WO2019028395A1 - Pi3 kinase inhibitors and uses thereof - Google Patents

Pi3 kinase inhibitors and uses thereof Download PDF

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Publication number
WO2019028395A1
WO2019028395A1 PCT/US2018/045230 US2018045230W WO2019028395A1 WO 2019028395 A1 WO2019028395 A1 WO 2019028395A1 US 2018045230 W US2018045230 W US 2018045230W WO 2019028395 A1 WO2019028395 A1 WO 2019028395A1
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optionally substituted
alkyl
compound
heteroaryl
heterocycloalkyl
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PCT/US2018/045230
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French (fr)
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Bohan Jin
Qing Dong
Gene Hung
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Fronthera U.S. Pharmaceuticals Llc
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Publication of WO2019028395A1 publication Critical patent/WO2019028395A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • compositions comprising said compounds.
  • the subject compounds and compositions are useful as PI3 Kinase inhibitors.
  • the subject compounds and compositions are useful for the treatment of cancer, inflammatory diseases, and cardiovascular diseases.
  • R 7 and R 8 are taken together to form an oxo
  • Y is N or CR Y when is a double bond; or Y is NR Y3 or CR Y1 R Y2 when is a single bond;
  • R a and R b are taken together with the nitrogen atom to which they are attached to form an optionally substituted heterocycloalkyl
  • each R c is optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; and n is 1-3.
  • each R 1 is independently hydrogen, halogen, -CN, -OH, -OMe, -NH 2 , Ci-C 6 alkyl, or Ci-C 6 haloalkyl; and n is 1 or 2.
  • each R 1 is hydrogen.
  • R 3 is optionally substituted Ci-C 6 alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl. In some embodiments of a compound of Formula (I), R 3 is optionally substituted aryl.
  • R 4 is hydrogen, halogen, -CN, -OH, -OMe, -NH 2 , Ci-C ⁇ 5 alkyl, or Ci-C 6 haloalkyl. In some embodiments of a compound of Formula (I), R 4 is hydrogen.
  • R 5 and R 6 are independently hydrogen, halogen, Ci-C 6 alkyl, or Ci-C 6 haloalkyl.
  • the compound is of Formula (la):
  • R 2 is halogen, -CN, -OR a , -NR a R b , optionally substituted Ci-C 6 alkyl, optionally substituted Ci-C 6 heteroalkyl, or optionally substituted C 2 - C 6 alkynyl.
  • R 2 is halogen, optionally substituted Ci-C 6 alkyl, or optionally substituted C 2 -C 6 alkynyl.
  • R 2 is halogen.
  • R 2 is Ci- C ⁇ 5 alkyl or Ci-C 6 haloalkyl.
  • R 2 is C 2 -C 6 alkynyl optionally substituted with optionally substituted Ci-C 6 alkyl, optionally substituted Ci-C 6 heteroalkyl, optionally substituted cycloalkyl, optionally substituted (Ci-C 6 alkyl)cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted (Ci-C 6 alkyl)heterocycloalkyl, optionally substituted aryl, optionally substituted (Ci-C 6 alkyl)aryl, optionally substituted heteroaryl, or optionally substituted (Ci-C ⁇ 5 alkyl)heteroaryl.
  • R 2 is C 2 -C 6 alkynyl optionally substituted with optionally substituted Ci-C 6 alkyl, optionally substituted Ci-C 6 heteroalkyl, optionally substituted cycloalkyl, optionally substituted (Ci-
  • R 7 and R 8 are taken together to form an oxo.
  • R 9 is hydrogen, halogen, -CN, -OH, -OMe, -NH 2 , Ci-C 6 alkyl, or Ci-C 6 haloalkyl. In some embodiments of a compound of Formula (I) or (la), R 9 is -NH 2 .
  • R 10 is hydrogen or optionally substituted Ci-C 6 alkyl. In some embodiments of a compound of Formula (I) or (la), R 10 is Ci-C 6 alkyl.
  • X is CR X ; and Y is N. In some embodiments of a compound of Formula (I) or (la), Y is CR Y ; and X is N. In some embodiments of a compound of Formula (I) or (la), X is CR X ; and Y is CR Y .
  • R x is hydrogen, halogen, -CN, -OH, -OMe, -NH 2 , Ci-Q alkyl, or Ci-C 6 haloalkyl
  • R Y is hydrogen, halogen, -CN, -OH, -OMe, -NH 2 , Ci- C ⁇ 5 alkyl, or Ci-C 6 haloalkyl.
  • R x is hydrogen; and R Y is hydrogen.
  • X is CR R ; and Y is CR R .
  • R X1 and R X2 are independently hydrogen, halogen, -CN, -OH, -OMe, -NH 2 , d-Q, alkyl, or C C 6 haloalkyl; and R Y1 and R Y2 are independently hydrogen, halogen, -CN, -OH, -OMe, -NH 2 , Ci-C 6 alkyl, or Ci-C 6 haloalkyl.
  • R and R are hydrogen; and R and R are hydrogen.
  • each R a and R b are independently hydrogen or optionally substituted Ci-C 6 alkyl; or R a and R b are taken together with the nitrogen atom to which they are attached to form an optionally substituted heterocycloalkyl.
  • each R c is optionally substituted Ci-C 6 alkyl.
  • heterocycloalkyl optionally substituted (Ci-C 6 alkyl)heterocycloalkyl, optionally substituted aryl, optionally substituted (Ci-C 6 alkyl)aryl, optionally substituted heteroaryl, or optionally substituted (Ci-C 6 alkyl)heteroaryl;
  • R 12 is optionally substituted Ci-C 6 alkyl, optionally substituted Ci-C 6 heteroalkyl, optionally substituted cycloalkyl, optionally substituted (Ci-C 6 alkyl)cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted (Ci-C 6 alkyl)heterocycloalkyl, optionally substituted aryl, optionally substituted (Ci-C 6 alkyl)aryl, optionally substituted heteroaryl, or optionally substituted (Ci-C 6 alkyl)heteroaryl;
  • Ci-C 6 alkyl optionally substituted Ci-C 6 heteroalkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted cycloalkyl, optionally substituted (Ci-C 6 alkyl)cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted (Ci-C 6 alkyl)heterocycloalkyl, optionally substituted aryl, optionally substituted (Ci-C ⁇ 5 alkyl)aryl, optionally substituted heteroaryl, or optionally substituted (Ci-C 6 alkyl)heteroaryl;
  • Ring A is an optionally substituted heteroaryl or an optionally substituted heterocycloalkyl; each R a and R b are independently hydrogen, optionally substituted Ci-C 6 alkyl, optionally
  • substituted C 2 -C 6 alkenyl optionally substituted C 2 -C 6 alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
  • R a and R b are taken together with the nitrogen atom to which they are attached to form an optionally substituted heterocycloalkyl
  • each R c is optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; and nl is 1-3.
  • each R 11 is independently hydrogen, halogen, -CN, -OH, -OMe, -NH 2 , Ci-C 6 alkyl, or Ci-C 6 haloalkyl; and nl is 1 or 2. In some embodiments of a compound of Formula (II), each R 11 is hydrogen.
  • R 13 is optionally substituted Ci-C 6 alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl. In some embodiments of a compound of Formula (II), R 13 is optionally substituted aryl.
  • R 14 is hydrogen, halogen, -CN, -OH, - OMe, -NH 2 , Ci-C 6 alkyl, or Ci-C 6 haloalkyl. In some embodiments of a compound of Formula (II), R 14 is hydrogen.
  • R 15 and R 16 are independently hydrogen, halogen, Ci-C 6 alkyl, or Ci-C 6 haloalkyl.
  • the compound is of Formula (Ila):
  • R 12 is optionally substituted heterocycloalkyl or optionally substituted heteroaryl. In some embodiments of a compound of Formula (II) or (Ila), R 12 is optionally substituted heteroaryl. In some embodiments of a compound of Formula (II) or (Ila), R 12 is an optionally substituted 5-membered heteroaryl. In some embodiments of a compound of Formula (II) or (Ila), R 12 is a 5-membered heteroaryl optionally substituted with halogen, -CN, -OH, - OMe, -NH 2 , d-C 6 alkyl, or d-C 6 haloalkyl.
  • Ring A is an optionally substituted heteroaryl. In some embodiments of a compound of Formula (II) or (Ila), Ring A is an optionally substituted N-linked heteroaryl. In some embodiments of a compound of Formula (II) or (Ila), Ring A is an optionally substituted C-linked heteroaryl. In some embodiments of a compound of Formula (II) or (Ila), Ring A is an optionally substituted heterocycloalkyl. In some embodiments of a compound of Formula (II) or (Ila), Ring A is an optionally substituted N-linked heterocycloalkyl. In some embodiments of a compound of Formula (II) or (Ila), Ring A is an optionally substituted N-linked heterocycloalkyl. In some
  • Ring A is an optionally substituted C-linked heterocycloalkyl.
  • Ring A is optionally substituted with oxo, halogen, -CN, -OH, -OMe, -NH 2 , Ci-C 6 alkyl, or Ci-C 6 haloalkyl.
  • each R a and R b are independently hydrogen or optionally substituted Ci-C 6 alkyl; or R a and R b are taken together with the nitrogen atom to which they are attached to form an optionally substituted heterocycloalkyl.
  • each R c is optionally substituted Ci-C 6 alkyl.
  • heterocycloalkyl optionally substituted (Ci-C 6 alkyl)heterocycloalkyl, optionally substituted aryl, optionally substituted (Ci-C 6 alkyl)aryl, optionally substituted heteroaryl, or optionally substituted (Ci-C 6 alkyl)heteroaryl;
  • Ci-C 6 alkyl optionally substituted Ci-C 6 heteroalkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted cycloalkyl, optionally substituted (Ci-C 6 alkyl)cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted (Ci-C 6 alkyl)heterocycloalkyl, optionally substituted aryl, optionally substituted (Ci-C ⁇ 5 alkyl)aryl, optionally substituted heteroaryl, or optionally substituted (Ci-C 6 alkyl)heteroaryl;
  • each R a and R b are independently hydrogen, optionally substituted Ci-C 6 alkyl, optionally
  • substituted C 2 -C 6 alkenyl optionally substituted C 2 -C 6 alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
  • R a and R b are taken together with the nitrogen atom to which they are attached to form an optionally substituted heterocycloalkyl
  • each R c is optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; and n2 is 1-3.
  • each R 21 is independently hydrogen, halogen, -CN, -OH, -OMe, -NH 2 , Ci-C 6 alkyl, or Ci-C 6 haloalkyl; and n2 is 1 or 2.
  • each R 21 is hydrogen.
  • R 23 is optionally substituted Ci-C 6 alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl. In some embodiments of a compound of Formula (III), R 23 is optionally substituted aryl.
  • R 24 is hydrogen, halogen, -CN, -OH, - OMe, -NH 2 , Ci-C ⁇ 5 alkyl, or Ci-C 6 haloalkyl. In some embodiments of a compound of Formula (III), R 24 is hydrogen.
  • R 25 and R 26 are independently hydrogen, halogen, Ci-C 6 alkyl, or Ci-C 6 haloalkyl.
  • R 27 is hydrogen or Ci-C 6 alkyl.
  • the compound is of Formula (Ilia) :
  • R 22 is halogen, -CN, -OR a , - NR a R b , optionally substituted Ci-C 6 alkyl, optionally substituted Ci-C 6 heteroalkyl, or optionally substituted C 2 -C 6 alkynyl.
  • R 22 is halogen, optionally substituted Ci-C 6 alkyl, or optionally substituted C 2 -C 6 alkynyl.
  • R 22 is halogen.
  • R 22 is d-C 6 alkyl or d-C 6 haloalkyl.
  • R 22 is C 2 -C 6 alkynyl optionally substituted with optionally substituted Ci-C 6 alkyl, optionally substituted Ci-C 6 heteroalkyl, optionally substituted cycloalkyl, optionally substituted (Ci-C 6 alkyl)cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted (Ci-C 6
  • R 22 is C 2 -C 6 alkynyl optionally substituted with optionally substituted heteroaryl.
  • R 28 is halogen, - CN, -OR a , -NR a R b , optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkynyl, or optionally substituted heteroaryl.
  • R 28 is halogen, - CN, -OMe, -NH 2 , Ci-C 6 alkyl, Ci-C 6 haloalkyl, C 2 -C 6 alkynyl, or heteroaryl.
  • R is hydrogen or optionally substituted Ci-C 6 alkyl.
  • R 29 is Ci-C 6 alkyl.
  • each R a and R b are independently hydrogen or optionally substituted Ci-C 6 alkyl; or R a and R b are taken together with the nitrogen atom to which they are attached to form an optionally substituted heterocycloalkyl.
  • each R c is optionally substituted Ci-C 6 alkyl.
  • R 32 is optionally substituted Ci-C 6 alkyl, optionally substituted Ci-C 6 heteroalkyl, optionally substituted cycloalkyl, optionally substituted (Ci-C 6 alkyl)cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted (Ci-C 6 alkyl)heterocycloalkyl, optionally substituted aryl, optionally substituted (Ci-C 6 alkyl)aryl, optionally substituted heteroaryl, or optionally substituted (Ci-C 6 alkyl)heteroaryl;
  • Ci-C 6 alkyl optionally substituted Ci-C 6 heteroalkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted cycloalkyl, optionally substituted (Ci-C 6 alkyl)cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted (Ci-C 6 alkyl)heterocycloalkyl, optionally substituted aryl, optionally substituted (Ci-C ⁇ 5 alkyl)aryl, optionally substituted heteroaryl, or optionally substituted (Ci-C 6
  • Ring B is an optionally substituted 5-membered heteroaryl
  • each R a and R b are independently hydrogen, optionally substituted Ci-C 6 alkyl, optionally
  • substituted C 2 -C 6 alkenyl optionally substituted C 2 -C 6 alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
  • R a and R b are taken together with the nitrogen atom to which they are attached to form an optionally substituted heterocycloalkyl
  • each R c is optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; and n3 is 1-3.
  • each R 1 is independently hydrogen, halogen, -CN, -OH, -OMe, -NH 2 , Ci-C 6 alkyl, or Ci-C 6 haloalkyl; and n3 is 1 or 2.
  • each R 31 is hydrogen.
  • R 33 is optionally substituted Ci-C 6 alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl. In some embodiments of a compound of Formula (IV), R is optionally substituted aryl.
  • R 34 is hydrogen, halogen, -CN, -OH, - OMe, -NH 2 , Ci-C ⁇ 5 alkyl, or Ci-C 6 haloalkyl. In some embodiments of a compound of Formula (IV), R 34 is hydrogen.
  • R 35 and R 36 are independently hydrogen, halogen, Ci-C 6 alkyl, or Ci-C 6 haloalkyl.
  • R 37 is hydrogen or Ci-C 6 alkyl.
  • the compound is of Formula (IVa):
  • R is optionally substituted heterocycloalkyl or optionally substituted heteroaryl.
  • R 32 is optionally substituted heteroaryl.
  • R 32 is an optionally substituted 5-membered heteroaryl.
  • R 32 is a 5- membered heteroaryl optionally substituted with halogen, -CN, -OH, -OMe, -NH 2 , Ci-C 6 alkyl, or Ci-C 6 haloalkyl.
  • Ring B is selected from optionally substituted: pyrrole, thiophene, furan, imidazole, pyrazole, thiazole, isothiazole, oxazole, isoxazole, triazole, and tetrazole. In some embodiments of a compound of Formula (IV) or (Via), Ring B is optionally substituted pyrazole.
  • Ring B is optionally substituted with halogen, -CN, -OR a , -NR a R b , optionally substituted Ci-C ⁇ 5 alkyl, optionally substituted C 2 -C 6 alkynyl, or optionally substituted heteroaryl.
  • Ring B is optionally substituted with halogen, - CN, -OMe, -NH 2 , Ci-C 6 alkyl, Ci-C 6 haloalkyl, C 2 -C 6 alkynyl, or heteroaryl.
  • each R a and R b are
  • each R c is optionally substituted Ci-C 6 alkyl.
  • PI3 kinases phosphoinositide 3' OH kinase family
  • the subject compounds and compositions are useful for the treatment of cancers and inflammatory diseases.
  • PBK phosphoinositide 3-kinase pathway
  • PIP3 is a critical second messenger which recruits proteins that contain pleckstrin homology domains to the cell membrane where they are activated. The most studied of these proteins is AKT which promotes cell survival, growth, and proliferation.
  • the PBK family consists of 15 proteins that share sequence homology, particularly within their kinase domains, but have distinct substrate specificities and modes of regulation.
  • Class I PBKs are heterodimers consisting of a pi 10 catalytic subunit complexed to one of several regulatory subunits collectively referred to as p85 and have been the most extensively studied in the context of tumorgenesis.
  • the class 1A PBK catalytic subunits comprise the pi lOalpha, pi lObeta, and pi lOdelta isoforms, which associate with one of five different regulatory subunits encoded by three separate genes.
  • a single class IB PBK catalytic isoform pi lOgamma interacts with one of two associated regulatory subunits.
  • Class 1 PBKs are primarily responsible for phosphorylating the critical PIP2 signaling molecule.
  • mice which lack PBKgamma and PBKdelta are viable, fertile, and have a normal life span although they show an altered immune system.
  • PBKgamma deficiency leads to impaired recruitment of macrophages and neutrophils to sites of inflammation as well as impaired T cell activation.
  • PBKdelta- mutant mice have specific defects in B cell signaling that lead to impaired B cell development and reduced antibody responses after antigen stimulation.
  • PBKgamma-mutant mice are largely protected from disease in mouse models of rheumatoid arthritis (RA) and asthma.
  • RA rheumatoid arthritis
  • SLE systemic lupus nephritis
  • mice and wild-type mice treated with a selective inhibitor of PBKdelta have been shown to have attenuated allergic airway inflammation and hyper-responsiveness in a mouse model of asthma and to have attenuated disease in a model of RA.
  • the PBKbeta isoform has been implicated as necessary for transformation induced by the loss or inactivation of the PTEN tumor suppressor both in vitro and in vivo. Consistent with this finding, overexpression of the PIK3CB gene has been identified in some bladder, colon, glioblastomas and leukemias and siRNA mediated knockdown of pi lObeta in glioblastoma cell lines results in suppression of tumor growth in vitro and in vivo.
  • pi 1013 was reported to be essential to the transformed phenotype in a PTEN-null prostate cancer model.
  • fibrogenesis including systemic sclerosis (SSc), arthritis, nephropahty, liver cirrhosis, and some cancers, are related to PTEN deficiency and corresponding PBK-Akt overexpression.
  • SSc systemic sclerosis
  • nephropahty nephropahty
  • liver cirrhosis nephropahty
  • PBK-Akt PBK-Akt overexpression
  • Alkyl refers to an optionally substituted straight-chain, or optionally substituted branched- chain saturated hydrocarbon monoradical having from one to about ten carbon atoms, or from one to six carbon atoms, wherein a sp3 -hybridized carbon of the alkyl residue is attached to the rest of the molecule by a single bond.
  • Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl- 1-propyl, 2-methyl-2 -propyl, 2-methyl-l -butyl, 3 -methyl- 1 -butyl, 2-methyl-3-butyl, 2,2-dimethyl-l - propyl, 2-methyl-l -pentyl, 3 -methyl- 1-pentyl, 4-methyl-l-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-l -butyl, 3,3-dimethyl-l -butyl, 2-ethyl-l -butyl, n-butyl, isobutyl, sec- butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl and hexyl, and longer
  • a numerical range such as "Ci-C 6 alkyl” means that the alkyl group consists of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term "alkyl” where no numerical range is designated.
  • the alkyl is a Ci-Cio alkyl, a C 1 -C9 alkyl, a Ci-Cg alkyl, a C 1 -C7 alkyl, a Ci-C 6 alkyl, a C 1 -C5 alkyl, a C 1 -C4 alkyl, a C 1 -C3 alkyl, a Ci-C 2 alkyl, or a Ci alkyl.
  • an alkyl group is optionally substituted as described below, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • the alkyl is optionally substituted with oxo, halogen, -CN, -CF 3 , -OH, -OMe, -NH 2 , or -N0 2 .
  • the alkyl is optionally substituted with oxo, halogen, -CN, -CF 3 , -OH, or -OMe.
  • Alkenyl refers to an optionally substituted straight-chain, or optionally substituted branched- chain hydrocarbon monoradical having one or more carbon-carbon double-bonds and having from two to about ten carbon atoms, more preferably two to about six carbon atoms, wherein an sp2 -hybridized carbon of the alkenyl residue is attached to the rest of the molecule by a single bond.
  • the group may be in either the cis or trans conformation about the double bond(s), and should be understood to include both isomers.
  • a numerical range such as "C 2 -C 6 alkenyl” means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term "alkenyl" where no numerical range is designated.
  • the alkenyl is a C 2 -Ci 0 alkenyl, a C 2 -C 9 alkenyl, a C 2 -C 8 alkenyl, a C 2 -C 7 alkenyl, a C 2 -C 6 alkenyl, a C 2 -C 5 alkenyl, a C 2 -C 4 alkenyl, a C 2 -C 3 alkenyl, or a C 2 alkenyl.
  • an alkenyl group is optionally substituted as described below, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • an alkenyl is optionally substituted with oxo, halogen, -CN, -CF 3 , -OH, -OMe, -NH 2 , or -N0 2 .
  • an alkenyl is optionally substituted with oxo, halogen, -CN, -CF 3 , -OH, or -OMe.
  • Alkynyl refers to an optionally substituted straight-chain or optionally substituted branched- chain hydrocarbon monoradical having one or more carbon-carbon triple-bonds and having from two to about ten carbon atoms, more preferably from two to about six carbon atoms. Examples include, but are not limited to ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl and the like.
  • C 2 -C 6 alkynyl means that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term "alkynyl” where no numerical range is designated.
  • the alkynyl is a C 2 -Ci 0 alkynyl, a C 2 -C 9 alkynyl, a C 2 -C 8 alkynyl, a C 2 -C 7 alkynyl, a C 2 -C 6 alkynyl, a C 2 -C 5 alkynyl, a C 2 -C 4 alkynyl, a C 2 -C 3 alkynyl, or a C 2 alkynyl.
  • an alkynyl group is optionally substituted as described below, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • an alkynyl is optionally substituted with oxo, halogen, -CN, -CF 3 , -OH, -OMe, -NH 2 , or -N0 2 .
  • an alkynyl is optionally substituted with oxo, halogen, -CN, -CF 3 , -OH, or -OMe.
  • Alkylene refers to a straight or branched divalent hydrocarbon chain. Unless stated otherwise specifically in the specification, an alkylene group may be optionally substituted as described below, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an alkylene is optionally substituted with oxo, halogen, -CN, -CF 3 , -OH, -OMe, -NH 2 , or -N0 2 . In some embodiments, an alkylene is optionally substituted with oxo, halogen, -CN, -CF 3 , -OH, or -OMe.
  • Alkoxy refers to a radical of the formula -OR a where R a is an alkyl radical as defined.
  • an alkoxy group may be optionally substituted as described below, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • an alkoxy is optionally substituted with oxo, halogen, -CN, -CF 3 , -OH, -OMe, -NH 2 , or -N0 2 .
  • an alkoxy is optionally substituted with oxo, halogen, -CN, -CF 3 , -OH, or -OMe.
  • Aryl refers to a radical derived from a hydrocarbon ring system comprising hydrogen, 6 to 30 carbon atoms and at least one aromatic ring.
  • the aryl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the aryl is bonded through an aromatic ring atom) or bridged ring systems.
  • the aryl is a 6- to 10-membered aryl.
  • the aryl is a 6-membered aryl.
  • Aryl radicals include, but are not limited to, aryl radicals derived from the hydrocarbon ring systems of anthrylene, naphthylene, phenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as- indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene.
  • the aryl is phenyl.
  • an aryl may be optionally substituted as described below, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • an aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF 3 , -OH, -OMe, -NH 2 , or -N0 2 .
  • an aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe.
  • Cycloalkyl refers to a stable, partially or fully saturated, monocyclic or polycyclic carbocyclic ring, which may include fused (when fused with an aryl or a heteroaryl ring, the cycloalkyl is bonded through a non-aromatic ring atom) or bridged ring systems.
  • Representative cycloalkyls include, but are not limited to, cycloalkyls having from three to fifteen carbon atoms (C3-C15 cycloalkyl), from three to ten carbon atoms (C 3 -Ci 0 cycloalkyl), from three to eight carbon atoms (C 3 -C 8 cycloalkyl), from three to six carbon atoms (C 3 -C 6 cycloalkyl), from three to five carbon atoms (C 3 -C 5 cycloalkyl), or three to four carbon atoms (C 3 -C 4 cycloalkyl).
  • the cycloalkyl is a 3- to 6-membered cycloalkyl.
  • the cycloalkyl is a 5 - to 6-membered cycloalkyl.
  • Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • Polycyclic cycloalkyls or carbocycles include, for example, adamantyl, norbornyl, decalinyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decalin, trans-decalin, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, and bicyclo[3.3.2]decane, and
  • Partially saturated cycloalkyls include, for example cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.
  • a cycloalkyl is optionally substituted as described below, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF 3 , -OH, -OMe, -NH 2 , or -N0 2 .
  • a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe.
  • Halo or “halogen” refers to bromo, chloro, fluoro or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro.
  • Haloalkyl refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl,
  • Heterocycloalkyl refers to a stable 3- to 24-membered partially or fully saturated ring radical comprising 2 to 23 carbon atoms and from one to 8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous and sulfur.
  • the heterocycloalkyl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused (when fused with an aryl or a heteroaryl ring, the heterocycloalkyl is bonded through a non-aromatic ring atom) or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heterocycloalkyl radical may be optionally oxidized; the nitrogen atom may be optionally quatemized.
  • the heterocycloalkyl is a 3- to 6-membered heterocycloalkyl.
  • the heterocycloalkyl is a 5 - to 6-membered heterocycloalkyl.
  • heterocycloalkyl radicals include, but are not limited to, aziridinyl, azetidinyl, dioxolanyl, thienyl[l,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl
  • heterocycloalkyl also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides and the oligosaccharides. Unless otherwise noted, heterocycloalkyls have from 2 to 10 carbons in the ring.
  • the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including the heteroatoms) that make up the heterocycloalkyl (i.e. skeletal atoms of the heterocycloalkyl ring).
  • a heterocycloalkyl is optionally substituted as described below, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • a heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, - CF 3 , -OH, -OMe, -NH 2 , or -N0 2 .
  • a heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe.
  • Heteroalkyl refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g. -NH-, -N(alkyl)-), sulfur, or combinations thereof.
  • a heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl.
  • a heteroalkyl is a Ci-C 6 heteroalkyl.
  • Heteroalkyl is optionally substituted as described below, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl,
  • a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF 3 , -OH, -OMe, -NH 2 , or -N0 2 .
  • a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe.
  • Heteroaryl refers to a 5 - to 14-membered ring system radical comprising hydrogen atoms, one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous and sulfur, and at least one aromatic ring.
  • the heteroaryl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the heteroaryl is bonded through an aromatic ring atom) or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heteroaryl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized.
  • the heteroaryl is a 5- to 10-membered heteroaryl.
  • the heteroaryl is a 5 - to 6-membered heteroaryl.
  • Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][l,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[l,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl,
  • a heteroaryl is optionally substituted as described below, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • a heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF 3 , -OH, -OMe, -NH 2 , or -N0 2 .
  • a heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe.
  • All the above groups may be either substituted or unsubstituted.
  • substituted as used herein means any of the above groups (e.g., alkyl, alkylene, alkoxy, aryl, cycloalkyl, haloalkyl, heterocyclyl and/or heteroaryl) may be further functionalized wherein at least one hydrogen atom is replaced by a bond to a non-hydrogen atom substituent.
  • a substituted group may include one or more substituents selected from: oxo, amino, -C0 2 H, nitrile, nitro, hydroxyl, thiooxy, alkyl, alkylene, alkoxy, aryl, cycloalkyl, heterocyclyl, heteroaryl, dialkylamines, arylamines, alkylarylamines, diarylamines, trialkylammonium (-N + R 3 ), N-oxides, imides, and enamines; a silicon atom in groups such as trialkylsilyl groups, dialkylarylsilyl groups, alkyldiarylsilyl groups, triarylsilyl groups, perfluoroalkyl, or perfluoroalkoxy, for example, trifluoromethyl or trifluoromethoxy.
  • Substituted also means any of the above groups in which one or more hydrogen atoms are replaced by a higher-order bond (e.g. , a double- or triple-bond) to a heteroatom such as oxygen in oxo, carbonyl, carboxyl, and ester groups; and nitrogen in groups such as imines, oximes, hydrazones, and nitriles.
  • a higher-order bond e.g. , a double- or triple-bond
  • nitrogen in groups such as imines, oximes, hydrazones, and nitriles.
  • R g and R h are the same or different and independently hydrogen, alkyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl and/or heteroarylalkyl.
  • each of the foregoing substituents may also be optionally substituted with one or more of the above substituents.
  • any of the above groups may be substituted to include one or more internal oxygen, sulfur, or nitrogen atoms.
  • an alkyl group may be substituted with one or more internal oxygen atoms to form an ether or polyether group.
  • an alkyl group may be substituted with one or more internal sulfur atoms to form a thioether, disulfide, etc.
  • treat do not necessarily imply 100% or complete treatment, prevention, amelioration, or inhibition. Rather, there are varying degrees of treatment, prevention, amelioration, and inhibition of which one of ordinary skill in the art recognizes as having a potential benefit or therapeutic effect.
  • the disclosed methods can provide any amount of any level of treatment, prevention, amelioration, or inhibition of the disorder in a mammal.
  • a disorder, including symptoms or conditions thereof may be reduced by, for example, about 100%, about 90%, about 80%, about 70%, about 60%, about 50%, about 40%, about 30%, about 20%, or about 10%.
  • treatment, prevention, amelioration, or inhibition provided by the methods disclosed herein can include treatment, prevention, amelioration, or inhibition of one or more conditions or symptoms of the disorder, e.g., cancer or an inflammatory disease.
  • treatment,” “prevention,” “amelioration,” or “inhibition” encompass delaying the onset of the disorder, or a symptom or condition thereof.
  • an "effective amount” or “therapeutically effective amount,” as used herein, refer to a sufficient amount of a compound di sclosed herein being administered which will relieve to some extent one or more of the symptoms of the disease or condition being treated, e.g., cancer or an inflammatory disease. In some embodiments, the result is a reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system.
  • an "effective amount” for therapeutic uses is the amount of the composition comprising a compound disclosed herein required to provide a clinically significant decrease in disease symptoms.
  • an appropriate "effective" amount in any individual case is determined using techniques, such as a dose escalation study.
  • Described herein are compounds of Formula (I), (la), (II), (Ila), (IIP), (HI), (ma), (IV), or (IVa) that are PI3 Kinase inhibitors. These compounds, and compositions comprising these compounds, are useful for the treatment of cancer and inflammatory diseases.
  • heterocycloalkyl optionally substituted (Ci-C 6 alkyl)heterocycloalkyl, optionally substituted aryl, optionally substituted (Ci-C 6 alkyl)aryl, optionally substituted heteroaryl, or optionally substituted (Ci-C 6 alkyl)heteroaryl;
  • X is N or CR X when is a double bond; or X is NR X3 or CR X1 R X2 when is a single bond;
  • Y is N or CR Y when is a double bond; or Y is NR Y3 or CR Y1 R Y2 when is a single bond;
  • each R a and R b are independently hydrogen, optionally substituted Ci-C 6 alkyl, optionally
  • substituted C 2 -C 6 alkenyl optionally substituted C 2 -C 6 alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
  • R a and R b are taken together with the nitrogen atom to which they are attached to form an optionally substituted heterocycloalkyl
  • each R c is optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; and n is 1-3.
  • n is 1. In some embodiments of a compound of Formula (I), n is 2. In some embodiments of a compound of Formula (I), n is 3.
  • each R 1 is independently hydrogen, halogen, -CN, -OH, -OMe, -NH 2 , Ci-C 6 alkyl, or Ci-C 6 haloalkyl; and n is 1 or 2.
  • each R 1 is independently hydrogen, halogen, Ci-C 6 alkyl, or Ci-C 6 haloalkyl; and n is 1 or 2.
  • R 1 is halogen, Ci-C 6 alkyl, or Ci-C 6 haloalkyl; and n is 1.
  • R 1 is halogen; and n is 1.
  • each R 1 is hydrogen.
  • R 3 is optionally substituted Ci-C 6 alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl. In some embodiments of a compound of Formula (I), R 3 is optionally substituted aryl. In some embodiments of a compound of Formula (I), R 3 is optionally substituted with halogen, -CN, -OH, -OMe, -NH 2 , Ci-C 6 alkyl, or Ci-C 6 haloalkyl.
  • R 3 is optionally substituted with halogen, Ci-C 6 alkyl, or Ci-C 6 haloalkyl. In some embodiments of a compound of Formula (I), R 3 is unsubstituted aryl or unsusbituted heteroaryl. In some embodiments of a compound of Formula (I), R 3 is unsubstituted aryl. In some embodiments of a compound of Formula (I), R 3 is unsubstituted phenyl.
  • R 4 is hydrogen, halogen, -CN, -OH, -OMe, -NH 2 , Ci-C ⁇ 5 alkyl, or Ci-C 6 haloalkyl. In some embodiments of a compound of Formula (I), R 4 is hydrogen, halogen, Ci-C 6 alkyl, or Ci-C 6 haloalkyl. In some embodiments of a compound of Formula (I), R 4 is hydrogen or halogen. In some embodiments of a compound of Formula (I), R 4 is hydrogen.
  • R 5 and R 6 are independently hydrogen, halogen, Ci-C 6 alkyl, or Ci-C 6 haloalkyl. In some embodiments of a compound of Formula (I), R 5 and R 6 are independently hydrog en or Ci-Cg alkyl.
  • the compound is of Formula (la), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
  • R 2 is halogen, -CN, -OR a , -NR a R b , optionally substituted Ci-C 6 alkyl, optionally substituted Ci-C 6 heteroalkyl, or optionally substituted C 2 - C 6 alkynyl.
  • R 2 is halogen, optionally substituted Ci-C 6 alkyl, or optionally substituted C 2 -C 6 alkynyl.
  • R 2 is halogen.
  • R 2 is fluoro or chloro. In some embodiments of a compound of Formula (I) or (la), R 2 is chloro. In some embodiments of a compound of Formula (I) or (la), R 2 is Ci-C 6 alkyl or Ci-C 6 haloalkyl. In some embodiments of a compound of Formula (I) or (la), R 2 is methyl.
  • R 2 is C 2 -C 6 alkynyl optionally substituted with optionally substituted Ci-C 6 alkyl, optionally substituted Ci-C 6 heteroalkyl, optionally substituted cycloalkyl, optionally substituted (Ci-C 6 alkyl)cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted (Ci-C 6
  • R 2 is C 2 -C 6 alkynyl optionally substituted with optionally substituted heteroaryl. In so odiments of a compound of Formula (I) or (la), R 2 is C 2 -C 6 alkynyl optionally
  • R 7 and R 8 are taken together to form an oxo.
  • R 7 and R 8 are independently hydrogen, halogen, -CN, -OH, -OMe, -NH 2 , Ci-C 6 alkyl, or Ci-C 6 haloalkyl.
  • R 9 is hydrogen, halogen, -CN, -OH, -OMe, -NH 2 , Ci-C 6 alkyl, or Ci-C 6 haloalkyl. In some embodiments of a compound of Formula (I) or (la), R 9 is -NH 2 . [0090] In some embodiments of a compound of Formula (I) or (la), R is hydrogen or optionally substituted Ci-C 6 alkyl. In some embodiments of a compound of Formula (I) or (la), R 10 is Ci-C 6 alkyl.
  • a compound of Formula (I) or (la) is a double bond. In some embodiments of a compound of Formula (I) or (la), is a double bond; X is CR X ; and Y is N. In some embodiments of a compound of Formula (I) or (la), is a double bond; Y is CR Y ; and X is N. In some embodiments of a compound of Formula (I) or (la), is a double bond; X is CR X ; and Y is CR Y .
  • R x is hydrogen, halogen, -CN, -OH, - OMe, -NH 2 , d-C 6 alkyl, or d-C 6 haloalkyl
  • R Y is hydrogen, halogen, -CN, -OH, -OMe, -NH 2 , d-Q, alkyl, or Ci-C 6 haloalkyl.
  • R x is hydrogen, halogen, Ci-C 6 alkyl, or Ci-C 6 haloalkyl
  • R Y is hydrogen, halogen, Ci-C 6 alkyl, or Ci-C 6 haloalkyl.
  • R x is hydrogen; and R Y is hydrogen.
  • a compound of Formula (I) or (la) is a single bond; X is NR ; and Y is CR ⁇ R 1 '. In some embodiments of a compound of Formula (I) or (la), is
  • X is CR R ; and Y is NR 1 J .
  • a compound of Formula (I) or (la) is a single bond; X is NR X3 ; and Y is NR Y3 .
  • R X1 and R X2 are independently hydrogen, halogen, -CN, -OH, -OMe, -NH 2 , d-C 6 alkyl, or d-C 6 haloalkyl; and R Y1 and R Y2 are independently hydrogen, halogen, -CN, -OH, -OMe, -NH 2 , Ci-C 6 alkyl, or Ci-C 6 haloalkyl.
  • R X1 and R X2 are independently hydrogen, halogen, Ci-C ⁇ 5 alkyl, or Ci-C 6 haloalkyl; and R Y1 and R Y2 are independently hydrogen, halogen, Ci-C 6 alkyl, or Ci-C ⁇ 5 haloalkyl. In some embodiments of a compound of Formula (I) or (la), R X1 and R X2 are hydrogen;
  • Y 1 Y2 Y3 and R and R are hydrogen.
  • R and R are independently hydrogen, Ci-C 6 alkyl, or Ci-C 6 haloalkyl.
  • R X3 and R Y3 are independently hydrog en or ⁇ d alkyl.
  • each R a and R b are independently hydrogen or optionally substituted Ci-C 6 alkyl; or R a and R b are taken together with the nitrogen atom to which they are attached to form an optionally substituted heterocycloalkyl.
  • each R c is optionally substituted Ci- C ⁇ 5 alkyl.
  • heterocycloalkyl optionally substituted (Ci-C 6 alkyl)heterocycloalkyl, optionally substituted aryl, optionally substituted (Ci-C 6 alkyl)aryl, optionally substituted heteroaryl, or optionally substituted (Ci-C 6 alkyl)heteroaryl;
  • R 12 is optionally substituted Ci-C 6 alkyl, optionally substituted Ci-C 6 heteroalkyl, optionally substituted cycloalkyl, optionally substituted (Ci-C 6 alkyl)cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted (Ci-C 6 alkyl)heterocycloalkyl, optionally substituted aryl, optionally substituted (Ci-C 6 alkyl)aryl, optionally substituted heteroaryl, or optionally substituted (Ci-C 6 alkyl)heteroaryl;
  • Ci-C 6 alkyl optionally substituted Ci-C 6 heteroalkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted cycloalkyl, optionally substituted (Ci-C 6 alkyl)cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted (Ci-C 6 alkyl)heterocycloalkyl, optionally substituted aryl, optionally substituted (Ci-C ⁇ 5 alkyl)aryl, optionally substituted heteroaryl, or optionally substituted (Ci-C 6 alkyl)heteroaryl;
  • Ring A is an optionally substituted heteroaryl or an optionally substituted heterocycloalkyl; each R a and R b are independently hydrogen, optionally substituted Ci-C 6 alkyl, optionally
  • substituted C 2 -C 6 alkenyl optionally substituted C 2 -C 6 alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
  • R a and R b are taken together with the nitrogen atom to which they are attached to form an optionally substituted heterocycloalkyl
  • each R c is optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; and nl is 1-3.
  • nl is 1. In some embodiments of a compound of Formula (II), nl is 2. In some embodiments of a compound of Formula (II), nl is 3.
  • each R 11 is independently hydrogen, halogen, -CN, -OH, -OMe, -NH 2 , Ci-C 6 alkyl, or Ci-C 6 haloalkyl; and nl is 1 or 2.
  • each R 11 is independently hydrogen, halogen, Ci-C 6 alkyl, or Ci-C 6 haloalkyl; and nl is 1 or 2.
  • R 11 is halogen, Ci-C 6 alkyl, or Ci-C 6 haloalkyl; and nl is 1.
  • R 11 is halogen; and nl is 1.
  • each R 11 is hydrogen.
  • R 13 is optionally substituted Ci-C 6 alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl. In some embodiments of a compound of Formula (II), R 13 is optionally substituted aryl. In some embodiments of a compound of Formula (II), R 13 is optionally substituted with halogen, -CN, -OH, -OMe, -NH 2 , Ci-C 6 alkyl, or Ci-C 6 haloalkyl.
  • R 13 is optionally substituted with halogen, Ci-C 6 alkyl, or Ci-C 6 haloalkyl. In some embodiments of a compound of Formula (II), R 13 is unsubstituted aryl or unsusbituted heteroaryl. In some embodiments of a compound of Formula (II), R 13 is unsubstituted aryl. In some embodiments of a compound of Formula (II), R 13 is unsubstituted phenyl.
  • R 14 is hydrogen, halogen, -CN, -OH, - OMe, -NH 2 , Ci-C ⁇ 5 alkyl, or Ci-C 6 haloalkyl. In some embodiments of a compound of Formula (II), R 14 is hydrogen, halogen, Ci-C 6 alkyl, or Ci-C 6 haloalkyl. In some embodiments of a compound of Formula (II), R 14 is hydro gen or halogen. In some embodiments of a compound of Formula (II), R 14 is hydrogen.
  • R and R are independently hydrogen, halogen, Ci-C 6 alkyl, or Ci-C 6 haloalkyl.
  • R 15 and R 16 are independently hydrogen or Ci-C 6 alkyl.
  • the compound is of Formula (Ila), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
  • R is optionally substituted heterocycloalkyl or optionally substituted heteroaryl.
  • R 12 is optionally substituted heteroaryl.
  • R 12 is an optionally substituted 5-membered heteroaryl.
  • R 12 is a 5- membered heteroaryl optionally substituted with halogen, -CN, -OH, -OMe, -NH 2 , Ci-C 6 alkyl, or Ci-C 6
  • R is .
  • Ring A is an optionally substituted heteroaryl. In some embodiments of a compound of Formula (II) or (Ila), Ring A is an optionally substituted N-linked heteroaryl. In some embodiments of a compound of Formula (II) or (Ila), Ring A is an optionally substituted C-linked heteroaryl. In some embodiments of a compound of Formula (II) or (Ila), Ring A is an optionally substituted heterocycloalkyl. In some embodiments of a compound of Formula (II) or (Ila), Ring A is an optionally substituted N-linked heterocycloalkyl.
  • Ring A is optionally substituted with oxo, halogen, -CN, -OH, -OMe, -NH 2 , Ci-C 6 alkyl, or Ci-C 6 haloalkyl.
  • Y is N or CR Y when is a double bond; or Y is NR Y3 or CR Y1 R Y2 when is a single bond;
  • R 17 and R 18 on the same carbon are taken together to form an oxo.
  • R 17 and R 18 are independently hydrogen, halogen, -CN, -OH, -OMe, -NH 2 , Ci-C 6 alkyl, or Ci-C 6 haloalkyl.
  • R 19 is hydrogen, halogen, -CN, - OH, -OMe, -NH 2 , Ci-C 6 alkyl, or Ci-C 6 haloalkyl. In some embodiments of a compound of Formula (II) or (Ila), R 19 is -NH 2 .
  • R 20 is hydrogen or optionally substituted Ci-C 6 alkyl. In some embodiments of a compound of Formula (II) or (Ila), R 20 is Ci-C 6 alkyl.
  • a compound of Formula (II) or (Ila) is a double bond.
  • a compound of Formula (II) or (Ila) is a double bond;
  • X is CR X ; and
  • Y is N.
  • a compound of Formula (II) or (Ila) is a double bond;
  • X is CR X ; and
  • Y is CR Y .
  • R x is hydrogen, halogen, -CN, -OH, -OMe, -NH 2 , Ci-Q alkyl, or Ci-C 6 haloalkyl
  • R Y is hydrogen, halogen, -CN, -OH, -OMe, -NH 2 , Ci- C ⁇ 5 alkyl, or Ci-C 6 haloalkyl.
  • R x is hydrogen, halogen, Ci-C 6 alkyl, or Ci-C 6 haloalkyl; and R Y is hydrogen, halogen, Ci-C 6 alkyl, or Ci-C 6 haloalkyl.
  • R x is hydrogen; and R Y is hydrogen.
  • a compound of Formula (II) or (Ila) is a single bond; X is CR X1 R X2 ; and Y is CR Y1 R Y2 . In some embodiments of a compound of Formula (II) or (Ila), is a single bond; X is
  • a compound of Formula (II) or (Ila) is a single bond; X is CR R ; and Y is NR . In some embodiments of a compound of Formula (II) or (Ila), is a single bond; X is NR X3 ; and Y is NR Y3 .
  • R X1 and R X2 are independently hydrogen, halogen, -CN, -OH, -OMe, -NH 2 , d-Q, alkyl, or C C 6 haloalkyl; and R Y1 and R Y2 are independently hydrogen, halogen, -CN, -OH, -OMe, -NH 2 , Ci-C 6 alkyl, or Ci-C 6 haloalkyl.
  • R X1 and R X2 are independently hydrogen, halogen, Ci-C 6 alkyl, or Ci-C 6 haloalkyl; and R Y1 and R Y2 are independently hydrogen, halogen, Ci-C 6 alkyl, or Ci-C 6 haloalkyl.
  • R X1 and R X2 are hydrogen;
  • Yl Y2 Y3 and R and R are hydrogen.
  • R and R are independently hydrogen, Ci-C 6 alkyl, or Ci-C 6 haloalkyl.
  • R X3 and R Y3 are independently hydrog en or alkyl.
  • Ring A is
  • each R a and R b are
  • R a and R b are taken together with the nitrogen atom to which they are attached to form an optionally substituted heterocycloalkyl.
  • each R c is optionally substituted Ci-C 6 alkyl.
  • heterocycloalkyl optionally substituted (Ci-C 6 alkyl)heterocycloalkyl, optionally substituted aryl, optionally substituted (Ci-C 6 alkyl)aryl, optionally substituted heteroaryl, or optionally substituted (Ci-C 6 alkyl)heteroaryl;
  • Ci-C 6 alkyl optionally substituted Ci-C 6 heteroalkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted cycloalkyl, optionally substituted (Ci-C 6 alkyl)cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted (Ci-C 6 alkyl)heterocycloalkyl, optionally substituted aryl, optionally substituted (Ci-C ⁇ 5 alkyl)aryl, optionally substituted heteroaryl, or optionally substituted (Ci-C 6 alkyl)heteroaryl;
  • each R a and R b are independently hydrogen, optionally substituted Ci-C 6 alkyl, optionally
  • substituted C 2 -C 6 alkenyl optionally substituted C 2 -C 6 alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
  • R a and R b are taken together with the nitrogen atom to which they are attached to form an optionally substituted heterocycloalkyl
  • each R c is optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; and n2 is 1-3.
  • heterocycloalkyl optionally substituted (Ci-C 6 alkyl)heterocycloalkyl, optionally substituted aryl, optionally substituted (Ci-C 6 alkyl)aryl, optionally substituted heteroaryl, or optionally substituted (Ci-C 6 alkyl)heteroaryl;
  • Ci-C 6 alkyl optionally substituted Ci-C 6 heteroalkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted cycloalkyl, optionally substituted (Ci-C 6 alkyl)cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted (Ci-C 6 alkyl)heterocycloalkyl, optionally substituted aryl, optionally substituted (Ci-C ⁇ 5 alkyl)aryl, optionally substituted heteroaryl, or optionally substituted (Ci-C 6 alkyl)heteroaryl;
  • each R a and R b are independently hydrogen, optionally substituted Ci-C 6 alkyl, optionally
  • substituted C 2 -C 6 alkenyl optionally substituted C 2 -C 6 alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
  • R a and R b are taken together with the nitrogen atom to which they are attached to form an optionally substituted heterocycloalkyl; each R c is optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; and n2 is 1-3.
  • n2 is 1. In some embodiments of a compound of Formula (III) or (III'), n2 is 2. In some embodiments of a compound of Formula (III) or ( ⁇ ), ⁇ 2 is 3.
  • each R 21 is independently hydrogen, halogen, -CN, -OH, -OMe, -NH 2 , Ci-C 6 alkyl, or Ci-C 6 haloalkyl; and n2 is 1 or 2.
  • each R 21 is independently hydrogen, halogen, Ci- C 6 alkyl, or Ci-C 6 haloalkyl; and n2 is 1 or 2.
  • R 21 is halogen, Ci-C 6 alkyl, or Ci-C 6 haloalkyl; and n2 is 1.
  • R 21 is halogen; and n2 is 1.
  • each R 21 is hydrogen.
  • R 23 is optionally substituted Ci- C ⁇ 5 alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl. In some embodiments of a compound of Formula (III) or ( ⁇ ), R 23 is optionally substituted aryl. In some embodiments of a compound of Formula (III) or ( ⁇ ), R 23 is optionally substituted with halogen, -CN, -OH, -OMe, -NH 2 , Ci-C 6 alkyl, or Ci-C 6 haloalkyl.
  • R 23 is optionally substituted with halogen, Ci-C 6 alkyl, or Ci-C 6 haloalkyl. In some embodiments of a compound of Formula (III) or ( ⁇ ), R 23 is unsubstituted aryl or unsusbituted heteroaryl. In some embodiments of a compound of Formula (III) or ( ⁇ ), R 23 is unsubstituted aryl. In some embodiments of a compound of Formula (III) or ( ⁇ ), R 23 is unsubstituted phenyl.
  • R 24 is hydrogen, halogen, -CN, -OH, -OMe, -NH 2 , Ci-C 6 alkyl, or Ci-C 6 haloalkyl. In some embodiments of a compound of Formula (III) or (III'), R 24 is hydrogen, halogen, Ci-C 6 alkyl, or Ci-C 6 haloalkyl. In some embodiments of a compound of Formula (III) or ( ⁇ ), R 24 is hydrogen or halogen. In some embodiments of a compound of Formula (III) or (III'), R 24 is hydrogen.
  • R 25 and R 26 are independently hydrogen, halogen, Ci-C 6 alkyl, or Ci-C 6 haloalkyl. In some embodiments of a compound of Formula (III) or (III ), R 25 and R 26 are independently hydrog en or alkyl.
  • R 27 is hydrogen or Ci-C 6 alkyl. In some embodiments of a compound of Formula (III) or ( ⁇ ), R 27 is hydrogen.
  • the compound is, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: Formula (Ilia).
  • R is halogen, -CN, - OR a , -NR a R b , optionally substituted Ci-C 6 alkyl, optionally substituted Ci-C 6 heteroalkyl, or optionally substituted C 2 -C 6 alkynyl.
  • R 22 is halogen, optionally substituted Ci-C 6 alkyl, or optionally substituted C 2 -C 6 alkynyl.
  • R 22 is halogen. In some embodiments of a compound of Formula (III), ( ⁇ ), or (Ilia), R 22 is fluoro or chloro. In some embodiments of a compound of Formula (III), (IIP), or (Ilia), R 22 is chloro. In some embodiments of a compound of Formula (III), (IIP), or (Ilia), R 22 is Ci-C 6 alkyl or Ci-C 6 haloalkyl. In some embodiments of a compound of Formula (III), (III'), or (Ilia), R 22 is methyl.
  • R 22 is C 2 -C ⁇ 5 alkynyl optionally substituted with optionally substituted Ci-C 6 alkyl, optionally substituted Ci-C ⁇ 5 heteroalkyl, optionally substituted cycloalkyl, optionally substituted (Ci-C 6 alkyl)cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted (Ci-C 6 alkyl)heterocycloalkyl, optionally substituted aryl, optionally substituted (Ci-C 6 alkyl)aryl, optionally substituted heteroaryl, or optionally substituted (Ci-C 6 alkyl)heteroaryl.
  • R 22 is C 2 -C 6 alkynyl optionally substituted with optionally substituted heteroaryl. In some embodiments of a compound of Formula (III), (IIP), or (Ilia), R 22 is C 2 -C 6 alkynyl optionally substituted
  • R 28 is halogen, -CN, - OR a , -NR a R b , optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkynyl, or optionally substituted heteroaryl.
  • R 28 is halogen, -CN, -OMe, -NH 2 , Ci-C 6 alkyl, Ci-C 6 haloalkyl, C 2 -C 6 alkynyl, or heteroaryl.
  • R 28 is halogen.
  • R is hydrogen or optionally substituted Ci-C 6 alkyl.
  • R 29 is d-C 6 alkyl.
  • each R a and R b are independently hydrogen or optionally substituted Ci-C 6 alkyl; or R a and R b are taken together with the nitrogen atom to which they are attached to form an optionally substituted heterocycloalkyl.
  • each R c is optionally substituted Ci-C 6 alkyl.
  • R 32 is optionally substituted Ci-C 6 alkyl, optionally substituted Ci-C 6 heteroalkyl, optionally substituted cycloalkyl, optionally substituted (Ci-C 6 alkyl)cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted (Ci-C 6 alkyl)heterocycloalkyl, optionally substituted aryl, optionally substituted (Ci-C 6 alkyl)aryl, optionally substituted heteroaryl, or optionally substituted (Ci-C 6 alkyl)heteroaryl;
  • Ci-C 6 alkyl optionally substituted Ci-C 6 heteroalkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted cycloalkyl, optionally substituted (Ci-C 6 alkyl)cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted (Ci-C 6 alkyl)heterocycloalkyl, optionally substituted aryl, optionally substituted (Ci-C ⁇ 5 alkyl)aryl, optionally substituted heteroaryl, or optionally substituted (Ci-C 6 alkyl)heteroaryl;
  • Ring B is an optionally substituted 5-membered heteroaryl
  • each R a and R b are independently hydrogen, optionally substituted Ci-C 6 alkyl, optionally
  • substituted C 2 -C 6 alkenyl optionally substituted C 2 -C 6 alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
  • R a and R b are taken together with the nitrogen atom to which they are attached to form an optionally substituted heterocycloalkyl
  • each R c is optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; and n3 is 1-3.
  • n3 is 1. In some embodiments of a compound of Formula (IV), n3 is 2. In some embodiments of a compound of Formula (IV), n3 is 3.
  • each R 31 is independently hydrogen, halogen, -CN, -OH, -OMe, -NH 2 , Ci-C 6 alkyl, or Ci-C 6 haloalkyl; and n3 is 1 or 2.
  • each R 31 is independently hydrogen, halogen, Ci-C 6 alkyl, or Ci-C 6 haloalkyl; and n3 is 1 or 2.
  • R 31 is halogen, Ci-C 6 alkyl, or Ci-C 6 haloalkyl; and n3 is 1.
  • R 31 is halogen; and n is 1.
  • each R 31 is hydrogen.
  • R 33 is optionally substituted Ci-Cg alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl. In some embodiments of a compound of Formula (IV), R 33 is optionally substituted aryl. In some embodiments of a compound of Formula (IV), R 33 is optionally substituted with halogen, -CN, -OH, -OMe, -NH 2 , Ci-C 6 alkyl, or Ci-C 6 haloalkyl.
  • R 33 is optionally substituted with halogen, Ci-C 6 alkyl, or Ci-C 6 haloalkyl. In some embodiments of a compound of Formula (IV), R 33 is unsubstituted aryl or unsusbituted heteroaryl. In some embodiments of a compound of Formula (IV), R 33 is unsubstituted aryl. In some embodiments of a compound of Formula (IV), R 33 is unsubstituted phenyl.
  • R 34 is hydrogen, halogen, -CN, -OH, - OMe, -NH 2 , Ci-C ⁇ 5 alkyl, or Ci-C 6 haloalkyl. In some embodiments of a compound of Formula (IV), R 34 is hydrogen, halogen, Ci-C 6 alkyl, or Ci-C 6 haloalkyl. In some embodiments of a compound of Formula (IV), R 34 is hydro gen or halogen. In some embodiments of a compound of Formula (IV), R 34 is hydrogen.
  • R 35 and R 36 are independently hydrogen, halogen, Ci-C 6 alkyl, or Ci-C 6 haloalkyl. In some embodiments of a compound of Formula (IV), R 35 and R 36 are independently hydrog en or Ci-C6 alkyl.
  • R 37 is hydrogen or Ci-C 6 alkyl. In some embodiments of a compound of Formula (IV), R 37 is hydrogen.
  • the compound is of Formula (IVa), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
  • R is optionally substituted heterocycloalkyl or optionally substituted heteroaryl.
  • R 32 is optionally substituted heteroaryl.
  • R 32 is an optionally substituted 5-membered heteroaryl.
  • R 32 is a 5-membered heteroaryl optionally substituted with halogen, -CN, -OH, -OMe, -NH 2 , Ci-C 6 alkyl, or Ci-C 6 haloalkyl.
  • R 32 is
  • Ring B is selected from optionally substituted: pyrrole, thiophene, furan, imidazole, pyrazole, thiazole, isothiazole, oxazole, isoxazole, triazole, and tetrazole. In some embodiments of a compound of Formula (IV) or Formula (IVa), Ring B is optionally substituted pyrazole.
  • Ring B is optionally substituted with halogen, -CN, -OR a , -NR a R b , optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkynyl, or optionally substituted heteroaryl.
  • Ring B is optionally substituted with halogen, -CN, -OMe, -NH 2 , Ci-C 6 alkyl, Ci-C 6 haloalkyl, C 2 -C 6 alkynyl, or heteroaryl.
  • Ring B is
  • R 38 is halogen, -CN, -OR a , -NR a R b , optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkynyl, or optionally substituted heteroaryl.
  • R 38 is halogen, -CN, -OMe, -NH 2 , Ci-C 6 alkyl, Ci-C 6 haloalkyl, C 2 -C 6 alkynyl, or heteroaryl.
  • R 38 is halogen.
  • R 39 is hydrogen or optionally substituted Ci-C 6 alkyl. In some embodiments of a compound of Formula (IV) or Formula (IVa), R 39 is d-C 6 alkyl.
  • each R a and R b are independently hydrogen or optionally substituted Ci-C 6 alkyl; or R a and R b are taken together with the nitrogen atom to which they are attached to form an optionally substituted heterocycloalkyl.
  • each R c is optionally substituted Ci-C 6 alkyl.
  • the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein possess one or more double bonds. The compounds presented herein include all cis, trans, syn, anti,
  • Z isomers as well as the corresponding mixtures thereof. In some situations, the compounds described herein possess one or more chiral centers and each center exists in the R configuration, or S configuration. The compounds described herein include all diastereomeric, enantiomeric, and epimeric forms as well as the corresponding mixtures thereof.
  • mixtures of enantiomers and/or diastereoisomers, resulting from a single preparative step, combination, or interconversion are useful for the applications described herein.
  • the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers and recovering the optically pure enantiomers.
  • dissociable complexes are preferred.
  • the diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and are separated by taking advantage of these dissimilarities.
  • the diastereomers are separated by chiral chromatography, or preferably, by separation/resolution techniques based upon differences in solubility.
  • the optically pure enantiomer is then recovered, along with the resolving agent. Labeled compounds
  • the compounds described herein exist in their isotopically-labeled forms.
  • the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds.
  • the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds as pharmaceutical compositions.
  • the compounds disclosed herein include isotopically-labeled compounds, which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes that can be incorporated into compounds of Formula (I), (la), (II), (Ila), ( ⁇ '), (III), (Ilia), (IV), or (IVa), or a solvate, or stereoisomer thereof, include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, and chloride, such as 2 H, 3 ⁇ 4, 1 C, 14 C, 15 N, 18 0, 17 0, 1 P, 2 P, 5 S, 18 F, and 6 C1, respectively.
  • isotopically-labeled compounds for example those into which radioactive isotopes such as H and 14 C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., H and carbon-14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavy isotopes such as deuterium, / ' . e.
  • the isotopically labeled compound or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is prepared by any suitable method.
  • the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.
  • the compounds described herein exist as their pharmaceutically acceptable salts.
  • the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts.
  • the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions.
  • the compounds described herein possess acidic or basic groups and therefor react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt.
  • these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein, or by separately reacting a purified compound in its free form with a suitable acid or base, and isolating the salt thus formed.
  • Examples of pharmaceutically acceptable salts include those salts prepared by reaction of the compounds described herein with a mineral, organic acid, or inorganic base, such salts including acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyn-l,4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne-l,6-dioate
  • the compounds described herein can be prepared as pharmaceutically acceptable salts formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, including, but not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid metaphosphoric acid, and the like; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-
  • those compounds described herein which comprise a free acid group react with a suitable base, such as the hydroxide, carbonate, bicarbonate, sulfate, of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine.
  • a suitable base such as the hydroxide, carbonate, bicarbonate, sulfate, of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine.
  • Representative salts include the alkali or alkaline earth salts, like lithium, sodium, potassium, calcium, and magnesium, and aluminum salts and the like.
  • bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N + (Ci_ 4 alkyl) 4 , and the like.
  • Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like. It should be understood that the compounds described herein also include the quaternization of any basic nitrogen-containing groups they contain. In some embodiments, water or oil-soluble or dispersible products are obtained by such quaternization.
  • the compounds described herein exist as solvates.
  • the invention provides for methods of treating diseases by administering such solvates.
  • the invention further provides for methods of treating diseases by administering such solvates as pharmaceutical compositions.
  • Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and, in some embodiments, are formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein can be conveniently prepared or formed during the processes described herein. By way of example only, hydrates of the compounds described herein can be conveniently prepared by recrystallization from an aqueous/organic solvent mixture, using organic solvents including, but not limited to, dioxane, tetrahydrofuran, or methanol. In addition, the compounds provided herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.
  • Suitable reference books and treatise that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation include for example, “Synthetic Organic Chemistry”, John Wiley & Sons, Inc., New York; S. R. Sandler et al, "Organic Functional Group Preparations,” 2nd Ed., Academic Press, New York, 1983; H. O. House, “Modern Synthetic Reactions", 2nd Ed., W. A. Benjamin, Inc. Menlo Park, Calif. 1972; T. L. Gilchrist, "Heterocyclic Chemistry", 2nd Ed., John Wiley & Sons, New York, 1992; J.
  • the compound of Formula (I), (la), (II), (Ila), ( ⁇ '), (III), (Ilia), (IV), or (rVa) as described herein is administered as a pure chemical.
  • the compound of Formula (I), (la), (II), (Ila), (IIP), (III), (Ilia), (IV), or (IVa) described herein is combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, physiologically suitable (or acceptable) excipient, or physiologically suitable (or acceptable) carrier) selected on the basis of a chosen route of administration and standard pharmaceutical practice as described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21 st Ed. Mack Pub. Co., Easton, PA (2005)).
  • a pharmaceutical composition comprising a compound of Formula (I), (la), (II), (Ila), ( ⁇ ), (III), (Ilia), (IV), or (IVa) described herein, or a pharmaceutically acceptable salt, solvate, or steroisomer thereof, and a pharmaceutically acceptable excipient.
  • the compound of Formula (I), (la), (II), (Ila), ( ⁇ '), (III), (Ilia), (IV), or (IVa) provided herein is substantially pure, in that it contains less than about 5%, or less than about 1%, or less than about 0.1%, of other organic small molecules, such as unreacted intermediates or synthesis by-products that are created, for example, in one or more of the steps of a synthesis method.
  • compositions are administered in a manner appropriate to the disease to be treated (or prevented).
  • An appropriate dose and a suitable duration and frequency of administration will be determined by such factors as the condition of the patient, the type and severity of the patient's disease, the particular form of the active ingredient, and the method of administration.
  • an appropriate dose and treatment regimen provides the composition(s) in an amount sufficient to provide therapeutic and/or prophylactic benefit (e.g., an improved clinical outcome, such as more frequent complete or partial remissions, or longer disease-free and/or overall survival, or a lessening of symptom severity.
  • Optimal doses are generally determined using experimental models and/or clinical trials. The optimal dose depends upon the body mass, weight, or blood volume of the patient.
  • the pharmaceutical composition is formulated for oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, intrapulmonary, intradermal, intrathecal and epidural and intranasal administration.
  • Parenteral administration includes intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration.
  • Suitable doses and dosage regimens are determined by conventional range-finding techniques known to those of ordinary skill in the art. Generally, treatment is initiated with smaller dosages that are less than the optimum dose of the compound disclosed herein. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached. In some embodiments, the present method involve the administration of about 0.1 ⁇ g to about 50 mg of at least one compound of the invention per kg body weight of the subject. For a 70 kg patient, dosages of from about 10 ⁇ g to about 200 mg of the compound disclosed herein would be more commonly used, depending on a subject's physiological response.
  • the dose of the compound described herein for methods of treating a disease as described herein is about 0.001 to about 1 mg/kg body weight of the subject per day, for example, about 0.001 mg, about 0.002 mg, about 0.005 mg, about 0.010 mg, 0.015 mg, about 0.020 mg, about 0.025 mg, about 0.050 mg, about 0.075 mg, about 0.1 mg, about 0.15 mg, about 0.2 mg, about 0.25 mg, about 0.5 mg, about 0.75 mg, or about 1 mg/kg body weight per day.
  • the dose of compound described herein for the described methods is about 1 to about 1000 mg/kg body weight of the subject being treated per day, for example, about 1 mg, about 2 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 500 mg, about 750 mg, or about 1000 mg per day.
  • the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or steroisomer thereof are useful as inhibitors of PI3 Kinase and, therefore, useful in the treatment of diseases or disorders in which it is believed PI3 Kinase activity plays a role.
  • the disease or disorder is cancer.
  • the disease or disorder is an inflammatory disease.
  • the disease or disorder is a cardiovascular disease.
  • PI3K associated disease or disorder in a subject in need thereof comprising the step of administering to the subject an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
  • the PI3K associated disease or disorder is selected from inflammatory disease, glomerulonephritis, uveitis, hepatic diseases or disorders, renal diseases or disorders, chronic obstructive pulmonary disease, rheumatoid arthritis, inflammatory bowel disease, vasculitis, dermatitis, osteoarthritis, inflammatory muscle disease, allergic rhinitis, vaginitis, interstitial cystitis, scleroderma, osteoporosis, eczema, allogeneic or xenogeneic transplantation, graft rejection, graft-versus-host disease, lupus erythematosus, pulmonary fibrosis, dermatomyositis, thyroiditis, myasthenia gravis, autoimmune hemolytic anemia, cystic fibrosis, chronic relapsing hepatitis, primary biliary cirrhosis, allergic conjunctivitis, hepatitis, hepatitis
  • the cancer is chemoresistant cancer, radio resistant cancer, anti-hormonal therapy resistant cancer, or treatment refractory cancer.
  • the cancer is relapsed cancer, persistent cancer, or recurrent cancer.
  • Another embodiment provided herein describes a method of reducing incidences of cancer recurrence.
  • a method for treating a therapy-resistant cancer is also provided here in some embodiments, is metastasic cancer.
  • the cancer treatable with the methods provided herein includes, but is not limited to, (1) leukemias, including, but not limited to, acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemias such as myeloblastic, promyelocytic, myelomonocytic, monocytic, erythroleukemia leukemias and myelodysplastic syndrome or a symptom thereof (such as anemia, thrombocytopenia, neutropenia, bicytopenia, or pancytopenia), refractory anemia (RA), RA with ringed sideroblasts (RARS), RA with excess blasts (RAEB), RAEB in transformation (RAEB-T), preleukemia, and chronic myelomonocytic leukemia (CMML); (2) chronic leukemias, including, but not limited to, chronic myelocytic (granulocytic) leukemia, chronic lymphocytic leukemia, and chronic lymphocy
  • breast cancer including, but not limited to, adenocarcinoma, lobular (small cell) carcinoma, intraductal carcinoma, medullary breast cancer, mutinous breast cancer, tubular breast cancer, papillary breast cancer, primary cancers, Paget's disease, and inflammatory breast cancer;
  • adrenal cancer including, but not limited to, pheochromocytom and adrenocortical carcinoma;
  • thyroid cancer including, but not limited to, papillary or follicular thyroid cancer, medullary thyroid cancer, and anaplastic thyroid cancer;
  • pancreatic cancer including, but not limited to, insulinoma, gastrinoma, glucagonoma, vipoma, somatostatin -secreting tumor, and carcinoid or islet cell tumor;
  • pituitary cancer including, but limited to, Cu
  • adenocarcinoma adenocarcinoma
  • uterine cancer including, but not limited to, endometrial carcinoma and uterine sarcoma
  • ovarian cancer including, but not limited to, ovarian epithelial carcinoma, borderline tumor, germ cell tumor, and stromal tumor
  • esophageal cancer including, but not limited to, squamous cancer, adenocarcinoma, adenoid cystic carcinoma, mucoepidermoid carcinoma,
  • stomach cancer including, but not limited to, adenocarcinoma, fungating
  • lung cancer including, but not limited to, non-small cell lung cancer, squamous cell carcinoma (epidermoid carcinoma), adenocarcinoma, large-cell carcinoma, and small-cell lung cancer; (31) testicular cancer, including, but not limited to, germinal tumor, seminoma, anaplastic, classic (typical), spermatocytic, nonseminoma, embryonal carcinoma, teratoma carcinoma, and chori
  • the cancer treatable with the methods provided herein is a hematological malignancy.
  • the hematological malignancy is a T-cell malignancy.
  • T-cell malignancies include peripheral T-cell lymphoma not otherwise specified (PTCL- NOS), anaplastic large cell lymphoma, angioimmunoblastic lymphoma, cutaneous T-cell lymphoma, adult T-cell leukemia/lymphoma (ATLL), blastic NK-cell lymphoma, enteropathy -type T-cell lymphoma, hematosplenic gamma-delta T-cell lymphoma, lymphoblastic lymphoma, nasal NK/T-cell lymphomas, or treatment-related T-cell lymphomas.
  • PTCL- NOS peripheral T-cell lymphoma not otherwise specified
  • anaplastic large cell lymphoma angioimmunoblastic lymphoma
  • ATLL adult T-cell leukemia/lymphoma
  • the hematological malignancy is a B-cell malignancy.
  • B-cell malignancies include acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), acute monocytic leukemia (AMoL), chronic lymphocytic leukemia (CLL), high-risk chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), high-risk small lymphocytic lymphoma (SLL), follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), Waldenstrom's macroglobulinemia, multiple myeloma, extranodal marginal zone B cell lymphoma, nodal marginal zone B cell lymphoma, Burkitfs lymphoma, non-Burkitt high grade B cell lymphoma,
  • ALL acute lymphoblastic leukemia
  • the B-cell malignancy is diffuse large B-cell lymphoma (DLBCL).
  • the DLBCL is an activated B-cell DLBCL (ABC-DLBCL), a germinal center B-cell like DLBCL (GBC-DLBCL), a double hit DLBCL (DH-DLBCL), or a triple hit DLBCL (TH-DLBCL).
  • the cancer is selected from a hematological cancer, a solid tumor cancer, hematopoietic tumors of lymphoid lineage, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, hairy cell lymphoma, Burkett's lymphoma, hematopoietic tumors of myeloid lineage, bladder cancer, breast cancer, colon cancer, kidney cancer, liver cancer, lung cancer, small cell lung cancer, esophageal cancer, gall bladder cancer, ovarian cancer, pancreatic cancer, stomach cancer, cervical cancer, thyroid cancer, prostate cancer, skin cancer, squamous cell carcinoma, tumors of mesenchymal origin, fibrosarcoma, rhabdomyosarcoma, tumors of the central and peripheral nervous system, astrocytoma, neuroblastoma, glioma, schwannoma, melanoma, seminoma, teratocarcinoma,
  • the cancer is a hematological cancer selected from chronic lymphocytic leukemia (CLL) and multiple myeloma (MM).
  • the cancer is a solid tumor cancer selected from lung cancer, breast cancer, colon cancer, prostate cancer, pancreatic cancer, and glioblastoma.
  • Exemplary inflammatory diseases include, but are not limited to, inflammation associated with acne, anemia (e.g., aplastic anemia, haemolytic autoimmune anaemia), asthma, arteritis (e.g., polyarteritis, temporal arteritis, periarteritis nodosa, Takayasu's arteritis), arthritis (e.g., crystalline arthritis, osteoarthritis, psoriatic arthritis, gout flare, gouty arthritis, reactive arthritis, rheumatoid arthritis and Reiter's arthritis), ankylosing spondylitis, amylosis, amyotrophic lateral sclerosis, autoimmune diseases, allergies or allergic reactions, atherosclerosis, bronchitis, bursitis, chronic prostatitis, conjunctivitis, Chagas disease, chronic obstructive pulmonary disease, cermatomyositis, diverticulitis, diabetes (e.g., type I diabetes mell
  • GORD gastroesophageal reflux disease
  • IBD inflammatory bowel disease
  • IBS inflammatory bowel syndrome
  • lupus multiple sclerosis, morphea, myeasthenia gravis, myocardial ischemia, nephrotic syndrome, pemphigus vulgaris, pernicious aneaemia, peptic ulcers, polymyositis, primary biliary cirrhosis, neuroinflammation associated with brain disorders (e.g., Parkinson's disease, Huntington's disease, and Alzheimer's disease), prostatitis, chronic bowel disease (IBD) (e.g., Crohn's disease, ulcerative colitis, collagenous colitis, lymphocytic colitis, ischaemic colitis, diversion colitis, Behcet's syndrome, indeterminate colitis) and inflammatory bowel syndrome (IBS)), lupus, multiple sclerosis, morphea, myeasthenia gravis, myocardial ischemia, nephrotic syndrome,
  • trauma or injury e.g., frostbite, chemical irritants, toxins, scarring, burns, physical injury
  • vasculitis vitiligo and Wegener's granulomatosis.
  • the inflammatory disorder is selected from arthritis (e.g., rheumatoid arthritis), inflammatory bowel disease, inflammatory bowel syndrome, asthma, psoriasis, endometriosis, interstitial cystitis and prostatistis.
  • the inflammatory condition is an acute inflammatory condition (e.g., for example, inflammation resulting from infection).
  • the inflammatory condition is a chronic inflammatory condition (e.g., conditions resulting from asthma, arthritis and inflammatory bowel disease).
  • the compounds disclosed herein are also useful in treating inflammation associated with trauma and non-inflammatory myalgia.
  • the inflammatory disease is selected from chronic obstructive pulmonary disease (COPD), asthma, hypoxia-induced inflammation, rheumatoid arthritis, chronic bronchitis, atopic dermatitis, inflammatory bowel disease, allergic rhinitis, and ulcerative colitis.
  • COPD chronic obstructive pulmonary disease
  • asthma hypoxia-induced inflammation
  • rheumatoid arthritis chronic bronchitis
  • atopic dermatitis inflammatory bowel disease
  • allergic rhinitis allergic rhinitis
  • ulcerative colitis ulcerative colitis
  • PI3K associated disease or disorder that is a cardiovascular disease in a subject in need thereof, comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
  • Exemplary cardiovascular diseases include, but are not limited to, atherosclerosis, stenosis, restenosis, hypertension, pulmonary arterial hypertension (PAH), heart failure, left ventricular hypertrophy (LVH), myocardial infarction, acute coronary syndrome, stroke, transient ischemic attack, impaired circulation, heart disease, cholesterol and plaque formation, ischemia, ischemia reperfusion injury, peripheral vascular disease, myocardial infection, cardiac disease (e.g, risk stratification of chest pain and interventional procedures), cardiopulmonary resuscitation, kidney failure, thrombosis (e.g., venous thrombosis, deep vein thrombosis, portal vein thrombosis, renal vein thrombosis, jugular vein thrombosis, cerebral venous sinus thrombosis, arterial thrombosis, etc.), thrombus formation, thrombotic event or complication, Budd-Chiari syndrome, Paget-Schroetter disease, coronary heart disease, coronary heart disease
  • cerebrovascular disease or any other cardiovascular disease related to obesity or an overweight condition.
  • the cardiovascular disease is selected from hypertension and pulmonary arterial hypertension (PAH).
  • PAH pulmonary arterial hypertension
  • the compound of Formula (I), (la), (II), (Ila), (IIP), (HI), (IHa), (IV), or (rVa), or a pharmaceutically acceptable salt, solvate, or steroisomer thereof, is administered in combination with a second therapeutic agent.
  • the benefit experienced by a patient is increased by administering one of the compounds described herein with a second therapeutic agent (which also includes a therapeutic regimen) that also has therapeutic benefit.
  • a compound of Formula (I), (la), (II), (Ila), (IIP), (HI), (IHa), (IV), or (rVa), or a pharmaceutically acceptable salt, solvate, or steroisomer thereof is co-administered with a second therapeutic agent, wherein the compound of Formula (I), (la), (II), (Ila), ( ⁇ ), (HI), (Ilia), (IV), or (IVa), or a pharmaceutically acceptable salt, solvate, or steroisomer thereof, and the second therapeutic agent modulate different aspects of the disease, disorder or condition being treated, thereby providing a greater overall benefit than administration of either therapeutic agent alone.
  • different therapeutically -effective dosages of the compounds disclosed herein will be utilized in formulating a pharmaceutical composition and/or in treatment regimens when the compounds disclosed herein are administered in combination with a second therapeutic agent.
  • Therapeutically-effective dosages of drugs and other agents for use in combination treatment regimens are optionally determined by means similar to those set forth hereinabove for the actives themselves.
  • the methods of prevention/treatment described herein encompasses the use of metronomic dosing, i.e., providing more frequent, lower doses in order to minimize toxic side effects.
  • a combination treatment regimen encompasses treatment regimens in which administration of a compound of Formula (I), (la), (II), (Ila), ( ⁇ ), (HI), (Ilia), (IV), or (IVa), or a pharmaceutically acceptable salt, solvate, or steroisomer thereof, is initiated prior to, during, or after treatment with a second agent described herein, and continues until any time during treatment with the second agent or after termination of treatment with the second agent.
  • Combination treatment further includes periodic treatments that start and stop at various times to assist with the clinical management of the patient.
  • the dosage regimen to treat, prevent, or ameliorate the condition(s) for which relief is sought is modified in accordance with a variety of factors (e.g. the disease, disorder or condition from which the subject suffers; the age, weight, sex, diet, and medical condition of the subject).
  • factors e.g. the disease, disorder or condition from which the subject suffers; the age, weight, sex, diet, and medical condition of the subject.
  • the dosage regimen actually employed varies and, in some embodiments, deviates from the dosage regimens set forth herein.
  • dosages of the co-administered compounds vary depending on the type of co-drug employed, on the specific drug employed, on the disease or condition being treated, and so forth.
  • the compound provided herein when co-administered with a second therapeutic agent, is administered either simultaneously with the second therapeutic agent, or sequentially.
  • the multiple therapeutic agents are administered in any order or even simultaneously. If administration is simultaneous, the multiple therapeutic agents are, by way of example only, provided in a single, unified form, or in multiple forms (e.g., as a single pill or as two separate pills).
  • the compounds described herein are used as a prophylactic and are administered continuously to subjects with a propensity to develop conditions or diseases in order to prevent the occurrence of the disease or condition.
  • the compounds and compositions are administered to a subject during or as soon as possible after the onset of the symptoms.
  • a compound described herein is administered as soon as is practicable after the onset of a disease or condition is detected or suspected, and for a length of time necessary for the treatment of the disease.
  • the length required for treatment varies, and the treatment length is adjusted to suit the specific needs of each subject.
  • a compound described herein or a formulation containing the compound is administered for at least 2 weeks, about 1 month to about 5 years.
  • the second therapeutic agent is an adjuvant. In certain embodiments, the second therapeutic agent is an anti-cancer agent. In certain embodiments, the second therapeutic agent is an antiemetic. In certain embodiments, the second therapeutic agent is an anti -infective agent. In certain embodiments, the second therapeutic agent is an antiviral agent. In certain embodiments, the second therapeutic agent is an antibacterial agent.
  • the compound of Formula (I), (la), (II), (Ila), (IIP), (HI), (IHa), (IV), or (IVa), or a pharmaceutically acceptable salt, solvate, or steroisomer thereof is administered in combination with an adjuvant.
  • an adjuvant i.e., by itself the adjuvant has minimal therapeutic benefit, but in combination with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced.
  • the compound of Formula (I), (la), (II), (Ila), (IIP), (HI), (IHa), (IV), or (IVa), or a pharmaceutically acceptable salt, solvate, or steroisomer thereof is administered in combination with an additional therapeutic agent selected from an anti -cancer agent, an antiinflammatory agent, an immunosuppressive agent, a steroid, a non-steroidal anti-inflammatory agent, an antihistamine, an analgesic, and any combinations.
  • an additional therapeutic agent selected from an anti -cancer agent, an antiinflammatory agent, an immunosuppressive agent, a steroid, a non-steroidal anti-inflammatory agent, an antihistamine, an analgesic, and any combinations.
  • the compound of Formula (I), (la), (II), (Ila), (IIP), (HI), (IHa), (IV), or (rVa), or a pharmaceutically acceptable salt, solvate, or steroisomer thereof, is administered in combination with an anti-cancer agent.
  • the anti -cancer agent is a hormone blocking therapy.
  • Hormone blocking therapy includes the use of agents that block the production of estrogens or block the estrogen receptors.
  • hormone blocking therapy includes the use of estrogen receptor modulators and/aromatase inhibitors.
  • Estrogen receptor modulators include triphenylethylene derivatives (e.g.
  • Aromatase inhibitors include steroidal aromatase inhibitors and non-steroidal aromatase inhibitors. Steroidal aromatase inhibitors include, but are not limited to, exemestane. Non-steroidal aromatase inhibitors include, but are not limited to, anastrozole and letrozole.
  • compounds disclosed herein are used in combination with one or more passive immunotherapies, including but not limited to, naked monoclonal antibody drugs and conjugated monoclonal antibody drugs.
  • naked monoclonal antibody drugs include, but are not limited to, rituximab, an antibody against the CD20 antigen; trastuzumab, an antibody against the HER2 protein; alemtuzumab, an antibody against the CD52 antigen; cetuximab, an antibody against the EGFR protein; and bevacizumab which is an anti-angiogenesis inhibitor of VEGF protein.
  • conjugated monoclonal antibodies include, but are not limited to, radiolabeled antibody ibritumomab tiuxetan; radiolabeled antibody tositumomab; and immunotoxin gemtuzumab ozogamicin which contains calicheamicin; BL22, an anti-CD22 monoclonal antibody-immunotoxin conjugate; radiolabeled antibodies such as OncoScint (Registered trademark) and ProstaScint (Registered trademark) ; brentuximab vedotin; and ado-trastuzumab emtansine.
  • therapeutic antibodies include, but are not limited to, abciximab, an antibody against the glycoprotein Ilb/IIIa receptor on platelets; daclizumab, an immunosuppressive, humanized anti-CD25 monoclonal antibody; edrecolomab , a murine anti-17-IA cell surface antigen IgG2a antibody; BEC2, a murine anti-idiotype (GD3 epitope) IgG antibody; IMC-C225, a chimeric anti-EGFR IgG antibody; VITAXIN (Registered Trademark) a humanized anti-aVbeta 3 integrin antibody; Campath 1H/LDP-03, a humanized anti CD52 IgGl antibody; Smart M195, a humanized anti-CD33 IgG antibody; epratuzumab, a humanized anti-CD22 IgG antibody; Lymphoscan; visilizumab; CM3, a humanized anti-ICAM3
  • the second therapeutic agent for use in combination with a compound of Formula (I), (la), (II), (Ha), ( ⁇ ), (HI), (Ula), (IV), or (IVa), or a pharmaceutically acceptable salt, solvate, or steroisomer thereof include one or more of the following: abiraterone; abarelix; adriamycin; actinomycin; acivicin; aclarubicin; acodazole hydrochloride; acronine; adozelesin; aldesleukin;
  • alemtuzumab allopurinol; alitretinoin; altretamine; ambomycin; ametantrone acetate; aminoglutethimide; aminolevulinic acid; amifostine; amsacrine; anastrozole; anthramycin; aprepitant; arsenic trioxide; asparaginase; asperlin; azacitidine; azetepa; azotomycin; batimastat; bendamustine hydrochloride; benzodepa; bevacizumab; bexarotene; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate; bizelesin; bleomycin; bleomycin sulfate; bortezomib; brequinar sodium; bropirimine;
  • busulfan cactinomycin; calusterone; caracemide; carbetimer; carboplatin; carmustine; carubicin hydrochloride; carzelesin; capecitabine; cedefingol; cetuximab; chlorambucil; cirolemycin; cisplatin; cladribine; clofarabine; crisnatol mesylate; cyclophosphamide; cytarabine; dacarbazine; dasatinib;
  • daunorubicin hydrochloride dactinomycin; darbepoetin alfa; decitabine; degarelix; denileukin diftitox; dexormaplatin; dexrazoxane hydrochloride; dezaguanine; dezaguanine mesylate; diaziquone; docetaxel; doxorubicin; doxorubicin hydrochloride; droloxifene; droloxifene citrate; dromostanolone propionate; duazomycin; edatrexate; eflornithine hydrochloride; elsamitrucin; eltrombopag olamine; enloplatin; enpromate; epipropidine; epirubicin hydrochloride; epoetin alfa; erbulozole; erlotinib hydrochloride; esorubicin hydrochloride; estramustine
  • etoposide phosphate etoprine; everolimus; exemestane; fadrozole hydrochloride; trasrabine; fenretinide; filgrastim; floxuridine; fludarabine phosphate; fluorouracil; fluorocitabine; fosquidone; fostriecin sodium; fulvestrant; gefitinib; gemcitabine; gemcitabine hydrochloride; gemcitabine cisplatin;
  • gemtuzumab ozogamicin goserelin acetate; histrelin acetate; hydroxyurea; idarubicin hydrochloride; ifosfamide; iimofosine; ibritumomab tiuxetan; idarubicin; ifosfamide; imatinib mesylate; imiquimod; interleukin II (including recombinant interleukin II, or rlL2), interferon alfa-2a; interferon alfa-2b; interferon alfa-nl; interferon alfa-n3; interferon beta-la; interferon gamma-lb; iproplatin; irinotecan hydrochloride; ixabepilone; lanreotide acetate; lapatinib; lenalidomide; letrozole; leuprolide acetate; leucovorin calcium; leuprol
  • methotrexate methotrexate; methotrexate sodium; methoxsalen; metoprine; meturedepa; mitindomide; mitocarcin; mitocromin; mitogillin; mitomalcin; mitomycin C; mitosper; mitotane; mitoxantrone hydrochloride; mycophenolic acid; nandrolone phenpropionate; nelarabine; nilotinib; nocodazoie; nofetumomab;
  • palonosetron hydrochloride pamidronate; pegfilgrastim; pemetrexed disodium; pentostatin;
  • talisomycin tamoxifen citrate; tecogalan sodium; tegafur; teloxantrone hydrochloride; temozolomide; temoporfin; temsirolimus; teniposide; teroxirone; testolactone; thalidomide; thiamiprine; thioguanine; thiotepa; tiazofurin; tirapazamine; topotecan hydrochloride; toremifene; tositumomab and I 131 Iodine tositumomab; trastuzumab; trestolone acetate; tretinoin; triciribine phosphate; trimetrexate; trimetrexate glucuronate; triptorelin; tubulozole hydrochloride; uracil mustard; uredepa; valrubicin; vapreotide; verteporfin; vinblastine; vinblastine
  • the second therapeutic agent is an alkylating agent.
  • alkylating agents for use in combination with a compound of Formula (I), (la), (II), (Ha), ( ⁇ ), (HI), (Ilia), (IV), or (IVa), or a pharmaceutically acceptable salt, solvate, or steroisomer thereof, include, but are not limited to, nitrogen mustards (e.g., mechloroethamine, cyclophosphamide, chlorambucil, meiphalan, etc.), ethylenimine and methylmelamines (e.g., hexamethlymelamine, thiotepa), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine, lomusitne, semustine, streptozocin, etc.), or triazenes (decarbazine, etc.).
  • nitrogen mustards e.g., mechloroe
  • platinum coordination complexes e.g., cisplatin, carboblatin
  • anthracenedione e.g., mitoxantrone
  • substituted urea e.g., hydroxyurea
  • methyl hydrazine derivative e.g., procarbazine
  • adrenocortical suppressant e.g., mitotane, aminoglutethimide
  • the second therapeutic agent is an immunotherapy agent.
  • immunotherapy agents for use in combination with a compound of Formula (I), (la), (II), (Ha), ( ⁇ ), (III), (Ilia), (IV), or (IVa), or a pharmaceutically acceptable salt, solvate, or steroisomer thereof, include, but are not limited to, checkpoint inhibitors (e.g. anti-PDl and anti-PD-Ll inhibitors), cancer vaccines (e.g., sipuleucel-T), oncolytic viruses (e.g., talimogene laherparepvec), cytokines (e.g., IL-2 and INF- alpha), CAR-T cells.
  • checkpoint inhibitors e.g. anti-PDl and anti-PD-Ll inhibitors
  • cancer vaccines e.g., sipuleucel-T
  • oncolytic viruses e.g., talimogene laherparepvec
  • cytokines e.g.,
  • a compound of Formula (I), (la), (II), (Ila), (IIP), (HI), (IHa), (IV), or (IVa), or a pharmaceutically acceptable salt, solvate, or steroisomer thereof is used in combination with anti-emetic agents to treat nausea or emesis, which results from the use of a compound of Formula (I), (la), (II), (Ha), ( ⁇ ), (HI), (Ilia), (IV), or (IVa), or a pharmaceutically acceptable salt, solvate, or steroisomer thereof, anti -cancer agent(s) and/or radiation therapy.
  • Anti -emetic agents include, but are not limited to: neurokinin- 1 receptor antagonists, 5HT3 receptor antagonists (such as ondansetron, granisetron, tropisetron, palonosetron, and zatisetron), GABAB receptor agonists (such as baclofen), corticosteroids (such as dexamethasone, prednisone, prednisolone, or others), dopamine antagonists (such as, but not limited to, domperidone, droperidol, haloperidol, chlorpromazine, promethazine,
  • 5HT3 receptor antagonists such as ondansetron, granisetron, tropisetron, palonosetron, and zatisetron
  • GABAB receptor agonists such as baclofen
  • corticosteroids such as dexamethasone, prednisone, prednisolone, or others
  • dopamine antagonists such as, but not limited to, domperi
  • prochlorperazine, metoclopramide antihistamines (HI histamine receptor antagonists, such as but not limited to, cyclizine, diphenhydramine, dimenhydrinate, meclizine, promethazine, hydroxyzine), cannabinoids (such as but not limited to, cannabis, marinol, dronabinol), and others (such as, but not limited to, trimethobenzamide; ginger, emetrol, propofol).
  • a compound of Formula (I), (la), (II), (Ila), (IIP), (HI), (IHa), (IV), or (IVa), or a pharmaceutically acceptable salt, solvate, or steroisomer thereof is used in combination with an agent useful in the treatment of anemia.
  • an agent useful in the treatment of anemia is, for example, a continuous eythropoiesis receptor activator (such as epoetin-a).
  • a compound of Formula (I), (la), (II), (Ila), (IIP), (HI), (IHa), (IV), or (IVa), or a pharmaceutically acceptable salt, solvate, or steroisomer thereof is used in combination with an agent useful in the treatment of neutropenia.
  • agents useful in the treatment of neutropenia include, but are not limited to, a hematopoietic growth factor which regulates the production and function of neutrophils such as a human granulocyte colony stimulating factor, (G-CSF).
  • G-CSF human granulocyte colony stimulating factor
  • Examples of a G-CSF include filgrastim.
  • a compound of Formula (I), (la), (II), (Ila), ( ⁇ '), (III), (Ilia), (IV), or (IVa), or a pharmaceutically acceptable salt, solvate, or steroisomer thereof is administered to a mammal in combination with a non-steroidal anti -inflammatory drug (NSAID).
  • NSAID non-steroidal anti -inflammatory drug
  • NSAIDs include, but are not limited to: aspirin, salicylic acid, gentisic acid, choline magnesium salicylate, choline salicylate, choline magnesium salicylate, choline salicylate, magnesium salicylate, sodium salicylate, diflunisal, carprofen, fenoprofen, fenoprofen calcium, fluorobiprofen, ibuprofen, ketoprofen, nabutone, ketolorac, ketorolac tromethamine, naproxen, oxaprozin, diclofenac, etodolac, indomethacin, sulindac, tolmetin,
  • meclofenamate meclofenamate sodium, mefenamic acid, piroxicam, meloxicam, COX-2 specific inhibitors (such as, but not limited to, celecoxib, rofecoxib, valdecoxib, parecoxib, etoricoxib, lumiracoxib, CS-502, JTE-522, L-745 337, and NS398).
  • COX-2 specific inhibitors such as, but not limited to, celecoxib, rofecoxib, valdecoxib, parecoxib, etoricoxib, lumiracoxib, CS-502, JTE-522, L-745 337, and NS398).
  • a compound of Formula (I), (la), (II), (Ila), (IIP), (III), (Ilia), (IV), or (IVa), or a pharmaceutically acceptable salt, solvate, or steroisomer thereof is used in combination with radiation therapy (or radiotherapy).
  • Radiation therapy is the treatment of cancer and other diseases with ionizing radiation.
  • Radiation therapy is optionally used to treat localized solid tumors, such as cancers of the skin, tongue, larynx, brain, breast, prostate, colon, uterus, and/or cervix. It is also optionally used to treat leukemia and lymphoma (cancers of the blood-forming cells and lymphatic system, respectively).
  • Example 1 General Procedure for synthesis of (S)-3-amino-5-iodo-l-methyl-N-(l-(8-((l-methyl- lH-pyrazol-4-yl)ethynyl)-l-oxo-2-phenyl-l,2-dihydroisoquinolin-3-yl)ethyl)-lH-pyrazole-4- carboxamide
  • Example la (cas: 105-56-6,10 mL, 0.10 mol) and Example lb (cas: 545-06-2, 27 g, 0.19 mol) in EtOH (36 mL) was added TEA (7 mL, 0.01 mmol) at 0°C and the mixture was stirred from 0°C to r.t. for 2 hours.
  • TEA 7 mL, 0.01 mmol
  • Example lc (20 g, 77.8 mmol) and Example Id (8.9 g, 77.8 mmol) in DMF (350 mL) was stirred at 100°C for 2 hours. The mixture was diluted with water and extracted by DCM (500 mL*2). The combined organic phase was washed with brine, dried over Na 2 S0 4 , filtrated and concentrated under reduced pressure. The residue was purified by silica gel chromatography
  • Example le 500 mg, 2.7 mmol
  • CELL 790 mg, 3.0 mmol
  • isopentyl nitrite 630 mg, 5.4 mmol
  • MeCN MeCN
  • Example lg 145 mg, 0.5 mmol
  • HOBt 34 mg, 0.3 mmol
  • EDCI 144 mg, 0.8 mmol
  • TEA 152 mg, 1.5 mmol
  • DCM 3mL
  • Example lh 184 mg, 0.5 mmol
  • the mixture was diluted with water and extracted by DCM (100 mL*2).
  • the combined organic phase was washed with brine, dried over Na 2 S0 4 , filtrated and concentrated under reduced pressure.
  • Example 2a To a solution of Example 2a ( 17.0 g, 100 mmol) and DMF (0.3 g, 5 mmol) in DCM (100 mL) was added oxalyl dichloride (9.3 mL, 1 10 mmol) dropwise. The mixture was stirred at room temperature for 2 hours. The mixture was then concentrated in vacuo, and the residue was dissolved in DCM ( 10 mL) and the resulting solution was used directly in the next step.
  • oxalyl dichloride 9.3 mL, 1 10 mmol
  • Example 2b Under an inert atmosphere, to a mixture of Example 2b (13.7 g, 55.9 mmol) in THF (100 inL) was added «-BuLi (2.5 mol/L, 44.7 mL, 1 1 1.8 mmoL) dropwise over 30 min at -30°C, which was stirred at room temperature for 1 hour. The resulting solution was used for next step directly.
  • Example 2c cas: 87694-49-3, 19.5 g, 83.9 mmol
  • THF 100 mL
  • z-PrMgCl 1 mol/L, 92.2 mL, 92.2 mmol
  • Example 2e To a solution of Example 2e (312 mg, 2.0 mmol), HATU (760 mg, 2.0 mmol) and TEA (404 mg, 4.0 mmol) in DCM (20 mL) was added Example 2d (596 mg, 2.0 mmol). The mixture was stirred at room temperature for 2 hours. The mixture was diluted with water, and extracted with DCM. The organic layers were combined and concentrated. The residue was purified by silica gel chromatography
  • Example le 1.0 g, 5.4 mmol
  • dioxane 15 mL
  • 1M LiOH 1M LiOH
  • the resulting mixture was heated at 70°C for overnight, which was then concentrated.
  • the pH of the residue was adjusted to 5-6, and the precipitate was filtered to afford the crude product Example 2e (540 mg, yield 64%) as a dark red solid.
  • Example 2i (cas: 39806-90-1, 15.0 g, 72.1 mmol), PPh 3 (3.8 g, 14.4 mmol), Cul(0.9 g, 4.8 mmol), Pd(OAc) 2 (1.06 g, 4.8 mmol) and DIPEA (13 mL, 95.2 mmol) in DMF (100 mL) was injected Example 2j (cas: 1066-54-2, 10.6 g, 108.2 mmol) under N 2 atmosphere. The resulting mixture was stirred at 60°C for 1.5 hours. After cooling, H 2 0 (1 L) was added to the mixture, which was extracted with EtOAc (500 mL*2).
  • Example 2g 50 mg, 0.11 mmol
  • Example 2h 14mg, 0.13 mmol
  • Pd(CH 3 CN) 2 Cl 2 3 mg, 0.011 mmol
  • Cs 2 CO 3 107 mg, 0.33 mmol
  • Xphos(16 mg, 0.033 mmol) in CH 3 CN(1 mL) was stirred at 85°C for 2 hours. The mixture was filtered and the filtrate was concentrated.
  • Example 2d A mixture of Example 2d (4.5 g, 15.1 mmol),di-tert-butyl dicarbonate (3.6 g, 16.6 mmol) and TEA (3.1 g, 30.2 mmol) in DCM (45 mL) was stirred at ambient temperature for 16 hours. Water was added, and the mixture was extracted with DCM (50 mL*3). The combined organic layers were dried over Na 2 S0 4 , filtered and concentrated to give crude product Example 4a (5.6 g, yield93 %) as a white solid.
  • LC-MS [M+ l] + 399.0
  • Example 4a 1.0 g, 2.5 mmol
  • Example 2h 320 mg, 3.0 mmol
  • Pd(CH 3 CN) 2 Cl 2 65 mg, 0.25 mmol
  • Cs 2 C0 3 2.5 g, 7.5 mmol
  • Xphos 360 mg, 0.75 mmol
  • CH 3 CN 15 mL
  • the mixture was filtered and the filtrate was concentrated.
  • LC-MS: [M+l] + 469.0 Step 3: Example lh
  • Example 4d (10 g, 64.5 mmol) was dissolved into AcCl (40 mL) at 0°C, and the mixture was stirred at reflux for 4 hours. The reaction was cooled to r.t., diluted with ice water and stirred at r.t. for another 16 hours. The mixture was filtered and dried to give the desired product Example 4e (11 g, yield 86%) as a white solid.
  • LC-MS [M+l] + 275.9/277.9
  • Example 4c 80mg, 0.36 mmol in DMF were added HOBt (25 mg, 0.18 mmol), EDCI (105 mg, 0.55 mmol) and TEA (110 mg, 1.09 mmol). The mixture was stirred at ambient temperature for 30 min. Then, Example lh (150mg, 0.40 mmol) was added, and the resulting mixture was allowed to stir at r.t. for 16 hours. The reaction mixture was diluted with water and EtOAc, extracted and concentrated.
  • Example 7 General Procedure for synthesis of (S)-3,5-diamino-l-methyl-N-(l-(8-((l-methyl-lH- pyrazol-4-yl)ethynyl)-l-oxo-2-phenyl-l,2-dihydroisoquinolin-3-yl)ethyl)-lH-pyrazole-4- carboxamide
  • Example 2e (lOOmg, 0.64 mmol), HOBt (43 mg, 0.32 mmol), EDCI (185 mg, 0.96 mmol), and TEA (194 mg, 1.92 mmol) in DMF (3 mL) was stirred at ambient temperature for 15 min. Then, Example lh (260mg, 0.71 mmol) was added, and the resulting mixture was allowed to stir at r.t. for 16 hours. The reaction mixture was diluted with water and EtOAc, extracted and concentrated.
  • Example 8 General Procedure for synthesis of (S)-3-amino-5-ethynyl-l-methyl-N-(l-(8-((l-methyl- lH-pyrazol-4-yl)ethynyl)-l-oxo-2-phenyl-l,2-dihydroisoquinolin-3-yl)ethyl)-lH-pyrazole-4- carboxamide
  • Example 4 A solution of Example 4 (100 mg, 0.18 mmol), Example 2j (cas: 1066-54-2, 26 mg, 0.26 mmol), Pd(PPh 3 ) 2 Cl 2 (14 mg, 0.02 mmol), Cul (4 mg, 0.02mmol) and TEA (91 mg, 0.9 mmol) in dioxane (1 mL) was stirred under N 2 at 80°C for 16 hours. The mixture was diluted with water and extracted by EtOAc (100 mL*2). The combined organic phase was washed with brine, dried over Na 2 S0 4 , filtrated and concentrated under reduced pressure.
  • Example 9a (cas: 13331-23-2, 30mg, 0.26 mmol) in dioxane/H 2 0 (4 mL/1 mL) were added Pd(dppf)Cl 2 (7.7 mg, 0.011 mmol) and Na 2 C0 3 (34 mg, 0.32 mmol). The mixture was degassed by nitrogen for three times and heated at 100°C for 4 hours. The reaction mixture was filtered, washed with EtOAc and concentrated.
  • Example 10 General Procedure for synthesis of (S)-3-amino-l-methyl-N-(l-(8-((l-methyl-lH- pyrazol-4-yl)ethynyl)-l-oxo-2-phenyl-l,2-dihydroisoquinolin-3-yl)ethyl)-5-(pyridin-2-yl)-lH- pyrazole-4-carboxamide
  • Example 10a (cas: 17997-47-6, 78 mg, 0.21 mmol) under N 2 , which was then stirred at 110°C for 20hours. The mixture was quenched with sat. KF aqueous solution and extracted by DCM (100 mL*2). The combined organic phase was washed with brine, dried over Na 2 S0 4 , filtrated and concentrated under reduced pressure.
  • Example 11 General Procedure for synthesis of (S)-3-amino-5-cyano-l-methyl-N-(l-(8-((l-methyl- lH-pyrazol-4-yl)ethynyl)-l-oxo-2-phenyl-l,2-dihydroisoquinolin-3-yl)ethyl)-lH-pyrazole-4- carboxamide
  • Example 4 In a 5-mL microwave tube were charged with Example 4 (80mg, 0.14 mmol), dppf (cas: 12150- 46-8, 8 mg, 0.014 mmol), zinc dust (2.3 mg, 0.035 mmol) and Pd 2 (dba) 3 (6 mg, 0.007 mmol).
  • DMA (cas: 127-19-5, 1 mL) was added via a syringe. The mixture was degassed by nitrogen for three times, sealed, and then heated at 120°C by MW for 1 hour. The reaction mixture was filtered, washed with water and extracted by EtOAc (30 mL*2).
  • Example 4c To a solution of Example 4c (260mg, 1.18 mmol) in DCM (10 mL) were added HATU (674 mg, 1.77 mmol) and TEA (360 mg, 3.55 mmol). The mixture was stirred at ambient temperature for 30 min. Then Example 2d (423mg, 1.42 mmol) was added, and the resulting mixture was allowed to stir at r.t. for 16 hours. The reaction mixture was diluted with water and DCM, extracted and concentrated.
  • Example 4g step 1 Example 13a step 2
  • Example 13b step 3 Example 13
  • LC-MS [M+l] + 167.0 Step 3: Example 13
  • Example 13b 100 mg crude, 0.6 mmol
  • Example 2d 180 mg, 0.6 mmol
  • EDCI 128 mg, 0.66 mmol
  • HOBt 90 mg, 0.66 mmol
  • Et 3 N 182 mg, 1.8 mmol
  • Example 14 and 15 General Procedure for synthesis of (S)-3-amino-5-chloro-l-methyl-N-(l-(8-((l- methyl-lH-pyrazol-4-yl)ethynyl)-l-oxo-2-phenyl-l,2-dihydroisoquinolin-3-yl)ethyl)-lH-pyrazole-4- carboxamide (14) and (S)-5-amino-3-chloro-l-methyl-N-(l-(8-((l-methyl-lH-pyrazol-4-yl)ethynyl)- l-oxo-2-phenyl-l,2-dihydroisoquinolin-3-yl)ethyl)-lH-pyrazole-4-carboxamide (15)
  • Step 2 Example 14b and Example 15b
  • Example 14a To a solution of Example 14a (1.5 g, 7.9 mmol) in dry THF (40 mL) was added NaH (350 mg, 8.7 mmol) at 0°C, followed by addition of Mel (0.7 mL, 12.0 mmol) after 30 min. Then the mixture was stirred at r.t. for 16 hours. The mixture was diluted with water and extracted by EtOAc (200 mL*2). The combined organic phase was washed with brine, dried over Na 2 S0 4 , filtrated and concentrated under reduced pressure.
  • Example 14b and Example 15b 200 mg, 1.0 mmol
  • LiOH.H 2 0 126 mg, 3.0 mmol
  • THF/EtOH/H 2 0 5 mL/3 mL/1 inL
  • the combined organic phase was washed with brine, dried over Na 2 S0 4 , filtrated and concentrated under reduced pressure to give the crude product Example 14c and Example 15c as a mixture (two regioisomers, 300 mg, yield >100%) as a yellow solid, which was used in the next step without further purification.
  • LC-MS [M+l] + 175.9
  • Step 4 Example 14 and Example 15
  • Example 14c and Example 15c A solution of Example 14c and Example 15c (175 mg, 1.0 mmol), HOBt (68 mg, 0.5 mmol), EDCI (288 mg, 1.5 mmol) and TEA (303 mg, 3.0 mmol) in DCM (5 mL) was stirred 30 min, followed by addition of Example lh (368 mg, 1.0 mmol). The mixture was stirred at r.t. for 16 hours. The mixture was diluted with water and extracted by DCM/MeOH (100 mL/20 mL*2). The combined organic phase was washed with brine, dried over Na 2 S0 4 , filtrated and concentrated under reduced pressure.
  • Example 14c Step 4 Example 16 [00246] To a solution of Example 14c (175 mg, 1 mmol), HOBt (68 mg, 0.5 mmol), EDCI (288 mg, 1.5 mmol) and TEA (303 mg, 3 mmol) in DCM (5 mL) was added Example 2d (298 mg, 1 mmol) after stirring for 30 min. The mixture was stirred at r.t. for 16 hours. The mixture was diluted with water and extracted by DCM (100 mL*2). The combined organic phase was washed with brine, dried over Na 2 S0 4 , filtrated and concentrated under reduced pressure.
  • Example 17 General Procedure for synthesis of (S)-3-amino-l,5-dimethyl-N-(l-(8-((l-methyl-lH- pyrazol-4-yl)ethynyl)-l-oxo-2-phenyl-l,2-dihydroisoquinolin-3-yl)ethyl)-lH-pyrazole-4- carboxamide
  • Example 217c 70 mg, 0.4 mmol
  • HOBt 30 mg, 0.2 mmol
  • EDCI 126 mg, 0.6 mmol
  • TEA 133 mg, 1.2 mmol
  • Examplelh 165 mg, 04 mmol was added to the above mixture, which was stirred at r.t. for another 16 hours.
  • the mixture was diluted with water and extracted by DCM (100 mL*2).
  • the combined organic phase was washed with brine, dried over Na 2 S0 4 , filtrated and concentrated under reduced pressure.
  • the residue was purified by Prep-HPLC (by Ultimate XB-C18, 50 x 250 mm, 10 ⁇ , speed: 80 mL/min, eluent:
  • kinase-tagged T7 phage strains were prepared in an E. coli host derived from the BL21 strain. E. coli were grown to log-phase and infected with T7 phage and incubated with shaking at 32°C until lysis. The lysates were centrifuged and filtered to remove cell debris. The remaining kinases were produced in HEK-293 cells and subsequently tagged with DNA for qPCR detection. Streptavidin -coated magnetic beads were treated with biotinylated small molecule ligands for 30 minutes at room temperature to generate affinity resins for kinase assays.
  • Binding reactions were assembled by combining kinases, liganded affinity beads, and test compounds in lx binding buffer (20% SeaBlock, 0.17x PBS, 0.05% Tween 20, 6 mM DTT). Test compounds were prepared as 11 IX stocks in 100% DMSO. Kds were determined using an 11 -point 3-fold compound dilution series with three DMSO control points.
  • All compounds for Kd measurements are distributed by acoustic transfer (non -contact dispensing) in 100% DMSO. The compounds were then diluted directly into the assays such that the final concentration of DMSO was 0.9%. All reactions performed in polypropylene 384-well plate. Each was a final volume of 0.02 ml. The assay plates were incubated at room temperature with shaking for 1 hour and the affinity beads were washed with wash buffer (lx PBS, 0.05% Tween 20). The beads were then re-suspended in elution buffer (lx PBS, 0.05% Tween 20, 0.5 ⁇ non-biotinylated affinity ligand) and incubated at room temperature with shaking for 30 minutes. The kinase concentration in the eluates was measured by qPCR.
  • Binding constants were calculated with a standard dose-response curve using the Hill equation:

Abstract

Described herein are PI3 Kinase inhibitors and pharmaceutical compositions comprising said compounds. The subject compounds and compositions are useful for the treatment of cancer, cardiovascular diseases, and inflammatory diseases.

Description

PI3 KINASE INHIBITORS AND USES THEREOF
CROSS-REFERENCE
[0001] This patent application claims the benefit of U.S. Provisional Application No. 62/540,983, filed August 3, 2017, which is incorporated herein by reference in its entirety.
BACKGROUND
[0001] A need exists in the art for an effective treatment of cancer and inflammatory diseases.
BRIEF SUMMARY OF THE INVENTION
[0002] Provided herein are compounds of Formula (I), (la), (II), (Ila), (IIP), (HI), (ma), (IV), or (IVa), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and pharmaceutical compositions comprising said compounds. The subject compounds and compositions are useful as PI3 Kinase inhibitors. Furthermore, the subject compounds and compositions are useful for the treatment of cancer, inflammatory diseases, and cardiovascular diseases.
[0003] Disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
Figure imgf000002_0001
ormula (I)
wherein
each R1 is independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=0)Rc, -N02, -NRaRb, -
S(=0)2Rc, -NRaS(=0)2Rc, -S(=0)2NRaRb, -C(=0)Rc, -OC(=0)Rc, -C(=0)ORa, -OC(=0)ORa, -C(=0)NRaRb, -OC(=0)NRaRb, -NRaC(=0)NRaRb, -NRaC(=0)Rc, -NRaC(=0)ORa, optionally substituted Ci-C6 alkyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted cycloalkyl, optionally substituted (Ci-C6 alkyl)cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted (Ci-C6 alkyl)heterocycloalkyl, optionally substituted aryl, optionally substituted (Ci-C6 alkyl)aryl, optionally substituted heteroaryl, or optionally substituted (Ci-C6 alkyl)heteroaryl;
R2 is halogen, -CN, -ORa, -SRa, -S(=0)Rc, -N02, -NRaRb, -S(=0)2Rc, -NRaS(=0)2Rc, - S(=0)2NRaRb, -C(=0)Rc, -OC(=0)Rc, -C(=0)ORa, -OC(=0)ORa, -C(=0)NRaRb, - OC(=0)NRaRb, -NRaC(=0)NRaRb, -NRaC(=0)Rc, -NRaC(=0)ORa, optionally substituted d- C6 alkyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted cycloalkyl, optionally substituted (Ci-C<5 alkyl)cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted (Ci- C6 alkyl)heterocycloalkyl, optionally substituted aryl, optionally substituted (Ci-C6 alkyl)aryl, optionally substituted heteroaryl, or optionally substituted (Ci-C6 alkyl)heteroaryl;
R3 is -SRa, -S(=0)Rc, -S(=0)2Rc, -S(=0)2NRaRb, -C(=0)Rc, -C(=0)NRaRb, optionally substituted Ci-C6 alkyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted cycloalkyl, optionally substituted (Ci-C6 alkyl)cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted (Ci- C6 alkyl)heterocycloalkyl, optionally substituted aryl, optionally substituted (Ci-C6 alkyl)aryl, optionally substituted heteroaryl, or optionally substituted (Ci-C6 alkyl)heteroaryl;
R4 is hydrogen, halogen, -CN, -ORa, -SRa, -S(=0)Rc, -N02, -NRaRb, -S(=0)2Rc, -NRaS(=0)2Rc, - S(=0)2NRaRb, -C(=0)Rc, -OC(=0)Rc, -C(=0)ORa, -OC(=0)ORa, -C(=0)NRaRb, - OC(=0)NRaRb, -NRaC(=0)NRaRb, -NRaC(=0)Rc, -NRaC(=0)ORa, optionally substituted C C6 alkyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted cycloalkyl, optionally substituted (Ci-C<5 alkyl)cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted (Ci- C6 alkyl)heterocycloalkyl, optionally substituted aryl, optionally substituted (Ci-C6 alkyl)aryl, optionally substituted heteroaryl, or optionally substituted (Ci-C6 alkyl)heteroaryl;
R5 and R6 are independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=0)Rc, -N02, -NRaRb, - S(=0)2Rc, -NRaS(=0)2Rc, -S(=0)2NRaRb, -C(=0)Rc, -OC(=0)Rc, -C(=0)ORa, -OC(=0)ORa, -C(=0)NRaRa, -OC(=0)NRaRb, -NRaC(=0)NRaRb, -NRaC(=0)Rc, -NRaC(=0)ORc, optionally substituted Ci-C6 alkyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, or optionally substituted C2-C6 alkynyl;
R7 and R8 are independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=0)Rc, -N02, -NRaRb, - S(=0)2Rc, -NRaS(=0)2Rc, -S(=0)2NRaRb, -C(=0)Rc, -OC(=0)Rc, -C(=0)ORa, -OC(=0)ORa, -C(=0)NRaRa, -OC(=0)NRaRb, -NRaC(=0)NRaRb, -NRaC(=0)Rc, -NRaC(=0)ORc, optionally substituted Ci-C6 alkyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, or optionally substituted C2-C6 alkynyl;
or R7 and R8 are taken together to form an oxo;
R9 is hydrogen, halogen, -CN, -ORa, -SRa, -S(=0)Rc, -N02, -NRaRb, -S(=0)2Rc, -NRaS(=0)2Rc, - S(=0)2NRaRb, -C(=0)Rc, -OC(=0)Rc, -C(=0)ORa, -OC(=0)ORa, -C(=0)NRaRb, - OC(=0)NRaRb, -NRaC(=0)NRaRb, -NRaC(=0)Rc, -NRaC(=0)ORa, optionally substituted C C6 alkyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted cycloalkyl, optionally substituted (Ci-C<5 alkyl)cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted (Ci- C6 alkyl)heterocycloalkyl, optionally substituted aryl, optionally substituted (Ci-C6 alkyl)aryl, optionally substituted heteroaryl, or optionally substituted (Ci-C6 alkyl)heteroaryl; R10 is hydrogen, -SRa, -S(=0)Rc, -S(=0)2Rc, -S(=0)2NRaRb, -C(=0)Rc, -C(=0)NRaRb, optionally substituted Ci-C6 alkyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted cycloalkyl, optionally substituted (Ci-C6 alkyl)cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted (Ci-C6 alkyl)heterocycloalkyl, optionally substituted aryl, optionally substituted (Ci-C6 alkyl)aryl, optionally substituted heteroaryl, or optionally substituted (Ci-C6 alkyl)heteroaryl;
is a double bond or a single bond;
X is N or CRX when is a double bond; or X is NRX3 or CRX1RX2 when = is a single bond;
Rx, RX1, and RX2 are independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=0)Rc, -N02, - NRaRb, -S(=0)2Rc, -NRaS(=0)2Rc, -S(=0)2NRaRb, -C(=0)Rc, -OC(=0)Rc, -C(=0)ORa, - OC(=0)ORa, -C(=0)NRaRb, -OC(=0)NRaRb, -NRaC(=0)NRaRb, -NRaC(=0)Rc, - NRaC(=0)ORa, optionally substituted Ci-C6 alkyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted cycloalkyl, optionally substituted (Ci-C6 alkyl)cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted (Ci-C6 alkyl)heterocycloalkyl, optionally substituted aryl, optionally substituted (Ci-C6 alkyl)aryl, optionally substituted heteroaryl, or optionally substituted (Ci-C6 alkyl)heteroaryl;
Y is N or CRY when is a double bond; or Y is NRY3 or CRY1RY2 when is a single bond;
RY, RY1, and RY2 are independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=0)Rc, -N02, - NRaRb, -S(=0)2Rc, -NRaS(=0)2Rc, -S(=0)2NRaRb, -C(=0)Rc, -OC(=0)Rc, -C(=0)ORa, - OC(=0)ORa, -C(=0)NRaRb, -OC(=0)NRaRb, -NRaC(=0)NRaRb, -NRaC(=0)Rc, - NRaC(=0)ORa, optionally substituted Ci-C6 alkyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted cycloalkyl, optionally substituted (Ci-C6 alkyl)cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted (Ci-C6 alkyl)heterocycloalkyl, optionally substituted aryl, optionally substituted (Ci-C6 alkyl)aryl, optionally substituted heteroaryl, or optionally substituted (Ci-C6 alkyl)heteroaryl;
RX3 and RY3 are independently hydrogen, -SRa, -S(=0)Rc, -S(=0)2Rc, -S(=0)2NRaRb, -C(=0)Rc, - C(=0)NRaRb, optionally substituted Ci-C6 alkyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted cycloalkyl, optionally substituted (Ci-C6 alkyl)cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted (Ci-C6 alkyl)heterocycloalkyl, optionally substituted aryl, optionally substituted (Ci-C6 alkyl)aryl, optionally substituted heteroaryl, or optionally substituted (Ci-C6 alkyl)heteroaryl; each Ra and Rb are independently hydrogen, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
or Ra and Rb are taken together with the nitrogen atom to which they are attached to form an optionally substituted heterocycloalkyl;
each Rc is optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; and n is 1-3.
[0004] In some embodiments of a compound of Formula (I), each R1 is independently hydrogen, halogen, -CN, -OH, -OMe, -NH2, Ci-C6 alkyl, or Ci-C6 haloalkyl; and n is 1 or 2.
[0005] In some embodiments of a compound of Formula (I), each R1 is hydrogen.
[0006] In some embodiments of a compound of Formula (I), R3 is optionally substituted Ci-C6 alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl. In some embodiments of a compound of Formula (I), R3 is optionally substituted aryl.
[0007] In some embodiments of a compound of Formula (I), R4 is hydrogen, halogen, -CN, -OH, -OMe, -NH2, Ci-C<5 alkyl, or Ci-C6 haloalkyl. In some embodiments of a compound of Formula (I), R4 is hydrogen.
[0008] In some embodiments of a compound of Formula (I), R5 and R6 are independently hydrogen, halogen, Ci-C6 alkyl, or Ci-C6 haloalkyl.
[0009] In some embodiments of a compound of Formula (I), the compound is of Formula (la):
Figure imgf000005_0001
Formula (la).
[0010] In some embodiments of a compound of Formula (I) or (la), R2 is halogen, -CN, -ORa, -NRaRb, optionally substituted Ci-C6 alkyl, optionally substituted Ci-C6 heteroalkyl, or optionally substituted C2- C6 alkynyl. In some embodiments of a compound of Formula (I) or (la), R2 is halogen, optionally substituted Ci-C6 alkyl, or optionally substituted C2-C6 alkynyl. In some embodiments of a compound of Formula (I) or (la), R2 is halogen. In some embodiments of a compound of Formula (I) or (la), R2 is Ci- C<5 alkyl or Ci-C6 haloalkyl. In some embodiments of a compound of Formula (I) or (la), R2 is C2-C6 alkynyl optionally substituted with optionally substituted Ci-C6 alkyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted cycloalkyl, optionally substituted (Ci-C6 alkyl)cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted (Ci-C6 alkyl)heterocycloalkyl, optionally substituted aryl, optionally substituted (Ci-C6 alkyl)aryl, optionally substituted heteroaryl, or optionally substituted (Ci-C<5 alkyl)heteroaryl. In some embodiments of a compound of Formula (I) or (la), R2 is C2-C6 alkynyl optionally substituted with optionally substituted heteroaryl.
[0011] In some embodiments of a compound of Formula (I) or (la), R7 and R8 are taken together to form an oxo.
[0012] In some embodiments of a compound of Formula (I) or (la), R9 is hydrogen, halogen, -CN, -OH, -OMe, -NH2, Ci-C6 alkyl, or Ci-C6 haloalkyl. In some embodiments of a compound of Formula (I) or (la), R9 is -NH2.
[0013] In some embodiments of a compound of Formula (I) or (la), R10 is hydrogen or optionally substituted Ci-C6 alkyl. In some embodiments of a compound of Formula (I) or (la), R10 is Ci-C6 alkyl.
[0014] In some embodiments of a compound of Formula (I) or (la), is a double bond.
[0015] In some embodiments of a compound of Formula (I) or (la), X is CRX; and Y is N. In some embodiments of a compound of Formula (I) or (la), Y is CRY; and X is N. In some embodiments of a compound of Formula (I) or (la), X is CRX; and Y is CRY.
[0016] In some embodiments of a compound of Formula (I) or (la), Rx is hydrogen, halogen, -CN, -OH, -OMe, -NH2, Ci-Q alkyl, or Ci-C6 haloalkyl; and RY is hydrogen, halogen, -CN, -OH, -OMe, -NH2, Ci- C<5 alkyl, or Ci-C6 haloalkyl. In some embodiments of a compound of Formula (I) or (la), Rx is hydrogen; and RY is hydrogen.
[0017] In some embodiments of a compound of Formula (I) or (la), is a single bond.
Yl Y2
[0018] In some embodiments of a compound of Formula (I) or (la), X is CR R ; and Y is CR R .
[0019] In some embodiments of a compound of Formula (I) or (la), RX1 and RX2 are independently hydrogen, halogen, -CN, -OH, -OMe, -NH2, d-Q, alkyl, or C C6 haloalkyl; and RY1 and RY2 are independently hydrogen, halogen, -CN, -OH, -OMe, -NH2, Ci-C6 alkyl, or Ci-C6 haloalkyl. In some embodiments of a compound of Formula (I) or (la), R and R are hydrogen; and R and R are hydrogen.
[0020] In some embodiments of a compound of Formula (I) or (la), each Ra and Rb are independently hydrogen or optionally substituted Ci-C6 alkyl; or Ra and Rb are taken together with the nitrogen atom to which they are attached to form an optionally substituted heterocycloalkyl. In some embodiments of a compound of Formula (I) or (la), each Rc is optionally substituted Ci-C6 alkyl.
[0021] Also disclosed herein is a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
Figure imgf000007_0001
wherein
each R11 is independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=0)Rc, -N02, -NRaRb, -
S(=0)2Rc, -NRaS(=0)2Rc, -S(=0)2NRaRb, -C(=0)Rc, -OC(=0)Rc, -C(=0)ORa, -OC(=0)ORa, -C(=0)NRaRb, -OC(=0)NRaRb, -NRaC(=0)NRaRb, -NRaC(=0)Rc, -NRaC(=0)ORa, optionally substituted Ci-C6 alkyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted cycloalkyl, optionally substituted (Ci-C6 alkyl)cycloalkyl, optionally substituted
heterocycloalkyl, optionally substituted (Ci-C6 alkyl)heterocycloalkyl, optionally substituted aryl, optionally substituted (Ci-C6 alkyl)aryl, optionally substituted heteroaryl, or optionally substituted (Ci-C6 alkyl)heteroaryl;
R12 is optionally substituted Ci-C6 alkyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted cycloalkyl, optionally substituted (Ci-C6 alkyl)cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted (Ci-C6 alkyl)heterocycloalkyl, optionally substituted aryl, optionally substituted (Ci-C6 alkyl)aryl, optionally substituted heteroaryl, or optionally substituted (Ci-C6 alkyl)heteroaryl;
R13 is -SRa, -S(=0)Rc, -S(=0)2Rc, -S(=0)2NRaRb, -C(=0)Rc, -C(=0)NRaRb, optionally
substituted Ci-C6 alkyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted cycloalkyl, optionally substituted (Ci-C6 alkyl)cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted (Ci-C6 alkyl)heterocycloalkyl, optionally substituted aryl, optionally substituted (Ci-C<5 alkyl)aryl, optionally substituted heteroaryl, or optionally substituted (Ci-C6 alkyl)heteroaryl;
R14 is hydrogen, halogen, -CN, -ORa, -SRa, -S(=0)Rc, -N02, -NRaRb, -S(=0)2Rc, -NRaS(=0)2Rc, -S(=0)2NRaRb, -C(=0)Rc, -OC(=0)Rc, -C(=0)ORa, -OC(=0)ORa, -C(=0)NRaRb, - OC(=0)NRaRb, -NRaC(=0)NRaRb, -NRaC(=0)Rc, -NRaC(=0)ORa, optionally substituted d- C6 alkyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted cycloalkyl, optionally substituted (Ci-C<5 alkyl)cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted (Ci- C6 alkyl)heterocycloalkyl, optionally substituted aryl, optionally substituted (Ci-C6 alkyl)aryl, optionally substituted heteroaryl, or optionally substituted (Ci-C6 alkyl)heteroaryl; R15 and R16 are independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=0)Rc, -N02, -NRaRb, - S(=0)2Rc, -NRaS(=0)2Rc, -S(=0)2NRaRb, -C(=0)Rc, -OC(=0)Rc, -C(=0)ORa, -OC(=0)ORa, -C(=0)NRaRa, -OC(=0)NRaRb, -NRaC(=0)NRaRb, -NRaC(=0)Rc, -NRaC(=0)ORc, optionally substituted Ci-C6 alkyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, or optionally substituted C2-C6 alkynyl;
Ring A is an optionally substituted heteroaryl or an optionally substituted heterocycloalkyl; each Ra and Rb are independently hydrogen, optionally substituted Ci-C6 alkyl, optionally
substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
or Ra and Rb are taken together with the nitrogen atom to which they are attached to form an optionally substituted heterocycloalkyl;
each Rc is optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; and nl is 1-3.
[0022] In some embodiments of a compound of Formula (II), each R11 is independently hydrogen, halogen, -CN, -OH, -OMe, -NH2, Ci-C6 alkyl, or Ci-C6 haloalkyl; and nl is 1 or 2. In some embodiments of a compound of Formula (II), each R11 is hydrogen.
[0023] In some embodiments of a compound of Formula (II), R13 is optionally substituted Ci-C6 alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl. In some embodiments of a compound of Formula (II), R13 is optionally substituted aryl.
[0024] In some embodiments of a compound of Formula (II), R14 is hydrogen, halogen, -CN, -OH, - OMe, -NH2, Ci-C6 alkyl, or Ci-C6 haloalkyl. In some embodiments of a compound of Formula (II), R14 is hydrogen.
[0025] In some embodiments of a compound of Formula (II), R15 and R16 are independently hydrogen, halogen, Ci-C6 alkyl, or Ci-C6 haloalkyl.
[0026] In some embodiments of a compound of Formula (II), the compound is of Formula (Ila):
Figure imgf000008_0001
[0027] In some embodiments of a compound of Formula (II) or (Ila), R12 is optionally substituted heterocycloalkyl or optionally substituted heteroaryl. In some embodiments of a compound of Formula (II) or (Ila), R12 is optionally substituted heteroaryl. In some embodiments of a compound of Formula (II) or (Ila), R12 is an optionally substituted 5-membered heteroaryl. In some embodiments of a compound of Formula (II) or (Ila), R12 is a 5-membered heteroaryl optionally substituted with halogen, -CN, -OH, - OMe, -NH2, d-C6 alkyl, or d-C6 haloalkyl.
[0028] In some embodiments of a compound of Formula (II) or (Ila), Ring A is an optionally substituted heteroaryl. In some embodiments of a compound of Formula (II) or (Ila), Ring A is an optionally substituted N-linked heteroaryl. In some embodiments of a compound of Formula (II) or (Ila), Ring A is an optionally substituted C-linked heteroaryl. In some embodiments of a compound of Formula (II) or (Ila), Ring A is an optionally substituted heterocycloalkyl. In some embodiments of a compound of Formula (II) or (Ila), Ring A is an optionally substituted N-linked heterocycloalkyl. In some
embodiments of a compound of Formula (II) or (Ila), Ring A is an optionally substituted C-linked heterocycloalkyl. In some embodiments of a compound of Formula (II) or (Ila), Ring A is optionally substituted with oxo, halogen, -CN, -ORa, -SRa, -S(=0)Rc, -N02, -NRaRb, -S(=0)2Rc, -NRaS(=0)2Rc, - S(=0)2NRaRb, -C(=0)Rc, -OC(=0)Rc, -C(=0)ORa, -OC(=0)ORa, -C(=0)NRaRb, -OC(=0)NRaRb, - NRaC(=0)NRaRb, -NRaC(=0)Rc, -NRaC(=0)ORa, optionally substituted Ci-C6 alkyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl. In some embodiments of a compound of Formula (II) or (Ila), Ring A is optionally substituted with oxo, halogen, -CN, -OH, -OMe, -NH2, Ci-C6 alkyl, or Ci-C6 haloalkyl.
[0029] In some embodiments of a compound of Formula (II) or (Ila), each Ra and Rb are independently hydrogen or optionally substituted Ci-C6 alkyl; or Ra and Rb are taken together with the nitrogen atom to which they are attached to form an optionally substituted heterocycloalkyl.
[0030] In some embodiments of a compound of Formula (II) or (Ila), each Rc is optionally substituted Ci-C6 alkyl.
[0031] Also disclosed herein is a compound of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
Figure imgf000009_0001
Formula (III)
wherein each R21 is independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=0)Rc, -N02, -NRaRb, -
S(=0)2Rc, -NRaS(=0)2Rc, -S(=0)2NRaRb, -C(=0)Rc, -OC(=0)Rc, -C(=0)ORa, -OC(=0)ORa, -C(=0)NRaRb, -OC(=0)NRaRb, -NRaC(=0)NRaRb, -NRaC(=0)Rc, -NRaC(=0)ORa, optionally substituted Ci-C6 alkyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted cycloalkyl, optionally substituted (Ci-C6 alkyl)cycloalkyl, optionally substituted
heterocycloalkyl, optionally substituted (Ci-C6 alkyl)heterocycloalkyl, optionally substituted aryl, optionally substituted (Ci-C6 alkyl)aryl, optionally substituted heteroaryl, or optionally substituted (Ci-C6 alkyl)heteroaryl;
R22 is halogen, -CN, -ORa, -SRa, -S(=0)Rc, -N02, -NRaRb, -S(=0)2Rc, -NRaS(=0)2Rc, - S(=0)2NRaRb, -C(=0)Rc, -OC(=0)Rc, -C(=0)ORa, -OC(=0)ORa, -C(=0)NRaRb, - OC(=0)NRaRb, -NRaC(=0)NRaRb, -NRaC(=0)Rc, -NRaC(=0)ORa, optionally substituted C C6 alkyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted cycloalkyl, optionally substituted (Ci-C<5 alkyl)cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted (Ci- C<5 alkyl)heterocycloalkyl, optionally substituted aryl, optionally substituted (Ci-C6 alkyl)aryl, optionally substituted heteroaryl, or optionally substituted (Ci-C6 alkyl)heteroaryl;
R23 is -SRa, -S(=0)Rc, -S(=0)2Rc, -S(=0)2NRaRb, -C(=0)Rc, -C(=0)NRaRb, optionally
substituted Ci-C6 alkyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted cycloalkyl, optionally substituted (Ci-C6 alkyl)cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted (Ci-C6 alkyl)heterocycloalkyl, optionally substituted aryl, optionally substituted (Ci-C<5 alkyl)aryl, optionally substituted heteroaryl, or optionally substituted (Ci-C6 alkyl)heteroaryl;
R24 is hydrogen, halogen, -CN, -OH, -ORa, -SRa, -S(=0)Rc, -N02, -NRaRb, -S(=0)2Rc, - NRaS(=0)2Rc, -S(=0)2NRaRb, -C(=0)Rc, -OC(=0)Rc, -C(=0)ORa, -OC(=0)ORa, - C(=0)NRaRb, -OC(=0)NRaRb, -NRaC(=0)NRaRb, -NRaC(=0)Rc, -NRaC(=0)ORa, optionally substituted Ci-C6 alkyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted cycloalkyl, optionally substituted (Ci-C6 alkyl)cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted (Ci-C6 alkyl)heterocycloalkyl, optionally substituted aryl, optionally substituted (Ci-C6 alkyl)aryl, optionally substituted heteroaryl, or optionally substituted (Ci-C6 alkyl)heteroaryl;
R25 and R26 are independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=0)Rc, -N02, -NRaRb, - S(=0)2Rc, -NRaS(=0)2Rc, -S(=0)2NRaRb, -C(=0)Rc, -OC(=0)Rc, -C(=0)ORa, -OC(=0)ORa, -C(=0)NRaRa, -OC(=0)NRaRb, -NRaC(=0)NRaRb, -NRaC(=0)Rc, -NRaC(=0)ORc, optionally substituted Ci-C6 alkyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, or optionally substituted C2-C6 alkynyl; R27 is hydrogen, -SRa, -S(=0)Rc, -S(=0)2Rc, -S(=0)2NRaRb, -C(=0)Rc, -C(=0)NRaRb, optionally substituted Ci-C6 alkyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted cycloalkyl, optionally substituted (Ci-C6 alkyl)cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted (Ci-C6 alkyl)heterocycloalkyl, optionally substituted aryl, optionally substituted (Ci-C6 alkyl)aryl, optionally substituted heteroaryl, or optionally substituted (Ci-C6 alkyl)heteroaryl;
R28 is halogen, -CN, -ORa, -SRa, -S(=0)Rc, -N02, -NRaRb, -S(=0)2Rc, -NRaS(=0)2Rc, - S(=0)2NRaRb, -C(=0)Rc, -OC(=0)Rc, -C(=0)ORa, -OC(=0)ORa, -C(=0)NRaRb, - OC(=0)NRaRb, -NRaC(=0)NRaRb, -NRaC(=0)Rc, -NRaC(=0)ORa, optionally substituted C C6 alkyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted cycloalkyl, optionally substituted (Ci-C6 alkyl)cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted (Ci- C6 alkyl)heterocycloalkyl, optionally substituted aryl, optionally substituted (Ci-C6 alkyl)aryl, optionally substituted heteroaryl, or optionally substituted (Ci-C6 alkyl)heteroaryl;
R29 is hydrogen, -SRa, -S(=0)Rc, -S(=0)2Rc, -S(=0)2NRaRb, -C(=0)Rc, -C(=0)NRaRb, optionally substituted Ci-C6 alkyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted cycloalkyl, optionally substituted (Ci-C6 alkyl)cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted (Ci-C6 alkyl)heterocycloalkyl, optionally substituted aryl, optionally substituted (Ci-C<5 alkyl)aryl, optionally substituted heteroaryl, or optionally substituted (Ci-C6 alkyl)heteroaryl;
each Ra and Rb are independently hydrogen, optionally substituted Ci-C6 alkyl, optionally
substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
or Ra and Rb are taken together with the nitrogen atom to which they are attached to form an optionally substituted heterocycloalkyl;
each Rc is optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; and n2 is 1-3.
[0032] In some embodiments of a compound of Formula (III), each R21 is independently hydrogen, halogen, -CN, -OH, -OMe, -NH2, Ci-C6 alkyl, or Ci-C6 haloalkyl; and n2 is 1 or 2.
[0033] In some embodiments of a compound of Formula (III), each R21 is hydrogen.
[0034] In some embodiments of a compound of Formula (III), R23 is optionally substituted Ci-C6 alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl. In some embodiments of a compound of Formula (III), R23 is optionally substituted aryl.
[0035] In some embodiments of a compound of Formula (III), R24 is hydrogen, halogen, -CN, -OH, - OMe, -NH2, Ci-C<5 alkyl, or Ci-C6 haloalkyl. In some embodiments of a compound of Formula (III), R24 is hydrogen.
[0036] In some embodiments of a compound of Formula (III), R25 and R26 are independently hydrogen, halogen, Ci-C6 alkyl, or Ci-C6 haloalkyl.
[0037] In some embodiments of a compound of Formula (III), R27 is hydrogen or Ci-C6 alkyl.
[0038] In some embodiments of a compound of Formula (III), the compound is of Formula (Ilia) :
Figure imgf000012_0001
Formula (Ilia).
[0039] In some embodiments of a compound of Formula (III) or (Ilia), R22 is halogen, -CN, -ORa, - NRaRb, optionally substituted Ci-C6 alkyl, optionally substituted Ci-C6 heteroalkyl, or optionally substituted C2-C6 alkynyl. In some embodiments of a compound of Formula (III) or (Ilia), R22 is halogen, optionally substituted Ci-C6 alkyl, or optionally substituted C2-C6 alkynyl. In some embodiments of a compound of Formula (III) or (Ilia), R22 is halogen. In some embodiments of a compound of Formula (III) or (Ilia), R22 is d-C6 alkyl or d-C6 haloalkyl. In some embodiments of a compound of Formula (III) or (Ilia), R22 is C2-C6 alkynyl optionally substituted with optionally substituted Ci-C6 alkyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted cycloalkyl, optionally substituted (Ci-C6 alkyl)cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted (Ci-C6
alkyl)heterocycloalkyl, optionally substituted aryl, optionally substituted (Ci-C6 alkyl)aryl, optionally substituted heteroaryl, or optionally substituted (Ci-C6 alkyl)heteroaryl. In some embodiments of a compound of Formula (III) or (Ilia), R22 is C2-C6 alkynyl optionally substituted with optionally substituted heteroaryl.
[0040] In some embodiments of a compound of Formula (III) or (Ilia), R28 is halogen, -CN, -ORa, - NRaRb, -C(=0)ORa, -C(=0)NRaRb, optionally substituted Ci-C6 alkyl, optionally substituted d-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl. In some embodiments of a compound of Formula (III) or (Ilia), R28 is halogen, - CN, -ORa, -NRaRb, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkynyl, or optionally substituted heteroaryl. In some embodiments of a compound of Formula (III) or (Ilia), R28 is halogen, - CN, -OMe, -NH2, Ci-C6 alkyl, Ci-C6 haloalkyl, C2-C6 alkynyl, or heteroaryl. [0041] In some embodiments of a compound of Formula (III) or (Ilia), R is hydrogen or optionally substituted Ci-C6 alkyl. In some embodiments of a compound of Formula (III) or (Ilia), R29 is Ci-C6 alkyl.
[0042] In some embodiments of a compound of Formula (III) or (Ilia), each Ra and Rb are independently hydrogen or optionally substituted Ci-C6 alkyl; or Ra and Rb are taken together with the nitrogen atom to which they are attached to form an optionally substituted heterocycloalkyl. In some embodiments of a compound of Formula (III) or (Ilia), each Rc is optionally substituted Ci-C6 alkyl.
[0043] Also disclosed herein is a compound of Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
Figure imgf000013_0001
wherein
each R31 is independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=0)Rc, -N02, -NRaRb, -
S(=0)2Rc, -NRaS(=0)2Rc, -S(=0)2NRaRb, -C(=0)Rc, -OC(=0)Rc, -C(=0)ORa, -OC(=0)ORa, -C(=0)NRaRb, -OC(=0)NRaRb, -NRaC(=0)NRaRb, -NRaC(=0)Rc, -NRaC(=0)ORa, optionally substituted Ci-C6 alkyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted cycloalkyl, optionally substituted (Ci-C6 alkyl)cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted (Ci-C6 alkyl)heterocycloalkyl, optionally substituted aryl, optionally substituted (Ci-C6 alkyl)aryl, optionally substituted heteroaryl, or optionally substituted (Ci-C6 alkyl)heteroaryl;
R32 is optionally substituted Ci-C6 alkyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted cycloalkyl, optionally substituted (Ci-C6 alkyl)cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted (Ci-C6 alkyl)heterocycloalkyl, optionally substituted aryl, optionally substituted (Ci-C6 alkyl)aryl, optionally substituted heteroaryl, or optionally substituted (Ci-C6 alkyl)heteroaryl;
R33 is -SRa, -S(=0)Rc, -S(=0)2Rc, -S(=0)2NRaRb, -C(=0)Rc, -C(=0)NRaRb, optionally
substituted Ci-C6 alkyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted cycloalkyl, optionally substituted (Ci-C6 alkyl)cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted (Ci-C6 alkyl)heterocycloalkyl, optionally substituted aryl, optionally substituted (Ci-C<5 alkyl)aryl, optionally substituted heteroaryl, or optionally substituted (Ci-C6
alkyl)heteroaryl;
R34 is hydrogen, halogen, -CN, -ORa, -SRa, -S(=0)Rc, -N02, -NRaRb, -S(=0)2Rc, -NRaS(=0)2Rc, -S(=0)2NRaRb, -C(=0)Rc, -OC(=0)Rc, -C(=0)ORa, -OC(=0)ORa, -C(=0)NRaRb, - OC(=0)NRaRb, -NRaC(=0)NRaRb, -NRaC(=0)Rc, -NRaC(=0)ORa, optionally substituted d- C6 alkyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted cycloalkyl, optionally substituted (Ci-C6 alkyl)cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted (Ci- C6 alkyl)heterocycloalkyl, optionally substituted aryl, optionally substituted (Ci-C6 alkyl)aryl, optionally substituted heteroaryl, or optionally substituted (Ci-C6 alkyl)heteroaryl;
R35 and R36 are independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=0)Rc, -N02, -NRaRb, - S(=0)2Rc, -NRaS(=0)2Rc, -S(=0)2NRaRb, -C(=0)Rc, -OC(=0)Rc, -C(=0)ORa, -OC(=0)ORa, -C(=0)NRaRa, -OC(=0)NRaRb, -NRaC(=0)NRaRb, -NRaC(=0)Rc, -NRaC(=0)ORc, optionally substituted Ci-C6 alkyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, or optionally substituted C2-C6 alkynyl;
R37 is hydrogen, -SRa, -S(=0)Rc, -S(=0)2Rc, -S(=0)2NRaRb, -C(=0)Rc, -C(=0)NRaRb, optionally substituted Ci-C6 alkyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted cycloalkyl, optionally substituted (Ci-C6 alkyl)cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted (Ci-C6 alkyl)heterocycloalkyl, optionally substituted aryl, optionally substituted (Ci-C<5 alkyl)aryl, optionally substituted heteroaryl, or optionally substituted (Ci-C6 alkyl)heteroaryl;
Ring B is an optionally substituted 5-membered heteroaryl;
each Ra and Rb are independently hydrogen, optionally substituted Ci-C6 alkyl, optionally
substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
or Ra and Rb are taken together with the nitrogen atom to which they are attached to form an optionally substituted heterocycloalkyl;
each Rc is optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; and n3 is 1-3.
[0044] In some embodiments of a compound of Formula (IV), each R 1 is independently hydrogen, halogen, -CN, -OH, -OMe, -NH2, Ci-C6 alkyl, or Ci-C6 haloalkyl; and n3 is 1 or 2.
[0045] In some embodiments of a compound of Formula (IV), each R31 is hydrogen.
[0046] In some embodiments of a compound of Formula (IV), R33 is optionally substituted Ci-C6 alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl. In some embodiments of a compound of Formula (IV), R is optionally substituted aryl.
[0047] In some embodiments of a compound of Formula (IV), R34 is hydrogen, halogen, -CN, -OH, - OMe, -NH2, Ci-C<5 alkyl, or Ci-C6 haloalkyl. In some embodiments of a compound of Formula (IV), R34 is hydrogen.
[0048] In some embodiments of a compound of Formula (IV), R35 and R36 are independently hydrogen, halogen, Ci-C6 alkyl, or Ci-C6 haloalkyl.
[0049] In some embodiments of a compound of Formula (IV), R37 is hydrogen or Ci-C6 alkyl.
[0050] In some embodiments of a compound of Formula (IV), the compound is of Formula (IVa):
Figure imgf000015_0001
[0051] In some embodiments of a compound of Formula (IV) or (Via), R is optionally substituted heterocycloalkyl or optionally substituted heteroaryl. In some embodiments of a compound of Formula (IV) or (Via), R32 is optionally substituted heteroaryl.
[0052] In some embodiments of a compound of Formula (IV) or (Via), R32 is an optionally substituted 5-membered heteroaryl. In some embodiments of a compound of Formula (IV) or (Via), R32 is a 5- membered heteroaryl optionally substituted with halogen, -CN, -OH, -OMe, -NH2, Ci-C6 alkyl, or Ci-C6 haloalkyl.
[0053] In some embodiments of a compound of Formula (IV) or (Via), Ring B is selected from optionally substituted: pyrrole, thiophene, furan, imidazole, pyrazole, thiazole, isothiazole, oxazole, isoxazole, triazole, and tetrazole. In some embodiments of a compound of Formula (IV) or (Via), Ring B is optionally substituted pyrazole. In some embodiments of a compound of Formula (IV) or (Via), the optional substituent on Ring B is halogen, -CN, -ORa, -SRa, -S(=0)Rc, -N02, -NRaRb, -S(=0)2Rc, - NRaS(=0)2Rc, -S(=0)2NRaRb, -C(=0)Rc, -OC(=0)Rc, -C(=0)ORa, -OC(=0)ORa, -C(=0)NRaRb, - OC(=0)NRaRb, -NRaC(=0)NRaRb, -NRaC(=0)Rc, -NRaC(=0)ORa, optionally substituted d-C6 alkyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2- C6 alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl. In some embodiments of a compound of Formula (IV) or (Via), Ring B is optionally substituted with halogen, -CN, -ORa, -NRaRb, optionally substituted Ci-C<5 alkyl, optionally substituted C2-C6 alkynyl, or optionally substituted heteroaryl. In some embodiments of a compound of Formula (IV) or (Via), Ring B is optionally substituted with halogen, - CN, -OMe, -NH2, Ci-C6 alkyl, Ci-C6 haloalkyl, C2-C6 alkynyl, or heteroaryl.
[0054] In some embodiments of a compound of Formula (IV) or (Via), each Ra and Rb are
independently hydrogen or optionally substituted Ci-C6 alkyl; or Ra and Rb are taken together with the nitrogen atom to which they are attached to form an optionally substituted heterocycloalkyl. In some embodiments of a compound of Formula (IV) or (Via), each Rc is optionally substituted Ci-C6 alkyl.
INCORPORATION BY REFERENCE
[0055] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference for the specific purposes identified herein.
DETAILED DESCRIPTION OF THE INVENTION
[0056] Disclosed herein are compounds of Formula (I), (la), (II), (Ila), (ΙΙΙ'), (III), (Ilia), (IV), or (IVa), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, for the modulation, notably the inhibition of the activity or function of the phosphoinositide 3' OH kinase family (hereinafter PI3 kinases), suitably, PBKalpha, PBKdelta, PBKbeta, and/or PBKgamma. Furthermore, the subject compounds and compositions are useful for the treatment of cancers and inflammatory diseases.
[0057] The phosphoinositide 3-kinase (PBK) pathway is among the most commonly activated in human cancer and the importance in carcinogenesis is well established. Initiation of signaling begins with the phosphorylation of phosphatidylinositol-4, 5-bisphosphate (PIP2) to produce phosphatidylinositol-3, 4, 5- P3 (PIP3). PIP3 is a critical second messenger which recruits proteins that contain pleckstrin homology domains to the cell membrane where they are activated. The most studied of these proteins is AKT which promotes cell survival, growth, and proliferation.
[0058] The PBK family consists of 15 proteins that share sequence homology, particularly within their kinase domains, but have distinct substrate specificities and modes of regulation. Class I PBKs are heterodimers consisting of a pi 10 catalytic subunit complexed to one of several regulatory subunits collectively referred to as p85 and have been the most extensively studied in the context of tumorgenesis. The class 1A PBK catalytic subunits comprise the pi lOalpha, pi lObeta, and pi lOdelta isoforms, which associate with one of five different regulatory subunits encoded by three separate genes. A single class IB PBK catalytic isoform pi lOgamma interacts with one of two associated regulatory subunits. Class 1 PBKs are primarily responsible for phosphorylating the critical PIP2 signaling molecule.
[0059] The differential tissue distribution of the PBK isoforms factors in their distinct biological functions. Genetic ablation of either PBKalpha or PBKbeta results in embryonic lethality, indicating that PBKalpha and PBKbeta have essential and non-redundant functions, at least during development. In contrast, mice which lack PBKgamma and PBKdelta are viable, fertile, and have a normal life span although they show an altered immune system. PBKgamma deficiency leads to impaired recruitment of macrophages and neutrophils to sites of inflammation as well as impaired T cell activation. PBKdelta- mutant mice have specific defects in B cell signaling that lead to impaired B cell development and reduced antibody responses after antigen stimulation. [0060] The phenotypes of the P Kgamma and PBKdelta-mutant mice suggest that these enzymes may play a role in inflammation and other immune-based diseases and this is borne out in preclinical models. PBKgamma-mutant mice are largely protected from disease in mouse models of rheumatoid arthritis (RA) and asthma. In addition, treatment of wild-type mice with a selective inhibitor of PBKgamma was shown to reduce glomerulonephritis and prolong survival in the MRL-lpr model of systemic lupus nephritis (SLE) and to suppress joint inflammation and damage in models of RA. Similarly, both PBKdelta-mutant mice and wild-type mice treated with a selective inhibitor of PBKdelta have been shown to have attenuated allergic airway inflammation and hyper-responsiveness in a mouse model of asthma and to have attenuated disease in a model of RA.
[0061] The link between the PBK pathway and cancer was confirmed by a study which identified somatic mutations in the PIK3CA gene encoding the pi lOalpha protein. Subsequently, mutations in PIK3CA have been identified in numerous cancers including colorectal, breast, glioblastomas ovarian and lung. In contrast to PIK3CA, no somatic mutations in the beta isoform have been identified.
However, in overexpression studies, the PBKbeta isoform has been implicated as necessary for transformation induced by the loss or inactivation of the PTEN tumor suppressor both in vitro and in vivo. Consistent with this finding, overexpression of the PIK3CB gene has been identified in some bladder, colon, glioblastomas and leukemias and siRNA mediated knockdown of pi lObeta in glioblastoma cell lines results in suppression of tumor growth in vitro and in vivo. More recent data using shRNA demonstrated that downregulation of pi lObeta and not pi lOalpha resulted in PBK pathway inactivation and subsequent inactivation of tumor cell growth in PTEN deficient cancers cells both in vitro and in vivo. Consistent with a role of PIK3CB signaling in PTEN null tumors, pi 1013 was reported to be essential to the transformed phenotype in a PTEN-null prostate cancer model.
Further, it has been reported that fibrogenesis, including systemic sclerosis (SSc), arthritis, nephropahty, liver cirrhosis, and some cancers, are related to PTEN deficiency and corresponding PBK-Akt overexpression. Taken together, these findings indicate PBK pi lObeta as a promising target for cancer and other syndromes related to PTEN loss.
Definitions
[0062] As used herein and in the appended claims, the singular forms "a," "and," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "an agent" includes a plurality of such agents, and reference to "the cell" includes reference to one or more cells (or to a plurality of cells) and equivalents thereof known to those skilled in the art, and so forth. When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulae, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included. The term "about" when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range, in some instances, will vary between 1% and 15% of the stated number or numerical range. The term "comprising" (and related terms such as "comprise" or "comprises" or "having" or "including") is not intended to exclude that in other certain embodiments, for example, an embodiment of any composition of matter, composition, method, or process, or the like, described herein, "consist of or "consist essentially of the described features.
[0063] As used in the specification and appended claims, unless specified to the contrary, the following terms have the meaning indicated below.
[0064] "Alkyl" refers to an optionally substituted straight-chain, or optionally substituted branched- chain saturated hydrocarbon monoradical having from one to about ten carbon atoms, or from one to six carbon atoms, wherein a sp3 -hybridized carbon of the alkyl residue is attached to the rest of the molecule by a single bond. Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl- 1-propyl, 2-methyl-2 -propyl, 2-methyl-l -butyl, 3 -methyl- 1 -butyl, 2-methyl-3-butyl, 2,2-dimethyl-l - propyl, 2-methyl-l -pentyl, 3 -methyl- 1-pentyl, 4-methyl-l-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-l -butyl, 3,3-dimethyl-l -butyl, 2-ethyl-l -butyl, n-butyl, isobutyl, sec- butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl and hexyl, and longer alkyl groups, such as heptyl, octyl, and the like. Whenever it appears herein, a numerical range such as "Ci-C6 alkyl" means that the alkyl group consists of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term "alkyl" where no numerical range is designated. In some embodiments, the alkyl is a Ci-Cio alkyl, a C1-C9 alkyl, a Ci-Cg alkyl, a C1-C7 alkyl, a Ci-C6 alkyl, a C1-C5 alkyl, a C1-C4 alkyl, a C1-C3 alkyl, a Ci-C2 alkyl, or a Ci alkyl. Unless stated otherwise specifically in the specification, an alkyl group is optionally substituted as described below, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkyl is optionally substituted with oxo, halogen, -CN, -CF3, -OH, -OMe, -NH2, or -N02. In some embodiments, the alkyl is optionally substituted with oxo, halogen, -CN, -CF3, -OH, or -OMe.
[0065] "Alkenyl" refers to an optionally substituted straight-chain, or optionally substituted branched- chain hydrocarbon monoradical having one or more carbon-carbon double-bonds and having from two to about ten carbon atoms, more preferably two to about six carbon atoms, wherein an sp2 -hybridized carbon of the alkenyl residue is attached to the rest of the molecule by a single bond. The group may be in either the cis or trans conformation about the double bond(s), and should be understood to include both isomers. Examples include, but are not limited to ethenyl (-CH=CH2), 1-propenyl (-CH2CH=CH2), isopropenyl [-C(CH3)=CH2], butenyl, 1,3-butadienyl and the like. Whenever it appears herein, a numerical range such as "C2-C6 alkenyl" means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term "alkenyl" where no numerical range is designated. In some embodiments, the alkenyl is a C2-Ci0 alkenyl, a C2-C9 alkenyl, a C2-C8 alkenyl, a C2-C7 alkenyl, a C2-C6 alkenyl, a C2-C5 alkenyl, a C2-C4 alkenyl, a C2-C3 alkenyl, or a C2 alkenyl. Unless stated otherwise specifically in the specification, an alkenyl group is optionally substituted as described below, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an alkenyl is optionally substituted with oxo, halogen, -CN, -CF3, -OH, -OMe, -NH2, or -N02. In some embodiments, an alkenyl is optionally substituted with oxo, halogen, -CN, -CF3, -OH, or -OMe.
[0066] "Alkynyl" refers to an optionally substituted straight-chain or optionally substituted branched- chain hydrocarbon monoradical having one or more carbon-carbon triple-bonds and having from two to about ten carbon atoms, more preferably from two to about six carbon atoms. Examples include, but are not limited to ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl and the like. Whenever it appears herein, a numerical range such as "C2-C6 alkynyl" means that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term "alkynyl" where no numerical range is designated. In some embodiments, the alkynyl is a C2-Ci0 alkynyl, a C2-C9 alkynyl, a C2-C8 alkynyl, a C2-C7 alkynyl, a C2-C6 alkynyl, a C2-C5 alkynyl, a C2-C4 alkynyl, a C2-C3 alkynyl, or a C2 alkynyl. Unless stated otherwise specifically in the specification, an alkynyl group is optionally substituted as described below, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an alkynyl is optionally substituted with oxo, halogen, -CN, -CF3, -OH, -OMe, -NH2, or -N02. In some embodiments, an alkynyl is optionally substituted with oxo, halogen, -CN, -CF3, -OH, or -OMe.
[0067] "Alkylene" refers to a straight or branched divalent hydrocarbon chain. Unless stated otherwise specifically in the specification, an alkylene group may be optionally substituted as described below, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an alkylene is optionally substituted with oxo, halogen, -CN, -CF3, -OH, -OMe, -NH2, or -N02. In some embodiments, an alkylene is optionally substituted with oxo, halogen, -CN, -CF3, -OH, or -OMe.
[0068] "Alkoxy" refers to a radical of the formula -ORa where Ra is an alkyl radical as defined.
Unless stated otherwise specifically in the specification, an alkoxy group may be optionally substituted as described below, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an alkoxy is optionally substituted with oxo, halogen, -CN, -CF3, -OH, -OMe, -NH2, or -N02. In some embodiments, an alkoxy is optionally substituted with oxo, halogen, -CN, -CF3, -OH, or -OMe.
[0069] "Aryl" refers to a radical derived from a hydrocarbon ring system comprising hydrogen, 6 to 30 carbon atoms and at least one aromatic ring. The aryl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the aryl is bonded through an aromatic ring atom) or bridged ring systems. In some embodiments, the aryl is a 6- to 10-membered aryl. In some embodiments, the aryl is a 6-membered aryl. Aryl radicals include, but are not limited to, aryl radicals derived from the hydrocarbon ring systems of anthrylene, naphthylene, phenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as- indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. In some embodiments, the aryl is phenyl. Unless stated otherwise specifically in the specification, an aryl may be optionally substituted as described below, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -N02. In some embodiments, an aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe.
[0070] "Cycloalkyl" refers to a stable, partially or fully saturated, monocyclic or polycyclic carbocyclic ring, which may include fused (when fused with an aryl or a heteroaryl ring, the cycloalkyl is bonded through a non-aromatic ring atom) or bridged ring systems. Representative cycloalkyls include, but are not limited to, cycloalkyls having from three to fifteen carbon atoms (C3-C15 cycloalkyl), from three to ten carbon atoms (C3-Ci0 cycloalkyl), from three to eight carbon atoms (C3-C8 cycloalkyl), from three to six carbon atoms (C3-C6 cycloalkyl), from three to five carbon atoms (C3-C5 cycloalkyl), or three to four carbon atoms (C3-C4 cycloalkyl). In some embodiments, the cycloalkyl is a 3- to 6-membered cycloalkyl. In some embodiments, the cycloalkyl is a 5 - to 6-membered cycloalkyl. Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyls or carbocycles include, for example, adamantyl, norbornyl, decalinyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decalin, trans-decalin, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, and bicyclo[3.3.2]decane, and
7,7-dimethyl-bicyclo[2.2.1]heptanyl. Partially saturated cycloalkyls include, for example cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless stated otherwise specifically in the specification, a cycloalkyl is optionally substituted as described below, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -N02. In some embodiments, a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe.
[0071] "Halo" or "halogen" refers to bromo, chloro, fluoro or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro.
[0072] "Haloalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl,
2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like.
[0073] "Heterocycloalkyl" refers to a stable 3- to 24-membered partially or fully saturated ring radical comprising 2 to 23 carbon atoms and from one to 8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous and sulfur. Unless stated otherwise specifically in the specification, the heterocycloalkyl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused (when fused with an aryl or a heteroaryl ring, the heterocycloalkyl is bonded through a non-aromatic ring atom) or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heterocycloalkyl radical may be optionally oxidized; the nitrogen atom may be optionally quatemized. In some embodiments, the heterocycloalkyl is a 3- to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 5 - to 6-membered heterocycloalkyl. Examples of such heterocycloalkyl radicals include, but are not limited to, aziridinyl, azetidinyl, dioxolanyl, thienyl[l,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomo holinyl,
ΐηϊαηιοφΐιοΐϊηνΐ,
Figure imgf000021_0001
l,l-dioxo-thiomoφholinyl, 1,3-dihydroisobenzofuran-l-yl, 3- oxo-l,3-dihydroisobenzofuran-l-yl, methyl-2-oxo-l,3-dioxol-4-yl, and 2-oxo-l,3-dioxol-4-yl. The term heterocycloalkyl also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides and the oligosaccharides. Unless otherwise noted, heterocycloalkyls have from 2 to 10 carbons in the ring. It is understood that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including the heteroatoms) that make up the heterocycloalkyl (i.e. skeletal atoms of the heterocycloalkyl ring). Unless stated otherwise specifically in the specification, a heterocycloalkyl is optionally substituted as described below, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, a heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, - CF3, -OH, -OMe, -NH2, or -N02. In some embodiments, a heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe.
[0074] "Heteroalkyl" refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g. -NH-, -N(alkyl)-), sulfur, or combinations thereof. A heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. In one aspect, a heteroalkyl is a Ci-C6 heteroalkyl. Unless stated otherwise specifically in the specification, a Heteroalkyl is optionally substituted as described below, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl,
heterocycloalkyl, heteroaryl, and the like. In some embodiments, a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -N02. In some embodiments, a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe.
[0075] "Heteroaryl" refers to a 5 - to 14-membered ring system radical comprising hydrogen atoms, one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous and sulfur, and at least one aromatic ring. The heteroaryl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the heteroaryl is bonded through an aromatic ring atom) or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heteroaryl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized. In some embodiments, the heteroaryl is a 5- to 10-membered heteroaryl. In some embodiments, the heteroaryl is a 5 - to 6-membered heteroaryl. Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][l,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[l,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1 -phenyl -lH-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless stated otherwise specifically in the specification, a heteroaryl is optionally substituted as described below, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, a heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -N02. In some embodiments, a heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe.
[0076] All the above groups may be either substituted or unsubstituted. The term "substituted" as used herein means any of the above groups (e.g., alkyl, alkylene, alkoxy, aryl, cycloalkyl, haloalkyl, heterocyclyl and/or heteroaryl) may be further functionalized wherein at least one hydrogen atom is replaced by a bond to a non-hydrogen atom substituent. Unless stated specifically in the specification, a substituted group may include one or more substituents selected from: oxo, amino, -C02H, nitrile, nitro, hydroxyl, thiooxy, alkyl, alkylene, alkoxy, aryl, cycloalkyl, heterocyclyl, heteroaryl, dialkylamines, arylamines, alkylarylamines, diarylamines, trialkylammonium (-N+R3), N-oxides, imides, and enamines; a silicon atom in groups such as trialkylsilyl groups, dialkylarylsilyl groups, alkyldiarylsilyl groups, triarylsilyl groups, perfluoroalkyl, or perfluoroalkoxy, for example, trifluoromethyl or trifluoromethoxy. "Substituted" also means any of the above groups in which one or more hydrogen atoms are replaced by a higher-order bond (e.g. , a double- or triple-bond) to a heteroatom such as oxygen in oxo, carbonyl, carboxyl, and ester groups; and nitrogen in groups such as imines, oximes, hydrazones, and nitriles. For example, "substituted" includes any of the above groups in which one or more hydrogen atoms are replaced with -NH2, -NRgC(=0)NRgRh, -NRgC(=0)ORh, -NRgS02Rh, -OC(=0)NRgRh, -ORg, -SRg, - SORg, -S02Rg, -OS02Rg, -S02ORg, =NS02Rg, and -S02NRgRh. In the foregoing, Rg and Rh are the same or different and independently hydrogen, alkyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl and/or heteroarylalkyl. In addition, each of the foregoing substituents may also be optionally substituted with one or more of the above substituents. Furthermore, any of the above groups may be substituted to include one or more internal oxygen, sulfur, or nitrogen atoms. For example, an alkyl group may be substituted with one or more internal oxygen atoms to form an ether or polyether group. Similarly, an alkyl group may be substituted with one or more internal sulfur atoms to form a thioether, disulfide, etc.
[0077] The terms "treat," "prevent," "ameliorate," and "inhibit," as well as words stemming therefrom, as used herein, do not necessarily imply 100% or complete treatment, prevention, amelioration, or inhibition. Rather, there are varying degrees of treatment, prevention, amelioration, and inhibition of which one of ordinary skill in the art recognizes as having a potential benefit or therapeutic effect. In this respect, the disclosed methods can provide any amount of any level of treatment, prevention, amelioration, or inhibition of the disorder in a mammal. For example, a disorder, including symptoms or conditions thereof, may be reduced by, for example, about 100%, about 90%, about 80%, about 70%, about 60%, about 50%, about 40%, about 30%, about 20%, or about 10%. Furthermore, the treatment, prevention, amelioration, or inhibition provided by the methods disclosed herein can include treatment, prevention, amelioration, or inhibition of one or more conditions or symptoms of the disorder, e.g., cancer or an inflammatory disease. Also, for purposes herein, "treatment," "prevention," "amelioration," or "inhibition" encompass delaying the onset of the disorder, or a symptom or condition thereof.
[0078] The terms "effective amount" or "therapeutically effective amount," as used herein, refer to a sufficient amount of a compound di sclosed herein being administered which will relieve to some extent one or more of the symptoms of the disease or condition being treated, e.g., cancer or an inflammatory disease. In some embodiments, the result is a reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an "effective amount" for therapeutic uses is the amount of the composition comprising a compound disclosed herein required to provide a clinically significant decrease in disease symptoms. In some embodiments, an appropriate "effective" amount in any individual case is determined using techniques, such as a dose escalation study.
Compounds
[0079] Described herein are compounds of Formula (I), (la), (II), (Ila), (IIP), (HI), (ma), (IV), or (IVa) that are PI3 Kinase inhibitors. These compounds, and compositions comprising these compounds, are useful for the treatment of cancer and inflammatory diseases.
[0080] Diclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
Figure imgf000023_0001
Formula (I)
wherein
each R1 is independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=0)Rc, -N02, -NRaRb, -
S(=0)2Rc, -NRaS(=0)2Rc, -S(=0)2NRaRb, -C(=0)Rc, -OC(=0)Rc, -C(=0)ORa, -OC(=0)ORa, -C(=0)NRaRb, -OC(=0)NRaRb, -NRaC(=0)NRaRb, -NRaC(=0)Rc, -NRaC(=0)ORa, optionally substituted Ci-C6 alkyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted cycloalkyl, optionally substituted (Ci-C6 alkyl)cycloalkyl, optionally substituted
heterocycloalkyl, optionally substituted (Ci-C6 alkyl)heterocycloalkyl, optionally substituted aryl, optionally substituted (Ci-C6 alkyl)aryl, optionally substituted heteroaryl, or optionally substituted (Ci-C6 alkyl)heteroaryl;
R2 is halogen, -CN, -ORa, -SRa, -S(=0)Rc, -N02, -NRaRb, -S(=0)2Rc, -NRaS(=0)2Rc, - S(=0)2NRaRb, -C(=0)Rc, -OC(=0)Rc, -C(=0)ORa, -OC(=0)ORa, -C(=0)NRaRb, - OC(=0)NRaRb, -NRaC(=0)NRaRb, -NRaC(=0)Rc, -NRaC(=0)ORa, optionally substituted C C6 alkyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted cycloalkyl, optionally substituted (Ci-C6 alkyl)cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted (Ci- C6 alkyl)heterocycloalkyl, optionally substituted aryl, optionally substituted (Ci-C6 alkyl)aryl, optionally substituted heteroaryl, or optionally substituted (Ci-C6 alkyl)heteroaryl;
R3 is -SRa, -S(=0)Rc, -S(=0)2Rc, -S(=0)2NRaRb, -C(=0)Rc, -C(=0)NRaRb, optionally substituted Ci-C6 alkyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted cycloalkyl, optionally substituted (Ci-C<5 alkyl)cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted (Ci- C6 alkyl)heterocycloalkyl, optionally substituted aryl, optionally substituted (Ci-C6 alkyl)aryl, optionally substituted heteroaryl, or optionally substituted (Ci-C6 alkyl)heteroaryl;
R4 is hydrogen, halogen, -CN, -ORa, -SRa, -S(=0)Rc, -N02, -NRaRb, -S(=0)2Rc, -NRaS(=0)2Rc, - S(=0)2NRaRb, -C(=0)Rc, -OC(=0)Rc, -C(=0)ORa, -OC(=0)ORa, -C(=0)NRaRb, - OC(=0)NRaRb, -NRaC(=0)NRaRb, -NRaC(=0)Rc, -NRaC(=0)ORa, optionally substituted d- C6 alkyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted cycloalkyl, optionally substituted (Ci-C6 alkyl)cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted (Ci- C6 alkyl)heterocycloalkyl, optionally substituted aryl, optionally substituted (Ci-C6 alkyl)aryl, optionally substituted heteroaryl, or optionally substituted (Ci-C6 alkyl)heteroaryl;
R5 and R6 are independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=0)Rc, -N02, -NRaRb, - S(=0)2Rc, -NRaS(=0)2Rc, -S(=0)2NRaRb, -C(=0)Rc, -OC(=0)Rc, -C(=0)ORa, -OC(=0)ORa, -C(=0)NRaRa, -OC(=0)NRaRb, -NRaC(=0)NRaRb, -NRaC(=0)Rc, -NRaC(=0)ORc, optionally substituted Ci-C6 alkyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, or optionally substituted C2-C6 alkynyl;
R7 and R8 are independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=0)Rc, -N02, -NRaRb, - S(=0)2Rc, -NRaS(=0)2Rc, -S(=0)2NRaRb, -C(=0)Rc, -OC(=0)Rc, -C(=0)ORa, -OC(=0)ORa, -C(=0)NRaRa, -OC(=0)NRaRb, -NRaC(=0)NRaRb, -NRaC(=0)Rc, -NRaC(=0)ORc, optionally substituted Ci-C6 alkyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, or optionally substituted C2-C6 alkynyl;
or R7 and R8 are taken together to form an oxo; R9 is hydrogen, halogen, -CN, -ORa, -SRa, -S(=0)Rc, -N02, -NRaRb, -S(=0)2Rc, -NRaS(=0)2Rc, - S(=0)2NRaRb, -C(=0)Rc, -OC(=0)Rc, -C(=0)ORa, -OC(=0)ORa, -C(=0)NRaRb, - OC(=0)NRaRb, -NRaC(=0)NRaRb, -NRaC(=0)Rc, -NRaC(=0)ORa, optionally substituted d- C<5 alkyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted cycloalkyl, optionally substituted (Ci-C6 alkyl)cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted (Ci- C6 alkyl)heterocycloalkyl, optionally substituted aryl, optionally substituted (Ci-C6 alkyl)aryl, optionally substituted heteroaryl, or optionally substituted (Ci-C6 alkyl)heteroaryl;
R10 is hydrogen, -SRa, -S(=0)Rc, -S(=0)2Rc, -S(=0)2NRaRb, -C(=0)Rc, -C(=0)NRaRb, optionally substituted Ci-C6 alkyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted cycloalkyl, optionally substituted (Ci-C6 alkyl)cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted (Ci-C6 alkyl)heterocycloalkyl, optionally substituted aryl, optionally substituted (Ci-C6 alkyl)aryl, optionally substituted heteroaryl, or optionally substituted (Ci-C6 alkyl)heteroaryl;
is a double bond or a single bond;
X is N or CRX when is a double bond; or X is NRX3 or CRX1RX2 when is a single bond;
Rx, RX1, and RX2 are independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=0)Rc, -N02, - NRaRb, -S(=0)2Rc, -NRaS(=0)2Rc, -S(=0)2NRaRb, -C(=0)Rc, -OC(=0)Rc, -C(=0)ORa, - OC(=0)ORa, -C(=0)NRaRb, -OC(=0)NRaRb, -NRaC(=0)NRaRb, -NRaC(=0)Rc, - NRaC(=0)ORa, optionally substituted Ci-C6 alkyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted cycloalkyl, optionally substituted (Ci-C6 alkyl)cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted (Ci-C6 alkyl)heterocycloalkyl, optionally substituted aryl, optionally substituted (Ci-C6 alkyl)aryl, optionally substituted heteroaryl, or optionally substituted (Ci-C6 alkyl)heteroaryl;
Y is N or CRY when is a double bond; or Y is NRY3 or CRY1RY2 when is a single bond;
RY, RY1, and RY2 are independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=0)Rc, -N02, - NRaRb, -S(=0)2Rc, -NRaS(=0)2Rc, -S(=0)2NRaRb, -C(=0)Rc, -OC(=0)Rc, -C(=0)ORa, - OC(=0)ORa, -C(=0)NRaRb, -OC(=0)NRaRb, -NRaC(=0)NRaRb, -NRaC(=0)Rc, - NRaC(=0)ORa, optionally substituted Ci-C6 alkyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted cycloalkyl, optionally substituted (Ci-C6 alkyl)cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted (Ci-C6 alkyl)heterocycloalkyl, optionally substituted aryl, optionally substituted (Ci-C6 alkyl)aryl, optionally substituted heteroaryl, or optionally substituted (Ci-C6 alkyl)heteroaryl; RX3 and RY3 are independently hydrogen, -SRa, -S(=0)Rc, -S(=0)2Rc, -S(=0)2NRaRb, -C(=0)Rc, - C(=0)NRaRb, optionally substituted Ci-C6 alkyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted cycloalkyl, optionally substituted (Ci-C6 alkyl)cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted (Ci-C6 alkyl)heterocycloalkyl, optionally substituted aryl, optionally substituted (Ci-C6 alkyl)aryl, optionally substituted heteroaryl, or optionally substituted (Ci-C6 alkyl)heteroaryl;
each Ra and Rb are independently hydrogen, optionally substituted Ci-C6 alkyl, optionally
substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
or Ra and Rb are taken together with the nitrogen atom to which they are attached to form an optionally substituted heterocycloalkyl;
each Rc is optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; and n is 1-3.
[0081] In some embodiments of a compound of Formula (I), n is 1. In some embodiments of a compound of Formula (I), n is 2. In some embodiments of a compound of Formula (I), n is 3.
[0082] In some embodiments of a compound of Formula (I), each R1 is independently hydrogen, halogen, -CN, -OH, -OMe, -NH2, Ci-C6 alkyl, or Ci-C6 haloalkyl; and n is 1 or 2. In some embodiments of a compound of Formula (I), each R1 is independently hydrogen, halogen, Ci-C6 alkyl, or Ci-C6 haloalkyl; and n is 1 or 2. In some embodiments of a compound of Formula (I), R1 is halogen, Ci-C6 alkyl, or Ci-C6 haloalkyl; and n is 1. In some embodiments of a compound of Formula (I), R1 is halogen; and n is 1. In some embodiments of a compound of Formula (I), each R1 is hydrogen.
[0083] In some embodiments of a compound of Formula (I), R3 is optionally substituted Ci-C6 alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl. In some embodiments of a compound of Formula (I), R3 is optionally substituted aryl. In some embodiments of a compound of Formula (I), R3 is optionally substituted with halogen, -CN, -OH, -OMe, -NH2, Ci-C6 alkyl, or Ci-C6 haloalkyl. In some embodiments of a compound of Formula (I), R3 is optionally substituted with halogen, Ci-C6 alkyl, or Ci-C6 haloalkyl. In some embodiments of a compound of Formula (I), R3 is unsubstituted aryl or unsusbituted heteroaryl. In some embodiments of a compound of Formula (I), R3 is unsubstituted aryl. In some embodiments of a compound of Formula (I), R3 is unsubstituted phenyl.
[0084] In some embodiments of a compound of Formula (I), R4 is hydrogen, halogen, -CN, -OH, -OMe, -NH2, Ci-C<5 alkyl, or Ci-C6 haloalkyl. In some embodiments of a compound of Formula (I), R4 is hydrogen, halogen, Ci-C6 alkyl, or Ci-C6 haloalkyl. In some embodiments of a compound of Formula (I), R4 is hydrogen or halogen. In some embodiments of a compound of Formula (I), R4 is hydrogen. [0085] In some embodiments of a compound of Formula (I), R5 and R6 are independently hydrogen, halogen, Ci-C6 alkyl, or Ci-C6 haloalkyl. In some embodiments of a compound of Formula (I), R5 and R6 are independently hydrog en or Ci-Cg alkyl.
[0086] In some embodiments of a compound of Formula (I), the compound is of Formula (la), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
Figure imgf000027_0001
Formula (la).
[0087] In some embodiments of a compound of Formula (I) or (la), R2 is halogen, -CN, -ORa, -NRaRb, optionally substituted Ci-C6 alkyl, optionally substituted Ci-C6 heteroalkyl, or optionally substituted C2- C6 alkynyl. In some embodiments of a compound of Formula (I) or (la), R2 is halogen, optionally substituted Ci-C6 alkyl, or optionally substituted C2-C6 alkynyl. In some embodiments of a compound of Formula (I) or (la), R2 is halogen. In some embodiments of a compound of Formula (I) or (la), R2 is fluoro or chloro. In some embodiments of a compound of Formula (I) or (la), R2 is chloro. In some embodiments of a compound of Formula (I) or (la), R2 is Ci-C6 alkyl or Ci-C6 haloalkyl. In some embodiments of a compound of Formula (I) or (la), R2 is methyl. In some embodiments of a compound of Formula (I) or (la), R2 is C2-C6 alkynyl optionally substituted with optionally substituted Ci-C6 alkyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted cycloalkyl, optionally substituted (Ci-C6 alkyl)cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted (Ci-C6
alkyl)heterocycloalkyl, optionally substituted aryl, optionally substituted (Ci-C6 alkyl)aryl, optionally substituted heteroaryl, or optionally substituted (Ci-C6 alkyl)heteroaryl. In some embodiments of a compound of Formula (I) or (la), R2 is C2-C6 alkynyl optionally substituted with optionally substituted heteroaryl. In so odiments of a compound of Formula (I) or (la), R2 is C2-C6 alkynyl optionally
substituted with
Figure imgf000027_0002
[0088] In some embodiments of a compound of Formula (I) or (la), R7 and R8 are taken together to form an oxo. In some embodiments of a compound of Formula (I) or (la), R7 and R8 are independently hydrogen, halogen, -CN, -OH, -OMe, -NH2, Ci-C6 alkyl, or Ci-C6 haloalkyl.
[0089] In some embodiments of a compound of Formula (I) or (la), R9 is hydrogen, halogen, -CN, -OH, -OMe, -NH2, Ci-C6 alkyl, or Ci-C6 haloalkyl. In some embodiments of a compound of Formula (I) or (la), R9 is -NH2. [0090] In some embodiments of a compound of Formula (I) or (la), R is hydrogen or optionally substituted Ci-C6 alkyl. In some embodiments of a compound of Formula (I) or (la), R10 is Ci-C6 alkyl.
[0091] In some embodiments of a compound of Formula (I) or (la), is a double bond. In some embodiments of a compound of Formula (I) or (la), is a double bond; X is CRX; and Y is N. In some embodiments of a compound of Formula (I) or (la), is a double bond; Y is CRY; and X is N. In some embodiments of a compound of Formula (I) or (la), is a double bond; X is CRX; and Y is CRY. In some embodiments of a compound of Formula (I) or (la), Rx is hydrogen, halogen, -CN, -OH, - OMe, -NH2, d-C6 alkyl, or d-C6 haloalkyl; and RY is hydrogen, halogen, -CN, -OH, -OMe, -NH2, d-Q, alkyl, or Ci-C6 haloalkyl. In some embodiments of a compound of Formula (I) or (la), Rx is hydrogen, halogen, Ci-C6 alkyl, or Ci-C6 haloalkyl; and RY is hydrogen, halogen, Ci-C6 alkyl, or Ci-C6 haloalkyl. In some embodiments of a compound of Formula (I) or (la), Rx is hydrogen; and RY is hydrogen.
[0092] In some embodiments of a compound of Formula (I) or (la), is a single bond.
[0093] In some embodiments of a compound of Formula (I) or (la), is a single bond; X is
Yl Y2
CR R ; and Y is CR R . In some embodiments of a compound of Formula (I) or (la), is a single bond; X is NR ; and Y is CR^R1'. In some embodiments of a compound of Formula (I) or (la), is
Y3
a sing le bond; X is CR R ; and Y is NR1 J. In some embodiments of a compound of Formula (I) or (la), is a single bond; X is NRX3; and Y is NRY3.
[0094] In some embodiments of a compound of Formula (I) or (la), RX1 and RX2 are independently hydrogen, halogen, -CN, -OH, -OMe, -NH2, d-C6 alkyl, or d-C6 haloalkyl; and RY1 and RY2 are independently hydrogen, halogen, -CN, -OH, -OMe, -NH2, Ci-C6 alkyl, or Ci-C6 haloalkyl. In some embodiments of a compound of Formula (I) or (la), RX1 and RX2 are independently hydrogen, halogen, Ci-C<5 alkyl, or Ci-C6 haloalkyl; and RY1 and RY2 are independently hydrogen, halogen, Ci-C6 alkyl, or Ci-C<5 haloalkyl. In some embodiments of a compound of Formula (I) or (la), RX1 and RX2 are hydrogen;
Y 1 Y2 Y3 and R and R are hydrogen. In some embodiments of a compound of Formula (I) or (la), R and R are independently hydrogen, Ci-C6 alkyl, or Ci-C6 haloalkyl. In some embodiments of a compound of Formula (I) or (la), RX3 and RY3 are independently hydrog en or ~d alkyl.
In some embodiments of a compound of Formula (I) or (la),
Figure imgf000028_0001
[0095] In some embodiments of a compound of Formula (I) or (la), each Ra and Rb are independently hydrogen or optionally substituted Ci-C6 alkyl; or Ra and Rb are taken together with the nitrogen atom to which they are attached to form an optionally substituted heterocycloalkyl.
[0096] In some embodiments of a compound of Formula (I) or (la), each Rc is optionally substituted Ci- C<5 alkyl.
[0097] Also disclosed herein is a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
Figure imgf000029_0001
wherein
each R11 is independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=0)Rc, -N02, -NRaRb, -
S(=0)2Rc, -NRaS(=0)2Rc, -S(=0)2NRaRb, -C(=0)Rc, -OC(=0)Rc, -C(=0)ORa, -OC(=0)ORa, -C(=0)NRaRb, -OC(=0)NRaRb, -NRaC(=0)NRaRb, -NRaC(=0)Rc, -NRaC(=0)ORa, optionally substituted Ci-C6 alkyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted cycloalkyl, optionally substituted (Ci-C6 alkyl)cycloalkyl, optionally substituted
heterocycloalkyl, optionally substituted (Ci-C6 alkyl)heterocycloalkyl, optionally substituted aryl, optionally substituted (Ci-C6 alkyl)aryl, optionally substituted heteroaryl, or optionally substituted (Ci-C6 alkyl)heteroaryl;
R12 is optionally substituted Ci-C6 alkyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted cycloalkyl, optionally substituted (Ci-C6 alkyl)cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted (Ci-C6 alkyl)heterocycloalkyl, optionally substituted aryl, optionally substituted (Ci-C6 alkyl)aryl, optionally substituted heteroaryl, or optionally substituted (Ci-C6 alkyl)heteroaryl;
R13 is -SRa, -S(=0)Rc, -S(=0)2Rc, -S(=0)2NRaRb, -C(=0)Rc, -C(=0)NRaRb, optionally
substituted Ci-C6 alkyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted cycloalkyl, optionally substituted (Ci-C6 alkyl)cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted (Ci-C6 alkyl)heterocycloalkyl, optionally substituted aryl, optionally substituted (Ci-C<5 alkyl)aryl, optionally substituted heteroaryl, or optionally substituted (Ci-C6 alkyl)heteroaryl;
R14 is hydrogen, halogen, -CN, -ORa, -SRa, -S(=0)Rc, -N02, -NRaRb, -S(=0)2Rc, -NRaS(=0)2Rc, -S(=0)2NRaRb, -C(=0)Rc, -OC(=0)Rc, -C(=0)ORa, -OC(=0)ORa, -C(=0)NRaRb, - OC(=0)NRaRb, -NRaC(=0)NRaRb, -NRaC(=0)Rc, -NRaC(=0)ORa, optionally substituted d- C6 alkyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted cycloalkyl, optionally substituted (Ci-C<5 alkyl)cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted (Ci- C6 alkyl)heterocycloalkyl, optionally substituted aryl, optionally substituted (Ci-C6 alkyl)aryl, optionally substituted heteroaryl, or optionally substituted (Ci-C6 alkyl)heteroaryl; R15 and R16 are independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=0)Rc, -N02, -NRaRb, - S(=0)2Rc, -NRaS(=0)2Rc, -S(=0)2NRaRb, -C(=0)Rc, -OC(=0)Rc, -C(=0)ORa, -OC(=0)ORa, -C(=0)NRaRa, -OC(=0)NRaRb, -NRaC(=0)NRaRb, -NRaC(=0)Rc, -NRaC(=0)ORc, optionally substituted Ci-C6 alkyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, or optionally substituted C2-C6 alkynyl;
Ring A is an optionally substituted heteroaryl or an optionally substituted heterocycloalkyl; each Ra and Rb are independently hydrogen, optionally substituted Ci-C6 alkyl, optionally
substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
or Ra and Rb are taken together with the nitrogen atom to which they are attached to form an optionally substituted heterocycloalkyl;
each Rc is optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; and nl is 1-3.
[0098] In some embodiments of a compound of Formula (II), nl is 1. In some embodiments of a compound of Formula (II), nl is 2. In some embodiments of a compound of Formula (II), nl is 3.
[0099] In some embodiments of a compound of Formula (II), each R11 is independently hydrogen, halogen, -CN, -OH, -OMe, -NH2, Ci-C6 alkyl, or Ci-C6 haloalkyl; and nl is 1 or 2. In some embodiments of a compound of Formula (II), each R11 is independently hydrogen, halogen, Ci-C6 alkyl, or Ci-C6 haloalkyl; and nl is 1 or 2. In some embodiments of a compound of Formula (II), R11 is halogen, Ci-C6 alkyl, or Ci-C6 haloalkyl; and nl is 1. In some embodiments of a compound of Formula (II), R11 is halogen; and nl is 1. In some embodiments of a compound of Formula (II), each R11 is hydrogen.
[00100] In some embodiments of a compound of Formula (II), R13 is optionally substituted Ci-C6 alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl. In some embodiments of a compound of Formula (II), R13 is optionally substituted aryl. In some embodiments of a compound of Formula (II), R13 is optionally substituted with halogen, -CN, -OH, -OMe, -NH2, Ci-C6 alkyl, or Ci-C6 haloalkyl. In some embodiments of a compound of Formula (II), R13 is optionally substituted with halogen, Ci-C6 alkyl, or Ci-C6 haloalkyl. In some embodiments of a compound of Formula (II), R13 is unsubstituted aryl or unsusbituted heteroaryl. In some embodiments of a compound of Formula (II), R13 is unsubstituted aryl. In some embodiments of a compound of Formula (II), R13 is unsubstituted phenyl.
[00101] In some embodiments of a compound of Formula (II), R14 is hydrogen, halogen, -CN, -OH, - OMe, -NH2, Ci-C<5 alkyl, or Ci-C6 haloalkyl. In some embodiments of a compound of Formula (II), R14 is hydrogen, halogen, Ci-C6 alkyl, or Ci-C6 haloalkyl. In some embodiments of a compound of Formula (II), R14 is hydro gen or halogen. In some embodiments of a compound of Formula (II), R14 is hydrogen. [00102] In some embodiments of a compound of Formula (II), R and R are independently hydrogen, halogen, Ci-C6 alkyl, or Ci-C6 haloalkyl. In some embodiments of a compound of Formula (II), R15 and R16 are independently hydrogen or Ci-C6 alkyl.
[00103] In some embodiments of a compound of Formula (II), the compound is of Formula (Ila), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
Figure imgf000031_0001
[00104] In some embodiments of a compound of Formula (II) or (Ila), R is optionally substituted heterocycloalkyl or optionally substituted heteroaryl. In some embodiments of a compound of Formula (II) or (Ila), R12 is optionally substituted heteroaryl.
[00105] In some embodiments of a compound of Formula (II) or (Ila), R12 is an optionally substituted 5-membered heteroaryl. In some embodiments of a compound of Formula (II) or (Ila), R12 is a 5- membered heteroaryl optionally substituted with halogen, -CN, -OH, -OMe, -NH2, Ci-C6 alkyl, or Ci-C6
haloalkyl. In some embodiments of a compound of Formula (II) or (Ila), R is
Figure imgf000031_0002
.
[00106] In some embodiments of a compound of Formula (II) or (Ila), Ring A is an optionally substituted heteroaryl. In some embodiments of a compound of Formula (II) or (Ila), Ring A is an optionally substituted N-linked heteroaryl. In some embodiments of a compound of Formula (II) or (Ila), Ring A is an optionally substituted C-linked heteroaryl. In some embodiments of a compound of Formula (II) or (Ila), Ring A is an optionally substituted heterocycloalkyl. In some embodiments of a compound of Formula (II) or (Ila), Ring A is an optionally substituted N-linked heterocycloalkyl. In some embodiments of a compound of Formula (II) or (Ila), Ring A is an optionally substituted C-linked heterocycloalkyl. In some embodiments of a compound of Formula (II) or (Ila), Ring A is optionally substituted with oxo, halogen, -CN, -ORa, -SRa, -S(=0)Rc, -N02, -NRaRb, -S(=0)2Rc, -NRaS(=0)2Rc, - S(=0)2NRaRb, -C(=0)Rc, -OC(=0)Rc, -C(=0)ORa, -OC(=0)ORa, -C(=0)NRaRb, -OC(=0)NRaRb, - NRaC(=0)NRaRb, -NRaC(=0)Rc, -NRaC(=0)ORa, optionally substituted C C6 alkyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl. In some embodiments of a compound of Formula (II) or (Ila), Ring A is optionally substituted with oxo, halogen, -CN, -OH, -OMe, -NH2, Ci-C6 alkyl, or Ci-C6 haloalkyl. In
some embodiments of a compound of Formula (II) or (Ila), Ring A
Figure imgf000032_0001
wherein:
R17 and R18 are independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=0)Rc, -N02, -NRaRb, - S(=0)2Rc, -NRaS(=0)2Rc, -S(=0)2NRaRb, -C(=0)Rc, -OC(=0)Rc, -C(=0)ORa, -OC(=0)ORa, -C(=0)NRaRa, -OC(=0)NRaRb, -NRaC(=0)NRaRb, -NRaC(=0)Rc, -NRaC(=0)ORc, optionally substituted Ci-C6 alkyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, or optionally substituted C2-C6 alkynyl;
or R17 and R18 on the same carbon are taken together to form an oxo;
R19 is hydrogen, halogen, -CN, -ORa, -SRa, -S(=0)Rc, -N02, -NRaRb, -S(=0)2Rc, -NRaS(=0)2Rc, -S(=0)2NRaRb, -C(=0)Rc, -OC(=0)Rc, -C(=0)ORa, -OC(=0)ORa, -C(=0)NRaRb, - OC(=0)NRaRb, -NRaC(=0)NRaRb, -NRaC(=0)Rc, -NRaC(=0)ORa, optionally substituted C C6 alkyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted cycloalkyl, optionally substituted (Ci-C6 alkyl)cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted (Ci- C6 alkyl)heterocycloalkyl, optionally substituted aryl, optionally substituted (Ci-C6 alkyl)aryl, optionally substituted heteroaryl, or optionally substituted (Ci-C6 alkyl)heteroaryl;
R20 is hydrogen, -SRa, -S(=0)Rc, -S(=0)2Rc, -S(=0)2NRaRb, -C(=0)Rc, -C(=0)NRaRb, optionally substituted Ci-C6 alkyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted cycloalkyl, optionally substituted (Ci-C6 alkyl)cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted (Ci-C6 alkyl)heterocycloalkyl, optionally substituted aryl, optionally substituted (Ci-C<5 alkyl)aryl, optionally substituted heteroaryl, or optionally substituted (Ci-C6 alkyl)heteroaryl;
is a double bond or a single bond;
X is N or CRX when is a double bond; or X is NRX3 or CRX1RX2 when = is a single bond;
Rx, RX1, and RX2 are independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=0)Rc, -N02, - NRaRb, -S(=0)2Rc, -NRaS(=0)2Rc, -S(=0)2NRaRb, -C(=0)Rc, -OC(=0)Rc, -C(=0)ORa, - OC(=0)ORa, -C(=0)NRaRb, -OC(=0)NRaRb, -NRaC(=0)NRaRb, -NRaC(=0)Rc, - NRaC(=0)ORa, optionally substituted Ci-C6 alkyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted cycloalkyl, optionally substituted (Ci-C6 alkyl)cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted (Ci-C6 alkyl)heterocycloalkyl, optionally substituted aryl, optionally substituted (Ci-C6 alkyl)aryl, optionally substituted heteroaryl, or optionally substituted (Ci-C6 alkyl)heteroaryl;
Y is N or CRY when is a double bond; or Y is NRY3 or CRY1RY2 when is a single bond;
RY RY1, and RY2 are independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=0)Rc, -N02, - NRaRb, -S(=0)2Rc, -NRaS(=0)2Rc, -S(=0)2NRaRb, -C(=0)Rc, -OC(=0)Rc, -C(=0)ORa, - OC(=0)ORa, -C(=0)NRaRb, -OC(=0)NRaRb, -NRaC(=0)NRaRb, -NRaC(=0)Rc, - NRaC(=0)ORa, optionally substituted Ci-C6 alkyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted cycloalkyl, optionally substituted (Ci-C6 alkyl)cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted (Ci-C6 alkyl)heterocycloalkyl, optionally substituted aryl, optionally substituted (Ci-C6 alkyl)aryl, optionally substituted heteroaryl, or optionally substituted (Ci-C6 alkyl)heteroaryl; and
RX3 and RY3 are independently hydrogen, -SRa, -S(=0)Rc, -S(=0)2Rc, -S(=0)2NRaRb, -C(=0)Rc, - C(=0)NRaRb, optionally substituted Ci-C6 alkyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted cycloalkyl, optionally substituted (Ci-C6 alkyl)cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted (Ci-C6 alkyl)heterocycloalkyl, optionally substituted aryl, optionally substituted (Ci-C6 alkyl)aryl, optionally substituted heteroaryl, or optionally substituted (Ci-C6 alkyl)heteroaryl.
[00107] In some embodiments of a compound of Formula (II) or (Ila), R17 and R18 on the same carbon are taken together to form an oxo. In some embodiments of a compound of Formula (II) or (Ila), R17 and R18 are independently hydrogen, halogen, -CN, -OH, -OMe, -NH2, Ci-C6 alkyl, or Ci-C6 haloalkyl.
[00108] In some embodiments of a compound of Formula (II) or (Ila), R19 is hydrogen, halogen, -CN, - OH, -OMe, -NH2, Ci-C6 alkyl, or Ci-C6 haloalkyl. In some embodiments of a compound of Formula (II) or (Ila), R19 is -NH2.
[00109] In some embodiments of a compound of Formula (II) or (Ila), R20 is hydrogen or optionally substituted Ci-C6 alkyl. In some embodiments of a compound of Formula (II) or (Ila), R20 is Ci-C6 alkyl.
[00110] In some embodiments of a compound of Formula (II) or (Ila), is a double bond. In some embodiments of a compound of Formula (II) or (Ila), is a double bond; X is CRX; and Y is N. In some embodiments of a compound of Formula (II) or (Ila), is a double bond; Y is CRY; and X is N. In some embodiments of a compound of Formula (II) or (Ila), is a double bond; X is CRX; and Y is CRY. In some embodiments of a compound of Formula (II) or (Ila), Rx is hydrogen, halogen, -CN, -OH, -OMe, -NH2, Ci-Q alkyl, or Ci-C6 haloalkyl; and RY is hydrogen, halogen, -CN, -OH, -OMe, -NH2, Ci- C<5 alkyl, or Ci-C6 haloalkyl. In some embodiments of a compound of Formula (II) or (Ila), Rx is hydrogen, halogen, Ci-C6 alkyl, or Ci-C6 haloalkyl; and RY is hydrogen, halogen, Ci-C6 alkyl, or Ci-C6 haloalkyl. In some embodiments of a compound of Formula (II) or (Ila), Rx is hydrogen; and RY is hydrogen. [00111] In some embodiments of a compound of Formula (II) or (Ila), is a single bond. In some embodiments of a compound of Formula (II) or (Ila), is a single bond; X is CRX1RX2; and Y is CRY1RY2. In some embodiments of a compound of Formula (II) or (Ila), is a single bond; X is
Yl Y2
NR ; and Y is CR R . In some embodiments of a compound of Formula (II) or (Ila), is a single bond; X is CR R ; and Y is NR . In some embodiments of a compound of Formula (II) or (Ila), is a single bond; X is NRX3; and Y is NRY3.
[00112] In some embodiments of a compound of Formula (II) or (Ila), RX1 and RX2 are independently hydrogen, halogen, -CN, -OH, -OMe, -NH2, d-Q, alkyl, or C C6 haloalkyl; and RY1 and RY2 are independently hydrogen, halogen, -CN, -OH, -OMe, -NH2, Ci-C6 alkyl, or Ci-C6 haloalkyl. In some embodiments of a compound of Formula (II) or (Ila), RX1 and RX2 are independently hydrogen, halogen, Ci-C6 alkyl, or Ci-C6 haloalkyl; and RY1 and RY2 are independently hydrogen, halogen, Ci-C6 alkyl, or Ci-C6 haloalkyl. In some embodiments of a compound of Formula (II) or (Ila), RX1 and RX2 are hydrogen;
Yl Y2 Y3 and R and R are hydrogen. In some embodiments of a compound of Formula (II) or (Ila), R and R are independently hydrogen, Ci-C6 alkyl, or Ci-C6 haloalkyl. In some embodiments of a compound of Formula (II) or (Ila), RX3 and RY3 are independently hydrog en or alkyl.
In some embodiments of a compound of Formula (II) or (Ila), Ring A is
Figure imgf000034_0001
[00113] In some embodiments of a compound of Formula (II) or (Ila), each Ra and Rb are
independently hydrogen or optionally substituted Ci-C6 alkyl; or Ra and Rb are taken together with the nitrogen atom to which they are attached to form an optionally substituted heterocycloalkyl.
[00114] In some embodiments of a compound of Formula (II) or (Ila), each Rc is optionally substituted Ci-C6 alkyl.
[00115] Also disclosed is a compound of Formula (ΠΓ), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
Figure imgf000034_0002
wherein
each R21 is independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=0)Rc, -N02, -NRaRb, -
S(=0)2Rc, -NRaS(=0)2Rc, -S(=0)2NRaRb, -C(=0)Rc, -OC(=0)Rc, -C(=0)ORa, -OC(=0)ORa, -C(=0)NRaRb, -OC(=0)NRaRb, -NRaC(=0)NRaRb, -NRaC(=0)Rc, -NRaC(=0)ORa, optionally substituted Ci-C6 alkyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted cycloalkyl, optionally substituted (Ci-C6 alkyl)cycloalkyl, optionally substituted
heterocycloalkyl, optionally substituted (Ci-C6 alkyl)heterocycloalkyl, optionally substituted aryl, optionally substituted (Ci-C6 alkyl)aryl, optionally substituted heteroaryl, or optionally substituted (Ci-C6 alkyl)heteroaryl;
R22 is halogen, -CN, -ORa, -SRa, -S(=0)Rc, -N02, -NRaRb, -S(=0)2Rc, -NRaS(=0)2Rc, - S(=0)2NRaRb, -C(=0)Rc, -OC(=0)Rc, -C(=0)ORa, -OC(=0)ORa, -C(=0)NRaRb, - OC(=0)NRaRb, -NRaC(=0)NRaRb, -NRaC(=0)Rc, -NRaC(=0)ORa, optionally substituted C C6 alkyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted cycloalkyl, optionally substituted (Ci-C6 alkyl)cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted (Ci- C6 alkyl)heterocycloalkyl, optionally substituted aryl, optionally substituted (Ci-C6 alkyl)aryl, optionally substituted heteroaryl, or optionally substituted (Ci-C6 alkyl)heteroaryl;
R23 is -SRa, -S(=0)Rc, -S(=0)2Rc, -S(=0)2NRaRb, -C(=0)Rc, -C(=0)NRaRb, optionally
substituted Ci-C6 alkyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted cycloalkyl, optionally substituted (Ci-C6 alkyl)cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted (Ci-C6 alkyl)heterocycloalkyl, optionally substituted aryl, optionally substituted (Ci-C<5 alkyl)aryl, optionally substituted heteroaryl, or optionally substituted (Ci-C6 alkyl)heteroaryl;
R24 is hydrogen, halogen, -CN, -OH, -ORa, -SRa, -S(=0)Rc, -N02, -NRaRb, -S(=0)2Rc, - NRaS(=0)2Rc, -S(=0)2NRaRb, -C(=0)Rc, -OC(=0)Rc, -C(=0)ORa, -OC(=0)ORa, - C(=0)NRaRb, -OC(=0)NRaRb, -NRaC(=0)NRaRb, -NRaC(=0)Rc, -NRaC(=0)ORa, optionally substituted Ci-C6 alkyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted cycloalkyl, optionally substituted (Ci-C6 alkyl)cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted (Ci-C6 alkyl)heterocycloalkyl, optionally substituted aryl, optionally substituted (Ci-C6 alkyl)aryl, optionally substituted heteroaryl, or optionally substituted (Ci-C6 alkyl)heteroaryl;
R25 and R26 are independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=0)Rc, -N02, -NRaRb, - S(=0)2Rc, -NRaS(=0)2Rc, -S(=0)2NRaRb, -C(=0)Rc, -OC(=0)Rc, -C(=0)ORa, -OC(=0)ORa, -C(=0)NRaRa, -OC(=0)NRaRb, -NRaC(=0)NRaRb, -NRaC(=0)Rc, -NRaC(=0)ORc, optionally substituted Ci-C6 alkyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, or optionally substituted C2-C6 alkynyl;
R27 is hydrogen, -SRa, -S(=0)Rc, -S(=0)2Rc, -S(=0)2NRaRb, -C(=0)Rc, -C(=0)NRaRb, optionally substituted Ci-C6 alkyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted cycloalkyl, optionally substituted (Ci-C6 alkyl)cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted (Ci-C6 alkyl)heterocycloalkyl, optionally substituted aryl, optionally substituted (Ci-C6 alkyl)aryl, optionally substituted heteroaryl, or optionally substituted (Ci-C6 alkyl)heteroaryl;
R28 is hydrogen, halogen, -CN, -ORa, -SRa, -S(=0)Rc, -N02, -NRaRb, -S(=0)2Rc, -NRaS(=0)2Rc, -S(=0)2NRaRb, -C(=0)Rc, -OC(=0)Rc, -C(=0)ORa, -OC(=0)ORa, -C(=0)NRaRb, - OC(=0)NRaRb, -NRaC(=0)NRaRb, -NRaC(=0)Rc, -NRaC(=0)ORa, optionally substituted C C6 alkyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted cycloalkyl, optionally substituted (Ci-C6 alkyl)cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted (Ci- C6 alkyl)heterocycloalkyl, optionally substituted aryl, optionally substituted (Ci-C6 alkyl)aryl, optionally substituted heteroaryl, or optionally substituted (Ci-C6 alkyl)heteroaryl;
R29 is hydrogen, -SRa, -S(=0)Rc, -S(=0)2Rc, -S(=0)2NRaRb, -C(=0)Rc, -C(=0)NRaRb, optionally substituted Ci-C6 alkyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted cycloalkyl, optionally substituted (Ci-C6 alkyl)cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted (Ci-C6 alkyl)heterocycloalkyl, optionally substituted aryl, optionally substituted (Ci-C<5 alkyl)aryl, optionally substituted heteroaryl, or optionally substituted (Ci-C6 alkyl)heteroaryl;
each Ra and Rb are independently hydrogen, optionally substituted Ci-C6 alkyl, optionally
substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
or Ra and Rb are taken together with the nitrogen atom to which they are attached to form an optionally substituted heterocycloalkyl;
each Rc is optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; and n2 is 1-3.
[00116] Also disclosed is a compound of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
Figure imgf000037_0001
ormula (III) wherein
each R21 is independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=0)Rc, -N02, -NRaRb, -
S(=0)2Rc, -NRaS(=0)2Rc, -S(=0)2NRaRb, -C(=0)Rc, -OC(=0)Rc, -C(=0)ORa, -OC(=0)ORa, -C(=0)NRaRb, -OC(=0)NRaRb, -NRaC(=0)NRaRb, -NRaC(=0)Rc, -NRaC(=0)ORa, optionally substituted Ci-C6 alkyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted cycloalkyl, optionally substituted (Ci-C6 alkyl)cycloalkyl, optionally substituted
heterocycloalkyl, optionally substituted (Ci-C6 alkyl)heterocycloalkyl, optionally substituted aryl, optionally substituted (Ci-C6 alkyl)aryl, optionally substituted heteroaryl, or optionally substituted (Ci-C6 alkyl)heteroaryl;
R22 is halogen, -CN, -ORa, -SRa, -S(=0)Rc, -N02, -NRaRb, -S(=0)2Rc, -NRaS(=0)2Rc, - S(=0)2NRaRb, -C(=0)Rc, -OC(=0)Rc, -C(=0)ORa, -OC(=0)ORa, -C(=0)NRaRb, - OC(=0)NRaRb, -NRaC(=0)NRaRb, -NRaC(=0)Rc, -NRaC(=0)ORa, optionally substituted C C6 alkyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted cycloalkyl, optionally substituted (Ci-C<5 alkyl)cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted (Ci- C<5 alkyl)heterocycloalkyl, optionally substituted aryl, optionally substituted (Ci-C6 alkyl)aryl, optionally substituted heteroaryl, or optionally substituted (Ci-C6 alkyl)heteroaryl;
R23 is -SRa, -S(=0)Rc, -S(=0)2Rc, -S(=0)2NRaRb, -C(=0)Rc, -C(=0)NRaRb, optionally
substituted Ci-C6 alkyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted cycloalkyl, optionally substituted (Ci-C6 alkyl)cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted (Ci-C6 alkyl)heterocycloalkyl, optionally substituted aryl, optionally substituted (Ci-C<5 alkyl)aryl, optionally substituted heteroaryl, or optionally substituted (Ci-C6 alkyl)heteroaryl;
R24 is hydrogen, halogen, -CN, -OH, -ORa, -SRa, -S(=0)Rc, -N02, -NRaRb, -S(=0)2Rc, - NRaS(=0)2Rc, -S(=0)2NRaRb, -C(=0)Rc, -OC(=0)Rc, -C(=0)ORa, -OC(=0)ORa, - C(=0)NRaRb, -OC(=0)NRaRb, -NRaC(=0)NRaRb, -NRaC(=0)Rc, -NRaC(=0)ORa, optionally substituted Ci-C6 alkyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted cycloalkyl, optionally substituted (Ci-C6 alkyl)cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted (Ci-C6 alkyl)heterocycloalkyl, optionally substituted aryl, optionally substituted (Ci-C6 alkyl)aryl, optionally substituted heteroaryl, or optionally substituted (Ci-C6 alkyl)heteroaryl;
R25 and R26 are independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=0)Rc, -N02, -NRaRb, - S(=0)2Rc, -NRaS(=0)2Rc, -S(=0)2NRaRb, -C(=0)Rc, -OC(=0)Rc, -C(=0)ORa, -OC(=0)ORa, -C(=0)NRaRa, -OC(=0)NRaRb, -NRaC(=0)NRaRb, -NRaC(=0)Rc, -NRaC(=0)ORc, optionally substituted Ci-C6 alkyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, or optionally substituted C2-C6 alkynyl;
R27 is hydrogen, -SRa, -S(=0)Rc, -S(=0)2Rc, -S(=0)2NRaRb, -C(=0)Rc, -C(=0)NRaRb, optionally substituted Ci-C6 alkyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted cycloalkyl, optionally substituted (Ci-C6 alkyl)cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted (Ci-C6 alkyl)heterocycloalkyl, optionally substituted aryl, optionally substituted (Ci-C<5 alkyl)aryl, optionally substituted heteroaryl, or optionally substituted (Ci-C6 alkyl)heteroaryl;
R28 is halogen, -CN, -ORa, -SRa, -S(=0)Rc, -N02, -NRaRb, -S(=0)2Rc, -NRaS(=0)2Rc, - S(=0)2NRaRb, -C(=0)Rc, -OC(=0)Rc, -C(=0)ORa, -OC(=0)ORa, -C(=0)NRaRb, - OC(=0)NRaRb, -NRaC(=0)NRaRb, -NRaC(=0)Rc, -NRaC(=0)ORa, optionally substituted d- C6 alkyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted cycloalkyl, optionally substituted (Ci-C<5 alkyl)cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted (Ci- C6 alkyl)heterocycloalkyl, optionally substituted aryl, optionally substituted (Ci-C6 alkyl)aryl, optionally substituted heteroaryl, or optionally substituted (Ci-C6 alkyl)heteroaryl;
R29 is hydrogen, -SRa, -S(=0)Rc, -S(=0)2Rc, -S(=0)2NRaRb, -C(=0)Rc, -C(=0)NRaRb, optionally substituted Ci-C6 alkyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted cycloalkyl, optionally substituted (Ci-C6 alkyl)cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted (Ci-C6 alkyl)heterocycloalkyl, optionally substituted aryl, optionally substituted (Ci-C6 alkyl)aryl, optionally substituted heteroaryl, or optionally substituted (Ci-C6 alkyl)heteroaryl;
each Ra and Rb are independently hydrogen, optionally substituted Ci-C6 alkyl, optionally
substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
or Ra and Rb are taken together with the nitrogen atom to which they are attached to form an optionally substituted heterocycloalkyl; each Rc is optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; and n2 is 1-3.
[00117] In some embodiments of a compound of Formula (III) or (III'), n2 is 1. In some embodiments of a compound of Formula (III) or (III'), n2 is 2. In some embodiments of a compound of Formula (III) or (ΙΙΓ), η2 is 3.
[00118] In some embodiments of a compound of Formula (III) or (III'), each R21 is independently hydrogen, halogen, -CN, -OH, -OMe, -NH2, Ci-C6 alkyl, or Ci-C6 haloalkyl; and n2 is 1 or 2. In some embodiments of a compound of Formula (III) or (ΙΙΓ), each R21 is independently hydrogen, halogen, Ci- C6 alkyl, or Ci-C6 haloalkyl; and n2 is 1 or 2. In some embodiments of a compound of Formula (III) or (ΙΙΓ), R21 is halogen, Ci-C6 alkyl, or Ci-C6 haloalkyl; and n2 is 1. In some embodiments of a compound of Formula (III) or (ΙΙΓ), R21 is halogen; and n2 is 1. In some embodiments of a compound of Formula (III) or (III ), each R21 is hydrogen.
[00119] In some embodiments of a compound of Formula (III) or (III ), R23 is optionally substituted Ci- C<5 alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl. In some embodiments of a compound of Formula (III) or (ΙΙΓ), R23 is optionally substituted aryl. In some embodiments of a compound of Formula (III) or (ΙΙΓ), R23 is optionally substituted with halogen, -CN, -OH, -OMe, -NH2, Ci-C6 alkyl, or Ci-C6 haloalkyl. In some embodiments of a compound of Formula (III) or (ΙΙΓ), R23 is optionally substituted with halogen, Ci-C6 alkyl, or Ci-C6 haloalkyl. In some embodiments of a compound of Formula (III) or (ΙΙΓ), R23 is unsubstituted aryl or unsusbituted heteroaryl. In some embodiments of a compound of Formula (III) or (ΙΙΓ), R23 is unsubstituted aryl. In some embodiments of a compound of Formula (III) or (ΙΙΓ), R23 is unsubstituted phenyl.
[00120] In some embodiments of a compound of Formula (III) or (III'), R24 is hydrogen, halogen, -CN, -OH, -OMe, -NH2, Ci-C6 alkyl, or Ci-C6 haloalkyl. In some embodiments of a compound of Formula (III) or (III'), R24 is hydrogen, halogen, Ci-C6 alkyl, or Ci-C6 haloalkyl. In some embodiments of a compound of Formula (III) or (ΙΙΓ), R24 is hydrogen or halogen. In some embodiments of a compound of Formula (III) or (III'), R24 is hydrogen.
[00121] In some embodiments of a compound of Formula (III) or (ΙΙΓ), R25 and R26 are independently hydrogen, halogen, Ci-C6 alkyl, or Ci-C6 haloalkyl. In some embodiments of a compound of Formula (III) or (III ), R25 and R26 are independently hydrog en or alkyl.
[00122] In some embodiments of a compound of Formula (III), R27 is hydrogen or Ci-C6 alkyl. In some embodiments of a compound of Formula (III) or (ΙΙΓ), R27 is hydrogen.
[00123] In some embodiments of a compound of Formula (III) or (III'), the compound is, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
Figure imgf000040_0001
Formula (Ilia).
[00124] In some embodiments of a compound of Formula (III), (HI ), or (Ilia), R is halogen, -CN, - ORa, -NRaRb, optionally substituted Ci-C6 alkyl, optionally substituted Ci-C6 heteroalkyl, or optionally substituted C2-C6 alkynyl. In some embodiments of a compound of Formula (III), (ΠΓ), or (Ilia), R22 is halogen, optionally substituted Ci-C6 alkyl, or optionally substituted C2-C6 alkynyl. In some
embodiments of a compound of Formula (III), (ΠΓ), or (Ilia), R22 is halogen. In some embodiments of a compound of Formula (III), (ΠΓ), or (Ilia), R22 is fluoro or chloro. In some embodiments of a compound of Formula (III), (IIP), or (Ilia), R22 is chloro. In some embodiments of a compound of Formula (III), (IIP), or (Ilia), R22 is Ci-C6 alkyl or Ci-C6 haloalkyl. In some embodiments of a compound of Formula (III), (III'), or (Ilia), R22 is methyl. In some embodiments of a compound of Formula (III), (IIP), or (Ilia), R22 is C2-C<5 alkynyl optionally substituted with optionally substituted Ci-C6 alkyl, optionally substituted Ci-C<5 heteroalkyl, optionally substituted cycloalkyl, optionally substituted (Ci-C6 alkyl)cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted (Ci-C6 alkyl)heterocycloalkyl, optionally substituted aryl, optionally substituted (Ci-C6 alkyl)aryl, optionally substituted heteroaryl, or optionally substituted (Ci-C6 alkyl)heteroaryl. In some embodiments of a compound of Formula (III), (IIP), or (Ilia), R22 is C2-C6 alkynyl optionally substituted with optionally substituted heteroaryl. In some embodiments of a compound of Formula (III), (IIP), or (Ilia), R22 is C2-C6 alkynyl optionally substituted
Figure imgf000040_0002
with
[00125] In some embodiments of a compound of Formula (III), (IIP), or (Ilia), R is halogen, -CN, - ORa, -NRaRb, -C(=0)ORa, -C(=0)NRaRb, optionally substituted d-Q, alkyl, optionally substituted d-Q, heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl.
[00126] In some embodiments of a compound of Formula (III), (IIP), or (Ilia), R28 is halogen, -CN, - ORa, -NRaRb, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkynyl, or optionally substituted heteroaryl. In some embodiments of a compound of Formula (III), (IIP), or (Ilia), R28 is halogen, -CN, -OMe, -NH2, Ci-C6 alkyl, Ci-C6 haloalkyl, C2-C6 alkynyl, or heteroaryl. In some embodiments of a compound of Formula (III), (IIP), or (Ilia), R28 is halogen. [00127] In some embodiments of a compound of Formula (III), (HI ), or (Ilia), R is hydrogen or optionally substituted Ci-C6 alkyl. In some embodiments of a compound of Formula (III), (III'), or (Ilia), R29 is d-C6 alkyl.
[00128] In some embodiments of a compound of Formula (III), (III ), or (Ilia), each Ra and Rb are independently hydrogen or optionally substituted Ci-C6 alkyl; or Ra and Rb are taken together with the nitrogen atom to which they are attached to form an optionally substituted heterocycloalkyl.
[00129] In some embodiments of a compound of Formula (III), (III ), or (Ilia), each Rc is optionally substituted Ci-C6 alkyl.
[00130] Also disclosed herein is a compound of Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
Figure imgf000041_0001
wherein
each R31 is independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=0)Rc, -N02, -NRaRb, -
S(=0)2Rc, -NRaS(=0)2Rc, -S(=0)2NRaRb, -C(=0)Rc, -OC(=0)Rc, -C(=0)ORa, -OC(=0)ORa, -C(=0)NRaRb, -OC(=0)NRaRb, -NRaC(=0)NRaRb, -NRaC(=0)Rc, -NRaC(=0)ORa, optionally substituted Ci-C6 alkyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted cycloalkyl, optionally substituted (Ci-C6 alkyl)cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted (Ci-C6 alkyl)heterocycloalkyl, optionally substituted aryl, optionally substituted (Ci-C6 alkyl)aryl, optionally substituted heteroaryl, or optionally substituted (Ci-C6 alkyl)heteroaryl;
R32 is optionally substituted Ci-C6 alkyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted cycloalkyl, optionally substituted (Ci-C6 alkyl)cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted (Ci-C6 alkyl)heterocycloalkyl, optionally substituted aryl, optionally substituted (Ci-C6 alkyl)aryl, optionally substituted heteroaryl, or optionally substituted (Ci-C6 alkyl)heteroaryl;
R33 is -SRa, -S(=0)Rc, -S(=0)2Rc, -S(=0)2NRaRb, -C(=0)Rc, -C(=0)NRaRb, optionally
substituted Ci-C6 alkyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted cycloalkyl, optionally substituted (Ci-C6 alkyl)cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted (Ci-C6 alkyl)heterocycloalkyl, optionally substituted aryl, optionally substituted (Ci-C<5 alkyl)aryl, optionally substituted heteroaryl, or optionally substituted (Ci-C6 alkyl)heteroaryl;
R34 is hydrogen, halogen, -CN, -ORa, -SRa, -S(=0)Rc, -N02, -NRaRb, -S(=0)2Rc, -NRaS(=0)2Rc, -S(=0)2NRaRb, -C(=0)Rc, -OC(=0)Rc, -C(=0)ORa, -OC(=0)ORa, -C(=0)NRaRb, - OC(=0)NRaRb, -NRaC(=0)NRaRb, -NRaC(=0)Rc, -NRaC(=0)ORa, optionally substituted C C6 alkyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted cycloalkyl, optionally substituted (Ci-C6 alkyl)cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted (Ci- C6 alkyl)heterocycloalkyl, optionally substituted aryl, optionally substituted (Ci-C6 alkyl)aryl, optionally substituted heteroaryl, or optionally substituted (Ci-C6 alkyl)heteroaryl;
R35 and R36 are independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=0)Rc, -N02, -NRaRb, - S(=0)2Rc, -NRaS(=0)2Rc, -S(=0)2NRaRb, -C(=0)Rc, -OC(=0)Rc, -C(=0)ORa, -OC(=0)ORa, -C(=0)NRaRa, -OC(=0)NRaRb, -NRaC(=0)NRaRb, -NRaC(=0)Rc, -NRaC(=0)ORc, optionally substituted Ci-C6 alkyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, or optionally substituted C2-C6 alkynyl;
R37 is hydrogen, -SRa, -S(=0)Rc, -S(=0)2Rc, -S(=0)2NRaRb, -C(=0)Rc, -C(=0)NRaRb, optionally substituted Ci-C6 alkyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted cycloalkyl, optionally substituted (Ci-C6 alkyl)cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted (Ci-C6 alkyl)heterocycloalkyl, optionally substituted aryl, optionally substituted (Ci-C<5 alkyl)aryl, optionally substituted heteroaryl, or optionally substituted (Ci-C6 alkyl)heteroaryl;
Ring B is an optionally substituted 5-membered heteroaryl;
each Ra and Rb are independently hydrogen, optionally substituted Ci-C6 alkyl, optionally
substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
or Ra and Rb are taken together with the nitrogen atom to which they are attached to form an optionally substituted heterocycloalkyl;
each Rc is optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; and n3 is 1-3.
[00131] In some embodiments of a compound of Formula (IV), n3 is 1. In some embodiments of a compound of Formula (IV), n3 is 2. In some embodiments of a compound of Formula (IV), n3 is 3.
[00132] In some embodiments of a compound of Formula (IV), each R31 is independently hydrogen, halogen, -CN, -OH, -OMe, -NH2, Ci-C6 alkyl, or Ci-C6 haloalkyl; and n3 is 1 or 2. In some embodiments of a compound of Formula (IV), each R31 is independently hydrogen, halogen, Ci-C6 alkyl, or Ci-C6 haloalkyl; and n3 is 1 or 2. In some embodiments of a compound of Formula (IV), R31 is halogen, Ci-C6 alkyl, or Ci-C6 haloalkyl; and n3 is 1. In some embodiments of a compound of Formula (IV), R31 is halogen; and n is 1. In some embodiments of a compound of Formula (IV), each R31 is hydrogen.
[00133] In some embodiments of a compound of Formula ( ), R33 is optionally substituted Ci-Cg alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl. In some embodiments of a compound of Formula (IV), R33 is optionally substituted aryl. In some embodiments of a compound of Formula (IV), R33 is optionally substituted with halogen, -CN, -OH, -OMe, -NH2, Ci-C6 alkyl, or Ci-C6 haloalkyl. In some embodiments of a compound of Formula (IV), R33 is optionally substituted with halogen, Ci-C6 alkyl, or Ci-C6 haloalkyl. In some embodiments of a compound of Formula (IV), R33 is unsubstituted aryl or unsusbituted heteroaryl. In some embodiments of a compound of Formula (IV), R33 is unsubstituted aryl. In some embodiments of a compound of Formula (IV), R33 is unsubstituted phenyl.
[00134] In some embodiments of a compound of Formula (IV), R34 is hydrogen, halogen, -CN, -OH, - OMe, -NH2, Ci-C<5 alkyl, or Ci-C6 haloalkyl. In some embodiments of a compound of Formula (IV), R34 is hydrogen, halogen, Ci-C6 alkyl, or Ci-C6 haloalkyl. In some embodiments of a compound of Formula (IV), R34 is hydro gen or halogen. In some embodiments of a compound of Formula (IV), R34 is hydrogen.
[00135] In some embodiments of a compound of Formula (IV), R35 and R36 are independently hydrogen, halogen, Ci-C6 alkyl, or Ci-C6 haloalkyl. In some embodiments of a compound of Formula (IV), R35 and R36 are independently hydrog en or Ci-C6 alkyl.
[00136] In some embodiments of a compound of Formula (IV), R37 is hydrogen or Ci-C6 alkyl. In some embodiments of a compound of Formula (IV), R37 is hydrogen.
[00137] In some embodiments of a compound of Formula (IV), the compound is of Formula (IVa), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
Figure imgf000043_0001
[00138] In some embodiments of a compound of Formula (IV) or Formula (IVa), R is optionally substituted heterocycloalkyl or optionally substituted heteroaryl. In some embodiments of a compound of Formula (IV) or Formula (IVa), R32 is optionally substituted heteroaryl. In some embodiments of a compound of Formula (IV) or Formula (IVa), R32 is an optionally substituted 5-membered heteroaryl. In some embodiments of a compound of Formula (IV) or Formula (IVa), R32 is a 5-membered heteroaryl optionally substituted with halogen, -CN, -OH, -OMe, -NH2, Ci-C6 alkyl, or Ci-C6 haloalkyl. In some
embodiments of a compound of Formula (IV) or Formula (IVa), R32 is
Figure imgf000044_0001
[00139] In some embodiments of a compound of Formula (IV) or Formula (IVa), Ring B is selected from optionally substituted: pyrrole, thiophene, furan, imidazole, pyrazole, thiazole, isothiazole, oxazole, isoxazole, triazole, and tetrazole. In some embodiments of a compound of Formula (IV) or Formula (IVa), Ring B is optionally substituted pyrazole. In some embodiments of a compound of Formula (IV) or Formula (IVa), Ring B is optionally substituted with halogen, -CN, -ORa, -SRa, -S(=0)Rc, -N02, - NRaRb, -S(=0)2Rc, -NRaS(=0)2Rc, -S(=0)2NRaRb, -C(=0)Rc, -OC(=0)Rc, -C(=0)ORa, -OC(=0)ORa, - C(=0)NRaRb, -OC(=0)NRaRb, -NRaC(=0)NRaRb, -NRaC(=0)Rc, -NRaC(=0)ORa, optionally substituted Ci-C6 alkyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl. In some embodiments of a compound of Formula (IV) or Formula (IVa), Ring B is optionally substituted with halogen, -CN, -ORa, -NRaRb, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkynyl, or optionally substituted heteroaryl. In some embodiments of a compound of Formula (IV) or Formula (IVa), Ring B is optionally substituted with halogen, -CN, -OMe, -NH2, Ci-C6 alkyl, Ci-C6 haloalkyl, C2-C6 alkynyl, or heteroaryl.
iments of a compound of Formula (IV) or Formula (IVa), Ring B is
Figure imgf000044_0002
R38 is halogen, -CN, -ORa, -SRa, -S(=0)Rc, -N02, -NRaRb, -S(=0)2Rc, -NRaS(=0)2Rc, - S(=0)2NRaRb, -C(=0)Rc, -OC(=0)Rc, -C(=0)ORa, -OC(=0)ORa, -C(=0)NRaRb, - OC(=0)NRaRb, -NRaC(=0)NRaRb, -NRaC(=0)Rc, -NRaC(=0)ORa, optionally substituted C C6 alkyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted cycloalkyl, optionally substituted (Ci-C6 alkyl)cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted (Ci- C6 alkyl)heterocycloalkyl, optionally substituted aryl, optionally substituted (Ci-C6 alkyl)aryl, optionally substituted heteroaryl, or optionally substituted (Ci-C6 alkyl)heteroaryl; and
R39 is hydrogen, -SRa, -S(=0)Rc, -S(=0)2Rc, -S(=0)2NRaRb, -C(=0)Rc, -C(=0)NRaRb, optionally substituted Ci-C6 alkyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted cycloalkyl, optionally substituted (Ci-C6 alkyl)cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted (Ci-C6 alkyl)heterocycloalkyl, optionally substituted aryl, optionally substituted (Ci-C<5 alkyl)aryl, optionally substituted heteroaryl, or optionally substituted (Ci-C6
alkyl)heteroaryl.
[00141] In some embodiments of a compound of Formula (IV) or Formula (IVa), R38 is halogen, -CN, - ORa, -NRaRb, -C(=0)ORa, -C(=0)NRaRb, optionally substituted Ci-C6 alkyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl. In some embodiments of a compound of Formula (IV) or Formula (IVa), R38 is halogen, -CN, -ORa, -NRaRb, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkynyl, or optionally substituted heteroaryl. In some embodiments of a compound of Formula (IV) or Formula (IVa), R38 is halogen, -CN, -OMe, -NH2, Ci-C6 alkyl, Ci-C6 haloalkyl, C2-C6 alkynyl, or heteroaryl. In some embodiments of a compound of Formula (IV) or Formula (IVa), R38 is halogen.
[00142] In some embodiments of a compound of Formula (IV) or Formula (IVa), R39 is hydrogen or optionally substituted Ci-C6 alkyl. In some embodiments of a compound of Formula (IV) or Formula (IVa), R39 is d-C6 alkyl.
[00143] In some embodiments of a compound of Formula (IV) or Formula (IVa), each Ra and Rb are independently hydrogen or optionally substituted Ci-C6 alkyl; or Ra and Rb are taken together with the nitrogen atom to which they are attached to form an optionally substituted heterocycloalkyl.
[00144] In some embodiments of a compound of Formula (IV) or Formula (IVa), each Rc is optionally substituted Ci-C6 alkyl.
[00145] In some embodiments is a compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, having a structure selected from:
Figure imgf000045_0001
(S)-3-(l-(3 -amino- 1 -methyl -4 -oxo- 1,4- dihydro-5H-pyrazolo [3 ,4-d]pyrimidin-5 - yl)ethyl)-8-((l-methyl-lH-pyrazol-4- yl)ethynyl)-2-phenylisoquinolin- 1 (2H)-one
(S)-3 -amino-5 -bromo- 1 -methyl -N-( 1 -(8- ((1 -methyl - 1 H-pyrazol -4 -yl)ethynyl) - 1 - oxo-2 -phenyl- 1 ,2-dihydroisoquinolin-3 - yl)ethyl)-lH-pyrazole-4-carboxamide
(S)-3,5-diamino-l-methyl-N-(l-(8-((l- methyl - 1 H-pyrazol -4 -yl)ethynyl) - 1 -oxo -2 - phenyl-l,2-dihydroisoquinolin-3-yl)ethyl)- 1 H-pyrazole -4 -carboxamide
Figure imgf000047_0001
(S)-3 -amino-5 -cyano- 1 -methyl -N-( 1 -(8- ((1 -methyl - 1 H-pyrazol -4 -yl)ethynyl) - 1 - oxo-2 -phenyl- 1 ,2-dihydroisoquinolin-3 - yl)ethyl)-lH-pyrazole-4-carboxamide
(S)-3 -amino-5 -bromo-N-( 1 -(8-chloro- 1 - oxo-2 -phenyl- 1 ,2-dihydroisoquinolin-3 - yl)ethyl)-l-methyl-lH-pyrazole-4- carboxamide
(S)-3-amino-N-(l-(8-chloro-l -oxo-2- phenyl-l,2-dihydroisoquinolin-3-yl)ethyl)- 5-cyano-l-methyl-lH-pyrazole-4- carboxamide
(S)-3 -amino-5 -chloro- 1 -methyl-N-( 1 -(8- ((1 -methyl - 1 H-pyrazol -4 -yl)ethynyl) - 1 - oxo-2 -phenyl- 1 ,2-dihydroisoquinolin-3 - yl)ethyl)-lH-pyrazole-4-carboxamide
Figure imgf000049_0001
[00146] In some embodiments is a compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, having a structure selected from:
Figure imgf000050_0001
Further Forms of Compounds Disclosed Herein
Isomers/Stereoisomers
[00147] In some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein possess one or more double bonds. The compounds presented herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as the corresponding mixtures thereof. In some situations, the compounds described herein possess one or more chiral centers and each center exists in the R configuration, or S configuration. The compounds described herein include all diastereomeric, enantiomeric, and epimeric forms as well as the corresponding mixtures thereof. In additional embodiments of the compounds and methods provided herein, mixtures of enantiomers and/or diastereoisomers, resulting from a single preparative step, combination, or interconversion are useful for the applications described herein. In some embodiments, the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers and recovering the optically pure enantiomers. In some embodiments, dissociable complexes are preferred. In some embodiments, the diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and are separated by taking advantage of these dissimilarities. In some embodiments, the diastereomers are separated by chiral chromatography, or preferably, by separation/resolution techniques based upon differences in solubility. In some embodiments, the optically pure enantiomer is then recovered, along with the resolving agent. Labeled compounds
[00148] In some embodiments, the compounds described herein exist in their isotopically-labeled forms. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds as pharmaceutical compositions. Thus, in some embodiments, the compounds disclosed herein include isotopically-labeled compounds, which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of Formula (I), (la), (II), (Ila), (ΙΙΙ'), (III), (Ilia), (IV), or (IVa), or a solvate, or stereoisomer thereof, include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, and chloride, such as 2H, ¾, 1 C, 14C, 15N, 180, 170, 1P, 2P, 5S, 18F, and 6C1, respectively. Compounds described herein, and the metabolites, pharmaceutically acceptable salts, esters, prodrugs, solvate, hydrates or derivatives thereof which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention. Certain isotopically-labeled compounds, for example those into which radioactive isotopes such as H and 14C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., H and carbon-14, i.e., 14C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavy isotopes such as deuterium, /'. e. , 2H, produces certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements. In some embodiments, the isotopically labeled compound or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is prepared by any suitable method.
[00149] In some embodiments, the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.
Pharmaceutically acceptable salts
[00150] In some embodiments, the compounds described herein exist as their pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions.
[00151] In some embodiments, the compounds described herein possess acidic or basic groups and therefor react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein, or by separately reacting a purified compound in its free form with a suitable acid or base, and isolating the salt thus formed.
[00152] Examples of pharmaceutically acceptable salts include those salts prepared by reaction of the compounds described herein with a mineral, organic acid, or inorganic base, such salts including acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyn-l,4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne-l,6-dioate, hydroxybenzoate, γ-hydroxybutyrate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, monohydrogenphosphate, 1-napthalenesulfonate, 2-napthalenesulfonate, nicotinate, nitrate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate, thiocyanate,
tosylateundeconate, and xylenesulfonate.
[00153] Further, the compounds described herein can be prepared as pharmaceutically acceptable salts formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, including, but not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid metaphosphoric acid, and the like; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2- hydroxyethanesulfonic acid, benzenesulfonic acid, 2 -naphthalene sulfonic acid, 4-methylbicyclo- [2.2.2]oct-2-ene-l-carboxylic acid, glucoheptonic acid, 4,4'-methylenebis-(3-hydroxy-2-ene-l- carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and muconic acid.
[00154] In some embodiments, those compounds described herein which comprise a free acid group react with a suitable base, such as the hydroxide, carbonate, bicarbonate, sulfate, of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine. Representative salts include the alkali or alkaline earth salts, like lithium, sodium, potassium, calcium, and magnesium, and aluminum salts and the like. Illustrative examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N+(Ci_4 alkyl)4, and the like.
[00155] Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like. It should be understood that the compounds described herein also include the quaternization of any basic nitrogen-containing groups they contain. In some embodiments, water or oil-soluble or dispersible products are obtained by such quaternization.
Solvates
[00156] In some embodiments, the compounds described herein exist as solvates. The invention provides for methods of treating diseases by administering such solvates. The invention further provides for methods of treating diseases by administering such solvates as pharmaceutical compositions.
[00157] Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and, in some embodiments, are formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein can be conveniently prepared or formed during the processes described herein. By way of example only, hydrates of the compounds described herein can be conveniently prepared by recrystallization from an aqueous/organic solvent mixture, using organic solvents including, but not limited to, dioxane, tetrahydrofuran, or methanol. In addition, the compounds provided herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.
Tautomers
[00158] In some situations, compounds exist as tautomers. The compounds described herein include all possible tautomers within the formulas described herein. Tautomers are compounds that are
interconvertible by migration of a hydrogen atom, accompanied by a switch of a single bond and adjacent double bond. In bonding arrangements where tautomerization is possible, a chemical equilibrium of the tautomers will exist. All tautomeric forms of the compounds disclosed herein are contemplated. The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH.
Preparation of the Compounds
[00159] The compounds used in the reactions described herein are made according to organic synthesis techniques known to those skilled in this art, starting from commercially available chemicals and/or from compounds described in the chemical literature. "Commercially available chemicals" are obtained from standard commercial sources including Acros Organics (Pittsburgh, PA), Aldrich Chemical (Milwaukee, WI, including Sigma Chemical and Fluka), Apin Chemicals Ltd. (Milton Park, UK), Avocado Research (Lancashire, U.K.), BDH Inc. (Toronto, Canada), Bionet (Cornwall, U.K.), Chemservice Inc. (West Chester, PA), Crescent Chemical Co. (Hauppauge, NY), Eastman Organic Chemicals, Eastman Kodak Company (Rochester, NY), Fisher Scientific Co. (Pittsburgh, PA), Fisons Chemicals (Leicestershire, UK), Frontier Scientific (Logan, UT), ICN Biomedicals, Inc. (Costa Mesa, CA), Key Organics (Cornwall, U.K.), Lancaster Synthesis (Windham, NH), Maybridge Chemical Co. Ltd. (Cornwall, U.K.), Parish Chemical Co. (Orem, UT), Pfaltz & Bauer, Inc. (Waterbury, CN), Polyorganix (Houston, TX), Pierce Chemical Co. (Rockford, IL), Riedel de Haen AG (Hanover, Germany), Spectrum Quality Product, Inc. (New Brunswick, NJ), TCI America (Portland, OR), Trans World Chemicals, Inc. (Rockville, MD), and Wako Chemicals USA, Inc. (Richmond, VA).
[00160] Suitable reference books and treatise that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation, include for example, "Synthetic Organic Chemistry", John Wiley & Sons, Inc., New York; S. R. Sandler et al, "Organic Functional Group Preparations," 2nd Ed., Academic Press, New York, 1983; H. O. House, "Modern Synthetic Reactions", 2nd Ed., W. A. Benjamin, Inc. Menlo Park, Calif. 1972; T. L. Gilchrist, "Heterocyclic Chemistry", 2nd Ed., John Wiley & Sons, New York, 1992; J. March, "Advanced Organic Chemistry: Reactions, Mechanisms and Structure", 4th Ed., Wiley-Interscience, New York, 1992. Additional suitable reference books and treatise that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation, include for example, Fuhrhop, J. and Penzlin G. "Organic Synthesis: Concepts, Methods, Starting Materials", Second, Revised and Enlarged Edition (1994) John Wiley & Sons ISBN: 3-527-29074-5; Hoffman, R.V. "Organic Chemistry, An Intermediate Text" (1996) Oxford University Press, ISBN 0-19-509618-5; Larock, R. C. "Comprehensive Organic Transformations: A Guide to Functional Group Preparations" 2nd Edition (1999) Wiley-VCH, ISBN: 0-471-19031-4; March, J. "Advanced Organic Chemistry: Reactions, Mechanisms, and Structure" 4th Edition (1992) John Wiley & Sons, ISBN: 0-471-60180-2; Otera, J. (editor) "Modern Carbonyl Chemistry" (2000) Wiley-VCH, ISBN: 3-527-29871-1; Patai, S. "Patai's 1992 Guide to the Chemistry of Functional Groups" (1992) Interscience ISBN: 0-471-93022-9;
Solomons, T. W. G. "Organic Chemistry" 7th Edition (2000) John Wiley & Sons, ISBN: 0-471-19095-0; Stowell, J.C., "Intermediate Organic Chemistry" 2nd Edition (1993) Wiley-Interscience, ISBN: 0-471- 57456-2; "Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's
Encyclopedia" (1999) John Wiley & Sons, ISBN: 3 -527-29645 -X, in 8 volumes; "Organic Reactions" (1942-2000) John Wiley & Sons, in over 55 volumes; and "Chemistry of Functional Groups" John Wiley & Sons, in 73 volumes.
[00161] Specific and analogous reactants are optionally identified through the indices of known chemicals prepared by the Chemical Abstract Service of the American Chemical Society, which are available in most public and university libraries, as well as through on-line. Chemicals that are known but not commercially available in catalogs are optionally prepared by custom chemical synthesis houses, where many of the standard chemical supply houses (e.g., those listed above) provide custom synthesis services. A reference for the preparation and selection of pharmaceutical salts of the compounds described herein is P. H. Stahl & C. G. Wermuth "Handbook of Pharmaceutical Salts", Verlag Helvetica Chimica Acta, Zurich, 2002. Pharmaceutical Compositions
[00162] In certain embodiments, the compound of Formula (I), (la), (II), (Ila), (ΙΙΙ'), (III), (Ilia), (IV), or (rVa) as described herein is administered as a pure chemical. In some embodiments, the compound of Formula (I), (la), (II), (Ila), (IIP), (III), (Ilia), (IV), or (IVa) described herein is combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, physiologically suitable (or acceptable) excipient, or physiologically suitable (or acceptable) carrier) selected on the basis of a chosen route of administration and standard pharmaceutical practice as described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21st Ed. Mack Pub. Co., Easton, PA (2005)).
[00163] Accordingly, provided herein is a pharmaceutical composition comprising a compound of Formula (I), (la), (II), (Ila), (ΠΓ), (III), (Ilia), (IV), or (IVa) described herein, or a pharmaceutically acceptable salt, solvate, or steroisomer thereof, and a pharmaceutically acceptable excipient.
[00164] In certain embodiments, the compound of Formula (I), (la), (II), (Ila), (ΙΙΙ'), (III), (Ilia), (IV), or (IVa) provided herein is substantially pure, in that it contains less than about 5%, or less than about 1%, or less than about 0.1%, of other organic small molecules, such as unreacted intermediates or synthesis by-products that are created, for example, in one or more of the steps of a synthesis method.
[00165] Pharmaceutical compositions are administered in a manner appropriate to the disease to be treated (or prevented). An appropriate dose and a suitable duration and frequency of administration will be determined by such factors as the condition of the patient, the type and severity of the patient's disease, the particular form of the active ingredient, and the method of administration. In general, an appropriate dose and treatment regimen provides the composition(s) in an amount sufficient to provide therapeutic and/or prophylactic benefit (e.g., an improved clinical outcome, such as more frequent complete or partial remissions, or longer disease-free and/or overall survival, or a lessening of symptom severity. Optimal doses are generally determined using experimental models and/or clinical trials. The optimal dose depends upon the body mass, weight, or blood volume of the patient.
[00166] In some embodiments, the pharmaceutical composition is formulated for oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, intrapulmonary, intradermal, intrathecal and epidural and intranasal administration. Parenteral administration includes intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration.
[00167] Suitable doses and dosage regimens are determined by conventional range-finding techniques known to those of ordinary skill in the art. Generally, treatment is initiated with smaller dosages that are less than the optimum dose of the compound disclosed herein. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached. In some embodiments, the present method involve the administration of about 0.1 μg to about 50 mg of at least one compound of the invention per kg body weight of the subject. For a 70 kg patient, dosages of from about 10 μg to about 200 mg of the compound disclosed herein would be more commonly used, depending on a subject's physiological response. [00168] By way of example only, the dose of the compound described herein for methods of treating a disease as described herein is about 0.001 to about 1 mg/kg body weight of the subject per day, for example, about 0.001 mg, about 0.002 mg, about 0.005 mg, about 0.010 mg, 0.015 mg, about 0.020 mg, about 0.025 mg, about 0.050 mg, about 0.075 mg, about 0.1 mg, about 0.15 mg, about 0.2 mg, about 0.25 mg, about 0.5 mg, about 0.75 mg, or about 1 mg/kg body weight per day. In some embodiments, the dose of compound described herein for the described methods is about 1 to about 1000 mg/kg body weight of the subject being treated per day, for example, about 1 mg, about 2 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 500 mg, about 750 mg, or about 1000 mg per day.
Methods of Treatment
[00169] The compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or steroisomer thereof, are useful as inhibitors of PI3 Kinase and, therefore, useful in the treatment of diseases or disorders in which it is believed PI3 Kinase activity plays a role. In some embodiments, the disease or disorder is cancer. In some embodiments, the disease or disorder is an inflammatory disease. In some embodiments, the disease or disorder is a cardiovascular disease.
[00170] Disclosed herein are methods of treating a PI3K associated disease or disorder in a subject in need thereof comprising the step of administering to the subject an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
[00171] In some embodiments, the PI3K associated disease or disorder is selected from inflammatory disease, glomerulonephritis, uveitis, hepatic diseases or disorders, renal diseases or disorders, chronic obstructive pulmonary disease, rheumatoid arthritis, inflammatory bowel disease, vasculitis, dermatitis, osteoarthritis, inflammatory muscle disease, allergic rhinitis, vaginitis, interstitial cystitis, scleroderma, osteoporosis, eczema, allogeneic or xenogeneic transplantation, graft rejection, graft-versus-host disease, lupus erythematosus, pulmonary fibrosis, dermatomyositis, thyroiditis, myasthenia gravis, autoimmune hemolytic anemia, cystic fibrosis, chronic relapsing hepatitis, primary biliary cirrhosis, allergic conjunctivitis, hepatitis, atopic dermatitis, asthma, Sjogren's syndrome, organ transplant rejection, multiple sclerosis, Guillain-Barre, autoimmune uveitis, autoimmune hemolytic anemia, pernicious anemia, autoimmune thrombocytopenia, temporal arteritis, anti-phospholipid syndrome, vasculitides such as Wegener's granulomatosis, Behcet's disease, psoriasis, dermatitis herpetiformis, pemphigus vulgaris, vitiligo, Crohn's disease, colitis, ulcerative colitis, primary biliary cirrhosis, autoimmune hepatitis, Type 1 or immune-mediated diabetes mellitus, Grave's disease. Hashimoto's thyroiditis, autoimmune oophoritis and orchitis, autoimmune disorder of the adrenal gland, systemic lupus erythematosus, polymyositis, dermatomyositis, ankylosing spondylitis, transplant rejection, skin graft rejection, arthritis, bone diseases associated with increased bone resorption, ileitis, Barrett's syndrome, adult respiratory distress syndrome, chronic obstructive airway disease, corneal dystrophy, trachoma, onchocerciasis, sympathetic ophthalmitis, endophthalmitis, gingivitis, periodontitis, tuberculosis, leprosy, uremic complications, nephrosis, sclerodermatitis, psoriasis, chronic demyelinating diseases of the nervous system, AIDS- related neurodegeneration, Alzheimer's disease, infectious meningitis, encephalomyelitis, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis viral or autoimmune encephalitis, autoimmune disorders, immune -complex vasculitis, systemic lupus and erythematodes, systemic lupus erythematosus (SLE), ischemic heart disease hypercholesterolemia, atherosclerosis, preeclampsia, chronic liver failure, brain and spinal cord trauma, hypertension, pulmonary arterial hypertension (PAH), cardiomyopathy, diabetic cardiomyopathy, and cancer.
Cancer
[00172] Disclosed herein are methods of treating a PI3K associated disease or disorder that is cancer in a subject in need thereof, comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
[00173] In some embodiments, the cancer is chemoresistant cancer, radio resistant cancer, anti-hormonal therapy resistant cancer, or treatment refractory cancer. In some embodiments, the cancer is relapsed cancer, persistent cancer, or recurrent cancer. Another embodiment provided herein describes a method of reducing incidences of cancer recurrence. Also provided here in some embodiments, is a method for treating a therapy-resistant cancer. In some embodiments, the cancer is metastasic cancer.
[00174] In certain embodiments, the cancer treatable with the methods provided herein includes, but is not limited to, (1) leukemias, including, but not limited to, acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemias such as myeloblastic, promyelocytic, myelomonocytic, monocytic, erythroleukemia leukemias and myelodysplastic syndrome or a symptom thereof (such as anemia, thrombocytopenia, neutropenia, bicytopenia, or pancytopenia), refractory anemia (RA), RA with ringed sideroblasts (RARS), RA with excess blasts (RAEB), RAEB in transformation (RAEB-T), preleukemia, and chronic myelomonocytic leukemia (CMML); (2) chronic leukemias, including, but not limited to, chronic myelocytic (granulocytic) leukemia, chronic lymphocytic leukemia, and hairy cell leukemia; (3) polycythemia vera; (4) lymphomas, including, but not limited to, Hodgkin's disease and non-Hodgkin's disease; (5) multiple myelomas, including, but not limited to, smoldering multiple myeloma, non- secretory myeloma, osteosclerotic myeloma, plasma cell leukemia, solitary plasmacytoma, and extramedullary plasmacytoma; (6) Waldenstrom's macroglobulinernia; (7) monoclonal gammopathy of undetermined significance; (8) benign monoclonal gammopathy; (9) heavy chain disease; (10) bone and connective tissue sarcomas, including, but not limited to, bone sarcoma, osteosarcoma, chondrosarcoma, Ewing's sarcoma, malignant giant cell tumor, fibrosarcoma of bone, chordoma, periosteal sarcoma, soft- tissue sarcomas, angiosarcoma (hemangiosarcoma), fibrosarcoma, Kaposi's sarcoma, leiomyosarcoma, liposarcoma, lymphangiosarcoma, metastatic cancers, neurilemmoma, rhabdomyosarcoma, and synovial sarcoma; ( 1 1) brain tumors, including, but not limited to, glioma, astrocytoma, brain stem glioma, ependymoma, aligodendrogliorna, nonglial tumor, acoustic neurinoma, craniopharyngioma,
medulloblastoma, meningioma, pineocytoma, pineoblastoma, and primary brain lymphoma; ( 12) breast cancer, including, but not limited to, adenocarcinoma, lobular (small cell) carcinoma, intraductal carcinoma, medullary breast cancer, mutinous breast cancer, tubular breast cancer, papillary breast cancer, primary cancers, Paget's disease, and inflammatory breast cancer; (13) adrenal cancer, including, but not limited to, pheochromocytom and adrenocortical carcinoma; (14) thyroid cancer, including, but not limited to, papillary or follicular thyroid cancer, medullary thyroid cancer, and anaplastic thyroid cancer; (15) pancreatic cancer, including, but not limited to, insulinoma, gastrinoma, glucagonoma, vipoma, somatostatin -secreting tumor, and carcinoid or islet cell tumor; ( 16) pituitary cancer, including, but limited to, Cushing's disease, prol actin-secreting tumor, acromegaly, and diabetes insipius; (17) eye cancer, including, but not limited, to ocular melanoma such as iris melanoma, choroidal melanoma, and cilliary body melanoma, and retinoblastoma; ( 18) vaginal cancer, including, but not limited to, squamous cell carcinoma, adenocarcinoma, and melanoma; (19) vulvar cancer, including, but not limited to, squamous cell carcinoma, melanoma, adenocarcinoma, basal cell carcinoma, sarcoma, and Paget' s disease; (20) cervical cancers, including, but not limited to, squamous cell carcinoma, and
adenocarcinoma; (21) uterine cancer, including, but not limited to, endometrial carcinoma and uterine sarcoma; (22) ovarian cancer, including, but not limited to, ovarian epithelial carcinoma, borderline tumor, germ cell tumor, and stromal tumor; (23) esophageal cancer, including, but not limited to, squamous cancer, adenocarcinoma, adenoid cystic carcinoma, mucoepidermoid carcinoma,
adenosquamous carcinoma, sarcoma, melanoma, plasmacytoma, verrucous carcinoma, and oat cell (small cell) carcinoma; (24) stomach cancer, including, but not limited to, adenocarcinoma, fungating
(polypoid), ulcerating, superficial spreading, diffusely spreading, malignant lymphoma, liposarcoma, fibrosarcoma, and carcinosarcoma; (25) colon cancer; (26) rectal cancer; (27) liver cancer, including, but not limited to, hepatocellular carcinoma and hepatoblastoma; (28) gallbladder cancer, including, but not limited to, adenocarcinoma; (29) cholangiocarcinomas, including, but not limited to, pappillary, nodular, and diffuse; (30) lung cancer, including, but not limited to, non-small cell lung cancer, squamous cell carcinoma (epidermoid carcinoma), adenocarcinoma, large-cell carcinoma, and small-cell lung cancer; (31) testicular cancer, including, but not limited to, germinal tumor, seminoma, anaplastic, classic (typical), spermatocytic, nonseminoma, embryonal carcinoma, teratoma carcinoma, and choriocarcinoma (yolk-sac tumor); (32) prostate cancer, including, but not limited to, adenocarcinoma, leiomyosarcoma, and rhabdomyosarcoma; (33) penal cancer; (34) oral cancer, including, but not limited to, squamous cell carcinoma; (35) basal cancer; (36) salivary gland cancer, including, but not limited to, adenocarcinoma, mucoepidermoid carcinoma, and adenoidcystic carcinoma; (37) pharynx cancer, including, but not limited to, squamous cell cancer and verrucous; (38) skin cancer, including, but not limited to, basal cell carcinoma, squamous cell carcinoma and melanoma, superficial spreading melanoma, nodular melanoma, lentigo malignant melanoma, and acral lentiginous melanoma; (39) kidney cancer, including, but not limited to, renal cell cancer, adenocarcinoma, hypernephroma, fibrosarcoma, and transitional cell cancer (renal pelvis and/or uterer); (40) Wilms' tumor; (41) bladder cancer, including, but not limited to, transitional cell carcinoma, squamous cell cancer, adenocarcinoma, and carcinosarcoma; (42) reproductive cancers, such as cervical cancer, uterus cancer, ovarian cancer, or testicular cancer; (43) esophagus cancer; (44) laryngeal cancer; (45) head and neck cancers (including mouth, nose, throat, larynx, sinuses, or salivary glands cancers); and other cancer, including, not limited to, myxosarcoma, osteogenic sarcoma, endotheliosarcoma, lymphangio-endotheliosarcoma, mesothelioma, synovioma, hemangioblastoma, epithelial carcinoma, cystadenocarcinoma, bronchogenic carcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, and papillary adenocarcinomas (See Fishman et al., 1985, Medicine, 2d Ed., J.B. Lippincott Co., Philadelphia and Murphy et al., 1997, Informed Decisions: The Complete Book of Cancer Diagnosis, Treatment, and Recovery, Viking Penguin, Penguin Books U.S.A., Inc., United States of America).
[00175] In certain embodiments, the cancer treatable with the methods provided herein is a hematological malignancy. In certain embodiments, the hematological malignancy is a T-cell malignancy. In certain embodiments, T-cell malignancies include peripheral T-cell lymphoma not otherwise specified (PTCL- NOS), anaplastic large cell lymphoma, angioimmunoblastic lymphoma, cutaneous T-cell lymphoma, adult T-cell leukemia/lymphoma (ATLL), blastic NK-cell lymphoma, enteropathy -type T-cell lymphoma, hematosplenic gamma-delta T-cell lymphoma, lymphoblastic lymphoma, nasal NK/T-cell lymphomas, or treatment-related T-cell lymphomas.
[00176] In certain embodiments, the hematological malignancy is a B-cell malignancy. In certain embodiments, B-cell malignancies include acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), acute monocytic leukemia (AMoL), chronic lymphocytic leukemia (CLL), high-risk chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), high-risk small lymphocytic lymphoma (SLL), follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), Waldenstrom's macroglobulinemia, multiple myeloma, extranodal marginal zone B cell lymphoma, nodal marginal zone B cell lymphoma, Burkitfs lymphoma, non-Burkitt high grade B cell lymphoma, primary mediastinal B-cell lymphoma (PMBL), immunoblastic large cell lymphoma, precursor B -lymphoblastic lymphoma, B cell prolymphocyte leukemia, lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, mediastinal (thymic) large B cell lymphoma, intravascular large B cell lymphoma, primary effusion lymphoma, or lymphomatoid granulomatosis. In certain embodiments, the B-cell malignancy is diffuse large B-cell lymphoma (DLBCL). In certain embodiments, the DLBCL is an activated B-cell DLBCL (ABC-DLBCL), a germinal center B-cell like DLBCL (GBC-DLBCL), a double hit DLBCL (DH-DLBCL), or a triple hit DLBCL (TH-DLBCL).
[00177] In some embodiments, the cancer is selected from a hematological cancer, a solid tumor cancer, hematopoietic tumors of lymphoid lineage, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, hairy cell lymphoma, Burkett's lymphoma, hematopoietic tumors of myeloid lineage, bladder cancer, breast cancer, colon cancer, kidney cancer, liver cancer, lung cancer, small cell lung cancer, esophageal cancer, gall bladder cancer, ovarian cancer, pancreatic cancer, stomach cancer, cervical cancer, thyroid cancer, prostate cancer, skin cancer, squamous cell carcinoma, tumors of mesenchymal origin, fibrosarcoma, rhabdomyosarcoma, tumors of the central and peripheral nervous system, astrocytoma, neuroblastoma, glioma, schwannoma, melanoma, seminoma, teratocarcinoma, osteosarcoma, xenoderoma pigmentosum, keratoctanthoma, thyroid follicular cancer, Kaposi's sarcoma, and glioblastoma. In some embodiments, the cancer is a hematological cancer selected from chronic lymphocytic leukemia (CLL) and multiple myeloma (MM). In some embodiments, the cancer is a solid tumor cancer selected from lung cancer, breast cancer, colon cancer, prostate cancer, pancreatic cancer, and glioblastoma.
Inflammatory Diseases
[00178] Disclosed herein are methods of treating a PI3K associated disease or disorder that is an inflammatory disease in a subject in need thereof, comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
[00179] Exemplary inflammatory diseases include, but are not limited to, inflammation associated with acne, anemia (e.g., aplastic anemia, haemolytic autoimmune anaemia), asthma, arteritis (e.g., polyarteritis, temporal arteritis, periarteritis nodosa, Takayasu's arteritis), arthritis (e.g., crystalline arthritis, osteoarthritis, psoriatic arthritis, gout flare, gouty arthritis, reactive arthritis, rheumatoid arthritis and Reiter's arthritis), ankylosing spondylitis, amylosis, amyotrophic lateral sclerosis, autoimmune diseases, allergies or allergic reactions, atherosclerosis, bronchitis, bursitis, chronic prostatitis, conjunctivitis, Chagas disease, chronic obstructive pulmonary disease, cermatomyositis, diverticulitis, diabetes (e.g., type I diabetes mellitus, type 2 diabetes mellitus), a skin condition (e.g., psoriasis, eczema, burns, dermatitis, pruritus (itch)), endometriosis, Guillain-Barre syndrome, infection, ischaemic heart disease, Kawasaki disease, glomerulonephritis, gingivitis, hypersensitivity, headaches (e.g., migraine headaches, tension headaches), ileus (e.g., postoperative ileus and ileus during sepsis), idiopathic thrombocytopenic purpura, interstitial cystitis (painful bladder syndrome), gastrointestinal disorder (e.g., selected from peptic ulcers, regional enteritis, diverticulitis, gastrointestinal bleeding, eosinophilic gastrointestinal disorders (e.g., eosinophilic esophagitis, eosinophilic gastritis, eosinophilic
gastroenteritis, eosinophilic colitis), gastritis, diarrhea, gastroesophageal reflux disease (GORD, or its synonym GERD), inflammatory bowel disease (IBD) (e.g., Crohn's disease, ulcerative colitis, collagenous colitis, lymphocytic colitis, ischaemic colitis, diversion colitis, Behcet's syndrome, indeterminate colitis) and inflammatory bowel syndrome (IBS)), lupus, multiple sclerosis, morphea, myeasthenia gravis, myocardial ischemia, nephrotic syndrome, pemphigus vulgaris, pernicious aneaemia, peptic ulcers, polymyositis, primary biliary cirrhosis, neuroinflammation associated with brain disorders (e.g., Parkinson's disease, Huntington's disease, and Alzheimer's disease), prostatitis, chronic
inflammation associated with cranial radiation injury, pelvic inflammatory disease, polymyalgia rheumatic, reperfusion injury, regional enteritis, rheumatic fever, systemic lupus erythematosus, scleroderma, scierodoma, sarcoidosis, spondyloarthopathies, Sjogren's syndrome, thyroiditis, transplantation rejection, tendonitis, trauma or injury (e.g., frostbite, chemical irritants, toxins, scarring, burns, physical injury), vasculitis, vitiligo and Wegener's granulomatosis. In certain embodiments, the inflammatory disorder is selected from arthritis (e.g., rheumatoid arthritis), inflammatory bowel disease, inflammatory bowel syndrome, asthma, psoriasis, endometriosis, interstitial cystitis and prostatistis. In certain embodiments, the inflammatory condition is an acute inflammatory condition (e.g., for example, inflammation resulting from infection). In certain embodiments, the inflammatory condition is a chronic inflammatory condition (e.g., conditions resulting from asthma, arthritis and inflammatory bowel disease). In some embodiments, the compounds disclosed herein are also useful in treating inflammation associated with trauma and non-inflammatory myalgia.
[00180] In some embodiments, the inflammatory disease is selected from chronic obstructive pulmonary disease (COPD), asthma, hypoxia-induced inflammation, rheumatoid arthritis, chronic bronchitis, atopic dermatitis, inflammatory bowel disease, allergic rhinitis, and ulcerative colitis.
Cardiovascular Diseases
[00181] Disclosed herein are methods of treating a PI3K associated disease or disorder that is a cardiovascular disease in a subject in need thereof, comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
[00182] Exemplary cardiovascular diseases include, but are not limited to, atherosclerosis, stenosis, restenosis, hypertension, pulmonary arterial hypertension (PAH), heart failure, left ventricular hypertrophy (LVH), myocardial infarction, acute coronary syndrome, stroke, transient ischemic attack, impaired circulation, heart disease, cholesterol and plaque formation, ischemia, ischemia reperfusion injury, peripheral vascular disease, myocardial infection, cardiac disease (e.g, risk stratification of chest pain and interventional procedures), cardiopulmonary resuscitation, kidney failure, thrombosis (e.g., venous thrombosis, deep vein thrombosis, portal vein thrombosis, renal vein thrombosis, jugular vein thrombosis, cerebral venous sinus thrombosis, arterial thrombosis, etc.), thrombus formation, thrombotic event or complication, Budd-Chiari syndrome, Paget-Schroetter disease, coronary heart disease, coronary artery disease, need for coronary revascularization, peripheral artery disease, a pulmonary circulatory disease, pulmonary embolism, a cerebrovascular disease, cellular proliferation and endothelial dysfunction, graft occlusion or failure, need for or an adverse clinical outcome after peripheral bypass graft surgery, need for or an adverse clinical outcome after coronary artery bypass (CABG) surgery, failure or adverse outcome after angioplasty, internal mammary artery graft failure, vein graft failure, autologous vein grafts, vein graft occlusion, ischaemic diseases, intravascular coagulation,
cerebrovascular disease, or any other cardiovascular disease related to obesity or an overweight condition.
[00183] In some embodimenst, the cardiovascular disease is selected from hypertension and pulmonary arterial hypertension (PAH).
Combination Therapy
[00184] In certain instances, the compound of Formula (I), (la), (II), (Ila), (IIP), (HI), (IHa), (IV), or (rVa), or a pharmaceutically acceptable salt, solvate, or steroisomer thereof, is administered in combination with a second therapeutic agent.
[00185] In some embodiments, the benefit experienced by a patient is increased by administering one of the compounds described herein with a second therapeutic agent (which also includes a therapeutic regimen) that also has therapeutic benefit.
[00186] In one specific embodiment, a compound of Formula (I), (la), (II), (Ila), (IIP), (HI), (IHa), (IV), or (rVa), or a pharmaceutically acceptable salt, solvate, or steroisomer thereof, is co-administered with a second therapeutic agent, wherein the compound of Formula (I), (la), (II), (Ila), (ΠΓ), (HI), (Ilia), (IV), or (IVa), or a pharmaceutically acceptable salt, solvate, or steroisomer thereof, and the second therapeutic agent modulate different aspects of the disease, disorder or condition being treated, thereby providing a greater overall benefit than administration of either therapeutic agent alone.
[00187] In any case, regardless of the disease, disorder or condition being treated, the overall benefit experienced by the patient is simply additive of the two therapeutic agents or the patient experiences a synergistic benefit.
[00188] In certain embodiments, different therapeutically -effective dosages of the compounds disclosed herein will be utilized in formulating a pharmaceutical composition and/or in treatment regimens when the compounds disclosed herein are administered in combination with a second therapeutic agent.
Therapeutically-effective dosages of drugs and other agents for use in combination treatment regimens are optionally determined by means similar to those set forth hereinabove for the actives themselves. Furthermore, the methods of prevention/treatment described herein encompasses the use of metronomic dosing, i.e., providing more frequent, lower doses in order to minimize toxic side effects. In some embodiments, a combination treatment regimen encompasses treatment regimens in which administration of a compound of Formula (I), (la), (II), (Ila), (ΠΓ), (HI), (Ilia), (IV), or (IVa), or a pharmaceutically acceptable salt, solvate, or steroisomer thereof, is initiated prior to, during, or after treatment with a second agent described herein, and continues until any time during treatment with the second agent or after termination of treatment with the second agent. It also includes treatments in which a compound of Formula (I), (la), (II), (Ila), (ΠΓ), (HI), (Ilia), (IV), or (IVa), or a pharmaceutically acceptable salt, solvate, or steroisomer thereof, and the second agent being used in combination are administered simultaneously or at different times and/or at decreasing or increasing intervals during the treatment period. Combination treatment further includes periodic treatments that start and stop at various times to assist with the clinical management of the patient.
[00189] It is understood that the dosage regimen to treat, prevent, or ameliorate the condition(s) for which relief is sought, is modified in accordance with a variety of factors (e.g. the disease, disorder or condition from which the subject suffers; the age, weight, sex, diet, and medical condition of the subject). Thus, in some instances, the dosage regimen actually employed varies and, in some embodiments, deviates from the dosage regimens set forth herein.
[00190] For combination therapies described herein, dosages of the co-administered compounds vary depending on the type of co-drug employed, on the specific drug employed, on the disease or condition being treated, and so forth. In additional embodiments, when co-administered with a second therapeutic agent, the compound provided herein is administered either simultaneously with the second therapeutic agent, or sequentially.
[00191] In combination therapies, the multiple therapeutic agents (one of which is one of the compounds described herein) are administered in any order or even simultaneously. If administration is simultaneous, the multiple therapeutic agents are, by way of example only, provided in a single, unified form, or in multiple forms (e.g., as a single pill or as two separate pills). [00192] The compounds of Formula (I), (la), (II), (Ila), (IIP), (HI), (IHa), (IV), or (IVa), or a
pharmaceutically acceptable salt, solvate, or steroisomer thereof, as well as combination therapies, are administered before, during or after the occurrence of a disease or condition, and the timing of administering the composition containing a compound varies. Thus, in one embodiment, the compounds described herein are used as a prophylactic and are administered continuously to subjects with a propensity to develop conditions or diseases in order to prevent the occurrence of the disease or condition. In another embodiment, the compounds and compositions are administered to a subject during or as soon as possible after the onset of the symptoms. In specific embodiments, a compound described herein is administered as soon as is practicable after the onset of a disease or condition is detected or suspected, and for a length of time necessary for the treatment of the disease. In some embodiments, the length required for treatment varies, and the treatment length is adjusted to suit the specific needs of each subject. For example, in specific embodiments, a compound described herein or a formulation containing the compound is administered for at least 2 weeks, about 1 month to about 5 years.
[00193] In certain embodiments, the second therapeutic agent is an adjuvant. In certain embodiments, the second therapeutic agent is an anti-cancer agent. In certain embodiments, the second therapeutic agent is an antiemetic. In certain embodiments, the second therapeutic agent is an anti -infective agent. In certain embodiments, the second therapeutic agent is an antiviral agent. In certain embodiments, the second therapeutic agent is an antibacterial agent.
[00194] In some embodiments, the compound of Formula (I), (la), (II), (Ila), (IIP), (HI), (IHa), (IV), or (IVa), or a pharmaceutically acceptable salt, solvate, or steroisomer thereof, is administered in combination with an adjuvant. In one embodiment, the therapeutic effectiveness of one of the compounds described herein is enhanced by administration of an adjuvant (i.e., by itself the adjuvant has minimal therapeutic benefit, but in combination with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced).
[00195] In some embodiments, the compound of Formula (I), (la), (II), (Ila), (IIP), (HI), (IHa), (IV), or (IVa), or a pharmaceutically acceptable salt, solvate, or steroisomer thereof, is administered in combination with an additional therapeutic agent selected from an anti -cancer agent, an antiinflammatory agent, an immunosuppressive agent, a steroid, a non-steroidal anti-inflammatory agent, an antihistamine, an analgesic, and any combinations.
[00196] In some embodiments, the compound of Formula (I), (la), (II), (Ila), (IIP), (HI), (IHa), (IV), or (rVa), or a pharmaceutically acceptable salt, solvate, or steroisomer thereof, is administered in combination with an anti-cancer agent.
[00197] In some embodiments, the anti -cancer agent is a hormone blocking therapy. Hormone blocking therapy includes the use of agents that block the production of estrogens or block the estrogen receptors. In some embodiments, hormone blocking therapy includes the use of estrogen receptor modulators and/aromatase inhibitors. Estrogen receptor modulators include triphenylethylene derivatives (e.g.
tamoxifen, toremifene, droloxifene, 3-hydroxytamoxifen, idoxifene, TAT-59 (a phosphorylated derivative of 4-hydroxytamoxifen) and GW5638 (a carboxylic acid derivative of tamoxifen)); non- steroidal estrogen receptor modulators (e.g. raloxifene, LY353381 (SERM3) and LY357489); steroidal estrogen receptor modulators (e.g. ICI-182,780). Aromatase inhibitors include steroidal aromatase inhibitors and non-steroidal aromatase inhibitors. Steroidal aromatase inhibitors include, but are not limited to, exemestane. Non-steroidal aromatase inhibitors include, but are not limited to, anastrozole and letrozole.
[00198] In certain embodiments, compounds disclosed herein are used in combination with one or more passive immunotherapies, including but not limited to, naked monoclonal antibody drugs and conjugated monoclonal antibody drugs. Examples of naked monoclonal antibody drugs that can be used include, but are not limited to, rituximab, an antibody against the CD20 antigen; trastuzumab, an antibody against the HER2 protein; alemtuzumab, an antibody against the CD52 antigen; cetuximab, an antibody against the EGFR protein; and bevacizumab which is an anti-angiogenesis inhibitor of VEGF protein.
[00199] Examples of conjugated monoclonal antibodies include, but are not limited to, radiolabeled antibody ibritumomab tiuxetan; radiolabeled antibody tositumomab; and immunotoxin gemtuzumab ozogamicin which contains calicheamicin; BL22, an anti-CD22 monoclonal antibody-immunotoxin conjugate; radiolabeled antibodies such as OncoScint (Registered trademark) and ProstaScint (Registered trademark) ; brentuximab vedotin; and ado-trastuzumab emtansine.
[00200] Further examples of therapeutic antibodies that can be used include, but are not limited to, abciximab, an antibody against the glycoprotein Ilb/IIIa receptor on platelets; daclizumab, an immunosuppressive, humanized anti-CD25 monoclonal antibody; edrecolomab , a murine anti-17-IA cell surface antigen IgG2a antibody; BEC2, a murine anti-idiotype (GD3 epitope) IgG antibody; IMC-C225, a chimeric anti-EGFR IgG antibody; VITAXIN (Registered Trademark) a humanized anti-aVbeta 3 integrin antibody; Campath 1H/LDP-03, a humanized anti CD52 IgGl antibody; Smart M195, a humanized anti-CD33 IgG antibody; epratuzumab, a humanized anti-CD22 IgG antibody; Lymphoscan; visilizumab; CM3, a humanized anti-ICAM3 antibody; IDEC-114 a primatized anti-CD80 antibody; IDEC-131 a humanized anti-CD40L antibody; IDEC-151 a primatized anti-CD4 antibody; IDEC-152 a primatized anti-CD23 antibody; SMART anti-CD3, a humanized anti-CD3 IgG; 5G1.1, a humanized anti-complement factor 5 (C5) antibody; D2E7, a humanized anti-TNF-alpha antibody; CDP870, a humanized anti-TNF-alpha Fab fragment; IDEC-151, a primatized anti-CD4 IgGl antibody; MDX-CD4, a human anti-CD4 IgG antibody; CD20-streptdavidin (+biotin -yttrium 90); CDP571, a humanized anti- TNF-alpha IgG4 antibody; LDP-02, a humanized anti-alpha 4beta 7 antibody; OrthoClone OKT4A, a humanized anti-CD4 IgG antibody; ANTOVA (Registered Trademark) , a humanized anti-CD40L IgG antibody; ANTEGREN (Registered Trademark) , a humanized anti-VLA-4 IgG antibody; and CAT-152, a human anti-TGF-beta 2 antibody.
[00201] In some embodiments, the second therapeutic agent for use in combination with a compound of Formula (I), (la), (II), (Ha), (ΠΓ), (HI), (Ula), (IV), or (IVa), or a pharmaceutically acceptable salt, solvate, or steroisomer thereof, include one or more of the following: abiraterone; abarelix; adriamycin; actinomycin; acivicin; aclarubicin; acodazole hydrochloride; acronine; adozelesin; aldesleukin;
alemtuzumab; allopurinol; alitretinoin; altretamine; ambomycin; ametantrone acetate; aminoglutethimide; aminolevulinic acid; amifostine; amsacrine; anastrozole; anthramycin; aprepitant; arsenic trioxide; asparaginase; asperlin; azacitidine; azetepa; azotomycin; batimastat; bendamustine hydrochloride; benzodepa; bevacizumab; bexarotene; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate; bizelesin; bleomycin; bleomycin sulfate; bortezomib; brequinar sodium; bropirimine;
busulfan; cactinomycin; calusterone; caracemide; carbetimer; carboplatin; carmustine; carubicin hydrochloride; carzelesin; capecitabine; cedefingol; cetuximab; chlorambucil; cirolemycin; cisplatin; cladribine; clofarabine; crisnatol mesylate; cyclophosphamide; cytarabine; dacarbazine; dasatinib;
daunorubicin hydrochloride; dactinomycin; darbepoetin alfa; decitabine; degarelix; denileukin diftitox; dexormaplatin; dexrazoxane hydrochloride; dezaguanine; dezaguanine mesylate; diaziquone; docetaxel; doxorubicin; doxorubicin hydrochloride; droloxifene; droloxifene citrate; dromostanolone propionate; duazomycin; edatrexate; eflornithine hydrochloride; elsamitrucin; eltrombopag olamine; enloplatin; enpromate; epipropidine; epirubicin hydrochloride; epoetin alfa; erbulozole; erlotinib hydrochloride; esorubicin hydrochloride; estramustine; estramustine phosphate sodium; etanidazole; etoposide;
etoposide phosphate; etoprine; everolimus; exemestane; fadrozole hydrochloride; fazarabine; fenretinide; filgrastim; floxuridine; fludarabine phosphate; fluorouracil; fluorocitabine; fosquidone; fostriecin sodium; fulvestrant; gefitinib; gemcitabine; gemcitabine hydrochloride; gemcitabine cisplatin;
gemtuzumab ozogamicin; goserelin acetate; histrelin acetate; hydroxyurea; idarubicin hydrochloride; ifosfamide; iimofosine; ibritumomab tiuxetan; idarubicin; ifosfamide; imatinib mesylate; imiquimod; interleukin II (including recombinant interleukin II, or rlL2), interferon alfa-2a; interferon alfa-2b; interferon alfa-nl; interferon alfa-n3; interferon beta-la; interferon gamma-lb; iproplatin; irinotecan hydrochloride; ixabepilone; lanreotide acetate; lapatinib; lenalidomide; letrozole; leuprolide acetate; leucovorin calcium; leuprolide acetate; levamisole; liposomal cytarabine; liarozole hydrochloride;
lometrexol sodium; lomustine; losoxantrone hydrochloride; masoprocol; maytansine; mechlorethamine hydrochloride; megestrol acetate; melengestrol acetate; melphalan; menogaril; mercaptopurine;
methotrexate; methotrexate sodium; methoxsalen; metoprine; meturedepa; mitindomide; mitocarcin; mitocromin; mitogillin; mitomalcin; mitomycin C; mitosper; mitotane; mitoxantrone hydrochloride; mycophenolic acid; nandrolone phenpropionate; nelarabine; nilotinib; nocodazoie; nofetumomab;
nogalamycin; ofatumumab; oprelvekin; ormaplatin; oxaliplatin; oxisuran; paclitaxel; palifermin;
palonosetron hydrochloride; pamidronate; pegfilgrastim; pemetrexed disodium; pentostatin;
panitumumab; pazopanib hydrochloride; pemetrexed disodium; plerixafor; pralatrexate; pegaspargase; peliomycin; pentamustine; peplomycin sulfate; perfosfamide; pipobroman; piposulfan; piroxantrone hydrochloride; plicamycin; plomestane; porfimer sodium; porfiromycin; prednimustine; procarbazine hydrochloride; puromycin; puromycin hydrochloride; pyrazofurin; quinacrine; raloxifene hydrochloride; rasburicase; recombinant HPV bivalent vaccine; recombinant HPV quadrivalent vaccine; riboprine; rogletimide; rituximab; romidepsin; romiplostim; safingol; safingol hydrochloride; sargramostim;
semustine; simtrazene; sipuleucel-T; sorafenib; sparfbsate sodium; sparsomycin; spirogermanium hydrochloride; spiromustine; spiroplatin; streptonigrin; streptozocin; sulofenur; sunitinib malate;
talisomycin; tamoxifen citrate; tecogalan sodium; tegafur; teloxantrone hydrochloride; temozolomide; temoporfin; temsirolimus; teniposide; teroxirone; testolactone; thalidomide; thiamiprine; thioguanine; thiotepa; tiazofurin; tirapazamine; topotecan hydrochloride; toremifene; tositumomab and I 131 Iodine tositumomab; trastuzumab; trestolone acetate; tretinoin; triciribine phosphate; trimetrexate; trimetrexate glucuronate; triptorelin; tubulozole hydrochloride; uracil mustard; uredepa; valrubicin; vapreotide; verteporfin; vinblastine; vinblastine sulfate; vincristine sulfate; vindesine; vindesine sulfate; vinepidine sulfate; vinglycinate sulfate; vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate; vinzolidine sulfate; vorinostat; vorozole; zeniplatin; zinostatin; zoledronic acid; and zorubicin hydrochloride.
[00202] In some embodiments, the second therapeutic agent is an alkylating agent. Examples of alkylating agents for use in combination with a compound of Formula (I), (la), (II), (Ha), (ΠΓ), (HI), (Ilia), (IV), or (IVa), or a pharmaceutically acceptable salt, solvate, or steroisomer thereof, include, but are not limited to, nitrogen mustards (e.g., mechloroethamine, cyclophosphamide, chlorambucil, meiphalan, etc.), ethylenimine and methylmelamines (e.g., hexamethlymelamine, thiotepa), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine, lomusitne, semustine, streptozocin, etc.), or triazenes (decarbazine, etc.).
[00203] Other agents that are optionally used in the methods and compositions described herein for the treatment or prevention of cancer include platinum coordination complexes (e.g., cisplatin, carboblatin), anthracenedione (e.g., mitoxantrone), substituted urea (e.g., hydroxyurea), methyl hydrazine derivative (e.g., procarbazine), adrenocortical suppressant (e.g., mitotane, aminoglutethimide).
[00204] In some embodiments, the second therapeutic agent is an immunotherapy agent. Examples of immunotherapy agents for use in combination with a compound of Formula (I), (la), (II), (Ha), (ΠΓ), (III), (Ilia), (IV), or (IVa), or a pharmaceutically acceptable salt, solvate, or steroisomer thereof, include, but are not limited to, checkpoint inhibitors (e.g. anti-PDl and anti-PD-Ll inhibitors), cancer vaccines (e.g., sipuleucel-T), oncolytic viruses (e.g., talimogene laherparepvec), cytokines (e.g., IL-2 and INF- alpha), CAR-T cells.
[00205] In some embodiments, a compound of Formula (I), (la), (II), (Ila), (IIP), (HI), (IHa), (IV), or (IVa), or a pharmaceutically acceptable salt, solvate, or steroisomer thereof, is used in combination with anti-emetic agents to treat nausea or emesis, which results from the use of a compound of Formula (I), (la), (II), (Ha), (ΠΓ), (HI), (Ilia), (IV), or (IVa), or a pharmaceutically acceptable salt, solvate, or steroisomer thereof, anti -cancer agent(s) and/or radiation therapy. Anti -emetic agents include, but are not limited to: neurokinin- 1 receptor antagonists, 5HT3 receptor antagonists (such as ondansetron, granisetron, tropisetron, palonosetron, and zatisetron), GABAB receptor agonists (such as baclofen), corticosteroids (such as dexamethasone, prednisone, prednisolone, or others), dopamine antagonists (such as, but not limited to, domperidone, droperidol, haloperidol, chlorpromazine, promethazine,
prochlorperazine, metoclopramide), antihistamines (HI histamine receptor antagonists, such as but not limited to, cyclizine, diphenhydramine, dimenhydrinate, meclizine, promethazine, hydroxyzine), cannabinoids (such as but not limited to, cannabis, marinol, dronabinol), and others (such as, but not limited to, trimethobenzamide; ginger, emetrol, propofol). [00206] In some embodiments, a compound of Formula (I), (la), (II), (Ila), (IIP), (HI), (IHa), (IV), or (IVa), or a pharmaceutically acceptable salt, solvate, or steroisomer thereof, is used in combination with an agent useful in the treatment of anemia. Such an anemia treatment agent is, for example, a continuous eythropoiesis receptor activator (such as epoetin-a).
[00207] In some embodiments, a compound of Formula (I), (la), (II), (Ila), (IIP), (HI), (IHa), (IV), or (IVa), or a pharmaceutically acceptable salt, solvate, or steroisomer thereof, is used in combination with an agent useful in the treatment of neutropenia. Examples of agents useful in the treatment of neutropenia include, but are not limited to, a hematopoietic growth factor which regulates the production and function of neutrophils such as a human granulocyte colony stimulating factor, (G-CSF). Examples of a G-CSF include filgrastim.
[00208] In one embodiment, a compound of Formula (I), (la), (II), (Ila), (ΙΙΙ'), (III), (Ilia), (IV), or (IVa), or a pharmaceutically acceptable salt, solvate, or steroisomer thereof, is administered to a mammal in combination with a non-steroidal anti -inflammatory drug (NSAID). NSAIDs include, but are not limited to: aspirin, salicylic acid, gentisic acid, choline magnesium salicylate, choline salicylate, choline magnesium salicylate, choline salicylate, magnesium salicylate, sodium salicylate, diflunisal, carprofen, fenoprofen, fenoprofen calcium, fluorobiprofen, ibuprofen, ketoprofen, nabutone, ketolorac, ketorolac tromethamine, naproxen, oxaprozin, diclofenac, etodolac, indomethacin, sulindac, tolmetin,
meclofenamate, meclofenamate sodium, mefenamic acid, piroxicam, meloxicam, COX-2 specific inhibitors (such as, but not limited to, celecoxib, rofecoxib, valdecoxib, parecoxib, etoricoxib, lumiracoxib, CS-502, JTE-522, L-745 337, and NS398).
[00209] In some embodiments, a compound of Formula (I), (la), (II), (Ila), (IIP), (III), (Ilia), (IV), or (IVa), or a pharmaceutically acceptable salt, solvate, or steroisomer thereof, is used in combination with radiation therapy (or radiotherapy). Radiation therapy is the treatment of cancer and other diseases with ionizing radiation. Radiation therapy is optionally used to treat localized solid tumors, such as cancers of the skin, tongue, larynx, brain, breast, prostate, colon, uterus, and/or cervix. It is also optionally used to treat leukemia and lymphoma (cancers of the blood-forming cells and lymphatic system, respectively).
Examples
Example 1: General Procedure for synthesis of (S)-3-amino-5-iodo-l-methyl-N-(l-(8-((l-methyl- lH-pyrazol-4-yl)ethynyl)-l-oxo-2-phenyl-l,2-dihydroisoquinolin-3-yl)ethyl)-lH-pyrazole-4- carboxamide
Figure imgf000068_0001
Example 1a Step 1 Example 1c Step 2 Example 1e Step 3
Figure imgf000068_0002
Example 1f Step 4 Example 1g Step 5 Example 1
Step 1: Example lc
[00210] To a solution of Example la (cas: 105-56-6,10 mL, 0.10 mol) and Example lb (cas: 545-06-2, 27 g, 0.19 mol) in EtOH (36 mL) was added TEA (7 mL, 0.01 mmol) at 0°C and the mixture was stirred from 0°C to r.t. for 2 hours. The mixture was concentrated under reduced pressure and purified by silica gel chromatography (Petroleum Ether/EtOAc = 5/1) to give the desired product Example lc (20 g, yield 42%) as a white solid.
LCMS [M+l]+= 256.9/258.8
Step 2: Example le
[00211] A solution of Example lc (20 g, 77.8 mmol) and Example Id (8.9 g, 77.8 mmol) in DMF (350 mL) was stirred at 100°C for 2 hours. The mixture was diluted with water and extracted by DCM (500 mL*2). The combined organic phase was washed with brine, dried over Na2S04, filtrated and concentrated under reduced pressure. The residue was purified by silica gel chromatography
(DCM/MeOH = 20/1) to give the desired product Example le (6.5 g, yield 46%) as a white solid. LCMS [M+l]+= 185.0
Step 3: Example If
[00212] A solution of Example le (500 mg, 2.7 mmol), CELL (790 mg, 3.0 mmol) and isopentyl nitrite (630 mg, 5.4 mmol) in MeCN (10 mL) was stirred at 100°Cfor 2 hours. The mixture was concentrated and purified by silica gel chromatography (Petroleum Ether/EtOAc = 3/1) to give the desired product Example If (350 mg, yield 44%) as a yellow solid.
LCMS [M+l]+= 295.6 Step 4: Example lg
[00213] A solution of Example If (350 mg, 1.2 mmol) and LiOH.H20 (126 mg, 3.6 mmol) in dioxane/H20 (3 mL/3 mL) was stirred at 70°C for 16 hours. The mixture was concentrated and acidified by IN HC1 to pH = 5. The mixture was extracted by DCM/MeOH (200 mL/20 mL). The combined organic phase was washed with brine, dried over Na2S04, filtrated and concentrated to give the desired product Example lg (145 mg, yield 45%) as a yellow solid. LCMS [M+l]+= 267.9
Step 5: Example 1
[00214] A solution of Example lg (145 mg, 0.5 mmol), HOBt (34 mg, 0.3 mmol), EDCI (144 mg, 0.8 mmol) and TEA (152 mg, 1.5 mmol) in DCM (3mL) was stirred at r.t. for 30 min. Then Example lh (184 mg, 0.5 mmol) was added and the resulting mixture was stirred at r.t. for 16 hours. The mixture was diluted with water and extracted by DCM (100 mL*2). The combined organic phase was washed with brine, dried over Na2S04, filtrated and concentrated under reduced pressure. The residue was purified by Prep-HPLC (by Ultimate XB-C18, 50 x 250 mm, 10 μιη, speed: 80 mL/min, eluent: H20/CH3CN = from 55/45 to 30/70 over 40 min, Ret.Time = 15.8 min)to give the desired product Example 1 (35 mg, yield 11%) as a yellow solid. LCMS [M+l]+= 617.9
'HNMR (400 MHz, Chloroform- ) δ 7.67-7.60 (m, 2H), 7.58-7.50 (m, 5H), 7.47-7.41 (m, 2H), 7.34 (dd, J= 7.8, 1.8 Hz, 1H), 6.77 (d, J= 6.7 Hz, 1H), 6.59 (s, 1H), 5.39 (s, 2H), 4.74 (m, 1H), 3.84 (s, 3H), 3.60 (s, 3H), 1.37 (d, J= 6.8 Hz, 3H).
Example 2: General Procedure for synthesis of (S)-3-(l-(3-amino-l-methyl-4-oxo-l,4-dihydro-5H- pyrazolo[3,4-d]pyrimidin-5-yl)ethyl)-8-((l-methyl-lH-pyrazol-4-yl)ethynyl)-2-phenylisoquinolin- l(2H)-one
HATU TEA/DCM/r.t./2 h
Figure imgf000070_0001
2) HCI/MeOH/r.t.
Example 2a Step 1 Example 2b Step 2 Example 2d Step 3
Figure imgf000070_0002
Example 2f Step 4 Example 2g Step 8 Example 2
Figure imgf000070_0003
Example 1e Step 5 Example 2e
Figure imgf000070_0004
Example 2i Step 6 Example 2k Step 7 Example 2h
Step 1: Example 2b
[00215] To a solution of Example 2a ( 17.0 g, 100 mmol) and DMF (0.3 g, 5 mmol) in DCM (100 mL) was added oxalyl dichloride (9.3 mL, 1 10 mmol) dropwise. The mixture was stirred at room temperature for 2 hours. The mixture was then concentrated in vacuo, and the residue was dissolved in DCM ( 10 mL) and the resulting solution was used directly in the next step.
[00216] To a solution of aniline (9.8 g, 105 mmol) and TEA (21.2 g, 210 mmol) in DCM ( 100 mL) was added above solution dropwise, while the reaction temperature was maintained between 25 °C to 40°C in an ice-water bath. The resulting mixture was stirred at room temperature for another 2 hours. Then, water ( 100 mL) was added, and the organic layers were separated and washed with water (50mL*2), dried over Na2S04 and filtered. The filtrate was concentrated in vacuo. The crude product was suspended in tert- butyl methyl ether and stirred at room temperature for 30 min. The precipitate was collected by filtration, rinsed with fert-butyl methyl ether, and further dried in vacuo to afford the desired product Example 2b ( 13.7 g, yield 56%) as a white solid. LC-MS [M+l]+ = 246.0
1HNMR (400 MHz, Chloroform- ) δ 7.63 (d, J = 7.6 Hz, 2H), 7.42-7.33 (m, 3H), 7.25-7.13 (m, 3H),
2.43 (s, 3H).
Step 2: Example 2d
[00217] Under an inert atmosphere, to a mixture of Example 2b (13.7 g, 55.9 mmol) in THF (100 inL) was added «-BuLi (2.5 mol/L, 44.7 mL, 1 1 1.8 mmoL) dropwise over 30 min at -30°C, which was stirred at room temperature for 1 hour. The resulting solution was used for next step directly. To a solution of Example 2c (cas: 87694-49-3, 19.5 g, 83.9 mmol) in THF (100 mL) was added z-PrMgCl ( 1 mol/L, 92.2 mL, 92.2 mmol) dropwise over 30 min. The reaction mixture was stirred at -30°C for 1 hour, which was then added to the above mixture dropwise at -30°C. The resulted solution was stirred at -15°C for 3 hours, and then quenched with water ( 120 mL), followed by addition of EtOAc (300 mL). The organic layer was washed with NH4C1 (sat.), and brine, and concentrated in vacuo to give yellowish oil, which was used for next step directly without further purification. To the solution of above yellowish oil in methanol (90 mL) was added concentrated HC1 (90 mL) at room temperature. The resulting solution was stirred at 95°C for 16 hours and then cooled to room temperature. The mixture was washed with brine, and concentrated in vacuo. The residue was extracted with EtOAc, and the organic layers were basified with NaHC03 powder to pH = 8.5, and then extracted with DCM. The combined organic phases were washed with brine, concentrated and the residue was purified by silica gel chromatography (DCM/MeOH = 10/1) to give the desired product Example 2d (8.0 g, yield 48%) as a light yellow solid.
1HNMR (400 MHz, Chloroform-£/)5 7.47 (m, 6H), 7.26 (d, J = 6.7 Hz, 2H), 6.70 (s, 1H), 3.70 (q, J = 6.5 Hz, 1H), 1.25 (d, J = 6.5 Hz, 3H).
Step 3: Example 2f
[00218] To a solution of Example 2e (312 mg, 2.0 mmol), HATU (760 mg, 2.0 mmol) and TEA (404 mg, 4.0 mmol) in DCM (20 mL) was added Example 2d (596 mg, 2.0 mmol). The mixture was stirred at room temperature for 2 hours. The mixture was diluted with water, and extracted with DCM. The organic layers were combined and concentrated. The residue was purified by silica gel chromatography
(DCM/MeOH = 20/1) to give the desired product Example 2f (640 mg, yield 73%) as a white solid. LC- MS [M+l]+ = 437.1
Step 4: Example 2g
[00219] A mixture of Example 2f (88 mg, 0.2 mmol) and triethyl orthoformate (33mg, 0.22 mmol) and TsOH.H20 (4mg, 0.02mmol) in toluene (2 mL) was stirred at 120°C for 16 hours. The mixture was diluted with sat.NaHC03, and then extracted with EtOAc. The organic layers were combined, dried over Na2S04j and concentrated. The residue was purified by silica gel chromatography (DCM/MeOH = 20/1) to give the desired product Example 2g (50 mg, yield 56%) as brown oil. LC-MS [M+l]+ = 447.0
Step 5: Example 2e
[00220] To a solution of Example le (1.0 g, 5.4 mmol) in dioxane (15 mL) was added 1M LiOH (aq. 16.3 mL, 16.3 mmol). The resulting mixture was heated at 70°C for overnight, which was then concentrated. The pH of the residue was adjusted to 5-6, and the precipitate was filtered to afford the crude product Example 2e (540 mg, yield 64%) as a dark red solid.
LC-MS: [M+l]+ = 157.0
Step 6: Example 2k
[00221] To a suspension of Example 2i (cas: 39806-90-1, 15.0 g, 72.1 mmol), PPh3 (3.8 g, 14.4 mmol), Cul(0.9 g, 4.8 mmol), Pd(OAc)2 (1.06 g, 4.8 mmol) and DIPEA (13 mL, 95.2 mmol) in DMF (100 mL) was injected Example 2j (cas: 1066-54-2, 10.6 g, 108.2 mmol) under N2 atmosphere. The resulting mixture was stirred at 60°C for 1.5 hours. After cooling, H20 (1 L) was added to the mixture, which was extracted with EtOAc (500 mL*2). The organic layers were combined, washed with brine, dried, filtered and concentrated. The residue was purified by silica gel chromatography (Petroleum ether/EtOAc = 5/1) to give the desired product Example 2k (8.6 g, yield 57%) asa brown solid.LC-MS [M+l]+ = 179.1 Step 7: Example 2h
[00222] To a solution of Example 2k (8.6 g, 48.3 mmol) in MeOH (200 mL) was added K2C03 (13.3 g, 96.6 mmol). The resulting mixture was stirred at r.t. for 2 hours. EtOAc (200mL) was added to the mixture, which was filtered. The precipitate was washed with EtOAc (10 mL*3). The filtration was concentrated in vacuo and the residue was purified by silica gel chromatography (Petroleum ether/EtOAc = 5/1) to give the desired product Example 2h (3.3g, yield 64%) as a pale green solid. LC-MS [M+l]+ = 107.1
Step 8: Example 2
[00223] Under an inert atmosphere, a mixture of Example 2g (50 mg, 0.11 mmol), Example 2h (14mg, 0.13 mmol), Pd(CH3CN)2Cl2 (3 mg, 0.011 mmol), Cs2CO3(107 mg, 0.33 mmol) and Xphos(16 mg, 0.033 mmol) in CH3CN(1 mL) was stirred at 85°C for 2 hours. The mixture was filtered and the filtrate was concentrated. The residue was purified by Prep-HPLC (by Ultimate XB-C18, 50 x 250 mm, ΙΟμπι, speed: 80 mL/min, eluent: A/B=H20/CH3CN = from 75/25 to 50/50 over 40 min, Ret. Time = 19.14 min)to afford the desired product Example 2 (7.4 mg, yield 14%) as a white solid.LC-MS [M+l]+ = 517.0
1HNMPv (400 MHz,DMSO-t ) δ 7.97 (d, J= 9.3 Hz, 2H), 7.73-7.69 (m, 2H), 7.62 (dd, J= 4.8, 4.0 Hz, 1H), 7.58 (s, 1H), 7.54-7.48 (m, 1H), 7.43 (d, J= 8.1 Hz, 1H), 7.36 (t, J= 7.4 Hz, 1H), 7.16 (td, J= 7.8, 1.2 Hz, 1H), 6.87 (d, J= 6.1 Hz, 2H), 5.40 (m, 1H), 5.23 (s, 2H), 3.80 (s, 3H), 3.60 (s, 3H), 1.56 (d, J = 6.8 Hz, 3H).
Example 4: General Procedure for synthesis of (S)-3-amino-5-bromo-l-methyl-N-(l-(8-((l-methyl- lH-pyrazol-4-yl)ethynyl)-l-oxo-2-phenyl-l,2-dihydroisoquinolin-3-yl)ethyl)-lH-pyrazole-4- carboxamide
Figure imgf000073_0001
Example 1 h Step 8 Example 4
Figure imgf000073_0002
Example 4d Step 4 Example 4e Step 5 Example 4f Step 6 Example 4g Step 7 Example 4c
Step 1: Example 4a
[00224] A mixture of Example 2d (4.5 g, 15.1 mmol),di-tert-butyl dicarbonate (3.6 g, 16.6 mmol) and TEA (3.1 g, 30.2 mmol) in DCM (45 mL) was stirred at ambient temperature for 16 hours. Water was added, and the mixture was extracted with DCM (50 mL*3). The combined organic layers were dried over Na2S04, filtered and concentrated to give crude product Example 4a (5.6 g, yield93 %) as a white solid.LC-MS [M+ l]+ = 399.0
Step 2: Example 4b
[00225] Under an inert atmosphere, a mixture of Example 4a (1.0 g, 2.5 mmol), Example 2h (320 mg, 3.0 mmol), Pd(CH3CN)2Cl2 (65 mg, 0.25 mmol), Cs2C03(2.5 g, 7.5 mmol) and Xphos (360 mg, 0.75 mmol) in CH3CN ( 15 mL) was stirred at 85°C for 2 hours. The mixture was filtered and the filtrate was concentrated. The residue was purified by silica gel chromatography (Petroleum Ether/EtOAc = 50/50) to afford the desired product Example 4b (880 mg, yield 75%) as a yellow solid. LC-MS: [M+l]+ = 469.0 Step 3: Example lh
[00226] To a solution of Example 4b (880mg, 1.88 mmol) in DCM (4 mL)/EtOAc (2 mL) was added con. HC1 (2 drops), at which point large amount yellow solid precipitated out. The mixture continued stirring for about 1 min and quenched by sat. NaHC03 to pH = 7-8, and then extracted with DCM (20 mL*2). The organic layers were dried over Na2S04, filtered and concentrated to give the crude product Example lh (550 mg, yield 80%) as a yellow solid. LC-MS [(M-18)/2+l]+ = 176.5 Step 4: Example 4e
[00227] Example 4d (10 g, 64.5 mmol) was dissolved into AcCl (40 mL) at 0°C, and the mixture was stirred at reflux for 4 hours. The reaction was cooled to r.t., diluted with ice water and stirred at r.t. for another 16 hours. The mixture was filtered and dried to give the desired product Example 4e (11 g, yield 86%) as a white solid.
Step 5: Example 4f
[00228] To a solution of Example 4e (10 g, 51 mmol) and NaOAc (28 g, 341 mmol) in EtOH (200 mL) was added dropwise Br2 (11 mL, 203 mmol), which was stirred at r.t. for 5 hours. The reaction was diluted with water and extracted by EtOAc (300 mL*3). The combined organic layer was concentrated in vacuo and the residue was purified by silica gel column (Petroleum Ether/EtOAc = 5/1) to give the desired product Example 4f (11.8 g, yield 84%) as a yellow solid. LC-MS [M+l]+ = 275.9/277.9
Step 6: Example 4g
[00229] To a solution of Example 4f (9.3 g, 33.7 mmol) in dry THF (160 mL) was added NaH (1.5 g, 37.1 mmol) at 0°C. The resulting mixture was stirred at 0°C for 30 min. Then, Mel (6 mL, 97.7 mmol) was added at 0°C and the mixture was warmed up to r.t. for 16 hours with stirring. The reaction was diluted with water and extracted by DCM (300 mL*3). The combined organic layer was concentrated and the residue was purified by silica gel chromatography (Petroleum Ether/EtOAc = 3/1) to give the desired product Example 4g (5 g, yield 51%) as a white solid. LC-MS [M+l]+ = 289.9/291.9
Step 7: Example 4c
[00230] A solution of Example 4g (2.0 g, 6.8 mmol) and LiOH.H20 (870 mg, 20.6 mmol) in
dioxane/H20 (30 mL/ 30 mL) was stirred at 70°C for 16 hours. The mixture was concentrated, the pH of which was adjusted to 5 by IN HC1 (aq.). The precipitate was filtered and dried to give the desired product Example 4c (1.3 g, yield 86%) as a white solid.
LC-MS [M+l]+ = 219.9/221.9
Step 8: Example 4
[00231] To a solution of Example 4c (80mg, 0.36 mmol) in DMF were added HOBt (25 mg, 0.18 mmol), EDCI (105 mg, 0.55 mmol) and TEA (110 mg, 1.09 mmol). The mixture was stirred at ambient temperature for 30 min. Then, Example lh (150mg, 0.40 mmol) was added, and the resulting mixture was allowed to stir at r.t. for 16 hours. The reaction mixture was diluted with water and EtOAc, extracted and concentrated. The residue was purified by Prep-HPLC (by Ultimate XB-C18, 50 x 250 mm, 10 μπι, speed: 80 mL/min, eluent: H20/CH3CN = from 65/35 to 40/60 over 40 min, Ret. Time = 20.5 min)to give the desired product Example 4 (67 mg, yield 33%) as an off-white solid.LC-MS [M+l]+ =569.9/571.9 'HNMR (400 MHz, Chloroform- ) δ 7.68-7.61 (m, 2H), 7.59-7.41 (m, 7H), 7.33 (dd, J= 7.7, 2.0 Hz, 1H), 6.55 (s, 1H), 6.46 (d, J= 6.8 Hz, 1H), 4.95 (s, 2H), 4.78-4.72(m, 1H), 3.85 (s, 3H), 3.74 (s, 3H), 1.37 (d, J= 6.8 Hz, 3H).
Example 7: General Procedure for synthesis of (S)-3,5-diamino-l-methyl-N-(l-(8-((l-methyl-lH- pyrazol-4-yl)ethynyl)-l-oxo-2-phenyl-l,2-dihydroisoquinolin-3-yl)ethyl)-lH-pyrazole-4- carboxamide
Figure imgf000075_0001
Example 1 h Step 1 Example 7
[00232] A solution of Example 2e (lOOmg, 0.64 mmol), HOBt (43 mg, 0.32 mmol), EDCI (185 mg, 0.96 mmol), and TEA (194 mg, 1.92 mmol) in DMF (3 mL) was stirred at ambient temperature for 15 min. Then, Example lh (260mg, 0.71 mmol) was added, and the resulting mixture was allowed to stir at r.t. for 16 hours. The reaction mixture was diluted with water and EtOAc, extracted and concentrated. The residue was purified by Prep-HPLC (by Ultimate XB-C18, 50 x 250 mm, 10 μπι, speed: 80 mL/min, eluent: H20/CH3CN = from 80/20 to 55/45 over 40 min, Ret. Time = 26.3 min)to give the desired product Example 7 (9 mg, yield 3 %) as a white solid. LC-MS [M+l]+ =507.0
'HNMR (400 MHz, DMSO- 6) δ 7.99 (s, 1H), 7.66-7.39 (m, 9H), 7.06 (d, J= 6.4 Hz, 1H), 6.77 (s, 1H),
5.97 (s, 2H), 4.82 (s, 2H), 4.37 (m, 1H), 3.81 (s, 3H), 3.30 (s, 3H), 1.22 (d, J= 6.7 Hz, 3H).
Example 8: General Procedure for synthesis of (S)-3-amino-5-ethynyl-l-methyl-N-(l-(8-((l-methyl- lH-pyrazol-4-yl)ethynyl)-l-oxo-2-phenyl-l,2-dihydroisoquinolin-3-yl)ethyl)-lH-pyrazole-4- carboxamide
Figure imgf000075_0002
Example 4 Step 1 Example 8a Step 2 Example 8
Step 1: Example 8a
[00233] A solution of Example 4 (100 mg, 0.18 mmol), Example 2j (cas: 1066-54-2, 26 mg, 0.26 mmol), Pd(PPh3)2Cl2 (14 mg, 0.02 mmol), Cul (4 mg, 0.02mmol) and TEA (91 mg, 0.9 mmol) in dioxane (1 mL) was stirred under N2 at 80°C for 16 hours. The mixture was diluted with water and extracted by EtOAc (100 mL*2). The combined organic phase was washed with brine, dried over Na2S04, filtrated and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Petroleum Ether/EtOAc = 2/1) to give the desired product Example 8a (60 mg, yield 57%) as a white solid. LC-MS [M+l]+= 588.0
Step 2: Example 8
[00234] A solution of Example 8a (60 mg, 0.1 mmol) and K2C03 (28 mg, 0.2 mmol) in MeOH (1 niL) was stirred at r.t. for 30 min. The mixture was diluted with water and extracted by EtOAc (30 mL*2). The combined organic phase was washed with brine, dried over Na2S04, filtrated and concentrated under reduced pressure. The residue was purified by Prep-HPLC (by Ultimate XB-C18, 50 x 250 mm, 10 μπι, speed: 80 mL/min, eluent: H20/CH3CN = from 65/35 to 40/60 over 40 min, Ret. Time = 20.2 min) to give the desired product Example 8 (2 mg, yield 4%) as a white solid. LC-MS [M+l]+= 516.0 lH NMR (400 MHz, DMSO δ 7.99 (s, 1H), 7.64 (d, J= 7.5 Hz, 1H), 7.62-7.47 (m, 6H), 7.44 (s, 1H), 7.38 id. ./ 7.7 Hz, 1H), 7.32 (d. ·/ 6.8 Hz, 1H), 6.75 (s, 1H), 5.39 (d. ·/ 3.5 Hz, 3H), 4.44 (m, 1H), 3.81 (s, 3H), 3.68 (s, 3H), 1.26 (d, J= 6.8 Hz, 3H).
Example 9: General Procedure for synthesis of (S)-3-amino-5-(furan-2-yl)-l-methyl-N-(l-(8-((l- methyl-lH-pyrazol-4-yl)ethynyl)-l-oxo-2-phenyl-l,2-dihydroisoquinolin-3-yl)ethyl)-lH-pyrazole-4- carboxamide
Figure imgf000076_0001
Example 4 Step 1 Example 9
[00235] To a solution of Example 4 (60mg, 0.11 mmol), Example 9a (cas: 13331-23-2, 30mg, 0.26 mmol) in dioxane/H20 (4 mL/1 mL) were added Pd(dppf)Cl2 (7.7 mg, 0.011 mmol) and Na2C03 (34 mg, 0.32 mmol). The mixture was degassed by nitrogen for three times and heated at 100°C for 4 hours. The reaction mixture was filtered, washed with EtOAc and concentrated. The residue was purified by Prep- HPLC (by Ultimate XB-C18, 50 x 250 mm, 10 μιη, speed: 80 mL/min, eluent: H20/CH3CN = from 65/35 to 35/65 over 40 min, Ret. Time = 21.1 min) to give the desired product Example 9 (10 mg, yield 17%) as a yellow solid. LC-MS [M/2+l]+ = 279.5
'HNMR (400 MHz, Chloroform- ) δ 7.65 (s, 1H), 7.64-7.61 (m, 1H), 7.60 (d, J= 1.9 Hz, 1H), 7.58 (s, 1H), 7.53 (d, J= 2.8 Hz, 1H), 7.52-7.48 (m, 2H), 7.45 (d, J= 7.1 Hz, 1H), 7.42-7.38 (m, 1H), 7.34 (d, J = 7.7 Hz, 1H), 7.29 (d, J= 7.4 Hz, 1H), 6.73 (d, J= 3.4 Hz, 1H), 6.62 (dd, J= 3.4, 1.9 Hz, 1H), 6.28 (s, 1H), 5.97 (d, J= 6.8 Hz, 1H), 4.61 (m, 1H), 3.85 (s, 3H), 3.66 (s, 3H), 1.16 (d, J= 6.8 Hz, 3H).
Example 10: General Procedure for synthesis of (S)-3-amino-l-methyl-N-(l-(8-((l-methyl-lH- pyrazol-4-yl)ethynyl)-l-oxo-2-phenyl-l,2-dihydroisoquinolin-3-yl)ethyl)-5-(pyridin-2-yl)-lH- pyrazole-4-carboxamide
Figure imgf000077_0001
Example 4 Step 1 Example 10
[00236] To a solution of Example 4 (100 mg, 0.18 mmol) and Pd(PPh3)4 in dioxane ( 1 mL) was added Example 10a (cas: 17997-47-6, 78 mg, 0.21 mmol) under N2, which was then stirred at 110°C for 20hours. The mixture was quenched with sat. KF aqueous solution and extracted by DCM (100 mL*2). The combined organic phase was washed with brine, dried over Na2S04, filtrated and concentrated under reduced pressure. The residue was purified by Prep-HPLC (by Ultimate XB-C18, 50 x 250 mm, 10 μπι, speed: 80 mL/min, eluent: H20/CH3CN = from 65/35 to 40/60 over 30 min, Ret. Time = 15.6 min) to give the desired product Example 10 (3 mg, yield 3%) as a white solid. LC-MS [M+l]+=569.0
'HNMR (400 MHz, DMSO- 6) δ 8.78 (d, J= 6.8 Hz, 1H), 8.66 (d, J= 4.8 Hz, 1H), 8.04 (t, J= 7.6 Hz, 1H), 7.98 (s, 1H), 7.77 (d, J= 7.9 Hz, 1H), 7.65 (t, J= 7.7 Hz, 1H), 7.58-7.42 (m, 7H), 7.37 (d, J= 7.7 Hz, 1H), 7.08 (d, J= 6.8 Hz, 1H), 6.33 (s, 1H), 5.36 (s, 2H), 4.33 (m, 1H), 3.80 (s, 3H), 3.62 (s, 3H), 1.15 (d, J= 6.8 Hz, 3H).
Example 11: General Procedure for synthesis of (S)-3-amino-5-cyano-l-methyl-N-(l-(8-((l-methyl- lH-pyrazol-4-yl)ethynyl)-l-oxo-2-phenyl-l,2-dihydroisoquinolin-3-yl)ethyl)-lH-pyrazole-4- carboxamide
Figure imgf000078_0001
Example 4 Step 1 Example 11
[00237] In a 5-mL microwave tube were charged with Example 4 (80mg, 0.14 mmol), dppf (cas: 12150- 46-8, 8 mg, 0.014 mmol), zinc dust (2.3 mg, 0.035 mmol) and Pd2(dba)3 (6 mg, 0.007 mmol). DMA (cas: 127-19-5, 1 mL) was added via a syringe. The mixture was degassed by nitrogen for three times, sealed, and then heated at 120°C by MW for 1 hour. The reaction mixture was filtered, washed with water and extracted by EtOAc (30 mL*2). The organic layers were concentrated and purified by Prep-HPLC (by Ultimate XB-C18, 50 x 250 mm, 10 μιη, speed: 80 mL/min, eluent: H20/CH3CN = from 65/35 to 40/60 over 40 min, Ret. Time = 22.2 min) to give the pure product Example 11 (16 mg, yield 22%) as a white solid. LC-MS [M+l]+ = 517.0
'HNMR (400 MHz, Chloroform- ) δ 7.64 (s, 1H), 7.62 (d, J= 1.3 Hz, 1H), 7.57 (s, 1H), 7.56 (d, J= 4.6 Hz, 1H), 7.54 (d, J= 6.1 Hz, 1H), 7.51 (dd, J= 4.1, 2.0 Hz, 1H), 7.50-7.47 (m, 1H), 7.47-7.44 (m, 1H), 7.42 (dd, J= 7.9, 1.3 Hz, 1H), 7.35-7.31 (m, 1H), 6.55 (s, 1H), 6.15 (d, J= 6.8 Hz, 1H), 4.74 (m, 1H), 3.90 (s, 3H), 3.85 (s, 3H), 1.37 (d, J= 6.8 Hz, 3H).
Example 12: General Procedure for synthesis of (S)-3-amino-5-bromo-N-(l-(8-chloro-l-oxo-2- phenyl-l,2-dihydroisoquinolin-3-yl)ethyl)-l-methyl-lH-pyrazole-4-carboxamide
Figure imgf000078_0002
Example 4c Step 1 Example 12
[00238] To a solution of Example 4c (260mg, 1.18 mmol) in DCM (10 mL) were added HATU (674 mg, 1.77 mmol) and TEA (360 mg, 3.55 mmol). The mixture was stirred at ambient temperature for 30 min. Then Example 2d (423mg, 1.42 mmol) was added, and the resulting mixture was allowed to stir at r.t. for 16 hours. The reaction mixture was diluted with water and DCM, extracted and concentrated. The residue was purified by silica gel chromatography (Petroleum Ether/EtOAc = 10/90) to give crude product (210 mg), which was further purified by Prep-HPLC (by Ultimate XB-C18, 50 x 250 mm, 10 μπι, speed: 80 mL/min, eluent: H20/CH3CN = from 60/40 to 35/65 over 40 min, Ret. Time = 16-18 min) to give the pure product Example 12 (29 mg, yield 5%) as a white solid.
LC-MS [M+l]+ =499.9/501.8
'HNMR (400 MHz, Chloroform- ) δ 7.54-7.42 (m, 6H), 7.38 (dd, J= 7.1, 2.1 Hz, 1H), 7.30 (dd, J= 7.3, 2.2 Hz, 1H), 6.53 (s, 1H), 6.48 (d, J= 6.6 Hz, 1H), 4.76 (m, 1H), 3.74 (s, 3H), 1.36 (d, J= 6.8 Hz, 3H). Example 13: General Procedure for synthesis of (S)-3-amino-N-(l-(8-chloro-l-oxo-2-phenyl-l,2- dihydroisoquinolin-3-yl)ethyl)-5-cyano-l-methyl-lH-pyrazole-4-carboxamide
Figure imgf000079_0001
Example 4g step 1 Example 13a step 2 Example 13b step 3 Example 13
Step 1: Example 13a
[00239] To a solution of Example 4g (2 g, 6.92 mmol) in NMP (20 mL) was added CuCN (1.2 g, 13.84 mmol) and KI (115 mg, 0.69 mmol). The mixture was stirred at 160 °C for 2 hours, which was purified by silica gel chromatography (Petroleum Ether/EtOAc=l/l) directly to give desired product Example 13a (1.0 g with NMP, crude yield 60%) as light brown oil.
LC-MS [M+l]+ = 237.0
Step 2: Example 13b
[00240] To a solution of Example 13a (1.0 g crude, 4.2 mmol) in dioxane (10 mL) was added LiOH.H20 (550 mg, 12.5 mmol) in water (5 mL). The resulting mixture was stirred at 70°C for 16 hours, which was then acidified with 0.5 N HC1 (aq.) to pH = 4, extracted with EtOAc, and concentrated to give the crude desired product Example 13b (100 mg, crude yield 14%) as a light brown solid. LC-MS [M+l]+ = 167.0 Step 3: Example 13
[00241] A mixture of Example 13b (100 mg crude, 0.6 mmol), Example 2d (180 mg, 0.6 mmol), EDCI (128 mg, 0.66 mmol), HOBt (90 mg, 0.66 mmol) and Et3N (182 mg, 1.8 mmol) in DMF (2 mL)/THF (2 mL) was stirred at r.t. for 16 hours. The mixture was diluted with water, extracted with EtOAc, and concentrated. The residue was purified by prep-TLC (Petroleum Ether/EtOAc = 1/1) and prep-HPLC (by Ultimate XB-C18, 50 x 250 mm, 10 μιη, speed: 80 mL/min, eluent: H20/CH3CN = from60/40 to 35/65 over 40 min, Ret. Time = 17.9 min) to give the desired product Example 13 (7 mg, yield 3%) as a white solid.
LC-MS [M+l]+ = 446.9
'HNMR (400 MHz, DMSO- 6) δ 8.12 (d, J= 6.9 Hz, 1H), 7.63 (t, J= 7.8 Hz, 1H), 7.57-7.43 (m, 5H), 7.42-7.34 (m, 2H), 6.83 (s, 1H), 5.46 (s, 2H), 4.42 (m, lH), 3.78 (s, 3H), 1.25 (d, J= 6.8 Hz, 3H). Example 14 and 15: General Procedure for synthesis of (S)-3-amino-5-chloro-l-methyl-N-(l-(8-((l- methyl-lH-pyrazol-4-yl)ethynyl)-l-oxo-2-phenyl-l,2-dihydroisoquinolin-3-yl)ethyl)-lH-pyrazole-4- carboxamide (14) and (S)-5-amino-3-chloro-l-methyl-N-(l-(8-((l-methyl-lH-pyrazol-4-yl)ethynyl)- l-oxo-2-phenyl-l,2-dihydroisoquinolin-3-yl)ethyl)-lH-pyrazole-4-carboxamide (15)
Figure imgf000080_0001
Example 4d Step 1 Example 14a Step 2 Example 14b Example 15b Step 3
Figure imgf000080_0002
Example 14c Example 15c Step 4 Example 14 Example 15
Step 1: Example 14a
[00242] To a solution of Example 4d (2.0 g, 13.0 mmol) in DMF (65 mL) was added NCS (2.2 g, 16.8 mmol) carefully and stirred at r.t. for 3 hours. The mixture was diluted with water and extracted by EtOAc (200 mL*2). The combined organic phase was washed with brine, dried over Na2S04, filtrated and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Petroleum Ether/EtOAc = 1/1) to give the desired product Example 14a (1.6 g, yield 65%) as yellow oil. LC-MS [M+l]+= 189.9
Step 2: Example 14b and Example 15b
[00243] To a solution of Example 14a (1.5 g, 7.9 mmol) in dry THF (40 mL) was added NaH (350 mg, 8.7 mmol) at 0°C, followed by addition of Mel (0.7 mL, 12.0 mmol) after 30 min. Then the mixture was stirred at r.t. for 16 hours. The mixture was diluted with water and extracted by EtOAc (200 mL*2). The combined organic phase was washed with brine, dried over Na2S04, filtrated and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Petroleum Ether/EtOAc = 2/1) to give the crude product Example 14b and Example 15b as a mixture (two regioisomers, 700 mg, yield 44%) as yellow oil.
LC-MS [M+l]+= 203.9 Step 3: Example 14c and Examplel5c
[00244] A solution of Example 14b and Example 15b (200 mg, 1.0 mmol) and LiOH.H20 (126 mg, 3.0 mmol) in THF/EtOH/H20 (5 mL/3 mL/1 inL) was stirred at 50°C for 16 hours. The mixture was concentrated and acidified by IN HC1 to pH = 5, and extracted by DCM/MeOH (80 mL/15 mL*2). The combined organic phase was washed with brine, dried over Na2S04, filtrated and concentrated under reduced pressure to give the crude product Example 14c and Example 15c as a mixture (two regioisomers, 300 mg, yield >100%) as a yellow solid, which was used in the next step without further purification. LC-MS [M+l]+= 175.9
Step 4: Example 14 and Example 15
[00245] A solution of Example 14c and Example 15c (175 mg, 1.0 mmol), HOBt (68 mg, 0.5 mmol), EDCI (288 mg, 1.5 mmol) and TEA (303 mg, 3.0 mmol) in DCM (5 mL) was stirred 30 min, followed by addition of Example lh (368 mg, 1.0 mmol). The mixture was stirred at r.t. for 16 hours. The mixture was diluted with water and extracted by DCM/MeOH (100 mL/20 mL*2). The combined organic phase was washed with brine, dried over Na2S04, filtrated and concentrated under reduced pressure. The residue was purified by Prep-HPLC (by Ultimate XB-C18, 50 x 250 mm, 10 μπι, speed: 80 mL/min, eluent: H20/CH3CN = from 65/35 to 32/68 over 50 min) to give the desired product Example 14 (Ret. Time = 18 min, 20 mg, yield 4%) as a white solid (LC-MS [M+l]+= 526.0) and Example 15 (Ret. Time = 22.9 min, 28 mg, yield 5%) as a white solid (LC-MS [M+l]+= 526.0).
¾ NMR for Example 14 (400 MHz, Chloroform- ) δ 7.65-7.40 (m, 9H), 7.35-7.30 (m, 1H), 6.53 (s,
1H), 6.28 (d, J= 6.9 Hz, 1H), 4.75 (m, 1H), 3.85 (s, 3H), 3.69 (s, 3H), 1.36 (d, J= 6.8 Hz, 3H).
¾ NMR for Example 15 (400 MHz, Chloroform- ) δ 7.64-7.40 (m, 9H), 7.35-7.31 (m, 1H), 6.55 (d, J =
6.5 Hz, 2H), 4.70 (m, 1H), 3.84 (s, 3H), 3.53 (d, J= 1.7 Hz, 3H), 1.35 (d, J= 6.8 Hz, 3H).
Example 16: General Procedure for synthesis of (S)-3-amino-5-chloro-N-(l-(8-chloro-l-oxo-2- phenyl-l,2-dihydroisoquinolin-3-yl)ethyl)-l-methyl-lH-pyrazole-4-carboxamide
Figure imgf000081_0001
Example 4d Step 1 Example 14a Step 2 Example 14b
Figure imgf000081_0002
Step 3 Example 14c Step 4 Example 16 [00246] To a solution of Example 14c (175 mg, 1 mmol), HOBt (68 mg, 0.5 mmol), EDCI (288 mg, 1.5 mmol) and TEA (303 mg, 3 mmol) in DCM (5 mL) was added Example 2d (298 mg, 1 mmol) after stirring for 30 min. The mixture was stirred at r.t. for 16 hours. The mixture was diluted with water and extracted by DCM (100 mL*2). The combined organic phase was washed with brine, dried over Na2S04, filtrated and concentrated under reduced pressure. The residue was purified by Prep-HPLC (by Ultimate XB-C18, 50 x 250 mm, 10 μιη, speed: 80 mL/min, eluent: H20/CH3CN = from 60/40 to 30/70 over 40 min, Ret. Time = 18 min) to give Example 16 (25 mg, yield 5%) as a white solid. LC-MS [M+l]+= 455.9
'HNMR (400 MHz, Chloroform- ) δ 7.56-7.43 (m, 6H), 7.38 (dd, J= 7.1, 2.1 Hz, 1H), 7.31-7.28 (m, 1H), 6.52 (s, 1H), 6.30 (d, J= 6.6 Hz, 1H), 4.92 (s, 2H), 4.75 (m, 1H), 3.69 (s, 3H), 1.36 (d, J= 6.9 Hz, 3H).
Example 17: General Procedure for synthesis of (S)-3-amino-l,5-dimethyl-N-(l-(8-((l-methyl-lH- pyrazol-4-yl)ethynyl)-l-oxo-2-phenyl-l,2-dihydroisoquinolin-3-yl)ethyl)-lH-pyrazole-4- carboxamide
Figure imgf000082_0001
Example 17a Step 1 Example 17b Step 2
Figure imgf000082_0002
Example 17c Step 3 Example 17
Step 1: Example 17b
[00247] To a solution of Example 17a (cas: 23286-70-6, 900 mg, 5.3 mmol) in THF (25 mL) was added NaH (234 mg, 5.8 mmol) at 0°C, which was stirred for 30 min. Mel (0.7 mL, 10.6 mmol)was then added to the above mixture, which was stirred at r.t. for 16 hours. The mixture was diluted with water and extracted by EtOAc (200 mL*2). The combined organic phase was washed with brine, dried over Na2S04, filtrated and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Petroleum Ether/EtOAc = 3/1) to give the desired product Example 17b (325 mg, yield 33%) as a yellow solid.
LC-MS [M+l]+= 184.0
Step 2: Example 17c
[00248] A solution of Example 17b (325 mg, 1.8 mmol) and LiOH.H20 (227 mg, 5.4 mmol) in 1,4- dioxane/H20 (5 mL/5 mL) was stirred at 70°C for 16 hours. The mixture was concentrated and acidified by IN HC1 to pH = 5. The mixture was filtered to give the desired product Example 17c (70 mg, yield 21%) as a yellow solid.LC-MS [M+l]+= 156.0
Step 3: Example 17
[00249] A solution of Example 217c (70 mg, 0.4 mmol), HOBt (30 mg, 0.2 mmol), EDCI (126 mg, 0.6 mmol) and TEA (133 mg, 1.2 mmol) in DCM (3mL) was stirred at r.t. for 30 min. Then, Examplelh (165 mg, 04 mmol) was added to the above mixture, which was stirred at r.t. for another 16 hours. The mixture was diluted with water and extracted by DCM (100 mL*2). The combined organic phase was washed with brine, dried over Na2S04, filtrated and concentrated under reduced pressure. The residue was purified by Prep-HPLC (by Ultimate XB-C18, 50 x 250 mm, 10 μπι, speed: 80 mL/min, eluent:
H2O/CH3CN = from 75/25 to 50/50 over 40 min, Ret. Time = 27.6 min) to give the desired product
Example 17 (34 mg, yield 15%) as a yellow solid. LC-MS [M+l]+= 506.0
'HNMR (400 MHz, Chloroform- ) δ 7.64-7.31 (m, 10H), 6.71 (d, J= 6.9 Hz, 1H), 6.51 (s, 1H), 4.74 (m, 1H), 3.85 (s, 3H), 3.64 (s, 3H), 2.43 (s, 3H), 1.33 (d, J= 6.8 Hz, 3H).
Example Bl: Kinase Assay
Kinase Assay
[00250] Kinase-tagged T7 phage strains were prepared in an E. coli host derived from the BL21 strain. E. coli were grown to log-phase and infected with T7 phage and incubated with shaking at 32°C until lysis. The lysates were centrifuged and filtered to remove cell debris. The remaining kinases were produced in HEK-293 cells and subsequently tagged with DNA for qPCR detection. Streptavidin -coated magnetic beads were treated with biotinylated small molecule ligands for 30 minutes at room temperature to generate affinity resins for kinase assays. The liganded beads were blocked with excess biotin and washed with blocking buffer (SeaBlock (Pierce), 1% BSA, 0.05% Tween 20, 1 mM DTT) to remove unbound ligand and to reduce non-specific binding. Binding reactions were assembled by combining kinases, liganded affinity beads, and test compounds in lx binding buffer (20% SeaBlock, 0.17x PBS, 0.05% Tween 20, 6 mM DTT). Test compounds were prepared as 11 IX stocks in 100% DMSO. Kds were determined using an 11 -point 3-fold compound dilution series with three DMSO control points. All compounds for Kd measurements are distributed by acoustic transfer (non -contact dispensing) in 100% DMSO. The compounds were then diluted directly into the assays such that the final concentration of DMSO was 0.9%. All reactions performed in polypropylene 384-well plate. Each was a final volume of 0.02 ml. The assay plates were incubated at room temperature with shaking for 1 hour and the affinity beads were washed with wash buffer (lx PBS, 0.05% Tween 20). The beads were then re-suspended in elution buffer (lx PBS, 0.05% Tween 20, 0.5 μΜ non-biotinylated affinity ligand) and incubated at room temperature with shaking for 30 minutes. The kinase concentration in the eluates was measured by qPCR.
Compound Handling
[00251] An 11-point 3-fold serial dilution of each test compound was prepared in 100% DMSO at lOOx final test concentration and subsequently diluted to lx in the assay (final DMSO concentration = 1%). Most Kds were determined using a compound top concentration = 30,000 nM. If the initial Kd determined was < 0.5 nM (the lowest concentration tested), the measurement was repeated with a serial dilution starting at a lower top concentration. A Kd value reported as 40,000 nM indicates that the Kd was determined to be >30,000 nM.
Binding Constant
[00252] Binding constants (Kds) were calculated with a standard dose-response curve using the Hill equation:
Sigraai - Background
Response = Background ÷
[00253] The Hill Slope was set to -1.
[00254] Curves were fitted using a non-linear least square fit with the Levenberg-Marquardt algorithm.
[00255] Pi3k Kds for the compounds disclosed herein are shown in table 1 :
TABLE 1
Figure imgf000084_0001

Claims

WHAT IS CLAIMED IS:
A compound of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
Figure imgf000085_0001
wherein
each R21 is independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=0)Rc, -N02, -NRaRb, -
S(=0)2Rc, -NRaS(=0)2Rc, -S(=0)2NRaRb, -C(=0)Rc, -OC(=0)Rc, -C(=0)ORa, -OC(=0)ORa, -C(=0)NRaRb, -OC(=0)NRaRb, -NRaC(=0)NRaRb, -NRaC(=0)Rc, -NRaC(=0)ORa, optionally substituted Ci-C6 alkyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted cycloalkyl, optionally substituted (Ci-C6 alkyl)cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted (Ci-C6 alkyl)heterocycloalkyl, optionally substituted aryl, optionally substituted (Ci-C6 alkyl)aryl, optionally substituted heteroaryl, or optionally substituted (Ci-C6 alkyl)heteroaryl;
R22 is halogen, -CN, -ORa, -SRa, -S(=0)Rc, -N02, -NRaRb, -S(=0)2Rc, -NRaS(=0)2Rc, - S(=0)2NRaRb, -C(=0)Rc, -OC(=0)Rc, -C(=0)ORa, -OC(=0)ORa, -C(=0)NRaRb, - OC(=0)NRaRb, -NRaC(=0)NRaRb, -NRaC(=0)Rc, -NRaC(=0)ORa, optionally substituted d- C6 alkyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted cycloalkyl, optionally substituted (C1-C5 alkyl)cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted (Ci- C6 alkyl)heterocycloalkyl, optionally substituted aryl, optionally substituted (Ci-C6 alkyl)aryl, optionally substituted heteroaryl, or optionally substituted (Ci-C6 alkyl)heteroaryl;
R23 is -SRa, -S(=0)Rc, -S(=0)2Rc, -S(=0)2NRaRb, -C(=0)Rc, -C(=0)NRaRb, optionally
substituted Ci-C6 alkyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted cycloalkyl, optionally substituted (Ci-C6 alkyl)cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted (Ci-C6 alkyl)heterocycloalkyl, optionally substituted aryl, optionally substituted (Ci-C6 alkyl)aryl, optionally substituted heteroaryl, or optionally substituted (Ci-C6 alkyl)heteroaryl; R24 is hydrogen, halogen, -CN, -OH, -ORa, -SRa, -S(=0)Rc, -N02, -NRaRb, -S(=0)2Rc, - NRaS(=0)2Rc, -S(=0)2NRaRb, -C(=0)Rc, -OC(=0)Rc, -C(=0)ORa, -OC(=0)ORa, - C(=0)NRaRb, -OC(=0)NRaRb, -NRaC(=0)NRaRb, -NRaC(=0)Rc, -NRaC(=0)ORa, optionally substituted Ci-C6 alkyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted cycloalkyl, optionally substituted (Ci-C6 alkyl)cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted (Ci-C6 alkyl)heterocycloalkyl, optionally substituted aryl, optionally substituted (Ci-C6 alkyl)aryl, optionally substituted heteroaryl, or optionally substituted (Ci-C6 alkyl)heteroaryl;
R25 and R26 are independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=0)Rc, -N02, -NRaRb, - S(=0)2Rc, -NRaS(=0)2Rc, -S(=0)2NRaRb, -C(=0)Rc, -OC(=0)Rc, -C(=0)ORa, -OC(=0)ORa, -C(=0)NRaRa, -OC(=0)NRaRb, -NRaC(=0)NRaRb, -NRaC(=0)Rc, -NRaC(=0)ORc, optionally substituted Ci-C6 alkyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, or optionally substituted C2-C6 alkynyl;
R27 is hydrogen, -SRa, -S(=0)Rc, -S(=0)2Rc, -S(=0)2NRaRb, -C(=0)Rc, -C(=0)NRaRb, optionally substituted Ci-C6 alkyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted cycloalkyl, optionally substituted (Ci-C6 alkyl)cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted (Ci-C6 alkyl)heterocycloalkyl, optionally substituted aryl, optionally substituted (Ci-C<5 alkyl)aryl, optionally substituted heteroaryl, or optionally substituted (Ci-C6 alkyl)heteroaryl;
R28 is halogen, -CN, -ORa, -SRa, -S(=0)Rc, -N02, -NRaRb, -S(=0)2Rc, -NRaS(=0)2Rc, - S(=0)2NRaRb, -C(=0)Rc, -OC(=0)Rc, -C(=0)ORa, -OC(=0)ORa, -C(=0)NRaRb, - OC(=0)NRaRb, -NRaC(=0)NRaRb, -NRaC(=0)Rc, -NRaC(=0)ORa, optionally substituted C C6 alkyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted cycloalkyl, optionally substituted (Ci-C6 alkyl)cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted (Ci- C6 alkyl)heterocycloalkyl, optionally substituted aryl, optionally substituted (Ci-C6 alkyl)aryl, optionally substituted heteroaryl, or optionally substituted (Ci-C6 alkyl)heteroaryl;
R29 is hydrogen, -SRa, -S(=0)Rc, -S(=0)2Rc, -S(=0)2NRaRb, -C(=0)Rc, -C(=0)NRaRb, optionally substituted Ci-C6 alkyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted cycloalkyl, optionally substituted (Ci-C6 alkyl)cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted (Ci-C6 alkyl)heterocycloalkyl, optionally substituted aryl, optionally substituted (Ci-C<5 alkyl)aryl, optionally substituted heteroaryl, or optionally substituted (Ci-C6 alkyl)heteroaryl;
each Ra and Rb are independently hydrogen, optionally substituted Ci-C6 alkyl, optionally
substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
or Ra and Rb are taken together with the nitrogen atom to which they are attached to form an optionally substituted heterocycloalkyl;
each Rc is optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; and n2 is 1-3.
2. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:
each R21 is independently hydrogen, halogen, -CN, -OH, -OMe, -NH2, Ci-C6 alkyl, or Ci-C6 haloalkyl; and n2 is 1 or 2.
3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:
each R21 is hydrogen.
4. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt, solvate, or
stereoisomer thereof wherein:
R23 is optionally substituted Ci-C6 alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl.
5. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt, solvate, or
stereoisomer thereof wherein:
R23 is optionally substituted aryl.
6. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt, solvate, or
stereoisomer thereof wherein:
R24 is hydrogen, halogen, -CN, -OH, -OMe, -NH2, d-Q, alkyl, or d-Q, haloalkyl.
7. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt, solvate, or
stereoisomer thereof wherein:
R24 is hydrogen.
8. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt, solvate, or
stereoisomer thereof wherein:
R25 and R26 are independently hydrogen, halogen, Ci-C6 alkyl, or Ci-C6 haloalkyl.
9. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt, solvate, or
stereoisomer thereof wherein:
R27 is hydrogen or Ci-C6 alkyl.
10. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt, solvate, or
stereoisomer thereof wherein the compound of Formula (III) is of Formula (Ilia):
Figure imgf000088_0001
Formula (Ilia).
The compound of any one of claims 1-10, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:
R22 is halogen, -CN, -ORa, -NRaRb, optionally substituted Ci-C6 alkyl, optionally substituted Ci-
C<5 heteroalkyl, or optionally substituted C2-C6 alkynyl.
The compound of any one of claims 1-11, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:
R22 is halogen, optionally substituted Ci-C6 alkyl, or optionally substituted C2-C6 alkynyl.
The compound of any one of claims 1-12, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:
R22 is halogen.
The compound of any one of claims 1-12, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:
R22 is Ci-C6 alkyl or Ci-C6 haloalkyl.
The compound of any one of claims 1-12, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:
R22 is C2-C6 alkynyl optionally substituted with optionally substituted Ci-C6 alkyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted cycloalkyl, optionally substituted (Ci-C6 alkyl)cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted (Ci-C6 alkyl)heterocycloalkyl, optionally substituted aryl, optionally substituted (Ci-C6 alkyl)aryl, optionally substituted heteroaryl, or optionally substituted (Ci-C6 alkyl)heteroaryl.
The compound of any one of claims 1-12 or 15, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:
R22 is C2-C<5 alkynyl optionally substituted with optionally substituted heteroaryl.
The compound of any one of claims 1-16, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:
R28 is halogen, -CN, -ORa, -NRaRb, -C(=0)ORa, -C(=0)NRaRb, optionally substituted Ci-C6 alkyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl. The compound of any one of claims 1-17, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:
R28 is halogen, -CN, -ORa, -NRaRb, optionally substituted Ci-C6 alkyl, optionally substituted C2
C<5 alkynyl, or optionally substituted heteroaryl.
The compound of any one of claims 1-18, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:
R28 is halogen, -CN, -OMe, -NH2, Ci-C6 alkyl, Ci-C6 haloalkyl, C2-C6 alkynyl, or heteroaryl. The compound of any one of claims 1-19, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:
R29 is hydrogen or optionally substituted Ci-C6 alkyl.
The compound of any one of claims 1-20, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:
R29 is d-C6 alkyl.
The compound of any one of claims 1-21, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:
each Ra and Rb are independently hydrogen or optionally substituted Ci-C6 alkyl; or Ra and Rb are taken together with the nitrogen atom to which they are attached to form an optionally substituted heterocycloalkyl.
The compound of any one of claims 1-22, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:
each Rc is optionally substituted Ci-C6 alkyl.
A compound of Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
Figure imgf000089_0001
wherein
each R31 is independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=0)Rc, -N02, -NRaRb, -
S(=0)2Rc, -NRaS(=0)2Rc, -S(=0)2NRaRb, -C(=0)Rc, -OC(=0)Rc, -C(=0)ORa, -OC(=0)ORa, -C(=0)NRaRb, -OC(=0)NRaRb, -NRaC(=0)NRaRb, -NRaC(=0)Rc, -NRaC(=0)ORa, optionally substituted Ci-C6 alkyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted cycloalkyl, optionally substituted (Ci-C6 alkyl)cycloalkyl, optionally substituted
heterocycloalkyl, optionally substituted (Ci-C6 alkyl)heterocycloalkyl, optionally substituted aryl, optionally substituted (Ci-C6 alkyl)aryl, optionally substituted heteroaryl, or optionally substituted (Ci-C6 alkyl)heteroaryl;
R32 is optionally substituted Ci-C6 alkyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted cycloalkyl, optionally substituted (Ci-C6 alkyl)cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted (Ci-C6 alkyl)heterocycloalkyl, optionally substituted aryl, optionally substituted (Ci-C6 alkyl)aryl, optionally substituted heteroaryl, or optionally substituted (Ci-C6 alkyl)heteroaryl;
R33 is -SRa, -S(=0)Rc, -S(=0)2Rc, -S(=0)2NRaRb, -C(=0)Rc, -C(=0)NRaRb, optionally
substituted Ci-C6 alkyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted cycloalkyl, optionally substituted (Ci-C6 alkyl)cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted (Ci-C6 alkyl)heterocycloalkyl, optionally substituted aryl, optionally substituted (Ci-C<5 alkyl)aryl, optionally substituted heteroaryl, or optionally substituted (Ci-C6 alkyl)heteroaryl;
R34 is hydrogen, halogen, -CN, -ORa, -SRa, -S(=0)Rc, -N02, -NRaRb, -S(=0)2Rc, -NRaS(=0)2Rc, -S(=0)2NRaRb, -C(=0)Rc, -OC(=0)Rc, -C(=0)ORa, -OC(=0)ORa, -C(=0)NRaRb, - OC(=0)NRaRb, -NRaC(=0)NRaRb, -NRaC(=0)Rc, -NRaC(=0)ORa, optionally substituted d- C6 alkyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted cycloalkyl, optionally substituted (Ci-C<5 alkyl)cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted (Ci- C<5 alkyl)heterocycloalkyl, optionally substituted aryl, optionally substituted (Ci-C6 alkyl)aryl, optionally substituted heteroaryl, or optionally substituted (Ci-C6 alkyl)heteroaryl;
R35 and R36 are independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=0)Rc, -N02, -NRaRb, - S(=0)2Rc, -NRaS(=0)2Rc, -S(=0)2NRaRb, -C(=0)Rc, -OC(=0)Rc, -C(=0)ORa, -OC(=0)ORa, -C(=0)NRaRa, -OC(=0)NRaRb, -NRaC(=0)NRaRb, -NRaC(=0)Rc, -NRaC(=0)ORc, optionally substituted Ci-C6 alkyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, or optionally substituted C2-C6 alkynyl;
R37 is hydrogen, -SRa, -S(=0)Rc, -S(=0)2Rc, -S(=0)2NRaRb, -C(=0)Rc, -C(=0)NRaRb, optionally substituted Ci-C6 alkyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted cycloalkyl, optionally substituted (Ci-C6 alkyl)cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted (Ci-C6 alkyl)heterocycloalkyl, optionally substituted aryl, optionally substituted (Ci-C<5 alkyl)aryl, optionally substituted heteroaryl, or optionally substituted (Ci-C6 alkyl)heteroaryl;
Ring B is an optionally substituted 5-membered heteroaryl; each Ra and Rb are independently hydrogen, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
or Ra and Rb are taken together with the nitrogen atom to which they are attached to form an optionally substituted heterocycloalkyl;
each Rc is optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; and n3 is 1-3.
25. The compound of claim 24, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:
each R31 is independently hydrogen, halogen, -CN, -OH, -OMe, -NH2, Ci-C6 alkyl, or Ci-C6 haloalkyl; and n3 is 1 or 2.
26. The compound of claim 24 or 25, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:
each R31 is hydrogen.
27. The compound of any one of claims 24-26, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:
R33 is optionally substituted Ci-C6 alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl.
28. The compound of any one of claims 24-27, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:
R33 is optionally substituted aryl.
29. The compound of any one of claims 24-28, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:
R34 is hydrogen, halogen, -CN, -OH, -OMe, -NH2, d-Q, alkyl, or d-Q, haloalkyl.
30. The compound of any one of claims 24-29, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:
R34 is hydrogen.
31. The compound of any one of claims 24-30, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:
R35 and R36 are independently hydrogen, halogen, Ci-C6 alkyl, or Ci-C6 haloalkyl.
32. The compound of any one of claims 24-31, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:
R37 is hydrogen or Ci-C6 alkyl.
33. The compound of any one of claims 24-32, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein the compound of Formula (IV) is of Formula (IVa):
Figure imgf000092_0001
34. The compound of any one of claims 24-33, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:
R32 is optionally substituted heterocycloalkyl or optionally substituted heteroaryl.
35. The compound of any one of claims 24-34, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:
R32 is optionally substituted heteroaryl.
36. The compound of any one of claims 24-35, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:
R32 is an optionally substituted 5-membered heteroaryl.
37. The compound of any one of claims 24-36, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:
R32 is a 5-membered heteroaryl optionally substituted with halogen, -CN, -OH, -OMe, -NH2, Ci- C6 alkyl, or Ci-C6 haloalkyl.
38. The compound of any one of claims 24-37, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:
Ring B is selected from optionally substituted: pyrrole, thiophene, furan, imidazole, pyrazole, thiazole, isothiazole, oxazole, isoxazole, triazole, and tetrazole.
39. The compound of any one of claims 24-38, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:
Ring B is optionally substituted pyrazole.
40. The compound of any one of claims 24-39, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:
Ring B is optionally substituted with halogen, -CN, -ORa, -SRa, -S(=0)Rc, -N02, -NRaRb, -
S(=0)2Rc, -NRaS(=0)2Rc, -S(=0)2NRaRb, -C(=0)Rc, -OC(=0)Rc, -C(=0)ORa, -OC(=0)ORa, -C(=0)NRaRb, -OC(=0)NRaRb, -NRaC(=0)NRaRb, -NRaC(=0)Rc, -NRaC(=0)ORa, optionally substituted Ci-C6 alkyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl. The compound of any one of claims 24-40, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:
Ring B is optionally substituted with halogen, -CN, -ORa, -NRaRb, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkynyl, or optionally substituted heteroaryl.
The compound of any one of claims 24-41, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:
Ring B is optionally substituted with is halogen, -CN, -OMe, -NH2, Ci-C6 alkyl, Ci-C6 haloalkyl,
C2-C6 alkynyl, or heteroaryl.
The compound of any one of claims 24-42, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:
each Ra and Rb are independently hydrogen or optionally substituted Ci-C6 alkyl; or Ra and Rb are taken together with the nitrogen atom to which they are attached to form an optionally substituted heterocycloalkyl.
The compound of any one of claims 24-43, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:
each Rc is optionally substituted Ci-C6 alkyl.
A compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
Figure imgf000093_0001
wherein
each R1 is independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=0)Rc, -N02, -NRaRb, -
S(=0)2Rc, -NRaS(=0)2Rc, -S(=0)2NRaRb, -C(=0)Rc, -OC(=0)Rc, -C(=0)ORa, -OC(=0)ORa, -C(=0)NRaRb, -OC(=0)NRaRb, -NRaC(=0)NRaRb, -NRaC(=0)Rc, -NRaC(=0)ORa, optionally substituted Ci-C6 alkyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted cycloalkyl, optionally substituted (Ci-C6 alkyl)cycloalkyl, optionally substituted
heterocycloalkyl, optionally substituted (Ci-C6 alkyl)heterocycloalkyl, optionally substituted aryl, optionally substituted (Ci-C6 alkyl)aryl, optionally substituted heteroaryl, or optionally substituted (Ci-C6 alkyl)heteroaryl;
R2 is halogen, -CN, -ORa, -SRa, -S(=0)Rc, -N02, -NRaRb, -S(=0)2Rc, -NRaS(=0)2Rc, - S(=0)2NRaRb, -C(=0)Rc, -OC(=0)Rc, -C(=0)ORa, -OC(=0)ORa, -C(=0)NRaRb, - OC(=0)NRaRb, -NRaC(=0)NRaRb, -NRaC(=0)Rc, -NRaC(=0)ORa, optionally substituted d- C<5 alkyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted cycloalkyl, optionally substituted (Ci-C<5 alkyl)cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted (Ci- C6 alkyl)heterocycloalkyl, optionally substituted aryl, optionally substituted (Ci-C6 alkyl)aryl, optionally substituted heteroaryl, or optionally substituted (Ci-C6 alkyl)heteroaryl;
R3 is -SRa, -S(=0)Rc, -S(=0)2Rc, -S(=0)2NRaRb, -C(=0)Rc, -C(=0)NRaRb, optionally substituted Ci-C6 alkyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted cycloalkyl, optionally substituted (Ci-C6 alkyl)cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted (Ci- C6 alkyl)heterocycloalkyl, optionally substituted aryl, optionally substituted (Ci-C6 alkyl)aryl, optionally substituted heteroaryl, or optionally substituted (Ci-C6 alkyl)heteroaryl;
R4 is hydrogen, halogen, -CN, -ORa, -SRa, -S(=0)Rc, -N02, -NRaRb, -S(=0)2Rc, -NRaS(=0)2Rc, - S(=0)2NRaRb, -C(=0)Rc, -OC(=0)Rc, -C(=0)ORa, -OC(=0)ORa, -C(=0)NRaRb, - OC(=0)NRaRb, -NRaC(=0)NRaRb, -NRaC(=0)Rc, -NRaC(=0)ORa, optionally substituted d- C<5 alkyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted cycloalkyl, optionally substituted (Ci-C<5 alkyl)cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted (Ci- C6 alkyl)heterocycloalkyl, optionally substituted aryl, optionally substituted (Ci-C6 alkyl)aryl, optionally substituted heteroaryl, or optionally substituted (Ci-C6 alkyl)heteroaryl;
R5 and R6 are independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=0)Rc, -N02, -NRaRb, - S(=0)2Rc, -NRaS(=0)2Rc, -S(=0)2NRaRb, -C(=0)Rc, -OC(=0)Rc, -C(=0)ORa, -OC(=0)ORa, -C(=0)NRaRa, -OC(=0)NRaRb, -NRaC(=0)NRaRb, -NRaC(=0)Rc, -NRaC(=0)ORc, optionally substituted Ci-C6 alkyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, or optionally substituted C2-C6 alkynyl;
R7 and R8 are independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=0)Rc, -N02, -NRaRb, - S(=0)2Rc, -NRaS(=0)2Rc, -S(=0)2NRaRb, -C(=0)Rc, -OC(=0)Rc, -C(=0)ORa, -OC(=0)ORa, -C(=0)NRaRa, -OC(=0)NRaRb, -NRaC(=0)NRaRb, -NRaC(=0)Rc, -NRaC(=0)ORc, optionally substituted Ci-C6 alkyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, or optionally substituted C2-C6 alkynyl;
or R7 and R8 are taken together to form an oxo;
R9 is hydrogen, halogen, -CN, -ORa, -SRa, -S(=0)Rc, -N02, -NRaRb, -S(=0)2Rc, -NRaS(=0)2Rc, - S(=0)2NRaRb, -C(=0)Rc, -OC(=0)Rc, -C(=0)ORa, -OC(=0)ORa, -C(=0)NRaRb, - OC(=0)NRaRb, -NRaC(=0)NRaRb, -NRaC(=0)Rc, -NRaC(=0)ORa, optionally substituted d- C6 alkyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted cycloalkyl, optionally substituted (Ci-C6 alkyl)cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted (Ci- C<5 alkyl)heterocycloalkyl, optionally substituted aryl, optionally substituted (Ci-C6 alkyl)aryl, optionally substituted heteroaryl, or optionally substituted (Ci-C6 alkyl)heteroaryl;
R10 is hydrogen, -SRa, -S(=0)Rc, -S(=0)2Rc, -S(=0)2NRaRb, -C(=0)Rc, -C(=0)NRaRb, optionally substituted Ci-C6 alkyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted cycloalkyl, optionally substituted (Ci-C6 alkyl)cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted (Ci-C6 alkyl)heterocycloalkyl, optionally substituted aryl, optionally substituted (Ci-C6 alkyl)aryl, optionally substituted heteroaryl, or optionally substituted (Ci-C6 alkyl)heteroaryl;
is a double bond or a single bond;
X is N or CRX when = is a double bond; or X is NRX3 or CRX1RX2 when = is a single bond;
Rx, RX1, and RX2 are independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=0)Rc, -N02, - NRaRb, -S(=0)2Rc, -NRaS(=0)2Rc, -S(=0)2NRaRb, -C(=0)Rc, -OC(=0)Rc, -C(=0)ORa, - OC(=0)ORa, -C(=0)NRaRb, -OC(=0)NRaRb, -NRaC(=0)NRaRb, -NRaC(=0)Rc, - NRaC(=0)ORa, optionally substituted Ci-C6 alkyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted cycloalkyl, optionally substituted (Ci-C6 alkyl)cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted (Ci-C6 alkyl)heterocycloalkyl, optionally substituted aryl, optionally substituted (Ci-C6 alkyl)aryl, optionally substituted heteroaryl, or optionally substituted (Ci-C6 alkyl)heteroaryl;
Y is N or CRY when is a double bond; or Y is NRY3 or CRY1RY2 when is a single bond;
RY, RY1, and RY2 are independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=0)Rc, -N02, - NRaRb, -S(=0)2Rc, -NRaS(=0)2Rc, -S(=0)2NRaRb, -C(=0)Rc, -OC(=0)Rc, -C(=0)ORa, - OC(=0)ORa, -C(=0)NRaRb, -OC(=0)NRaRb, -NRaC(=0)NRaRb, -NRaC(=0)Rc, - NRaC(=0)ORa, optionally substituted Ci-C6 alkyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted cycloalkyl, optionally substituted (Ci-C6 alkyl)cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted (Ci-C6 alkyl)heterocycloalkyl, optionally substituted aryl, optionally substituted (Ci-C6 alkyl)aryl, optionally substituted heteroaryl, or optionally substituted (Ci-C6 alkyl)heteroaryl;
RX3 and RY3 are independently hydrogen, -SRa, -S(=0)Rc, -S(=0)2Rc, -S(=0)2NRaRb, -C(=0)Rc, - C(=0)NRaRb, optionally substituted Ci-C6 alkyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted cycloalkyl, optionally substituted (Ci-C6 alkyl)cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted (Ci-C6 alkyl)heterocycloalkyl, optionally substituted aryl, optionally substituted (Ci-C6 alkyl)aryl, optionally substituted heteroaryl, or optionally substituted (Ci-C6 alkyl)heteroaryl;
each Ra and Rb are independently hydrogen, optionally substituted Ci-C6 alkyl, optionally
substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
or Ra and Rb are taken together with the nitrogen atom to which they are attached to form an optionally substituted heterocycloalkyl;
each Rc is optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; and n is 1-3.
46. The compound of claim 45, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:
each R1 is independently hydrogen, halogen, -CN, -OH, -OMe, -NH2, Ci-C6 alkyl, or Ci-C6 haloalkyl; and n is 1 or 2.
47. The compound of claim 45 or 46, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:
each R1 is hydrogen.
48. The compound of any one of claims 45-47, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:
R3 is optionally substituted Ci-C6 alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl.
49. The compound of any one of claims 45-48, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:
R3 is optionally substituted aryl.
50. The compound of any one of claims 45-49, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:
R4 is hydrogen, halogen, -CN, -OH, -OMe, -NH2, d-Q, alkyl, or C C6 haloalkyl.
51. The compound of any one of claims 45-50, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:
R4 is hydrogen.
52. The compound of any one of claims 45-51, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:
R5 and R6 are independently hydrogen, halogen, Ci-C6 alkyl, or Ci-C6 haloalkyl.
53. The compound of any one of claims 45-52, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein the compound of Formula (I) is of Formula (la):
Figure imgf000097_0001
Formula (la).
54. The compound of any one of claims 45-53, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:
R2 is halogen, -CN, -ORa, -NRaRb, optionally substituted Ci-C6 alkyl, optionally substituted Ci- C<5 heteroalkyl, or optionally substituted C2-C6 alkynyl.
55. The compound of any one of claims 45-54, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:
R2 is halogen, optionally substituted Ci-C6 alkyl, or optionally substituted C2-C6 alkynyl.
56. The compound of any one of claims 45-55, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:
R2 is halogen.
57. The compound of any one of claims 45-55, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:
R2 is Ci-C6 alkyl or Ci-C6 haloalkyl.
58. The compound of any one of claims 45-55, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:
R2 is C2-C<5 alkynyl optionally substituted with optionally substituted Ci-C6 alkyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted cycloalkyl, optionally substituted (Ci-C6 alkyl)cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted (Ci-C6 alkyl)heterocycloalkyl, optionally substituted aryl, optionally substituted (Ci-C6 alkyl)aryl, optionally substituted heteroaryl, or optionally substituted (Ci-C6 alkyl)heteroaryl.
59. The compound of any one of claims 45-55 or 58, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:
R2 is C2-C<5 alkynyl optionally substituted with optionally substituted heteroaryl.
60. The compound of any one of claims 45-59, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:
R7 and R8 are taken together to form an oxo.
61. The compound of any one of claims 45-60, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:
R9 is hydrogen, halogen, -CN, -OH, -OMe, -NH2, Ci-C6 alkyl, or Ci-C6 haloalkyl.
62. The compound of any one of claims 45-61, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:
R9 is -NH2.
63. The compound of any one of claims 45-62, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:
R10 is hydrogen or optionally substituted Ci-C6 alkyl.
64. The compound of any one of claims 45-63, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:
R10 is d-C6 alkyl.
65. The compound of any one of claims 45-64, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:
is a double bond.
66. The compound of claim 65, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:
X is CRX; and
Y is N.
67. The compound of claim 65, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:
Y is CRY; and
X is N.
68. The compound of claim 65, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:
X is CRX; and
Y is CRY.
69. The compound of any one of claims 66-68, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:
Rx is hydrogen, halogen, -CN, -OH, -OMe, -NH2, d-C6 alkyl, or d-C6 haloalkyl; and RY is hydrogen, halogen, -CN, -OH, -OMe, -NH2, d-C6 alkyl, or d-C6 haloalkyl.
70. The compound of any one of claims 66-69, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:
Rx is hydrogen; and
RY is hydrogen.
71. The compound of any one of claims 45-64, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:
is a single bond.
72. The compound claim 71, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:
X is CRX1RX2; and Y is CRY1RY2.
73. The compound claim 72, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:
RX1 and RX2 are independently hydrogen, halogen, -CN, -OH, -OMe, -NH2, Ci-C6 alkyl, or Ci-C6 haloalkyl; and
RY1 and RY2 are independently hydrogen, halogen, -CN, -OH, -OMe, -NH2, C1-C5 alkyl, or C1-C5 haloalkyl.
74. The compound claim 72 or 73, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:
RX1 and RX2 are hydrogen; and
RY1 and RY2 are hydrogen.
75. The compound of any one of claims 45-74, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:
each Ra and Rb are independently hydrogen or optionally substituted Ci-C6 alkyl; or Ra and Rb are taken together with the nitrogen atom to which they are attached to form an optionally substituted heterocycloalkyl.
76. The compound of any one of claims 45-75, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:
each Rc is optionally substituted Ci-C6 alkyl.
77. A compound or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof selected from:
Figure imgf000100_0001
-99-
Figure imgf000101_0001
- 100-
78. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof of any of claims 1 -77 and a pharmaceutically acceptable excipient.
79. A method of treating a PI3K associated disease or disorder in a subject in need thereof, the
method comprising administering an effective amount of a compound or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof of any of claims 1 -77 or a pharmaceutical composition of claim 78.
80. The method of claim 79, wherein the PI3K associated disease or disorder is selected from
inflammatory disease, glomerulonephritis, uveitis, hepatic diseases or disorders, renal diseases or disorders, chronic obstructive pulmonary disease, rheumatoid arthritis, inflammatory bowel disease, vasculitis, dermatitis, osteoarthritis, inflammatory muscle disease, allergic rhinitis, vaginitis, interstitial cystitis, scleroderma, osteoporosis, eczema, allogeneic or xenogeneic transplantation, graft rejection, graft-versus-host disease, lupus erythematosus, pulmonary fibrosis, dermatomyositis, thyroiditis, myasthenia gravis, autoimmune hemolytic anemia, cystic fibrosis, chronic relapsing hepatitis, primary biliary cirrhosis, allergic conjunctivitis, hepatitis, atopic dermatitis, asthma, Sjogren's syndrome, organ transplant rejection, multiple sclerosis, Guillain-Barre, autoimmune uveitis, autoimmune hemolytic anemia, pernicious anemia, autoimmune thrombocytopenia, temporal arteritis, anti-phospholipid syndrome, vasculitides such as Wegener's granulomatosis, Behcet's disease, psoriasis, dermatitis herpetiformis, pemphigus vulgaris, vitiligo, Crohn's disease, colitis, ulcerative colitis, primary biliary cirrhosis, autoimmune hepatitis, Type 1 or immune-mediated diabetes mellitus, Grave's disease.
Hashimoto's thyroiditis, autoimmune oophoritis and orchitis, autoimmune disorder of the adrenal gland, systemic lupus erythematosus, polymyositis, dermatomyositis, ankylosing spondylitis, transplant rejection, skin graft rejection, arthritis, bone diseases associated with increased bone resorption, ileitis, Barrett's syndrome, adult respiratory distress syndrome, chronic obstructive airway disease, corneal dystrophy, trachoma, onchocerciasis, sympathetic ophthalmitis, endophthalmitis, gingivitis, periodontitis, tuberculosis, leprosy, uremic complications, nephrosis, sclerodermatitis, psoriasis, chronic demyelinating diseases of the nervous system, AIDS -related neurodegeneration, Alzheimer's disease, infectious meningitis, encephalomyelitis, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis viral or autoimmune encephalitis, autoimmune disorders, immune -complex vasculitis, systemic lupus and erythematodes, systemic lupus erythematosus (SLE), ischemic heart disease hypercholesterolemia, atherosclerosis, preeclampsia, chronic liver failure, brain and spinal cord trauma, hypertension, pulmonary arterial hypertension (PAH), cardiomyopathy, diabetic cardiomyopathy, and cancer.
81. The method of claim 80, wherein the PI3K associated disease or disorder is cancer.
82. The method of claim 81, wherein the cancer is selected from a hematological cancer, a solid tumor cancer, hematopoietic tumors of lymphoid lineage, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, hairy cell lymphoma, Burkett's lymphoma, hematopoietic tumors of myeloid lineage, bladder cancer, breast cancer, colon cancer, kidney cancer, liver cancer, lung cancer, small cell lung cancer, esophageal cancer, gall bladder cancer, ovarian cancer, pancreatic cancer, stomach cancer, cervical cancer, thyroid cancer, prostate cancer, skin cancer, squamous cell carcinoma, tumors of mesenchymal origin, fibrosarcoma, rhabdomyosarcoma, tumors of the central and peripheral nervous system, astrocytoma, neuroblastoma, glioma, schwannoma, melanoma, seminoma, teratocarcinoma, osteosarcoma, xenoderoma pigmentosum,
keratoctanthoma, thyroid follicular cancer, Kaposi's sarcoma, and glioblastoma.
83. The method of claim 82, wherein the cancer is a hematological cancer selected from chronic lymphocytic leukemia (CLL) and multiple myeloma (MM).
84. The method of claim 82, wherein the cancer is a solid tumor cancer selected from lung cancer, breast cancer, colon cancer, prostate cancer, pancreatic cancer, and glioblastoma.
85. The method of claim 80, wherein the PI3K associated disease or disorder is inflammatory
disease.
86. The method of claim 85, wherein the inflammatory disease is selected from chronic obstructive pulmonary disease (COPD), asthma, hypoxia-induced inflammation, rheumatoid arthritis, chronic bronchitis, atopic dermatitis, inflammatory bowel disease, allergic rhinitis, and ulcerative colitis.
87. The method of claim 80, wherein the PI3K associated disease or disorder is cardiovascular disease.
88. The method of claim 87, wherein the cardiovascular disease is selected from hypertension and pulmonary arterial hypertension (PAH).
89. The method of any one of claims 79-88, further comprising administering to the subject in need thereof an additional therapeutic agent selected from an anti -cancer agent, an anti-inflammatory agent, an immunosuppressive agent, a steroid, a non-steroidal anti-inflammatory agent, an antihistamine, an analgesic, and any combinations.
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