WO2022236578A1 - Exocyclic amino quinazoline derivatives as kras inhibitors - Google Patents

Exocyclic amino quinazoline derivatives as kras inhibitors Download PDF

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Publication number
WO2022236578A1
WO2022236578A1 PCT/CN2021/092773 CN2021092773W WO2022236578A1 WO 2022236578 A1 WO2022236578 A1 WO 2022236578A1 CN 2021092773 W CN2021092773 W CN 2021092773W WO 2022236578 A1 WO2022236578 A1 WO 2022236578A1
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heterocyclyl
compound
pharmaceutically acceptable
acceptable salt
heterocyclylalkyl
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PCT/CN2021/092773
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French (fr)
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Jiping Fu
Yan Lou
Yongfeng SUN
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Nikang Therapeutics, Inc.
Shanghai Blueray Biopharma Co., Ltd.
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Priority to PCT/CN2021/092773 priority Critical patent/WO2022236578A1/en
Priority to PCT/CN2022/091243 priority patent/WO2022237649A1/en
Publication of WO2022236578A1 publication Critical patent/WO2022236578A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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

  • the present disclosure provides certain exocyclic amino quinazoline derivatives compounds that inhibit certain K-Ras proteins and are therefore useful for the treatment of cancers mediated by such proteins. Also provided are pharmaceutical compositions containing such compounds and processes for preparing such compounds.
  • Kirsten Rat Sarcoma 2 Viral Oncogene Homolog (KRAS) gene is a prevalent oncogene that encodes a small GTPase transductor protein called K-Ras.
  • K-Ras can serve as a molecular switch by cyling between active GTP-bound and inactive GDP-bound forms (see Science 2001; 294: 1299–304. ) .
  • K-Ras signaling is activated by RAS guanine nucleotide exchange factors (GEFs) , e.g., Son of Sevenless homologue (SOS) protein, that facilitate the GDP to GTP exchange of K-Ras (see Curr Biol 2005; 15: 563–74. ) .
  • GEFs RAS guanine nucleotide exchange factors
  • SOS Son of Sevenless homologue
  • GAPs GTPase-activating proteins
  • K-Ras plays a crucial role in the regulation of cell proliferation, differentiation and survival by signaling through several major downstream pathways, including the MAPK, the PI3K and the Ral-GEFs pathways (see Lung Cancer 2018; 124: 53–64) , among them the MAPK pathway is the best characterized (see Mol. Cell Biol. 1995; 15: 6443–6453. ) .
  • K-Ras-GTP binds to and activates RAF kinases, which phosphorylates MEK and subsequently phosphorylates ERK. Phospho-ERK can further activate downstream cytosolic proteins and which then translocate to the nucleus to drive the expression of diverse genes, propagating the growth signal.
  • PI3K pathway is also involved in RAS-mediated tumorigenesis (see Cell 2007; 129: 957–968. ) .
  • PI3K phosphorylates PIP2 to form PIP3, activates PDK1 and then phosphorylates AKT.
  • pAKT yields phosphorylation of several physiological substrates, e.g., mTOR, FOXO and NF- ⁇ B that promote metabolism, cell-cycle progression, resistance to apoptosis, cell survival and migration.
  • the Ral-GEFs signaling pathway plays a key role in RAS-mediated oncogenesis as well (see Proc. Natl. Acad. Sci. U.S.A.
  • RALGDS The K-Ras effector, RALGDS, stimulates the RAS family RAL-A/B small GTPases for the subsequent signaling cascades. RALGDS can also promote the JNK pathway to stimulate transcription of pro-survival and cell-cycle progression genes for cell proliferation and survival.
  • KRAS gene is the most frequently mutated oncogene in human cancer. KRAS mutations are associated with poor clinical outcome and found at high frequency in pancreatic cancer ( ⁇ 90%) , colorectal cancer ( ⁇ 44%) and non-small-cell lung cancer (NSCLC) ( ⁇ 29%) (see Cancer Discov. 2021; 11: 1–16) . KRAS mutations are also present in breast cancer, liver cancer, biliary tract malignancies, endometrial cancer, cervical cancer, bladder cancer and myeloid leukemia.
  • K-Ras G12C offers special opportunity, because it harbors a non-native cysteine residue, which can act as nucleophile and therefore can be targeted by covelent attachment.
  • covelent inhibitors including AMG510, MRTX849, JNJ-74699157 and LY349944631, are in clinical trials for treating cancer patients with KRAS G12C mutation (see ACS Cent. Sci. 2020; 6: 1753-1761) . These compounds ocuppy a dynamic pocket in the switch II region of K-Ras thereby irreversibly locking K-Ras G12C in inactive GDP-bound state.
  • KRAS mutations including G12C, enrich predominantly active-state protein in cancer cells, sufficient residual GTPase activity and nucleotide cycling are required for effective inhibition of K-Ras by inactive state-selective drugs (see Cell 2020; 183 (4) : 850-859) .
  • Inhibitors of active form of K-Ras should be more effective at suppressing cell growth and survival, as well as less susceptible to adaptive resistance than inhibitors binding to its inactive form.
  • K-ras G12C mutant Compared to K-ras G12C mutant, other prevalent K-Ras mutant, such as G12D, does not contain non-native cysteine residue and cycles through inactive state at extremely low rate, thus making non-G12C mutant-specific drug discovery challenging.
  • U, V, and W are CH; or one or two of U, V, and W are N and the other of U, V, and W are CH;
  • ring A is cycloaminyl, bicycloaminyl, bridged cycloaminyl, or spiroaminyl;
  • R 1b is absent, alkyl, alkynyl, cycloalkyl, halo, haloalkyl, hydroxy, alkoxy, cyano, hydroxyalkyl, alkoxyalkyl, cyanoalkyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, or dialkylaminocarbonylalkyl,
  • R 1c is absent, alkyl, halo, hydroxy, or cyano
  • R 2 is absent, deuterium, alkyl, alkenyl, alkynyl, halo, haloalkyl, alkoxy, hydroxy, or cyano, provided that, R 2 is absent when two of U, V, and W are N;
  • R 3 is absent, deuterium, alkyl, halo, haloalkyl, alkoxy, cycloalkyl, cycloalkyloxy, hydroxy, cyano, or monocyclic heterocyclyl optionally substituted with halo, alkoxy, hydroxy, or cyano;
  • R 4 is:
  • R 11 is hydrogen, alkyl, hydroxyalkyl, - (alkylene) -NR 12 R 13 (where alkylene is substituted with R a , R b , and R c independently selected from hydrogen, alkyl, cycloalkyl, halo, haloalkyl, hydroxy, alkoxy, cyano, oxo, hydroxyalkyl, alkylamino, dialkylamino, dialkylaminocarbonylalkyl, aryl, heteroaryl, and heterocyclyl, R 12 is hydrogen or alkyl, and R 13 is hydrogen, alkyl, acyl, hydroxyalkyl, or heteroalkyl) , aryl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, bicyclic heterocyclyl, bicyclic heterocyclylalkyl,
  • R 16 is hydrogen, deuterium, alkyl, halo, haloalkyl, cycloalkyl, bridged cycloalkyl, fused cycloalkyl, spiro cycloalkyl, heterocyclyl, bicyclic heterocyclyl, phosphinyl bicyclic heterocyclyl, bridged heterocyclyl, fused heterocyclyl, or spiro heterocyclyl; or
  • R 15 and R 16 together with the carbon atom to which are attached form cycloalkyl, bridged cycloalkyl, fused cycloalkyl, spiro cycloalkyl, heterocyclyl, bridged heterocyclyl, fused heterocyclyl, or spiro heterocyclyl, wherein:
  • a pharmaceutical composition comprising a compound of Formula ( (I) (or any of the embodiments thereof described herein) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
  • a method of inhibiting K-Ras in particular K-Ras G12D, in a cell, comprising contacting the cell with a compound of Formula (I) (or any of the embodiments thereof described herein) .
  • the contacting is in vitro.
  • the contacting is in vivo.
  • a method of inhibiting cell proliferation in vitro or in vivo comprising contacting a cell with a compound of Formula (I) (or any of the embodiments thereof described herein) or a pharmaceutical composition thereof as disclosed herein.
  • the contacting is in vitro.
  • the contacting is in vivo.
  • a method of treating cancer in a patient preferably the patient is in need of such treatment, which method comprises administering to the patient, preferably a patient in need of such treatment, a therapeutically effective amount of a compound of Formula (I) (or any of the embodiments thereof described herein) or a pharmaceutically acceptable salt thereof or a a pharmaceutical composition thereof as disclosed herein.
  • a method of treating cancer associated with K-Ras, in particular K-Ras G12D, in a patient, preferably the patient is in need of such treatment comprises administering to the patient, preferably a patient in need of such treatment, a therapeutically effective amount of a compound of Formula (I) (or any of the embodiments thereof described herein) or a pharmaceutically acceptable salt thereof or a a pharmaceutical composition thereof as disclosed herein.
  • a compound of Formula (I) (or any embodiments thereof described herein) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof as disclosed herein for use as a medicament.
  • the medicament is useful for the treatment of cancer.
  • a compound of Formula (I) (or any embodiments thereof described herein) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof as disclosed herein for use in the treatment of cancer.
  • a compound of Formula (I) (or any embodiments thereof described herein) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof as disclosed herein for use in the treatment of cancers associated with KRas, in particular cancers associated with K-Ras G12D.
  • a compound of Formula (I) (or any embodiments thereof described herein) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof as disclosed herein for use in inhibiting K-Ras, in particular K-Ras G12D.
  • any of the aforementioned aspects involving the treatment of cancer are further embodiments comprising administering the compound of Formula (I) (or any embodiments thereof disclosed herein) , or a pharmaceutically acceptable salt thereof in combination with at least one additional anticancer agent.
  • the agents can be administered simultaneously or sequentially.
  • Alkylene means a linear saturated divalent hydrocarbon radical of one to six carbon atoms or a branched saturated divalent hydrocarbon radical of three to six carbon atoms unless otherwise stated e.g., methylene, ethylene, propylene, 1-methylpropylene, 2-methylpropylene, butylene, pentylene, and the like.
  • Alkenyl means a linear monovalent hydrocarbon radical of two to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbon atoms containing a double bond e.g., ethenyl, propenyl, 2-propenyl, butenyl, pentenyl, and the like.
  • Alkynyl means a linear monovalent hydrocarbon radical of two to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbon atoms containing a triple bond e.g., ethynyl, propynyl, 2-propynyl, butynyl, and the like.
  • Alkylsulfonyl means a –SO 2 R radical where R is alkyl as defined above, e.g., methylsulfonyl, ethylsulfonyl, and the like.
  • Alkylamino means a –NHR radical where R is alkyl as defined above, e.g., methylamino, ethylamino, and the like.
  • Alkylaminocarbonyl means a –CONHR radical where R is alkyl as defined above, e.g., methylaminocarbonyl, ethylaminocarbonyl, and the like.
  • Alkylaminocarbonylalkyl means a – (alkylene) -CONHR radical where R alkyl and alkyene and alkyl are as defined above, e.g., methylaminocarbonylmethyl, ethylaminocarbonylmethyl, and the like.
  • Alkylsulfonyl means a -SO 2 R radical where R is alkyl as defined above, e.g., methylsulfonyl, ethylsulfonyl, and the like.
  • Alkylsulfonylalkyl means a – (alkylene) -SO 2 R radical where R is alkyl as defined above, e.g., methylsulfonylmethyl, ethylsulfonylmethyl, and the like.
  • Alkoxy means a -OR radical where R is alkyl as defined above, e.g., methoxy, ethoxy, propoxy, or 2-propoxy, n-, iso-, or tert-butoxy, and the like.
  • Alkoxyalkyl means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted with at least one alkoxy group, such as one or two alkoxy groups, as defined above, e.g., 2-methoxyethyl, 1-, 2-, or 3-methoxypropyl, 2-ethoxyethyl, and the like.
  • Alkoxyalkyloxy means a -OR radical where R is alkoxyalkyl as defined above. Examples include, but are not limited to, 2-methoxyethyloxy, 1-, 2-, or 3-methoxypropyloxy, 2-ethoxyethyloxy, and the like.
  • the alkylidene group, methylidienyl is enclosed by the box which is indicated by the arrow.
  • Alkoxycarbonyl means a –C (O) OR radical where R is alkyl as defined above, e.g., methoxycarbonyl, ethoxycarbonyl, and the like.
  • “Acyl” means a –C (O) R radical where R is alkyl, haloalkyl, cycloalkyl, optionally substituted phenyl, optionally substituted heteroaryl, or optionally substituted heterocyclyl, as defined herein, e.g., methylcarbonyl, ethylcarbonyl, benzoyl, trifluoromethylcarbonyl, cyclopropylcarbonyl, and the like.
  • R is alkyl
  • acyl is also referred to herein as alkylcarbonyl.
  • Amino means —NH 2 radical.
  • Aminoalkyl means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted with –NR’R” where R’ and R” are independently hydrogen, alkyl, cycloalkyl, cycloalkylalkyl (wherein cycloalkyl and cycloalkyl ring in cycloalkylalkyl is optionally substituted with one, two, or three substituents independently selected from alkyl, hydroxyalkyl, haloalkyl, halo, hydroxy, alkoxy, -NH 2 , alkylamino, dialkylamino, and cyano) , hydroxyalkyl, alkoxyalkyl, alkylcarbonyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl, each as defined herein,
  • Aminocarbonyl means —CONH 2 radical.
  • Aminocarbonylalkyl means a – (alkylene) -CONH 2 radical where alkyene is as defined above, e.g., aminocarbonylmethyl, aminocarbonylmethyl, and the like.
  • Aryl means a monovalent monocyclic or fused bicyclic aromatic hydrocarbon radical of 6 to 10 ring atoms e.g., phenyl or naphthyl.
  • Alkyl means a – (alkylene) -R radical where R is aryl as defined above. Examples include, but are not limited to, benzyl, phenethyl, and the like.
  • Bicycloaminyl means a saturated monovalent fused bicyclic ring of 5 to 10 ring atoms in which one ring atom is nitrogen and an additional ring atom can be a heteroatom independently selected from N, O, and S (O) n , where n is an integer from 0 to 2, the remaining ring atoms being C. Additionally, one or two ring carbon atoms of the bicycloaminyl group can optionally be replaced by a –CO-group. Representative examples include, but is not limited to, 3-azabicyclo [3.1.0] hexan-3-yl, 3-azabicyclo [4.1.0] heptan-3-yl, and the like.
  • Bicyclic heterocyclyl means a saturated monovalent fused bicyclic ring of 8 to 12 ring atoms in which one or two ring atoms are heteroatom independently selected from N, O, and S (O) n , where n is an integer from 0 to 2, the remaining ring atoms being C, unless stated otherwise. Additionally, one or two ring carbon atoms in the heterocyclyl ring can optionally be replaced by a –CO-group. More specifically the term bicyclic heterocyclyl includes, but is not limited to, hexahydro-1H-pyrrolizinyl, and the like.
  • Bicyclic heterocyclylalkyl means a – (alkylene) -R radical where R is bicyclic heterocyclyl as defined above. Examples include, but are not limited to, hexahydro-1H-pyrrolizinylmethyl, hexahydro-1H-pyrrolizinylethyl, and the like.
  • Bridged cycloalkyl means a saturated monocyclic ring having 5 to 8 ring carbon ring atoms in which two non-adjacent ring atoms are linked by a (CRR’) n group where n is 1 to 3 and R and R’ are independently H or methyl (also may be referred to herein as “bridging” group) .
  • bridged cycloalkyl is optionally substituted with one or two substituents independently selected from alkyl, halo, alkoxy, hydroxy, and cyano. Examples include, but are not limited to, bicyclo [1.1.1] pentyl, bicyclo [2.1.1] hexyl, bicyclo [2.2.2] -octyl, and the like.
  • “Bridged cycloaminyl” means a saturated monovalent monocyclic ring of 5 to 9 ring atoms in which one ring atom is nitrogen and in which two non-adjacent ring atoms are linked by a (CRR’) m1 group where m1 is 1 to 3 and R and R’ are independently H or methyl (also may be referred to herein as “bridging” group) and further wherein an additional ring atom of bridged cycloaminyl ring, including an atom in the bridging group, can be a heteroatom independently selected from N, O, and S (O) n , where n is an integer from 0 to 2, the remaining ring atoms being C.
  • bridged cycloaminyl includes, but is not limited to, 2-azabicyclo [2.2.1] heptan-2-yl, 3-azabicyclo [3.1.1] heptan-3-yl, 3-azabicyclo [3.2.1] octan-3-yl, and the like.
  • “Bridged heterocyclyl” means a saturated monocyclic ring having 5 to 9 ring carbon ring atoms in which two non-adjacent ring atoms are linked by a (CRR’) n1 group where n1 is 1 to 3 and R and R’ are independently H or methyl (also may be referred to herein as “bridging” group) and further wherein one or two ring carbon atoms, including an atom in the bridging group, is replaced by a heteroatom selected from N, O, and S (O) n, where n is an integer from 0 to 2.
  • Bridged heterocyclyl is optionally substituted with one or two substituents independently selected from alkyl, halo, alkoxy, hydroxy, and cyano.
  • Examples include, but are not limited to, 2-azabicyclo [2.2.2] octane, quinuclidine, 7-oxabicyclo [2.2.1] heptane, 1-azabicyclo [2.2.1] heptane, 2-azabicyclo [2.2.1] heptane, 3 ⁇ 2 -azabicyclo [3.1.0] hexane, and the like.
  • “Bridged heterocyclylalkyl” means a – (alkylene) -R radical where R is bridged heterocyclyl as defined above. Examples include, but are not limited to, 2-azabicyclo [2.2.2] -octylmethyl, 3 ⁇ 2 -azabicyclo [3.1.0] hexylethyl, and the like.
  • Cycloalkyl means a monocyclic saturated monovalent hydrocarbon radical of three to ten carbon atoms. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
  • Cycloalkylene means a monocyclic saturated divalent hydrocarbon radical of three to ten carbon atoms. Examples include, but are not limited to, 1, 1-cyclopropylene, 1, 1-cyclobutylene, 1, 1-cyclopentylene, and the like.
  • Cycloalkylalkyl means a – (alkylene) -R radical where R is cycloalkyl as defined above. Examples include, but are not limited to, cyclopropylmethyl cyclobutylethyl, cyclopentylmethyl, cyclohexylmethyl, and the like.
  • Cycloalkyloxy means a -OR radical where R is cycloalkyl as defined above. Examples include, but are not limited to, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like.
  • Cyanoalkyl means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted with cyano e.g., cyanomethyl, cyanoethyl, and the like.
  • Cyanoalkynyl means an alkynyl radical as defined above where one of the hydrogen atom in the alkynyl chain is replace by a cyano. Examples include, but are not limited to, -C ⁇ C (CN) , - CH 2 C ⁇ C (CN) , and the like.
  • Carboxy means —COOH.
  • Cycloaminyl means a saturated monovalent monocyclic ring of 4 to 8 ring atoms in which one ring atom is nitrogen and an additional ring atom can be a heteroatom independently selected from N, O, and S (O) n , where n is an integer from 0 to 2, the remaining ring atoms being C. Additionally, one or two ring carbon atoms of the cycloaminyl group can optionally be replaced by a –CO-group.
  • cycloaminyl includes, but is not limited to, pyrrolidinyl, piperidinyl, homopiperidinyl, 2-oxopyrrolidinyl, 2-oxopiperidinyl, morpholinyl, piperazinyl, thiomorpholinyl, and the like.
  • Dialkylamino means a –NRR’ radical where R and R’ are independently alkyl as defined above, e.g., dimethylamino, methylethylamino, and the like.
  • Dialkylaminocarbonyl means a -CONR’R” radical where where R’ and R” are independently alkyl as defined herein, e.g., dimethylaminocarbonyl, ethylmethylaminocarbonyl, and the like.
  • Dialkylaminocarbonylalkyl means a – (alkylene) –CONR’R” radical where R’ and R” are independently alkyl as defined herein, e.g., dimethylaminocarbonylmethyl, dimethylaminocarbonylethyl, and the like.
  • “Fused bicyclic heterocyclyl” means an 8 to 10 membered bicyclic heterocyclyl as defined herein, where two adjacent ring atoms of the bicyclic heterocyclyl are fused to two adjacent ring members of phenyl or a five or six membered heteroaryl, each as defined herein, unless stated otherwise.
  • bicyclic heterocyclyl includes, but is not limited to, 2, 3-dihydro-1H-pyrrolo [2, 1-a] isoindol-9b (5H) -yl, 2, 3-dihydro-1H-pyrrolo [1, 2-a] indol-9a (9H) -yl, 1, 5, 6, 8-tetrahydropyrrolo [3, 2-a] pyrrolizin-3b (4H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl, and the like.
  • “Fused bicyclic heterocyclylalkyl” means a – (alkylene) -R radical where R is fused bicyclic heterocyclyl as defined above. Examples include, but are not limited to, hexahydro-1H-pyrrolizinylmethyl, hexahydro-1H-pyrrolizinylethyl, 2, 3-dihydro-1H-pyrrolo [2, 1-a] isoindol- 9b (5H) -ylmethyl, 2, 3-dihydro-1H-pyrrolo [1, 2-a] indol-9a (9H) -ylmethyl, and the like.
  • fused cycloalkyl as used herein, means cycloalkyl as defined above where two adjacent ring atoms of the cycloalkyl ring are fused to two adjacent ring members of phenyl or a five or six membered heteroaryl, each as defined herein, unless stated otherwise.
  • the fused heterocyclyl can be attached at any atom of the ring.
  • Non limiting examples of the fused cycloalkyl include bicyclo [4.1.0] hepta-1, 3, 5-triene, bicyclo [4.2.0] octa-1, 3, 5-triene, and the like.
  • “Fused heterocyclyl” as used herein means a saturated a heterocyclyl as defined herein where two adjacent ring atoms of the heterocyclyl ring are fused to two adjacent ring members of a cycloalkyl, phenyl or a five or six membered heteroaryl, each as defined herein, unless stated otherwise.
  • the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom (s) are optionally quaternized and one or two carbon atoms of the fused ring atoms in the saturated monocyclic ring includes the two common ring vertices shared with the fused phenyl or five or six membered heteroaryl.
  • the fused heterocyclyl can be attached at any atom of the ring.
  • Non limiting examples of the fused heterocycloalkyl include 2, 3-dihydrobenzo [b] [1, 4] -dioxinyl, 2-oxabicyclo [3.1.0] hexanyl, indolin-2-one-1-yl, indolinyl, and the like.
  • “Fused heterocyclylalkyl” as used herein, means a – (alkylene) -R radical where R is fused heterocyclyl, as defined herein.
  • “Fused tricyclic heterocyclyl” means a saturated monovalent fused tricyclic ring of 9 to 16 ring atoms, preferably 10 to 14 ring atoms, in which one or two ring atoms are heteroatoms independently selected from N, O, and S (O) n , where n is an integer from 0 to 2, the remaining ring atoms being C, unless stated otherwise, and where two adjacent ring atoms of the tricyclic heterocyclyl (preferably two adjacent ring atoms of a ring other than the central ring of the tricyclic heterocyclyl) are fused to two adjacent ring members of cycloalkyl, phenyl or a five or six membered heteroaryl, each as defined herein, unless stated otherwise.
  • the term bicyclic heterocyclyl includes, but is not limited to,
  • “Fused tricyclic heterocyclylalkyl” means a – (alkylene) -R radical where R is fused tricyclic heterocyclyl as defined above. Examples include, but are not limited to,
  • Halo means fluoro, chloro, bromo, or iodo, preferably fluoro or chloro.
  • Haloalkyl means alkyl radical as defined above, which is substituted with one or more halogen atoms, e.g., one to five halogen atoms, such as fluorine or chlorine, including those substituted with different halogens, e.g., -CH 2 Cl, -CF 3 , -CHF 2 , -CH 2 CF 3 , -CF 2 CF 3 ,
  • fluoroalkenyl When the alkenyl is substituted with only fluoro, it can be referred to in this Application as fluoroalkenyl.
  • the group pointed to by the arrow is the haloalkenylidine group, difluoromethyldienyl.
  • Haloalkoxy means a –OR radical where R is haloalkyl as defined above e.g., -OCF 3 ,
  • R is haloalkyl where the alkyl is substituted with only fluoro, it is referred to in this Application as fluoroalkoxy.
  • Hydroalkyl means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted with one or two hydroxy groups, provided that if two hydroxy groups are present they are not both on the same carbon atom.
  • Representative examples include, but are not limited to, hydroxymethyl, 2-hydroxy-ethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1- (hydroxymethyl) -2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2, 3-dihydroxypropyl, 1- (hydroxymethyl) -2-hydroxyethyl, 2, 3-dihydroxybutyl, 3, 4-dihydroxybutyl and 2- (hydroxymethyl) -3-hydroxypropyl, preferably 2-hydroxyethyl, 2, 3-dihydroxypropyl, and 1- (hydroxymethyl) -2-hydroxyethyl.
  • Heteroalkyl mean alkyl radical as defined above wherein one or two carbon atoms are replaced by O, NR (R is H or alkyl) , or S, provided the heteroalkyl group is attached to the remainder of the molecule via a carbon atom, e.g., methoxymethyl, methylethylaminoethyl, and the like.
  • Heteroaryl means a monovalent monocyclic or fused bicyclic aromatic radical of 5 to 10 ring atoms, unless otherwise stated, where one or more, (in one embodiment, one, two, or three) , ring atoms are heteroatom selected from N, O, and S, the remaining ring atoms being carbon.
  • Representative examples include, but are not limited to, pyrrolyl, thienyl, thiazolyl, imidazolyl, furanyl, indolyl, isoindolyl, oxazolyl, isoxazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, tetrazolyl, and the like.
  • the terms “heteroaryl” and “aryl” are mutually exclusive. When the heteroaryl ring contains 5-or 6 ring atoms it is also referred to herein as 5-or 6-membered heteroaryl.
  • Heterocyclyl means a saturated or unsaturated monovalent monocyclic group of 4 to 8 ring atoms in which one or two ring atoms are heteroatom independently selected from N, O, and S (O) n , where n is an integer from 0 to 2, the remaining ring atoms being C, unless stated otherwise. Additionally, one or two ring carbon atoms in the heterocyclyl ring can optionally be replaced by a –CO-group.
  • heterocyclyl includes, but is not limited to, pyrrolidinyl, piperidinyl, homopiperidinyl, 2-oxopyrrolidinyl, 2-oxopiperidinyl, morpholinyl, piperazinyl, tetrahydro-pyranyl, thiomorpholinyl, and the like.
  • the heterocyclyl ring is unsaturated it can contain one or two ring double bonds provided that the ring is not aromatic.
  • saturated heterocyclyl When the heterocyclyl ring is saturated, it is referred to herein as saturated heterocyclyl.
  • Heterocyclylalkyl or “heterocycloalkyl” means a – (alkylene) -R radical where R is heterocyclyl ring as defined above e.g., tetraydrofuranylmethyl, piperazinylmethyl, morpholinylethyl, and the like.
  • Optionally substituted aryl means aryl as defined above, that is optionally substituted with one, two, or three substituents independently selected from alkyl, hydroxyl, cycloalkyl, carboxy, alkoxycarbonyl, hydroxy, alkoxy, alkylsulfonyl, amino, alkylamino, dialkylamino, halo, haloalkyl, haloalkoxy, and cyano.
  • substituents independently selected from alkyl, hydroxyl, cycloalkyl, carboxy, alkoxycarbonyl, hydroxy, alkoxy, alkylsulfonyl, amino, alkylamino, dialkylamino, halo, haloalkyl, haloalkoxy, and cyano.
  • aryl is phenyl
  • optionally substituted aryl is referred to herein as optionally substituted phenyl.
  • Optionally substituted aralkyl means — (alkylene) -R where R is optionally substituted aryl as defined above.
  • Optionally substituted heteroaryl means heteroaryl as defined above that is optionally substituted with one, two, or three substituents independently selected from alkyl, alkylsulfonyl, hydroxyl, cycloalkyl, carboxy, alkoxycarbonyl, hydroxy, alkoxy, halo, haloalkyl, haloalkoxy, amino, alkylamino, dialkylamino, and cyano.
  • Optionally substituted heteroaralkyl means — (alkylene) -R where R is optionally substituted heteroaryl as defined above.
  • Optionally substituted heterocyclyl means heterocyclyl as defined above that is optionally substituted with one, two, or three substituents independently selected from alkyl, alkylsulfonyl, alkylcarbonyl, hydroxyl, cycloalkyl, cycloalkylalkyl, carboxy, alkoxycarbonyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, aminoalkyl, cyanoalkyl, halo, haloalkyl, haloalkoxy, and cyano, unless stated otherwise.
  • Optionally substituted heterocyclylalkyl means — (alkylene) -R where R is optionally substituted heterocyclyl as defined above.
  • Phosphinyl bicyclic heterocyclylalkyl means an — (alkylene) -R radical where R is phosphinyl bicyclic heterocyclyl as defined above. Examples include, but are not limited to, and the like.
  • Tricyclic heterocyclyl means a saturated monovalent fused tricyclic ring of 9 to 14, preferably 12 to 14, ring atoms in which one, two, or three ring atoms are heteroatom independently selected from N, O, and S (O) n , where n is an integer from 0 to 2, the remaining ring atoms being C, unless stated otherwise. Additionally, one or two ring carbon atoms in the heterocyclyl ring can optionally be replaced by a –CO-group.
  • the term bicyclic heterocyclyl includes, but is not limited to, and the like.
  • Tricyclic heterocyclylalkyl means a – (alkylene) -R radical where R is tricyclic heterocyclyl as defined above. Examples include, but are not limited to,
  • the present disclosure also includes protected derivatives of compounds of Formula (I) .
  • compounds of Formula (I) when compounds of Formula (I) contain groups such as hydroxy, carboxy, or any group containing a nitrogen atom (s) , these groups can be protected with suitable protecting groups.
  • suitable protecting groups A comprehensive list of suitable protective groups can be found in T. W. Greene, Protective Groups in Organic Synthesis, 5 th Ed., John Wiley &Sons, Inc. (2014) , the disclosure of which is incorporated herein by reference in its entirety.
  • the protected derivatives of compounds of the present disclosure can be prepared by methods well known in the art.
  • the present disclosure also includes polymorphic forms and deuterated forms of the compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • prodrug refers to a compound that is made more active in vivo.
  • Certain compounds Formula (I) may also exist as prodrugs, as described in Hydrolysis in Drug and Prodrug Metabolism: Chemistry, Biochemistry, and Enzymology (Testa, Bernard and Mayer, Joachim M. Wiley-VHCA, Zurich, Switzerland 2003) .
  • Prodrugs of the compounds described herein are structurally modified forms of the compound that readily undergo chemical changes under physiological conditions to provide the active compound. Prodrugs are often useful because, in some situations, they may be easier to administer than the compound, or parent drug. They may, for instance, be bioavailable by oral administration whereas the parent drug is not.
  • prodrug derivatives are known in the art, such as those that rely on hydrolytic cleavage or oxidative activation of the prodrug.
  • An example, without limitation, of a prodrug would be a compound which is administered as an ester (the “prodrug” ) , but then is metabolically hydrolyzed to the carboxylic acid, the active entity. Additional examples include peptidyl derivatives of a compound.
  • a “pharmaceutically acceptable salt” of a compound means a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound.
  • Such salts include:
  • acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as formic acid, acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3- (4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1, 2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic
  • a metal ion e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion
  • organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like.
  • the compounds of Formula (I) may have asymmetric centers.
  • Compounds of Formula (I) containing an asymmetrically substituted atom may be isolated in optically active or racemic forms.
  • Individual stereoisomers of compounds can be prepared synthetically from commercially available starting materials which contain chiral centers or by preparation of mixtures of enantiomeric products followed by separation such as conversion to a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques, direct separation of enantiomers on chiral chromatographic columns, or any other appropriate method known in the art. All chiral, diastereomeric, all mixtures of chiral or diastereomeric forms, and racemic forms are within the scope of this disclosure, unless the specific stereochemistry or isomeric form is specifically indicated. It will also be understood by a person of ordinary skill in the art that when a compound is denoted as (R) stereoisomer, it may contain the corresponding (S) stereoisomer as an impurity and vice versa.
  • Certain compounds of Formula (I) can exist as tautomers and/or geometric isomers. All possible tautomers and cis and trans isomers, as individual forms and mixtures thereof are within the scope of this disclosure. Additionally, as used herein the term alkyl includes all the possible isomeric forms of said alkyl group albeit only a few examples are set forth. Furthermore, when the cyclic groups such as aryl is substituted, it includes all the positional isomers albeit only a few examples are set forth. Furthermore, all hydrates of a compound of Formula (I) are within the scope of this disclosure.
  • the compounds of Formula (I) may also contain unnatural amounts of isotopes at one or more of the atoms that constitute such compounds.
  • Unnatural amounts of an isotope may be defined as ranging from the amount found in nature to an amount 100%of the atom in question. that differ only in the presence of one or more isotopically enriched atoms.
  • Exemplary isotopes that can be incorporated into compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 32 P, 33 P, 35 S, 18 F, 36 Cl, 123 I, and 125 1, respectively.
  • Isotopically labeled compounds e.g., those labeled with 3 H and 14 C
  • Tritiated (i.e., 3 H) and carbon-14 (i.e., 14 C) isotopes can be useful for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., 2 H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) .
  • substituents such as deuterium (i.e., 2 H)
  • substitution with heavier isotopes such as deuterium (i.e., 2 H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) .
  • compounds of Formula (IA’) , (I’) , (I) , (IIA’) , (II’) , or (II) including in Tables 1 and 2 below one or more hydrogen atoms are replaced by 2 H or 3 H, or one or more carbon atoms are replaced by 13 C-or
  • Positron emitting isotopes such as 15 O, 13 N, 11 C, and 15 F are useful for positron emission tomography (PET) studies to examine substrate receptor occupancy.
  • Isotopically labeled compounds can generally be prepared by following procedures analogous to those disclosed in the Schemes or in the Examples herein, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
  • “Spiro cycloalkyl” means a saturated bicyclic monovalent ring having 6 to 10 ring atoms in which the rings are connected through only one atom, the connecting atom is also called the spiroatom, most often a quaternary carbon ( “spiro carbon” ) . Unless stated otherwise, spiro cycloalkyl is optionally substituted with one or two substituents independently selected from alkyl, halo, alkoxy, hydroxy, and cyano.
  • Examples include, but are not limited to, Representative examples include, but are not limited to, spiro [3.3] heptan-2-yl, spiro [3.4] octan-6-yl, spiro [3.5] -nonan-7-yl, and the like.
  • “Spiroaminyl” means a saturated monovalent bicyclic ring of 6 to 12 ring atoms in which one ring atom is nitrogen and an additional ring atom can be a heteroatom independently selected from N, O, and S (O) n , where n is an integer from 0 to 2, the remaining ring atoms being C, and further wherein the two rings are connected through only one atom, the connecting atom is also called the spiroatom, most often a quaternary carbon ( "spiro carbon” ) .
  • spiro cycloaminyl include, 2-azaspiro [3.3] heptan-2-yl, 5-azaspiro [2.4] heptan-5-yl, 3-azaspiro [5.5] undecan-3-yl, 8-azaspiro [4.5] decan-8-yl, 6-azaspiro [3.4] octan-6-yl, 2-azaspiro [4.4] nonan-2-yl, but is not limited to, and the like.
  • “Spiro heterocyclyl” means a saturated bicyclic monovalent ring having 5 to 10 ring atoms in which one, two, or three ring atoms are heteroatom selected from N, O, and S (O) n, where n is an integer from 0 to 2, the remaining ring atoms being C and the rings are connected through only one atom, the connecting atom is also called the spiroatom, most often a quaternary carbon ( "spiro carbon” ) . Unless stated otherwise, spiroheterocyclyl is optionally substituted with one or two substituents independently selected from alkyl, halo, alkoxy, hydroxy, and cyano.
  • Examples include, but are not limited to, Representative examples include, but are not limited to, 2, 6-diazaspiro [3.3] hept-2-yl, 2, 6-diazaspiro [3.4] oct-6-yl, 2-azaspiro [3.4] oct-2-yl, 2-azaspiro [3.5] -non2-yl, 2, 7-diazaspiro [4.4] non-2-yl, and the like.
  • disease as used herein is intended to be generally synonymous, and is used interchangeably with, the terms “disorder, ” “syndrome, ” and “condition” (as in medical condition) , in that all reflect an abnormal condition of the human or animal body or of one of its parts that impairs normal functioning, is typically manifested by distinguishing signs and symptoms, and causes the human or animal to have a reduced duration or quality of life.
  • combination therapy means the administration of two or more therapeutic agents to treat a disease or disorder described in the present disclosure. Such administration encompasses co-administration of these therapeutic agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of active ingredients or in multiple, separate capsules for each active ingredient. In addition, such administration also encompasses use of each type of therapeutic agent in a sequential manner. In either case, the treatment regimen will provide beneficial effects of the drug combination in treating the conditions or disorders described herein.
  • patient is generally synonymous with the term “subject” and includes all mammals including humans. Examples of patients include humans, livestock such as cows, goats, sheep, pigs, and rabbits, and companion animals such as dogs, cats, rabbits, and horses. Preferably, the patient is a human.
  • Treating” or “treatment” of a disease includes:
  • treating or treatment of a disease includes inhibiting the disease, i.e., delaying, arresting or reducing the development or severity of the disease or its clinical symptoms; or relieving the disease, i.e., causing regression of the disease or its clinical symptoms.
  • inhibitors and “reducing, “ or any variation of these terms in relation of K-Ras G12D, includes any measurable decrease or complete inhibition to achieve a desired result. For example, there may be a decrease of about, at most about, or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or more, or any range derivable therein, reduction of K-Ras G12D GTPase activity; a decrease of K-Ras G12D GTP binding affinity or an increase of G12D GDP binding affinity; an increase of GTP off rate or a decrease of GDP off rate; a decrease of signaling transduction molecules levels downstream in the K-Ras pathway, e.g., a decrease in pERK level; and/or a decrease of K-Ras complex binding to downstream signaling molecules compared to normal.
  • the present disclosure includes:
  • the compound of embodiment 1, or a pharmaceutically acceptable salt thereof is wherein ring A is cycloaminyl.
  • the compound of embodiment 1, or a pharmaceutically acceptable salt thereof is wherein ring A is bridged cycloaminyl.
  • the compound of embodiment 1, or a pharmaceutically acceptable salt thereof is wherein ring A is spiroaminyl.
  • the compound of embodiment 1, or a pharmaceutically acceptable salt thereof is wherein ring A is bicycloaminyl.
  • the compound of embodiment 1, or a pharmaceutically acceptable salt thereof is wherein cycloaminyl is a ring of formula (a) :
  • X is CH, NH, O, or S
  • m is 0 to 3
  • n is 0 to 2
  • provided m+n is not greater than 4.
  • the compound of embodiment 2, or a pharmaceutically acceptable salt thereof is wherein ring A is cycloaminyl according to formula (a) : where X is CH, O, or S, m is 0 to 2, and n is 0 to 3, provided that m+n is not greater than 4.
  • the compound of any one of embodiments 6 to 8, 9, and 10, or a pharmaceutically acceptable salt thereof is where m is 0 and n are each 0.
  • the compound of any one of embodiments 6 to 8, 9, and 10, or a pharmaceutically acceptable salt thereof is where m is 0 and n is 1.
  • the compound of any one of embodiments 6 to 8, 9, and 10, or a pharmaceutically acceptable salt thereof is where m is 0 and n is 2.
  • the compound of any one of embodiments 6 to 8, 9, and 10, or a pharmaceutically acceptable salt thereof is where m is 1 and n is 1.
  • the compound of any one of embodiments 6 to 8, 9, and 10, or a pharmaceutically acceptable salt thereof is where m is 1 and n is 2.
  • the compound of any one of embodiments 6 to 8, 9, and 10, or a pharmaceutically acceptable salt thereof is where m is 1 and n is 3.
  • the compound of embodiment 1, or a pharmaceutically acceptable salt thereof is wherein bridged cycloaminyl is a ring of formula (b) :
  • the compound of embodiment 3, or a pharmaceutically acceptable salt thereof is wherein ring A is bridged cycloaminyl accordingly to formula (b) :
  • n1 is 0 or 1
  • n2 is 1 or 2
  • X 1 is a CH, O, or S.
  • the compound of embodiment 17, 18 or 19, or a pharmaceutically acceptable salt thereof is wherein X 1 is CH.
  • the compound of embodiment 17, 18 or 19, or a pharmaceutically acceptable salt thereof is wherein X 1 is NH, O, or S.
  • the compound of embodiment 17, 18 or 19, or a pharmaceutically acceptable salt thereof is wherein X 1 is a NH or O.
  • the compound of embodiment 1, 3, 17, 18, 19, or 20, or a pharmaceutically acceptable salt thereof is wherein bridged cycloaminyl is a ring of formula:
  • the compound of embodiment 1 or 4, or a pharmaceutically acceptable salt thereof is wherein the spiroaminyl is a ring of formula (c) :
  • X is CH, O, or NH and m2, n3, p, and q are each 0 to 3, provided that m2 + n3 + p + q is not greater than 7.
  • the compound of embodiment 25, or a pharmaceutically acceptable salt thereof is wherein X 1 is CH.
  • the compound of embodiment 25, or a pharmaceutically acceptable salt thereof is wherein X 1 is O.
  • the compound of embodiment 1, 4, 25, or 26, or a pharmaceutically acceptable salt thereof is wherein spiroaminyl is a ring of formula:
  • each of the spiroaminyl is substituted with R 1a , R 1b , and R 1c .
  • the compound of embodiment 1, 4, 25, or 26, or a pharmaceutically acceptable salt thereof is wherein the spiroaminyl is a ring of formula:
  • each of the spiroaminyl is additionally substituted with R 1b and R 1c , preferably R 1b .
  • the compound of embodiment 1 or 5, or a pharmaceutically acceptable salt thereof is wherein the bicycloaminyl is a ring of formula (d) :
  • X 2 is CH, O, S, or NH and m3, n4, p1, and q2 are each 0 to 3, provided that m2 + n3 +p + q is not greater than 6 and the bicyclaminyl is substituted with R 1a , R 1b , and R 1c .
  • the compound of embodiment 25, or a pharmaceutically acceptable salt thereof is wherein X 2 is CH.
  • the compound of embodiment 25, or a pharmaceutically acceptable salt thereof is wherein X 2 is O.
  • the compound of embodiment 1, 5, 30, or 31, or a pharmaceutically acceptable salt thereof is wherein the bicycloaminyl is a ring of formula:
  • the compound of embodiment 1, 5, 30, or 31, or a pharmaceutically acceptable salt thereof is wherein the bicycloaminyl is a ring of formula:
  • the compound of any one of embodiments 1 to 33a, or a pharmaceutically acceptable salt thereof, is wherein R 1a is hydroxy.
  • the compound of any one of embodiments 1 to 33a and 35, or a pharmaceutically acceptable salt thereof is wherein R 1a is amino, aminomethyl, aminoethyl, methylamino, ethylamino, cyclopropylamino, aminocarbonyl, methoxycarbonylamino, cyanomethylamino, 2, 2, 2-trifluoroethylamino, acetylamino, methylsulfonylamino, piperidin-4-ylamino, tetrahydropyran-4-ylamino, oxetan-3-ylamino, imidazol-2-ylamino, or oxazol-2-ylamino.
  • the compound of any one of embodiments 1 to 33a and 35, or a pharmaceutically acceptable salt thereof, is wherein R 1a is amino.
  • the compound of any one of embodiments 1 to 33a and 35, or a pharmaceutically acceptable salt thereof is wherein R 1a is aminomethyl, methylamino, ethylamino, or cyclopropylamino, preferably aminomethyl.
  • the compound of any one of embodiments 1 to 33a, or a pharmaceutically acceptable salt thereof is wherein R 1a is -Q 2 -R 10 .
  • the compound of any one of embodiments 1 to 42, or a pharmaceutically acceptable salt thereof is wherein R 1c is absent, hydroxy, cyano, or fluoro, preferably absent.
  • the compound of any one of embodiments 1 to 43, or a pharmaceutically acceptable salt thereof is wherein R 1b is absent, cyano, fluoro, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, fluoromethyl, cyclopropyl, hydroxy, methoxy, hydroxymethyl, methoxymethyl, cyanomethyl, dimethylcarbonyl, or dimethylcarbonylmethyl.
  • the compound of any one of embodiments 1 to 46, or a pharmaceutically acceptable salt thereof has a structure of formula (Ia) as follows:
  • the compound of any one of embodiments 1 to 46, or a pharmaceutically acceptable salt thereof has a structure of formula (Ib) as follows:
  • the compound of any one of embodiments 1 to 46, or a pharmaceutically acceptable salt thereof has a structure of formula (Ic) as follows:
  • the compound of any one of embodiments 1 to 46, or a pharmaceutically acceptable salt thereof has a structure of formula (Id) as follows:
  • the compound of any one of embodiments 1 to 46, or a pharmaceutically acceptable salt thereof has a structure of formula (Ie) as follows:
  • the compound of any one of embodiments 1 to 51, or a pharmaceutically acceptable salt thereof is wherein Q is bond and R 5 is cycloalkyl, fused cycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl, wherein aryl, aryl in aralkyl, heteroaryl, and heteroaryl in heteroaralkyl are substituted with R aa , R bb , R cc and R dd wherein R aa and R bb are independently selected from hydrogen, alkyl, cycloalkyl, halo, haloalkyl, haloalkoxy, hydroxy, alkoxy, heteroalkyl, hydroxyalkyl, amino, and cyano, R cc is hydrogen, alkenyl, alkynyl, cyanoalkynyl, or halo, and R dd is hydrogen, alkyl, cycloalkyl, halo,
  • the compound of any one of embodiments 1 to 51, or a pharmaceutically acceptable salt thereof is wherein Q is alkylene and R 5 is cycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl, wherein aryl, aryl in aralkyl, heteroaryl, and heteroaryl in heteroaralkyl are substituted with R aa , R bb , R cc and R dd wherein R aa and R bb are independently selected from hydrogen, alkyl, cycloalkyl, halo, haloalkyl, haloalkoxy, hydroxy, alkoxy, heteroalkyl, hydroxyalkyl, amino, and cyano, R cc is hydrogen or halo, and R dd is hydrogen, alkyl, cycloalkyl, halo, haloalkyl, haloalkoxy, alkoxy, heteroalkyl, hydroxyalkyl, amino, and cyan
  • the compound of any one of embodiments 1 to 51, or a pharmaceutically acceptable salt thereof is wherein Q is -C (O) -and R 5 is cycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl, wherein aryl, aryl in aralkyl, heteroaryl, and heteroaryl in heteroaralkyl are substituted with R aa , R bb , R cc and R dd wherein R aa and R bb are independently selected from hydrogen, alkyl, cycloalkyl, halo, haloalkyl, haloalkoxy, hydroxy, alkoxy, heteroalkyl, hydroxyalkyl, amino, and cyano, R cc is hydrogen or halo, and R dd is hydrogen, alkyl, cycloalkyl, halo, haloalkyl, haloalkoxy, alkoxy, heteroalkyl, haloalkyl
  • the compound of any one of embodiments 1 to 51, or a pharmaceutically acceptable salt thereof is wherein Q is bond and R 5 is phenyl or naphthyl substituted with R aa , R bb , and R dd where R aa and R bb are independently selected from hydrogen, alkyl, halo, haloalkyl, hydroxy, alkoxy, haloalkoxy, cycloalkyl, amino, cyano, and hydroxyalkyl and R dd is hydrogen, alkyl, cycloalkyl, halo, haloalkyl, haloalkoxy, alkoxy, heteroalkyl, hydroxyalkyl, amino, cyano, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl.
  • the compound of any one of embodiments 1 to 56, or a pharmaceutically acceptable salt thereof is wherein R aa and R bb independently selected from hydrogen, methyl, ethyl, fluoro, chloro, trifluoromethyl, difluoromethyl, trifluoromethoxy, hydroxy, methyl, ethoxy, cyclopropyl, amino, cyano, and hydroxymethyl, R cc is hydrogen, ethynyl, 2-cyanoethyn-1-yl, or fluoro, and R dd is hydrogen, methyl, fluoro, amino, or cyclopropyl.
  • the compound of embodiment 1 to 51 and 59, or a pharmaceutically acceptable salt thereof is wherein R 5 is Q is bond and R 5 is bicyclic heteroaryl (e,g, quinolinyl, isoquinolinyl, or indazolyl) , substituted with R aa , R bb , R cc and R dd .
  • R 5 is Q is bond and R 5 is bicyclic heteroaryl (e,g, quinolinyl, isoquinolinyl, or indazolyl) , substituted with R aa , R bb , R cc and R dd .
  • the compound of any one of embodiments 1 to 51 and 59 to 61, or a pharmaceutically acceptable salt thereof is wherein the heteroaryl is substituted with R aa , R bb , and R dd where R aa and R bb independently selected from hydrogen, alkyl, halo, haloalkyl, hydroxy, alkoxy, haloalkoxy, cycloalkyl, amino, cyano, and hydroxyalkyl and R dd is hydrogen, alkyl, cycloalkyl, halo, haloalkyl, haloalkoxy, alkoxy, heteroalkyl, hydroxyalkyl, amino, cyano, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl.
  • the compound of any one of embodiments 1 to 51 and 59 to 61, or a pharmaceutically acceptable salt thereof is wherein R aa and R bb are independently selected from hydrogen, methyl, ethyl, fluoro, chloro, trifluoromethyl, difluoromethyl, trifluoromethoxy, hydroxy, methyl, ethoxy, cyclopropyl, amino, cyano, and hydroxymethyl, R cc is hydrogen or fluoro, and R dd is hydrogen, methyl, fluoro, amino, or cyclopropyl.
  • the compound of any one of embodiments 1 to 64, or a pharmaceutically acceptable salt thereof is wherein R 2 is absent, halo, or alkyl, and R 3 absent, halo, cycloalkyloxy, or alkyl.
  • the compound of any one of embodiments 1 to 65, or a pharmaceutically acceptable salt thereof is wherein R 2 is absent or chloro and R 3 is absent, fluoro, or cyclopropyloxy.
  • the compound of any one of embodiments 1 to 67, or a pharmaceutically acceptable salt thereof is wherein R 4 is -Z-R 11 where Z is a bond, O, NH, N (alkyl) , or S; and R 11 is alkyl, hydroxyalkyl, - (alkylene) -NR 12 R 13 (where alkylene is substituted with R a , R b , and R c independently selected from hydrogen, alkyl, cycloalkyl, halo, haloalkyl, hydroxy, alkoxy, cyano, oxo, hydroxyalkyl, alkylamino, dialkylamino, dialkylaminocarbonylalkyl, aryl, heteroaryl, and heterocyclyl, R 12 is hydrogen or alkyl, and R 13 is hydrogen, alkyl, acyl, hydroxyalkyl, or heteroalkyl) , aryl, heteroaryl, heteroaralkyl, heterocyclo, R 12 is hydrogen or al
  • the compound of any one of the embodiments 1 to 68, or a pharmaceutically acceptable salt thereof, is wherein Z is O.
  • the compound of any one of the embodiments 1 to 68, or a pharmaceutically acceptable salt thereof, is wherein Z is NH.
  • the compound of any one of the embodiments 1 to 68, or a pharmaceutically acceptable salt thereof, is wherein Z is bond.
  • the compound of any one of embodiments 1 to 71, or a pharmaceutically acceptable salt thereof is wherein R 11 is hydroxyalkyl, - (alkylene) -NR 12 R 13 (where alkylene is substituted with R a , R b , and R c independently selected from hydrogen, alkyl, hydroxy, and hydroxyalkyl, R 12 is hydrogen or alkyl, and R 13 is hydrogen, alkyl, or hydroxyalkyl) , heteroaralkyl, heterocyclyl, heterocyclylalkyl, bicyclic heterocyclyl, bicyclic heterocyclylalkyl, bridged heterocyclylalkyl, fused heterocyclylalkyl, and spiro heterocyclylalkyl, wherein heterocyclyl, by itself or as part of heterocyclylalkyl, bicyclic heterocyclyl, by itself or as part of bicyclic heterocyclylalkyl, bridged heterocyclyl as part of bridged heterocyclyl, wherein heterocycly
  • the compound of any one of embodiments 1 to 67, or a pharmaceutically acceptable salt thereof is wherein R 4 is -Z-R 11 where Z is a bond, O, NH, N (alkyl) , or S; and R 11 is phenyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, bicyclic heterocyclyl, bicyclic heterocyclylalkyl, bridged heterocyclyl, bridged heterocyclylalkyl, fused heterocyclyl, fused heterocyclylalkyl, spiro heterocyclyl, or spiro heterocyclylalkyl, wherein phenyl, heteroaryl, by itself or as part of heteroaralkyl, heterocyclyl, by itself or as part of heterocyclylalkyl, bicyclic heterocyclyl, by itself or as part of bicyclic heterocyclylalkyl, bridged heterocyclyl, by itself or as part of bridged heterocyclyl, wherein phen
  • R 15 and R 16 together with the carbon atom to which are attached form cycloalkyl, bridged cycloalkyl, fused cycloalkyl, spiro cycloalkyl, heterocyclyl, bridged heterocyclyl, fused heterocyclyl, or spiro heterocyclyl, wherein:
  • the starting materials and reagents used in preparing these compounds are either available from commercial suppliers such as Aldrich Chemical Co., (Milwaukee, Wis. ) , Bachem (Torrance, Calif. ) , or Sigma (St. Louis, Mo.
  • the reactions described herein take place at atmospheric pressure over a temperature range from about –78 °C to about 150 °C, such as from about 0 °C to about 125 °C and further such as at about room (or ambient) temperature, e.g., about 20 °C.
  • Compounds of Formula (I) can be synthesized from compounds of formula 1-e by coupling with compounds of formula 1-f in the presence of coupling reagent such as PyBOP.
  • one of the amine group in compound of formula 1-f can be protected with a suitable amino protecting group such as Boc, CBz as in compounds of formula 1-g.
  • Coupling reaction between 1-e and 1-g, followed by removing the amine protecting group can provide compound of Formula (I) where one of R 6 or R 7 is hydrogen which can be converted to corresponding compound of Formula (I) where both R 6 or R 7 are other than hydrogen by methods known in the art.
  • Compounds of formula 1-g are generally commercially available or they can be made by methods known in the art.
  • (R) -2-methyl-N- (8-azaspiro [4.5] decan-1-yl) propane-2-sulfinamide can be prepared by method described in Example 2 below; and (9H-fluoren-9-yl) methyl (4, 4-difluoropyrrolidin-3-yl) carbamate, (9H-fluoren-9-yl) methyl ( (1R, 5S, 8s) -3-azabicyclo [3.2.1] octan-8-yl) carbamate, (9H-fluoren-9-yl) methyl (3-azabicyclo [3.1.1] heptan-6-yl) carbamate and (9H-fluoren-9-yl) methyl (2-azabicyclo [2.2.1] heptan-6-yl) carbamate can be prepared as described in Example 10 below.
  • tert-Butyl (4-hydroxypyrrolidin-3-yl) carbamate can be prepared by method disclosed in PCT application publication WO2008020229.
  • Condensation between methyl proline 2, aldehyde and acrylate provides an adduct 3, which upon removal of the benzyl group under standard reaction condition such as hydrogenation in the presence of Pd in carbon catalyst provides alcohol 4.
  • Reaction of 4 with TsCl in the presence of a base such as TEA provides compound 5.
  • the ester groups of 5 can be reduced with a reducing reagent such as LiAlH 4 or DIABL to provide diol 5a.
  • Treatment of 5a with a base such as NaH provides compound 5b.
  • R 11 -OH where R 11 is 4, 4a, 7, 8, 9, 9a-hexahydroisoxazolo [4', 3': 4, 5] cyclopenta- [1, 2-b] pyrrolizin-8a (6H) -yl can be synthesized by the Method (b) below.
  • Compound 11 can be converted to oxime 12 by reacting 11 with hydroxyamine under conditions well known in the art. Chlorination of 12 with a chlorinating agent such as NCS, followed by treating with a suitable base such as DIPEA or TEA can cause cyclization of 12 to provide compound 13.
  • Compound 13 can be deprotonated with a suitable base such as LDA and then alkylated with 1-bromo-3-chloropropane to provide compound 14.
  • the Boc group can be removed under acid condition such as TFA in DCM and the resulting amine compound can be cyclized in the presence of a base such as K 2 CO 3 to provide 15, which can be reduced with a suitable base such as LiBH 4 to provide compound 16.
  • R 11 -OH where R 11 is 6, 7, 8, 8a-tetrahydro-5H, 9H-pyrazolo [1', 5': 1, 5] pyrrolo [3, 4-b] -pyrrolizin-7a (3bH) -yl can be synthesized by the method (c) below:
  • R 11 -OH where R 11 is 2- (fluoromethylene) tetrahydro-1H-pyrrolizin-7a (5H) -yl can be synthesized by the method (d) below:
  • Compound 29 can undergo cyclization with 3-chloro-2- (chloromethyl) prop-1-ene in the presence of a base such as LHMDS to provide compound 30.
  • a base such as LHMDS
  • Reduction of the keto group in compound 30 with a suitable reducing reagent such as LiAlH 4 provides compound 31.
  • Cleavage of the olefin in 31 with ozone provides ketone 32, which can be converted to 33 under standard Wittig olefination condition.
  • the present disclosure provides treatment of cancer mediated by K-ras, in particular with G12D mutant.
  • the cancer is pancreatic cancer, colorectal cancer, lung cancer, gall bladder cancer, thyroid cancer, and bile duct cancer.
  • the lung cancer is a non-small cell lung carcinoma (NSCLC) , for example adenocarcinoma, squamous-cell lung carcinoma or large-cell lung carcinoma.
  • the lung cancer is a small cell lung carcinoma.
  • Other lung cancers treatable with the disclosed compounds include, but are not limited to, glandular tumors, carcinoid tumors and undifferentiated carcinomas.
  • K-ras G12D mutations are observed in hematological malignancies that affect blood, bone marrow, and/or lymph nodes.
  • the compounds of Formula (I) or a pharmaceutically acceptable salt thereof can be used for the treatment of acute lymphoblastic leukemia (ALL) , acute myelogenous leukemia (AML) , chronic lymphocytic leukemia (CLL) , small lymphocytic lymphoma (SLL) , chronic myelogenous leukemia (CML) , acute monocytic leukemia (AMoL) and/or other leukemias, lymphomas such as all subtypes of Hodgkins lymphoma or non- Hodgkins lymphoma, plasma cell malignancies such as multiple myeloma, mantle cell lymphoma, and Waldenstrom’s macroglubunemia.
  • ALL acute lymphoblastic leukemia
  • AML acute myelogenous leukemia
  • CLL chronic lymphocy
  • the compounds of Formula (I) can be used for the treatment of a hyperproliferative disorder or metastasis in human who suffers from a cancer such as acute myeloid leukemia, cancer in adolescents, adrenocortical carcinoma childhood, AIDS related cancers (e.g.
  • Lymphoma and Kaposi's Sarcoma anal cancer, appendix cancer, astrocytomas, atypical teratoid, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brain stem glioma, brain tumor, breast cancer, bronchial tumors, Burkitt lymphoma, carcinoid tumor, atypical teratoid, embryonal tumors, germ cell tumor, primary lymphoma, cervical cancer, childhood cancers, chordoma, cardiac tumors, chronic lymphocytic leukemia (CLL) , chronic myelogenous leukemia (CML) , chronic myleoproliferative disorders, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, extrahepatic ductal carcinoma in situ (DCIS) , embryonal tumors, CNS cancer, endometrial cancer, ependymoma, esophageal cancer, esthe
  • the compounds of Formula (I) , or a pharmaceutically acceptable salt thereof can also be used for the treatment of a non-cancerous hyperproliferative disorder such as benign hyperplasia of the skin (e.g., psoriasis) , restenosis, or prostate (e.g., benign prostatic hypertrophy (BPH) ) .
  • a non-cancerous hyperproliferative disorder such as benign hyperplasia of the skin (e.g., psoriasis) , restenosis, or prostate (e.g., benign prostatic hypertrophy (BPH) ) .
  • the K-Ras G12D activity of the compounds of Formula (I) , or a pharmaceutically acceptable salt thereof can be tested using the in vitro assay described in Biological Examples 1 and 2 below.
  • the compounds Formula (I) (unless stated otherwise, reference to compound/compounds of Formula (I) herein includes any embodiments thereof described herein or a pharmaceutically acceptable salt thereof) will be administered in a therapeutically effective amount by any of the accepted modes of administration for agents that serve similar utilities.
  • Therapeutically effective amounts of compounds Formula (I) may range from about 0.01 to about 500 mg per kg patient body weight per day, which can be administered in single or multiple doses.
  • a suitable dosage level may be from about 0.1 to about 250 mg/kg per day; about 0.5 to about 100 mg/kg per day.
  • a suitable dosage level may be about 0.01 to about 250 mg/kg per day, about 0.05 to about 100 mg/kg per day, or about 0.1 to about 50 mg/kg per day.
  • the dosage can be about 0.05 to about 0.5, about 0.5 to about 5 or about 5 to about 50 mg/kg per day.
  • the compositions can be provided in the form of tablets containing about 1.0 to about 1000 milligrams of the active ingredient, particularly about 1, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900, and 1000 milligrams of the active ingredient.
  • the actual amount of the compound Formula (IA’) , (I’) , (I) , (IIA’) , (II’) , or (II) i.e., the active ingredient, will depend upon numerous factors such as the severity of the disease to be treated, the age and relative health of the patient, the potency of the compound being utilized, the route and form of administration, and other factors.
  • compounds Formula (I) will be administered as pharmaceutical compositions by any one of the following routes: oral, systemic (e.g., transdermal, intranasal or by suppository) , or parenteral (e.g., intramuscular, intravenous or subcutaneous) administration.
  • routes oral, systemic (e.g., transdermal, intranasal or by suppository) , or parenteral (e.g., intramuscular, intravenous or subcutaneous) administration.
  • parenteral e.g., intramuscular, intravenous or subcutaneous
  • compositions can take the form of tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols, or any other appropriate compositions.
  • formulations in the form of tablets, pills or capsules, including enteric coated or delayed release tablets, pills or capsules are preferred.
  • compositions are comprised of in general, a compound of Formula (I) in combination with at least one pharmaceutically acceptable excipient.
  • Acceptable excipients are generally non-toxic, aid administration, and do not adversely affect the therapeutic benefit of the compound of Formula (I) .
  • excipient may be any solid, liquid, semi-solid or, in the case of an aerosol composition, gaseous excipient that is generally available to one of skill in the art.
  • Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk and the like.
  • Liquid and semisolid excipients may be selected from glycerol, propylene glycol, water, ethanol and various oils, including those of petroleum, animal, vegetable or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc.
  • Preferred liquid carriers, particularly for injectable solutions include water, saline, aqueous dextrose, and glycols.
  • the compounds of Formula (I) may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion.
  • Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative.
  • the compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • the formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in powder form or in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, saline or sterile pyrogen-free water, immediately prior to use.
  • sterile liquid carrier for example, saline or sterile pyrogen-free water
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
  • Formulations for parenteral administration include aqueous and non-aqueous (oily) sterile injection solutions of the active compounds which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes.
  • Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran.
  • the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
  • the compounds of Formula (I) may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection.
  • the compounds may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • compositions may take the form of tablets, lozenges, pastilles, or gels formulated in conventional manner.
  • Such compositions may comprise the active ingredient in a flavored basis such as sucrose and acacia or tragacanth.
  • the compounds of Formula (I) may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter, polyethylene glycol, or other glycerides.
  • Certain compounds of Formula (I) may be administered topically, that is by non-systemic administration. This includes the application of a compound of Formula (I) externally to the epidermis or the buccal cavity and the instillation of such a compound into the ear, eye and nose, such that the compound does not significantly enter the blood stream.
  • systemic administration refers to oral, intravenous, intraperitoneal and intramuscular administration.
  • Formulations suitable for topical administration include liquid or semi-liquid preparations suitable for penetration through the skin to the site of inflammation such as gels, liniments, lotions, creams, ointments or pastes, and drops suitable for administration to the eye, ear or nose.
  • the active ingredient for topical administration may comprise, for example, from 0.001%to 10%w/w (by weight) of the formulation. In certain embodiments, the active ingredient may comprise as much as 10%w/w. In other embodiments, it may comprise less than 5%w/w. In certain embodiments, the active ingredient may comprise from 2%w/w to 5%w/w. In other embodiments, it may comprise from 0.1%to 1%w/w of the formulation.
  • compounds of Formula (I) may be conveniently delivered from an insufflator, nebulizer pressurized packs or other convenient means of delivering an aerosol spray.
  • Pressurized packs may comprise a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • the compounds of Formula (I) may take the form of a dry powder composition, for example a powder mix of the compound and a suitable powder base such as lactose or starch.
  • the powder composition may be presented in unit dosage form, in for example, capsules, cartridges, gelatin or blister packs from which the powder may be administered with the aid of an inhalator or insufflator.
  • suitable pharmaceutical excipients and their formulations are described in Remington’s Pharmaceutical Sciences, edited by E. W. Martin (Mack Publishing Company, 20th ed., 2000) .
  • the level of the compound of Formula (I) in a formulation can vary within the full range employed by those skilled in the art.
  • the formulation will contain, on a weight percent (wt. %) basis, from about 0.01-99.99 wt. %of a compound of Formula (I) based on the total formulation, with the balance being one or more suitable pharmaceutical excipients.
  • the compound is present at a level of about 1-80 wt. %.
  • the compounds of Formula (I) , or a pharmaceutically acceptable salt thereof may be used in combination with one or more other drugs in the treatment of diseases or conditions for which compounds of Formula (I) , or the other drugs may have utility.
  • Such other drug (s) may be administered, by a route and in an amount commonly used therefore, contemporaneously or sequentially with a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • a pharmaceutical composition in unit dosage form containing such other drugs and the compound of Formula (I) , or a pharmaceutically acceptable salt thereof can be used.
  • compositions of the present disclosure also include those that contain one or more other drugs, in addition to a compound of Formula (I) , or a pharmaceutically acceptable salt thereof.
  • the combination therapy may also include therapies in which the compound of Formula (I) , or a pharmaceutically acceptable salt thereof and one or more other drugs are administered on different overlapping schedules. It is also contemplated that when used in combination with one or more other active ingredients, the compounds of Formula (I) , and the other active ingredients may be used in lower doses than when each is used singly.
  • the weight ratio of the compound of this disclosure to the second active ingredient may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used.
  • the patient can be treated with a compound of Formula (I) , or a pharmaceutically acceptable salt thereof in any combination with one or more other anti-cancer agents including but not limited to:
  • MAP kinase pathway (RAS/RAF/MEK/ERK) inhibitors including but not limited to: Vemurafanib (PLX4032, CAS No. 918504-65-1) , Dabrafenib (CAS No. 1195765-45-7) , Encorafenib (LGX818 CAS No. 1269440-17-6) , TQ-B3233, XL-518 (Cas No. 1029872-29-4, available from ACC Corp) ; trametinib (CAS No. 871700-17-3) , selumetinib (AZD6244 CAS No. 606143-52-6) , TQ-B3234, PD184352 (CAS No.
  • SHP2 inhibitors including but not limited to: SHP099 (CAS No. 2200214-93-1) , TNO155 (CAS No. 1801765-04-7) , RMC4630, JAB-3312, JAB-3068 and ERAS-601;
  • SOS1 inhibitors including but not limited to BI1701963 and BAY-293;
  • CSF1R inhibitors PLX3397, LY3022855,
  • CSF1R antibodies IMC-054, RG7l55
  • TGF beta receptor kinase inhibitor such as LY2157299
  • BTK inhibitor such as ibrutinib; BCR-ABL inhibitors: Imatinib (CAS No. 152459-95-5) ; Inilotinib hydrochloride; Nilotinib (CAS No. 923288-95-3) ; Dasatinib (BMS-345825 CAS No. 302962-49-8) ; Bosutinib (SKI-606 CAS No. 380843-75-4) ; Ponatinib (AP24534 CAS No. 943319-70-8) ; Bafetinib (INNO406 CAS No. 859212-16-1) ; Danusertib (PHA-739358 CAS No.
  • ALK inhibitors PF-2341066 ( crizotinib) ; 5-chloro-N4- (2- (isopropyl-sulfonyl) phenyl) -N2- (2-methoxy-4- (4- (4-methylpiper azin-l-yl) piperidin-l-yl) phenyl) pyrimidine-2, 4-diamine; GSK1838705A (CAS No. 1116235-97-2) ; CH5424802 (CAS No. 1256580-46-7) ; Ceritinib (ZYKADIA CAS No. 1032900-25-6) ; TQ-B3139, and TQ-B3101;
  • PI3K inhibitors 4- [2- (lH-Indazol-4-yl) -6- [ [4- (methylsulfonyl) -piperazin-l-yl] methyl] thieno [3, 2-d] pyrimidin-4-yl] mocpholine (also known as GDC 0941 and described in PCT Publication Nos. WO 09/036082 and WO 09/055730) , BEZ235 or NVP-BEZ235 (CAS No. 915019-65-7) , disclosed in PCT Publication No. WO 06/122806) ;
  • VEGF receptor inhibitors Bevacizumab (sold under the trademark by Genentech/Roche) , axitinib, (N-methyl-2- [ [3- [ (E) -2-pyridin-2-ylethenyl] -lH-indazol-6-yl] sulfanyl] benzamide, also known as AG013736, and described in PCT Publication No.
  • pasireotide also known as SOM230, and described in PCT Publication No. WO 02/010192
  • sorafenib sold under the tradename CAS No. 284461-73-0
  • AL-2846 AL-2846
  • MET inhibitor such as foretinib (CAS No. 849217-64-7) , cabozantinib (CAS No. 1140909-48-3) , capmatinib (CAS No. 1029712-80-8) , tepotinib (CAS No. 1100598-32-0) , savolitinib (CAS No. 1313725-88-0, or crizotinib (CAS No. 877399-52-5) ;
  • FLT3 inhibitors -sunitinib malate (CAS No. 341031-54-7, sold under the tradename by Pfizer) ; PKC412 (CAS No. 120685-11-2, midostaurin) ; tandutinib (CAS No. 387867-13-2) , sorafenib (CAS No. 284461-73-0) , lestaurtinib (CAS No. : 111358-88-4) , KW-2449 (CAS No. 1000669-72-6) , quizartinib (AC220, CAS No. 950769-58-1) , or crenolanib (CAS No. 670220-88-9) ;
  • Epidermal growth factor receptor (EGFR) inhibitors Gefitnib (sold under the tradename ) , N- [4- [ (3-Chloro-4-fluorophenyl) amino] -7- [ [ (3"S") -tetrahydro-3-furanyl] oxy] -6-quinazolinyl] -4 (dimethylamino) -2-butenamide, sold under the tradename by Boehringer Ingelheim) , cetuximab (sold under the tradename by Bristol-Myers Squibb) , or panitumumab (sold under the tradename by Amgen) ;
  • HER2 receptor inhibitors Trastuzumab (sold under the trademark by Genentech/Roche) , neratinib (also known as HKI-272, (2E) -N- [4- [ [3-chloro-4- [ (pyridin-2-yl) methoxy] phenyl] amino] -3-cyano-7-ethoxyquinolin-6-yl] -4- (d imethylamino) but-2-enamide, and described PCT Publication No. WO 05/028443) , lapatinib (CAS No.
  • lapatinib ditosylate (CAS No: 388082-77-7) (sold under the trademark by GlaxoSmithKline) ; or Trastuzumab emtansine (in the United States, ado-trastuzumab emtansine, trade name Kadcyla) -an antibody-drug conjugate consisting of the monoclonal antibody trastuzumab (Herceptin) linked to the cytotoxic agent mertansine (DM1) ;
  • HER dimerization inhibitors Pertuzumab (sold under the trademark by Genentech) ;
  • FGFR inhibitors Erdafitinib (CAS No. 1346242-81-6) , Pemigatinib (CAS No. 1513857-77-6) or Infigratinib (CAS No. 872511-34-7)
  • Aurora kinase inhibitors TAS-119 (CAS No. 1453099-83-6) , LY3295668 (CAS No. 1919888-06-4) , or alisertib (CAS No. 1028486-01-2) ;
  • CD20 antibodies Rituximab (sold under the trademarks and by Genentech/Roche) , tositumomab (sold under the trademarks by GlaxoSmithKline) , or ofatumumab (sold under the trademark by GlaxoSmithKline) ;
  • Tyrosine kinase inhibitors Erlotinib hydrochloride (CAS No. 183319-69-9, sold under the trademark by Genentech/Roche) , Linifanib (N- [4- (3-amino-lH-indazol-4-yl) phenyl] -N'- (2-fluoro-5-methylphenyl) urea, also known as ABT 869, available from Genentech) , sunitinib malate (CAS No.
  • DNA Synthesis inhibitors Capecitabine (CAS No. 154361-50-9) (sold under the trademark by Roche) , gemcitabine hydrochloride (CAS No. 122111-03-9) (sold under the trademark by Eli Lilly and Company) , or nelarabine ( (2R3S, 4R, 5R) -2- (2-amino-6-methoxy-purin-9-yl) -5- (hydroxymet hyl) oxolane-3, 4-diol, sold under the tradenames and by GlaxoSmithKline) ;
  • Antineoplastic agents oxaliplatin (CAS No. 61825-94-3) (sold under the tradename ay Sanofi-Aventis and described in US Patent No. 4,169,846) ;
  • G-CSF modulators Human Granulocyte colony-stimulating factor (G-CSF) modulators: Filgrastim (sold under the tradename by Amgen) ;
  • Immunomodulators Afutuzumab (available from ) , pegfilgrastim (sold under the tradename by Amgen) , lenalidomide (CAS No. 191732-72-6, also known as CC-5013, sold under the tradename ) , or thalidomide (CAS No. 50-35-1, sold under the tradename ) ;
  • CD40 inhibitors Dacetuzumab (also known as SGN-40 or huS2C6, available from Seattle Genetics, Inc) ;
  • PARAs Pro-apoptotic receptor agonists
  • MCL-1 inhibitors MIK665 (CAS No. 1799631-75-6, S64315) , AMG 397, and AZD5991 (CAS No. 2143010-83-5) ;
  • Aromatase inhibitors Exemestane (CAS No. 107868-30-4, sold under the trademark by Pfizer) , letrozole (CAS No. 112809-51-5, sold under the tradename by Novartis) , or anastrozole (CAS No. 120511-73-1, sold under the tradename );
  • Topoisomerase I inhibitors Irinotecan (CAS No. 97682-44-5, sold under the trademark by Pfizer) , topotecan hydrochloride (CAS No. 119413-54-6, sold under the tradename by GlaxoSmithKline) ;
  • HIF-2 ⁇ inhibitors such as PT2977 (1672668-24-4) , NKT2152, or PT2385 (CAS No. 1672665-49-4) ;
  • Osteoclastic bone resorption inhibitors l-Hydroxy-2-imidazol-l-yl-phosphonoethyl) phosphonic acid monohydrate (sold under the tradename by Novartis) ;
  • CD33 Antibody Drug Conjugates Gemtuzumab ozogamicin (sold under the tradename by Pfizer/Wyeth) ;
  • Synthetic Interleukin-11 (IL-l 1) : oprelvekin (sold under the tradename by Pfizer/Wyeth) ;
  • Receptor Activator for Nuclear Factor k B (RANK) inhibitors Denosumab (sold under the tradename by Amgen) ;
  • Thrombopoietin mimetic peptibodies Romiplostim (sold under the tradename
  • IGF-1R antibodies Anti-insulin-like Growth Factor-l receptor (IGF-1R) antibodies: Figitumumab (also known as CP-751, 871, available from ACC Corp) , robatumumab (CAS No. 934235-44-6) ;
  • Anti-CSl antibodies Elotuzumab (HuLuc63, CAS No. 915296-00-3) ;
  • CD52 antibodies Alemtuzumab (sold under the tradename ) ;
  • Histone deacetylase inhibitors Voninostat (sold under the tradename by Merck) ;
  • Alkylating agents Temozolomide (sold under the tradenames and by Schering-Plough/Merck) , dactinomycin (also known as actinomycin-D and sold under the tradename ) , melphalan (also known as L-PAM, L-sarcolysin, and phenylalanine mustard, sold under the tradename ) , altretamine (also known as hexamethylmelamine (HMM) , sold under the tradename ) , carmustine (sold under the tradename ) , bendamustine (sold under the tradename ) , busulfan (sold under the tradenames and ) , carboplatin (sold under the tradename ) , lomustine (also known as CCNU, sold under the tradename ) , cisplatin (also known as CDDP, sold under the tradenames and ) , chlorambucil (sold under the tradename ) , cyclophospham
  • Anti -microtubule agents Estramustine (CAS No. 52205-73-9, sold under the tradename );
  • Cathepsin K inhibitors Odanacatib (CAS No. 603139-19-1, also know as MK-0822 available from Lanzhou Chon Chemicals, ACC Corp., and ChemieTek, and described in PCT Publication no. WO 03/075836) ;
  • HSP Heat Shock Protein
  • Anti-mitotic agents Docetaxel (CAS No. 114977-28-5, sold under the tradename by Sanofi-Aventis) ; Adrenal steroid inhibitors: aminoglutethimide (CAS No. 125-84-8, sold under the tradename
  • CDK inhibitors including but not limited to: Alvocidib (CAS No. 146426-40-6, pan-CDK inhibitor, also known as flovopirdol or HMR-1275, 2- (2-chlorophenyl) -5, 7-dihydroxy-8- [ (3S, 4R) -3-hydroxy-l -methyl -4-piperidinyl] -4-chromenone, and described in US Patent No. 5, 621, 002) ;
  • CDK4/6 inhibitors pabociclib (CAS No. 827022-33-3) , ribociclib (CAS No. 1211441-98-3) , abemaciclib (CAS No. 1231929-97-7) , PF-06873600 (CAS No. 2185857-97-8) , NUV-422 and Trilaciclib (CAS No. 1374743-00-6) ;
  • CDK9 inhibtiors AZD 4573 (CAS No. 2057509-72-3) , P276-00 (CAS No. 920113-03-7) , AT7519 (CAS No. 844442-38-2) , CYC065 (CAS No. 1070790-89-4) or TP-1287;
  • GnRH Gonadotropin-releasing hormone receptor agonists: Leuprolide or leuprolide acetate (sold under the tradenames by Bayer AG, by Sanofi-Aventis and by Abbott Lab) ;
  • 5HTla receptor agonists Xaliproden (also known as SR57746, l- [2- (2-naphthyl) ethyl] -4- [3- (trifluoromethyl) phenyl] -l, 2, 3, 6-tetrahydropyridine, and described in US Patent No. 5,266,573) ;
  • Iron Chelating agents Deferasinox (CAS No. 201530-41-8, sold under the tradename by Novartis) ;
  • Anti-metabolites Claribine (2-chlorodeoxyadenosine, sold under the tradename ) , 5-fluorouracil (sold under the tradename ) , 6-thioguanine (sold under the tradename ) , pemetrexed (sold under the tradename ) , cytarabine (also known as arabinosylcytosine (Ara-C) , sold under the tradename ) , cytarabine liposomal (also known as Liposomal Ara-C, sold under the tradename DepoCyt TM ) , decitabine (sold under the tradename ) , hydroxyurea (sold under the tradenames Droxia TM and Mylocel TM ) , fludarabine (sold under the tradename ) , floxuridine (sold under the tradename ) , cladribine (also known as 2-chlorodeoxyadenosine (2-CdA) sold
  • Demethylating agents 5-azacitidine (CAS No. 320-67-2, sold under the tradename ) , decitabine (CAS No. 2353-33-5, sold under the tradename ) ;
  • Paclitaxel protein-bound (sold under the tradename ) , vinblastine (also known as vinblastine sulfate, vincaleukoblastine and VLB, sold under the tradenames and ) , vincristine (also known as vincristine sulfate, LCR, and VCR, sold under the tradenames and ) , vinorelbine (sold under the tradename ) , or paclitaxel (sold under the tradenames Taxol and Onxal TM ) ;
  • Retinoids Ali tretinoin (sold under the tradename ) , tretinoin (all-trans retinoic acid, also known as ATRA, sold under the tradename ) , Isotretinoin (13-cis-retinoic acid, sold under the tradenames ) , or bexarotene (sold under the tradename );
  • Glucocorticosteroids Hydrocortisone (also known as cortisone, hydrocortisone sodium succinate, hydrocortisone sodium phosphate, and sold under the tradenames Hydrocortisone Phosphate, Hydrocort and ) , dexamethazone ( (8S, 9R, lOS, l lS, l3S, l4S, l6R, l7R) -9-fluoro-l 1, 17-dihydroxy-17- (2-hydroxyacetyl) -l0, l3, l6-trimethyl-6, 7, 8, 9, 10, 1 l, l2, l3, l4, l5, l6, l7-dodecahydro-3H-cyclopenta [a] phenanthren-3-one) , prednisolone (sold under the tradenames and ) , prednisone (sold under the tradenames Liquid and ) , or methylprednisolone (also
  • Cytokines interleukin-2 (also known as aldesleukin and IL-2, sold under the tradename ) , interleukin-11 (also known as oprevelkin, sold under the tradename ) , alpha interferon alfa (also known as IFN-alpha, sold under the tradenames A, and );
  • Anti-estrogens tamoxifen (CAS No. 10540-29-1, sold under the tradename ) ; or Toremifene (CAS No. 89778-27-8, sold under the tradename ) ;
  • immune-modulatory agents also include those that block immune cell migration such as antagonists to chemokine receptors, including CCR2 and CCR4; Sting agonists and Toll receptor agonists.
  • Other anti-cancer agents also include those that augment the immune system such as adjuvants or adoptive T cell transfer. Compounds of this application may be effective in combination with CAR (Chimeric antigen receptor) T cell treatment as a booster for T cell activation.
  • CAR Chimeric antigen receptor
  • Step 2 8- ( (triisopropylsilyl) ethynyl) naphthalene-1, 3-diol
  • Step 3 3- (methoxymethoxy) -8- ( (triisopropylsilyl) ethynyl) naphthalene-1-phenol
  • Step 4 Trifluoromethanesulfonic acid (3- (methoxymethoxy) -8- ( (triisopropylsilyl) ethynyl) -naphthalene-1-yl) ester
  • Step 1 2, 4, 7 -tricholro-8-fluoropyrido [4, 3-d] pyrimidine
  • Step 3 7-chloro-8-fluoro-2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -4- (2- (trimethylsilyl) -ethoxy) pyrido [4, 3-d] pyrimidine
  • Step 4 8-fluoro-7- (3- (methoxymethoxy) -8- ( (triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -4- (2- (trimethylsilyl) ethoxy) pyrido [4, 3-d] pyrimidine
  • Step 5 7- (8-ethynyl-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-4-ol
  • Step 7 4- (4- (3-aminopyrrolidin-1-yl) -8-fluoro-2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -pyrido [4, 3-d] pyrimidin-7-yl) -5-ethynylnaphthalen-2-ol
  • Step 1 tert-butyl 1- ( ( (R) -tert-butylsulfinyl) amino) -8-azaspiro [4.5] decane-8-carboxylate
  • Step 2 (R) -2-methyl-N- (8-azaspiro [4.5] decan-1-yl) propane-2-sulfinamide
  • Step 3 (R) -N- (8- (7- (8-ethynyl-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-4-yl) -8-azaspiro [4.5] decan-1-yl) -2-methylpropane-2-sulfinamide
  • Step 4 4- (4- (1-amino-8-azaspiro [4.5] decan-8-yl) -8-fluoro-2- ( (tetrahydro-1H-pyrrolizin- 7a (5H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5-ethynylnaphthalen-2-ol
  • Step 1 tert-butyl 6- ( ( ( (9H-fluoren-9-yl) methoxy) carbonyl) amino) -1, 4-oxazepane-4-carboxylate
  • Step 2 (9H-fluoren-9-yl) methyl (1, 4-oxazepan-6-yl) carbamate
  • Step 3 (9H-fluoren-9-yl) methyl (4- (7- (8-ethynyl-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-4-yl) -1, 4-oxazepan-6-yl) carbamate
  • Step 4 4- (7- (8-ethynyl-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-4-yl) -1, 4-oxazepan-6-amine
  • Step 5 4- (4- (6-amino-1, 4-oxazepan-4-yl) -8-fluoro-2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5-ethynylnaphthalen-2-ol
  • test compound The ability of the compound of Formula (I) or a pharmaceutically acceptable salt thereof (test compound) to inhibit K-Ras G12D activity can be tested in a cellular assay as described below.
  • LS180 cells (harbor KRAS G12D mutation) are seeded in 96-well plates and cultured overnight (20,000 cells per well, 200 ⁇ l total volume) . On the following morning, cells are treated with test compound, with starting concentration at 10 ⁇ M and 1/2 log dilution down to 1 nM for 3 hours at 37°C. DMSO treatment serves as control. p-ERK is then measured using Advanced Phospho-ERK 1/2 (Thr202/Tyr204) Assay Kit (Cisbio, Cat#64AERPET) following the manufacturer’s instruction. Briefly, medium is removed and 40 ⁇ l 1 ⁇ lysis buffer is added to each well, followed by 30 minutes incubation on a plate shaker at room temperature.
  • lysate is transferred to a white low volume 384-well plate.
  • Acceptor d2 antibody and Cryptate antibody are diluted (1: 20) with detection buffer and gently mixed (1: 1) according to manufacturer's instruction.
  • 2 ⁇ l antibodies mix is added to the cell lysate and the plate is wrapped with foil, shaken for 1-2 minutes on a plate reader, and incubated for >4 hours at room temperature. Signal is then measured on a plate reader. Percentage inhibition is calculated with DMSO treatment as 100%of signal, and IC50 is calculated by Graphpad Prism 7.
  • test compound The ability of the compound of Formula (I) or a pharmaceutically acceptable salt thereof (test compound) to inhibit K-Ras G12D activity can be tested in a cellular assay as described below.
  • LS180 cells (harbor KRAS G12D mutation) are seeded in 96-well plates and cultured overnight (20,000 cells per well, 200 ⁇ l total volume) . On the following morning, cells are treated with test compound, with starting concentration at 10 ⁇ M and 1/2 log dilution down to 1 nM for 3 hours at 37°C. DMSO treatment serves as control. p-ERK is then measured using Advanced Phospho-ERK 1/2 (Thr202/Tyr204) Assay Kit (Cisbio, Cat#64AERPET) following the manufacturer’s instruction. Briefly, medium is removed and 40 ⁇ l 1 ⁇ lysis buffer is added to each well, followed by 30 minutes incubation on a plate shaker at room temperature.
  • lysate is transferred to a white low volume 384-well plate.
  • Acceptor d2 antibody and Cryptate antibody are diluted (1: 20) with detection buffer and gently mixed (1: 1) according to manufacturer's instruction.
  • 2 ⁇ l antibodies mix is added to the cell lysate and the plate is wrapped with foil, shaken for 1-2 minutes on a plate reader, and incubated for >4 hours at room temperature. Signal is then measured on a plate reader. Percentage inhibition is calculated with DMSO treatment as 100%of signal, and IC50 is calculated by Graphpad Prism 7.
  • Compound of the disclosure e.g., compound 1 in 2%HPMC, 1%Tween 80 in DI water, pH 2.2 with MSA, q.s. to at least 20 mg/mL
  • a pharmaceutical composition for inhalation delivery 20 mg of a compound disclosed herein is mixed with 50 mg of anhydrous citric acid and 100 mL of 0.9%sodium chloride solution. The mixture is incorporated into an inhalation delivery unit, such as a nebulizer, which is suitable for inhalation administration.
  • an inhalation delivery unit such as a nebulizer
  • a pharmaceutical topical gel composition 100 mg of a compound disclosed herein is mixed with 1.75 g of hydroxypropyl cellulose, 10 mL of propylene glycol, 10 mL of isopropyl myristate and 100 mL of purified alcohol USP. The resulting gel mixture is then incorporated into containers, such as tubes, which are suitable for topical administration.
  • a pharmaceutical ophthalmic solution composition 100 mg of a compound disclosed herein is mixed with 0.9 g of NaCl in 100 mL of purified water and filtered using a 0.2 micron filter. The resulting isotonic solution is then incorporated into ophthalmic delivery units, such as eye drop containers, which are suitable for ophthalmic administration.
  • a pharmaceutical nasal spray solution 10 g of a compound disclosed herein is mixed with 30 mL of a 0.05M phosphate buffer solution (pH 4.4) .
  • the solution is placed in a nasal administrator designed to deliver 100 ul of spray for each application.

Abstract

The present disclosure provides certain quinazoline derivatives that inhibit certain K-Ras proteins and are therefore useful for the treatment of cancers mediated by such proteins. Also provided are pharmaceutical compositions containing such compounds and processes for preparing such compounds.

Description

EXOCYCLIC AMINO QUINAZOLINE DERIVATIVES AS KRAS INHIBITORS
Field of the disclosure
The present disclosure provides certain exocyclic amino quinazoline derivatives compounds that inhibit certain K-Ras proteins and are therefore useful for the treatment of cancers mediated by such proteins. Also provided are pharmaceutical compositions containing such compounds and processes for preparing such compounds.
Background
Kirsten Rat Sarcoma 2 Viral Oncogene Homolog (KRAS) gene is a prevalent oncogene that encodes a small GTPase transductor protein called K-Ras. K-Ras can serve as a molecular switch by cyling between active GTP-bound and inactive GDP-bound forms (see Science 2001; 294: 1299–304. ) . K-Ras signaling is activated by RAS guanine nucleotide exchange factors (GEFs) , e.g., Son of Sevenless homologue (SOS) protein, that facilitate the GDP to GTP exchange of K-Ras (see Curr Biol 2005; 15: 563–74. ) . The interaction between K-Ras and GTPase-activating proteins (GAPs) such as p120GAP and neurofibromin, potentiates K-Ras intrinsic GTPase activity and accelerates GTP hydrolysis and diminishing K-Ras signaling (see Curr. Biol. 2005; 15: 563–74. ) .
K-Ras plays a crucial role in the regulation of cell proliferation, differentiation and survival by signaling through several major downstream pathways, including the MAPK, the PI3K and the Ral-GEFs pathways (see Lung Cancer 2018; 124: 53–64) , among them the MAPK pathway is the best characterized (see Mol. Cell Biol. 1995; 15: 6443–6453. ) . K-Ras-GTP binds to and activates RAF kinases, which phosphorylates MEK and subsequently phosphorylates ERK. Phospho-ERK can further activate downstream cytosolic proteins and which then translocate to the nucleus to drive the expression of diverse genes, propagating the growth signal.
PI3K pathway is also involved in RAS-mediated tumorigenesis (see Cell 2007; 129: 957–968. ) . Upon activation by K-Ras-GTP, PI3K phosphorylates PIP2 to form PIP3, activates PDK1 and then phosphorylates AKT. pAKT yields phosphorylation of several physiological substrates, e.g., mTOR, FOXO and NF-κB that promote metabolism, cell-cycle progression, resistance to apoptosis, cell survival and migration. The Ral-GEFs signaling pathway plays a key role in RAS-mediated oncogenesis as well (see Proc. Natl. Acad. Sci. U.S.A. 1994; 91: 11089–11093. ) . The K-Ras effector, RALGDS, stimulates the RAS family RAL-A/B small GTPases for the subsequent signaling cascades. RALGDS can also promote the JNK pathway to stimulate transcription of pro-survival and cell-cycle progression genes for cell proliferation and survival.
KRAS gene is the most frequently mutated oncogene in human cancer. KRAS mutations are associated with poor clinical outcome and found at high frequency in pancreatic cancer (～90%) , colorectal cancer (～44%) and non-small-cell lung cancer (NSCLC) (～29%) (see Cancer Discov. 2021; 11: 1–16) . KRAS mutations are also present in breast cancer, liver cancer, biliary tract malignancies, endometrial cancer, cervical cancer, bladder cancer and myeloid leukemia. The most common KRAS mutations are observed at residues G12 (77%) , G13 (10%) , and Q61 (6%) , and the most predominant KRAS variant in human malignancies is G12D (35%) , followed by G12V (29%) , G12C (21%) , G12A (7%) , G12R (5%) , and G12S (3%) (see Cancer Discov. 2021; 11: 1-16) . These mutations perturbate GTP hydrolysis of K-Ras by interfering with GAP binding/stimulation and/or reducing K-Ras intrinsic GTPase activity, resulting in constitutive activation of the protein and K-Ras signaling.
Targeting KRAS signaling has been a long pursuit in drug discovery. Among KRAS mutants, K-Ras G12C offers special opportunity, because it harbors a non-native cysteine residue, which can act as nucleophile and therefore can be targeted by covelent attachment. Several such covelent inhibitors, including AMG510, MRTX849, JNJ-74699157 and LY349944631, are in clinical trials for treating cancer patients with KRAS G12C mutation (see ACS Cent. Sci. 2020; 6: 1753-1761) . These compounds ocuppy a dynamic pocket in the switch II region of K-Ras thereby irreversibly locking K-Ras G12C in inactive GDP-bound state. Since KRAS mutations, including G12C, enrich predominantly active-state protein in cancer cells, sufficient residual GTPase activity and nucleotide cycling are required for effective inhibition of K-Ras by inactive state-selective drugs (see Cell 2020; 183 (4) : 850-859) . Currently, there are no molecules in clinical trial that can inhibit K-Ras G12C by binding to its active GTP form or both GTP and GDP forms. Inhibitors of active form of K-Ras should be more effective at suppressing cell growth and survival, as well as less susceptible to adaptive resistance than inhibitors binding to its inactive form. Compared to K-ras G12C mutant, other prevalent K-Ras mutant, such as G12D, does not contain non-native cysteine residue and cycles through inactive state at extremely low rate, thus making non-G12C mutant-specific drug discovery challenging.
Given the role of K-Ras mutants in human malignancy, there is still unmet medical need for development of new treatments for cancer patients with KRAS mutations. The present disclosure fulfills this and related needs.
Summary
In a first aspect, provided is a compound of Formula (I) :
Figure PCTCN2021092773-appb-000001
wherein:
U, V, and W are CH; or one or two of U, V, and W are N and the other of U, V, and W are CH;
ring A is cycloaminyl, bicycloaminyl, bridged cycloaminyl, or spiroaminyl;
R 1a is hydroxy, -Q 1-NR 6R 7 (where Q 1 is bond, alkylene, -C (=O) -, R 6 is hydrogen or alkyl, and R 7 is hydrogen, alkyl, haloalkyl, cycloalkyl, alkylcarbonyl, alkylsulfonyl, alkoxycarbonyl, cyanaoalkyl, saturated heterocyclyl, or 5-or 6-membered heteroaryl ) , -NHC (=NH) (alkyl) , - NHC (=NH) NH 2, -NHC (=O) NR 8R 9 (where R 8 and R 9 are independently hydrogen or alkyl) , or -Q 2-R 10 (where Q 2 is bond, alkylene, -C (=O) -and R 10 is heterocyclyl, spiro heterocyclyl, bridged heterocyclyl, fused heterocyclyl or 5-or 6-membered heteroaryl wherein the heteroaryl contains a nitrogen atom and optionally contains one or two additional heteroatoms selected from N, O, or S; wherein the heterocyclyl, spiro heterocyclyl, bridged heterocyclyl, fused heterocyclyl and 5-or 6-membered heteroaryl ring are substituted with one or two substituents independently selected from hydrogen, alkyl, halo, cyano, or amino, provided that, when Q 2 is a bond and the heterocyclyl, spiro heterocyclyl, bridged heterocyclyl, and fused heterocyclyl of R 10 contains two nitrogen ring atoms, then at least one of the substituents is amino) ; provided that, when a second ring atom of ring A isis a nitrogen atom, then R 1a is not hydroxy;
R 1b is absent, alkyl, alkynyl, cycloalkyl, halo, haloalkyl, hydroxy, alkoxy, cyano, hydroxyalkyl, alkoxyalkyl, cyanoalkyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, or dialkylaminocarbonylalkyl,
R 1c is absent, alkyl, halo, hydroxy, or cyano;
R 2 is absent, deuterium, alkyl, alkenyl, alkynyl, halo, haloalkyl, alkoxy, hydroxy, or cyano, provided that, R 2 is absent when two of U, V, and W are N;
R 3 is absent, deuterium, alkyl, halo, haloalkyl, alkoxy, cycloalkyl, cycloalkyloxy, hydroxy, cyano, or monocyclic heterocyclyl optionally substituted with halo, alkoxy, hydroxy, or cyano;
R 4 is:
(i) -Z-R 11 where Z is a bond, O, NH, N (alkyl) , or S; and R 11 is hydrogen, alkyl, hydroxyalkyl, - (alkylene) -NR 12R 13 (where alkylene is substituted with R a, R b, and R c independently selected from hydrogen, alkyl, cycloalkyl, halo, haloalkyl, hydroxy, alkoxy, cyano, oxo, hydroxyalkyl, alkylamino, dialkylamino, dialkylaminocarbonylalkyl, aryl, heteroaryl, and  heterocyclyl, R 12 is hydrogen or alkyl, and R 13 is hydrogen, alkyl, acyl, hydroxyalkyl, or heteroalkyl) , aryl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, bicyclic heterocyclyl, bicyclic heterocyclylalkyl, phosphinyl bicyclic heterocyclyl, phosphinyl bicyclic heterocyclylalkyl, fused bicyclic heterocyclylalkyl, tricyclic heterocyclyl, tricyclic heterocyclylalkyl, fused tricyclic heterocyclyl, fused tricyclic heterocyclylalkyl, bridged heterocyclyl, bridged heterocyclylalkyl, fused heterocyclyl, fused heterocyclylalkyl, spiro heterocyclyl, or spiro heterocyclylalkyl, wherein aryl, heteroaryl, by itself or as part of heteroaralkyl, heterocyclyl, by itself or as part of heterocyclylalkyl, bicyclic heterocyclyl, by itself or as part of bicyclic heterocyclylalkyl, phosphinyl bicyclic heterocyclyl, by itself or as part of phosphinyl bicyclic heterocyclylalkyl, fused bicyclic heterocyclyl as part of fused bicyclic heterocyclylalkyl, tricyclic heterocyclyl, by itself or as part of tricyclic heterocyclylalkyl, fused tricyclic heterocyclyl, by itself or as part of fused tricyclic heterocyclylalkyl, bridged heterocyclyl, by itself or as part of bridged heterocyclylalkyl, fused heterocyclyl, by itself or as part of fused heterocyclylalkyl, and spiro heterocyclyl, by itself or as part of spiro heterocyclylalkyl, are substituted with R d, R e, and R f independently selected from hydrogen, alkyl, alkenyl, haloalkenyl, cycloalkyl, cycloalkyloxy, cycloalkylalkyl, bridged cycloalkyl, halo, haloalkyl, haloalkoxy, hydroxy, alkoxy, alkylidienyl, haloalkylidienyl, alkoxyalkylidienyl, alkoxyalkyl, alkoxyalkyloxy, alkylsulfonyl, alkylsulfonylalkyl, dialkyl (oxo) phosphinyl, dialkyl (oxo) phosphinylalkyl, acyl, cyano, oxo, hydroxyalkyl, alkylamino, dialkylamino, dialkylaminocarbonylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, and optionally substituted heterocyclyl; or
(ii) -CR 14=CR 15R 16 where R 14 and R 15 are independently selected from hydrogen, deuterium, alkyl, halo, and haloalkyl; and
R 16 is hydrogen, deuterium, alkyl, halo, haloalkyl, cycloalkyl, bridged cycloalkyl, fused cycloalkyl, spiro cycloalkyl, heterocyclyl, bicyclic heterocyclyl, phosphinyl bicyclic heterocyclyl, bridged heterocyclyl, fused heterocyclyl, or spiro heterocyclyl; or
R 15 and R 16 together with the carbon atom to which are attached form cycloalkyl, bridged cycloalkyl, fused cycloalkyl, spiro cycloalkyl, heterocyclyl, bridged heterocyclyl, fused heterocyclyl, or spiro heterocyclyl, wherein:
(a) the groups alkyl, cycloalkyl, bridged cycloalkyl, fused cycloalkyl, spiro cycloalkyl, heterocyclyl, bicyclic heterocyclyl, phosphinyl bicyclic heterocyclyl, bridged heterocyclyl, fused heterocyclyl, and spiro heterocyclyl of R 15; and (b) the groups cycloalkyl, bridged cycloalkyl, fused cycloalkyl, spiro cycloalkyl, heterocyclyl, bridged heterocyclyl, fused heterocyclyl, and spiro heterocyclyl formed by R 15 and R 16 together, are independently substituted with R h, R i, and R j independently selected from hydrogen, alkyl, halo, haloalkyl, hydroxyalkyl, alkylidienyl, alkoxyalkylidienyl, alkoxyalkyl, alkylsulfonylalkyl, dialkyl (oxo) phosphinyl, dialkyl (oxo) phosphinylalkyl, cyano, cycloalkyl, bridged cycloalkyl, optionally substituted  heterocyclyl, -O (alk)  z1R k, -O (alk) OR l, -S (O) R m, -S (O)  2R n, -NR pC (O) R o, -NR rSO 2R q, -OC (O) NR sR t, -C (O) NR uR v, -S (O)  2NR wR x, and -NR yR z, where z1 is 0 or 1, alk is alkylene, and R k, R l, R m, R n, R o, R p, R q, R r, R s, R t, R u, R v, R w, R x, R y, and R z are independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, halo, hydroxyalkyl, alkoxyalkyl, and aminoalkyl; and Q is bond, alkylene, or -C (=O) -; and
R 5 is cycloalkyl, fused cycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl, wherein aryl, aryl in aralkyl, heteroaryl, and heteroaryl in heteroaralkyl are independently substituted with R aa, R bb, R cc and R dd wherein R aa and R bb are independently selected from hydrogen, alkyl, cycloalkyl, halo, haloalkyl, haloalkoxy, hydroxy, alkoxy, heteroalkyl, hydroxyalkyl, alkylcarbonyl, amino, and cyano, R cc is hydrogen, alkenyl, alkynyl, cyanoalkynyl, or halo, and R dd is hydrogen, alkyl, cycloalkyl, halo, haloalkyl, haloalkoxy, alkoxy, heteroalkyl, hydroxyalkyl, amino, cyano, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; or
a pharmaceutically acceptable salt thereof.
In a second aspect, provided is a pharmaceutical composition comprising a compound of Formula ( (I) (or any of the embodiments thereof described herein) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
In a third aspect, provided is a method of inhibiting K-Ras, in particular K-Ras G12D, in a cell, comprising contacting the cell with a compound of Formula (I) (or any of the embodiments thereof described herein) . In one embodiment of the third aspect, the contacting is in vitro. In another embodiment of the third aspect, the contacting is in vivo.
In a fourth aspect, provided is a method of inhibiting cell proliferation in vitro or in vivo, comprising contacting a cell with a compound of Formula (I) (or any of the embodiments thereof described herein) or a pharmaceutical composition thereof as disclosed herein. In one embodiment of the fourth aspect, the contacting is in vitro. In another embodiment of the fourth aspect, the contacting is in vivo.
In a fifth aspect, provided is a method of treating cancer in a patient, preferably the patient is in need of such treatment, which method comprises administering to the patient, preferably a patient in need of such treatment, a therapeutically effective amount of a compound of Formula (I) (or any of the embodiments thereof described herein) or a pharmaceutically acceptable salt thereof or a a pharmaceutical composition thereof as disclosed herein.
In a sixth aspect, provided is a method of treating cancer associated with K-Ras, in particular K-Ras G12D, in a patient, preferably the patient is in need of such treatment, which method comprises administering to the patient, preferably a patient in need of such treatment, a therapeutically effective amount of a compound of Formula (I) (or any of the embodiments thereof  described herein) or a pharmaceutically acceptable salt thereof or a a pharmaceutical composition thereof as disclosed herein.
In a seventh aspect, provided is a compound of Formula (I) , (or any embodiments thereof described herein) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof as disclosed herein for use as a medicament. In one embodiment, the medicament is useful for the treatment of cancer.
In an eighth aspect, provided is a compound of Formula (I) , (or any embodiments thereof described herein) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof as disclosed herein for use in the treatment of cancer.
In a ninth aspect, provided is a compound of Formula (I) , (or any embodiments thereof described herein) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof as disclosed herein for use in the treatment of cancers associated with KRas, in particular cancers associated with K-Ras G12D.
In a tenth aspect, provided is a compound of Formula (I) , (or any embodiments thereof described herein) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof as disclosed herein for use in inhibiting K-Ras, in particular K-Ras G12D.
In any of the aforementioned aspects involving the treatment of cancer, are further embodiments comprising administering the compound of Formula (I) (or any embodiments thereof disclosed herein) , or a pharmaceutically acceptable salt thereof in combination with at least one additional anticancer agent. When combination therapy is used, the agents can be administered simultaneously or sequentially.
Detailed Description
Definitions:
Unless otherwise stated, the following terms used in the specification and claims are defined for the purposes of this Application and have the following meaning:
“Alkyl” means a linear saturated monovalent hydrocarbon radical of one to six carbon atoms or a branched saturated monovalent hydrocarbon radical of three to six carbon atoms, e.g., methyl, ethyl, propyl, 2-propyl, butyl, pentyl, and the like. It will be recognized by a person skilled in the art that the term “alkyl” may include “alkylene” groups.
“Alkylene” means a linear saturated divalent hydrocarbon radical of one to six carbon atoms or a branched saturated divalent hydrocarbon radical of three to six carbon atoms unless otherwise stated e.g., methylene, ethylene, propylene, 1-methylpropylene, 2-methylpropylene, butylene, pentylene, and the like.
“Alkenyl” means a linear monovalent hydrocarbon radical of two to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbon atoms containing a double bond e.g., ethenyl, propenyl, 2-propenyl, butenyl, pentenyl, and the like.
“Alkynyl” means a linear monovalent hydrocarbon radical of two to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbon atoms containing a triple bond e.g., ethynyl, propynyl, 2-propynyl, butynyl, and the like.
“Alkylsulfonyl” means a –SO 2R radical where R is alkyl as defined above, e.g., methylsulfonyl, ethylsulfonyl, and the like.
“Alkylamino” means a –NHR radical where R is alkyl as defined above, e.g., methylamino, ethylamino, and the like.
“Alkylaminocarbonyl” means a –CONHR radical where R is alkyl as defined above, e.g., methylaminocarbonyl, ethylaminocarbonyl, and the like.
“Alkylaminocarbonylalkyl” means a – (alkylene) -CONHR radical where R alkyl and alkyene and alkyl are as defined above, e.g., methylaminocarbonylmethyl, ethylaminocarbonylmethyl, and the like.
“Alkylsulfonyl” means a -SO 2R radical where R is alkyl as defined above, e.g., methylsulfonyl, ethylsulfonyl, and the like.
“Alkylsulfonylalkyl” means a – (alkylene) -SO 2R radical where R is alkyl as defined above, e.g., methylsulfonylmethyl, ethylsulfonylmethyl, and the like.
“Alkoxy” means a -OR radical where R is alkyl as defined above, e.g., methoxy, ethoxy, propoxy, or 2-propoxy, n-, iso-, or tert-butoxy, and the like.
“Alkoxyalkyl” means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted with at least one alkoxy group, such as one or two alkoxy groups, as defined above, e.g., 2-methoxyethyl, 1-, 2-, or 3-methoxypropyl, 2-ethoxyethyl, and the like.
“Alkoxyalkyloxy” means a -OR radical where R is alkoxyalkyl as defined above. Examples include, but are not limited to, 2-methoxyethyloxy, 1-, 2-, or 3-methoxypropyloxy, 2-ethoxyethyloxy, and the like.
“Alkylidienyl” means refers to a group of formula R= where R is alkyl as defined above. Examples include, but are not limited to, methylidienyl (H 2C=) , ethylidienyl (CH 3CH=) , hexylidienyl (CH 3 (CH 2)  4CH=) , and the like. For example, in the compound below:
Figure PCTCN2021092773-appb-000002
the alkylidene group, methylidienyl, is enclosed by the box which is indicated by the arrow.
“Alkoxyalkylidienyl” means refers to a group of formula =R where R is alkoxyalkyl as defined above. Examples include, but are not limited to, methoxethylidienyl (CH 3OCH 2CH=) , ethoxyethylidienyl (C 2H 5OCH 2CH=) , and the like. For example, in the compound below:
Figure PCTCN2021092773-appb-000003
the alkoxyalkyldienyl group, methoxethylidienyl, is enclosed by the box which is indicated by the arrow.
“Alkoxycarbonyl” means a –C (O) OR radical where R is alkyl as defined above, e.g., methoxycarbonyl, ethoxycarbonyl, and the like.
“Acyl” means a –C (O) R radical where R is alkyl, haloalkyl, cycloalkyl, optionally substituted phenyl, optionally substituted heteroaryl, or optionally substituted heterocyclyl, as defined herein, e.g., methylcarbonyl, ethylcarbonyl, benzoyl, trifluoromethylcarbonyl, cyclopropylcarbonyl, and the like. When R is alkyl, acyl is also referred to herein as alkylcarbonyl.
“Amino” means –NH 2 radical.
“Aminoalkyl” means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted with –NR’R” where R’ and R” are independently hydrogen, alkyl, cycloalkyl, cycloalkylalkyl (wherein cycloalkyl and cycloalkyl ring in cycloalkylalkyl is optionally substituted with one, two, or three substituents independently selected from alkyl, hydroxyalkyl, haloalkyl, halo, hydroxy, alkoxy, -NH 2, alkylamino, dialkylamino, and cyano) , hydroxyalkyl, alkoxyalkyl, alkylcarbonyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl, each as defined herein, e.g., aminomethyl, aminoethyl, methylaminomethyl, and the like.
“Aminocarbonyl” means –CONH 2 radical.
“Aminocarbonylalkyl” means a – (alkylene) -CONH 2 radical where alkyene is as defined above, e.g., aminocarbonylmethyl, aminocarbonylmethyl, and the like.
“Aryl” means a monovalent monocyclic or fused bicyclic aromatic hydrocarbon radical of 6 to 10 ring atoms e.g., phenyl or naphthyl.
“Aralkyl” means a – (alkylene) -R radical where R is aryl as defined above. Examples include, but are not limited to, benzyl, phenethyl, and the like.
“Bicycloaminyl” means a saturated monovalent fused bicyclic ring of 5 to 10 ring atoms in which one ring atom is nitrogen and an additional ring atom can be a heteroatom independently selected from N, O, and S (O)  n, where n is an integer from 0 to 2, the remaining ring atoms being C. Additionally, one or two ring carbon atoms of the bicycloaminyl group can optionally be replaced by a –CO-group. Representative examples include, but is not limited to, 3-azabicyclo [3.1.0] hexan-3-yl, 3-azabicyclo [4.1.0] heptan-3-yl, and the like.
“Bicyclic heterocyclyl” means a saturated monovalent fused bicyclic ring of 8 to 12 ring atoms in which one or two ring atoms are heteroatom independently selected from N, O, and S (O)  n, where n is an integer from 0 to 2, the remaining ring atoms being C, unless stated otherwise. Additionally, one or two ring carbon atoms in the heterocyclyl ring can optionally be replaced by a –CO-group. More specifically the term bicyclic heterocyclyl includes, but is not limited to, hexahydro-1H-pyrrolizinyl, and the like.
“Bicyclic heterocyclylalkyl” means a – (alkylene) -R radical where R is bicyclic heterocyclyl as defined above. Examples include, but are not limited to, hexahydro-1H-pyrrolizinylmethyl, hexahydro-1H-pyrrolizinylethyl, and the like.
“Bridged cycloalkyl” means a saturated monocyclic ring having 5 to 8 ring carbon ring atoms in which two non-adjacent ring atoms are linked by a (CRR’) n group where n is 1 to 3 and R and R’ are independently H or methyl (also may be referred to herein as “bridging” group) . Unless otherwise stated, bridged cycloalkyl is optionally substituted with one or two substituents independently selected from alkyl, halo, alkoxy, hydroxy, and cyano. Examples include, but are not limited to, bicyclo [1.1.1] pentyl, bicyclo [2.1.1] hexyl, bicyclo [2.2.2] -octyl, and the like.
“Bridged cycloaminyl” means a saturated monovalent monocyclic ring of 5 to 9 ring atoms in which one ring atom is nitrogen and in which two non-adjacent ring atoms are linked by a (CRR’) m1 group where m1 is 1 to 3 and R and R’ are independently H or methyl (also may be referred to herein as “bridging” group) and further wherein an additional ring atom of bridged cycloaminyl ring, including an atom in the bridging group, can be a heteroatom independently selected from N, O, and S (O)  n, where n is an integer from 0 to 2, the remaining ring atoms being C. Representative examples of bridged cycloaminyl includes, but is not limited to, 2-azabicyclo [2.2.1] heptan-2-yl, 3-azabicyclo [3.1.1] heptan-3-yl, 3-azabicyclo [3.2.1] octan-3-yl, and the like.
“Bridged heterocyclyl” means a saturated monocyclic ring having 5 to 9 ring carbon ring atoms in which two non-adjacent ring atoms are linked by a (CRR’) n1 group where n1 is 1 to 3 and R and R’ are independently H or methyl (also may be referred to herein as “bridging” group) and further wherein one or two ring carbon atoms, including an atom in the bridging group, is replaced by a heteroatom selected from N, O, and S (O) n, where n is an integer from 0 to 2. Bridged heterocyclyl is optionally substituted with one or two substituents independently selected from alkyl, halo, alkoxy, hydroxy, and cyano. Examples include, but are not limited to, 2-azabicyclo [2.2.2] octane, quinuclidine, 7-oxabicyclo [2.2.1] heptane, 1-azabicyclo [2.2.1] heptane, 2-azabicyclo [2.2.1] heptane, 3λ 2-azabicyclo [3.1.0] hexane, and the like.
“Bridged heterocyclylalkyl” means a – (alkylene) -R radical where R is bridged heterocyclyl as defined above. Examples include, but are not limited to, 2-azabicyclo [2.2.2] -octylmethyl, 3λ 2-azabicyclo [3.1.0] hexylethyl, and the like.
“Cycloalkyl” means a monocyclic saturated monovalent hydrocarbon radical of three to ten carbon atoms. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
“Cycloalkylene” means a monocyclic saturated divalent hydrocarbon radical of three to ten carbon atoms. Examples include, but are not limited to, 1, 1-cyclopropylene, 1, 1-cyclobutylene, 1, 1-cyclopentylene, and the like.
“Cycloalkylalkyl” means a – (alkylene) -R radical where R is cycloalkyl as defined above. Examples include, but are not limited to, cyclopropylmethyl cyclobutylethyl, cyclopentylmethyl, cyclohexylmethyl, and the like.
“Cycloalkyloxy” means a -OR radical where R is cycloalkyl as defined above. Examples include, but are not limited to, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like.
“Cyanoalkyl” means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted with cyano e.g., cyanomethyl, cyanoethyl, and the like.
“Cyanoalkynyl” means an alkynyl radical as defined above where one of the hydrogen atom in the alkynyl chain is replace by a cyano. Examples include, but are not limited to, -C≡C (CN) , - CH 2C≡C (CN) , and the like.
“Carboxy” means –COOH.
“Cycloaminyl” means a saturated monovalent monocyclic ring of 4 to 8 ring atoms in which one ring atom is nitrogen and an additional ring atom can be a heteroatom independently selected from N, O, and S (O)  n, where n is an integer from 0 to 2, the remaining ring atoms being C. Additionally, one or two ring carbon atoms of the cycloaminyl group can optionally be replaced by a –CO-group. More specifically the term cycloaminyl includes, but is not limited to, pyrrolidinyl, piperidinyl, homopiperidinyl, 2-oxopyrrolidinyl, 2-oxopiperidinyl, morpholinyl, piperazinyl, thiomorpholinyl, and the like. “Deuterium” mean refers to  2H or D.
“Dialkylamino” means a –NRR’ radical where R and R’ are independently alkyl as defined above, e.g., dimethylamino, methylethylamino, and the like.
“Dialkylaminocarbonyl” means a -CONR’R” radical where where R’ and R” are independently alkyl as defined herein, e.g., dimethylaminocarbonyl, ethylmethylaminocarbonyl, and the like.
“Dialkylaminocarbonylalkyl” means a – (alkylene) –CONR’R” radical where R’ and R” are independently alkyl as defined herein, e.g., dimethylaminocarbonylmethyl, dimethylaminocarbonylethyl, and the like.
“Dialkyl (oxo) phosphinyl” means a -P (=O) RR’ radical where R and R’ are independently alkyl as defined above, e.g., dimethyl (oxo) phosphinyl, diethyl (oxo) phosphinyl, and the like.
“Dialkyl (oxo) phosphinylalkyl” means a – (alkylene) -P (=O) RR’ radical where R and R’ are independently alkyl as defined above radical where R is alkyl as defined above, e.g., dimethyl (oxo) phosphinylmethyl, diethyl (oxo) phosphinylethyl, and the like.
“Fused bicyclic heterocyclyl” means an 8 to 10 membered bicyclic heterocyclyl as defined herein, where two adjacent ring atoms of the bicyclic heterocyclyl are fused to two adjacent ring members of phenyl or a five or six membered heteroaryl, each as defined herein, unless stated otherwise. More specifically the term bicyclic heterocyclyl includes, but is not limited to, 2, 3-dihydro-1H-pyrrolo [2, 1-a] isoindol-9b (5H) -yl, 2, 3-dihydro-1H-pyrrolo [1, 2-a] indol-9a (9H) -yl, 1, 5, 6, 8-tetrahydropyrrolo [3, 2-a] pyrrolizin-3b (4H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl, and the like.
“Fused bicyclic heterocyclylalkyl” means a – (alkylene) -R radical where R is fused bicyclic heterocyclyl as defined above. Examples include, but are not limited to, hexahydro-1H-pyrrolizinylmethyl, hexahydro-1H-pyrrolizinylethyl, 2, 3-dihydro-1H-pyrrolo [2, 1-a] isoindol- 9b (5H) -ylmethyl, 2, 3-dihydro-1H-pyrrolo [1, 2-a] indol-9a (9H) -ylmethyl, and the like.
“Fused cycloalkyl” as used herein, means cycloalkyl as defined above where two adjacent ring atoms of the cycloalkyl ring are fused to two adjacent ring members of phenyl or a five or six membered heteroaryl, each as defined herein, unless stated otherwise. The fused heterocyclyl can be attached at any atom of the ring. Non limiting examples of the fused cycloalkyl include bicyclo [4.1.0] hepta-1, 3, 5-triene, bicyclo [4.2.0] octa-1, 3, 5-triene, and the like.
“Fused heterocyclyl” as used herein, means a saturated a heterocyclyl as defined herein where two adjacent ring atoms of the heterocyclyl ring are fused to two adjacent ring members of a cycloalkyl, phenyl or a five or six membered heteroaryl, each as defined herein, unless stated otherwise. The nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom (s) are optionally quaternized and one or two carbon atoms of the fused ring atoms in the saturated monocyclic ring includes the two common ring vertices shared with the fused phenyl or five or six membered heteroaryl. The fused heterocyclyl can be attached at any atom of the ring. Non limiting examples of the fused heterocycloalkyl include 2, 3-dihydrobenzo [b] [1, 4] -dioxinyl, 2-oxabicyclo [3.1.0] hexanyl, indolin-2-one-1-yl, indolinyl, and the like.
“Fused heterocyclylalkyl” as used herein, means a – (alkylene) -R radical where R is fused heterocyclyl, as defined herein.
“Fused tricyclic heterocyclyl” means a saturated monovalent fused tricyclic ring of 9 to 16 ring atoms, preferably 10 to 14 ring atoms, in which one or two ring atoms are heteroatoms independently selected from N, O, and S (O)  n, where n is an integer from 0 to 2, the remaining ring atoms being C, unless stated otherwise, and where two adjacent ring atoms of the tricyclic heterocyclyl (preferably two adjacent ring atoms of a ring other than the central ring of the tricyclic heterocyclyl) are fused to two adjacent ring members of cycloalkyl, phenyl or a five or six  membered heteroaryl, each as defined herein, unless stated otherwise. The term bicyclic heterocyclyl includes, but is not limited to,
Figure PCTCN2021092773-appb-000004
and the like.
“Fused tricyclic heterocyclylalkyl” means a – (alkylene) -R radical where R is fused tricyclic heterocyclyl as defined above. Examples include, but are not limited to,
Figure PCTCN2021092773-appb-000005
and the like.
“Halo” means fluoro, chloro, bromo, or iodo, preferably fluoro or chloro.
“Haloalkyl” means alkyl radical as defined above, which is substituted with one or more halogen atoms, e.g., one to five halogen atoms, such as fluorine or chlorine, including those substituted with different halogens, e.g., -CH 2Cl, -CF 3, -CHF 2, -CH 2CF 3, -CF 2CF 3,
-CF (CH 3)  2, and the like. When the alkyl is substituted with only fluoro, it can be referred to in this Application as fluoroalkyl.
“Haloalkenyl” means alkenyl radical as defined above, which is substituted with one or more halogen atoms, e.g., one to five halogen atoms, such as fluorine or chlorine, including those substituted with different halogens, e.g., -CH=CHF, -CH=CF 2, and the like. When the alkenyl is substituted with only fluoro, it can be referred to in this Application as fluoroalkenyl.
“Haloalkylidienyl” means refers to a group of formula =R where R is haloalkyl as defined above. Examples include, but are not limited to, difluoromethyldienyl (=CF 2) , fluoroethylidienyl (=CHCHF 2) , and the like. For example, in the compound below:
Figure PCTCN2021092773-appb-000006
the group pointed to by the arrow is the haloalkenylidine group, difluoromethyldienyl.
“Haloalkoxy” means a –OR radical where R is haloalkyl as defined above e.g., -OCF 3,
-OCHF 2, and the like. When R is haloalkyl where the alkyl is substituted with only fluoro, it is referred to in this Application as fluoroalkoxy.
“Hydroxyalkyl” means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted with one or two hydroxy groups, provided that if two hydroxy groups are present they are not both on the same carbon atom. Representative examples include, but are not limited to, hydroxymethyl, 2-hydroxy-ethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1- (hydroxymethyl) -2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2, 3-dihydroxypropyl, 1- (hydroxymethyl) -2-hydroxyethyl, 2, 3-dihydroxybutyl, 3, 4-dihydroxybutyl and 2- (hydroxymethyl) -3-hydroxypropyl, preferably 2-hydroxyethyl, 2, 3-dihydroxypropyl, and 1- (hydroxymethyl) -2-hydroxyethyl.
“Heteroalkyl” mean alkyl radical as defined above wherein one or two carbon atoms are replaced by O, NR (R is H or alkyl) , or S, provided the heteroalkyl group is attached to the remainder of the molecule via a carbon atom, e.g., methoxymethyl, methylethylaminoethyl, and the like.
“Heteroaryl” means a monovalent monocyclic or fused bicyclic aromatic radical of 5 to 10 ring atoms, unless otherwise stated, where one or more, (in one embodiment, one, two, or three) , ring atoms are heteroatom selected from N, O, and S, the remaining ring atoms being carbon. Representative examples include, but are not limited to, pyrrolyl, thienyl, thiazolyl, imidazolyl, furanyl, indolyl, isoindolyl, oxazolyl, isoxazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, tetrazolyl, and the like. As defined herein, the terms “heteroaryl” and “aryl” are mutually exclusive. When the heteroaryl ring contains 5-or 6 ring atoms it is also referred to herein as 5-or 6-membered heteroaryl.
“Heteroaralkyl” means a - (alkylene) -R radical where R is heteroaryl as defined above, e.g., pyridinylmethyl, and the like. When the heteroaryl ring in heteroaralkyl contains 5-or 6 ring atoms it is also referred to herein as 5-or 6-membered heteroaralkyl.
“Heterocyclyl” means a saturated or unsaturated monovalent monocyclic group of 4 to 8 ring atoms in which one or two ring atoms are heteroatom independently selected from N, O, and S (O)  n, where n is an integer from 0 to 2, the remaining ring atoms being C, unless stated otherwise. Additionally, one or two ring carbon atoms in the heterocyclyl ring can optionally be replaced by a –CO-group. More specifically the term heterocyclyl includes, but is not limited to, pyrrolidinyl, piperidinyl, homopiperidinyl, 2-oxopyrrolidinyl, 2-oxopiperidinyl, morpholinyl, piperazinyl, tetrahydro-pyranyl, thiomorpholinyl, and the like. When the heterocyclyl ring is unsaturated it can contain one or two ring double bonds provided that the ring is not aromatic. _When the heterocyclyl ring is saturated, it is referred to herein as saturated heterocyclyl.
“Heterocyclylalkyl” or “heterocycloalkyl” means a – (alkylene) -R radical where R is heterocyclyl ring as defined above e.g., tetraydrofuranylmethyl, piperazinylmethyl, morpholinylethyl, and the like.
“Oxo, ” as used herein, alone or in combination, refers to = (O) .
“Optionally substituted aryl” means aryl as defined above, that is optionally substituted with one, two, or three substituents independently selected from alkyl, hydroxyl, cycloalkyl, carboxy, alkoxycarbonyl, hydroxy, alkoxy, alkylsulfonyl, amino, alkylamino, dialkylamino, halo, haloalkyl, haloalkoxy, and cyano. When aryl is phenyl, optionally substituted aryl is referred to herein as optionally substituted phenyl.
“Optionally substituted aralkyl” means – (alkylene) -R where R is optionally substituted aryl as defined above.
“Optionally substituted heteroaryl” means heteroaryl as defined above that is optionally substituted with one, two, or three substituents independently selected from alkyl, alkylsulfonyl, hydroxyl, cycloalkyl, carboxy, alkoxycarbonyl, hydroxy, alkoxy, halo, haloalkyl, haloalkoxy, amino, alkylamino, dialkylamino, and cyano.
“Optionally substituted heteroaralkyl” means – (alkylene) -R where R is optionally substituted heteroaryl as defined above.
“Optionally substituted heterocyclyl” means heterocyclyl as defined above that is optionally substituted with one, two, or three substituents independently selected from alkyl, alkylsulfonyl, alkylcarbonyl, hydroxyl, cycloalkyl, cycloalkylalkyl, carboxy, alkoxycarbonyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, aminoalkyl, cyanoalkyl, halo, haloalkyl, haloalkoxy, and cyano, unless stated otherwise.
“Optionally substituted heterocyclylalkyl” means – (alkylene) -R where R is optionally substituted heterocyclyl as defined above.
“Phosphinyl bicyclic heterocyclyl” means a saturated monovalent fused bicyclic ring of 8 to 12 ring atoms in which one ring atom is phosphorus atom which is substituted with = (O) R (where R is alkyl as defined herein) and one additional ring atom can be a heteroatom selected from N, O, and S (O)  n, where n is an integer selected from 0 to 2, the remaining ring atoms being C, unless stated otherwise. Additionally, one or two ring carbon atoms in the heterocyclyl ring can optionally be replaced by a –CO-group. More specifically the term phosphinyl bicyclic heterocyclyl includes, but is not limited to, 
Figure PCTCN2021092773-appb-000007
and the like.
“Phosphinyl bicyclic heterocyclylalkyl” means an – (alkylene) -R radical where R is phosphinyl bicyclic heterocyclyl as defined above. Examples include, but are not limited to, 
Figure PCTCN2021092773-appb-000008
and the like.
“Tricyclic heterocyclyl” means a saturated monovalent fused tricyclic ring of 9 to 14, preferably 12 to 14, ring atoms in which one, two, or three ring atoms are heteroatom independently selected from N, O, and S (O)  n, where n is an integer from 0 to 2, the remaining ring atoms being C, unless stated otherwise. Additionally, one or two ring carbon atoms in the heterocyclyl ring can optionally be replaced by a –CO-group. The term bicyclic heterocyclyl includes, but is not limited to,
Figure PCTCN2021092773-appb-000009
and the like.
“Tricyclic heterocyclylalkyl” means a – (alkylene) -R radical where R is tricyclic heterocyclyl as defined above. Examples include, but are not limited to,
Figure PCTCN2021092773-appb-000010
and the like.
The present disclosure also includes protected derivatives of compounds of Formula (I) . For example, when compounds of Formula (I) contain groups such as hydroxy, carboxy, or any group containing a nitrogen atom (s) , these groups can be protected with suitable protecting groups. A comprehensive list of suitable protective groups can be found in T. W. Greene, Protective Groups in Organic Synthesis, 5 th Ed., John Wiley &Sons, Inc. (2014) , the disclosure of which is incorporated herein by reference in its entirety. The protected derivatives of compounds of the present disclosure can be prepared by methods well known in the art.
The present disclosure also includes polymorphic forms and deuterated forms of the compound of Formula (I) or a pharmaceutically acceptable salt thereof.
The term “prodrug” refers to a compound that is made more active in vivo. Certain compounds Formula (I) may also exist as prodrugs, as described in Hydrolysis in Drug and Prodrug Metabolism: Chemistry, Biochemistry, and Enzymology (Testa, Bernard and Mayer, Joachim M. Wiley-VHCA, Zurich, Switzerland 2003) . Prodrugs of the compounds described herein are structurally modified forms of the compound that readily undergo chemical changes under physiological conditions to provide the active compound. Prodrugs are often useful because, in some situations, they may be easier to administer than the compound, or parent drug. They may, for instance, be bioavailable by oral administration whereas the parent drug is not. A wide variety of  prodrug derivatives are known in the art, such as those that rely on hydrolytic cleavage or oxidative activation of the prodrug. An example, without limitation, of a prodrug would be a compound which is administered as an ester (the “prodrug” ) , but then is metabolically hydrolyzed to the carboxylic acid, the active entity. Additional examples include peptidyl derivatives of a compound.
A “pharmaceutically acceptable salt” of a compound means a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. Such salts include:
acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as formic acid, acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3- (4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1, 2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic 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, muconic acid, and the like; or
salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like. It is understood that the pharmaceutically acceptable salts are non-toxic. Additional information on suitable pharmaceutically acceptable salts can be found in Remington’s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, PA, 1985, which is incorporated herein by reference in its entirety.
The compounds of Formula (I) may have asymmetric centers. Compounds of Formula (I) containing an asymmetrically substituted atom may be isolated in optically active or racemic forms. Individual stereoisomers of compounds can be prepared synthetically from commercially available starting materials which contain chiral centers or by preparation of mixtures of enantiomeric products followed by separation such as conversion to a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques, direct separation of enantiomers on chiral chromatographic columns, or any other appropriate method known in the art. All chiral, diastereomeric, all mixtures of chiral or diastereomeric forms, and racemic forms are within the scope of this disclosure, unless the specific stereochemistry or isomeric form is specifically indicated. It will also be understood by a person of ordinary skill in the art that when a compound is  denoted as (R) stereoisomer, it may contain the corresponding (S) stereoisomer as an impurity and vice versa.
Certain compounds of Formula (I) can exist as tautomers and/or geometric isomers. All possible tautomers and cis and trans isomers, as individual forms and mixtures thereof are within the scope of this disclosure. Additionally, as used herein the term alkyl includes all the possible isomeric forms of said alkyl group albeit only a few examples are set forth. Furthermore, when the cyclic groups such as aryl is substituted, it includes all the positional isomers albeit only a few examples are set forth. Furthermore, all hydrates of a compound of Formula (I) are within the scope of this disclosure.
The compounds of Formula (I) may also contain unnatural amounts of isotopes at one or more of the atoms that constitute such compounds. Unnatural amounts of an isotope may be defined as ranging from the amount found in nature to an amount 100%of the atom in question. that differ only in the presence of one or more isotopically enriched atoms. Exemplary isotopes that can be incorporated into compounds of the present invention, such as a compound of Formula (I) (and any embodiment thereof disclosed herein including specific compounds) include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as  2H,  3H,  11C,  13C,  14C,  13N,  15N,  15O,  17O,  18O,  32P,  33P,  35S,  18F,  36Cl,  123I, and  1251, respectively. Isotopically labeled compounds (e.g., those labeled with  3H and  14C) can be useful in compound or substrate tissue distribution assays. Tritiated (i.e.,  3H) and carbon-14 (i.e.,  14C) isotopes can be useful for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e.,  2H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) . In some embodiments, in compounds of Formula (IA’) , (I’) , (I) , (IIA’) , (II’) , or (II) , including in Tables 1 and 2 below one or more hydrogen atoms are replaced by  2H or  3H, or one or more carbon atoms are replaced by  13C-or  14C-enriched carbon. Positron emitting isotopes such as  15O,  13N,  11C, and  15F are useful for positron emission tomography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds can generally be prepared by following procedures analogous to those disclosed in the Schemes or in the Examples herein, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
A “pharmaceutically acceptable carrier or excipient” means a carrier or an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes a carrier or an excipient that is acceptable for veterinary use as well as human pharmaceutical use.
“A pharmaceutically acceptable carrier/excipient” as used in the specification and claims includes both one and more than one such excipient.
“Spiro cycloalkyl" means a saturated bicyclic monovalent ring having 6 to 10 ring atoms in which the rings are connected through only one atom, the connecting atom is also called the spiroatom, most often a quaternary carbon ( "spiro carbon" ) . Unless stated otherwise, spiro cycloalkyl is optionally substituted with one or two substituents independently selected from alkyl, halo, alkoxy, hydroxy, and cyano. Examples include, but are not limited to, Representative examples include, but are not limited to, spiro [3.3] heptan-2-yl, spiro [3.4] octan-6-yl, spiro [3.5] -nonan-7-yl, and the like.
“Spiroaminyl” means a saturated monovalent bicyclic ring of 6 to 12 ring atoms in which one ring atom is nitrogen and an additional ring atom can be a heteroatom independently selected from N, O, and S (O)  n, where n is an integer from 0 to 2, the remaining ring atoms being C, and further wherein the two rings are connected through only one atom, the connecting atom is also called the spiroatom, most often a quaternary carbon ( "spiro carbon" ) . Representative examples of spiro cycloaminyl include, 2-azaspiro [3.3] heptan-2-yl, 5-azaspiro [2.4] heptan-5-yl, 3-azaspiro [5.5] undecan-3-yl, 8-azaspiro [4.5] decan-8-yl, 6-azaspiro [3.4] octan-6-yl, 2-azaspiro [4.4] nonan-2-yl, but is not limited to, and the like.
“Spiro heterocyclyl" means a saturated bicyclic monovalent ring having 5 to 10 ring atoms in which one, two, or three ring atoms are heteroatom selected from N, O, and S (O) n, where n is an integer from 0 to 2, the remaining ring atoms being C and the rings are connected through only one atom, the connecting atom is also called the spiroatom, most often a quaternary carbon ( "spiro carbon" ) . Unless stated otherwise, spiroheterocyclyl is optionally substituted with one or two substituents independently selected from alkyl, halo, alkoxy, hydroxy, and cyano. Examples include, but are not limited to, Representative examples include, but are not limited to, 2, 6-diazaspiro [3.3] hept-2-yl, 2, 6-diazaspiro [3.4] oct-6-yl, 2-azaspiro [3.4] oct-2-yl, 2-azaspiro [3.5] -non2-yl, 2, 7-diazaspiro [4.4] non-2-yl, and the like.
“Spiro heterocyclylalkyl” means a – (alkylene) -R radical where R is spiro heterocyclyl ring as defined above e.g., t2-azaspiro [3.4] octylmethyl, 2, 6-diazaspiro [3.3] hept-2-ylmethyl, 2, 6-diazaspiro [3.4] oct-2-ylethyl, 2, 6-diazaspiro [3.4] oct-6-ylethyl, and the like.
The term “about, ” as used herein, is intended to qualify the numerical values which it modifies, denoting such a value as variable within a margin of error. When no particular margin of error, such as a standard deviation to a mean value given in a chart or table of data, is recited, the term “about” should be understood to mean that range which would encompass ± 10%, preferably ± 5%, the recited value and the range is included.
The phrase optionally substituted aryl in the definition of R dd in Formula (I) (and similar phrases used to define other groups in Formula (I) is intended to cover aryl that is unsubstituted and aryl that is substituted with substituents denoted in the definition thereof in this Application.
Certain structures provided herein are drawn with one or more floating substituents. Unless provided otherwise or otherwise clear from the context, the substituent (s) may be present on any atom of the ring through which they are drawn, where chemically feasible and valency rules permitting. For example, in the structure of Formula (I) :
Figure PCTCN2021092773-appb-000011
R 2 and R 3 groups are floating substituents and can replace the hydrogen atom of any one of U, V, and W of the
Figure PCTCN2021092773-appb-000012
portion of the quinazoline ring ring when U, V, and W are CH.
The term “disease” as used herein is intended to be generally synonymous, and is used interchangeably with, the terms “disorder, ” “syndrome, ” and “condition” (as in medical condition) , in that all reflect an abnormal condition of the human or animal body or of one of its parts that impairs normal functioning, is typically manifested by distinguishing signs and symptoms, and causes the human or animal to have a reduced duration or quality of life.
The term “combination therapy” means the administration of two or more therapeutic agents to treat a disease or disorder described in the present disclosure. Such administration encompasses co-administration of these therapeutic agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of active ingredients or in multiple, separate capsules for each active ingredient. In addition, such administration also encompasses use of each type of therapeutic agent in a sequential manner. In either case, the treatment regimen will provide beneficial effects of the drug combination in treating the conditions or disorders described herein.
The term “patient” is generally synonymous with the term “subject” and includes all mammals including humans. Examples of patients include humans, livestock such as cows, goats, sheep, pigs, and rabbits, and companion animals such as dogs, cats, rabbits, and horses. Preferably, the patient is a human.
“Treating” or “treatment” of a disease includes:
(1) preventing the disease, i.e. causing the clinical symptoms of the disease not to develop in a mammal that may be exposed to or predisposed to the disease but does not yet experience or display symptoms of the disease;
(2) inhibiting the disease, i.e., delaying, arresting or reducing the development or severity of the disease or its clinical symptoms; or
(3) relieving the disease, i.e., causing regression of the disease or its clinical symptoms.
In one embodiment, treating or treatment of a disease includes inhibiting the disease, i.e., delaying, arresting or reducing the development or severity of the disease or its clinical symptoms; or relieving the disease, i.e., causing regression of the disease or its clinical symptoms.
A “therapeutically effective amount” means the amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof that, when administered to a patient for treating a disease, is sufficient to affect such treatment for the disease. The “therapeutically effective amount” will vary depending on the compound, the disease and its severity and the age, weight, etc., of the mammal to be treated. The therapeutically effective amount of a K-ras inhibitor disclosed herein can be administered to the patient in a single dosage form or multiples thereof. For example, 600 mg dose of a K-ras inhibitor can be administered in a single 600 mg tablet or two 300 mg tablets.
The terms "inhibiting" and "reducing, " or any variation of these terms in relation of K-Ras G12D, includes any measurable decrease or complete inhibition to achieve a desired result. For example, there may be a decrease of about, at most about, or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or more, or any range derivable therein, reduction of K-Ras G12D GTPase activity; a decrease of K-Ras G12D GTP binding affinity or an increase of G12D GDP binding affinity; an increase of GTP off rate or a decrease of GDP off rate; a decrease of signaling transduction molecules levels downstream in the K-Ras pathway, e.g., a decrease in pERK level; and/or a decrease of K-Ras complex binding to downstream signaling molecules compared to normal.
Compounds of Formula (I) are provided in Compound Table 1 below:
Compound Table 1
Figure PCTCN2021092773-appb-000013
Figure PCTCN2021092773-appb-000014
Figure PCTCN2021092773-appb-000015
Figure PCTCN2021092773-appb-000016
Figure PCTCN2021092773-appb-000017
Contemplated compounds Formula (I) are provided in Compound Table 2 below:
Compound Table 2
Figure PCTCN2021092773-appb-000018
Figure PCTCN2021092773-appb-000019
Figure PCTCN2021092773-appb-000020
Figure PCTCN2021092773-appb-000021
Figure PCTCN2021092773-appb-000022
Figure PCTCN2021092773-appb-000023
Embodiments:
In further embodiments 1-80 below, the present disclosure includes:
1. In embodiment 1, provided is a compound of Formula (I) as defined in the first aspect of the Summary, or a pharmaceutically acceptable salt thereof.
2. In embodiment 2, the compound of embodiment 1, or a pharmaceutically acceptable salt thereof, is wherein ring A is cycloaminyl.
3. In embodiment 3, the compound of embodiment 1, or a pharmaceutically acceptable salt thereof, is wherein ring A is bridged cycloaminyl.
4. In embodiment 4, the compound of embodiment 1, or a pharmaceutically acceptable salt thereof, is wherein ring A is spiroaminyl.
5. In embodiment 5, the compound of embodiment 1, or a pharmaceutically acceptable salt thereof, is wherein ring A is bicycloaminyl.
6. In embodiment 6, the compound of embodiment 1, or a pharmaceutically acceptable salt thereof, is wherein cycloaminyl is a ring of formula (a) : 
Figure PCTCN2021092773-appb-000024
where X is CH, NH, O, or S, m is 0 to 3, and n is 0 to 2, provided m+n is not greater than 4.
7. In embodiment 7, the compound of embodiment 2, or a pharmaceutically acceptable salt thereof, is wherein ring A is cycloaminyl according to formula (a) : 
Figure PCTCN2021092773-appb-000025
where X is CH, O, or S, m is 0 to 2, and n is 0 to 3, provided that m+n is not greater than 4.
8. In embodiment 8, the compound of embodiment 6 or 7, or a pharmaceutically acceptable salt thereof, is wherein cycloaminyl is a ring of formula (a1) : 
Figure PCTCN2021092773-appb-000026
8a. In embodiment 8, the compound of embodiment 6, 7, or 8, or a pharmaceutically acceptable salt thereof, is wherein cycloaminyl is a ring of formula:
Figure PCTCN2021092773-appb-000027
9. In embodiment 9, the compound of embodiment 6 or 7, or a pharmaceutically acceptable salt thereof, is wherein cycloaminyl is a ring of formula (a2) : 
Figure PCTCN2021092773-appb-000028
10. In embodiment 10, the compound of embodiment 6 or 7, or a pharmaceutically acceptable salt thereof, is wherein X is O or S, preferably O.
11. In embodiment 11, the compound of any one of embodiments 6 to 8, 9, and 10, or a pharmaceutically acceptable salt thereof, is where m is 0 and n are each 0.
12. In embodiment 12, the compound of any one of embodiments 6 to 8, 9, and 10, or a pharmaceutically acceptable salt thereof, is where m is 0 and n is 1.
13. In embodiment 13, the compound of any one of embodiments 6 to 8, 9, and 10, or a pharmaceutically acceptable salt thereof, is where m is 0 and n is 2.
14. In embodiment 14, the compound of any one of embodiments 6 to 8, 9, and 10, or a pharmaceutically acceptable salt thereof, is where m is 1 and n is 1.
15. In embodiment 15, the compound of any one of embodiments 6 to 8, 9, and 10, or a pharmaceutically acceptable salt thereof, is where m is 1 and n is 2.
16. In embodiment 15, the compound of any one of embodiments 6 to 8, 9, and 10, or a pharmaceutically acceptable salt thereof, is where m is 1 and n is 3.
16a. In embodiment 16a, the compound of embodiment 6, 7, or 16, or a pharmaceutically acceptable salt thereof, is wherein cycloaminyl is a ring of formula:
Figure PCTCN2021092773-appb-000029
17. In embodiment 17, the compound of embodiment 1, or a pharmaceutically acceptable salt thereof, is wherein bridged cycloaminyl is a ring of formula (b) : 
Figure PCTCN2021092773-appb-000030
where m1 is 1 or 2, n1 is 0 or 1, n2 is 1 or 2, X 1 is bond, CH, NH, O, or S
18. In embodiment 18, the compound of embodiment 3, or a pharmaceutically acceptable salt thereof, is wherein ring A is bridged cycloaminyl accordingly to formula (b) :
Figure PCTCN2021092773-appb-000031
where m1 is 1 or 2, n1 is 0 or 1, n2 is 1 or 2, X 1 is a CH, O, or S.
19. In embodiment 19, the compound of embodiment 17 or 18, or a pharmaceutically acceptable salt thereof, is wherein bridged cycloaminyl is a ring of formula (b1) : 
Figure PCTCN2021092773-appb-000032
20. In embodiment 20, the compound of embodiment 17, 18 or 19, or a pharmaceutically acceptable salt thereof, is wherein X 1 is CH.
21. In embodiment 21, the compound of embodiment 17, 18 or 19, or a pharmaceutically acceptable salt thereof, is wherein X 1 is NH, O, or S.
22. In embodiment 20, the compound of embodiment 17, 18 or 19, or a pharmaceutically acceptable salt thereof, is wherein X 1 is a NH or O.
23. In embodiment 23, the compound of embodiment 1, 3, 17, 18, 19, or 20, or a pharmaceutically acceptable salt thereof, is wherein bridged cycloaminyl is a ring of formula:
Figure PCTCN2021092773-appb-000033
24. In embodiment 24, the compound of embodiment 1, 3, 17, 18, 19, or 20, or a pharmaceutically acceptable salt thereof, is wherein bridged cycloaminyl is a ring of formula:
Figure PCTCN2021092773-appb-000034
25. In embodiment 25, the compound of embodiment 1 or 4, or a pharmaceutically acceptable salt thereof, is wherein the spiroaminyl is a ring of formula (c) :
Figure PCTCN2021092773-appb-000035
where X is CH, O, or NH and m2, n3, p, and q are each 0 to 3, provided that m2 + n3 + p + q is not greater than 7.
26. In embodiment 26, the compound of embodiment 25, or a pharmaceutically acceptable salt thereof, is wherein X 1 is CH.
27. In embodiment 27, the compound of embodiment 25, or a pharmaceutically acceptable salt thereof, is wherein X 1 is O.
28. In embodiment 28, the compound of embodiment 1, 4, 25, or 26, or a pharmaceutically acceptable salt thereof, is wherein spiroaminyl is a ring of formula:
Figure PCTCN2021092773-appb-000036
where each of the spiroaminyl is substituted with R 1a, R 1b, and R 1c.
29. In embodiment 29, the compound of embodiment 1, 4, 25, or 26, or a pharmaceutically acceptable salt thereof, is wherein the spiroaminyl is a ring of formula:
Figure PCTCN2021092773-appb-000037
and each of the spiroaminyl is additionally substituted with R 1b and R 1c, preferably R 1b.
30. In embodiment 30, the compound of embodiment 1 or 5, or a pharmaceutically acceptable salt thereof, is wherein the bicycloaminyl is a ring of formula (d) :
Figure PCTCN2021092773-appb-000038
where X 2 is CH, O, S, or NH and m3, n4, p1, and q2 are each 0 to 3, provided that m2 + n3 +p + q is not greater than 6 and the bicyclaminyl is substituted with R 1a, R 1b, and R 1c.
31. In embodiment 31, the compound of embodiment 25, or a pharmaceutically acceptable salt thereof, is wherein X 2 is CH.
32. In embodiment 32, the compound of embodiment 25, or a pharmaceutically acceptable salt thereof, is wherein X 2 is O.
33. In embodiment 33, the compound of embodiment 1, 5, 30, or 31, or a pharmaceutically acceptable salt thereof, is wherein the bicycloaminyl is a ring of formula:
Figure PCTCN2021092773-appb-000039
33a. In embodiment 33a, the compound of embodiment 1, 5, 30, or 31, or a pharmaceutically acceptable salt thereof, is wherein the bicycloaminyl is a ring of formula:
Figure PCTCN2021092773-appb-000040
34. In embodiment 34, the compound of any one of embodiments 1 to 33a, or a pharmaceutically acceptable salt thereof, is wherein R 1a is hydroxy.
35. In embodiment 35, the compound of any one of embodiments 1 to 33a, or a pharmaceutically acceptable salt thereof, is wherein R 1a is -Q 1-NR 6R 7.
36. In embodiment 36, the compound of any one of embodiments 1 to 33a and 35, or a pharmaceutically acceptable salt thereof, is wherein R 1a is amino, aminomethyl, aminoethyl, methylamino, ethylamino, cyclopropylamino, aminocarbonyl, methoxycarbonylamino, cyanomethylamino, 2, 2, 2-trifluoroethylamino, acetylamino, methylsulfonylamino, piperidin-4-ylamino, tetrahydropyran-4-ylamino, oxetan-3-ylamino, imidazol-2-ylamino, or oxazol-2-ylamino.
37. In embodiment 37, the compound of any one of embodiments 1 to 33a and 35, or a pharmaceutically acceptable salt thereof, is wherein R 1a is amino.
38. In embodiment 38, the compound of any one of embodiments 1 to 33a and 35, or a pharmaceutically acceptable salt thereof, is wherein R 1a is aminomethyl, methylamino, ethylamino, or cyclopropylamino, preferably aminomethyl.
39. In embodiment 39, the compound of any one of embodiments 1 to 33a, or a pharmaceutically acceptable salt thereof, is wherein R 1a is -NHC (=NH) (alkyl) , -NHC (=NH) NH 2, or -NHC (=O) NR 8R 9.
40. In embodiment 40, the compound of any one of embodiments 1 to 33a and 39, or a pharmaceutically acceptable salt thereof, is wherein R 1a is -NHC (=NH) CH 3, -NHC (=NH) NH 2, or NHC (=O) N (CH 3)  2.
41. In embodiment 41, the compound of any one of embodiments 1 to 33a, or a pharmaceutically acceptable salt thereof, is wherein R 1a is -Q 2-R 10.
42. In embodiment 42, the compound of any one of embodiments 1 to 33a and 41, or a pharmaceutically acceptable salt thereof, is wherein R 1a is azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-carbonyl, 2-methylimidazol-1-yl, 2-methyl-4, 5-dihydroimidazol-1-yl, morpholin-4-yl, 2-aminoimidazol-1-yl, 2-amino-4, 5-dihydroimidazol-1-yl, imidazol-2-yl, imidazole-1-yl, or 4, 5-dihydroimidazol-1-yl.
43. In embodiment 43, the compound of any one of embodiments 1 to 42, or a pharmaceutically acceptable salt thereof, is wherein R 1c is absent, hydroxy, cyano, or fluoro, preferably absent.
44. In embodiment 44, the compound of any one of embodiments 1 to 43, or a pharmaceutically acceptable salt thereof, is wherein R 1b is absent, cyano, fluoro, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, fluoromethyl, cyclopropyl, hydroxy, methoxy, hydroxymethyl, methoxymethyl, cyanomethyl, dimethylcarbonyl, or dimethylcarbonylmethyl.
45. In embodiment 45, the compound of any one of embodiments 1 to 43, or a pharmaceutically acceptable salt thereof, wherein R 1b is absent, cyano, or cyanomethyl.
46. In embodiment 46, the compound of embodiment 1, or a pharmaceutically acceptable salt thereof, is wherein
Figure PCTCN2021092773-appb-000041
is:
Figure PCTCN2021092773-appb-000042
Figure PCTCN2021092773-appb-000043
47. In embodiment 47, the compound of any one of embodiments 1 to 46, or a pharmaceutically acceptable salt thereof, has a structure of formula (Ia) as follows:
Figure PCTCN2021092773-appb-000044
48. In embodiment 48, the compound of any one of embodiments 1 to 46, or a pharmaceutically acceptable salt thereof, has a structure of formula (Ib) as follows:
Figure PCTCN2021092773-appb-000045
49. In embodiment 49, the compound of any one of embodiments 1 to 46, or a pharmaceutically acceptable salt thereof, has a structure of formula (Ic) as follows:
Figure PCTCN2021092773-appb-000046
50. In embodiment 50, the compound of any one of embodiments 1 to 46, or a pharmaceutically acceptable salt thereof, has a structure of formula (Id) as follows:
Figure PCTCN2021092773-appb-000047
51. In embodiment 51, the compound of any one of embodiments 1 to 46, or a pharmaceutically acceptable salt thereof, has a structure of formula (Ie) as follows:
Figure PCTCN2021092773-appb-000048
52. In embodiment 52, the compound of any one of embodiments 1 to 51, or a pharmaceutically acceptable salt thereof, is wherein Q is bond and R 5 is cycloalkyl, fused cycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl, wherein aryl, aryl in aralkyl, heteroaryl, and heteroaryl in heteroaralkyl are substituted with R aa, R bb, R cc and R dd wherein R aa and R bb are independently selected from hydrogen, alkyl, cycloalkyl, halo, haloalkyl, haloalkoxy, hydroxy, alkoxy, heteroalkyl, hydroxyalkyl, amino, and cyano, R cc is hydrogen, alkenyl, alkynyl, cyanoalkynyl, or halo, and R dd is hydrogen, alkyl, cycloalkyl, halo, haloalkyl, haloalkoxy, alkoxy, heteroalkyl, hydroxyalkyl, amino, cyano, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl.
53. In embodiment 53, the compound of any one of embodiments 1 to 51, or a pharmaceutically acceptable salt thereof, is wherein Q is alkylene and R 5 is cycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl, wherein aryl, aryl in aralkyl, heteroaryl, and heteroaryl in heteroaralkyl are substituted with R aa, R bb, R cc and R dd wherein R aa and R bb are independently selected from hydrogen, alkyl, cycloalkyl, halo, haloalkyl, haloalkoxy, hydroxy, alkoxy, heteroalkyl, hydroxyalkyl, amino, and cyano, R cc is hydrogen or halo, and R dd is hydrogen, alkyl, cycloalkyl, halo, haloalkyl, haloalkoxy, alkoxy, heteroalkyl, hydroxyalkyl, amino, cyano, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl.
54. In embodiment 54, the compound of any one of embodiments 1 to 51, or a pharmaceutically acceptable salt thereof, is wherein Q is -C (O) -and R 5 is cycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl, wherein aryl, aryl in aralkyl, heteroaryl, and heteroaryl in heteroaralkyl are substituted with R aa, R bb, R cc and R dd wherein R aa and R bb are independently selected from hydrogen, alkyl, cycloalkyl, halo, haloalkyl, haloalkoxy, hydroxy, alkoxy, heteroalkyl, hydroxyalkyl, amino, and cyano, R cc is hydrogen or halo, and R dd is hydrogen, alkyl,  cycloalkyl, halo, haloalkyl, haloalkoxy, alkoxy, heteroalkyl, hydroxyalkyl, amino, cyano, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl.
55. In embodiment 55, the compound of any one of embodiments 1 to 51, or a pharmaceutically acceptable salt thereof, is wherein R 5 is cycloalkyl, fused cycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl, wherein aryl, aryl in aralkyl, heteroaryl, and heteroaryl in heteroaralkyl are substituted with R aa, R bb, R cc and R dd wherein R aa and R bb are independently selected from hydrogen, alkyl, cycloalkyl, halo, haloalkyl, haloalkoxy, hydroxy, alkoxy, heteroalkyl, hydroxyalkyl, amino, and cyano, R cc is hydrogen, alkenyl, alkynyl, cyanoalkynyl, or halo, and R dd is hydrogen, alkyl, cycloalkyl, halo, haloalkyl, haloalkoxy, alkoxy, heteroalkyl, hydroxyalkyl, amino, cyano, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl.
56. In embodiment 56, the compound of any one of embodiments 1 to 51, or a pharmaceutically acceptable salt thereof, is wherein Q is bond and R 5 is phenyl or naphthyl substituted with R aa, R bb, R cc and R dd.
57. In embodiment 57, the compound of any one of embodiments 1 to 51, or a pharmaceutically acceptable salt thereof, is wherein Q is bond and R 5 is phenyl or naphthyl substituted with R aa, R bb, and R dd where R aa and R bb are independently selected from hydrogen, alkyl, halo, haloalkyl, hydroxy, alkoxy, haloalkoxy, cycloalkyl, amino, cyano, and hydroxyalkyl and R dd is hydrogen, alkyl, cycloalkyl, halo, haloalkyl, haloalkoxy, alkoxy, heteroalkyl, hydroxyalkyl, amino, cyano, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl.
58. In embodiment 58, the compound of any one of embodiments 1 to 56, or a pharmaceutically acceptable salt thereof, is wherein R aa and R bb independently selected from hydrogen, methyl, ethyl, fluoro, chloro, trifluoromethyl, difluoromethyl, trifluoromethoxy, hydroxy, methyl, ethoxy, cyclopropyl, amino, cyano, and hydroxymethyl, R cc is hydrogen, ethynyl, 2-cyanoethyn-1-yl, or fluoro, and R dd is hydrogen, methyl, fluoro, amino, or cyclopropyl.
59. In embodiment 59, the compound of any one of embodiments 1 to 51, or a pharmaceutically acceptable salt thereof, is wherein Q is bond and R 5 is heteroaryl substituted with R aa, R bb, R cc and R dd.
60. In embodiment 60, the compound of embodiment 1 to 51 and 59, or a pharmaceutically acceptable salt thereof, is wherein Q is bond and R 5 is a monocyclic heteroaryl (e.g., pyridyl, pyrimidinyl) substituted with R aa, R bb, R cc and R dd.
61. In embodiment 61, the compound of embodiment 1 to 51 and 59, or a pharmaceutically acceptable salt thereof, is wherein R 5 is Q is bond and R 5 is bicyclic heteroaryl (e,g, quinolinyl, isoquinolinyl, or indazolyl) , substituted with R aa, R bb, R cc and R dd.
62. In embodiment 62, the compound of any one of embodiments 1 to 51 and 59 to 61, or a pharmaceutically acceptable salt thereof, is wherein the heteroaryl is substituted with R aa, R bb, and R dd where R aa and R bb independently selected from hydrogen, alkyl, halo, haloalkyl, hydroxy, alkoxy, haloalkoxy, cycloalkyl, amino, cyano, and hydroxyalkyl and R dd is hydrogen, alkyl, cycloalkyl, halo, haloalkyl, haloalkoxy, alkoxy, heteroalkyl, hydroxyalkyl, amino, cyano, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl.
63. In embodiment 63, the compound of any one of embodiments 1 to 51 and 59 to 61, or a pharmaceutically acceptable salt thereof, is wherein R aa and R bb are independently selected from hydrogen, methyl, ethyl, fluoro, chloro, trifluoromethyl, difluoromethyl, trifluoromethoxy, hydroxy, methyl, ethoxy, cyclopropyl, amino, cyano, and hydroxymethyl, R cc is hydrogen or fluoro, and R dd is hydrogen, methyl, fluoro, amino, or cyclopropyl.
64. In embodiment 30, the compound of any one of embodiments 1 to 51, or a pharmaceutically acceptable salt thereof, is wherein Q is bond and R 5 is:
Figure PCTCN2021092773-appb-000049
65. In embodiment 65, the compound of any one of embodiments 1 to 64, or a pharmaceutically acceptable salt thereof, is wherein R 2 is absent, halo, or alkyl, and R 3 absent, halo, cycloalkyloxy, or alkyl.
66. In embodiment 66, the compound of any one of embodiments 1 to 65, or a pharmaceutically acceptable salt thereof, wherein R 2 and R 3 are each absent.
67. In embodiment 67, the compound of any one of embodiments 1 to 65, or a pharmaceutically acceptable salt thereof, is wherein R 2 is absent or chloro and R 3 is absent, fluoro, or cyclopropyloxy.
68. In embodiment 68, the compound of any one of embodiments 1 to 67, or a pharmaceutically acceptable salt thereof, is wherein R 4 is -Z-R 11 where Z is a bond, O, NH, N (alkyl) , or S; and R 11 is alkyl, hydroxyalkyl, - (alkylene) -NR 12R 13 (where alkylene is substituted with R a, R b, and R c independently selected from hydrogen, alkyl, cycloalkyl, halo, haloalkyl, hydroxy, alkoxy, cyano, oxo, hydroxyalkyl, alkylamino, dialkylamino, dialkylaminocarbonylalkyl, aryl, heteroaryl, and heterocyclyl, R 12 is hydrogen or alkyl, and R 13 is hydrogen, alkyl, acyl, hydroxyalkyl, or heteroalkyl) , aryl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, bicyclic heterocyclyl, bicyclic heterocyclyl, bicyclic heterocyclylalkyl, bridged heterocyclyl, bridged heterocyclylalkyl, fused heterocyclyl, fused heterocyclylalkyl, spiro heterocyclyl, or spiro heterocyclylalkyl, wherein aryl, heteroaryl, by itself or as part of heteroaralkyl, heterocyclyl, by itself or as part of heterocyclylalkyl, bicyclic heterocyclyl, by itself or as part of bicyclic heterocyclylalkyl, bridged heterocyclyl, by itself or as part of bridged heterocyclylalkyl, fused heterocyclyl, by itself or as part of fused heterocyclylalkyl, and spiro heterocyclyl, by itself or as part of spiro heterocyclylalkyl, are substituted with R d, R e, and R f independently selected from hydrogen, alkyl, cycloalkyl, cycloalkyloxy, cycloalkylalkyl, bridged cycloalkyl, halo, haloalkyl, haloalkoxy, hydroxy, alkoxy, alkoxyalkyl, alkoxyalkyloxy, acyl, cyano, oxo, hydroxyalkyl, alkylamino, dialkylamino, dialkylaminocarbonylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, and optionally substituted heterocyclyl.
69. In embodiment 69, the compound of any one of the embodiments 1 to 68, or a pharmaceutically acceptable salt thereof, is wherein Z is O.
70. In embodiment 70, the compound of any one of the embodiments 1 to 68, or a pharmaceutically acceptable salt thereof, is wherein Z is NH.
71. In embodiment 71, the compound of any one of the embodiments 1 to 68, or a pharmaceutically acceptable salt thereof, is wherein Z is bond.
72. In embodiment 72, the compound of any one of embodiments 1 to 71, or a pharmaceutically acceptable salt thereof, is wherein R 11 is hydroxyalkyl, - (alkylene) -NR 12R 13 (where alkylene is substituted with R a, R b, and R c independently selected from hydrogen, alkyl, hydroxy, and hydroxyalkyl, R 12 is hydrogen or alkyl, and R 13 is hydrogen, alkyl, or hydroxyalkyl) , heteroaralkyl, heterocyclyl, heterocyclylalkyl, bicyclic heterocyclyl, bicyclic heterocyclylalkyl,  bridged heterocyclylalkyl, fused heterocyclylalkyl, and spiro heterocyclylalkyl, wherein heterocyclyl, by itself or as part of heterocyclylalkyl, bicyclic heterocyclyl, by itself or as part of bicyclic heterocyclylalkyl, bridged heterocyclyl as part of bridged heterocyclylalkyl, fused heterocyclyl as part of fused heterocyclylalkyl, and spiro heterocyclyl as part of spiro heterocyclylalkyl, are substituted with R d, R e, and R f independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, halo, hydroxy, alkoxy, alkoxyalkyl, acyl, hydroxyalkyl, alkylamino, dialkylamino, cyano, and optionally substituted aralkyl.
73. In embodiment 73, the compound of any one of embodiments 1 to 71, or a pharmaceutically acceptable salt thereof, is wherein R 11 is 2-dimethylaminoethyl, diethylaminoethyl, 3-methylaminoprop-2-yl, 3-dimethylaminopropyl, 3-dimethylaminoprop-2-yl, 4-dimethylaminobut-2-yl, 4-dimethylaminobut-3-yl, 4-dimethylaminobutyl, 2-dimethylamino-3-hydroxypropyl, 2-dimethylaminoprop-1-yl, 4-methylpiperazin-1-yl, 4- (2-hydroxyethyl) piperazin-1-yl, 4-methylpiperazin-2-yl) methyl, 3- (4-methylpiperazin-1-yl) propyl, 4-dimethylamino-piperidin-1-yl, 1-methylpiperidin-4-yl, piperidin-2-ylmethyl, 2-piperidin-1-ylethyl, 3-piperidin-1-ylpropyl, 3-piperidin-1-ylprop-2-yl, 1-methylpiperidin-3-yl, 2-oxopiperidin-6-ylmethyl, 2- (4-cyanopiperidin-1-yl) ethyl, 2- (2-methylpiperidin-1-yl) ethyl, 2- (4-methylpiperidin-1-yl) ethyl, 3-methoxypiperidin-1-ylethyl, 4-methoxypiperidin-1-ylethyl, 1-cyclopropylpiperidin-4-yl, 2- (4, 4-difluoropiperidin-1-yl) ethyl, 2- (3-fluoropiperidin-1-yl) ethyl, 1-methylpiperidin-3-ylmethyl, pyrrolidin-1-yl, pyrrolidin-2-ylmethyl, pyrrolidin-3-ylmethyl, pyrrolidin-1-ylethyl, 3-pyrrolidin-1-ylprop-2-yl, 1-methylpyrrolidin-3-yl, 3-pyrrolidin-1-ylpropyl, 3-fluoropyrrolidin-1-ylethyl, 3, 3-difluoropyrrolidin-1-ylethyl, 3-dimethylaminopyrrolidin-1-yl, 2-oxopyrrolidin-5-ylmethyl, 2- (3-methoxypyrrolidin-1-yl) ethyl, 3- (3-methoxypyrrolidin-1-yl) propyl. 3-methoxypyrrolidin-1-yl) prop-2-yl. 3- (3-hydroxypyrrolidin-1-yl) prop-2-yl, 1-methylpyrrolidin-3-ylmethyl, 1-methylpyrrolidin-2-ylmethyl, 1-ethylpyrrolidin-2-ylmethyl, 1-methylpyrrolidin-3-ylmethyl, 2- (1-methylpyrrolidin-2-yl) ethyl, 1- (2-hydroxyethyl) pyrrolidin-3-ylmethyl, 1- (2-methoxyethyl) -pyrrolidin-3-ylmethyl, 1-isopropylpyrrolidin-3-ylmethyl, 5, 5-dimethylpyrrolidin-2-yl, 1-benzylpyrrolidin-3-ylmethyl, 1-cyclopropylpyrrolidin-3-ylmethyl, 3- (3, 4-difluoropyrrolidin-1-yl) propyl, 3-hydroxy-1-methylpyrrolidin-2-ylmethyl, 4-hydroxy-1-methylpyrrolidin-2-ylmethyl, 3-fluoro-1-methylpyrrolidin-2-ylmethyl, 4-fluoro-1-methylpyrrolidin-2-ylmethyl, 4, 4-difluoro-1-methylpyrrolidin-2-ylmethyl, 4-methoxy-1-methylpyrrolidin-2-ylmethyl, 1, 2-dimethylpyrrolidin-2-ylmethyl, 1-isopropylpyrrolidin-2-ylmethyl, 1-cyclopropylmethylpyrrolidin-2-ylmethyl, 1, 5, 5-trimethylpyrrolidin-2-yl, 4-methoxy-1-methylpyrrolidin-2-ylmethyl, 4-methoxy-1-ethylpyrrolidin-2-ylmethyl, morpholin-4-yl, 2-morpholin-4-ylethyl, 3-morpholin-4-ylpropyl, 3-morpholin-3-ylprop-2-yl, 4-morpholin-4-ylbutyl, 4-morpholin-4-ylbut-2-yl, 4-methylmorpholin-2-ylmethyl, 4-methylmorpholin-3-ylmethyl, 5-methylmorpholin-3-ylmethyl, 5, 5-dimethylmorpholin-3-ylmethyl, 2- ( (1S, 4R) -2-azabicyclo [2.2.1 ] heptan-2-yl) ethyl, 2-pyridin-2-ylethyl, or 3- (3-azabicyclo [3.1.0] -hexan-3-ylpropyl.
74. In embodiment 74, the compound of any one of embodiments 1 to 67, or a pharmaceutically acceptable salt thereof, is wherein R 4 is -Z-R 11 where Z is a bond, O, NH, N (alkyl) , or S; and R 11 is phenyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, bicyclic heterocyclyl, bicyclic heterocyclylalkyl, bridged heterocyclyl, bridged heterocyclylalkyl, fused heterocyclyl, fused heterocyclylalkyl, spiro heterocyclyl, or spiro heterocyclylalkyl, wherein phenyl, heteroaryl, by itself or as part of heteroaralkyl, heterocyclyl, by itself or as part of heterocyclylalkyl, bicyclic heterocyclyl, by itself or as part of bicyclic heterocyclylalkyl, bridged heterocyclyl, by itself or as part of bridged heterocyclylalkyl, fused heterocyclyl, by itself or as part of fused heterocyclylalkyl, and spiro heterocyclyl, by itself or as part of spiro heterocyclylalkyl, are substituted with R d, R e, and R f independently selected from hydrogen, alkyl, cycloalkyl, cycloalkyloxy, cycloalkylalkyl, bridged cycloalkyl, halo, haloalkyl, haloalkoxy, hydroxy, alkoxy, alkylidienyl, haloalkyldienyl, alkoxyalkylidienyl, alkoxyalkyl, alkoxyalkyloxy, alkylsulfonyl, alkylsulfonylalkyl, dialkyl (oxo) phosphinyl, dialkyl (oxo) phosphinylalkyl, acyl, cyano, oxo, hydroxyalkyl, alkylamino, dialkylamino, dialkylaminocarbonylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, and optionally substituted heterocyclyl.
75. In embodiment 75, the compound of any one of embodiments 1 to 67, or a pharmaceutically acceptable salt thereof, is wherein R 4 is:
Figure PCTCN2021092773-appb-000050
76. In embodiment 41, the compound of any one of embodiments 1 to 67, or a pharmaceutically acceptable salt thereof, is wherein R 4 is -CR 14=CR 15R 16 where R 14 and R 15 are independently selected from hydrogen, deuterium, alkyl, halo, and haloalkyl; and R 16 is hydrogen, deuterium, alkyl, halo, haloalkyl, cycloalkyl, bridged cycloalkyl, fused cycloalkyl, spiro cycloalkyl, heterocyclyl, bicyclic heterocyclyl, bridged heterocyclyl, fused heterocyclyl, or spiro heterocyclyl; or
R 15 and R 16 together with the carbon atom to which are attached form cycloalkyl, bridged cycloalkyl, fused cycloalkyl, spiro cycloalkyl, heterocyclyl, bridged heterocyclyl, fused heterocyclyl, or spiro heterocyclyl, wherein:
(a) the groups alkyl, cycloalkyl, bridged cycloalkyl, fused cycloalkyl, spiro cycloalkyl, heterocyclyl, bicyclic heterocyclyl, bridged heterocyclyl, fused heterocyclyl, and spiro  heterocyclyl of R 16; and (b) the groups cycloalkyl, bridged cycloalkyl, fused cycloalkyl, spiro cycloalkyl, heterocyclyl, bridged heterocyclyl, fused heterocyclyl, or spiro heterocyclyl formed by R 15 and R 16 together, are independently substituted with R h, R i, and R j where R h, R i and R j are independently selected from hydrogen, alkyl, halo, haloalkyl, hydroxyalkyl, alkoxyalkyl, cyano, cycloalkyl, bridged cycloalkyl, heterocyclyl, -O (alk)  z1R k, -O (alk) OR l, -S (O) R m, -S (O)  2R n, -NR pC (O) R o, -NR rSO 2R q, -OC (O) NR sR t, -C (O) NR uR v, -S (O)  2NR wR x, and -NR yR z, where z1 is 0 or 1, alk is alkylene, and R k, R l, R m, R n, R o, R p, R q, R r, R s, R t, R u, R v, R w, R x, R y, and R zare independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, halo, hydroxyalkyl, alkoxyalkyl, and aminoalkyl..
77. In embodiment 77, the compound of any one of embodiments 1 to 67, or a pharmaceutically acceptable salt thereof, is wherein R 4 is:
Figure PCTCN2021092773-appb-000051
78. In embodiment 78, the compound any one of embodiment 1 to 67, or a pharmaceutically acceptable salt thereof, is wherein R 4 is:
Figure PCTCN2021092773-appb-000052
79. In embodiment 79, the compound any one of embodiment 1 to 67, or a pharmaceutically acceptable salt thereof, is wherein R 4 is is -Z-R 11 where Z is O; and R 11 is, phosphinyl bicyclic heterocyclylalkyl, fused bicyclic heterocyclylalkyl, tricyclic heterocyclyl, tricyclic heterocyclylalkyl, fused tricyclic heterocyclyl, fused tricyclic heterocyclylalkyl, , or bicyclic heterocyclylalkyl wherein phosphinyl bicyclic heterocyclyl, by itself of as part of phosphinyl bicyclic heterocyclylalkyl, fused bicyclic heterocyclyl as part of fused bicyclic heterocyclylalkyl, tricyclic heterocyclyl, by itself or as part of tricyclic heterocyclylalkyl and fused tricyclic heterocyclyl, by itself or as part of fused tricyclic heterocyclylalkylare substituted with R d, R e, and R f independently selected from hydrogen, alkyl, alkenyl, haloalkenyl, cycloalkyl, cycloalkyloxy, cycloalkylalkyl, bridged cycloalkyl, halo, haloalkyl, haloalkoxy, hydroxy, alkoxy, alkylidienyl, haloalkylidienyl, alkoxyalkylidienyl, alkoxyalkyl, alkoxyalkyloxy, alkylsulfonyl, alkylsulfonylalkyl, dialkyl (oxo) phosphinyl, dialkyl (oxo) phosphinylalkyl, acyl, cyano, oxo, hydroxyalkyl, alkylamino, dialkylamino, dialkylaminocarbonylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, and optionally substituted heterocyclyl; and
bicyclic heterocyclyl as part of fused bicyclic heterocyclylalkyl are substituted with alkylidene or haloalkylidene.
80. In embodiment 80, the compound of embodiment 79, or a pharmaceutically acceptable salt thereof, is wherein R 4 is:
Figure PCTCN2021092773-appb-000053
General Synthetic Scheme
Compounds Formula (I) can be made by the methods depicted in the reaction schemes shown below.
The starting materials and reagents used in preparing these compounds are either available from commercial suppliers such as Aldrich Chemical Co., (Milwaukee, Wis. ) , Bachem (Torrance, Calif. ) , or Sigma (St. Louis, Mo. ) or are prepared by methods known to those skilled in the art following procedures set forth in references such as Fieser and Fieser’s Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991) ; Rodd’s Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989) ; Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991) , March’s Advanced Organic Chemistry, (John Wiley and Sons, 4th Edition) and Larock’s Comprehensive Organic Transformations (VCH Publishers Inc., 1989) . These schemes are merely illustrative of some methods by which the compounds Formula (I) can be synthesized, and various modifications to these schemes can be made and will be suggested to one skilled in the art reading this disclosure. The starting materials and the  intermediates, and the final products of the reaction may be isolated and purified if desired using conventional techniques, including but not limited to filtration, distillation, crystallization, chromatography and the like. Such materials may be characterized using conventional means, including physical constants and spectral data.
Unless specified to the contrary, the reactions described herein take place at atmospheric pressure over a temperature range from about –78 ℃ to about 150 ℃, such as from about 0 ℃ to about 125 ℃ and further such as at about room (or ambient) temperature, e.g., about 20 ℃.
Compounds of Formula (I) where R 1a is -Q 1-NR 6R 7 and R 4 is -O-R 11, and other groups are as defined in the Summary can be prepared as illustrated and described in Scheme 1 below.
Scheme 1
Figure PCTCN2021092773-appb-000054
Compounds of formula 1-a where X a is halo such as chloro, bromo, or iodo and other groups are as defined in the summary can be converted to compound of formula 1-b, where PG 1 is a suitable hydroxy protecting group by reacting with a suitable nucleophile in the presence of a base. For example compounds 1-b where PG 1 is trimethylsilylethoxymethyl can be synthesized by reacting 1-a with 2- (trimethylsilyl) ethan-1-ol and t-BuOK. Displacement of the chloro group at C- 2 position of compound 1-b with a hydroxy compound of formula R 11-OH where R 11 is as defined in the Summary provides a compound of formula 1-c. Hydroxy compounds of formula R 11-OH are either commercially available or can be made by methods known in the art. For example, 2- (pyrrolidin-1-yl) ethan-1-ol, (S) - (1-methylpyrrolidin-2-yl) methanol and (hexahydropentalen- 3a (1H) -yl) methanol are commercially available or can be prepared by methods disclosed in PCT application publication Nos. WO2019099524 and WO2020146613 or as illustrated and described in Methods (a) to (d) below. Compounds of formula 1-d where R 4 is other than -O-R 11 can be prepared by methods well known in the art such as PCT application publication No. WO2019099524.
Various R 5 group, other than hydrogen, and Q 1 is a bond, can be installed in compound 1-c by reacting compound 1-c and a suitable organometallic reagent of formula R 5-M where R 5 is alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl and M is boronic acid, boronic ester, or stannane, under Suzuki, Negeshi, and Stille reaction conditions to provide a compound of formula 1-d.
Removal of hydroxy protecting group PG 1 in 1-d under standard reaction condition provides a compound of formula 1-e. For example, when trimethylsilylethoxymethyl group can be removed by treating 1-d with fluoride such as CsF.
Compounds of Formula (I) can be synthesized from compounds of formula 1-e by coupling with compounds of formula 1-f in the presence of coupling reagent such as PyBOP. Alternatively, one of the amine group in compound of formula 1-f can be protected with a suitable amino protecting group such as Boc, CBz as in compounds of formula 1-g. Coupling reaction between 1-e and 1-g, followed by removing the amine protecting group can provide compound of Formula (I) where one of R 6 or R 7 is hydrogen which can be converted to corresponding compound of Formula (I) where both R 6 or R 7 are other than hydrogen by methods known in the art. Compounds of formula 1-g are generally commercially available or they can be made by methods known in the art. For example, (R) -2-methyl-N- (8-azaspiro [4.5] decan-1-yl) propane-2-sulfinamide can be prepared by method described in Example 2 below; and (9H-fluoren-9-yl) methyl (4, 4-difluoropyrrolidin-3-yl) carbamate, (9H-fluoren-9-yl) methyl ( (1R, 5S, 8s) -3-azabicyclo [3.2.1] octan-8-yl) carbamate, (9H-fluoren-9-yl) methyl (3-azabicyclo [3.1.1] heptan-6-yl) carbamate and (9H-fluoren-9-yl) methyl (2-azabicyclo [2.2.1] heptan-6-yl) carbamate can be prepared as described in Example 10 below. tert-Butyl (4-hydroxypyrrolidin-3-yl) carbamate can be prepared by method disclosed in PCT application publication WO2008020229.
Compounds of formula 1-a can be prepared by methods well known in the art. For example,
1. Compounds of Formula 1-a where X a is halogen, U is CH, V is N, W is CH, R 2 and R 3 are as defined in the Summary (or any embodiments thereof) can be prepared as illustrated and described below.
Figure PCTCN2021092773-appb-000055
Iodination of a compound of formula 2-a where X a is a halo and R 2 and R 3 are as defined in the Summary, with NIS and a suitable acid such as TsOH provides an iodo compound of formula 2-b. The iodine in 2-b can be converted to ethyl carboxylate under carbonylation condition including Pd catalyst such as Pd (PPh 3)  4 in carbon monoxide atmosphere and ethanol solvent to provide a compound of formula 2-c. Compound 2-c can react with triphosgene to provide trichloroacetamido compound of formula 2-d, which upon treatment with ammonia in an organic solvent such as methanol, undergoes cyclization to provide compound of formula 2-e. Compounds of formula 2-a are either commercially available or can be made by methods known in the art. For example, 2-chloro-3-fluoropyridin-4-amine and 2-chloropyridin-4-amine are commercially available.
2. Compounds of Formula 1-a where X a is halogen, U, V and W are CH, R 2 and R 3 are as defined in the Summary (or any embodiments thereof) can be by reacting a compound of formula 
Figure PCTCN2021092773-appb-000056
with urea at elevated temperature. Compounds of formula 1 are either commercially available or can be made by methods known in the art. For example, 2-amino-4-bromo-5-chloro-3-fluorobenzoic acid, 2-amino-4-bromo-3-fluorobenzoic acid and 2-amino-4-bromobenzoic acid are commercially available.
Certain compound of formula R 11-OH can be prepared as described below in Method (a) to (c) below.
Method (a)
R 11-OH where R 11 is hexahydro-1H-furo [3, 4-b] pyrrolizin-7a (5H) -ylmethyl can be synthesized by the Method (a) below.
Figure PCTCN2021092773-appb-000057
Condensation between methyl proline 2, aldehyde and acrylate provides an adduct 3, which upon removal of the benzyl group under standard reaction condition such as hydrogenation in the presence of Pd in carbon catalyst provides alcohol 4. Reaction of 4 with TsCl in the presence of a base such as TEA provides compound 5. The ester groups of 5 can be reduced with a reducing reagent such as LiAlH 4 or DIABL to provide diol 5a. Treatment of 5a with a base such as NaH provides compound 5b.
Method (b) :
R 11-OH where R 11 is 4, 4a, 7, 8, 9, 9a-hexahydroisoxazolo [4', 3': 4, 5] cyclopenta- [1, 2-b] pyrrolizin-8a (6H) -yl can be synthesized by the Method (b) below.
Figure PCTCN2021092773-appb-000058
Aldol reaction between compound 6 and formaldehyde, followed by protecting the resulted alcohol with a suitable protecting group Pg such as PMB or TBS, provides compound of formula 7. Reduction of the keto group in 7 with a reducing reagent such as DIBAL can provide a hemiaminal compound 8. Subsequent treatment of 8 with acidic methanol can afford the methoxy analogue of formula 9. Treatment of 9 with a Lewis acid such as BF 3·OEt and allenyltributyl-stannane can provide compound 10. The alcohol protecting group P-g in 10 can be removed and resulting alcohol can be oxidized under standard oxidation condition such Dess-Martin or Swern  condition to provide compound 11. Compound 11 can be converted to oxime 12 by reacting 11 with hydroxyamine under conditions well known in the art. Chlorination of 12 with a chlorinating agent such as NCS, followed by treating with a suitable base such as DIPEA or TEA can cause cyclization of 12 to provide compound 13. Compound 13 can be deprotonated with a suitable base such as LDA and then alkylated with 1-bromo-3-chloropropane to provide compound 14. The Boc group can be removed under acid condition such as TFA in DCM and the resulting amine compound can be cyclized in the presence of a base such as K 2CO 3 to provide 15, which can be reduced with a suitable base such as LiBH 4 to provide compound 16.
Method (c) :
R 11-OH where R 11 is 6, 7, 8, 8a-tetrahydro-5H, 9H-pyrazolo [1', 5': 1, 5] pyrrolo [3, 4-b] -pyrrolizin-7a (3bH) -yl can be synthesized by the method (c) below:
Figure PCTCN2021092773-appb-000059
Reaction between amine 17 and pyrazole aldehyde 18 where Pg 1 is a suitable amino protecting group can provide imine 19 which can undergo [3+2] cycloaddition with methyl acrylate to provide compound 20. The methyl ester of compound 20 can be selectively reduced with a reducing reagent such as LiBH 4, followed by hydroboration of the resulting alcohol 21 can provide compound 22. Removal of the amino protecting group in 22, followed cyclization of the resulting diol 23 by converting the hydroxyl groups to leaving groups such as halide or mesylate provides compound 24. Reduction of the ester group in 24 with a suitable reducing reagent such as LiBH 4 provides compound 25.
Method (d) :
R 11-OH where R 11 is 2- (fluoromethylene) tetrahydro-1H-pyrrolizin-7a (5H) -yl can be synthesized by the method (d) below:
Figure PCTCN2021092773-appb-000060
Compound 29 can undergo cyclization with 3-chloro-2- (chloromethyl) prop-1-ene in the presence of a base such as LHMDS to provide compound 30. Reduction of the keto group in compound 30 with a suitable reducing reagent such as LiAlH 4 provides compound 31. Cleavage of the olefin in 31 with ozone provides ketone 32, which can be converted to 33 under standard Wittig olefination condition.
Compounds of Formula (I) where R 4 is -CR 14=CR 15R 16 and other groups are as defined in the Summary can be prepared as described in Scheme 2 below.
Scheme 2
Figure PCTCN2021092773-appb-000061
Treatment of a compound of formula 1-b with a boronic ester of formula CR 15R 16= CR 14B (OR)  2 where R is alkyl or CR 16R 15=CR 14B (-OC (CH 3)  2CH 3)  2)  2-O-) where R 14, R 15 and R 16 as defined in Summary, under Suzuki coupling conditions provides a compound of formula 2-a, which can be converted to a compound of Formula (I) as described in Scheme 1 above.
Boronic esters of formula CR 15R 16= CR 14B (OR)  2 are either commercially available or they can be prepared by methods well known in the art. For example, 2-methyl-1- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1-propene and 2- (cyclopentylidenemethyl) -4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane are commercially available.
Utility
The present disclosure provides treatment of cancer mediated by K-ras, in particular with G12D mutant. In some embodiments, the cancer is pancreatic cancer, colorectal cancer, lung cancer, gall bladder cancer, thyroid cancer, and bile duct cancer. In certain embodiments the lung cancer is a non-small cell lung carcinoma (NSCLC) , for example adenocarcinoma, squamous-cell lung carcinoma or large-cell lung carcinoma. In some embodiments, the lung cancer is a small cell  lung carcinoma. Other lung cancers treatable with the disclosed compounds include, but are not limited to, glandular tumors, carcinoid tumors and undifferentiated carcinomas.
K-ras G12D mutations are observed in hematological malignancies that affect blood, bone marrow, and/or lymph nodes. As such the compounds of Formula ( (I) or a pharmaceutically acceptable salt thereof can be used for the treatment of acute lymphoblastic leukemia (ALL) , acute myelogenous leukemia (AML) , chronic lymphocytic leukemia (CLL) , small lymphocytic lymphoma (SLL) , chronic myelogenous leukemia (CML) , acute monocytic leukemia (AMoL) and/or other leukemias, lymphomas such as all subtypes of Hodgkins lymphoma or non- Hodgkins lymphoma, plasma cell malignancies such as multiple myeloma, mantle cell lymphoma, and Waldenstrom’s macroglubunemia.
The compounds of Formula (I) , or a pharmaceutically acceptable salt thereof can be used for the treatment of a hyperproliferative disorder or metastasis in human who suffers from a cancer such as acute myeloid leukemia, cancer in adolescents, adrenocortical carcinoma childhood, AIDS related cancers (e.g. Lymphoma and Kaposi's Sarcoma) , anal cancer, appendix cancer, astrocytomas, atypical teratoid, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brain stem glioma, brain tumor, breast cancer, bronchial tumors, Burkitt lymphoma, carcinoid tumor, atypical teratoid, embryonal tumors, germ cell tumor, primary lymphoma, cervical cancer, childhood cancers, chordoma, cardiac tumors, chronic lymphocytic leukemia (CLL) , chronic myelogenous leukemia (CML) , chronic myleoproliferative disorders, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, extrahepatic ductal carcinoma in situ (DCIS) , embryonal tumors, CNS cancer, endometrial cancer, ependymoma, esophageal cancer, esthesioneuroblastoma, ewing sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, eye cancer, fibrous histiocytoma of bone, gall bladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumors (GIST) , germ cell tumor, gestational trophoblastic tumor, hairy cell leukemia, head and neck cancer, heart cancer, liver cancer, Hodgkin lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumors, pancreatic neuroendocrine tumors, kidney cancer, laryngeal cancer, lip and oral cavity cancer, liver cancer, lobular carcinoma in situ (LCIS) , lung cancer, lymphoma, metastatic squamous neck cancer with occult primary, midline tract carcinoma, mouth cancer, multiple endocrine neoplasia syndromes, multiple myeloma/plasma cell neoplasm, mycosis fungoides, myelodysplastic syndromes, myelodysplastic/myeloproliferative neoplasms, multiple myeloma, merkel cell carcinoma, malignant mesothelioma, malignant fibrous histiocytoma of bone and osteosarcoma, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-hodgkin lymphoma, non-small cell lung cancer (NSCLC) , oral cancer, lip and oral cavity cancer, oropharyngeal cancer, ovarian cancer, pancreatic cancer, papillomatosis, paraganglioma, paranasal sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pleuropulmonary blastoma, primary central nervous system (CNS) lymphoma, prostate cancer,  rectal cancer, transitional cell cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer, stomach (gastric) cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, T-Cell lymphoma, testicular cancer, throat cancer, thymoma and thymic carcinoma, thyroid cancer, transitional cell cancer of the renal pelvis and ureter, trophoblastic tumor, unusual cancers of childhood, urethral cancer, uterine sarcoma, vaginal cancer, vulvar cancer, or viral-induced cancer. The compounds of Formula (I) , or a pharmaceutically acceptable salt thereof can also be used for the treatment of a non-cancerous hyperproliferative disorder such as benign hyperplasia of the skin (e.g., psoriasis) , restenosis, or prostate (e.g., benign prostatic hypertrophy (BPH) ) .
Testing
The K-Ras G12D activity of the compounds of Formula (I) , or a pharmaceutically acceptable salt thereof can be tested using the in vitro assay described in Biological Examples 1 and 2 below.
Pharmaceutical Compositions
In general, the compounds Formula (I) (unless stated otherwise, reference to compound/compounds of Formula (I) herein includes any embodiments thereof described herein or a pharmaceutically acceptable salt thereof) will be administered in a therapeutically effective amount by any of the accepted modes of administration for agents that serve similar utilities. Therapeutically effective amounts of compounds Formula (I) may range from about 0.01 to about 500 mg per kg patient body weight per day, which can be administered in single or multiple doses. A suitable dosage level may be from about 0.1 to about 250 mg/kg per day; about 0.5 to about 100 mg/kg per day. A suitable dosage level may be about 0.01 to about 250 mg/kg per day, about 0.05 to about 100 mg/kg per day, or about 0.1 to about 50 mg/kg per day. Within this range the dosage can be about 0.05 to about 0.5, about 0.5 to about 5 or about 5 to about 50 mg/kg per day. For oral administration, the compositions can be provided in the form of tablets containing about 1.0 to about 1000 milligrams of the active ingredient, particularly about 1, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900, and 1000 milligrams of the active ingredient. The actual amount of the compound Formula (IA’) , (I’) , (I) , (IIA’) , (II’) , or (II) , i.e., the active ingredient, will depend upon numerous factors such as the severity of the disease to be treated, the age and relative health of the patient, the potency of the compound being utilized, the route and form of administration, and other factors.
In general, compounds Formula (I) will be administered as pharmaceutical compositions by any one of the following routes: oral, systemic (e.g., transdermal, intranasal or by suppository) , or parenteral (e.g., intramuscular, intravenous or subcutaneous) administration. The preferred manner of administration is oral using a convenient daily dosage regimen, which can be adjusted according to the degree of affliction. Compositions can take the form of tablets, pills, capsules,  semisolids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols, or any other appropriate compositions.
The choice of formulation depends on various factors such as the mode of drug administration (e.g., for oral administration, formulations in the form of tablets, pills or capsules, including enteric coated or delayed release tablets, pills or capsules are preferred) and the bioavailability of the drug substance.
The compositions are comprised of in general, a compound of Formula (I) in combination with at least one pharmaceutically acceptable excipient. Acceptable excipients are generally non-toxic, aid administration, and do not adversely affect the therapeutic benefit of the compound of Formula (I) . Such excipient may be any solid, liquid, semi-solid or, in the case of an aerosol composition, gaseous excipient that is generally available to one of skill in the art.
Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk and the like. Liquid and semisolid excipients may be selected from glycerol, propylene glycol, water, ethanol and various oils, including those of petroleum, animal, vegetable or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc. Preferred liquid carriers, particularly for injectable solutions, include water, saline, aqueous dextrose, and glycols.
The compounds of Formula (I) may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. The formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in powder form or in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, saline or sterile pyrogen-free water, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
Formulations for parenteral administration include aqueous and non-aqueous (oily) sterile injection solutions of the active compounds which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain  suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
In addition to the formulations described previously, the compounds of Formula (I) may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
For buccal or sublingual administration, the compositions may take the form of tablets, lozenges, pastilles, or gels formulated in conventional manner. Such compositions may comprise the active ingredient in a flavored basis such as sucrose and acacia or tragacanth.
The compounds of Formula (I) may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter, polyethylene glycol, or other glycerides.
Certain compounds of Formula (I) may be administered topically, that is by non-systemic administration. This includes the application of a compound of Formula (I) externally to the epidermis or the buccal cavity and the instillation of such a compound into the ear, eye and nose, such that the compound does not significantly enter the blood stream. In contrast, systemic administration refers to oral, intravenous, intraperitoneal and intramuscular administration.
Formulations suitable for topical administration include liquid or semi-liquid preparations suitable for penetration through the skin to the site of inflammation such as gels, liniments, lotions, creams, ointments or pastes, and drops suitable for administration to the eye, ear or nose. The active ingredient for topical administration may comprise, for example, from 0.001%to 10%w/w (by weight) of the formulation. In certain embodiments, the active ingredient may comprise as much as 10%w/w. In other embodiments, it may comprise less than 5%w/w. In certain embodiments, the active ingredient may comprise from 2%w/w to 5%w/w. In other embodiments, it may comprise from 0.1%to 1%w/w of the formulation.
For administration by inhalation, compounds of Formula (I) may be conveniently delivered from an insufflator, nebulizer pressurized packs or other convenient means of delivering an aerosol spray. Pressurized packs may comprise a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. Alternatively, for administration by inhalation or insufflation, the compounds of Formula (I) may take the form of a dry powder composition, for example a powder mix of the compound and a suitable powder base such as lactose or starch. The powder composition may be presented in unit dosage form, in for example, capsules, cartridges, gelatin or blister packs from which the powder may be administered with the aid of an inhalator or  insufflator. Other suitable pharmaceutical excipients and their formulations are described in Remington’s Pharmaceutical Sciences, edited by E. W. Martin (Mack Publishing Company, 20th ed., 2000) .
The level of the compound of Formula (I) in a formulation can vary within the full range employed by those skilled in the art. Typically, the formulation will contain, on a weight percent (wt. %) basis, from about 0.01-99.99 wt. %of a compound of Formula (I) based on the total formulation, with the balance being one or more suitable pharmaceutical excipients. For example, the compound is present at a level of about 1-80 wt. %.
Combinations and Combination Therapies
The compounds of Formula (I) , or a pharmaceutically acceptable salt thereof may be used in combination with one or more other drugs in the treatment of diseases or conditions for which compounds of Formula (I) , or the other drugs may have utility. Such other drug (s) may be administered, by a route and in an amount commonly used therefore, contemporaneously or sequentially with a compound of Formula (I) or a pharmaceutically acceptable salt thereof. When a compound of Formula (I) , or a pharmaceutically acceptable salt thereof is used contemporaneously with one or more other drugs, a pharmaceutical composition in unit dosage form containing such other drugs and the compound of Formula (I) , or a pharmaceutically acceptable salt thereof can be used. Accordingly, the pharmaceutical compositions of the present disclosure also include those that contain one or more other drugs, in addition to a compound of Formula (I) , or a pharmaceutically acceptable salt thereof. The combination therapy may also include therapies in which the compound of Formula (I) , or a pharmaceutically acceptable salt thereof and one or more other drugs are administered on different overlapping schedules. It is also contemplated that when used in combination with one or more other active ingredients, the compounds of Formula (I) , and the other active ingredients may be used in lower doses than when each is used singly.
The weight ratio of the compound of this disclosure to the second active ingredient may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used.
Where the subject in need is suffering from or at risk of suffering from cancer, the patient can be treated with a compound of Formula (I) , or a pharmaceutically acceptable salt thereof in any combination with one or more other anti-cancer agents including but not limited to:
MAP kinase pathway (RAS/RAF/MEK/ERK) inhibitors including but not limited to: Vemurafanib (PLX4032, CAS No. 918504-65-1) , Dabrafenib (CAS No. 1195765-45-7) , Encorafenib (LGX818 CAS No. 1269440-17-6) , TQ-B3233, XL-518 (Cas No. 1029872-29-4, available from ACC Corp) ; trametinib (CAS No. 871700-17-3) , selumetinib (AZD6244 CAS No. 606143-52-6) , TQ-B3234, PD184352 (CAS No. 212631-79-3) , PD325901 (CAS No. 391210-10- 9) , TAK-733 (CAS No. 1035555-63-5) , pimasertinib (CAS No. 1236699-92-5) , binimetinib (CAS No.606143-89-9) , refametinib (CAS No. 923032-37-5) , cobimetinib (GDC-0973 CAS No. 934660-93-2) , AZD8330 (CAS No. 869357-68-6) , BVD-523 (CAS No. 869886-67-9) , LTT462 (CAS No. 869886-67-9) , , AMG510 (CAS No. 2296729-00-3) , ARS853 (CAS No. 1629268-00-3) , and any RAS inhibitors disclosed in patents WO2016049565, W020l6l64675, W020l6l68540, WO2017015562, WO2017058728, WO2017058768, WO2017058792, W020l7058805, W02017058807, W02017058902, WO2017058915, W02017070256, WO2017087528, W02017100546, WO2017172979, W02017201161, WO2018064510, WO2018068017, and WO2018119183;
SHP2 inhibitors including but not limited to: SHP099 (CAS No. 2200214-93-1) , TNO155 (CAS No. 1801765-04-7) , RMC4630, JAB-3312, JAB-3068 and ERAS-601;
SOS1 inhibitors including but not limited to BI1701963 and BAY-293;
CSF1R inhibitors (PLX3397, LY3022855, ) and CSF1R antibodies (IMC-054, RG7l55) ;
TGF beta receptor kinase inhibitor such as LY2157299;
BTK inhibitor such as ibrutinib; BCR-ABL inhibitors: Imatinib (CAS No. 152459-95-5) ; Inilotinib hydrochloride; Nilotinib (CAS No. 923288-95-3) ; Dasatinib (BMS-345825 CAS No. 302962-49-8) ; Bosutinib (SKI-606 CAS No. 380843-75-4) ; Ponatinib (AP24534 CAS No. 943319-70-8) ; Bafetinib (INNO406 CAS No. 859212-16-1) ; Danusertib (PHA-739358 CAS No. 827318-97-8) , AT9283 (CAS No. 896466-04-9) ; Saracatinib (AZD0530 CAS No. 379231-04-6) ; and PF-03814735 (CAS 942487-16-3) ;
ALK inhibitors: PF-2341066 (
Figure PCTCN2021092773-appb-000062
crizotinib) ; 5-chloro-N4- (2- (isopropyl-sulfonyl) phenyl) -N2- (2-methoxy-4- (4- (4-methylpiper azin-l-yl) piperidin-l-yl) phenyl) pyrimidine-2, 4-diamine; GSK1838705A (CAS No. 1116235-97-2) ; CH5424802 (CAS No. 1256580-46-7) ; Ceritinib (ZYKADIA CAS No. 1032900-25-6) ; TQ-B3139, and TQ-B3101;
PI3K inhibitors: 4- [2- (lH-Indazol-4-yl) -6- [ [4- (methylsulfonyl) -piperazin-l-yl] methyl] thieno [3, 2-d] pyrimidin-4-yl] mocpholine (also known as GDC 0941 and described in PCT Publication Nos. WO 09/036082 and WO 09/055730) , BEZ235 or NVP-BEZ235 (CAS No. 915019-65-7) , disclosed in PCT Publication No. WO 06/122806) ;
Vascular Endothelial Growth Factor (VEGF) receptor inhibitors: Bevacizumab (sold under the trademark
Figure PCTCN2021092773-appb-000063
by Genentech/Roche) , axitinib, (N-methyl-2- [ [3- [ (E) -2-pyridin-2-ylethenyl] -lH-indazol-6-yl] sulfanyl] benzamide, also known as AG013736, and described in PCT Publication No. WO 01/002369) , Brivanib Alaninate ( (S) - ( (R) -l- (4- (4-Fluoro-2-methyl4H-indol-5-yloxy) -5-methylpyrrolo [2, l-f] [l, 2, 4] triazin-6-yloxy) propan-2-yl) 2-aminopropanoate, also known as BMS-582664) , motesanib (N- (2, 3-dihydro-3, 3-dimethyl-lH-indol-6-yl) -2- [ (4-pyridinylmethyl) amino] -3-pyridinecarboxamide, and described in PCT Publication No. WO 02/066470) , pasireotide (also known as SOM230, and described in PCT Publication No. WO 02/010192) , sorafenib (sold under the tradename
Figure PCTCN2021092773-appb-000064
CAS No. 284461-73-0) ; or AL-2846;
MET inhibitor such as foretinib (CAS No. 849217-64-7) , cabozantinib (CAS No. 1140909-48-3) , capmatinib (CAS No. 1029712-80-8) , tepotinib (CAS No. 1100598-32-0) , savolitinib (CAS No. 1313725-88-0, or crizotinib (CAS No. 877399-52-5) ;
FLT3 inhibitors -sunitinib malate (CAS No. 341031-54-7, sold under the tradename
Figure PCTCN2021092773-appb-000065
by Pfizer) ; PKC412 (CAS No. 120685-11-2, midostaurin) ; tandutinib (CAS No. 387867-13-2) , sorafenib (CAS No. 284461-73-0) , lestaurtinib (CAS No. : 111358-88-4) , KW-2449 (CAS No. 1000669-72-6) , quizartinib (AC220, CAS No. 950769-58-1) , or crenolanib (CAS No. 670220-88-9) ;
Epidermal growth factor receptor (EGFR) inhibitors: Gefitnib (sold under the tradename 
Figure PCTCN2021092773-appb-000066
) , N- [4- [ (3-Chloro-4-fluorophenyl) amino] -7- [ [ (3"S") -tetrahydro-3-furanyl] oxy] -6-quinazolinyl] -4 (dimethylamino) -2-butenamide, sold under the tradename
Figure PCTCN2021092773-appb-000067
by Boehringer Ingelheim) , cetuximab (sold under the tradename
Figure PCTCN2021092773-appb-000068
by Bristol-Myers Squibb) , or panitumumab (sold under the tradename
Figure PCTCN2021092773-appb-000069
by Amgen) ;
HER2 receptor inhibitors: Trastuzumab (sold under the trademark
Figure PCTCN2021092773-appb-000070
by Genentech/Roche) , neratinib (also known as HKI-272, (2E) -N- [4- [ [3-chloro-4- [ (pyridin-2-yl) methoxy] phenyl] amino] -3-cyano-7-ethoxyquinolin-6-yl] -4- (d imethylamino) but-2-enamide, and described PCT Publication No. WO 05/028443) , lapatinib (CAS No. 231277-92-2) or lapatinib ditosylate (CAS No: 388082-77-7) (sold under the trademark
Figure PCTCN2021092773-appb-000071
by GlaxoSmithKline) ; or Trastuzumab emtansine (in the United States, ado-trastuzumab emtansine, trade name Kadcyla) -an antibody-drug conjugate consisting of the monoclonal antibody trastuzumab (Herceptin) linked to the cytotoxic agent mertansine (DM1) ;
HER dimerization inhibitors: Pertuzumab (sold under the trademark
Figure PCTCN2021092773-appb-000072
by Genentech) ;
FGFR inhibitors: Erdafitinib (CAS No. 1346242-81-6) , Pemigatinib (CAS No. 1513857-77-6) or Infigratinib (CAS No. 872511-34-7)
Aurora kinase inhibitors: TAS-119 (CAS No. 1453099-83-6) , LY3295668 (CAS No. 1919888-06-4) , or alisertib (CAS No. 1028486-01-2) ;
CD20 antibodies: Rituximab (sold under the trademarks
Figure PCTCN2021092773-appb-000073
and
Figure PCTCN2021092773-appb-000074
by Genentech/Roche) , tositumomab (sold under the trademarks
Figure PCTCN2021092773-appb-000075
by GlaxoSmithKline) , or ofatumumab (sold under the trademark
Figure PCTCN2021092773-appb-000076
by GlaxoSmithKline) ;
Tyrosine kinase inhibitors: Erlotinib hydrochloride (CAS No. 183319-69-9, sold under the trademark
Figure PCTCN2021092773-appb-000077
by Genentech/Roche) , Linifanib (N- [4- (3-amino-lH-indazol-4-yl) phenyl] -N'- (2-fluoro-5-methylphenyl) urea, also known as ABT 869, available from Genentech) , sunitinib malate (CAS No. 341031-54-7, sold under the tradename
Figure PCTCN2021092773-appb-000078
by Pfizer) , bosutinib (4- [ (2, 4-dichloro-5-methoxyphenyl) amino] -6-methoxy-7- [3- (4-methylpiperazin4-yl) propoxy] quinoline-3-car bonitrile, also known as SKI-606, and described in US Patent No. 6, 780, 996) , dasatinib (CAS No. 302962-49-8, sold under the tradename
Figure PCTCN2021092773-appb-000079
by Bristol-Myers Squibb) , armala  (CAS No. 444731-52-6, also known as pazopanib, sold under the tradename
Figure PCTCN2021092773-appb-000080
by GlaxoSmithKline) , imatinib (CAS No. 152459-95-5) and imatinib mesylate (CAS No. 220127-57-1) (sold under the tradenames
Figure PCTCN2021092773-appb-000081
and
Figure PCTCN2021092773-appb-000082
by Novartis) ;
DNA Synthesis inhibitors: Capecitabine (CAS No. 154361-50-9) (sold under the trademark 
Figure PCTCN2021092773-appb-000083
by Roche) , gemcitabine hydrochloride (CAS No. 122111-03-9) (sold under the trademark
Figure PCTCN2021092773-appb-000084
by Eli Lilly and Company) , or nelarabine ( (2R3S, 4R, 5R) -2- (2-amino-6-methoxy-purin-9-yl) -5- (hydroxymet hyl) oxolane-3, 4-diol, sold under the tradenames
Figure PCTCN2021092773-appb-000085
and
Figure PCTCN2021092773-appb-000086
by GlaxoSmithKline) ;
Antineoplastic agents: oxaliplatin (CAS No. 61825-94-3) (sold under the tradename 
Figure PCTCN2021092773-appb-000087
ay Sanofi-Aventis and described in US Patent No. 4,169,846) ;
Human Granulocyte colony-stimulating factor (G-CSF) modulators: Filgrastim (sold under the tradename
Figure PCTCN2021092773-appb-000088
by Amgen) ;
Immunomodulators: Afutuzumab (available from
Figure PCTCN2021092773-appb-000089
) , pegfilgrastim (sold under the tradename
Figure PCTCN2021092773-appb-000090
by Amgen) , lenalidomide (CAS No. 191732-72-6, also known as CC-5013, sold under the tradename
Figure PCTCN2021092773-appb-000091
) , or thalidomide (CAS No. 50-35-1, sold under the tradename
Figure PCTCN2021092773-appb-000092
) ;
CD40 inhibitors: Dacetuzumab (also known as SGN-40 or huS2C6, available from Seattle Genetics, Inc) ;
Pro-apoptotic receptor agonists (PARAs) : Dulanermin (also known as AMG-951, available from Amgen/Genentech) ;
Hedgehog antagonists: 2-chloro-N- [4-chloro-3- (2-pyridinyl) phenyl] -4- (methylsulfony 1) -benzamide (also known as GDC-0449, and described in PCT Publication No. WO 06/028958) ;
Phospholipase A2 inhibitors: Anagrelide (CAS No. 58579-51-4, sold under the tradename 
Figure PCTCN2021092773-appb-000093
);
BCL-2 inhibitors: 4- [4- [ [2- (4-chlorophenyl) -5, 5-dimethyl-l-cyclohexen-l-yl] met hyl] -1-piperazinyl] -N- [ [4- [ [ (lR) -3- (4-morpholinyl) -l- [ (phenylthio) m ethyl] propyl] amino] -3- [ (trifluoromethyl) sulfonyl] phenyl] sulfonyl] benzamide (also known as ABT-263 and described in PCT Publication No. WO 09/155386) ;
MCL-1 inhibitors: MIK665 (CAS No. 1799631-75-6, S64315) , AMG 397, and AZD5991 (CAS No. 2143010-83-5) ; Aromatase inhibitors: Exemestane (CAS No. 107868-30-4, sold under the trademark
Figure PCTCN2021092773-appb-000094
by Pfizer) , letrozole (CAS No. 112809-51-5, sold under the tradename 
Figure PCTCN2021092773-appb-000095
by Novartis) , or anastrozole (CAS No. 120511-73-1, sold under the tradename 
Figure PCTCN2021092773-appb-000096
);
Topoisomerase I inhibitors: Irinotecan (CAS No. 97682-44-5, sold under the trademark 
Figure PCTCN2021092773-appb-000097
by Pfizer) , topotecan hydrochloride (CAS No. 119413-54-6, sold under the tradename
Figure PCTCN2021092773-appb-000098
by GlaxoSmithKline) ;
Topoisomerase II inhibitors: etoposide (CAS No. 33419-42-0, also known as VP-16 and Etoposide phosphate, sold under the tradenames
Figure PCTCN2021092773-appb-000099
and
Figure PCTCN2021092773-appb-000100
) , or teniposide (CAS No. 29767-20-2, also known as VM-26, sold under the tradename
Figure PCTCN2021092773-appb-000101
) ; mTOR inhibitors: Temsirolimus (CAS No. 162635-04-3, sold under the tradename
Figure PCTCN2021092773-appb-000102
by Pfizer) , ridaforolimus (CAS No. 572924-54-0, formally known as deferolimus, AP23573 and MK8669, and described in PCT Publication No. WO 03/064383) , or everolimus (CAS No. 159351-69-6, sold under the tradename
Figure PCTCN2021092773-appb-000103
by Novartis) ;
Proteasome inhibitor such as carfilzomib (CAS No. 868540-17-4) , MLN9708 (CAS No. 1201902-80-8) , delanzomib (CAS No. 847499-27-8) , or bortezomib (CAS No. 179324-69-7) ;
BET inhibitors such as INCB054329 (CAS No. 1628607-64-6) , OTX015 (CAS No. 202590-98-5) , or CPI-0610 (CAS No. 1380087-89-7) ;
LSD1 inhibitors such as GSK2979552, or INCB059872;
HIF-2α inhibitors such as PT2977 (1672668-24-4) , NKT2152, or PT2385 (CAS No. 1672665-49-4) ;
Osteoclastic bone resorption inhibitors: l-Hydroxy-2-imidazol-l-yl-phosphonoethyl) phosphonic acid monohydrate (sold under the tradename
Figure PCTCN2021092773-appb-000104
by Novartis) ;
CD33 Antibody Drug Conjugates: Gemtuzumab ozogamicin (sold under the tradename 
Figure PCTCN2021092773-appb-000105
by Pfizer/Wyeth) ;
CD22 Antibody Drug Conjugates: Inotuzumab ozogamicin (also referred to as CMC-544 and WAY-207294, available from Hangzhou Sage Chemical Co., Ltd. ) ;
CD20 Antibody Drug Conjugates: Ibritumomab tiuxetan (sold under the tradename 
Figure PCTCN2021092773-appb-000106
);
Somatostain analogs: octreotide (also known as octreotide acetate, sold under the tradenames 
Figure PCTCN2021092773-appb-000107
and Sandostatin
Figure PCTCN2021092773-appb-000108
) ;
Synthetic Interleukin-11 (IL-l 1) : oprelvekin (sold under the tradename
Figure PCTCN2021092773-appb-000109
by Pfizer/Wyeth) ;
Synthetic erythropoietin: Darbepoetin alfa (sold under the tradename
Figure PCTCN2021092773-appb-000110
by Amgen) ;
Receptor Activator for Nuclear Factor k B (RANK) inhibitors: Denosumab (sold under the tradename
Figure PCTCN2021092773-appb-000111
by Amgen) ;
Thrombopoietin mimetic peptibodies: Romiplostim (sold under the tradename
Figure PCTCN2021092773-appb-000112
by Amgen;
Cell growth stimulators: Palifermin (sold under the tradename
Figure PCTCN2021092773-appb-000113
by Amgen) ;
Anti-insulin-like Growth Factor-l receptor (IGF-1R) antibodies: Figitumumab (also known as CP-751, 871, available from ACC Corp) , robatumumab (CAS No. 934235-44-6) ;
Anti-CSl antibodies: Elotuzumab (HuLuc63, CAS No. 915296-00-3) ;
CD52 antibodies: Alemtuzumab (sold under the tradename
Figure PCTCN2021092773-appb-000114
) ;
Histone deacetylase inhibitors: Voninostat (sold under the tradename
Figure PCTCN2021092773-appb-000115
by Merck) ;
Alkylating agents: Temozolomide (sold under the tradenames
Figure PCTCN2021092773-appb-000116
and
Figure PCTCN2021092773-appb-000117
by Schering-Plough/Merck) , dactinomycin (also known as actinomycin-D and sold under the tradename
Figure PCTCN2021092773-appb-000118
) , melphalan (also known as L-PAM, L-sarcolysin, and phenylalanine mustard, sold under the tradename
Figure PCTCN2021092773-appb-000119
) , altretamine (also known as hexamethylmelamine (HMM) , sold under the tradename
Figure PCTCN2021092773-appb-000120
) , carmustine (sold under the tradename
Figure PCTCN2021092773-appb-000121
) , bendamustine (sold under the tradename
Figure PCTCN2021092773-appb-000122
) , busulfan (sold under the tradenames 
Figure PCTCN2021092773-appb-000123
and
Figure PCTCN2021092773-appb-000124
) , carboplatin (sold under the tradename
Figure PCTCN2021092773-appb-000125
) , lomustine (also known as CCNU, sold under the tradename
Figure PCTCN2021092773-appb-000126
) , cisplatin (also known as CDDP, sold under the tradenames
Figure PCTCN2021092773-appb-000127
and
Figure PCTCN2021092773-appb-000128
) , chlorambucil (sold under the tradename 
Figure PCTCN2021092773-appb-000129
) , cyclophosphamide (sold under the tradenames
Figure PCTCN2021092773-appb-000130
and
Figure PCTCN2021092773-appb-000131
) , dacarbazine (also known as DTIC, DIC and imidazole carboxamide, sold under the tradename DTIC
Figure PCTCN2021092773-appb-000132
) , altretamine (also known as hexamethylmelamine (HMM) sold under the tradename
Figure PCTCN2021092773-appb-000133
) , ifosfamide (sold under the tradename
Figure PCTCN2021092773-appb-000134
) , procarbazine (sold under the tradename
Figure PCTCN2021092773-appb-000135
) , mechlorethamine (also known as nitrogen mustard, mustine and mechloroethamine hydrochloride, sold under the tradename
Figure PCTCN2021092773-appb-000136
) , streptozocin (sold under the tradename
Figure PCTCN2021092773-appb-000137
) , thiotepa (also known as thiophosphoamide, TESPA and TSPA, sold under the tradename 
Figure PCTCN2021092773-appb-000138
Biologic response modifiers: bacillus calmette-guerin (sold under the tradenames
Figure PCTCN2021092773-appb-000139
and
Figure PCTCN2021092773-appb-000140
BCG) , or Denileukin diftitox (sold under the tradename
Figure PCTCN2021092773-appb-000141
) ;
Anti-tumor antibiotics: doxorubicin (sold under the tradenames
Figure PCTCN2021092773-appb-000142
and
Figure PCTCN2021092773-appb-000143
) , bleomycin (sold under the tradename
Figure PCTCN2021092773-appb-000144
) , daunorubicin (also known as dauorubicin hydrochloride, daunomycin, and rubidomycin hydrochloride, sold under the tradename 
Figure PCTCN2021092773-appb-000145
) , daunorubicin liposomal (daunorubicin citrate liposome, sold under the tradename 
Figure PCTCN2021092773-appb-000146
) , mitoxantrone (also known as DHAD, sold under the tradename
Figure PCTCN2021092773-appb-000147
) , epirubicin (sold under the tradename Ellence TM) , idarubicin (sold under the tradenames 
Figure PCTCN2021092773-appb-000148
Idamycin
Figure PCTCN2021092773-appb-000149
) , or mitomycin C (sold under the tradename
Figure PCTCN2021092773-appb-000150
) ;
Anti -microtubule agents: Estramustine (CAS No. 52205-73-9, sold under the tradename 
Figure PCTCN2021092773-appb-000151
);
Cathepsin K inhibitors: Odanacatib (CAS No. 603139-19-1, also know as MK-0822 available from Lanzhou Chon Chemicals, ACC Corp., and ChemieTek, and described in PCT Publication no. WO 03/075836) ;
Epothilone B analogs: Ixabepilone (CAS No. 219989-84-1, sold under the tradename 
Figure PCTCN2021092773-appb-000152
by Bristol-Myers Squibb) ;
Heat Shock Protein (HSP) inhibitors: Tanespimycin (l7-allylamino-l7-demethoxygeldanamycin, also known as KOS-953 and 17-AAG, available from SIGMA, and described in US Patent No. 4,261,989) , NVP-HSP990 (CAS No. 934343-74-5) , AUY922 (CAS No. 747412-49-3) , AT13387 (CAS No. 912999-49-6) , STA-9090 (CAS No. 888216-25-9) , Debio  0932, KW-2478 (CAS No. 819812-04-9) , XL888 (CAS No. 1149705-71-4) , CNF2024 (CAS No. 848695-25-0) , and TAS-116 (CAS No. 1260533-36-5) ;
TpoR agonists: Eltrombopag (sold under the tradenames
Figure PCTCN2021092773-appb-000153
and
Figure PCTCN2021092773-appb-000154
by GlaxoSmithKline) ;
Anti-mitotic agents: Docetaxel (CAS No. 114977-28-5, sold under the tradename
Figure PCTCN2021092773-appb-000155
by Sanofi-Aventis) ; Adrenal steroid inhibitors: aminoglutethimide (CAS No. 125-84-8, sold under the tradename
Figure PCTCN2021092773-appb-000156
Anti-androgens: Nilutamide (CAS No. 63612-50-0, sold under the tradenames
Figure PCTCN2021092773-appb-000157
and
Figure PCTCN2021092773-appb-000158
) , bicalutamide (CAS No. 90357-06-5, sold under tradename
Figure PCTCN2021092773-appb-000159
) , or flutamide (CAS No. 13311-84-7, sold under the tradename Fulexin TM) ;
Androgens: Fluoxymesterone (CAS No. 76-43-7, sold under the tradename
Figure PCTCN2021092773-appb-000160
) ;
CDK (CDK1, CDK2, CDK3, CDK5, CDK7, CDK8, or CDK9) inhibitors including but not limited to: Alvocidib (CAS No. 146426-40-6, pan-CDK inhibitor, also known as flovopirdol or HMR-1275, 2- (2-chlorophenyl) -5, 7-dihydroxy-8- [ (3S, 4R) -3-hydroxy-l -methyl -4-piperidinyl] -4-chromenone, and described in US Patent No. 5, 621, 002) ;
CDK2 inhibitor PF-07104091;
CDK4/6 inhibitors: pabociclib (CAS No. 827022-33-3) , ribociclib (CAS No. 1211441-98-3) , abemaciclib (CAS No. 1231929-97-7) , PF-06873600 (CAS No. 2185857-97-8) , NUV-422 and Trilaciclib (CAS No. 1374743-00-6) ;
CDK7 inhibitors CT7001 (CAS No. 1805789-54-1) and SY-1365 (CAS No. 1816989-16-8) ;
CDK9 inhibtiors AZD 4573 (CAS No. 2057509-72-3) , P276-00 (CAS No. 920113-03-7) , AT7519 (CAS No. 844442-38-2) , CYC065 (CAS No. 1070790-89-4) or TP-1287;
Gonadotropin-releasing hormone (GnRH) receptor agonists: Leuprolide or leuprolide acetate (sold under the tradenames
Figure PCTCN2021092773-appb-000161
by Bayer AG, 
Figure PCTCN2021092773-appb-000162
by Sanofi-Aventis and
Figure PCTCN2021092773-appb-000163
by Abbott Lab) ;
Taxane anti-neoplastic agents: Cabazitaxel (l-hydroxy-7 , 10 -dimethoxy-9-oxo-5, 20-epoxytax-l l-ene-2a, 4, l3a-triyl-4-acetate-2-benzoate-l3- [ (2R, 3S) -3- { [ (tert-butoxy) carbonyl] -amino} -2-hydroxy-3-phenylpropanoate) , or larotaxel ( (2a, 3x, 4a, 5b, 7a, 10b, 13a) -4, l0-bis (acetyloxy) -l3- ( { (2R, 3S) -3- [ (tert-butoxycarbonyl) amino] -2-hydroxy-3-phenylpropanoyl} oxy) -l-hydroxy-9-oxo-5, 20-epoxy-7, l9-cyclotax-ll-en-2-yl benzoate) ;
5HTla receptor agonists: Xaliproden (also known as SR57746, l- [2- (2-naphthyl) ethyl] -4- [3- (trifluoromethyl) phenyl] -l, 2, 3, 6-tetrahydropyridine, and described in US Patent No. 5,266,573) ;
HPC vaccines: 
Figure PCTCN2021092773-appb-000164
sold by GlaxoSmithKline, 
Figure PCTCN2021092773-appb-000165
sold by Merck;
Iron Chelating agents: Deferasinox (CAS No. 201530-41-8, sold under the tradename 
Figure PCTCN2021092773-appb-000166
by Novartis) ;
Anti-metabolites: Claribine (2-chlorodeoxyadenosine, sold under the tradename
Figure PCTCN2021092773-appb-000167
) , 5-fluorouracil (sold under the tradename
Figure PCTCN2021092773-appb-000168
) , 6-thioguanine (sold under the tradename 
Figure PCTCN2021092773-appb-000169
) , pemetrexed (sold under the tradename
Figure PCTCN2021092773-appb-000170
) , cytarabine (also known as arabinosylcytosine (Ara-C) , sold under the tradename
Figure PCTCN2021092773-appb-000171
) , cytarabine liposomal (also known as Liposomal Ara-C, sold under the tradename DepoCyt TM) , decitabine (sold under the tradename
Figure PCTCN2021092773-appb-000172
) , hydroxyurea (sold under the tradenames
Figure PCTCN2021092773-appb-000173
Droxia TM and Mylocel TM) , fludarabine (sold under the tradename
Figure PCTCN2021092773-appb-000174
) , floxuridine (sold under the tradename
Figure PCTCN2021092773-appb-000175
) , cladribine (also known as 2-chlorodeoxyadenosine (2-CdA) sold under the tradename Leustatin TM) , methotrexate (also known as amethopterin, methotrexate sodim (MTX) , sold under the tradenames
Figure PCTCN2021092773-appb-000176
and Trexall TM) , or pentostatin (sold under the tradename 
Figure PCTCN2021092773-appb-000177
);
Bisphosphonates: Pamidronate (CAS No. 57248-88-1, sold under the tradename
Figure PCTCN2021092773-appb-000178
) , zoledronic acid CAS No. 118072-93-8 (sold under the tradename
Figure PCTCN2021092773-appb-000179
) ;
Demethylating agents: 5-azacitidine (CAS No. 320-67-2, sold under the tradename
Figure PCTCN2021092773-appb-000180
) , decitabine (CAS No. 2353-33-5, sold under the tradename
Figure PCTCN2021092773-appb-000181
) ;
Plant Alkaloids: Paclitaxel protein-bound (sold under the tradename
Figure PCTCN2021092773-appb-000182
) , vinblastine (also known as vinblastine sulfate, vincaleukoblastine and VLB, sold under the tradenames 
Figure PCTCN2021092773-appb-000183
and
Figure PCTCN2021092773-appb-000184
) , vincristine (also known as vincristine sulfate, LCR, and VCR, sold under the tradenames
Figure PCTCN2021092773-appb-000185
and
Figure PCTCN2021092773-appb-000186
) , vinorelbine (sold under the tradename 
Figure PCTCN2021092773-appb-000187
) , or paclitaxel (sold under the tradenames Taxol and Onxal TM) ;
Retinoids: Ali tretinoin (sold under the tradename
Figure PCTCN2021092773-appb-000188
) , tretinoin (all-trans retinoic acid, also known as ATRA, sold under the tradename
Figure PCTCN2021092773-appb-000189
) , Isotretinoin (13-cis-retinoic acid, sold under the tradenames
Figure PCTCN2021092773-appb-000190
Figure PCTCN2021092773-appb-000191
) , or bexarotene (sold under the tradename 
Figure PCTCN2021092773-appb-000192
);
Glucocorticosteroids: Hydrocortisone (also known as cortisone, hydrocortisone sodium succinate, hydrocortisone sodium phosphate, and sold under the tradenames
Figure PCTCN2021092773-appb-000193
Hydrocortisone Phosphate, 
Figure PCTCN2021092773-appb-000194
Hydrocort
Figure PCTCN2021092773-appb-000195
and
Figure PCTCN2021092773-appb-000196
) , dexamethazone ( (8S, 9R, lOS, l lS, l3S, l4S, l6R, l7R) -9-fluoro-l 1, 17-dihydroxy-17- (2-hydroxyacetyl) -l0, l3, l6-trimethyl-6, 7, 8, 9, 10, 1 l, l2, l3, l4, l5, l6, l7-dodecahydro-3H-cyclopenta [a] phenanthren-3-one) , prednisolone (sold under the tradenames
Figure PCTCN2021092773-appb-000197
and
Figure PCTCN2021092773-appb-000198
) , prednisone (sold under the tradenames
Figure PCTCN2021092773-appb-000199
Liquid
Figure PCTCN2021092773-appb-000200
and
Figure PCTCN2021092773-appb-000201
) , or methylprednisolone (also known as 6-Methylprednisolone, Methylprednisolone Acetate, Methylprednisolone Sodium Succinate, sold under the tradenames
Figure PCTCN2021092773-appb-000202
Figure PCTCN2021092773-appb-000203
and
Figure PCTCN2021092773-appb-000204
) ;
Cytokines: interleukin-2 (also known as aldesleukin and IL-2, sold under the tradename 
Figure PCTCN2021092773-appb-000205
) , interleukin-11 (also known as oprevelkin, sold under the tradename
Figure PCTCN2021092773-appb-000206
) ,  alpha interferon alfa (also known as IFN-alpha, sold under the tradenames
Figure PCTCN2021092773-appb-000207
A, and 
Figure PCTCN2021092773-appb-000208
);
Estrogen receptor downregulators: Fulvestrant (CAS No. 129453-61-8, sold under the tradename
Figure PCTCN2021092773-appb-000209
) ;
Anti-estrogens: tamoxifen (CAS No. 10540-29-1, sold under the tradename
Figure PCTCN2021092773-appb-000210
) ; or Toremifene (CAS No. 89778-27-8, sold under the tradename
Figure PCTCN2021092773-appb-000211
) ;
Selective estrogen receptor modulators (SERMs) : Raloxifene (CAS No. 84449-90-1, sold under the tradename
Figure PCTCN2021092773-appb-000212
) ;
Leutinizing hormone releasing hormone (LFfRH) agonists: Goserelin (CAS No. 145781-92-6, sold under the tradename
Figure PCTCN2021092773-appb-000213
) ; Progesterones: megestrol (also known as megestrol acetate, CAS No. 595-33-5, sold under the tradename
Figure PCTCN2021092773-appb-000214
) ;
Miscellaneous cytotoxic agents: Arsenic trioxide (sold under the tradename
Figure PCTCN2021092773-appb-000215
) , or asparaginase (also known as L-asparaginase, Erwinia L-asparaginase, sold under the tradenames 
Figure PCTCN2021092773-appb-000216
and
Figure PCTCN2021092773-appb-000217
) ;
Exemplary immune checkpoint inhibitors include inhibitors (smack molecules or biologies) against immune checkpoint molecules such as CD27, CD28, CD40, CD 122, CD96, CD73, CD39, CD47, 0X40, GITR, CSF1R, JAK, PI3K delta, PI3K gamma, TAM kinase, arginase, CD137 (also known as 4-1BB) , ICOS, A2AR, A2BR, HIF-2a, B7-H3, B7-H4, BTLA, CTLA-4, LAG3, TIM3, VISTA, CD96, TIGIT, PD-l, PD-L1 and PD-L2. In some embodiments, the immune checkpoint molecule is a stimulatory checkpoint molecule selected from CD27, CD28, CD40, ICOS, 0X40, GITR, CD137 and STING. In some embodiments, the immune checkpoint molecule is an inhibitory checkpoint molecule selected from B7-H3, B7-H4, BTLA, CTLA-4, IDO, TDO, Arginase, KIR, LAG3, PD-l, TIM3, CD96, TIGIT and VISTA. In some embodiments, the compounds provided herein can be used in combination with one or more agents selected from KIR inhibitors, TIGIT inhibitors, LAIR1 inhibitors, CD 160 inhibitors, 2B4 inhibitors and TGFR beta inhibitors.
In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of PD-l, e.g., an anti-PD-l monoclonal antibody. In some embodiments, the anti-PD-l monoclonal antibody is nivolumab, pembrolizumab (also known as MK-3475) , pidilizumab, SHR-1210, PDR001, or AMP -224. In some embodiments, the anti-PD-l monoclonal antibody is nivolumab, or pembrolizumab or PDR001. In some embodiments, the anti -PD 1 antibody is pembrolizumab.
In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of PD-L1, e.g., an anti-PD-Ll monoclonal antibody. In some embodiments, the anti-PD-Ll monoclonal antibody is BMS-935559, MEDI4736, MPDL3280A (also known as RG7446) , or MSB0010718C. In some embodiments, the anti-PD-Ll monoclonal antibody is MPDL3280A (atezolizumab) or MEDI4736 (durvalumab) . In some embodiments, the anti-PD-L1 small molecule inhibitor is INCB86550.
In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of CTLA-4, e.g., an anti-CTLA-4 antibody. In some embodiments, the anti-CTLA-4 antibody is ipilimumab or tremelimumab. In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of LAG3, e.g., an anti-LAG3 antibody. In some embodiments, the anti-LAG3 antibody is BMS-986016 or LAG525. In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of GITR, e.g., an anti-GITR antibody. In some embodiments, the anti-GITR antibody is TRX518 or, MK-4166, INCAGN01876 or MK-1248. In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of 0X40, e.g., an anti-OX40 antibody or OX40L fusion protein. In some embodiments, the anti-OX40 antibody is MED 10562 or, INCAGN01949, GSK2831781, GSK-3174998, MOXR-0916, PF-04518600 or LAG525. In some embodiments, the OX40L fusion protein is MEDI6383.
Compounds of the invention can also be used to increase or enhance an immune response, including increasing the immune response to an antigen; to improve immunization, including increasing vaccine efficacy; and to increase inflammation. In some embodiments, the compounds of the invention can be sued to enhance the immune response to vaccines including, but not limited, Listeria vaccines, oncolytic viral vaccines, and cancer vaccines such as 
Figure PCTCN2021092773-appb-000218
(granulocyte-macrophage colony-stimulating factor (GM-CF) gene-transfected tumor cell vaccine) . Anti-cancer vaccines include dendritic cells, synthetic peptides, DNA vaccines and recombinant viruses. Other immune-modulatory agents also include those that block immune cell migration such as antagonists to chemokine receptors, including CCR2 and CCR4; Sting agonists and Toll receptor agonists. Other anti-cancer agents also include those that augment the immune system such as adjuvants or adoptive T cell transfer. Compounds of this application may be effective in combination with CAR (Chimeric antigen receptor) T cell treatment as a booster for T cell activation.
A compound of the invention can also be used in combination with the following adjunct therapies: Anti-nausea drugs: NK-l receptor antagonists: Casopitant (sold under the tradenames 
Figure PCTCN2021092773-appb-000219
and
Figure PCTCN2021092773-appb-000220
by GlaxoSmithKline) ; and Cytoprotective agents: Amifostine (sold under the tradename
Figure PCTCN2021092773-appb-000221
) , leucovorin (also known as calcium leucovorin, citrovorum factor and folinic acid) . The disclosure of the PCT applications referred to herein above are incorporated herein by reference in their entirety.
Examples
The following preparations of compounds of Formula (I) are given to enable those skilled in the art to more clearly understand and to practice the present disclosure. They should not be considered as limiting the scope of the disclosure, but merely as being illustrative and representative thereof.
Synthetic Examples
Intermediate1
Synthesis of triisopropyl ( (6- (methoxymethoxy) -8- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2- yl) -naphthalen-1-yl) ethynyl) silane
Figure PCTCN2021092773-appb-000222
Step 1: (bromoethynyl) triisopropylsilane
Ethynyltriisopropylsilane (24.0 g, 131mmol) , N-bromosuccinimide (26.9 g, 151mmol) and silver nitrate (2.22 g, 13.0 mmol) were dissolved in acetone (20.0 mL) . The reaction was stirred under nitrogen atmosphere at 25 ℃ for 1 h. The reaction solution was concentrated, petroleum ether was added to form a slurry and the slurry was filtered. The filtrate is concentrated to obtain the title compound as a colorless oily product (34.0 g, 98.8%) .
Step 2: 8- ( (triisopropylsilyl) ethynyl) naphthalene-1, 3-diol
Naphthalene-1, 3-diol (10.0 g, 62.4 mmol) , 2- (bromoethynyl) triisopropylsilane (17.9 g, 68.6 mmol) potassium acetate (12.2 g, 124 mmol) and dichloro bis- (4-methyl) isopropylphenyl) ruthenium (II) (3.82 g, 6.24 mmol) were dissolved in dioxane (100 mL) . The mixture was stirred under nitrogen atmosphere at 110 ℃ for 2 h and then concentrated. The residue was purified by silica gel column to obtain the title compound as a black solid 8- ( (triisopropylsilyl) ethynyl) naphthalene-1, 3-diol (6.50g, 30.5%yield) .
Step 3: 3- (methoxymethoxy) -8- ( (triisopropylsilyl) ethynyl) naphthalene-1-phenol
At 0℃, chloromethyl methyl ether (1.61g, 20.0 mmol) was added dropwise to 8- ( (triisopropyl-silyl) ethynyl) naphthalene-1, 3-diol (6.50g, 19.0mmol) and diisopropylethylamine (4.93g, 38.1 mmol) in dichloromethane (60.0mL) , and the reaction temperature was raised to 20℃after completion of the addition. After 2 h, the reaction solution was quenched with water and 1M hydrochloric acid. After adjusting the pH to 6-7, the reaction mixture was extracted with dichloromethane, filtered, dried, and concentrated. The crude product was purified by flash silica gel column to obtain the title compound as a black oil.
Step 4: Trifluoromethanesulfonic acid (3- (methoxymethoxy) -8- ( (triisopropylsilyl) ethynyl) -naphthalene-1-yl) ester
At -40 ℃, trifluoromethanesulfonic anhydride (4.11g, 14.5 mmol) was added dropwise to 3- (methoxymethoxy) -8- ( (triisopropylsilyl) ethynyl) naphthalene-1-ol (3.50g, 9.10mmol) and diisopropylethylamine (4.70g, 36.4mmol) in dichloromethane (30.0mL) and the reaction mixture was stirred at this temperature for 0.5 h. The reaction mixture was added to water, and extracted with dichloromethane, dried and filtered. The organic phase was concentrated and the crude  product was purified by a flash silica gel column to obtain the title compound (4.70 g, 99.9%yield) .
Step 5: triisopropyl ( (6- (methoxymethoxy) -8- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane-2-yl-naphthalene-1-yl) ethynyl) silaneIn the glove box, 3- (methoxymethoxy) -8- ( (triisopropylsilyl) -ethynyl) naphthalene-1-yl triflate (2.80 g, 5.42 mmol) , pinacol diborate (2.48 g, 9.76 mmol) , Pd (dppf) Cl2 (397 mg, 0.542 mmol) , potassium acetate (1.33 g, 13.6 mmol) were added to dioxane (15 mL) and the reaction mixture was heated at 120℃ for 12 h. The reaction solution was concentrated and purified by column chromatography to obtain the the title compound as an orange solid (4.53g, 56.2%yield) .
Example 1
Synthesis of 4- (4- (3-aminopyrrolidin-1-yl) -8-fluoro-2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -pyrido [4, 3-d] pyrimidin-7-yl) -5-ethynylnaphthalen-2-ol
Figure PCTCN2021092773-appb-000223
Step 1: 2, 4, 7 -tricholro-8-fluoropyrido [4, 3-d] pyrimidine
Figure PCTCN2021092773-appb-000224
To 7-chloro-8-fluoro-pyrido [4, 3-d] pyrimidine-2, 4-diol (2.70 g, 12.5 mmol) in toluene (30 mL) was added phosphorus oxychloride (5.76 g, 37.6 mmol) and DIPEA (3.56 g, 27.6 mmol) . After heating the reaction solution at 110℃ for 12 h, the reaction solution was cooled to rt and concentrated. The resulting crude product was adjusted to pH 8 with saturated aqueous sodium bicarbonate solution and the solid formed was collected by filtration. The filter cake was washed with water and slurried with water at 20 ℃. The solid was dried in vacuo to obtain the title compound as a yellow solid (2.66 g, 69.5%) .
Step 2: 2, 7-dichloro-8-fluoro-4- (2- (trimethylsilyl) ethoxy) pyrido [4, 3-d] pyrimidine
Figure PCTCN2021092773-appb-000225
Potassium tert-butoxide (1M, 12.4 mL) was added dropwise to a solution of 2, 4, 7-trichloro-8-fluoropyrido [4, 3-d] pyrimidine (3.0 0 g, 11.8 mmol) and 2- (trimethylsilyl) ethanol (1.19 g, 10.1 mmol) in THF (15.0 mL) at -60 ℃. The resulting mixture was stirred at this temperature for 1 h and then quenched with water. The aqueous layer was separated and extracted with ethyl  acetate. The combined organic layers were dried (Na 2SO 4) , filtered and concentrated. The crude product was purified by FC to obtain the title compound as a pink solid (3.10 g, 59.4%) .
Step 3: 7-chloro-8-fluoro-2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -4- (2- (trimethylsilyl) -ethoxy) pyrido [4, 3-d] pyrimidine
Figure PCTCN2021092773-appb-000226
2,7-Dichloro-8-fluoro-4- (2- (trimethylsilyl) ethoxy) pyrido [4, 3-d] pyrimidine (3.00 g, 8.98 mmol) , (hexahydro-1H-pyrrolazine-7a-yl) methanol (2.53 g, 17.9 mmol) and DIPEA (2.90 g, 22.4 mmol) were mixed in dioxane (30.0 mL) and the reaction was carried out at 80 ℃ for 12 h under N 2. The reaction solution was added to water, extracted with ethyl acetate, and the organic phase was dried and concentrated. The crude product was purified by FC to obtain the title compound as a yellow solid (2.80 g, 56.8%) .
Step 4: 8-fluoro-7- (3- (methoxymethoxy) -8- ( (triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -4- (2- (trimethylsilyl) ethoxy) pyrido [4, 3-d] pyrimidine
Figure PCTCN2021092773-appb-000227
7-Chloro-8-fluoro-2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -4- (2- (trimethylsilyl) ethoxy) pyrido [4, 3-d] pyrimidine (2.40 g, 5.47 mmol) , triisopropyl ( (6- (methoxy-methoxy) -8- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) naphthalen-1-yl) ethynyl) silane (4.33 g, 8.75 mmol, synthesized according to WO2021041671A1) , K 2CO 3 (2.27 g, 16.4 mmol) , and Mesylate [ (di (1-adamantyl) -n-butylphosphine) -2- (2′-amino-1, 1′-biphenyl) ] palladium (II) (126 mg, 0.178 mmol, cataCXium-A-Pd-G3) were added to a mixture of ethylene glycol dimethyl ether (20.0 mL) and H 2O (2.00 mL) . The resulting mixture was stirred at 85 ℃ for 12 h under N 2 and then poured into water and extracted with ethyl acetate. The organic phase was dried sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column to obtain the title compound as a yellow solid (3.10 g, 56.6%) .
Step 5: 7- (8-ethynyl-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-4-ol
Figure PCTCN2021092773-appb-000228
8-Fluoro-7- (3- (methoxymethoxy) -8- ( (triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -4- (2- (trimethylsilyl) ethoxy) pyrido [4, 3-d] pyrimidine (3.00 g, 3.89 mmoL) and CsF (2.41 g, 15.8 mmol) were dissolved in N, N-dimethylformamide (15.0 mL) , and placed under N 2. The resulting mixture was stirred at 60 ℃for 1 h, and then concentrated. The crude product was purified by FC to give the title compound as a yellow solid (960 mg, 40.4%) .
Step 6: tert-butyl (1- (7- (8-ethynyl-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-4-yl) pyrrolidin-3-yl) carbamate
Figure PCTCN2021092773-appb-000229
To a solution of 7- (8-ethynyl-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-4-ol (25 mg, 0.049 mmol) in DMF (2 mL) were added tert-butyl pyrrolidin-3-ylcarbamate (13 mg, 0.074 mmol) , ( (1H-benzo [d] [1, 2, 3] triazol-1-yl) oxy) -tri (pyrrolidin-1-yl) phosphonium hexafluorophosphate (V) (33 mg, 0.064 mmol) and DIPEA (13 mg, 0.098 mmol) . The mixture was stirred at 45 ℃ for 16 h and then purified by C18 column eluting with H 2O (0.5%NH 4HCO 3) : MeOH (10%-90%) to give the title compound as a white solid (18 mg, 53%) .
Step 7: 4- (4- (3-aminopyrrolidin-1-yl) -8-fluoro-2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -pyrido [4, 3-d] pyrimidin-7-yl) -5-ethynylnaphthalen-2-ol
Figure PCTCN2021092773-appb-000230
To a solution of tert-butyl (1- (7- (8-ethynyl-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-4-yl) pyrrolidin-3-yl) carbamate (20 mg, 0.029 mmol ) in 1 mL of MeOH was added 0.1 mL of conc. HCl. The  mixture was stirred at 25 ℃ for 0.5 h. The reaction solution was purified by C18 column eluting with H 2O (0.5%NH 4HCO 3) : MeOH (10%-90%) to give (10 mg, 64%) of the title compound as a yellow solid.  1H NMR (400 MHz, MeOD) δ ppm 9.19 (s, 1H) , 7.84 –7.75 (m, 1H) , 7.49 (dd, J =7.1, 1.1 Hz, 1H) , 7.42 –7.35 (m, 1H) , 7.31 (d, J = 2.6 Hz, 1H) , 7.16 (t, J = 2.7 Hz, 1H) , 4.39 – 4.28 (m, 2H) , 4.28 –3.99 (m, 3H) , 3.79 (dd, J = 10.9, 8.4 Hz, 2H) , 3.25 –3.12 (m, 2H) , 3.08 (s, 1H) , 2.78 (dd, J = 10.7, 6.5 Hz, 2H) , 2.33 (d, J = 15.1 Hz, 1H) , 2.09 (dd, J = 12.6, 6.4 Hz, 2H) , 2.06 –1.84 (m, 5H) , 1.85 –1.69 (m, 2H) . LCMS: m/z 539.1 [M+H]  +.
Example 2
Synthesis of 4- (4- (1-amino-8-azaspiro [4.5] decan-8-yl) -8-fluoro-2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5-ethynylnaphthalen-2-ol
Figure PCTCN2021092773-appb-000231
Step 1: tert-butyl 1- ( ( (R) -tert-butylsulfinyl) amino) -8-azaspiro [4.5] decane-8-carboxylate
Figure PCTCN2021092773-appb-000232
To the solution of tert-butyl (1E) -1- { [ (R) -2-methylpropane-2-sulfinyl] imino} -8-azaspiro- [4.5] decane-8-carboxylate (1 g, 2.8 mmol, synthesized according to WO2016203405A1) in THF (15 mL) was added NaBH 4 (320 mg, 8.4mmol) at 0 ℃, and the mixture was stirred at 40 ℃ for 2 h. After adding water, the reaction mixture was extracted with EA. The organic layer was dried over Na 2SO 4, filtered and concentrated to give the title compound (1 g, 100%) .
Step 2: (R) -2-methyl-N- (8-azaspiro [4.5] decan-1-yl) propane-2-sulfinamide
Figure PCTCN2021092773-appb-000233
To the solution of tert-butyl 1- { [ (R) -2-methylpropane-2-sulfinyl] amino} -8-azaspiro- [4.5] decane-8-carboxylate (1 g, 2.8mmol) in DCM (15 mL) was added TFA (1.59 g, 14.0 mmol) , and the mixture was stirred at rt for 3 h. Water was added and the pH was adjusted to 9 with 2N NaOH. The mixture was extracted with DCM and the combined organic layers was dried and concentrated to give the title compound (560 mg, 78%) .
Step 3: (R) -N- (8- (7- (8-ethynyl-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-4-yl) -8-azaspiro [4.5] decan-1-yl) -2-methylpropane-2-sulfinamide
Figure PCTCN2021092773-appb-000234
A mixture of 7- (8-ethynyl-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-4-ol (30 mg, 0.058 mmol) , (R) -N- (8-azaspiro [4.5] decan-1-yl) -2-methylpropane-2-sulfinamide (59 mg, 0.23mmol) , PyBOP (45 mg, 0.087mmol) and DIPEA (38 mg, 0.29mmol) in DMF (1.5 mL) were stirred at 35 ℃ for 16 h. The reaction mixture was purified by preparative C18 HPLC [10-100%MeOH/H 2O with 0.1%NH 4HCO 3] to afford the title compound (30 mg, 47%) .
Step 4: 4- (4- (1-amino-8-azaspiro [4.5] decan-8-yl) -8-fluoro-2- ( (tetrahydro-1H-pyrrolizin- 7a (5H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5-ethynylnaphthalen-2-ol
Figure PCTCN2021092773-appb-000235
A mixture of (R) -N- (8- (7- (8-ethynyl-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-4-yl) -8-azaspiro [4.5] -decan-1-yl) -2-methylpropane-2-sulfinamide (24.9 mg) in MeOH (0.5 mL) and HCl/Dioxane (2 mL, 4M) was stirred at rt for 3 h. The reaction mixture was concentrated and the residue was dissolved in MeOH (7 M NH 3 in MeOH) and purified by preparative C18 HPLC [10-100% MeOH/H 2O with 0.1%NH 4HCO 3] to afford the title compound (16 mg, 80%) .  1H NMR (400 MHz, Methanol-d4) δ ppm 8.99 (s, 1H) , 7.84 –7.78 (m, 1H) , 7.50 (dd, J = 7.1, 1.1 Hz, 1H) , 7.42 –7.36 (m, 1H) , 7.32 (d, J = 2.6 Hz, 1H) , 7.16 (d, J = 2.5 Hz, 1H) , 4.56 (t, J = 13.4 Hz, 2H) , 4.32 (s, 2H) , 3.68 –3.58 (m, 2H) , 3.17 (dt, J = 11.7, 6.0 Hz, 2H) , 3.06 (d, J = 4.6 Hz, 1H) , 2.94 (td, J = 7.5, 3.3 Hz, 1H) , 2.80 (dt, J = 10.7, 6.5 Hz, 2H) , 2.10 (dt, J = 12.4, 6.3 Hz, 3H) , 2.00 –1.69 (m, 12H) , 1.60 –1.49 (m, 3H) . LCMS: m/z 607.3 [M+H]  +.
Example 3
Synthesis of 4- (4- (6-amino-1, 4-oxazepan-4-yl) -8-fluoro-2- ( (tetrahydro-1H-pyrrolizin- 7a(5H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5-ethynylnaphthalen-2-ol
Figure PCTCN2021092773-appb-000236
Step 1: tert-butyl 6- ( ( ( (9H-fluoren-9-yl) methoxy) carbonyl) amino) -1, 4-oxazepane-4-carboxylate
Figure PCTCN2021092773-appb-000237
To a mixture of tert-butyl 6-amino-1, 4-oxazepane-4-carboxylate (50 mg, 0.23 mmol) in dioxane: H 2O (1 mL/0.5 mL) were added (9H-fluoren-9-yl) methyl chloroformate (89 mg, 0.35 mmol) and Na 2CO 3 (73 mg, 0.69 mmol) and the mixture was stirred at 25 ℃ for 1 h. The reaction solution was concentrated in vacuo and the residue was purified by a FC eluting with PE: EA (0%-30%) to obtain the title compound as a white solid (60 mg, 60%) .
Step 2: (9H-fluoren-9-yl) methyl (1, 4-oxazepan-6-yl) carbamate
Figure PCTCN2021092773-appb-000238
HCl (4M in Dioxane, 0.33 mL) was added dropwise to a solution of tert-butyl 6- ( ( ( (9H-fluoren-9-yl) methoxy) carbonyl) amino) -1, 4-oxazepane-4-carboxylate (50 mg, 0.11 mmol) in MeOH (1.0 mL) at 25 ℃. The resulting mixture was stirred at 25 ℃ 1 h. After concentrating under vacuo, the residue was used directly in next step.
Step 3: (9H-fluoren-9-yl) methyl (4- (7- (8-ethynyl-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-4-yl) -1, 4-oxazepan-6-yl) carbamate
Figure PCTCN2021092773-appb-000239
To a solution of 7- (8-ethynyl-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-4-ol (25 mg, 0.049 mmol) in DMF (2 ml) were added (9H-fluoren-9-yl) methyl N- (1, 4-oxazepan-6-yl) carbamate (25 mg, 0.074 mmol) , benzotriazole-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (33 mg,  0.064 mmol) and DIPEA (12 mg, 0.098 mmol) , and the mixture was stirred at 25 ℃ for 16 h. The reaction solution was purified with C18 column eluting with H 2O (0.5%NH4HCO3) : MeOH (10%-90%) to give the title compound as a yellow solid (20 mg, 49%) .
Step 4: 4- (7- (8-ethynyl-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-4-yl) -1, 4-oxazepan-6-amine
Figure PCTCN2021092773-appb-000240
To a solution of (9H-fluoren-9-yl) methyl (4- (7- (8-ethynyl-3- (methoxymethoxy) -naphthalen-1-yl) -8-fluoro-2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-4-yl) -1, 4-oxazepan-6-yl) carbamate (30 mg, 0.036 mmol ) in DMF (0.5 mL ) was added piperidine/DMF (0.5 ml, v/v=1/5) and the mixture was stirred at 25 ℃ for 0.5 h. The reaction solution was purified with C18 column eluting with H 2O (0.5%NH 4HCO 3) : MeOH (10%to 90%) to give the title compound as a yellow solid (15 mg, 68%) .
Step 5: 4- (4- (6-amino-1, 4-oxazepan-4-yl) -8-fluoro-2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5-ethynylnaphthalen-2-ol
Figure PCTCN2021092773-appb-000241
To a solution of 4- (7- (8-ethynyl-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-4-yl) -1, 4-oxazepan-6-amine (20 mg, 0.033 mmol) in MeOH (1 ml) was added 0.1 mL of conc. HCl and the mixture was stirred at 25 ℃ for 1 h. The reaction solution was purified by C18 column eluting with H 2O (0.5%NH 4HCO 3) : MeOH (10%-90%) to give the title compound as a yellow solid (11 mg, 58.62%) . LCMS: M/Z 569.1 (M+H)  +.  1H NMR (400 MHz, MeOD) δ ppm 9.22 –9.08 (m, 1H) , 7.81 (d, J =8.2 Hz, 1H) , 7.49 (d, J = 6.8 Hz, 1H) , 7.38 (t, J = 7.7 Hz, 1H) , 7.32 (s, 1H) , 7.18 –7.11 (m, 1H) , 4.56 –4.27 (m, 3H) , 4.09 (dd, J = 14.0, 8.3 Hz, 2H) , 3.99 –3.74 (m, 3H) , 3.66 –3.42 (m, 2H) , 3.17 (t, J = 14.0, 6.2 Hz, 3H) , 3.04 (t, J = 7.1 Hz, 1H) , 2.81 (dd, J = 9.3, 5.5 Hz, 2H) , 2.11 (m, J = 12.5, 6.3 Hz, 2H) , 2.03 –1.72 (m, 6H) .
Example 2
p-ERK Cellular Assay
The ability of the compound of Formula (I) or a pharmaceutically acceptable salt thereof (test compound) to inhibit K-Ras G12D activity can be tested in a cellular assay as described below.
LS180 cells (harbor KRAS G12D mutation) are seeded in 96-well plates and cultured overnight (20,000 cells per well, 200 μl total volume) . On the following morning, cells are treated with test compound, with starting concentration at 10 μM and 1/2 log dilution down to 1 nM for 3 hours at 37℃. DMSO treatment serves as control. p-ERK is then measured using Advanced Phospho-ERK 1/2 (Thr202/Tyr204) Assay Kit (Cisbio, Cat#64AERPET) following the manufacturer’s instruction. Briefly, medium is removed and 40 μl 1× lysis buffer is added to each well, followed by 30 minutes incubation on a plate shaker at room temperature. Then 8 μl of lysate is transferred to a white low volume 384-well plate. Acceptor d2 antibody and Cryptate antibody are diluted (1: 20) with detection buffer and gently mixed (1: 1) according to manufacturer's instruction. 2 μl antibodies mix is added to the cell lysate and the plate is wrapped with foil, shaken for 1-2 minutes on a plate reader, and incubated for >4 hours at room temperature. Signal is then measured on a
Figure PCTCN2021092773-appb-000242
plate reader. Percentage inhibition is calculated with DMSO treatment as 100%of signal, and IC50 is calculated by Graphpad Prism 7.
Figure PCTCN2021092773-appb-000243
Figure PCTCN2021092773-appb-000244
Figure PCTCN2021092773-appb-000245
Example 2
p-ERK Cellular Assay
The ability of the compound of Formula (I) or a pharmaceutically acceptable salt thereof (test compound) to inhibit K-Ras G12D activity can be tested in a cellular assay as described below.
LS180 cells (harbor KRAS G12D mutation) are seeded in 96-well plates and cultured overnight (20,000 cells per well, 200 μl total volume) . On the following morning, cells are treated with test compound, with starting concentration at 10 μM and 1/2 log dilution down to 1 nM for 3 hours at 37℃. DMSO treatment serves as control. p-ERK is then measured using Advanced Phospho-ERK 1/2 (Thr202/Tyr204) Assay Kit (Cisbio, Cat#64AERPET) following the manufacturer’s instruction. Briefly, medium is removed and 40 μl 1× lysis buffer is added to each well, followed by 30 minutes incubation on a plate shaker at room temperature. Then 8 μl of lysate is transferred to a white low volume 384-well plate. Acceptor d2 antibody and Cryptate antibody are diluted (1: 20) with detection buffer and gently mixed (1: 1) according to manufacturer's instruction. 2 μl antibodies mix is added to the cell lysate and the plate is wrapped with foil, shaken for 1-2 minutes on a plate reader, and incubated for >4 hours at room temperature. Signal is then measured on a
Figure PCTCN2021092773-appb-000246
plate reader. Percentage inhibition is calculated with DMSO treatment as 100%of signal, and IC50 is calculated by Graphpad Prism 7.
Formulation
Examples
The following are representative pharmaceutical formulations containing a compound of the present disclosure.
Tablet Formulation
The following ingredients are mixed intimately and pressed into single scored tablets.
Figure PCTCN2021092773-appb-000247
Capsule Formulation
The following ingredients are mixed intimately and loaded into a hard-shell gelatin capsule.
Figure PCTCN2021092773-appb-000248
Injectable Formulation
Compound of the disclosure (e.g., compound 1) in 2%HPMC, 1%Tween 80 in DI water, pH 2.2 with MSA, q.s. to at least 20 mg/mL
Inhalation Composition
To prepare a pharmaceutical composition for inhalation delivery, 20 mg of a compound disclosed herein is mixed with 50 mg of anhydrous citric acid and 100 mL of 0.9%sodium chloride solution. The mixture is incorporated into an inhalation delivery unit, such as a nebulizer, which is suitable for inhalation administration.
Topical Gel Composition
To prepare a pharmaceutical topical gel composition, 100 mg of a compound disclosed herein is mixed with 1.75 g of hydroxypropyl cellulose, 10 mL of propylene glycol, 10 mL of isopropyl myristate and 100 mL of purified alcohol USP. The resulting gel mixture is then incorporated into containers, such as tubes, which are suitable for topical administration.
Ophthalmic Solution Composition
To prepare a pharmaceutical ophthalmic solution composition, 100 mg of a compound disclosed herein is mixed with 0.9 g of NaCl in 100 mL of purified water and filtered using a 0.2 micron filter. The resulting isotonic solution is then incorporated into ophthalmic delivery units, such as eye drop containers, which are suitable for ophthalmic administration.
Nasal spray solution
To prepare a pharmaceutical nasal spray solution, 10 g of a compound disclosed herein is mixed with 30 mL of a 0.05M phosphate buffer solution (pH 4.4) . The solution is placed in a nasal administrator designed to deliver 100 ul of spray for each application.

Claims (79)

  1. A compound of Formula (I) :
    Figure PCTCN2021092773-appb-100001
    wherein:
    U, V, and W are CH; or one or two of U, V, and W are N and the other of U, V, and W are CH;
    ring A is cycloaminyl, bicycloaminyl, bridged cycloaminyl, or spiroaminyl;
    R 1a is hydroxy, -Q 1-NR 6R 7 (where Q 1 is a bond, alkylene, or -C (=O) -, R 6 is hydrogen or alkyl, and R 7 is hydrogen, alkyl, haloalkyl, cycloalkyl, alkylcarbonyl, alkylsulfonyl, alkoxycarbonyl, cyanaoalkyl, saturated heterocyclyl, or 5-or 6-membered heteroaryl ) , -NHC (=NH) (alkyl) , -NHC (=NH) NH 2, -NHC (=O) NR 8R 9 (where R 8 and R 9 are independently hydrogen or alkyl) , or -Q 2-R 10 (where Q 2 is bond, alkylene, -C (=O) -and R 10 is heterocyclyl, spiro heterocyclyl, bridged heterocyclyl, fused heterocyclyl or 5-or 6-membered heteroaryl wherein the heteroaryl contains a nitrogen atom and optionally contains one or two additional heteroatoms selected from N, O, or S; wherein the heterocyclyl, spiro heterocyclyl, bridged heterocyclyl, fused heterocyclyl and 5-or 6-membered heteroaryl ring are unsubstituted or substituted with one or two substituents independently selected from alkyl, halo, cyano, and amino, provided that, when Q 2 is a bond and the heterocyclyl, spiro heterocyclyl, bridged heterocyclyl, and fused heterocyclyl of R 10 contains two nitrogen ring atoms
    , then at least one of the substituents is amino) ; provided that, when a second ring atom of ring A is a nitrogen atom, then R 1a is not hydroxy;
    R 1b is absent, alkyl, alkynyl, cycloalkyl, halo, haloalkyl, hydroxy, alkoxy, cyano, hydroxyalkyl, alkoxyalkyl, cyanoalkyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, or dialkylaminocarbonylalkyl,
    R 1c is absent, alkyl, halo, hydroxy, or cyano;
    R 2 is absent, deuterium, alkyl, alkenyl, alkynyl, halo, haloalkyl, alkoxy, hydroxy, or cyano, provided that, R 2 is absent when two of U, V, and W are N;
    R 3 is absent, deuterium, alkyl, halo, haloalkyl, alkoxy, cycloalkyl, cycloalkyloxy, hydroxy, cyano, or monocyclic heterocyclyl optionally substituted with halo, alkoxy, hydroxy, or cyano;
    R 4 is:
    (i) -Z-R 11 where Z is a bond, O, NH, N (alkyl) , or S; and R 11 is hydrogen, alkyl, hydroxyalkyl, - (alkylene) -NR 12R 13 (where alkylene is substituted with R a, R b, and R c independently selected from hydrogen, alkyl, cycloalkyl, halo, haloalkyl, hydroxy, alkoxy, cyano, oxo, hydroxyalkyl, alkylamino, dialkylamino, dialkylaminocarbonylalkyl, aryl, heteroaryl, and heterocyclyl, R 12 is hydrogen or alkyl, and R 13 is hydrogen, alkyl, acyl, hydroxyalkyl, or heteroalkyl) , aryl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, bicyclic heterocyclyl, bicyclic heterocyclylalkyl, phosphinyl bicyclic heterocyclyl, phosphinyl bicyclic heterocyclylalkyl, fused bicyclic heterocyclylalkyl, tricyclic heterocyclyl, tricyclic heterocyclylalkyl, fused tricyclic heterocyclyl, fused tricyclic heterocyclylalkyl, bridged heterocyclyl, bridged heterocyclylalkyl, fused heterocyclyl, fused heterocyclylalkyl, spiro heterocyclyl, or spiro heterocyclylalkyl, wherein aryl, heteroaryl, by itself or as part of heteroaralkyl, heterocyclyl, by itself or as part of heterocyclylalkyl, bicyclic heterocyclyl, by itself or as part of bicyclic heterocyclylalkyl, phosphinyl bicyclic heterocyclyl, by itself or as part of phosphinyl bicyclic heterocyclylalkyl, fused bicyclic heterocyclyl as part of fused bicyclic heterocyclylalkyl, tricyclic heterocyclyl, by itself or as part of tricyclic heterocyclylalkyl, fused tricyclic heterocyclyl, by itself or as part of fused tricyclic heterocyclylalkyl, bridged heterocyclyl, by itself or as part of bridged heterocyclylalkyl, fused heterocyclyl, by itself or as part of fused heterocyclylalkyl, and spiro heterocyclyl, by itself or as part of spiro heterocyclylalkyl, are substituted with R d, R e, and R f independently selected from hydrogen, alkyl, alkenyl, haloalkenyl, cycloalkyl, cycloalkyloxy, cycloalkylalkyl, bridged cycloalkyl, halo, haloalkyl, haloalkoxy, hydroxy, alkoxy, alkylidienyl, haloalkylidienyl, alkoxyalkylidienyl, alkoxyalkyl, alkoxyalkyloxy, alkylsulfonyl, alkylsulfonylalkyl, dialkyl (oxo) phosphinyl, dialkyl (oxo) phosphinylalkyl, acyl, cyano, oxo, hydroxyalkyl, alkylamino, dialkylamino, dialkylaminocarbonylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, and optionally substituted heterocyclyl; or
    (ii) -CR 14=CR 15R 16 where R 14 and R 15 are independently selected from hydrogen, deuterium, alkyl, halo, and haloalkyl; and
    R 16 is hydrogen, deuterium, alkyl, halo, haloalkyl, cycloalkyl, bridged cycloalkyl, fused cycloalkyl, spiro cycloalkyl, heterocyclyl, bicyclic heterocyclyl, phosphinyl bicyclic heterocyclyl, bridged heterocyclyl, fused heterocyclyl, or spiro heterocyclyl; or
    R 15 and R 16 together with the carbon atom to which are attached form cycloalkyl, bridged cycloalkyl, fused cycloalkyl, spiro cycloalkyl, heterocyclyl, bridged heterocyclyl, fused heterocyclyl, or spiro heterocyclyl, wherein:
    (a) the groups alkyl, cycloalkyl, bridged cycloalkyl, fused cycloalkyl, spiro cycloalkyl, heterocyclyl, bicyclic heterocyclyl, phosphinyl bicyclic heterocyclyl, bridged heterocyclyl, fused heterocyclyl, and spiro heterocyclyl of R 15; and (b) the groups cycloalkyl, bridged cycloalkyl, fused cycloalkyl, spiro cycloalkyl, heterocyclyl, bridged heterocyclyl, fused heterocyclyl, and spiro heterocyclyl formed by R 15 and R 16 together, are independently substituted with R h, R i, and R j independently selected from hydrogen, alkyl, halo, haloalkyl, hydroxyalkyl, alkylidienyl, alkoxyalkylidienyl, alkoxyalkyl, alkylsulfonylalkyl, dialkyl (oxo) phosphinyl, dialkyl (oxo) phosphinylalkyl, cyano, cycloalkyl, bridged cycloalkyl, optionally substituted heterocyclyl, -O (alk)  z1R k, -O (alk) OR l, -S (O) R m, -S (O)  2R n, -NR pC (O) R o, -NR rSO 2R q, -OC (O) NR sR t, -C (O) NR uR v, -S (O)  2NR wR x, and -NR yR z, where z1 is 0 or 1, alk is alkylene, and R k, R l, R m, R n, R o, R p, R q, R r, R s, R t, R u, R v, R w, R x, R y, and R z are independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, halo, hydroxyalkyl, alkoxyalkyl, and aminoalkyl; and
    Q is a bond, alkylene, or -C (=O) -; and
    R 5 is, cycloalkyl, fused cycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl, wherein aryl, aryl in aralkyl, heteroaryl, and heteroaryl in heteroaralkyl are independently substituted with R aa, R bb, R cc and R dd wherein R aa and R bb are independently selected from hydrogen, alkyl, cycloalkyl, halo, haloalkyl, haloalkoxy, hydroxy, alkoxy, heteroalkyl, hydroxyalkyl, alkylcarbonyl, amino, and cyano, R cc is hydrogen, alkenyl, alkynyl, cyanoalkynyl, or halo, and R dd is hydrogen, alkyl, cycloalkyl, halo, haloalkyl, haloalkoxy, alkoxy, heteroalkyl, hydroxyalkyl, amino, cyano, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; or
    a pharmaceutically acceptable salt thereof.
  2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein ring A is cycloaminyl.
  3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein ring A is bridged cycloaminyl.
  4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein ring A is spiroaminyl.
  5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein ring A is bicycloaminyl.
  6. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein cycloaminyl is a ring of formula (a) : 
    Figure PCTCN2021092773-appb-100002
    where X is CH, NH, O, or S, m is 0 to 3, and n is 0 to 2, provided m+n is not greater than 4.
  7. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein ring A is cycloaminyl according to formula (a) : 
    Figure PCTCN2021092773-appb-100003
    where X is CH, O, or S, m is 0 to 2, and n is 0 to 3, provided that m+n is not greater than 4.
  8. The compound of claim 6 or 7, or a pharmaceutically acceptable salt thereof, wherein cycloaminyl is a ring of formula (a1) : 
    Figure PCTCN2021092773-appb-100004
    8a. The compound of claim 6, 7, or 8, or a pharmaceutically acceptable salt thereof, wherein cycloaminyl is a ring of formula:
    Figure PCTCN2021092773-appb-100005
  9. The compound of claim 6, or a pharmaceutically acceptable salt thereof, wherein cycloaminyl is a ring of formula (a2) : 
    Figure PCTCN2021092773-appb-100006
  10. The compound of claim 6 or 7, or a pharmaceutically acceptable salt thereof, wherein X is O or S, preferably O.
  11. The compound of any one of claims 6 to 8, 9, and 10, or a pharmaceutically acceptable salt thereof, is where m is 0 and n is 0.
  12. The compound of any one of claims 6 to 8, 9, and 10, or a pharmaceutically acceptable salt thereof, is where m is 0 and n is 1.
  13. The compound of any one of claims 6 to 8, 9, and 10, or a pharmaceutically acceptable salt thereof, is where m is 0 and n is 2.
  14. The compound of any one of claims 6 to 8, 9, and 10, or a pharmaceutically acceptable salt thereof, is where m is 1 and n is 1.
  15. The compound of any one of claims 6 to 8, 9, and 10, or a pharmaceutically acceptable salt thereof, is where m is 1 and n is 2.
  16. The compound of any one of claims 6 to 8, 9, and 10, or a pharmaceutically acceptable salt thereof, is where m is 1 and n is 3.
    16a. The compound of claim 6 or 16, or a pharmaceutically acceptable salt thereof, wherein cycloaminyl is a ring of formula: 
    Figure PCTCN2021092773-appb-100007
  17. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein bridged cycloaminyl is a ring of formula (b) : 
    Figure PCTCN2021092773-appb-100008
    where m1 is 1 or 2, n1 is 0 or 1, n2 is 1 or 2, X 1 is bond, CH, NH, O, or S.
  18. The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein ring A is bridged cycloaminyl accordingly to formula (b) : 
    Figure PCTCN2021092773-appb-100009
    where m1 is 1 or 2, n1 is 0 or 1, n2 is 1 or 2, X 1 is a CH, O, or S.
  19. The compound of claim 17 or 18, or a pharmaceutically acceptable salt thereof, wherein bridged cycloaminyl is a ring of formula (b1) : 
    Figure PCTCN2021092773-appb-100010
  20. The compound of claim 17, 18 or 19, or a pharmaceutically acceptable salt thereof, wherein X 1 is CH.
  21. The compound of claim 17, 18 or 19, or a pharmaceutically acceptable salt thereof, wherein X 1 is NH, O, or S.
  22. The compound of claim 17, 18 or 19, or a pharmaceutically acceptable salt thereof, wherein X 1 is a NH or O.
  23. The compound of claim 1, 3, 17, 18, 19, or 20, or a pharmaceutically acceptable salt thereof, wherein bridged cycloaminyl is a ring of formula:
    Figure PCTCN2021092773-appb-100011
  24. The compound of claim 1, 3, 17, 18, 19, or 20, or a pharmaceutically acceptable salt thereof, wherein bridged cycloaminyl is a ring of formula:
    Figure PCTCN2021092773-appb-100012
  25. The compound of claim 1 or 4, or a pharmaceutically acceptable salt thereof, wherein the spiroaminyl is a ring of formula (c) :
    Figure PCTCN2021092773-appb-100013
    where X 1 is CH, O, or NH and m2, n3, p, and q are each 0 to 3, provided that m2 + n3 + p +q is not greater than 7.
  26. The compound of claim 25, or a pharmaceutically acceptable salt thereof, wherein X 1 is CH.
  27. The compound of claim 25, or a pharmaceutically acceptable salt thereof, wherein X 1 is O.
  28. The compound of claim 1, 4, 25, or 26, or a pharmaceutically acceptable salt thereof, wherein spiroaminyl is a ring of formula:
    Figure PCTCN2021092773-appb-100014
    where each of the spiroaminyl is substituted with R 1a, R 1b, and R 1c.
  29. The compound of claim 1, 4, 25, or 26, or a pharmaceutically acceptable salt thereof, wherein spiroaminyl is a ring of formula:
    Figure PCTCN2021092773-appb-100015
    and each of the spiroaminyl is additionally substituted with R 1b and R 1c, preferably R 1b.
  30. The compound of claim 1 or 5, or a pharmaceutically acceptable salt thereof, wherein the bicycloaminyl is a ring of formula (d) :
    Figure PCTCN2021092773-appb-100016
    where X 2 is CH, O, S, or NH and m3, n4, p1, and q2 are each 0 to 3, provided that m2 + n3 +p + q is not greater than 6 and the bicycloaminyl is substituted with R 1a, R 1b, and R 1c.
  31. The compound of claim 25, or a pharmaceutically acceptable salt thereof, wherein X 2 is CH.
  32. The compound of claim 25, or a pharmaceutically acceptable salt thereof, wherein X 2 is O.
  33. The compound of claim 1, 5, 30, or 31, or a pharmaceutically acceptable salt thereof, wherein bicycloaminyl is a ring of formula:
    Figure PCTCN2021092773-appb-100017
    33a. The compound of claim 1, 5, 30, or 31, or a pharmaceutically acceptable salt thereof, wherein bicycloaminyl is a ring of formula:
    Figure PCTCN2021092773-appb-100018
  34. The compound of any one of claims 1 to 33a, or a pharmaceutically acceptable salt thereof, wherein R 1a is hydroxy.
  35. The compound of any one of claims 1 to 33a, or a pharmaceutically acceptable salt thereof, wherein R 1a is -Q 1-NR 6R 7.
  36. The compound of any one of claims 1 to 33a and 35, or a pharmaceutically acceptable salt thereof, wherein R 1a is amino, aminomethyl, aminoethyl, methylamino, ethylamino, cyclopropylamino, aminocarbonyl, methoxycarbonylamino, cyanomethylamino, 2, 2, 2-trifluoroethylamino, acetylamino, methylsulfonylamino, piperidin-4-ylamino, tetrahydropyran-4-ylamino, oxetan-3-ylamino, imidazol-2-ylamino, or oxazol-2-ylamino.
  37. The compound of any one of claims 1 to 33a and 35, or a pharmaceutically acceptable salt thereof, wherein R 1a is amino.
  38. The compound of any one of claims 1 to 33a and 35, or a pharmaceutically acceptable salt thereof, wherein R 1a is aminomethyl, methylamino, ethylamino, or cyclopropylamino, preferably aminomethyl.
  39. The compound of any one of claims 1 to 33a, or a pharmaceutically acceptable salt thereof, wherein R 1a is -NHC (=NH) (alkyl) , -NHC (=NH) NH 2, or -NHC (=O) NR 8R 9.
  40. The compound of any one of claims 1 to 33a and 39, or a pharmaceutically acceptable salt thereof, wherein R 1a is -NHC (=NH) CH 3, -NHC (=NH) NH 2, or NHC (=O) N (CH 3)  2.
  41. The compound of any one of claims 1 to 33a, or a pharmaceutically acceptable salt thereof, wherein R 1a is -Q 2-R 10.
  42. The compound of any one of claims 1 to 33a and 41, or a pharmaceutically acceptable salt thereof, wherein R 1a is azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-carbonyl, 2-methylimidazol-1-yl, 2-methyl-4, 5-dihydroimidazol-1-yl, morpholin-4-yl, 2-aminoimidazol-1-yl, 2-amino-4, 5-dihydroimidazol-1-yl, imidazol-2-yl, imidazole-1-yl, or 4, 5-dihydroimidazol-1-yl.
  43. The compound of any one of claims 1 to 42, or a pharmaceutically acceptable salt thereof, wherein R 1c is absent, hydroxy, cyano, or fluoro, preferably absent.
  44. The compound of any one of claims 1 to 43, or a pharmaceutically acceptable salt thereof, wherein R 1b is absent, cyano, fluoro, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, fluoromethyl, cyclopropyl, hydroxy, methoxy, hydroxymethyl, methoxymethyl, cyanomethyl, dimethylcarbonyl, or dimethylcarbonylmethyl.
  45. The compound of any one of claims 1 to 43, or a pharmaceutically acceptable salt thereof, wherein R 1b is absent, cyano, or cyanomethyl.
  46. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein
    Figure PCTCN2021092773-appb-100019
    is:
    Figure PCTCN2021092773-appb-100020
    Figure PCTCN2021092773-appb-100021
  47. The compound of any one of claims 1 to 46, or a pharmaceutically acceptable salt thereof, has a structure of formula (Ia) as follows:
    Figure PCTCN2021092773-appb-100022
  48. The compound of any one of claims 1 to 46, or a pharmaceutically acceptable salt thereof, has a structure of formula (Ib) as follows:
    Figure PCTCN2021092773-appb-100023
  49. The compound of any one of claims 1 to 46, or a pharmaceutically acceptable salt thereof, has a structure of formula (Ic) as follows:
    Figure PCTCN2021092773-appb-100024
  50. The compound of any one of claims 1 to 46, or a pharmaceutically acceptable salt thereof, has a structure of formula (Id) as follows:
    Figure PCTCN2021092773-appb-100025
  51. The compound of any one of claims 1 to 46, or a pharmaceutically acceptable salt thereof, has a structure of formula (Ie) as follows:
    Figure PCTCN2021092773-appb-100026
  52. The compound of any one of claims 1 to 51, or a pharmaceutically acceptable salt thereof, wherein Q is bond and R 5 is cycloalkyl, fused cycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl, wherein aryl, aryl in aralkyl, heteroaryl, and heteroaryl in heteroaralkyl are substituted with R aa, R bb, R cc and R dd wherein R aa and R bb are independently selected from hydrogen, alkyl, cycloalkyl, halo, haloalkyl, haloalkoxy, hydroxy, alkoxy, heteroalkyl, hydroxyalkyl, amino, and cyano, R cc is hydrogen, alkenyl, alkynyl, cyanoalkynyl, or halo, and R dd is hydrogen, alkyl, cycloalkyl, halo, haloalkyl, haloalkoxy, alkoxy, heteroalkyl, hydroxyalkyl, amino, cyano, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl.
  53. The compound of any one of claims 1 to 51, or a pharmaceutically acceptable salt thereof, wherein Q is alkylene and R 5 is cycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl, wherein aryl, aryl in aralkyl, heteroaryl, and heteroaryl in heteroaralkyl are substituted with R aa, R bb, R cc and R dd wherein R aa and R bb are independently selected from hydrogen, alkyl, cycloalkyl, halo, haloalkyl, haloalkoxy, hydroxy, alkoxy, heteroalkyl, hydroxyalkyl, amino, and cyano, R cc is hydrogen or halo, and R dd is hydrogen, alkyl, cycloalkyl, halo, haloalkyl, haloalkoxy, alkoxy, heteroalkyl, hydroxyalkyl, amino, cyano, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl.
  54. The compound of any one of claims 1 to 51, or a pharmaceutically acceptable salt thereof, wherein Q is -C (O) -and R 5 is cycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl, wherein aryl, aryl in aralkyl, heteroaryl, and heteroaryl in heteroaralkyl are substituted with R aa, R bb, R cc and R dd wherein R aa and R bb are independently selected from hydrogen, alkyl, cycloalkyl, halo, haloalkyl, haloalkoxy, hydroxy, alkoxy, heteroalkyl, hydroxyalkyl, amino, and cyano, R cc is hydrogen or halo, and R dd is hydrogen, alkyl, cycloalkyl, halo, haloalkyl, haloalkoxy, alkoxy,  heteroalkyl, hydroxyalkyl, amino, cyano, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl.
  55. The compound of any one of claims 1 to 51, or a pharmaceutically acceptable salt thereof, wherein R 5 is cycloalkyl, fused cycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl, wherein aryl, aryl in aralkyl, heteroaryl, and heteroaryl in heteroaralkyl are substituted with R aa, R bb, R cc and R dd wherein R aa and R bb are independently selected from hydrogen, alkyl, cycloalkyl, halo, haloalkyl, haloalkoxy, hydroxy, alkoxy, heteroalkyl, hydroxyalkyl, amino, and cyano, R cc is hydrogen, alkenyl, alkynyl, cyanoalkynyl, or halo, and R dd is hydrogen, alkyl, cycloalkyl, halo, haloalkyl, haloalkoxy, alkoxy, heteroalkyl, hydroxyalkyl, amino, cyano, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl.
  56. The compound of any one of claims 1 to 51, or a pharmaceutically acceptable salt thereof, wherein Q is bond and R 5 is phenyl or naphthyl substituted with R aa, R bb, R cc and R dd.
  57. The compound of any one of claims 1 to 51, or a pharmaceutically acceptable salt thereof, wherein Q is bond and R 5 is phenyl or naphthyl substituted with R aa, R bb, and R dd where R aa and R bb are independently selected from hydrogen, alkyl, halo, haloalkyl, hydroxy, alkoxy, haloalkoxy, cycloalkyl, amino, cyano, and hydroxyalkyl and R dd is hydrogen, alkyl, cycloalkyl, halo, haloalkyl, haloalkoxy, alkoxy, heteroalkyl, hydroxyalkyl, amino, cyano, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl.
  58. The compound of any one of claims 1 to 56, or a pharmaceutically acceptable salt thereof, wherein R aa and R bb independently selected from hydrogen, methyl, ethyl, fluoro, chloro, trifluoromethyl, difluoromethyl, trifluoromethoxy, hydroxy, methyl, ethoxy, cyclopropyl, amino, cyano, and hydroxymethyl, R cc is hydrogen, ethynyl, 2-cyanoethyn-1-yl, or fluoro, and R dd is hydrogen, methyl, fluoro, amino, or cyclopropyl.
  59. The compound of any one of claims 1 to 51, or a pharmaceutically acceptable salt thereof, wherein Q is bond and R 5 is heteroaryl substituted with R aa, R bb, R cc and R dd.
  60. The compound of claim 1 to 51 and 59, or a pharmaceutically acceptable salt thereof, wherein Q is bond and R 5 is a monocyclic heteroaryl (e.g., pyridyl, pyrimidinyl) substituted with R aa, R bb, R cc and R dd.
  61. The compound of claim 1 to 51 and 59, or a pharmaceutically acceptable salt thereof, wherein R 5 is Q is bond and R 5 is bicyclic heteroaryl (e, g, quinolinyl, isoquinolinyl, or indazolyl) , substituted with R aa, R bb, R cc and R dd.
  62. The compound of any one of claims 1 to 51 and 59 to 61, or a pharmaceutically acceptable salt thereof, wherein the heteroaryl is substituted with R aa, R bb, and R dd where R aa and R bb independently selected from hydrogen, alkyl, halo, haloalkyl, hydroxy, alkoxy, haloalkoxy, cycloalkyl, amino, cyano, and hydroxyalkyl and R dd is hydrogen, alkyl, cycloalkyl, halo, haloalkyl,  haloalkoxy, alkoxy, heteroalkyl, hydroxyalkyl, amino, cyano, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl.
  63. The compound of any one of claims 1 to 51 and 59 to 61, or a pharmaceutically acceptable salt thereof, wherein R aa and R bb are independently selected from hydrogen, methyl, ethyl, fluoro, chloro, trifluoromethyl, difluoromethyl, trifluoromethoxy, hydroxy, methyl, ethoxy, cyclopropyl, amino, cyano, and hydroxymethyl, R cc is hydrogen or fluoro, and R dd is hydrogen, methyl, fluoro, amino, or cyclopropyl.
  64. The compound of any one of claims 1 to 51, or a pharmaceutically acceptable salt thereof, wherein Q is bond and R 5 is:
    Figure PCTCN2021092773-appb-100027
  65. The compound of any one of claims 1 to 64, or a pharmaceutically acceptable salt thereof, wherein R 2 is absent, halo, or alkyl, and R 3 absent, halo, cycloalkyloxy, or alkyl.
  66. The compound of any one of claims 1 to 65, or a pharmaceutically acceptable salt thereof, wherein R 2 and R 3 are each absent.
  67. The compound of any one of claims 1 to 65, or a pharmaceutically acceptable salt thereof, wherein R 2 is absent or chloro and R 3 is absent, fluoro, or cyclopropyloxy.
  68. The compound of any one of claims 1 to 67, or a pharmaceutically acceptable salt thereof, wherein R 4 is -Z-R 11 where Z is a bond, O, NH, N (alkyl) , or S; and R 11 is alkyl, hydroxyalkyl, - (alkylene) -NR 12R 13 (where alkylene is substituted with R a, R b, and R c independently selected from hydrogen, alkyl, cycloalkyl, halo, haloalkyl, hydroxy, alkoxy, cyano, oxo, hydroxyalkyl, alkylamino, dialkylamino, dialkylaminocarbonylalkyl, aryl, heteroaryl, and heterocyclyl, R 12 is hydrogen or alkyl, and R 13 is hydrogen, alkyl, acyl, hydroxyalkyl, or heteroalkyl) , aryl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, bicyclic heterocyclyl, bicyclic heterocyclyl, bicyclic heterocyclylalkyl, bridged heterocyclyl, bridged heterocyclylalkyl, fused heterocyclyl, fused heterocyclylalkyl, spiro heterocyclyl, or spiro heterocyclylalkyl, wherein aryl, heteroaryl, by itself or as part of heteroaralkyl, heterocyclyl, by itself or as part of heterocyclylalkyl, bicyclic heterocyclyl, by itself or as part of bicyclic heterocyclylalkyl, bridged heterocyclyl, by itself or as part of bridged heterocyclylalkyl, fused heterocyclyl, by itself or as part of fused heterocyclylalkyl, and spiro heterocyclyl, by itself or as part of spiro heterocyclylalkyl, are substituted with R d, R e, and R f independently selected from hydrogen, alkyl, cycloalkyl, cycloalkyloxy, cycloalkylalkyl, bridged cycloalkyl, halo, haloalkyl, haloalkoxy, hydroxy, alkoxy, alkoxyalkyl, alkoxyalkyloxy, acyl, cyano, oxo, hydroxyalkyl, alkylamino, dialkylamino, dialkylaminocarbonylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, and optionally substituted heterocyclyl.
  69. The compound of any one of the claims 1 to 68, or a pharmaceutically acceptable salt thereof, wherein Z is O.
  70. The compound of any one of the claims 1 to 68, or a pharmaceutically acceptable salt thereof, wherein Z is NH.
  71. The compound of any one of the claims 1 to 68, or a pharmaceutically acceptable salt thereof, wherein Z is bond.
  72. The compound of any one of claims 1 to 71, or a pharmaceutically acceptable salt thereof, wherein R 11 is hydroxyalkyl, - (alkylene) -NR 12R 13 (where alkylene is substituted with R a, R b, and R c independently selected from hydrogen, alkyl, hydroxy, and hydroxyalkyl, R 12 is hydrogen or alkyl, and R 13 is hydrogen, alkyl, or hydroxyalkyl) , heteroaralkyl, heterocyclyl, heterocyclylalkyl, bicyclic heterocyclyl, bicyclic heterocyclylalkyl, bridged heterocyclylalkyl, fused heterocyclylalkyl, and spiro heterocyclylalkyl, wherein heterocyclyl, by itself or as part of heterocyclylalkyl, bicyclic heterocyclyl, by itself or as part of bicyclic heterocyclylalkyl, bridged heterocyclyl as part of bridged heterocyclylalkyl, fused heterocyclyl as part of fused heterocyclylalkyl, and spiro heterocyclyl as part of spiro heterocyclylalkyl, are substituted with R d, R e, and R f independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, halo, hydroxy,  alkoxy, alkoxyalkyl, acyl, hydroxyalkyl, alkylamino, dialkylamino, cyano, and optionally substituted aralkyl.
  73. The compound of any one of claims 1 to 71, or a pharmaceutically acceptable salt thereof, wherein R 11 is 2-dimethylaminoethyl, diethylaminoethyl, 3-methylaminoprop-2-yl, 3-dimethylaminopropyl, 3-dimethylaminoprop-2-yl, 4-dimethylaminobut-2-yl, 4-dimethylaminobut-3-yl, 4-dimethylaminobutyl, 2-dimethylamino-3-hydroxypropyl, 2-dimethylaminoprop-1-yl, 4-methylpiperazin-1-yl, 4- (2-hydroxyethyl) piperazin-1-yl, 4-methylpiperazin-2-yl) methyl, 3- (4-methylpiperazin-1-yl) propyl, 4-dimethylamino-piperidin-1-yl, 1-methylpiperidin-4-yl, piperidin-2-ylmethyl, 2-piperidin-1-ylethyl, 3-piperidin-1-ylpropyl, 3-piperidin-1-ylprop-2-yl, 1-methylpiperidin-3-yl, 2-oxopiperidin-6-ylmethyl, 2- (4-cyanopiperidin-1-yl) ethyl, 2- (2-methylpiperidin-1-yl) ethyl, 2- (4-methylpiperidin-1-yl) ethyl, 3-methoxypiperidin-1-ylethyl, 4-methoxypiperidin-1-ylethyl, 1-cyclopropylpiperidin-4-yl, 2- (4, 4-difluoropiperidin-1-yl) ethyl, 2- (3-fluoropiperidin-1-yl) ethyl, 1-methylpiperidin-3-ylmethyl, pyrrolidin-1-yl, pyrrolidin-2-ylmethyl, pyrrolidin-3-ylmethyl, pyrrolidin-1-ylethyl, 3-pyrrolidin-1-ylprop-2-yl, 1-methylpyrrolidin-3-yl, 3-pyrrolidin-1-ylpropyl, 3-fluoropyrrolidin-1-ylethyl, 3, 3-difluoropyrrolidin-1-ylethyl, 3-dimethylaminopyrrolidin-1-yl, 2-oxopyrrolidin-5-ylmethyl, 2- (3-methoxypyrrolidin-1-yl) ethyl, 3- (3-methoxypyrrolidin-1-yl) propyl. 3-methoxypyrrolidin-1-yl) prop-2-yl. 3- (3-hydroxypyrrolidin-1-yl) prop-2-yl, 1-methylpyrrolidin-3-ylmethyl, 1-methylpyrrolidin-2-ylmethyl, 1-ethylpyrrolidin-2-ylmethyl, 1-methylpyrrolidin-3-ylmethyl, 2- (1-methylpyrrolidin-2-yl) ethyl, 1- (2-hydroxyethyl) pyrrolidin-3-ylmethyl, 1- (2-methoxyethyl) -pyrrolidin-3-ylmethyl, 1-isopropylpyrrolidin-3-ylmethyl, 5, 5-dimethylpyrrolidin-2-yl, 1-benzylpyrrolidin-3-ylmethyl, 1-cyclopropylpyrrolidin-3-ylmethyl, 3- (3, 4-difluoropyrrolidin-1-yl) propyl, 3-hydroxy-1-methylpyrrolidin-2-ylmethyl, 4-hydroxy-1-methylpyrrolidin-2-ylmethyl, 3-fluoro-1-methylpyrrolidin-2-ylmethyl, 4-fluoro-1-methylpyrrolidin-2-ylmethyl, 4, 4-difluoro-1-methylpyrrolidin-2-ylmethyl, 4-methoxy-1-methylpyrrolidin-2-ylmethyl, 1, 2-dimethylpyrrolidin-2-ylmethyl, 1-isopropylpyrrolidin-2-ylmethyl, 1-cyclopropylmethylpyrrolidin-2-ylmethyl, 1, 5, 5-trimethylpyrrolidin-2-yl, 4-methoxy-1-methylpyrrolidin-2-ylmethyl, 4-methoxy-1-ethylpyrrolidin-2-ylmethyl, morpholin-4-yl, 2-morpholin-4-ylethyl, 3-morpholin-4-ylpropyl, 3-morpholin-3-ylprop-2-yl, 4-morpholin-4-ylbutyl, 4-morpholin-4-ylbut-2-yl, 4-methylmorpholin-2-ylmethyl, 4-methylmorpholin-3-ylmethyl, 5-methylmorpholin-3-ylmethyl, 5, 5-dimethylmorpholin-3-ylmethyl, 2- ( (1S, 4R) -2-azabicyclo [2.2.1 ] heptan-2-yl) ethyl, 2-pyridin-2-ylethyl, or 3- (3-azabicyclo [3.1.0] -hexan-3-ylpropyl.
  74. The compound of any one of claims 1 to 67, or a pharmaceutically acceptable salt thereof, wherein R 4 is -Z-R 11 where Z is a bond, O, NH, N (alkyl) , or S; and R 11 is phenyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, bicyclic heterocyclyl, bicyclic heterocyclylalkyl, bridged heterocyclyl, bridged heterocyclylalkyl, fused heterocyclyl, fused heterocyclylalkyl, spiro heterocyclyl, or spiro heterocyclylalkyl, wherein phenyl, heteroaryl, by  itself or as part of heteroaralkyl, heterocyclyl, by itself or as part of heterocyclylalkyl, bicyclic heterocyclyl, by itself or as part of bicyclic heterocyclylalkyl, bridged heterocyclyl, by itself or as part of bridged heterocyclylalkyl, fused heterocyclyl, by itself or as part of fused heterocyclylalkyl, and spiro heterocyclyl, by itself or as part of spiro heterocyclylalkyl, are substituted with R d, R e, and R f independently selected from hydrogen, alkyl, cycloalkyl, cycloalkyloxy, cycloalkylalkyl, bridged cycloalkyl, halo, haloalkyl, haloalkoxy, hydroxy, alkoxy, alkylidienyl, haloalkyldienyl, alkoxyalkylidienyl, alkoxyalkyl, alkoxyalkyloxy, alkylsulfonyl, alkylsulfonylalkyl, dialkyl (oxo) phosphinyl, dialkyl (oxo) phosphinylalkyl, acyl, cyano, oxo, hydroxyalkyl, alkylamino, dialkylamino, dialkylaminocarbonylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, and optionally substituted heterocyclyl.
  75. The compound of any one of claims 1 to 67, or a pharmaceutically acceptable salt thereof, wherein R 4 is:
    Figure PCTCN2021092773-appb-100028
  76. The compound any one of claim 1 to 67, or a pharmaceutically acceptable salt thereof, wherein R 4 is is -Z-R 11 where Z is O; and R 11 is, phosphinyl bicyclic heterocyclylalkyl, fused bicyclic heterocyclylalkyl, tricyclic heterocyclyl, tricyclic heterocyclylalkyl, fused tricyclic heterocyclyl, fused tricyclic heterocyclylalkyl, , or bicyclic heterocyclylalkyl wherein phosphinyl bicyclic heterocyclyl, by itself of as part of phosphinyl bicyclic heterocyclylalkyl, fused bicyclic heterocyclyl as part of fused bicyclic heterocyclylalkyl, tricyclic heterocyclyl, by itself or as part of tricyclic heterocyclylalkyl and fused tricyclic heterocyclyl, by itself or as part of fused tricyclic heterocyclylalkylare substituted with R d, R e, and R f independently selected from hydrogen, alkyl, alkenyl, haloalkenyl, cycloalkyl, cycloalkyloxy, cycloalkylalkyl, bridged cycloalkyl, halo, haloalkyl, haloalkoxy, hydroxy, alkoxy, alkylidienyl, haloalkylidienyl, alkoxyalkylidienyl, alkoxyalkyl, alkoxyalkyloxy, alkylsulfonyl, alkylsulfonylalkyl, dialkyl (oxo) phosphinyl, dialkyl (oxo) phosphinylalkyl, acyl, cyano, oxo, hydroxyalkyl, alkylamino, dialkylamino, dialkylaminocarbonylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, and optionally substituted heterocyclyl; and
    bicyclic heterocyclyl as part of fused bicyclic heterocyclylalkyl are substituted with alkylidene or haloalkylidene.
  77. The compound of claim 76, or a pharmaceutically acceptable salt thereof, wherein R 4 is:
    Figure PCTCN2021092773-appb-100029
    Figure PCTCN2021092773-appb-100030
  78. A pharmaceutical composition comprising a compound of any one of claims 1 to 77 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
  79. A method of treating cancer in a patient, preferably the patient is in need of such treatment, which method comprises administering to the patient, a therapeutically effective amount of a pharmaceutical composition comprising a compound of any one of claims 1 to 77, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
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WO2023138583A1 (en) * 2022-01-21 2023-07-27 上海湃隆生物科技有限公司 Heterocyclic compound, pharmaceutical composition and use thereof
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