WO2022156761A1 - Indènes spirocycliques - Google Patents

Indènes spirocycliques Download PDF

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WO2022156761A1
WO2022156761A1 PCT/CN2022/073129 CN2022073129W WO2022156761A1 WO 2022156761 A1 WO2022156761 A1 WO 2022156761A1 CN 2022073129 W CN2022073129 W CN 2022073129W WO 2022156761 A1 WO2022156761 A1 WO 2022156761A1
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alkyl
compound
solvate
group
salt
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PCT/CN2022/073129
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Chao Li
Jianyong Chen
Wenliang HU
Chengzhe Wu
Liugen LI
Gaojie YE
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Ascentage Pharma (Suzhou) Co., Ltd.
Ascentage Pharma Group Corp Limited
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Publication of WO2022156761A1 publication Critical patent/WO2022156761A1/fr

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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Definitions

  • the present disclosure provides KRAS inhibitors, synthetic intermediates used to prepare KRAS inhibitors, and therapeutic methods of treating conditions and diseases, e.g., cancer, wherein the inhibition of KRAS provides a benefit.
  • RAS represents a group of monomeric globular proteins of 189 amino acids (21 kDa molecular mass) that are associated with the plasma membrane and that bind either GDP or GTP.
  • RAS acts as a molecular switch. When RAS contains bound GDP, it is in the resting or off position and is “inactive” . In response to exposure of the cell to certain growth promoting stimuli, RAS is induced to exchange its bound GDP for a GTP. With GTP bound, RAS is "switched on” and is able to interact with and activate other proteins (its "downstream targets” ) .
  • the RAS protein itself has a very low intrinsic ability to hydrolyze GTP back to GDP, thus turning itself into the off state.
  • GTPase-activating proteins GTPase-activating proteins
  • Any mutation in RAS that affects its ability to interact with GAP or to convert GTP back to GDP will result in a prolonged activation of the protein and consequently a prolonged signal to the cell telling it to continue to grow and divide. Because these signals result in cell growth and division, overactive RAS signaling may ultimately lead to cancer.
  • the most notable members of the RAS are HRAS, KRAS, and NRAS.
  • RAS proteins contain a G domain that is responsible for the enzymatic activity of RAS, i.e., the guanine nucleotide binding and the hydrolysis (GTPase reaction) . It also contains a C-terminal extension, known as the CAAX box, which may be post-translationally modified, and is responsible for targeting the protein to the membrane.
  • the G domain is approximately 21-25 kDa in size and it contains a phosphate binding loop (P-loop) .
  • the P-loop represents the pocket where the nucleotides are bound in the protein, and this is the rigid part of the domain with conserved amino acid residues that are essential for nucleotide binding and hydrolysis (Glycine 12, Threonine 26 and Lysine 16) .
  • the G domain also contains the Switch I (residues 30-40) and Switch II (residues 60-76) regions, both of which are the dynamic parts of the protein which are often represented as the "spring-loaded” mechanism because of their ability to switch between the resting and loaded state.
  • the key interaction is the hydrogen bonds formed by Threonine-35 and glycine-60 with the gamma-phosphate of GTP that maintain the Switch 1 and Switch 2 regions, respectively, in their active conformation. After hydrolysis of GTP and release of phosphate, these two relax into the inactive GDP conformation.
  • KRAS Mutations in the KRAS gene are common events in human tumorigenesis. Indeed, mutations in KRAS are prevalent in the some of the most deadly cancer types: pancreatic (95%) , colorectal (45%) , and lung (35%) . The most common KRAS mutations are found at residue G12 and G13 in the P-loop and at residue Q61.
  • KRAS-G12C mutations comprise a patient population with a worldwide annual incidence of >100,000 individuals. See, e.g., Fell et al., ASC Med. Chem. Lett. 9: 1230-1234 (2016) ; Shin et al., ACS Med. Chem. Lett. 10: 1302-1308 (2019) ; Canon et al., Nature 575: 217–223 (2019) . There exists a need in the art for KRAS inhibitors for the treatment of cancer and other diseases.
  • the present disclosure provides compounds represented by any one of Formulae I-XV, LXII, or LXIII, below, and the pharmaceutically acceptable salts and solvates, e.g., hydrates, thereof, collectively referred to as "Compounds of the Disclosure.
  • Compounds of the Disclosure are KRAS inhibitors and are thus useful in treating or preventing diseases or conditions such as cancer wherein the inhibition of KRAS provides a benefit.
  • the present disclosure provides compounds represented by any one of Formulae XVI-LXI, below, and the pharmaceutically acceptable salts and solvates, e.g., hydrates, thereof, collectively referred to as "Intermediates of the Disclosure. " Intermediates of the Disclosure are synthetic intermediates that can be used to prepare Compounds of the Disclosure.
  • the present disclosure provides methods of treating or preventing a condition or disease by administering a therapeutically effective amount of a Compound of the Disclosure to a subject, e.g., a human patient, in need thereof.
  • the disease or condition of interest that is treatable or preventable by inhibition or of KRAS is, for example, a cancer, a chronic autoimmune disorder, an inflammatory condition, a proliferative disorder, sepsis, or a viral infection.
  • methods of preventing the proliferation of unwanted proliferating cells such as in cancer, in a subject comprising administering a therapeutically effective amount of a Compound of the Disclosure to a subject at risk of developing a condition characterized by unwanted proliferating cells.
  • Compounds of the Disclosure may reduce the proliferation of unwanted cells by inducing apoptosis in those cells.
  • Compounds of the Disclosure are administered in combination with an optional therapeutic agent.
  • the present disclosure provides a method of inhibiting KRAS in a subject, comprising administering to the subject a therapeutically effective amount of a Compound of the Disclosure.
  • the present disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising a Compound of the Disclosure and an excipient and/or pharmaceutically acceptable carrier.
  • the present disclosure provides a composition comprising a Compound of the Disclosure and an excipient and/or pharmaceutically acceptable carrier for use treating or preventing diseases or conditions wherein inhibition of KRAS provides a benefit, e.g., cancer.
  • the present disclosure provides a composition
  • a composition comprising: (a) a Compound of the Disclosure; (b) a second therapeutically active agent; and (c) optionally an excipient and/or pharmaceutically acceptable carrier.
  • the present disclosure provides a Compound of the Disclosure for use in the treatment or prevention of a disease or condition of interest, e.g., cancer.
  • the present disclosure provides a use of a Compound of the Disclosure for the manufacture of a medicament for treating a disease or condition of interest, e.g., cancer.
  • the present disclosure provides a kit comprising a Compound of the Disclosure, and, optionally, a packaged composition comprising an optional therapeutic agent useful in the treatment of a disease or condition of interest, and a package insert containing directions for use in the treatment of a disease or condition, e.g., cancer.
  • the present disclosure provides methods of preparing Compounds of the Disclosure and Intermediates of the Disclosure.
  • Compounds of the Disclosure are compounds of Formula I:
  • X represents a 6-to 12-membered monocyclic or bicyclic heterocyclo
  • R 1a is selected from the group consisting of C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, and C 3 -C 6 cycloalkyl;
  • R 4a , R 4b , and R 4c are independently selected from the group consisting of hydrogen, halogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, (amino) C 1 -C 4 alkyl, (hydroxy) C 1 -C 4 alkyl, (alkoxy) C 1 -C 4 alkyl, and (heterocyclo) C 1 -C 4 alkyl;
  • R 5a is selected from the group consisting of hydrogen, halogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, (amino) C 1 -C 4 alkyl, (hydroxy) C 1 -C 4 alkyl, (alkoxy) C 1 -C 4 alkyl, and (heterocyclo) C 1 -C 4 alkyl;
  • R 4e , R 4f , and R 4g are independently selected from the group consisting of hydrogen, halogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, (amino) C 1 -C 4 alkyl, (hydroxy) C 1 -C 4 alkyl, (alkoxy) C 1 -C 4 alkyl, and (heterocyclo) C 1 -C 4 alkyl;
  • R 5b is selected from the group consisting of hydrogen, halogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, (amino) C 1 -C 4 alkyl, (hydroxy) C 1 -C 4 alkyl, (alkoxy) C 1 -C 4 alkyl, and (heterocyclo) C 1 -C 4 alkyl;
  • R 2b and R 2c are independently selected from the group consisting of hydrogen and C 1 -C 4 alkyl; or
  • R 5c is selected from the group consisting hydrogen and C 1 -C 4 alkyl
  • R 5d and R 5e are independently selected from the group consisting hydrogen and C 1 -C 4 alkyl; or
  • R 5d and R 5e taken together with the nitrogen atom to which they are attached form an optionally substituted 4-to 8-membered heterocyclo;
  • R 5f and R 5g are independently selected from the group consisting hydrogen and C 1 -C 4 alkyl; or
  • R 5f and R 5g taken together with the nitrogen atom to which they are attached form an optionally substituted 4-to 8-membered heterocyclo;
  • L is selected from the group consisting of -O-, -S-, and -N (R 7 ) -; or L is a bond;
  • R 7 is selected from the group consisting of hydrogen and C 1 -C 4 alkyl
  • R 3 is selected from the group consisting of hydrogen, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, (amino) C 1 -C 4 alkyl, (hydroxy) C 1 -C 4 alkyl, (alkoxy) C 1 -C 4 alkyl, (carboxamido) C 1 -C 4 alkyl, (heterocyclo) C 1 -C 4 alkyl, (aryl) C 1 -C 4 alkyl, and (hetereoaryl) C 1 -C 4 alkyl;
  • A is selected from the group consisting of - (CR 6a R 6b ) m -, -O-, -S-, and -N (R 7a ) -;
  • a 1 is selected from the group consisting of - (CR 6c R 6d ) n -, -O-, -S-, and -N (R 7b ) -;
  • a 2 is selected from the group consisting of - (CR 6e R 6f ) o -, -O-, -S-, and -N (R 7c ) -;
  • a 3 is selected from the group consisting of - (CR 6g R 6h ) p -, -O-, -S-, and -N (R 7d ) -;
  • a 4 is selected from the group consisting of -O-, -S-, and -N (R 7e ) -; or A 4 is a bond,
  • R 6a , R 6b , R 6c , R 6d , R 6e , R 6f , R 6g , and R 6h are each independently selected from the group consisting of hydrogen and C 1 -C 4 alkyl;
  • n 0, 1, or 2;
  • n 0, 1, or 2;
  • o 0, 1, or 2;
  • p 0, 1, or 2;
  • R 7a , R 7b , R 7c , R 7d , and R 7e are independently selected from the group consisting of hydrogen and C 1 -C 4 alkyl;
  • E 1 is - (CR 8e R 8f ) r -q is 0 or 1;
  • r is 0 or 1;
  • R 8a and R 8b are each independently selected from the group consisting of hydrogen and C 1 -C 4 alkyl;
  • R 8e and R 8f are each independently selected from the group consisting of hydrogen and C 1 -C 4 alkyl;
  • R 8c is selected from the group consisting of hydrogen, halo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, and C 3 -C 6 cycloalkyl;
  • R 8d is selected from the group consisting of hydrogen, halo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, and C 3 -C 6 cycloalkyl;
  • R 10 is selected from the group consisting of hydrogen, C 1 -C 4 alkyl and C 3 -C 6 cycloalkyl;
  • Compounds of the Disclosure are compounds of Formula I, wherein q is 0 and r is 0, or a pharmaceutically acceptable salt or solvate thereof.
  • Compounds of the Disclosure are compounds of Formula I, wherein q is 0 and r is 1, or a pharmaceutically acceptable salt or solvate thereof.
  • Compounds of the Disclosure are compounds of Formula I, wherein q is 1 and r is 0, or a pharmaceutically acceptable salt or solvate thereof.
  • Compounds of the Disclosure are compounds of Formula II:
  • R 3 , A, A 1 , A 2 , A 3 , A 4 , E, E 1 , R 8c , R 8d , L, Q, Z, are as defined in connection with Formula I, or a pharmaceutically acceptable salt or solvate thereof.
  • Compounds of the Disclosure are compounds of Formula II, wherein q is 0 and r is 0, or a pharmaceutically acceptable salt or solvate thereof.
  • Compounds of the Disclosure are compounds of Formula II, wherein q is 0 and r is 1, or a pharmaceutically acceptable salt or solvate thereof.
  • Compounds of the Disclosure are compounds of Formula II, wherein q is 1 and r is 0, or a pharmaceutically acceptable salt or solvate thereof.
  • Compounds of the Disclosure are compounds of Formula III:
  • R 3 , A, A 1 , A 2 , A 3 , A 4 , E, E 1 , R 8c , R 8d , L, Q, Z, are as defined in connection with Formula I, or a pharmaceutically acceptable salt or solvate thereof.
  • Compounds of the Disclosure are compounds of Formula III, wherein q is 0 and r is 0, or a pharmaceutically acceptable salt or solvate thereof.
  • Compounds of the Disclosure are compounds of Formula III, wherein q is 0 and r is 1, or a pharmaceutically acceptable salt or solvate thereof.
  • Compounds of the Disclosure are compounds of Formula III, wherein q is 1 and r is 0, or a pharmaceutically acceptable salt or solvate thereof.
  • Compounds of the Disclosure are compounds of Formula IV:
  • R 11a , R 11b , R 11c , and R 11d are independently selected from the group consisting of hydrogen, halo, cyano, hydroxy, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 3 -C 6 cycloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, and (hydroxy) C 1 -C 4 alkyl; and R 3 , A, A 1 , A 2 , A 3 , A 4 , E, R 8c , R 8d , L, Q, and Z are as defined in connection with Formula I, or a pharmaceutically acceptable salt or solvate thereof.
  • Compounds of the Disclosure are compounds of Formula V:
  • R 11a , R 11b , R 11c , R 11d , R 3 , A, A 1 , A 2 , A 3 , A 4 , E, R 8c , R 8d , L, Q, and Z are as defined in connection with Formula IV, or a pharmaceutically acceptable salt or solvate thereof.
  • Compounds of the Disclosure are compounds of Formula VI:
  • R 11a , R 11b , R 11c , R 11d , R 3 , A, A 1 , A 2 , A 3 , A 4 , E, R 8c , R 8d , L, Q, and Z are as defined in connection with Formula IV, or a pharmaceutically acceptable salt or solvate thereof.
  • Compounds of the Disclosure are compounds of Formula VII:
  • R 11a , R 11b , R 11c , R 11d , R 3 , A, E, R 8c , R 8d , L, Q, and Z are as defined in connection with Formula IV, or a pharmaceutically acceptable salt or solvate thereof.
  • Compounds of the Disclosure are compounds of Formula VIII:
  • R 11a , R 11b , R 11c , R 11d , R 3 , A, E, R 8c , R 8d , L, Q, and Z are as defined in connection with Formula IV, or a pharmaceutically acceptable salt or solvate thereof.
  • Compounds of the Disclosure are compounds of Formula IX:
  • R 11a , R 11b , R 11c , R 11d , R 3 , A, E, R 8c , R 8d , L, Q, and Z are as defined in connection with Formula IV, or a pharmaceutically acceptable salt or solvate thereof.
  • Compounds of the Disclosure are compounds of any one of Formulae I-IX, wherein A is - (CH 2 ) m -and m is 0 or 1, or a pharmaceutically acceptable salt or solvate thereof. In another embodiment, m is 1.
  • Compounds of the Disclosure are compounds of Formula X:
  • R 11a , R 11b , R 11c , R 11d , R 3 , A 1 , A 3 , E, R 8c , R 8d , L, Q, and Z are as defined in connection with Formula IV, or a pharmaceutically acceptable salt or solvate thereof.
  • Compounds of the Disclosure are compounds of Formula XI:
  • R 11a , R 11b , R 11c , R 11d , R 3 , A 1 , A 3 , E, R 8c , R 8d , L, Q, and Z are as defined in connection with Formula IV, or a pharmaceutically acceptable salt or solvate thereof.
  • Compounds of the Disclosure are compounds of Formula XII:
  • R 11a , R 11b , R 11c , R 11d , R 3 , A 1 , A 3 , E, R 8c , R 8d , L, Q, and Z are as defined in connection with Formula IV, or a pharmaceutically acceptable salt or solvate thereof.
  • Compounds of the Disclosure are compounds of Formula XIII:
  • a 2 is selected from the group consisting of -O-, -S-, and -N (R 7c ) -; R 7c , R 3 , A 1 , E, R 8c , R 8d , L, Q, and Z are as defined in connection with Formula I, and R 11a , R 11b , R 11c , and R 11d are as defined in connection with Formula IV, or a pharmaceutically acceptable salt or solvate thereof.
  • Compounds of the Disclosure are compounds of Formula XIV:
  • a 2 is selected from the group consisting of -O-, -S-, and -N (R 7c ) -; R 7c , R 3 , A 1 , E, R 8c , R 8d L, Q, and Z are as defined in connection with Formula I, and R 11a , R 11b , R 11c , and R 11d are as defined in connection with Formula IV, or a pharmaceutically acceptable salt or solvate thereof.
  • Compounds of the Disclosure are compounds of Formula XV:
  • a 2 is selected from the group consisting of -O-, -S-, and -N (R 7c ) -; R 7c , R 3 , A 1 , E, R 8c , R 8d L, Q, and Z are as defined in connection with Formula I, and R 11a , R 11b , R 11c , and R 11d are as defined in connection with Formula IV, or a pharmaceutically acceptable salt or solvate thereof.
  • Compounds of the Disclosure are compounds of any one of Formulae I-XV, wherein E is - (CH 2 ) q -, or a pharmaceutically acceptable salt or solvate thereof.
  • Compounds of the Disclosure are compounds of any one of Formulae I-XV, wherein E is - (CH 2 ) q -; and q is 1, or a pharmaceutically acceptable salt or solvate thereof.
  • Compounds of the Disclosure are compounds of any one of Formulae I-XV, wherein q is 0, i.e., E is a bond, or a pharmaceutically acceptable salt or solvate thereof.
  • Compounds of the Disclosure are compounds of any one of Formulae I-XV, wherein L is -O-, or a pharmaceutically acceptable salt or solvate thereof.
  • Compounds of the Disclosure are compounds of any one of Formulae I-XV, wherein R 3 is selected from the group consisting of (amino) C 1 -C 4 alkyl, (carboxamido) C 1 -C 4 alkyl, and (heterocyclo) C 1 -C 4 alkyl, or a pharmaceutically acceptable salt or solvate thereof.
  • Compounds of the Disclosure are compounds of any one of Formulae I-XV, wherein R 3 is (heterocyclo) CH 2 -, or a pharmaceutically acceptable salt or solvate thereof.
  • Compounds of the Disclosure are compounds of any one of Formulae I-XV, wherein R 3 is (heterocyclo) CH 2 -and the heterocyclo is an optionally substituted 8-to 12-membered bicyclic group containing one or two nitrogen atoms, or a pharmaceutically acceptable salt or solvate thereof.
  • the heterocyclo is an 8-membered bicyclic group containing one nitrogen atom.
  • Compounds of the Disclosure are compounds of any one of Formulae I-XV, wherein R 3 is:
  • X is selected from the group consisting of -O-and -CR 22a R 22b -;
  • each R 21 is independently selected from the group consisting of halo, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, and (hydroxyl) C 1 -C 3 alkyl;
  • R 22a and R 22b are independently selected from the group consisting of hydrogen, halo, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, and (hydroxyl) C 1 -C 3 alkyl; or
  • R 22a and R 22b taken together with the carbon atom to which they are attached form an optionally substituted 3-to 6-membered cycloalkyl
  • u is 1, 2, or 3;
  • v 0, 1, or 2.
  • Compounds of the Disclosure are compounds of any one of Formulae I-XV, wherein R 3 is selected from the group consisting of:
  • Compounds of the Disclosure are compounds of any one of Formulae I-XV, wherein R 3 is:
  • Compounds of the Disclosure are compounds of any one of Formulae I-XV, wherein R 3 is selected from the group consisting of:
  • Compounds of the Disclosure are compounds of any one of Formulae I-XV, wherein Z is selected from the group consisting of:
  • Compounds of the Disclosure are compounds of any one of Formulae I-XV, wherein R 2a is -CH 2 CN, or a pharmaceutically acceptable salt or solvate thereof.
  • Compounds of the Disclosure are compounds of any one of Formulae I-XV, wherein R 1 is selected from the group consisting of:
  • Compounds of the Disclosure are compounds of any one of Formulae I-XV, wherein R 1 is:
  • Compounds of the Disclosure are compounds of any one of Formulae I-XV, wherein R 1 is:
  • Compounds of the Disclosure are compounds of Formula LXII:
  • R 8c and R 8d are as defined in connection with Formula I;
  • R 11a , R 11b , R 11c , and R 11d are as defined in connection with Formula IV;
  • R 22a and R 22b are independently selected from the group consisting of hydrogen, halo, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, and (hydroxyl) C 1 -C 3 alkyl; or
  • R 22a and R 22b taken together with the carbon atom to which they are attached form an optionally substituted 3-to 6-membered cycloalkyl
  • R 23 is selected from the group consisting of hydrogen and fluoro
  • Compounds of the Disclosure are compounds of Formula LXIII:
  • R 8c , R 8d , R 11a , R 11b , R 11c , R 11d , R 22a , R 22b , and R 23 are as defined in connection with Formula LXII, or a pharmaceutically acceptable salt or solvate thereof.
  • Compounds of the Disclosure are any one or more of the compounds listed in Table 1, or a pharmaceutically acceptable salt or solvate thereof.
  • the present disclosure encompasses the preparation and use of salts of Compounds of the Disclosure.
  • pharmaceutically acceptable salt refers to salts or zwitterionic forms of Compounds of the Disclosure that are suitable for administration to a subject, e.g., a human. Salts of Compounds of the Disclosure can be prepared during the final isolation and purification of the compounds or separately by reacting the compound with a suitable acid.
  • the pharmaceutically acceptable salts of Compounds of the Disclosure can be acid addition salts formed with pharmaceutically acceptable acids.
  • acids which can be employed to form pharmaceutically acceptable salts include inorganic acids such as nitric, boric, hydrochloric, hydrobromic, sulfuric, and phosphoric, and organic acids such as oxalic, maleic, succinic, and citric.
  • Non-limiting examples of salts of Compounds of the Disclosure include, but are not limited to, the hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, 2-hydroxyethansulfonate, phosphate, hydrogen phosphate, acetate, adipate, alginate, aspartate, benzoate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerolphsphate, hemisulfate, heptanoate, hexanoate, formate, succinate, fumarate, maleate, ascorbate, isethionate, salicylate, methanesulfonate, mesitylenesulfonate, naphthylenesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylproprionate, pic
  • available amino groups present in the compounds of the disclosure can be quaternized with methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dimethyl, diethyl, dibutyl, and diamyl sulfates; decyl, lauryl, myristyl, and steryl chlorides, bromides, and iodides; and benzyl and phenethyl bromides.
  • any reference Compounds of the Disclosure appearing herein is intended to include compounds of Compounds of the Disclosure as well as pharmaceutically acceptable salts, hydrates, or solvates thereof.
  • solvates typically do not significantly alter the physiological activity or toxicity of the compounds, and as such may function as pharmacological equivalents.
  • solvate as used herein is a combination, physical association and/or solvation of a compound of the present disclosure with a solvent molecule such as, e.g. a disolvate, monosolvate or hemisolvate, where the ratio of solvent molecule to compound of the present disclosure is about 2: 1, about 1: 1 or about 1: 2, respectively.
  • This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding.
  • solvate can be isolated, such as when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid.
  • solvate encompasses both solution-phase and isolatable solvates.
  • Compounds of the Disclosure can be present as solvated forms with a pharmaceutically acceptable solvent, such as water, methanol, and ethanol, and it is intended that the disclosure includes both solvated and unsolvated forms of Compounds of the Disclosure.
  • a pharmaceutically acceptable solvent such as water, methanol, and ethanol
  • solvate is a hydrate.
  • a "hydrate” relates to a particular subgroup of solvates where the solvent molecule is water.
  • Solvates typically can function as pharmacological equivalents. Preparation of solvates is known in the art. See, for example, M.
  • a typical, non-limiting, process of preparing a solvate would involve dissolving a Compound of the Disclosure in a desired solvent (organic, water, or a mixture thereof) at temperatures above 20 °C to about 25 °C, then cooling the solution at a rate sufficient to form crystals, and isolating the crystals by known methods, e.g., filtration.
  • Analytical techniques such as infrared spectroscopy can be used to confirm the presence of the solvate in a crystal of the solvate.
  • the disclosure also provides synthetic intermediates, collectively referred to as "Intermediates of the Disclosure, " that can be used to prepare Compounds of the Disclosure.
  • Intermediates of the Disclosure are compounds of Formula XVI:
  • Z 1 is selected from the group consisting of halo, -OR 17 , and
  • X represents a 6-to 12-membered monocyclic or bicyclic heterocyclo
  • R 14a is C 1 -C 6 alkyl
  • R 14b is selected from the group consisting of C 1 -C 6 alkyl, C 2 -C 6 alkenyl, and aralkyl;
  • R 18 is selected from the group consisting of C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, and optionally substituted phenyl;
  • R 19 is selected from the group consisting of hydrogen and C 1 -C 4 alkyl;
  • R 20 is C 1 -C 4 alkyl;
  • L is selected from the group consisting of -O-, -S-, and -N (R 7 ) -; or L is a bond;
  • R 7 is selected from the group consisting of hydrogen and C 1 -C 4 alkyl
  • R 3 is selected from the group consisting of hydrogen, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, (amino) C 1 -C 4 alkyl, (hydroxy) C 1 -C 4 alkyl, (alkoxy) C 1 -C 4 alkyl, (carboxamido) C 1 -C 4 alkyl, (heterocyclo) C 1 -C 4 alkyl, (aryl) C 1 -C 4 alkyl, and (hetereoaryl) C 1 -C 4 alkyl;
  • R 2b and R 2c are independently selected from the group consisting of hydrogen and C 1 -C 4 alkyl; or
  • R 5c is selected from the group consisting hydrogen and C 1 -C 4 alkyl
  • R 5d and R 5e are independently selected from the group consisting hydrogen and C 1 -C 4 alkyl; or
  • R 5d and R 5e taken together with the nitrogen atom to which they are attached form an optionally substituted 4-to 8-membered heterocyclo;
  • R 5f and R 5g are independently selected from the group consisting hydrogen and C 1 -C 4 alkyl; or
  • R 5f and R 5g taken together with the nitrogen atom to which they are attached form an optionally substituted 4-to 8-membered heterocyclo;
  • A is selected from the group consisting of - (CR 6a R 6b ) m -, -O-, -S-, and -N (R 7a ) -;
  • a 1 is selected from the group consisting of - (CR 6c R 6d ) n -, -O-, -S-, and -N (R 7b ) -;
  • a 2 is selected from the group consisting of - (CR 6e R 6f ) o -, -O-, -S-, and -N (R 7c ) -;
  • a 3 is selected from the group consisting of - (CR 6g R 6h ) p -, -O-, -S-, and -N (R 7d ) -;
  • a 4 is selected from the group consisting of -O-, -S-, and -N (R 7e ) -; or A 4 is a bond,
  • R 6a , R 6b , R 6c , R 6d , R 6e , R 6f , R 6g , and R 6h are each independently selected from the group consisting of hydrogen and C 1 -C 4 alkyl;
  • n 0, 1, or 2;
  • n 0, 1, or 2;
  • o 0, 1, or 2;
  • p 0, 1, or 2;
  • R 7a , R 7b , R 7c , R 7d , and R 7e are independently selected from the group consisting of hydrogen and C 1 -C 4 alkyl;
  • E is - (CR 8a R 8b ) q -;
  • E 1 is - (CR 8e R 8f ) r --;
  • q is 0 or 1
  • r is 0 or 1;
  • R 8a and R 8b are each independently selected from the group consisting of hydrogen and C 1 -C 4 alkyl;
  • R 8c is selected from the group consisting of hydrogen, halo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, and C 3 -C 6 cycloalkyl;
  • R 8d is selected from the group consisting of hydrogen, halo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, and C 3 -C 6 cycloalkyl;
  • R 8e and R 8f are each independently selected from the group consisting of hydrogen and C 1 -C 4 alkyl; or
  • R 10 is selected from the group consisting of hydrogen, C 1 -C 4 alkyl and C 3 -C 6 cycloalkyl;
  • Compounds of the Disclosure are compounds of Formula XVI, wherein q is 0 and r is 0, or a salt or solvate thereof.
  • Compounds of the Disclosure are compounds of Formula XVI, wherein q is 0 and r is 1, or a salt or solvate thereof.
  • Compounds of the Disclosure are compounds of Formula XVI, wherein q is 1 and r is 0, or a salt or solvate thereof.
  • R 12 , A, A 1 , A 2 , A 3 , A 4 , E, E 1 , R 8c , R 8d , Q, Z 1 are as defined in connection with Formula XVI, or a salt or solvate thereof.
  • Compounds of the Disclosure are compounds of Formula XVII, wherein q is 0 and r is 0, or a salt or solvate thereof.
  • Compounds of the Disclosure are compounds of Formula XVII, wherein q is 0 and r is 1, or a salt or solvate thereof.
  • Compounds of the Disclosure are compounds of Formula XVII, wherein q is 1 and r is 0, or a salt or solvate thereof.
  • R 12 , A, A 1 , A 2 , A 3 , A 4 , E, E 1 , R 8c , R 8d , Q, Z 1 are as defined in connection with Formula XVI, or a salt or solvate thereof.
  • Compounds of the Disclosure are compounds of Formula XVIII, wherein q is 0 and r is 0, or a salt or solvate thereof.
  • Compounds of the Disclosure are compounds of Formula XVIII, wherein q is 0 and r is 1, or a salt or solvate thereof.
  • Compounds of the Disclosure are compounds of Formula XVIII, wherein q is 1 and r is 0, or a salt or solvate thereof.
  • R 11a , R 11b , R 11c , and R 11d are independently selected from the group consisting of hydrogen, halo, cyano, hydroxy, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 3 -C 6 cycloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, and (hydroxy) C 1 -C 4 alkyl; and R 12 , A, A 1 , A 2 , A 3 , A 4 , E, R 8c , R 8d , Q, and Z 1 are as defined in connection with Formula XVI, or a salt or solvate thereof.
  • R 11a , R 11b , R 11c , R 11d , R 12 , A, A 1 , A 2 , A 3 , A 4 , E, R 8c , R 8d , Q, and Z 1 are as defined in connection with Formula XIX, or a salt or solvate thereof.
  • R 11a , R 11b , R 11c , R 11d , R 12 , A, A 1 , A 2 , A 3 , A 4 , E, R 8c , R 8d , Q, and Z 1 are as defined in connection with Formula XIX, or a salt or solvate thereof.
  • R 11a , R 11b , R 11c , R 11d , R 12 , A, E, R 8c , R 8d , Q, and Z 1 are as defined in connection with Formula XIX, or a salt or solvate thereof.
  • R 11a , R 11b , R 11c , R 11d , R 12 , A, E, R 8c , R 8d , Q, and Z 1 are as defined in connection with Formula XIX, or a salt or solvate thereof.
  • R 11a , R 11b , R 11c , R 11d , R 12 , A, E, R 8c , R 8d , Q, and Z 1 are as defined in connection with Formula XIX, or a salt or solvate thereof.
  • Intermediates of the Disclosure are compounds of any one of Formulae XVI-XIX, wherein A is- (CH 2 ) m -and m is 0 or 1, or a salt or solvate thereof. In another embodiment, m is 1, or a salt or solvate thereof .
  • R 11a , R 11b , R 11c , R 11d , R 12 , A 1 , A 3 , E, R 8c , R 8d , Q, and Z 1 are as defined in connection with Formula XIX, or a salt or solvate thereof.
  • R 11a , R 11b , R 11c , R 11d , R 12 , A 1 , A 3 , E, R 8c , R 8d , Q, and Z 1 are as defined in connection with Formula XIX, or a salt or solvate thereof.
  • R 11a , R 11b , R 11c , R 11d , R 12 , A 1 , A 3 , E, R 8c , R 8d , Q, and Z 1 are as defined in connection with Formula XIX, or a salt or solvate thereof.
  • a 2 is selected from the group consisting of -O-, -S-, and -N (R 7c ) -; R 7c , R 12 , A 1 , E, R 8c , R 8d , Q, and Z 1 are as defined in connection with Formula XVI, and R 11a , R 11b , R 11c , and R 11d are as defined in connection with Formula XIX, or a salt or solvate thereof.
  • a 2 is selected from the group consisting of -O-, -S-, and -N (R 7c ) -; R 7c , R 12 , A 1 , E, R 8c , R 8d , Q, and Z 1 are as defined in connection with Formula XVI, and R 11a , R 11b , R 11c , and R 11d are as defined in connection with Formula XIX, or a salt or solvate thereof.
  • a 2 is selected from the group consisting of -O-, -S-, and -N (R 7c ) -; R 7c , R 12 , A 1 , E, R 8c , R 8d , Q, and Z 1 are as defined in connection with Formula XVI, and R 11a , R 11b , R 11c , and R 11d are as defined in connection with Formula XIX, or a salt or solvate thereof.
  • Intermediates of the Disclosure are compounds of any one of Formula XVI-XXX, wherein E is - (CH 2 ) q -, or a salt or solvate thereof.
  • Intermediates of the Disclosure are compounds of any one of Formula XVI-XXX, wherein E is - (CH 2 ) q -; and q is 1, or a salt or solvate thereof.
  • Intermediates of the Disclosure are compounds of any one of Formula XVI-XXX, wherein q is 0, or a salt or solvate thereof.
  • Intermediates of the Disclosure are compounds of any one of Formula XVI-XXX, wherein Z 1 is -OR 17 , or a salt or solvate thereof.
  • R 17 is hydrogen.
  • R 17 is -CF 3 .
  • Intermediates of the Disclosure are compounds of any one of Formula XVI-XXX, wherein Z 1 halo, or a salt or solvate thereof.
  • Intermediates of the Disclosure are compounds of any one of Formula XVI-XXX, wherein Z 1 is selected from the group consisting of:
  • Intermediates of the Disclosure are compounds of any one of Formula XVI-XXX, wherein R 13 is hydrogen, or a salt or solvate thereof.
  • R 14b is -C (CH 3 ) 3 .
  • Intermediates of the Disclosure are compounds of any one of Formula XVI-XXX, wherein R 2a is -CH 2 CN, or a salt or solvate thereof.
  • Intermediates of the Disclosure are compounds of any one of Formula XVI-XXX, wherein R 12 is -SR 19 , or a salt or solvate thereof.
  • R 19 is hydrogen.
  • R 19 is -CH 3.
  • R 20 is methyl.
  • Intermediates of the Disclosure are compounds of any one of Formula XVI-XXX, wherein R 12 is chloro, or a salt or solvate thereof.
  • Intermediates of the Disclosure are compounds of any one of Formula XVI-XXX, wherein R 12 is -LR 3 , or a salt or solvate thereof.
  • L is -O-.
  • R 3 is selected from the group consisting of (amino) C 1 -C 4 alkyl, (carboxamido) C 1 -C 4 alkyl, and (heterocyclo) C 1 -C 4 alkyl.
  • R 3 is (heterocyclo) CH 2 -.
  • Intermediates of the Disclosure are any one or more of the compounds listed in Table 2, or a salt or solvate thereof.
  • A is selected from the group consisting of - (CR 6a R 6b ) m -, -O-, -S-, and -N (R 7a ) -;
  • a 1 is selected from the group consisting of - (CR 6c R 6d ) n -, -O-, -S-, and -N (R 7b ) -;
  • a 2 is selected from the group consisting of - (CR 6e R 6f ) o -, -O-, -S-, and -N (R 7c ) -;
  • a 3 is selected from the group consisting of - (CR 6g R 6h ) p -, -O-, -S-, and -N (R 7d ) -;
  • a 4 is selected from the group consisting of -O-, -S-, and -N (R 7e ) -; or A 4 is a bond,
  • R 6a , R 6b , R 6c , R 6d , R 6e , R 6f , R 6g , and R 6h are each independently selected from the group consisting of hydrogen and C 1 -C 4 alkyl;
  • n 0, 1, or 2;
  • n 0, 1, or 2;
  • o 0, 1, or 2;
  • p 0, 1, or 2;
  • R 7a , R 7b , R 7c , R 7d , and R 7e are independently selected from the group consisting of hydrogen and C 1 -C 4 alkyl;
  • E is - (CR 8a R 8b ) q -;
  • E 1 is - (CR 8e R 8f ) r -;
  • q is 0 or 1
  • r is 0 or 1;
  • R 8a and R 8b are each independently selected from the group consisting of hydrogen and C 1 -C 4 alkyl;
  • R 8c is selected from the group consisting of hydrogen, halo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, and C 3 -C 6 cycloalkyl;
  • R 8d is selected from the group consisting of hydrogen, halo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, and C 3 -C 6 cycloalkyl;
  • R 8e and R 8f are each independently selected from the group consisting of hydrogen and C 1 -C 4 alkyl;
  • Compounds of the Disclosure are compounds of Formula XXXI, wherein q is 0 and r is 0, or a salt or solvate thereof.
  • Compounds of the Disclosure are compounds of Formula XXXI, wherein q is 0 and r is 1, or a salt or solvate thereof.
  • Compounds of the Disclosure are compounds of Formula XXXI, wherein q is 1 and r is 0, or a salt or solvate thereof.
  • A, A 1 , A 2 , A 3 , A 4 , E, E 1 , R 8c , R 8d are as defined in connection with Formula XXXI, or a salt or solvate thereof.
  • A, A 1 , A 2 , A 3 , A 4 , E, E 1 , R 8c , R 8d are as defined in connection with Formula XXXI, or a salt or solvate thereof.
  • R 11a , R 11b , R 11c , and R 11d are independently selected from the group consisting of hydrogen, halo, cyano, hydroxy, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 3 -C 6 cycloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, and (hydroxy) C 1 -C 4 alkyl; and A, A 1 , A 2 , A 3 , A 4 , E, R 8c , and R 8d , are as defined in connection with Formula XXXI, or a salt or solvate thereof.
  • R 11a , R 11b , R 11c , R 11d , A, A 1 , A 2 , A 3 , A 4 , E, R 8c , and R 8d are as defined in connection with Formula XXXIV, or a salt or solvate thereof.
  • R 11a , R 11b , R 11c , R 11d , A, A 1 , A 2 , A 3 , A 4 , E, R 8c , and R 8d are as defined in connection with Formula XXXIV, or a salt or solvate thereof.
  • R 11a , R 11b , R 11c , R 11d , A, E, R 8c , and R 8d are as defined in connection with Formula XXXIV, or a salt or solvate thereof.
  • R 11a , R 11b , R 11c , R 11d , A, E, R 8c , and R 8d are as defined in connection with Formula XXXIV, or a salt or solvate thereof.
  • R 11a , R 11b , R 11c , R 11d , A, E, R 8c , and R 8d are as defined in connection with Formula XXXIV, or a salt or solvate thereof.
  • Intermediates of the Disclosure are compounds of any one of Formulae XXXI-XXXIX, wherein A is - (CH 2 ) m -and m is 0 or 1, or a salt or solvate thereof. In another embodiment, m is 1.
  • R 11a , R 11b , R 11c , R 11d , A 1 , A 3 , E, R 8c , and R 8d are as defined in connection with Formula XXXIV, or a salt or solvate thereof.
  • R 11a , R 11b , R 11c , R 11d , A 1 , A 3 , E, R 8c , and R 8d are as defined in connection with Formula XXXIV, or a salt or solvate thereof.
  • R 11a , R 11b , R 11c , R 11d , A 1 , A 3 , E, R 8c , and R 8d are as defined in connection with Formula XXXIV, or a salt or solvate thereof.
  • a 2 is selected from the group consisting of -O-, -S-, and -N (R 7c ) -; R 11a , R 11b , R 11c , R 11d , A 1 , E, R 8c , and R 8d are as defined in connection with Formula XXXIV; and R 7c , R 8a , R 8b , and q are as defined in connection with Formula XXXI, or a salt or solvate thereof.
  • a 2 , E, R 11a , R 11b , R 11c , R 11d , A 1 , R 8c , R 8d are as defined in connection with Formula XLIII, or a salt or solvate thereof.
  • a 2 , E, R 11a , R 11b , R 11c , R 11d , A 1 , R 8c , R 8d are as defined in connection with Formula XLIII, or a salt or solvate thereof.
  • Intermediates of the Disclosure are compounds of any one of Formulae XXXI-XLV, wherein E is - (CH 2 ) q -; , or a salt or solvate thereof.
  • Intermediates of the Disclosure are compounds of any one of Formulae XXXI-XLV, wherein q is 1, or a salt or solvate thereof.
  • Intermediates of the Disclosure are compounds of any one of Formulae XXXI-XLV, wherein E is a bond, i.e., E is - (CR 8a R 8b ) q and q is 0.
  • R 16 is C 1 -C 6 alkyl
  • A is selected from the group consisting of - (CR 6a R 6b ) m -, -O-, -S-, and -N (R 7a ) -;
  • a 1 is selected from the group consisting of - (CR 6c R 6d ) n -, -O-, -S-, and -N (R 7b ) -;
  • a 2 is selected from the group consisting of - (CR 6e R 6f ) o -, -O-, -S-, and -N (R 7c ) -;
  • a 3 is selected from the group consisting of - (CR 6g R 6h ) p -, -O-, -S-, and -N (R 7d ) -;
  • a 4 is selected from the group consisting of -O-, -S-, and -N (R 7e ) -; or A 4 is a bond,
  • R 6a , R 6b , R 6c , R 6d , R 6e , R 6f , R 6g , and R 6h are each independently selected from the group consisting of hydrogen and C 1 -C 4 alkyl;
  • n 0, 1, or 2;
  • n 0, 1, or 2;
  • o 0, 1, or 2;
  • p 0, 1, or 2;
  • R 7a , R 7b , R 7c , R 7d , and R 7e are independently selected from the group consisting of hydrogen and C 1 -C 4 alkyl;
  • E is - (CR 8a R 8b ) q -;
  • E 1 is - (CR 8e R 8f ) r -;
  • q is 0 or 1
  • r is 0 or 1;
  • R 8a and R 8b are each independently selected from the group consisting of hydrogen and C 1 -C 4 alkyl;
  • R 8c is selected from the group consisting of hydrogen, halo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, and C 3 -C 6 cycloalkyl;
  • R 8d is selected from the group consisting of hydrogen, halo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, and C 3 -C 6 cycloalkyl;
  • R 8e and R 8f are each independently selected from the group consisting of hydrogen and C 1 -C 4 alkyl;
  • Compounds of the Disclosure are compounds of Formula XLVI, wherein q is 0 and r is 0, or a salt or solvate thereof.
  • Compounds of the Disclosure are compounds of Formula XLVI, wherein q is 0 and r is 1, or a salt or solvate thereof.
  • Compounds of the Disclosure are compounds of Formula XLVI, wherein q is 1 and r is 0, or a salt or solvate thereof.
  • R 15 , A, A 1 , A 2 , A 3 , A 4 , E, E 1 , R 8c , R 8d are as defined in connection with Formula XLVI, or a salt or solvate thereof.
  • Compounds of the Disclosure are compounds of Formula XLVII, wherein q is 0 and r is 0, or a salt or solvate thereof.
  • Compounds of the Disclosure are compounds of Formula XLVII, wherein q is 0 and r is 1, or a salt or solvate thereof.
  • Compounds of the Disclosure are compounds of Formula XLVII, wherein q is 1 and r is 0, or a salt or solvate thereof.
  • R 15 , A, A 1 , A 2 , A 3 , A 4 , E, E 1 , R 8c , R 8d are as defined in connection with Formula XLVI, or a salt or solvate thereof.
  • Compounds of the Disclosure are compounds of Formula XLVIII, wherein q is 0 and r is 0, or a salt or solvate thereof.
  • Compounds of the Disclosure are compounds of Formula XLVIII, wherein q is 0 and r is 1, or a salt or solvate thereof.
  • Compounds of the Disclosure are compounds of Formula XLVIII, wherein q is 1 and r is 0, or a salt or solvate thereof.
  • R 11a , R 11b , R 11c , and R 11d are independently selected from the group consisting of hydrogen, halo, cyano, hydroxy, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 3 -C 6 cycloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, and (hydroxy) C 1 -C 4 alkyl; and R 15 , A, A 1 , A 2 , A 3 , A 4 , E, R 8c , and R 8d are as defined in connection with Formula XLVI, or a salt or solvate thereof.
  • R 11a , R 11b , R 11c , R 11d , R 15 , A, A 1 , A 2 , A 3 , A 4 , E, R 8c , and R 8d are as defined in connection with Formula XLIX, or a salt or solvate thereof.
  • R 11a , R 11b , R 11c , R 11d , R 15 , A, A 1 , A 2 , A 3 , A 4 , E, R 8c , and R 8d are as defined in connection with Formula XLIX, or a salt or solvate thereof.
  • R 11a , R 11b , R 11c , R 11d , R 15 , A, E, R 8c , and R 8d are as defined in connection with Formula XLIX, or a salt or solvate thereof.
  • R 11a , R 11b , R 11c , R 11d , R 15 , A, E, R 8c , and R 8d are as defined in connection with Formula XLIX, or a salt or solvate thereof.
  • R 11a , R 11b , R 11c , R 11d , R 15 , A, E, R 8c , and R 8d are as defined in connection with Formula XLIX, or a salt or solvate thereof.
  • Intermediates of the Disclosure are compounds of any one of Formulae XLVI-LIV, wherein A is - (CH 2 ) m -and m is 0 or 1, or a salt or solvate thereof. In another embodiment, m is 1.
  • R 11a , R 11b , R 11c , R 11d , R 15 , A 1 , A 3 , E, R 8c , and R 8d are as defined in connection with Formula XLIX, or a salt or solvate thereof.
  • R 11a , R 11b , R 11c , R 11d , R 15 , A 1 , A 3 , E, R 8c , and R 8d are as defined in connection with Formula XLIX, or a salt or solvate thereof.
  • R 11a , R 11b , R 11c , R 11d , R 15 , A 1 , A 3 , E, E 1 , and E 2 are as defined in connection with Formula XLIX, or a salt or solvate thereof.
  • a 2 is selected from the group consisting of -O-, -S-, and -N (R 7c ) -; R 11a , R 11b , R 11c , R 11d , R 15 , A 1 , E, R 8c , and R 8d are as defined in connection with Formula XLIX; and R 7c is as defined in connection with Formula XLVI, or a salt or solvate thereof.
  • a 2 , E, R 11a , R 11b , R 11c , R 11d , R 15 , A 1 , R 8c , and R 8d are as defined in connection with Formula LIX, or a salt or solvate thereof.
  • a 2 , E, R 11a , R 11b , R 11c , R 11d , R 15 , A 1 , R 8c , and R 8d are as defined in connection with Formula LIX, or a salt or solvate thereof.
  • Intermediates of the Disclosure are compounds of any one of Formulae XLIX-LXI, wherein R 11a is selected from the group consisting of halo, cyano, hydroxy, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 3 -C 6 cycloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, and (hydroxy) C 1 -C 4 alkyl; and R 11b , R 11c , and R 11d are independently selected from the group consisting of hydrogen, halo, cyano, hydroxy, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 3 -C 6 cycloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, and (hydroxy) C 1 -C 4 alkyl, or a salt or solvate thereof.
  • Intermediates of the Disclosure are compounds of any one of Formulae XLIX-LXI, wherein R 11b is selected from the group consisting of halo, cyano, hydroxy, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 3 -C 6 cycloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, and (hydroxy) C 1 -C 4 alkyl; and R 11a , R 11c , and R 11d are independently selected from the group consisting of hydrogen, halo, cyano, hydroxy, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 3 -C 6 cycloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, and (hydroxy) C 1 -C 4 alkyl, or a salt or solvate thereof.
  • Intermediates of the Disclosure are compounds of any one of Formulae XLIX-LXI, wherein R 11c is selected from the group consisting of halo, cyano, hydroxy, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 3 -C 6 cycloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, and (hydroxy) C 1 -C 4 alkyl; and R 11a , R 11b , and R 11d are independently selected from the group consisting of hydrogen, halo, cyano, hydroxy, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 3 -C 6 cycloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, and (hydroxy) C 1 -C 4 alkyl, or a salt or solvate thereof.
  • Intermediates of the Disclosure are compounds of any one of Formulae XLIX-LXI, wherein R 11d is selected from the group consisting of halo, cyano, hydroxy, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 3 -C 6 cycloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, and (hydroxy) C 1 -C 4 alkyl; and R 11a , R 11b , and R 11c are independently selected from the group consisting of hydrogen, halo, cyano, hydroxy, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 3 -C 6 cycloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, and (hydroxy) C 1 -C 4 alkyl, or a salt or solvate thereof.
  • Intermediates of the Disclosure are compounds of any one of Formulae XLVI-LXI, wherein E is - (CH 2 ) q -; , or a salt or solvate thereof.
  • Intermediates of the Disclosure are compounds of any one of Formulae XLVI-LXI, wherein E is - (CH 2 ) -, or a salt or solvate thereof.
  • Intermediates of the Disclosure are compounds of any one of Formulae XLVI-LXI, wherein E is is - (CR 8a R 8b ) q and q is 0, or a salt or solvate thereof.
  • Intermediates of the Disclosure are compounds of any one of Formulae XLVI-LXI, wherein R 15 is hydrogen, or a salt or solvate thereof.
  • Intermediates of the Disclosure are compounds selected from any one or more of the compounds of Table 3, or a salt or solvate thereof.
  • the disclosure also provides methods of preparing Compounds of the Disclosure and/or Intermediates of the Disclosure.
  • KRAS e.g., KRAS-G12C
  • Compounds of the Disclosure are useful in methods of treating or preventing a disease or condition wherein inhibition of KRAS provides a benefit.
  • diseases and conditions are cancers and proliferative diseases.
  • such a cancer is referred to as a "KRAS-mediated cancer.
  • KRAS-mediated cancers are known in the art.
  • the therapeutic methods of this disclosure comprise administering a therapeutically effective amount of a Compound of the Disclosure to a subject, e.g., human, in need thereof.
  • the present methods also encompass optionally administering an optional therapeutic agent to the subject in addition to the Compound of the Disclosure.
  • the optional therapeutic agent is selected from drugs known as useful in treating the disease or condition afflicting the subject in need thereof, e.g., a chemotherapeutic agent and/or radiation known as useful in treating a particular cancer.
  • the present disclosure relates to a method of treating an individual suffering from a disease or condition wherein inhibition of KRAS provides a benefit, the method comprising administering a therapeutically effective amount of a Compound of the Disclosure.
  • Compounds of the Disclosure are inhibitors of KRAS, a number of diseases and conditions mediated by KRAS can be treated by employing these compounds.
  • the present disclosure is thus directed generally to a method for treating a condition or disorder responsive to KRAS inhibition in a subject, e.g., a human subject, suffering from, or at risk of suffering from, the condition or disorder, the method comprising administering to the subject an effective amount of one or more Compounds of the Disclosure.
  • the present disclosure is directed to a method of inhibiting KRAS, e.g., KRAS-G12C, in a subject in need thereof, said method comprising administering to the subject an effective amount of at least one Compound of the Disclosure.
  • KRAS e.g., KRAS-G12C
  • the methods of the present disclosure can be accomplished by administering a Compound of the Disclosure as the neat compound or as a pharmaceutical composition.
  • Administration of a pharmaceutical composition, or neat compound of a Compound of the Disclosure can be performed during or after the onset of the disease or condition of interest.
  • the pharmaceutical compositions are sterile, and contain no toxic, carcinogenic, or mutagenic compounds that would cause an adverse reaction when administered.
  • kits comprising a Compound of the Disclosure and, optionally, an optional therapeutic agent, packaged separately or together, and an insert having instructions for using these active agents.
  • a Compound of the Disclosure is administered in conjunction with an optional therapeutic agent useful in the treatment of a disease or condition wherein inhibition of KRAS provides a benefit.
  • the optional therapeutic agent is different from the Compound of the Disclosure.
  • a Compound of the Disclosure and the optional therapeutic agent can be administered simultaneously or sequentially to achieve the desired effect.
  • the Compound of the Disclosure and optional therapeutic agent can be administered from a single composition or two separate compositions.
  • the optional therapeutic agent is administered in an amount to provide its desired therapeutic effect.
  • the effective dosage range for each optional therapeutic agent is known in the art, and the optional therapeutic agent is administered to an individual in need thereof within such established ranges.
  • a Compound of the Disclosure and the optional therapeutic agent can be administered together as a single-unit dose or separately as multi-unit doses, wherein the Compound of the Disclosure is administered before the optional therapeutic agent or vice versa.
  • One or more doses of the Compound of the Disclosure and/or one or more dose of the optional therapeutic agent can be administered.
  • the Compound of the Disclosure therefore can be used in conjunction with one or more optional therapeutic agents, for example, but not limited to, anticancer agents.
  • Diseases and conditions treatable by the methods of the present disclosure include, but are not limited to, cancer and other proliferative disorders, inflammatory diseases, sepsis, autoimmune disease, and viral infection.
  • a human subject is treated with a Compound of the Disclosure, or a pharmaceutical composition comprising a Compound of the Disclosure, wherein the compound is administered in an amount sufficient to inhibit KRAS protein in the subject.
  • the present disclosure provides a method of treating cancer in a subject comprising administering a therapeutically effective amount of a Compound of the Disclosure. While not being limited to a specific mechanism, in some embodiments, Compounds of the Disclosure treat cancer by inhibiting KRAS.
  • the cancer is a KRAS-mutant cancer. In another embodiment, the cancer is a KRAS-G12C-mutant cancer.
  • the KRAS-mutant cancer is lung cancer, pancreatic cancer, or colorectal cancer.
  • the KRAS-mutant cancer is lung cancer.
  • the KRAS-mutant cancer is non-small cell lung cancer.
  • the KRAS-mutant cancer is pancreatic cancer.
  • the KRAS-mutant cancer is colorectal cancer.
  • the present disclosure provides a method of treating a benign proliferative disorder, such as, but are not limited to, benign soft tissue tumors, bone tumors, brain and spinal tumors, eyelid and orbital tumors, granuloma, lipoma, meningioma, multiple endocrine neoplasia, nasal polyps, pituitary tumors, prolactinoma, pseudotumor cerebri, seborrheic keratoses, stomach polyps, thyroid nodules, cystic neoplasms of the pancreas, hemangiomas, vocal cord nodules, polyps, and cysts, Castleman disease, chronic pilonidal disease, dermatofibroma, pilar cyst, pyogenic granuloma, and juvenile polyposis syndrome.
  • a benign proliferative disorder such as, but are not limited to, benign soft tissue tumors, bone tumors, brain and spinal tumors, eyelid and orbital tumors, granul
  • Compounds of the Disclosure can also treat infectious and noninfectious inflammatory events and autoimmune and other inflammatory diseases by administration of an effective amount of a present compound to a mammal, in particular a human in need of such treatment.
  • autoimmune and inflammatory diseases, disorders, and syndromes treated using the compounds and methods described herein include inflammatory pelvic disease, urethritis, skin sunburn, sinusitis, pneumonitis, encephalitis, meningitis, myocarditis, nephritis, osteomyelitis, myositis, hepatitis, gastritis, enteritis, dermatitis, gingivitis, appendicitis, pancreatitis, cholocystitus, agammaglobulinemia, psoriasis, allergy, Crohn's disease, irritable bowel syndrome, ulcerative colitis, Sjogren's disease, tissue graft rejection, hyperacute rejection of transplanted organs, asthma, allergic rhinitis,
  • the present disclosure provides a method of treating systemic inflammatory response syndromes, such as LPS-induced endotoxic shock and/or bacteria-induced sepsis by administration of an effective amount of a Compound of the Disclosure to a mammal, in particular a human in need of such treatment.
  • systemic inflammatory response syndromes such as LPS-induced endotoxic shock and/or bacteria-induced sepsis
  • the present disclosure provides a method for treating viral infections and diseases.
  • viral infections and diseases treated using the compounds and methods described herein include episome-based DNA viruses including, but not limited to, human papillomavirus, Herpesvirus, Epstein-Barr virus, human immunodeficiency virus, hepatitis B virus, and hepatitis C virus.
  • the present disclosure provides therapeutic method of modulating protein methylation, gene expression, cell proliferation, cell differentiation and/or apoptosis in vivo in diseases mentioned above, in particular cancer, inflammatory disease, and/or viral disease is provided by administering a therapeutically effective amount of a Compound of the Disclosure to a subject in need of such therapy.
  • the present disclosure provides a method of regulating endogenous or heterologous promoter activity by contacting a cell with a Compound of the Disclosure.
  • a therapeutically effective amount of a Compound of the Disclosure is administered to a human being in need thereof. Whether such a treatment is indicated depends on the individual case and is subject to medical assessment (diagnosis) that takes into consideration signs, symptoms, and/or malfunctions that are present, the risks of developing particular signs, symptoms and/or malfunctions, and other factors.
  • a Compound of the Disclosure can be administered by any suitable route, for example by oral, buccal, inhalation, sublingual, rectal, vaginal, intracisternal or intrathecal through lumbar puncture, transurethral, nasal, percutaneous, i.e., transdermal, or parenteral (including intravenous, intramuscular, subcutaneous, intracoronary, intradermal, intramammary, intraperitoneal, intraarticular, intrathecal, retrobulbar, intrapulmonary injection and/or surgical implantation at a particular site) administration.
  • Parenteral administration can be accomplished using a needle and syringe or using a high pressure technique.
  • compositions include those wherein a Compound of the Disclosure is administered in an effective amount to achieve its intended purpose.
  • the exact formulation, route of administration, and dosage is determined by an individual physician in view of the diagnosed condition or disease. Dosage amount and interval can be adjusted individually to provide levels of a Compound of the Disclosure that is sufficient to maintain therapeutic effects.
  • Toxicity and therapeutic efficacy of the Compounds of the Disclosure can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the maximum tolerated dose (MTD) of a compound, which defines as the highest dose that causes no toxicity in animals.
  • MTD maximum tolerated dose
  • the dose ratio between the maximum tolerated dose and therapeutic effects (e.g. inhibiting of tumor growth) is the therapeutic index.
  • the dosage can vary within this range depending upon the dosage form employed, and the route of administration utilized. Determination of a therapeutically effective amount is well within the capability of those skilled in the art, especially in light of the detailed disclosure provided herein.
  • a therapeutically effective amount of a Compound of the Disclosure required for use in therapy varies with the nature of the condition being treated, the length of time that activity is desired, and the age and the condition of the subject, and ultimately is determined by the attendant physician. Dosage amounts and intervals can be adjusted individually to provide plasma levels of the Compound of the Disclosure that are sufficient to maintain the desired therapeutic effects.
  • the desired dose can be administered in a single dose, or as multiple doses administered at appropriate intervals, for example as one, two, three, four or more subdoses per day. Multiple doses often are desired, or required.
  • a Compound of the Disclosure can be administered at a frequency of: four doses delivered as one dose per day at four-day intervals (q4d x 4) ; four doses delivered as one dose per day at three-day intervals (q3d x 4) ; one dose delivered per day at five-day intervals (qd x 5) ; one dose per week for three weeks (qwk3) ; five daily doses, with two days rest, and another five daily doses (5/2/5) ; or, any dose regimen determined to be appropriate for the circumstance.
  • a Compound of the Disclosure used in a method of the present disclosure can be administered in an amount of about 0.005 to about 500 milligrams per dose, about 0.05 to about 250 milligrams per dose, or about 0.5 to about 100 milligrams per dose.
  • a Compound of the Disclosure can be administered, per dose, in an amount of about 0.005, about 0.05, about 0.5, about 5, about 10, about 20, about 30, about 40, about 50, about 100, about 150, about 200, about 250, about 300, about 350, about 400, about 450, or about 500 milligrams, including all doses between 0.005 and 500 milligrams.
  • the dosage of a composition containing a Compound of the Disclosure, or a composition containing the same can be from about 1 ng/kg to about 200 mg/kg, about 1 ⁇ g/kg to about 100 mg/kg, or about 1 mg/kg to about 50 mg/kg.
  • the dosage of a composition can be at any dosage including, but not limited to, about 1 ⁇ g/kg.
  • the dosage of a composition may be at any dosage including, but not limited to, about 1 ⁇ g/kg, about 10 ⁇ g/kg, about 25 ⁇ g/kg, about 50 ⁇ g/kg, about 75 ⁇ g/kg, about 100 ⁇ g/kg, about 125 ⁇ g/kg, about 150 ⁇ g/kg, about 175 ⁇ g/kg, about 200 ⁇ g/kg, about 225 ⁇ g/kg, about 250 ⁇ g/kg, about 275 ⁇ g/kg, about 300 ⁇ g/kg, about 325 ⁇ g/kg, about 350 ⁇ g/kg, about 375 ⁇ g/kg, about 400 ⁇ g/kg, about 425 ⁇ g/kg, about 450 ⁇ g/kg, about 475 ⁇ g/kg, about 500 ⁇ g/kg, about 525 ⁇ g/kg, about 550 ⁇ g/kg, about 575 ⁇ g/kg, about 600 ⁇ g/kg, about 625 ⁇ g/kg, about 650 ⁇ g/
  • the above dosages are exemplary of the average case, but there can be individual instances in which higher or lower dosages are merited, and such are within the scope of this disclosure.
  • the physician determines the actual dosing regimen that is most suitable for an individual subject, which can vary with the age, weight, and response of the particular subject.
  • compositions for use in accordance with the present disclosure are formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and/or auxiliaries that facilitate processing of Compound of the Disclosure.
  • compositions can be manufactured, for example, by conventional mixing, dissolving, granulating, dragee-making, emulsifying, encapsulating, entrapping, or lyophilizing processes. Proper formulation is dependent upon the route of administration chosen.
  • a therapeutically effective amount of the Compound of the Disclosure is administered orally, the composition typically is in the form of a tablet, capsule, powder, solution, or elixir.
  • the composition additionally can contain a solid carrier, such as a gelatin or an adjuvant.
  • the tablet, capsule, and powder contain about 0.01%to about 95%, and preferably from about 1%to about 50%, of a Compound of the Disclosure.
  • a liquid carrier such as water, petroleum, or oils of animal or plant origin
  • the liquid form of the composition can further contain physiological saline solution, dextrose or other saccharide solutions, or glycols.
  • the composition When administered in liquid form, the composition contains about 0.1%to about 90%, and preferably about 1%to about 50%, by weight, of a Compound of the Disclosure.
  • composition When a therapeutically effective amount of a Compound of the Disclosure is administered by intravenous, cutaneous, or subcutaneous injection, the composition is in the form of a pyrogen-free, parenterally acceptable aqueous solution.
  • parenterally acceptable aqueous solution having due regard to pH, isotonicity, stability, and the like, is within the skill in the art.
  • a preferred composition for intravenous, cutaneous, or subcutaneous injection typically contains, an isotonic vehicle.
  • Compounds of the Disclosure can be readily combined with pharmaceutically acceptable carriers well-known in the art. Standard pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, 19th ed. 1995. Such carriers enable the active agents to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a subject to be treated.
  • Pharmaceutical preparations for oral use can be obtained by adding the Compound of the Disclosure to a solid excipient, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients include, for example, fillers and cellulose preparations. If desired, disintegrating agents can be added.
  • Compound of the Disclosure can be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion.
  • Formulations for injection can be presented in unit dosage form, e.g., in ampules or in multidose containers, with an added preservative.
  • the compositions can take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and can contain formulatory agents such as suspending, stabilizing, and/or dispersing agents.
  • compositions for parenteral administration include aqueous solutions of the active agent in water-soluble form.
  • suspensions of a Compound of the Disclosure can be prepared as appropriate oily injection suspensions.
  • Suitable lipophilic solvents or vehicles include fatty oils or synthetic fatty acid esters.
  • Aqueous injection suspensions can contain substances which increase the viscosity of the suspension.
  • the suspension also can contain suitable stabilizers or agents that increase the solubility of the compounds and allow for the preparation of highly concentrated solutions.
  • a present composition can be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
  • Compounds of the Disclosure also can be formulated in rectal compositions, such as suppositories or retention enemas, e.g., containing conventional suppository bases.
  • the Compound of the Disclosure also can be formulated as a depot preparation.
  • Such long-acting formulations can be administered by implantation (for example, subcutaneously or intramuscularly) or by intramuscular injection.
  • the Compound of the Disclosure can be formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion exchange resins.
  • the Compounds of the Disclosure can be administered orally, buccally, or sublingually in the form of tablets containing excipients, such as starch or lactose, or in capsules or ovules, either alone or in admixture with excipients, or in the form of elixirs or suspensions containing flavoring or coloring agents.
  • excipients such as starch or lactose
  • capsules or ovules either alone or in admixture with excipients, or in the form of elixirs or suspensions containing flavoring or coloring agents.
  • Such liquid preparations can be prepared with pharmaceutically acceptable additives, such as suspending agents.
  • Compound of the Disclosure also can be injected parenterally, for example, intravenously, intramuscularly, subcutaneously, or intracoronarily.
  • the Compound of the Disclosure are typically used in the form of a sterile aqueous solution which can contain other substances, for example, salts or monosaccharides, such as mannitol or glucose, to make the solution isotonic with blood.
  • a sterile aqueous solution which can contain other substances, for example, salts or monosaccharides, such as mannitol or glucose, to make the solution isotonic with blood.
  • a Compound of the Disclosure is administered to a subject having a disease, disorder, or condition, e.g., cancer, as a single agent.
  • a Compound of the Disclosure is administered to a subject having a disease, disorder, or condition, e.g., cancer, in combination with one or more optional therapeutic agents.
  • a Compound of the Disclosure is administered in combination with one optional therapeutic agent.
  • a Compound of the Disclosure is administered in combination with two optional therapeutic agents.
  • a Compound of the Disclosure is administered in combination with three optional therapeutic agents.
  • Optional therapeutic agents useful in treating cancer patients include those known in the art as well as those developed in the future.
  • Optional therapeutic agents are administered in an amount to provide their desired therapeutic effect.
  • the effective dosage range for each optional therapeutic agent is known in the art, and the optional therapeutic agent is administered to an individual in need thereof within such established ranges.
  • a Compound of the Disclosure and the optional therapeutic agent (s) can be administered together as a single-unit dose or separately as multi-unit doses, and in any order, e.g., wherein a Compound of the Disclosure is administered before the optional therapeutic agent (s) , or vice versa.
  • One or more doses of a Compound of the Disclosure and the optional therapeutic agent (s) can be administered to the subject.
  • the disclosure provides the following particular embodiments in connection with treating a disease in a subject.
  • Embodiment I A method of treating a subject, the method comprising administering to the subject a therapeutically effective amount of a Compound of the Disclosure, wherein the subject has cancer, a chronic autoimmune disorder, an inflammatory condition, a proliferative disorder, sepsis, or a viral infection.
  • Embodiment II The method Embodiment I, wherein the subject has cancer.
  • Embodiment III The method of Embodiment II, wherein the cancer is a KRAS-mutant cancer.
  • Embodiment IV The method of Embodiments II or III, wherein the cancer is lung cancer, pancreatic cancer, or colorectal cancer.
  • Embodiment V The method of Embodiment IV, wherein the cancer is non-small cell lung cancer.
  • Embodiment VI The method of any one of Embodiments I-V further comprising administering a therapeutically effective amount of an optional therapeutic agent useful in the treatment of the disease or condition, e.g., an immune checkpoint inhibitor or other anticancer agent.
  • an optional therapeutic agent useful in the treatment of the disease or condition e.g., an immune checkpoint inhibitor or other anticancer agent.
  • Embodiment VII The method of any one of Embodiments I-VI, wherein the Compound of the Disclosure is a compound of any one of Formulae IV-XV, or a pharmaceutically acceptable salt or solvate thereof.
  • Embodiment VIII The method of any one of Embodiments I-VI, wherein the Compound of the Disclosure is a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof.
  • Embodiment IX A pharmaceutical composition comprising a Compound of the Disclosure and a pharmaceutically acceptable excipient for use in treating cancer, a chronic autoimmune disorder, an inflammatory condition, a proliferative disorder, sepsis, or a viral infection.
  • Embodiment X The pharmaceutical composition of Embodiment IX for use in treating cancer.
  • Embodiment XI The pharmaceutical composition of Embodiment X, wherein the cancer is a KRAS-mutant cancer.
  • Embodiment XII The pharmaceutical composition of Embodiment X or XI, wherein the cancer is lung cancer, pancreatic cancer, or colorectal cancer.
  • Embodiment XIII The pharmaceutical composition of Embodiment XII, wherein the cancer is non-small cell lung cancer.
  • Embodiment XIV The pharmaceutical composition of any one of Embodiments IX-XIII, wherein the Compound of the Disclosure is a compound of any one of Formulae IV-XV, or a pharmaceutically acceptable salt or solvate thereof.
  • Embodiment XV The pharmaceutical composition of any one of Embodiments IX-XIII, wherein the Compound of the Disclosure is a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof.
  • Embodiment XVI. A Compound of the Disclosure for use in treatment of cancer, a chronic autoimmune disorder, an inflammatory condition, a proliferative disorder, sepsis, or a viral infection.
  • Embodiment XVII The compound of Embodiment XVI for use in treating cancer.
  • Embodiment XVIII The compound of Embodiment XVII, wherein the cancer is a KRAS-mutant cancer.
  • Embodiment XIX The compound of Embodiment XVII or XVIII, wherein the cancer is lung cancer, pancreatic cancer, or colorectal cancer.
  • Embodiment XX The compound of Embodiment XIX, wherein the cancer is non-small cell lung cancer.
  • Embodiment XXI The compound of any one of Embodiments XVI-XX, wherein the Compound of the Disclosure is a compound of any one of Formulae IV-XV, or a pharmaceutically acceptable salt or solvate thereof.
  • Embodiment XXII The compound of any one of Embodiments XVI-XX, wherein the Compound of the Disclosure is a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof.
  • Embodiment XXIII Use of a Compound of the Disclosure for the manufacture of a medicament for treatment of cancer, a chronic autoimmune disorder, an inflammatory condition, a proliferative disorder, sepsis, or a viral infection.
  • Embodiment XXIV The use of Embodiment XXIII for the treatment of cancer.
  • Embodiment XXV The use of Embodiment XXIV, wherein the cancer is a KRAS-mutant cancer.
  • Embodiment XXVI The use of Embodiments XXIV or XXV, wherein the cancer is lung cancer, pancreatic cancer, or colorectal cancer.
  • Embodiment XXVII The use of Embodiment XXVI, wherein the cancer is non-small cell lung cancer.
  • Embodiment XXVIII The use of any one of Embodiments XXIII-XXVII, wherein the Compound of the Disclosure is a compound of any one of Formulae IV-XV, or a pharmaceutically acceptable salt or solvate thereof.
  • Embodiment XXIX The use of any one of Embodiments XXIII-XXVII, wherein the Compound of the Disclosure is a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof.
  • Embodiment XXX A method of inhibiting KRAS within a cell of a subject in need thereof, the method comprising administering to the subject a Compound of the Disclosure, or a pharmaceutically acceptable salt or solvate thereof.
  • Embodiment XXXI The method of Embodiment XXX, wherein the Compound of the Disclosure is a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof.
  • kits which comprise a Compound of the Disclosure (or a composition comprising a Compound of the Disclosure) packaged in a manner that facilitates their use to practice methods of the present disclosure.
  • the kit includes a Compound of the Disclosure (or a composition comprising a Compound of the Disclosure) packaged in a container, such as a sealed bottle or vessel, with a label affixed to the container or included in the kit that describes use of the compound or composition to practice the method of the disclosure, e.g., the method of any one of Embodiments I-VI.
  • the compound or composition is packaged in a unit dosage form.
  • the kit further can include a device suitable for administering the composition according to the intended route of administration.
  • a disease or condition wherein inhibition of KRAS provides a benefit pertains to a disease or condition in which KRAS is important or necessary, e.g., for the onset, progress, expression of that disease or condition, or a disease or a condition which is known to be treated by an KRAS inhibitor.
  • examples of such conditions include, but are not limited to, a cancer, a chronic autoimmune disease, an inflammatory disease, a proliferative disease, sepsis, and a viral infection.
  • One of ordinary skill in the art is readily able to determine whether a compound treats a disease or condition mediated by a KRAS inhibitor for any particular cell type, for example, by assays which conveniently can be used to assess the activity of particular compounds. See, e.g., Yue and Turkson, Expert Opinion Invest Drugs 18: 45-56 (2009) .
  • KRAS refers collectively to the wild-type KRAS gene and protein, and mutant forms thereof. The mutations found most frequently in the KRAS gene are primarily at codons 12, 13, or 61. KRAS mutations also occur in codons 63, 117, 119, and 146. Liu et al., Acta Pharmaceutica Sinica B 9: 871–879 (2019) .
  • KRAS inhibitor refers a compound that inhibits wild-type KRAS and/or mutant KRAS, and includes electrophilic compounds that form irreversible covalent bonds with the KRAS protein.
  • KRAS ihibitors that form irreversible covalent bonds with the nucleophilic sulfur atom of Cys-12 and thus target the KRAS-G12C mutation and leave wild-type KRAS untouched.
  • KRAS-mutant cancer refers to a cancer that contains a KRAS mutatation.
  • KRAS-mutant cancers include, but are not limited to, KRAS-mutant lung cancer, KRAS-mutant pancreatic cancer, or KRAS-mutant colorectal cancer.
  • the KRAS-mutant cancer has a KRAS-G12C mutation.
  • optional therapeutic agent refers to a therapeutic agent different from a Compound of the Disclosure and that is known to treat the disease or condition of interest.
  • the optional therapeutic agent can be a known chemotherapeutic drug, like taxol, or radiation, for example.
  • disease or "condition” denotes disturbances and/or anomalies that as a rule are regarded as being pathological conditions or functions, and that can manifest themselves in the form of particular signs, symptoms, and/or malfunctions.
  • Compounds of the Disclosure are inhibitors of KRAS and can be used in treating or preventing diseases and conditions wherein inhibition of KRAS provides a benefit.
  • the terms “treat, “ “treating, “ “treatment, “ and the like refer to eliminating, reducing, or ameliorating a disease or condition, and/or symptoms associated therewith. Although not precluded, treating a disease or condition does not require that the disease, condition, or symptoms associated therewith be completely eliminated.
  • the term “treat” and synonyms contemplate administering a therapeutically effective amount of a Compound of the Disclosure to a subject in need of such treatment.
  • the treatment can be orientated symptomatically, for example, to suppress symptoms. It can be effected over a short period, be oriented over a medium term, or can be a long-term treatment, for example within the context of a maintenance therapy.
  • prevent, “preventing, “ and “prevention” refer to a method of preventing the onset of a disease or condition and/or its attendant symptoms or barring a subject from acquiring a disease.
  • prevent, “preventing, “ and “prevention” also include delaying the onset of a disease and/or its attendant symptoms and reducing a subject's risk of acquiring a disease.
  • prevent may include “prophylactic treatment, " which refers to reducing the probability of redeveloping a disease or condition, or of a recurrence of a previously-controlled disease or condition, in a subject who does not have, but is at risk of or is susceptible to, redeveloping a disease or condition or a recurrence of the disease or condition.
  • terapéuticaally effective amount refers to an amount of the active ingredient (s) that is (are) sufficient, when administered by a method of the disclosure, to efficaciously deliver the active ingredient (s) for the treatment of condition or disease of interest to a subject in need thereof.
  • the therapeutically effective amount of the agent may reduce (i.e., retard to some extent or stop) unwanted cellular proliferation; reduce the number of cancer cells; reduce the tumor size; inhibit (i.e., retard to some extent or stop) cancer cell infiltration into peripheral organs; inhibit (i.e., retard to some extent or stop) tumor metastasis; inhibit, to some extent, tumor growth; and/or relieve, to some extent, one or more of the symptoms associated with the cancer.
  • the administered compound or composition prevents growth and/or kills existing cancer cells, it may be cytostatic and/or cytotoxic.
  • tainer means any receptacle and closure therefore suitable for storing, shipping, dispensing, and/or handling a pharmaceutical product.
  • insert means information accompanying a pharmaceutical product that provides a description of how to administer the product, along with the safety and efficacy data required to allow the physician, pharmacist, and subject to make an informed decision regarding use of the product.
  • the package insert generally is regarded as the "label" for a pharmaceutical product.
  • Constant administration means that two or more agents are administered concurrently to the subject being treated.
  • each agent is administered either simultaneously or sequentially in any order at different points in time.
  • if not administered simultaneously it is meant that they are administered to a subject in a sequence and sufficiently close in time so as to provide the desired therapeutic effect and can act in concert.
  • a Compound of the Disclosure can be administered at the same time or sequentially in any order at different points in time as an optional therapeutic agent.
  • a Compound of the Disclosure and the optional therapeutic agent can be administered separately, in any appropriate form and by any suitable route.
  • a Compound of the Disclosure and the optional therapeutic agent are not administered concurrently, it is understood that they can be administered in any order to a subject in need thereof.
  • a Compound of the Disclosure can be administered prior to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before) , concomitantly with, or subsequent to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) the administration of an optional therapeutic agent treatment modality (e.g., radiotherapy) , to a subject in need thereof.
  • an optional therapeutic agent treatment modality e.g., radiotherapy
  • a Compound of the Disclosure and the optional therapeutic agent are administered 1 minute apart, 10 minutes apart, 30 minutes apart, less than 1 hour apart, 1 hour apart, 1 hour to 2 hours apart, 2 hours to 3 hours apart, 3 hours to 4 hours apart, 4 hours to 5 hours apart, 5 hours to 6 hours apart, 6 hours to 7 hours apart, 7 hours to 8 hours apart, 8 hours to 9 hours apart, 9 hours to 10 hours apart, 10 hours to 11 hours apart, 11 hours to 12 hours apart, no more than 24 hours apart or no more than 48 hours apart.
  • the components of the combination therapies are administered at about 1 minute to about 24 hours apart.
  • halo as used herein by itself or as part of another group refers to -Cl, -F, -Br, or -I.
  • nitro as used herein by itself or as part of another group refers to -NO 2 .
  • cyano as used herein by itself or as part of another group refers to -CN.
  • hydroxy as herein used by itself or as part of another group refers to -OH.
  • alkyl refers to a straight-or branched-chain aliphatic hydrocarbon containing one to twelve carbon atoms, i.e., a C 1 -C 12 alkyl, or the number of carbon atoms designated, e.g., a C 1 alkyl such as methyl, a C 2 alkyl such as ethyl, etc.
  • the alkyl is a C 1 -C 10 alkyl.
  • the alkyl is a C 1 -C 6 alkyl.
  • the alkyl is a C 1 -C 4 alkyl.
  • the alkyl is a C 1 -C 3 alkyl, i.e., methyl, ethyl, propyl, or isopropyl.
  • Non-limiting exemplary C 1 -C 12 alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, iso-butyl, 3-pentyl, hexyl, heptyl, octyl, nonyl, and decyl.
  • one or more of the hydrogen atoms of the alkyl group are replaced by deuterium atoms, i.e., the alkyl group is isotopically-labeled with deuterium.
  • a non-limiting exemplarly deteuterated alkyl group is-CD 3 .
  • none of the hydrogen atoms of the alkyl group are replaced by deuterium atoms, i.e., the alkyl group i s isotopically-labeled with deuterium .
  • R 56a is hydrogen or alkyl
  • R 56b is alkyl, haloalkyl, optionally substituted cycloalkyl, alkoxy, (alkoxy) alkyl, (aryl) alkyl, (heteroaryl) alkyl, (amino) alkyl, (hydroxy) alkyl, (cyano) alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycle, optionally substituted C 6 -C 10 aryl, or optionally substituted heteroaryl;
  • R 56c is hydrogen or alkyl
  • R 56d is alkyl, haloalkyl, optionally substituted cycloalkyl, alkoxy, (alkoxy) alkyl, (aryl) alkyl, (heteroaryl) alkyl, (amino) alkyl, (hydroxy) alkyl, (cyano) alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycle, optionally substituted C 6 -C 10 aryl, or optionally substituted heteroaryl;
  • R 56e is alkyl, haloalkyl, optionally substituted cycloalkyl, alkoxy, (alkoxy) alkyl, (aryl) alkyl, (heteroaryl) alkyl, (amino) alkyl, (hydroxy) alkyl, (cyano) alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycle, optionally substituted C 6 -C 10 aryl, or optionally substituted heteroaryl;
  • R 57 is haloalkyl, optionally substituted cycloalkyl, alkoxy, (alkoxy) alkyl, (aryl) alkyl, (heteroaryl) alkyl, (amino) alkyl, (hydroxy) alkyl, (cyano) alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycle, or optionally substituted heteroaryl; and
  • R 58 is haloalkyl, optionally substituted cycloalkyl, alkoxy, (alkoxy) alkyl, (aryl) alkyl, (heteroaryl) alkyl, (amino) alkyl, (hydroxy) alkyl, (cyano) alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycle, or optionally substituted heteroaryl.
  • alkenyl refers to an alkyl group containing one, two, or three carbon-to-carbon double bonds.
  • the alkenyl group is a C 2 -C 6 alkenyl group.
  • the alkenyl group is a C 2 -C 4 alkenyl group.
  • the alkenyl group has one carbon-to-carbon double bond.
  • Non-limiting exemplary alkenyl groups include ethenyl, propenyl, isopropenyl, butenyl, sec-butenyl, pentenyl, and hexenyl.
  • alkenyl as used herein by itself or as part of another refers to an alkenyl group that is either unsubstituted or substituted with one, two or three substituents, wherein each substituent is independently halo, nitro, cyano, hydroxy, amino (e.g., alkylamino, dialkylamino) , haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclo.
  • alkynyl refers to an alkyl group containing one, two, or three carbon-to-carbon triple bonds.
  • the alkynyl is a C 2 -C 6 alkynyl.
  • the alkynyl is a C 2 -C 4 alkynyl.
  • the alkynyl has one carbon-to-carbon triple bond.
  • Non-limiting exemplary alkynyl groups include ethynyl, propynyl, butynyl, 2-butynyl, pentynyl, and hexynyl groups.
  • alkynyl refers to an alkynyl group that is either unsubstituted or substituted with one, two or three substituents, wherein each substituent is independently halo, nitro, cyano, hydroxy, amino, e.g., alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocycl
  • haloalkyl refers to an alkyl group substituted by one or more fluorine, chlorine, bromine, and/or iodine atoms.
  • the alkyl is substituted by one, two, or three fluorine and/or chlorine atoms.
  • the alkyl is substituted by one, two, or three fluorine atoms.
  • the alkyl is a C 1 -C 6 alkyl.
  • the alkyl is a C 1 -C 4 alkyl.
  • the alkyl group is a C 1 or C 2 alkyl.
  • Non-limiting exemplary haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, 1, 1-difluoroethyl, 2, 2-difluoroethyl, 2, 2, 2-trifluoroethyl, 3, 3, 3-trifluoropropyl, 4, 4, 4-trifluorobutyl, and trichloromethyl groups.
  • hydroxyalkyl or " (hydroxy) alkyl” as used herein by themselves or as part of another group refer to an alkyl group substituted with one, two, or three hydroxy groups.
  • the alkyl is a C 1 -C 6 alkyl.
  • the alkyl is a C 1 -C 4 alkyl.
  • the alkyl is a C 1 or C 2 alkyl.
  • the hydroxyalkyl is a monohydroxyalkyl group, i.e., substituted with one hydroxy group.
  • the hydroxyalkyl group is a dihydroxyalkyl group, i.e., substituted with two hydroxy groups.
  • Non-limiting exemplary (hydroxy) alkyl groups include hydroxymethyl, hydroxyethyl, hydroxypropyl and hydroxybutyl groups, such as 1-hydroxyethyl, 2-hydroxyethyl, 1, 2-dihydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 3-hydroxybutyl, 4-hydroxybutyl, 2-hydroxy-1-methylpropyl, and 1, 3-dihydroxyprop-2-yl.
  • alkoxy refers to an alkyl group attached to a terminal oxygen atom.
  • the alkyl is a C 1 -C 6 alkyl and resulting alkoxy is thus referred to as a "C 1 -C 6 alkoxy.
  • the alkyl is a C 1 -C 4 alkyl group and resulting alkoxy is thus referred to as a C 1 -C 4 alkoxy.
  • Non-limiting exemplary alkoxy groups include methoxy, ethoxy, and tert-butoxy.
  • haloalkoxy refers to a haloalkyl group attached to a terminal oxygen atom.
  • the haloalkyl group is a C 1 -C 6 haloalkyl.
  • the haloalkyl group is a C 1 -C 4 haloalkyl group.
  • Non-limiting exemplary haloalkoxy groups include fluoromethoxy, difluoromethoxy, trifluoromethoxy, and 2, 2, 2-trifluoroethoxy.
  • alkylthio refers to an alkyl group attached to a terminal sulfur atom.
  • the alkyl group is a C 1 -C 4 alkyl group.
  • Non-limiting exemplary alkylthio groups include -SCH 3 , and -SCH 2 CH 3 .
  • alkoxyalkyl or " (alkoxy) alkyl” as used herein by themselves or as part of another group refers to an alkyl group substituted with one alkoxy group.
  • the alkoxy is a C 1 -C 6 alkoxy.
  • the alkoxy is a C 1 -C 4 alkoxy.
  • the alkyl is a C 1 -C 6 alkyl.
  • the alkyl is a C 1 -C 4 alkyl.
  • Non-limiting exemplary alkoxyalkyl groups include methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, propoxymethyl, iso-propoxymethyl, propoxyethyl, propoxypropyl, butoxymethyl, tert-butoxymethyl, isobutoxymethyl, sec-butoxymethyl, and pentyloxymethyl.
  • heteroalkyl refers to unsubstituted straight-or branched-chain aliphatic hydrocarbons containing from three to twenty chain atoms, i.e., 3-to 20-membered heteroalkyl, or the number of chain atoms designated, wherein at least one -CH 2 -is replaced with at least one of -O-, -N (H) -, -N (C 1 -C 4 alkyl) -, or -S-.
  • one -CH 2 -group is replaced with one -O-group.
  • two -CH 2 -groups are replaced with two -O-groups.
  • three -CH 2 -groups are replaced with three -O-groups.
  • Non-limiting exemplary heteroalkyl groups include -CH 2 OCH 3 , -CH 2 OCH 2 CH 2 CH 3 , -CH 2 CH 2 CH 2 OCH 3 , -CH 2 CH 2 OCH 2 CH 2 OCH 2 CH 3 , -CH 2 CH 2 OCH 2 CH 2 OCH- 2 CH 2 OCH 2 CH 3 .
  • cycloalkyl refers to saturated and partially unsaturated, e.g., containing one or two double bonds, monocyclic, bicyclic, or tricyclic aliphatic hydrocarbons containing three to twelve carbon atoms, i.e., a C 3-12 cycloalkyl, or the number of carbons designated, e.g., a C 3 cycloalkyl such a cyclopropyl, a C 4 cycloalkyl such as cyclobutyl, etc.
  • the cycloalkyl is bicyclic, i.e., it has two rings.
  • the cycloalkyl is monocyclic, i.e., it has one ring.
  • the cycloalkyl is a C 3-8 cycloalkyl.
  • the cycloalkyl is a C 3-6 cycloalkyl, i.e., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • the cycloalkyl is a C 5 cycloalkyl, i.e., cyclopentyl.
  • the cycloalkyl is a C 6 cycloalkyl, i.e., cyclohexyl.
  • Non-limiting exemplary C 3-12 cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, decalin, adamantyl, cyclohexenyl, and spiro [3.3] heptane.
  • cycloalkyl refers to a cycloalkyl group that is either unsubstituted or substituted with one, two, or three substituents, wherein each substituent is independently halo, nitro, cyano, hydroxy, amino (e.g., -NH 2 , alkylamino, dialkylamino, aralkylamino, hydroxyalkylamino, or (heterocyclo) alkylamino) , heteroalkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyl, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy
  • Non-limiting exemplary optionally substituted cycloalkyl groups include:
  • heterocyclo refers to saturated and partially unsaturated, e.g., containing one or two double bonds, monocyclic, bicyclic, or tricyclic groups containing three to fourteen ring members, i.e., a 3-to 14-membered heterocyclo, comprising one, two, three, or four heteroatoms.
  • Each heteroatom is independently oxygen, sulfur, or nitrogen.
  • heterocyclo also includes groups having fused optionally substituted aryl or optionally substituted heteroaryl groups such as indoline, indolin-2-one, 2, 3-dihydro-1H-pyrrolo [2, 3-c] pyridine, 2, 3, 4, 5-tetrahydro-1H-benzo [d] azepine, or 1, 3, 4, 5-tetrahydro-2H-benzo [d] azepin-2-one.
  • the heterocyclo group is a 8-to12-membered cyclic group containing two rings and one or two nitrogen atoms. The heterocyclo can be linked to the rest of the molecule through any available carbon or nitrogen atom.
  • Non-limiting exemplary heterocyclo groups include:
  • optionally substituted heterocyclo refers to a heterocyclo group that is either unsubstituted or substituted with one to four substituents, wherein each substituent is independently halo, nitro, cyano, hydroxy, amino, (e.g., -NH 2 , alkylamino, dialkylamino, aralkylamino, hydroxyalkylamino, or (heterocyclo) alkylamino) , heteroalkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyl, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, optionally
  • aryl refers to an aromatic ring system having six to fourteen carbon atoms, i.e., C 6 -C 14 aryl.
  • Non-limiting exemplary aryl groups include phenyl (abbreviated as "Ph” ) , naphthyl, phenanthryl, anthracyl, indenyl, azulenyl, biphenyl, biphenylenyl, and fluorenyl groups.
  • the aryl group is phenyl or naphthyl.
  • the aryl group is phenyl.
  • aryl that is either unsubstituted or substituted with one to five substituents, wherein the substituents are each independently halo, nitro, cyano, hydroxy, amino, (e.g., -NH 2 , alkylamino, dialkylamino, aralkylamino, hydroxyalkylamino, or (heterocyclo) alkylamino) , heteroalkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyl, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, optionally
  • the optionally substituted aryl is an optionally substituted phenyl. In another embodiment, the optionally substituted phenyl has four substituents. In another embodiment, the optionally substituted phenyl has three substituents. In another embodiment, the optionally substituted phenyl has two substituents. In another embodiment, the optionally substituted phenyl has one substituent.
  • Non-limiting exemplary optionally substituted aryl groups include 2-methylphenyl, 2-methoxyphenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 3-methylphenyl, 3-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 4-methylphenyl, 4-ethylphenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 2, 6-di-fluorophenyl, 2, 6-di-chlorophenyl, 2-methyl, 3-methoxyphenyl, 2-ethyl, 3-methoxyphenyl, 3, 4-di-methoxyphenyl, 3, 5-di-fluorophenyl 3, 5-di-methylphenyl, 3, 5-dimethoxy, 4-methylphenyl, 2-fluoro-3-chlorophenyl, 3-chloro-4-fluorophenyl, and 2-phenylpropan-2-amine.
  • optionally substituted aryl includes aryl groups having fused optionally substituted cycloalkyl groups and fused optionally substituted heterocyclo groups.
  • Non-limiting xamples include: 2, 3-dihydro-1H-inden-1-yl, 1, 2, 3, 4-tetrahydronaphthalen-1-yl, 1, 3, 4, 5-tetrahydro-2H-benzo [c] azepin-2-yl, 1, 2, 3, 4-tetrahydroisoquinolin-1-yl, and 2-oxo-2, 3, 4, 5-tetrahydro-1H-benzo [d] azepin-1-yl.
  • heteroaryl refers to monocyclic and bicyclic aromatic ring systems having five to 14 fourteen ring members, i.e., a 5-to 14-membered heteroaryl, comprising one, two, three, or four heteroatoms.
  • Each heteroatom is independently oxygen, sulfur, or nitrogen.
  • the heteroaryl has three heteroatoms.
  • the heteroaryl has two heteroatoms.
  • the heteroaryl has one heteroatom.
  • the heteroaryl is a 5-to 10-membered heteroaryl.
  • the heteroaryl has 5 ring atoms, e.g., thienyl, a 5-membered heteroaryl having four carbon atoms and one sulfur atom.
  • the heteroaryl has 6 ring atoms, e.g., pyridyl, a 6-membered heteroaryl having five carbon atoms and one nitrogen atom.
  • Non-limiting exemplary heteroaryl groups include thienyl, benzo [b] thienyl, naphtho [2, 3-b] thienyl, thianthrenyl, furyl, benzofuryl, pyranyl, isobenzofuranyl, benzooxazonyl, chromenyl, xanthenyl, 2H-pyrrolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, cinnolinyl, quinazolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl, ⁇ -carbolin
  • the heteroaryl is chosen from thienyl (e.g., thien-2-yl and thien-3-yl) , furyl (e.g., 2-furyl and 3-furyl) , pyrrolyl (e.g., 1H-pyrrol-2-yl and 1H-pyrrol-3-yl) , imidazolyl (e.g., 2H-imidazol-2-yl and 2H-imidazol-4-yl) , pyrazolyl (e.g., 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, and 1H-pyrazol-5-yl) , pyridyl (e.g., pyridin-2-yl, pyridin-3-yl, and pyridin-4-yl) , pyrimidinyl (e.g., pyrimidin-2-yl, pyrimidin-4-yl, and pyrimidin-5
  • optionally substituted heteroaryl refers to a heteroaryl that is either unsubstituted or substituted with one to four substituents, wherein the substituents are independently halo, nitro, cyano, hydroxy, amino, (e.g., -NH 2 , alkylamino, dialkylamino, aralkylamino, hydroxyalkylamino, or (heterocyclo) alkylamino) , heteroalkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyl, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, optional
  • the optionally substituted heteroaryl has two substituents. In another embodiment, the optionally substituted heteroaryl has one substituent. Any available carbon or nitrogen atom can be substituted.
  • aryloxy as used herein by itself or as part of another group refers to an optionally substituted aryl attached to a terminal oxygen atom.
  • a non-limiting exemplary aryloxy group is PhO-.
  • aralkyloxy refers to an aralkyl attached to a terminal oxygen atom.
  • a non-limiting exemplary aralkyloxy group is PhCH 2 O-.
  • (cyano) alkyl refers to an alkyl substituted with one, two, or three cyano groups. In one embodiment, the alkyl is substituted with one cyano group. In another embodiment, the alkyl is a C 1 -C 6 alkyl. In another embodiment, the alkyl is a C 1 -C 4 alkyl and thus the (cyano) alkyl is referred to as a (cyano) C 1 -C 4 alkyl.
  • Non-limiting exemplary (cyano) alkyl groups include -CH 2 CN, -CH 2 CH 2 CN and -CH 2 CH 2 CH 2 CN.
  • (cycloalkyl) alkyl refers to an alkyl substituted with one or two optionally substituted cycloalkyl groups.
  • the cycloalkyl group (s) is an optionally substituted C 3 -C 6 cycloalkyl.
  • the alkyl is a C 1 -C 6 alkyl.
  • the alkyl is a C 1 -C 4 alkyl.
  • the alkyl is a C 1 or C 2 alkyl.
  • the alkyl is substituted with one optionally substituted cycloalkyl group.
  • the alkyl is substituted with two optionally substituted cycloalkyl groups.
  • Non-limiting exemplary (cycloalkyl) alkyl groups include:
  • sulfonamido refers to a radical of the formula -SO 2 NR 50a R 50b , wherein R 50a and R 50b are each independently hydrogen, alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclo, optionally substituted aryl, or optionally substituted heteroaryl; or R 50a and R 50b taken together with the nitrogen to which they are attached form a 3-to 8-membered optionally substituted heterocyclo group.
  • Non-limiting exemplary sulfonamido groups include -SO 2 NH 2 , -SO 2 N (H) CH 3 , and -SO 2 N (H) Ph.
  • (carboxamido) alkyl refers to an alkyl substituted with one carboxamido group.
  • the alkyl is a C 1 -C 6 alkyl.
  • the alkyl is a C 1 -C 4 alkyl.
  • the alkyl is a C 1 or C 2 alkyl.
  • the alkyl is a C 1 -C 4 alkyl.
  • a non-limiting exemplary alkylcarbonyl group is -COCH 3 .
  • a non-limiting exemplary arylcarbonyl group is -COPh.
  • alkylsulfonyl as used herein by itself or as part of another group refers to a sulfonyl group, i.e., -SO 2 -, substituted by an alkyl group.
  • a non-limiting exemplary alkylsulfonyl group is -SO 2 CH 3 .
  • arylsulfonyl as used herein by itself or as part of another group refers to a sulfonyl group, i.e., -SO 2 -, substituted by an optionally substituted aryl group.
  • a non-limiting exemplary arylsulfonyl group is -SO 2 Ph.
  • mercaptoalkyl as used herein by itself or as part of another group refers to an alkyl substituted by a -SH group.
  • (heterocyclo) alkyl refers to an alkyl substituted with one, two, or three optionally substituted heterocyclo groups.
  • the alkyl is substituted with one optionally substituted 5-to 8-membered heterocyclo group.
  • alkyl is a C 1 -C 6 alkyl.
  • alkyl is a C 1 -C 4 alkyl.
  • the heterocyclo group can be linked to the alkyl group through a carbon or nitrogen atom.
  • Non-limiting exemplary (heterocyclo) alkyl groups include:
  • R 54a is hydrogen or alkyl
  • R 54b is hydrogen, alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclo, optionally substituted aryl, or optionally substituted heteroaryl.
  • (heteroaryl) alkyl refers to an alkyl substituted with one or two optionally substituted heteroaryl groups.
  • the alkyl group is substituted with one optionally substituted 5-to 14-membered heteroaryl group.
  • the alkyl group is substituted with two optionally substituted 5-to 14-membered heteroaryl groups.
  • the alkyl group is substituted with one optionally substituted 5-to 9-membered heteroaryl group.
  • the alkyl group is substituted with two optionally substituted 5-to 9-membered heteroaryl groups.
  • the alkyl group is substituted with one optionally substituted 5-or 6-membered heteroaryl group. In another embodiment, the alkyl group is substituted with two optionally substituted 5-or 6-membered heteroaryl groups. In one embodiment, the alkyl group is a C 1 -C 6 alkyl. In another embodiment, the alkyl group is a C 1 -C 4 alkyl. In another embodiment, the alkyl group is a C 1 or C 2 alkyl.
  • Non-limiting exemplary (heteroaryl) alkyl groups include:
  • aralkyl or " (aryl) alkyl” as used herein by themselves or as part of another group refers to an alkyl substituted with one, two, or three optionally substituted aryl groups.
  • the alkyl is substituted with one optionally substituted aryl group.
  • the alkyl is substituted with two optionally substituted aryl groups.
  • the aryl is an optionally substituted phenyl or optionally substituted naphthyl.
  • the aryl is an optionally substituted phenyl.
  • the alkyl is a C 1 -C 6 alkyl.
  • the alkyl is a C 1 -C 4 alkyl.
  • the alkyl is a C 1 or C 2 alkyl.
  • Non-limiting exemplary (aryl) alkyl groups include benzyl, phenethyl, -CHPh 2 , and -CH (4-F-Ph) 2 .
  • R 60a and R 60b are each independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, haloalkyl, (alkoxy) alkyl, (hydroxy) alkyl, (cyano) alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclo, optionally substituted aryl, optionally substituted heteroaryl, (aryl) alkyl, (cycloalkyl) alkyl, (heterocyclo) alkyl, or (heteroaryl) alkyl; or R 60a and R 60b taken together with the nitrogen to which they are attached from a 4-to 8-membered optionally substituted heterocyclo group.
  • R 60a and R 60b are each independently hydrogen or C 1 -C 6 alkyl.
  • amino refers to a radical of the formula -NR 55a R 55b , wherein R 55a and R 55b are independently hydrogen, optionally substituted alkyl, haloalkyl, (hydroxy) alkyl, (alkoxy) alkyl, (amino) alkyl, heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocyclo, optionally substituted aryl, optionally substituted heteroaryl, (aryl) alkyl, (cycloalkyl) alkyl, (heterocyclo) alkyl, or (heteroaryl) alkyl.
  • the amino is -NH 2 .
  • the amino is an "alkylamino, " i.e., an amino group wherein R 55a is C 1-6 alkyl and R 55b is hydrogen. In one embodiment, R 55a is C 1 -C 4 alkyl.
  • Non-limiting exemplary alkylamino groups include -N (H) CH 3 and -N (H) CH 2 CH 3 .
  • the amino is a "dialkylamino, " i.e., an amino group wherein R 55a and R 55b are each independently C 1-6 alkyl. In one embodiment, R 55a and R 55b are each independently C 1 -C 4 alkyl.
  • Non-limiting exemplary dialkylamino groups include -N (CH 3 ) 2 and -N (CH 3 ) CH 2 CH (CH 3 ) 2 .
  • the amino is a "hydroxyalkylamino, " i.e., an amino group wherein R 55a is (hydroxy) alkyl and R 55b is hydrogen or C 1 -C 4 alkyl.
  • the amino is a "cycloalkylamino, " i.e., an amino group wherein R 55a is optionally substituted cycloalkyl and R 55b is hydrogen or C 1 -C 4 alkyl.
  • the amino is a "aralkylamino, " i.e., an amino group wherein R 55a is aralkyl and R 55b is hydrogen or C 1 -C 4 alkyl.
  • aralkylamino groups include -N (H) CH 2 Ph, -N (H) CHPh 2 , and -N (CH 3 ) CH 2 Ph.
  • the amino is a " (cycloalkyl) alkylamino, " i.e., an amino group wherein R 55a is (cycloalkyl) alkyl and R 55b is hydrogen or C 1 -C 4 alkyl.
  • Non-limiting exemplary (cycloalkyl) alkylamino groups include:
  • the amino is a " (heterocyclo) alkylamino, " i.e., an amino group wherein R 55a is (heterocyclo) alkyl and R 55b is hydrogen or C 1 -C 4 alkyl.
  • Non-limiting exemplary (heterocyclo) alkylamino groups include:
  • (amino) alkyl refers to an alkyl substituted with one amino group.
  • the amino group is -NH 2 .
  • the amino group is an alkylamino.
  • the amino group is a dialkylamino.
  • the alkyl is a C 1 -C 6 alkyl.
  • the alkyl is a C 1 -C 4 alkyl.
  • Non-limiting exemplary (amino) alkyl groups include -CH 2 NH 2 , CH 2 CH 2 N (H) CH 3 , -CH 2 CH 2 N (CH 3 ) 2 , CH 2 N (H) cyclopropyl, -CH 2 N (H) cyclobutyl, and -CH 2 N (H) cyclohexyl, and -CH 2 CH 2 CH 2 N (H) CH 2 Ph and -CH 2 CH 2 CH 2 N (H) CH 2 (4-CF 3 -Ph) .
  • the present disclosure encompasses any of the Compounds of the Disclosure being isotopically-labelled (i.e., radiolabeled) by having one or more atoms replaced by an atom having a different atomic mass or mass number.
  • isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as 2 H (or deuterium (D) ) , 3 H, 11 C, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 Cl, respectively, e.g., 3 H, 11 C, and 14 C.
  • Isotopically-labelled Compounds of the Disclosure can be prepared by methods known in the art.
  • Compounds of the Disclosure contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms.
  • the present disclosure encompasses the use of all such possible forms, as well as their racemic and resolved forms and mixtures thereof.
  • the individual enantiomers can be separated according to methods known in the art in view of the present disclosure.
  • the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that they include both E and Z geometric isomers. All tautomers are also encompassed by the present disclosure.
  • stereoisomers is a general term for all isomers of individual molecules that differ only in the orientation of their atoms in space. It includes enantiomers and isomers of compounds with more than one chiral center that are not mirror images of one another (diastereomers) .
  • chiral center or "asymmetric carbon atom” refers to a carbon atom to which four different groups are attached.
  • enantiomer and “enantiomeric” refer to a molecule that cannot be superimposed on its mirror image and hence is optically active wherein the enantiomer rotates the plane of polarized light in one direction and its mirror image compound rotates the plane of polarized light in the opposite direction.
  • racemic refers to a mixture of equal parts of enantiomers and which mixture is optically inactive.
  • Compounds of the Disclosure are racemic.
  • absolute configuration refers to the spatial arrangement of the atoms of a chiral molecular entity (or group) and its stereochemical description, e.g., R or S.
  • enantiomeric excess refers to a measure for how much of one enantiomer is present compared to the other.
  • the percent enantiomeric excess is defined as ( [a] obs / [a] max ) *100, where [a] obs is the optical rotation of the mixture of enantiomers and [a] max is the optical rotation of the pure enantiomer. Determination of enantiomeric excess is possible using a variety of analytical techniques, including NMR spectroscopy, chiral column chromatography or optical polarimetry.
  • the isomers, e.g., diastereomers and/or enantiomers, of a compound of Formula I, wherein Q is N-are resolved using chiral chromatography techniques, e.g., by supercritical fluid chromatography (SFC) using a chiral, e.g., ID, column.
  • SFC supercritical fluid chromatography
  • a base e.g., NaOH.
  • the isomers, e.g., diastereomers and/or enantiomers, of a compound of Formula I, wherein Q is N-are resolved using chiral chromatography techniques, e.g., by supercritical fluid chromatography (SFC) using a chiral, e.g., ID, column.
  • SFC supercritical fluid chromatography
  • Step 4 Synthesis of tert-butyl 3- (cyanomethyl) piperazine-1-carboxylate
  • Step 5 Synthesis of tert-butyl (S) -3- (cyanomethyl) piperazine-1-carboxylate and tert-butyl (R) -3- (cyanomethyl) piperazine-1-carboxylate
  • tert-Butyl 3- (cyanomethyl) piperazine-1-carboxylate (Step 4, 31.4 g) was subjected to chiral SFC resolution with CHIRALCEL AY-H column to provide the title compounds (Isomer A: 14.9 g, 100%ee; Isomer B: 14.8 g, 99.7%ee) as white solid.
  • Step 1 Synthesis of 2'-bromo-5, 6-dihydro- [1, 1'-biphenyl] -3 (4H) -one
  • Step 2 Synthesis of 3- (2-bromophenyl) -3-vinylcyclohexan-1-one
  • Step 3 Synthesis of 3- (2- (prop-1-en-2-yl) phenyl) -3-vinylcyclohexan-1-one
  • Step 4 Synthesis of 3'-methylspiro [cyclohexane-1, 1'-inden] -3-one
  • Step 5 Synthesis of methyl 3'-methyl-3-oxospiro [cyclohexane-1, 1'-indene] -4-carboxylate
  • Step 1 Synthesis of 2'-vinyl-5, 6-dihydro- [1, 1'-biphenyl] -3 (4H) -one
  • Step 2 Synthesis of 3-vinyl-3- (2-vinylphenyl) cyclohexan-1-one
  • Step 3 Synthesis of spiro [cyclohexane-1, 1'-inden] -3-one
  • Step 4 Synthesis of dispiro [indene-1, 1'-cyclohexane-3', 2”- [1, 3] dioxolane]
  • Step 5 Synthesis of dispiro [indene-1, 1'-cyclohexane-3', 2”- [1, 3] dioxolan] -3 (2H) -one
  • step 4 the mixture of dispiro [indene-1, 1'-cyclohexane-3', 2”- [1, 3] dioxolane] (step 4, 10.5 g, 43.3 mmol) and 9-BBN in THF (0.5 M, 260 mL) was stirred at 70°C for 4 h. Concentrated in vacuo to give the residue, which was dissolved in dry DCM (300 mL) and then PCC (93.3 g, 433 mmol, 10.0 eq) was added dropwise. The reaction was stirred at room temperature for 2 h.
  • the first eluting stereoisomer (8.6 g, 100%ee) was arbitrarily designated as having S stereochemistry at the spirocarbon atom pending further analysis.
  • the second eluting stereoisomer (7.8 g, 99%ee) was arbitrarily designated as having R stereochemistry at the spirocarbon atom pending further analysis.
  • Step 6 Synthesis of (R) -2, 2-difluorodispiro [indene-1, 1'-cyclohexane-3', 2”- [1, 3] dioxolan] -3 (2H) -one
  • Step 7 Synthesis of (R) -2, 2-difluoro-3-methylene-2, 3-dihydrodispiro [indene-1, 1'-cyclohexane-3', 2”- [1, 3] dioxolane]
  • (S) -2, 2-Difluoro-3-methylene-2, 3-dihydrodispiro [indene-1, 1'-cyclohexane-3', 2”- [1, 3] dioxolane] is prepared in essentially the same way using (S) -2, 2-difluorodispiro [indene-1, 1'-cyclohexane-3', 2”- [1, 3] dioxolan] -3 (2H) -one as the starting intermediate.
  • Step 8 Synthesis of (R) -2-fluoro-3-methyldispiro [indene-1, 1'-cyclohexane-3', 2”- [1, 3] dioxolane]
  • (S) -2-Fluoro-3-methyldispiro [indene-1, 1'-cyclohexane-3', 2”- [1, 3] dioxolane] is prepared in essentially the same way using (S) -2, 2-difluoro-3-methylene-2, 3-dihydrodispiro [indene-1, 1'-cyclohexane-3', 2”- [1, 3] dioxolane] as the starting intermediate.
  • Step 9 Synthesis of (R) -2'-fluoro-3'-methylspiro [cyclohexane-1, 1'-inden] -3-one
  • Step 10 Synthesis of methyl (1R) -2'-fluoro-3'-methyl-3-oxospiro [cyclohexane-1, 1'-indene] -4-carboxylate
  • Step 1 Synthesis of (1R) -2, 2-difluoro-2, 3-dihydrodispiro [indene-1, 1'-cyclohexane-3', 2”- [1, 3] dioxolan] -3-ol
  • Step 2 Synthesis of (1R) -2, 2, 3-trifluoro-2, 3-dihydrodispiro [indene-1, 1'-cyclohexane-3', 2”- [1, 3] dioxolane]
  • (1S) -2, 2, 3-Trifluoro-2, 3-dihydrodispiro [indene-1, 1'-cyclohexane-3', 2”- [1, 3] dioxolane] is prepared in essentially the same way using (1S) -2, 2-difluoro-2, 3-dihydrodispiro [indene-1, 1'-cyclohexane-3', 2”- [1, 3] dioxolan] -3-ol as the starting intermediate.
  • Step 3 Synthesis of (R) -2, 3-difluorodispiro [indene-1, 1'-cyclohexane-3', 2”- [1, 3] dioxolane]
  • Step 4 Synthesis of (R) -2', 3'-difluorospiro [cyclohexane-1, 1'-inden] -3-one
  • Step 5 Synthesis of methyl (1R) -2', 3'-difluoro-3-oxospiro [cyclohexane-1, 1'-indene] -4-carboxylate
  • Step 1 Synthesis of (1R) -3- (trifluoromethyl) -2, 3-dihydrodispiro [indene-1, 1'-cyclohexane-3', 2”- [1, 3] dioxolan] -3-ol
  • Step 2 Synthesis of (1R) -3'-hydroxy-3'- (trifluoromethyl) -2', 3'-dihydrospiro [cyclohexane-1, 1'-inden] -3-one
  • Step 3 Synthesis of methyl (1R) -3'-hydroxy-3-oxo-3'- (trifluoromethyl) -2', 3'-dihydrospiro [cyclohexane-1, 1'-indene] -4-carboxylate
  • Step 4 Synthesis of methyl (1S) -3-oxo-3'- (trifluoromethyl) spiro [cyclohexane-1, 1'-indene] -4-carboxylate
  • Methyl (1R) -3-oxo-3'- (trifluoromethyl) spiro [cyclohexane-1, 1'-indene] -4-carboxylate is prepared in essentially the same way using (1S) -3'-hydroxy-3-oxo-3'- (trifluoromethyl) -2', 3'-dihydrospiro [cyclohexane-1, 1'-indene] -4-carboxylate as the starting intermediate.
  • Step 1 Synthesis of 2-bromo-2, 3-dihydrodispiro [indene-1, 1'-cyclohexane-3', 2”- [1, 3] dioxolan] -3-ol
  • Step 2 Synthesis of 2-bromodispiro [indene-1, 1'-cyclohexane-3', 2”- [1, 3] dioxolane]
  • Step 3 Synthesis of 2'-bromospiro [cyclohexane-1, 1'-inden] -3-one
  • Step 4 Synthesis of 2'-methylspiro [cyclohexane-1, 1'-inden] -3-one
  • Step 5 Synthesis of methyl 2'-methyl-3-oxospiro [cyclohexane-1, 1'-indene] -4-carboxylate
  • n-butyllithium (19.61 g, 306 mmol) in Hexane was added to methyltriphenylphosphonium bromide (117 g, 328 mmol) in THF (300 mL) at 0 °C dropwise over 60 mins, and then the mixture was stirred for 1 h at this temperature, 2-bromo-6-chlorobenzaldehyde (60 g, 273 mmol) in THF (200 mL) was added.
  • Step 2 Synthesis of 3'-chloro-2'-vinyl-5, 6-dihydro- [1, 1'-biphenyl] -3 (4H) -one
  • Step 3 Synthesis of 3- (3-chloro-2-vinylphenyl) -3-vinylcyclohexan-1-one
  • Step 4 Synthesis of 4'-chlorospiro [cyclohexane-1, 1'-inden] -3-one
  • Step 5 Synthesis of 4-chlorodispiro [indene-1, 1'-cyclohexane-3', 2”- [1, 3] dioxolane]
  • Step 6 Synthesis of 4-chlorodispiro [indene-1, 1'-cyclohexane-3', 2”- [1, 3] dioxolan] -3 (2H) -one
  • Step 7 Synthesis of (1R) -4-chloro-3- (trifluoromethyl) -2, 3-dihydrodispiro [indene-1, 1'-cyclohexane-3', 2”- [1, 3] dioxolan] -3-ol
  • Step 8 Synthesis of (1R) -4'-chloro-3'-hydroxy-3'- (trifluoromethyl) -2', 3'-dihydrospiro [cyclohexane-1, 1'-inden] -3-one
  • Step 9 Synthesis of methyl (1R) -4'-chloro-3'-hydroxy-3-oxo-3'- (trifluoromethyl) -2', 3'-dihydrospiro [cyclohexane-1, 1'-indene] -4-carboxylate
  • Step 10 Synthesis of methyl (1S) -4'-chloro-3-oxo-3'- (trifluoromethyl) spiro [cyclohexane-1, 1'-indene] -4-carboxylate
  • Step 1 Synthesis of (1S) -4-chloro-3- (trifluoromethyl) -2, 3-dihydrodispiro [indene-1, 1'-cyclohexane-3', 2”- [1, 3] dioxolan] -3-ol
  • Step 2 Synthesis of (1S) -4'-chloro-3'-hydroxy-3'- (trifluoromethyl) -2', 3'-dihydrospiro [cyclohexane-1, 1'-inden] -3-one
  • Step 3 Synthesis of methyl (1S) -4'-chloro-3'-hydroxy-3-oxo-3'- (trifluoromethyl) -2', 3'-dihydrospiro [cyclohexane-1, 1'-indene] -4-carboxylate
  • Step 4 Synthesis of methyl (1R) -4'-chloro-3-oxo-3'- (trifluoromethyl) spiro [cyclohexane-1, 1'-indene] -4-carboxylate
  • Step 1 Synthesis of (1R) -4-chloro-3-methyl-2, 3-dihydrodispiro [indene-1, 1'-cyclohexane-3', 2”- [1, 3] dioxolan] -3-ol
  • Step 2 Synthesis of (S) -4'-chloro-3'-methylspiro [cyclohexane-1, 1'-inden] -3-one
  • Step 3 Synthesis of methyl (1S) -4'-chloro-3'-methyl-3-oxospiro [cyclohexane-1, 1'-indene] -4-carboxylate
  • Methyl (1R) -4'-chloro-3'-methyl-3-oxospiro [cyclohexane-1, 1'-indene] -4-carboxylate is prepared in essentially the same way using (R) -4'-chloro-3'-methylspiro [cyclohexane-1, 1'-inden] -3-one as the starting intermediate.

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Abstract

L'invention concerne des composés représentés par la formule (I) : dans laquelle R 3, R 8c, R 8d, A, A 1, A 2, A 3, A 4, E, E 1, L, Q, Z et (II) sont tels que définis dans la description, et les sels et solvates pharmaceutiquement acceptables de ceux-ci. Les composés de formule I sont des inhibiteurs de KRAS et sont donc utiles pour traiter le cancer et d'autres maladies.
PCT/CN2022/073129 2021-01-21 2022-01-21 Indènes spirocycliques WO2022156761A1 (fr)

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