WO2023193759A1 - Hpk1 antagonists and uses thereof - Google Patents
Hpk1 antagonists and uses thereof Download PDFInfo
- Publication number
- WO2023193759A1 WO2023193759A1 PCT/CN2023/086571 CN2023086571W WO2023193759A1 WO 2023193759 A1 WO2023193759 A1 WO 2023193759A1 CN 2023086571 W CN2023086571 W CN 2023086571W WO 2023193759 A1 WO2023193759 A1 WO 2023193759A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- alkyl
- compound
- heterocycloalkyl
- cycloalkyl
- stereoisomer
- Prior art date
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- 239000005557 antagonist Substances 0.000 title description 7
- 101100177670 Caenorhabditis elegans hpk-1 gene Proteins 0.000 title 1
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- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
- 125000005580 triphenylene group Chemical group 0.000 description 1
- 125000005455 trithianyl group Chemical group 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/12—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 three hetero rings
- C07D471/14—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
Definitions
- a new cancer treatment paradigm has emerged that harnesses the patient's own immune system to overcome immunoevasive strategies utilized by many cancers and to enhance anti-tumor immunity.
- One such strategy is to inhibit negative regulators of immune responses that normally function to maintain peripheral tolerance, allowing tumor antigens to be recognized as non-self entities.
- HPK1 The hematopoietic progenitor kinase 1 (HPK1) is an example of a negative regulator of dendritic cell activation, and T and B cell responses that can be targeted to enhance anti-tumor immunity.
- HPK1 is expressed predominantly by hematopoietic cells, including early progenitors.
- T cells it is believed that HPK1 negatively regulates T cell activation by reducing the persistence of signaling microclusters by phosphorylating SLP76 at Ser376 and Gads at Thr254, which leads to the recruitment of 14-3-3 proteins that bind to the phosphorylated SLP76 and Gads, releasing the SLP76-Gads-14-3-3 complex from LAT-containing microclusters.
- HPK1 can also become activated in response to prostaglandin E2, which is often secreted by tumors, contributing to the escape of tumor cells from the immune system.
- Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
- R 1 on the same carbon are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R 1a ;
- R 1 on the different atoms are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R 1a ;
- R 1a on the same carbon are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R;
- R 1a on the different atoms are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R;
- n 0-6;
- L is -O-, -S-, or -NR 2 -;
- R 2 is hydrogen, -CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, or heterocycloalkyl;
- W is N or CR W ;
- Z is N or CR Z ;
- X is C (R X ) 2 , O, S, or NR X1
- Y is C (R Y ) 2 , O, S, or NR Y1 ;
- X is CR X or N
- Y is CR Y or N
- R X1 is hydrogen, -CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, or heterocycloalkyl;
- R Y1 is hydrogen, -CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, or heterocycloalkyl;
- R 3 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, or heterocycloalkyl;
- Ring B is a bicyclic ring
- R 4 on the different atoms are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R 4a ;
- R 4a on the same carbon are taken together to form a cycloalkyl or heterocycloalkyl; each independently optionally substituted with one or more R;
- R 4a on the different atoms are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each independently optionally substituted with one or more R;
- n 0-6;
- each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene (cycloalkyl) , C 1 -C 6 alkylene (heterocycloalkyl) , C 1 -C 6 alkylene (aryl) , or C 1 -C 6 alkylene (heteroaryl) , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
- each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene (cycloalkyl) , C 1 -C 6 alkylene (heterocycloalkyl) , C 1 -C 6 alkylene (aryl) , or C 1 -C 6 alkylene (heteroaryl) , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
- R c and R d are each independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene (cycloalkyl) , C 1 -C 6 alkylene (heterocycloalkyl) , C 1 -C 6 alkylene (aryl) , or C 1 -C 6 alkylene (heteroaryl) , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
- R c and R d are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R;
- the compound is of Formula (Ia) :
- the compound is of Formula (Ib) :
- the compound is of Formula (Ic) :
- the compound is of Formula (Id) :
- the compound is of Formula (Ie) :
- Ring C is heterocycloalkyl or heteroaryl
- R 1 on the same carbon are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R 1a ;
- R 1 on the different atoms are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R 1a ;
- R 1a on the same carbon are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R;
- R 1a on the different atoms are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R;
- n 0-6;
- L is -O-, -S-, or -NR 2 -;
- R 2 is hydrogen, -CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, or heterocycloalkyl;
- W is N or CR W ;
- Z is N or CR Z ;
- X is C (R X ) 2 , O, S, or NR X1
- Y is C (R Y ) 2 , O, S, or NR Y1 ;
- X is CR X or N
- Y is CR Y or N
- R X1 is hydrogen, -CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, or heterocycloalkyl;
- R Y1 is hydrogen, -CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, or heterocycloalkyl;
- R 3 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, or heterocycloalkyl;
- Ring D is a 3-to 5-membered ring
- R 4 on the different atoms are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R 4a ;
- R 4a on the same carbon are taken together to form a cycloalkyl or heterocycloalkyl; each independently optionally substituted with one or more R;
- R 4a on the different atoms are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each independently optionally substituted with one or more R;
- n 0-6;
- each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene (cycloalkyl) , C 1 -C 6 alkylene (heterocycloalkyl) , C 1 -C 6 alkylene (aryl) , or C 1 -C 6 alkylene (heteroaryl) , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
- each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene (cycloalkyl) , C 1 -C 6 alkylene (heterocycloalkyl) , C 1 -C 6 alkylene (aryl) , or C 1 -C 6 alkylene (heteroaryl) , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
- R c and R d are each independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene (cycloalkyl) , C 1 -C 6 alkylene (heterocycloalkyl) , C 1 -C 6 alkylene (aryl) , or C 1 -C 6 alkylene (heteroaryl) , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
- R c and R d are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R;
- the compound is of Formula (IIa) :
- the compound is of Formula (IIb) :
- the compound is of Formula (IIc) :
- the compound is of Formula (IId) :
- the compound is of Formula (IIe) :
- composition comprising a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable excipient.
- HPK1-mediated disorder is a proliferative disorder.
- the proliferative disorder is cancer.
- the proliferative disorder is associated with one or more activating mutations in HPK1.
- the HPK1-mediated disorder is a chronic viral infection.
- Also disclosed herein is a method of increasing the efficacy of vaccination in a patient comprising administering to said patient a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or a pharmaceutical composition disclosed herein.
- Carboxyl refers to -COOH.
- Cyano refers to -CN.
- Alkyl refers to a straight-chain, or branched-chain saturated hydrocarbon monoradical having from one to about ten carbon atoms, more preferably one to six carbon atoms. Examples include, but are not limited to methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2, 2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2, 2-dimethyl-1-butyl, 3, 3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopent
- a numerical range such as “C 1 -C 6 alkyl” or “C 1-6 alkyl” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated.
- the alkyl is a C 1- 10 alkyl.
- the alkyl is a C 1-6 alkyl.
- the alkyl is a C 1-5 alkyl.
- the alkyl is a C 1-4 alkyl.
- the alkyl is a C 1-3 alkyl.
- an alkyl group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
- the alkyl is optionally substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH 2 , or -NO 2 .
- the alkyl is optionally substituted with halogen, -CN, -OH, or -OMe.
- the alkyl is optionally substituted with halogen.
- Alkenyl refers to a straight-chain, or branched-chain hydrocarbon monoradical having one or more carbon-carbon double-bonds and having from two to about ten carbon atoms, more preferably two to about six carbon atoms.
- a numerical range such as “C 2 -C 6 alkenyl” or “C 2 - 6 alkenyl” means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkenyl” where no numerical range is designated.
- an alkenyl group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
- the alkenyl is optionally substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH 2 , or -NO 2 .
- the alkenyl is optionally substituted with halogen, -CN, -OH, or -OMe.
- the alkenyl is optionally substituted with halogen.
- Alkynyl refers to a straight-chain or branched-chain hydrocarbon monoradical having one or more carbon-carbon triple-bonds and having from two to about ten carbon atoms, more preferably from two to about six carbon atoms. Examples include, but are not limited to ethynyl, 2-propynyl, 2-butynyl, 1, 3-butadiynyl and the like.
- a numerical range such as “C 2 -C 6 alkynyl” or “C 2-6 alkynyl” means that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkynyl” where no numerical range is designated.
- an alkynyl group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
- the alkynyl is optionally substituted with oxo, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH 2 , or -NO 2 .
- the alkynyl is optionally substituted with halogen, -CN, -OH, or -OMe.
- the alkynyl is optionally substituted with halogen.
- Alkylene refers to a straight or branched divalent hydrocarbon chain. Unless stated otherwise specifically in the specification, an alkylene group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkylene is optionally substituted with oxo, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH 2 , or -NO 2 . In some embodiments, the alkylene is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkylene is optionally substituted with halogen.
- Alkoxy refers to a radical of the formula -OR a where R a is an alkyl radical as defined. Unless stated otherwise specifically in the specification, an alkoxy group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkoxy is optionally substituted with halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH 2 , or -NO 2 . In some embodiments, the alkoxy is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkoxy is optionally substituted with halogen.
- Aryl refers to a radical derived from a hydrocarbon ring system comprising 6 to 30 carbon atoms and at least one aromatic ring.
- the aryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the aryl is bonded through an aromatic ring atom) or bridged ring systems.
- the aryl is a 6-to 10-membered aryl.
- the aryl is a 6-membered aryl (phenyl) .
- Aryl radicals include, but are not limited to, aryl radicals derived from the hydrocarbon ring systems of anthrylene, naphthylene, phenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene.
- an aryl may be optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
- the aryl is optionally substituted with halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
- the aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe. In some embodiments, the aryl is optionally substituted with halogen.
- Cycloalkyl refers to a partially or fully saturated, monocyclic, or polycyclic carbocyclic ring, which may include fused (when fused with an aryl or a heteroaryl ring, the cycloalkyl is bonded through a non-aromatic ring atom) , spiro, or bridged ring systems. In some embodiments, the cycloalkyl is fully saturated.
- Representative cycloalkyls include, but are not limited to, cycloalkyls having from three to fifteen carbon atoms (C 3 -C 15 cycloalkyl or C 3 -C 15 cycloalkenyl) , from three to ten carbon atoms (C 3 -C 10 cycloalkyl or C 3 -C 10 cycloalkenyl) , from three to eight carbon atoms (C 3 -C 8 cycloalkyl or C 3 -C 8 cycloalkenyl) , from three to six carbon atoms (C 3 -C 6 cycloalkyl or C 3 -C 6 cycloalkenyl) , from three to five carbon atoms (C 3 -C 5 cycloalkyl or C 3 -C 5 cycloalkenyl) , or three to four carbon atoms (C 3 -C 4 cycloalkyl or C 3 -C 4 cycloalkenyl) .
- the cycloalkyl is a 3-to 10-membered cycloalkyl or a 3-to 10-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 3-to 6-membered cycloalkyl or a 3-to 6-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 5-to 6-membered cycloalkyl or a 5-to 6-membered cycloalkenyl.
- Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
- Polycyclic cycloalkyls include, for example, adamantyl, norbornyl, decalinyl, bicyclo [3.3.0] octane, bicyclo [4.3.0] nonane, cis-decalin, trans-decalin, bicyclo [2.1.1] hexane, bicyclo [2.2.1] heptane, bicyclo [2.2.2] octane, bicyclo [3.2.2] nonane, and bicyclo [3.3.2] decane, and 7, 7-dimethyl-bicyclo [2.2.1] heptanyl.
- Partially saturated cycloalkyls include, for example cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.
- a cycloalkyl is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
- a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
- a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe.
- the cycloalkyl is optionally substituted with halogen.
- Halo or “halogen” refers to bromo, chloro, fluoro or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro.
- Haloalkyl refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, fluorochloromethyl, difluorochloromethyl, trichloromethyl, 2, 2, 2-trifluoroethyl, 1, 2-difluoroethyl, 3-bromo-2-fluoropropyl, 1, 2-dibromoethyl, and the like.
- “Hydroxyalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more hydroxyls. In some embodiments, the alkyl is substituted with one hydroxyl. In some embodiments, the alkyl is substituted with one, two, or three hydroxyls. Hydroxyalkyl include, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl is hydroxymethyl.
- Aminoalkyl refers to an alkyl radical, as defined above, that is substituted by one or more amines. In some embodiments, the alkyl is substituted with one amine. In some embodiments, the alkyl is substituted with one, two, or three amines. Aminoalkyl include, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the aminoalkyl is aminomethyl.
- Heteroalkyl refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g., -NH-, -N (alkyl) -) , sulfur, phosphorus, or combinations thereof.
- a heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl.
- a heteroalkyl is a C 1 -C 6 heteroalkyl wherein the heteroalkyl is comprised of 1 to 6 carbon atoms and one or more atoms other than carbon, e.g., oxygen, nitrogen (e.g.
- heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl.
- heteroalkyl are, for example, -CH 2 OCH 3 , -CH 2 CH 2 OCH 3 , -CH 2 CH 2 OCH 2 CH 2 OCH 3 , -CH (CH 3 ) OCH 3 , -CH 2 NHCH 3 , -CH 2 N (CH 3 ) 2 , -CH 2 CH 2 NHCH 3 , or -CH 2 CH 2 N (CH 3 ) 2 .
- a heteroalkyl is optionally substituted for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
- a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
- a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe. In some embodiments, the heteroalkyl is optionally substituted with halogen.
- Heterocycloalkyl refers to a 3-to 24-membered partially or fully saturated ring radical comprising 2 to 23 carbon atoms and from one to 8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, silicon, and sulfur. In some embodiments, the heterocycloalkyl is fully saturated. In some embodiments, the heterocycloalkyl comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heterocycloalkyl comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heterocycloalkyl comprises one to three nitrogens. In some embodiments, the heterocycloalkyl comprises one or two nitrogens.
- the heterocycloalkyl comprises one nitrogen. In some embodiments, the heterocycloalkyl comprises one nitrogen and one oxygen.
- the heterocycloalkyl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with an aryl or a heteroaryl ring, the heterocycloalkyl is bonded through a non-aromatic ring atom) , spiro, or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heterocycloalkyl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized.
- heterocycloalkyls include, but are not limited to, heterocycloalkyls having from two to fifteen carbon atoms (C 2 -C 15 heterocycloalkyl or C 2 -C 15 heterocycloalkenyl) , from two to ten carbon atoms (C 2 -C 10 heterocycloalkyl or C 2 -C 10 heterocycloalkenyl) , from two to eight carbon atoms (C 2 -C 8 heterocycloalkyl or C 2 -C 8 heterocycloalkenyl) , from two to seven carbon atoms (C 2 -C 7 heterocycloalkyl or C 2 -C 7 heterocycloalkenyl) , from two to six carbon atoms (C 2 -C 6 heterocycloalkyl or C 2 -C 6 heterocycloalkenyl) , from two to five carbon atoms (C 2 -C 5 heterocycloalkyl or C 2 -C 5 heterocycloalkenyl) , or two
- heterocycloalkyl radicals include, but are not limited to, aziridinyl, azetidinyl, oxetanyl, dioxolanyl, thienyl [1, 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
- heterocycloalkyl also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides, and the oligosaccharides.
- heterocycloalkyls have from 2 to 10 carbons in the ring. It is understood that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including the heteroatoms) that make up the heterocycloalkyl (i.e. skeletal atoms of the heterocycloalkyl ring) .
- the heterocycloalkyl is a 3-to 8-membered heterocycloalkyl.
- the heterocycloalkyl is a 3-to 7-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3-to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 4-to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 5-to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3-to 8-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3-to 7-membered heterocycloalkenyl.
- the heterocycloalkyl is a 3-to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 4-to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 5-to 6-membered heterocycloalkenyl.
- a heterocycloalkyl may be optionally substituted as described below, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
- the heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
- the heterocycloalkyl is optionally substituted with halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe. In some embodiments, the heterocycloalkyl is optionally substituted with halogen.
- Heteroaryl refers to a 5-to 14-membered ring system radical comprising one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, and sulfur, and at least one aromatic ring.
- the heteroaryl comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur.
- the heteroaryl comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen.
- the heteroaryl comprises one to three nitrogens.
- the heteroaryl comprises one or two nitrogens.
- the heteroaryl comprises one nitrogen.
- the heteroaryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the heteroaryl is bonded through an aromatic ring atom) or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heteroaryl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized.
- the heteroaryl is a 5-to 10-membered heteroaryl.
- the heteroaryl is a 5-to 6-membered heteroaryl.
- the heteroaryl is a 6-membered heteroaryl.
- the heteroaryl is a 5-membered heteroaryl.
- examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo [b] [1, 4] dioxepinyl, 1, 4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl) , benzotriazolyl, benzo [4, 6] imidazo [1, 2-a] pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, di
- a heteroaryl may be optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
- the heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
- the heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe. In some embodiments, the heteroaryl is optionally substituted with halogen.
- an optionally substituted group may be un-substituted (e.g., -CH 2 CH 3 ) , fully substituted (e.g., -CF 2 CF 3 ) , mono-substituted (e.g., -CH 2 CH 2 F) or substituted at a level anywhere in-between fully substituted and mono-substituted (e.g., -CH 2 CHF 2 , -CH 2 CF 3 , -CF 2 CH 3 , -CFHCHF 2 , etc. ) .
- any substituents described should generally be understood as having a maximum molecular weight of about 1,000 daltons, and more typically, up to about 500 daltons.
- one or more when referring to an optional substituent means that the subject group is optionally substituted with one, two, three, four, or more substituents. In some embodiments, the subject group is optionally substituted with one, two, three or four substituents. In some embodiments, the subject group is optionally substituted with one, two, or three substituents. In some embodiments, the subject group is optionally substituted with one or two substituents. In some embodiments, the subject group is optionally substituted with one substituent. In some embodiments, the subject group is optionally substituted with two substituents.
- an “effective amount” or “therapeutically effective amount” refers to an amount of a compound administered to a mammalian subject, either as a single dose or as part of a series of doses, which is effective to produce a desired therapeutic effect.
- treat, ” “treating” or “treatment, ” as used herein, include alleviating, abating, or ameliorating at least one symptom of a disease or condition, preventing additional 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.
- a “disease or disorder associated with HPK1” or, alternatively, “a HPK1-mediated disease or disorder” means any disease or other deleterious condition in which HPK1, or a mutant thereof, is known or suspected to play a role.
- HPK1 antagonist or a “HPK1 inhibitor” is a molecule that reduces, inhibits, or otherwise diminishes one or more of the biological activities of HPK1 (e.g., serine/threonine kinase activity, recruitment to the TCR complex upon TCR activation, interaction with a protein binding partner, such as SLP76) .
- Antagonism using the HPK1 antagonist does not necessarily indicate a total elimination of the HPK1 activity.
- the activity could decrease by a statistically significant amount including, for example, a decrease of at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 95%or 100%of the activity of HPK1 compared to an appropriate control.
- the HPK1 antagonist reduces, inhibits, or otherwise diminishes the serine/threonine kinase activity of HPK1.
- the HPK1 antagonist reduces, inhibits, or otherwise diminishes the HPK1-mediated phosphorylation of SLP76 and/or Gads.
- the presently disclosed compounds bind directly to HPK1 and inhibit its kinase activity.
- Described herein are compounds, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof useful in the treatment of a disease or disorder associated with HPK1.
- Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
- R 1 on the same carbon are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R 1a ;
- R 1 on the different atoms are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R 1a ;
- R 1a on the same carbon are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R;
- R 1a on the different atoms are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R;
- n 0-6;
- L is -O-, -S-, or -NR 2 -;
- R 2 is hydrogen, -CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, or heterocycloalkyl;
- W is N or CR W ;
- Z is N or CR Z ;
- X is C (R X ) 2 , O, S, or NR X1
- Y is C (R Y ) 2 , O, S, or NR Y1 ;
- X is CR X or N
- Y is CR Y or N
- R X1 is hydrogen, -CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, or heterocycloalkyl;
- R Y1 is hydrogen, -CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, or heterocycloalkyl;
- R 3 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, or heterocycloalkyl;
- Ring B is a bicyclic ring
- R 4 on the different atoms are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R 4a ;
- R 4a on the same carbon are taken together to form a cycloalkyl or heterocycloalkyl; each independently optionally substituted with one or more R;
- R 4a on the different atoms are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each independently optionally substituted with one or more R;
- n 0-6;
- each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene (cycloalkyl) , C 1 -C 6 alkylene (heterocycloalkyl) , C 1 -C 6 alkylene (aryl) , or C 1 -C 6 alkylene (heteroaryl) , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
- each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene (cycloalkyl) , C 1 -C 6 alkylene (heterocycloalkyl) , C 1 -C 6 alkylene (aryl) , or C 1 -C 6 alkylene (heteroaryl) , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
- R c and R d are each independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene (cycloalkyl) , C 1 -C 6 alkylene (heterocycloalkyl) , C 1 -C 6 alkylene (aryl) , or C 1 -C 6 alkylene (heteroaryl) , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
- R c and R d are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R;
- the compound is of Formula (Ia) :
- X is C (R X ) 2 or NR X1 ; and Y is C (R Y ) 2 or NR Y1 .
- X is C (R X ) 2 ; and Y is C (R Y ) 2 .
- X is C (R X ) 2 ; and Y is C (R Y ) 2 , O, S, or NR Y1 .
- X is C (R X ) 2 ; and Y is C (R Y ) 2 , O, or NR Y1 .
- X is C (R X ) 2 ; and Y is C (R Y ) 2 or O.
- the compound is of Formula (Ib) :
- the compound is of Formula (Ic) :
- the compound is of Formula (Id) :
- the compound is of Formula (Ie) :
- each R X is independently hydrogen, halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
- each R X is independently hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
- each R X is independently hydrogen or C 1 -C 6 alkyl.
- each R X is hydrogen.
- each R Y is independently hydrogen, halogen, -CN, -OH, -OR a , -SH, -SR a , -NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
- each R Y is independently hydrogen, halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
- each R Y is independently hydrogen or halogen.
- each R Y is independently hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I) , (Ia) - (Ic) , or (Ie) , each R Y is hydrogen.
- R X1 is hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (I) or (Ia) , R X1 is hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I) or (Ia) , R X1 is hydrogen.
- R Y1 is hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (I) or (Ia) , R Y1 is hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I) or (Ia) , R Y1 is hydrogen.
- Ring A is aryl or heteroaryl. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , Ring A is phenyl. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , Ring A is heteroaryl. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , Ring A is 5-or 6-membered heteroaryl. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , Ring A is 6-membered heteroaryl.
- Ring A is pyridinyl. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , Ring A is 5-membered heteroaryl. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , Ring A is bicyclic or tricyclic heteroaryl. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , Ring A is bicyclic heteroaryl. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , Ring A is tricyclic heteroaryl.
- each R 1 is independently halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R 1a .
- each R 1 is independently halogen, -OH, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 heteroalkyl, heterocycloalkyl, or heteroaryl; wherein each alkyl, heterocycloalkyl, and heteroaryl is independently optionally substituted with one or more R 1a .
- each R 1 is independently C 1 -C 6 alkyl or heterocycloalkyl; wherein each alkyl and heterocycloalkyl is independently optionally substituted with one or more R 1a .
- each R 1 is independently heterocycloalkyl optionally substituted with one or more R 1a .
- two R 1 on the same atom are taken together to form an oxo.
- two R 1 on the same carbon are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R 1a .
- two R 1 on the different atoms are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R 1a .
- each R 1a is independently cycloalkyl or heterocycloalkyl; wherein each cycloalkyl and heterocycloalkyl is independently optionally substituted with one or more R.
- each R 1a is independently heterocycloalkyl; optionally substituted with one or more R.
- the heterocycloalkyl is a bicyclic heterocycloalkyl (e.g., a spiro cyclic ring) .
- each R 1a is independently -NR c R d .
- two R 1a on the same atom are taken together to form an oxo.
- two R 1a on the same carbon are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R.
- two R 1a on the different atoms are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R.
- n is 1-4. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , n is 2-4. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , n is 1 or 2. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , n is 0. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , n is 1. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , n is 2. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , n is 3.
- At least two R 1 independently comprises a cyclic group. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , two R 1 each independently comprises a cyclic group. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , at least two R 1 are independently selected from a cyclic group. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , at least an R 1 comprises a substituted cyclic group.
- At least one R 1 comprises a halogen substituted cyclic group. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , at least one R 1 comprises a halogen (e.g., fluoro) substituted heterocycloalkyl. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , at least one R 1 comprises a halogen (e.g., fluoro) substituted cycloalkyl.
- Ring E is cycloalkyl or heterocycloalkyl
- p 0, 1, 2, 3, or 4.
- Ring E is cycloalkyl
- Ring E is heterocycloalkyl. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , Ring E is a monocyclic heterocycloalkyl. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , Ring E is a bicyclic heterocycloalkyl. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , Ring E is a pyrrolidinyl.
- each R 5 is independently halogen, -CN, -OH, -OCF 3 , -OCClF 2 , -NH 2 , -NHC 1 -C 3 alkyl, -N (C 1 -C 3 alkyl) 2 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, or C 3 -C 6 cycloalkyl.
- each R 5 is independently halogen, -CN, -OH, -NH 2 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , each R 5 is independently halogen, -OH, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy.
- each R 5 is independently halogen, -OH, or C 1 -C 6 alkoxy. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , each R 5 is independently halogen.
- p is 0, 1, or 2. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , p is 0 or 1. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , p is 1 or 2. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , p is 0. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , p is 1. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , p is 2.
- a compound of Formula (I) or (Ia) - (Ie) is In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , is In some embodiments of a compound of Formula (Id) or (Ie) , is In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , is not In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , is In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , is In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , is In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , is In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , is In some embodiments of a compound of Formula (I) or (Ia) - (I
- Ring B is a bicyclic heteroaryl or heterocycloalkyl. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , Ring B is a bicyclic heteroaryl. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , Ring B is a bicyclic partially saturated ring. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , Ring B is a bicyclic fully saturated ring. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , Ring B is a bicyclic unsaturated ring.
- each R 4 is independently halogen, -CN, -OH, -OR a , -SF 3 , - SF 5 , -NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; wherein each alkyl is independently optionally substituted with one or more R 4a .
- one or more R 4 is -OCF 3 , OCClF 2, -SCF 3 , or -SCClF 2 .
- each R 4 is independently halogen, -SF 3 , -SF 5 , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , each R 4 is independently halogen or C 1 -C 6 alkyl.
- two R 4 on the different atoms are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R 4a .
- two R 4 on the same carbon are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R 1a .
- each R 4a is independently halogen, -CN, -OH, -OR a , -SH, -SR a , -SF 3 , -SF 5 , -NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; wherein each alkyl is independently optionally substituted with one or more R.
- each R 4a is independently halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; wherein each alkyl is independently optionally substituted with one or more R.
- each R 4a is independently halogen, -CN, -OH, -OR a , -SH, -SR a , -SF 3 , -SF 5 , -NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
- each R 4a is independently halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
- m is 0-4. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , m is 0-2. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , m is 1 or 2. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , m is 0. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , m is 1. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , m is 2. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , m is 3.
- a compound of Formula (I) or (Ia) - (Ie) is In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , is In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , is In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , is
- R 3 is hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , R 3 is hydrogen.
- W is N. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , W is CR W .
- R W is hydrogen, halogen, -CN, -OH, -OR a (e.g., -OCF 3 or OCClF 2 ) , SH, -SR a (e.g., -SCF 3 or -SCClF 2 ) , -SF 3 , -SF 5 , -NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
- -OR a e.g., -OCF 3 or OCClF 2
- SH e.g., -SR a (e.g., -SCF 3 or -SCClF 2 )
- -SF 3 e.g., -SF 3 , -SF 5 , -NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
- R W is hydrogen, halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , R W is hydrogen.
- Z is N. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , Z is CR Z .
- R Z is hydrogen, halogen, -CN, -OH, -OR a (e.g., -OCF 3 or OCClF 2 ) , SH, -SR a (e.g., -SCF 3 or -SCClF 2 ) , -SF 3, -SF 5, -NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
- -OR a e.g., -OCF 3 or OCClF 2
- SH e.g., -SR a (e.g., -SCF 3 or -SCClF 2 )
- -SF 3 e.g., -SF 3 or -SCClF 2
- R Z is hydrogen, halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , R Z is hydrogen.
- L is -O-. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , L is -S-. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , L is -NR 2 -.
- R 2 is hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , R 2 is C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , R 2 is hydrogen.
- Ring C is heterocycloalkyl or heteroaryl
- R 1 on the same carbon are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R 1a ;
- R 1 on the different atoms are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R 1a ;
- R 1a on the same carbon are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R;
- R 1a on the different atoms are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R;
- n 0-6;
- L is -O-, -S-, or -NR 2 -;
- R 2 is hydrogen, -CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, or heterocycloalkyl;
- W is N or CR W ;
- Z is N or CR Z ;
- X is C (R X ) 2 , O, S, or NR X1
- Y is C (R Y ) 2 , O, S, or NR Y1 ;
- X is CR X or N
- Y is CR Y or N
- R X1 is hydrogen, -CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, or heterocycloalkyl;
- R Y1 is hydrogen, -CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, or heterocycloalkyl;
- R 3 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, or heterocycloalkyl;
- Ring D is a 3-to 5-membered ring
- R 4 on the different atoms are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R 4a ;
- R 4a on the same carbon are taken together to form a cycloalkyl or heterocycloalkyl; each independently optionally substituted with one or more R;
- R 4a on the different atoms are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each independently optionally substituted with one or more R;
- n 0-6;
- each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene (cycloalkyl) , C 1 -C 6 alkylene (heterocycloalkyl) , C 1 -C 6 alkylene (aryl) , or C 1 -C 6 alkylene (heteroaryl) , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
- each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene (cycloalkyl) , C 1 -C 6 alkylene (heterocycloalkyl) , C 1 -C 6 alkylene (aryl) , or C 1 -C 6 alkylene (heteroaryl) , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
- R c and R d are each independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene (cycloalkyl) , C 1 -C 6 alkylene (heterocycloalkyl) , C 1 -C 6 alkylene (aryl) , or C 1 -C 6 alkylene (heteroaryl) , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
- R c and R d are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R;
- the compound is not
- the compound is of Formula (IIa) :
- X is C (R X ) 2 or NR X1 ; and Y is C (R Y ) 2 or NR Y1 .
- X is C (R X ) 2 ; and Y is C (R Y ) 2 .
- X is C (R X ) 2 ; and Y is C (R Y ) 2 , O, S, or NR Y1 .
- X is C (R X ) 2 ; and Y is C (R Y ) 2 , O, or NR Y1 .
- X is C (R X ) 2 ; and Y is C (R Y ) 2 or O.
- the compound is of Formula (IIb) :
- the compound is of Formula (IIc) :
- the compound is of Formula (IId) :
- the compound is of Formula (IIe) :
- each R X is independently hydrogen, halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
- each R X is independently hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
- each R X is independently hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (II) or (IIa) - (IId) , each R X is hydrogen.
- each R Y is independently hydrogen, halogen, -CN, -OH, -OR a , -SH, -SR a , -NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
- each R Y is independently hydrogen, halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
- each R Y is independently hydrogen or halogen.
- each R Y is independently hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (II) , (IIa) - (IIc) , or (IIe) , each R Y is hydrogen.
- R X1 is hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (II) or (IIa) , R X1 is hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (II) or (IIa) , R X1 is hydrogen.
- R Y1 is hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (II) or (IIa) , R Y1 is hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (II) or (IIa) , R Y1 is hydrogen.
- Ring C is heteroaryl. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , Ring C is 5-or 6-membered heteroaryl. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , Ring C is 6-membered heteroaryl. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , Ring C is pyridinyl.
- Ring C is bicyclic or tricyclic heteroaryl. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , Ring C is bicyclic heteroaryl. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , Ring C is tricyclic heteroaryl.
- each R 1 is independently halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R 1a .
- each R 1 is independently halogen, -OH, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 heteroalkyl, heterocycloalkyl, or heteroaryl; wherein each alkyl, heterocycloalkyl, and heteroaryl is independently optionally substituted with one or more R 1a .
- each R 1 is independently C 1 -C 6 alkyl or heterocycloalkyl; wherein each alkyl and heterocycloalkyl is independently optionally substituted with one or more R 1a .
- two R 1 on the same atom are taken together to form an oxo.
- two R 1 on the same carbon are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R 1a .
- two R 1 on the different atoms are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R 1a .
- each R 1a is independently cycloalkyl or heterocycloalkyl; wherein each cycloalkyl and heterocycloalkyl is independently optionally substituted with one or more R.
- each R 1a is independently heterocycloalkyl optionally substituted with one or more R.
- two R 1a on the same atom are taken together to form an oxo.
- two R 1a on the same carbon are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R.
- two R 1a on the different atoms are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R.
- n is 1-4. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , n is 1-3. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , n is 1 or 2. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , n is 2-4. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , n is 0.
- n is 1. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , n is 2. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , n is 3.
- At least two R 1 independently comprises a cyclic group. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , at least two R 1 each independently comprises a cyclic group. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , at least two R 1 are independently selected from a cyclic group. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , at least an R 1 comprises a substituted cyclic group.
- At least one R 1 comprises a halogen substituted cyclic group. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , at least one R 1 comprises a halogen (e.g., fluoro) substituted heterocycloalkyl. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , at least one R 1 comprises a halogen (e.g., fluoro) substituted cycloalkyl.
- Ring E is cycloalkyl or heterocycloalkyl
- p 0, 1, 2, 3, or 4.
- Ring E is cycloalkyl.
- Ring E is heterocycloalkyl. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , Ring E is a monocyclic heterocycloalkyl. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , Ring E is a bicyclic heterocycloalkyl. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , Ring E is a pyrrolidinyl.
- each R 5 is independently halogen, -CN, -OH, -OCF 3 , -OCClF 2 , -NH 2 , -NHC 1 -C 3 alkyl, -N (C 1 -C 3 alkyl) 2 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, or C 3 -C 6 cycloalkyl.
- each R 5 is independently halogen, -CN, -OH, -NH 2 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkyl.
- each R 5 is independently halogen, -OH, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy.
- each R 5 is independently halogen, -OH, or C 1 -C 6 alkoxy. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , each R 5 is independently halogen.
- p is 0, 1, or 2. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , p is 0 or 1. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , p is 1 or 2. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , p is 0. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , p is 1. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , p is 2.
- a compound of Formula (II) or (IIa) - (IIe) is In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , is not In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , is
- Ring D is a 5-membered ring.
- Ring D is cyclopropyl.
- Ring D is a 5-membered ring comprising 1 to 4 heteroatoms selected from the group consisting of O, S, or N.
- Ring D is a 5-membered ring comprising 1 to 3 heteroatoms selected from the group consisting of O or N.
- Ring D is a 5-membered ring comprising 1 to 3 heteroatoms that are N.
- Ring D is imidazolyl, pyrazolyl. or oxadiazolyl. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , Ring D is imidazolyl. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , Ring D is pyrazolyl.
- Ring D is not imidazolyl.
- one or more R 4 is -OCF 3 , OCClF 2, -SCF 3 , or -SCCl
- each R 4 is independently aryl or heteroaryl; wherein each aryl and heteroaryl is independently optionally substituted with one or more R 4a .
- two R 4 on the same carbon are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R 4a .
- two R 4 on the different atoms are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R 4a .
- each R 4a is independently halogen, -CN, -OH, -OR a , -SH, -SR a , -SF 3 , -SF 5 , -NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; wherein each alkyl is independently optionally substituted with one or more R.
- each R 4a is independently halogen, -CN, - OH, -OR a , -NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; wherein each alkyl is independently optionally substituted with one or more R.
- each R 4a is independently aryl.
- m is 0-4. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , m is 0-2. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , m is 1 or 2. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , m is 0. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , m is 1. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , m is 2.
- R 3 is hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , R 3 is hydrogen.
- W is N. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , W is CR W .
- R W is hydrogen, halogen, -CN, -OH, -OR a (e.g., -OCF 3 or OCClF 2 ) , SH, -SR a (e.g., -SCF 3 or -SCClF 2 ) , -SF 3, -SF 5, -NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
- R W is hydrogen, halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , R W is hydrogen.
- Z is N. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , Z is CR Z .
- R z is hydrogen, halogen, -CN, -OH, -OR a (e.g., -OCF 3 or OCClF 2 ) , SH, -SR a (e.g., -SCF 3 or -SCClF 2 ) , -SF 3, -SF 5, -NR c R d , C 1 - C 6 alkyl, or C 1 -C 6 haloalkyl.
- -OR a e.g., -OCF 3 or OCClF 2
- SH e.g., -SR a (e.g., -SCF 3 or -SCClF 2 )
- -SF 3 e.g., -SF 3 or -SCClF 2
- R Z is hydrogen, halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
- R Z is hydrogen.
- L is -O-. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , L is -S-. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , L is -NR 2 -.
- R 2 is hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , R 2 is C 1 -C 6 alkyl. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , R 2 is hydrogen.
- each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene (cycloalkyl) , C 1 -C 6 alkylene (heterocycloalkyl) , C 1 -C 6 alkylene (aryl) , or C 1 -C 6 alkylene (heteroaryl) ; wherein each alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R.
- each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or cycloalkyl, heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R.
- each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene (cycloalkyl) , C 1 -C 6 alkylene (heterocycloalkyl) , C 1 -C 6 alkylene (aryl) , or C 1 -C 6 alkylene (heteroaryl) .
- each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or cycloalkyl, heterocycloalkyl. In some embodiments of a compound disclosed herein, each R a is independently C 1 -C 6 alkyl or C 1 -C 6 haloalkyl. In some embodiments of a compound disclosed herein, each R a is independently C 1 -C 6 alkyl.
- each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene (cycloalkyl) , C 1 -C 6 alkylene (heterocycloalkyl) , C 1 -C 6 alkylene (aryl) , or C 1 -C 6 alkylene (heteroaryl) ; wherein each alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R.
- each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or cycloalkyl, heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R.
- each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene (cycloalkyl) , C 1 -C 6 alkylene (heterocycloalkyl) , C 1 -C 6 alkylene (aryl) , or C 1 -C 6 alkylene (heteroaryl) .
- each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or cycloalkyl, heterocycloalkyl. In some embodiments of a compound disclosed herein, each R b is independently hydrogen, C 1 -C 6 alkyl or C 1 -C 6 haloalkyl. In some embodiments of a compound disclosed herein, each R b is independently hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound disclosed herein, each R b is hydrogen. In some embodiments of a compound disclosed herein, each R b is independently C 1 -C 6 alkyl.
- each R c and R d are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene (cycloalkyl) , C 1 -C 6 alkylene (heterocycloalkyl) , C 1 -C 6 alkylene (aryl) , or C 1 -C 6 alkylene (heteroaryl) ; wherein each alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R.
- each R c and R d are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or cycloalkyl, heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R.
- each R c and R d are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene (cycloalkyl) , C 1 -C 6 alkylene (heterocycloalkyl) , C 1 -C 6 alkylene (aryl) , or C 1 -C 6 alkylene (heteroaryl) .
- each R c and R d are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or cycloalkyl, heterocycloalkyl. In some embodiments of a compound disclosed herein, each R c and R d are independently hydrogen, C 1 -C 6 alkyl or C 1 -C 6 haloalkyl. In some embodiments of a compound disclosed herein, each R c and R d are independently hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound disclosed herein, each R c and R d are hydrogen. In some embodiments of a compound disclosed herein, each R c and R d are independently C 1 -C 6 alkyl.
- R c and R d are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R.
- each R is independently halogen, -CN, -OH, -SH, -SF 3 , -SF 5 , -SCF 3 , -SCClF 2, -NH 2 , -NHCH 3 , -N (CH 3 ) 2 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, or C 3 -C 6 cycloalkyl; or two R on the same atom form an oxo.
- each R is independently halogen, -CN, -OH, -NH 2 , -NHCH 3 , -N (CH 3 ) 2 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, or C 3 -C 6 cycloalkyl; or two R on the same atom form an oxo.
- each R is independently halogen, -CN, -OH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkyl; or two R on the same atom form an oxo. In some embodiments of a compound disclosed herein, each R is independently halogen, -CN, -OH, or C 1 -C 6 alkyl; or two R on the same atom form an oxo. In some embodiments of a compound disclosed herein, each R is independently halogen, -OH, or C 1 -C 6 alkyl. In some embodiments of a compound disclosed herein, each R is independently halogen or C 1 -C 6 alkyl. In some embodiments of a compound disclosed herein, each R is independently halogen.
- one or more of R, R 1 , R 1a , R 2 , R 3 , R 4 , R 4a , R 5 , R X , R X1 , R Y , R Y1 , R W , R Z , R a , R b , R c , and R d groups comprise deuterium at a percentage higher than the natural abundance of deuterium.
- one or more 1 H are replaced with one or more deuteriums in one or more of the following groups R, R 1 , R 1a , R 2 , R 3 , R 4 , R 4a , R 5 , R X , R X1 , R Y , R Y1 , R W , R Z , R a , R b , R c , and R d .
- the abundance of deuterium in each of R, R 1 , R 1a , R 2 , R 3 , R 4 , R 4a , R 5 , R X , R X1 , R Y , R Y1 , R W , R Z , R a , R b , R c , and R d is independently at least 1%, 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 100%by molar.
- one or more 1 H of Ring A, Ring B, Ring C, Ring D, or Ring E are replaced with one or more deuteriums.
- the compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is one of the compounds in Table 1 or Table 2.
- the compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is one of the compounds in Table 3.
- the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein possess one or more double bonds. The compounds presented herein include all cis, trans, syn, anti,
- Z) isomers as well as the corresponding mixtures thereof. In some situations, the compounds described herein possess one or more chiral centers and each center exists in the R configuration, or S configuration. The compounds described herein include all diastereomeric, enantiomeric, and epimeric forms as well as the corresponding mixtures thereof.
- mixtures of enantiomers and/or diastereoisomers, resulting from a single preparative step, combination, or interconversion are useful for the applications described herein.
- the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers and recovering the optically pure enantiomers.
- dissociable complexes are preferred.
- the diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.
- the diastereomers are separated by chiral chromatography, or preferably, by separation/resolution techniques based upon differences in solubility.
- the optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that would not result in racemization.
- the compounds described herein exist in their isotopically-labeled forms.
- the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds.
- the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds as pharmaceutical compositions.
- the compounds disclosed herein include isotopically-labeled compounds, which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
- isotopes examples include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, and chloride, such as 2 H (D) , 3 H, 13 C, 14 C, l5 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 Cl, respectively.
- Compounds described herein, and the pharmaceutically acceptable salts, solvates, or stereoisomers thereof which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention.
- isotopically-labeled compounds for example those into which radioactive isotopes such as 3 H and 14 C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3 H and carbon-14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability.
- the abundance of deuterium in each of the substituents disclosed herein is independently at least 1%, 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 100%by molar.
- one or more of the substituents disclosed herein comprise deuterium at a percentage higher than the natural abundance of deuterium.
- one or more 1 H are replaced with one or more deuteriums in one or more of the substituents disclosed herein.
- the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.
- the compounds described herein exist as their pharmaceutically acceptable salts.
- the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts.
- the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions.
- the compounds described herein possess acidic or basic groups and therefore react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt.
- these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein, or a solvate, or stereoisomer thereof, or by separately reacting a purified compound in its free form with a suitable acid or base, and isolating the salt thus formed.
- Examples of pharmaceutically acceptable salts include those salts prepared by reaction of the compounds described herein with a mineral, organic acid or inorganic base, such salts including, acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyn-1, 4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne-1, 6-dioate, hydroxybenzoate,
- the compounds described herein can be prepared as pharmaceutically acceptable salts formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, including, but not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid metaphosphoric acid, and the like; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3- (4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1, 2-ethanedis
- other acids such as oxalic, while not in themselves pharmaceutically acceptable, are employed in the preparation of salts useful as intermediates in obtaining the compounds disclosed herein, solvate, or stereoisomer thereof and their pharmaceutically acceptable acid addition salts.
- those compounds described herein which comprise a free acid group react with a suitable base, such as the hydroxide, carbonate, bicarbonate, sulfate, of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine.
- a suitable base such as the hydroxide, carbonate, bicarbonate, sulfate, of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine.
- Representative salts include the alkali or alkaline earth salts, like lithium, sodium, potassium, calcium, and magnesium, and aluminum salts and the like.
- bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N + (C 1-4 alkyl) 4 , and the like.
- Organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like. It should be understood that the compounds described herein also include the quaternization of any basic nitrogen-containing groups they contain. In some embodiments, water or oil-soluble or dispersible products are obtained by such quaternization.
- the compounds described herein exist as solvates.
- the invention provides for methods of treating diseases by administering such solvates.
- the invention further provides for methods of treating diseases by administering such solvates as pharmaceutical compositions.
- Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and, in some embodiments, are formed with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein can be conveniently prepared or formed during the processes described herein. By way of example only, hydrates of the compounds described herein can be conveniently prepared from an aqueous/organic solvent mixture, using organic solvents including, but not limited to, dioxane, tetrahydrofuran or methanol.
- the compounds provided herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.
- Tautomers are compounds that are interconvertible by migration of a hydrogen atom, accompanied by a switch of a single bond and adjacent double bond. In bonding arrangements where tautomerization is possible, a chemical equilibrium of the tautomers will exist. All tautomeric forms of the compounds disclosed herein are contemplated. The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH.
- HPK1 also referred to as mitogen activated protein kinase 1 or MAP4K1
- MAP4K1 mitogen activated protein kinase 1
- HPK1 functions as a MAP4K by phosphorylating and activating MAP3K proteins, including MEKK1, MLK3 and TAK1, leading to the activation of the MAPK Jnk.
- the presently disclosed compounds bind directly to HPK1 and inhibit its kinase activity. In some embodiments, the presently disclosed compounds reduce, inhibit, or otherwise diminish the HPK1-mediated phosphorylation of SLP76 and/or Gads.
- the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof are used in a method for inhibiting HPK1.
- Such methods comprise contacting HPK1 with an effective amount of a presently disclosed compound.
- contact is intended bringing the compound within close enough proximity to an isolated HPK1 enzyme or a cell expressing HPK1 (e.g., T cell, B cell, dendritic cell) such that the compound is able to bind to and inhibit the activity of HPK1.
- the compound can be contacted with HPK1 in vitro or in vivo via administration of the compound to a subject.
- any method known in the art to measure the kinase activity of HPK1 may be used to determine if HPK1 has been inhibited, including in vitro kinase assays, immunoblots with antibodies specific for phosphorylated targets of HPK1, such as SLP76 and Gads, or the measurement of a downstream biological effect of HPK1 kinase activity, such as the recruitment of 14-3-3 proteins to phosphorylated SLP7 and Gads, release of the SLP76-Gads-14-3-3 complex from LAT-containing microclusters, or T or B cell activation.
- in vitro kinase assays immunoblots with antibodies specific for phosphorylated targets of HPK1, such as SLP76 and Gads
- a downstream biological effect of HPK1 kinase activity such as the recruitment of 14-3-3 proteins to phosphorylated SLP7 and Gads, release of the SLP76-Gads-14-3-3 complex from LAT-containing microclusters, or
- the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof are used to treat a HPK1-dependent disorder.
- a “HPK1-dependent disorder” is a pathological condition in which HPK1 activity is necessary for the genesis or maintenance of the pathological condition.
- the HPK1-dependent disorder is cancer.
- the compounds disclosed herein are used in enhancing an immune response in a subject in need thereof.
- enhancing an immune response refers to an improvement in any immunogenic response to an antigen.
- improvements in an immunogenic response to an antigen include enhanced maturation or migration of dendritic cells, enhanced activation of T cells (e.g., CD4 T cells, CD8 T cells) , enhanced T cell (e.g., CD4 T cell, CD8 T cell) proliferation, enhanced B cell proliferation, increased survival of T cells and/or B cells, improved antigen presentation by antigen presenting cells (e.g., dendritic cells) , improved antigen clearance, increase in production of cytokines by T cells (e.g., interleukin-2) , increased resistance to prostaglandin E2-induced immune suppression, and enhanced priming and/or cytolytic activity of CD8 T cells.
- the CD8 T cells in the subject have enhanced priming, activation, proliferation and/or cytolytic activity relative to prior to the administration of the compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
- the CD8 T cell priming is characterized by elevated CD44 expression and/or enhanced cytolytic activity in CD8 T cells.
- the CD8 T cell activation is characterized by an elevated frequency of ⁇ -IFN+ CD8 T cells.
- the CD8 T cell is an antigen-specific T-cell.
- the antigen presenting cells in the subject have enhanced maturation and activation relative to prior to the administration of a compound disclosed herein.
- the antigen presenting cells are dendritic cells.
- the maturation of the antigen presenting cells is characterized by an increased frequency of CD83+ dendritic cells.
- the activation of the antigen presenting cells is characterized by elevated expression of CD80 and CD86 on dendritic cells.
- the serum levels of cytokine IL-10 and/or chemokine IL-8, a human homolog of murine KC, in the subject are reduced relative to prior to the administration of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
- HPK1 activation which functions as a negative regulator of TCR-induced AP-1 response pathway. It is believed that HPK1 negatively regulates T cell activation by reducing the persistence of signaling microclusters by phosphorylating SLP76 at Ser376 and Gads at Thr254, which leads to the recruitment of 14-3-3 proteins that bind to the phosphorylated SLP76 and Gads, releasing the SLP76-Gads-14-3-3 complex from LAT-containing microclusters, which leads to T cell dysfunction, including anergy and exhaustion.
- disfunction in the context of immune dysfunction, refers to a state of reduced immune responsiveness to antigenic stimulation.
- the term includes the common elements of both exhaustion and/or anergy in which antigen recognition may occur, but the ensuing immune response is ineffective to control infection or tumor growth.
- disfunctional also includes refractory or unresponsive to antigen recognition, specifically, impaired capacity to translate antigen recognition into downstream T-cell effector functions, such as proliferation, cytokine production (e.g., IL-2, ⁇ -IFN) and/or target cell killing.
- cytokine production e.g., IL-2, ⁇ -IFN
- T cell anergy refers to the state of unresponsiveness to antigen stimulation resulting from incomplete or insufficient signals delivered through the T-cell receptor (e.g. increase in intracellular Ca+2 in the absence of ras-activation) .
- T cell anergy can also result upon stimulation with antigen in the absence of co-stimulation, resulting in the cell becoming refractory to subsequent activation by the antigen even in the context of costimulation.
- the unresponsive state can often be overridden by the presence of Interleukin-2. Anergic T-cells do not undergo clonal expansion and/or acquire effector functions.
- exhaustion refers to T cell exhaustion as a state of T cell dysfunction that arises from sustained TCR signaling that occurs during many chronic infections and cancer. It is distinguished from anergy in that it arises not through incomplete or deficient signaling, but from sustained signaling. It is defined by poor effector function, sustained expression of inhibitory receptors and a transcriptional state distinct from that of functional effector or memory T cells. Exhaustion prevents optimal control of infection and tumors. Exhaustion can result from both extrinsic negative regulatory pathways (e.g., immunoregulatory cytokines) as well as cell intrinsic negative regulatory (costimulatory) pathways (PD-1, B7-H3, B7-H4, etc. ) .
- extrinsic negative regulatory pathways e.g., immunoregulatory cytokines
- costimulatory costimulatory
- administration of the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, results in an enhancement of T cell function.
- Enhancing T cell function means to induce, cause, or stimulate a T cell to have a sustained or amplified biological function, or renew or reactivate exhausted or inactive T cells.
- enhancing T cell function include: increased secretion of cytokines (e.g., ⁇ -interferon, IL-2, IL-12, and TNF ⁇ ) , increased proliferation, increased antigen responsiveness (e.g., viral, pathogen, or tumor clearance) relative to such levels before the intervention, and increased effector granule production by CD8 T cells, such as granzyme B.
- the level of enhancement is as least 50%, alternatively 60%, 70%, 80%, 90%, 100%, 120%, 150%, 200%. The manner of measuring this enhancement is known to one of ordinary skill in the art.
- T cell dysfunctional disorder is a disorder or condition of T cells characterized by decreased responsiveness to antigenic stimulation.
- a T cell dysfunctional disorder is a disorder that is specifically associated with increased kinase activity of HPK1.
- a T cell dysfunctional disorder is one in which T cells are anergic or have decreased ability to secrete cytokines, proliferate, or execute cytolytic activity.
- the decreased responsiveness results in ineffective control of a pathogen or tumor expressing an immunogen. Examples of T cell dysfunctional disorders characterized by T-cell dysfunction include unresolved acute infection, chronic infection, and tumor immunity.
- the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof are used in treating conditions where enhanced immunogenicity is desired, such as increasing tumor immunogenicity for the treatment of cancer.
- Immunogenicity refers to the ability of a particular substance to provoke an immune response. Tumors are immunogenic and enhancing tumor immunogenicity aids in the clearance of the tumor cells by the immune response.
- Tumor immunity refers to the process in which tumors evade immune recognition and clearance. Thus, as a therapeutic concept, tumor immunity is “treated” when such evasion is attenuated, and the tumors are recognized and attacked by the immune system. Examples of tumor recognition include tumor binding, tumor shrinkage and tumor clearance.
- a method of treating cancer in a subject in need thereof comprising administering to the subject an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
- the subject has melanoma.
- the melanoma may be at early stage or at late stage.
- the subject has colorectal cancer.
- the colorectal cancer may be at early stage or at late stage.
- the subject has non-small cell lung cancer.
- the non-small cell lung cancer may be at early stage or at late stage.
- the subject has pancreatic cancer.
- the pancreatic cancer may be at early stage or late state.
- the subject has a hematological malignancy.
- the hematological malignancy may be at early stage or late stage.
- the subject has ovarian cancer.
- the ovarian cancer may be at early stage or at late stage.
- the subject has breast cancer.
- the breast cancer may be at early stage or at late stage.
- the subject has renal cell carcinoma.
- the renal cell carcinoma may be at early stage or at late stage.
- the cancer has elevated levels of T-cell infiltration.
- provided herein is a method of treating a viral infection in a subject in need thereof comprising administering to the subject an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
- the viral infection is a chronic viral infection.
- provided herein is a method of increasing the efficacy of vaccination in a patient comprising administering to the patient a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or a pharmaceutical composition disclosed herein.
- compositions containing the compound (s) described herein are administered for therapeutic treatments.
- the compositions are administered to a patient already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest at least one of the symptoms of the disease or condition. Amounts effective for this use depend on the severity and course of the disease or condition, previous therapy, the patient’s health status, weight, and response to the drugs, and the judgment of the treating physician. Therapeutically effective amounts are optionally determined by methods including, but not limited to, a dose escalation and/or dose ranging clinical trial.
- the administration of the compounds are administered chronically, that is, for an extended period of time, including throughout the duration of the patient’s life in order to ameliorate or otherwise control or limit the symptoms of the patient’s disease or condition.
- a maintenance dose is administered if necessary. Subsequently, in specific embodiments, the dosage, or the frequency of administration, or both, is reduced, as a function of the symptoms.
- the amount of a given agent that corresponds to such an amount varies depending upon factors such as the particular compound, disease condition and its severity, the identity (e.g., weight, sex) of the subject or host in need of treatment, but nevertheless is determined according to the particular circumstances surrounding the case, including, e.g., the specific agent being administered, the route of administration, the condition being treated, and the subject or host being treated.
- doses employed for adult human treatment are typically in the range of 0.01 mg-5000 mg per day.
- the daily dosages appropriate for the compound described herein, or a pharmaceutically acceptable salt thereof are from about 0.01 to about 50 mg/kg per body weight.
- the daily and unit dosages are altered depending on a number of variables including, but not limited to, the activity of the compound used, the disease or condition to be treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition being treated, and the judgment of the practitioner.
- Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ophthalmic, pulmonary, transmucosal, transdermal, vaginal, otic, nasal, and topical administration.
- parenteral delivery includes intramuscular, subcutaneous, intravenous, intramedullary injections, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injections.
- a compound as described herein is administered in a local rather than systemic manner, for example, via injection of the compound directly into an organ, often in a depot preparation or sustained release formulation.
- long acting formulations are administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection.
- the drug is delivered in a targeted drug delivery system, for example, in a liposome coated with organ specific antibody.
- the liposomes are targeted to and taken up selectively by the organ.
- the compound as described herein is provided in the form of a rapid release formulation, in the form of an extended release formulation, or in the form of an intermediate release formulation.
- the compounds described herein are administered to a subject in need thereof, either alone or in combination with pharmaceutically acceptable carriers, excipients, or diluents, in a pharmaceutical composition, according to standard pharmaceutical practice. In some embodiments, the compounds described herein are administered to animals.
- compositions comprising a compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and at least one pharmaceutically acceptable excipient.
- Pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable excipients that facilitate processing of the active compounds into preparations that can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen.
- a summary of pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995) ; Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A.
- the pharmaceutically acceptable excipient is selected from carriers, binders, filling agents, suspending agents, flavoring agents, sweetening agents, disintegrating agents, dispersing agents, surfactants, lubricants, colorants, diluents, solubilizers, moistening agents, plasticizers, stabilizers, penetration enhancers, wetting agents, anti-foaming agents, antioxidants, preservatives, and any combinations thereof.
- the pharmaceutical formulations described herein include, but are not limited to, aqueous liquid dispersions, liquids, gels, syrups, elixirs, slurries, suspensions, self-emulsifying dispersions, solid solutions, liposomal dispersions, aerosols, solid oral dosage forms, powders, immediate release formulations, controlled release formulations, fast melt formulations, tablets, capsules, pills, powders, dragees, effervescent formulations, lyophilized formulations, delayed release formulations, extended release formulations, pulsatile release formulations, multiparticulate formulations, and mixed immediate and controlled release formulations.
- Disclosed herein are methods of treating a disease or disorder associated with HPK1 using a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, in combination with an additional therapeutic agent.
- the additional therapeutic agent is administered at the same time as the compound disclosed herein. In some embodiments, the additional therapeutic agent and the compound disclosed herein are administered sequentially. In some embodiments, the additional therapeutic agent is administered less frequently than the compound disclosed herein. In some embodiments, the additional therapeutic agent is administered more frequently than the compound disclosed herein. In some embodiments, the additional therapeutic agent is administered prior than the administration of the compound disclosed herein. In some embodiments, the additional therapeutic agent is administered after the administration of the compound disclosed herein.
- the additional therapeutic agent is an anti-cancer agent.
- Step 1 Procedure for preparation of 1-2
- Step 2 Procedure for preparation of 1-3
- Step 3 Procedure for preparation of 1-4
- Step 5 Procedure for preparation of 1-6
- Step 1 Procedure for preparation of 2-2
- Step 3 Procedure for preparation of 2-4
- Step 4 Procedure for preparation of 3-5
- Step 5 Procedure for preparation of 3-6
- Step 4 Procedure for preparation of 4-6
- Step 1 Procedure for preparation of 5-2
- Step 3 Procedure for preparation of 6-3
- Step 12 Procedure for preparation of Example 15-P1 an d 15-P2
- the 15-11 (16 mg, 0.033 mmol) was further purified by pre-SFC (column: DAICEL CHIRALCEL OD (250mm*30mm, 10um) ; mobile phase: [0.1%NH 3 H 2 O ETOH] ; B%: 60%-60%, min) to afford two fractions.
- Step 1 Procedure for preparation of 20-1
- Step 5 Procedure for preparation of 24-5
- INT 24-4 (0.38 g, 1.21 mmol) in DCM (0.5 mL) being cooled to 0 °C was added TEA (0.34 mL, 2.42 mmol) , followed by MsCl (0.11 mL, 1.45 mmol) dropwise. After additional, the resulting mixture was stirred at 20 °C for 30 mins under N 2 . The reaction mixture was concentrated to afford the INT 24-5 (0.42 g, 1.06 mmol, 87.5%) as a yellow solid, which was used in next step without further purification.
- Example A The data for Example A is shown in Table 4.
- HPK1 IC 50 (nM) 0 ⁇ A ⁇ 100; 100 ⁇ B ⁇ 500; 500 ⁇ C ⁇ 5000
- Example B Cellar p-SLP76 assay
- Example B Seed cells into the culture plate, then add compounds into the cells, incubate at 37 °C &5%CO 2 ; Add CD3 antibody into cells, incubate at 37 °C &5%CO 2 . After that lyse cell with lysis buffer on ice, transfer the cell lysis into a 96-well plate and store at -80 °C. p-SLP76 was detected by ELISA Kit. The data for Example B is shown in Table 5.
- p-SLP76 IC 50 (nM) 0 ⁇ A ⁇ 100; 100 ⁇ B ⁇ 500; 500 ⁇ C ⁇ 5000; D>5000
- Example C Cellar IL-2 assay
- Human Pan T cells were isolated from PBMC, then coat the plate with anti-human CD3, seed cells into the culture plate, add compounds into the cells, incubate at 37°C &5%CO 2 . Collect supernatant after 24 hours and store it in -80 °C, after that, IL-2 was detected by ELISA Kit.
- the data for Example C is shown in Table 6.
- IL-2 IC 50 (nM) 0 ⁇ A ⁇ 300; 300 ⁇ B ⁇ 1000; C>1000
Abstract
Described herein are HPK1inhibitors and pharmaceutical compositions comprising said inhibitors. The subject compounds and compositions are useful for the treatment of a disease or disorder associated with HPK1.
Description
CROSS-REFERENCE
This patent application claims the benefit of International Application No. PCT/CN2022/085581, filed April 7, 2022; which is incorporated herein by reference in its entirety.
A new cancer treatment paradigm has emerged that harnesses the patient's own immune system to overcome immunoevasive strategies utilized by many cancers and to enhance anti-tumor immunity. One such strategy is to inhibit negative regulators of immune responses that normally function to maintain peripheral tolerance, allowing tumor antigens to be recognized as non-self entities.
The hematopoietic progenitor kinase 1 (HPK1) is an example of a negative regulator of dendritic cell activation, and T and B cell responses that can be targeted to enhance anti-tumor immunity. HPK1 is expressed predominantly by hematopoietic cells, including early progenitors. In T cells, it is believed that HPK1 negatively regulates T cell activation by reducing the persistence of signaling microclusters by phosphorylating SLP76 at Ser376 and Gads at Thr254, which leads to the recruitment of 14-3-3 proteins that bind to the phosphorylated SLP76 and Gads, releasing the SLP76-Gads-14-3-3 complex from LAT-containing microclusters. HPK1 can also become activated in response to prostaglandin E2, which is often secreted by tumors, contributing to the escape of tumor cells from the immune system.
There is a need for novel and potent HPK1 antagonists.
SUMMARY
Disclosed herein is a compound of Formula (I) , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
wherein:
Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R1 is independently halogen, -CN, -NO2, -OH, -ORa, -OC (=O) Ra, -OC (=O) ORb, -OC (=O) NRcRd, -SH, -SRa, -SF3, -SF5, -S (=O) Ra, -S (=O) 2Ra, -S (=O) 2NRcRd, -NRcRd, -NRbC (=O) NRcRd, -NRbC (=O) Ra, -NRbC (=O) ORb, -NRbS (=O) 2Ra, -P (=O) RaNRcRd, -P (=O) RaORb, -P (=O) RaRb, -C (=O) Ra, -C (=O) ORb, -C (=O) NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R1a;
or two R1 on the same atom are taken together to form an oxo;
or two R1 on the same carbon are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R1a;
or two R1 on the different atoms are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R1a;
each R1a is independently halogen, -CN, -NO2, -OH, -ORa, -OC (=O) Ra, -OC (=O) ORb, -OC (=O) NRcRd, -SH, -SRa, -SF3, -SF5, -S (=O) Ra, -S (=O) 2Ra, -S (=O) 2NRcRd, -NRcRd, -NRbC (=O) NRcRd, -NRbC (=O) Ra, -NRbC (=O) ORb, -NRbS (=O) 2Ra, -P (=O) RaNRcRd, -P (=O) RaORb, -P (=O) RaRb, -C (=O) Ra, -C (=O) ORb, -C (=O) NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
or two R1a on the same atom are taken together to form an oxo;
or two R1a on the same carbon are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R;
or two R1a on the different atoms are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R;
n is 0-6;
L is -O-, -S-, or -NR2-;
R2 is hydrogen, -CN, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl;
W is N or CRW;
RW is hydrogen, -SH, -SRa, -SF3, -SF5, halogen, -CN, -OH, -ORa, -NRcRd, -P (=O) RaNRcRd, -P (=O) RaORb, -P (=O) RaRb, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl;
Z is N or CRZ;
RZ is hydrogen, -SH, -SRa, -SF3, -SF5, halogen, -CN, -OH, -ORa, -NRcRd, -P (=O) RaNRcRd, -P (=O) RaORb, -P (=O) RaRb, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl;
is a single bond; X is C (RX) 2, O, S, or NRX1; and Y is C (RY) 2, O, S, or NRY1;
oris a double bond; X is CRX or N; and Y is CRY or N;
each RX is independently hydrogen, -SH, -SRa, -SF3, -SF5, halogen, -CN, -OH, -ORa, -NRcRd, -P (=O) RaNRcRd, -P (=O) RaORb, -P (=O) RaRb, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl;
RX1 is hydrogen, -CN, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl;
each RY is independently hydrogen, -SH, -SRa, -SF3, -SF5, halogen, -CN, -OH, -ORa, -NRcRd, -P (=O) RaNRcRd, -P (=O) RaORb, -P (=O) RaRb, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl;
RY1 is hydrogen, -CN, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl;
R3 is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl;
Ring B is a bicyclic ring;
each R4 is independently halogen, -CN, -NO2, -OH, -ORa, -OC (=O) Ra, -OC (=O) ORb, -OC (=O) NRcRd, -SH, -SRa, -SF3, -SF5, -S (=O) Ra, -S (=O) 2Ra, -S (=O) 2NRcRd, -NRcRd, -NRbC (=O) NRcRd, -NRbC (=O) Ra, -NRbC (=O) ORb, -NRbS (=O) 2Ra, -P (=O) RaNRcRd, -P (=O) RaORb, -P (=O) RaRb, -C (=O) Ra, -C (=O) ORb, -C (=O) NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R4a;
or two R4 on the same atom are taken together to form an oxo;
or two R4 on the different atoms are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R4a;
each R4a is independently halogen, -CN, -NO2, -OH, -ORa, -OC (=O) Ra, -OC (=O) ORb, -OC (=O) NRcRd, -SH, -SRa, -SF3, -SF5, -S (=O) Ra, -S (=O) 2Ra, -S (=O) 2NRcRd, -NRcRd, -NRbC (=O) NRcRd, -NRbC (=O) Ra, -NRbC (=O) ORb, -NRbS (=O) 2Ra, -P (=O) RaNRcRd, -P (=O) RaORb, -P (=O) RaRb, -C (=O) Ra, -C (=O) ORb, -C (=O) NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
or two R4a on the same atom are taken together to form an oxo;
or two R4a on the same carbon are taken together to form a cycloalkyl or heterocycloalkyl; each independently optionally substituted with one or more R;
or two R4a on the different atoms are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each independently optionally substituted with one or more R;
m is 0-6;
each Ra is independently C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene (cycloalkyl) , C1-C6alkylene (heterocycloalkyl) , C1-C6alkylene (aryl) , or C1-C6alkylene (heteroaryl) , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
each Rb is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene (cycloalkyl) , C1-C6alkylene (heterocycloalkyl) , C1-C6alkylene (aryl) , or C1-C6alkylene (heteroaryl) , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
Rc and Rd are each independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene (cycloalkyl) , C1-C6alkylene (heterocycloalkyl) , C1-C6alkylene (aryl) , or C1-C6alkylene (heteroaryl) , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
or Rc and Rd are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R; and
each R is independently halogen, -CN, -OH, -SH, -OCF3, -OCClF2, -SF3, -SF5, -SCF3, -SCClF2, -S (=O) C1-C3alkyl, -S (=O) 2C1-C3alkyl, -S (=O) 2NH2, -S (=O) 2NHC1-C3alkyl, -S (=O) 2N (C1-C3alkyl) 2, -NH2, -NHC1-C3alkyl, -N (C1-C3alkyl) 2, -P (=O) (C1-C3alkyl) N (C1-C3alkyl) 2, -P (=O) (C1-C3alkyl) O (C1-C3alkyl) , -P (=O) (C1-C3alkyl) 2, -C (=O) C1-C3alkyl, -C (=O) OH, -C (=O) OC1-C3alkyl, -C (=O) NH2, -C (=O) NHC1-C3alkyl, -C (=O) N (C1-C3alkyl) 2, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, or C3-C6cycloalkyl;
or two R on the same atom form an oxo;
or two R on the same carbon are taken together to form a cycloalkyl or heterocycloalkyl;
or two R on the different atoms are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl.
In some embodiments of a compound of Formula (I) , the compound is of Formula (Ia) :
In some embodiments of a compound of Formula (I) , the compound is of Formula (Ib) :
In some embodiments of a compound of Formula (I) , the compound is of Formula (Ic) :
In some embodiments of a compound of Formula (I) , the compound is of Formula (Id) :
In some embodiments of a compound of Formula (I) , the compound is of Formula (Ie) :
Also disclosed herein is a compound of Formula (II) , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
wherein:
Ring C is heterocycloalkyl or heteroaryl;
each R1 is independently halogen, -CN, -NO2, -OH, -ORa, -OC (=O) Ra, -OC (=O) ORb, -OC (=O) NRcRd, -SH, -SRa, -SF3, -SF5, -S (=O) Ra, -S (=O) 2Ra, -S (=O) 2NRcRd, -NRcRd, -NRbC (=O) NRcRd, -NRbC (=O) Ra, -NRbC (=O) ORb, -NRbS (=O) 2Ra, -P (=O) RaNRcRd, -P (=O) RaORb, -P (=O) RaRb, -C (=O) Ra, -C (=O) ORb, -C (=O) NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R1a;
or two R1 on the same atom are taken together to form an oxo;
or two R1 on the same carbon are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R1a;
or two R1 on the different atoms are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R1a;
each R1a is independently halogen, -CN, -NO2, -OH, -ORa, -OC (=O) Ra, -OC (=O) ORb, -OC (=O) NRcRd, -SH, -SRa, -SF3, -SF5, -S (=O) Ra, -S (=O) 2Ra, -S (=O) 2NRcRd, -NRcRd, -NRbC (=O) NRcRd, -NRbC (=O) Ra, -NRbC (=O) ORb, -NRbS (=O) 2Ra, -P (=O) RaNRcRd, -P (=O) RaORb, -P (=O) RaRb , -C (=O) Ra, -C (=O) ORb, -C (=O) NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
or two R1a on the same atom are taken together to form an oxo;
or two R1a on the same carbon are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R;
or two R1a on the different atoms are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R;
n is 0-6;
L is -O-, -S-, or -NR2-;
R2 is hydrogen, -CN, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl;
W is N or CRW;
RW is hydrogen, -SH, -SRa, -SF3, -SF5, halogen, -CN, -OH, -ORa, -NRcRd, -P (=O) RaNRcRd, -P (=O) RaORb, -P (=O) RaRb, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl;
Z is N or CRZ;
RZ is hydrogen, -SH, -SRa, -SF3, -SF5, halogen, -CN, -OH, -ORa, -NRcRd, -P (=O) RaNRcRd, -P (=O) RaORb, -P (=O) RaRb, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl;
is a single bond; X is C (RX) 2, O, S, or NRX1; and Y is C (RY) 2, O, S, or NRY1;
oris a double bond; X is CRX or N; and Y is CRY or N;
each RX is independently hydrogen, -SH, -SRa, -SF3, -SF5, halogen, -CN, -OH, -ORa, -NRcRd, -P (=O) RaNRcRd, -P (=O) RaORb, -P (=O) RaRb, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl;
RX1 is hydrogen, -CN, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl;
each RY is independently hydrogen, -SH, -SRa, -SF3, -SF5, halogen, -CN, -OH, -ORa, -NRcRd, -P (=O) RaNRcRd, -P (=O) RaORb, -P (=O) RaRb, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl;
RY1 is hydrogen, -CN, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl;
R3 is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl;
Ring D is a 3-to 5-membered ring;
each R4 is independently halogen, -CN, -NO2, -OH, -ORa, -OC (=O) Ra, -OC (=O) ORb, -OC (=O) NRcRd, -SH, -SRa, -SF3, -SF5, -S (=O) Ra, -S (=O) 2Ra, -S (=O) 2NRcRd, -NRcRd, -NRbC (=O) NRcRd, -NRbC (=O) Ra, -NRbC (=O) ORb, -NRbS (=O) 2Ra, -P (=O) RaNRcRd, -P (=O) RaORb, -P (=O) RaRb, -C (=O) Ra, -C (=O) ORb, -C (=O) NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R4a;
or two R4 on the same atom are taken together to form an oxo;
or two R4 on the different atoms are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R4a;
each R4a is independently halogen, -CN, -NO2, -OH, -ORa, -OC (=O) Ra, -OC (=O) ORb, -OC (=O) NRcRd, -SH, -SRa, -SF3, -SF5, -S (=O) Ra, -S (=O) 2Ra, -S (=O) 2NRcRd, -NRcRd, -
NRbC (=O) NRcRd, -NRbC (=O) Ra, -NRbC (=O) ORb, -NRbS (=O) 2Ra, -P (=O) RaNRcRd, -P (=O) RaORb, -P (=O) RaRb, -C (=O) Ra, -C (=O) ORb, -C (=O) NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
or two R4a on the same atom are taken together to form an oxo;
or two R4a on the same carbon are taken together to form a cycloalkyl or heterocycloalkyl; each independently optionally substituted with one or more R;
or two R4a on the different atoms are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each independently optionally substituted with one or more R;
m is 0-6;
each Ra is independently C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene (cycloalkyl) , C1-C6alkylene (heterocycloalkyl) , C1-C6alkylene (aryl) , or C1-C6alkylene (heteroaryl) , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
each Rb is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene (cycloalkyl) , C1-C6alkylene (heterocycloalkyl) , C1-C6alkylene (aryl) , or C1-C6alkylene (heteroaryl) , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
Rc and Rd are each independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene (cycloalkyl) , C1-C6alkylene (heterocycloalkyl) , C1-C6alkylene (aryl) , or C1-C6alkylene (heteroaryl) , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
or Rc and Rd are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R; and
each R is independently halogen, -CN, -OH, -SH, -OCF3, -OCClF2, -SF3, -SF5, -SCF3, -SCClF2, -S (=O) C1-C3alkyl, -S (=O) 2C1-C3alkyl, -S (=O) 2NH2, -S (=O) 2NHC1-C3alkyl, -S (=O) 2N (C1-C3alkyl) 2, -NH2, -NHC1-C3alkyl, -N (C1-C3alkyl) 2, -P (=O) (C1-C3alkyl) N (C1-C3alkyl) 2, -P (=O) (C1-C3alkyl) O (C1-C3alkyl) , -P (=O) (C1-C3alkyl) 2, -C (=O) C1-C3alkyl, -C (=O) OH, -C (=O) OC1-C3alkyl, -C (=O) NH2, -C (=O) NHC1-C3alkyl, -C (=O) N (C1-C3alkyl) 2, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, or C3-C6cycloalkyl;
or two R on the same atom form an oxo;
or two R on the same carbon are taken together to form a cycloalkyl or heterocycloalkyl;
or two R on the different atoms are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl.
In some embodiments of a compound of Formula (II) , the compound is of Formula (IIa) :
In some embodiments of a compound of Formula (II) , the compound is of Formula (IIb) :
In some embodiments of a compound of Formula (II) , the compound is of Formula (IIc) :
In some embodiments of a compound of Formula (II) , the compound is of Formula (IId) :
In some embodiments of a compound of Formula (II) , the compound is of Formula (IIe) :
Also disclosed herein is a pharmaceutical composition comprising a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable excipient.
Also disclosed herein is a method of treating a HPK1-mediated disorder in a patient comprising administering to said patient a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or a pharmaceutical composition disclosed herein. In some embodiments, the HPK1-mediated disorder is a proliferative disorder. In some embodiments, the proliferative disorder is cancer. In some embodiments, the proliferative disorder is associated with one or more activating mutations in HPK1. In some embodiments, the HPK1-mediated disorder is a chronic viral infection.
Also disclosed herein is a method of increasing the efficacy of vaccination in a patient comprising administering to said patient a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or a pharmaceutical composition disclosed herein.
INCORPORATION BY REFERENCE
All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.
Definitions
In the following description, certain specific details are set forth in order to provide a thorough understanding of various embodiments. However, one skilled in the art will understand that the invention may be practiced without these details. In other instances, well-known structures have not been shown or described in detail to avoid unnecessarily obscuring descriptions of the embodiments. Unless the context requires otherwise, throughout the specification and claims which follow, the word “comprise” and variations thereof, such as, “comprises” and “comprising” are to be construed in an open, inclusive sense, that is, as “including, but not limited to. ” Further, headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed invention.
Reference throughout this specification to “some embodiments” or “an embodiment” means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrases “in one embodiment” or “in an embodiment” in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments. Also, as used in this specification and the appended claims, the singular forms “a, ” “an, ” and “the” include plural referents unless the content clearly dictates otherwise. It should also be noted that the term “or” is generally employed in its sense including “and/or” unless the content clearly dictates otherwise.
The terms below, as used herein, have the following meanings, unless indicated otherwise:
“oxo” refers to =O.
“Carboxyl” refers to -COOH.
“Cyano” refers to -CN.
“Alkyl” refers to a straight-chain, or branched-chain saturated hydrocarbon monoradical having from one to about ten carbon atoms, more preferably one to six carbon atoms. Examples include, but are not limited to methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2, 2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2, 2-dimethyl-1-butyl, 3, 3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl and hexyl, and longer alkyl groups, such as heptyl, octyl and the like. Whenever it appears herein, a numerical range such as “C1-C6 alkyl” or “C1-6alkyl” , means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated. In some embodiments, the alkyl is a C1-
10alkyl. In some embodiments, the alkyl is a C1-6alkyl. In some embodiments, the alkyl is a C1-5alkyl. In some embodiments, the alkyl is a C1-4alkyl. In some embodiments, the alkyl is a C1-3alkyl. Unless
stated otherwise specifically in the specification, an alkyl group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkyl is optionally substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkyl is optionally substituted with halogen.
“Alkenyl” refers to a straight-chain, or branched-chain hydrocarbon monoradical having one or more carbon-carbon double-bonds and having from two to about ten carbon atoms, more preferably two to about six carbon atoms. The group may be in either the cis or trans conformation about the double bond (s) , and should be understood to include both isomers. Examples include, but are not limited to ethenyl (-CH=CH2) , 1-propenyl (-CH2CH=CH2) , isopropenyl [-C (CH3) =CH2] , butenyl, 1, 3-butadienyl and the like. Whenever it appears herein, a numerical range such as “C2-C6 alkenyl” or “C2-6alkenyl” , means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkenyl” where no numerical range is designated. Unless stated otherwise specifically in the specification, an alkenyl group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkenyl is optionally substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkenyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkenyl is optionally substituted with halogen.
“Alkynyl” refers to a straight-chain or branched-chain hydrocarbon monoradical having one or more carbon-carbon triple-bonds and having from two to about ten carbon atoms, more preferably from two to about six carbon atoms. Examples include, but are not limited to ethynyl, 2-propynyl, 2-butynyl, 1, 3-butadiynyl and the like. Whenever it appears herein, a numerical range such as “C2-C6 alkynyl” or “C2-6alkynyl” , means that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkynyl” where no numerical range is designated. Unless stated otherwise specifically in the specification, an alkynyl group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkynyl is optionally substituted with oxo, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkynyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkynyl is optionally substituted with halogen.
“Alkylene” refers to a straight or branched divalent hydrocarbon chain. Unless stated otherwise specifically in the specification, an alkylene group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate,
aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkylene is optionally substituted with oxo, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkylene is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkylene is optionally substituted with halogen.
“Alkoxy” refers to a radical of the formula -ORa where Ra is an alkyl radical as defined. Unless stated otherwise specifically in the specification, an alkoxy group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkoxy is optionally substituted with halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkoxy is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkoxy is optionally substituted with halogen.
“Aryl” refers to a radical derived from a hydrocarbon ring system comprising 6 to 30 carbon atoms and at least one aromatic ring. The aryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the aryl is bonded through an aromatic ring atom) or bridged ring systems. In some embodiments, the aryl is a 6-to 10-membered aryl. In some embodiments, the aryl is a 6-membered aryl (phenyl) . Aryl radicals include, but are not limited to, aryl radicals derived from the hydrocarbon ring systems of anthrylene, naphthylene, phenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. Unless stated otherwise specifically in the specification, an aryl may be optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the aryl is optionally substituted with halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the aryl is optionally substituted with halogen.
“Cycloalkyl” refers to a partially or fully saturated, monocyclic, or polycyclic carbocyclic ring, which may include fused (when fused with an aryl or a heteroaryl ring, the cycloalkyl is bonded through a non-aromatic ring atom) , spiro, or bridged ring systems. In some embodiments, the cycloalkyl is fully saturated. Representative cycloalkyls include, but are not limited to, cycloalkyls having from three to fifteen carbon atoms (C3-C15 cycloalkyl or C3-C15 cycloalkenyl) , from three to ten carbon atoms (C3-C10 cycloalkyl or C3-C10 cycloalkenyl) , from three to eight carbon atoms (C3-C8 cycloalkyl or C3-C8 cycloalkenyl) , from three to six carbon atoms (C3-C6 cycloalkyl or C3-C6 cycloalkenyl) , from three to five carbon atoms (C3-C5 cycloalkyl or C3-C5 cycloalkenyl) , or three to four carbon atoms (C3-C4 cycloalkyl or C3-C4 cycloalkenyl) . In some embodiments, the cycloalkyl is a 3-to 10-membered cycloalkyl or a 3-to 10-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 3-to 6-membered cycloalkyl or a 3-to 6-membered cycloalkenyl. In some
embodiments, the cycloalkyl is a 5-to 6-membered cycloalkyl or a 5-to 6-membered cycloalkenyl. Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyls include, for example, adamantyl, norbornyl, decalinyl, bicyclo [3.3.0] octane, bicyclo [4.3.0] nonane, cis-decalin, trans-decalin, bicyclo [2.1.1] hexane, bicyclo [2.2.1] heptane, bicyclo [2.2.2] octane, bicyclo [3.2.2] nonane, and bicyclo [3.3.2] decane, and 7, 7-dimethyl-bicyclo [2.2.1] heptanyl. Partially saturated cycloalkyls include, for example cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless stated otherwise specifically in the specification, a cycloalkyl is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the cycloalkyl is optionally substituted with halogen.
“Halo” or “halogen” refers to bromo, chloro, fluoro or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro.
“Haloalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, fluorochloromethyl, difluorochloromethyl, trichloromethyl, 2, 2, 2-trifluoroethyl, 1, 2-difluoroethyl, 3-bromo-2-fluoropropyl, 1, 2-dibromoethyl, and the like.
“Hydroxyalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more hydroxyls. In some embodiments, the alkyl is substituted with one hydroxyl. In some embodiments, the alkyl is substituted with one, two, or three hydroxyls. Hydroxyalkyl include, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl is hydroxymethyl.
“Aminoalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more amines. In some embodiments, the alkyl is substituted with one amine. In some embodiments, the alkyl is substituted with one, two, or three amines. Aminoalkyl include, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the aminoalkyl is aminomethyl.
“Heteroalkyl” refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g., -NH-, -N (alkyl) -) , sulfur, phosphorus, or combinations thereof. A heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. In one aspect, a heteroalkyl is a C1-C6 heteroalkyl wherein the heteroalkyl is comprised of 1 to 6 carbon atoms and one or more atoms other than carbon, e.g., oxygen, nitrogen (e.g. -NH-, -N (alkyl) -) , sulfur, phosphorus, or combinations thereof wherein the heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. Examples of such heteroalkyl
are, for example, -CH2OCH3, -CH2CH2OCH3, -CH2CH2OCH2CH2OCH3, -CH (CH3) OCH3, -CH2NHCH3, -CH2N (CH3) 2, -CH2CH2NHCH3, or -CH2CH2N (CH3) 2. Unless stated otherwise specifically in the specification, a heteroalkyl is optionally substituted for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroalkyl is optionally substituted with halogen.
“Heterocycloalkyl” refers to a 3-to 24-membered partially or fully saturated ring radical comprising 2 to 23 carbon atoms and from one to 8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, silicon, and sulfur. In some embodiments, the heterocycloalkyl is fully saturated. In some embodiments, the heterocycloalkyl comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heterocycloalkyl comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heterocycloalkyl comprises one to three nitrogens. In some embodiments, the heterocycloalkyl comprises one or two nitrogens. In some embodiments, the heterocycloalkyl comprises one nitrogen. In some embodiments, the heterocycloalkyl comprises one nitrogen and one oxygen. Unless stated otherwise specifically in the specification, the heterocycloalkyl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with an aryl or a heteroaryl ring, the heterocycloalkyl is bonded through a non-aromatic ring atom) , spiro, or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heterocycloalkyl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized. Representative heterocycloalkyls include, but are not limited to, heterocycloalkyls having from two to fifteen carbon atoms (C2-C15 heterocycloalkyl or C2-C15 heterocycloalkenyl) , from two to ten carbon atoms (C2-C10 heterocycloalkyl or C2-C10 heterocycloalkenyl) , from two to eight carbon atoms (C2-C8 heterocycloalkyl or C2-C8 heterocycloalkenyl) , from two to seven carbon atoms (C2-C7 heterocycloalkyl or C2-C7 heterocycloalkenyl) , from two to six carbon atoms (C2-C6 heterocycloalkyl or C2-C6 heterocycloalkenyl) , from two to five carbon atoms (C2-C5 heterocycloalkyl or C2-C5 heterocycloalkenyl) , or two to four carbon atoms (C2-C4 heterocycloalkyl or C2-C4 heterocycloalkenyl) . Examples of such heterocycloalkyl radicals include, but are not limited to, aziridinyl, azetidinyl, oxetanyl, dioxolanyl, thienyl [1, 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-thiomorpholinyl, 1, 1-dioxo-thiomorpholinyl, 1, 3-dihydroisobenzofuran-1-yl, 3-oxo-1, 3-dihydroisobenzofuran-1-yl, methyl-2-oxo-1, 3-dioxol-4-yl, and 2-oxo-1, 3-dioxol-4-yl. The term heterocycloalkyl also includes all ring
forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides, and the oligosaccharides. In some embodiments, heterocycloalkyls have from 2 to 10 carbons in the ring. It is understood that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including the heteroatoms) that make up the heterocycloalkyl (i.e. skeletal atoms of the heterocycloalkyl ring) . In some embodiments, the heterocycloalkyl is a 3-to 8-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3-to 7-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3-to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 4-to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 5-to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3-to 8-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3-to 7-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3-to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 4-to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 5-to 6-membered heterocycloalkenyl. Unless stated otherwise specifically in the specification, a heterocycloalkyl may be optionally substituted as described below, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the heterocycloalkyl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heterocycloalkyl is optionally substituted with halogen.
“Heteroaryl” refers to a 5-to 14-membered ring system radical comprising one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, and sulfur, and at least one aromatic ring. In some embodiments, the heteroaryl comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heteroaryl comprises one to three nitrogens. In some embodiments, the heteroaryl comprises one or two nitrogens. In some embodiments, the heteroaryl comprises one nitrogen. The heteroaryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the heteroaryl is bonded through an aromatic ring atom) or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heteroaryl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized. In some embodiments, the heteroaryl is a 5-to 10-membered heteroaryl. In some embodiments, the heteroaryl is a 5-to 6-membered heteroaryl. In some embodiments, the heteroaryl is a 6-membered heteroaryl. In some embodiments, the heteroaryl is a 5-membered heteroaryl. Examples include, but are not limited to, azepinyl, acridinyl,
benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo [b] [1, 4] dioxepinyl, 1, 4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl) , benzotriazolyl, benzo [4, 6] imidazo [1, 2-a] pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl) . Unless stated otherwise specifically in the specification, a heteroaryl may be optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroaryl is optionally substituted with halogen.
The term “optional” or “optionally” means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. For example, “optionally substituted alkyl” means either “alkyl” or “substituted alkyl” as defined above. Further, an optionally substituted group may be un-substituted (e.g., -CH2CH3) , fully substituted (e.g., -CF2CF3) , mono-substituted (e.g., -CH2CH2F) or substituted at a level anywhere in-between fully substituted and mono-substituted (e.g., -CH2CHF2, -CH2CF3, -CF2CH3, -CFHCHF2, etc. ) . It will be understood by those skilled in the art with respect to any group containing one or more substituents that such groups are not intended to introduce any substitution or substitution patterns that are sterically impractical and/or synthetically non-feasible. Thus, any substituents described should generally be understood as having a maximum molecular weight of about 1,000 daltons, and more typically, up to about 500 daltons.
The term “one or more” when referring to an optional substituent means that the subject group is optionally substituted with one, two, three, four, or more substituents. In some embodiments, the subject group is optionally substituted with one, two, three or four substituents. In some embodiments, the subject group is optionally substituted with one, two, or three substituents. In some embodiments, the subject group is optionally substituted with one or two substituents. In some embodiments, the subject group is optionally substituted with one substituent. In some embodiments, the subject group is optionally substituted with two substituents.
An “effective amount” or “therapeutically effective amount” refers to an amount of a compound administered to a mammalian subject, either as a single dose or as part of a series of doses, which is effective to produce a desired therapeutic effect.
The terms “treat, ” “treating” or “treatment, ” as used herein, include alleviating, abating, or ameliorating at least one symptom of a disease or condition, preventing additional 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.
As used herein, a “disease or disorder associated with HPK1” or, alternatively, “a HPK1-mediated disease or disorder” means any disease or other deleterious condition in which HPK1, or a mutant thereof, is known or suspected to play a role.
As used herein, a “HPK1 antagonist” or a “HPK1 inhibitor” is a molecule that reduces, inhibits, or otherwise diminishes one or more of the biological activities of HPK1 (e.g., serine/threonine kinase activity, recruitment to the TCR complex upon TCR activation, interaction with a protein binding partner, such as SLP76) . Antagonism using the HPK1 antagonist does not necessarily indicate a total elimination of the HPK1 activity. Instead, the activity could decrease by a statistically significant amount including, for example, a decrease of at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 95%or 100%of the activity of HPK1 compared to an appropriate control. In some embodiments, the HPK1 antagonist reduces, inhibits, or otherwise diminishes the serine/threonine kinase activity of HPK1. In some of these embodiments, the HPK1 antagonist reduces, inhibits, or otherwise diminishes the HPK1-mediated phosphorylation of SLP76 and/or Gads. The presently disclosed compounds bind directly to HPK1 and inhibit its kinase activity.
Compounds
Described herein are compounds, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof useful in the treatment of a disease or disorder associated with HPK1.
Disclosed herein is a compound of Formula (I) , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
wherein:
Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R1 is independently halogen, -CN, -NO2, -OH, -ORa, -OC (=O) Ra, -OC (=O) ORb, -OC (=O) NRcRd, -SH, -SRa, -SF3, -SF5, -S (=O) Ra, -S (=O) 2Ra, -S (=O) 2NRcRd, -NRcRd, -NRbC (=O) NRcRd, -NRbC (=O) Ra, -NRbC (=O) ORb, -NRbS (=O) 2Ra, -P (=O) RaNRcRd, -P (=O) RaORb, -P (=O) RaRb, -C (=O) Ra, -C (=O) ORb, -C (=O) NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R1a;
or two R1 on the same atom are taken together to form an oxo;
or two R1 on the same carbon are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R1a;
or two R1 on the different atoms are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R1a;
each R1a is independently halogen, -CN, -NO2, -OH, -ORa, -OC (=O) Ra, -OC (=O) ORb, -OC (=O) NRcRd, -SH, -SRa, -SF3, -SF5, -S (=O) Ra, -S (=O) 2Ra, -S (=O) 2NRcRd, -NRcRd, -NRbC (=O) NRcRd, -NRbC (=O) Ra, -NRbC (=O) ORb, -NRbS (=O) 2Ra, -P (=O) RaNRcRd, -P (=O) RaORb, -P (=O) RaRb, -C (=O) Ra, -C (=O) ORb, -C (=O) NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
or two R1a on the same atom are taken together to form an oxo;
or two R1a on the same carbon are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R;
or two R1a on the different atoms are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R;
n is 0-6;
L is -O-, -S-, or -NR2-;
R2 is hydrogen, -CN, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl;
W is N or CRW;
RW is hydrogen, -SH, -SRa, -SF3, -SF5, halogen, -CN, -OH, -ORa, -NRcRd, -P (=O) RaNRcRd, -P (=O) RaORb, -P (=O) RaRb, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl;
Z is N or CRZ;
RZ is hydrogen, -SH, -SRa, -SF3, -SF5, halogen, -CN, -OH, -ORa, -NRcRd, -P (=O) RaNRcRd, -P (=O) RaORb, -P (=O) RaRb, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl;
is a single bond; X is C (RX) 2, O, S, or NRX1; and Y is C (RY) 2, O, S, or NRY1;
oris a double bond; X is CRX or N; and Y is CRY or N;
each RX is independently hydrogen, -SH, -SRa, -SF3, -SF5, halogen, -CN, -OH, -ORa, -NRcRd, -P (=O) RaNRcRd, -P (=O) RaORb, -P (=O) RaRb, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl;
RX1 is hydrogen, -CN, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl;
each RY is independently hydrogen, -SH, -SRa, -SF3, -SF5, halogen, -CN, -OH, -ORa, -NRcRd, -P (=O) RaNRcRd, -P (=O) RaORb, -P (=O) RaRb, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl;
RY1 is hydrogen, -CN, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl;
R3 is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl;
Ring B is a bicyclic ring;
each R4 is independently halogen, -CN, -NO2, -OH, -ORa, -OC (=O) Ra, -OC (=O) ORb, -OC (=O) NRcRd, -SH, -SRa, -SF3, -SF5, -S (=O) Ra, -S (=O) 2Ra, -S (=O) 2NRcRd, -NRcRd, -NRbC (=O) NRcRd, -NRbC (=O) Ra, -NRbC (=O) ORb, -NRbS (=O) 2Ra, -P (=O) RaNRcRd, -P (=O) RaORb, -P (=O) RaRb, -C (=O) Ra, -C (=O) ORb, -C (=O) NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R4a;
or two R4 on the same atom are taken together to form an oxo;
or two R4 on the different atoms are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R4a;
each R4a is independently halogen, -CN, -NO2, -OH, -ORa, -OC (=O) Ra, -OC (=O) ORb, -OC (=O) NRcRd, -SH, -SRa, -SF3, -SF5, -S (=O) Ra, -S (=O) 2Ra, -S (=O) 2NRcRd, -NRcRd, -NRbC (=O) NRcRd, -NRbC (=O) Ra, -NRbC (=O) ORb, -NRbS (=O) 2Ra, -P (=O) RaNRcRd, -P (=O) RaORb, -P (=O) RaRb, -C (=O) Ra, -C (=O) ORb, -C (=O) NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
or two R4a on the same atom are taken together to form an oxo;
or two R4a on the same carbon are taken together to form a cycloalkyl or heterocycloalkyl; each independently optionally substituted with one or more R;
or two R4a on the different atoms are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each independently optionally substituted with one or more R;
m is 0-6;
each Ra is independently C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene (cycloalkyl) , C1-C6alkylene (heterocycloalkyl) , C1-C6alkylene (aryl) , or C1-C6alkylene (heteroaryl) , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
each Rb is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene (cycloalkyl) , C1-C6alkylene (heterocycloalkyl) , C1-C6alkylene (aryl) , or C1-C6alkylene (heteroaryl) , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
Rc and Rd are each independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene (cycloalkyl) , C1-C6alkylene (heterocycloalkyl) , C1-C6alkylene (aryl) , or C1-C6alkylene (heteroaryl) , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
or Rc and Rd are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R; and
each R is independently halogen, -CN, -OH, -SH, -OCF3, -OCClF2, -SF3, -SF5, -SCF3, -SCClF2, -S (=O) C1-C3alkyl, -S (=O) 2C1-C3alkyl, -S (=O) 2NH2, -S (=O) 2NHC1-C3alkyl, -S (=O) 2N (C1-C3alkyl) 2, -NH2, -NHC1-C3alkyl, -N (C1-C3alkyl) 2, -P (=O) (C1-C3alkyl) N (C1-C3alkyl) 2, -P (=O) (C1-C3alkyl) O (C1-C3alkyl) , -P (=O) (C1-C3alkyl) 2, -C (=O) C1-C3alkyl, -C (=O) OH, -C (=O) OC1-C3alkyl, -C (=O) NH2, -C (=O) NHC1-C3alkyl, -C (=O) N (C1-C3alkyl) 2, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, or C3-C6cycloalkyl;
or two R on the same atom form an oxo;
or two R on the same carbon are taken together to form a cycloalkyl or heterocycloalkyl;
or two R on the different atoms are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl.
In some embodiments of a compound of Formula (I) , the compound is of Formula (Ia) :
In some embodiments of a compound of Formula (I) or (Ia) , X is C (RX) 2 or NRX1; and Y is C (RY) 2 or NRY1. In some embodiments of a compound of Formula (I) or (Ia) , X is C (RX) 2; and Y is C (RY) 2. In some embodiments of a compound of Formula (I) or (Ia) , X is C (RX) 2; and Y is C (RY) 2, O, S, or NRY1. In some embodiments of a compound of Formula (I) or (Ia) , X is C (RX) 2; and Y is C (RY) 2, O, or NRY1. In some embodiments of a compound of Formula (I) or (Ia) , X is C (RX) 2; and Y is C (RY) 2 or O.
In some embodiments of a compound of Formula (I) , the compound is of Formula (Ib) :
In some embodiments of a compound of Formula (I) , the compound is of Formula (Ic) :
In some embodiments of a compound of Formula (I) , the compound is of Formula (Id) :
In some embodiments of a compound of Formula (I) , the compound is of Formula (Ie) :
In some embodiments of a compound of Formula (I) or (Ia) - (Id) , each RX is independently hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (I) or (Ia) - (Id) , each RX is independently hydrogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (I) or (Ia) - (Id) , each RX is independently hydrogen or C1-C6alkyl. In some embodiments of a compound of Formula (I) or (Ia) - (Id) , each RX is hydrogen.
In some embodiments of a compound of Formula (I) , (Ia) - (Ic) , or (Ie) , each RY is independently hydrogen, halogen, -CN, -OH, -ORa, -SH, -SRa, -NRcRd, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (I) , (Ia) - (Ic) , or (Ie) , each RY is independently hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (I) , (Ia) - (Ic) , or (Ie) , each RY is independently hydrogen or halogen. In some embodiments of a compound of Formula (I) , (Ia) - (Ic) , or (Ie) , each RY is independently hydrogen or C1-C6alkyl. In some embodiments of a compound of Formula (I) , (Ia) - (Ic) , or (Ie) , each RY is hydrogen.
In some embodiments of a compound of Formula (I) or (Ia) , RX1 is hydrogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (I) or (Ia) , RX1 is hydrogen or C1-C6alkyl. In some embodiments of a compound of Formula (I) or (Ia) , RX1 is hydrogen.
In some embodiments of a compound of Formula (I) or (Ia) , RY1 is hydrogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (I) or (Ia) , RY1 is hydrogen or C1-C6alkyl. In some embodiments of a compound of Formula (I) or (Ia) , RY1 is hydrogen.
In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , Ring A is aryl or heteroaryl. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , Ring A is phenyl. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , Ring A is heteroaryl. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , Ring A is 5-or 6-membered heteroaryl. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , Ring A is 6-membered heteroaryl. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , Ring A is pyridinyl. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , Ring A is 5-membered heteroaryl. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , Ring A is bicyclic or tricyclic heteroaryl. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , Ring A is bicyclic heteroaryl. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , Ring A is tricyclic heteroaryl.
In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , each R1 is independently halogen, -CN, -OH, -ORa, -NRcRd, -C (=O) Ra, -C (=O) ORb, -C (=O) NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R1a. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , each R1 is independently halogen, -CN, -OH, -ORa, -NRcRd, -C (=O) NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R1a. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , each R1 is independently halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R1a. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , each R1 is independently halogen, -OH, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6heteroalkyl, heterocycloalkyl, or heteroaryl; wherein each alkyl, heterocycloalkyl, and heteroaryl is independently optionally substituted with one or more R1a. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , each R1 is independently C1-C6alkyl or heterocycloalkyl; wherein each alkyl and heterocycloalkyl is independently optionally substituted with one or more R1a. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , each R1 is independently heterocycloalkyl optionally substituted with one or more R1a. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , two R1 on the same atom are taken together to form an oxo. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , two R1 on the same carbon are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R1a. In some embodiments of a
compound of Formula (I) or (Ia) - (Ie) , two R1 on the different atoms are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R1a.
In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , each R1a is independently halogen, -CN, -OH, -ORa, -NRcRd, -NRbC (=O) NRcRd, -C (=O) Ra, -C (=O) ORb, -C (=O) NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound of Formula (Ia) , (Id) , or (Ie) , each R1a is independently halogen, -CN, -OH, -ORa, -NRcRd, -NRbC (=O) NRcRd, -C (=O) Ra, -C (=O) ORb, -C (=O) NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , each R1a is independently halogen, -CN, -OH, -ORa, -NRbC (=O) NRcRd, -C (=O) Ra, -C (=O) ORb, -C (=O) NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , each R1a is independently halogen, -CN, -OH, -ORa, -NRcRd, -NRbC (=O) NRcRd, C1-C6alkyl, C1-C6haloalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound of Formula (Ia) , (Id) , or (Ie) , each R1a is independently halogen, -CN, -OH, -ORa, -NRcRd, -NRbC (=O) NRcRd, C1-C6alkyl, C1-C6haloalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , each R1a is independently halogen, -CN, -OH, -ORa, -NRbC (=O) NRcRd, C1-C6alkyl, C1-C6haloalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , each R1a is independently cycloalkyl or heterocycloalkyl; wherein each cycloalkyl and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , each R1a is independently heterocycloalkyl; optionally substituted with one or more R. In some embodiments, the heterocycloalkyl is a bicyclic heterocycloalkyl (e.g., a spiro cyclic ring) . In some embodiments of a compound of Formula (Ia) , (Id) , or (Ie) , each R1a is independently -NRcRd. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , two R1a on the same atom are taken together to form an oxo. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , two R1a on the same carbon are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , two R1a on the different atoms are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R.
In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , n is 1-4. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , n is 2-4. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , n is 1 or 2. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , n is 0. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , n is 1. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , n is 2. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , n is 3.
In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , at least two R1 independently comprises a cyclic group. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , two R1 each independently comprises a cyclic group. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , at least two R1 are independently selected from a cyclic group. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , at least an R1 comprises a substituted cyclic group. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , at least one R1 comprises a halogen substituted cyclic group. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , at least one R1 comprises a halogen (e.g., fluoro) substituted heterocycloalkyl. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , at least one R1 comprises a halogen (e.g., fluoro) substituted cycloalkyl.
In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , iswherein:
Ring E is cycloalkyl or heterocycloalkyl;
each R5 is independently halogen, -CN, -OH, -SH, -OCF3, -OCClF2, -SF3, -SF5, -SCF3, -SCClF2, -S (=O) C1-C3alkyl, -S (=O) 2C1-C3alkyl, -S (=O) 2NH2, -S (=O) 2NHC1-C3alkyl, -S (=O) 2N (C1-C3alkyl) 2, -NH2, -NHC1-C3alkyl, -N (C1-C3alkyl) 2, -P (=O) (C1-C3alkyl) N (C1-C3alkyl) 2, -P (=O) (C1-C3alkyl) O (C1-C3alkyl) , -P (=O) (C1-C3alkyl) 2, -C (=O) C1-C3alkyl, -C (=O) OH, -C (=O) OC1-C3alkyl, -C (=O) NH2, -C (=O) NHC1-C3alkyl, -C (=O) N (C1-C3alkyl) 2, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, or C3-C6cycloalkyl; and
p is 0, 1, 2, 3, or 4.
In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , Ring E is cycloalkyl.
In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , Ring E is heterocycloalkyl. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , Ring E is a monocyclic heterocycloalkyl. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , Ring E
is a bicyclic heterocycloalkyl. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , Ring E is a pyrrolidinyl.
In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , each R5 is independently halogen, -CN, -OH, -OCF3, -OCClF2, -NH2, -NHC1-C3alkyl, -N (C1-C3alkyl) 2, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, or C3-C6cycloalkyl. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , each R5 is independently halogen, -CN, -OH, -NH2, C1-C6alkyl, C1-C6alkoxy, or C1-C6haloalkyl. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , each R5 is independently halogen, -OH, C1-C6alkyl, or C1-C6alkoxy. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , each R5 is independently halogen, -OH, or C1-C6alkoxy. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , each R5 is independently halogen.
In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , p is 0, 1, or 2. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , p is 0 or 1. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , p is 1 or 2. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , p is 0. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , p is 1. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , p is 2.
In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , is
In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , isIn some embodiments of a compound of Formula (Id) or (Ie) , isIn some embodiments of a compound of Formula (I) or (Ia) - (Ie) , is notIn some embodiments of a compound of Formula (I) or (Ia) - (Ie) , is
In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , isIn some embodiments of a compound of Formula (I) or (Ia) - (Ie) , isIn some embodiments of a compound of Formula (I) or (Ia) - (Ie) , isIn some embodiments of a compound of Formula (I) or (Ia) - (Ie) , is
In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , is
In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , Ring B is a bicyclic heteroaryl or heterocycloalkyl. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , Ring B is a bicyclic heteroaryl. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , Ring B is a bicyclic partially saturated ring. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , Ring B is a bicyclic fully saturated ring. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , Ring B is a bicyclic unsaturated ring.
In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , each R4 is independently halogen, -CN, -NO2, -OH, -ORa, -OC (=O) Ra, -OC (=O) ORb, -OC (=O) NRcRd, -SH, -SRa, -SF3, -SF5, -S (=O) Ra, -S (=O) 2Ra, -S (=O) 2NRcRd, -NRcRd, -NRbC (=O) NRcRd, -NRbC (=O) Ra, -NRbC (=O) ORb, -NRbS (=O) 2Ra, -P (=O) RaNRcRd, -P (=O) RaORb, -P (=O) RaRb, -C (=O) Ra, -C (=O) ORb, -C (=O) NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , each R4 is independently halogen, -CN, -OH, -ORa (e.g., -OCF3 or OCClF2) , -SH, -SRa (e.g., SCF3 or -SCClF2) , -SF3, -SF5, -NRcRd, -C (=O) Ra, -C (=O) ORb, -C (=O) NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R4a. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , each R4 is independently halogen, -CN, -OH, -ORa -SF3, -SF5, -NRcRd, -C (=O) Ra, -C (=O) ORb, -C (=O) NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R4a. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , each R4 is independently halogen, -CN, -OH, -ORa, -SF3, -
SF5, -NRcRd, C1-C6alkyl, or C1-C6haloalkyl; wherein each alkyl is independently optionally substituted with one or more R4a. In some embodiments, one or more R4 is -OCF3, OCClF2, -SCF3, or -SCClF2. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , each R4 is independently halogen, -SF3, -SF5, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , each R4 is independently halogen or C1-C6alkyl. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , two R4 on the different atoms are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R4a. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , two R4 on the same carbon are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R1a.
In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , each R4 is independently halogen, -CN, -OH, -ORa, -NRcRd, -C (=O) Ra, -C (=O) ORb, -C (=O) NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, or aryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, and aryl is independently optionally substituted with one or more R4a.
In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , each R4a is independently halogen, -CN, -OH, -ORa, -SF3, -SF5, -NRcRd, -C (=O) Ra, -C (=O) ORb, -C (=O) NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , each R4a is independently halogen, -CN, -OH, -ORa (e.g., -OCF3 or OCClF2) , -SH, -SRa (e.g., SCF3 or -SCClF2) , -SF3, -SF5, -NRcRd, -C (=O) Ra, -C (=O) ORb, -C (=O) NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R.
In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , each R4a is independently halogen, -CN, -OH, -ORa, -SH, -SRa, -SF3, -SF5, -NRcRd, C1-C6alkyl, or C1-C6haloalkyl; wherein each alkyl is independently optionally substituted with one or more R. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , each R4a is independently halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, or C1-C6haloalkyl; wherein each alkyl is independently optionally substituted with one or more R. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , each R4a is independently halogen, -CN, -OH, -ORa, -SH, -SRa, -SF3, -SF5, -NRcRd, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , each R4a is independently halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, or C1-C6haloalkyl.
In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , m is 0-4. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , m is 0-2. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , m is 1 or 2. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , m is 0. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , m is 1. In
some embodiments of a compound of Formula (I) or (Ia) - (Ie) , m is 2. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , m is 3.
In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , is
In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , isIn some embodiments of a compound of Formula (I) or (Ia) - (Ie) , isIn some embodiments of a compound of Formula (I) or (Ia) - (Ie) , is
In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , R3 is hydrogen or C1-C6alkyl. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , R3 is hydrogen.
In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , W is N. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , W is CRW.
In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , RW is hydrogen, halogen, -CN, -OH, -ORa (e.g., -OCF3 or OCClF2) , SH, -SRa (e.g., -SCF3 or -SCClF2) , -SF3, -SF5, -NRcRd, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , RW is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , RW is hydrogen.
In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , Z is N. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , Z is CRZ.
In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , RZ is hydrogen, halogen, -CN, -OH, -ORa (e.g., -OCF3 or OCClF2) , SH, -SRa (e.g., -SCF3 or -SCClF2) , -SF3, -SF5, -NRcRd, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , RZ is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , RZ is hydrogen.
In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , L is -O-. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , L is -S-. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , L is -NR2-.
In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , R2 is hydrogen or C1-C6alkyl. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , R2 is C1-C6alkyl. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , R2 is hydrogen.
Also disclosed herein is a compound of Formula (II) , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
wherein:
Ring C is heterocycloalkyl or heteroaryl;
each R1 is independently halogen, -CN, -NO2, -OH, -ORa, -OC (=O) Ra, -OC (=O) ORb, -OC (=O) NRcRd, -SH, -SRa, -SF3, -SF5, -S (=O) Ra, -S (=O) 2Ra, -S (=O) 2NRcRd, -NRcRd, -NRbC (=O) NRcRd, -NRbC (=O) Ra, -NRbC (=O) ORb, -NRbS (=O) 2Ra, -P (=O) RaNRcRd, -P (=O) RaORb, -P (=O) RaRb, -C (=O) Ra, -C (=O) ORb, -C (=O) NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R1a;
or two R1 on the same atom are taken together to form an oxo;
or two R1 on the same carbon are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R1a;
or two R1 on the different atoms are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R1a;
each R1a is independently halogen, -CN, -NO2, -OH, -ORa, -OC (=O) Ra, -OC (=O) ORb, -OC (=O) NRcRd, -SH, -SRa, -SF3, -SF5, -S (=O) Ra, -S (=O) 2Ra, -S (=O) 2NRcRd, -NRcRd, -NRbC (=O) NRcRd, -NRbC (=O) Ra, -NRbC (=O) ORb, -NRbS (=O) 2Ra, -P (=O) RaNRcRd, -P (=O) RaORb, -P (=O) RaRb , -C (=O) Ra, -C (=O) ORb, -C (=O) NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
or two R1a on the same atom are taken together to form an oxo;
or two R1a on the same carbon are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R;
or two R1a on the different atoms are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R;
n is 0-6;
L is -O-, -S-, or -NR2-;
R2 is hydrogen, -CN, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl;
W is N or CRW;
RW is hydrogen, -SH, -SRa, -SF3, -SF5, halogen, -CN, -OH, -ORa, -NRcRd, -P (=O) RaNRcRd, -P (=O) RaORb, -P (=O) RaRb, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl;
Z is N or CRZ;
RZ is hydrogen, -SH, -SRa, -SF3, -SF5, halogen, -CN, -OH, -ORa, -NRcRd, -P (=O) RaNRcRd, -P (=O) RaORb, -P (=O) RaRb, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl;
is a single bond; X is C (RX) 2, O, S, or NRX1; and Y is C (RY) 2, O, S, or NRY1;
oris a double bond; X is CRX or N; and Y is CRY or N;
each RX is independently hydrogen, -SH, -SRa, -SF3, -SF5, halogen, -CN, -OH, -ORa, -NRcRd, -P (=O) RaNRcRd, -P (=O) RaORb, -P (=O) RaRb, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl;
RX1 is hydrogen, -CN, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl;
each RY is independently hydrogen, -SH, -SRa, -SF3, -SF5, halogen, -CN, -OH, -ORa, -NRcRd, -P (=O) RaNRcRd, -P (=O) RaORb, -P (=O) RaRb, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl;
RY1 is hydrogen, -CN, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl;
R3 is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl;
Ring D is a 3-to 5-membered ring;
each R4 is independently halogen, -CN, -NO2, -OH, -ORa, -OC (=O) Ra, -OC (=O) ORb, -OC (=O) NRcRd, -SH, -SRa, -SF3, -SF5, -S (=O) Ra, -S (=O) 2Ra, -S (=O) 2NRcRd, -NRcRd, -NRbC (=O) NRcRd, -NRbC (=O) Ra, -NRbC (=O) ORb, -NRbS (=O) 2Ra, -P (=O) RaNRcRd, -P (=O) RaORb, -P (=O) RaRb, -C (=O) Ra, -C (=O) ORb, -C (=O) NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R4a;
or two R4 on the same atom are taken together to form an oxo;
or two R4 on the different atoms are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R4a;
each R4a is independently halogen, -CN, -NO2, -OH, -ORa, -OC (=O) Ra, -OC (=O) ORb, -OC (=O) NRcRd, -SH, -SRa, -SF3, -SF5, -S (=O) Ra, -S (=O) 2Ra, -S (=O) 2NRcRd, -NRcRd, -NRbC (=O) NRcRd, -NRbC (=O) Ra, -NRbC (=O) ORb, -NRbS (=O) 2Ra, -P (=O) RaNRcRd, -P (=O) RaORb, -P (=O) RaRb, -C (=O) Ra, -C (=O) ORb, -C (=O) NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
or two R4a on the same atom are taken together to form an oxo;
or two R4a on the same carbon are taken together to form a cycloalkyl or heterocycloalkyl; each independently optionally substituted with one or more R;
or two R4a on the different atoms are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each independently optionally substituted with one or more R;
m is 0-6;
each Ra is independently C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene (cycloalkyl) , C1-C6alkylene (heterocycloalkyl) , C1-C6alkylene (aryl) , or C1-C6alkylene (heteroaryl) , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
each Rb is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene (cycloalkyl) , C1-C6alkylene (heterocycloalkyl) , C1-C6alkylene (aryl) , or C1-C6alkylene (heteroaryl) , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
Rc and Rd are each independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene (cycloalkyl) , C1-C6alkylene (heterocycloalkyl) , C1-C6alkylene (aryl) , or C1-C6alkylene (heteroaryl) , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
or Rc and Rd are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R; and
each R is independently halogen, -CN, -OH, -SH, -OCF3, -OCClF2, -SF3, -SF5, -SCF3, -SCClF2, -S (=O) C1-C3alkyl, -S (=O) 2C1-C3alkyl, -S (=O) 2NH2, -S (=O) 2NHC1-C3alkyl, -S (=O) 2N (C1-C3alkyl) 2, -NH2, -NHC1-C3alkyl, -N (C1-C3alkyl) 2, -P (=O) (C1-C3alkyl) N (C1-C3alkyl) 2, -P (=O) (C1-C3alkyl) O (C1-C3alkyl) , -P (=O) (C1-C3alkyl) 2, -C (=O) C1-C3alkyl, -C (=O) OH, -C (=O) OC1-C3alkyl, -C (=O) NH2, -C (=O) NHC1-C3alkyl, -C (=O) N (C1-C3alkyl) 2, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, or C3-C6cycloalkyl;
or two R on the same atom form an oxo;
or two R on the same carbon are taken together to form a cycloalkyl or heterocycloalkyl;
or two R on the different atoms are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl.
In some embodiments of a compound of Formula (II) , the compound is not
In some embodiments of a compound of Formula (II) , the compound is of Formula (IIa) :
In some embodiments of a compound of Formula (II) or (IIa) , X is C (RX) 2 or NRX1; and Y is C (RY) 2 or NRY1. In some embodiments of a compound of Formula (II) or (IIa) , X is C (RX) 2; and Y
is C (RY) 2. In some embodiments of a compound of Formula (II) or (IIa) , X is C (RX) 2; and Y is C (RY) 2, O, S, or NRY1. In some embodiments of a compound of Formula (II) or (IIa) , X is C (RX) 2; and Y is C (RY) 2, O, or NRY1. In some embodiments of a compound of Formula (II) or (IIa) , X is C (RX) 2; and Y is C (RY) 2 or O.
In some embodiments of a compound of Formula (II) , the compound is of Formula (IIb) :
In some embodiments of a compound of Formula (II) , the compound is of Formula (IIc) :
In some embodiments of a compound of Formula (II) , the compound is of Formula (IId) :
In some embodiments of a compound of Formula (II) , the compound is of Formula (IIe) :
In some embodiments of a compound of Formula (II) or (IIa) - (IId) , each RX is independently hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (II) or (IIa) - (IId) , each RX is independently hydrogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (II) or (IIa) - (IId) , each RX is independently hydrogen or C1-C6alkyl. In some embodiments of a compound of Formula (II) or (IIa) - (IId) , each RX is hydrogen.
In some embodiments of a compound of Formula (II) , (IIa) - (IIc) , or (IIe) , each RY is independently hydrogen, halogen, -CN, -OH, -ORa, -SH, -SRa, -NRcRd, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (II) , (IIa) - (IIc) , or (IIe) , each RY is independently hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (II) , (IIa) - (IIc) , or (IIe) , each RY is independently hydrogen or halogen. In some embodiments of a compound of Formula (II) , (IIa) - (IIc) , or (IIe) , each RY is independently hydrogen or C1-C6alkyl. In some embodiments of a compound of Formula (II) , (IIa) - (IIc) , or (IIe) , each RY is hydrogen.
In some embodiments of a compound of Formula (II) or (IIa) , RX1 is hydrogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (II) or (IIa) , RX1 is hydrogen or C1-C6alkyl. In some embodiments of a compound of Formula (II) or (IIa) , RX1 is hydrogen.
In some embodiments of a compound of Formula (II) or (IIa) , RY1 is hydrogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (II) or (IIa) , RY1 is hydrogen or C1-C6alkyl. In some embodiments of a compound of Formula (II) or (IIa) , RY1 is hydrogen.
In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , Ring C is heteroaryl. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , Ring C is 5-or 6-membered heteroaryl. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , Ring C is 6-membered heteroaryl. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , Ring C is pyridinyl. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , Ring C is bicyclic or tricyclic heteroaryl. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , Ring C is bicyclic heteroaryl. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , Ring C is tricyclic heteroaryl.
In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , each R1 is independently halogen, -CN, -OH, -ORa, -NRcRd, -C (=O) Ra, -C (=O) ORb, -C (=O) NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R1a. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , each R1 is independently halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R1a. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , each R1 is independently halogen, -OH, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6heteroalkyl, heterocycloalkyl, or heteroaryl; wherein each alkyl, heterocycloalkyl, and heteroaryl is independently optionally substituted with one or more R1a. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , each R1 is independently C1-C6alkyl or heterocycloalkyl; wherein each alkyl and heterocycloalkyl is independently optionally substituted with one or more R1a. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , two R1 on the same atom are taken together to form an oxo.
In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , two R1 on the same carbon are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R1a. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , two R1 on the different atoms are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R1a.
In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , each R1a is independently halogen, -CN, -OH, -ORa, -NRcRd, -NRbC (=O) NRcRd, -C (=O) Ra, -C (=O) ORb, -C (=O) NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , each R1a is independently halogen, -CN, -OH, -ORa, -NRbC (=O) NRcRd, -C (=O) Ra, -C (=O) ORb, -C (=O) NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , each R1a is independently halogen, -CN, -OH, -ORa, -NRcRd, -NRbC (=O) NRcRd, C1-C6alkyl, C1-C6haloalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , each R1a is independently halogen, -CN, -OH, -ORa, -NRbC (=O) NRcRd, C1-C6alkyl, C1-C6haloalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) ,
each R1a is independently cycloalkyl or heterocycloalkyl; wherein each cycloalkyl and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , each R1a is independently heterocycloalkyl optionally substituted with one or more R. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , two R1a on the same atom are taken together to form an oxo. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , two R1a on the same carbon are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , two R1a on the different atoms are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R.
In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , n is 1-4. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , n is 1-3. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , n is 1 or 2. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , n is 2-4. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , n is 0. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , n is 1. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , n is 2. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , n is 3.
In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , at least two R1 independently comprises a cyclic group. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , two R1 each independently comprises a cyclic group. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , at least two R1 are independently selected from a cyclic group. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , at least an R1 comprises a substituted cyclic group. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , at least one R1 comprises a halogen substituted cyclic group. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , at least one R1 comprises a halogen (e.g., fluoro) substituted heterocycloalkyl. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , at least one R1 comprises a halogen (e.g., fluoro) substituted cycloalkyl.
In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , iswherein:
Ring E is cycloalkyl or heterocycloalkyl;
each R5 is independently halogen, -CN, -OH, -SH, -OCF3, -OCClF2, -SF3, -SF5, -SCF3, -SCClF2, -S (=O) C1-C3alkyl, -S (=O) 2C1-C3alkyl, -S (=O) 2NH2, -S (=O) 2NHC1-C3alkyl, -S (=O) 2N (C1-
C3alkyl) 2, -NH2, -NHC1-C3alkyl, -N (C1-C3alkyl) 2, -P (=O) (C1-C3alkyl) N (C1-C3alkyl) 2, -P (=O) (C1-C3alkyl) O (C1-C3alkyl) , -P (=O) (C1-C3alkyl) 2, -C (=O) C1-C3alkyl, -C (=O) OH, -C (=O) OC1-C3alkyl, -C (=O) NH2, -C (=O) NHC1-C3alkyl, -C (=O) N (C1-C3alkyl) 2, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, or C3-C6cycloalkyl; and
p is 0, 1, 2, 3, or 4.
In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , Ring E is cycloalkyl.
In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , Ring E is heterocycloalkyl. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , Ring E is a monocyclic heterocycloalkyl. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , Ring E is a bicyclic heterocycloalkyl. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , Ring E is a pyrrolidinyl.
In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , each R5 is independently halogen, -CN, -OH, -OCF3, -OCClF2, -NH2, -NHC1-C3alkyl, -N (C1-C3alkyl) 2, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, or C3-C6cycloalkyl. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , each R5 is independently halogen, -CN, -OH, -NH2, C1-C6alkyl, C1-C6alkoxy, or C1-C6haloalkyl. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , each R5 is independently halogen, -OH, C1-C6alkyl, or C1-C6alkoxy. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , each R5 is independently halogen, -OH, or C1-C6alkoxy. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , each R5 is independently halogen.
In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , p is 0, 1, or 2. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , p is 0 or 1. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , p is 1 or 2. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , p is 0. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , p is 1. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , p is 2.
In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , isIn some embodiments of a compound of Formula (II) or (IIa) - (IIe) ,
is notIn some embodiments of a compound of Formula (II) or (IIa) - (IIe) , is
In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , Ring D is a 5-membered ring.
In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , Ring D is cyclopropyl.
In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , Ring D is a 5-membered ring comprising 1 to 4 heteroatoms selected from the group consisting of O, S, or N.
In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , Ring D is a 5-membered ring comprising 1 to 3 heteroatoms selected from the group consisting of O or N.
In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , Ring D is a 5-membered ring comprising 1 to 3 heteroatoms that are N.
In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , Ring D is imidazolyl, pyrazolyl. or oxadiazolyl. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , Ring D is imidazolyl. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , Ring D is pyrazolyl.
In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , Ring D is not imidazolyl.
In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , each R4 is independently halogen, -CN, -NO2, -OH, -ORa, -OC (=O) Ra, -OC (=O) ORb, -OC (=O) NRcRd, -SH, -SRa, -SF3, -SF5, -S (=O) Ra, -S (=O) 2Ra, -S (=O) 2NRcRd, -NRcRd, -NRbC (=O) NRcRd, -NRbC (=O) Ra, -NRbC (=O) ORb, -NRbS (=O) 2Ra, -P (=O) RaNRcRd, -P (=O) RaORb, -P (=O) RaRb, -C (=O) Ra, -C (=O) ORb, -C (=O) NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R4a.
In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , each R4 is independently halogen, -CN, -OH, -ORa (e.g., -OCF3 or OCClF2) , -SH, -SRa (e.g., SCF3 or -SCClF2) , -NRcRd, -C (=O) Ra, -C (=O) ORb, -C (=O) NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, or aryl; wherein each alkyl, cycloalkyl,
heterocycloalkyl, and aryl is independently optionally substituted with one or more R4a. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , each R4 is independently halogen, -CN, -OH, -ORa, -NRcRd, -C (=O) Ra, -C (=O) ORb, -C (=O) NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, or aryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, and aryl is independently optionally substituted with one or more R4a. In some embodiments, one or more R4 is -OCF3, OCClF2, -SCF3, or -SCClF2.
In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , each R4 is independently halogen, -CN, -OH, -ORa, -NRcRd, -C (=O) NRcRd, C1-C6alkyl, or C1-C6haloalkyl; wherein each alkyl is independently optionally substituted with one or more R4a.
In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , each R4 is independently halogen, -C (=O) NRcRd, C1-C6alkyl, or C1-C6haloalkyl; wherein each alkyl is independently optionally substituted with one or more R4a.
In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , each R4 is independently -C (=O) NRcRd, C1-C6alkyl, C1-C6haloalkyl, aryl, or heteroaryl; wherein each alkyl, aryl, and heteroaryl is independently optionally substituted with one or more R4a.
In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , each R4 is independently aryl or heteroaryl; wherein each aryl and heteroaryl is independently optionally substituted with one or more R4a.
In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , two R4 on the same carbon are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R4a. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , two R4 on the different atoms are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R4a.
In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , each R4a is independently halogen, -CN, -OH, -ORa (e.g., -OCF3 or OCClF2) , -SH, -SRa (e.g., SCF3 or -SCClF2) , -SF3, -SF5, -NRcRd, -C (=O) Ra, -C (=O) ORb, -C (=O) NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , each R4a is independently halogen, -CN, -OH, -ORa, -NRcRd, -C (=O) Ra, -C (=O) ORb, -C (=O) NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R.
In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , each R4a is independently halogen, -CN, -OH, -ORa, -SH, -SRa, -SF3, -SF5, -NRcRd, C1-C6alkyl, or C1-C6haloalkyl; wherein each alkyl is independently optionally substituted with one or more R. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , each R4a is independently halogen, -CN, -
OH, -ORa, -NRcRd, C1-C6alkyl, or C1-C6haloalkyl; wherein each alkyl is independently optionally substituted with one or more R.
In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , each R4a is independently aryl.
In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , m is 0-4. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , m is 0-2. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , m is 1 or 2. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , m is 0. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , m is 1. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , m is 2.
In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , is
In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , R3 is hydrogen or C1-C6alkyl. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , R3 is hydrogen.
In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , W is N. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , W is CRW.
In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , RW is hydrogen, halogen, -CN, -OH, -ORa (e.g., -OCF3 or OCClF2) , SH, -SRa (e.g., -SCF3 or -SCClF2) , -SF3, -SF5, -NRcRd, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , RW is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , RW is hydrogen.
In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , Z is N. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , Z is CRZ.
In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , Rz is hydrogen, halogen, -CN, -OH, -ORa (e.g., -OCF3 or OCClF2) , SH, -SRa (e.g., -SCF3 or -SCClF2) , -SF3, -SF5, -NRcRd, C1-
C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , RZ is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , RZ is hydrogen.
In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , L is -O-. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , L is -S-. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , L is -NR2-.
In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , R2 is hydrogen or C1-C6alkyl. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , R2 is C1-C6alkyl. In some embodiments of a compound of Formula (II) or (IIa) - (IIe) , R2 is hydrogen.
In some embodiments of a compound disclosed herein, each Ra is independently C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene (cycloalkyl) , C1-C6alkylene (heterocycloalkyl) , C1-C6alkylene (aryl) , or C1-C6alkylene (heteroaryl) ; wherein each alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Ra is independently C1-C6alkyl, C1-C6haloalkyl, or cycloalkyl, heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Ra is independently C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene (cycloalkyl) , C1-C6alkylene (heterocycloalkyl) , C1-C6alkylene (aryl) , or C1-C6alkylene (heteroaryl) . In some embodiments of a compound disclosed herein, each Ra is independently C1-C6alkyl, C1-C6haloalkyl, or cycloalkyl, heterocycloalkyl. In some embodiments of a compound disclosed herein, each Ra is independently C1-C6alkyl or C1-C6haloalkyl. In some embodiments of a compound disclosed herein, each Ra is independently C1-C6alkyl.
In some embodiments of a compound disclosed herein, each Rb is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene (cycloalkyl) , C1-C6alkylene (heterocycloalkyl) , C1-C6alkylene (aryl) , or C1-C6alkylene (heteroaryl) ; wherein each alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Rb is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, or cycloalkyl, heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Rb is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene (cycloalkyl) , C1-C6alkylene (heterocycloalkyl) , C1-C6alkylene (aryl) , or C1-C6alkylene (heteroaryl) . In some embodiments of a compound disclosed herein, each Rb is
independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, or cycloalkyl, heterocycloalkyl. In some embodiments of a compound disclosed herein, each Rb is independently hydrogen, C1-C6alkyl or C1-C6haloalkyl. In some embodiments of a compound disclosed herein, each Rb is independently hydrogen or C1-C6alkyl. In some embodiments of a compound disclosed herein, each Rb is hydrogen. In some embodiments of a compound disclosed herein, each Rb is independently C1-C6alkyl.
In some embodiments of a compound disclosed herein, each Rc and Rd are independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene (cycloalkyl) , C1-C6alkylene (heterocycloalkyl) , C1-C6alkylene (aryl) , or C1-C6alkylene (heteroaryl) ; wherein each alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Rc and Rd are independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, or cycloalkyl, heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Rc and Rd are independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene (cycloalkyl) , C1-C6alkylene (heterocycloalkyl) , C1-C6alkylene (aryl) , or C1-C6alkylene (heteroaryl) . In some embodiments of a compound disclosed herein, each Rc and Rd are independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, or cycloalkyl, heterocycloalkyl. In some embodiments of a compound disclosed herein, each Rc and Rd are independently hydrogen, C1-C6alkyl or C1-C6haloalkyl. In some embodiments of a compound disclosed herein, each Rc and Rd are independently hydrogen or C1-C6alkyl. In some embodiments of a compound disclosed herein, each Rc and Rd are hydrogen. In some embodiments of a compound disclosed herein, each Rc and Rd are independently C1-C6alkyl.
In some embodiments of a compound disclosed herein, Rc and Rd are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R.
In some embodiments of a compound disclosed herein, each R is independently halogen, -CN, -OH, -SH, -SF3, -SF5, -SCF3, -SCClF2, -NH2, -NHCH3, -N (CH3) 2, -C (=O) CH3, -C (=O) OH, -C (=O) OCH3, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, or C3-C6cycloalkyl; or two R on the same atom form an oxo. In some embodiments of a compound disclosed herein, each R is independently halogen, -CN, -OH, -NH2, -NHCH3, -N (CH3) 2, -C (=O) CH3, -C (=O) OH, -C (=O) OCH3, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, or C3-C6cycloalkyl; or two R on the same atom form an oxo. In some embodiments of a compound disclosed herein, each R is independently halogen, -CN, -OH, -SH, -SF3, -SF5, -SCF3, -SCClF2, -NH2, -NHCH3, -N (CH3) 2, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, or C3-C6cycloalkyl; or two R on the same atom form an oxo. In some embodiments of a compound disclosed herein, each R is independently
halogen, -CN, -OH, -NH2, -NHCH3, -N (CH3) 2, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, or C3-C6cycloalkyl; or two R on the same atom form an oxo. In some embodiments of a compound disclosed herein, each R is independently halogen, -CN, -OH, C1-C6alkyl, C1-C6alkoxy, or C1-C6haloalkyl; or two R on the same atom form an oxo. In some embodiments of a compound disclosed herein, each R is independently halogen, -CN, -OH, or C1-C6alkyl; or two R on the same atom form an oxo. In some embodiments of a compound disclosed herein, each R is independently halogen, -OH, or C1-C6alkyl. In some embodiments of a compound disclosed herein, each R is independently halogen or C1-C6alkyl. In some embodiments of a compound disclosed herein, each R is independently halogen.
In some embodiments of a compound disclosed herein, one or more of R, R1, R1a, R2, R3, R4, R4a, R5, RX, RX1, RY, RY1, RW, RZ, Ra, Rb, Rc, and Rd groups comprise deuterium at a percentage higher than the natural abundance of deuterium.
In some embodiments of a compound disclosed herein, one or more 1H are replaced with one or more deuteriums in one or more of the following groups R, R1, R1a, R2, R3, R4, R4a, R5, RX, RX1, RY, RY1, RW, RZ, Ra, Rb, Rc, and Rd.
In some embodiments of a compound disclosed herein, the abundance of deuterium in each of R, R1, R1a, R2, R3, R4, R4a, R5, RX, RX1, RY, RY1, RW, RZ, Ra, Rb, Rc, and Rd is independently at least 1%, 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 100%by molar.
In some embodiments of a compound disclosed herein, one or more 1H of Ring A, Ring B, Ring C, Ring D, or Ring E are replaced with one or more deuteriums.
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.
In some embodiments the compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is one of the compounds in Table 1 or Table 2.
TABLE 1
TABLE 2
In some embodiments the compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is one of the compounds in Table 3.
TABLE 3
Further Forms of Compounds Disclosed Herein
Isomers/Stereoisomers
In some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein possess one or more double bonds. The compounds presented herein include all cis, trans, syn, anti, entgegen (E) , and zusammen (Z) isomers as well as the corresponding mixtures thereof. In some situations, the compounds described herein possess one or more chiral centers and each center exists in the R configuration, or S configuration. The compounds described herein include all diastereomeric, enantiomeric, and epimeric forms as well as the corresponding mixtures thereof. In additional embodiments of the compounds and methods provided herein, mixtures of enantiomers and/or diastereoisomers, resulting from a single preparative step, combination, or interconversion are useful for the applications described herein. In some
embodiments, the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers and recovering the optically pure enantiomers. In some embodiments, dissociable complexes are preferred. In some embodiments, the diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc. ) and are separated by taking advantage of these dissimilarities. In some embodiments, the diastereomers are separated by chiral chromatography, or preferably, by separation/resolution techniques based upon differences in solubility. In some embodiments, the optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that would not result in racemization.
Labeled compounds
In some embodiments, the compounds described herein exist in their isotopically-labeled forms. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds as pharmaceutical compositions. Thus, in some embodiments, the compounds disclosed herein include isotopically-labeled compounds, which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds disclosed herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, and chloride, such as 2H (D) , 3H, 13C, 14C, l5N, 18O, 17O, 31P, 32P, 35S, 18F, and 36Cl, respectively. Compounds described herein, and the pharmaceutically acceptable salts, solvates, or stereoisomers thereof which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention. Certain isotopically-labeled compounds, for example those into which radioactive isotopes such as 3H and 14C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3H and carbon-14, i.e., 14C, isotopes are particularly preferred for their ease of preparation and detectability.
In some embodiments, the abundance of deuterium in each of the substituents disclosed herein is independently at least 1%, 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 100%by molar. In some embodiments, one or more of the substituents disclosed herein comprise deuterium at a percentage higher than the natural abundance of deuterium. In some embodiments, one or more 1H are replaced with one or more deuteriums in one or more of the substituents disclosed herein.
In some embodiments, the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.
Pharmaceutically acceptable salts
In some embodiments, the compounds described herein exist as their pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions.
In some embodiments, the compounds described herein possess acidic or basic groups and therefore react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein, or a solvate, or stereoisomer thereof, or by separately reacting a purified compound in its free form with a suitable acid or base, and isolating the salt thus formed.
Examples of pharmaceutically acceptable salts include those salts prepared by reaction of the compounds described herein with a mineral, organic acid or inorganic base, such salts including, acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyn-1, 4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne-1, 6-dioate, hydroxybenzoate, γ-hydroxybutyrate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate, metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, monohydrogenphosphate, 1-napthalenesulfonate, 2-napthalenesulfonate, nicotinate, nitrate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate, thiocyanate, tosylate, undecanoate, and xylenesulfonate.
Further, the compounds described herein can be prepared as pharmaceutically acceptable salts formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, including, but not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid metaphosphoric acid, and the like; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3- (4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1, 2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo- [2.2.2] oct-2-ene-1-carboxylic acid, glucoheptonic acid,
4, 4’-methylenebis- (3-hydroxy-2-ene-1 -carboxylic acid) , 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid and muconic acid. In some embodiments, other acids, such as oxalic, while not in themselves pharmaceutically acceptable, are employed in the preparation of salts useful as intermediates in obtaining the compounds disclosed herein, solvate, or stereoisomer thereof and their pharmaceutically acceptable acid addition salts.
In some embodiments, those compounds described herein which comprise a free acid group react with a suitable base, such as the hydroxide, carbonate, bicarbonate, sulfate, of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine. Representative salts include the alkali or alkaline earth salts, like lithium, sodium, potassium, calcium, and magnesium, and aluminum salts and the like. Illustrative examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N+ (C1-4 alkyl) 4, and the like.
Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like. It should be understood that the compounds described herein also include the quaternization of any basic nitrogen-containing groups they contain. In some embodiments, water or oil-soluble or dispersible products are obtained by such quaternization.
Solvates
In some embodiments, the compounds described herein exist as solvates. The invention provides for methods of treating diseases by administering such solvates. The invention further provides for methods of treating diseases by administering such solvates as pharmaceutical compositions.
Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and, in some embodiments, are formed with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein can be conveniently prepared or formed during the processes described herein. By way of example only, hydrates of the compounds described herein can be conveniently prepared from an aqueous/organic solvent mixture, using organic solvents including, but not limited to, dioxane, tetrahydrofuran or methanol. In addition, the compounds provided herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.
Tautomers
In some situations, compounds exist as tautomers. The compounds described herein include all possible tautomers within the formulas described herein. Tautomers are compounds that are interconvertible by migration of a hydrogen atom, accompanied by a switch of a single bond and
adjacent double bond. In bonding arrangements where tautomerization is possible, a chemical equilibrium of the tautomers will exist. All tautomeric forms of the compounds disclosed herein are contemplated. The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH.
Method of Treatment
The presently disclosed compounds, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, find use in inhibiting the activity of the enzyme HPK1. HPK1, also referred to as mitogen activated protein kinase 1 or MAP4K1, is a member of the germinal center kinase subfamily of Ste20-related serine/threonine kinases. HPK1 functions as a MAP4K by phosphorylating and activating MAP3K proteins, including MEKK1, MLK3 and TAK1, leading to the activation of the MAPK Jnk.
The presently disclosed compounds, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, bind directly to HPK1 and inhibit its kinase activity. In some embodiments, the presently disclosed compounds reduce, inhibit, or otherwise diminish the HPK1-mediated phosphorylation of SLP76 and/or Gads.
In some embodiments, the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, are used in a method for inhibiting HPK1. Such methods comprise contacting HPK1 with an effective amount of a presently disclosed compound. By “contact” is intended bringing the compound within close enough proximity to an isolated HPK1 enzyme or a cell expressing HPK1 (e.g., T cell, B cell, dendritic cell) such that the compound is able to bind to and inhibit the activity of HPK1. The compound can be contacted with HPK1 in vitro or in vivo via administration of the compound to a subject.
Any method known in the art to measure the kinase activity of HPK1 may be used to determine if HPK1 has been inhibited, including in vitro kinase assays, immunoblots with antibodies specific for phosphorylated targets of HPK1, such as SLP76 and Gads, or the measurement of a downstream biological effect of HPK1 kinase activity, such as the recruitment of 14-3-3 proteins to phosphorylated SLP7 and Gads, release of the SLP76-Gads-14-3-3 complex from LAT-containing microclusters, or T or B cell activation.
In some embodiments, the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, are used to treat a HPK1-dependent disorder. As used herein, a “HPK1-dependent disorder” is a pathological condition in which HPK1 activity is necessary for the genesis or maintenance of the pathological condition. In some embodiments, the HPK1-dependent disorder is cancer.
In some embodiments, the compounds disclosed herein are used in enhancing an immune response in a subject in need thereof.
As used herein, “enhancing an immune response” refers to an improvement in any immunogenic response to an antigen. Non-limiting examples of improvements in an immunogenic response to an antigen include enhanced maturation or migration of dendritic cells, enhanced activation of T cells (e.g., CD4 T cells, CD8 T cells) , enhanced T cell (e.g., CD4 T cell, CD8 T cell) proliferation, enhanced B cell proliferation, increased survival of T cells and/or B cells, improved antigen presentation by antigen presenting cells (e.g., dendritic cells) , improved antigen clearance, increase in production of cytokines by T cells (e.g., interleukin-2) , increased resistance to prostaglandin E2-induced immune suppression, and enhanced priming and/or cytolytic activity of CD8 T cells.
In some embodiments, the CD8 T cells in the subject have enhanced priming, activation, proliferation and/or cytolytic activity relative to prior to the administration of the compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, the CD8 T cell priming is characterized by elevated CD44 expression and/or enhanced cytolytic activity in CD8 T cells. In some embodiments, the CD8 T cell activation is characterized by an elevated frequency of γ-IFN+ CD8 T cells. In some embodiments, the CD8 T cell is an antigen-specific T-cell.
In some embodiments, the antigen presenting cells in the subject have enhanced maturation and activation relative to prior to the administration of a compound disclosed herein. In some embodiments, the antigen presenting cells are dendritic cells. In some embodiments, the maturation of the antigen presenting cells is characterized by an increased frequency of CD83+ dendritic cells. In some embodiments, the activation of the antigen presenting cells is characterized by elevated expression of CD80 and CD86 on dendritic cells.
In some embodiments, the serum levels of cytokine IL-10 and/or chemokine IL-8, a human homolog of murine KC, in the subject are reduced relative to prior to the administration of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
Engagement of the TCR leads to HPK1 activation, which functions as a negative regulator of TCR-induced AP-1 response pathway. It is believed that HPK1 negatively regulates T cell activation by reducing the persistence of signaling microclusters by phosphorylating SLP76 at Ser376 and Gads at Thr254, which leads to the recruitment of 14-3-3 proteins that bind to the phosphorylated SLP76 and Gads, releasing the SLP76-Gads-14-3-3 complex from LAT-containing microclusters, which leads to T cell dysfunction, including anergy and exhaustion.
The term “dysfunction” in the context of immune dysfunction, refers to a state of reduced immune responsiveness to antigenic stimulation. The term includes the common elements of both exhaustion and/or anergy in which antigen recognition may occur, but the ensuing immune response is ineffective to control infection or tumor growth.
The term “dysfunctional, ” as used herein, also includes refractory or unresponsive to antigen recognition, specifically, impaired capacity to translate antigen recognition into downstream
T-cell effector functions, such as proliferation, cytokine production (e.g., IL-2, γ-IFN) and/or target cell killing.
The term “anergy” refers to the state of unresponsiveness to antigen stimulation resulting from incomplete or insufficient signals delivered through the T-cell receptor (e.g. increase in intracellular Ca+2 in the absence of ras-activation) . T cell anergy can also result upon stimulation with antigen in the absence of co-stimulation, resulting in the cell becoming refractory to subsequent activation by the antigen even in the context of costimulation. The unresponsive state can often be overridden by the presence of Interleukin-2. Anergic T-cells do not undergo clonal expansion and/or acquire effector functions.
The term “exhaustion” refers to T cell exhaustion as a state of T cell dysfunction that arises from sustained TCR signaling that occurs during many chronic infections and cancer. It is distinguished from anergy in that it arises not through incomplete or deficient signaling, but from sustained signaling. It is defined by poor effector function, sustained expression of inhibitory receptors and a transcriptional state distinct from that of functional effector or memory T cells. Exhaustion prevents optimal control of infection and tumors. Exhaustion can result from both extrinsic negative regulatory pathways (e.g., immunoregulatory cytokines) as well as cell intrinsic negative regulatory (costimulatory) pathways (PD-1, B7-H3, B7-H4, etc. ) .
In some embodiments, administration of the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, results in an enhancement of T cell function.
“Enhancing T cell function” means to induce, cause, or stimulate a T cell to have a sustained or amplified biological function, or renew or reactivate exhausted or inactive T cells. Examples of enhancing T cell function include: increased secretion of cytokines (e.g., γ-interferon, IL-2, IL-12, and TNFα) , increased proliferation, increased antigen responsiveness (e.g., viral, pathogen, or tumor clearance) relative to such levels before the intervention, and increased effector granule production by CD8 T cells, such as granzyme B. In one embodiment, the level of enhancement is as least 50%, alternatively 60%, 70%, 80%, 90%, 100%, 120%, 150%, 200%. The manner of measuring this enhancement is known to one of ordinary skill in the art.
In some embodiments, the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, are useful in treating T cell dysfunctional disorders. A “T cell dysfunctional disorder” is a disorder or condition of T cells characterized by decreased responsiveness to antigenic stimulation. In a particular embodiment, a T cell dysfunctional disorder is a disorder that is specifically associated with increased kinase activity of HPK1. In another embodiment, a T cell dysfunctional disorder is one in which T cells are anergic or have decreased ability to secrete cytokines, proliferate, or execute cytolytic activity. In a specific aspect, the decreased responsiveness results in ineffective control of a pathogen or tumor expressing an immunogen. Examples of T cell
dysfunctional disorders characterized by T-cell dysfunction include unresolved acute infection, chronic infection, and tumor immunity.
In some embodiments, the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, are used in treating conditions where enhanced immunogenicity is desired, such as increasing tumor immunogenicity for the treatment of cancer.
“Immunogenicity” refers to the ability of a particular substance to provoke an immune response. Tumors are immunogenic and enhancing tumor immunogenicity aids in the clearance of the tumor cells by the immune response.
“Tumor immunity” refers to the process in which tumors evade immune recognition and clearance. Thus, as a therapeutic concept, tumor immunity is “treated” when such evasion is attenuated, and the tumors are recognized and attacked by the immune system. Examples of tumor recognition include tumor binding, tumor shrinkage and tumor clearance.
In some embodiments, provided herein is a method of treating cancer in a subject in need thereof comprising administering to the subject an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, the subject has melanoma. The melanoma may be at early stage or at late stage. In some embodiments, the subject has colorectal cancer. The colorectal cancer may be at early stage or at late stage. In some embodiments, the subject has non-small cell lung cancer. The non-small cell lung cancer may be at early stage or at late stage. In some embodiments, the subject has pancreatic cancer. The pancreatic cancer may be at early stage or late state. In some embodiments, the subject has a hematological malignancy. The hematological malignancy may be at early stage or late stage. In some embodiments, the subject has ovarian cancer. The ovarian cancer may be at early stage or at late stage. In some embodiments, the subject has breast cancer. The breast cancer may be at early stage or at late stage. In some embodiments, the subject has renal cell carcinoma. The renal cell carcinoma may be at early stage or at late stage. In some embodiments, the cancer has elevated levels of T-cell infiltration.
In some embodiments, provided herein is a method of treating a viral infection in a subject in need thereof comprising administering to the subject an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, the viral infection is a chronic viral infection.
In some embodiments, provided herein is a method of increasing the efficacy of vaccination in a patient comprising administering to the patient a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or a pharmaceutical composition disclosed herein.
Dosing
In certain embodiments, the compositions containing the compound (s) described herein are administered for therapeutic treatments. In certain therapeutic applications, the compositions are
administered to a patient already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest at least one of the symptoms of the disease or condition. Amounts effective for this use depend on the severity and course of the disease or condition, previous therapy, the patient’s health status, weight, and response to the drugs, and the judgment of the treating physician. Therapeutically effective amounts are optionally determined by methods including, but not limited to, a dose escalation and/or dose ranging clinical trial.
In certain embodiments wherein the patient’s condition does not improve, upon the doctor’s discretion the administration of the compounds are administered chronically, that is, for an extended period of time, including throughout the duration of the patient’s life in order to ameliorate or otherwise control or limit the symptoms of the patient’s disease or condition.
Once improvement of the patient’s conditions has occurred, a maintenance dose is administered if necessary. Subsequently, in specific embodiments, the dosage, or the frequency of administration, or both, is reduced, as a function of the symptoms.
The amount of a given agent that corresponds to such an amount varies depending upon factors such as the particular compound, disease condition and its severity, the identity (e.g., weight, sex) of the subject or host in need of treatment, but nevertheless is determined according to the particular circumstances surrounding the case, including, e.g., the specific agent being administered, the route of administration, the condition being treated, and the subject or host being treated.
In some embodiments, doses employed for adult human treatment are typically in the range of 0.01 mg-5000 mg per day. In some embodiments, the daily dosages appropriate for the compound described herein, or a pharmaceutically acceptable salt thereof, are from about 0.01 to about 50 mg/kg per body weight. In various embodiments, the daily and unit dosages are altered depending on a number of variables including, but not limited to, the activity of the compound used, the disease or condition to be treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition being treated, and the judgment of the practitioner.
Routes of Administration
Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ophthalmic, pulmonary, transmucosal, transdermal, vaginal, otic, nasal, and topical administration. In addition, by way of example only, parenteral delivery includes intramuscular, subcutaneous, intravenous, intramedullary injections, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injections.
In certain embodiments, a compound as described herein is administered in a local rather than systemic manner, for example, via injection of the compound directly into an organ, often in a depot preparation or sustained release formulation. In specific embodiments, long acting formulations are administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Furthermore, in other embodiments, the drug is delivered in a targeted drug delivery system,
for example, in a liposome coated with organ specific antibody. In such embodiments, the liposomes are targeted to and taken up selectively by the organ. In yet other embodiments, the compound as described herein is provided in the form of a rapid release formulation, in the form of an extended release formulation, or in the form of an intermediate release formulation.
Pharmaceutical Compositions/Formulations
The compounds described herein are administered to a subject in need thereof, either alone or in combination with pharmaceutically acceptable carriers, excipients, or diluents, in a pharmaceutical composition, according to standard pharmaceutical practice. In some embodiments, the compounds described herein are administered to animals.
In another aspect, provided herein are pharmaceutical compositions comprising a compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and at least one pharmaceutically acceptable excipient. Pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable excipients that facilitate processing of the active compounds into preparations that can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. A summary of pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995) ; Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams &Wilkins1999) , herein incorporated by reference for such disclosure.
In some embodiments, the pharmaceutically acceptable excipient is selected from carriers, binders, filling agents, suspending agents, flavoring agents, sweetening agents, disintegrating agents, dispersing agents, surfactants, lubricants, colorants, diluents, solubilizers, moistening agents, plasticizers, stabilizers, penetration enhancers, wetting agents, anti-foaming agents, antioxidants, preservatives, and any combinations thereof.
The pharmaceutical formulations described herein include, but are not limited to, aqueous liquid dispersions, liquids, gels, syrups, elixirs, slurries, suspensions, self-emulsifying dispersions, solid solutions, liposomal dispersions, aerosols, solid oral dosage forms, powders, immediate release formulations, controlled release formulations, fast melt formulations, tablets, capsules, pills, powders, dragees, effervescent formulations, lyophilized formulations, delayed release formulations, extended release formulations, pulsatile release formulations, multiparticulate formulations, and mixed immediate and controlled release formulations.
Combination
Disclosed herein are methods of treating a disease or disorder associated with HPK1 using a
compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, in combination with an additional therapeutic agent.
In some embodiments, the additional therapeutic agent is administered at the same time as the compound disclosed herein. In some embodiments, the additional therapeutic agent and the compound disclosed herein are administered sequentially. In some embodiments, the additional therapeutic agent is administered less frequently than the compound disclosed herein. In some embodiments, the additional therapeutic agent is administered more frequently than the compound disclosed herein. In some embodiments, the additional therapeutic agent is administered prior than the administration of the compound disclosed herein. In some embodiments, the additional therapeutic agent is administered after the administration of the compound disclosed herein.
In some embodiments, the additional therapeutic agent is an anti-cancer agent.
Examples
Example 1
Step 1: Procedure for preparation of 1-2
To a solution of methyl 6-aminopicolinate 1-1 (20.0 g, 131.58 mmol) in MeCN (300 mL) were added NBS (25.76 g, 144.74 mmol) , and the reaction was stirred at 25 ℃ for 1 h. The reaction was quenched with 10%Na2S2O3 solution and then added water (600 mL) and extracted with EtOAc (300 mL*3) . The combined organic layer were washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified using silica gel column chromatography to afford 1-2 (25.0 g, 83%yield) as a white solid. LC-MS (ESI+) : m/z 232.9 (M+H) +.
Step 2: Procedure for preparation of 1-3
To a solution of 1-2 (25.0 g, 108.70 mmol) and DMAP (1.33 g, 10.87 mmol) in dioxane (300 mL) was added Boc2O (47.39 g, 217.40 mmol) , and the reaction was stirred at 70 ℃ for 2 hr. The reaction mixture was poured into H2O (600 mL) and then extracted with EtOAc (300 mL*3) . The combined organic layer was washed with brine (300 mL*3) , dried over Na2SO4, and concentrated to give crude product, which was purified by Flash Chromatography to afford 1-3 (40.0 g, 85%yield) as a yellow solid. LC-MS (ESI+) : m/z 333.0 (M-100+H) +.
Step 3: Procedure for preparation of 1-4
To a solution of 1-3 (40.0 g, 93.02 mmol) in CH3OH (500 mL) was added NaBH4 (7.07 g, 186.05 mmol) , and the reaction was stirred at 70 ℃ for 2 hr. The reaction was quenched with water (100 mL) at 0 ℃. The solvent was removed under vacuum then added water (300 mL) , and extracted with EtOAc (300 mL*3) . The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified using silica gel column chromatography to afford 1-4 (22.0 g, 78%yield) as a white solid.
LC-MS (ESI+) : m/z 305.1 (M+H) +.
Step 4: Procedure for preparation of 1-5
To a solution of 1-4 (22.0 g, 72.60 mmol) and DIEA (47.70 g, 217.80 mmol) in DCM (400 mL) was added MsCl (12.41 g, 108.90 mmol) , and the reaction was stirred at 0 ℃ for 1 hr. The reaction mixture was poured into H2O (500 mL) and then extracted with DCM (200 mL*3) . The combined organic layer was washed with brine (200 mL*3) , dried over Na2SO4, and concentrated to afford 1-5 (20.0 g, 76%yield) as a yellow solid. LC-MS (ESI+) : m/z 382.0 (M+H) +.
Step 5: Procedure for preparation of 1-6
To a solution of 1-5 (20.0 g, 54.90 mmol) and DIEA (880 mg, 164.83 mmol) in ACN (300 mL) was added dimethylamine in THF (54.90 mL, 109.80 mmol, 2.0 M) , and the reaction was stirred at 70 ℃ for 1 hr. The reaction mixture was poured into H2O (900 mL) and then extracted with EtOAc (300 mL*3) . The combined organic layer was washed with brine (300 mL*3) , dried over Na2SO4, and concentrated. The residue was purified using silica gel column chromatography to afford 1-6 (15.0 g, 82%yield) as a yellow solid. LC-MS (ESI+) : m/z 330.1 (M+H) +.
Step 6: Procedure for preparation of 1-8
To a solution of 1-6 (15.0 g, 45.45 mmol) and 1-7 (14.32 g, 68.18 mmol) in dioxane/H2O = 5: 1 (300 mL: 60 mL) were added K3PO4 (28.91 g, 136.35 mmol) , XPhosPdG3 (3.85 g, 4.55 mmol) , and the reaction was stirred at 140 ℃ for 4 hr. The reaction mixture was poured into H2O (600 mL) and then extracted with EtOAc (500 mL*3) . The combined organic layer was washed with brine (500 mL*3) , dried over Na2SO4, and concentrated to give crude product, which was purified by Flash Chromatography to afford 1-8 (8.0 g, 53%yield) as a yellow solid. LC-MS (ESI+) : m/z 334.3 (M+H) +.
Ste 7: Procedure for preparation of 1-9
To a solution of 1-8 (8.0 g, 24.02 mmol) in methanol (100 mL) was added Pd/C (1.6 g, 20%) , and the reaction was heated and stirred at 25 ℃ for 4 hr under H2 atmosphere. The reaction was filtered through a Celite pad, and the filtrate was concentrated to afford 1-9 (6.0 g, 75%yield) as a yellow solid. LC-MS (ESI+) : m/z 336.3 (M+H) +.
Ste 8: Procedure for preparation of 1-10
To a solution of 1-9 (6.0 g, 17.91 mmol) in DCM (50.0 mL) were added TFA (17.0 mL) , and the reaction was stirred at 25 ℃ for 4 hr. The solvent was removed under vacuum to afford 1-10 (4.0 g, 95%yield) as a yellow solid. LC-MS (ESI+) : m/z 236.3 (M+H) +.
Step 9: Procedure for preparation of 1-12
To a solution of 7-fluoroimidazo [3, 2-a] pyridine 1-11 (5 g, 36.730 mmol) in CHCl3 (100 mL) were added NBS (9.81 g, 55.094 mmol) , and the reaction was stirred at 25 ℃ for 2 hr. The reaction was diluted with DCM (200ml) and water (100ml) . The organic layer was separated, washed with further saturated NaCl solution, and concentrated in vacuo. The residue was purified using silica gel column chromatography to afford the title compound 1-12 (3.2 g, 40.52%) as a white solid. LC-MS (ESI) : m/z 215.0 (M+H) +.
Step 10: Procedure for preparation of 1-13
To a solution of 1-12 (800 mg, 3.72 mmol) in anhydrous THF (10 mL) at -15 ℃ under a nitrogen atmosphere was treated dropwise with isopropylmagnesium chloride lithium chloride complex solution (1.3 M in THF, 4.464 mmol) . After stirring for 15 min, tributyltin chloride (1332 mg, 4.092mmol) was added. After warming to 25 ℃ and stirring for 1 h. The reaction was quenched with a saturated NH4Cl solution and extracted into EtOAc (2 x 20 ml) . The combined extracts were dried over MgSO4 and concentrated in vacuo to afford the 1-13 (1.5 g, 75%) as a yellow oil. LC-MS (ESI) : m/z 427.2 (M+H) +.
Step 11: Procedure for preparation of 1-15
To a solution of 1-14 (5 g, 24.15 mmol) in H2SO4 (30 mL) was added 1, 3, 5-trichloro-1, 3, 5-triazinane-2, 4, 6-trione (11.18 g, 48.30 mmol) at 0 ℃, and the reaction was stirred at 25 ℃ for another 16 hr. The reaction mixture was poured into ice water (100 mL) , and filtered through a Celite pad, the filtrate was added water (100 mL) and extracted with EtOAc (100 mL*3) . The combined organic layers were washed with brine (50 mL) , dried over anhydrous sodium sulfate, and concentrated to give crude product, which was purified by Flash Chromatography to afford 1-15 (3.0 g, 52%yield) as a yellow solid. LC-MS (ESI+) : m/z 241.9 (M+H) +.
Step 12: Procedure for preparation of 1-16
To a solution of 1-15 (3.0 g, 12.45 mmol) in DCM (30 mL) were added m-CPBA (3.23 g, 18.68 mmol) , and the reaction was stirred at 25 ℃ for 16 hr. The reaction was quenched with 10%Na2S2O3 solution (30 mL) and then added water (30 mL) and extracted with DCM (50 mL*3) . The combined organic layers were washed with brine (80 mL) , dried over anhydrous sodium sulfate and concentrated. The residue was purified using silica gel column chromatography to afford 1-16 (2.2 g, 60%yield) as a white solid. LC-MS (ESI+) : m/z 257.9 (M+H) +.
Step 13: Procedure for preparation of 1-17
To a solution of 1-16 (2.2 g, 8.56 mmol) in Ac2O (10.0 mL) was stirred at 120 ℃ for 2 hr. The solvent was removed under vacuum to give crude product, then to the mixture was added aq. NaOH solution (10.0 mL, 2.0 mol/L) . The mixture was stirred at 100 ℃ for another 2 hr. The reaction mixture was poured into H2O (40 mL) and then extracted with EtOAc (50 mL*3) . The combined organic layer was washed with brine (50 mL*3) , dried over Na2SO4, and concentrated to give crude product, which was purified by Flash Chromatography to afford 1-17 (800 mg, 37%yield) as a white solid. LC-MS (ESI+) : m/z 257.9 (M+H) +.
Step 14: Procedure for preparation of 1-18
To a solution of 1-17 (800.0 mg, 3.11 mmol) in THF (20 mL) was added NaH (186.60 mg, 4.67 mmol 60%) at 0 ℃ under N2 atmosphere, and the reaction was stirred at 0 ℃ for 1 hr. Then SEMCl (1.03 g, 6.22 mmol) was added to the reaction at 0 ℃, and the reaction was stirred at 25 ℃ for another 3 hr. The reaction was quenched with NH4Cl solution and then added water (30 mL) and extracted with EtOAc (30 mL*3) . The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified using silica gel column chromatography to afford 1-18 (750.0 mg, 63%yield) as oil. LC-MS (ESI+) : m/z 388.0 (M+H) +.
Step 15: Procedure for preparation of 1-19
To a solution of 1-18 (750.0 mg, 1.94 mmol) and 1-13 (1.24 g, 2.90 mmol) in THF (30 mL) was added Pd (PPh3) 2Cl2 (134 mg, 0.19 mmol) , and the reaction was stirred at 70 ℃ for 16 hr. The reaction mixture was poured into H2O (60 mL) and then extracted with EtOAc (50 mL*3) . The combined organic layer was washed with brine (50 mL*3) , dried over Na2SO4, and concentrated to give crude product, which was purified by Flash Chromatography to afford 1-19 (500 mg, 58%yield) as a white solid. LC-MS (ESI+) : m/z 444.1 (M+H) +.
Step 16: Procedure for preparation of 1-20
To a solution of 1-19 (200.0 mg, 0.45 mmol) and 1-10 (211.0 mg, 0.90 mmol) in THF (10 mL) were added Cs2CO3 (439.0 mg, 1.35 mmol) , XantPhos (52.0 mg, 0.09 mmol) , and Pd2 (dba) 3 (45.8 mg, 0.05 mmol) , and the reaction was stirred at 100 ℃ for 16 hr. The reaction mixture was poured into H2O (50 mL) and then extracted with EtOAc (50 mL*3) . The combined organic layer was washed with brine (50 mL*3) , dried over Na2SO4, and concentrated to give crude product, which was purified by Flash Chromatography to afford 1-20 (100.0 mg, 36%yield) as a white solid. LC-MS (ESI+) : m/z 643.4 (M+H) +.
Step 17: Procedure for preparation of Example 1
To a solution of 1-20 (100 mg, 0.16 mmol) in DCM (2.0 mL) was added TFA (2.0 mL) , and the reaction was stirred at 25 ℃ for 1 hr. The solvent was removed under vacuum to give crude intermediate product, then to the mixture was added NH3 in CH3OH (5 mL) . The mixture was stirred at 25 ℃ for another 1 hr. The solvent was removed under vacuum. The residue was purified by prep-HPLC to give example 1 (10.3 mg, 13%yield) as a white solid. LC-MS (ESI+) : m/z 513.3 (M+H) +. 1H NMR (400 MHz, DMSO-d6) δ 12.84 (s, 1H) , 11.77 (s, 1H) , 9.71 (s, 1H) , 8.54 (d, J = 8.8 Hz, 1H) , 8.25-8.10 (m, 2H) , 7.95 (dd, J = 8.8, 2.4 Hz, 1H) , 7.78 (dd, J = 40.0, 8.8 Hz, 2H) , 7.33 (td, J = 8.0, 2.0Hz, 1H) , 7.25-7.13 (m, 2H) , 6.11 (d, J = 8.0Hz, 1H) , 4.61 (d, J = 4.0Hz, 3H) , 3.98 (dd, J = 10.0, 4.0Hz, 3H) , 3.51 (td, J = 12.0, 2.0Hz, 2H) , 2.82 (d, J = 8.0 Hz, 1H) , 2.14-1.43 (m, 6H) .
Example 2
Step 1: Procedure for preparation of 2-2
To a solution of 2-1 (5 g, 0.2898 mmol) in MeOH (50 mL) were added H2SO4 (1 mL, 18.762 mmol) and the reaction was stirred at 60 ℃ overnight. The reaction was diluted with EtOAc (100 mL) and water (100 mL) . The organic layer was separated, washed with brine (50 mL) , and concentrated in vacuo. The residue was purified using silica gel column chromatography to afford the title compound 2-2 (4.5 g, 81.20%yield) . 1H NMR (400 MHz, DMSO-d6) δ 10.11 (s, 1H) , 7.35 (d, J = 8.8 Hz, 1H) , 7.18 (d, J = 3.0 Hz, 1H) , 6.96 (dd, J = 8.8, 3.0 Hz, 1H) , 3.84 (s, 3H) .
Step 2: 2 Procedure for preparation of 2-3
To a solution of 2-2 (4 g, 0.2144 mmol) in TFA (50 mL) were added 1, 3, 5, 7-tetrazatricyclo [3.3.1.13
, 7] decane (4.86 g, 0.1608 mmol) and the reaction was stirred at 75 ℃ for 2 hr. The reaction mixture was filtered through normal funnel. The reaction was diluted with EA (100
mL) and water (100 mL) . The organic layer was separated, washed with brine (50 mL) , and concentrated in vacuo. The residue was purified using silica gel column chromatography to afford the title compound 2-3 (2.1 g, 45%yield) . 1H NMR (400 MHz, DMSO-d6) δ 11.40 (s, 1H) , 10.26 (s, 1H) , 7.65 (d, J = 8.8 Hz, 1H) , 7.13 (d, J = 8.8 Hz, 1H) , 3.83 (s, 3H) .
Step 3: Procedure for preparation of 2-4
To a solution of methyl 2-3 (2.1 g, 0.489 mmol) in EtOH (30 mL) were added Hydrazine (0.94 mL, 2.974 mmol) , the reaction mixture stirred at 80 ℃ overnight. Then vacuum spin drying, petroleum ether beating, get crude product, used for the next reaction, the organic layer was collected, concentrated in vacuo, and dried to afford the title compound 2-4 (1.5 g, 54%yield) . 1H NMR (400 MHz, DMSO-d6) δ 12.33 (s, 1H) , 8.36 (s, 1H) , 7.49 (d, J = 8.6 Hz, 1H) , 7.07 (d, J = 8.6 Hz, 1H) .
Step 4: Procedure for preparation of 2-6
To a solution of 2-4 (1.1 g, 0.6024 mmol) in DCM (20 mL) were added TEA (1.555 mL, 11.191mmol) , 2-5 (1.5 g, 4.197 mmol) , and the reaction was stirred at room temperature for 3 hr. The reaction was diluted with EA (50 mL) and water (50 mL) . The organic layer was separated, washed with brine (30 mL) , and concentrated in vacuo. The residue was purified using silica gel column chromatography to afford the title compound 2-6 (900 mg, 70%yield) . 1H NMR (400 MHz, DMSO-d6) δ 13.09 (s, 1H) , 8.25 (s, 1H) , 8.03 (qd, J = 8.8, 1.6 Hz, 2H) .
Step 5: Procedure for preparation of 2-7
To a solution of 2-6 (50 mg, 0.152 mmol) in THF (10 mL) were added 1-13 (64 mg, 0.152 mmol) , Pd (PPh3) 2Cl2 (11 mg, 0.015 mmol) , and the reaction was stirred at 70 ℃ overnight. The reaction was diluted with EA (40 mL) and water (30 mL) . The organic layer was separated, washed with brine (20 mL) , and concentrated in vacuo. The residue was purified using silica gel column chromatography to afford the title compound 2-7 (25 mg, 52%yield) . LC-MS (ESI) : m/z 315.1 (M+H) +.
Step 6: Procedure for preparation of Ex2
To a solution of 2-7 (25 mg, 0.079 mmol) and 1-10 (37.5 mg, 0.16 mmol) in dioxane (1 mL) were added Cs2CO3 (77 mg, 0.238 mmol) , XantPhos (4 mg, 0.008 mmol) , and Pd2 (dba) 3 (7.27 mg, 0.008 mmol) , and the reaction was stirred at 120 ℃ for 3 hr. The reaction mixture was filtered through normal funnel. The reaction was diluted with EA (20 mL) and water (10 mL) . The organic layer was separated, washed with brine (5 mL) , and concentrated in vacuo. The residue was purified by Prep-HPLC to afford the title compound example 2 (5 mg, 12.25%yield) . LC-MS (ESI) : m/z 514.3 (M+H) +. 1H NMR (400 MHz, DMSO-d6) δ 12.94 (s, 1H) , 12.27 (s, 1H) , 8.19 (d, J = 8.0 Hz, 1H) , 8.89 (d, J = 8.0 Hz, 1H) , 7.77 (d, J = 12.0 Hz, 2H) , 7.57 (d, J = 8.0 Hz, 1H) , 7.21 (s, 2H) , 7.05-7.00 (m, 1H) , 6.66 (s, 2H) , 5.34-5.32 (m, 2H) , 4.13-4.09 (m, 2H) , 3.99-3.96 (m, 3H) , 2.08-1.98 (m, 6H) , 1.48-1.46 (m, 4H) .
Example 3
Step 1: Procedure for preparation of 3-2
To a solution of 3-1 (400 mg, 1.48 mmol) and DMAP (12 mg, 0.148 mmol) in dioxane (10 mL) were added TEA (449 mg, 4.44 mmol) , and Boc2O (387 mg, 1.77 mmol) , and the reaction was stirred at 25 ℃ for 6 hr. The reaction mixture was poured into H2O (30 mL) and then extracted with EtOAc (30 mL*3) . The combined organic layer was washed with brine (30 mL) , dried over Na2SO4,
and concentrated to give crude product, which was purified by Flash Chromatography to afford 3-2 (500 mg, 91%yield) as a yellow solid. LC-MS (ESI+) : m/z 763.0 (2M+Na) +.
Step 2: Procedure for preparation of 3-3
To a solution of 3-2 (450 mg, 1.21 mmol) and 1-13 (777 mg, 1.82 mmol) in THF (20 mL) were added Pd (PPh3) 2Cl2 (85 mg, 0.12 mmol) and the reaction was stirred at 80 ℃ under N2 for 16 h. The reaction mixture was poured into H2O (30 mL) and then extracted with EtOAc (30 mL*3) . The combined organic layer was washed with brine (30 mL) , dried over Na2SO4, and concentrated to give crude product, which was purified by Flash Chromatography to afford 3-3 (300 mg, 58%yield) as a yellow solid. LC-MS (ESI+) : m/z 427.6 (M+H) +.
Step 3: Procedure for preparation of 3-4
To a solution of 3-3 (300 mg, 0.70 mmol) in EtOH/H2O=5: 1 (20 mL: 4 mL) was added Fe (197 mg, 3.52 mmol) , and NH4Cl (440 mg, 7.04 mmol) , the reaction was heated and stirred at 75 ℃ for 3 hr. The reaction was filtered through a Celite pad, and the filtrate was concentrated in vacuo, then added water (50 mL) and extracted with EtOAc (50 mL × 3) . The combined organic layers were washed with brine (30 mL*3) , dried over anhydrous sodium sulfate, and concentrated to give crude product, which was purified by Flash Chromatography to afford 3-4 (210 mg, 75%yield) as a yellow solid. LC-MS (ESI+) : m/z 397.2 (M+H) +.
Step 4: Procedure for preparation of 3-5
To a solution of 3-4 (150 mg, 0.37 mmol) in MeCN (10 mL) was added tert-butylnitrite (193 mg, 1.89 mmol) at 0 ℃ for 30 min. Then CuBr2 (840 mg, 3.7 mmol) was added to the reaction at 0 ℃, and the reaction was stirred at 25 ℃ for 16 hr. The reaction mixture was poured into ice water (20 mL) , and filtered through a Celite pad, the filtrate was added water (30 mL) and extracted with EtOAc (50 mL*3) . The combined organic layers were washed with brine (10 mL*3) , dried over anhydrous sodium sulfate, and concentrated to give crude product, which was purified by Flash Chromatography to afford 3-5 (100 mg, 57%yield) as a yellow solid. LC-MS (ESI+) : m/z 460.2 (M+H) +.
Step 5: Procedure for preparation of 3-6
To a solution of 3-5 (90 mg, 0.19 mmol) , Pd2 (dba) 3 (17 mg, 0.019mmol) , XantPhos (9 mg, 0.019 mmol) , Cs2CO3 (190 mg, 0.57 mmol) and 1-10 (55 mg, 0.23 mmol) in dioxane (2 mL) at 23 ℃, and the reaction was stirred at 120 ℃ for 2 hr under N2. The reaction mixture was poured into H2O (20 mL) and then extracted with EtOAc (30 mL*3) . The combined organic layer was washed with brine (20 mL) , dried over Na2SO4, and concentrated to give crude product. The residue was purified by Prep-TLC to 3-6 (40 mg, 33%yield) as a yellow solid. LC-MS (ESI+) : m/z 615.4 (M+H) +.
Step 6: Procedure for preparation of Example 3
To a solution of 3-6 (40 mg, 0.065mmol) was added 4M HCl/dioxane (3 mL) , and the reaction was stirred at 25 ℃ for 2 hr. The solvent was removed under vacuum to give crude product. The residue was purified by example 3 (15 mg, 45%yield) as a yellow solid. LC-MS (ESI+) : m/z 515.3 (M+H) +. 1H NMR (400 MHz, DMSO-d6) δ 11.97 (s, 1H) , 8.70 (s, 1H) , 8.34-8.11 (m, 2H) , 7.67-7.46 (m, 4H) , 6.93 (s, 2H) , 3.97-3.95 (m, 2H) , 3.92-3.87 (m, 2H) , 3.25-3.14 (m, 3H) , 2.50 (s, 6H) , 2.31-2.29 (s, 4H) , 1.64 (m, 4H) .
Example 4
Step 1: Procedure for preparation of 4-2
To a solution of 2, 3-dibromo-5-chloropyridine 4-1 (14 g, 51.60 mmol) in THF (60 mL) was added monolithium magnesium dichloride propan-2-ide (39.70 mL, 51.60 mmol) dropwise at -40 ℃ under N2 and the reaction was stirred at -40 ℃ for 1 hr. DMF (30 mL, 389.11 mmol) was added dropwise at -40 ℃. The re action mixture was stirred at 25 ℃ for l h. The reaction mixture was quenched by aq. HCl (80 ml, 1M) . The resulting mixture was extracted with ethyl acetate (4 x 100 ml) . The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography on silica gel to afford the title compound 2-bromo-5-chloronicotinaldehyde 4-2 (7.5 g, 65.94%yield) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 10.11 (s, 1H) , 8.76 (s, 1H) , 8.24 (s, 1H) .
Step 2: Procedure for preparation of 4-3
To a solution of 4-2 (7.5 g, 34.02 mmol) in MeOH (85 mL) was added trimethoxymethane (10.83 g, 102.06 mmol) , p-Toluenesulfonic acid (0.59 g, 3.40 mmol) , and the reaction was stirred at 80 ℃ overnight. The resulting suspension was concentrated under reduce pressure to give a residue, which was purified by column chromatography on silica gel to afford the title compound 2-bromo-5-chloro-3- (dimethoxymethyl) pyridine 4-3 (5.5 g, 60.66%yield) as a yellow oil. LC-MS (ESI) : m/z 268.1 (M+H) +.
Step 3: Procedure for preparation of 4-4
A solution of LDA (2M in THF, 42.21 mmol) in dry THF (10 mL) at -50 ℃ under a nitrogen atmosphere was treated dropwise with a solution of 4-3 (5.5 g, 20.64 mmol) in dry THF (10 mL) over 40 min. After the addition, the mixture was stirred for an additional 40 min. Methyl chloromethanoate (7.98 g, 84.421 mmol) was added dropwise and stirred at -50 ℃ for 40 min. The reaction was quenched by saturated aq. NaHCO3 solution (50 mL) and extracted with EtOAc (50 mL x 3) . The combined organic layer was washed with brine (50 mL) , dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue, which was purified by column chromatography on silica gel to afford the title compound methyl 2-bromo-5-chloro-3- (dimethoxymethyl) isonicotinate 4-4 (2.7 g, 29.56%yield) as a pale yellow oil. LC-MS (ESI) : m/z 324.1 (M+H) +.
Step 4: Procedure for preparation of 4-6
To a solution of methyl 2-bromo-5-chloro-3- (dimethoxymethyl) isonicotinate 4-4 (1.20 g, 3.70 mmol) in dioxane (8 mL) and H2O (1 mL) was added 4-5 (0.72 g, 4.07 mmol) , K2CO3 (1.53 g, 11.09 mmol) , Pd (dppf) Cl2 (0.27 g, 0.37 mmol) , and the reaction was stirred at 100 ℃ for 2 hr. To the reaction mixture was added water (40 mL) . The aqueous layer was extracted with EtOAc (20 mL x 2) . The combined organic layer was washed with brine (20 mL) , dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography on silica gel to afford the title compound methyl 5-chloro-3- (dimethoxymethyl) -2- (1-methyl-1H-pyrrolo [2, 3-b] pyridin-4-yl) isonicotinate 4-6 (. 650 mg, 46.90%yield) as a yellow solid. LC-MS (ESI) : m/z 376.1 (M+H) +.
Step 5: Procedure for preparation of 4-7
To a solution of methyl 5-chloro-3- (dimethoxymethyl) -2- (1-methyl-1H-pyrrolo [2, 3-b] pyridin-4-yl) isonicotinate 4-6 (650 mg, 1.73 mmol) in DCM (10 mL) was added TFA (10 ml) , and the reaction was stirred at 20 ℃ for 12 hr. The mixture was concentrated under reduced pressure to give the title compound methyl 5-chloro-3-formyl-2- (1-methyl-1H-pyrrolo [2, 3-b] pyridin-4-yl) isonicotinate 4-7 (680 mg, 95.42%yield) as a light yellow solid. LC-MS (ESI) : m/z 330.1 (M+H) +.
Step 6: Procedure for preparation of 4-8
To a solution of methyl 5-chloro-3-formyl-2- (1-methyl-1H-pyrrolo [2, 3-b] pyridin-4-yl) isonicotinate 4-7 (680 mg, 1.66 mmol) in MeOH (10 mL) was added NH2NH2. H2O (2.50 ml) , and the reaction was stirred at 20 ℃ for 12 hr. The reaction was concentrated under reduce pressure to give a crude, to which was added petroleum ether (30 mL) and stirred for 30 min. Filtered and the filter cake was dried in vacuo to afford the title compound 8-chloro-5- (1-methyl-1H-pyrrolo [2, 3-b] pyridin-4-yl) pyrido [3, 4-d] pyridazin-1 (2H) -one 4-8 (270 mg, 52.51%yield) as a yellow solid.
LC-MS (ESI) : m/z 312.1 (M+H) +.
Step 7: Procedure for preparation of 4-9
To a solution of 4-8 (270 mg, 0.87 mmol) in acetonitrile (20 mL) was added DMAP (53.08 mg, 0.43 mmol) and di-tert-butyl dicarbonate (0.24 mL, 1.04 mmol) at 0 ℃. The reaction was stirred at 20 ℃ for 2 hr. To the reaction mixture was added water (40 mL) and the aqueous layer was extracted
with EtOAc (20 mL x 2) . The combined organic layer was washed with brine (20 mL) , dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography on silica gel to afford the 4-9 (220 mg, 61.63%yield) as a light yellow solid. LC-MS (ESI) : m/z 412.0 (M+H) +.
Step 8: Procedure for preparation of Example 4
To a solution of 4-9 (70 mg, 0.17 mmol) in dioxane (2 mL) was added Cs2CO3 (166.53 mg, 0.51 mmol) , XantPhos (9.86 mg, 0.017 mmol) , and Pd2 (dba) 3 (13.79 mg, 0.017 mmol) , and the reaction was stirred at 120 ℃ for 3 hr. The reaction mixture was filtered and the filtrate was diluted with EtOAc (20 mL) and water (10 mL) . The organic layer was separated, washed with brine (5 mL) , concentrated under reduced pressure to give a residue, which was purified by prep-HPLC to afford example 4 (5 mg, 5.76%yield) as a white solid. LC-MS (ESI) : m/z 511.3 (M+H) +. 1H NMR (400 MHz, DMSO-d6) δ 13.17 (s, 1H) , 11.74 (s, 1H) , 10.48 (s, 1H) , 8.44 (d, J = 4.8 Hz, 1H) , 8.04 (s, 1H) , 7.75 (d, J = 8.4 Hz, 1H) , 7.62 (d, J = 3.6 Hz, 1H) , 7.31 (d, J = 4.8 Hz, 1H) , 7.03 (d, J = 8.4 Hz, 1H) , 6.35 (d, J = 3.2 Hz, 1H) , 3.97 (d, J = 11.2 Hz, 2H) , 3.91 (s, 3H) , 3.61 (s, 2H) , 3.47 –3.44 (m, 2H) , 3.21 –3.19 (m, 1H) , 2.24 (s, 6H) , 1.70 –1.68 (m, 4H)
Example 5
Step 1: Procedure for preparation of 5-2
To a solution of 5-bromo-2-chlorobenzoic acid 5-1 (3 g, 12.74 mmol) in DMA (30 mL) was added dimethyl (1-diazo-2-oxopropyl) phosphonate (2.69 g, 14.01 mmol) , KOAc (1 . 01 g, 10.19 mmol) , and bis (1, 2, 3, 4, 5-pentamethylcyclopentane) bis [dichlororhodium (II) ] (0.20 g, 0.32 mmol) . The reaction was stirred at 100 ℃ for 12 hr. To the reaction mixture was added water (50 mL) . The aqueous layer was extracted with EA (50 mL x 2) . The combined organic layer was washed with brine (100 mL) , dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was
purified by flash chromatography on silica gel to give 5-2 (1.10 g, 31.57%yield) as a white solid. LC-MS (ESI) : m/z 275.0 (M+H) +.
Step 2: Procedure for preparation of 5-3
To a solution of 5-2 (1.10 g, 4.02 mmol) in MeOH (10 mL) was added ammonia (5.74 mL, 40.22 mmol) , and the reaction was stirred at 80 ℃ for 12 hr in sealed tube. The mixture was concentrated under reduced pressure to give 5-3 (750 mg, 68.43%yield) as a white solid. LC-MS (ESI) : m/z 274.0 (M+H) +.
Step 3: Procedure for preparation of 5-4
To a solution of 5-3 (750 mg, 2.75 mmol) in ACN (4 mL) was added DMAP (403.45 mg, 3.30 mmol) , (2-methylprop-2-yl) oxidanecarboxylic anhydride (1.264 mL, 5.50 mmol) , and the reaction was stirred at 25 ℃ for 12 hr. To the reaction mixture was added water (40 mL) . The aqueous layer was extracted with EtOAc (20 mL x 2) . The combined organic layer was washed with brine (20 mL) , dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue , which was purified by flash chromatography on silica gel to give 5-4 (500 mg, 48.76%yield) as a yellow solid. LC-MS (ESI) : m/z 273.9 (M-100) +.
Step 4: Procedure for preparation of 5-5
To a solution of 5-4 (250 mg, 0.67 mmol) in THF (4 mL) was added Pd (dppf) Cl2 (49.09 mg, 0.07 mmol) , 7-fluoro-3- (tributylstannyl) imidazo [1, 2-a] pyridine (313.77 mg, 0.74 mmol) , and the reaction was stirred at 70 ℃ for 4 hr. To the reaction mixture was added water (40 mL) . The aqueous layer was extracted with EtOAc (20 mL x 2) . The combined organic layer was washed with brine (20 mL) , dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was
purified by flash chromatography on silica gel to give 5-5 (150 mg, 52.26%yield) as a white solid. LC-MS (ESI) : m/z 429.9 (M+H) +.
Step 5: Procedure for preparation of Example 5
To a solution of 5-5 (150 mg, 0.35 mmol) in dioxane (3 mL) was added 1-10 (99 mg, 0.42 mmol) , Pd2 (dba) 3 (32.10 mg, 0.04 mmol) , XantPhos (20.29 mg, 0.04 mmol) and Cs2CO3 (342.68 mg, 1.05 mmol) . The reaction was stirred at 140 ℃ for 2 hr. To the reaction mixture was added water (40 mL) . The aqueous layer was extracted with EA (20 mL x 2) . The combined organic layer was washed with brine (20 mL) , dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by flash chromatography on silica gel to give example 5 (31 mg, 16.77%yield) as a yellow solid. LC-MS (ESI) : m/z 527.4 (M+H) +. 1H NMR (400 MHz, DMSO-d6) δ 12.73 (s, 1H) , 11.58 (s, 1H) , 8.78 (d, J = 8.6 Hz, 1H) , 7.89 (t, J = 6.8 Hz, 1H) , 7.68 (d, J = 8.4 Hz, 1H) , 7.63 (s, 1H) , 7.59 (d, J = 8.6 Hz, 1H) , 7.54 –7.52 (m, 1H) , 7.01 –6.89 (m, 2H) , 5.72 (s, 1H) , 4.02 –3.92 (m, 2H) , 3.65 (s, 2H) , 3.47 –3.41 (m, 2H) , 3.23 –3.15 (m, 1H) , 2.28 (s, 6H) , 2.10 (s, 3H) , 1.68 –1.66 (m, 4H) .
Example 6
Step 1: Procedure for preparation of 6-1
To a solution of 1-4 (12.69 g, 41.86 mmol) and 4- (4, 4, 5, 5-tetramethyl-1, 3-dioxolan-2-yl) -3, 6-dihydro-2H-pyran (11.55 g, 54.42 mmol) in dioxane (180 mL) and H2O (23 mL) was added K2CO3 (17.35 g, 125.58 mmol) , followed by XPhos-Pd-G3 (3.55 g, 4.19 mmol) , the mixture was stirred at 130 ℃ under N2 for 4 hr. After the reaction was completed, the reaction mixture was filtered and the filtrate was poured into H2O (200 mL) and extracted with EtOAc (100 mL x 3) . The combined organic layer was washed with brine (200 mL) , dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography on silica gel to give 6-1 (15 g, 98%yield) as a yellow solid. LC-MS (ESI+) : m/z 307.2 (M+H) +.
Step 2: Procedure for preparation of 6-2
To a solution of 6-1 (15.829 g, 51.668 mmol) in MeOH (650 mL) was added Pd/C 10% (3 g, 2.82 mmol) and Pd (OH) 2 (3 g, 4.27 mmol) , followed by acetic acid (1.48 mL, 25.83 mmol) , and the mixture was stirred at 20 ℃ under H2 (15 psi) for 5 hr. The reaction was filtered and the cake was washed with MeOH (50 mL x 3) , combined organic layer was concentrated to move off most of solvent, the residue was poured into H2O (200 mL) and adjusted pH with saturated NaHCO3 solution to pH~7, then extracted with EtOAc (300 mL x 3) . The combined organic layer was washed with brine (300 mL x 3) , dried over Na2SO4, filtered, and concentrated to give a residue, which was purified by column chromatography on silica gel to give 6-2 (10.8 g, 68%yield) as a white solid. LC-MS (ESI+) : m/z 309.2 (M+H) +. 1H NMR (400 MHz, DMSO-d6) δ 9.63 (s, 1H) , 7.69 (d, J = 8.0 Hz, 1H) , 7.64 (d, J = 8.0 Hz, 1H) , 5.02 (t, J = 8.0 Hz, 1H) , 4.55 (d, J = 4.0 Hz, 2H) , 3.95-3.91 (m, 2H) , 3.43 (td, J = 12.0, 4.0 Hz, 2H) , 3.04-2.96 (m, 1H) , 1.73 –1.55 (m, 4H) , 1.46 (s, 9H) .
Step 3: Procedure for preparation of 6-3
To a solution of 6-2 (300 mg, 0.97 mmol) in DCM (10 mL) was added TFA (5 mL) , and the reaction was stirred at 20 ℃ for 2 hr. The solvent was removed under reduced pressure to give 6-3 as a yellow solid. LC-MS (ESI) : m/z 209.2 (M+H) +.
Step 4: Procedure for preparation of Example 6
To a solution of 6-3 (120 mg, 0.57 mmol) in dioxane (4 mL) was added 2-7 (181 mg, 0.57 mmol) , Cs2CO3 (375 mg, 1.15 mmol) , XantPhos (100 mg, 0.17 mmol) , Pd2 (dba) 3 (105 mg, 0.11 mmol) and the reaction was stirred at 140 ℃ for 5 hr in sealed tube. After the reaction was completed, the
reaction was filtered and the cake was washed with EtOAc (3 mL x 3) . The combined organic layer was adjusted pH to ~1, separated and the aqueous phase was extracted with EtOAc (8 mL) to move off impurities. Then the aqueous phase was basified pH to ~10 by aq. NaOH (1N) , extracted with DCM (15 mL x 2) . The combined organic layer was washed with brine (15 mL) , dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by flash chromatography on silica gel to give example 6 (15 mg, 8.03%yield) as a yellow solid. LC-MS (ESI) : m/z 487.1 (M+H) +. 1H NMR (400 MHz, DMSO-d6) δ 12.95 (s, 1H) , 12.28 (s, 1H) , 9.21 (d, J = 8.8 Hz, 1H) , 8.26 (dd, J = 7.6, 5.6 Hz, 1H) , 7.88 (d, J = 8.8 Hz, 2H) , 7.84 (s, 1H) , 7.74 –7.65 (m, 2H) , 7.10 – 7.08 (m, 1H) , 6.99 (d, J = 8.4 Hz, 1H) , 5.20 (s, 1H) , 4.65 (s, 2H) , 3.95 (dd, J = 10.3, 3.8 Hz, 2H) , 3.48 –3.44 (m, 2H) , 3.17 –3.14 (m, 1H) , 1.74 –1.64 (m, 4H) .
Example 7
Step 1: Procedure for preparation of 7-1
To a solution of 6-2 (2 g, 6.49 mmol) and DIEA (2.144 mL, 12.97 mmol) in DCM (23 mL) was added MsCl (0.89 g, 7.78 mmol) dropwise at 0 ℃ under N2, the mixture was stirred at 20 ℃ for 0.5 hr. The reaction was quenched by H2O (10 mL) and then extracted with DCM (10 mL x 3) . The combined organic layer was washed with brine (20 mL) , dried over Na2SO4, filtered, and concentrated under reduced pressure to give 7-1 (2.67 g, crude) as a white solid. LC-MS (ESI+) : m/z 387.2 (M+H) +.
Step 2: Procedure for preparation of 7-2
To a solution of 7-1 (0.67 g, 1.73 mmol) and 3-methoxytetrahydropyrrole chlorane (1.19 g, 8.668 mmol) in CH3CN (8 mL) was added DIEA (0.86 mL, 5.20 mmol) , the reaction mixture was stirred at 20 ℃ for 2 hr. After the reaction was completed, the reaction was poured into water (20 mL) and extracted with DCM (10 mL x 3) . The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by flash chromatography on silica gel to give 7-2 (460 mg, 70.28%yield) as a light yellow solid. LCMS: (ESI+) : m/z 378.6 (M+H) +. 1H NMR (400 MHz, DMSO-d6) δ 9.50 (s, 1H) , 7.64 (m, 2H) , 4.64 (s, 1H) , 4.16 (dq, J = 8.0, 4.0 Hz,
1H) , 3.93 (dd, J = 12.0, 4.0 Hz, 2H) , 3.70 (brs, 2H) , 3.45 –3.37 (m, 3H) , 3.18 –3.12 (m, 1H) , 2.68 –2.59 (m, 2H) , 2.49 -2.36 (m, 2H) , 1.93 (dq, J = 12.0, 8.0 Hz, 1H) , 1.67 –1.57 (m, 4H) , 1.45 (s, 9H) .
Step 3: Procedure for preparation of 7-3
To a solution of 7-2 (460 mg, 1.22 mmol) in DCM (5 mL) was added TFA (5 mL, 67.32 mmol) . The reaction mixture was stirred at 20 ℃ for 0.5 h. The resulting mixture was concentrated to give a residue, which was then diluted with DCM (10 mL) and water (10 mL) , adjusted pH to ~9 and extracted with DCM (10 mL x 2) . The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to give 7-3 (260 mg, 76.15%yield) as a brown solid. LC-MS (ESI+) : m/z 278.6 (M+H) +. 1H NMR (400 MHz, DMSO-d6) δ 7.28 (d, J = 8.0 Hz, 1H) , 6.33 (d, J = 8.0 Hz, 1H) , 5.59 (s, 2H) , 4.58 (d, J = 4.0 Hz, 1H) , 4.13 (dq, J = 8.0, 4.0 Hz, 1H) , 3.91 (dt, J = 12.0, 4.0 Hz, 2H) , 3.58 –3.45 (m, 2H) , 3.41 –3.39 (m, 2H) , 3.06 –2.98 (m, 1H) , 2.68 (dd, J = 8.0, 4.0 Hz, 1H) , 2.60 –2.52 (m, 1H) , 2.41 –2.38 (m, 1H) , 2.28 (dd, J = 8.0, 4.0 Hz, 1H) , 1.91 (dq, J = 12.0, 4.0 Hz, 1H) , 1.60 –1.48 (m, 5H) .
Step 4: Procedure for preparation of Example7
To a solution of 2-7 (120 mg, 0.38 mmol) and 7-3 (21.28 mg, 0.076 mmol) in dioxane (3.60 mL) was added Cs2CO3 (248.64 mg, 0.76 mmol) , Pd2 (dba) 3 (69.88 mg, 0.076 mmol) and Xantphos (66.23 mg, 0.11 mmol) , then the mixture was stirred at 140 ℃ for 4 hr. After the reaction was completed, the reaction was filtered and the cake was washed with EtOAc (3 mL x 3) . The combined organic layer was adjusted pH to ~1 with aq. HCl (1N) , separated and the aqueous phase was extracted with EtOAc (5 mL) to remove off impurities. Then the aqueous phase was adjusted pH to ~10 by aq. NaOH (1N) , extracted with DCM (10 mL x 3) , the combined organic layer was washed with brine (10 mL) , dried
over Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by flash chromatography on silica gel to give example 7 (50 mg, 21%yield) as a yellow solid. LC-MS (ESI+) : m/z 556.3 (M+H) +. HPLC Ret time=6.491 min. 1H NMR (400 MHz, DMSO-d6) δ 12.93 (s, 1H) , 12.27 (s, 1H) , 9.26 (d, J = 8.0 Hz, 1H) , 8.18 (t, J = 8.0 Hz, 1H) , 7.87 (d, J = 8.0 Hz, 1H) , 7.76 (d, J = 12.0 Hz, 2H) , 7.69 (d, J = 8.0 Hz, 1H) , 7.56 (dd, J = 12.0, 4.0 Hz, 1H) , 6.99 –6.91 (m, 2H) , 4.70 (brs, 1H) , 4.19 (brs, 1H) , 3.95 (d, J = 8.0 Hz, 2H) , 3.83 (brs, 2H) , 3.52 –3.38 (m, 4H) , 3.19 –3.08 (m, 1H) , 2.77 –2.53 (m, 2H) , 2.04 –1.90 (m, 1H) , 1.65 –1.57 (m, 4H) , 1.55 (s, 1H) .
Example 8
Step 1: Procedure for preparation of 8-1
To a solution of 7-1 (0.67 g, 1.73 mmol) in CH3CN (8 mL) was added (3R) -3-fluorotetrahydropyrrole (1.09 g, 8.67 mmol) and DIEA (1.72 mL, 10.40 mmol) . The mixture was stirred at 20 ℃ for 3 hr. After the reaction was completed, the reaction was poured into water (20 mL) and extracted with DCM (10 mL x 3) . The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by flash chromatography on silica gel to give 8-1 (440 mg, 60.2%yield) as a yellow solid. LCMS: (ESI+) : m/z 380.3 (M+H) +. 1H NMR (400 MHz, DMSO-d6) δ 9.52 (s, 1H) , 7.65 (s, 2H) , 5.28 –5.04 (m, 1H) , 3.93 (dd, J = 12.0, 4.0 Hz, 2H) , 3.70 (s, 2H) , 3.41 (td, J = 8.0, 4.0 Hz, 2H) , 3.17 –3.15 (m, 1H) , 2.84 –2.71 (m, 2H) , 2.68-2.56 (m, 1H) , 2.33 (q, J = 8.0 Hz, 1H) , 2.20 –1.97 (m, 1H) , 1.88-1.73 (m, 1H) , 1.63 (m, 4H) , 1.45 (s, 9H) .
Step 2: Procedure for preparation of 8-2
To a solution of 8-1 (353 mg, 0.93 mmol) in DCM (4 mL) was added TFA (4 mL) . The mixture was stirred at 20 ℃ for 30 min. The reaction was concentrated to give a residue, which was diluted with DCM (10 mL) and water (10 mL) , adjusted pH to ~9 and extracted with DCM (10 mL x 2) . The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced
pressure to give 8-2 (297 mg, crude) as a yellow solid, which was used in next step directly without further purification. LC-MS (ESI+) : m/z 280.2 (M+H) +.
Step 3: Procedure for preparation of Example 8
To a solution of 2-7 (130 mg, 0.41 mmol) and 8-2 (138.48 mg, 0.50 mmol) in dioxane (3.6 mL) was added Cs2CO3 (269.13 mg, 0.826 mmol) , Pd2 (dba) 3 (75.64 mg, 0.083 mmol) and XantPhos (71.69 mg, 0.124 mmol) , and the mixture was stirred at 140 ℃ for 5 hr under N2 atmosphere. Then the reaction was filtered and the cake was washed with EtOAc (3 mL x 3) . The combined organic layer was adjusted pH to ~1, separated and the aqueous phase was extracted with EtOAc (5 mL) to move off impurities. Then the aqueous phase was adjusted pH to ~10 by aq. NaOH (1N) , extracted with DCM (15 mL x 3) , the combined organic layer was washed with brine (15 mL) , dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by pre-HPLC to give Ex8 (20 mg, 8.7%yield) as a yellow solid. LC-MS (ESI+) : m/z 558.4 (M+H) +. 1H NMR (400 MHz, CDCl3) δ 12.06 (s, 1H) , 10.30 (s, 1H) , 9.39 (s, 1H) , 7.96 –7.71 (m, 3H) , 7.67 (s, 1H) , 7.56 (d, J = 8.0 Hz, 1H) , 7.35 (dd, J = 8.0, 4.0 Hz, 1H) , 6.90 (d, J = 8.0 Hz, 1H) , 6.71 (td, J = 8.0, 4.0 Hz, 1H) , 5.41 –4.96 (m, 1H) , 4.09 (dd, J = 12.0, 4.0 Hz, 2H) , 3.95 (brs, 1H) , 3.54 (t, J = 12.0 Hz, 2H) , 3.06 –3.01 (m, 2H) , 2.32 –2.00 (m, 2H) , 1.68 –1.50 (m, 8H) .
Example 9
Step 1: Procedure for preparation of 9-1
To a solution of 7-1 (1.09 g, 8.67 mmol) and DIEA (1.72 mL, 10.40 mmol) . The mixture was stirred at 20 ℃ for 3 hr. After the reaction was completed, the reaction was poured into water (20 mL) and extracted with DCM (10 mL x 3) . The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduce pressure to give a residue, which was purified by flash chromatography on silica gel to give 9-1 (353 mg, 48%yield) as a light yellow solid. LCMS: (ESI+) : m/z 380.7 (M+H) +.
1H NMR (400 MHz, DMSO-d6) δ 9.51 (s, 1H) , 7.65 (s, 2H) , 5.27 –5.03 (m, 1H) , 3.97 –3.89 (m, 2H) , 3.70 (s, 2H) , 3.43 –3.41 (m, 2H) , 3.14 –3.11 (m, 1H) , 2.85 –2.71 (m, 2H) , 2.62 –2.58 (m, 1H) , 2.33 (q, J = 8.0 Hz, 1H) , 2.08 –2.05 (m, 1H) , 1.81 –1.78 (m, 1H) , 1.73 –1.58 (m, 4H) , 1.45 (s, 9H) .
Step 2: Procedure for preparation of 9-2
To a solution of 9-1 (353 mg, 0.93 mmol) in DCM (4 mL) was added TFA (4 mL) . The mixture was stirred at 20 ℃ for 30 min. The reaction was concentrated to give a residue, which was then diluted with DCM (10 mL) and water (10 mL) , adjusted pH to ~9 and extracted with DCM (10 mL x 2) . The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to give 9-2 (226 mg, 65.19%yield) as an off-white solid. LC-MS (ESI+) : m/z 280.6 (M+H) +. 1H NMR (400 MHz, DMSO-d6) δ 7.30 (d, J = 8.0 Hz, 1H) , 6.35 (d, J = 8.0 Hz, 1H) , 5.62 (s, 2H) , 5.25 –5.03 (m, 1H) , 3.95 –3.86 (m, 2H) , 3.57 (s, 2H) , 3.39 (dd, J = 12.0, 4.0 Hz, 2H) , 3.04 –3.02 (m, 1H) , 2.83 –2.70 (m, 2H) , 2.66 –2.51 (m, 1H) , 2.30 (q, J = 8.0 Hz, 1H) , 2.09 –2.07 (m, 1H) , 1.83 –1.79 (m, 1H) , 1.65 –1.48 (m, 4H) .
Step 3: Procedure for preparation of Example 9
To a solution of 2-7 (120 mg, 0.38 mmol) and 9-2 (127.68 mg, 0.46 mmol) in dioxane (3.60 mL) was added Cs2CO3 (248.19 mg, 0.76 mmol) , Pd2 (dba) 3 (69.75 mg, 0.076 mmol) and XantPhos (66.11 mg, 0.11 mmol) , and the mixture was stirred at 140 ℃ for 5 hr under N2 atmosphere. After the reaction was completed, the reaction was filtered and the cake was washed with EtOAc (3 mL x 3) . The combined organic layer was adjusted pH to ~1, separated and the aqueous phase was extracted with EtOAc (5 mL) to move off impurities. Then the aqueous phase was adjusted pH to ~10 by aq. NaOH (1N) , extracted with DCM (10 mL x 2) , the combined organic layer was washed with brine (10 mL) ,
dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by flash chromatography on silica gel to give example 9 (26 mg, 11%yield) as a yellow solid. LC-MS (ESI+) : m/z 558.3 (M+H) +. 1H NMR (300 MHz, DMSO-d6) δ 12.91 (s, 1H) , 12.27 (s, 1H) , 9.26 (d, J = 6.0 Hz, 1H) , 8.16 (dd, J = 6.0, 3.2 Hz, 1H) , 7.84 (d, J = 6.0 Hz, 1H) , 7.74 (d, J = 9.2 Hz, 2H) , 7.68 (d, J = 6.0 Hz, 1H) , 7.54 (dd, J = 6.0, 3.0 Hz, 1H) , 6.96 –6.91 (m, 2H) , 5.23 –5.09 (m, 1H) , 3.93 (d, J = 9.0 Hz, 2H) , 3.81 (brs, 2H) , 3.43 (brt, J = 9.0 Hz, 2H) , 3.14 (brd, J = 3.0 Hz, 1H) , 2.91-2.82 (m, 2H) , 2.70-2.62 (m, 1H) , 2.41-2.31 (m, 1H) , 2.15 -2.01 (m, 1H) , 1.66 –1.63 (m, 5H) .
Example 10
Step 1: Procedure for preparation of 10-1
To a solution of 7-1 (680 mg, 1.76 mmol) and DIEA (681 mg, 5.28 mmol) in ACN (10 mL) was added 3-methoxypyrrolidine (266 mg, 2.64 mmol) , and the reaction was stirred at 70 ℃ for 0.5 hr. The reaction mixture was poured into H2O (50 mL) and then extracted with EtOAc (30 mL x 3) . The combined organic layer was washed with brine (300 mLx3) , dried over Na2SO4, and concentrated to give a residue, which was purified by column chromatography on silica gel to give 10-1 (430 mg, 62.5%yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 9.59 (s, 1H) , 7.65 (s, 2H) , 3.93 (dd, J = 10.4, 3.6 Hz, 2H) , 3.82 (t, J = 6.4, 3.2 Hz, 1H) , 3.65 (s, 2H) , 3.44 –3.40 (m, 2H) , 3.13 (s, 4H) , 2.68 (dd, J = 10.0, 6.0 Hz, 1H) , 2.59 –2.51 (m, 2H) , 2.48 –2.34 (m, 2H) , 2.01-1.92 (m, 1H) , 1.62 –1.58 (m, 4H) , 1.45 (s, 9H) .
Step 2: Procedure for preparation of 10-2
To a solution of 10-1 (430 mg, 1.09 mmol) in DCM (10 mL) was added TFA (3 mL) , and the reaction was stirred at 25 ℃ for 4 hr. The solvent was removed in vacuum to afford 10-2 (300 mg, 93.70%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 7.30 (d, J = 8.4 Hz, 1H) , 6.35 (d, J = 8.4 Hz, 1H) , 5.64 (s, 2H) , 3.93 –3.87 (m, 2H) , 3.86 –3.84 (m, 1H) , 3.61 (s, 2H) , 3.39 –3.37 (m, 3H) , 3.15 –3.13 (m, 4H) , 3.03 –2.93 (m, 1H) , 2.76 –2.74 (m, 1H) , 2.62 –2.60 (m, 1H) , 2.01 –1.87 (m, 1H) , 1.69 –1.50 (m, 5H) .
Step 3: Procedure for preparation of Example 10
To a solution of 10-2 (100 mg, 0.34 mmol) in dioxane (3 mL) was added 2-7 (108 mg, 0.34 mmol) , Cs2CO3 (223.63 mg, 0.69 mmol) , Pd2 (dba) 3 (62.85 mg, 0.069 mmol) , and XantPhos (59.57 mg, 0.10 mmol) , and the reaction was stirred at 140 ℃ for 4 hr. To the reaction mixture was added water (40 mL) . The aqueous phase was extracted with EtOAc (10 mL) to move off impurities. Then the aqueous phase was adjusted pH to ~10 by aq. NaOH (1N) , extracted with DCM (15 mL x 2) , the combined organic layer was washed with brine (15 mL) , dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by flash chromatography on silica gel to give example 10 (16 mg, 8.18%) as a yellow solid. LC-MS (ESI) : m/z 570.3 (M+H) +. 1H NMR (400 MHz, DMSO-d6) δ 12.93 (s, 1H) , 12.28 (s, 1H) , 9.27 (s, 1H) , 8.17 (t, J = 6.8 Hz, 1H) , 7.87 (d, J = 8.8 Hz, 1H) , 7.76 (d, J = 9.2 Hz, 2H) , 7.69 (d, J = 8.4 Hz, 1H) , 7.56 (d, J = 10.2 Hz, 1H) , 6.97 –6.94 (m, 2H) , 3.95 (d, J = 11.2 Hz, 2H) , 3.85 –3.81 (m, 2H) , 3.46 –3.42 (m, 2H) , 3.25 –3.21 (m, 3H) , 3.12 (s, 3H) , 2.65 –2.61 (m, 3H) , 1.98 –1.96 (m, 2H) , 1.66 –1.62 (m, 4H) .
Example 11
Step 1: Procedure for preparation of 11-1
To a solution of 1-5 (1.28 g, 2.66 mmol) in MeOH (10 mL) was added ammonia in MeOH (7.0 M, 1.91 ML, 13.3 mmol) , and the reaction was stirred at 25 ℃ for 3 hr. The reaction mixture was poured into H2O (10 mL) and then extracted with EtOAc (30 mL x 3) . The combined organic layer was washed with brine (30 mL x 2) , dried over Na2SO4, and concentrated. The residue was purified by column chromatography on silica gel to afford the title compound 11-1 (800 mg, 73.39%yield) as a yellow solid. LC-MS (ESI+) : m/z 304.1 (M+H) +.
Step 2: Procedure for preparation of 11-2
To a solution of 11-1 (600 mg, 1.49 mmol) in THF (15 mL) was added TEA (453 mg, 4.48 mmol) and CDI (484 mg, 2.99 mmol) . After the mixture stirred at 25 ℃ for 30 min, then cyclopropanamine (105 mg, 1.79 mmol) was added at 25 ℃. The reaction was stirred at 25 ℃ for 16 hr. The resulting mixture was diluted with dichloromethane (100 mL) and water (50 mL) . The organic layer was separated, washed with brine (30 mL) , dried over sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel to give the title compound 11-2 (500 mg, 69.06%yield) as a yellow solid. LC-MS (ESI+) : m/z 387.2 (M+H) +.
Step 3: Procedure for preparation of 11-3
To a solution of 11-2 (500 mg, 1.03 mmol) and 1-7 (260 mg, 1.23 mmol) in dioxane/H2O = 5/1 (10 mL: 2 mL) was added K2CO3 (427 mg, 3.09 mmol) , XPhosPdG3 (87 mg, 0.10 mmol) , and the reaction was stirred at 100 ℃ for 16 hr. The reaction mixture was poured into H2O (60 mL) and then extracted with EtOAc (50 mL x 3) . The combined organic layer was washed with brine (50 mL) , dried over Na2SO4, and concentrated to give crude product, which was purified by column chromatography on silica gel to give the title compound 11-3 (120 mg, 23.80%yield) as a yellow solid. LC-MS (ESI+) : m/z 389.4 (M+H) +.
Step 4: Procedure for preparation of 11-4
To a solution of 11-3 (120 mg, 0.24 mmol) in methanol (10 mL) was added Pd (OH) 2/C (60 mg, 20%) , and the reaction was stirred at 25 ℃ for 16 hr under H2 atmosphere. The reaction was filtered through a Celite pad and the filtrate was concentrated to afford 11-4 (110 mg, 91.66%yield) as a yellow solid. LC-MS (ESI+) : m/z 391.4 (M+H) +.
Step 5: Procedure for preparation of 11-5
To a solution of 11-4 (110 mg, 0.22 mmol) in DCM (6 mL) were added TFA (2 mL) , and the reaction was stirred at 25 ℃ for 3 hr. The solvent was removed under vacuum to afford 11-5 (60 mg, 92.3%yield) as a yellow solid. LC-MS (ESI+) : m/z 291.4 (M+H) +.
Step 6: Procedure for preparation of Example 11
To a solution of 11-5 (50 mg, 0.17 mmol) and 2-7 (71 mg, 0.17 mmol) in dioxane (2 mL) was added Cs2CO3 (168 mg, 0.51 mmol) , XantPhos (19 mg, 0.03 mmol) , and Pd2 (dba) 3 (15 mg, 0.01 mmol) , and the reaction was stirred at 120 ℃ for 2 hr. The reaction mixture was poured into H2O (20 mL) and then extracted with EtOAc (20 mL x 3) . The combined organic layer was washed with brine (20 mL) , dried over Na2SO4, and concentrated to give crude product, which was purified by Prep-HPLC to afford example 11 (5 mg, 5%yield) as a white solid. LC-MS (ESI+) : m/z 569.4 (M+H) +. 1H NMR (400 MHz, DMSO-d6) δ 13.00 (s, 1H) , 12.33 (s, 1H) , 9.19 (d, J = 8.8 Hz, 1H) , 8.45 (t, J = 6.4 Hz, 1H) , 8.27 (s, 1H) , 8.01 (s, 2H) , 7.87 (d, J = 8.8 Hz, 1H) , 7.70 (d, J = 8.4 Hz, 1H) , 7.43 (t, J = 7.6 Hz, 1H) , 6.98 (d, J = 8.0 Hz, 1H) , 6.36 (s, 2H) , 4.47 (s, 2H) , 3.99 –3.95 (m, 2H) , 3.46-3.51 (m, 2H) , 3.03-3.06 (m, 1H) , 2.43 (s, 1H) , 1.62-1.74 (m, 4H) , 0.58 –0.47 (m, 2H) , 0.28-0.32 (m, 2H) .
Example 12
Step 1: Procedure for preparation of 12-1
To a solution of 2-amino-6-chloronicotinonitrile (0.75 g, 4.88 mmol) in THF (20 mL) were added copper iodide (1.4 g, 7.35 mmol) , 2-methyl-2-nitropropane (2.4 mL, 22.1 mmol) , and diiodomethane (3.2 mL, 39.7 mmol) , and the reaction was stirred at room temperature for 1 hour. The reaction mixture was diluted with H2O (20 mL) and extracted with DCM (20 mL *3) . The
combined organic layers were washed with brine (20 mL) , dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was triturated with PE/TBME (v/v = 3/1, 15 mL) . The precipitate was collected by filter. INT 12-1 (700 mg, 60%yield) was obtained as a brown solid. 1H NMR (400 MHz, DMSO-d6) : 8.26 (m, J = 8.4 Hz, 1 H) , 7.81 (br s, J = 8.4 Hz, 1 H)
Step 2: Procedure for preparation of 12-2
INT 12-1 (500 mg, 1.89 mmol) and tert-butyl 4-oxopiperidine-1-carboxylate (377 mg, 1.89 mmol) were dissolved in dry THF (10 mL) and the reaction mixture was cooled down to -65℃ under N2. Isopropylmagnesium chloride-lithium chloride complex (1.89 mL, 2.46 mmol) was added dropwise and the reaction mixture was stirred for further 10 min at this temperature. Afterwards the reaction mixture was allowed to warm to 25 ℃, stirred for 20 minutes and methanol (4 mL, 19.7 mmol) was added. The reaction mixture was cooled to 0℃ and 50%aqueous sulfuric acid solution (10 mL) was added dropwise. The reaction mixture was warmed to 25 ℃ and stirred for 16 hours. The mixture was filtrated and the solid was dried in vacuum. INT 12-2 (290 mg, yield 64%) was obtained as a white solid. LC-MS (ESI+) : m/z 239.1 (M+H) +. 1H NMR (400 MHz, DMSO-d6) : 9.14 -8.89 (m, 1H) , 8.83 -8.58 (m, 1H) , 8.39 (d, J = 8.1 Hz, 1H) , 7.82 (d, J = 8.2 Hz, 1H) , 3.53 -3.44 (m, 2H) , 3.30 -3.16 (m, 2H) , 2.42 -2.27 (m, 2H) , 2.06 (d, J = 14.3 Hz, 2H) .
Step 3: Procedure for preparation of 12-3
To a solution of 12-2 (1.77 g, 5.22 mmol) in toluene (40 mL) was added bis (2-methylpropyl) aluminum hydride (13.1 mL, 13.1 mmol) at -78℃. And the reaction mixture was stirred at -78℃ for 1.5 hours. The reaction was quenched with sat. NH4Cl (30 mL) dropwise at -78℃. Then the mixture was warmed to room temperature slowly and stirred for 30 min. The reaction mixture was filtered and the filtrate was extracted with EA (100 mL*3) . The combined organic layers were washed with brine (100 mL) , dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue which was purified by column chromatography (PE/EtOAc = 35-65%) . INT 12-3 (900 mg, yield 51%) was obtained as a white solid. LC-MS (ESI+) : m/z 240.8 (M+H) +. 1H NMR (400 MHz,
CDCl3) : 7.73 (d, J = 8.0 Hz, 1H) , 7.33 (d, J = 8.0 Hz, 1H) , 6.48 (d, J = 6.0 Hz, 1H) , 4.26 -4.14 (m, 1H) , 3.44 (d, J = 6.5 Hz, 1H) , 3.24 (br s, 2H) , 2.21 -2.07 (m, 2H) , 1.75 (d, J = 12.5 Hz, 1H) , 1.56 (d, J = 13.6 Hz, 1H) , 1.49 (s, 9H) .
Step 4: Procedure for preparation of 12-4
To a solution of 12-3 (900 mg, 2.641 mmol) in DCM (5 mL) was added dropwise TFA (9.81 mL, 132 mmol) at 0℃, and the reaction was stirred at 0 ℃ for 30 mins. Triethylsilane (1.07 g, 9.24 mmol) was added dropwise to the mixture at 0 ℃. The mixture was warmed slowly to 20℃ and stirred at 20℃ for 18 hours. Then TFA (9.81 mL, 132 mmol) was added to the mixture, and the mixture was stirred at 20 ℃ for 16 hours. The mixture was concentrated under reduced pressure. 12-4 (800 mg, crude) was obtained as a white solid. LC-MS (ESI+) : m/z 224.8 (M+H) +. 1H NMR (400 MHz, DMSO-d6) : 7.94 -7.81 (m, 1H) , 7.88 (d, J = 8.0 Hz, 1H) , 7.49 (d, J = 7.6 Hz, 1H) , 5.06 (s, 2H) , 3.38 (d, J = 12.8 Hz, 2H) , 3.22 -3.07 (m, 2H) , 2.13-2.08 (m, 2H) , 1.86 (br d, J = 13.6 Hz, 2H) .
Step 5: Procedure for preparation of 12-5
To a solution of 12-4 (200 mg, 0.890 mmol) in MeOH (10 mL) were added formaldehyde (0.331 mL, 4.451 mmol) and HOAc (83.05 mg, 0.445 mmol) , and the reaction mixture was stirred at room temperature for 30 min. Then sodium triacetyloxyboranuide (37.7 mg, 0.178 mmol) was added. The reaction was stirred at room temperature for 18 hours. The reaction mixture was quenched with 20 mL of sat. NaHCO3, concentrated to remove MeOH. The residue was extracted with DCM (20 mL x 3) , the combined extracts was washed with brine (20 mL) , dried over Na2SO4, filtered, and concentrated in vacuum. 12-5 (216 mg, yield 86%) was obtained as a white solid. LC-MS (ESI+) : m/z 238.8 (M+H) +.
Step 6: Procedure for preparation of 12-6
A mixture of 12-5 (210 mg, 0.880 mmol) , 2-methylpropan-2-yl aminomethanoate (412.37 mg, 3.520 mmol) , Cs2CO3 (1.72 g, 5.280 mmol) and XantPhos (203.68 mg, 0.352 mmol) in dioxane (10 mL) was degassed and purged with Ar for 3 times, and then Pd2 (dba) 3 (161.17 mg, 0.176 mmol) was added. The mixture was degassed and purged with Ar for 3 times and stirred at 115 ℃ for 16 hours under Ar atmosphere. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (4 gSilica Flash Column, Eluent of 0~10%MeOH/DCM gradient @40 mL/min) . INT 12-6 (115 mg, 0.233 mmol) was obtained as a brown solid. LC-MS (ESI+) : m/z 319.9 (M+H) +. 1H NMR (400 MHz, CDCl3) : 7.83 (d, J = 8.4 Hz, 1H) , 7.50 (d, J = 8.4 Hz, 1H) , 7.21 (br s, 1H) , 5.01 (s, 2H) , 2.86 (d, J = 11.4 Hz, 2H) , 2.38 (s, 5H) , 2.17 -2.06 (m, 2H) , 1.68 (d, J = 12.4 Hz, 2H) , 1.53 (s, 9H) .
Step 7: Procedure for preparation of 12-7
A mixture of 12-6 (140 mg, 0.438 mmol) in formic acid (10 mL) was stirred at 20℃ for 2 hours. The reaction mixture was concentrated in vacuum. 12-7 (145 mg, yield 42%) was obtained as brown gum oil. LC-MS (ESI+) : m/z 286.2 (M+H) +. 1H NMR (400 MHz, CDCl3) : 7.33 (d, J = 8.3 Hz, 1H) , 6.36 (d, J = 8.3 Hz, 1H) , 5.04 -4.76 (m, 2H) , 3.29 -3.05 (m, 3H) , 2.92 -2.68 (m, 1H) , 2.03 (dd, J = 9.2, 13.2 Hz, 2H) , 1.82 -1.55 (m, 2H) .
Step 8: Procedure for preparation of Example 12
To a solution of 2-7 (15 mg, 0.048 mmol) in dioxane (2 mL) was added 12-7 (10 mg, 0.046 mmol) and Cs2CO3 (38.83 mg, 0.119 mmol) . The reaction mixture was purged with N2 for 3 times. tris [ (1E, 4E) -1, 5-diphenylpenta-1, 4-dien-3-one] bis [palladium (0) ] (8.73 mg, 0.010 mmol) and [5- (diphenylphosphanyl) -9, 9-dimethyl-9H-xanthen-4-yl] diphenylphosphane (8.27 mg, 0.014 mmol) were added. The reaction mixture was purged with N2 for 3 times and stirred at 100℃ for 2 hours. The mixture was filtered, concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Welch Xtimate C18 150*30mm*5um; mobile phase: [water (FA) -ACN] ; B%: 5%-35%, 7min) . Ex12 (0.89 mg, 4%yield) was obtained. LC-MS (ESI+) : m/z 498.1 (M+H) +. 1H NMR (400 MHz, CDCl3) : 12.27 (s, 1H) , 9.80 (s, 1H) , 9.52 (d, J = 8.4 Hz, 1H) , 7.99 (s, 1H) , 7.94 (d, J = 6.4 Hz, 2H) , 7.69 (s, 1H) , 7.52 -7.45 (m, 1H) , 7.40 -7.31 (m, 1H) , 6.84 (d, J = 8.4 Hz, 1H) , 6.79 -6.70 (m, 1H) , 5.08 (s, 2H) , 3.26 (br s, 2H) , 2.89 (br s, 2H) , 2.65 (br s, 4H) , 1.89 -1.82 (m, 3H) . 19F NMR (376 MHz, CDCl3) : -111.76 --114.18 (m, 1F) .
Example 13
Step 1: Procedure for preparation of 13-1
A mixture of 2-6 (400 mg, 1.217 mmol) , KOAc (597 mg, 6.086 mmol) , Pd (dppf) Cl2 (149 mg, 0.183 mmol) and 4, 4, 5, 5-tetramethyl-2- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1, 3, 2-dioxaborolane (464 mg, 1.826 mmol) in dioxane (30 mL) was degassed and purged with N2. The mixture was stirred at 90 ℃ for 3 hours. The reaction mixture was concentrated in vacuum. The residue was diluted with 20 mL of water and extracted with EtOAc (20 mL *2) , the combined extracts was washed with brine (20 mL) , dried over Na2SO4, filtered, and concentrated in vacuum. The residue was purified by purified by flash silica gel chromatography (4 g
Silica Flash Column, Eluent of 0~50%Ethyl acetate/Petroleum ether gradient @25 mL/min) . INT 13-1 (300 mg, yield 80%) was obtained as a white solid. LC-MS (ESI+) : m/z 306.9 (M+H) +. 1H NMR (400 MHz, CDCl3) : 10.00 (br s, 1H) , 9.00 (s, 1H) , 8.12 (d, J = 8.0 Hz, 1H) , 7.65 (d, J = 8.0 Hz, 1H) , 1.33 (s, 12H) .
Step 2: Procedure for preparation of 13-2
To a suspension of glyoxal (2.34 g, 40.3 mmol) and ammonia carbonic acid (6.37 g, 80.6 mmol) in EtOH (5 mL) and H2O (10 mL) was added 2-fluorobenzaldehyde (5 g, 40.3 mmol) dropwise at 0 ℃. The mixture was stirred at 25 ℃ for 24 hours. The mixture was concentrated under reduced pressure. The residue was diluted with CH2Cl2 (80 mL) and washed with brine (30 mL) . The organic layer was dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash silica gel chromatography (20 gSilica Flash Column, Eluent of 0~3%MeOH /CH2Cl2 gradient @25 mL/min) . INT 13-2 (1.00 g, yield 15%) as a white solid. LC-MS (ESI+) : m/z 162.8 (M+H) +. 1H NMR (400MHz, CDCl3) : 8.32 (dt, J = 2.0, 8.0 Hz, 1H) , 7.41 -7.32 (m, 1H) , 7.31 -7.26 (m, 2H) , 7.23 (s, 2H) , 7.22 -7.14 (m, 1H)
Step 3: Procedure for preparation of 13-3
To a solution of 13-2 (500 mg, 3.08 mmol) in THF (10 mL) were added NaH (136 mg, 3.39 mmol) . The reaction mixture was stirred at 0 ℃ for 15 min. Then SEM-CI (771 mg, 4.63 mmol) was added. And the reaction was stirred at room temperature for 18 hours. The reaction was quenched with sat. NH4Cl (10 mL) and extracted with EA (15 mL *3) . The combined organic layer was washed with brine (20 mL) , dried over Na2SO4, filtrated, and concentrated in vacuum. 13-3 (1.1 g, crude) was obtained as light brown oil. LC-MS (ESI+) : m/z 292.9 (M+H) +.
Step 4: Procedure for preparation of 13-4
To a solution of 13-3 (1.1 g, 2.52 mmol) in THF (10 mL) were added NBS (0.45 g, 2.52 mmol) , and the reaction was stirred at 25 ℃ for 18 hours. The reaction was quenched with sat. NaHCO3 (20 mL) and extracted with EA (20 mL *3) . The combined organic layer was washed with brine (30 mL) , filtrated, and concentrated in vacuum. The residue was purified by flash silica gel chromatography (20 gSilica Flash Column, Eluent of 0~50%Ethyl acetate/Petroleum ether gradient @25 mL/min) . INT 13-4 (620 mg, yield 55%) was obtained as light brown oil. LC-MS (ESI+) : m/z 371.0 (M+H) +.
Step 5: Procedure for preparation of 13-5
To a solution of 13-4 (140 mg, 0.457 mmol) , 13-1 (101 mg, 0.470 mmol) and K3PO4 (194 mg, 0.913 mmol) in dioxane /water (15 mL /4 mL) was added Xhpos Pd G2 (29.8 mg, 0.046 mmol) under N2 atmosphere. After addition, the reaction mixture was stirred at 100℃ for 3 hours. The reaction mixture was filtered, concentrated in vacuum. The residue was diluted with water (15 mL) , extracted with EtOAc (20 mL *2) . The combined extracts were washed with brine (20 mL) , dried over Na2SO4, filtered, and concentrated in vacuum. The residue was purified by purified by flash silica gel chromatography (4 gSilica Flash Column, Eluent of 0~100%Ethyl acetate/Petroleum ether then 0%~10%MeOH /Ethyl acetate gradient @25 mL/min) . INT 13-5 (25.0 mg, yield 9%) was obtained as a white solid. LC-MS (ESI+) : m/z 471.1 (M+H) +.
Step 6: Procedure for preparation of 13-6
To a solution of 13-5 (58 mg, 0.123 mmol) in dioxane (2 mL) was added INT 1-10 (29.0 mg, 0.123 mmol) and cesium carbonate (80.2 mg, 0.246 mmol) . The reaction mixture was purged with N2 for 3 times. tris [ (1E, 4E) -1, 5-diphenylpenta-1, 4-dien-3-one] bis [palladium (0) ] (22.6 mg, 0.025
mmol) and [5- (diphenylphosphanyl) -9, 9-dimethyl-9H-xanthen-4-yl] diphenylphosphane (21.4 mg, 0.037 mmol) were added. The reaction mixture was purged with N2 for 3 times and stirred at 100 ℃ for 16 hours. The reaction mixture was filtered, the filtrate was concentrated in vacuum. The residue was purified by pre-HPLC: Xtimate C18 150*40mm*10um, Mobile Phase: A: water (FA) , B: acetonitrile, gradient condition: from 15%B to 45%B, Flow rate: 55 mL/min) . 13-6 (15 mg, yield 18%) was obtained as a white solid. LC-MS (ESI+) : m/z 670.3 (M+H) +.
Step 7: Procedure for preparation of Example 13
To a solution of 13-6 (10 mg, 0.015 mmol) in DCM (1 mL) were added HCl/dioxane (0.5 mL) and the reaction was stirred at room temperature for 18 hours. The reaction was concentrated in vacuum. The residue was purified by pre-HPLC Welch Xtimate C18 150*30mm*5um, Mobile Phase: A: (water (FA) -ACN) , B: acetonitrile, gradient condition: from 8%B to 38%B, Flow rate: 25 mL/min) . Ex13 (4.55 mg, yield 47%) was obtained. LC-MS (ESI+) : m/z 540.2 (M+H) +. 1H NMR (400 MHz, CD3OD) : 8.78 (d, J = 8.8 Hz, 1H) , 8.41 (s, 1H) , 8.11 -7.99 (m, 2H) , 7.97 (s, 1H) , 7.89 (d, J = 8.7 Hz, 1H) , 7.84 -7.76 (m, 1H) , 7.59 -7.48 (m, 2H) , 7.29 (d, J = 8.8 Hz, 1H) , 4.70 (s, 2H) , 4.10 (dd, J = 3.6, 11.2 Hz, 2H) , 3.67 (t, J = 10.8 Hz, 2H) , 3.11 (s, 6H) , 3.08 -2.99 (m, 1H) , 1.91-1.84 (m, 2H) , 1.78 -1.66 (m, 2H) . 19F NMR (376 MHz, CD3OD) : -115.64 (s, 1F) .
Example 14
Step 1: Procedure for preparation of 14-1
To a solution of Ex6 (15 mg, 0.031 mmol) in DCM (1 mL) was added DIEA (0.031 mL, 0.185 mmol) and then methanesulfonyl chloride (10 mg, 0.087 mmol) was added slowly at 0℃ and the
mixture was stirred at 25 C for 3 hours. Aqueous NaHCO3 (3 mL) was added to the reaction mixture and extracted with DCM (3 mL *3) . The organic layer was washed with brine (5 mL) , dried over Na2SO4, filtered, and concentrated under vacuum. INT 14-1 (15 mg, yield 86%) was obtained as a white solid. LC-MS (ESI+) : m/z 565.2 (M+H) +.
Step 2: Procedure for preparation of Example 14
To a solution of 1, 1-difluoro-5-azaspiro [2.3] hexane-methane hydrogen chloride (21.1 mg, 0.177 mmol) in MeCN (1 mL) were added DIEA (0.040 mL, 0.245 mmol) . Then 14-1 (20 mg, 0.035 mmol) was added, and the reaction mixture was stirred at 70℃ for 18 hours. The mixture was purified by pre-HPLC Welch Xtimate C18 150*30mm*5um, Mobile Phase: A: (water (FA) -ACN) , B: acetonitrile, gradient condition: from 7%B to 37%B, Flow rate: 25 mL/min) . Ex14 (2.06 mg, yield 10%) was obtained. LC-MS (ESI+) : m/z 588.4 (M+H) +. 1H NMR (400 MHz, CD3OD) : 9.34 -9.17 (m, 1H) , 8.17 -8.05 (m, 1H) , 7.95 -7.87 (m, 1H) , 7.83 (s, 1H) , 7.77 -7.68 (m, 2H) , 7.44 -7.36 (m, 1H) , 7.05 -6.99 (m, 1H) , 6.98 -6.90 (m, 1H) , 4.31 -4.00 (m, 3H) , 4.31 -4.00 (m, 1H) , 3.85 (br d, J = 8.4 Hz, 2H) , 3.77 -3.57 (m, 4H) , 3.14 -3.00 (m, 1H) , 1.91 -1.72 (m, 4H) , 1.58 -1.42 (m, 2H) . 19F NMR (376 MHz, CD3OD) : -113.95 (br s, 1F) , -141.09 (br s, 2F) .
Example 15-P1 and 15-P2
Step 1: Procedure for preparation of 15-1
To a solution of 6- { [ (3S) -3-fluorotetrahydro-1H-pyrrol-1-yl] methyl} -5- (3, 4, 5, 6-tetrahydro-2H-pyran-4-yl) pyridin-2-amine (150 mg, 0.487 mmol) in H2O (2 mL) were added hydrogen chloride (0.10 mL, 1.219 mmol) . Sodium nitrite (84.1 mg, 1.219 mmol) aqueous solution was dropwise added at 0℃. After dripping and stirring for 1 hr. Then copper chloride (96.5 mg, 0.975 mmol) was dropwise added, the temperature rises and thickens. After the dripping, the temperature was 22℃, stirring for 2
hrs. The mixture was filtered and the filtrate was concentrated under reduced pressure to give a crude product. The aqueous mixture was alkalized with 1M NaOH and adjusted to pH = 9, and extracted with DCM (25 mL *3) . The combined extracts were dried (Na2SO4) , filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (12gSilica Flash Column, Eluent of 0~20%Methanol/Dichloromethane ether gradient @15mL/min) . INT 15-1 (210 mg, 0.497 mmol, 48.9%yield) was obtained as a white solid. LC-MS (ESI+) : m/z 298.9 (M+H) +.
Step 2: Procedure for preparation of 15-2
To a solution of 5-bromo-8-nitroisoquinoline (300 mg, 1.185 mmol) in DCM (10 mL) were added a solution of mCPBA (286.40 mg, 1.660 mmol) in DCM (2 mL) at 0 ℃, and the reaction was stirred at 20℃ for 18 hrs. The reaction was diluted with dichloromethane (10 mL) , washed with aqueous sodium bicarbonate (15 mL) , 10%aqueous sodium thiosulfate (15 mL) , and with brine (15 mL) . The organic solution was dried over anhydrous sodium sulfate, filtered, and volatiles evaporated to give a crude as a yellow solid. The crude product 15-2 was used for next step without further purification. LC-MS (ESI+) : m/z 268.9 (M+H) +.
Step 3: Procedure for preparation of 15-3
To a solution of 15-2 (1 g, 3.717 mmol) in AC2O (8 mL, 85.180 mmol) at 140 ℃ for 3 hours. The mixture was left to warm to room temperature was added K2CO3 (6 mL) and stirred one hour. The mixture was diluted with H2O (20 mL) and extracted with EA (15 mL *3) . The combined organic layers were washed with brine (25 mL) , dried over Na2SO4, filtered, and concentrated under reduced pressure to give a crude. The residue was purified by flash silica gel chromatography (12 gSilica Flash Column, Eluent of 0~60%Ethyl acetate/Petroleum ether gradient @20 mL/min) . 15-3 (197 mg, 19.70%yield) was obtained. LC-MS (ESI+) : m/z 268.7 (M+H) +. 1H NMR 1H NMR (400 MHz, DMSO-d6 ) δ: 6.78 -6.82 (m, 1 H) 7.49 -7.54 (m, 1 H) 7.70 (d, J=8.34 Hz, 1 H) 8.22 (d, J=8.23 Hz, 1 H) 11.96 -12.06 (m, 1 H) .
Step 4: Procedure for preparation of 15-4
To a stirring solution of NaH (36.72 mg, 0.918 mmol) in dry THF (5 mL) and 15-3 (190 mg, 0.706 mmol) in THF (5 mL) was added dropwise at 0-5 ℃ under N2.1-chloro-5, 5-dimethyl-2-oxa-5-silahexane (176.60 mg, 1.059 mmol) was added after 30 min at 0-5 ℃ and the mixture was allowed to warm to room temperature. The mixture was poured into a saturated aqueous solution of NH4Cl (15 mL) . The aqueous phase was extracted with EtOAc (15 mL) . The combined organic phases were dried over Na2SO4. Removal of the solvent in vacuum gave a crude. The resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate = 4/1 to 1/2) . INT 15-4 (292 mg, 0.439 mmol, 62.13%yield) was obtained as reddish brown oil. LC-MS (ESI+) : m/z 398.7 (M+H) +.
Step 5: Procedure for preparation of 15-5
A mixture of 1-phenyl-1H-pyrazole (10 g, 69.4 mmol) , PhSSPh (1.51 g, 6.94 mmol) and 1, 3-diiodo-4, 4-dimethyl-2-oxotetrahydro-1H-imidazol-5-one (21.1 g, 55.5 mmol) in MeCN (100 mL) was stirred at 25 ℃ for 1hr. After adding an aqueous solution of sodium thiosulfate, extraction was performed with dichloromethane. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue obtained is chromatographed on silica gel (PE: EA=95: 5) to give INT 15-5 (20 g, 91.6 mmol, 95%yield) as a white solid. LC-MS (ESI+) : m/z 270.8 (M+H) +. 1H NMR 1H NMR (400 MHz, DMSO-d6 ) δ: 8.73 (s, 1H) , 7.88 -7.80 (m, 3H) , 7.55 -7.47 (m, 2H) , 7.37 -7.30 (m, 1H) .
Step 6: Procedure for preparation of 15-6
A mixture of 15-5 (2 g, 7.41 mmol) , TEA (1.441 mL, 10.367 mmol) , potassium; ethenyl (trifluoro) boranuide (1.19 g, 8.886 mmol ) and Pd (dppf) Cl2 (0.54 g, 0.741 mmol) in n-PrOH (20
mL) was stirred at 100 ℃ for 20 hrs under N2 atmosphere. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The reaction mixture was diluted with H2O (20 mL) and extracted with DCM (30 mL *3) . The combined organic layers were washed with brine (20 mL) , dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (80 gSilica Flash Column, Eluent of 0~20%Ethyl acetate/Petroleum ether gradient @60 mL/min) to give 15-6 (2.5 g, 4.498 mmol, 36%yield) as a yellow oil. LC-MS (ESI+) : m/z 171.1 (M+H) +. 1H NMR 1H NMR (400 MHz, DMSO-d6 ) δ: 8.61 (s, 1H) , 7.94 (s, 1H) , 7.82 (dd, J = 1.0, 8.6 Hz, 2H) , 7.49 (t, J = 8.0 Hz, 2H) , 7.37 -7.24 (m, 1H) , 6.68 -6.53 (m, 1H) , 5.65 (dd, J = 1.5, 17.7 Hz, 1H) , 5.15 (dd, J = 1.5, 11.0 Hz, 1H) .
Step 7: Procedure for preparation of 15-7
To a stirring slurry of CdCl2 (314 mg, 2.35 mmol) in THF (2 mL) under N2 at 25 ℃ was added TMEDA (546 mg, 4.70 mmol) . The resulting blue reaction mixture was allowed to stir for 20 mins. To the reaction mixture was added a solution of 15-6 (100 mg, 0.587 mmol) in THF (2 mL) followed by a solution of 2- (dichloromethyl) -4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane (248 mg, 1.17 mmol) and LiI (314 mg, 2.35 mmol) in THF (1 mL) . The resulting greenish blue reaction mixture was allowed to stir for 16 hrs. The reaction mixture was filtered, concentrated. The mixture was diluted with EA (10 mL) and washed with H2O (10 mL *2) . The combined organic layers were washed with brine (10 mL) , dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (20gSilica Flash Column, Eluent of 0~10%Ethyl acetate/Petroleum ether gradient @30mL/min) to give INT 15-7 (50 mg, 0.148 mmol, 25%yield) as a yellow oil. LC-MS (ESI+) : m/z 311.4 (M+H) +.
Step 8: Procedure for preparation of 15-8
To a solution of 15-4 (150 mg, 0.376 mmol) in dioxane (3 mL) and H2O (0.3 mL) was added 15-7 (117 mg, 0.376 mmol) , K2CO3 (13.4 mg, 0.097 mmol) and Pd (dppf) Cl2
. CH2Cl2 (2.63 mg, 0.003 mmol) . The mixture was stirred at 105℃ for 18 hrs under N2 atmosphere. The mixture was diluted with EA (10 mL) and filtered, and the filtrate was washed with brine (10 mL*2) . The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give 15-8 (260 mg, 0.357 mmol, 95%yield) as a brown oil, which was used for next step without further purification. LC-MS (ESI+) : m/z 503.1 (M+H) +.
Step 9: Procedure for preparation of 15-9
To a solution of 15-8 (230 mg, 0.458 mmol) in EtOH (3.2 mL) and H2O (0.8 mL) were added Fe (256 mg, 4.58 mmol) and NH4Cl (245 mg, 4.58 mmol) . The reaction was stirred at 80℃ for 2 hrs. The mixture was filtered and the cake was washed with EtOH (5 mL*2) . The filtrate was concentrated under reduced pressure to removed EtOH to give a residue, which was diluted with EA (10 mL) and washed with H2O (10 mL) and brine (10 mL) . The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (12gSilica Flash Column, Eluent of 0~50%Ethyl acetate/Petroleum ether gradient @25mL/min) to give 15-9 (146 mg, 0.293 mmol, 64%yield) as a yellow oil. LC-MS (ESI+) : m/z 473.1 (M+H) +.
Step 10: Procedure for preparation of 15-10
To a mixture of 15-9 (130 mg, 0.275 mmol) in dioxane (5 mL) was added 15-1 (82 mg, 0.275 mmol) , Cs2CO3 (269 mg, 0.825 mmol) , Xantphos (64 mg, 0.110 mmol) and Pd2 (dba) 3 (75.5 mg, 0.083
mmol) . The mixture was stirred at 140℃ for 16 hrs under N2 atmosphere. The reaction was filtered and the filter cake was washed by EA (5 mL) . The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (12gSilica Flash Column, Eluent of 0~55%Ethyl acetate/Petroleum ether gradient @25 mL/min) . INT 15-10 (177 mg, 0.217 mmol, 79%yield) was obtained as a yellow solid. LC-MS (ESI+) : m/z 735.3 (M+H) +.
Step 11: Procedure for preparation of 15-11
To a solution of 15-100 (50 mg, 0.068 mmol) in DCM (1 mL) was added TFA (1 mL) . The mixture was stirred at 25 ℃ for 1 hr. The mixture was concentrated under reduced pressure to give a crude product. The residue was purified by prep-HPLC (column: Boston Green ODS 150*30mm*5um; mobile phase: [water (FA) -ACN] ; B%: 30%-60%, 7min) to give 15-11 (2.33 mg, 0.004 mmol, 6%yield) as a white solid. LC-MS (ESI+) : m/z 605.4 (M+H) +. 1H NMR (400 MHz, CDCl3) δ = 12.14 (s, 1H) , 9.66 -8.25 (m, 2H) , 7.81 (s, 1H) , 7.74 -7.59 (m, 3H) , 7.54 -7.40 (m, 4H) , 7.33 -7.27 (m, 1H) , 7.18 -6.99 (m, 1H) , 6.94 -6.80 (m, 2H) , 5.44 -5.11 (m, 2H) , 4.15 -3.98 (m, 4H) , 3.63 -3.47 (m, 2H) , 3.33 -3.04 (m, 4H) , 2.34 -2.04 (m, 3H) , 1.94 -1.84 (m, 1H) , 1.83 -1.64 (m, 4H) , 1.54 -1.42 (m, 1H) , 1.36 -1.27 (m, 1H) .
Step 12: Procedure for preparation of Example 15-P1 an d 15-P2
The 15-11 (16 mg, 0.033 mmol) was further purified by pre-SFC (column: DAICEL CHIRALCEL OD (250mm*30mm, 10um) ; mobile phase: [0.1%NH3H2O ETOH] ; B%: 60%-60%, min) to afford two fractions.
Ex15-P1 tR = 2.0 min (4.29 mg, 21%yield) was obtained. LC-MS (ESI+) : m/z 605.4 (M+H) +. 1H NMR (400 MHz, CD3OD) δ = 8.71 (d, J = 8.4 Hz, 1H) , 8.17 (s, 1H) , 7.74 (d, J = 7.6 Hz, 2H) , 7.69 (s, 1H) , 7.61 (d, J = 8.4 Hz, 1H) , 7.53 -7.46 (m, 3H) , 7.35 -7.29 (m, 1H) , 7.17 (d, J = 7.2 Hz, 1H) , 6.98 (d, J = 7.6 Hz, 1H) , 6.90 (d, J = 8.4 Hz, 1H) , 5.29 -5.12 (m, 1H) , 4.08 -4.02 (m, 2H) , 3.98 -3.86 (m, 2H) , 3.63 -3.55 (m, 2H) , 3.20 -3.01 (m, 3H) , 2.90 -2.75 (m, 1H) , 2.61 (br s, 1H) , 2.36 -2.13 (m, 2H) , 2.11 -1.91 (m, 2H) , 1.87 -1.68 (m, 4H) , 1.54 -1.44 (m, 1H) , 1.43 -1.35 (m, 1H) .
Ex15-P2 tR = 5.1 min (4.31 mg, 21%yield) was obtained. LC-MS (ESI+) : m/z 605.4 (M+H) +. 1H NMR (400 MHz, CD3OD) δ = 8.72 (d, J = 8.4 Hz, 1H) , 8.17 (s, 1H) , 7.74 (d, J = 7.6 Hz, 2H) , 7.69 (s, 1H) , 7.61 (d, J = 8.4 Hz, 1H) , 7.53 -7.45 (m, 3H) , 7.35 -7.29 (m, 1H) , 7.17 (d, J = 7.2 Hz, 1H) , 6.98 (d, J = 7.2 Hz, 1H) , 6.90 (d, J = 8.4 Hz, 1H) , 5.33 -5.09 (m, 1H) , 4.11 -4.01 (m, 2H) , 3.99 -3.84 (m, 2H) , 3.67 -3.52 (m, 2H) , 3.24 -3.17 (m, 1H) , 3.11 -2.99 (m, 2H) , 2.92-2.71 (m, 1H) , 2.59 (br d, J = 7.6 Hz, 1H) , 2.37 -2.14 (m, 2H) , 2.10 -1.89 (m, 2H) , 1.85 -1.68 (m, 4H) , 1.53 -1.43 (m, 1H) , 1.42 -1.36 (m, 1H) .
Example 16
Step 1: Procedure for preparation of 16-1
To a solution of 2, 5-dichloropyridine-4-carbaldehyde (1.00 g, 5.68 mmol) in MeOH (15 mL) were added trimethoxymethane (0.90 g, 8.52 mmol) , and 4-methylbenzenesulfonic acid (0.10 g, 0.568 mmol) . After addition, the resulting mixture was stirred at 80 ℃ for 3 hrs. The reaction mixture was poured into water (40 mL) , and extracted with EtOAc (20 mL*2) . The combined organic layers were washed with brine (20 mL) , dried over Na2SO4, filtered, and concentrated to give a residue, which was purified by column chromatography on silica gel eluting with methanol (from 0%to 5%) in dichloromethane to afford the INT 16-1 (1.10 g, 4.21 mmol, 74.2%yield) as a yellow solid. LC-MS (ESI+) : m/z 222.0 (M+H) +.
Step 2: Procedure for preparation of 16-2
To a solution of 16-1 (0.80 g, 3.60 mmol) and N, N, N', N'-tetramethylethylenediamine (0.59 mL, 3.96 mmol) in THF (16 mL) was added LDA (2.70 mL, 5.40 mmol, 2M in THF) under N2 at -65 ℃. After addition, the mixture was stirred for 0.5 hr, then a solution of methyl carbonochloridate (0.84 mL, 10.81 mmol) in THF (2 mL) was added dropwise. The resulting mixture was stirred at -65~-20 ℃ for 1 hr. The reaction was poured into saturated NH4Cl (50 mL) and then extracted with EtOAc (50 mL*2) . The combined organic layers were washed with brine (30 mL) , dried on Na2SO4, filtered, and concentrated to give a residue, which was purified by column chromatography on silica gel eluting with ethyl acetate (from 0%to 20%) in dichloromethane to afford the title compound (0.42 g, 1.05 mmol, 29.1%yield) as light yellow oil. LC-MS (ESI+) : m/z 280.0 (M+H) +. 1H NMR (400 MHz, CDCl3) δ 8.40 (s, 1H) , 5.50 (s, 1H) , 3.93 (s, 3H) , 3.40 (s, 6H) .
Step 3: Procedure for preparation of 16-3
To a solution of INT 16-2 (30.00 mg, 0.11 mmol) and INT 16-3 (25.10 mg, 0.11 mmol) in dioxane (0.6 mL) were added Xantphos (12.39 mg, 0.021 mmol) , Cs2CO3 (69.79 mg, 0.21 mmol) , followed by Pd2 (dba) 3 (9.81 mg, 0.011 mmol) . After addition, the reaction mixture was purged with N2 for 1 min and stirred at 100 ℃ under N2 for 16 hrs. After cooling to room temperature, the resulting mixture was filtered, the filter cake was washed with EtOAc (2 mL) and the organic layer was concentrated to give a residue, which was purified by pre-TLC (PE: EtOAc = 0/1, v/v) to afford the title compound (13.00 mg, 0.024 mmol, 22.9%yield) as a yellow solid. LC-MS (ESI+) : m/z 478.2 (M+H) +. 1H NMR (400 MHz, CDCl3) δ 8.20 (s, 1H) , 7.45 (d, J = 8.0, Hz, 1H) , 7.22 (d, J = 8.0 Hz, 1H) , 7.17 (s, 1H) , 7.14 (s, 1H) , 5.40 (s, 1H) , 4.07 (dd, J = 8.0, 4.0 Hz, 2H) , 3.90 (s, 3H) , 3.56 -3.50 (m, 2H) , 3.46 (s, 6H) , 3.40 -3.36 (m, 2H) , 3.18 -3.05 (m, 1H) , 2.22 (s, 6H) , 1.86 -1.73 (m, 4H) .
Step 4: Procedure for preparation of 16-4
To a solution of INT 16-3 (110.00 mg, 0.23 mmol) in DCM (1 mL) was added TFA (0.51 mL, 6.67 mmol) dropwise at 20 ℃. After addition, the reaction mixture was stirred at 20 ℃ for 12 hrs. The reaction was diluted with DCM (10 mL) and washed with saturated NaHCO3 solution (5 mL) , followed by brine (5 mL) , dried over Na2SO4, filtered, and concentrated to give a residue, which was purified by column chromatography on silica gel eluting with ethyl acetate (from 0%to 100%) in petroleum ether to afford the title compound (66.00 mg, 0.15 mmol, 63.1%yield) as light yellow oil. LC-MS (ESI+) : m/z 432.3 (M+H) +.
Step 5: Procedure for preparation of 16-5
To a solution INT 16-4 (35.00 mg, 0.081 mmol) in EtOH (2 mL) was added NH2NH2. H2O (0.51 mL, 8.91 mmol) . After addition, the resulting mixture was stirred at 60 ℃ for 8 hrs. Then reaction was concentrated to give a residue, which was purified by pre-TLC (DCM: MeOH = 10/1, v/v) to afford the title compound (12.00 mg, 0.029 mmol, 35.8%yield) as a yellow solid.
LC-MS (ESI+) : m/z 414.3 (M+H) +.
Step 6: Procedure for preparation of Example 16
To a solution of INT 16-5 (12.00 mg, 0.029 mmol) and INT 1-13 (49.31 mg, 0.058 mmol) in DMF (0.24 mL) were added Pd (OAc) 2 (1.30 mg, 0.006 mmol) , XPhos (8.30 mg, 0.017 mmol) . After addition, the reaction mixture was purged with N2 for 1 min and then stirred at 140 ℃ under N2 for 6 hrs. After cooling to room temperature, the reaction was poured into 10 mL of water and extracted with EtOAc (10 mL*3) , the combined organic layers were washed with brine (10 mL) , dried over Na2SO4, filtered, and concentrated to give a residue, which was purified by pre-TLC (DCM: MeOH = 10/1, v/v) to afford the title compound (1.50 mg, 0.003 mmol, 10.1%yield) . LC-MS (ESI+) : m/z 514.4 (M+H) +. 1H NMR (400 MHz, DMSO-d6) δ 13.35 (brs, 1H) , 11.72 (s, 1H) , 8.59 (s, 1H) , 8.31 (t, J = 8.0 Hz, 1H) ,
7.95 (d, J = 8.0, 1H) , 7.80 (d, J = 8.0 Hz, 2H) , 7.62 (d, J = 8.0 Hz, 1H) , 7.57 (s, 1H) , 7.38 (d, J = 8.0 Hz, 1H) , 7.04 (t, J = 8.0 Hz, 1H) , 4.02 (d, J = 8.0 Hz, 2H) , 3.51-3.46 (m, 4H) , 3.26-3.17 (m, 1H) , 2.25 (s, 6H) , 1.83-1.67 (m, 4H) .
Example 17
Step 1: Procedure for preparation of 17-1
To a solution of 1, 2, 3, 4-tetrahydro-1, 5-naphthyridine (5.00 g, 37.30 mmol) in MeCN (50 mL) was added NBS (7.30 g , 41.00 mmol) at 0 ℃. After addition, the mixture was stirred at 25 ℃ for 3 hrs under N2. The mixture was extracted with EtOAc (50 mL*3) . The combined organic layers were dried over Na2SO4, filtered, and concentrated to give a residue, which was purified by column chromatography on silica gel eluting with ethyl acetate (from 0%to 20%) in petroleum ether to afford INT 17-1 (4.98 g, 23.49 mmol, 63.2%yield) as a yellow solid. LC-MS (ESI+) : m/z 213.2 (M+H) +.
Step 2: Procedure for preparation of 17-2
To a solution of INT 17-1 (3.73 g, 17.50 mmol) in THF (30 mL) were added TEA (7.28 ml, 52.50 mmol) , DMAP (0.21 g, 1.75 mmol) , followed by Boc2O (4.82 ml, 21.00 mmol) . After addition, the mixture was stirred at 80 ℃ for 12 hrs. After cooling to room temperature, the resulting mixture was poured to water (50 mL) and extracted with EtOAc (20 mL*3) . The combined organic layers were washed with brine (30 mL) , dried over Na2SO4, filtered, and concentrated to give a residue, which was purified by column chromatography on silica gel eluting with ethyl acetate (from 0%to 20%) in petroleum ether to afford the INT 17-2 (3.68 g, 11.79 mmol, 67.3%yield) as a yellow solid. LC-MS (ESI+) : m/z 313.2 (M+H) +.
Step 3: Procedure for preparation of 17-3
To a solution of 17-2 (3.68 g, 11.80 mmol) in dioxane (30 mL) were added diphenylmethanimine (2.37 ml, 14.16 mmol) , Cs2CO3 (11.50 g , 35.40 mmol) , Xantphos (0.68 g, 1.18 mmol) , Pd2 (dba) 3 (1.07 g , 1.18 mmol) . After addition, the mixture bubbled with N2 for 1 min and stirred at 100 ℃ for 12 hrs. After cooling to room temperature, the mixture was filtered and the filtrate was
purified by column chromatography on silica gel eluting with ethyl acetate (from 25%to 50%) in petroleum ether to afford INT 17-3 (4.59 g, 14.71 mmol, 94.2%yield) as a yellow solid. LC-MS (ESI+) : m/z 414.3 (M+H) +.
Step 4: Procedure for preparation of 17-4
To a solution of INT 17-3 (4.59 g, 11.10 mmol) in MeOH (45 mL) was added NH2OH. HCl (1.54 g, 22.20 mmol) at 0 ℃. After that, the mixture was stirred at 25 ℃ for 12 hrs. The resulting mixture was evaporated to dryness and poured to water (50 mL) , extracted with EtOAc (100 mL*3) . The combined organic layers were washed with brine (50 mL) , dried over Na2SO4, filtered, and concentrated to give a residue, which was purified by column chromatography on silica gel eluting with ethyl acetate (from 0%to 50%) in petroleum ether to afford 17-4 (1.71 g, 6.86 mmol, 62.7%yield) as a white solid. LC-MS (ESI+) : m/z 250.3 (M+H) +.
Step 5: Procedure for preparation of 17-5
To a solution of 17-4 (1.71 g, 6.86 mmol) in n-BuOH (10 mL) was added chloroacetaldehyde (0.52 ml, 8.22 mmol) at 25 ℃. After that, the mixture was stirred at 130 ℃ for 3 hrs. The mixture was poured to water (30 mL) and extracted with EtOAc (20 mL*3) . The combined organic layers were washed with brine (20 mL) , dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography on silica gel eluting with methanol (from 0%to 5%) in dichloromethane to afford 17-5 (0.92 g, 3.36 mmol, 49.1%yield) as a white solid. LC-MS (ESI+) : m/z 274.3 (M+H) +.
Step 6: Procedure for preparation of 17-6
To a solution of INT 17-5 (0.30 g, 1.09 mmol) in DCM (15 mL) was added NBS (0.20 g , 1.09 mmol) at 0 ℃. After that, the mixture was stirred at 0 ℃ for 1 h. Then the reaction mixture was poured into water (20 mL) and extracted with DCM (30 mL*3) , the combined organic layers were washed with brine (20 mL) , dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography on silica gel eluting with methanol (from
0%to 5%) in dichloromethane to afford the INT 17-6 (0.22 g, 0.62 mmol, 57.1%yield) as a yellow solid. LC-MS (ESI+) : m/z 352.2 (M+H) +. 1H NMR (400 MHz, DMSO-d6) δ 7.84 (d, J = 8.0 Hz, 1H) , 7.46 (d, J = 8.0 Hz, 1H) , 5.94 (s, 1H) , 4.23 -4.21 (m, 2H) , 3.84 -3.81 (m, 2H) , 2.40 -2.38 (m, 2H) , 1.43 (s, 9H) .
Step 7: Procedure for preparation of 17-7
To a solution of 2-6 (2.00 g, 6.09 mmol) in dioxane (30 mL) were added Pd (dppf) Cl2 (0.44 g, 0.61 mmol) , KOAc (1.79 g, 18.29 mmol) and 4, 4, 4', 4', 5, 5, 5', 5'-octamethyl-2, 2'-bi (1, 3, 2-dioxaborolane) (1.86 g, 7.31 mmol) . After addition, the mixture was degassed and purged with N2 for 3 times and stirred at 130 ℃ under N2 for 5 hrs. After cooling to room temperature, the reaction mixture was poured into water (50 mL) and extracted with EtOAc (60 mL*3) , the combined organic layers were washed with brine (20 mL) , dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue, which was purified by column chromatography on silica gel eluting with methanol (from 0%to 5%) in dichloromethane to afford the INT 17-7 (1.10 g, 3.58 mmol, 61.1%yield) as a yellow solid. LC-MS (ESI+) : m/z 306.7 (M+H) +.
Step 8: Procedure for preparation of 17-8
To a solution of INT 17-7 (0.14 g, 0.45 mmol) in dioxane/H2O (2 mL: 0.25 ml) were added Pd (dppf) Cl2 (33.00 mg, 0.04 mmol) , NaHCO3 (0.12 g, 1.36 mmol) and 17-6 (0.18 g, 0.51 mmol) . After addition, the mixture was exchanged with N2 for 3 times and stirred at 100 ℃ under N2 for 2 hrs. After cooling to room temperature, the reaction mixture was poured into water (30 mL) and extracted with EtOAc (30 mL*3) , the combined organic layers were washed with brine (20 mL) , dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by prep-TLC (DCM: MeOH = 20: 1, v/v) to afford the 17-8 (70.00 mg, 0.15 mmol, 33.9%yield) as a yellow solid. LC-MS (ESI+) : m/z 452.3 (M+H) +.
Step 9: Procedure for preparation of 17-9
To a solution of INT 17-8 (70.00 mg, 0.15 mmol) and 1-10 (36.00 mg, 0.15 mmol) in dioxane (3.5 mL) were added Pd2 (dba) 3 (14.00 mg, 0.01 mmol) , XantPhos (18.00 mg, 0.03 mmol) and Cs2CO3 (0.10 g, 0.31 mmol) . After addition, the mixture was exchanged with N2 for 3 times and stirred at 140 ℃ under N2 for 5 hrs. After cooling to room temperature, the reaction mixture was poured into water (20 mL) and extracted with EtOAc (20 mL*3) , the combined organic layers was washed with brine (20 mL) , dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by prep-TLC (DCM: MeOH = 15: 1, v/v) to afford INT 17-9 (40.00 mg, 0.06 mmol, 25.0%yield) as a yellow solid. LC-MS (ESI+) : m/z 551.3 (M+H-Boc) +.
Step 10: Procedure for preparation of Example 17
To a solution of 17-9 (40.00 mg, 0.06 mmol) in DCM (3 mL) was added TFA (1 mL) at 0 ℃. After addition, the mixture was stirred at 25 ℃ for 3 hrs. The resulting mixture was diluted with DCM (30 mL) and adjusted pH to ~7 with saturated NaHCO3 and then washed with brine (10 mL) , dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by prep-TLC (DCM: MeOH = 10: 1, v/v) to afford Ex17 (5.00 mg, 0.01 mmol, 15.1%yield) . LC-MS (ESI+) : m/z 551.4 (M+H) +. 1H NMR (400 MHz, DMSO-d6) δ 9.21-9.19 (m, 1H) , 7.64-7.58 (m, 1H) , 7.36 (d, J = 4.0 Hz, 1H) , 7.35 (s, 1H) , 7.33 (s, 1H) , 7.23 (s, 1H) , 7.21 (d, J = 4.0 Hz, 1H) , 7.20 (d, J = 4.0 Hz, 1H) , 6.83 (d, J = 8.0 Hz, 1H) , 3.96 (d, J = 12.0 Hz, 2H) , 3.80 (m, 2H) , 3.62 (s, 2H) , 3.50 (t, J = 12.0 Hz, 2H) , 3.38 (m, 1H) , 3.06–2.97 (m, 2H) , 2.28 (s, 6H) , 2.09 –1.99 (m, 2H) , 1.64 (s, 2H) , 1.60 (d, J = 6.0 Hz, 2H) .
Example 18
Step 1: Procedure for preparation of 18-1
To a solution of ethyl 1- (2, 2, 2-trifluoroethyl) -1H-imidazole-2-carboxylate (0.61 g, 2.74 mmol) in DMF (12 mL) was added NBS (0.49 g, 2.74 mmol) and the reaction was stirred at 25 ℃ for 12 hrs. The reaction was quenched with 10%Na2S2O3 solution and then water (30 mL) , extracted with EtOAc (50 mL*3) . The combined organic layers was washed with brine (50 mL) , dried over Na2SO4, filtrated, and concentrated under reduced pressure to give a residue, which was purified by column chromatography on silica gel eluting with ethyl acetate (from 0%to 10%) in petroleum ether to afford the INT 18-1 (0.35 g, 1.15 mmol, 41.9%yield) as yellow oil. LC-MS (ESI+) : m/z 301.1 (M+H) +.
Step 2: Procedure for preparation of 18-2
To a solution of 18-1 (0.35 g, 1.15 mmol) in MeOH: H2O (7 ml: 1ml) was added NaOH (0.14 g, 3.46 mmol) at 0 ℃. After addition, the mixture was stirred at 25 ℃ for 12 hrs. The resulting mixture was adjusted pH to ~2 with 1M HCl and then concentrated to give the crude product (0.30 g, 1.10 mmol, 96.1%yield) as a white solid. LC-MS (ESI-) : m/z 271.3 (M-H) -.
Step 3: Procedure for preparation of 18-3
To a solution of 18-2 (0.28 g, 1.02 mmol) in DMF (5 ml) were added 3-methoxyazetidine (0.13 g, 1.54 mmol) , HATU (0.47 g, 1.23 mmol) and TEA (0.66 g, 5.14 mmol) . After addition, the mixture was stirred at 25 ℃ for 3 hrs. The resulting mixture was poured to water (20 mL) and extracted with EtOAc (20 mL*3) , the combined organic layers were washed with brine (20 mL) , dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography on silica gel eluting with ethyl acetate (from 0%to 50%) in petroleum ether to
afford the INT 18-3 (0.11 g, 0.32 mmol, 31.3%yield) as a yellow solid. LC-MS (ESI+) : m/z 342.1 (M+H) +. 1H NMR (400 MHz, DMSO-d6) δ 7.46 (s, 1H) , 5.26 -5.22 (m, 2H) , 4.86 -4.81 (m, 1H) , 4.51 -4.51 (m, 1H) , 4.27 -4.23 (m, 2H) , 4.04 -4.01 (m, 1H) , 3.33 (s, 3H) .
Step 4: Procedure for preparation of 18-4
To a solution of INT 18-3 (0.11 g, 0.32 mmol) in dioxane/H2O (2 mL: 0.25 ml) were added Pd (PPh3) 2Cl2 (22.00 mg, 0.03 mmol) , NaHCO3 (81.00 mg, 0.96 mmol) and 17-7 (0.11 g, 0.35 mmol) . After addition, the mixture was exchanged with N2 for 3 times and stirred at 100 ℃ under N2 for 1 hr. After cooling to room temperature, the reaction mixture was poured into water (30 mL) and extracted with EtOAc (30 mL*3) , the combined organic layers were washed with brine (20 mL) , dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by prep-TLC (DCM: MeOH = 20: 1, v/v) to afford the title compound (0.11 g, 0.25 mmol, 78.1%yield) as a yellow solid. LC-MS (ESI+) : m/z 442.2 (M+H) +.
Step 5: Procedure for preparation of Example 18
To a solution of INT 18-4 (0.10 g, 0.22 mmol) and 6- ( (dimethylamino) methyl) -5- (tetrahydro-2H-pyran-4-yl) pyridin-2-amine (64.00 mg, 0.27 mmol) in dioxane (3 mL) were added Pd2 (dba) 3 (41.00 mg, 0.04 mmol) , XantPhos (39.00 mg, 0.06 mmol) and Cs2CO3 (0.15 g, 0.45 mmol) . After addition, the mixture was exchanged with N2 for 3 times and stirred at 140 ℃ under N2 for 3 hrs. After cooling to
room temperature, the reaction mixture was poured into water (20 mL) and extracted with EtOAc (20 mL*3) . The combined organic layers was washed with brine (20 mL) , dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by prep-TLC with (DCM: MeOH = 15: 1, v/v) to afford the Ex18 (15.00 mg, 0.02 mmol, 10.3%yield) . LC-MS (ESI+) : m/z 641.3 (M+H) +. 1H NMR (400 MHz, DMSO-d6) δ 12.84 (s, 1H) , 12.28 (s, 1H) , 9.18 (d, J = 12.0 Hz, 1H) , 9.12 (s, 1H) , 8.04 (d, J = 12.0 Hz, 1H) , 8.00 (s, 1H) , 7.69 (d, J = 8.0 Hz, 1H) , 6.92 (d, J = 8.0 Hz, 1H) , 5.66 -5.52 (m, 2H) , 4.92 -4.81 (m, 1H) , 4.49 -4.39 (m, 1H) , 4.35 -4.24 (m, 2H) , 4.00 -3.87 (m, 3H) , 3.58 (s, 2H) , 3.48 -3.41 (m, 2H) , 3.27 (s, 3H) , 3.21 (m, 1H) , 2.24 (s, 6H) , 1.74 -1.63 (m, 4H) .
Example 19
Step 1: Procedure for preparation of 19-1
To a solution of 5-bromo-1-methyl-1H-imidazole (2.00 g, 12.42 mmol) in THF (40 mL) was added LDA (6.83 mL, 13.67 mmol, 2M in THF) at -65 ℃ under N2 and stirred for 0.5 hr. Then, a solution of methyl carbonochloridate (4.80 mL, 62.11 mmol) in THF (20 mL) was added dropwise at -65 ℃. The reaction mixture was stirred at -65 ℃ for 2 hrs. The resulting mixture was quenched by 30 mL saturated NH4Cl solution and extracted with EtOAc (30 mL*3) . The combined organic layers were washed with brine (50 mL) , dried on Na2SO4, filtered, and concentrated to give a residue, which was purified by column chromatography on silica gel eluting with ethyl acetate (from 0%to 50%) in petroleum ether to afford the INT 19-1 (1.10 g, 4.92 mmol, 39.6%yield) as a light yellow solid. LC-MS (ESI+) : m/z 218.9 (M+H) +.
Step 2: Procedure for preparation of 19-2
A mixture of INT 19-1 (0.60 g, 2.74 mmol) and 2-methoxy-N-methylethan-1-amine (1.47 mL, 13.70 mmol) was stirred at 120 ℃ under N2 for 3 hrs. The reaction was purified by pre-TLC (PE: EtOAc = 1: 1, v/v) to afford the title compound (0.12 g, 0.42 mmol, 15.2%yield) as light yellow oil. LC-MS (ESI+) : m/z 276.2 (M+H) +.
Step 3: Procedure for preparation of 19-3
To a solution of INT 19-2 (0.12 g, 0.42 mmol) and 17-7 (0.19 g, 0.63 mmol) in dioxane (4.5 mL) and H2O (1.5 mL) was added NaHCO3 (76.97 mg, 0.92 mmol) , followed by Pd (PPh3) 2Cl2 (29.23 mg, 0.042 mmol) . After addition, the reaction mixture was purged with N2 for 3 mins and stirred at 100 ℃ under N2 for 1 hr. After cooling to room temperature, the reaction was poured into 5 mL of water and extracted with EtOAc (5 mL*4) . The combined organic layers were washed with brine (5 mL) , dried on Na2SO4, filtered, and concentrated to give a residue, which was purified by pre-TLC (DCM: MeOH = 20: 1, v/v) to afford the 19-3 (65.00 mg, 0.17 mmol, 41.5%yield) as a light yellow solid. LC-MS (ESI+) : m/z 376.2 (M+H) +.
Step 4: Procedure for preparation of Example 19
To a solution of 19-3 (65.00 mg, 0.17 mmol) and 1-10 (52.91 mg, 0.23 mmol) in dioxane (2 mL) were added Xantphos (30.02 mg, 0.052 mmol) , Cs2CO3 (112.71 mg, 0.35 mmol) and followed by Pd2 (dba) 3 (31.68 mg, 0.035 mmol) . After addition, the reaction mixture was purged with N2 for 1 min and stirred at 140 ℃ under N2 for 4 hrs. After cooling to room temperature, the reaction was filtered and the cake was washed with EtOAc (3 mL*3) . The combined organic layers were concentrated to give a residue, which was purified by pre-TLC (DCM: MeOH = 10: 1, v/v) for three times to afford the Ex19 (15.00 mg, 0.026 mmol, 15.1%yield) . LC-MS (ESI+) : m/z 575.4 (M+H) +. 1H NMR (400 MHz, DMSO-d6) δ 12.99 (s, 1H) , 12.27 (s, 1H) , 9.20 (s, 1H) , 8.00 -7.82 (m, 2H) , 7.78 (d, J = 8.0 Hz, 1H) , 7.22 -7.14 (m, 1H) , 7.04 (d, J = 8.0 Hz, 1H) , 4.03 (d, J = 12.0 Hz, 2H) , 3.97 -3.92 (m, 1H) , 3.75 -3.70 (m, 1H) , 3.65 (d, J = 8.0 Hz, 1H) , 3.61 -3.47 (m, 7H) , 3.37 (s, 3H) , 3.24 (s, 3H) , 3.11 (s, 2H) , 2.49 -2.18 (m, 6H) , 1.79 -1.66 (m, 4H) .
Example 20
Step 1: Procedure for preparation of 20-1
To a solution of 5-bromo-8-chloroisoquinolin-1 (2H) -one (0.60 g, 2.34 mmol) in DMA (12 ml) was added Selected-F (1244 mg, 3.54 mmol) . After addition, the mixture was stirred at 150 ℃ for 0.5 h under N2 atmosphere. After cooling to room temperature, the reaction mixture was poured into water (30 mL) and extracted with EtOAc (30 mL*3) . The combined organic layers were washed with brine (30 mL) , dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography on silica gel eluting with ethyl acetate (from 0%to 50%) in petroleum ether to afford the INT 20-1 (0.42 g, 1.52 mmol, 65.4%yield) as a yellow solid. LC-MS (ESI+) : m/z 276.1 (M+H) +. 1H NMR (400 MHz, DMSO-d6) δ 11.49 (s, 1H) , 8.03 (d, J = 8.0 Hz, 1H) ) , 7.57 -7.42 (m, 2H) .
Step 2: Procedure for preparation of 20-2
To a solution of INT 20-1 (0.30 g, 1.09 mmol) in THF (20 mL) were added NaH (87.00 mg, 3.06 mmol) at 0 ℃ under N2 atmosphere. After addition, the reaction was stirred at 0 ℃ for 1 hr. Then SEM-Cl (217.00 g, 1.31 mmol) was added to the reaction at 0 ℃ and the reaction was stirred at 25 ℃ for further 3 hrs. The resulting mixture was quenched by saturated NH4Cl solution (5 mL) and then added water (30 mL) , extracted with EtOAc (30 mL*3) . The combined organic layers were washed with brine (30 mL) , dried over Na2SO4, and concentrated to give a residue, which was purified by column chromatography on silica gel eluting with ethyl acetate (from 0%to 75%) in petroleum ether to afford the INT 20-2 (0.28 g, 0.69 mmol 63.4%yield) as yellow oil. LC-MS (ESI+) : m/z 406.0 (M+H) +.
Step 3: Procedure for preparation of 20-3
To a solution of INT 20-2 (0.10 g, 0.24 mmol) in dioxane (3 mL) were added Pd (OAc) 2 (4.00 mg, 0.02 mmol) , KOAc (72.00 mg, 0.74 mmol) and 7-fluoroimidazo [1, 2-a] pyridine (40.00 mg, 0.29 mmol) . After addition, the mixture was degassed and purged with N2 for 3 times and stirred at 120 ℃ under N2 for 12 hrs. After cooling to room temperature, the reaction mixture was poured into water (30 mL) and extracted with EtOAc (30 mL*3) , the combined organic layers were washed with brine (20 mL) , dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by prep-TLC (DCM: MeOH = 20: 1, v/v) to afford the 20-3 (45.00 mg, 0.09 mmol, 39.8%yield) as a yellow solid. LC-MS (ESI+) : m/z 462.3 (M+H) +.
Step 4: Procedure for preparation of 20-4
To a solution of 20-3 (45.00 mg, 0.09 mmol) and INT 1-10 (27.00 mg, 0.11 mmol) in dioxane (1 mL) were added Pd2 (dba) 3 (9.00 mg, 0.01 mmol) , XantPhos (11.00 mg, 0.02 mmol) and Cs2CO3 (63.00 mg, 0.19 mmol) . After addition, the mixture was degassed and purged with N2 for 3 times and stirred at 140 ℃ under N2 for 3 hrs. After cooling to room temperature, the reaction mixture was poured into water (10 mL) and extracted with EtOAc (20 mL*3) . The combined organic layers were washed with brine (20 mL) , dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by prep-TLC with (DCM: MeOH = 15: 1, v/v) to afford the INT 20-4 (35.00 mg, 0.05 mmol, 54.6%yield) as a yellow solid. LC-MS (ESI+) : m/z 661.4 (M+H) +.
Step 5: Procedure for preparation of Example 20
To a solution of INT 20-4 (30.00 mg, 0.4 mmol) in DCM (2 mL) was added TFA (2 mL) . After addition, the reaction was stirred at 25℃ for 1 hr. The solvent was removed under vacuum to give crude intermediate, to which was added NH3 in CH3OH (2 ml) . The mixture was stirred at 25℃ for
another 1 hr. The solvent was removed under vacuum, which was purified by prep-TLC with (DCM: MeOH = 10: 1, v/v) to afford Ex20 (5.00 mg, 0.01 mmol, 17.8%yield) . LC-MS (ESI+) : m/z 531.2 (M+H) +. 1H NMR (400 MHz, DMSO-d6) δ 13.0 (s, 1H) , 11.62 (m, 1H) , 9.01 (d, J = 8.0 Hz, 1H) , 8.03 -8.02 (m, 1H) , 8.00 -7.86 (m, 1H) , 7.84 -7.72 (m, 1H) , 7.70 -7.65 (m, 1H) , 7.62 -7.59 (m, 1H) , 7.47 -7.41 (m, 1H) , 6.97 -6.89 (m, 1H) , 6.87 -6.85 (m, 1H) , 3.99 -3.92 (m, 2H) , 3.59 (s, 2H) , 3.51 -3.45 (m, 2H) , 3.23 -3.21 (m, 1H) , 2.23 (s, 6H) , 1.69 -1.66 (m, 4H) .
Example 21
Step 1: Procedure for preparation of 21-1
To a solution of imidazo [1, 2-a] pyridine-7-carbonitrile (0.20 g, 1.39 mmol) in dioxane (3 mL) were added Pd (OAc) 2 (23.00 mg, 0.14 mmol) , KOAc (0.41 g, 4.19 mmol) and INT 1-18 (0.54 g, 1.39 mmol) . After addition, the mixture was degassed and purged with N2 for 3 times and stirred at 120 ℃ under N2 for 12 hrs. After cooling to room temperature, the reaction mixture was poured into water (30 mL) and extracted with EtOAc (30 mL*3) . The combined organic layers were washed with brine (20 mL) , dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography on silica gel eluting with MeOH (from 0%to 10%) in DCM to afford the 21-1 (0.14 g, 0.31 mmol, 22.2%yield) as a yellow solid. LC-MS (ESI+) : m/z 451.2 (M+H) +.
Step 2: Procedure for preparation of 21-2
To a solution of INT 21-1 (0.13 g, 0.28 mmol) and 1-10 (67.00 mg, 0.28 mmol) in dioxane (3.5 mL) were added Pd2 (dba) 3 (26.00 mg, 0.03 mmol) , XantPhos (33.00 mg, 0.05 mmol) and Cs2CO3 (0.19 g, 0.57 mmol) . After addition, the mixture was exchanged with N2 for 3 times and stirred at 140 ℃ under N2 for 5 hrs. After cooling to room temperature, the reaction mixture was poured into water (20 mL) and extracted with EtOAc (20 mL*3) , the combined organic layers was washed with brine (20 mL) ,
dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by prep-TLC with (DCM: MeOH = 15: 1, v/v) to afford the INT 21-2 (70.00 mg, 0.10 mmol, 37.4%yield) as a yellow solid. LC-MS (ESI+) : m/z 650.4 (M+H) +.
Step 3: Procedure for preparation of Example 21
To a solution of INT 21-2 (70.00 mg, 0.10 mmol) in DCM (2 mL) was added TFA (2 mL) and the reaction was stirred at 25 ℃ for 1 hr. The solvent was removed under vacuum to give crude intermediate product, to which was added NH3 in CH3OH (2 ml) . The mixture was stirred at 25 ℃ for another 1 hr. The solvent was removed under vacuum, which was purified by prep-TLC (DCM: MeOH = 10: 1, v/v) to afford the Ex21 (15.00 mg, 0.03 mmol, 26.7%yield) . LC-MS (ESI+) : m/z 520.4 (M+H) +. 1H NMR (400 MHz, DMSO-d6) δ 12.81 (s, 1H) , 11.63 (d, J = 4.0 Hz, 1H) , 8.92 (s, 1H) , 8.48 (s, 1H) , 8.06 (d, J = 8.0 Hz, 1H) , 8.00 (s, 1H) , 7.71 (d, J = 8.0 Hz, 2H) , 7.18-7.16 (m, 2H) , 6.97 (d, J = 8.0 Hz, 1H) , 5.87 (d, J = 8.0 Hz, 1H) , 4.02-3.96 (m, 2H) , 3.62-3.60 (m, 2H) , 3.50-3.43 (m, 2H) , 3.24-3.17 (m, 1H) , 2.32 (s, 6H) , 1.73-1.63 (m, 4H) .
Example 22
Step 1: Procedure for preparation of 22-1
To a solution of INT 1-19 (1.90 g, 4.28 mmol) and 9-2 (1.20 g, 4.28 mmol) in dioxane (20 mL) were added XantPhos (0.73 g, 1.28 mmol) and Cs2CO3 (2.79 g, 8.56 mmol) , followed by Pd2 (dba) 3 (0.78 g, 0.86 mmol) . After addition, the mixture was degassed and purged with N2 for three times and stirred at 130 ℃ under N2 for 3 hrs. After cooling to room temperature, the resulting mixture was filtered, and the cake was washed with EtOAc (30 mL*3) . The combined organic layers were washed with water (50 mL) , followed by brine (30 mL) , dried over Na2SO4, filtered, and concentrated under reduced
pressure to give a residue, which was purified by column chromatography on silica gel eluting with methanol (from 0%to 5%) in dichloromethane to afford INT 22-1 (1.50 g, 2.18 mmol, 51%yield) as a yellow solid. LC-MS (ESI+) : m/z 687.4 (M+H) +.
Step 2: Procedure for preparation of Example 22
To a solution of INT 22-1 (1.50 g, 2.18 mmol) in DCM (10 mL) was added TFA (10 mL, 131 mmol) dropwise. After addition, the resulting mixture was stirred at 30 ℃ for 1 hr. The reaction was diluted with 50 mL DCM and then adjusted pH with saturated NaHCO3 solution to 7~8 and the organic layer was washed with brine (50 mL) , dried over Na2SO4, filtered, and concentrated to give a residue, which was dissolved in MeOH (10 mL) and 10 mL NH3 in MeOH (7 M in MeOH) was added. The mixture was stirred at 25 ℃ for 0.5 hr. Then, the resulting mixture was concentrated to give a residue, which was triturated with EtOAc (50 mL) at 50 ℃ for 16 hrs, filtered and the cake was washed with EtOAc (5 mL*2) . The filter cake was then triturated with MeOH (200 mL) at 70 ℃ for 6 hrs. After cooling to 25 ℃ slowly, The mixture was filtered, the cake was washed with MeOH (5 mL*2) , collected the solid and dried to afford Ex22 (2.40 g, 4.31 mmol, 74.5%yield) . LC-MS (ESI+) : m/z 557.4 (M+H) +. 1H NMR (400 MHz, DMSO-d6) δ 12.80 (s, 1H) , 11.58 (d, J = 4.0 Hz, 1H) , 8.97 (d, J = 8.8 Hz, 1H) , 7.92 (dd, J = 8.4 Hz, 1H) , 7.71 -7.60 (m, 3H) , 7.54 (dd, J = 12.0, 4.0 Hz, 1H) , 7.14 (dd, J = 8.0, 8.0 Hz, 1H) , 6.97 -6.86 (m, 2H) , 5.88 (d, J = 8.0 Hz, 1H) , 5.26 -5.10 (m, 1H) , 3.97 -3.93 (m, 2H) , 3.86 -3.79 (m, 2H) , 3.48 -3.41 (m, 2H) , 3.20 -3.13 (m, 1H) , 2.99 -2.80 (m, 2H) , 2.75 -2.63 (m, 1H) , 2.44 -2.38 (m, 1H) , 2.25 -2.02 (m, 1H) , , 1.92 -1.77 (m, 1H) , 1.73 -1.62 (m, 4H) .
Example 23
Step 1: Procedure for preparation of 23-1
To a solution of 8, 9-dihydro-7H-pyrano [3, 2-b] imidazo [2, 1-f] pyridine (0.16 g, 0.93 mmol) in DCM (10 mL) was added NBS (0.16 g, 0.88 mmol) and the reaction was stirred at 0 ℃ for 15 mins. The reaction was quenched with 10%Na2S2O3 solution and water (30 mL) , extracted with EtOAc (50 mL*3) . The combined organic layers were washed with brine (50 mL) , dried over Na2SO4, filtrated,
and concentrated under reduced pressure to give a residue, which was purified by column chromatography on silica gel eluting with ethyl acetate (from 0%to 50%) in petroleum ether to afford INT 23-1 (0.13 g, 0.85 mmol, 54.9%yield) as a yellow solid. LC-MS (ESI+) : m/z 252.9 (M+H) +. 1H NMR (400 MHz, DMSO-d6) δ 7.53 (s, 1H) , 7.40 (d, J = 8.0 Hz, 1H) , 6.96 (d, J = 12.0 Hz, 1H) , 4.15 -4.12 (m, 2H) , 3.55 –3.52 (m, 2H) , 2.07 -2.01 (m, 2H) .
Step 2: Procedure for preparation of 23-2
To a solution of INT 23-1 (70.00 mg, 0.27 mmol) in dioxane (2.0 mL) and H2O (0.4 mL) were added 8-chloro-2- (5, 5-dimethyl-2-oxa-5-silahex-1-yl) -5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1, 2-dihydroisoquinolin-1-one (0.14 g, 0.33 mmol) , Pd (dppf) Cl2 (20.00 mg, 0.03 mmol) and NaHCO3 (69.00 mg, 0.83 mmol) . After addition, the mixture was exchanged with N2 for 3 times and stirred at 100 ℃ under N2 for 2 hrs. After cooling to room temperature, the reaction mixture was poured into water (30 mL) and extracted with EtOAc (30 mL*3) . The combined organic layers were washed with brine (20 mL) , dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by prep-TLC (DCM: MeOH = 20: 1, v/v) to afford INT 23-2 (44.00 mg, 0.09 mmol, 32.3%yield) as yellow oil. LC-MS (ESI+) : m/z 482.2 (M+H) +.
Step 3: Procedure for preparation of 23-3
To a solution of INT 23-2 (44.00 mg, 0.09 mmol) in dioxane (1 mL) were added 9-2 (30.00 mg, 0.11 mmol) , Pd (dba) 3 (15.00 mg, 0.02 mmol) , Xantphos (16.00 mg, 0.03 mmol) and Cs2CO3 (59.00 mg, 0.18 mmol) . After addition, the mixture was exchanged with N2 for 3 times and stirred at 140 ℃ under N2 for 3 hrs. After cooling to room temperature, the reaction mixture was poured into water (20 mL) and extracted with EtOAc (20 mL*3) , the combined organic layers was washed with brine (20 mL) , dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was
purified by prep-TLC with (DCM: MeOH = 15: 1, v/v) to afford the INT 23-3 (29.00 mg, 0.04 mmol, 43.8%yield) as yellow oil. LC-MS (ESI+) : m/z 725.2 (M+H) +.
Step 4: Procedure for preparation of Example 23
To a solution of INT 23-3 (29.00 mg, 0.04 mmol) in DCM (2 mL) was added TFA (2 mL) , and the reaction was stirred at 25℃ for 2 hrs. The solvent was removed under vacuum to give crude product, to which was added NH3 in CH3OH (2 ml) . The mixture was stirred at 25 ℃ for another 1 hr. The solvent was removed under vacuum to give a residue, which was purified by prep-TLC with (DCM: MeOH = 10: 1, v/v) to afford the Ex23 (10.50 mg, 0.017 mmol, 44.1%yield) . LC-MS (ESI+) : m/z 595.4 (M+H) +. 1H NMR (400 MHz, DMSO-d6) δ 12.7 (s, 1H) , 11.5 (s, 1H) , 8.89 -8.87 (m, 1H) , 8.17 -8.14 (m, 1H) , 7.66 -7.63 (m, 2H) , 7.49 -7.46 (m, 1H) , 7.13 -7.10 (m, 1H) , 6.93 -6.90 (m, 2H) , 5.75 (d, J = 8.0 Hz, 1H) , 5.18-5.13 (m, 1H) , 4.06 -4.03 (m, 1H) , 3.93 -3.88 (m, 5H) , 2.86 -2.83 (m, 3H) , 2.75 -2.73 (m, 1H) , 2, 64 (d, J = 8 Hz, 1H) , 2.39 -2.42 (m, 3H) , 2.13 -2.11 (m, 2H) , 1.88 -1.83 (m, 1H) , 1.70 -1.65 (m, 6H) .
Example 24
Step 1: Procedure for preparation of 24-1
To a solution of methyl 2-amino-5-bromothiazole-4-carboxylate (3.0 g, 12.65 mmol) in DCM (50 mL) were added (Boc) 2O (3.20 mL, 13.92 mmol) , DMAP (0.20 g, 1.26 mmol) and TEA (5.26 mL, 37.96 mmol) . After additional, the resulting mixture was stirred at 20 ℃ for 3 hrs. The reaction mixture was partitioned between water (100 mL) and EtOAc (100 mL*3) . The combined organic layers were washed with brine (100 mL) . dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography on silica gel eluting with ethyl acetate (from 0%to 40%) in petroleum ether to afford the title compound to afford the INT 24-1 (2.00 g, 5.93
mmol, 46.9%yield) as a white solid. LC-MS (ESI+) : m/z 337.1 (M+H) +. 1HNMR (400 MHz, DMSO-d6) δ 12.08 (s, 1H) , 3.81 (s, 3H) , 1.49 (s, 9H) .
Step 2: Procedure for preparation of 24-2
A mixture of 24-1 (1.40 g, 6.52 mmol) , Pd (dppf) Cl2 (0.40 g, 0.59 mmol) , K2CO3 (2.50 g, 17.79 mmol) in dioxane (10 mL) and H2O (2 mL) was degassed and purged with N2 for 3 times, then the reaction was stirred at 110 ℃ for 2 hrs under N2 atmosphere. Then the resulting mixture was cooled down to room temperature and partitioned between water (50 mL) and EtOAc (60 mL) , the organic phase was separated, washed with brine (50 mL) . dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography on silica gel eluting with ethyl acetate (from 0%to 10%) in petroleum ether to afford the title compound to afford INT 24-2 (1.80 g, 5.29 mmol, 89.2%yield) was obtained as a white oil. LC-MS (ESI+) : m/z 341.3 (M+H) +. 1HNMR (400MHz, DMSO-d6) δ 11.74 (brs, 1H) , 6.05 -5.99 (m, 1H) , 4.19 (q, J= 4.0 Hz, 2H) , 3.80 -3.78 (m, 1H) , 3.77 (s, 3H) , 3.18 (d, J=4.0 Hz, 1H) , 2.39 -2.30 (m, 2H) , 1.48 (s, 9H) .
Step 3: Procedure for preparation of 24-3
To a solution of 24-2 (1.80 g, 5.29 mmol) in MeOH (100 mL) was added Pd/C 10% (0.30 g, 2.82 mmol) , Pd (OH) 2 (0.30 g, 2.14 mmol) and AcOH (0.03 mL, 0.53 mmol) , after additional, the mixture was degassed and purged with H2 for three times, and stirred at 10 ℃ for 24 hrs under H2 (15 Psi) . The reaction was filtered and concentrated to give a residue, and then was dissolved in DCM (30 mL) , washed with saturated Na2CO3 (20 mL) , followed by brine (10 mL) , dried over Na2SO4, filtered, and concentrated to afford the 24-3 (1.40 g, 4.09 mmol, 77.3%yield) , which was used in next step without further purification as a white solid. LC-MS (ESI+) : m/z 343.3 (M+H) +.
Step 4: Procedure for preparation of 24-4
To a solution of INT 24-3 (400.00 mg, 1.17 mmol) in THF (2 mL) being cooled to 0 ℃ was added LiBH4 (2.92 mL, 5.84 mmol) under N2, after additional, the reaction mixture was stirred at 10 ℃ under N2 for 1 hr. The reaction was poured into 10 mL of water and extracted with EtOAc (10 mL*3) , the combined organic layers were washed with brine (10 mL) , dried over Na2SO4, filtered, and concentrated to give a residue, which was purified by column chromatography on silica gel eluting with ethyl acetate (from 0%to 35%) in petroleum ether to afford the title compound to afford the 24-4 (0.33 g, 1.05 mmol, 90.1%yield) as a white solid. LC-MS (ESI+) : m/z 315.3 (M+H) +.
Step 5: Procedure for preparation of 24-5
To a solution of INT 24-4 (0.38 g, 1.21 mmol) in DCM (0.5 mL) being cooled to 0 ℃ was added TEA (0.34 mL, 2.42 mmol) , followed by MsCl (0.11 mL, 1.45 mmol) dropwise. After additional, the resulting mixture was stirred at 20 ℃ for 30 mins under N2. The reaction mixture was concentrated to afford the INT 24-5 (0.42 g, 1.06 mmol, 87.5%) as a yellow solid, which was used in next step without further purification.
Step 6: Procedure for preparation of 24-6
To a solution of 24-5 (0.42 g, 1.25 mmol) in CH3CN (4 mL) was added DIEA (0.62 mL, 3.75 mmol) and dimethylamine (3.13 mL, 6.25 mmol) , after additional, the reaction mixture was stirred at 10 ℃ for 3 hrs. After completed, the mixture was concentrated to give a residue, which was purified by column chromatography on silica gel eluting with MeOH (from 0%to 10%) in DCM to afford INT 24-6 (0.15 g, 0.44 mmol, 35.4%yield) as a white solid. LC-MS (ESI+) : m/z 342.3 (M+H) +.
Step 7: Procedure for preparation of 24-7
To a solution of INT 24-6 (0.15 g, 0.44 mmol) in DCM (1 mL) was added TFA (1 mL, 13.06 mmol) , after additional, the reaction was stirred at 10℃ for 30 mins and then it was diluted with DCM (10 mL) , washed with saturated NaHCO3 (6 mL*2) and then separated, the organic layer was washed with brine (10 mL) , dried over Na2SO4, filtered and concentrated to afford the 24-7 (60.00 mg, 0.25 mmol, 56.2%yield) as a yellow solid, which was used in next step directly. LC-MS (ESI+) : m/z 242.4 (M+H) +.
Step 8: Procedure for preparation of Example 24
To a solution of INT 2-7 (28.00 mg, 0.089 mmol) and 24-7 (28.00 mg, 0.097 mmol) in dioxane (0.7 mL) were added Pd2 (dba) 3 (16.30 mg, 0.018 mmol) , (R) -BINAP (16.60 mg, 0.027 mmol) and Cs2CO3 (72.50 mg, 0.22 mmol) , after additional, the resulting mixture was purged with N2 for 1 mins and stirred at 140 ℃ for 4 hrs under N2. The reaction was cooled down to room temperature and filtered and the cake was washed with EtOAc (2 mL*3) , the combined organic layers were concentrated to give a residue, which was purified by pre-TLC (DCM/MeOH=10/1, twice) to afford the Ex24 (7.50 mg, 0.014 mmol, 16.2%yield) . LC-MS (ESI+) : m/z 520.3 (M+H) +. 1H NMR (400 MHz, DMSO-d6) δ 13.10 (brs, 1H) , 12.89 (s, 1H) , 8.80 (d, J = 12.0 Hz, 1H) , 8.22 (dd, J = 8.0, 4.0 Hz, 1H) , 8.00 (d, J = 8.0 Hz, 1H) , 7.87 (s, 1H) , 7.77 (s, 1H) , 7.58 (dd, J = 8.0, 4.0 Hz, 1H) , 6.97 (td, J = 8.0, 4.0 Hz, 1H) , 3.93 (dd, J = 12.0, 4.0 Hz, 2H) , 3.53 -3.39 (m, 4H) , 3.30 -3.24 (m, 1H) , 2.22 (s, 6H) , 1.83 (brd, J = 12.0 Hz, 2H) , 1.65 -1.52 (m, 2H) .
Example 25
Step 1: Procedure for preparation of 25-1
To a mixture of 6-chloro-5-iodopyridin-2-amine (2.30 g, 9.04 mmol) and 2- (3, 6-dihydro-2H-pyran-4-yl) -4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane (1.90 g, 9.04 mmol) in dioxane (30 mL) and H2O (10 mL) were added Pd (dppf) Cl2. CH2Cl2 (0.74 g, 0.91 mmol) and K2CO3 (2.50 g, 18.08 mmol) , the reaction was degassed and purged with N2 for three times and stirred at 100 ℃ under N2 atmosphere for 3 hrs. After cooled down to room temperature, the reaction mixture was washed with H2O (30 mL*2) . dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography on silica gel eluting with ethyl acetate (from 0%to 30%) in petroleum ether to afford the INT 25-1 (2.20 g, 10.44 mmol, 96.0%yield) as a yellow solid. LC-MS (ESI+) : m/z 211.3 (M+H) +.
Step 2: Procedure for preparation of 25-2
To a mixture of 25-1 (14.00 mg, 0.066 mmol) and (1- (tert-butoxycarbonyl) -1H-pyrrol-2-yl) boronic acid (14.02 mg, 0.066 mmol) in dioxane (0.3 mL) and H2O (0.1 mL) were added Pd (dppf) Cl2. CH2Cl2 (5.43 mg, 0.007mmol) and K2CO3 (18.37 mg, 0.13 mmol) , the reaction was degassed and purged with N2 for three times and stirred at 100 ℃ under N2 atmosphere for 3 hrs. After cooled down to room temperature, the reaction mixture was concentrated under reduced pressure to give a residue, which was purified by prep-TLC (PE: EA = 3: 1, v/v) to afford the INT 25-2 (12.00 mg, 0.035 mmol, 52.9%yield) as a yellow gum. LC-MS (ESI+) : m/z 342.4 (M+H) +.
Step 3: Procedure for preparation of 25-3
To a solution of 25-2 (1.80 g, 5.27 mmol) in MeOH (60 mL) and EtOAc (60 mL) were added Pd/C 10% (0.28 g, 2.64 mmol) , Pd (OH) 2 (0.37 g, 2.64 mmol) and AcOH (0.01mL) . After addition, the
reaction was degassed and purged with H2 for three times, and then stirred at 30 ℃ under H2 atmosphere (15 Psi) for 18 hrs. The mixture was filtered through a celite pad and the cake was washed with MeOH (5 mL*3) , the combined organic layers were concentrated to give a residue, which was purified by column chromatography on silica gel eluting with ethyl acetate (from 0%to 30%) in petroleum ether to afford INT 25-3 (1.00 g, 2.88 mmol, 54.6%yield) as yellow oil. LC-MS (ESI+) : m/z 348.4 (M+H) +.
Step 4: Procedure for preparation of 25-4
To a mixture of INT 25-3 (0.20 g, 0.57 mmol) in dioxane (2 mL) were added 1-19 (0.26 g, 0.57 mmol) , Pd2 (dba) 3 (105.42 mg, 0.12 mmol) , Xantphos (99.92 mg, 0.17mmol) and Cs2CO3 (375.09 mg, 1.15 mmol) . After addition, the reaction was purged with N2 for 1 min and then stirred at 140 ℃ under N2 atmosphere for 3 hrs. Then the reaction mixture was cooled down to room temperature, filtered and the cake was washed with EtOAc (5 mL*3) , the combined organic layers were concentrated under reduced pressure to give a residue, which was purified by column chromatography on silica gel eluting with ethyl acetate (from 0%to 50%) in petroleum ether to afford the INT 25-4 (0.29 g, 0.38 mmol, 65.8%yield) as a yellow solid. LC-MS (ESI+) : m/z 755.4 (M+H) +.
Step 5: Procedure for preparation of Example 25
A solution of INT 25-4 (0.29 g, 0.38 mmol) in TFA (2 mL) was stirred at 30 ℃ for 1 hr. The mixture was diluted with DCM (10 mL) , then adjusted pH to ~9 and extracted with EtOAc (10 mL*4) . The combined organic layers were dried over Na2SO4, filtered, and concentrated to give a residue, which was purified by prep-TLC (DCM: MeOH = 10: 1, v/v) to afford Ex25 (40.00 mg, 0.076 mmol, 20.1%yield) . LC-MS (ESI+) : m/z 525.4 (M+H) +. 1H NMR (400 MHz, DMSO-d6) δ 12.74 (s, 1H) , 8.69 (d, J = 12.0 Hz, 1H) , 7.92 (dd, J = 8.0, 4.0 Hz, 1H) , 7.77 -7.61 (m, 3H) , 7.54 (dd, J = 12.0, 4.0 Hz, 1H) , 7.14
(d, J = 4.0 Hz, 1H) , 6.99 -6.87 (m, 2H) , 5.88 (d, J = 8.0 Hz, 1H) , 4.51 (t, J = 8.0 Hz, 1H) , 3.97 -3.93 (m, 2H) , 3.52 -3.46 (m, 2H) , 3.32 -3.24 (m, 3H) , 3.14 -3.03 (m, 1H) , 2.94-2.83 (m, 1H) , 2.21 -2.11 (m, 1H) , 1.93-1.82 (m, 2H) , 1.82 -1.60 (m, 4H) , 1.58 -1.55 (m, 1H) .
Example A: Enzymatic Assay
Kinase reaction
1) Prepared 2x kinase solution
1. Prepared a solution of MAP4K1 in 1x kinase buffer at 2-fold the final concentration of each reagent in the assay.
2. Added 5 μl of kinase solution to each well of the assay plate, except for control wells without enzyme (added 5 μl of 1x kinase buffer instead) .
3. Shook the plate. Incubated at room temperature for 10 min.
2) Prepared 2x substrate solution
1. Prepared substrate solution of Fluorescein-PKC and ATP in 1x kinase reaction buffer at 2-fold of the final concentration of each reagent desired in the assay.
2. Added 5 μl of substrate solution to each well of the assay plate to start reaction.
3. Shook the plate.
3) Kinase reaction
Covered the assay plate and incubate at room temperature for 90 minutes.
2. Kinase detection
1) Prepared detection solution of 2-fold of final concentration in Antibody Dilution Buffer.
2) Added 10 μl of detection solution to each well of the assay plate to stop the reaction.
3) Mixed briefly with centrifuge and incubated at room temperature 60 minutes before reading on a plate reader for fluorescence.
3. Data reading
Collected data on Envision with excitation at 340nm and emission at 520 nm and 495 nm.
4. Curve fitting
1. Copied values of RFU from Envision program.
2. Calculated Ratio of RFU 520nm /RFU 495nm
3. Converted Ratio values to percent inhibition values.
Percent inhibition = (max-sample Ratio) / (max-min) *100.
“min” means the Ratio of no enzyme control and “max” means the Ratio of DMSO control.
4. Data was presented in MS Excel and the curves fitted by XLFit excel add-in version 5.4.0.8
IC50 calculation equation is: Y=Bottom + (Top-Bottom) / (1+ (IC50/X) ^HillSlope
The data for Example A is shown in Table 4.
TABLE 4
HPK1 IC50 (nM) : 0<A≤100; 100<B≤500; 500<C≤5000
NT: not tested
Example B: Cellar p-SLP76 assay
Seed cells into the culture plate, then add compounds into the cells, incubate at 37 ℃ &5%CO2; Add CD3 antibody into cells, incubate at 37 ℃ &5%CO2. After that lyse cell with lysis buffer on ice, transfer the cell lysis into a 96-well plate and store at -80 ℃. p-SLP76 was detected by ELISA Kit. The data for Example B is shown in Table 5.
TABLE 5
p-SLP76 IC50 (nM) : 0<A≤100; 100<B≤500; 500<C≤5000; D>5000
Example C: Cellar IL-2 assay
Human Pan T cells were isolated from PBMC, then coat the plate with anti-human CD3, seed cells into the culture plate, add compounds into the cells, incubate at 37℃ &5%CO2. Collect supernatant after 24 hours and store it in -80 ℃, after that, IL-2 was detected by ELISA Kit. The data for Example C is shown in Table 6.
TABLE 6
IL-2 IC50 (nM) : 0<A≤300; 300<B≤1000; C>1000
Claims (137)
- A compound of Formula (I) , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
wherein:Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;each R1 is independently halogen, -CN, -NO2, -OH, -ORa, -OC (=O) Ra, -OC (=O) ORb, -OC (=O) NRcRd, -SH, -SRa, -SF3, -SF5, -S (=O) Ra, -S (=O) 2Ra, -S (=O) 2NRcRd, -NRcRd, -NRbC (=O) NRcRd, -NRbC (=O) Ra, -NRbC (=O) ORb, -NRbS (=O) 2Ra, -P (=O) RaNRcRd, -P (=O) RaORb, -P (=O) RaRb , -C (=O) Ra, -C (=O) ORb, -C (=O) NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R1a;or two R1 on the same atom are taken together to form an oxo;or two R1 on the same carbon are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R1a;or two R1 on the different atoms are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R1a;each R1a is independently halogen, -CN, -NO2, -OH, -ORa, -OC (=O) Ra, -OC (=O) ORb, -OC (=O) NRcRd, -SH, -SRa, -SF3, -SF5, -S (=O) Ra, -S (=O) 2Ra, -S (=O) 2NRcRd, -NRcRd, -NRbC (=O) NRcRd, -NRbC (=O) Ra, -NRbC (=O) ORb, -NRbS (=O) 2Ra, -P (=O) RaNRcRd, -P (=O) RaORb, -P (=O) RaRb , -C (=O) Ra, -C (=O) ORb, -C (=O) NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;or two R1a on the same atom are taken together to form an oxo;or two R1a on the same carbon are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R;or two R1a on the different atoms are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R;n is 0-6;L is -O-, -S-, or -NR2-;R2 is hydrogen, -CN, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl;W is N or CRW;RW is hydrogen, -SH, -SRa, -SF3, -SF5, halogen, -CN, -OH, -ORa, -NRcRd, -P (=O) RaNRcRd, -P (=O) RaORb, -P (=O) RaRb, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl;Z is N or CRZ;RZ is hydrogen, -SH, -SRa, -SF3, -SF5, halogen, -CN, -OH, -ORa, -NRcRd, -P (=O) RaNRcRd, -P (=O) RaORb, -P (=O) RaRb, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl;is a single bond; X is C (RX) 2, O, S, or NRX1; and Y is C (RY) 2, O, S, or NRY1;or is a double bond; X is CRX or N; and Y is CRY or N;each RX is independently hydrogen, -SH, -SRa, -SF3, -SF5, halogen, -CN, -OH, -ORa, -NRcRd, -P (=O) RaNRcRd, -P (=O) RaORb, -P (=O) RaRb, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl;RX1 is hydrogen, -CN, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl;each RY is independently hydrogen, -SH, -SRa, -SF3, -SF5, halogen, -CN, -OH, -ORa, -NRcRd, -P (=O) RaNRcRd, -P (=O) RaORb, -P (=O) RaRb, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl;RY1 is hydrogen, -CN, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl;R3 is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl;Ring B is a bicyclic ring;each R4 is independently halogen, -CN, -NO2, -OH, -ORa, -OC (=O) Ra, -OC (=O) ORb, -OC (=O) NRcRd, -SH, -SRa, -SF3, -SF5, -S (=O) Ra, -S (=O) 2Ra, -S (=O) 2NRcRd, -NRcRd, -NRbC (=O) NRcRd, -NRbC (=O) Ra, -NRbC (=O) ORb, -NRbS (=O) 2Ra, -P (=O) RaNRcRd, -P (=O) RaORb, -P (=O) RaRb, -C (=O) Ra, -C (=O) ORb, -C (=O) NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R4a;or two R4 on the same atom are taken together to form an oxo;or two R4 on the different atoms are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R4a;each R4a is independently halogen, -CN, -NO2, -OH, -ORa, -OC (=O) Ra, -OC (=O) ORb, -OC (=O) NRcRd, -SH, -SRa, -SF3, -SF5, -S (=O) Ra, -S (=O) 2Ra, -S (=O) 2NRcRd, -NRcRd, -NRbC (=O) NRcRd, -NRbC (=O) Ra, -NRbC (=O) ORb, -NRbS (=O) 2Ra, -P (=O) RaNRcRd, -P (=O) RaORb, -P (=O) RaRb, -C (=O) Ra, -C (=O) ORb, -C (=O) NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;or two R4a on the same atom are taken together to form an oxo;or two R4a on the same carbon are taken together to form a cycloalkyl or heterocycloalkyl; each independently optionally substituted with one or more R;or two R4a on the different atoms are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each independently optionally substituted with one or more R;m is 0-6;each Ra is independently C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene (cycloalkyl) , C1-C6alkylene (heterocycloalkyl) , C1-C6alkylene (aryl) , or C1-C6alkylene (heteroaryl) , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;each Rb is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene (cycloalkyl) , C1-C6alkylene (heterocycloalkyl) , C1-C6alkylene (aryl) , or C1-C6alkylene (heteroaryl) , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;Rc and Rd are each independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene (cycloalkyl) , C1-C6alkylene (heterocycloalkyl) , C1-C6alkylene (aryl) , or C1-C6alkylene (heteroaryl) , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;or Rc and Rd are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R; andeach R is independently halogen, -CN, -OH, -SH, -OCF3, -OCClF2, -SF3, -SF5, -SCF3, -SCClF2, -S (=O) C1-C3alkyl, -S (=O) 2C1-C3alkyl, -S (=O) 2NH2, -S (=O) 2NHC1-C3alkyl, -S (=O) 2N (C1-C3alkyl) 2, -NH2, -NHC1-C3alkyl, -N (C1-C3alkyl) 2, -P (=O) (C1-C3alkyl) N (C1-C3alkyl) 2, -P (=O) (C1-C3alkyl) O (C1-C3alkyl) , -P (=O) (C1-C3alkyl) 2, -C (=O) C1-C3alkyl, -C (=O) OH, -C (=O) OC1-C3alkyl, -C (=O) NH2, -C (=O) NHC1-C3alkyl, -C (=O) N (C1-C3alkyl) 2, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, or C3-C6cycloalkyl;or two R on the same atom form an oxo;or two R on the same carbon are taken together to form a cycloalkyl or heterocycloalkyl;or two R on the different atoms are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. - The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein the compound is of Formula (Ia) :
- The compound of claim 2, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein X is C (RX) 2 or NRX1; and Y is C (RY) 2 or NRY1.
- The compound of claim 2 and 3, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein X is C (RX) 2; and Y is C (RY) 2.
- The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein the compound is of Formula (Ib) :
- The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein the compound is of Formula (Ic) :
- The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein the compound is of Formula (Id) :
- The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein the compound is of Formula (Ie) :
- The compound of any one of claims 1-7, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each RX is independently hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, or C1-C6haloalkyl.
- The compound of any one of claims 1-7 or 9, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each RX is independently hydrogen, C1-C6alkyl, or C1-C6haloalkyl.
- The compound of any one of claims 1-6 or 8-10, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each RY is independently hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, or C1-C6haloalkyl.
- The compound of any one of claims 1-6 or 8-11, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each RY is independently hydrogen or halogen.
- The compound of any one of claims 1-3, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein RX1 is hydrogen, C1-C6alkyl, or C1-C6haloalkyl.
- The compound of any one of claims 1-3, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein RY1 is hydrogen, C1-C6alkyl, or C1-C6haloalkyl.
- The compound of any one of claims 1-14, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is aryl or heteroaryl.
- The compound of any one of claims 1-14, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is phenyl.
- The compound of any one of claims 1-14, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is heteroaryl.
- The compound of any one of claims 1-14, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is 5-or 6-membered heteroaryl.
- The compound of any one of claims 1-14, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is 6-membered heteroaryl.
- The compound of any one of claims 1-14, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is pyridinyl.
- The compound of any one of claims 1-14, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is bicyclic or tricyclic heteroaryl.
- The compound of any one of claims 1-21, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R1 is independently halogen, -CN, -OH, -ORa, -NRcRd, -C (=O) Ra, -C (=O) ORb, -C (=O) NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R1a.
- The compound of any one of claims 1-21, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R1 is independently halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R1a.
- The compound of any one of claims 1-21, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R1 is independently halogen, -OH, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6heteroalkyl, heterocycloalkyl, or heteroaryl; wherein each alkyl, heterocycloalkyl, and heteroaryl is independently optionally substituted with one or more R1a.
- The compound of any one of claims 1-21, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R1 is independently C1-C6alkyl or heterocycloalkyl; wherein each alkyl and heterocycloalkyl is independently optionally substituted with one or more R1a.
- The compound of any one of claims 1-21, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein two R1 on the same atom are taken together to form an oxo.
- The compound of any one of claims 1-21, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein two R1 on the same carbon are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R1a.
- The compound of any one of claims 1-21, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein two R1 on the different atoms are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R1a.
- The compound of any one of claims 1-28, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R1a is independently halogen, -CN, -OH, -ORa, -NRcRd, -NRbC (=O) NRcRd, -C (=O) Ra, -C (=O) ORb, -C (=O) NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R.
- The compound of any one of claims 1-28, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R1a is independently halogen, -CN, -OH, -ORa, -NRcRd, -NRbC (=O) NRcRd, C1-C6alkyl, C1-C6haloalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R.
- The compound of any one of claims 1-28, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R1a is independently cycloalkyl or heterocycloalkyl; wherein each cycloalkyl and heterocycloalkyl is independently optionally substituted with one or more R.
- The compound of any one of claims 1-28, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein two R1a on the same atom are taken together to form an oxo.
- The compound of any one of claims 1-28, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein two R1a on the same carbon are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R.
- The compound of any one of claims 1-28, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein two R1a on the different atoms are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R.
- The compound of any one of claims 1-34, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein n is 1-4.
- The compound of any one of claims 1-34, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein n is 2-4.
- The compound of any one of claims 1-34, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein n is 2.
- The compound of any one of claims 1-34, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein n is 3.
- The compound of any one of claims 1-21, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, whereiniswherein:Ring E is cycloalkyl or heterocycloalkyl;each R5 is independently halogen, -CN, -OH, -SH, -OCF3, -OCClF2, -SF3, -SF5, -SCF3, -SCClF2, -S (=O) C1-C3alkyl, -S (=O) 2C1-C3alkyl, -S (=O) 2NH2, -S (=O) 2NHC1-C3alkyl, -S (=O) 2N (C1-C3alkyl) 2, -NH2, -NHC1-C3alkyl, -N (C1-C3alkyl) 2, -P (=O) (C1-C3alkyl) N (C1-C3alkyl) 2, -P (=O) (C1-C3alkyl) O (C1-C3alkyl) , -P (=O) (C1-C3alkyl) 2, -C (=O) C1-C3alkyl, -C (=O) OH, -C (=O) OC1-C3alkyl, -C (=O) NH2, -C (=O) NHC1-C3alkyl, -C (=O) N (C1-C3alkyl) 2, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, or C3-C6cycloalkyl; andp is 0, 1, 2, 3, or 4.
- The compound of claim 39, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring E is heterocycloalkyl.
- The compound of claim 39 or 40, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R5 is independently halogen, -OH, or C1-C6alkoxy.
- The compound of any one of claims 39-41, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R5 is independently halogen.
- The compound of any one of claims 39-42, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein p is 0, 1, or 2.
- The compound of any one of claims 39-43, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein p is 1 or 2.
- The compound of any one of claims 39-44, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R1 is independently heterocycloalkyl independently optionally substituted with one or more R1a.
- The compound of any one of claims 1-14, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, whereinis
- The compound of any one of claims 1-14, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, whereinis
- The compound of any one of claims 1-47, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring B is a bicyclic heteroaryl or heterocycloalkyl.
- The compound of any one of claims 1-47, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring B is a bicyclic heteroaryl.
- The compound of any one of claims 1-47, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring B is a bicyclic partially saturated ring.
- The compound of any one of claims 1-47, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring B is a bicyclic fully saturated ring.
- The compound of any one of claims 1-47, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring B is a bicyclic unsaturated ring.
- The compound of any one of claims 1-52, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R4 is independently halogen, -CN, -OH, -ORa, -SF3, -SF5, -NRcRd, -C (=O) Ra, -C (=O) ORb, -C (=O) NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R4a.
- The compound of any one of claims 1-52, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R4 is independently halogen, -CN, -OH, -ORa, -SF3, -SF5, -NRcRd, C1-C6alkyl, or C1-C6haloalkyl; wherein each alkyl is independently optionally substituted with one or more R4a.
- The compound of any one of claims 1-52, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R4 is independently halogen, -SF3, -SF5, C1-C6alkyl, or C1-C6haloalkyl.
- The compound of any one of claims 1-52, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R4 is independently halogen or C1-C6alkyl.
- The compound of any one of claims 1-52, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein two R4 on the different atoms are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R4a.
- The compound of any one of claims 1-57, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R4a is independently halogen, -CN, -OH, -ORa, -NRcRd, -C (=O) Ra, -C (=O) ORb, -C (=O) NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R.
- The compound of any one of claims 1-57, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R4a is independently halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, or C1-C6haloalkyl; wherein each alkyl is independently optionally substituted with one or more R.
- The compound of any one of claims 1-57, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R4a is independently halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, or C1-C6haloalkyl.
- The compound of any one of claims 1-60, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein m is 0-4.
- The compound of any one of claims 1-60, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein m is 0-2.
- The compound of any one of claims 1-60, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein m is 1.
- The compound of any one of claims 1-47, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, whereinis
- A compound of Formula (II) , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
wherein:Ring C is heterocycloalkyl or heteroaryl;each R1 is independently halogen, -CN, -NO2, -OH, -ORa, -OC (=O) Ra, -OC (=O) ORb, -OC (=O) NRcRd, -SH, -SRa, -SF3, -SF5, -S (=O) Ra, -S (=O) 2Ra, -S (=O) 2NRcRd, -NRcRd, -NRbC (=O) NRcRd, -NRbC (=O) Ra, -NRbC (=O) ORb, -NRbS (=O) 2Ra, -P (=O) RaNRcRd, -P (=O) RaORb, -P (=O) RaRb, -C (=O) Ra, -C (=O) ORb, -C (=O) NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R1a;or two R1 on the same atom are taken together to form an oxo;or two R1 on the same carbon are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R1a;or two R1 on the different atoms are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R1a;each R1a is independently halogen, -CN, -NO2, -OH, -ORa, -OC (=O) Ra, -OC (=O) ORb, -OC (=O) NRcRd, -SH, -SRa, -SF3, -SF5, -S (=O) Ra, -S (=O) 2Ra, -S (=O) 2NRcRd, -NRcRd, -NRbC (=O) NRcRd, -NRbC (=O) Ra, -NRbC (=O) ORb, -NRbS (=O) 2Ra, -P (=O) RaNRcRd, -P (=O) RaORb, -P (=O) RaRb, -C (=O) Ra, -C (=O) ORb, -C (=O) NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;or two R1a on the same atom are taken together to form an oxo;or two R1a on the same carbon are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R;or two R1a on the different atoms are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R;n is 0-6;L is -O-, -S-, or -NR2-;R2 is hydrogen, -CN, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl;W is N or CRW;RW is hydrogen, -SH, -SRa, -SF3, -SF5, halogen, -CN, -OH, -ORa, -NRcRd, -P (=O) RaNRcRd, -P (=O) RaORb, -P (=O) RaRb, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl;Z is N or CRZ;RZ is hydrogen, -SH, -SRa, -SF3, -SF5, halogen, -CN, -OH, -ORa, -NRcRd, -P (=O) RaNRcRd, -P (=O) RaORb, -P (=O) RaRb, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl;is a single bond; X is C (RX) 2, O, S, or NRX1; and Y is C (RY) 2, O, S, or NRY1;oris a double bond; X is CRX or N; and Y is CRY or N;each RX is independently hydrogen, -SH, -SRa, -SF3, -SF5, halogen, -CN, -OH, -ORa, -NRcRd, -P (=O) RaNRcRd, -P (=O) RaORb, -P (=O) RaRb, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl;RX1 is hydrogen, -CN, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl;each RY is independently hydrogen, -SH, -SRa, -SF3, -SF5, halogen, -CN, -OH, -ORa, -NRcRd, -P (=O) RaNRcRd, -P (=O) RaORb, -P (=O) RaRb, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl;RY1 is hydrogen, -CN, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl;R3 is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl;Ring D is a 3-to 5-membered ring;each R4 is independently halogen, -CN, -NO2, -OH, -ORa, -OC (=O) Ra, -OC (=O) ORb, -OC (=O) NRcRd, -SH, -SRa, -SF3, -SF5, -S (=O) Ra, -S (=O) 2Ra, -S (=O) 2NRcRd, -NRcRd, -NRbC (=O) NRcRd, -NRbC (=O) Ra, -NRbC (=O) ORb, -NRbS (=O) 2Ra, -P (=O) RaNRcRd, -P (=O) RaORb, -P (=O) RaRb, - C (=O) Ra, -C (=O) ORb, -C (=O) NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R4a;or two R4 on the same atom are taken together to form an oxo;or two R4 on the different atoms are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R4a;each R4a is independently halogen, -CN, -NO2, -OH, -ORa, -OC (=O) Ra, -OC (=O) ORb, -OC (=O) NRcRd, -SH, -SRa, -SF3, -SF5, -S (=O) Ra, -S (=O) 2Ra, -S (=O) 2NRcRd, -NRcRd, -NRbC (=O) NRcRd, -NRbC (=O) Ra, -NRbC (=O) ORb, -NRbS (=O) 2Ra, -P (=O) RaNRcRd, -P (=O) RaORb, -P (=O) RaRb, -C (=O) Ra, -C (=O) ORb, -C (=O) NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;or two R4a on the same atom are taken together to form an oxo;or two R4a on the same carbon are taken together to form a cycloalkyl or heterocycloalkyl; each independently optionally substituted with one or more R;or two R4a on the different atoms are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each independently optionally substituted with one or more R;m is 0-6;each Ra is independently C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene (cycloalkyl) , C1-C6alkylene (heterocycloalkyl) , C1-C6alkylene (aryl) , or C1-C6alkylene (heteroaryl) , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;each Rb is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene (cycloalkyl) , C1-C6alkylene (heterocycloalkyl) , C1-C6alkylene (aryl) , or C1-C6alkylene (heteroaryl) , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;Rc and Rd are each independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene (cycloalkyl) , C1-C6alkylene (heterocycloalkyl) , C1-C6alkylene (aryl) , or C1-C6alkylene (heteroaryl) , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;or Rc and Rd are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R; andeach R is independently halogen, -CN, -OH, -SH, -OCF3, -OCClF2, -SF3, -SF5, -SCF3, -SCClF2, -S (=O) C1-C3alkyl, -S (=O) 2C1-C3alkyl, -S (=O) 2NH2, -S (=O) 2NHC1-C3alkyl, -S (=O) 2N (C1-C3alkyl) 2, -NH2, -NHC1-C3alkyl, -N (C1-C3alkyl) 2, -P (=O) (C1-C3alkyl) N (C1-C3alkyl) 2, -P (=O) (C1-C3alkyl) O (C1-C3alkyl) , -P (=O) (C1-C3alkyl) 2, -C (=O) C1-C3alkyl, -C (=O) OH, -C (=O) OC1-C3alkyl, -C (=O) NH2, -C (=O) NHC1-C3alkyl, -C (=O) N (C1-C3alkyl) 2, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, or C3-C6cycloalkyl;or two R on the same atom form an oxo;or two R on the same carbon are taken together to form a cycloalkyl or heterocycloalkyl;or two R on the different atoms are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. - The compound of claim 65, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein the compound is of Formula (IIa) :
- The compound of claim 65, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein X is C (RX) 2 or NRX1; and Y is C (RY) 2 or NRY1.
- The compound of claim 65 or 67, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein X is C (RX) 2; and Y is C (RY) 2.
- The compound of claim 65, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein the compound is of Formula (IIb) :
- The compound of claim 65, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein the compound is of Formula (IIc) :
- The compound of claim 65, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein the compound is of Formula (IId) :
- The compound of claim 65, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein the compound is of Formula (IIe) :
- The compound of any one of claims 65-71, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each RX is independently hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, or C1-C6haloalkyl.
- The compound of any one of claims 65-71 or 73, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each RX is independently hydrogen, C1-C6alkyl, or C1-C6haloalkyl.
- The compound of any one of claims 65-71 or 72-74, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each RY is independently hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, or C1-C6haloalkyl.
- The compound of any one of claims 65-71 or 72-75, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each RY is independently hydrogen or halogen.
- The compound of any one of claims 65-67, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein RX1 is hydrogen, C1-C6alkyl, or C1-C6haloalkyl.
- The compound of any one of claims 65-67, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein RY1 is hydrogen, C1-C6alkyl, or C1-C6haloalkyl.
- The compound of any one of claims 65-78, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring C is heteroaryl.
- The compound of any one of claims 65-78, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring C is 5-or 6-membered heteroaryl.
- The compound of any one of claims 65-78, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring C is 6-membered heteroaryl.
- The compound of any one of claims 65-78, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring C is pyridinyl.
- The compound of any one of claims 65-78, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring C is bicyclic or tricyclic heteroaryl.
- The compound of any one of claims 65-83, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R1 is independently halogen, -CN, -OH, -ORa, -NRcRd, -C (=O) Ra, -C (=O) ORb, -C (=O) NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R1a.
- The compound of any one of claims 65-83, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R1 is independently halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R1a.
- The compound of any one of claims 65-83, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R1 is independently halogen, -OH, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6heteroalkyl, heterocycloalkyl, or heteroaryl; wherein each alkyl, heterocycloalkyl, and heteroaryl is independently optionally substituted with one or more R1a.
- The compound of any one of claims 65-83, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein two R1 on the same atom are taken together to form an oxo.
- The compound of any one of claims 65-83, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein two R1 on the same carbon are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R1a.
- The compound of any one of claims 65-83, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein two R1 on the different atoms are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R1a.
- The compound of any one of claims 65-89, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R1a is independently halogen, -CN, -OH, -ORa, -NRcRd, -NRbC (=O) NRcRd, -C (=O) Ra, -C (=O) ORb, -C (=O) NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R.
- The compound of any one of claims 65-89, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R1a is independently halogen, -CN, -OH, -ORa, -NRcRd, -NRbC (=O) NRcRd, C1-C6alkyl, C1-C6haloalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R.
- The compound of any one of claims 65-89, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein two R1a on the same atom are taken together to form an oxo.
- The compound of any one of claims 65-89, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein two R1a on the same carbon are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R.
- The compound of any one of claims 65-89, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein two R1a on the different atoms are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R.
- The compound of any one of claims 65-94, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein n is 1-4.
- The compound of any one of claims 65-94, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein n is 2-4.
- The compound of any one of claims 65-94, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein n is 2.
- The compound of any one of claims 65-94, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein n is 3.
- The compound of any one of claims 65-83, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, whereiniswherein:Ring E is cycloalkyl or heterocycloalkyl;each R5 is independently halogen, -CN, -OH, -SH, -OCF3, -OCClF2, -SF3, -SF5, -SCF3, -SCClF2, -S (=O) C1-C3alkyl, -S (=O) 2C1-C3alkyl, -S (=O) 2NH2, -S (=O) 2NHC1-C3alkyl, -S (=O) 2N (C1-C3alkyl) 2, -NH2, -NHC1-C3alkyl, -N (C1-C3alkyl) 2, -P (=O) (C1-C3alkyl) N (C1-C3alkyl) 2, -P (=O) (C1-C3alkyl) O (C1-C3alkyl) , -P (=O) (C1-C3alkyl) 2, -C (=O) C1-C3alkyl, -C (=O) OH, -C (=O) OC1-C3alkyl, -C (=O) NH2, -C (=O) NHC1-C3alkyl, -C (=O) N (C1-C3alkyl) 2, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, or C3-C6cycloalkyl; andp is 0, 1, 2, 3, or 4.
- The compound of claim 99, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring E is heterocycloalkyl.
- The compound of claim 99 or 100, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R5 is independently halogen.
- The compound of any one of claims 99-101, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein p is 0, 1, or 2.
- The compound of any one of claims 99-101, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein p is 1 or 2.
- The compound of any one of claims 65-103, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring D is cyclopropyl.
- The compound of any one of claims 65-103, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring D is a 5-membered ring comprising 1 to 4 heteroatoms selected from the group consisting of O, S, or N.
- The compound of any one of claims 65-103, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring D is a 5-membered ring comprising 1 to 3 heteroatoms selected from the group consisting of O or N.
- The compound of any one of claims 65-103, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring D is a 5-membered ring comprising 1 to 3 heteroatoms that are N.
- The compound of any one of claims 65-107, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R4 is independently halogen, -CN, -OH, -ORa, -NRcRd, -C (=O) Ra, -C (=O) ORb, -C (=O) NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1- C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, or aryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, and aryl is independently optionally substituted with one or more R4a.
- The compound of any one of claims 65-107, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R4 is independently halogen, -CN, -OH, -ORa, -NRcRd, -C (=O) NRcRd, C1-C6alkyl, or C1-C6haloalkyl; wherein each alkyl is independently optionally substituted with one or more R4a.
- The compound of any one of claims 65-107, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R4 is independently halogen, -C (=O) NRcRd, C1-C6alkyl, or C1-C6haloalkyl; wherein each alkyl is independently optionally substituted with one or more R4a.
- The compound of any one of claims 65-110, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R4a is independently halogen, -CN, -OH, -ORa, -NRcRd, -C (=O) Ra, -C (=O) ORb, -C (=O) NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R.
- The compound of any one of claims 65-110, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R4a is independently halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, or C1-C6haloalkyl; wherein each alkyl is independently optionally substituted with one or more R.
- The compound of any one of claims 65-112, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein m is 0-4.
- The compound of any one of claims 65-112, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein m is 0-2.
- The compound of any one of claims 65-112, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein m is 1.
- The compound of any one of claims 65-103, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, whereinis
- The compound of any one of claims 1-116, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R3 is hydrogen or C1-C6alkyl.
- The compound of any one of claims 1-117, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R3 is hydrogen.
- The compound of any one of claims 1-118, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein W is N.
- The compound of any one of claims 1-118, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein W is CRW.
- The compound of any one of claims 1-118 or 120, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein RW is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, or C1-C6haloalkyl.
- The compound of any one of claims 1-118 or 120 or 121, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein RW is hydrogen.
- The compound of any one of claims 1-122, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Z is N.
- The compound of any one of claims 1-122, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Z is CRZ.
- The compound of any one of claims 1-122 or 124, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein RZ is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, or C1-C6haloalkyl.
- The compound of any one of claims 1-122 or 124 or 125, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein RZ is hydrogen.
- The compound of any one of claims 1-126, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein L is -NR2-.
- The compound of any one of claims 1-127, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R2 is hydrogen or C1-C6alkyl.
- The compound of any one of claims 1-128, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R2 is hydrogen.
- The compound of any one of claims 1-129, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein the compound is selected from a compound found in table 1 or table 2 or table 3.
- A pharmaceutical composition comprising the compound of any one of claims 1-130, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable excipient.
- A method of treating a HPK1-mediated disorder in a patient comprising administering to said patient the compound of any one of claims 1-130, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or the pharmaceutical composition of claim 131.
- The method of claim 132, wherein the HPK1-mediated disorder is a proliferative disorder.
- The method of claim 133, wherein the proliferative disorder is cancer.
- The method of claim 133 or 134, wherein the proliferative disorder is associated with one or more activating mutations in HPK1.
- The method of claim 132, wherein the HPK1-mediated disorder is a chronic viral infection.
- A method of increasing the efficacy of vaccination in a patient comprising administering to said patient the compound of any one of claims 1-130, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or the pharmaceutical composition of claim 131 as an adjuvant.
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