm building block with channel set to Alexa 488 to find the cytoplasm. Use select cell region with Channel set at Alexa 488 and region of interest as Nuclei and define outer border at 0 pm and inner at 45 pm to cover complete nuclei. Use select cell region with Channel set at Alexa 488 and region of interest as ring region and define outer border at -5 pm and inner at 0 pm to define a ring around the nucleus. Use the find calculate intensity parameter to calculate intensity of the nuclear region and the ring region. Define results as Number of nuclei and ratio of A/B where A is Intensity of Nuclei and B is intensity of the ring region.
Analytical Instrumentation and Purification:
[0591 Ϊ NMR Instrument Details: : Varian 400MHz, Probe-1 : Auto XID Probe 2: ATB.
|0592| LCMS Instrument Details: Shimadzu LCMS-2010EV system coupled to SPD-M20A PDA and ELS detectors. Softa model 400.
[0593] LCMS Method 1 - Acidic conditions
Column: X-Select C18 CSH (3.0*50) mm 2.5p; Make: Waters
Mobile Phase A: 0.05% formic acid in water: Acetonitrile ( 95:5); pH= 3.5
Mobile Phase B: 0.05% formic acid in Acetonitrile
Column oven temperature: 50 C
Flow rate: 1.2 ml/minute
PDA: 210nm Maxplot
Gradient program :
Time(min) A% B%
0.0 100 0 2.0 2 98
3.0 2 98
3.2 100 0
4.0 100 0
MS Parameters Mode: Dual (+/-)
Detector voltage: 1.5KV Scan rang: 80-2000amu Scan speed: 2000
[0594J LCMS Method 2 - Basic conditions
Column: X-Select C18 CSH (3.0*50) mm 2.5pm ; Make: Waters
Mobile Phase A : 5mM Ammonium Bicarb; pH= 8.8
Mobile Phase B: Acetonitrile
Column oven temperature: 50 C
Flow rate: 1.2 ml/minute
PDA: 210nm Maxplot
Gradient program :
Time(min) A% B%
0.0 100 0
2.0 2 98
3.0 2 98
3.2 100 0
4.0 100 0
MS Parameters Mode: Dual (+/-) Detector voltage: 1.5KV Scan rang: 80-2000amu Scan speed: 2000
}0595J HPLC Method 1 - Acidic Conditions
Column : X-Select CSH Cl 8 (4.6*150) mm; 5p; Make: Waters Mobile Phase: A - 0.1% Formic acid in water : Acetonitrile(95:05) ; pH=3.5 B - Acetonitrile Flow Rate: 1.0. mL/minute PDA : 210nm maxplot Gradient program :
Time(min) A% B%
0.0 95 5
1.0 95 5
8.0 0 100
12.0 0 100
14.0 95 5
18.0 95 5
10596] HPLC Method 2 - Basic Conditions
Column : Xbridge C18 (4.6*150) mm, 5m; Make: Waters Mobile Phase A - 0.1% NH3 in water; pH: 9.5
B - Acetonitrile Flow Rate: 1.2. mL/minute PDA : 210nm maxplot Gradient program :
Time(min) A% B%
0.0 98 2
6.0 0 85
8.0 0 85
9.0 0 100
12.0 0 100
14.0 98 2
18.0 98 2 f0597j Table 1 shows the activity of selected compounds of this invention in TFEB assays. The compound numbers correspond to the compound numbers above in Table A. Compounds having an activity designated as “++++” provided an ACso of < 2.00 mM; compounds having an activity designated as “+++” provided an ACso of 2.01-8.00 pM; compounds having an activity designated as “++” provided an ACso of 8.01-9.99 pM; and compounds having an activity designated as "+" provided an ACso of > 10.00 pM.
Table 1
Figure imgf000305_0001
Figure imgf000305_0002
Figure imgf000306_0001
Figure imgf000306_0002
Figure imgf000307_0001
Figure imgf000307_0002
Figure imgf000308_0002
Figure imgf000308_0001

Claims

1. A compound of Formula G :
Figure imgf000309_0001
G or a pharmaceutically acceptable salt thereof, wherein
A’ is a fused phenyl or 6-membered heteroaryl ring comprising 1 to 3 nitrogen atoms, optionally substituted with Ra;
X1 and X7 are each independently selected from N, NRa, C, CRa, and C(Ra)2, as valency permits, wherein X1 and X7 are N, C, or CRa when bound to Cy-L'-Z;
Cy is absent, or a bivalent moiety selected from 4- to 12-membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, P, and S, 5- to 12-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, Ci-6 aliphatic, C6-12 aryl, or C3-12 cycloalkyl, wherein Cy is optionally substituted with one or more of R1;
L1 is absent, -NR3-, -S-, C(0)NR3-, -C(0)-C(0)-, or an optionally substituted bivalent moiety selected from Ci-6 alkylenyl, C2-6 alkenylenyl, C2-6 alkynylenyl, C3-6 cycloalkyl, -NR3-CI-6 alkylenyl, -O-Co-6 alkylenyl, and -C(0)Co-6 alkylenyl;
L2 is an optionally substituted bivalent moiety selected from -(NR3)s-S(0)-Co-6 alkylenyl-, - (NR3)S-S(0)2-CO-6 alkylenyl-, -Ci-6 alkylenyl-S(0)-(NR3)s-, -Ci-6 alkylenyl-S(0)2-(NR3)s-, - (NR3)s-C 1-6 alkylenyl, -(NR3)s-C(0)-Co-6 alkylenyl, and 4- to 12-membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S;
V is Ci-6 aliphatic, C6-12 aryl, C3-12 cycloalkyl, 4- to 12-membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S, 5- to 12-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, or 5- to 16-membered monocyclic or polycyclic aryl, wherein Vis substituted with (R6)m;
Z is Ci-6 aliphatic, 2- to 10-membered heteroaliphatic, P(0)(R3)2, -C(0)Ci-6 aliphatic, C(0)N(R3)2, C6-12 aryl, C3-12 cycloalkyl, 4- to 16-membered monocyclic or polycyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S, or 5- to 12-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, wherein Z is substituted with (R2)q; each Ra is independently H, halo, CN, oxo, or an optionally substituted group selected from Ci-6 aliphatic and O-Ci-6 aliphatic; each R1 is independently selected from halo, oxo, N(R3)2, -OH, -CN, -C(0)N(R3)2, and an optionally substituted group selected from Ci-6 aliphatic and N(R3)-C(0)-CI-6 aliphatic; each R2 is independently selected from halo, oxo, -CN, -OH, 0-R2a, -C(0)-R2a, -C(0)0-R2a, and an optionally group selected from Ci-6 aliphatic, C6-12 aryl, and 5- to 12-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S; each R2a is independently H or an optionally substituted group selected from Ci-6 aliphatic, C3-12 cycloalphatic, and 4- to 12-membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S; each R3 is independently selected from H and optionally substituted Ci-6 aliphatic; each R5 is independently -OR3, C(0)-R3, P(0)(R3)2, -N(R3)2, or an optionally substituted group selected from from Ci-6 aliphatic, C3-12 cycloalkyl, and 4- to 12-membered heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S; each R6 is halo, -S(0)-R5, -S(0)2-R5, -S(0)(NH)-R5, -CN, -C(0)-R5, -C(0)0-R5, -C(0)-NH(R5), -C(0)-N(R5)2, -P(0)(R5)2, or an optionally substituted group selected from O-Ci-6 aliphatic, Ci-6 aliphatic, C3-C12 cycloalkyl, and C6-12 aryl; m is 0, 1, 2, 3, or 4; q is 0, 1, 2, 3, or 4; and s is 0 or 1.
2. The compound of claim 1, wherein A’ is fused phenyl or fused pyridinyl.
3. The compound of claim 1, wherein A’ is selected from:
Figure imgf000310_0001
4. The compound of any one of claims 1-3, wherein Cy is absent or 4- to 12-membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S.
5. The compound of any one of claims 1-4, wherein Cy is absent.
6. The compound of any one of claims 1-5, wherein L1 is absent, -NR3-, or optionally substituted Ci-6 alkylenyl.
7. The compound of any one of claims 1-6, wherein L1 is absent.
8. The compound of any one of claims 1-7, wherein L2 is absent,
-(NR3)S-S(0)-CO-6 alkylenyl, or -(NR3)s-S(0)2-Co-6 alkylenyl.
9. The compound of any one of claims 1-8, wherein L2 is absent, -(NR3)s-S(0)-, or -(NR3)S- S(0)2-.
10. The compound of any one of claims 1-9, wherein L2 is absent or
-(NR3)S-S(0)2-.
11. The compound of any one of claims 1-10, wherein L2 is -NR3-S(0)2-.
12. The compound of any one of claims 1-11, wherein Z is Ce-u aryl, 2- to 10-membered heteroaliphatic, 4- to 16-membered monocyclic or polycyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S, or 5- to 16-membered monocyclic or polycyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, wherein Z is substituted with (R2)q.
13. The compound of any one of claims 1-12, wherein Z is Ce-u aryl or 4- to 16-membered monocyclic or polycyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S.
14. The compound of any one of claims 1-13, wherein Z is Ce-u aryl.
15. The compound of any one of claims 1-13, wherein Z is 4- to 16-membered monocyclic or polycyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S.
16. The compound of claim 1, wherein Z is selected from Table Z.
17. The compound of any one of claims 1-16, wherein V is Ce-n aryl or 4- to 12-membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S.
18. The compound of any one of claims 1-16, wherein V is Ce-n aryl.
19. The compound of any one of claims 1-18, wherein R6 is halo, S(0)-R5, S(0)2-R5, S(0)(NH)-R5, or an optionally substituted O-Ci-6 aliphatic.
20. The compound of any one of claims 1-19, wherein R6 is S(0)-R5, S(0)2-R5, or an optionally substituted Ci-6 aliphatic.
21. The compound of any one of claims 1-19, wherein R6 is halo.
22. The compound of claim 21, wherein R6 is fluoro or chloro.
23. The compound of claim 20, wherein R6 is S(0)2-R5.
24. The compound of claim 23, wherein R6 is -S(0)2-CH3.
25. The compound of claim 23, wherein R6 is -S(0)2-N(CH3)2.
26. The compound of claim 1, wherein V is selected from Table V.
27. The compound of claim 1, wherein the compound is of formula Ila:
Figure imgf000313_0001
Ila or a pharmaceutically acceptable salt thereof, wherein X6 is selected from N or CH.
28. The compound of claim 1, wherein the compound is of formula IIa-1 :
Figure imgf000313_0002
or a pharmaceutically acceptable salt thereof.
29. The compound of claim 1, wherein the compound is of formula IIa-1-iii:
Figure imgf000313_0003
IIa-1-iii or a pharmaceutically acceptable salt thereof.
30. The compound of claim 1, wherein the compound is of formula IIa-1-ii:
Figure imgf000314_0001
IIa-1-ii or a pharmaceutically acceptable salt thereof.
31. The compound of claim 1, wherein the compound is of formula IIa-2-ii:
Figure imgf000314_0002
IIa-2-ii or a pharmaceutically acceptable salt thereof.
32. The compound of claim 1, wherein the compound is of formula IIa-2-i:
Figure imgf000314_0003
IIa-2-i or a pharmaceutically acceptable salt thereof.
33. The compound of claim 1, wherein the compound is of formula IIa-3-iii:
Figure imgf000315_0001
or a pharmaceutically acceptable salt thereof.
34. The compound of claim 1, wherein the compound is of formula IIa-3-i:
Figure imgf000315_0002
or a pharmaceutically acceptable salt thereof.
35. The compound of claim 1, wherein the compound is of formula IIa-3-ii:
Figure imgf000316_0001
or a pharmaceutically acceptable salt thereof.
36. The compound of claim 1, wherein the compound is of formula IIa-4:
Figure imgf000316_0002
or a pharmaceutically acceptable salt thereof.
37. The compound of claim 1, wherein the compound is of formula IIa-4-i:
Figure imgf000316_0003
or a pharmaceutically acceptable salt thereof.
38. The compound of claim 1, wherein the compound is of formula IIa-5:
Figure imgf000317_0001
IIa-5 or a pharmaceutically acceptable salt thereof.
39. The compound of claim 1, wherein the compound is of formula IIa-5-i:
Figure imgf000317_0002
IIa-5-ii or a pharmaceutically acceptable salt thereof.
40. The compound of claim 1, wherein the compound is of formula IIb-1 :
Figure imgf000317_0003
IIb-1 or a pharmaceutically acceptable salt thereof.
41. A compound of Formula IF:
Figure imgf000318_0001
or a pharmaceutically acceptable salt thereof, wherein
X1 , X2 , and X7 are each independently selected from N, NRa, C, CRa, and C(Ra)2 as valency permits, wherein Xr , X2”, and X7 are N, C, or CRa when bound to Cy-L'-Z or L2-V
X3”, X4 , X5 , and X6 are each independently selected from N, C, and CRa, wherein Xr , X4 , X5 , and X6 are C when bound to -Cy-L'-Z or -L2-V;
Cy is absent, or a bivalent moiety selected from 4- to 12-membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, P, and S, 5- to 12-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, Ci-6 aliphatic, or C3-12 cycloalkyl, wherein Cy is optionally substituted with one or more of
R1;
L1 is absent, -NR3-, -S-, C(0)NR3-, -C(0)-C(0)-, or an optionally substituted bivalent moiety selected from Ci-6 alkylenyl, C2-6 alkynylenyl, C3-6 cycloalkyl, -NR3-CI-6 alkylenyl, -O-Co-6 alkylenyl, and -C(0)Co-6 alkylenyl;
L2 is an optionally substituted bivalent moiety selected from -(NR3)s-S(0)-Co-6 alkylenyl-, - (NR3)S-S(0)2-CO-6 alkylenyl-, -Ci-6 alkylenyl-S(0)-(NR3)s-, -Ci-6 alkylenyl-S(0)2-(NR3)s-, - (NR3)s-Co-6 alkylenyl, -(NR3)s-C(0)-Co-6 alkylenyl, and 4- to 12-membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S;
V is Ci-6 aliphatic, C6-12 aryl, C3-12 cycloalkyl, 4- to 12-membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S, 5- to 12-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, or 5- to 16-membered monocyclic or polycyclic aryl, wherein Vis substituted with (R6)m;
Z is Ci-6 aliphatic, 2- to 10-membered heteroaliphatic, P(0)(R3)2, -C(0)Ci-6 aliphatic, C(0)N(R3)2, C6-12 aryl, C3-12 cycloalkyl, 4- to 16-membered monocyclic or polycyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S, or 5- to 12-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, wherein Z is substituted with (R2)q; each Ra is independently H, halo, CN, oxo, or an optionally substituted group selected from Ci-6 aliphatic and O-Ci-6 aliphatic; each R1 is independently selected from halo, oxo, N(R3)2, -OH, -CN, -C(0)N(R3)2, and an optionally substituted group selected from Ci-6 aliphatic and N(R3)-C(0)-CI-6 aliphatic; each R2 is independently selected from halo, oxo, -CN, -OH, 0-R2a, -C(0)-R2a, -C(0)0-R2a, and an optionally group selected from Ci-6 aliphatic, C6-12 aryl, and 5- to 12-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S; each R2a is independently H or an optionally substituted group selected from Ci-6 aliphatic, C3-12 cycloalphatic, and 4- to 12-membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S; each R3 is independently selected from H and optionally substituted Ci-6 aliphatic; each R5 is independently -OR3, C(0)-R3, P(0)(R3)2, -N(R3)2, or an optionally substituted group selected from from Ci-6 aliphatic, C3-12 cycloalkyl, and 4- to 12-membered heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S; each R6 is halo, -S(0)-R5, -S(0)2-R5, -S(0)(NH)-R5, -CN, -C(0)-R5, -C(0)0-R5, -C(0)-NH(R5), -C(0)-N(R5)2, -P(0)(R5)2, or an optionally substituted group selected from O-Ci-6 aliphatic, Ci-6 aliphatic, C3-C12 cycloalkyl, and C6-12 aryl; m is 0, 1, 2, 3, or 4; q is 0, 1, 2, 3, or 4; and s is 0 or 1.
42. A compound selected from Table A.
43. A compound selected from Table B.
44. A pharmaceutical composition comprising a compound of any one of claims 1-43 and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
45. A method of modulating TRPMLl comprising administering to a subject a compound of any one of claims 1-43.
46. A method of treating a disease, disorder, or condition in a subject comprising administering a compound of any one of claims 1-43.
47. The method of claim 46, wherein the disease, disorder, or condition is a lysosomal storage disorder.
48. The method of claim 47, wherein the lysosomal storage disorder is selected from Niemann- Pick C disease, Gaucher disease, and Pompe disease.
49. The method of claim 46, wherein the disease, disorder, or condition is age-related common neurodegenerative disease.
50. The method of claim 49, wherein the disease, disorder, or condition is selected from Alzheimer’s Disease, Parkinson’s Disease, and Huntington’s Disease.
51. The method of claim 46, wherein the disease, disorder, or condition is a type IV Mucolipidosis (ML4) neurodegenerative lysosomal storage disease caused by mutations in TRPMLl.
52. The method of claim 46, wherein the disease, disorder, or condition is a muscular disease, a liver disease, a metabolic disease, an atherosclerotic disease, an inflammatory bowel disease, an atherosclerotic disease, a neurodegenerative disease, an oncological disease, or an infectious disease.
53. The method of claim 52, wherein the disease, disorder, or condition is a muscular disease.
54. The method of claim 53, wherein the muscular disease is a muscular dystrophy.
55. The method of claim 54, wherein the muscular dystrophy is Duchenne muscular dystrophy.
56. The method of claim 52, wherein the disease, disorder, or condition is an infectious disease.
57. The method of claim 56, wherein the infectious disease is an infection of Heliobacter pylori or Mycobacterium tuberculosis.
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