WO2023030517A1 - Inhibiteurs de kras g12c et leurs utilisations - Google Patents

Inhibiteurs de kras g12c et leurs utilisations Download PDF

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WO2023030517A1
WO2023030517A1 PCT/CN2022/116994 CN2022116994W WO2023030517A1 WO 2023030517 A1 WO2023030517 A1 WO 2023030517A1 CN 2022116994 W CN2022116994 W CN 2022116994W WO 2023030517 A1 WO2023030517 A1 WO 2023030517A1
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compound
pharmaceutically acceptable
acceptable salt
alkyl
heterocyclyl
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PCT/CN2022/116994
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English (en)
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Zheng Wang
Ding Zhou
Ziqiang CHENG
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Suzhou Zanrong Pharma Limited
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Priority to CN202280008285.6A priority Critical patent/CN117222654A/zh
Publication of WO2023030517A1 publication Critical patent/WO2023030517A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed systems contains four or more hetero rings
    • 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 generally relates to novel compounds useful as inhibitors of the KRAS G12C, as well as pharmaceutical compositions comprising these compounds and methods of treatment by administration of these compounds or the pharmaceutical compositions.
  • RAS is one of the most well-known proto-oncogenes. Its gain-of-function mutations occur in approximately 30%of all human cancers. As the most frequently mutated RAS isoform, KRAS (Kirsten-rat sarcoma viral oncogene homolog) is intensively studied in the past years. KRAS and the highly related NRAS and HRAS GTPases hydrolyze guanosine triphosphate (GTP) to guanosine diphosphate (GDP) . They control diverse cellular functions by cycling between an active, GTP-bound and an inactive, GDP-bound conformation (Hobbs, G.A., et al. J. Cell Sci. 129, 1287–1292, (2016) ) .
  • GTP guanosine triphosphate
  • GDP guanosine diphosphate
  • KRAS is a prominent oncogene that has been proven to drive tumorigenesis (G G Jinesh, et al. Oncogene volume 37, pages 839–846 (2016) ) .
  • K-RAS also modulates numerous genetic regulatory mechanisms and forms a large tumorigenesis network.
  • KRAS gene encodes a 21 kDa protein, called KRAS, part of the RAS/MAPK pathway.
  • the KRAS protein is a GTPase, which means it binds to guanine nucleotides GDP and guanosine-triphosphate (GTP) with high affinity and can hydrolyze GTP to GDP (Dhirendra K. Simanshu, et al. Cell. 2017 Jun 29; 170 (1) : 17–33) .
  • GDP/GTP cycling is tightly regulated by a diverse family of multi-domain proteins: guanine nucleotide exchange-factors (GEFs) and GTPase-activating proteins (GAPs) .
  • GEFs stimulate the dissociation of GDP and subsequent association of GTP, activating KRAS proteins, while GAPs act to accelerate intrinsic GTP hydrolysis, converting KRAS to its inactive state (Dhirendra K. Simanshu, et al. Cell. 2017 Jun 29; 170 (1) : 17–33) .
  • the GTP bound form of KRAS is considered the active form, and downstream signaling effectors specifically bind to the GTP-bound form of KRAS.
  • the KRAS protein is turned off (inactivated) when the protein is bound to GDP and does not relay signals to the cell's nucleus.
  • KRAS mutations are present in up to 25%of cancers, the oncogenic variants have different prevalence rates in different cancers.
  • the G12C mutation one of the most common KRAS mutations, is present in an estimated around 14%of lung adenocarcinomas and in 3%of colon adenocarcinomas.
  • lung adenocarcinomas According to the American Cancer Society, around 200,000 patients are diagnosed each year with lung adenocarcinomas. That puts the KRAS-G12C population in the USA at 14,000–28,000 patients per year.
  • KRAS-G12C-positive colorectal cancer (CRC) closer to 3,000 patients are diagnosed each year.
  • KRAS-G12C accounts for over 40%of all KRAS mutations, and has therefore been a key target for cancer drug developers.
  • G12C is a single point mutation with a glycine-to-cysteine substitution at codon 12.
  • the presence of cysteine at position 12 in KRAS-G12C protects bound GTP from the rapid regulated hydrolysis catalyzed by GTPase activating protein (GAP) family proteins, resulting in overall pathway activation (Victoria Dunnett-Kane, et al. Cancers (Basel) 2021 Jan; 13 (1) : 151) .
  • GAP GTPase activating protein
  • the brain is a common site for metastasis in NSCLC patients, present in 25-30%of patients at diagnosis and the majority (40-50%) of patients will develop brain metastases during the course of their disease (Timothy G. et al. Transl Lung Cancer Res 2013; 2 (4) : 273-283) .
  • the prevalence of brain metastasis (BM) was high in patients with KRAS-G12C NSCLC; 28 %of patients had BM at diagnosis, and 40 %of patients developed BM during follow up (W. Cui, et al. Lung Cancer 146 (2020) 310–317) .
  • the incidence of BM from CRC ranges from 0.6 to 3.2 %.
  • Metastatic spread in CRC is thought to progress sequentially in many patients, from liver to lung and then to bone and brain as late sites of involvement. Strikingly, nearly two-thirds of the brain metastases identified occurred in RAS mutant mCRC and patients with KRAS-G12C-mutant mCRC have shorter overall survival (OS) than patients with other KRAS-mutant cancers (Sophie Müller. et al. Cancers 2021, 13, 900) .
  • Brain metastases from solid extracranial tumors is now estimated to be ⁇ 10 times higher than for primary malignant brain tumors (Kromer, C. et al. J. Neurooncol. 134, 55–64 (2017) ) .
  • Treatment options with lung cancer or colon adenocarcinomas brain metastases are limited and include local treatment (surgical resection, whole-brain radiation therapy (WBRT) , stereotactic radiosurgery (SRS) ) and systemic treatment (chemotherapy and targeted therapy) .
  • Local treatments are to reduce symptoms (palliative) but cause serious side effects (neurological damage, “tumor spill” , cognitive deterioration) .
  • Big problem for systemic treating brain metastases is that systemic drugs are unable to penetrate the blood-brain barrier (BBB) .
  • BBB blood-brain barrier
  • P-gp P-glycoprotein
  • BCRP breast cancer resistance protein
  • ARS-1620 was the first G12C specific inhibitor able to demonstrate in vivo efficacy, and since then several other related compounds with increased biological activity have been produced, the earliest of which to enter the clinic are Adagrasib (MRTX849) and Sotorasib (AMG-510) (Janes, M.R. et al. Cell, 172, 578–589. e17 (2018) ; Canon, J. et al. Nature, 575, 217–223 (2019) ; Hallin, J. et al. Cancer Discov., 10, 54–71 (2020) ) .
  • Adagrasib MRTX849
  • Sotorasib AMG-510
  • KRAS G12C appears to retain a near wild-type level of GTPase activity and undergoes nucleotide cycling in the cell. G12C inhibitors act by preventing further nucleotide exchange, thus “trapping” the protein in a state of inactivity (Janes, M.R. et al. Cell, 172, 578–589. e17 (2016) ) .
  • the intrinsic GTPase activity of KRAS-G12C accounts not only for the efficacy of direct inactive-state inhibitors, but also widens the possibility of effective upstream targeting in G12C-mutant cancers.
  • Brain metastases from solid extracranial tumors represent an unmet need of increasing relevance as their incidence is rising considerably.
  • the field of targeted therapies and immunotherapy in brain metastases is rapidly expanding.
  • KRAS-G12C variants are most commonly found in non-small cell lung cancer and colorectal cancer (CRC) .
  • NSCLC is the most common cause of BM and the development of BM in CRC is associated the KRAS-G12C mutation.
  • KRAS-G12C is one of the most common driver oncoproteins and is dependent on nucleotide exchange for activation and susceptible to drugs that block this process. Inactive state-selective inhibitors disrupt the cycle and trap KRAS-G12C in its GDP-bound state to suppress tumor growth in cancer patients.
  • KRAS-G12C-selective inhibitors that demonstrate sufficient efficacy for targeting KRAS-G12C, in particular new KRAS-G12C-selective inhibitors that are BBB penetrable and thus promising for treating patients of KRAS-G12C lung cancer and colorectal cancer, particularly those with brain metastasis.
  • novel compounds that are capable of inhibiting KRAS G12C proteins.
  • the compounds of the present disclosure are useful in the treatment of KRAS G12C-associated diseases such as cancers.
  • the present disclosure provides a compound having Formula (I) or Formula (II) :
  • G is C (R a ) or N;
  • R a is absent, hydrogen, deuterium, cyano, halogen, alkyl, haloalkyl, heteroalkyl, hydroxyalkyl, or -C (O) N (R c ) 2 ;
  • each R b is independently hydrogen, deuterium, halogen, cyano, alkyl, alkoxy, heteroalkyl, cycloalkyl, or heteroaryl, wherein the alkyl, heteroalkyl, cycloalkyl and heteroaryl are optionally substituted with one or more groups independently selected from the group consisting of hydroxyl, halogen, -NR c R d , and heterocyclyl optionally substituted with one or more groups selected from hydroxyl, halogen, cyano and amino;
  • each R c is independently hydrogen, alkyl, alkenyl, alkynyl or haloalkyl
  • R d is selected from the group consisting of alkyl optionally substituted with heteroaryl or -N (R c ) 2 , haloalkyl, -C (O) N (R c ) 2 , - (CH 2 ) n NHC (O) -alkyl, heterocyclyl, and heteroaryl, wherein the heterocyclyl and heteroaryl is optionally substituted with one or more groups independently selected from halogen, hydroxyl, amino, cyano, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, heteroalkyl, hydroxyalkyl, -O-haloalkyl and –S-haloalkyl;
  • W is CR e or N
  • R e is selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, -OR c , alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl, wherein alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl are optionally substituted with one or more groups independently selected from the group consisting of hydroxyl, halogen, cyano, -OR c , and -N (R c ) 2 ;
  • Q is CR f or N
  • R f is –Y- (CH 2 ) m -T-R g , wherein - (CH 2 ) m -is optionally substituted with hydroxyl, halogen, cyano or amino;
  • Y is selected from a bond, -O-, -S-, -N (R c ) -, or alkynyl;
  • T is selected from a bond, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one or more groups independently selected from oxo, hydroxyl, halogen, cyano, amino, alkyl, hydroxyalkyl or heteroaryl;
  • each R’ is independently selected from hydroxyl, halogen, -C (O) H, alkyl, alkoxy, haloalkyl, hydroxyalkyl, or -N (R c ) 2 ;
  • each R is independently selected from oxo, hydroxyl, halogen, alkyl, heteroalkyl, hydroxyalkyl, haloalkyl, alkoxy, -E-phenyl, -E-phenylSO 2 F, -N (R c ) 2 , -SO 2 F, -C (O) (alkyl) , or -C (O) (haloalkyl) , wherein the alkyl, heteroalkyl, hydroxyalkyl, haloalkyl, and alkoxy are optionally substituted with one or more groups independently selected from aryl, heteroaryl, or tert-butyldimethylsilyloxy;
  • E is a bond, -O-, or -NHC (O) -;
  • each of R 1a , R 1b , R 2a , R 2b , R 3a , R 3b , and R 4 is independently selected from absent, hydrogen, oxo, hydroxyl, halogen, cyano, alkyl, alkenyl, alkynyl, heteroalkyl, -C (O) OR c , -C (O) N (R c ) 2 , -N (R c ) 2 or heteroaryl, wherein the alkyl, alkenyl, alkynyl and heteroaryl are optionally substituted with one or more groups independently selected from cyano, hydroxyl, halogen, -OR c , or -N (R c ) 2 , or -SO 2 (R c ) ; or
  • R 1a , R 1b , R 2a , R 2b , R 3a , R 3b , and R 4 together with the carbon atom (s) they are attached form alkyl, alkenyl, cycloalkyl or heterocyclyl, said alkyl, cycloalkyl or heterocyclyl are optionally substituted with one or more groups independently selected from cyano, halogen, hydroxyl, amino, alkoxy, alkyl, alkenyl, or alkynyl;
  • L 1 is a bond, - [C (R h ) 2 ] u -*, - [C (R h ) 2 ] u -C (O) -*or –N (R c ) C (O) -*, wherein *denotes a point of attachment of L 1 to L 2 ;
  • L 2 is a bond, -O-, -N (R i ) -, or -S (O) v -;
  • each R h is independently selected from the group consisting of hydrogen, hydroxyl, halogen, cyano, amino, nitro, alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, and heterocyclyl, wherein alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, and heterocyclyl are optionally substituted with one or more group independently consisting of hydroxyl, halogen, cyano, amino, nitro, alkyl, alkoxy, haloalkyl, and hydroxyalkyl; or
  • R i is selected from absent, hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, or -C (O) -heterocyclyl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl and cycloalkyl are optionally substituted with one or more R”’, and the heterocyclyl portion in -C (O) -heterocyclyl is optionally substituted with one or more groups independently selected from halogen, hydroxyl, cyano, alkyl and -N (R c ) 2 ;
  • R h and R i together with the carbon atom and nitrogen atom they are attached respectively form a heterocyclyl or heteroaryl optionally substituted with one or more groups independently selected from cyano, halogen, hydroxyl, amino, nitro, alkoxy, haloalkyl, hydroxyalkyl, alkyl or -alkyl-N (R c ) 2 ;
  • each R”’ is independently selected from -N (R c ) 2 , hetercyclyl optionally substituted with one or more groups independently selected from halogen, hydroxyl, cyano, or alkyl;
  • L 3 is a bond, -C (O) -, or alkyl
  • R 5 is hydrogen, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more R j ;
  • each R j is independently selected from the group consisting of hydrogen, oxo, hydroxyl, halogen, cyano, amino, nitro, alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more group independently consisting of deuterium, hydroxyl, halogen, cyano, amino, nitro, alkyl, alkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • n 0, 1 or 2;
  • n is an integer from 0 to 4.
  • p is an integer from 0 to 2;
  • r is 1 or 2;
  • u is an integer from 0 to 4.
  • v is an integer from 0 to 2;
  • R a is present, R b is present and r is 2, or R a and R b and the carbon atom to which they are attached form cycloalkyl optionally substituted with one or more R e .
  • the present disclosure provides a compound having Formula (Ia) or Formula (Ic) :
  • ring A is a heterocyclyl or heteroaryl optionally substituted with one or more groups independently selected from cyano, halogen, hydroxyl, amino, alkyl, alkoxy, haloalkyl, hydroxyalkyl, or -alkyl-N (R c ) 2 .
  • the present disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of the present disclosure or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • the present disclosure provides a method for inhibiting KRas G12C activity in a subject in need thereof, comprising administering an effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of the present disclosure to the subject.
  • the present disclosure provides a method for treating a KRas G12C-associated cancer comprising administering an effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of the present disclosure to a subject in need thereof.
  • the present disclosure provides a method for treating cancer in a subject in need thereof, the method comprising:
  • the present disclosure provides use of the compound of the present disclosure or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of the present disclosure in the manufacture of a medicament for treating cancer.
  • the present disclosure provides a compound of present disclosure or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of the present disclosure, for use in the treatment of cancer.
  • linking substituents are described. It is specifically intended that each linking substituent includes both the forward and backward forms of the linking substituent.
  • -NR (CR’R”) -includes both -NR (CR’R”) -and - (CR’R”) NR-.
  • the Markush variables listed for that group are understood to be linking groups. For example, if the structure requires a linking group and the Markush group definition for that variable lists “alkyl” , then it is understood that the “alkyl” represents a linking alkylene group.
  • a dash “-” at the front or end of a chemical group is used, a matter of convenience, to indicate a point of attachment for a substituent.
  • -OH is attached through the carbon atom; chemical groups may be depicted with or without one or more dashes without losing their ordinary meaning.
  • a wavy line drawn through a line in a structure indicates a point of attachment of a group. Unless chemically or structurally required, no directionality is indicated or implied by the order in which a chemical group is written or named.
  • a solid line coming out of the center of a ring indicates that the point of attachment for a substituent on the ring can be at any ring atom.
  • any variable e.g., R i
  • its definition at each occurrence is independent of its definition at every other occurrence.
  • R i the definition at each occurrence is independent of its definition at every other occurrence.
  • the group may optionally be substituted with up to two R i moieties and R i at each occurrence is selected independently from the definition of R i .
  • combinations of substituents and/or variables are permissible, but only if such combinations result in stable compounds.
  • the term “compounds provided herein” refers to the compounds of Formula (I) , Formula (Ia) , Formula (Ib) , Formula (Ic) as well as the specific compounds disclosed herein.
  • C i-j indicates a range of the carbon atoms numbers, wherein i and j are integers and the range of the carbon atoms numbers includes the endpoints (i.e. i and j) and each integer point in between, and wherein j is greater than i.
  • C 1-6 indicates a range of one to six carbon atoms, including one carbon atom, two carbon atoms, three carbon atoms, four carbon atoms, five carbon atoms and six carbon atoms.
  • the term “C 1-12 ” indicates 1 to 12, particularly 1 to 10, particularly 1 to 8, particularly 1 to 6, particularly 1 to 5, particularly 1 to 4, particularly 1 to 3 or particularly 1 to 2 carbon atoms.
  • alkyl refers to a saturated linear or branched-chain hydrocarbon radical, which may be optionally substituted independently with one or more substituents described below.
  • C i-j alkyl refers to an alkyl having i to j carbon atoms.
  • alkyl groups contain 1 to 10 carbon atoms.
  • alkyl groups contain 1 to 9 carbon atoms.
  • alkyl groups contain 1 to 8 carbon atoms, 1 to 7 carbon atoms, 1 to 6 carbon atoms, 1 to 5 carbon atoms, 1 to 4 carbon atoms, 1 to 3 carbon atoms, or 1 to 2 carbon atoms.
  • C 1-10 alkyl examples include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, and decyl.
  • C 1-6 alkyl are methyl, ethyl, propyl, isopropyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2, 3-dimethyl-2-butyl, 3, 3-dimethyl-2-butyl, and the like.
  • alkenyl refers to linear or branched-chain hydrocarbon radical having at least one carbon-carbon double bond, which may be optionally substituted independently with one or more substituents described herein, and includes radicals having “cis” and “trans” orientations, or alternatively, “E” and “Z” orientations.
  • alkenyl groups contain 2 to 12 carbon atoms. In some embodiments, alkenyl groups contain 2 to 11 carbon atoms.
  • alkenyl groups contain 2 to 11 carbon atoms, 2 to 10 carbon atoms, 2 to 9 carbon atoms, 2 to 8 carbon atoms, 2 to 7 carbon atoms, 2 to 6 carbon atoms, 2 to 5 carbon atoms, 2 to 4 carbon atoms, 2 to 3 carbon atoms, and in some embodiments, alkenyl groups contain 2 carbon atoms.
  • alkenyl group include, but are not limited to, ethylenyl (or vinyl) , propenyl (allyl) , butenyl, pentenyl, 1-methyl-2 buten-1-yl, 5-hexenyl, and the like.
  • alkynyl refers to a linear or branched hydrocarbon radical having at least one carbon-carbon triple bond, which may be optionally substituted independently with one or more substituents described herein.
  • alkenyl groups contain 2 to 12 carbon atoms. In some embodiments, alkynyl groups contain 2 to 11 carbon atoms.
  • alkynyl groups contain 2 to 11 carbon atoms, 2 to 10 carbon atoms, 2 to 9 carbon atoms, 2 to 8 carbon atoms, 2 to 7 carbon atoms, 2 to 6 carbon atoms, 2 to 5 carbon atoms, 2 to 4 carbon atoms, 2 to 3 carbon atoms, and in some embodiments, alkynyl groups contain 2 carbon atoms.
  • alkynyl group include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, and the like.
  • alkoxy refers to an alkyl group, as previously defined, attached to the parent molecule through an oxygen atom.
  • C i-j alkoxy means that the alkyl moiety of the alkoxy group has i to j carbon atoms.
  • alkoxy groups contain 1 to 10 carbon atoms.
  • alkoxy groups contain 1 to 9 carbon atoms.
  • alkoxy groups contain 1 to 8 carbon atoms, 1 to 7 carbon atoms, 1 to 6 carbon atoms, 1 to 5 carbon atoms, 1 to 4 carbon atoms, 1 to 3 carbon atoms, or 1 to 2 carbon atoms.
  • C 1-6 alkoxy examples include, but are not limited to, methoxy, ethoxy, propoxy (e.g. n-propoxy and isopropoxy) , t-butoxy, neopentoxy, n-hexoxy, and the like.
  • amino refers to —NH 2 group. Amino groups may also be substituted with one or more groups such as alkyl, aryl, carbonyl or other amino groups.
  • aryl refers to monocyclic and polycyclic ring systems having a total of 5 to 20 ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 12 ring members.
  • aryl include, but are not limited to, phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents. Also included within the scope of the term “aryl” , as it is used herein, is a group in which an aromatic ring is fused to one or more additional rings.
  • polycyclic ring system In the case of polycyclic ring system, only one of the rings needs to be aromatic (e.g., 2, 3-dihydroindole) , although all of the rings may be aromatic (e.g., quinoline) .
  • the second ring can also be fused or bridged.
  • polycyclic aryl include, but are not limited to, benzofuranyl, indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, and the like.
  • Aryl groups can be substituted at one or more ring positions with substituents as described above.
  • cyano refers to —CN.
  • cyanoalkyl refers to an alkyl, as defined above, that is substituted by one or more cyano groups, as defined above.
  • cycloalkyl refers to a monovalent non-aromatic, saturated or partially unsaturated monocyclic and polycyclic ring system, in which all the ring atoms are carbon and which contains at least three ring forming carbon atoms.
  • the cycloalkyl may contain 3 to 12 ring forming carbon atoms, 3 to 10 ring forming carbon atoms, 3 to 9 ring forming carbon atoms, 3 to 8 ring forming carbon atoms, 3 to 7 ring forming carbon atoms, 3 to 6 ring forming carbon atoms, 3 to 5 ring forming carbon atoms, 4 to 12 ring forming carbon atoms, 4 to 10 ring forming carbon atoms, 4 to 9 ring forming carbon atoms, 4 to 8 ring forming carbon atoms, 4 to 7 ring forming carbon atoms, 4 to 6 ring forming carbon atoms, 4 to 5 ring forming carbon atoms.
  • Cycloalkyl groups may be saturated or partially unsaturated. Cycloalkyl groups may be substituted. In some embodiments, the cycloalkyl group may be a saturated cyclic alkyl group. In some embodiments, the cycloalkyl group may be a partially unsaturated cyclic alkyl group that contains at least one double bond or triple bond in its ring system. In some embodiments, the cycloalkyl group may be monocyclic or polycyclic. The fused, spiro and bridged ring systems are also included within the scope of this definition.
  • Examples of monocyclic cycloalkyl group include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl and cyclododecyl.
  • polycyclic cycloalkyl group examples include, but are not limited to, adamantyl, norbornyl, fluorenyl, spiro-pentadienyl, spiro [3.6] -decanyl, bicyclo [1, 1, 1] pentenyl, bicyclo [2, 2, 1] heptenyl, and the like.
  • halogen refers to an atom selected from fluorine (or fluoro) , chlorine (or chloro) , bromine (or bromo) and iodine (or iodo) .
  • haloalkyl refers to an alkyl, as defined above, that is substituted by one or more halogens, as defined above.
  • haloalkyl include, but are not limited to, trifluoromethyl, difluoromethyl, trichloromethyl, 2, 2, 2-trifluoroethyl, 1, 2-difluoroethyl, 3-bromo-2-fluoropropyl, 1, 2-dibromoethyl, and the like.
  • heteroatom refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen (including N-oxides) .
  • heteroalkyl refers to an alkyl, at least one of the carbon atoms of which is replaced with a heteroatom selected from N, O, or S.
  • the heteroalkyl may be a carbon radical or heteroatom radical (i.e., the heteroatom may appear in the middle or at the end of the radical) , and may be optionally substituted independently with one or more substituents described herein.
  • heteroalkyl encompasses alkoxy and heteroalkoxy radicals.
  • heteroalkenyl refers to an alkenyl, at least one of the carbon atoms of which is replaced with a heteroatom selected from N, O, or S.
  • the heteroalkenyl may be a carbon radical or heteroatom radical (i.e., the heteroatom may appear in the middle or at the end of the radical) , and may be optionally substituted independently with one or more substituents described herein.
  • heteroalkynyl refers to an alkynyl, at least one of the carbon atoms of which is replaced with a heteroatom selected from N, O, or S.
  • the heteroalkynyl may be a carbon radical or heteroatom radical (i.e., the heteroatom may appear in the middle or at the end of the radical) , and may be optionally substituted independently with one or more substituents described herein.
  • heteroaryl refers to an aryl group having, in addition to carbon atoms, one or more heteroatoms.
  • the heteroaryl group can be monocyclic. Examples of monocyclic heteroaryl include, but are not limited to, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, benzofuranyl and pteridinyl.
  • the heteroaryl group also includes polycyclic groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring.
  • polycyclic heteroaryl include, but are not limited to, indolyl, isoindolyl, benzothienyl, benzofuranyl, benzo [1, 3] dioxolyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, dihydroquinolinyl, dihydroisoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl
  • heterocyclyl refers to a saturated or partially unsaturated carbocyclyl group in which one or more ring atoms are heteroatoms independently selected from oxygen, sulfur, nitrogen, phosphorus, and the like, the remaining ring atoms being carbon, wherein one or more ring atoms may be optionally substituted independently with one or more substituents.
  • the heterocyclyl is a saturated heterocyclyl.
  • the heterocyclyl is a partially unsaturated heterocyclyl having one or more double bonds in its ring system.
  • the heterocyclyl may contains any oxidized form of carbon, nitrogen or sulfur, and any quaternized form of a basic nitrogen.
  • Heterocyclyl also includes radicals wherein the heterocyclyl radicals are fused with a saturated, partially unsaturated, or fully unsaturated (i.e., aromatic) carbocyclic or heterocyclic ring.
  • the heterocyclyl radical may be carbon linked or nitrogen linked where such is possible.
  • the heterocycle is carbon linked.
  • the heterocycle is nitrogen linked.
  • a group derived from pyrrole may be pyrrol-1-yl (nitrogen linked) or pyrrol-3-yl (carbon linked) .
  • a group derived from imidazole may be imidazol-1-yl (nitrogen linked) or imidazol-3-yl (carbon linked) .
  • 3-to 12-membered heterocyclyl refers to a 3-to 12-membered saturated or partially unsaturated monocyclic or polycyclic heterocyclic ring system having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • the fused, spiro and bridged ring systems are also included within the scope of this definition.
  • monocyclic heterocyclyl examples include, but are not limited to oxetanyl, 1, 1-dioxothietanylpyrrolidyl, tetrahydrofuryl, tetrahydrothienyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, thiazolyl, piperidyl, piperazinyl, piperidinyl, morpholinyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, pyridonyl, pyrimidonyl, pyrazinonyl, pyrimidonyl, pyridazonyl, pyrrolidinyl, triazinonyl, and the like.
  • fused heterocyclyl examples include, but are not limited to, phenyl fused ring or pyridinyl fused ring, such as quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, quinoxalinyl, quinolizinyl, quinazolinyl, azaindolizinyl, pteridinyl, chromenyl, isochromenyl, indolyl, isoindolyl, indolizinyl, indazolyl, purinyl, benzofuranyl, isobenzofuranyl, benzimidazolyl, benzothienyl, benzothiazolyl, carbazolyl, phenazinyl, phenothiazinyl, phenanthridinyl, hexahydro-1H-pyrrolizinyl, imidazo [1, 2-a] pyridin
  • spiro heterocyclyl examples include, but are not limited to, spiropyranyl, spirooxazinyl, and the like.
  • bridged heterocyclyl examples include, but are not limited to, morphanyl, hexamethylenetetraminyl, 3-aza-bicyclo [3.1.0] hexane, 8-aza-bicyclo [3.2.1] octane, 1-aza-bicyclo [2.2.2] octane, 1, 4-diazabicyclo [2.2.2] octane (DABCO) , and the like.
  • hydroxyl or “hydroxy” refers to —OH.
  • hydroxyalkyl refers to an alkyl, as defined above, substituted with one or more hydroxyl.
  • partially unsaturated refers to a radical that includes at least one double or triple bond.
  • partially unsaturated is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aromatic (i.e., fully unsaturated) moieties.
  • substitution or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and that the substitution results in a stable or chemically feasible compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc.
  • an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. It will be understood by those skilled in the art that substituents can themselves be substituted, if appropriate. Unless specifically stated as “unsubstituted” , references to chemical moieties herein are understood to include substituted variants. For example, reference to an “aryl” group or moiety implicitly includes both substituted and unsubstituted variants.
  • the present disclosure provides a compound having Formula (I) :
  • G is C (R a ) or N;
  • R a is absent, hydrogen, deuterium, cyano, halogen, alkyl, haloalkyl, heteroalkyl, hydroxyalkyl, or -C (O) N (R c ) 2 ;
  • each R b is independently hydrogen, deuterium, halogen, cyano, alkyl, alkoxy, heteroalkyl, cycloalkyl, or heteroaryl, wherein the alkyl, heteroalkyl, cycloalkyl, and heteroaryl are optionally substituted with one or more groups independently selected from the group consisting of hydroxyl, halogen, -NR c R d , and heterocyclyl optionally substituted with one or more groups selected from hydroxyl, halogen, cyano and amino;
  • each R c is independently hydrogen, alkyl, alkenyl, alkynyl or haloalkyl
  • R d is selected from the group consisting of alkyl optionally substituted with heteroaryl or -N (R c ) 2 , haloalkyl, -C (O) N (R c ) 2 , - (CH 2 ) n NHC (O) -alkyl, heterocyclyl, and heteroaryl, wherein the heterocyclyl and heteroaryl is optionally substituted with one or more groups independently selected from halogen, hydroxyl, amino, cyano, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, heteroalkyl, hydroxyalkyl, -O-haloalkyl and –S-haloalkyl;
  • W is CR e or N
  • R e is selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, -OR c , alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl, wherein alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl are optionally substituted with one or more groups independently selected from the group consisting of hydroxyl, halogen, cyano, -OR c , and -N (R c ) 2 ;
  • Q is CR f or N
  • R f is –Y- (CH 2 ) m -T-R g , wherein - (CH 2 ) m -is optionally substituted with hydroxyl, halogen, cyano or amino;
  • Y is selected from a bond, -O-, -S-, -N (R c ) -, or alkynyl;
  • T is selected from a bond, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one or more groups independently selected from oxo, hydroxyl, halogen, cyano, amino, alkyl, hydroxyalkyl or heteroaryl;
  • each R’ is independently selected from hydroxyl, halogen, -C (O) H, alkyl, alkoxy, haloalkyl, hydroxyalkyl, or -N (R c ) 2 ;
  • each R is independently selected from oxo, hydroxyl, halogen, alkyl, heteroalkyl, hydroxyalkyl, haloalkyl, alkoxy, -E-phenyl, -E-phenylSO 2 F, -N (R c ) 2 , -SO 2 F, -C (O) (alkyl) , or -C (O) (haloalkyl) , wherein the alkyl, heteroalkyl, hydroxyalkyl, haloalkyl, and alkoxy are optionally substituted with one or more groups independently selected from aryl, heteroaryl, or tert-butyldimethylsilyloxy;
  • E is a bond, -O-, or -NHC (O) -;
  • each of R 1a , R 1b , R 2a , R 2b , R 3a , R 3b , and R 4 is independently selected from absent, hydrogen, oxo, hydroxyl, halogen, cyano, alkyl, alkenyl, alkynyl, heteroalkyl, -C (O) OR c , -C (O) N (R c ) 2 , -N (R c ) 2 or heteroaryl, wherein the alkyl, alkenyl, alkynyl and heteroaryl are optionally substituted with one or more groups independently selected from cyano, hydroxyl, halogen, -OR c , -N (R c ) 2 , or -SO 2 (R c ) ; or
  • R 1a , R 1b , R 2a , R 2b , R 3a , R 3b , and R 4 together with the carbon atom (s) they are attached form alkyl, alkenyl, cycloalkyl or heterocyclyl, said alkyl, cycloalkyl or heterocyclyl are optionally substituted with one or more groups independently selected from cyano, halogen, hydroxyl, amino, alkoxy, alkyl, alkenyl, or alkynyl;
  • L 1 is a bond, - [C (R h ) 2 ] u -*, - [C (R h ) 2 ] u -C (O) -*or –N (R c ) C (O) -*, wherein *denotes a point of attachment of L 1 to L 2 ;
  • L 2 is a bond, -O-, -N (R i ) -, or -S (O) v -;
  • each R h is independently selected from the group consisting of hydrogen, hydroxyl, halogen, cyano, amino, nitro, alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, and heterocyclyl, wherein alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, and heterocyclyl are optionally substituted with one or more group independently consisting of hydroxyl, halogen, cyano, amino, nitro, alkyl, alkoxy, haloalkyl, and hydroxyalkyl; or
  • R i is selected from absent, hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, or -C (O) -heterocyclyl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl and cycloalkyl are optionally substituted with one or more R”’, and the heterocyclyl portion in -C (O) -heterocyclyl is optionally substituted with one or more groups independently selected from halogen, hydroxyl, cyano, alkyl and -N (R c ) 2 ;
  • R h and R i together with the carbon atom and nitrogen atom they are attached respectively form a heterocyclyl or heteroaryl optionally substituted with one or more groups independently selected from cyano, halogen, hydroxyl, amino, nitro, alkoxy, haloalkyl, hydroxyalkyl, alkyl or -alkyl-N (R c ) 2 ;
  • each R”’ is independently selected from -N (R c ) 2 , hetercyclyl optionally substituted with one or more groups independently selected from halogen, hydroxyl, cyano, or alkyl;
  • L 3 is a bond, -C (O) -, or alkyl
  • R 5 is hydrogen, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more R j ;
  • each R j is independently selected from the group consisting of hydrogen, oxo, hydroxyl, halogen, cyano, amino, nitro, alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more group independently consisting of deuterium, hydroxyl, halogen, cyano, amino, nitro, alkyl, alkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • n 0, 1 or 2;
  • n is an integer from 0 to 4.
  • p is an integer from 0 to 2;
  • r is 1 or 2;
  • u is an integer from 0 to 4.
  • v is an integer from 0 to 2;
  • R a is present, R b is present and r is 2, or R a and R b and the carbon atom to which they are attached form cycloalkyl optionally substituted with one or more R e .
  • both are single bond
  • G is C (R a )
  • R a is hydrogen
  • one is a single bond
  • the other is a double bond
  • G is C (R a )
  • R a is absent.
  • both are single bond
  • G is N.
  • R a is hydrogen, deuterium, cyano, halogen, or alkyl.
  • R a is hydrogen
  • one R b is hydrogen
  • the other R b is selected from the group consisting of hydrogen, alkyl, heteroalkyl, haloalkyl, heteroaryl, -alkyl-NR c R d , cycloalkyl, and -alkyl-heterocyclyl, wherein the heterocyclyl in -alkyl-heterocyclyl is optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano or amino.
  • R a and the two R b are deuterium.
  • R a is halogen, and the two R b are hydrogen.
  • Z is
  • Z is
  • R b is hydrogen or -alkyl-NR c R d .
  • Z is
  • R a is hydrogen
  • R b is hydrogen
  • W is N.
  • W is CR e .
  • R e is selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, -OR c , alkyl, alkenyl, and alkynyl, wherein alkyl, alkenyl, and alkynyl are optionally substituted with one or more groups independently selected from the group consisting of hydroxyl, halogen, cyano, -OR c , and -N (R c ) 2 .
  • R e is selected from the group consisting of halogen, hydrogen, halogen, hydroxyl, cyano, methoxy or ethynyl.
  • Q is N.
  • Q is CR f
  • R f is –Y- (CH 2 ) m -T-R g .
  • Y is a bond, -O-or -S-.
  • Y is -N (R c ) -.
  • Y is alkynyl. In certain embodiments, Y is C 2-6 alkynyl, C 2-5 alkynyl, C 2-4 alkynyl or C 2-3 alkynyl. In certain embodiments, Y is ethynyl.
  • m is 0.
  • m is 1, 2, or 3.
  • T is a bond
  • T is a heterocyclyl optionally substituted with one or more groups independently selected from oxo, hydroxyl, halogen, cyano, amino, alkyl, hydroxyalkyl or heteroaryl.
  • T is a heterocyclyl selected from the group consisting of:
  • each of which is optionally substituted with one or more groups independently selected from oxo, hydroxyl, halogen, cyano, amino, alkyl, hydroxyalkyl or heteroaryl.
  • Y is a bond
  • T is a bond
  • Y is a bond
  • m is 0, and T is a bond.
  • Y is a bond
  • T is heterocyclyl optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, amino, alkyl, hydroxyalkyl or heteroaryl.
  • Y is a bond
  • m is 0, and T is heterocyclyl optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, amino, alkyl, hydroxyalkyl or heteroaryl.
  • Y is -O-or -S-
  • T is a bond or heterocyclyl optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, amino, alkyl, hydroxyalkyl or heteroaryl.
  • Y is -O-or -S-
  • m is 1, 2 or 3
  • T is a bond or heterocyclyl optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, amino, alkyl, hydroxyalkyl or heteroaryl.
  • Y is -N (R c ) -, and T is a bond. In certain embodiments, Y is -N (R c ) -, m is 1 or 2, and T is a bond.
  • Y is alkynyl
  • T is a bond or heterocyclyl optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, amino, alkyl, hydroxyalkyl or heteroaryl.
  • Y is alkynyl
  • m is 0 or 1
  • T is a bond or heterocyclyl optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, amino, alkyl, hydroxyalkyl or heteroaryl.
  • R g is selected from the group consisting of hydrogen, hydroxyl, halogen, alkyl, -N (R c ) 2 , or -OR c .
  • R g is hydrogen, hydroxyl or halogen.
  • R g is alkyl. In certain embodiments, R g is C 1-6 alkyl, C 1-5 alkyl, C 1-4 alkyl, or C 1-3 alkyl. In certain embodiments, R g is alkyl, ethyl, or isopropyl.
  • R g is -N (R c ) 2 , wherein each R c is independently C 1-6 alkyl, C 1-5 alkyl, C 1-4 alkyl, or C 1-3 alkyl. In certain embodiments, each R c is methyl.
  • R g is -OR c , wherein R c is C 1-6 alkyl, C 1-5 alkyl, C 1-4 alkyl, or C 1-3 alkyl. In certain embodiments, R c is methyl.
  • Y is a bond, -O-, -S-or alkynyl
  • T is heterocyclyl optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, amino, alkyl, hydroxyalkyl or heteroaryl
  • R g is hydrogen, halogen, alkyl, -N (R c ) 2 , or -OR c .
  • Y is a bond, -O-, -S-, -N (R c ) or alkynyl
  • T is a bond
  • R g is -N (R c ) 2 .
  • each of R 1a , R 1b , R 2a , R 2b , R 3a , R 3b , and R 4 is independently selected from hydrogen, alkyl or heteroalkyl, wherein the alkyl and heteroaryl are optionally substituted with one or more groups independently selected from cyano, hydroxyl, halogen, -OR c , -N (R c ) 2 , or -SO 2 (R c ) .
  • each of R 1a , R 1b , R 2a , R 2b , R 3a , R 3b , and R 4 is independently selected from hydrogen.
  • one of R 1a , R 1b , R 2a , R 2b , R 3a , R 3b , and R 4 is C 1-6 alkyl, C 1-5 alkyl, C 1-4 alkyl, or C 1-3 alkyl, and the others are hydrogen. In certain embodiments, one of R 1a , R 1b , R 2a , R 2b , R 3a , R 3b , and R 4 is methyl, the others are hydrogen.
  • one of R 1a , R 1b , R 2a , R 2b , R 3a , R 3b , and R 4 is C 1-6 cyanoalkyl, C 1-5 cyanoalkyl, C 1-4 cyanoalkyl, or C 1-3 cyanoalkyl, and the others are hydrogen.
  • one of R 1a , R 1b , R 2a , R 2b , R 3a , R 3b , and R 4 is –CH 2 CN, the others are hydrogen.
  • one of R 1a , R 1b , R 2a , R 2b , R 3a , R 3b , and R 4 is C 1-6 haloalkyl, C 1-5 haloalkyl, C 1-4 haloalkyl, or C 1-3 haloalkyl, and the others are hydrogen.
  • one of R 1a , R 1b , R 2a , R 2b , R 3a , R 3b , and R 4 is –CH 2 F, the others are hydrogen.
  • one of R 1a , R 1b , R 2a , R 2b , R 3a , R 3b , and R 4 is C 2-6 heteroalkyl, C 2-5 heteroalkyl, C 2-4 heteroalkyl, or C 2-3 heteroalkyl, and the others are hydrogen.
  • one of R 1a , R 1b , R 2a , R 2b , R 3a , R 3b , and R 4 is –CH 2 OCH 3 , the others are hydrogen.
  • one of R 1a , R 1b , R 2a , R 2b , R 3a , R 3b , and R 4 is -C 1-6 alkyl-SO 2 CH 3 , -C 1-5 alkyl-SO 2 CH 3 , -C 1-4 alkyl-SO 2 CH 3 , -C 1-3 alkyl-SO 2 CH 3 , or -C 1-2 alkyl-SO 2 CH 3 , and the others are hydrogen.
  • one of R 1a , R 1b , R 2a , R 2b , R 3a , R 3b , and R 4 is –CH 2 SO 2 CH 3 , the others are hydrogen.
  • R 1a , R 1b , R 2a , R 2b , R 3a , R 3b , and R 4 together with the carbon atom (s) they are attached form an alkyl.
  • R 1a and R 3a together with the carbon atoms they are attached form propyl or butyl.
  • R 1a and R 4 together with the carbon atoms they are attached form propyl or butyl.
  • R 2a and R 3a together with the carbon atoms they are attached form propyl or butyl.
  • R 1a , R 1b , R 2a , R 2b , R 3a , R 3b , and R 4 together with the carbon atom (s) they are attached form an alkenyl.
  • R 1a and R 3a together with the carbon atoms they are attached form butenyl.
  • R 1a and R 4 together with the carbon atoms they are attached form butenyl.
  • R 2a and R 3a together with the carbon atoms they are attached form butenyl.
  • R 1a , R 1b , R 2a , R 2b , R 3a , R 3b , and R 4 together with the carbon atom (s) they are attached form a cycloalkyl or heterocyclyl.
  • R 1a and R 1b together with the carbon atom they both are attached form C 3-6 cycloalkyl or C 3-6 heterocyclyl.
  • R 2a and R 2b together with the carbon atom they both are attached form C 3-6 cycloalkyl or C 3-6 heterocyclyl.
  • R 3a and R 3b together with the carbon atom they both are attached form C 3-6 cycloalkyl or C 3-6 heterocyclyl.
  • R 1a and R 2a together with the carbon atom they both are attached form C 3-6 cycloalkyl or C 3-6 heterocyclyl.
  • R 3a and R 4 together with the carbon atom they both are attached form C 3-6 cycloalkyl or C 3-6 heterocyclyl.
  • L 1 is a bond
  • L 1 is - [C (R h ) 2 ] u -*. In certain embodiments, L 1 is - [C (R h ) 2 ] u -*, R h is hydrogen, and u is 0, 1, 2 or 3.
  • L 1 is - [C (R h ) 2 ] u -C (O) -*. In certain embodiments, L 1 is - [C (R h ) 2 ] u -C (O) -*, R h is hydrogen, and u is 0, 1, 2 or 3.
  • L 1 is –N (R c ) C (O) -*. In certain embodiments, L 1 is –N (R c ) C (O) -*, and R c is hydrogen.
  • L 1 is -S (O) v -.
  • L 2 is a bond
  • L 2 is -O-.
  • L 2 is -N (R i ) -. In certain embodiments, L 2 is -N (R i ) -, R i is hydrogen, alkyl, or -C (O) -heterocyclyl, wherein the alkyl is optionally substituted with one or more R”’, and the heterocyclyl portion in -C (O) -heterocyclyl is optionally substituted with one or more groups independently selected from alkyl or -N (R c ) 2 .
  • L 1 is - [C (R h ) 2 ] u -*
  • L 2 is -N (R i ) -
  • u is 1
  • R h and R i together with the carbon atom and nitrogen atom they are attached respectively form a heteroaryl optionally substituted with one or more groups independently selected from cyano, halogen, hydroxyl, haloalkyl, hydroxyalkyl, alkyl or -alkyl-N (R c ) 2 .
  • L 1 is - [C (R h ) 2 ] u -*
  • L 2 is -N (R i ) -
  • u is 1
  • R h and R i together with the carbon atom and nitrogen atom they are attached respectively form triazolyl or imidazolyl, each optionally substituted with one or more groups independently selected from cyano, halogen, hydroxyl, haloalkyl, hydroxyalkyl, alkyl or -alkyl-N (R c ) 2 .
  • L 1 is - [C (R h ) 2 ] u -C (O) -*
  • L 2 is -N (R i ) -
  • u is 0.
  • L 3 is a bond
  • L 3 is -C (O) -.
  • L 3 is alkyl. In certain embodiments, L 3 is C 1-6 alkyl, C 1-5 alkyl, C 1-4 alkyl, or C 1-3 alkyl.
  • R 5 is aryl optionally substituted with one or more R j .
  • R 5 is C 5-12 aryl, C 5-11 aryl, C 5-10 aryl, C 5-9 aryl, C 5-8 aryl or C 5- 7 aryl, each of which is optionally substituted with one or more R j .
  • R 5 is phenyl, naphthyl or 2, 3-dihydro-1H-indenyl, each of which is optionally substituted with one or more R j .
  • R j is hydroxyl, halogen, amino, alkyl, alkynyl, haloalkyl or cycloalkyl.
  • R 5 is heteroaryl optionally substituted with one or more R j .
  • R 5 is C 5-12 heteroaryl, C 5-11 heteroaryl, C 5-10 heteroaryl, C 5-9 heteroaryl, C 5-8 heteroaryl or C 5-7 heteroaryl, each of which is optionally substituted with one or more R j .
  • R 5 is pyridyl, quinolinyl, isoquinolinyl, indazolyl, or benzo [b] thiophenyl, each of which is optionally substituted with one or more R j .
  • R j is hydroxyl, halogen, amino, alkyl or alkynyl.
  • the present disclosure provides a compound having having Formula (Ia) , Formula (Ib) or Formula (Ic) :
  • ring A is a heterocyclyl or heteroaryl optionally substituted with one or more groups independently selected from cyano, halogen, hydroxyl, amino, alkyl, alkoxy, haloalkyl, hydroxyalkyl, or -alkyl-N (R c ) 2 .
  • both are single bond.
  • Q is CR f .
  • Q is N.
  • L 3 is a bond
  • R 5 is aryl or heteroaryl, each optionally substituted with one or more R j .
  • R 5 is selected from the group consisting of phenyl, naphthyl, 2, 3-dihydro-1H-indenyl, pyridinyl, quinolinyl, isoquinolinyl, indazolyl, and benzo [b] thiophenyl, each of which is optionally substituted with one or more R j .
  • u is 0 or 1.
  • the present disclosure provides a compound having a formula selected from the group consisting of:
  • prodrugs refers to compounds or pharmaceutically acceptable salts thereof which, when metabolized under physiological conditions or when converted by solvolysis, yield the desired active compound.
  • Prodrugs include, without limitation, esters, amides, carbamates, carbonates, ureides, solvates, or hydrates of the active compound.
  • the prodrug is inactive, or less active than the active compound, but may provide one or more advantageous handling, administration, and/or metabolic properties.
  • some prodrugs are esters of the active compound; during metabolysis, the ester group is cleaved to yield the active drug.
  • prodrugs are activated enzymatically to yield the active compound, or a compound which, upon further chemical reaction, yields the active compound.
  • Prodrugs may proceed from prodrug form to active form in a single step or may have one or more intermediate forms which may themselves have activity or may be inactive. Preparation and use of prodrugs is discussed in T. Higuchi and V. Stella, “Pro-drugs as Novel Delivery Systems” , Vol. 14 of the A.C.S. Symposium Series, in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987; in Prodrugs: Challenges and Rewards, ed. V. Stella, R. Borchardt, M. Hageman, R. Oliyai, H. Maag, J. Tilley, Springer-Verlag New York, 2007, all of which are hereby incorporated by reference in their entirety.
  • soft drug refers to compounds that exert a pharmacological effect but break down to inactive metabolites degradants so that the activity is of limited time. See, for example, “Soft drugs: Principles and methods for the design of safe drugs” , Nicholas Bodor, Medicinal Research Reviews, Vol. 4, No. 4, 449-469, 1984, which is hereby incorporated by reference in its entirety.
  • metabolite e.g., active metabolite overlaps with prodrug as described above.
  • metabolites are pharmacologically active compounds or compounds that further metabolize to pharmacologically active compounds that are derivatives resulting from metabolic process in the body of a subject.
  • metabolites may result from oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage, and the like, of the administered compound or salt or prodrug.
  • active metabolites are such pharmacologically active derivative compounds.
  • the prodrug compound is generally inactive or of lower activity than the metabolic product.
  • the parent compound may be either an active compound or may be an inactive prodrug.
  • Prodrugs and active metabolites may be identified using routine techniques know in the art. See, e.g., Bertolini et al, 1997, J Med Chem 40: 2011-2016; Shan et al., J Pharm Sci 86: 756-757; Bagshawe, 1995, DrugDev Res 34: 220-230; Wermuth, supra.
  • the term “pharmaceutically acceptable” indicates that the substance or composition is compatible chemically and/or toxicologically, with the other ingredients comprising a formulation, and/or the subjects being treated therewith.
  • the term “pharmaceutically acceptable salt” includes salts that retain the biological effectiveness of the free acids and bases of the specified compound and that are not biologically or otherwise undesirable.
  • Contemplated pharmaceutically acceptable salt forms include, but are not limited to, mono, bis, tris, tetrakis, and so on.
  • Pharmaceutically acceptable salts are non-toxic in the amounts and concentrations at which they are administered. The preparation of such salts can facilitate the pharmacological use by altering the physical characteristics of a compound without preventing it from exerting its physiological effect. Useful alterations in physical properties include lowering the melting point to facilitate transmucosal administration and increasing the solubility to facilitate administering higher concentrations of the drug.
  • Pharmaceutically acceptable salts include acid addition salts such as those containing sulfate, chloride, hydrochloride, fumarate, maleate, phosphate, sulfamate, acetate, citrate, lactate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexylsulfamate and quinate.
  • acid addition salts such as those containing sulfate, chloride, hydrochloride, fumarate, maleate, phosphate, sulfamate, acetate, citrate, lactate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexylsulfamate and quinate.
  • Pharmaceutically acceptable salts can be obtained from acids such as hydrochloric acid, maleic acid, sulfuric acid, phosphoric acid, sulfamic acid, acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexylsulfamic acid, fumaric acid, and quinic acid.
  • acids such as hydrochloric acid, maleic acid, sulfuric acid, phosphoric acid, sulfamic acid, acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexylsulfamic acid, fumaric acid, and quinic acid.
  • Pharmaceutically acceptable salts also include basic addition salts such as those containing benzathine, chloroprocaine, choline, diethanolamine, ethanolamine, t-butylamine, ethylenediamine, meglumine, procaine, aluminum, calcium, lithium, magnesium, potassium, sodium, ammonium, alkylamine, and zinc, when acidic functional groups, such as carboxylic acid or phenol are present.
  • acidic functional groups such as carboxylic acid or phenol are present.
  • salts can be prepared by standard techniques.
  • the free-base form of a compound can be dissolved in a suitable solvent, such as an aqueous or aqueous-alcohol solution containing the appropriate acid and then isolated by evaporating the solution.
  • the desired pharmaceutically acceptable salt may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, or with an organic acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alpha-hydroxy acid, such as citric acid or tartaric acid, an amino acid, such as aspartic acid or glutamic acid, an aromatic acid, such as benzoic acid or cinnamic acid, a sulfonic acid, such as p-toluenesulfonic acid or ethanesulfonic acid, or the like.
  • an inorganic acid such as hydrochloric acid
  • the desired pharmaceutically acceptable salt may be prepared by any suitable method, for example, treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary) , an alkali metal hydroxide or alkaline earth metal hydroxide, or the like.
  • an inorganic or organic base such as an amine (primary, secondary or tertiary) , an alkali metal hydroxide or alkaline earth metal hydroxide, or the like.
  • suitable salts include organic salts derived from amino acids, such as L-glycine, L-lysine, and L-arginine, ammonia, primary, secondary, and tertiary amines, and cyclic amines, such as hydroxyethylpyrrolidine, piperidine, morpholine or piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.
  • amino acids such as L-glycine, L-lysine, and L-arginine
  • ammonia primary, secondary, and tertiary amines
  • cyclic amines such as hydroxyethylpyrrolidine, piperidine, morpholine or piperazine
  • inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.
  • the compounds of present disclosure can exist in unsolvated forms, solvated forms (e.g., hydrated forms) , and solid forms (e.g., crystal or polymorphic forms) , and the present disclosure is intended to encompass all such forms.
  • solvate or “solvated form” refers to solvent addition forms that contain either stoichiometric or non-stoichiometric amounts of solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. If the solvent is water the solvate formed is a hydrate; and if the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more molecules of water with one molecule of the substance in which the water retains its molecular state as H 2 O. Examples of solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine.
  • crystal form As used herein, the terms “crystal form” , “crystalline form” , “polymorphic forms” and “polymorphs” can be used interchangeably, and mean crystal structures in which a compound (or a salt or solvate thereof) can crystallize in different crystal packing arrangements, all of which have the same elemental composition. Different crystal forms usually have different X-ray diffraction patterns, infrared spectral, melting points, density hardness, crystal shape, optical and electrical properties, stability and solubility. Recrystallization solvent, rate of crystallization, storage temperature, and other factors may cause one crystal form to dominate. Crystal polymorphs of the compounds can be prepared by crystallization under different conditions.
  • the present disclosure is also intended to include all isotopes of atoms in the compounds.
  • Isotopes of an atom include atoms having the same atomic number but different mass numbers.
  • hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, chlorine, bromide or iodine in the compounds of present disclosure are meant to also include their isotopes, such as but not limited to 1 H, 2 H, 3 H, 11 C, 12 C, 13 C, 14 C, 14 N, 15 N, 16 O, 17 O, 18 O, 31 P, 32 P, 32 S, 33 S, 34 S, 36 S, 17 F, 18 F, 19 F, 35 Cl, 37 Cl, 79 Br, 81 Br, 124 I, 127 I and 131 I.
  • hydrogen includes protium, deuterium and tritium.
  • carbon includes 12 C and 13 C.
  • tautomer or “tautomeric form” refers to structural isomers of different energies which are interconvertible via a low energy barrier. The presence and concentrations of the isomeric forms will depend on the environment the compound is found in and may be different depending upon, for example, whether the compound is a solid or is in an organic or aqueous solution.
  • proton tautomers include interconversions via migration of a proton, such as keto-enol, amide-imidic acid, lactam-lactim, imine-enamine isomerizations and annular forms where a proton can occupy two or more positions of a heterocyclic system.
  • Valence tautomers include interconversions by reorganization of some of the bonding electrons. Tautomers can be in equilibrium or sterically locked into one form by appropriate substitution.
  • Compounds of the present disclosure identified by name or structure as one particular tautomeric form are intended to include other tautomeric forms unless otherwise specified.
  • the compounds provided herein can be prepared using any known organic synthesis techniques and can be synthesized according to any of numerous possible synthetic routes
  • Reactions for preparing compounds of the present disclosure can be carried out in suitable solvents, which can be readily selected by one skilled in the art of organic synthesis.
  • suitable solvents can be substantially non-reactive with starting materials (reactants) , intermediates, or products at the temperatures at which the reactions are carried out, e.g. temperatures that can range from the solvent’s freezing temperature to the solvent's boiling temperature.
  • a given reaction can be carried out in one solvent or a mixture of more than one solvent.
  • suitable solvents for a particular reaction step can be selected by one skilled in the art.
  • Preparation of compounds of the present disclosure can involve the protection and deprotection of various chemical groups.
  • the need for protection and deprotection, and the selection of appropriate protecting groups, can be readily determined by one skilled in the art.
  • the chemistry of protecting groups can be found, for example, in T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 3rd Ed., Wiley &Sons, Inc., New York (1999) , in P. Kocienski, Protecting Groups, Georg Thieme Verlag, 2003, and in Peter G.M. Wuts, Greene's Protective Groups in Organic Synthesis, 5 th Edition, Wiley, 2014, all of which are incorporated herein by reference in its entirety.
  • Reactions can be monitored according to any suitable method known in the art.
  • product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g. 1 H or 13 C) , infrared spectroscopy, spectrophotometry (e.g. UV-visible) , mass spectrometry, or by chromatographic methods such as high performance liquid chromatography (HPLC) , liquid chromatography-mass spectroscopy (LCMS) , or thin layer chromatography (TLC) .
  • HPLC high performance liquid chromatography
  • LCMS liquid chromatography-mass spectroscopy
  • TLC thin layer chromatography
  • Compounds can be purified by one skilled in the art by a variety of methods, including high performance liquid chromatography (HPLC) ( “Preparative LC-MS Purification: Improved Compound Specific Method Optimization” Karl F. Blom, Brian Glass, Richard Sparks, Andrew P. Combs J. Combi. Chem. 2004, 6 (6) ,
  • the present disclosure provides compounds capable of inhibiting KRAS protein, in particular KRAS G12C protein.
  • beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total) , whether detectable or undetectable. “Therapy” can also mean prolonging survival as compared to expected survival if not receiving it.
  • Those in need of therapy include those already with the condition or disorder as well as those prone to have the condition or disorder or those in which the condition or disorder is to be prevented.
  • the term “therapy” also encompasses prophylaxis unless there are specific indications to the contrary.
  • the terms “therapeutic” and “therapeutically” should be interpreted in a corresponding manner.
  • prophylaxis is intended to have its normal meaning and includes primary prophylaxis to prevent the development of the disease and secondary prophylaxis whereby the disease has already developed and the patient is temporarily or permanently protected against exacerbation or worsening of the disease or the development of new symptoms associated with the disease.
  • treatment is used synonymously with “therapy” .
  • treat can be regarded as “applying therapy” where “therapy” is as defined herein.
  • the present disclosure provides use of the compound of the present disclosure or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of the present disclosure for use in therapy, for example, for use in therapy associated with KRAS protein, in particular, in therapy associated with KRAS G12C protein.
  • the present disclosure provides use of the compound of the present disclosure or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of the present disclosure, in the manufacture of a medicament for treating cancer.
  • the cancer is mediated by KRAS protein. In some embodiments, the cancer is mediated by KRAS G12C protein.
  • compositions comprising one or more compounds of the present disclosure, or a pharmaceutically acceptable salt thereof.
  • composition comprising one or more compounds of the present disclosure, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutical acceptable excipient.
  • composition refers to a formulation containing the molecules or compounds of the present disclosure in a form suitable for administration to a subject.
  • the term “pharmaceutically acceptable excipient” means an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes excipient that is acceptable for veterinary use as well as human pharmaceutical use.
  • a “pharmaceutically acceptable excipient” as used herein includes both one and more than one such excipient.
  • pharmaceutically acceptable excipient also encompasses “pharmaceutically acceptable carrier” and “pharmaceutically acceptable diluent” .
  • Solvents are generally selected based on solvents recognized by persons skilled in the art as safe to be administered to a mammal including humans.
  • safe solvents are non-toxic aqueous solvents such as water and other non-toxic solvents that are soluble or miscible in water.
  • Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycols (e.g., PEG 400, PEG 300) , etc. and mixtures thereof.
  • suitable excipients may include buffers such as phosphate, citrate and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol) ; low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, dis
  • suitable excipients may include one or more stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents and other known additives to provide an elegant presentation of the drug (i.e., a compound of the present disclosure or pharmaceutical composition thereof) or aid in the manufacturing of the pharmaceutical product (i.e., medicament) .
  • stabilizing agents i.e., surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents and other known additives to provide an elegant presentation of the drug (i.e., a compound of the present disclosure or pharmaceutical composition thereof) or aid in the manufacturing of the pharmaceutical product (i.e., medicament
  • the active pharmaceutical ingredients may also be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for example, hydroxymethylcellulose or gelatin-microcapsules and poly- (methylmethacylate) microcapsules, respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules) or in macroemulsions.
  • colloidal drug delivery systems for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules
  • a “liposome” is a small vesicle composed of various types of lipids, phospholipids and/or surfactant which is useful for delivery of a drug (such as the compounds disclosed herein and, optionally, a chemotherapeutic agent) to a mammal including humans.
  • a drug such as the compounds disclosed herein and, optionally, a chemotherapeutic agent
  • the components of the liposome are commonly arranged in a bilayer formation, similar to the lipid arrangement of biological membranes.
  • compositions provided herein can be in any form that allows for the composition to be administered to a subject, including, but not limited to a human, and formulated to be compatible with an intended route of administration.
  • compositions provided herein may be supplied in bulk or in unit dosage form depending on the intended administration route.
  • powders, suspensions, granules, tablets, pills, capsules, gelcaps, and caplets may be acceptable as solid dosage forms
  • emulsions, syrups, elixirs, suspensions, and solutions may be acceptable as liquid dosage forms.
  • emulsions and suspensions may be acceptable as liquid dosage forms
  • solutions, sprays, dry powders, and aerosols may be acceptable dosage form.
  • powders, sprays, ointments, pastes, creams, lotions, gels, solutions, and patches may be acceptable dosage form.
  • pessaries, tampons, creams, gels, pastes, foams and spray may be acceptable dosage form.
  • the quantity of active ingredient in a unit dosage form of composition is a therapeutically effective amount and is varied according to the particular treatment involved.
  • therapeutically effective amount refers to an amount of a molecule, compound, or composition comprising the molecule or compound to treat, ameliorate, or prevent an identified disease or condition, or to exhibit a detectable therapeutic or inhibitory effect. The effect can be detected by any assay method known in the art.
  • the precise effective amount for a subject will depend upon the subject’s body weight, size, and health; the nature and extent of the condition; the rate of administration; the therapeutic or combination of therapeutics selected for administration; and the discretion of the prescribing physician.
  • Therapeutically effective amounts for a given situation can be determined by routine experimentation that is within the skill and judgment of the clinician.
  • compositions of the present disclosure may be in a form of formulation for oral administration.
  • the pharmaceutical compositions of the present disclosure may be in the form of tablet formulations.
  • suitable pharmaceutically-acceptable excipients for a tablet formulation include, for example, inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate, granulating and disintegrating agents such as corn starch or algenic acid; binding agents such as starch; lubricating agents such as magnesium stearate, stearic acid or talc; preservative agents such as ethyl or propyl p-hydroxybenzoate, and anti-oxidants, such as ascorbic acid.
  • Tablet formulations may be uncoated or coated either to modify their disintegration and the subsequent absorption of the active ingredient within the gastrointestinal tract, or to improve their stability and/or appearance, in either case using conventional coating agents and procedures well known in the art.
  • the pharmaceutical compositions of the present disclosure may be in a form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil such as peanut oil, liquid paraffin, or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • water or an oil such as peanut oil, liquid paraffin, or olive oil.
  • the pharmaceutical compositions of the present disclosure may be in the form of aqueous suspensions, which generally contain the active ingredient in finely powdered form together with one or more suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents such as lecithin or condensation products of an alkylene oxide with fatty acids (for example polyoxethylene stearate) , or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate.
  • suspending agents such as sodium
  • the aqueous suspensions may also contain one or more preservatives (such as ethyl or propyl p-hydroxybenzoate, anti-oxidants (such as ascorbic acid) , coloring agents, flavoring agents, and/or sweetening agents (such as sucrose, saccharine or aspartame) .
  • preservatives such as ethyl or propyl p-hydroxybenzoate, anti-oxidants (such as ascorbic acid) , coloring agents, flavoring agents, and/or sweetening agents (such as sucrose, saccharine or aspartame) .
  • the pharmaceutical compositions of the present disclosure may be in the form of oily suspensions, which generally contain suspended active ingredient in a vegetable oil (such as arachis oil, olive oil, sesame oil or coconut oil) or in a mineral oil (such as liquid paraffin) .
  • the oily suspensions may also contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set out above, and flavoring agents may be added to provide a palatable oral preparation.
  • These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • the pharmaceutical compositions of the present disclosure may be in the form of oil-in-water emulsions.
  • the oily phase may be a vegetable oil, such as olive oil or arachis oil, or a mineral oil, such as for example liquid paraffin or a mixture of any of these.
  • Suitable emulsifying agents may be, for example, naturally-occurring gums such as gum acacia or gum tragacanth, naturally-occurring phosphatides such as soya bean, lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides (for example sorbitan monooleate) and condensation products of the said partial esters with ethylene oxide such as polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening, flavoring and preservative agents.
  • the pharmaceutical compositions provided herein may be in the form of syrups and elixirs, which may contain sweetening agents such as glycerol, propylene glycol, sorbitol, aspartame or sucrose, a demulcent, a preservative, a flavoring and/or coloring agent.
  • sweetening agents such as glycerol, propylene glycol, sorbitol, aspartame or sucrose, a demulcent, a preservative, a flavoring and/or coloring agent.
  • compositions of the present disclosure may be in a form of formulation for injection administration.
  • the pharmaceutical compositions of the present disclosure may be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension.
  • a sterile injectable preparation such as a sterile injectable aqueous or oleaginous suspension.
  • This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents, which have been mentioned above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1, 3-butanediol or prepared as a lyophilized powder.
  • a non-toxic parenterally acceptable diluent or solvent such as a solution in 1, 3-butanediol or prepared as a lyophilized powder.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile fixed oils may conventionally be employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono-or diglycerides.
  • fatty acids such as oleic acid may likewise be used in the preparation of injectables.
  • compositions of the present disclosure may be in a form of formulation for inhalation administration.
  • the pharmaceutical compositions of the present disclosure may be in the form of aqueous and nonaqueous (e.g., in a fluorocarbon propellant) aerosols containing any appropriate solvents and optionally other compounds such as, but not limited to, stabilizers, antimicrobial agents, antioxidants, pH modifiers, surfactants, bioavailability modifiers and combinations of these.
  • the carriers and stabilizers vary with the requirements of the particular compound, but typically include nonionic surfactants (Tweens, Pluronics, or polyethylene glycol) , innocuous proteins like serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars or sugar alcohols.
  • compositions of the present disclosure may be in a form of formulation for topical or transdermal administration.
  • the pharmaceutical compositions provided herein may be in the form of creams, ointments, gels and aqueous or oily solutions or suspensions, which may generally be obtained by formulating an active ingredient with a conventional, topically acceptable excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • a conventional, topically acceptable excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • compositions provided herein may be formulated in the form of transdermal skin patches that are well known to those of ordinary skill in the art.
  • excipients and carriers are generally known to those skilled in the art and are thus included in the present disclosure.
  • excipients and carriers are described, for example, in “Remingtons Pharmaceutical Sciences” Mack Pub. Co., New Jersey (1991) , in “Remington: The Science and Practice of Pharmacy” , Ed. University of the Sciences in Philadelphia, 21 st Edition, LWW (2005) , which are incorporated herein by reference.
  • the pharmaceutical compositions of the present disclosure can be formulated as a single dosage form.
  • the amount of the compounds provided herein in the single dosage form will vary depending on the subject treated and particular mode of administration.
  • the pharmaceutical compositions of the present disclosure can be formulated so that a dosage of between 0.001-1000 mg/kg body weight/day, for example, 0.01-800 mg/kg body weight/day, 0.01-700 mg/kg body weight/day, 0.01-600 mg/kg body weight/day, 0.01-500 mg/kg body weight/day, 0.01-400 mg/kg body weight/day, 0.01-300 mg/kg body weight/day, 0.1-200 mg/kg body weight/day, 0.1-150 mg/kg body weight/day, 0.1-100 mg/kg body weight/day, 0.5-100 mg/kg body weight/day, 0.5-80 mg/kg body weight/day, 0.5-60 mg/kg body weight/day, 0.5-50 mg/kg body weight/day, 1-50 mg/kg body weight/day, 1-45 mg/kg body weight/day, 1-40 mg/kg body weight/day, 1-35 mg/kg body weight/day, 1-30 mg/kg body weight/day, 1-25 mg/kg body weight/day of the
  • dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect, provided that such larger doses are first divided into several small doses for administration throughout the day.
  • routes of administration and dosage regimes see Chapter 25.3 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board) , Pergamon Press 1990, which is specifically incorporated herein by reference.
  • the pharmaceutical compositions of the present disclosure can be formulated as short-acting, fast-releasing, long-acting, and sustained-releasing. Accordingly, the pharmaceutical formulations of the present disclosure may also be formulated for controlled release or for slow release.
  • compositions comprising one or more molecules or compounds of the present disclosure or pharmaceutically acceptable salts thereof and a veterinary carrier.
  • Veterinary carriers are materials useful for the purpose of administering the composition and may be solid, liquid or gaseous materials which are otherwise inert or acceptable in the veterinary art and are compatible with the active ingredient. These veterinary compositions may be administered parenterally, orally or by any other desired route.
  • an article for distribution can include a container having deposited therein the compositions in an appropriate form.
  • suitable containers are well known to those skilled in the art and include materials such as bottles (plastic and glass) , sachets, ampoules, plastic bags, metal cylinders, and the like.
  • the container may also include a tamper-proof assemblage to prevent indiscreet access to the contents of the package.
  • the container has deposited thereon a label that describes the contents of the container. The label may also include appropriate warnings.
  • compositions may also be packaged in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water, for injection immediately prior to use.
  • sterile liquid carrier for example water
  • Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules and tablets of the kind previously described.
  • compositions comprise one or more compounds of the present disclosure, or a pharmaceutically acceptable salt thereof, as a first active ingredient, and a second active ingredient.
  • the second active ingredient has complementary activities to the compound provided herein such that they do not adversely affect each other.
  • Such ingredients are suitably present in combination in amounts that are effective for the purpose intended.
  • the present disclosure provides a method for treating cancer, comprising administering an effective amount of the compound or a pharmaceutically acceptable salt thereof or the pharmaceutical composition provided herein to a subject in need thereof.
  • the compounds or pharmaceutically acceptable salts thereof and the compositions provided herein may be used for the treatment of a KRAS G12C-associated cancer in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound provided herein, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound or pharmaceutically acceptable salt thereof.
  • the compounds or pharmaceutically acceptable salts thereof and the compositions provided herein may be used for the treatment of a wide variety of cancers including tumors such as lung, prostate, breast, brain, skin, cervical carcinomas, testicular carcinomas, etc. More particularly, cancers that may be treated by the compounds or pharmaceutically acceptable salts thereof and the compositions provided herein include, but are not limited to tumor types such as astrocytic, breast, cervical, colorectal, endometrial, esophageal, gastric, head and neck, hepatocellular, laryngeal, lung, oral, ovarian, prostate and thyroid carcinomas and sarcomas. More specifically, the compounds or pharmaceutically acceptable salts thereof and the compositions provided herein can be used to treat:
  • Cardiac Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma) , myxoma, rhabdomyoma, fibroma, lipoma and teratoma;
  • Lung bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma) , alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma;
  • Gastrointestinal esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma) , stomach (carcinoma, lymphoma, leiomyosarcoma) , pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma) , small bowel (adenocarcinoma, lymphoma, carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma) , large bowel (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma) ;
  • Genitourinary tract kidney (adenocarcinoma, Wilm's tumor (nephroblastoma) , lymphoma, leukemia) , bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma) , prostate (adenocarcinoma, sarcoma) , testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma) ;
  • liver hepatoma (hepatocellular carcinoma) , cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma;
  • Biliary tract gall bladder carcinoma, ampullary carcinoma, cholangiocarcinoma; Bone: osteogenic sarcoma (osteosarcoma) , fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma) , multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma (osteocartilaginous exostoses) , benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors;
  • Nervous system skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans) , meninges (meningioma, meningiosarcoma, gliomatosis) , brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma) , glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors) , spinal cord neurofibroma, meningioma, glioma, sarcoma) ;
  • Gynecological uterus (endometrial 'carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma) , granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma) , vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma) , vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma) , fallopian tubes (carcinoma) ;
  • Hematologic blood (myeloid leukemia (acute and chronic) , acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome) , Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma) ;
  • the cancer that can be treated with the compounds or pharmaceutically acceptable salts thereof and the compositions provided herein is non-small cell lung cancer, small cell lung cancer, colorectal cancer, rectal cancer or pancreatic cancer.
  • the cancer that can be treated with the compounds or pharmaceutically acceptable salts thereof and the compositions provided herein is non-small cell lung cancer or colorectal cancer, in particular, non-small cell lung cancer or colorectal cancer with brain metastasis.
  • the administering is conducted via a route selected from the group consisting of parenteral, intraperitoneal, intradermal, intracardiac, intraventricular, intracranial, intracerebrospinal, intrasynovial, intrathecal administration, intramuscular injection, intravitreous injection, intravenous injection, intra-arterial injection, oral, buccal, sublingual, transdermal, topical, intratracheal, intrarectal, subcutaneous, and topical administration.
  • the compounds, pharmaceutically acceptable salts thereof and pharmaceutical compositions comprising such compounds and salts also may be co-administered with other anti-neoplastic compounds, e.g., chemotherapy, or used in combination with other treatments, such as radiation or surgical intervention, either as an adjuvant prior to surgery or post-operatively.
  • other anti-neoplastic compounds e.g., chemotherapy
  • other treatments such as radiation or surgical intervention
  • the compounds, pharmaceutically acceptable salts thereof and pharmaceutical compositions comprising such compounds and salts can be administered simultaneously, separately or sequentially with one or more additional therapeutic agents.
  • the additional therapeutic agent is selected from an anti-PD-1 or PD-L1 antagonist, an MEK inhibitor, a CDK4/CDK6 inhibitor, an EGFR inhibitor, an ERK inhibitor, a SHP2 inhibitor, a SOS1 inhibitor, a mTOR inhibitor, a VEGFR inhibitor, EGFR antibody, a platinum agent or pemetrexed.
  • the anti-PD-1 antagonist is selected from nivolumab, pembrolizumab, or AMB 404.
  • the MEK inhibitor is trametinib.
  • the SHP2 inhibitor is RMC-4630.
  • the present disclosure also provides a method for treating cancer in a subject in need thereof, the method comprising:
  • the present disclosure provides a method for inhibiting KRAS G12C activity in a subject in need thereof, comprising administering the compound or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of the present disclosure to the subject.
  • the starting material of Formula (Ia’_1) is commercially available.
  • Compound of Formular (Ia’_2) may be prepared by the Curtius rearrangement reaction with a compound of Formula (Ia’_1) in the presence of diphenyl phosphorazidate (DPPA) under standard conditions.
  • DPPA diphenyl phosphorazidate
  • Compound of Formula (Ia’_3) may be prepared by the removing the Boc protective group of Compound of Formula (Ia’_2) with acid (e.g, TFA) under standard condition.
  • acid e.g, TFA
  • Compound of Formula (Ia’_5) may be prepared by the cyclization of a compound of Formula (Ia’_3) with Compound of Formula (Ia’_4) under standard conditions.
  • Compound of Formula (Ia’_6) may be prepared by the nitration reaction of a compound of Formula (Ia’_5) with nitric acid under standard conditions.
  • Compound of Formula (Ia’_7) may be prepared by the chlorination reaction of a compound of Formula (Ia’_6) with chloride reagents (e.g, POCl 3 ) in the presence of base (e.g, DIPEA) under standard conditions.
  • chloride reagents e.g, POCl 3
  • base e.g, DIPEA
  • Compound of Formula (Ia’_9) may be prepared by the substitution reaction with a compound of Formula (Ia’_7) and a compound of Formula (Ia’_8) in the presence of base (e.g, DIPEA, NaHCO 3 ) under standard conditions.
  • base e.g, DIPEA, NaHCO 3
  • Compound of Formula (Ia’_10) may be prepared by the reduction of a compound of Formula (Ia’_9) , followed by intramolecular cyclization under standard reduction conditions (e.g, Fe/NH 4 Cl) .
  • Compound of Formula (Ia’_11) may be prepared by the methylation reaction of a compound of Formula (Ia’_10) with methylation reagents (e.g, MeI) under standard conditions.
  • methylation reagents e.g, MeI
  • Compound of Formula (Ia’) may be prepared by the Suzuki coupling reaction of a compound of Formular (Ia’_11) with a compound of Formula (Ia’_12) in the presence of Palladium catalyst (e.g, PddppfCl 2 ) and base (e.g, Na 2 CO 3 ) under standard conditions.
  • Palladium catalyst e.g, PddppfCl 2
  • base e.g, Na 2 CO 3
  • Step 1 methyl 5- (2- (tert-butoxy) -1-cyano-2-oxoethyl) pyrazine-2-carboxylate
  • Step 8 5- ( ( (2-chloro-3-fluoropyridin-4-yl) amino) methylene) -2, 2-dimethyl-1, 3-dioxane-4, 6-dione
  • Step 11 4, 7-dichloro-8-fluoro-3-nitro-1, 6-naphthyridine
  • Step 12 methyl 1- (7-chloro-8-fluoro-3-nitro-1, 6-naphthyridin-4-yl) -5- (cyanomethyl) -4- (4-methoxybenzyl) piperazine-2-carboxylate
  • Step 13 2- (3-chloro-4-fluoro-10- (4-methoxybenzyl) -8-oxo-8, 8a, 9, 10, 11, 12-hexahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-11-yl) acetonitrile
  • Step 14 2- (3-chloro-4-fluoro-10- (4-methoxybenzyl) -7-methyl-8-oxo-8, 8a, 9, 10, 11, 12-hexahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-11-yl) acetonitrile
  • Step 15 2- (3- (8-chloronaphthalen-1-yl) -4-fluoro-10- (4-methoxybenzyl) -7-methyl-8-oxo-8, 8a, 9, 10, 11, 12-hexahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-11-yl) acetonitrile
  • Step 16 2- (3- (8-chloronaphthalen-1-yl) -4-fluoro-7-methyl-8-oxo-8, 8a, 9, 10, 11, 12-hexahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-11-yl) acetonitrile
  • Step 12 2- (10-acryloyl-3- (8-chloronaphthalen-1-yl) -4-fluoro-7-methyl-8-oxo-8, 8a, 9, 10, 11, 12-hexahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-11-yl) acetonitrile
  • Example 1A 2.7 mg/Example 1B: 16.5 mg
  • Example 1A MS Calcd: 540.2, MS (ESI) : 541.3 [M+H] + .
  • Example 1B MS Calcd: 540.2, MS (ESI) : 541.3 [M+H] + .
  • Step 1 2- (4-fluoro-3- (2-fluoro-6-hydroxyphenyl) -10- (4-methoxybenzyl) -7- methyl-8-oxo-8, 8a, 9, 10, 11, 12-hexahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-11-yl) acetonitrile
  • Step 2 2- (4-fluoro-3- (2-fluoro-6-hydroxyphenyl) -7-methyl-8-oxo-8, 8a, 9, 10, 11, 12-hexahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-11-yl) acetonitrile
  • Step 3 2- (10-acryloyl-11- (cyanomethyl) -4-fluoro-7-methyl-8-oxo-8, 8a, 9, 10, 11, 12-hexahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-3-yl) -3-fluorophenyl acrylate
  • Step 4 2- (10-acryloyl-4-fluoro-3- (2-fluoro-6-hydroxyphenyl) -7-methyl-8-oxo-8, 8a, 9, 10, 11, 12-hexahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-11-yl) acetonitrile
  • Example 2A 5.6mg
  • Example 2B 6.7mg
  • Example 2A MS (ESI) : 491.3 [M+H] + .
  • Example 2B MS (ESI) : 491.3 [M+H] + .
  • 1 H NMR 400 MHz, MeOD
  • Step 1 2- (4-fluoro-10- (4-methoxybenzyl) -3- (3- (methoxy methoxy) naphthalen-1-yl) -7-methyl-8-oxo-8, 8a, 9, 10, 11, 12-hexahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-11-yl) acetonitrile
  • Step 2 2- (4-fluoro-3- (3-hydroxynaphthalen-1-yl) -7-methyl-8-oxo-8, 8a, 9, 10, 11, 12-hexahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-11-yl) acetonitrile
  • Step 3 4- (10-acryloyl-11- (cyanomethyl) -4-fluoro-7-methyl-8-oxo-8, 8a, 9, 10, 11, 12-hexahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-3-yl) naphthalen-2-yl acrylate
  • Step4 2- (10-acryloyl-4-fluoro-3- (3-hydroxynaphthalen-1-yl) -7-methyl-8-oxo-8, 8a, 9, 10, 11, 12-hexahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-11-yl) acetonitrile
  • Example 3A 6.5mg
  • Example 3B 35.8 mg
  • Example 3A MS (ESI) : 523.3 [M+H] + .
  • Example 3B MS (ESI) : 523.3 [M+H] + .
  • 1 H NMR 400 MHz, MeOD
  • Step 1 2- (4-fluoro-10- (4-methoxybenzyl) -7-methyl-3- (8-methylnaphthalen-1-yl) -8-oxo-8, 8a, 9, 10, 11, 12-hexahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-11-yl) acetonitrile
  • Step 2 2- (4-fluoro-7-methyl-3- (8-methylnaphthalen-1-yl) -8-oxo-8, 8a, 9, 10, 11, 12-hexahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-11-yl) acetonitrile
  • Step 3 2- (10-acryloyl-4-fluoro-7-methyl-3- (8-methylnaphthalen-1-yl) -8-oxo-8, 8a, 9, 10, 11, 12-hexahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-11-yl) acetonitrile
  • Example 4A 1.9 mg;
  • Example 4B 2.1 mg, yield: 4.5%) .
  • Example 4A MS Calcd: 520.2, MS (ESI) : 521.2 [M+H] + .
  • Example 4B MS Calcd: 520.2, MS (ESI) : 521.2 [M+H] + .
  • Step1 2- (3-chloro-4-fluoro-7-methyl-8-oxo-8, 8a, 9, 10, 11, 12-hexahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-11-yl) acetonitrile
  • Step 2 2- (10-acryloyl-3-chloro-4-fluoro-7-methyl-8-oxo-8, 8a, 9, 10, 11, 12-hexahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-11-yl) acetonitrile
  • Step 3 t 2- (10-acryloyl-4-fluoro-7-methyl-8-oxo-3- (8- (triisopropylsilyl) ethynyl) naphthalen-1-yl) -8, 8a, 9, 10, 11, 12-hexahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-11-yl) acetonitrile
  • Step 4 2- (10-acryloyl-3- (8-ethynylnaphthalen-1-yl) -4-fluoro-7-methyl-8-oxo-8, 8a, 9, 10, 11, 12-hexahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-11-yl) acetonitrile
  • Step 1 tert-butyldimethyl ( (4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -5- ( (triisopropylsilyl) ethynyl) naphthalen-2-yl) oxy) silane
  • Step 2 2- (10-acryloyl-4-fluoro-3- (3-hydroxy-8- ( (triisopropylsilyl) ethynyl) naphthalen-1-yl) -7-methyl-8-oxo-8, 8a, 9, 10, 11, 12-hexahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-11- yl) acetonitrile
  • the reaction mixture was cooled to rt, diluted with water (40 mL) .
  • the mixture was extracted with EtOAc (20 mL x3) .
  • the combined organic layers were washed with brine (30 mL x 2) , dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography, elute with PE /EA (1: 5) to afford the desired product (30 mg, yield: 22%) .
  • Step 4 2- (10-acryloyl-3- (8-ethynyl-3-hydroxynaphthalen-1-yl) -4-fluoro-7-methyl-8-oxo-8, 8a, 9, 10, 11, 12-hexahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-11-yl) acetonitrile
  • Step 3 2- (3- (8-chloro-3- (methoxymethoxy) naphthalen-1-yl) -4-fluoro-10- (4-methoxybenzyl) -7-methyl-8-oxo-8, 8a, 9, 10, 11, 12-hexahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-11-yl) acetonitrile
  • Step 4 2- (3- (8-chloro-3-hydroxynaphthalen-1-yl) -4-fluoro-7-methyl-8-oxo-8, 8a, 9, 10, 11, 12-hexahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-11-yl) acetonitrile
  • Step 5 4- (10-acryloyl-11- (cyanomethyl) -4-fluoro-7-methyl-8-oxo-8, 8a, 9, 10, 11, 12-hexahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-3-yl) -5-chloronaphthalen-2-yl acrylate
  • Step 6 2- (10-acryloyl-3- (8-chloro-3-hydroxynaphthalen-1-yl) -4-fluoro-7-methyl-8-oxo-8, 8a, 9, 10, 11, 12-hexahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-11-yl) acetonitrile
  • Example 7A 1.5 mg/Example 7B: : 4.6 mg, Yield: 5.4%for two steps
  • Example 7A MS Calcd: 556.1, MS (ESI) : 557.1 [M+H] + .
  • Step 4 2- (8-chloro-7-fluoronaphthalen-1-yl) -4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane
  • Step 5 2- (3- (8-chloro-7-fluoronaphthalen-1-yl) -4-fluoro-10- (4-methoxybenzyl) -7-methyl-8-oxo-8, 8a, 9, 10, 11, 12-hexahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-11-yl) acetonitrile
  • Step 6 2- (3- (8-chloro-7-fluoronaphthalen-1-yl) -4-fluoro-7-methyl-8-oxo-8, 8a, 9, 10, 11, 12-hexahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-11-yl) acetonitrile
  • Step 7 2- (10-acryloyl-3- (8-chloro-7-fluoronaphthalen-1-yl) -4-fluoro-7-methyl-8-oxo-8, 8a, 9, 10, 11, 12-hexahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-11-yl) acetonitrile
  • the reaction mixture was stirred at 50°C for 3h. Then the reaction mixture was concentrated and the residue was adjusted to PH>7 with sat. NaHCO 3 aqueous. The resulting solution was extracted with EA. The combined organic layers were washed with sat. NaCl, dried over Na 2 SO 4 and concentrated. The crude was purified by pre-TLC to afford the desired product (116 mg, yield: 46%, 2 steps) .
  • Example 23A 2.1 mg/Example 23B: 5.1 mg
  • Example 23A MS (ESI) : 559.2 [M+H] + .
  • Example 23B MS (ESI) : 559.2 [M+H] + .
  • Step 1 2- (3- (8-chloro-7-fluoronaphthalen-1-yl) -4-fluoro-10- (2-fluoroacryloyl) -7-methyl-8-oxo-8, 8a, 9, 10, 11, 12-hexahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-11-yl) acetonitrile
  • Step 1 2- (3- (8-chloro-7-fluoronaphthalen-1-yl) -10- (4- (dimethylamino) but-2-enoyl) -4-fluoro-7-methyl-8-oxo-8, 8a, 9, 10, 11, 12-hexahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-11-yl) acetonitrile
  • Step 1 1- (tert-butyl) 3-methyl (S) -4- (7-chloro-8-fluoro-3-nitro-1, 6-naphthyridin-4-yl) piperazine-1, 3-dicarboxylate
  • Step 1 2- (3- (8-chloronaphthalen-1-yl) -4-fluoro-7-methyl-8-oxo-10- (3- (pyridin-2-yl) acryloyl) -8, 8a, 9, 10, 11, 12-hexahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-11-yl) acetonitrile
  • Step 4 1- (tert-butyl) 3-methyl (3S, 6R) -6- ( (methylsulfonyl) methyl) piperazine-1, 3- dicarboxylate
  • Step 7 tert-butyl (2R, 4aS) -10-chloro-9-fluoro-6-methyl-2- ( (methylsulfonyl) methyl) -5-oxo-1, 2, 4, 4a, 5, 6-hexahydro-3H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] quinoline-3-carboxylate
  • Step 8 tert-butyl (8aS, 11R) -3- (8-chloronaphthalen-1-yl) -4-fluoro-7-methyl-11- ( (methylsulfonyl) methyl) -8-oxo-7, 8, 8a, 9, 11, 12-hexahydro-10H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridine-10-carboxylate

Abstract

L'invention concerne de nouveaux composés utiles en tant qu'inhibiteurs de KRAS G12C, ainsi que des compositions pharmaceutiques comprenant ces composés et des procédés de traitement par administration de ces composés ou des compositions pharmaceutiques.
PCT/CN2022/116994 2021-09-06 2022-09-05 Inhibiteurs de kras g12c et leurs utilisations WO2023030517A1 (fr)

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CN113527299A (zh) * 2020-04-18 2021-10-22 上海凌达生物医药有限公司 一类含氮稠环类化合物、制备方法和用途
CN113563323A (zh) * 2020-04-29 2021-10-29 上海凌达生物医药有限公司 一类苯并噻唑基联芳基类化合物、制备方法和用途

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