Classifications

• • 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
• • 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
• • 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
  • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
• • 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
  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
  • A61K31/5375—1,4-Oxazines, e.g. morpholine
  • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
  • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
  • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
  • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
  • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
  • C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
  • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
  • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
  • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
  • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
  • C07D239/48—Two nitrogen atoms
• • 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
  • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
  • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
  • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • 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
  • C07D405/02—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 two hetero rings
  • C07D405/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
• • 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
  • 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

Definitions

• Autophagy is a central cellular mechanism for elimination of damaged proteins, protein complexes, and organelles. This conserved process plays crucial roles in the cellular response to nutrient deprivation and other stresses, in addition to being required for proper cellular and tissue homeostasis during embryonic development and in defense against pathogens. Defects in autophagy pathways are associated with certain human pathologies, including infectious diseases, neurodegenerative disorders, and cancer. In spite of these highly conserved fundamental cellular functions, the molecular and biochemical details of how autophagy is initiated for different cargoes, and the coordination of steps starting from autophagosome initiation to ultimate fusion with the lysosome remain poorly understood.
• ULK1 and ULK2 are important proteins that regulate autophagy in mammalian cells.
• ULK1 and ULK2 are activated under conditions of nutrient deprivation by several upstream signals, which is followed by the initiation of autophagy.
• ULK1 and ULK2 have been studied in the context of nutrient deprivation. While ULK1 appears to be the most essential for autophagy, in some instances, ULK1 and ULK2 show high functional redundancy. The kinase domains of ULK1 and ULK2 share 78% sequence homology, suggesting, in some instances, ULK2 may compensate for the loss of ULK1 in some instances. In some instances, nutrient dependent autophagy may only be eliminated if both ULK1 and ULK2 are inhibited. In some instances, inhibition of ULK1 alone is sufficient, e.g. for providing a therapeutic benefit, such as in any method provided herein, for normalizing autophagy in a cancer cell, or other beneficial result. In other instances, inhibition of ULK1 and ULK2 results in a therapeutic benefit, such as tumor shrinkage, tumor cell death, or slowed rate of tumor growth.
• a therapeutic benefit such as tumor shrinkage, tumor cell death, or slowed rate of tumor growth.
• the compounds provided herein are inhibitors of ULK. In some embodiments, the compounds inhibit ULK1. In some embodiments, the compounds are specific for ULK1. In some embodiments, the compounds inhibit both ULK1 and ULK2. In some embodiments, the diseases provided herein are treatable with an inhibitor specific for ULK1. In some instances, ULK2 may compensate for loss of ULK1 function. In some embodiments, the diseases provided herein require treatment with a compound that inhibits both ULK1 and ULK2.
• the compounds are useful for the treatment of various diseases, including cancer
• the present disclosure provides a compound having a structure of Formula (IA):
• R 1A is H, halogen, or substituted or unsubstituted alkyl
• X A is -NR 3A R 4A or -OR 4A ;
• R 3A is H, substituted or unsubstituted alkyl, or a bond with a substituent on an R 4A to form a heterocycle;
• R 6A is H or substituted or unsubstituted alkyl
• each R 10A and R 11A is independently H, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, hydroxyl, halogen, or R 10A and R 11A on the same atom join to form a cycloalkyl or heterocycloalkyl, or R 10A and R 11A on the same atom are taken together to form an oxo;
• R 71A is H, -CN, substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted C3-C10 alkyl, substituted or unsubstituted C4-C10 cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted;
• R 72A is H, -CN, substituted or unsubstituted methyl, substituted or unsubstituted ethyl, linear C3-C5 alkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; each R A is independently H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; n A is 1 or 2; m A is 1 or 2; wherein the sum of n and m is 2 or 3; p A is an integer from 0-3; and the nitrogen in the fused ring system is optionally quatemized with C1-C6 alkyl, or pharmaceutically acceptable salt thereof.
• R 1A is H, halogen, or C1-C6 alkyl. In some embodiments, R 1A is H or fluorine. In some embodiments, R 1A is H.
• R 2A is H, C1-C6 haloalkyl, or halogen. In some embodiments, R 2A is -CF3, or halogen. In some embodiments, R 2A is -CF3, -Cl, or -Br. In some embodiments, R 2A is -CF3. In some embodiments, R 2A is Br.
• X A is -NR 3A R 4A .
• R 3A is H or C1-C6 alkyl.
• R 3A is H, or -CH3.
• R 3A is H.
• R 4A is aryl or heteroaryl.
• R 4A is 6-membered aryl or heteroaryl. In some embodiments, R 4A is phenyl, pyridyl, or pyrimidinyl. In some embodiments, R 4A is phenyl. In some embodiments, R 4A is phenyl substituted with
• R 4A is
• R 4A is
• R 4A is cyclopropyl optionally substituted with one or more-OR A or substituted or unsubstituted alkyl.
• R 4A is cyclopropyl optionally substituted with OH or Ci-C 6 alkyl.
• R 4A is unsubstituted cyclopropyl.
• each R 5A is independently halogen, -OR A , - NR A R a , or unsubstituted C1-C6 alkyl.
• p A is 0 or 1. In some embodiments, p A is 0.
• R 6A is H or -CH3. In some embodiments, R 6A is H.
• R 7A is C1-C6 alkyl optionally substituted with hydroxyl or alkoxy.
• R 7A is H.
• R 7A is
• each R 10A and R 11A is independently H or substituted or unsubstituted alkyl, or R 10A and R 11A on the same atom join to form a cycloalkyl, or R 10A and R 11A on the same atom are taken together to form an oxo. In some embodiments, each R 10A and R 11A is independently H or substituted or unsubstituted alkyl, or R 10A and R 11A on the same atom are taken together to form an oxo. In some embodiments, each R 10A and R 11A is independently H. [0019] In some embodiments, n A is 1 and m A is 1. In some embodiments, n A is 1 and m A is 2. In some embodiments, n A is 2 and m A is 1.
• R 1B is H, halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted haloalkyl;
• R 2B is substituted C2 alkyl, substituted or unsubstituted C3-C10 alkyl, -NR 21B R 22B , or -OR 23B ;
• R 5B is H or halogen
• R 21B is -OR 26b , NR 27B R 28B substituted methyl, or substituted or unsubstituted C2-C10 alkyl;
• R 22B is H or substituted or unsubstituted alkyl
• R 21B and R 22B are taken together with the nitrogen atom to which they are attached to form a substituted or unsubstituted heterocycloalkyl containing at least one additional heteroatom selected from the group consisting of O, N, and S;
• R 23B is H or substituted or unsubstituted alkyl
• R 26B is H or substituted or unsubstituted alkyl
• R 27B and R 28B are each independently H or substituted or unsubstituted alkyl; or
• R 27B and R 28B are taken together with the nitrogen atom to which they are attached to form a substituted or unsubstituted heterocycloalkyl
• R 31B is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl
• R 32B is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl
• R 33B is H or substituted or unsubstituted alkyl
• R 32B and R 33B are taken together with the nitrogen atom to which they are attached to form a substituted or unsubstituted heterocycloalkyl; each R B is independently H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and n B is an integer from 0-4; or a pharmaceutically acceptable salt thereof.
• R 1B is halogen or C1-C6 haloalkyl. In some embodiments, R 1B is Cl, Br, or -CF 3 . In some embodiments, R 1B is -CF 3 . In some embodiments R 1B is Br. [0022] In some embodiments, R 2B is -NR 21B R 22B or -OR 23B . In some embodiments, R 2B is - NR 21B R 22B n ome embodiments, R 21B is substituted methyl or substituted or unsubstituted C2- Ce alkyl. In some embodiments, R 21B is substituted methyl or substituted C2-C4 alkyl. In some embodiments, R 21B is
• R 22B is H or -CH3. In some embodiments, R 22B is -CH3. In some embodiments, R 22B is H.
• R 2B is -OR 23B .
• R 23B is H or -CH3.
• R 23B is -CH3.
• R 3B is -NR 32B R 33B .
• R 32B is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, wherein the aryl or heteroaryl is
• R 32B is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, wherein the aryl or heteroaryl is
• R 33B H or C1-C6 alkyl. In some embodiments, R 33B is H or - CH3. In some embodiments, R 33B is H. In some embodiments, R 4B is independently halogen, -
• each R 4B is independently halogen, -OR B , or C1-C6 alkyl. In some embodiments, each R 4B is independently -OR B .
• n B is 0, 1, or 2. In some embodiments, n B is 0 or 1. In some embodiments, n B is 0.
• R 5B is H or F. In some embodiments, R 5B is H.
• R 1C is H, substituted or unsubstituted alkyl, or halogen
• R 2C is H, halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted haloalkyl;
• R 7C is H or substituted or unsubstituted alkyl
• X c is -O- or -NR 8C -;
• R 8C is H or substituted or unsubstituted alkyl
• R 9C and R 10C are each independently H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R 9C and R 10C are taken together with the carbon atom to which they are attached to form a substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocycloalkyl;
• R 41C and R 42C are each independently hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more R 45C ; or R 41C and R 42C are taken together with the nitrogen atom to which they are attached to form a substituted or unsubstituted heterocycloalkyl;
• R 43C is hydrogen, -CN, alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more R 45C ;
• each R c is independently H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; n c is an integer from 0-4; m c is an integer from 0-4; and with the proviso that when R 4C is -OMe and R 2C is halogen, then R 3C is not OH, or pharmaceutical
• R 1C is H or halogen. In some embodiments, R 1C is H or F. In some embodiments, R 1C is H.
• R 2C is halogen or C1-C6 haloalkyl. In some embodiments, R 2C is Br, Cl, or -CF3. In some embodiments, R 2C is Br.
• R 3C is -NR C R C and each R c is independently hydrogen, substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted cycloalkyl or both R c s are taken together with the nitrogen atom to which they are attached to form a substituted or unsubstituted heterocycloalkyl.
• R 3C is -NR C R C each R c is independently selected from H, , .
• R 3C is -
• NR R and both R s are taken together to form a heterocycloalkyl selected from
• R 3C is selected from
• R 3C is OR c and the R c of R 3C is hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
• R 4C is -NR 41C R 42C .
• R 41C and R 42C are each independently hydrogen, alkyl, or cycloalkyl, wherein the alkyl or cycloalkyl is optionally substituted with one or more R 45C or R 41C and R 42C are taken together with the nitrogen atom to which they are attached to form a substituted or unsubstituted heterocycloalkyl.
• R 41C and R 42C is independently H, , ,
• R 41C and R 42C are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl, wherein the heterocycloalkyl is . In some embodiments, R 41C and R 42C are taken together with the nitrogen atom to which they are attached to form [0040] In some embodiments, R 4C is -OR 43C . In some embodiments, R 43C is hydrogen or Ci- Ce alkyl optionally substituted with one or more R 45C . In some embodiments, R 43C is H, -CH 3 , -
• R 41C and R 42C are each independently hydrogen, substituted or unsubstituted C1-C6 alkyl, or cycloalkyl; wherein each alkyl or cycloalkyl is independently optionally substituted with one or more R 45C .
• R 41C and R 42C are each independently H, -CH3, or -CFhCFb.
• each R 5C is independently halogen, - CN, -OR c , or substituted or unsubstituted alkyl.
• each R 5C is independently halogen or -OR c .
• each R 5C is independently -0(Ci-C 6 alkyl).
• each R 5C is independently -OCH3.
• n c is 0, 1, or 2. In some embodiments, n c is 0 or 1. In some embodiments, n c is 0.
• each R 6C is independently halogen or -OR c .
• each R 6C is -0(Ci-C 6 alkyl).
• m c is 0, 1, or 2.
• m c is 2.
• m c is 2 and R 6C is -OCH3.
• m c is 0 or 1.
• m c is 0.
• R 7C is H or -CH3. In some embodiments, R 7C is H.
• X c is -NR 8 -.
• R 8C is H or -CH3. In some embodiments, R 8C is H.
• R 9C and R 10C are each independently H or substituted or unsubstituted alkyl. In some embodiments, R 9C and R 10C are each independently H or C1-C6 alkyl. In some embodiments, R 9C is -CH3 and R 10C is H. In some embodiments, R 9C and R 10C are each H.
• R 1D is H or halogen; m D is an integer from 1 to 3; n D is an integer from 1 to 6;
• R 1D is H or fluorine. In some embodiments, R 1D is H.
• R 2D is
• R 2 is
• R 2 is
• each R 20D is independently halogen, -CN, -OR°, or C1-C6 alkyl.
• m D is 0 or 1. In some embodiments, m D is 0.
• R 3D is
• each R° is independently H or -CH3. In some embodiments, each R D is independently H.
• R 3D is
• each R° and R° is independently H or -CH3. In some embodiments, one R° is H and one R° is
• p D is 0 or 1. In some embodiments, p D is 0.
• VE Formula (VE):
• R 1E is H, nitrile, or halogen
• R 2E is halogen, nitirile, methyl, cyclopropyl, or -CF3; R 3E is halogen,
• R 4E is aryl substituted with one or more -OR 35E , substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl,
• R 31E is H, Ci-C 6 alkyl, or cycloalkyl
• R 32E and R 33E are each independently H, substituted or unsubstituted C1-C6 alkyl, or cycloalkyl;
• R 34E is H, Ci-C 6 alkyl, or cycloalkyl; each R 35E is independently substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; each R E is independently hydrogen, C1-C6 alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more halogen, -OH, -NH2, substituted amino, cycloalkyl, oxo, or C1-C6 alkyl; wherein when then R 2E is not Br; and wherein when not n Cl ⁇ an,d D R4E i ⁇ s not
• R 1E is H or F. In some embodiments, R 1E is H.
• R 2E is Cl, Br, or -CF3. In some embodiments, R 2E is Br or - CF3. In some embodiments, R 3E is -SR 31E . In some embodiments, R 3E is -SH, -SCH3, or - SCH2CH3. In some embodiments, R 3E is -SCH3.
• R 3E is ,
• R 3E is
• p E is 0 or 1. In some embodiments, p E is 0.
• a pharmaceutical composition comprising the compound or pharmaceutically acceptable salt thereof of any one of the compounds provided herein and a pharmaceutically acceptable carrier.
• the pharmaceutical composition is formulated for intravenous or intraperitoneal injection.
• a method of treating a ULK1 or ULK2 mediated disease in a subject in need thereof comprising administering to the subject a compound or pharmaceutical composition of any one of the compounds provided herein.
• the ULK1 or ULK2 mediated disease is characterized by abnormal autophagy.
• the abnormal autophagy has been therapeutically induced.
• the disease is cancer.
• the cancer is lung cancer or pancreatic cancer.
• the lung cancer is non-small cell lung cancer (NSCLC).
• NSCLC non-small cell lung cancer
• the cancer is pancreatic cancer.
• the pancreatic cancer is pancreatic ductal adenocarcinoma (PD AC).
• the cancer is breast cancer.
• the breast cancer is triple negative breast cancer (TNBC).
• TSC Tuberous Sclerosis Complex
• LAM lymphangioleiomyomatosis
• the compound is co-administered with an additional therapeutic agent.
• the additional therapeutic agent is an mTOR inhibitor.
• the additional therapeutic agent is carboplatin.
• the additional therapeutic agent is an MEK inhibitor.
• the additional therapeutic agent is trametinib.
• the additional therapeutic agent is a PARP inhibitor.
• the additional therapeutic agent is olaparib.
• the additional therapeutic agent is a standard of care therapy.
• administering the compound degrades ATG13 in the subject.
• Alkyl refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, which may optionally be unsaturated with one or more double or triple bonds, and preferably having from one to fifteen carbon atoms ⁇ i.e., C 1 -C 15 alkyl).
• an alkyl comprises one to six carbon atoms ⁇ i.e., C 1 -C 6 alkyl).
• an alkyl comprises one to three carbon atoms ⁇ i.e., C 1 -C 3 alkyl).
• the alkyl group is selected from methyl, ethyl, 1 -propyl (77-propyl), 1-methylethyl (Ao-propyl), 1-butyl (77-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (/ ' .so- butyl), 1,1-dimethylethyl (fe/7-butyl), 1 -pentyl (7 -pentyl).
• the alkyl is attached to the rest of the molecule by a single bond.
• the term “alkyl” and its equivalents encompass linear, branched, and/or cyclic alkyl groups.
• an “alkyl” comprises both cyclic and acyclic (linear and/or branched) alkyl components.
• an alkyl group is described as “linear,” the referenced alkyl group is not substituted with additional alkyl groups and is unbranched.
• an alkyl group is described as “saturated,” the referenced alkyl group does not contain any double or triple carbon-carbon bonds (e.g. alkene or alkyne).
• Alkylene or "alkylene chain” refers to a divalent alkyl group.
• Aryl refers to an aromatic monocyclic or aromatic multicyclic hydrocarbon ring system.
• the aromatic monocyclic or aromatic multicyclic hydrocarbon ring system contains only hydrogen and carbon and from five to eighteen carbon atoms, where at least one of the rings in the ring system is aromatic, i.e., it contains a cyclic, delocalized (4n+2) p-electron system in accordance with the Hiickel theory.
• the ring system from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin and naphthalene.
• C x-y or “C x -C y ” when used in conjunction with a chemical moiety, such as alkyl, alkenyl, or alkynyl is meant to include groups that contain from x to y carbons in the chain.
• C x-y alkyl refers to saturated or unsaturated hydrocarbon groups, including straight-chain alkyl and branched-chain alkyl groups that contain from x to y carbons in the chain.
• C x-y alkenyl and C x-y alkynyl refer to unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond respectively.
• Cycloalkyl refers to a saturated ring in which each atom of the ring is carbon. Cycloalkyl may include monocyclic and polycyclic rings such as 3- to 10-membered monocyclic rings, 6- to 12-membered fused bicyclic rings, 6- to 12-membered spirocyclic rings, and 6- to 12- membered bridged rings. In certain embodiments, a cycloalkyl comprises three to ten carbon atoms. In other embodiments, a cycloalkyl comprises five to seven carbon atoms. The cycloalkyl may be attached to the rest of the molecule by a single bond.
• Examples of monocyclic cycloalkyls include, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
• Polycyclic cycloalkyl radicals include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl), norbomenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like.
• Halo or, alternatively, “halogen” or “halide,” means fluoro, chloro, bromo or iodo. In some embodiments, halo is fluoro, chloro, or bromo.
• Haloalkyl refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, for example, trifluoromethyl, dichloromethyl, bromomethyl, 2,2,2-trifluoroethyl, l-chloromethyl-2-fluoroethyl, and the like.
• the alkyl part of the haloalkyl radical is optionally substituted as described herein.
• Heteroalkyl refers to an alkyl group wherein one or more of the carbons of the alkyl group is replaced with a heteroatom.
• exemplary heteroatoms include N, O, Si, P, B, and S atoms, preferably N, O and S. Note that valency of heteroatoms may not be identical to that of a carbon atom, so, for example, a methylene (CH2) of an alkyl may be replaced with an NH group, S group, O group, or the like in a hetero alkyl.
• Heteroalkylene refers to an alkylene group wherein one or more of the carbons of the alkylene group is replaced with a heteroatom.
• exemplary heteroatoms include N, O, Si, P, B, and S atoms, preferably N, O and S.
• Heterocycloalkyl refers to a saturated or unstaturated (e.g., non-aromatic) ring with carbon atoms and at least one heteroatom (e.g., a cycloalkyl wherein one or more of the carbon groups is substituted with a heteroatom).
• exemplary heteroatoms include N, O, Si, P, B, and S atoms.
• Heterocyclo alkyl may include monocyclic and polycyclic rings such as 3- to 10- membered monocyclic rings, 6- to 12-membered fused bicyclic rings, 6- to 12-membered spirocyclic rings, and 6- to 12-membered bridged rings.
• heteroatoms in the heterocycloalkyl radical are optionally oxidized.
• One or more nitrogen atoms, if present, are optionally quatemized.
• the heterocycloalkyl is attached to the rest of the molecule through any atom of the heterocycloalkyl, valence permitting, such as any carbon or nitrogen atoms of the heterocycloalkyl.
• heterocycloalkyl radicals include, but are not limited to, 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, thiomorpholinyl, thiamorpholinyl, 1-oxo-
• Heteroaryl refers to an aromatic ring comprising carbon atoms and one or more heteroatoms.
• exemplary heteroatoms include N, O, Si, P, B, and S atoms.
• the heteroaryl ring may be selected from monocyclic or bicyclic and fused or bridged ring systems rings wherein at least one of the rings in the ring system is aromatic, i.e., it contains a cyclic, delocalized (4n+2) p-electron system in accordance with the Hiickel theory.
• the heteroatom(s) in the heteroaryl radical may be optionally oxidized.
• One or more nitrogen atoms, if present, are optionally quatemized.
• heteroaryl may be attached to the rest of the molecule through any atom of the heteroaryl, valence permitting, such as a carbon or nitrogen atom of the heteroaryl.
• heteroaryls include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[h][l,4]dioxepinyl, benzo[b][l,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benz
• salt or “pharmaceutically acceptable salt” refers to salts derived from a variety of organic and inorganic counter ions well known in the art.
• Pharmaceutically acceptable acid addition salts may be formed with inorganic acids and organic acids.
• Inorganic acids from which salts are derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
• Organic acids from which salts are derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, -tolucncsulfonic acid, salicylic acid, and the like.
• Pharmaceutically acceptable base addition salts may be formed with inorganic and organic bases.
• Inorganic bases from which salts are derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like.
• Organic bases from which salts are derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine.
• the pharmaceutically acceptable base addition salt is chosen from ammonium, potassium, sodium, calcium, and magnesium salts.
• phrases “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
• phrases “pharmaceutically acceptable excipient” or “pharmaceutically acceptable carrier” as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. Each carrier is “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
• materials which serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as com starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide;
• the term “prevent” or “preventing” as related to a disease or disorder may refer to a compound that, in a statistical sample, reduces the occurrence of the disorder or condition in the treated sample relative to an untreated control sample, or delays the onset or reduces the severity of one or more symptoms of the disorder or condition relative to the untreated control sample.
• substituted refers to moieties having substituents replacing a hydrogen on one or more carbons or heteroatoms of the structure. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds.
• the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds.
• the permissible substituents may be one or more and the same or different for appropriate organic compounds.
• the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms.
• Substituents may include any substituents described herein, for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxyl, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, an aralkyl, a carbocycle, a heterocycle, a
• each R a is independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, wherein each R a , valence permitting,
• each R b is independently selected from a direct bond or a straight or branched alkylene, alkenylene, or alkynylene chain, and each R c is a straight or branched alkylene, alkenylene or alkynylene chain.
• treat may include alleviating, abating or ameliorating a disease or condition symptoms, preventing additional symptoms, ameliorating or preventing the underlying causes of symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition either prophylactically and/or therapeutically.
• Compounds of the present invention also include crystalline and amorphous forms of those compounds, pharmaceutically acceptable salts, and active metabolites of these compounds having the same type of activity, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms of the compounds, as well as mixtures thereof.
• autophagy is a cellular response to loss of nutrients in which cells catabolize various proteins and organelles to provide building blocks and critical metabolites needed for cell survival.
• autophagy plays an important homeostatic role in many tissues by removing protein aggregates and defective organelles that accumulate with cellular damage over time. While genetics first defined the core components of autophagy conserved across all eukaryotes, the molecular details of how the different autophagy complexes regulate one another and the precise temporal and spatial ordering of biochemical events involved in autophagy induction are typically considered to be poorly understood currently.
• autophagy In healthy individuals, normal autophagy is, in certain instances, an important process for balancing sources of energy at critical times in development and in response to nutrient stress. In certain instances, autophagy also plays a housekeeping role in removing misfolded or aggregated proteins, clearing damaged organelles, such as mitochondria, endoplasmic reticulum and peroxisomes, as well as eliminating intracellular pathogens. Thus, autophagy is often thought of as a survival mechanism. In various instances, autophagy is either non-selective or selective in the removal of specific organelles, ribosomes and protein aggregates.
• autophagy promotes cellular senescence and cell surface antigen presentation, protects against genome instability and prevents or inhibits necrosis, giving it an important role in preventing, treating, or inhibiting diseases such as cancer, neurodegeneration, cardiomyopathy, diabetes, liver disease, autoimmune diseases and infections.
• defects in autophagy pathways are associated with a number of human pathologies, including infectious diseases, neurodegenerative disorders, and cancer.
• the role of autophagy differs in different stages of cancer development; for example, in some instances, initially, autophagy has a preventive effect against cancer, but once a tumor develops, the cancer cells, in certain instances, utilize autophagy for their own cytoprotection.
• the mutations that cause uncontrolled cell growth which results in the formation of tumors or other cancerous tissue also effectuates changes in autophagy. In some instances, these changes in the autophagic pathways in the cancer cells results in increased survivability and durability of cancer cells.
• the therapeutics rather than killing the cancer cells, the therapeutics merely have the effect of arresting cancer tissue growth, with the cancer tissue entering a cystostatic phase upon treatment. Consequently, in some instances, the cancerous tissue is not killed during treatment, the growth is simply arrested. Upon cessation of treatment, the cancerous tissue is able to resume growth, thus increasing symptoms and complications for the patient.
• the addition of a therapeutic that disrupts autophagy has the effect of converting the cytostatic response of the cancer cells to cancer cell death.
• the changes in autophagy caused by the cancer are important for the survival of the cancer cells.
• these cells rely on autophagy to properly regulate the consumption of nutrients to ensure the survival of the cells in conditions that would cause the death of a healthy cell.
• methods of inhibiting autophagy in cells present, in certain instances, a method of treating cancer without the need of an additional cancer therapeutic.
• ULK1 and/or ULK 2 are important protein in regulating autophagy in mammalian cells.
• ULK1 and/or ULK2 are activated under conditions of nutrient deprivation by several upstream signals, which is followed by the initiation of autophagy.
• the requirement for ULK1 and/or ULK2 in autophagy initiation has been studied in the context of nutrient deprivation.
• ULK1 complex combining ULK1, ATG (autophagy-related protein) 13 (ATG13), FIP200 (focal adhesion kinase family interacting protein of 200 kDa), and ATG101 is one of the first protein complexes that comes in to play in the initiation and formation of autophagosomes when an autophagic response is initiated.
• ULK1 is considered to be unique as a core conserved component of the autophagy pathway which is a serine/threonine kinase, making it a particularly unique target of opportunity for development of compounds to control autophagy.
• mice genetically engineered to completely lack ULK1 are viable with significant pathology.
• a ULK1 selective kinase inhibitor is well tolerated by normal tissues, but not by tumor cells that have become reliant on ULK1 mediated autophagy for survival.
• ULK2 takes over the functional role of ULK1 when ULK1 function has been inhibited.
• an inhibitor that is effective for both ULK1 and ULK2 is desirable to mitigate this effect.
• the present disclosure provides compounds and salts, and formulations thereof, for use in treating various diseases.
• the compounds are ULK inhibitors.
• the compounds of the present disclosure are ULK1 inhibitors.
• the compounds of the present disclosure are specific ULK1 inhibitors.
• the compounds are inhibitors of both ULK1 and ULK2.
• the present disclosure provides a compound having a structure of Formula (IA):
• R 1A is H, halogen, or substituted or unsubstituted alkyl
• X A is -NR 3A R 4A or -OR 4A ;
• R 3A is H, substituted or unsubstituted alkyl, or a bond with a substituent on an R 4A to form a heterocycle;
• R 6A is H or substituted or unsubstituted alkyl
• R 71A is H, -CN, substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted C 3 -C 10 alkyl, substituted or unsubstituted C 4 -C 10 cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted;
• R 72A is H, -CN, substituted or unsubstituted methyl, substituted or unsubstituted ethyl, linear C 3 -C 5 alkyl, substituted or unsubstituted C 3 -C 10 cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; each R A is independently H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; n A is 1 or 2; m A is 1 or 2; wherein the sum of n and m is 2 or 3; p A is an integer from 0-3, and the nitrogen in the fused ring system is optionally quatemized with C 1 -C 6 alkyl, or pharmaceutically acceptable salt thereof.
• R 1A is H, halogen, or C 1 -C 6 alkyl. In some embodiments, R 1A is H or fluorine. In some embodiments, R 1A is H. In some embodiments, R 1A is fluorine.
• R 2A is H, C 1 -C 6 haloalkyl, or halogen. In some embodiments, R 2A is -CF 3 , or halogen. In some embodiments, R 2A is -CF 3 , -Cl, or -Br. In some embodiments, R 2A is -CF 3 . In some embodiments, R 2A is Br. In some embodiments, R 2A is Cl. In some embodiments, R 2A is halogen. [00111] In some embodiments, X A is -NR 3A R 4A . In some embodiments, R 3A is H or C1-C6 alkyl. In some embodiments, R 3A is H, or -CH3. In some embodiments, R 3A is H. In some embodiments, R 3A is H or C1-C3 alkyl. In some embodiments, R 3A is H, methyl, or ethyl.
• R 4A is aryl or heteroaryl.
• R 4A is 6-membered aryl or heteroaryl. In some embodiments, R 4A is 6-membered aryl or 6-membered heteroaryl. In some embodiments, R 4A is phenyl, pyridyl, or pyrimidinyl. In some embodiments, R 4A is phenyl. In some embodiments, R 4A is phenyl substituted with
• R 4A is
• R 4A is cyclopropyl or cyclobutyl optionally substituted with one or more-OR A or substituted or unsubstituted alkyl. In some embodiments, R 4A is cyclopropyl optionally substituted with one or more-OR A or substituted or unsubstituted alkyl. In some embodiments, R 4A is cyclopropyl optionally substituted with OH or C1-C6 alkyl. In some embodiments, R 4A is unsubstituted cyclopropyl. In some embodiments, R 4A is unsubstituted cyclobutyl.
• each R 5A is independently halogen, -OR A , - NR A R a , or unsubstituted C1-C6 alkyl.
• p A is 0 or 1. In some embodiments, p A is 0. In some embodiments, p A is 2. In some embodiments, p A is 1. In some embodiments, p A is 1 or 2.
• R 6A is H or -CH3. In some embodiments, R 6A is H. In some embodiments, R 6A is H or C1-C3 alkyl. In some embodiments, R 6A is C1-C3 alkyl. In some embodiments, R 6A is -CH3.
• each R 10A and R 11A is independently H or substituted or unsubstituted alkyl, or R 10A and R 11A on the same atom join to form a cycloalkyl, or R 10A and R 11A on the same atom are taken together to form an oxo. In some embodiments, each R 10A and R 11A is independently H or substituted or unsubstituted alkyl, or R 10A and R 11A on the same atom are taken together to form an oxo. In some embodiments, each R 10A and R 11A is independently H or methyl. In some embodiments, each R 10A and R 11A is independently H.
• n A is 1 and m A is 1. In some embodiments, n A is 1 and m A is 2. In some embodiments, n A is 2 and m A is 1
• ULK1 inhibition assays were performed in a 5 uL reaction volume containing 2 ug/mL recombinant human ULK1 protein (1-649, SignalChem #U01-11G) and 80 ug/mL myelin basic protein (MBP, Sigma- Aldrich #M1891) in the presence of 25 uM ATP (Sigma- Aldrich A7699). ULK 1 inhibition was assessed after one hour. Compounds were tested in triplicate in a 16-dose IC50 mode with 3-fold serial dilution and a starting dose of 30 uM. Staurosporine, a non-selective protein kinase inhibitor, was used in the assay as a positive control.
• IC50S were also measured by ULK1 NanoBRET assay according to the following protocol: Human embryonic kidney cells (HEK293T) were transfected with NanoLuc®-ULKl Fusion Vector (Promega #NV2211) using jetPRIME transfection reagent (Polyplus Transfection #114-15). Following 24 h, cells were trypsinized and resuspended in Opti-MEM® I (IX), Reduced Serum Medium (Gibco, #11058-021). Approximately, 7,000 cells per well (in 34 pL total volume) were replated into non-binding surface 384 well plates.
• NanoBRET 20X Tracer K-5 reagent was prepared according to the manufacturer’s directions and 2 pL were added to each well of the 384 plate (assay plate).
• the assay plate was mixed on an orbital shaker for 15 seconds at 700 rpm.
• Compounds were serially diluted at 200X final concentration in 100% DMSO, then diluted to 10X final concentration in assay media (Opti-MEM® I, Reduced Serum Medium).
• 4 pL lOx test compounds were added to each well of the assay plate, followed by mixing at 700 rpm for 15 seconds.
• the assay plate was incubated for 2 h in a 37 C incubator with 5% C02 and then equilibrated to RT for 15 min.
• the 3X Complete Substrate plus Inhibitor Solution was prepared according to the manufacturer’s directions with a concentration of Extracellular NanoLuc® Inhibitor of 60 pM to be used at a working concentration of 20 pM.
• the 3X Complete Substrate plus Inhibitor Solution was mixed and 20 pL per well was added to the assay plate and incubated at RT for 2-3 min. Donor emission wavelength (450 nm) and acceptor emission wavelength (610 nm) were measured using an assay compatible luminometer (see manufacturer’s specifications).
• R 1B is H, halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted haloalkyl;
• R 2B is substituted C2 alkyl, substituted or unsubstituted C3-C10 alkyl, -NR 21B R 22B , or -OR 23B ;
• R 5B is H or halogen
• R 21B is -OR 26b , NR 27B R 28b , substituted methyl, or substituted or unsubstituted C2-C10 alkyl
• R 22B is H or substituted or unsubstituted alkyl
• R 21B and R 22B are taken together with the nitrogen atom to which they are attached to form a substituted or unsubstituted heterocycloalkyl containing at least one additional heteroatom selected from the group consisting of O, N, and S;
• R 23B is H or substituted or unsubstituted alkyl
• R 26B is H or substituted or unsubstituted alkyl
• R 27B and R 28B are each independently H or substituted or unsubstituted alkyl; or
• R 27B and R 28B are taken together with the nitrogen atom to which they are attached to form a substituted or unsubstituted heterocycloalkyl
• R 31B is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl
• R 32B is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl
• R 33B is H or substituted or unsubstituted alkyl
• R 32B and R 33B are taken together with the nitrogen atom to which they are attached to form a substituted or unsubstituted heterocycloalkyl; each R B is independently H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and n B is an integer from 0-4; or a pharmaceutically acceptable salt thereof.
• R 1B is halogen or C1-C6 haloalkyl. In some embodiments, R 1B is Cl, Br, or -CF3. In some embodiments, R 1B is -CF3. In some embodiments R 1B is Br. In some embodiments, R 1B is Cl.
• R 2B is -NR 21B R 22B or -OR 23B . In some embodiments, R 2B is - NR 21B R 22B n ome embodiments, R 21B is substituted methyl or substituted or unsubstituted C 2 - Ce alkyl. In some embodiments, R 21B is substituted methyl or substituted C 2 -C 4 alkyl. In some embodiments, R 21B is substituted C 2 -C 4 alkyl. In some embodiments, R 21B is
• R 22B is H or -CH3. In some embodiments, R 22B is -CH3. In some embodiments, R 22B is H. In some embodiments, R 22B is H, -CH3, -CH2CH3, or -
• R 2B is -OR 23B .
• R 23B is H or -CH3.
• R 23B is -CH3.
• R 23B is H.
• R 23B is H, -CH , -CH 2 CH 3 , or -CH 2 CH 2 CH 3 .
• R 3B is -NR 32B R 33B .
• R 32B is substituted or unsubstituted aryl fused with a 5- or 6-membered ring.
• R 32B is substituted or unsubstituted heteroaryl fused with a 5- or 6-membered ring.
• R 32B is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, wherein the aryl or heteroaryl is
• R 32B is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, wherein the aryl or heteroaryl is ts, R 32B is unsubstituted aryl or heteroaryl.
• R 33B H or C1-C6 alkyl. In some embodiments, R 33B H or C1-C3 alkyl. In some embodiments, R 33B is H or -CH3. In some embodiments, R 33B is H. In some embodiments, R 33B is -CH3.
• each R 4B is independently halogen, -OR B , or C1-C6 alkyl.
• each R 4B is independently -OR B .
• n B is 0, 1, or 2. In some embodiments, n B is 0 or 1. In some embodiments, n B is 0. In some embodiments, n B is 1. In some embodiments, n B is 2. In some embodiments, n B is 3. In some embodiments, n B is 4.
• R 5B is H or F. In some embodiments, R 5B is H. In some embodiments, R 5B is F. [00136] Any combination of the groups described above for the various variables is contemplated herein. Throughout the specification, groups and substituents thereof are chosen by one skilled in the field to provide stable moieties and compounds.
• IC50S are represented nM, with A representing IC50 ⁇ 100 nM, B representing 1000 nM > IC50 > 20 nM, and C representing IC50 > 1000 nM.
• NT indicates the compound was not tested.
• R 1C is H, substituted or unsubstituted alkyl, or halogen
• R 2C is H, halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted haloalkyl;
• R 7C is H or substituted or unsubstituted alkyl
• X c is -O- or -NR 8C -;
• R 8C is H or substituted or unsubstituted alkyl
• R 9C and R 10C are each independently H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R 9C and R 10C are taken together with the carbon atom to which they are attached to form a substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocycloalkyl;
• R 41C and R 42C are each independently hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more R 45C ; or R 41C and R 42C are taken together with the nitrogen atom to which they are attached to form a substituted or unsubstituted heterocycloalkyl;
• R 43C is hydrogen, -CN, alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more R 45C ;
• each R c is independently H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; n c is an integer from 0-4; m c is an integer from 0-4; and with the proviso that when R 4C is -OMe and R 2C is halogen, then R 3C is not OH, or pharmaceutical
• R 1C is H or halogen. In some embodiments, R 1C is H or F. In some embodiments, R 1C is H. In some embodiments, R 1C is F.
• R 2C is halogen or C1-C6 haloalkyl. In some embodiments, R 2C is Br, Cl, or -CF3. In some embodiments, R 2C is Br. In some embodiments, R 2C is Cl. In some embodiments, R 2C is -CF3.
• R 3C is -NR C R C and each R c is independently hydrogen, substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted cycloalkyl or both R c s are taken together with the nitrogen atom to which they are attached to form a substituted or unsubstituted heterocycloalkyl.
• R 3C is -NR C R C each R c is independently selected from H, , .
• R 3C is
• NR C R C and both R c s are taken together to form a heterocycloalkyl selected from
• R 3C is selected from
• R 3C is OR c and the R c of R 3C is hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
• R 4C is -NR 41C R 42C .
• R 41C and R 42C are each independently hydrogen, alkyl, or cycloalkyl, wherein the alkyl or cycloalkyl is optionally substituted with one or more R 45C or R 41C and R 42C are taken together with the nitrogen atom to which they are attached to form a substituted or unsubstituted heterocycloalkyl.
• R 41C and R 42C is independently H, , ,
• R 41C and R 42C are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl, wherein the heterocycloalkyl is . In some embodiments, R 41C and R 42C are taken together with the nitrogen atom to which they are attached to form [00148] In some embodiments, R 4C is -OR 43C . In some embodiments, R 43C is hydrogen or Ci- Ce alkyl optionally substituted with one or more R 45C . In some embodiments, R 43C is H, -CH3, -
• R 41C and R 42C are each independently hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, or cycloalkyl; wherein each alkyl or cycloalkyl is independently optionally substituted with one or more R 45C .
• R 41C and R 42C are each independently H, -CH 3 , or -CFhCFb.
• each R 5C is independently halogen, - CN, -OR c , or substituted or unsubstituted alkyl. In some embodiments, each R 5C is independently halogen or -OR c . In some embodiments, each R 5C is independently -0(Ci-C 6 alkyl). In some embodiments, each R 5C is independently -OCH 3 .
• n c is 0, 1, or 2. In some embodiments, n c is 0 or 1. In some embodiments, n c is 0. In some embodiments, n c is 1. In some embodiments, n c is 2. In some embodiments, n c is 3.
• each R 6C is independently halogen or -OR c .
• each R 6C is -0(Ci-C 6 alkyl).
• each R 6C is -OCH3.
• m c is 0, 1, or 2. In some embodiments, m c is 2. In some embodiments, m c is 2 and each R 6C is -OCH3. In some embodiments, m c is 0 or 1. In some embodiments, m c is 0. In some embodiments, m c is 1. In some embodiments, m c is 3.
• R 7C is H or -CH 3 . In some embodiments, R 7C is H. In some embodiments, R 7C is -CH 3 . In some embodiments, R 7C is H or C 1 -C 3 alkyl.
• X c is -NR 8 -.
• R 8C is H or -CH 3 .
• R 8C is H.
• R 8C is -CH 3 .
• R 8C is H or C 1 -C 3 alkyl.
• R 9C and R 10C are each independently H or substituted or unsubstituted alkyl.
• R 9C and R 10C are each independently H or C1-C6 alkyl.
• R 9C is -CFb and R 10C is H.
• R 9C and R 10C are each H.
• R 9C and R 10C are each independently H or -CH3.
• R 1D is H or fluorine. In some embodiments, R 1D is H. In some embodiments, R 1D is fluorine.
• R 2D is
• R 2 is
• R 2 is
• each R 20D is independently halogen, -CN, -OR°, or substituted or unsubstituted Ci-C 6 alkyl.
• each R 20D is independently halogen, -CN, -OR°, or C1-C6 alkyl.
• m D is 0 or 1. In some embodiments, m D is 0. In some embodiments, m D is 1.
• R 3D is
• each R° is independently H or -CH3. In some embodiments, each R D is independently H. In some embodiments, each R° of R 3D is independently H or -CH3. In some embodiments, each R° of R 3D is independently H.
• R 3D is
• each R° is independently H or -CH3.
• each R° of R 3D is independently H or -CH3
• one R° is of R 3D H and one R° of R 3D is embodiments, R 7D and R 8D are each independently H.
• each R 9D is independently halogen, -CN, -OR°, or C1-C6 alkyl.
• p D is 0 or 1. In some embodiments, p D is 0. In some embodiments, p D is 1.
• VE Formula (VE):
• R 1E is H, nitrile, or halogen
• R 2E is halogen, nitrile, methyl, cyclopropyl, or -CF3;
• R 3E is halogen,
• R 4E is aryl substituted with one or more -OR 35E , substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl,
• R 31E is H, C1-C6 alkyl, or cycloalkyl
• R 32E and R 33E are each independently H, substituted or unsubstituted C1-C6 alkyl, or cycloalkyl;
• R 34E is H, C1-C6 alkyl, or cycloalkyl; each R 35E is independently substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; each R E is independently hydrogen, C1-C6 alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more halogen, -OH, -NH2, substituted amino, cycloalkyl, oxo, or C1-C6 alkyl; or a pharmaceutically acceptable salt thereof.
• R 1E is H or F. In some embodiments, R 1E is H. In some embodiments, R 1E is nitirile.
• R 2E is Cl, Br, or -CF 3 . In some embodiments, R 2E is Br or - CF 3 . In some embodiments, R 2E is F. In some embodiments, R 2E is I. In some emobimdents, R 2E is nitrile. In some embodiments, R 2E is methyl. In some embodiments, R 2E is cyclopropyl.
• R 3E is -SR 31E . In some embodiments, R 3E is -SH, -SCH 3 , or - SCH 2 CH 3 . In some embodiments, R 3E is -SCH 3 .
• R 3E is ,
• R 3E is
• R 4E is
• R 4E is
• R 5E and R 6E are each independently H or -CH3. In some embodiments, R 5E and R 6E are each independently H.
• R 7E is independently halogen or -OCH 3 .
• R 7E is
• p E is 0 or 1. In some embodiments, p E is 0. In some embodiments, p E is 1.
• Illustrative compounds of Formula III and related analogs (Cl - C27), compounds of Formula IV and related analogs (D1-D6), and compounds of Formula V and related analogs (El- E13) are shown in Table 3 (along with their respective IC 50 values for ULK1 inhibition assay).
• IC 50S for ADP Glo assay are represented in nM, with A representing IC 50 ⁇ 5 nM, B representing 5 nM > IC 50 > 100 nM, and C representing IC 50 > 100 nM.
• IC 50S or nanoBRET assay are represented in nM, with A ⁇ 100 nM and B > 100 nM. NT indicates the compound was not tested.
• the invention provides salts of any one of the compounds described herein.
• Pharmaceutically-acceptable salts include, for example, acid-addition salts and base-addition salts.
• the acid that is added to the compound to form an acid-addition salt can be an organic acid or an inorganic acid.
• a base that is added to the compound to form a base-addition salt is an organic base or an inorganic base.
• a pharmaceutically-acceptable salt is a metal salt.
• metal salts arise from the addition of an inorganic base to a compound of the invention.
• the inorganic base consists of a metal cation paired with a basic counterion, such as, for example, hydroxide, carbonate, bicarbonate, or phosphate.
• the metal is an alkali metal, alkaline earth metal, transition metal, or main group metal.
• the metal is lithium, sodium, potassium, cesium, cerium, magnesium, manganese, iron, calcium, strontium, cobalt, titanium, aluminum, copper, cadmium, or zinc.
• a metal salt is a lithium salt, a sodium salt, a potassium salt, a cesium salt, a cerium salt, a magnesium salt, a manganese salt, an iron salt, a calcium salt, a strontium salt, a cobalt salt, a titanium salt, an aluminum salt, a copper salt, a cadmium salt, or a zinc salt.
• ammonium salts arise from the addition of ammonia or an organic amine to a compound of the invention.
• the organic amine is triethyl amine, diisopropyl amine, ethanol amine, diethanol amine, triethanol amine, morpholine, N-methylmorpholine, piperidine, N-methylpiperidine, N-ethylpiperidine, dibenzylamine, piperazine, pyridine, pyrrazole, pipyrrazole, imidazole, pyrazine, or pipyrazine.
• an ammonium salt is a triethyl amine salt, a diisopropyl amine salt, an ethanol amine salt, a diethanol amine salt, a triethanol amine salt, a morpholine salt, an N-methylmorpholine salt, a piperidine salt, an N-methylpiperidine salt, an N-ethylpiperidine salt, a dibenzylamine salt, a piperazine salt, a pyridine salt, a pyrrazole salt, an imidazole salt, or a pyrazine salt.
• acid addition salts arise from the addition of an acid to a compound of the invention.
• the acid is organic.
• the acid is inorganic.
• the acid is hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, nitrous acid, sulfuric acid, sulfurous acid, a phosphoric acid, isonicotinic acid, lactic acid, salicylic acid, tartaric acid, ascorbic acid, gentisinic acid, gluconic acid, glucaronic acid, saccaric acid, formic acid, benzoic acid, glutamic acid, pantothenic acid, acetic acid, propionic acid, butyric acid, fumaric acid, succinic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, oxalic acid, or maleic acid
• the salt is a hydrochloride salt, a hydrobromide salt, a hydroiodide salt, a nitrate salt, a nitrite salt, a sulfate salt, a sulfite salt, a phosphate salt, isonicotinate salt, a lactate salt, a salicylate salt, a tartrate salt, an ascorbate salt, a gentisinate salt, a gluconate salt, a glucaronate salt, a saccarate salt, a formate salt, a benzoate salt, a glutamate salt, a pantothenate salt, an acetate salt, a propionate salt, a butyrate salt, a fumarate salt, a succinate salt, a methanesulfonate (mesylate) salt, an ethanesulfonate salt, a benzenesulfonate salt, a p-tolu
• the compounds described herein may in some cases exist as diastereomers, enantiomers, or other stereoisomeric forms.
• the compounds and salts presented herein include all diastereomeric, enantiomeric, and epimeric forms as well as the appropriate mixtures thereof. Separation of stereoisomers may be performed by chromatography or by forming diastereomers and separating by recrystallization, or chromatography, or any combination thereof. (Jean Jacques, Andre Collet, Samuel H. Wilen, “Enantiomers, Racemates and Resolutions”, John Wiley And Sons, Inc., 1981, herein incorporated by reference for this disclosure). Stereoisomers may also be obtained by stereoselective synthesis.
• the present disclosure provides methods of producing the above-defined compounds.
• the compounds may be synthesized using any suitable techniques.
• these compounds are conveniently synthesized from readily available starting materials.
• Synthetic chemistry transformations and methodologies useful in synthesizing the compounds described herein are known in the art and include, for example, those described in R. Larock, Comprehensive Organic Transformations (1989); T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2d. Ed. (1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis (1995). ).
• synthesis and measurements of ULK1 inhibitory activity of the compounds described herein was performed using method analogous to those previously described in PCT International Application No. PCT/US2015/046777 which is hereby incorporated by reference in its entirety.
• the compounds of the present invention may be administered in various forms, including those detailed herein.
• the treatment with the compound may be a component of a combination therapy or an adjunct therapy, i.e. the subject or patient in need of the drug is treated or given another drug for the disease in conjunction with one or more of the instant compounds.
• this combination therapy is sequential therapy where the patient is treated first with one drug and then the other or the two drugs are given simultaneously.
• these are administered independently by the same route or by two or more different routes of administration depending on the dosage forms employed
• a “pharmaceutically acceptable carrier” is a pharmaceutically acceptable solvent, suspending agent or vehicle, for delivering the instant compounds to the animal or human.
• the carrier may be liquid or solid and is selected with the planned manner of administration in mind.
• Liposomes are also a pharmaceutically acceptable carrier.
• the dosage of the compounds administered in treatment will vary depending upon factors such as the pharmacodynamic characteristics of a specific chemotherapeutic agent and its mode and route of administration; the age, sex, metabolic rate, absorptive efficiency, health and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment being administered; the frequency of treatment with; and the desired therapeutic effect.
• a dosage unit of the compounds used in the method of the present invention may comprise a single compound or mixtures thereof with additional agents.
• the compounds are administered in oral dosage forms as tablets, capsules, pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions.
• the compounds may also be administered in intravenous (bolus or infusion), intraperitoneal, subcutaneous, or intramuscular form, or introduced directly, e.g. by injection, topical application, or other methods, into or onto a site of infection, all using dosage forms well known to those of ordinary skill in the pharmaceutical arts.
• the compounds used in the method of the present invention may be administered in admixture with suitable pharmaceutical diluents, extenders, excipients, or carriers (collectively referred to herein as a pharmaceutically acceptable carrier) suitably selected with respect to the intended form of administration and as consistent with conventional pharmaceutical practices.
• a pharmaceutically acceptable carrier suitably selected with respect to the intended form of administration and as consistent with conventional pharmaceutical practices.
• the unit will be in a form suitable for oral, rectal, topical, intravenous or direct injection or parenteral administration.
• the compounds are administered alone or mixed with a pharmaceutically acceptable carrier.
• this carrier is a solid or liquid, and the type of carrier is generally chosen based on the type of administration being used.
• the active agent is co-administered in the form of a tablet or capsule, liposome, as an agglomerated powder or in a liquid form.
• suitable solid carriers include lactose, sucrose, gelatin and agar.
• Capsule or tablets are easily formulated and made easy to swallow or chew; other solid forms include granules, and bulk powders. Tablets may contain suitable binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents, and melting agents.
• suitable liquid dosage forms include solutions or suspensions in water, pharmaceutically acceptable fats and oils, alcohols or other organic solvents, including esters, emulsions, syrups or elixirs, suspensions, solutions and/or suspensions reconstituted from non-effervescent granules and effervescent preparations reconstituted from effervescent granules.
• Such liquid dosage forms may contain, for example, suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, thickeners, and melting agents.
• Oral dosage forms optionally contain flavorants and coloring agents.
• Parenteral and intravenous forms may also include minerals and other materials to make them compatible with the type of injection or delivery system chosen.
• aspects of the invention include articles of manufacture, or kits, comprising the active agents described herein, and formulations thereof, as well as instructions for use.
• An article of manufacture, or kit can further contain at least one additional reagent, e.g., a chemotherapeutic drug, etc.
• Articles of manufacture and kits typically include a label indicating the intended use of their contents.
• label as used herein includes any writing, or recorded material supplied on or with a kit, or which otherwise accompanies a kit.
• the compounds used in the method of the present invention may also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamallar vesicles, and multilamellar vesicles.
• Liposomes may be formed from a variety of phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines.
• the compounds may be administered as components of tissue-targeted emulsions.
• the compounds used in the method of the present invention may also be coupled to soluble polymers as targetable drug carriers or as a prodrug.
• soluble polymers include polyvinylpyrrolidone, pyran copolymer, polyhydroxylpropylmethacrylamide-phenol, polyhydroxyethylasparta-midephenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues.
• the compounds may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, and crosslinked or amphipathic block copolymers of hydrogels.
• a class of biodegradable polymers useful in achieving controlled release of a drug
• a drug for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, and crosslinked or amphipathic block copolymers of hydrogels.
• Parenteral and intravenous forms may also include minerals and other materials to make them compatible with the type of injection or delivery system chosen.
• ULK inhibitors are used and/or useful in the treatment of cancer and/or ULK mediated disorders. Surprisingly, in certain instances, ULK inhibitors are efficacious as a monotherapy. In some instances, the ULK inhibitor inhibits ULK1. In some instances, the ULK inhibitor is a ULK1 specific inhibitor. In some instances, the ULK inhibitor inhibits both ULK1 and ULK2. In other instances, it is also surprising that ULK inhibitors are used/useful in augmenting or improving standard of care therapies.
• a method of treating a disease or disorder with a ULK inhibitor is administered alone to treat a disease or disorder.
• the method comprises administering to a subject in need thereof a therapeutically effective amount of a ULK inhibitor.
• the ULK inhibitor inhibits ULK1.
• the ULK inhibitor is a ULK1 specific inhibitor.
• the ULK inhibitor inhibits both ULK1 and ULK2.
• the ULK inhibitor is administered as a monotherapy.
• the ULK inhibitor is the sole therapeutic agent administered to the patient for the treatment of the disease or disorder.
• the ULK inhibitor is the sole anti cancer agent administered to the patient.
• the ULK inhibitor is administered as a monotherapy with additional inactive ingredients as part of a pharmaceutical formulation.
• the ULK inhibitor inhibits ULK1.
• the ULK inhibitor is a ULK1 specific inhibitor.
• the ULK inhibitor inhibits both ULK1 and ULK2.
• the disease or disorder is characterized by abnormal autophagy. In some embodiments, the abnormal autophagy is therapeutically induced. In some embodiments, the disease or disorder is refractory. In some embodiments, the disease or disorder is refractory to treatment with a non-ULK inhibitor therapeutic agent. In embodiments, the disease or disorder is resistant to treatment with a non-ULK inhibitor therapeutic agent.
• the disease or disorder treated with a ULK inhibitor as a monotherapy is cancer.
• the ULK inhibitor inhibits ULK1.
• the ULK inhibitor is a ULK1 specific inhibitor.
• the ULK inhibitor inhibits both ULK1 and ULK2.
• the cancer is lung cancer.
• the lung cancer is non-small cell lung cancer.
• the cancer is an advanced stage non-small cell lung cancer.
• the cancer comprises a tumor.
• the non-small cell lung cancer comprises a tumor.
• the non-small cell lung cancer is characterized by abnormal autophagy.
• the lung cancer is refractory.
• the lung cancer is refractory to treatment with carboplatin. In some embodiments, the non-small cell lung cancer is refractory. In some embodiments, the non-small cell lung cancer is refractory to treatment with carboplatin. In some embodiments, the lung cancer is characterized by cytostasis.
• the cancer is pancreatic cancer.
• the pancreatic cancer comprises a tumor.
• the pancreatic cancer is characterized by abnormal autophagy.
• the pancreatic cancer is refractory.
• the pancreatic cancer is characterized by cytostasis.
• the pancreatic cancer is pancreatic ductal adenocarcinoma (PD AC).
• the cancer is breast cancer.
• the breast cancer comprises a tumor.
• the breast cancer is characterized by abnormal autophagy.
• the breast cancer is refractory.
• the breast cancer is characterized by cytostasis.
• the breast cancer is triple negative breast cancer.
• the disease or disorder treated with a ULK inhibitor as a monotherapy is lymphoangiomyoleiomatosis.
• the disease or disorder treated with a ULK inhibitor as a monotherapy is tuberous sclerosis complex.
• the ULK inhibitor inhibits ULK1.
• the ULK inhibitor is a ULK1 specific inhibitor.
• the ULK inhibitor inhibits both ULK1 and ULK2.
• administering a ULK inhibitor slows progression of the disease or disorder. In some embodiments, administering a ULK inhibitor slows progression of the disease or disorder by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95%. In some embodiments, progression is measured by tumor growth. In some embodiments, administering a ULK inhibitor arrests cancer cell growth. In some embodiments, administering a ULK inhibitor reduces tumor volume. In some instances, the ULK inhibitor inhibits ULK1. In some instances, the ULK inhibitor is a ULK1 specific inhibitor. In some instances, the ULK inhibitor inhibits both ULK1 and ULK2.
• the method of treatment comprises decreasing phosphorylation of ATG13 in the subject. In some embodiments, the method comprises degrading ATG13 in diseased tissue of the subject. In some embodiments, administering the ULK inhibitor degrades ATG13.
• the subject comprises a mutation in at least one of KRAS, PTEN, TSC1, TSC2, PIk3CA, P53, STK11 (a.k.a. LKB1), KEAP1, NRF2, ALK4, GNAS, or EGFR.
• the subject comprises a mutation in at least one of SMAD4, pl6/CDKM2A, or BRCA2.
• Combination Therapy [00215]
• the compounds, or the pharmaceutically acceptable salts thereof, provided herein may be administered in combination with one or more therapeutic agents.
• the combination therapies of the present invention comprise a ULK inhibitor and an additional therapeutic agent.
• the ULK inhibitor inhibits ULK1.
• the ULK inhibitor is a ULK1 specific inhibitor.
• the ULK inhibitor inhibits both ULK1 and ULK2.
• there is an additional therapeutic benefit when compared to treatment with the additional therapeutic agent alone.
• the combination of the ULK inhibitor and the additional therapeutic agent shut down pathways of autophagy. This allows for enhanced cell death in diseased tissue, as the diseased cells will not be able to rely on autophagic processes for survival once the pathway is shut off with a ULK inhibitor.
• the addition of a ULK inhibitor allows for successful treatment of a disease that is otherwise refractory to treatment of the additional therapeutic agent by itself. In some embodiments, the addition of the ULK inhibitor enhances the efficacy of the additional therapeutic agent. In some embodiments, the addition of the ULK inhibitor has a synergistic effect with the additional therapeutic agent. In some embodiments, the additional therapeutic agent is a standard of care therapy.
• a method of treating a disease or disorder with a ULK inhibitor and an additional therapeutic agent comprises administering to a subject in need thereof a therapeutically effective amount of a ULK inhibitor. In some embodiments, the method comprises administering to a subject in need thereof a therapeutically effective amount of a ULK inhibitor and a therapeutically effective amount of an additional therapeutic agent. In some instances, the ULK inhibitor inhibits ULK1. In some instances, the ULK inhibitor is a ULK1 specific inhibitor. In some instances, the ULK inhibitor inhibits both ULK1 and ULK2.
• the disease or disorder is lymphoangiomyoleiomatosis. In some embodiments, the disease or disorder is tuberous sclerosis complex.
• the disease or disorder is cancer. In some embodiments, the disease or disorder is refractory cancer. In some embodiments, the cancer comprises a tumor. In some embodiments, the cancer is refractory to treatment with carboplatin. In some embodiments, the cancer is refractory to trametinib. In some embodiments, the cancer is refractory to an MEK inhibitor. In some embodiments, cancer is pancreatic cancer. In some embodiments, the cancer is lung cancer. In some embodiments, the lung cancer is non-small cell lung cancer. In some embodiments, the cancer is refractory to an mTOR inhibitor. In some embodiments, the cancer is refractory to rapamycin. In some embodiments, the cancer is refractory to treatment with a rapamycin analog.
• the cancer is pancreatic cancer and the additional therapeutic agent is trametinb.
• the cancer is pancreatic cancer and the additional therapeutic agent is an MEK inhibitor.
• the MEK inhibitor is trametinib, cobimetinib, binimetinib, or selumetinib.
• the cancer is pancreatic cancer and the additional therapeutic agent is gemcitabine.
• the cancer is pancreatic cancer and the additional therapeutic agent is a nucleoside analog.
• the cancer is pancreatic cancer and the additional therapeutic agent is gemcitabine, everolimus, erlotinib, or sunitinib.
• the additional therapeutic agent is FOLFIRINOX (5-fluorouracil, leucovorin, irinotecan, and oxaliplatin), gemcitabine, or gemcitabine/abraxane.
• the additional therapeutic agent is capeditabine, leucovorin, nab-paclitaxel, nanoliposomal irinotecan, gemcitabine/nab-paclitaxel, pembrolizumab, or cisplatin.
• the additional therapeutic agent is capeditabine, leucovorin, nab-paclitaxel, nanoliposomal irinotecan, gemcitabine/nab-paclitaxel, pembrolizumab, or cisplatin.
• the pancreatic cancer is pancreatic ductal adenocarcinoma (PDAC).
• the subject with pancreatic cancer comprises a mutation in at least one of SMAD4, pl6/CDKM2A, or BRCA2.
• the cancer is pancreatic cancer and the additional therapeutic agent is a standard of care therapy. [00221]
• the cancer is breast cancer.
• the cancer is breast cancer and the additional therapeutic agent is a standard of care therapy.
• the cancer is breast cancer and the additional therapeutic agent is anastrozole, exemestane, letrozole, or tamoxifen.
• the cancer is breast cancer and the additional therapeutic agent is a poly ADP ribose polymerase (PARP) inhibitor.
• PARP poly ADP ribose polymerase
• the PARP inhibitor is olaparib, rucaparib, niraparib, or talazoparib.
• the breast cancer is triple negative breast cancer (TNBC).
• the cancer is lung cancer and the additional therapeutic agent is carboplatin. In some embodiments, the cancer is lung cancer and the additional therapeutic agent is a carboplatin analog. In some embodiments, the cancer is non-small cell lung cancer and the additional therapeutic agent is carboplatin. In some embodiments, the cancer is non-small cell lung cancer and the additional therapeutic agent is a carboplatin analog. In some embodiments, the carboplatin analog is cisplatin or dicycloplatin. In some embodiments, the cancer is lung cancer and the additional therapeutic agent is erlotinib, gefitinib, osimertinib, or crizotinib.
• the cancer is non-small cell lung cancer and the additional therapeutic agent is erlotinib, gefitinib, osimertinib, or crizotinib.
• the cancer is lung cancer and the additional therapeutic agent is pemetrexed, docetaxol, or pembroluzimab.
• the cancer is non-small cell lung cancer and the additional therapeutic agent is pemetrexed, docetaxol, or pembroluzimab.
• the cancer is lung cancer and the additional therapeutic agent is gemcitabine, bortexomib, trastuzumab, vinorelbine, doxorubicin, irinotecan, temsirolimus, sunitinib, nivolumab, or bevacizumab.
• the cancer is lung cancer and the additional therapeutic agent is carboplatin/gemcitabine, carboplatin/paclitaxel/cetuximua, cisplatin/pemetrexed, cisplatin/docetaxel, cisplatin/docetaxel/bevacizumab, everolimus/nab-paclitaxel, or tremelimumab/durvalumab.
• the additional therapeutic agent is carboplatin/gemcitabine, carboplatin/paclitaxel/cetuximua, cisplatin/pemetrexed, cisplatin/docetaxel, cisplatin/docetaxel/bevacizumab, everolimus/nab-paclitaxel, or tremelimumab/durvalumab.
• the cancer is non-small cell lung cancer and the additional therapeutic agent is gemcitabine, bortexomib, trastuzumab, vinorelbine, doxorubicin, irinotecan, temsirolimus, sunitinib, nivolumab, or bevacizumab.
• the additional therapeutic agent is gemcitabine, bortexomib, trastuzumab, vinorelbine, doxorubicin, irinotecan, temsirolimus, sunitinib, nivolumab, or bevacizumab.
• the cancer is non-small cell lung cancer and the additional therapeutic agent is carboplatin/gemcitabine, carboplatin/paclitaxel/cetuximua, cisplatin/pemetrexed, cisplatin/docetaxel, cisplatin/docetaxel/bevacizumab, everolimus/nab-paclitaxel, or tremelimumab/durvalumab.
• the subject with lung cancer comprises a mutation in KRAS, PTEN, TSC1, TSC2, PIk3CA, P53, STK11 (a.k.a. LKB1), KEAP1, NRF2, ALK4, GNAS or EGFR.
• the additional therapeutic agent is carboplatin. In some embodiments, the additional therapeutic agent is carboplatin or a carboplatin analog. In some embodiments, the carboplatin analog is cisplatin or dicycloplatin.
• the additional therapeutic agent is erlotinib, gefitinib, osimertinib, or crizotinib. .
• the additional therapeutic agent is pemetrexed, docetaxol, or pembroluzimab.
• the additional therapeutic agent is carboplatin/gemcitabine, carboplatin/paclitaxel/cetuximua, cisplatin/pemetrexed, cisplatin/docetaxel, cisplatin/docetaxel/bevacizumab, everolimus/nab-paclitaxel, or tremelimumab/durvalumab .
• the additional therapeutic agent is anastrozole, exemestane, letrozole, or tamoxifen.
• the additional therapeutic agent is a poly ADP ribose polymerase (PARP) inhibitor.
• PARP poly ADP ribose polymerase
• the PARP inhibitor is olaparib, rucaparib, niraparib, or talazoparib.
• the additional therapeutic agent is gemcitabine, everolimus, erlotinib, or sunitinib.
• the additional therapeutic agent is a nucleoside analog.
• is FOLFIRINOX (5-fluorouracil, leucovorin, irinotecan, and oxaliplatin), gemcitabine, or gemcitabine/abraxane.
• the additional therapeutic agent is capeditabine, leucovorin, nab-paclitaxel, nanoliposomal irinotecan, gemcitabine/nab-paclitaxel, pembrolizumab, or cisplatin.
• the additional therapeutic agent is an MEK inhibitor. In some embodiments, the additional therapeutic agent is trametinib. In some embodiments, the MEK inhibitor is trametinib, cobimetinib, binimetinib, or selumetinib.
• the additional therapeutic agent is gemcitabine. In some embodiments, the additional therapeutic agent is a nucleoside analog.
• the additional therapeutic agent is an mTOR inhibitor.
• the additional therapeutic agent is rapamycin.
• mTOR inhibitor is rapamycin, sirolimus, temsirolimus, everolimus, ridaforolimus, NVPBEZ235, BGT226, XL765, GDC0980, SF1 126, PKI587, PFO4691502, GSK2126458, INK128, TORKiCC223, OSI027, AZD8055, AZD2014, and Palomid 529, metformin, or AICAR (5- amino-l-P-D-ribofuranosyl -imidazole-4- carboxamide).
• the additional therapeutic agent is a rapamycin analog.
• the disease or disorder is lymphoangiomyoleiomatosis and the additional therapeutic agent is an mTOR inhibitor.
• the disease or disorder is tuberous sclerosis complex and the additional therapeutic agent is an mTOR inhibitor.
• the additional therapeutic agent was previously administered to the subject without a ULK inhibitor. In some embodiments, the additional therapeutic agent induces a cytostatic response. In some embodiments, the additional therapeutic agent induces a cytostatic response when administered without a ULK inhibitor. In some embodiments, the additional therapeutic agent induces a cytostatic response in disease tissue. In some embodiments, the additional therapeutic agent induces a cytostatic response in the diseased tissue when the additional therapeutic agent was administered without a ULK inhibitor. In some instances, the ULK inhibitor inhibits ULK1. In some instances, the ULK inhibitor is a ULK1 specific inhibitor.
• the ULK inhibitor inhibits both ULK1 and ULK2
• the subject is treated with the additional therapeutic agent prior to treatment with the ULK inhibitor.
• treatment with the additional therapeutic agent is ceased prior to administration of the ULK inhibitor.
• treatment with the additional therapeutic agent produces a cytostatic response in diseased tissue.
• the ULK inhibitor and the additional therapeutic agent are administered concomitantly.
• the ULK inhibitor and the additional therapeutic agent are administered together at the start of treatment.
• the ULK inhibitor inhibits ULK1.
• the ULK inhibitor is a ULK1 specific inhibitor.
• the ULK inhibitor inhibits both ULK1 and ULK2.
• the disease or disorder is characterized by abnormal autophagy. In some embodiments, the abnormal autophagy is therapeutically induced. In some embodiments, the disease or disorder is refractory. In some embodiments, the disease or disorder is refractory to treatment with an additional therapeutic agent. In embodiments, the disease or disorder is resistant to treatment with an additional therapeutic agent.
• administering a ULK inhibitor slows progression of the disease or disorder. In some embodiments, administering a ULK inhibitor slows progression of the disease or disorder when compared to administration of the additional therapeutic agent with the ULK inhibitor. In some embodiments, administering a ULK inhibitor slows progression of the disease or disorder by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95%.
• administering a ULK slows the progression of the disease or disorder by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95% when compared to administration of the additional therapeutic agent with the ULK inhibitor.
• progression of the disease or disorder comprises growth of a tumor.
• progression is measured by tumor growth.
• administering a ULK inhibitor arrests cancer cell growth.
• administering a ULK inhibitor reduces tumor volume.
• the ULK inhibitor inhibits ULKE
• the ULK inhibitor is a ULK1 specific inhibitor. In some instances, the ULK inhibitor inhibits both ULK1 and ULK2.
• administering a ULK inhibitor enhances the efficacy of the additional therapeutic agent by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95%. In some embodiments, administering a ULK inhibitor enhances the efficacy of the additional therapeutic agent by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95% when compared to administration of the additional therapeutic agent with the ULK inhibitor. In some embodiments, the efficacy is measured by a change in the rate of tumor growth. In some embodiments, efficacy is measured by reduction of tumor volume. In some instances, the ULK inhibitor inhibits ULK1. In some instances, the ULK inhibitor is a ULK1 specific inhibitor. In some instances, the ULK inhibitor inhibits both ULK1 and ULK2.
• the method of treatment comprises decreasing phosphorylation of ATG13 in the subject. In some embodiments, the method comprises degrading ATG13 in diseased tissue of the subject. In some embodiments, administering a ULK inhibitor causes degradation of ATG13.
• the subject comprises a mutation in at least one of KRAS, PTEN, TSC1, TSC2, PIk3CA, P53, STK11 (a.k.a. LKB1), KEAP1, NRL2, ALK4, GNAS, or EGER.
• the subject comprises a mutation in at least one of SMAD4, pl6/CDKM2A, or BRCA2.
• Reactions conducted under microwave irradiation were performed in a CEM Discover microwave reactor using either CEM 10 mL reaction vessels or a ChemGlass heavy wall pressure vessel (100 mL, 38 mmxl90 mm). Reaction progress was monitored by reverse- phase HPLC and/or thin-layer chromatography (TLC). Liquid chromatography-mass spectrometry was performed using either Waters or Shimadzu 2010EV LCMS instruments using water and acetonitrile or methanol doped with 0.1% formic acid. TLC was performed using silica gel 60 F254 pre-coated plates (0.25 mm).
• Flash chromatography was performed using silica gel (32-63 pm particle size) or aluminum oxide (activated, basic, ⁇ 150 mesh size). Automated chromatographic purification was carried out using pre-packed silica or C18 cartridges (from RediSep and Luknova) and eluted using an ISCO Companion system. Reverse phase purifications were conducted using water and acetonitrile or methanol doped with 0.1% formic acid. All final product compounds were purified using one of these two chromotographic methods. Purity and characterization of compounds was established by a combination of TLC, liquid chromatography-mass spectroscopy (LC-MS) and Nuclear Magnetic Resonance (NMR) analytical techniques. 'H and 13 C NMR spectra were obtained on a Joel 400 spectrometer at 400 MHz and 101 MHz, respectively. Chemical shifts are reported in d (ppm) and were internally referenced to deuterated solvent signals.
• LC-MS liquid chromatography-mass spectroscopy
• DIPEA or DIEA N,N-diisopropylethylamine
• Product 102 is recovered after purification by flash chromatography on silica gel (DCM-EtOAc). [00246] Intermediate 102 and hydrogen chloride in water (0.489 ml, 1.468 mmol, 3M in water) are mixed in methanol (1 ml). Heated to 60° C. for 16 h and then concentrated. The solid is washed with DCM to give product 103.
• acylated compounds 104 compounds 103, acyl chloride 106, and triethylamine (0.026 ml, 0.187 mmol) are mixed in DMF (3 ml). Heated to 60° C. for 8 h. Add MeOH and concentrate. Product is recovered after flash chromatography on silica gel (DCM- EtOAc).
• Method 5 General procedure for the synthesis of 5-halo-/V 2 , F 4 -diarylpyrimidine 2,4-diamine and N 2 , F 4 -diaryl-5-methyl-pyrimidine 2,4-diamine derivatives (using reaction conditions C or D shown in General Scheme 3).
• N-Methyl-2-((2-((l,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)amino)benzamide (A120).
• the title compound was prepared by reaction of tert-butyl 6-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3,4- dihydroisoquinoline-2(lH)-carboxylate (320 mg, 0.75 mmol), and 2-amino-N-methylbenzamide (123 mg, 0.82 mmol) according to Method 2a.
• the title compound was prepared by reaction of tert-butyl 6-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3,4- dihydroisoquinoline-2(lH)-carboxylate (320 mg, 0.746 mmol), 2-hydroxy-N-methylbenzamide (124 mg, 0.821 mmol), and N,N-diisopropylethylamine (0.16 mL, 0.895 mmol) at 120 °C for 60 minutes according to Method 2c to afford the title compound as a colored solid (311 mg, 77%).
• LC-MS (ESI) calcd. for C27H29F3N5O4 [M+H] + : 544.22; found: 544.70.
• the title compound was prepared by reaction of tert- butyl 6-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3,4-dihydroisoquinoline-2(lH)- carboxylate (300 mg, 0.70 mmol), propan-2-amine (72 pL, 0.84 mmol), and N,N- diisopropylethylamine (0.15 mL, 0.84 mmol) at 120 °C for 10 minutes according to Method 2c.
• the crude product was purified by automated reverse phase chromatography to afford the title compound as a brown solid (309 mg, 98%).
• LC-MS (ESI) calcd. for C22H29F3N5O2 [M+H] + : 452.23; found: 453.05.
• the title compound was prepared by reaction of tert-butyl 6-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3,4-dihydroisoquinoline-2(lH)- carboxylate (320 mg, 0.75 mmol), indoline (0.10 mL, 0.89 mmol), and N,N- diisopropylethylamine (0.16 mL, 0.90 mmol) at 120 °C for 20 minutes according to Method 2c.
• the crude product was purified by automated reverse phase chromatography to afford the title compound as a colored solid (371 mg, 97%).
• LC-MS (ESI) calcd.
• the title compound was prepared by reaction of the crude salt, l-bromo-2-methoxy ethane (82 pL, 0.87 mmol), and triethylamine (0.40 mL, 2.9 mmol) heated at 80 °C for 18 hours similar to Method 3b.
• the crude product was purified by automated reverse phase chromatography to afford the title compound as an orange solid (224 mg, 66%).
• LC-MS (ESI) calcd. for C25H27F3N5O [M+H] + : 470.22; found: 470.65.
• Benzyl (l,2,3,4-tetrahydroisoquinolin-6-yl)carbamate To a solution of tert-butyl 6-amino-3,4-dihydroisoquinoline-2(lH)-carboxylate (2.0 g, 8.06 mmol) in THF (50 mL) was added Cbz-Cl (4.5 mL, 32.2 mmol) and saturated sodium bicarbonate solution (16 mL, 16.1 mmol). The mixture was stirred at room temperature for 15 hrs. The reaction mixture was quenched with water (50 mL), and then extracted with EA (50 mL x 3).
• the reaction mixture was cooled down and solvent was removed.
• the mixture was washed with water and extracted into dichloromethane (3 times).
• the combined organic layers were washed with brine, dried over anhydrous NaiSC and concentrated.
• the crude product was purified by normal phase chromatography (S1O2, MeOH/DCM gradient, 0 to 10%) to obtain the desired product as an off-white solid (0.55 g, 68%).
• the reaction mixture was concentrated in vacuo and neutralized with sat. NaHC0 3 .
• the product was extracted with DCM two times and the combined organic layers were washed with water, brine and dried over anhydrous Na 2 S0 4 and concentrated to obtain the desired product (0.42 g, 93%).
• the crude product was purified by normal phase chromatography (S1O2, MeOH/DCM gradient, 0 to 10%) to obtain the intermediate (2- ⁇ 6-[5- bromo-4-(2-methylcarbamoyl-phenylamino)-pyrimidin-2-ylamino]-3, 4-dihydro- lH-isoquinolin- 2-yl ⁇ -2-oxo-ethyl)-carbamic acid tert-butyl ester as an off-white solid (55 mg, 41%).
• the synthetic procedure is similar to the synthesis of Compound A127 except 2-[5-bromo-2-(l,2,3,4-tetrahydro-isoquinolin-7-ylamino)- pyrimidin-4-ylamino]-N-methyl-benzamide and l-bromo-2-methoxy-ethane were used instead of 2-[5-bromo-2-(l,2,3,4-tetrahydro-isoquinolin-6-ylamino)-pyrimidin-4-ylamino]-N-methyl- benzamide and 2-chloro-l-morpholin-4-yl-ethanone to obtain the desired product as an off-white solid (34 mg, 52%).
• the synthetic procedure is similar to the synthesis of Compound A139 except 2-[5-bromo-2-(l, 2,3,4- tetrahydro-isoquinolin-7-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide was used instead of 2-[5-bromo-2-( 1,2,3, 4-tetrahydro-isoquinolin-6-ylamino)-pyrimidin-4-ylamino]-N-methyl- benzamide to obtain the desired product as an off-white solid (29 mg, 49%).
• the synthetic procedure is similar to the synthesis of Compound A134 except 2-[5-bromo-2-(l,2,3,4-tetrahydro-isoquinolin-7- ylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide was used instead of 2-[5-bromo-2-(l, 2,3,4- tetrahydro-isoquinolin-6-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide to obtain the desired product as an off-white solid (26 mg, 43%).
• the synthetic procedure is similar to the synthesis of Compound A131 except 2-[5-bromo-2-(l,2,3,4-tetrahydro-isoquinolin-7-ylamino)- pyrimidin-4-ylamino]-N-methyl-benzamide was used instead of 2-[5-bromo-2-(l, 2,3,4- tetrahydro-isoquinolin-6-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide to obtain the desired product as an off-white solid (29 mg, 48%).
• the synthetic procedure is similar to the synthesis of Compound A144 except 2-[5-bromo-2-(l,2,3,4-tetrahydro-isoquinolin-7-ylamino)- pyrimidin-4-ylamino]-N-methyl-benzamide was used instead of 2-[5-bromo-2-(l, 2,3,4- tetrahydro-isoquinolin-6-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide to obtain the desired product as an off-white solid (25 mg, 42%).
• the synthetic procedure is similar to the synthesis of Compound A141 except 2-[5-bromo-2-(l,2,3,4-tetrahydro-isoquinolin-7-ylamino)- pyrimidin-4-ylamino]-N-methyl-benzamide was used instead of 2-[5-bromo-2-(l, 2,3,4- tetrahydro-isoquinolin-6-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide to obtain the desired product as an off-white solid (27 mg, 47%).
• the synthetic procedure is similar to the synthesis of Compound A142 except 2-[5-bromo-2-(l,2,3,4-tetrahydro-isoquinolin-7-ylamino)- pyrimidin-4-ylamino]-N-methyl-benzamide was used instead of 2-[5-bromo-2-(l, 2,3,4- tetrahydro-isoquinolin-6-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide to obtain the desired product as an off-white solid (28 mg, 48%).
• Nl-(4-((5-Bromo-2-chloropyrimidin-4- yl)oxy)-3-fluorophenyl)-N3-(4-fluorophenyl)malonamide (135 mg, 0.271 mmol) and 3,4,5- trimethoxyaniline (99.4 mg, 0.543 mmol) were dissolved in n-butanol (4 mL) and heated at 120 °C until completion by LCMS. The reaction mixture was concentrated in vacuo and purified by column chromatography. Solid (68 mg, 39%).
• the synthetic procedure is similar to the synthesis of Compound A127 except that 2-((5-bromo-2-((4-(piperazin-l-yl)phenyl)amino)pyrimidin-4-yl)amino)- V- methylbenzamide (315 mg, 607 miho ⁇ , 1 equiv.) was used instead of 2-[5-bromo-2-(l, 2,3,4- tetrahydro-isoquinolin-6-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide, 3-bromoprop- 1 - yne (107 mg, 718 pmol, 1.18 equiv.) was used instead of 2-chloro-l-morpholin-4-yl-ethanone, and potassium carbonate (252 mg, 1.82 mmol, 3 equiv.) was used instead of diisopropylethylamine.

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